Diterpenoid alkaloids of Aconitum laciniatum and mitigation of inflammation by 14-O-acetylneoline in a murine model of ulcerative colitis

PubMed Central

Wangchuk, Phurpa; Navarro, Severine; Shepherd, Catherine; Keller, Paul A.; Pyne, Stephen G.; Loukas, Alex

2015-01-01

Aconitum laciniatum is used in Bhutanese traditional medicine for treating various chronic infections and inflammatory conditions. We carried out in-depth isolation and characterization of the phytochemicals from the root component and determined the anti-inflammatory effects of the isolated compounds against chemically-induced colitis in mice. Five diterpenoid alkaloids - pseudaconitine, 14-veratroylpseudaconine, 14-O-acetylneoline, neoline, and senbusine A - were isolated from A. laciniatum for the first time. Two of the alkaloids were tested for anti-inflammatory properties in the TNBS-induced colitis model in mice. Various parameters were measured to assess pathology including weight loss, clinical and macroscopic scores, histological structure and IFN-γ production in the gut. Of the two alkaloids tested, 14-O-acetylneoline showed significant protection against different parameters of colitic inflammation. Compared to control mice that received TNBS alone, mice treated with 14-O-acetylneoline experienced significantly less weight loss and had significantly lower clinical scores, macroscopic pathology and grades of histological inflammation. Moreover, colonic IFN-γ mRNA levels were significantly reduced in mice that received 14-O-acetylneoline compared to control mice that received TNBS alone. This alkaloid is now considered a novel anti-colitis drug lead compound. PMID:26240038

A potentized homeopathic drug, Arsenicum Album 200, can ameliorate genotoxicity induced by repeated injections of arsenic trioxide in mice.

PubMed

Banerjee, P; Biswas, S J; Belon, P; Khuda-Bukhsh, A R

2007-09-01

Groundwater arsenic contamination has become a menacing global problem. No drug is available until now to combat chronic arsenic poisoning. To examine if a potentized homeopathic remedy, Arsenicum Album-200, can effectively combat chronic arsenic toxicity induced by repeated injections of Arsenic trioxide in mice, the following experimental design was adopted. Mice (Mus musculus) were injected subcutaneously with 0.016% arsenic trioxide at the rate of 1 ml/100 g body weight, at an interval of 7 days until they were killed at day 30, 60, 90 or 120 and were divided into three groups: (i) one receiving a daily dose of Arsenicum Album-200 through oral administration, (ii) one receiving the same dose of diluted succussed alcohol (Alcohol-200) and (iii) another receiving neither drug, nor succussed alcohol. The remedy or the placebo, as the case may be, was fed from the next day onwards after injection until the day before the next injection, and the cycle was repeated until the mice were killed. Two other control groups were also maintained: one receiving only normal diet, and the other receiving normal diet and succussed alcohol. Several toxicity assays, such as cytogenetical (chromosome aberrations, micronuclei, mitotic index, sperm head anomaly) and biochemical (acid and alkaline phosphatases, lipid peroxidation), were periodically made. Compared with controls, the drug fed mice showed reduced toxicity at statistically significant levels in respect of all the parameters studied, thereby indicating protective potentials of the homeopathic drug against chronic arsenic poisoning.

Passive transfer of affinity-purified anti-heart autoantibodies (AHA) from sera of patients with myocarditis induces experimental myocarditis in mice.

PubMed

Caforio, Alida L P; Angelini, Annalisa; Blank, Miri; Shani, Alice; Kivity, Shaye; Goddard, Gisele; Doria, Andrea; Schiavo, Alessandro; Testolina, Martina; Bottaro, Stefania; Marcolongo, Renzo; Thiene, Gaetano; Iliceto, Sabino; Shoenfeld, Yehuda

2015-01-20

Human autoimmune myocarditis is characterized by an increased frequency of serum organ and disease-specific anti-heart autoantibodies (AHA) in affected patients. To assess whether AHA are directly pathogenic, we used the passive transfer technique of AHA from patients to normal Balb/c mice to induce an experimental myocarditis. In keeping with a classical passive transfer experiment, sera from 5 AHA positive myocarditis patients (3 male, mean age 30 ± 11 years, 3 with giant cell and 2 with lymphocytic myocarditis) were affinity purified and injected into 25 Balb/c mice. As controls, affinity purified sera from 5 healthy donors were passively transferred to 25 Balb/c mice. Further 15 control mice were injected with phosphate-buffered saline and 9 mice did not receive any injection. In all patients cardiac-specific AHA of IgG class had been previously detected by an indirect immunofluorescence (IFL) technique on cryostat sections of O blood group human heart. The animals were sacrificed after 4 weeks and the hearts were blindly examined for histological evidence of myocarditis by an expert cardiac pathologist. Myocarditis was present in 13/25 (52%) of the mice which received affinity-purified IgG from patients. The findings of severe, moderate or mild myocarditis were more common in the mice which received affinity-purified IgG from patients (20%; 20% and 12%) than in control animals (2%, p=0.01; 0%, p=0.003; and 0%, p=0.04 respectively). These findings provide a new evidence for AHA-mediated pathogenicity in human myocarditis, according to Rose-Witebsky criteria. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Testosterone Plus Low-Intensity Physical Training in Late Life Improves Functional Performance, Skeletal Muscle Mitochondrial Biogenesis, and Mitochondrial Quality Control in Male Mice

PubMed Central

Guo, Wen; Wong, Siu; Li, Michelle; Liang, Wentao; Liesa, Marc; Serra, Carlo; Jasuja, Ravi; Bartke, Andrzej; Kirkland, James L.; Shirihai, Orian; Bhasin, Shalender

2012-01-01

Testosterone supplementation increases muscle mass in older men but has not been shown to consistently improve physical function and activity. It has been hypothesized that physical exercise is required to induce the adaptations necessary for translation of testosterone-induced muscle mass gain into functional improvements. However, the effects of testosterone plus low intensity physical exercise training (T/PT) on functional performance and bioenergetics are unknown. In this pilot study, we tested the hypothesis that combined administration of T/PT would improve functional performance and bioenergetics in male mice late in life more than low-intensity physical training alone. 28-month old male mice were randomized to receive T/PT or vehicle plus physical training (V/PT) for 2 months. Compare to V/PT control, administration of T/PT was associated with improvements in muscle mass, grip strength, spontaneous physical movements, and respiratory activity. These changes were correlated with increased mitochondrial DNA copy number and expression of markers for mitochondrial biogenesis. Mice receiving T/PT also displayed increased expression of key elements for mitochondrial quality control, including markers for mitochondrial fission-and-fusion and mitophagy. Concurrently, mice receiving T/PT also displayed increased expression of markers for reduced tissue oxidative damage and improved muscle quality. Conclusion: Testosterone administered with low-intensity physical training improves grip strength, spontaneous movements, and respiratory activity. These functional improvements were associated with increased muscle mitochondrial biogenesis and improved mitochondrial quality control. PMID:23240002

Antihyperglycemic and antihyperlipidemic effects of pirdot (saurauia vulcani korth.) leaves extract in mice

NASA Astrophysics Data System (ADS)

Hutahaean, Salomo; Tanjung, Masitta; Puspita Sari, Diah; Elfia Ningsih, Vevy

2018-03-01

Approximately eighty percent of deaths in diabetic patients result from atherosclerosis, which is related to hyperlipidemia tendencies in diabetes. In North Sumatra, the use of plant-based ingredients as diabetes therapy has long been recognized. One of the local species which traditionally used was the pirdot plant (Saurauia vulcani Korth.). In this paper, we report the antihyperglycemic and antihyperlipidemic effects of the extract of pirdot leaves in model mice. In experiment I, twenty - five alloxan-induced diabetic mice was divided randomly into five groups of 5 mice, namely: control diabetic mice; diabetic mice + metformin; and three groups diabetic mice + pirdot leaves extract of 100, 200, or 300 mg/kg BW respectively. All the treatments were given daily for 21 days by oral gavage. In experiment II, another twenty-five mice were divided randomly into five groups of 5 mice. The treatments were as follows: a control group that did not receive any treatment; hyperlipidemic control (received quail yolk diet) for 30 days; and three groups of hyperlipidemic mice + orally treated pirdot leaves extract at a dose of 100, 200, or 300 mg/kg BW respectively. The result showed the pirdot leaves extract has the potential as antihyperglycemic. The effects obtained are equivalent to the effects of antidiabetic drug metformin. On the other hand, the antihyperlipidemic effect was not conclusive, because the extract lowered total cholesterol significantly, but no significant effect on triglyceride, marked reduced LDL, but significantly decreased the HDL level.

The Protective Effect of Selenium on Oxidative Stress Induced by Waterpipe (Narghile) Smoke in Lungs and Liver of Mice.

PubMed

Charab, Mohamad A; Abouzeinab, Noura S; Moustafa, Mohamed E

2016-12-01

Waterpipe smoking is common in the Middle East populations and results in health problems. In this study, we investigated the effects of exposure of mice to waterpipe smoke on oxidative stress in lungs and liver and the effects of selenium administration before smoke exposure on the oxidative stress. Twenty-four mice were divided equally into four groups: (i) the control mice received no exposure or treatment; (ii) mice exposed to waterpipe smoke; (iii) mice received intraperitoneal injection of 0.59 μg selenium/kg body weight as sodium selenite 15 min before the exposure to waterpipe smoke; and (iv) mice received intraperitoneal injection of 1.78 μg selenium/kg body weight as sodium selenite 15 min before the exposure to waterpipe smoke. Mice were exposed to waterpipe smoke every other day for four times within 8 successive days. Malondialdehyde and nitric oxide levels were significantly higher in the lungs and liver, while the activities of superoxide dismutase, glutathione peroxidase-1, and catalase were significantly lower in the waterpipe smoke group when compared to control mice. Treating mice with 1.78 μg selenium/kg body weight significantly restored the normal levels of these parameters. Histological examinations of lungs and liver confirmed the protective actions of selenium against the effects of exposure to waterpipe smoke. In conclusion, exposure of mice to waterpipe smoke-induced oxidative stress in lungs and liver. Administration of low level of selenium, 1.78 μg selenium/kg body weight as sodium selenite, exerted protective effects against oxidative stress induced by exposure to waterpipe smoke.

Influence of heat, wind, and humidity on ultraviolet radiation injury.

PubMed

Owens, D W; Knox, J M

1978-12-01

We investigated the influence of heat, wind, and humidity on UVR-induced acute and chronic skin damage of experimental animals housed in environmental chambers and irradiated under controlled conditions. Hairless mice (strain HRS/J) irradiated after an increase of 10 degrees F in skin temperature had more skin damage than irradiated controls. Significantly more Swiss albino mice irradiated for 400 days while maintained at 90 degrees F developed tumors than did those receiving the same amount of UVR but maintained at room temperature. Mice exposed to UVR daily for 4 weeks while kept in wind of 7 mph had greater damage and slower recovery than animals irradiated but protected from wind. Wind also accelerated tumorigenesis in mice than received chronic UVR. Mice kept at 80% relative humidity and given a single dose of UVR had greater skin injury than animals irradiated while at 5% relative humidity. High midity also appears to accelerate skin cancer formation in animals that were exposed to chronic UVR.

Protective effect of Cassia fistula fruit extract on bromobenzene-induced nephrotoxicity in mice.

PubMed

Kalantari, Heibatullah; Jalali, Mohammadtaha; Jalali, Amir; Salimi, Abobakr; Alhalvachi, Foad; Varga, Balazs; Juhasz, Bela; Jakab, Anita; Kemeny-Beke, Adam; Gesztelyi, Rudolf; Tosaki, Arpad; Zsuga, Judit

2011-10-01

The efficacy of a crude hydro-alcoholic extract of Cassia fistula (golden shower tree) fruit to protect the kidney against bromobenzene-induced toxicity was studied. Negative control mice received normal saline; positive control mice were given 460 mg/kg of bromobenzene; Cassia fistula treated mice received 200, 400, 600 and 800 mg/kg of Cassia fistula fruit extract followed by 460 mg/kg bromobenzene (daily by oral gavage for 10 days). On the 11th day, the mice were sacrificed, blood samples were obtained to assess blood urea nitrogen (BUN) and creatinine levels, and kidneys were removed for histological examination. We found that bromobenzene induced significant nephrotoxicity reflected by an increase in levels of BUN and creatinine that was dose dependently prevented by the Cassia fistula fruit extract. The nephroprotective effect of the Cassia fistula fruit extract was confirmed by the histological examination of the kidneys. To the best of our knowledge, this is the first study to demonstrate the protective effect of Cassia fistula in nephrotoxicity.

Immunotherapy of BALB/c mice bearing Ehrlich ascites tumor with vitamin D-binding protein-derived macrophage activating factor.

PubMed

Yamamoto, N; Naraparaju, V R

1997-06-01

Vitamin D3-binding protein (DBP; human DBP is known as Gc protein) is the precursor of macrophage activating factor (MAF). Treatment of mouse DBP with immobilized beta-galactosidase or treatment of human Gc protein with immobilized beta-galactosidase and sialidase generated a remarkably potent MAF, termed DBPMAF or GcMAF, respectively. The domain of Gc protein responsible for macrophage activation was cloned and enzymatically converted to the cloned MAF, designated CdMAF. In Ehrlich ascites tumor-bearing mice, tumor-specific serum alpha-N-acetylgalactosaminidase (NaGalase) activity increased linearly with time as the transplanted tumor cells grew in the peritoneal cavity. Therapeutic effects of DBPMAF, GcMAF, and CdMAF on mice bearing Ehrlich ascites tumor were assessed by survival time, the total tumor cell count in the peritoneal cavity, and serum NaGalase activity. Mice that received a single administration of DBPMAF or GcMAF (100 pg/mouse) on the same day after transplantation of tumor (1 x 10(5) cells) showed a mean survival time of 35 +/- 4 days, whereas tumor-bearing controls had a mean survival time of 16 +/- 2 days. When mice received the second DBPMAF or GcMAF administration at day 4, they survived more than 50 days. Mice that received two DBPMAF administrations, at days 4 and 8 after transplantation of 1 x 10(5) tumor cells, survived up to 32 +/- 4 days. At day 4 posttransplantation, the total tumor cell count in the peritoneal cavity was approximately 5 x 10(5) cells. Mice that received two DBPMAF administrations, at days 0 and 4 after transplantation of 5 x 10(5) tumor cells, also survived up to 32 +/- 4 days, while control mice that received the 5 x 10(5) ascites tumor cells only survived for 14 +/- 2 days. Four DBPMAF, GcMAF, or CdMAF administrations to mice transplanted with 5 x 10(5) Ehrlich ascites tumor cells with 4-day intervals showed an extended survival of at least 90 days and an insignificantly low serum NaGalase level between days 30 and 90.

Cardiac Gene Expression Knockdown Using Small Inhibitory RNA-Loaded Microbubbles and Ultrasound

PubMed Central

McTiernan, Charles F.; Chen, Xucai; Klein, Edwin C.; Villanueva, Flordeliza S.

2016-01-01

RNA interference has potential therapeutic value for cardiac disease, but targeted delivery of interfering RNA is a challenge. Custom designed microbubbles, in conjunction with ultrasound, can deliver small inhibitory RNA to target tissues in vivo. The efficacy of cardiac RNA interference using a microbubble-ultrasound theranostic platform has not been demonstrated in vivo. Therefore, our objective was to test the hypothesis that custom designed microbubbles and ultrasound can mediate effective delivery of small inhibitory RNA to the heart. Microbubble and ultrasound mediated cardiac RNA interference was tested in transgenic mice displaying cardiac-restricted luciferase expression. Luciferase expression was assayed in select tissues of untreated mice (n = 14). Mice received intravenous infusion of cationic microbubbles bearing small inhibitory RNA directed against luciferase (n = 9) or control RNA (n = 8) during intermittent cardiac-directed ultrasound at mechanical index of 1.6. Simultaneous echocardiography in a separate group of mice (n = 3) confirmed microbubble destruction and replenishment during treatment. Three days post treatment, cardiac luciferase messenger RNA and protein levels were significantly lower in ultrasound-treated mice receiving microbubbles loaded with small inhibitory RNA directed against luciferase compared to mice receiving microbubbles bearing control RNA (23±7% and 33±7% of control mice, p<0.01 and p = 0.03, respectively). Passive cavitation detection focused on the heart confirmed that insonification resulted in inertial cavitation. In conclusion, small inhibitory RNA-loaded microbubbles and ultrasound directed at the heart significantly reduced the expression of a reporter gene. Ultrasound-targeted destruction of RNA-loaded microbubbles may be an effective image-guided strategy for therapeutic RNA interference in cardiac disease. PMID:27471848

Effect of pituitary hollow fiber units and thyroid supplementation on growth in the little mouse (41949)

NASA Technical Reports Server (NTRS)

Harkness, John E.; Hymer, W. C.; Rosenberger, James L.; Grindeland, Richard E.

1984-01-01

It is shown that the implantation of encapsulated pituitary cells into heterozygous lit/+ mice inhibited the average percentage change in weight gain as compared to controls. However, homozygous lit/lit mice receiving cell-filled capsules consistently had higher percentage weight gains than their control counterparts. It was also found that thyroid-supplemented mutant mice with pituitary cell implants had significantly higher organ and carcass weights than other mutant groups.

Zinc and glutamine improve brain development in suckling mice subjected to early postnatal malnutrition.

PubMed

Ladd, Fernando V L; Ladd, Aliny A B L; Ribeiro, Antônio Augusto C M; Costa, Samuel B C; Coutinho, Bruna P; Feitosa, George André S; de Andrade, Geanne M; de Castro-Costa, Carlos Maurício; Magalhães, Carlos Emanuel C; Castro, Ibraim C; Oliveira, Bruna B; Guerrant, Richard L; Lima, Aldo Angelo M; Oriá, Reinaldo B

2010-06-01

The effect of zinc and glutamine on brain development was investigated during the lactation period in Swiss mice. Malnutrition was induced by clustering the litter size from 6-7 pups/dam (nourished control) to 12-14 pups/dam (undernourished control) following birth. Undernourished groups received daily supplementation with glutamine by subcutaneous injections starting at day 2 and continuing until day 14. Glutamine (100 mM, 40-80 microL) was used for morphological and behavioral studies. Zinc acetate was added in the drinking water (500 mg/L) to the lactating dams. Synaptophysin and myelin basic protein brain expressions were evaluated by immunoblot. Zinc serum and brain levels and hippocampal neurotransmitters were also evaluated. Zinc with or without glutamine improved weight gain as compared to untreated, undernourished controls. In addition, zinc supplementation improved cliff avoidance and head position during swim behaviors especially on days 9 and 10. Using design-based stereological methods, we found a significant increase in the volume of CA1 neuronal cells in undernourished control mice, which was not seen in mice receiving zinc or glutamine alone or in combination. Undernourished mice given glutamine showed increased CA1 layer volume as compared with the other groups, consistent with the trend toward increased number of neurons. Brain zinc levels were increased in the nourished and undernourished-glutamine treated mice as compared to the undernourished controls on day 7. Undernourished glutamine-treated mice showed increased hippocampal gamma-aminobutyric acid and synaptophysin levels on day 14. We conclude that glutamine or zinc protects against malnutrition-induced brain developmental impairments. Copyright 2010 Elsevier Inc. All rights reserved.

Effect of Saffron on Metabolic Profile and Retina in Apolipoprotein E-Knockout Mice Fed a High-Fat Diet.

PubMed

Doumouchtsis, Evangelos K; Tzani, Aspasia; Doulamis, Ilias P; Konstantopoulos, Panagiotis; Laskarina-Maria, Korou; Agrogiannis, Georgios; Agapitos, Emmanouil; Moschos, Marilita M; Kostakis, Alkiviadis; Perrea, Despina N

2017-09-22

Saffron is a spice that has been traditionally used as a regimen for a variety of diseases due to its potent antioxidant attributes. It is well documented that impaired systemic oxidative status is firmly associated with diverse adverse effects including retinal damage. The aim of this study was to investigate the role of saffron administration against the retinal damage in apoE -/- mice fed a high-fat diet, since they constitute a designated experimental model susceptible to oxidative stress. Twenty-one mice were allocated into three groups: Group A (control, n = 7 c57bl/6 mice) received standard chow diet; Group B (high-fat, n = 7 apoE -/- mice) received a high-fat diet; and Group C (high-fat and saffron, n = 7 apoE -/- mice) received a high-fat diet and saffron (25 mg/kg/d) through their drinking water. The duration of the study was 20 weeks. Lipidemic profile, glucose, C-reactive protein (CRP), and total oxidative capacity (PerOX) were measured in blood serum. Histological analysis of retina was also conducted. Administration of saffron resulted in enhanced glycemic control and preservation of retinal thickness when compared with apoE -/- mice fed a high-fat diet. The outcomes of the study suggest the potential protective role of saffron against retinal damage induced by oxidative stress. Nevertheless, verification of these results in humans is required before any definite conclusions can be drawn.

Respiratory response to toluene diisocyanate depends on prior frequency and concentration of dermal sensitization in mice.

PubMed

Vanoirbeek, Jeroen A J; Tarkowski, Maciej; Ceuppens, Jan L; Verbeken, Erik K; Nemery, Benoit; Hoet, Peter H M

2004-08-01

Occupational asthma is the principal cause of work-related respiratory disease in the industrial world. In the absence of satisfactory models for predicting the potential of low molecular weight chemicals to cause asthma, we verified that dermal sensitization prior to intranasal challenge influences the respiratory response using toluene diisocyanate (TDI), a known respiratory sensitizer. BALB/c mice received TDI or vehicle (acetone/olive oil) on each ear on three consecutive days (days 1, 2, and 3; 0.3 or 3% TDI) or only once (day 1, 1% TDI). On day 7, the mice received similar dermal applications of vehicle or the same concentration of TDI as before ("boost"). On day 10, they received an intranasal dose of TDI (0.1%) or vehicle. Ventilatory function was monitored by whole body plethysmography for 40 min after intranasal application, and reactivity to inhaled methacholine was assessed 24 h later. Pulmonary inflammation was assessed by bronchoalveolar lavage and histology. Mice that received an intranasal dose of TDI without having received a prior dermal application of TDI did not exhibit any ventilatory response or inflammatory changes compared to vehicle controls. In contrast, mice that had received prior application(s) of TDI, even if only on day 7, exhibited the following: ventilatory responses, compatible with bronchoconstriction, immediately after intranasal application with TDI; enhanced methacholine responsiveness 24 h later; and pulmonary inflammation characterized by neutrophils. This was, however, not the case in mice that received the highest dermal amount of TDI (3% on days 1, 2, and 3). These findings suggest that respiratory response to TDI depends on prior frequency and concentration of dermal sensitization in mice.

Enterobacter cloacae administration induces hepatic damage and subcutaneous fat accumulation in high-fat diet fed mice.

PubMed

Keskitalo, Anniina; Munukka, Eveliina; Toivonen, Raine; Hollmén, Maija; Kainulainen, Heikki; Huovinen, Pentti; Jalkanen, Sirpa; Pekkala, Satu

2018-01-01

Accumulating evidence indicates that gut microbiota plays a significant role in obesity, insulin resistance and associated liver disorders. Family Enterobacteriaceae and especially Enterobacter cloacae strain B29 have been previously linked to obesity and hepatic damage. The underlying mechanisms, however, remain unclear. Therefore, we comprehensively examined the effects of E. cloacae subsp. cloacae (ATCC® 13047™) administration on host metabolism of mice fed with high-fat diet (HFD). C57BL/6N mice were randomly divided into HFD control, chow control, and E. cloacae treatment groups. The E. cloacae treatment group received live bacterial cells in PBS intragastrically twice a week, every other week for 13 weeks. Both control groups received PBS intragastrically. After the 13-week treatment period, the mice were sacrificed for gene and protein expression and functional analyses. Our results show that E. cloacae administration increased subcutaneous fat mass and the relative proportion of hypertrophic adipocytes. Both subcutaneous and visceral fat had signs of decreased insulin signaling and elevated lipolysis that was reflected in higher serum glycerol levels. In addition, E. cloacae -treated mice had significantly higher hepatic AST and AST/ALT ratio, and their liver histology indicated fibrosis, demonstrating that E. cloacae subsp. cloacae administration promotes hepatic damage in HFD fed mice.

Mumijo attenuates chemically induced inflammatory pain in mice.

PubMed

Malekzadeh, Golnaz; Dashti-Rahmatabadi, Mohammad Hossein; Zanbagh, Samira; Akhavi Mirab-bashii, Atefehsadat

2015-01-01

Mumijo (shilajit) has been well known in traditional medicine as a remedy for a number of diseases, such as bone fractures, wounds, inflammation, and headache. It is also widely used as an analgesic agent in folk medicine, but no scientific documentation exists concerning that effect. The current study was conducted to evaluate the ability of mumijo to reduce sensitivity to painful stimuli when compared with morphine sulfate and sodium diclofenac. A total of 176 animals were randomly and equally divided into 2 groups with 88 mice each-one for formalin test and the other for writhing test. For each test, the animals were allocated into 10 equal groups, based on the dosage of the analgesic, plus a negative control group, with 8 mice in each group. The analgesic effect of mumijo extract in doses of 0.75, 7.5, 75, and 750 mg/kg was assessed and compared witha group receiving distilled water-the negative control group, and that for groups receiving 1, 2, or 4 mg/kg of morphine sulfate or 10, 20, or 30 mg/kg of sodium diclofenac-the positive control groups. The results showed a significant decrease in pain intensity for all mice receiving doses of mumijo extract during a 1-h formalin test when compared with the distilled water group. For all the mumijo groups except the one receiving 750 mg/kg, the analgesic effect was significantly lower than that for the morphine sulfate group receiving 4 mg/kg. No significant differences existed between all mumijo and all diclofenac groups. In a writhing test, a significant inhibition of the pain response induced by acetic acid also occurred in all 4 mumijo-administered groups as opposed to the group receiving distilled water. No significant differences existed between the writhing response in groups receiving 75 and 750 mg/kg of mumijo and any doses of diclofenac or morphine. The comparison among the different doses of mumijo in the formalin test did not show any significant differences, but in the writhing test, the maximum dose showed a more effective analgesic action. The findings indicated a significant analgesic effect for mumijo extract on chronic pain in mice, occurring in a dose-independent manner.

Ameliorating Effect of Dietary Xylitol on Human Respiratory Syncytial Virus (hRSV) Infection.

PubMed

Xu, Mei Ling; Wi, Ga Ram; Kim, Hyoung Jin; Kim, Hong-Jin

2016-01-01

Human respiratory syncytial virus (hRSV) is the most common cause of bronchiolitis and pneumonia in infants. The lack of proper prophylactics and therapeutics for controlling hRSV infection has been of great concern worldwide. Xylitol is a well-known sugar substitute and its effect against bacteria in the oral cavity is well known. However, little is known of its effect on viral infections. In this study, the effect of dietary xylitol on hRSV infection was investigated in a mouse model for the first time. Mice received xylitol for 14 d prior to virus challenge and for a further 3 d post challenge. Significantly larger reductions in lung virus titers were observed in the mice receiving xylitol than in the controls receiving phosphate-buffered saline (PBS). In addition, fewer CD3(+) and CD3(+)CD8(+) lymphocytes, whose numbers reflect inflammatory status, were recruited in the mice receiving xylitol. These results indicate that dietary xylitol can ameliorate hRSV infections and reduce inflammation-associated immune responses to hRSV infection.

Effects of Cuminum cyminum L. essential oil on some epididymal sperm parameters and histopathology of testes following experimentally induced copper poisoning in mice.

PubMed

Sakhaee, E; Emadi, L; Azari, O; Kheirandish, R; Esmaili Nejad, M R; Shafiei Bafti, H

2016-06-01

Copper overload can cause sperm cell damage by inducing oxidative stress. On the other hand, cumin has a good antioxidant potential. Therefore, the aim of this study was to evaluate the effects of cumin on sperm quality and testicular tissue following experimentally induced copper poisoning in mice. Forty-eight mature male mice were divided into four equal groups as follows: group Cu which received 0.1 ml copper sulphate at dose of 100 mg kg(-1) , group Cc which received Cuminum cyminum at dose of 1 mg kg(-1) , treatment group which received copper sulphate (100 mg kg(-1) ) and treated with Cuminum cyminum (1 mg kg(-1) ), and control group which received the same volume of normal saline. Six mice in each group were sacrificed at week 4 and week 6. The results showed that sperm concentration, motility and viability in group Cu were significantly decreased at weeks 4 and 6, and severe degenerative changes were observed in testicular tissues in comparison with the control group. In treatment group, significant improvement in the sperm count, motility and viability, and normal architecture in most seminiferous tubules with organised epithelium was observed compared to the group Cu. The sperm quality parameters in the treatment group approached those of the control group. © 2015 Blackwell Verlag GmbH.

Evaluation of the initial and chronic phases of toxocariasis after consumption of liver treated by freezing or cooling.

PubMed

Dutra, Gisele Ferreira; Pinto, Nitza Souto França; da Costa de Avila, Luciana Farias; de Lima Telmo, Paula; da Hora, Vanusa Pousada; Martins, Lourdes Helena Rodrigues; Berne, Maria Elisabeth Aires; Scaini, Carlos James

2013-06-01

Human toxocariasis is a neglected parasitic zoonosis of worldwide distribution. The consumption of raw or undercooked meat and offal from paratenic hosts of the Toxocara canis nematode can cause infection in humans, but there have been a lack of studies examining specific prophylactic measures to combat this mode of transmission. The aim of this study was to evaluate the establishment of infection by T. canis larvae at the initial and chronic phases of visceral toxocariasis after the consumption of mouse liver subjected to cold treatment. This study was divided into two stages using groups (G) of five donor mice inoculated with 2,000 eggs of T. canis. Two days post-inoculation, the livers of donor mice in G1 and G2 were kept at -20 °C and between 0 and 4 °C, respectively, for 10 days. In the first stage of the study, the livers of mice from G1, G2, and G3 (control) were subjected to a tissue digestion technique and found to be positive for infection. In the second stage, which evaluated infection in mice that had consumed livers from donor mice, receiver mice of G4 and G7 were fed with livers of donor mice from G1 (freezing), receiver mice of G5 and G8 were fed with livers of donor mice from G2 (cooling), and receiver mice of G6 and G9 with livers from G3 (control). Then, the tissue digestion technique was performed for recovering larvae from organs and carcasses of mice, at 2 days (G4, G5, and G6) and 60 days after liver consumption (G7, G8, and G9). It was observed that freezing inhibited the viability of 100 % of the larvae, while cooling promoted 87.7 and 95.7 % reductions in the intensity of infection at 2 and 60 days after liver consumption, respectively. Under the studied conditions, cold treatment shows great potential to help control this parasitosis, both in the initial and chronic phases of toxocariasis.

In vivo study of the efficacy of the aromatic water of Zataria multiflora on hydatid cysts.

PubMed

Moazeni, Mohammad; Larki, Sara; Saharkhiz, Mohammad Jamal; Oryan, Ahmad; Ansary Lari, Maryam; Mootabi Alavi, Amir

2014-10-01

Gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS) were employed to determine the chemical composition of the essential oil (EO) from aromatic water (AW) of Zataria multiflora. Thymol (66.9%), carvacrol (15.2%), and carvone (7.3%) were found to be the major EO constituents. Eighty laboratory BALB/c mice were infected intraperitoneally by injection of 1,500 viable protoscolices and were divided into prevention (40 mice) and therapeutic (40 mice) groups. To prove the preventive effect of the Z. multiflora AW on development of hydatid cysts, the 40 infected mice were allocated into three treatment groups, including the albendazole group (10 mice that received 150 mg/kg body weight/day for 10 days), the Z. multiflora AW group (15 mice that received 20 ml/liter in drinking water for 8 months), and a control group (15 mice that received no treatment). To estimate the therapeutic effect of the Z. multiflora AW on the hydatid cyst, after 8 months of infection, the 15 remaining mice were allocated into three experimental treatment groups of five animals each, including the albendazole group (300 mg/kg/day for 20 days), Z. multiflora AW group (40 ml/liter in drinking water for 30 days), and control group (no treatment). All mice were then euthanized, and the sizes and weights of the cysts as well as their ultrastructural changes were investigated. The weights and sizes of the hydatid cysts significantly decreased upon treatment with the Z. multiflora AW in both the preventive and therapeutic groups (P < 0.05). The results of scanning electron microscopy also showed considerable damage in the germinal layer of the hydatid cysts recovered from the treated animals. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Attenuation of hepatotoxicity and oxidative stress in diabetes STZ-induced type 1 by biotin in Swiss albino mice

PubMed Central

Aldahmash, Badr Abdullah; El-Nagar, Doaa Mohamed; Ibrahim, Khalid Elfakki

2015-01-01

Diabetes mellitus is one of the major health problems. This study was designed to investigate the effect of biotin to regulate blood glucose level, reduced toxicity and oxidative stress in liver of diabetic mice STZ-induced type 1. Male mice were divided into three groups, the first one served as the control group, the second and the third groups received single ip dose of 150 mg/kg of STZ, the second group served as the untreated diabetic group, the third group received daily oral dose of 15 mg/kg of biotin, livers and liver index showed insignificant difference among groups. Blood glucose level showed a significant decrease in treated diabetic mice compared to untreated diabetic mice. Biochemical analysis showed a significant decrease in liver enzymes AST and ALT compared to the control group. Histopathological examination showed severe changes in untreated diabetic liver tissue manifested by dilated portal vein, leukocytic infiltration, fatty degeneration and moderate to severe histopathological score, whereas, treated diabetic mice with biotin showed reduction in hepatotoxicity represented by appearance of relative healthy hepatocytes and normal histopathological score. Immunohistochemistry of acrolein showed intense immunoreactions in liver section of untreated diabetic mice and faint immunoreactions in treated diabetic mice with biotin as evidence to oxidative stress reduction. PMID:26981014

Effects of Corticotropin Releasing Factor (CRF) on Sleep and Body Temperature Following Controllable Footshock Stress in Mice

PubMed Central

Yang, L; Wellman, LL; Tang, X; Sanford, LD

2011-01-01

Rapid eye movement sleep (REM) is increased after controllable stress (modeled by escapable footshock, ES) and decreased after uncontrollable stress (modeled by inescapable footshock, IS). Decreases in REM after IS are exacerbated by corticotropin releasing factor (CRF) and attenuated by a CRF antagonist. In this study, we trained mice with ES following injections of CRF, astressin (AST), or saline (SAL) to determine whether CRF would alter REM after ES. Male BALB/cJ mice (n=7) were implanted for recording sleep, activity and body temperature via telemetry and with a guide cannula aimed into a lateral ventricle. After recovery from surgery, sleep following exposure to a novel chamber was recorded as a handling control (HC). The mice received one day of training with ES without injection followed by weekly training sessions in which they received counterbalanced intracerebroventricular (ICV) microinjections of either SAL or CRF (days 7 & 14) or SAL or AST (days 21 & 28) prior to ES. On each experimental day, sleep was recorded for 20 hours. Compared to HC, the mice showed significantly increased REM when receiving either SAL or AST prior to ES whereas CRF prior to ES significantly reduced REM. Stress-induced hyperthermia had longer duration after ES compared to HC, and was not significantly altered by CRF or AST compared to SAL. The current results demonstrate that activity in the central CRF system is an important regulator of stress-induced alterations in REM. PMID:21651923

Abuse Pattern of Toluene Exposure Alters Mouse Behavior in a Waiting-for-Reward Operant Task

PubMed Central

Bowen, Scott E.; McDonald, Phillip

2009-01-01

Inhaling solvents for recreational purposes continues to be a world-wide public health concern. Toluene, a volatile solvent in many abused products, adversely affects the central nervous system. However, the long-term neurobehavioral effects of exposure to high-concentration, binge patterns typical of toluene abuse remain understudied. We studied the behavioral effects of repeated toluene exposure on cognitive function following binge toluene exposure on behavioral impulse control in Swiss Webster mice using a “wait-for-reward” operant task. Mice were trained on a fixed-ratio (FR) schedule using sweetened milk as a reward. Upon achieving FR15, a wait component was added which delivered free rewards in the absence of responses at increasing time intervals (2 sec, 4 sec, 6 sec, etc…). Mice continued to receive free rewards until they pressed a lever that reinstated the FR component (FR Reset). Once proficient in the FR-Wait task, mice were exposed to either 1,000 ppm, 3,600 ppm or 6,000 ppm toluene, or 0 ppm (air controls) for 30 min per day for 40 days. To avoid acute effects of toluene exposure, behavior was assessed 23 hours later. Repeated toluene exposure decreased response rates, the number of FR resets, and increased mean wait time, resulting in a higher response-to-reinforcer ratio than exhibited by controls. Mice receiving the higher exposure level (6,000 ppm) showed a dramatic decrease in the number of rewards received, which was reversed when toluene exposure ceased. Mice receiving the lower exposure level (1,000 ppm) showed little change in the number of rewards. These results indicate that repeated binge exposures to high concentrations of toluene can significantly interfere with performance as measured by a waiting-for-reward task, suggesting a significant impact on cognitive and/or psychomotor function. PMID:18832024

Germinated Brown Rice Attenuates Atherosclerosis and Vascular Inflammation in Low-Density Lipoprotein Receptor-Knockout Mice.

PubMed

Zhao, Ruozhi; Ghazzawi, Nora; Wu, Jiansu; Le, Khuong; Li, Chunyang; Moghadasian, Mohammed H; Siow, Yaw L; Apea-Bah, Franklin B; Beta, Trust; Yin, Zhengfeng; Shen, Garry X

2018-05-02

The present study investigates the impact of germinated brown rice (GBR) on atherosclerosis and the underlying mechanism in low-density lipoprotein receptor-knockout (LDLr-KO) mice. The intensity of atherosclerosis in aortas of LDLr-KO mice receiving diet supplemented with 60% GBR (weight/weight) was significantly less than that in mice fed with 60% white rice (WR) or control diet ( p < 0.05); all diets contained 0.06% cholesterol. WR or GBR diet did not significantly alter plasma total or LDL-cholesterol, fecal sterols, or glucose, or the activities of antioxidant enzymes, compared to the control diet. The adhesion of monocytes to aortas from LDLr-KO mice fed with WR diet was significantly more than that from mice receiving the control diet ( p < 0.01). GBR diet decreased monocyte adhesion to aortas compared to WR diet ( p < 0.01). GBR diet also reduced the levels of plasminogen activator inhibitor-1 (PAI-1), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α) in plasma, and the abundances of MCP-1, PAI-1, TNF-α, intracellular cell adhesion molecule-1, toll-like receptor-4, PAI-1, LDLr-like protein, and urokinase plasminogen activator and its receptor in aortas or hearts from LDLr-KO mice in comparison to the WR diet ( p < 0.05, 0.01, respectively). The findings suggest that GBR administration attenuated atherosclerosis and vascular inflammation in LDLr-KO mice compared to WR. The anti-atherosclerotic effect of GBR in LDLr-KO mice at least in part results from its anti-inflammatory activity.

RESISTANCE PRODUCED IN MICE BY EXPOSURE TO IRRADIATED SCHISTOSOMA MANSONI CERCARIAE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Radke, M.G.; Sadun, E.H.

1963-04-01

Studies were undertaken to determine whether gamma irradiation of cercariae might provide a means of investigating some of the mechanisms involved in the acquired resistance to schistosomiasis. Control mice received 200 nonirradiated cercariae, and other groups received the same number of cercariae that had been exposed to 6 different doses of Co/sup 60/ gamma irradiation varying from 1000--20000 rep. Eight weeks later the worms recovered were counted. Doses of 4000 rep or higher completely inhibited the development of schistosomes. A few stunted and underdeveloped worms were found in some of the mice receiving cercariae irradiated at 2500 and 3000 rep.more » Some adult schistosomes were observed in the groups receiving 1500 and 2000 rep and eggs were found in the liver but not in the stools of some mice. However, all of the mice exposed to cercariae irradiated with 1000 rep had eggs in liver and stools. The worm burden decreased regularly with increasing dosages up to 3000 rep, beyond which no worms were found at necropsy. The decrease in the number of worms mice acquired was linear only when cercariae were exposed from 1000to 2000 rep, however, even beyond such dosages, it followed a straight line when the logarithm of irradiation dose was plotied. Acquired resistance to S. mansoni was observed in mice following a previous exposure to irradiated cercariae. (TCO)« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Palm, Stig; Baeck, Tom; Claesson, Ingela

Purpose: To investigate the potential use of astatine-211 ({sup 211}At)-labeled trastuzumab for the treatment of HER-2-positive, radioresistant ovarian carcinoma. Methods and Materials: Four-week-old nude mice were inoculated intraperitoneally with 5 . 10{sup 6} SKOV-3 cells in 0.4 mL saline on Day 0. The endpoint was the total tumor weight in each mouse on Day 63. Three experiments were performed in which the response to single-dose and fractionated treatment with unlabeled and {sup 211}At-labeled antibody was evaluated. Results: Experiment 1 showed, for the same total amount of trastuzumab, a dose-response relationship between {sup 211}At activity (0-400 kBq on Day 7) andmore » therapeutic efficacy (p = 0.001). The effect of varying the amount of unlabeled trastuzumab was studied in Experiment 2. All mice, except for the controls, received 400 kBq {sup 211}At-trastuzumab, and different groups received 5, 50, or 500 {mu}g trastuzumab on Day 7. The increase from 5 to 50 {mu}g trastuzumab reduced the tumors by 78% in weight. No tumors were present in mice given 500 {mu}g trastuzumab. In Experiment 3, the effect of a fractionated treatment regimen was studied. Mice that received 100 kBq {sup 211}At-trastuzumab on Days 7 and 8 had a 42% smaller tumor burden than did controls. Groups of mice injected with 200 + 100 kBq on Days 7 and 21 and mice injected with 100 kBq on Days 7, 8, and 21 both had 24% less tumor weight than the corresponding controls. Conclusion: The combination of 500 {mu}g trastuzumab and 400 kBq {sup 211}At-trastuzumab had the greatest effect, with complete eradication of the tumors in this nude mouse model.« less

Arginine reduces Cryptosporidium parvum infection in undernourished suckling mice involving both nitric oxide synthase and arginase

PubMed Central

Castro, Ibraim C.; Oliveira, Bruna B.; Slowikowski, Jacek J.; Coutinho, Bruna P.; Siqueira, Francisco Júlio W.S.; Costa, Lourrany B.; Sevilleja, Jesus Emmanuel; Almeida, Camila A.; Lima, Aldo A.M.; Warren, Cirle A.; Oriá, Reinaldo B.; Guerrant, Richard L.

2011-01-01

Objective This study investigated the role of L-arginine supplementation to undernourished and Cryptosporidium parvum-infected suckling mice. Methods The following regimens were initiated on the 4th day of life and given subcutaneously daily: either 200mM of L-arginine or PBS for the C. parvum-infected controls. L-arginine-treated mice were grouped to receive either 20mM of NG-nitroarginine-methyl-ester (L-NAME) or PBS. Infected mice received orally 106 excysted-C. parvum oocysts on day 6 and were euthanized on day 14th at the infection peak. Results L-arginine improved weight gain compared to the untreated infected controls. L-NAME profoundly impaired body weight gain as compared to all other groups. Cryptosporidiosis was associated with ileal crypt hyperplasia, villus blunting, and inflammation. L-arginine improved mucosal histology following infection. L-NAME abrogated these arginine-induced improvements. Infected control mice showed an intense arginase expression, which was even greater with L-NAME. L-arginine reduced parasite burden, an effect that was reversed by L-NAME. C. parvum infection increased urine NO3-/NO2- concentration when compared to uninfected controls, which was increased by L-arginine supplementation, an effect that was also reversed by L-NAME. Conclusion These findings show a protective role of L-arginine during C. parvum infection in undernourished mice with involvement of arginase I and nitric oxide synthase enzymatic actions. PMID:22261576

7,12-Dimethylbenz[a]anthracene-Induced Malignancies in a Mouse Model of Menopause

PubMed Central

Marion, Samuel L; Watson, Jennifer; Sen, Nivedita; Brewer, Molly A; Barton, Jennifer K; Hoyer, Patricia B

2013-01-01

Ovarian cancer has a high mortality rate because there are few symptoms in early disease development. The incidence of ovarian cancer increases in women after menopause. Understanding early events in this disease can best be achieved by using animal models. Therefore, the objective of this study was to develop and track the onset of ovarian tumorigenesis in mice mimicking characteristics of postmenopausal epithelial cancer in women. Female B6C3F1 mice (age, 28 d) received 4-vinylcyclohexene diepoxide (VCD, 160 mg/kg IV daily for 20 d) to cause ovarian failure. Four months after VCD treatment, via surgical intervention, each mouse received a single injection of 7,12-dimethylbenz[a]anthracene (DMBA) or vehicle control (sesame oil) under the bursa of the right ovary to cause ovarian neoplasms. The experimental groups were untreated controls (Con–Con), DMBA-treatment only (Con–DMBA), VCD treatment only (VCD–Con), and VCD+DMBA-treated (VCD+DMBA) mice. At 3, 5, 7, and 9 mo after DMBA injection, ovaries were collected for histologic and immunohistochemical evaluation. No tumors developed in Con–Con mice. All VCD-treated mice (with or without DMBA) exhibited ovarian failure. Mice that received both VCD and DMBA exhibited tumors at 3 mo (50%), 5 mo (14%), 7 mo (90%), and 9 mo (57%) after DMBA treatment; 31% of the tumors were epithelial in origin. Our findings confirm that inducing ovarian tumors in mice by chemical means is an effective method for studying early stages of tumor development that may be relevant to epithelial ovarian cancers that arise in postmenopausal women. PMID:23561932

7,12-dimethylbenz[a]anthracene-induced malignancies in a mouse model of menopause.

PubMed

Marion, Samuel L; Watson, Jennifer; Sen, Nivedita; Brewer, Molly A; Barton, Jennifer K; Hoyer, Patricia B

2013-02-01

Ovarian cancer has a high mortality rate because there are few symptoms in early disease development. The incidence of ovarian cancer increases in women after menopause. Understanding early events in this disease can best be achieved by using animal models. Therefore, the objective of this study was to develop and track the onset of ovarian tumorigenesis in mice mimicking characteristics of postmenopausal epithelial cancer in women. Female B6C3F1 mice (age, 28 d) received 4-vinylcyclohexene diepoxide (VCD, 160 mg/kg IV daily for 20 d) to cause ovarian failure. Four months after VCD treatment, via surgical intervention, each mouse received a single injection of 7,12-dimethylbenz[a]anthracene (DMBA) or vehicle control (sesame oil) under the bursa of the right ovary to cause ovarian neoplasms. The experimental groups were untreated controls (Con-Con), DMBA-treatment only (Con-DMBA), VCD treatment only (VCD-Con), and VCD+DMBA-treated (VCD+DMBA) mice. At 3, 5, 7, and 9 mo after DMBA injection, ovaries were collected for histologic and immunohistochemical evaluation. No tumors developed in Con-Con mice. All VCD-treated mice (with or without DMBA) exhibited ovarian failure. Mice that received both VCD and DMBA exhibited tumors at 3 mo (50%), 5 mo (14%), 7 mo (90%), and 9 mo (57%) after DMBA treatment; 31% of the tumors were epithelial in origin. Our findings confirm that inducing ovarian tumors in mice by chemical means is an effective method for studying early stages of tumor development that may be relevant to epithelial ovarian cancers that arise in postmenopausal women.

Photoprotective effects of topical ginseng leaf extract using Ultraflo L against UVB-induced skin damage in hairless mice.

PubMed

Hong, Yang Hee; Lee, Hyun-Sun; Jung, Eun Young; Han, Sung-Hee; Park, Yooheon; Suh, Hyung Joo

2017-10-01

Abnormal activation of matrix metalloproteinases (MMPs) plays an important role in UV-induced wrinkle formation, which is a major dermatological problem. This formation occurs due to the degeneration of the extracellular matrix (ECM). In this study, we investigated the cutaneous photoprotective effects of Ultraflo L treated ginseng leaf (UTGL) in hairless mice. SKH-1 hairless mice (6 weeks of age) were randomly divided into four groups (8 mice/group). UTGL formulation was applied topically to the skin of the mice for 10 weeks. The normal control group received nonvehicle and was not irradiated with UVB. The UV control (UVB) group received nonvehicle and was exposed to gradient-UVB irradiation. The groups (GA) receiving topical application of UTGL formulation were subjected to gradient-UVB irradiation on 0.5 mg/cm 2 [GA-low (GA-L)] and 1.0 mg/cm 2 [(GA-high (GA-H)] of dorsal skin area, respectively. We found that topical treatment with UTGL attenuated UVB-induced epidermal thickness and impairment of skin barrier function. Additionally, UTGL suppressed the expression of MMP-2, -3, and -13 induced by UVB irradiation. Our results show that topical application of UTGL protects the skin against UVB-induced damage in hairless mice and suggest that UTGL can act as a potential agent for preventing and/or treating UVB-induced photoaging. UTGL possesses sunscreen properties and may exhibit photochemoprotective activities inside the skin of mice. Therefore, UTGL could be used as a potential therapeutic agent to protect the skin against UVB-induced photoaging.

Bacopa monniera Stabilized Silver Nanoparticles Attenuates Oxidative Stress Induced by Aluminum in Albino Mice.

PubMed

Mahitha, B; Deva Prasad Raju, B; Mallikarjuna, K; Durga Mahalakshmi, Ch N; Sushmal, N John

2015-02-01

In the recent years usage of nanomedicine plays a promising strategy in the improvement of medical treatment. The ecofriendly synthesized silver nanoparticles has introduced a new opportunity to increase the efficacy of drug by reducing its side effects. In the present study, we investigated the antioxidant property of Bacopa monniera stabilized silver nanoparticles against aluminum induced toxicity in albino mice. Forty male albino mice were randomly divided into five groups. First group was treated as control, second group received aluminum acetate (5 mg/kg b . w), third group received Bacopa monniera extract (5 mg/kg b . w), fourth group received BmSNPs (5 mg/kg b . w), fifth group received aluminum acetate plus BmSNPs. Exposure to aluminum acetate significantly increased lipid peroxidation levels with a significant decrease in the antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase activities in the brain, liver and kidney of mice. Degenerative changes were also observed in brain, liver and kidney of aluminum treated mice. No significant changes in the oxidative stress were observed in the Bacopa monniera and BmSNPs alone treated mice. Whereas, co-administration of BmSNPs to Al treated mice showed a significant decrease in lipid peroxidation levels with a significant increase of SOD, CAT and GPx indicating the antioxidant potential of nanoparticles and in counteracting Al induced oxidative stress and histological response in male albino mice. These findings clearly implicate that BmSNPs are able to eradicate the oxidative stress and prevent the tissue damage in aluminum exposed mice.

Effect of Lactobacillus johnsonii La1 on immune function and serum albumin in aged and malnourished aged mice.

PubMed

Kaburagi, Tomoko; Yamano, Toshihiko; Fukushima, Yoichi; Yoshino, Haruka; Mito, Natsuko; Sato, Kazuto

2007-04-01

Protein-energy malnutrition (PEM) is a serious nutritional problem that causes immune dysfunction in elderly people. Probiotic lactic acid bacteria may potentially modify immunity; however, there is little evidence to elucidate the influence of these bacteria on PEM in the elderly. The immune modulation effects of lactic acid bacterium Lactobacillus johnsonii La1 (La1) were examined in aged mice and aged mice with PEM. Twenty-month-old male 57BL6/n mice (n = 28) were divided into four groups and received the following diet for 14 d: a complete diet (20% protein) without Lal (control) or with Lal or a low-protein diet (5% protein) to induce PEM, with or without La1. All mice were immunized with diphtheria toxin (DT) with alfacalciferol at 7 d and sacrificed 14 d after starting the experimental diets. Serum albumin concentrations and body weight, both of which were reduced by the low-protein diet, were ameliorated by La1 intake and were the same as in mice receiving the control diet. Anti-DT immunoglobulin (Ig) A in fecal extract was increased by La1 intake in mice receiving the complete and low-protein diets. Serum anti-DT IgA, IgG, splenocyte proliferation, and CD8(+) T cells were reduced by the low-protein diet and restored by La1 intake. La1 enhances intestinal IgA production and helps recover nutritional status and systemic immune responses in aged mice with PEM. It is possible that La1 may contribute to immune system recovery in immunocompromised hosts such as elderly humans with PEM.

Cadmium Increases the Sensitivity of Adolescent Female Mice to Nicotine-Related Behavioral Deficits

PubMed Central

Adeniyi, Philip Adeyemi; Olatunji, Babawale Peter; Ishola, Azeez Olakunle; Ajonijebu, Duyilemi Chris; Ogundele, Olalekan Michael

2014-01-01

This study investigates spatial and nonspatial working memory, anxiety related behavior, and motor activities in cadmium and/or nicotine exposed female adolescent mice. P28 female adolescent mice (albino strain) were divided into four groups of five (n = 5) mice each. A set of mice (Nic) received subcutaneous nicotine (2.0 mg/kg) while a separate set (Cd) was treated with 2.0 mg/kg cadmium (subcutaneous). For the combined treatments of cadmium and nicotine, we administered 2.0 mg/kg Nicotine and 2.0 mg/kg of Cd. Subsequently, a separate group of animals (n = 5; control) received normal saline. The total duration of treatment for all groups was 28 days (P28–P56). At P56, the treatment was discontinued, after which the animals were examined in behavioural tests. Nicotine and cadmium increased the metabolism and food intake in the female adolescent mice. This also corresponded to an increase in weight when compared with the control. However, a combined nicotine-cadmium treatment induced a decline in weight of the animals versus the control. Also, nicotine administration increased the motor function, while cadmium and nicotine-cadmium treatment caused a decline in motor activity. Both nicotine and cadmium induced a reduction in memory index; however, nicotine-cadmium treatment induced the most significant decrease in nonspatial working memory. PMID:25477708

Interactive effects of ethanol on ulcerative colitis and its associated testicular dysfunction in pubertal BALB/c mice.

PubMed

Adedara, Isaac A; Ajayi, Babajide O; Awogbindin, Ifeoluwa O; Farombi, Ebenezer O

2017-11-01

Available epidemiological reports have indicated an increase in the incidence of ulcerative colitis, as well as alcohol consumption, globally. The present study investigated the possible interactive effects of ethanol consumption on ulcerative colitis and its associated testicular dysfunction using six groups of 12 pubertal mice each. Group I (Control) mice received drinking water alone. Group II mice received ethanol alone at 5 g/kg body weight. Group III mice received 2.5% dextran sulphate sodium (DSS) in drinking water followed by normal drinking water. Groups IV, V, and VI mice received DSS followed by ethanol at 1.25, 2.5, and 5 g/kg, respectively. Administration of ethanol to mice with ulcerative colitis intensified the disease-activity index with marked reduction in colon length, colon mass index, body weight gain, and organo-somatic indices of testes and epididymis when compared with the DSS-alone group. Moreover, ethanol exacerbated colitis-mediated decrease in enzymatic and non-enzymatic antioxidants but increased the oxidative stress and inflammatory biomarkers in the testes and epididymis. The diminution in luteinizing hormone, follicle stimulating hormone, and testosterone levels was intensified following administration of ethanol to mice with ulcerative colitis that were administered 5 g/kg ethanol alone. The decrease in sperm functional parameters and testicular spermatogenic indices as well as histopathological damage in colon, testes, and epididymis was aggravated following administration of ethanol to mice with ulcerative colitis. In conclusion, the exacerbating effects of ethanol on ulcerative colitis-induced testicular dysfunction are related to increased oxidative stress and inflammation in the treated mice. Copyright © 2017 Elsevier Inc. All rights reserved.

Obesity-induced oocyte mitochondrial defects are partially prevented and rescued by supplementation with co-enzyme Q10 in a mouse model

PubMed Central

Boots, C.E.; Boudoures, A.; Zhang, W.; Drury, A.; Moley, K.H.

2016-01-01

STUDY QUESTION Does supplementation with co-enzyme Q10 (CoQ10) improve the oocyte mitochondrial abnormalities associated with obesity in mice? SUMMARY ANSWER In an obese mouse model, CoQ10 improves the mitochondrial function of oocytes. WHAT IS KNOWN ALREADY Obesity impairs oocyte quality. Oocytes from mice fed a high-fat/high-sugar (HF/HS) diet have abnormalities in mitochondrial distribution and function and in meiotic progression. STUDY DESIGN, SIZE, DURATION Mice were randomly assigned to a normal, chow diet or an isocaloric HF/HS diet for 12 weeks. After 6 weeks on the diet, half of the mice receiving a normal diet and half of the mice receiving a HF/HS diet were randomly assigned to receive CoQ10 supplementation injections for the remaining 6 weeks. PARTICIPANTS/MATERIALS, SETTING, METHODS Dietary intervention was initiated on C57Bl6 female mice at 4 weeks of age, CoQ10 versus vehicle injections were assigned at 10 weeks, and assays were conducted at 16 weeks of age. Mice were super-ovulated, and oocytes were collected and stained to assess mitochondrial distribution, quantify reactive oxygen species (ROS), assess meiotic spindle formation, and measure metabolites. In vitro fertilization was performed, and blastocyst embryos were transferred into control mice. Oocyte number, fertilization rate, blastulation rate and implantation rate were compared between the four cohorts. Bivariate statistics were performed appropriately. MAIN RESULTS AND THE ROLE OF CHANCE HF/HS mice weighed significantly more than normal diet mice (29 versus 22 g, P< 0.001). CoQ10 supplementation did not influence weight. Levels of ATP, citrate, and phosphocreatine were lower and ROS levels were higher in HF/HS mice than in controls (P< 0.001). CoQ10 supplementation significantly increased the levels of metabolites and decreased ROS levels in oocytes from normal diet mice but not in oocytes from HF/HS mice. However, CoQ10 completely prevented the mitochondrial distribution abnormalities observed in the HF/HS mice. Overall, CoQ10 supplementation significantly increased the percentage of normal spindle and chromosome alignment (92.3 versus 80.2%, P= 0.039). In the sub-analysis by diet, the difference did not reach statistical significance. When undergoing IVF, there were no statistically significant differences in the number of mature oocytes, the fertilization rate, blastocyst formation rates, implantation rates, resorption rates or litter size between HF/HS mice receiving CoQ10 or vehicle injections. LIMITATIONS, REASONS FOR CAUTION Experiments were limited to one species and strain of mice. The majority of experiments were performed after ovulation induction, which may not represent natural cycle fertility. WIDER IMPLICATIONS OF THE FINDINGS Improvement in oocyte mitochondrial distribution and function of normal, chow-fed mice and HF/HS-fed mice demonstrates the importance of CoQ10 and the efficiency of the mitochondrial respiratory chain in oocyte competence. Clinical studies are now needed to evaluate the therapeutic potential of CoQ10 in women's reproductive health. STUDY FUNDING/COMPETING INTEREST(S) C.E.B. received support from the National Research Training Program in Reproductive Medicine sponsored by the National Institute of Health (T32 HD040135-13) and the Scientific Advisory Board of Vivere Health. K.H.M received support from the American Diabetes Association and the National Institute of Health (R01 HD083895). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER This study is not a clinical trial. PMID:27432748

Evaluation of protective efficacy of Spirulina platensis in Balb/C mice with candidiasis.

PubMed

Soltani, M; Khosravi, A-R; Asadi, F; Shokri, H

2012-12-01

This study was aimed at evaluating the immunostimulatory effect of Spirulina platensis in prophylaxis of Balb/C mice with systemic candidiasis. In first experiment, 40 mice were divided into four groups, ten mice per each group, for cytokines assay. Animals received a dose of 800mg/kg of S. platensis for 4days and then were intravenously inoculated with 1×10(6) Candida albicans. Control groups received 0.2mL and 0.1mL normal saline for prophylaxis and inoculation, respectively. Five mice from each group were euthanized after 24hours and 72hours and the serum levels of IFN-γ and TNF-α were measured by Enzyme-linked immunosorbent assay (ELISA) method. In second experiment, two mice groups with systemic candidiasis, 11 mice per each group, were included to evaluate the survival rate. Animals were monitored for 30days and the kidneys, liver, lungs and spleen were analyzed for fungal invasion. The results indicated that the Spirulina-treated mice produced more IFN-g and TNF-α level than their control groups. This infected group showed that the mean survival time (28.86±2.7) was significantly (P<0.05) higher than control group (13.9±3.34). They also exhibited that fungal clearance in selected organs at death time represents significant differences between spleen and liver (P<0.05). Prophylaxis with S. platensis had synergistic effect through producing cytokines such as TNF-α and IFN-γ. Our results provide important information for the potential application of S. platensis in the treatment and resistance of Balb/C mice with systemic candidiasis. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

[Effects of moxibustion with seed-sized moxa cone on apoptosis of myocardial cells after sport fatigue in mice].

PubMed

Xu, Huiqian; Hu, Yin; Gu, Yihuang; Zhang, Hongru

2015-03-01

To observe the effects of moxibustion on factors related with apoptosis of myocardial cells after sports fatigue in mice as well as the relationship among histone acetyltransferases p300 (p300), CREB binding protein (CBP) and cell apoptosis to discuss the role of p300 and CBP in moxibustion against apoptosis of myocardial cells. Sixty clean-grade male Kunming mice were randomly divided into a control group, a sport group and a moxibustion group, 20 cases in each one. Mice in all group received identical feeding environment. Mice in the control group did not received sport nor moxibustion; mice in the sport group and moxibustion group received non-weight swimming training which lasted from 30 min per day to 90 min per day gradually for 21 days; 1 h after swimming training, mice in the moxibustion group received moxibustion with seed-sized moxa cone at "Zusanli" (ST 36) and "Guanyuan" (CV 4), 5 cones at each acupoint, once a day for 21 days. 24 h after the final swimming training, cardiac muscle tissue was collected to test factor associated suicide (Fas), B cell lymphoma/lewkmia-2 (Bcl-2) by immunohistochemical method and expression of p300 and CBP. Compared with the control group, the apoptosis rate of myocardial cells in the sport group was significantly increased (P<0.01), and apoptosis body with dense distribution and deep coloring can be seen in the field of microscope; the expression of Fas protein was significantly increased (P<0.01), and expression of Bcl-2, p300 and CBP was reduced (all P<0.01). The equally distributed apoptosis body with slight coloring was seen in the moxibustion group. Compared with the sport group, the apoptosis rate of myocardial cells in the moxibustion group was significantly reduced (P<0.05); the expression of Fas protein was significantly reduced (P<0.05), and expression of Bcl-2, p300 and CBP was increased (all P<0.05). Moxibustion could promote the expression of p300 and CBP in myocardial cells after sports fatigue in mice to inhibit the starting of apoptotic process, therefore reducing the apoptosis of myocardial cells after heavy exercise and protecting heart function.

Assessment of the effect of prolonged forced swimming on CD-1 mice sperm morphology with and without antioxidant supplementation.

PubMed

Rodriguez, I; Diaz, A; Vaamonde, D

2016-04-01

As physical exercise has been shown to negatively affect sperm morphology, this study was undertaken to assess the effect of a 3-min forced swimming protocol during 50 days, with and without administration of antioxidants [N-acetylcysteine (NAC) and trans-resveratrol], on sperm morphology in CD-1 mice. Forty-four 13-week-old CD-1 mice were randomly allocated to four different groups: mice not submitted to exercise, control group (CG), mice submitted to swimming without administration of antioxidants (EX), mice submitted to swimming that received trans-resveratrol supplementation [exercise group (EX)+Resv] and mice submitted to swimming exercise that received NAC supplementation (EX+NAC). The EX showed 30.5% of spermatozoa with normal morphology, showing significant differences with regard to the CG, which showed 58.5%. The groups receiving antioxidant supplements showed significantly higher percentages of spermatozoa with normal morphology in comparison with the EX group (EX+Resv: 64.1%, EX+NAC: 48.2%). The imposed model of forced swimming caused alterations in sperm morphology. The antioxidants employed seem to be suitable antioxidants for avoiding exercise-associated sperm morphology anomalies in prolonged forced swimming exercise. Trans-resveratrol has proven to be more efficient for this purpose. © 2015 Blackwell Verlag GmbH.

Preventive activity of banana peel polyphenols on CCl4-induced experimental hepatic injury in Kunming mice.

PubMed

Wang, Rui; Feng, Xia; Zhu, Kai; Zhao, Xin; Suo, Huayi

2016-05-01

The aim of the present study was to evaluate the preventive effects of banana peel polyphenols (BPPs) against hepatic injury. Mice were divide into normal, control, 100 mg/kg and 200 mg/kg banana peel polyphenol and silymarin groups. All the mice except normal mice were induced with hepatic damage using CCl 4 . The serum and tissue levels of mice were determined by a kit and the tissues were further examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. BPPs reduced the serum levels of aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase in a CCl 4 -induced mouse model of hepatic injury. Furthermore, BPPs reduced the levels of malondialdehyde and triglyceride, while increasing glutathione levels in the serum and liver tissues of mice. In addition, the effects of 200 mg/kg treatment were more evident, and these effects were comparable to those of the drug silymarin. Serum levels of the cytokines, interleukin (IL)-6, IL-12, tumor necrosis factor (TNF)-α and interferon-γ, were reduced in the mice treated with BPPs compared with injury control group mice, and these levels were comparable to those of the normal and silymarin-treated groups. Histopathological examination indicated that BPPs were able to reduce the extent of CCl 4 -induced liver tissue injury and protect the liver cells. Furthermore, the mRNA and protein expression levels of the inflammation-associated factors cyclooxygenase-2, nitric oxide synthase, TNF-α and IL-1β were reduced in mice treated with BPPs compared with the control group mice. Mice that received 200 mg/kg BPP exhibited reduced expression levels of these factors compared with mice that received 100 mg/kg BPP. In conclusion, the results of the present study suggested that BPPs exert a good preventive effect against hepatic injury.

Hair Follicle Generation by Injections of Adult Human Follicular Epithelial and Dermal Papilla Cells into Nude Mice

PubMed Central

Nilforoushzadeh, Mohammadali; Rahimi Jameh, Elham; Jaffary, Fariba; Abolhasani, Ehsan; Keshtmand, Gelavizh; Zarkob, Hajar; Mohammadi, Parvaneh; Aghdami, Nasser

2017-01-01

Objective Dermal papilla and hair epithelial stem cells regulate hair formation and the growth cycle. Damage to or loss of these cells can cause hair loss. Although several studies claim to reconstitute hairs using rodent cells in an animal model, additional research is needed to develop a stable human hair follicle reconstitution protocol. In this study, we have evaluated hair induction by injecting adult cultured human dermal papilla cells and a mixture of hair epithelial and dermal papilla cells in a mouse model. Materials and Methods In this experimental study, discarded human scalp skins were used to obtain dermal papilla and hair epithelial cells. After separation, cells were cultured and assessed for their characteristics. We randomly allocated 15 C57BL/6 nude mice into three groups that received injections in their dorsal skin. The first group received cultured dermal papilla cells, the second group received a mixture of cultured epithelial and dermal papilla cells, and the third group (control) received a placebo [phosphate-buffered saline (PBS-)]. Results Histopathologic examination of the injection sites showed evidence of hair growth in samples that received cells compared with the control group. However, the group that received epithelial and dermal papilla cells had visible evidence of hair growth. PKH tracing confirmed the presence of transplanted cells in the new hair. Conclusion Our data showed that injection of a combination of adult human cultured dermal papilla and epithelial cells could induce hair growth in nude mice. This study emphasized that the combination of human adult cultured dermal papilla and epithelial cells could induce new hair in nude mice. PMID:28670518

The ginseng's fireness is associated with the lowering activity of liver Na(+)-K(+)-ATPase.

PubMed

Xu, Xu; Dou, Deqiang

2016-08-22

Ginseng is an herbal medicine used worldwide that possesses a wide range of pharmacological activities. However, its side effects are rarely discussed. The experience of Chinese medicine has revealed that taking ginseng at a high dose chronically can cause fireness, i.e., the ginseng-abuse syndrome. Here, we explored the mechanism of ginseng's fireness by comparing the energy metabolism of mice affected by red ginseng (RG), ginseng (GS), ginseng leaves (GL) and American ginseng (AG), which exhibit different drug properties according to the theory of TCM. KM mice were randomly divided into five groups (n≥30 per group) and administered distilled water or drugs, respectively. Mice receiving RG, GS, or GL received 4.5g/(kgday), while the mice receiving AG received 3g/(kgday). Control mice received distilled water. The duration of exposure for all groups was 31 days. The mice's physical characteristics, such as eye condition, rectal temperature, saliva secretion, urine, stool weight, blood coagulation time and swimming time, were measured at different times after administration. Energy metabolism indexes were measured via TSE phenoMaster/LabMaster animal monitoring system, including the mice' 24h oxygen consumption (VO2), carbon dioxide production (VCO2), heat production (H) and energy expenditure (EE). Biochemical indices were measured by ultraviolet spectrophotometer and microplate reader, including pyruvic acid content in serum and succinate dehydrogenase (SDH) activity, lactate dehydrogenase (LDH) activity, the Na(+)-K(+)-ATPase activity and the content of glycogen in the liver tissue. After 31 days of drug administration, mice in the RG and GS groups exhibited obviously more eye secretions, less saliva secretion and less urine. Compared with the control group, the swimming times of mice in the GS, AG and GL groups were significantly prolonged; the clotting time of mice in the GL was extended significantly; VCO2, H and EE of mice in the GS group were obviously increased; Pyruvate content of mice in the RG group showed an initial decrease followed by an increase; SDH activity of mice in the AG and GL groups was significantly inhibited; LDH activity of the mice showed no significant difference among different groups; Na(+)-K(+)-ATP enzyme activity of the RG and GS groups showed up-regulation initially and then down-regulation; the content of hepatic glycogen of mice in the GS and GL groups increased significantly. The results demonstrated that RG and GS with their warm drug nature could enhance the body's energy metabolism to produce their dryness to the body. The liver Na(+)-K(+)-ATP enzyme activity may be the primary index for indicating the fireness of ginseng. In addition, our results demonstrated that ginseng, especially red ginseng, is not suitable for long time application with a higher dose. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Effect of Diet High in Coconut Oil on Cardiovascular Disease Risk in ApoE Knockout and Wild Type Mice (Mus musculus)

DTIC Science & Technology

2016-04-07

Objective: We evaluated the risk of cardiovascular disease in both control and proatherosclerotic mice consuming diets high in coconut oil. Methods...The mice were weighed and randomly assigned to receive a custom diet with either coconut oil or milk fat. Both diets were formulated to have the...significant differences were seen between knockout and wildtype mice in aorta score regardless of diet, and in liver score with coconut oil diet

Neuroinflammatory and cognitive consequences of combined radiation and immunotherapy in a novel preclinical model

PubMed Central

McGinnis, Gwendolyn J.; Friedman, David; Young, Kristina H.; Torres, Eileen Ruth S.; Thomas, Charles R.; Gough, Michael J.; Raber, Jacob

2017-01-01

Background Cancer patients often report behavioral and cognitive changes following cancer treatment. These effects can be seen in patients who have not yet received treatment or have received only peripheral (non-brain) irradiation. Novel treatments combining radiotherapy (RT) and immunotherapy (IT) demonstrate remarkable efficacy with respect to tumor outcomes by enhancing the proinflammatory environment in the tumor. However, a proinflammatory environment in the brain mediates cognitive impairments in other neurological disorders and may affect brain function in cancer patients receiving these novel treatments. Currently, gaps exist as to whether these treatments impact the brain in individuals with or without tumors and with regard to the underlying mechanisms. Results Combined treatment with precision RT and checkpoint inhibitor IT achieved control of tumor growth. However, BALB/c mice receiving combined treatment demonstrated changes in measures of anxiety levels, regardless of tumor status. C57BL/6J mice with tumors demonstrated increased anxiety, except following combined treatment. Object recognition memory was impaired in C57BL/6J mice without tumors following combined treatment. All mice with tumors showed impaired object recognition, except those treated with RT alone. Mice with tumors demonstrated impaired amygdala-dependent cued fear memory, while maintaining hippocampus-dependent context fear memory. These behavioral alterations and cognitive impairments were accompanied by increased microglial activation in mice receiving immunotherapy alone or combined with RT. Finally, based on tumor status, there were significant changes in proinflammatory cytokines (IFN-γ, IL-6, IL-5, IL-2, IL-10) and a growth factor (FGF-basic). Materials and Methods Here we test the hypothesis that IT combined with peripheral RT have detrimental behavioral and cognitive effects as a result of an enhanced proinflammatory environment in the brain. BALB/c mice with or without injected hind flank CT26 colorectal carcinoma or C57BL/6J mice with or without Lewis Lung carcinoma were used for all experiments. Checkpoint inhibitor IT, using an anti-CTLA-4 antibody, and precision CT-guided peripheral RT alone and combined were used to closely model clinical treatment. We assessed behavioral and cognitive performance and investigated the immune environment using immunohistochemistry and multiplex assays to analyze proinflammatory mediators. Conclusions Although combined treatment achieved tumor growth control, it affected the brain and induced changes in measures of anxiety, cognitive impairments, and neuroinflammation. PMID:27893434

Association of Diet With Skin Histological Features in UV-B-Exposed Mice.

PubMed

Bhattacharyya, Tapan K; Hsia, Yvonne; Weeks, David M; Dixon, Tatiana K; Lepe, Jessica; Thomas, J Regan

2017-09-01

Long-term exposure to solar radiation produces deleterious photoaging of the skin. It is not known if diet can influence skin photoaging. To study the influence of a calorie-restricted diet and an obesity diet in mice exposed to long-term UV-B irradiation to assess if there is an association between diet and histopathological response to UV-B irradiation. In this animal model study in an academic setting, the dorsal skin of SKH1 hairless mice receiving normal, calorie-restricted, and obesity diets was exposed to UV-B irradiation 3 times a week for 10 weeks and were compared with corresponding controls. The mice were placed in the following groups, with 8 animals in each group: (1) intact control (C) with regular diet and no UV-B exposure, (2) intact control with UV-B exposure (CR), (3) calorie-restricted diet (CrC), (4) calorie-restricted diet with UV-B exposure (CrR), (5) obesity diet (OC), and (6) obesity diet with UV-B exposure (OR). The experiment was conducted during October through December 2013. Tissue processing and histological analysis were completed in 2016. Histomorphometric analysis was performed on paraffin-embedded skin sections stained by histological and immunohistochemical methods for estimation of epidermal thickness, epidermal proliferating cell nuclear antigen index, collagen I, elastic fibers, fibroblasts, mast cells, dermal cellularity, and adipose layer ratio. Changes in wrinkles were noted. Hairless female mice (age range, 6-8 weeks) were obtained. With a normal diet, changes from UV-B irradiation occurred in epidermal thickness, epidermal proliferating cell nuclear antigen index, collagen I, elastic fibers, fibroblasts, and mast cells, which were modestly influenced by an obesity diet. Calorie restriction influenced the skin in nonirradiated control animals, with higher values for most variables. After UV-B exposure in animals with calorie restriction, epidermal thickness was increased, but other variables were unaffected. Animals receiving the calorie-restricted diet lost weight when exposed to long-term UV-B irradiation. Wrinkles were reduced in the calorie-restricted control group and in UV-B-exposed animals who received the obesity diet. Dietary alterations seem to modify histopathological responses to UV-B exposure in the skin of hairless mice. NA.

Chronic ethanol administration inhibits calmodulin-dependent Ca++ uptake in synaptosomal membranes.

PubMed

Ross, D H

1986-06-01

Chronic ethanol administration inhibits ATP-dependent Ca++ uptake in a preparation of synaptic membranes prepared from mice following 1, 4 and 7 days of ethanol exposure in a liquid diet. Addition of calmodulin (2.5 micrograms) to membranes from mice receiving the control diet produced a slight stimulation of ATP dependent Ca++ uptake. Membranes from ETOH treated mice exhibited reduced capacity to take up Ca++ in ATP-dependent fashion. When calmodulin was added to membranes isolated from mice receiving ETOH on Days 1, 4 and 7 ATP-dependent Ca++ uptake was significantly stimulated (p less than 0.01) compared to (1) ETOH treated membranes in absence of calmodulin, and (2) control membranes. Behavioral tolerance as estimated by bar holding technique was found to be 25, 65 and 91 percent complete for Days 1, 4 and 7 respectively. These studies demonstrate that continued exposure of mice to ethanol via consumption of an ethanol containing liquid diet inhibits one of the mechanisms involving the cytosolic buffering of intracellular Ca++ in nerve terminals. This biochemical effect seen in parallel with the development of tolerance to ethanol impairment of bar holding suggests that increased cytosolic Ca++ may aid in central nervous system adaptation to ethanol.

Skin testing of guinea pigs and footpad testing of mice with a new antigen for detecting delayed hypersensitivity to Cryptococcus neoformans.

PubMed

Murphy, J W; Gregory, J A; Larsh, H W

1974-02-01

This study was undertaken to evaluate the potential of a cryptococcal culture filtrate antigen, cryptococcin C184, for detecting delayed hypersensitivity in Cryptococcus neoformans-injected animals. The antigen was tested on guinea pigs which had received saline or C. neoformans and on animals sensitized to Histoplasma capsulatum, Blastomyces dermatitidis, Candida albicans, or Sporothrix schenckii. A delayed-type hypersensitivity response was elicited by cryptococcin C184 in C. neoformans-injected guinea pigs, whereas no indurations or erythemas were seen at 48 h after skin testing of saline controls or heterologously sensitized guinea pigs. Besides being specific for Cryptococcus, the antigen showed a high degree of sensitivity and was reproducible. Footpad tests were conducted with the antigen on mice which had previously received either 10(5) viable C. neoformans cells or saline. Delayed hypersensitivity was indicated in the C. neoformans-injected mice by the increase in thickness of antigen-injected footpads when compared with the saline-injected footpads. In control mice, antigen- and saline-injected footpads were comparable in thickness 24 h after injection. Mice sensitized to B. dermatitidis were footpad tested with C184, and no cross-reactivity was demonstrated.

Lack of relation between drug-seeking behavior in an addiction model and the expression of behavioral sensitization in response to ethanol challenge in mice.

PubMed

Ribeiro, A F; Pigatto, G; Goeldner, F O; Lopes, J F; de Lacerda, R B

2008-01-01

Drug-induced sensitization has been associated with enhanced self-administration and may contribute to addiction. The possible association between sensitization and voluntary ethanol consumption using an addiction model was investigated. Mice (n = 60) were individually housed with ad libitum access to food and had free choice between ethanol (5% and 10%) and water in a four-phase paradigm: free choice (12 weeks), withdrawal (2 weeks), re-exposure (2 weeks), and quinine-adulteration (2 weeks). Control mice (n = 10) had access to water. Mice were characterized as addicted (n = 10, ethanol preference without reducing intake with adulterated ethanol), heavy (n = 22, ethanol preference but reduced intake with adulterated ethanol), and light (n = 21, water preference). Oral ethanol then was withdrawn, and 24 h later mice received a 2 g/kg ethanol (i.p.) challenge dose or saline, and ambulation was evaluated 10 min later. Half of the classified mice received daily 2 g/kg ethanol injections for 14 days, and ambulation was assessed 10 min after the last dose. Acute ethanol increased ambulation in all groups compared to the control group, and chronic ethanol induced sensitization, showing no difference among ethanol-treated mice. The data suggest that independent neural mechanisms are responsible for the development of addiction and sensitization.

Effects of Combined Treatment with Branched-Chain Amino Acids, Citric Acid, L-Carnitine, Coenzyme Q10, Zinc, and Various Vitamins in Tumor-Bearing Mice.

PubMed

Awa, Hiroko; Futamura, Akihiko; Higashiguchi, Takashi; Ito, Akihiro; Mori, Naoharu; Murai, Miyo; Ohara, Hiroshi; Chihara, Takeshi; Kaneko, Takaaki

2017-03-01

A functional dietary supplement (FDS) containing Coenzyme Q10, branched-chain amino acids and L-carnitine was administered to tumor-bearing mice, investigating its effects on tumor and muscle tissues. Experiment (A): B16 melanoma cells were implanted subcutaneously into the right side of the abdomen of 8- to 9-week-old C57BL/6J mice. The mice were divided into two groups: a FDS group that received oral administration of FDS (n=10), and a control group that received oral administration of glucose (n=10). The moribund condition was used as the endpoint, and median survival time was determined. Experiment (B): On day 21 after tumor implantation, tumors, soleus muscle, gastrocnemius muscle, and suprahyoid muscles were collected. Tumor and muscle weight and other aspects were evaluated in each group: FDS group (n=15) and control group (n=15). The median survival time was comparable (21 d in the FDS group vs. 18 d in the control group, p=0.30). However, cumulative food intake was significantly higher in the FDS group than the control group (p=0.011). Metastasis of melanoma to the lung was observed in the control group but not in the FDS group (p=0.043). The weight of the suprahyoid muscles was significantly higher in the FDS group than in the control group (p=0.0045). The weight of the tumor was significantly lower in the FDS group than in the control group (p=0.013). The results possibly suggest oral administration of FDS in tumor-bearing mice enhances the maintenance of suprahyoid muscles, resulting in an extended feeding period and suppression of tumor growth and metastasis.

Berberis vulgaris L. effects on oxidative stress and liver injury in lead-intoxicated mice.

PubMed

Laamech, Jawhar; El-Hilaly, Jaouad; Fetoui, Hamadi; Chtourou, Yassine; Gouitaa, Hanane; Tahraoui, Adel; Lyoussi, Badiaa

2017-03-01

Background Berberis vulgaris L. (BV), commonly known as "Aghriss" in Moroccan pharmacopoeia, is used to cure liver disorders and other diseases. The present study aimed to investigate the protective effect of BV aqueous extract against lead-induced toxicity in mice liver. Methods Sixty IOPS mice were divided into six groups and were treated as follows: group 1 (normal control) received double distilled water; group 2 (toxic control) received lead acetate (5 mg/kg body weight/day) in double distilled water for 40 days; groups 3-6 received BV aqueous extract at doses of 25, 50, 100 and 150 mg/kg body weight , respectively, once daily for 30 days from 11 day after beginning of lead acetate exposure to the end of the experiment. Results Toxic control group showed a significant alteration of serum alanine-aminotransferase (ALT), aspartate-aminotransferase (AST), total cholesterol (TC), total bilirubin (TB), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and reduced glutathione (GSH). Histological assessment of lead-intoxicated mice liver revealed alterations in hepatocytes and focal necrosis. BV treatment significantly prevented lead accumulation, increased ALT, AST, TC, and TB, inhibited lipid peroxidation and protein carbonyls(PCO) formation. Additionally, BV extract normalized the antioxidant enzymes (CAT, SOD and GPx), GSH and architecture of liver tissues. Conclusions BV aqueous extract exerts significant hepatoprotective effects against lead-induced oxidative stress and liver dysfunction. The BV effect may be mediated through the enhancement of antioxidant status, lead-chelating abilities and free radicals quenching.

Diet-induced obesity attenuates endotoxin-induced cognitive deficits.

PubMed

Setti, Sharay E; Littlefield, Alyssa M; Johnson, Samantha W; Kohman, Rachel A

2015-03-15

Activation of the immune system can impair cognitive function, particularly on hippocampus dependent tasks. Several factors such as normal aging and prenatal experiences can modify the severity of these cognitive deficits. One additional factor that may modulate the behavioral response to immune activation is obesity. Prior work has shown that obesity alters the activity of the immune system. Whether diet-induced obesity (DIO) influences the cognitive deficits associated with inflammation is currently unknown. The present study explored whether DIO alters the behavioral response to the bacterial endotoxin, lipopolysaccharide (LPS). Female C57BL/6J mice were fed a high-fat (60% fat) or control diet (10% fat) for a total of five months. After consuming their respective diets for four months, mice received an LPS or saline injection and were assessed for alterations in spatial learning. One month later, mice received a second injection of LPS or saline and tissue samples were collected to assess the inflammatory response within the periphery and central nervous system. Results showed that LPS administration impaired spatial learning in the control diet mice, but had no effect in DIO mice. This lack of a cognitive deficit in the DIO female mice is likely due to a blunted inflammatory response within the brain. While cytokine production within the periphery (i.e., plasma, adipose, and spleen) was similar between the DIO and control mice, the DIO mice failed to show an increase in IL-6 and CD74 in the brain following LPS administration. Collectively, these data indicate that DIO can reduce aspects of the neuroinflammatory response as well as blunt the behavioral reaction to an immune challenge. Copyright © 2014 Elsevier Inc. All rights reserved.

Early or late antibiotic intervention prevents Helicobacter pylori-induced gastric cancer in a mouse model.

PubMed

Zhang, Songhua; Lee, Dong Soo; Morrissey, Rhiannon; Aponte-Pieras, Jose R; Rogers, Arlin B; Moss, Steven F

2014-12-01

H. pylori infection causes gastritis, peptic ulcers and gastric cancer. Eradicating H. pylori prevents ulcers, but to what extent this prevents cancer remains unknown, especially if given after intestinal metaplasia has developed. H. pylori infected wild-type (WT) mice do not develop cancer, but mice lacking the tumor suppressor p27 do so, thus providing an experimental model of H. pylori-induced cancer. We infected p27-deficient mice with H. pylori strain SS1 at 6-8 weeks of age. Persistently H. pylori-infected WT C57BL/6 mice served as controls. Mice in the eradication arms received antimicrobial therapy (omeprazole, metronidazole and clarithromycin) either "early" (at 15 weeks post infection, WPI) or "late" at 45 WPI. At 70 WPI, mice were euthanized for H. pylori determination, histopathology and cytokine/chemokine expression. Persistently infected mice developed premalignant lesions including high-grade dysplasia, whereas those given antibiotics did not. Histologic activity scores in the eradication groups were similar to each other, and were significantly decreased compared with controls for inflammation, epithelial defects, hyperplasia, metaplasia, atrophy and dysplasia. IP-10 and MIG levels in groups that received antibiotics were significantly lower than controls. There were no significant differences in expression of IFN-γ, TNF-α, IL-1β, RANTES, MCP-1, MIP-1α or MIP-1β among the three groups. Thus, H. pylori eradication given either early or late after infection significantly attenuated gastric inflammation, gastric atrophy, hyperplasia, and dysplasia in the p27-deficient mice model of H. pylori-induced gastric cancer, irrespective of the timing of antibiotic administration. This was associated with reduced expression of IP-10 and MIG. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Dietary Pectin Increases Intestinal Crypt Stem Cell Survival following Radiation Injury.

PubMed

Sureban, Sripathi M; May, Randal; Qu, Dongfeng; Chandrakesan, Parthasarathy; Weygant, Nathaniel; Ali, Naushad; Lightfoot, Stan A; Ding, Kai; Umar, Shahid; Schlosser, Michael J; Houchen, Courtney W

2015-01-01

Gastrointestinal (GI) mucosal damage is a devastating adverse effect of radiation therapy. We have recently reported that expression of Dclk1, a Tuft cell and tumor stem cell (TSC) marker, 24h after high dose total-body gamma-IR (TBI) can be used as a surrogate marker for crypt survival. Dietary pectin has been demonstrated to possess chemopreventive properties, whereas its radioprotective property has not been studied. The aim of this study was to determine the effects of dietary pectin on ionizing radiation (IR)-induced intestinal stem cell (ISC) deletion, crypt and overall survival following lethal TBI. C57BL/6 mice received a 6% pectin diet and 0.5% pectin drinking water (pre-IR mice received pectin one week before TBI until death; post-IR mice received pectin after TBI until death). Animals were exposed to TBI (14 Gy) and euthanized at 24 and 84h post-IR to assess ISC deletion and crypt survival respectively. Animals were also subjected to overall survival studies following TBI. In pre-IR treatment group, we observed a three-fold increase in ISC/crypt survival, a two-fold increase in Dclk1+ stem cells, increased overall survival (median 10d vs. 7d), and increased expression of Dclk1, Msi1, Lgr5, Bmi1, and Notch1 (in small intestine) post-TBI in pectin treated mice compared to controls. We also observed increased survival of mice treated with pectin (post-IR) compared to controls. Dietary pectin is a radioprotective agent; prevents IR-induced deletion of potential reserve ISCs; facilitates crypt regeneration; and ultimately promotes overall survival. Given the anti-cancer activity of pectin, our data support a potential role for dietary pectin as an agent that can be administered to patients receiving radiation therapy to protect against radiation-induces mucositis.

Eucaloric Ketogenic Diet Reduces Hypoglycemia and Inflammation in Mice with Endotoxemia.

PubMed

Nandivada, Prathima; Fell, Gillian L; Pan, Amy H; Nose, Vania; Ling, Pei-Ra; Bistrian, Bruce R; Puder, Mark

2016-06-01

Dietary strategies to alter the immune response to acute inflammation have the potential to improve outcomes in critically ill patients. A eucaloric ketogenic diet (EKD), composed predominantly of fat with very small amounts of carbohydrate, can provide adequate caloric support while minimizing spikes in blood glucose and reducing oxidative stress. The purpose of this study was to evaluate the effects of an EKD on glycemic control and the inflammatory response after acute endotoxemia in mice. Mice received either an EKD or a carbohydrate-based control diet (CD) for 4 weeks. Animals subsequently underwent either a 2-h fast (postprandial) or an overnight fast (postabsorptive), and half of the animals in each diet group were randomized to receive either intraperitoneal lipopolysaccharide (1 mg/kg) or an equivalent volume of saline. Glycemic response, insulin resistance, inflammatory cytokine levels, and the expression of key inflammatory and metabolic genes were measured. After endotoxin challenge, hypoglycemia was more frequent in mice fed a CD than an EKD in the postprandial period. This was due in part to the preservation of hepatic glycogen stores despite endotoxin exposure and prolonged fasting in mice fed an EKD. Furthermore, mice fed the CD had higher levels of IL-6 and TNF-α in the postabsorptive period, with a fivefold higher expression of hepatic NFκB compared to mice fed the EKD in both fasting periods. These results suggest that the unique metabolic state induced by an EKD can alter the response to acute inflammation in mice.

Interaction of alcoholic extracts of hops with cocaine and paracetamol in mice.

PubMed

Horvat, Olga; Raskovic, Aleksandar; Jakovljevic, Vida; Sabo, Jan; Berenji, Janos

2007-01-01

This work describes a study of the interaction in the mouse model of alcoholic extracts of hops of Magnum, Aroma and wild genotypes with drugs that have excitatory effect on the cerebral cortex (cocaine) and analgesic action (paracetamol). Hop drying and preparation of the extracts were carried out according to standard pharmacological procedures for preparing total alcoholic extracts of dry herbs, consisting of one part of dry drug and two parts of 70% alcohol. The mice received four doses i.p. of 0.5% aqueous solutions of the above-mentioned extracts (10 ml/kg) 24, 16, 4 and 0.5 h prior to receiving cocaine (25 mg/kg) or paracetamol (80 mg/kg). The parameter investigated was the change in spontaneous motility of mice after combined treatment with the extracts and cocaine/paracetamol compared to control animals that received the same dose of the drug after treatment with physiological solution. Only the ethanolic extract of Magnum hops increased the spontaneous motility of mice, while none of the extracts showed analgesic action as measured by the hot-plate method. In the interaction with cocaine, the extract of Magnum hops suppressed almost completely the action of cocaine compared to controls. Extracts of the other hops also decreased the cocaine-induced locomotor activity of mice, but to a lesser extent. Hop extracts exhibited a significant pharmacological interaction with paracetamol, with the most pronounced increase in analgesic action being found for the ethanolic extract of Aroma hops and the tert-butanolic extract of wild hops.

Protective effect of N-acetylcysteine against ethanol-induced gastric ulcer: A pharmacological assessment in mice

PubMed Central

Jaccob, Ausama Ayoob

2015-01-01

Aim: Since there is an increasing need for gastric ulcer therapies with optimum benefit-risk profile. This study was conducted to investigate gastro-protective effects of N-acetylcysteine (NAC) against ethanol-induced gastric ulcer models in mice. Materials and Methods: A total of 41 mice were allocated into six groups consisted of 7 mice each. Groups 1 (normal control) and 2 (ulcer control) received distilled water at a dose of 10 ml/kg, groups 3, 4 and 5 were given NAC at doses 100, 300 and 500 mg/kg, respectively, and the 6th group received ranitidine (50 mg/kg). All drugs administered orally once daily for 7 days, on the 8th day absolute ethanol (7 ml/kg) was administrated orally to all mice to induce the acute ulcer except normal control group. Then 3 h after, all animals were sacrificed then consequently the stomachs were excised for examination. Results: NAC administration at the tested doses showed a dose-related potent gastro-protective effect with significant increase in curative ratio, PH of gastric juice and mucus content viscosity seen with the highest dose of NAC and it is comparable with that observed in ranitidine group. Conclusion: The present findings demonstrate that, oral NAC shows significant gastro-protective effects comparable to ranitidine confirmed by anti-secretory, cytoprotective, histological and biochemical data, but the molecular mechanisms behind such protection are complex. PMID:26401392

Suppression of Oxidative Stress by Resveratrol After Isometric Contractions in Gastrocnemius Muscles of Aged Mice

PubMed Central

Ryan, Michael J.; Jackson, Janna R.; Hao, Yanlei; Williamson, Courtney L.; Dabkowski, Erinne R.; Hollander, John M.

2010-01-01

This study tested the hypothesis that resveratrol supplementation would lower oxidative stress in exercised muscles of aged mice. Young (3 months) and aged (27 months) C57BL/6 mice received a control or a 0.05% trans-resveratrol-supplemented diet for 10 days. After 7 days of dietary intervention, 20 maximal electrically evoked isometric contractions were obtained from the plantar flexors of one limb in anesthetized mice. Exercise was conducted for three consecutive days. Resveratrol supplementation blunted the exercise-induced increase in xanthine oxidase activity in muscles from young (25%) and aged (53%) mice. Resveratrol lowered H2O2 levels in control (13%) and exercised (38%) muscles from aged animals, reduced Nox4 protein in both control and exercised muscles of young (30%) and aged mice (40%), and increased the ratio of reduced glutathione to oxidized glutathione in exercised muscles from young (38%) and aged (135%) mice. Resveratrol prevented the increase in lipid oxidation, increased catalase activity, and increased MnSOD activity in exercised muscles from aged mice. These data show that dietary resveratrol suppresses muscle indicators of oxidative stress in response to isometric contractions in aged mice. PMID:20507922

Treatment and prevention of chemotherapy-induced alopecia with PTH-CBD, a collagen-targeted parathyroid hormone analog, in a non-depilated mouse model

PubMed Central

Katikaneni, Ranjitha; Ponnapakkam, Tulasi; Matsushita, Osamu; Sakon, Joshua; Gensure, Robert

2014-01-01

Alopecia is a psychologically devastating complication of chemotherapy for which there is currently no effective therapy. PTH-CBD is a collagen-targeted parathyroid hormone analog that has shown promise as a therapy for alopecia disorders. To compare the efficacy of prophylactic versus therapeutic administration of PTH-CBD in chemotherapy-induced alopecia using a mouse model that mimics the cyclic chemotherapy dosing used clinically. C57BL/6J mice were treated with a single subcutaneous injection of PTH-CBD (320 mcg/kg) or vehicle control before or after hair loss developing from three courses of cyclophosphamide chemotherapy (50–150 mg/kg/week). Mice receiving chemotherapy alone developed hair loss and depigmentation over 6–12 months. Mice pretreated with PTH-CBD did not develop these changes and maintained a normal-appearing coat. Mice treated with PTH-CBD after development of hair loss showed a partial recovery. Observations of hair loss were confirmed quantitatively by gray scale analysis. Histological examination showed that in mice receiving chemotherapy alone, there were small, dystrophic hair follicles mostly in the catagen phase. Mice receiving PTH-CBD before chemotherapy showed a mix of normal-appearing telogen and anagen hair follicles with no evidence of dystrophy. Mice receiving PTH-CBD therapy after chemotherapy showed intermediate histological features. PTH-CBD was effective in both the prevention and the treatment of chemotherapy-induced alopecia in mice, but pretreatment appears to result in a better cosmetic outcome. PTH-CBD shows promise as an agent in the prevention of this complication of chemotherapy and improving the quality of life for cancer patients. PMID:24025564

Treatment and prevention of chemotherapy-induced alopecia with PTH-CBD, a collagen-targeted parathyroid hormone analog, in a non-depilated mouse model.

PubMed

Katikaneni, Ranjitha; Ponnapakkam, Tulasi; Matsushita, Osamu; Sakon, Joshua; Gensure, Robert

2014-01-01

Alopecia is a psychologically devastating complication of chemotherapy for which there is currently no effective therapy. PTH-CBD is a collagen-targeted parathyroid hormone analog that has shown promise as a therapy for alopecia disorders. This study compared the efficacy of prophylactic versus therapeutic administration of PTH-CBD in chemotherapy-induced alopecia using a mouse model that mimics the cyclic chemotherapy dosing used clinically. C57BL/6J mice were treated with a single subcutaneous injection of PTH-CBD (320 mcg/kg) or vehicle control before or after hair loss developing from three courses of cyclophosphamide chemotherapy (50-150 mg/kg/week). Mice receiving chemotherapy alone developed hair loss and depigmentation over 6-12 months. Mice pretreated with PTH-CBD did not develop these changes and maintained a normal-appearing coat. Mice treated with PTH-CBD after development of hair loss showed a partial recovery. Observations of hair loss were confirmed quantitatively by gray scale analysis. Histological examination showed that in mice receiving chemotherapy alone, there were small, dystrophic hair follicles mostly in the catagen phase. Mice receiving PTH-CBD before chemotherapy showed a mix of normal-appearing telogen and anagen hair follicles with no evidence of dystrophy. Mice receiving PTH-CBD therapy after chemotherapy showed intermediate histological features. PTH-CBD was effective in both the prevention and the treatment of chemotherapy-induced alopecia in mice, but pretreatment appears to result in a better cosmetic outcome. PTH-CBD shows promise as an agent in the prevention of this complication of chemotherapy and improving the quality of life for cancer patients.

Urtica dioica leaves modulates hippocampal smoothened-glioma associated oncogene-1 pathway and cognitive dysfunction in chronically stressed mice.

PubMed

Patel, Sita Sharan; Mahindroo, Neeraj; Udayabanu, Malairaman

2016-10-01

The present study was aimed to evaluate the effect of Urtica dioica (UD) extract against chronic unpredictable stress (CUS)-induced associative memory dysfunction and attempted to explore the possible mechanism. Male Swiss albino mice (25-30g) were divided into six groups, viz. group-I received 0.3% carboxymethyl cellulose and served as control (CTRL), group II was exposed to CUS (21days) and received vehicle (CUS), group III was subjected to CUS and received Hypericum perforatum extract (350mg/kg, p.o.) (CUS+HYP), group IV received Hypericum perforatum extract (350mg/kg, p.o.) (CTRL+HYP); group V was subjected to CUS and received UD extract (50mg/kg, p.o.) (CUS+UD), group VI received UD extract (50mg/kg, p.o.) (CTRL+UD). CUS significantly induced body weight loss (p<0.05) and associative memory impairment in step down task (p<0.05) as compared to control mice. CUS significantly downregulated Smo (p<0.05), Gli1 (p<0.01), cyclin D1 (p<0.05), BDNF (p<0.01), TrKB (p<0.01) and MAPK1 (p<0.01) mRNA expression in hippocampus as compared to control mice. CUS significantly increased the levels of TBARS (p<0.01) and nitric oxide (p<0.001), and decreased catalase (p<0.001) and total thiol (p<0.01) in plasma resulting in oxidative stress and inflammation. Chronic UD administration significantly reverted CUS mediated body weight loss (p<0.05) and cognitive impairment (p<0.05). UD administration significantly decreased the levels of TBARS (p<0.01) and nitric oxide (p<0.05), and increased the levels of catalase (p<0.01) and total thiol (p<0.05) in plasma. Chronic UD administration significantly upregulated hippocampal Smo (p<0.05), Gli1 (p<0.001), cyclin D1 (p<0.05), BDNF (p<0.05), TrKB (p<0.05) and MAPK1 (p<0.05) in stressed mice. Further, UD extract did not reverse cyclopamine induced downregulation of Gli1 and Ptch1 mRNA in hippocampal slices. UD modulated Smo-Gli1 pathway in the hippocampus as well as exerted anti-inflammatory and antioxidant effects. UD extract might prove to be effective for stress mediated neurological disorders. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Protective effect of Ginkgo biloba L. leaf extract against glyphosate toxicity in Swiss albino mice.

PubMed

Cavuşoğlu, Kültiğin; Yapar, Kürşad; Oruç, Ertan; Yalçın, Emine

2011-10-01

The aim of the present study was to investigate the protective role of Ginkgo biloba L. leaf extract against the active agent of Roundup® herbicide (Monsanto, Creve Coeur, MO, USA). The Swiss Albino mice were randomly divided into six groups, with each group consisting of six animals: Group I (control) received an intraperitoneal injection of dimethyl sulfoxide (0.2 mL, once only), Group II received glyphosate at a dose of 50 mg/kg of body weight, Group III received G. biloba at a dose of 50 mg/kg of body weight, Group IV received G. biloba at a dose of 150 mg/kg of body weight, Group V received G. biloba (50 mg/kg of body weight) and glyphosate (50 mg/kg of body weight), and Group VI received G. biloba (150 mg/kg of body weight) and glyphosate (50 mg/kg of body weight). The single dose of glyphosate was given intraperitoneally. Animals from all the groups were sacrificed at the end of 72 hours, and their blood, bone marrow, and liver and kidney tissues were analyzed for aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), creatinine, malondialdehyde (MDA), and glutathione (GSH) levels and the presence of micronucleus (MN), chromosomal aberrations (CAs), and pathological damages. The results indicated that serum AST, ALT, BUN, and creatinine levels significantly increased in mice treated with glyphosate alone compared with the other groups (P<.05). Besides, glyphosate-induced oxidative damage caused a significant decrease in GSH levels and a significant increase in MDA levels of the liver and kidney tissues. Moreover, glyphosate alone-treated mice presented higher frequencies of CAs, MNs, and abnormal metaphases compared with the controls (P<.05). These mice also displayed a lower mean mitotic index than the controls (P<.05). Treatment with G. biloba produced amelioration in indices of hepatotoxicity, nephrotoxicity, lipid peroxidation, and genotoxicity relative to Group II. Each dose of G. biloba provided significant protection against glyphosate-induced toxicity, and the strongest effect was observed at a dose of 150 mg/kg of body weight. Thus, in vivo results showed that G. biloba extract is a potent protector against glyphosate-induced toxicity, and its protective role is dose-dependent.

Adjunct antibody administration with standard treatment reduces relapse rates in a murine tuberculosis model of necrotic granulomas.

PubMed

Ordonez, Alvaro A; Pokkali, Supriya; Kim, Sunhwa; Carr, Brian; Klunk, Mariah H; Tong, Leah; Saini, Vikram; Chang, Yong S; McKevitt, Matthew; Smith, Victoria; Gossage, David L; Jain, Sanjay K

2018-01-01

Matrix metalloproteinase (MMP)-9 is a zinc-dependent protease associated with early immune responses to Mycobacterium tuberculosis infection, macrophage recruitment and granuloma formation. We evaluated whether adjunctive inhibition of MMP-9 could improve the response to standard TB treatment in a mouse model that develops necrotic lesions. Six weeks after an aerosol infection with M. tuberculosis, C3HeB/FeJ mice received standard TB treatment (12 weeks) comprising rifampin, isoniazid and pyrazinamide alone or in combination with either anti-MMP-9 antibody, etanercept (positive control) or isotype antibody (negative control) for 6 weeks. Anti-MMP-9 and the isotype control had comparable high serum exposures and expected terminal half-life. The relapse rate in mice receiving standard TB treatment was 46.6%. Compared to the standard TB treatment, relapse rates in animals that received adjunctive treatments with anti-MMP-9 antibody or etanercept were significantly decreased to 25.9% (P = 0.006) and 29.8% (P = 0.019) respectively, but were not different from the arm that received the isotype control antibody (25.9%). Immunostaining demonstrated localization of MMP-9 primarily in macrophages in both murine and human lung tissues infected with M. tuberculosis, suggesting the importance of MMP-9 in TB pathogenesis. These data suggest that the relapse rates in M. tuberculosis-infected mice may be non-specifically improved by administration of antibodies in conjunction with standard TB treatments. Future studies are needed to evaluate the mechanism(s) leading to improved outcomes with adjunctive antibody treatments.

Adjunct antibody administration with standard treatment reduces relapse rates in a murine tuberculosis model of necrotic granulomas

PubMed Central

Kim, Sunhwa; Carr, Brian; Klunk, Mariah H.; Tong, Leah; Saini, Vikram; Chang, Yong S.; McKevitt, Matthew; Smith, Victoria; Gossage, David L.; Jain, Sanjay K.

2018-01-01

Matrix metalloproteinase (MMP)-9 is a zinc-dependent protease associated with early immune responses to Mycobacterium tuberculosis infection, macrophage recruitment and granuloma formation. We evaluated whether adjunctive inhibition of MMP-9 could improve the response to standard TB treatment in a mouse model that develops necrotic lesions. Six weeks after an aerosol infection with M. tuberculosis, C3HeB/FeJ mice received standard TB treatment (12 weeks) comprising rifampin, isoniazid and pyrazinamide alone or in combination with either anti-MMP-9 antibody, etanercept (positive control) or isotype antibody (negative control) for 6 weeks. Anti-MMP-9 and the isotype control had comparable high serum exposures and expected terminal half-life. The relapse rate in mice receiving standard TB treatment was 46.6%. Compared to the standard TB treatment, relapse rates in animals that received adjunctive treatments with anti-MMP-9 antibody or etanercept were significantly decreased to 25.9% (P = 0.006) and 29.8% (P = 0.019) respectively, but were not different from the arm that received the isotype control antibody (25.9%). Immunostaining demonstrated localization of MMP-9 primarily in macrophages in both murine and human lung tissues infected with M. tuberculosis, suggesting the importance of MMP-9 in TB pathogenesis. These data suggest that the relapse rates in M. tuberculosis-infected mice may be non-specifically improved by administration of antibodies in conjunction with standard TB treatments. Future studies are needed to evaluate the mechanism(s) leading to improved outcomes with adjunctive antibody treatments. PMID:29758082

Protoporphyrin hepatopathy. Effects of cholic acid ingestion in murine griseofulvin-induced protoporphyria.

PubMed Central

Poh-Fitzpatrick, M B; Sklar, J A; Goldsman, C; Lefkowitch, J H

1983-01-01

Short-term effects of cholic acid ingestion on hepatic accumulation, fecal excretion, and blood levels of protoporphyrin were studied in vivo in griseofulvin-induced protoporphyric mice. Experimental mice that received feed with 2% griseofulvin and 0.5% cholic acid were compared with control mice that received feed with 2% griseofulvin for 4 wk. Five mice from each group were assessed each week for liver and blood porphyrin levels. Fecal protoporphyrin was compared weekly in the total pooled output of each population. Mean protoporphyrin levels were significantly lower for liver (P less than 0.0001), erythrocytes (P less than 0.05), and plasma (P less than 0.05), and higher for feces (P less than 0.001) for the mice that were fed cholic acid. Microscopic protoporphyrin deposits, inflammation, necrosis, and dysplasia were more severe in livers of control mice. A second experimental design compared four regimens in the feed given to all mice after 1-wk induction with 2% griseofulvin: (a) 0.5% cholic acid, (b) no adulterant, (c) 2% griseofulvin and 0.5% cholic acid, and (d) 2% griseofulvin. No difference in protoporphyrin removal from livers of mice in groups 1 and 2 was observed after 1 and 2 wk of these regimens. The apparent reduction in hepatic protoporphyrin content in mice of group 3 as compared with group 4 at weeks 2 and 3 was not significant at P less than 0.05. These data suggest that in selected circumstances, hepatic protoporphyrin secretion may be enhanced in protoporphyric disease states by bile salt supplementation. Images PMID:6630515

Cimetidine attenuates vinorelbine-induced phlebitis in mice by militating E-selectin expression.

PubMed

Wang, Zhuo; Ma, Lijuan; Wang, Xuebin; Cai, Heping; Huang, Jin; Liu, Jiyong; Hu, Jinhong; Su, Dingfeng

2014-08-01

We investigated E-selectin expression in mice and rabbits with vinorelbine-induced phlebitis and the effect of cimetidine. To find the relationship between E-selectin expression and vinorelbine-induced phlebitis. Mouse and rabbit model of vinorelbine-induced phlebitis was established by intravenous infusion of vinorelbine. Pathological observation, molecular-biological determination of E-selectin and protein function of it was evaluated. Grossly, we observed swelling, edema and cord-like vessel changes in mice receiving vinorelbine but only mild edema in mice pretreated with cimetidine. Pathological scoring yielded a total score of 37 for vinorelbine-treated mice and 17 for mice pretreated with cimetidine (P < 0.05). ELISA revealed that rabbits treated with vinorelbine had markedly higher serum contents of E-selectin than normal saline (NS) controls (vinorelbine 1.534 ± 0.449 vs. NS 0.746 ± 0.170 ng/mL, P < 0.05), which was markedly attenuated by cimetidine (cimetidine 0.717 ± 0.468 vs. vinorelbine 1.534 ± 0.449 ng/mL, P < 0.05). Rose Bengal staining assays showed that vinorelbine markedly increased the adhesion rate of neutrophils for endothelial cells (vinorelbine 38.70 ± 8.34% vs. controls 8.93 ± 4.85%, P < 0.01), which, however, was significantly suppressed by cimetidine (9.93 ± 5.91%, P < 0.01 vs. vinorelbine). In E-selectin knockout mice, we found no apparent difference in tail swelling in mice receiving vinorelbine or cimetidine and vinorelbine. In conclusion, cimetidine attenuates vinorelbine-induced phlebitis in mice probably by suppressing increased expression of E-selectin.

Interventional therapy for human breast cancer in nude mice with 131I gelatin microspheres (131I-GMSs) following intratumoral injection

PubMed Central

2014-01-01

Introduction The aim of this study was to investigate the effects of 131I gelatin microspheres (131I-GMS) on human breast cancer cells (MCF-7) in nude mice and the biodistribution of 131I-GMSs following intratumoral injections. Methods A total of 20 tumor-bearing mice were divided into a treatment group and control group and received intratumoral injections of 2.5 mci 131I-GMSs and nonradioactive GMSs, respectively. Tumor size was measured once per week. Another 16 mice received intratumoral injections of 0.4 mci 131I-GMSs and were subjected to single photon emission computed tomography (SPECT) scans and tissue radioactivity concentration measurements on day 1, 4, 8 and 16 postinjection. The 20 tumor-bearing mice received intratumoral injections of 0.4 mci [131I] sodium iodide solution and were subjected to SPECT scans and intratumoral radioactivity measurements at 1, 6, 24, 48 and 72 h postinjection. The tumors were collected for histological examination. Results The average tumor volume in the 131I-GMSs group on post-treatment day 21 decreased to 86.82 ± 63.6%, while it increased to 893.37 ± 158.12% in the control group (P < 0.01 vs. the 131I-GMSs group). 131I-GMSs provided much higher intratumoral retention of radioactivity, resulting in 19.93 ± 5.24% of the injected radioactivity after 16 days, whereas the control group retained only 1.83 ± 0.46% of the injected radioactivity within the tumors at 1 h postinjection. Conclusions 131I-GMSs suppressed the growth of MCF-7 in nude mice and provided sustained intratumoral radioactivity retention. The results suggest the potential of 131I-GMSs for clinical applications in radiotherapy for breast cancer. PMID:24958442

Effects of Stressor Predictability and Controllability on Sleep, Temperature, and Fear Behavior in Mice

PubMed Central

Yang, Linghui; Wellman, Laurie L.; Ambrozewicz, Marta A.; Sanford, Larry D.

2011-01-01

Study Objectives: Predictability and controllability are important factors in the persisting effects of stress. We trained mice with signaled, escapable shock (SES) and with signaled, inescapable shock (SIS) to determine whether shock predictability can be a significant factor in the effects of stress on sleep. Design: Male BALB/cJ mice were implanted with transmitters for recording EEG, activity, and temperature via telemetry. After recovery from surgery, baseline sleep recordings were obtained for 2 days. The mice were then randomly assigned to SES (n = 9) and yoked SIS (n = 9) conditions. The mice were presented cues (90 dB, 2 kHz tones) that started 5.0 sec prior to and co-terminated with footshocks (0.5 mA; 5.0 sec maximum duration). SES mice always received shock but could terminate it by moving to the non-occupied chamber in a shuttlebox. SIS mice received identical tones and shocks, but could not alter shock duration. Twenty cue-shock pairings (1.0-min interstimulus intervals) were presented on 2 days (ST1 and ST2). Seven days after ST2, SES and SIS mice, in their home cages, were presented with cues identical to those presented during ST1 and ST2. Setting: NA. Patients or Participants: NA. Interventions: NA. Measurements and Results: On each training and test day, EEG, activity and temperature were recorded for 20 hours. Freezing was scored in response to the cue alone. Compared to SIS mice, SES mice showed significantly increased REM after ST1 and ST2. Compared to SES mice, SIS mice showed significantly increased NREM after ST1 and ST2. Both groups showed reduced REM in response to cue presentation alone. Both groups showed similar stress-induced increases in temperature and freezing in response to the cue alone. Conclusions: These findings indicate that predictability (modeled by signaled shock) can play a significant role in the effects of stress on sleep. Citation: Yang L; Wellman LL; Ambrozewicz MA; Sanford LD. Effects of stressor predictability and controllability on sleep, temperature, and fear behavior in mice. SLEEP 2011;34(6):759-771. PMID:21629364

Caloric restriction and spatial learning in old mice.

PubMed

Bellush, L L; Wright, A M; Walker, J P; Kopchick, J; Colvin, R A

1996-08-01

Spatial learning in old mice (19 or 24 months old), some of which had been calorically restricted beginning at 14 weeks of age, was compared to that of young mice, in two separate experiments using a Morris water maze. In the first experiment, only old mice reaching criterion performance on a cued learning task were tested in a subsequent spatial task. Thus, all old mice tested for spatial learning had achieved escape latencies equivalent to those of young controls. Despite equivalent swimming speeds, only about half the old mice in each diet group achieved criterion performance in the spatial task. In the second experiment, old and young mice all received the same number of training trials in a cued task and then in a spatial task. Immediately following spatial training, they were given a 60-s probe trial, with no platform in the pool. Both groups of old mice spent significantly less time in the quadrant where the platform had been and made significantly fewer direct crosses over the previous platform location than did the young control group. As in Experiment 1, calorie restriction failed to provide protection against aging-related deficits. However, in both experiments, some individual old mice evidenced performance in spatial learning indistinguishable from that of young controls. Separate comparisons of "age-impaired" and "age-unimpaired" old mice with young controls may facilitate the identification of neurobiological mechanisms underlying age-related cognitive decline.

Role of SDF‐1:CXCR4 in Impaired Post‐Myocardial Infarction Cardiac Repair in Diabetes

PubMed Central

Mayorga, Maritza E.; Kiedrowski, Matthew; McCallinhart, Patricia; Forudi, Farhad; Ockunzzi, Jeremiah; Weber, Kristal; Chilian, William; Penn, Marc S.

2017-01-01

Abstract Diabetes is a risk factor for worse outcomes following acute myocardial infarction (AMI). In this study, we tested the hypothesis that SDF‐1:CXCR4 expression is compromised in post‐AMI in diabetes, and that reversal of this defect can reverse the adverse effects of diabetes. Mesenchymal stem cells (MSC) isolated from green fluorescent protein (GFP) transgenic mice (control MSC) were induced to overexpress stromal cell‐derived factor‐1 (SDF‐1). SDF‐1 expression in control MSC and SDF‐1‐overexpressing MSC (SDF‐1:MSC) were quantified using enzyme‐linked immunosorbent assay (ELISA). AMI was induced on db/db and control mice. Mice were randomly selected to receive infusion of control MSC, SDF‐1:MSC, or saline into the border zone after AMI. Serial echocardiography was used to assess cardiac function. SDF‐1 and CXCR4 mRNA expression in the infarct zone of db/db mice and control mice were quantified. Compared to control mice, SDF‐1 levels were decreased 82%, 91%, and 45% at baseline, 1 day and 3 days post‐AMI in db/db mice, respectively. CXCR4 levels are increased 233% at baseline and 54% 5 days post‐AMI in db/db mice. Administration of control MSC led to a significant improvement in ejection fraction (EF) in control mice but not in db/db mice 21 days after AMI. In contrast, administration of SDF‐1:MSC produced a significant improvement in EF in both control mice and db/db mice 21 days after AMI. The SDF‐1:CXCR4 axis is compromised in diabetes, which appears to augment the deleterious consequences of AMI. Over‐express of SDF‐1 expression in diabetes rescues cardiac function post AMI. Our results suggest that modulation of SDF‐1 may improve post‐AMI cardiac repair in diabetes. stem cells translational medicine 2018;7:115–124 PMID:29119710

Extra virgin olive oil intake delays the development of amyotrophic lateral sclerosis associated with reduced reticulum stress and autophagy in muscle of SOD1G93A mice.

PubMed

Oliván, Sara; Martínez-Beamonte, Roberto; Calvo, Ana C; Surra, Joaquín C; Manzano, Raquel; Arnal, Carmen; Osta, Rosario; Osada, Jesús

2014-08-01

Amyotrophic lateral sclerosis is a neurodegenerative disease associated with mutations in antioxidant enzyme Cu/Zn-superoxide dismutase 1. Albeit there is no treatment for this disease, new insights related to an exacerbated lipid metabolism have been reported. In connection with the hypermetabolic lipid status, the hypothesis whether nature of dietary fat might delay the progression of the disease was tested by using a transgenic mouse that overexpresses the human SOD1G93A variant. For this purpose, SOD1G93A mice were assigned randomly to one of the following three experimental groups: (1) a standard chow diet (control, n=21), (2) a chow diet enriched with 20% (w/w) extra virgin olive oil (EVOO, n=22) and (3) a chow diet containing 20% palm oil (palm, n=20). They received the diets for 8 weeks and the progression of the disease was assessed. On the standard chow diet, average plasma cholesterol levels were lower than those mice receiving the high-fat diets. Mice fed an EVOO diet showed a significant higher survival and better motor performance than control mice. EVOO group mice survived longer and showed better motor performance and larger muscle fiber area than animals receiving palm. Moreover, the EVOO-enriched diet improved the muscle status as shown by expression of myogenic factors (Myod1 and Myog) and autophagy markers (LC3 and Beclin1), as well as diminished endoplasmic reticulum (ER) stress through decreasing Atf6 and Grp78. Our results demonstrate that EVOO may be effective in increasing survival rate, improving motor coordination together with a potential amelioration of ER stress, autophagy and muscle damage. Copyright © 2014 Elsevier Inc. All rights reserved.

Effect of pulmonary irradiation from inhaled /sup 90/Y on immunity to Listeria monocytogenes in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sanchez, A.; Lundgren, D.L.; McClellan, R.O.

1976-01-01

The immunological response of mice subjected to irradiation from particles deposited in the lungs and challenged with Listeria monocytogenes was investigated. Mice, exposed by inhalation to /sup 90/Y (a beta-emitting radionuclide) in relatively insoluble fused aluminosilicate particles, were immunized with L. monocytogenes either before or after exposure. Two additional groups of mice were either immunized or irradiated only. A group of control mice received no irradiation or immunization. The beta radiation dose absorbed by the lungs of each mouse at time of challenge averaged 10,000 rads. Fourteen days after immunization, all mice were challenged with 2 LD/sub 50/ doses ofmore » L. monocytogenes via the respiratory route. Survival of all immunized mice either with or without exposure to /sup 90/Y varied from 90 to 100% as compared to 10 to 20% for the mice irradiated only and for control mice through 14 days after challenge. Pulmonary clearance of inhaled L. monocytogenes during the first 4 hr after challenge was suppressed in the mice irradiated only but not in those immunized only, or in the immunized and irradiated groups, and control mice. There appeared to be a suppression of proliferation of L. monocytogenes in lungs and spleen in the immunized groups 72 hr after challenge, whereas the lungs and spleens of the mice irradiated only and the control mice had extensive bacterial invasion. It was concluded that the 10,000 rads of beta radiation absorbed by the lungs did not suppress the immune mechanisms of the immunized mice.« less

Inhibitory effect of a mixture containing vitamin C, lysine, proline, epigallocatechin gallate, zinc and alpha-1-antitrypsin on lung carcinogenesis induced by benzo(a) pyrene in mice.

PubMed

Ibrahim, Ahmed Mohamed; Borai, Ibrahim Hassan; Ali, Mamdouh Moawad; Ghanem, Hala Mostafa; Hegazi, Azza El-Sayed Ahmed; Mousa, Amria Mamdouh

2013-05-01

This study was aimed to evaluate protective and therapeutic effects of a specific mixture, containing vitamin C, lysine, proline, epigallocatechin gallate and zinc, as well as alpha-1-antitrypsin protein on lung tumorigenesis induced by benzo(a) pyrene [B(a)P] in mice. Swiss albino mice were divided into two main experiments, experiment (1) the mice were injected with 100 mg/kg B(a)P and lasted for 28 weeks, while experiment (2) the mice were injected with 8 doses each of 50 mg/kg B(a)P and lasted for 16 weeks. Each experiment (1 and 2) divided into five groups, group (I) received vehicle, group (II) received the protector mixture, group (III) received the carcinogen B(a)P, group (IV) received the protector together with the carcinogen (simultaneously) and group (V) received the carcinogen then the protector (consecutively). Total sialic acid, thiobarbituric acid reactive substances, vascular epithelial growth factor, hydroxyproline levels, as well as elastase and gelatinase activities showed significant elevation in group (III) in the two experiments comparing to control group (P < 0.001). These biochemical alterations were associated with histopathological changes. Administration of the protector in group IV and group V causes significant decrease in such parameters with improvement in histopathological alterations with improvement in histopathological alterations when compared with group III in the two experiments (P < 0.001). The present protector mixture has the ability to suppress neoplastic alteration and restore the biochemical and histopathological parameters towards normal on lung carcinogenesis induced by benzo(a) pyrene in mice. Furthermore, the present mixture have more protective rather than therapeutic action.

Long-term effects of intragastic instillations of BDNPF:BDNPA in male Sprague-Dawley rats and female Swiss-Webster mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, D.M.; Drake, G.A.; London, J.E.

1981-07-01

Young male Sprague-Dawley rats were given a single dose of 1.3 g/kg body weight (BW) bis-dinitro-propyl-formal:bisdinitro-propyl-acetal (BDNPF:BDNPA) intragastrically (IG) and young female Swiss-Webster mice were given BDNPF:BDNPA either as a single dose (800 mg/kg/Bw) IG or a dose (500 mg/kg/BW) IG on each of 5 consecutive days. All animals were then maintained for the durations of their life spans and autopsied at death. The incidence of testicular Leydig cell tumors and subcutaneous fibrosarcomas in rats receiving the material was significantly elevated compared to controls, though treated animals' life spans were not significantly different from those of control animals. No significantmore » effects were seen in any of the mice receiving either a single dose or multiple doses of BDNPF:BDNPA compared to control animals. We suggest that another species of male Laboratory animals be treated with BDNPF:BDNPA to see if these findings can be replicated.« less

Potential preventive role of lactic acid bacteria against aflatoxin M₁ immunotoxicity and genotoxicity in mice.

PubMed

Ben Salah-Abbès, Jalila; Abbès, Samir; Jebali, Rania; Haous, Zohra; Oueslati, Ridha

2015-01-01

Aflatoxin M1 (AFM1) is a mycotoxin produced by numerous Aspergillus species in pre- or post-harvest cereals and milk. Exposure to AFM1 imparts potent economic losses in the livestock industry. Toxicologically, it also causes severe immune system problems. The aims of this study were to evaluate a new AFM1-binding/degrading microorganism for biologic detoxification, to examine its ability to degrade AFM1 in liquid medium, and to evaluate its potential for in vivo preventative effects against AFM1-induced immunotoxicity and genotoxicity in mice. Lactobacillus plantarum MON03 (LP) isolated from Tunisian artisanal butter was found to display significant binding ability to AFM1 in PBS (93%) within 24 h of incubation. Further, the LP was able to tolerate gastric acidity, bile salts, and adhere efficiently to Caco-3 cells in vitro. The in vivo study used Balb/c mice that received either vehicle (control), LP only (at 1 × 10(9)CFU/L, ∼1 mg/kg bw), AFM1 (100 mg/kg bw), or AFM1 + LP daily for 15 days (by gavage); two other groups received a single dose of colchicine (4 mg/kg) or mitomycin C (1 mg/kg) as positive controls for induction of micronuclei and chromosomal aberrations, respectively. The results showed that, compared to in control mice, AFM1 treatment led to significantly decreased body weight gains, and caused cytotoxic/genotoxic effects as indicated by increases in frequencies of polychromatic erythrocytes, as well as those with micronucleation (PCEMN) and chromosomal aberrations, among bone marrow cells. The concurrent administration of LP with AFM1 strongly reduced the adverse effects of AFM1 on each parameter. Mice receiving AFM1 + LP co-treatment displayed no significant differences in the assayed parameters as compared to the control mice. By itself, the bacteria caused no adverse effects. Based on the data, it is concluded that the test bacteria could potentially be beneficial in the detoxification of AFM1-contaminated foods and feeds for humans and animals.

Antibody-directed myostatin inhibition enhances muscle mass and function in tumor-bearing mice.

PubMed

Murphy, Kate T; Chee, Annabel; Gleeson, Ben G; Naim, Timur; Swiderski, Kristy; Koopman, René; Lynch, Gordon S

2011-09-01

Cancer cachexia describes the progressive skeletal muscle wasting and weakness in many cancer patients and accounts for >20% of cancer-related deaths. We tested the hypothesis that antibody-directed myostatin inhibition would attenuate the atrophy and loss of function in muscles of tumor-bearing mice. Twelve-week-old C57BL/6 mice received a subcutaneous injection of saline (control) or Lewis lung carcinoma (LLC) tumor cells. One week later, mice received either once weekly injections of saline (control, n = 12; LLC, n = 9) or a mouse chimera of anti-human myostatin antibody (PF-354, 10 mg·kg⁻¹·wk⁻¹, LLC+PF-354, n = 11) for 5 wk. Injection of LLC cells reduced muscle mass and maximum force of tibialis anterior (TA) muscles by 8-10% (P < 0.05), but the muscle atrophy and weakness were prevented with PF-354 treatment (P > 0.05). Maximum specific (normalized) force of diaphragm muscle strips was reduced with LLC injection (P < 0.05) but was not improved with PF-354 treatment (P > 0.05). PF-354 enhanced activity of oxidative enzymes in TA and diaphragm muscles of tumor-bearing mice by 118% and 89%, respectively (P < 0.05). Compared with controls, apoptosis that was not of myofibrillar or satellite cell origin was 140% higher in TA muscle cross sections from saline-treated LLC tumor-bearing mice (P < 0.05) but was not different in PF-354-treated tumor-bearing mice (P > 0.05). Antibody-directed myostatin inhibition attenuated the skeletal muscle atrophy and loss of muscle force-producing capacity in a murine model of cancer cachexia, in part by reducing apoptosis. The improvements in limb muscle mass and function highlight the therapeutic potential of antibody-directed myostatin inhibition for cancer cachexia.

HAMLET treatment delays bladder cancer development.

PubMed

Mossberg, Ann-Kristin; Hou, Yuchuan; Svensson, Majlis; Holmqvist, Bo; Svanborg, Catharina

2010-04-01

HAMLET is a protein-lipid complex that kills different types of cancer cells. Recently we observed a rapid reduction in human bladder cancer size after intravesical HAMLET treatment. In this study we evaluated the therapeutic effect of HAMLET in the mouse MB49 bladder carcinoma model. Bladder tumors were established by intravesical injection of MB49 cells into poly L-lysine treated bladders of C57BL/6 mice. Treatment groups received repeat intravesical HAMLET instillations and controls received alpha-lactalbumin or phosphate buffer. Effects of HAMLET on tumor size and putative apoptotic effects were analyzed in bladder tissue sections. Whole body imaging was used to study HAMLET distribution in tumor bearing mice compared to healthy bladder tissue. HAMLET caused a dose dependent decrease in MB49 cell viability in vitro. Five intravesical HAMLET instillations significantly decreased tumor size and delayed development in vivo compared to controls. TUNEL staining revealed selective apoptotic effects in tumor areas but not in adjacent healthy bladder tissue. On in vivo imaging Alexa-HAMLET was retained for more than 24 hours in the bladder of tumor bearing mice but not in tumor-free bladders or in tumor bearing mice that received Alexa-alpha-lactalbumin. Results show that HAMLET is active as a tumoricidal agent and suggest that topical HAMLET administration may delay bladder cancer development. Copyright (c) 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Effect of mTOR Inhibitors in Nude Mice with Endometrial Carcinoma and Variable PTEN Expression Status

PubMed Central

Fong, Pedro; Meng, Li-rong

2014-01-01

Background The aim of this study was to investigate the sensitivity to rapamycin of endometrial cancer cells with different phosphatase and tensin homologue (PTEN) expression to understand the mechanism of resistance to mammalian target of rapamycin (mTOR) inhibitors in the treatment of endometrial cancer. Material/Methods Twenty specific pathogen-free female BALB/c mice received transplants of either HEC-1A (PTEN-positive) or Ishikawa (PTEN-negative) cells. Mice in the treatment group were injected intraperitoneally once a week for 4 consecutive weeks. The control group was injected weekly with phosphate buffer saline (PBS) for 4 consecutive weeks. Tumor volume, tumor mass, growth curves, and inhibition rate were measured, after which the mice were killed. Results Both tumor growth rate and size were slower in the treatment group than in the control group for all mice that received transplants of either HEC-1A or Ishikawa cells. The tumor inhibition rates in the treatment group were 48.1% and 67.1% in mice transplanted with HEC-1A and Ishikawa cells, respectively. Conclusions The inhibitory effects of rapamycin were enhanced in PTEN-negative Ishikawa tumor cells compared with PTEN-positive HEC-1A cells, which could explain the reduced effect of rapalogues in some endometrial cancer patients and help to understand the mechanism of resistance to this drug. PMID:25266877

Physiological and behavioral responses in offspring mice following maternal exposure to sulfamonomethoxine during pregnancy.

PubMed

Zhang, Qiang; Zhang, Dan; Ye, Kui; Liu, Kaiyong; Sheng, Jie; Liu, Yehao; Hu, Chunqiu; Ruan, Liang; Li, Li; Tao, Fangbiao

2016-06-15

Sulfamonomethoxine (SMM), a veterinary antibiotic, is widely used in China. However, the impacts of maternal SMM exposure on neurobehavioral development in early life remain little known. In this study, we investigated the effects of maternal SMM exposure during pregnancy on behavioral and physiological responses in offspring mice. Pregnant mice were randomly divided into three SMM-treated groups, namely low-(10mg/kg/day), medium-(50mg/kg/day), and high-dose (200mg/kg/day), and a control group. The pregnant mice in the SMM-treated groups received SMM by gavage daily from gestational day 1-18, whereas those in the control received normal saline. On postnatal day (PND) 50, spatial memory was assessed using the Morris water maze test, and anxiety was measured using the elevated plus-maze and open field tests. The results showed significantly increased blood glucose in pups whose mothers received a high SMM dose. In addition, maternal SMM exposure increased anxiety-related activities among the offspring; spatial learning and memory were impaired more severely in the male offspring. The contents of tetrahydrobiopterin (BH4) and brain-derived neurotrophic factors (BDNF) on PND 22 were significantly reduced in the male offspring of the high-dose group compared with the controls. These findings indicate that SMM may be identified as a risk factor for cognitive and behavioral development on the basis of gender and that it may be associated with diminished BH4 and BDNF levels early in life. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Inhibition of pulmonary metastasis of melanoma b16fo cells in C57BL/6 mice by a nutrient mixture consisting of ascorbic Acid, lysine, proline, arginine, and green tea extract.

PubMed

Roomi, M Waheed; Roomi, Nusrath; Ivanov, Vadim; Kalinovsky, Tatiana; Niedzwiecki, Aleksandra; Rath, Matthias

2006-01-01

The authors investigated the effect of a nutrient mixture (NM) on lung metastasis by B16F0 melanoma cells in C57BL/6 female mice. Mice were divided into equal groups (1 to 6) and injected via tail vein with B16F0 cells (groups 1 to 4), B16FO cells pretreated with NM (group 5), or saline (group 6). Groups 1, 3, 4, 5, and 6 were fed the control diet and group 2 the 0.5% NM supplemented diet. Groups 3 and 4 received NM intraperitoneally (IP) and intravenously (IV), respectively. Two weeks later, pulmonary metastatic colonies were counted. Pulmonary colonization was reduced by 63% in mice supplemented with NM diet, by 86% in mice receiving NM by IP and IV injections, and completely inhibited in mice injected with melanoma cells pretreated with NM. These results show that NM is effective in inhibiting the metastasis of B16FO melanoma cells.

Conditional genetic deletion of PTEN after a spinal cord injury enhances regenerative growth of CST axons and motor function recovery in mice

PubMed Central

Danilov, Camelia A.; Steward, Oswald

2015-01-01

Previous studies indicate that conditional genetic deletion of phosphatase and tensin homolog (PTEN) in neonatal mice enhances the ability of axons to regenerate following spinal cord injury (SCI) in adults. Here, we assessed whether deleting PTEN in adult neurons post-SCI is also effective, and whether enhanced regenerative growth is accompanied by enhanced recovery of voluntary motor function. PTENloxP/loxP mice received moderate contusion injuries at cervical level 5 (C5). One group received unilateral injections of adeno-associated virus expressing CRE (AAV-CRE) into the sensorimotor cortex; controls received a vector expressing green fluorescent protein (AAV-GFP) or injuries only (no vector injections). Forelimb function was tested for 14 weeks post-SCI using a grip strength meter (GSM) and a hanging task. The corticospinal tract (CST) was traced by injecting mini-ruby BDA into the sensorimotor cortex. Forelimb gripping ability was severely impaired immediately post-SCI but recovered slowly over time. The extent of recovery was significantly greater in PTEN-deleted mice in comparison to either the AAV-GFP group or the injury only group. BDA tract tracing revealed significantly higher numbers of BDA-labeled axons in caudal segments in the PTEN-deleted group compared to control groups. In addition, in the PTEN-deleted group, there were exuberant collaterals extending from the main tract rostral to the lesion, into and around the scar tissue at the injury site. These results indicate that PTEN deletion in adult mice shortly post-SCI can enhance regenerative growth of CST axons and forelimb motor function recovery. PMID:25704959

Adiponectin attenuates kidney injury and fibrosis in deoxycorticosterone acetate-salt and angiotensin II induced CKD mice.

PubMed

Tian, Mi; Tang, Li; Wu, Yuanyuan; Beddhu, Srinivasan; Huang, Yufeng

2018-06-06

Adiponectin (ApN) is a multifunctional adipokine. However high, rather than low, concentrations of ApN are unexpectedly found in patients with chronic kidney disease (CKD) via an as yet unknown mechanism and the role of ApN in CKD is unclear. We, herein, investigated the effect of ApN overexpression on the progressive renal injury resulted from deoxycorticosterone acetate-salt (DOCA) and angiotensin II (Ang-II) infusion using a transgenic, inducible ApN-overexpressing mouse model. Three groups of mice (wild type receiving no infusion (WT), WT and cyp1a1 ApN transgenic mice (ApN-Tg) receiving DOCA+Ang-II infusion (WT/DOCA+Ang-II and ApN-Tg/DOCA+Ang-II)) were assigned to receive a normal food containing 0.15% of the transgene inducer indol-3-carbinol (I3C) for 3 weeks. The I3C-induced ApN-Tg/DOCA+Ang-II mice, not the WT or WT/DOCA+Ang-II mice, overexpressing ApN in liver resulted in 3.15-fold increases in circulating ApN than non-transgenic controls. Of note, these transgenic mice receiving DOCA+Ang-II infusion were still hypertensive but had much less albuminuria and glomerular and tubulointerstitial fibrosis, which were associated with ameliorated podocyte injury determined by ameliorated podocyte loss and foot process effacement; and alleviated tubular injury determined by ameliorated mRNA overexpression of KIM-1 and NGAL and mRNA decreases of cubilin and megalin in tubular cells, compared with WT/DOCA+Ang-II mice. In addition, renal production of NF-kB-p65, NAPDH oxidase-2 and p47phox, and MAPK-related cellular proliferation, which were induced in WT/DOCA+Ang-II mice, were markedly reduced in ApN-Tg/DOCA+Ang-II mice. These results indicate that elevated ApN in CKD mouse model is renal protective. Enhancing adiponectin production or signaling may have therapeutic potential for CKD.

Effect of Withania somnifera Root Extract on Spontaneous Estrogen Receptor-Negative Mammary Cancer in MMTV/Neu Mice

PubMed Central

KHAZAL, KAMEL F.; HILL, DONALD L.; GRUBBS, CLINTON J.

2015-01-01

The cancer-preventive activity of an extract of Withania somnifera (WS) roots was examined in female transgenic (MMTV/Neu) mice that received a diet containing the extract (750 mg/kg of diet) for 10 months. Mice in the treated group (N=35) had an average of 1.66 mammary carcinomas, and mice in the control group (N=33) had 2.48, a reduction of 33%. The average weights of the carcinomas were 2.36 g for mice in the treated group and 2.63 g for the controls, a difference of 10%. Labeling indices for Ki67 and proliferating cell nuclear antigen marker in mammary carcinomas of the treated group were 35% and 30% lower, respectively, than those of the corresponding control group. Expression of the chemokine was reduced by 50%. These results indicate that the root extract reduced the number of mammary carcinomas that developed and reduced the rate of cell division in the carcinomas. PMID:25368231

Triamcinolone Acetonide Decreases Outflow Facility in C57BL/6 Mouse Eyes

PubMed Central

Kumar, Sandeep; Shah, Shaily; Deutsch, Emily Rose; Tang, Hai Michael; Danias, John

2013-01-01

Purpose. To determine the effect of triamcinolone acetonide (TA) on outflow facility in mice. Methods. Animals received 20 μL of TA (40 mg/mL) suspension subconjunctivally either bilaterally or unilaterally and were euthanized after either 1 week or 3 weeks. Before mice were killed, IOP was measured with a rebound tonometer. Outflow facility was determined using simultaneous pressure and flow measurements. Another set of animals received bilateral injection of anecortave acetate (AA) with or without bilateral TA injection and their outflow facility was also determined. Myocilin expression was investigated in a subset of eyes using quantitative PCR (qPCR). Results. Outflow facility of eyes in animals receiving bilateral TA injection (TABL) and TA-treated eyes of animals receiving unilateral injection (TAUL) was significantly decreased compared to naïve control eyes (Cnaive) after 1 week and 3 weeks of TA treatment (ANOVA P < 0.01, P < 0.001, respectively). Eyes treated with AA (with or without TA) had higher outflow facility than animals treated with TA (P < 0.05). IOP data did not show any significant difference between groups. qPCR analysis revealed significant decrease in myocilin expression in eyes receiving AA compared to naïve control and TA-treated eyes (ANOVA P < 0.001). Conclusions. Steroid treatment significantly decreases outflow facility in C57BL/6 mice despite having small effect on IOP. This animal model can be useful for studying the pathogenesis of steroid-induced glaucoma. PMID:23322580

Synergistic effect of aged garlic extract and naltrexone on improving immune responses to experimentally induced fibrosarcoma tumor in BALB/c mice

PubMed Central

Ebrahimpour, Soheil; Tabari, Mohaddeseh Abouhosseini; Youssefi, Mohammad Reza; Aghajanzadeh, Hamid; Behzadi, Manijeh Yousefi

2013-01-01

Background: Garlic, a medicinal plant, and Naltrexone (NTX), an opioid receptor antagonist, both have immunomodulatory and antitumor effects. Current study was designed to evaluate synergistic antitumor effects of aged garlic extract (AGE) and NTX. Materials and Methods: WEHI-164 fibrosarcoma cells were implanted subcutaneously on day 0 into right flank of 80 BALB/c mice at age of 8 weeks. Mice were randomly categorized in four separate groups: The first group received AGE (100 mg/kg, i.p.), the second group received NTX (0.5 mg/kg, i.p.), the third group received both of them, and the fourth group received phosphate buffered saline as control group. Treatments were administered three times per week. Tumor growth was measured and morbidity was recorded. Subpopulations of CD4+/CD8+ T cells were determined using flowcytometery. WEHI-164 cell specific cytotoxicity of splenocytes and in vitro production of interferon-gamma (IFN-γ) and interleukin-4 (IL-4) cytokines were measured. All statistical analyses were conducted with SPSS 16 software and P < 0.05 was considered to be statistically significant. Results: The mice who received AGE+NTX had significantly longer survival time compared with the mice treated with AGE or NTX alone. An enhanced inhibitory effect on tumor growth was seen in combination therapy group. The CD4+/CD8+ ratio and in vitro IFN-γ production of splenocytes were significantly increased in AGE+NTX and NTX groups. WEHI-164 specific cytotoxicity of splenocytes was also significantly increased at 25:1 E:T ratio in AGE+NTX treated mice. Coadministration of AGE with NTX resulted in improvement of immune responses against experimentally implanted fibrosarcoma tumors in BALB/c mice. Conclusions: AGE showed synergistic effects with NTX on inhibition of tumor growth and increment of survival times. PMID:23901215

Cerebral cortical blood flow maps are reorganized in MAOB-deficient mice

PubMed Central

Scremin, Oscar U.; Holschneider, Daniel P.; Chen, Kevin; Li, Mingen G.; Shih, Jean C.

2014-01-01

Cerebral cortical blood flow (CBF) was measured autoradiographically in conscious mice without the monoamine oxidase B (MAOB) gene (KO, n = 11) and the corresponding wild-type animals (WILD, n = 11). Subgroups of animals of each genotype received a continuous intravenous infusion over 30 min of phenylethylamine (PEA), an endogenous substrate of MAOB, (8 nmol g−1 min−1 in normal saline at a volume rate of 0.11 μl g−1 min−1) or saline at the same volume rate. Maps of relative CBF distribution showed predominance of midline motor and sensory area CBF in KO mice over WILD mice that received saline. PEA enhanced CBF in lateral frontal and piriform cortex in both KO and WILD mice. These changes may reflect a differential activation due to chronic and acute PEA elevations on motor and olfactory function, as well as on the anxiogenic effects of this amine. In addition to its effects on regional CBF distribution, PEA decreased CBF globally in KO mice (range −31% to −41% decrease from control levels) with a lesser effect in WILD mice. It is concluded that MAOB may normally regulate CBF distribution and its response to blood PEA. PMID:10095040

Association of Diet With Skin Histological Features in UV-B–Exposed Mice

PubMed Central

Hsia, Yvonne; Weeks, David M.; Dixon, Tatiana K.; Lepe, Jessica; Thomas, J. Regan

2017-01-01

Importance Long-term exposure to solar radiation produces deleterious photoaging of the skin. It is not known if diet can influence skin photoaging. Objectives To study the influence of a calorie-restricted diet and an obesity diet in mice exposed to long-term UV-B irradiation to assess if there is an association between diet and histopathological response to UV-B irradiation. Design, Setting, and Participants In this animal model study in an academic setting, the dorsal skin of SKH1 hairless mice receiving normal, calorie-restricted, and obesity diets was exposed to UV-B irradiation 3 times a week for 10 weeks and were compared with corresponding controls. The mice were placed in the following groups, with 8 animals in each group: (1) intact control (C) with regular diet and no UV-B exposure, (2) intact control with UV-B exposure (CR), (3) calorie-restricted diet (CrC), (4) calorie-restricted diet with UV-B exposure (CrR), (5) obesity diet (OC), and (6) obesity diet with UV-B exposure (OR). The experiment was conducted during October through December 2013. Tissue processing and histological analysis were completed in 2016. Main Outcomes and Measures Histomorphometric analysis was performed on paraffin-embedded skin sections stained by histological and immunohistochemical methods for estimation of epidermal thickness, epidermal proliferating cell nuclear antigen index, collagen I, elastic fibers, fibroblasts, mast cells, dermal cellularity, and adipose layer ratio. Changes in wrinkles were noted. Results Hairless female mice (age range, 6-8 weeks) were obtained. With a normal diet, changes from UV-B irradiation occurred in epidermal thickness, epidermal proliferating cell nuclear antigen index, collagen I, elastic fibers, fibroblasts, and mast cells, which were modestly influenced by an obesity diet. Calorie restriction influenced the skin in nonirradiated control animals, with higher values for most variables. After UV-B exposure in animals with calorie restriction, epidermal thickness was increased, but other variables were unaffected. Animals receiving the calorie-restricted diet lost weight when exposed to long-term UV-B irradiation. Wrinkles were reduced in the calorie-restricted control group and in UV-B–exposed animals who received the obesity diet. Conclusions and Relevance Dietary alterations seem to modify histopathological responses to UV-B exposure in the skin of hairless mice. Level of Evidence NA. PMID:28418519

Exacerbating Effects of Human Parvovirus B19 NS1 on Liver Fibrosis in NZB/W F1 Mice

PubMed Central

Hsu, Tsai-Ching; Tsai, Chun-Chou; Chiu, Chun-Ching; Hsu, Jeng-Dong; Tzang, Bor-Show

2013-01-01

Systemic lupus erythematosus (SLE) is an autoimmune disorder with unknown etiology that impacts various organs including liver. Recently, human parvovirus B19 (B19) is recognized to exacerbate SLE. However, the effects of B19 on liver in SLE are still unclear. Herein we aimed to investigate the effects of B19 on liver in NZB/W F1 mice by injecting subcutaneously with PBS, recombinant B19 NS1, VP1u or VP2, respectively. Our experimental results revealed that B19 NS1 protein significantly enhanced the TGF-β/Smad fibrotic signaling by increasing the expressions of TGF-β, Smad2/3, phosphorylated Smad2/3, Smad4 and Sp1. The consequent fibrosis-related proteins, PAI-1 and α-SMA, were also significantly induced in livers of NZB/W F1 mice receiving B19 NS1 protein. Accordingly, markedly increased collagen deposition was also observed in livers of NZB/W F1 mice receiving B19 NS1 protein. However, no significant difference was observed in livers of NZB/W F1 mice receiving B19 VP1u or VP2 as compared to the controls. These findings indicate that B19 NS1 plays a crucial role in exacerbating liver fibrosis in NZB/W F1 mice through enhancing the TGF-â/Smad fibrotic signaling. PMID:23840852

[Killing effect of Huaier combined with DC-CIK on nude mice bearing colon cancer HT29 stem cells in vivo].

PubMed

Sun, Wen-Wen; Dou, Jin-Xia; Zhang, Lin; Qiao, Li-Kui; Shen, Na; Gao, Wen-Yuan

2018-01-01

To compare the therapeutic effects of different treatment methods on the nude mice bearing colon cancer HT29 cells. BalB/C nude mice colon cancer stem cell models were established and randomly divided into the following four groups, with 8 nude mice in each group: blank control group, DC-CIK group, Huaier group, and Huaier combined with DC-CIK group (combined treatment group). The mice in DC-CIK group and combined treatment group received 1×10⁶ DC-CIK cells treatment by tail vein injectionafter the tumor stem cells were inoculated for 4 days,2 times a week for three weeks. The mice in Huaier group and combined treatment group received intragastric administration at the dose of 20 g/60 kg body weight, 0.2 mL/time, once a day for a total of three weeks. The mice in control group received equal volume of normal saline. Tumor size and body weight of nude mice were measured every 2 days during treatment for three weeks in each group. After the treatment, the nude mice were sacrificed to measure the tumor weight and the tumor inhibition rate was calculated. The RT-PCR method was used to detect the expression levels of the key genes in the signal pathway. After the end of the treatment, the quality of the tumor in the Huaier group, DC-CIK group and combined treatment group was significantly lower than that in the control group; the quality in combined treatment group was significantly lower than that in Huaier group and DC-CIK group.Among them, the tumor inhibition rate reached 46.77% in the combined treatment group. In respect of changes in expression levels of key genes in the signaling pathway, the mRNA expression levels of key genes PI3KR1 and Akt in PI3K/Akt pathway, key genes Wnt1 and CTTNB1 in Wnt/ β -catenin pathway, and key genes Notch1, Notch2, Notch3 in Notch pathway in the combined treatment group were lower than those in DC-CIK group and Huaier group. The Huaier combined with DC-CIK group showed best therapeutic effect among different treatment methods for HT29 stemcell colon tumors in nude mice, providing a new idea for clinical treatment of colon cancer. Copyright© by the Chinese Pharmaceutical Association.

Effects of stressor predictability and controllability on sleep, temperature, and fear behavior in mice.

PubMed

Yang, Linghui; Wellman, Laurie L; Ambrozewicz, Marta A; Sanford, Larry D

2011-06-01

Predictability and controllability are important factors in the persisting effects of stress. We trained mice with signaled, escapable shock (SES) and with signaled, inescapable shock (SIS) to determine whether shock predictability can be a significant factor in the effects of stress on sleep. Male BALB/cJ mice were implanted with transmitters for recording EEG, activity, and temperature via telemetry. After recovery from surgery, baseline sleep recordings were obtained for 2 days. The mice were then randomly assigned to SES (n = 9) and yoked SIS (n = 9) conditions. The mice were presented cues (90 dB, 2 kHz tones) that started 5.0 sec prior to and co-terminated with footshocks (0.5 mA; 5.0 sec maximum duration). SES mice always received shock but could terminate it by moving to the non-occupied chamber in a shuttlebox. SIS mice received identical tones and shocks, but could not alter shock duration. Twenty cue-shock pairings (1.0-min interstimulus intervals) were presented on 2 days (ST1 and ST2). Seven days after ST2, SES and SIS mice, in their home cages, were presented with cues identical to those presented during ST1 and ST2. NA. NA. NA. On each training and test day, EEG, activity and temperature were recorded for 20 hours. Freezing was scored in response to the cue alone. Compared to SIS mice, SES mice showed significantly increased REM after ST1 and ST2. Compared to SES mice, SIS mice showed significantly increased NREM after ST1 and ST2. Both groups showed reduced REM in response to cue presentation alone. Both groups showed similar stress-induced increases in temperature and freezing in response to the cue alone. These findings indicate that predictability (modeled by signaled shock) can play a significant role in the effects of stress on sleep.

Induction of tolerance and prolongation of islet allograft survival by syngeneic hematopoietic stem cell transplantation in mice.

PubMed

Yang, Shi-feng; Xue, Wu-jun; Lu, Wan-hong; Xie, Li-yi; Yin, Ai-ping; Zheng, Jin; Sun, Ji-ping; Li, Yang

2015-10-01

Syngeneic or autologous hematopoietic stem cells transplantation (HSCT) has been proposed to treat autoimmune diseases because of its immunosuppressive and immunomodulatory effects, which can also contribute to posttransplant antirejection therapy. In this study, we explored the tolerogenic effect of syngeneic HSCT on prolonging islet allograft survival. C57BL/6 mice received syngeneic HSCT plus preconditioning with sublethal irradiation. Then islets of BALB/c mice were transplanted into the renal subcapsular of C57BL/6 mice after chemically induced into diabetes. HSCT mice exhibited improved islet allograft survival and increased serum insulin compared to control mice. Islet allografts of HSCT mice displayed lower level lymphocyte infiltration and stronger insulin staining than control mice. T cells of HSCT mice proliferated poorly in response to allogeneic splenocytes compared to control mice. Mice appeared reversed interferon-γ (IFN-γ)/interleukin-4 (IL-4) ratio to a Th2 immune deviation after syngeneic HSCT. The percentage of CD8(+) T cells was lower, while percentage of CD4(+)CD25(+)Foxp3(+) T regulatory cells (Tregs) was higher in HSCT mice than control mice. HSCT mice showed higher percentage of CTLA-4(+) T cells and expression of CTLA-4 mRNA than control mice. Targeting of CTLA-4 by intraperitoneal injection of anti-CTLA-4 mAb abrogated the effect of syngeneic HSCT on prolonging islet allograft survival, inhibiting activity of T cells in response to alloantigen, promoting Th1 to Th2 immune deviation and up regulating CD4(+)CD25(+)Foxp3(+) Tregs. Syngeneic HSCT plus preconditioning of sublethal irradiation induces tolerance and improves islet allograft survival in fully mismatched mice model. Th1 to Th2 immune deviation, increased CD4(+)CD25(+)Foxp3(+) Tregs and up-regulation of CTLA-4 maybe contribute to the tolerogenic effect induced by syngeneic HSCT. Copyright © 2015 Elsevier B.V. All rights reserved.

Protective effect of royal jelly on the sperm parameters and testosterone level and lipid peroxidation in adult mice treated with oxymetholone

PubMed Central

Zahmatkesh, Ensieh; Najafi, Gholamreza; Nejati, Vahid; Heidari, Reza

2014-01-01

Objectives : The aim of the present study was to evaluate protective effect of royal jelly on sperm parameters, testosterone level, and malondialdehyde (MDA) production in mice. Materials and Methods: Thirty-two adult male NMRI mice weighing 30±2 g were used. All the animals were divided into 4 groups. Control group: received saline 0.1 ml/mouse/day orally for 30 days. Royal jelly group (RJ): received royal jelly at dose of 100 mg/kg daily for 30 days orally. Oxymetholone group: the received Oxymetholone (OX) at dose of 5 mg/kg daily for 30 days orally. Royal jelly+Oxymetholone group: received royal jelly at dose of 100 mg/kg/day orally concomitant with OX administration. Sperm count, sperm motility, viability, maturity, and DNA integrity were analyzed. Furthermore, serum testosterone and MDA concentrations were determined. Results: In Oxymetholone group, sperm count, motility as well as testosterone concentration reduced significantly (p<0.05), while significant (p<0.05) increases in immature sperm, sperm with DNA damaged, and MDA concentration were announced in Oxymetholone group in comparison with control group and Royal jelly+Oxymetholone group. RJ caused partially amelioration in all of the above- mentioned parameters in Royal Jelly+Oxymetholone group. Conclusion: In conclusion, RJ may be used in combination with OX to improve OX-induced oxidative stress and male infertility. PMID:25050300

Effects of yak-activated protein on hematopoiesis and related cytokines in radiation-induced injury in mice.

PubMed

Duan, Yabin; Yao, Xingchen; Zhu, Junbo; Li, Yongping; Zhang, Juanling; Zhou, Xuejiao; Qiao, Yijie; Yang, Meng; Li, Xiangyang

2017-12-01

The aim of the present study was to investigate the protective effects of yak-activated protein on hematopoiesis and cytokine function in radiation-induced injury in mice. A total of 180 Kunming mice were randomly divided into three groups (A, B and C). Of these, 60 were randomly divided into a normal control group, a radiation model group, a positive control group and 3 yak-activated protein groups (high, medium and low dose groups; 10, 5 and 2.5 mg/kg, respectively). The other 120 mice were used for the subsequent experiments on days 7 and 14 following radiation. Yak-activated protein was administered orally to mice in the treatment groups and an equal volume of saline was administered orally to mice in the normal control and radiation model groups for 14 days. The positive control group received amifostine (150 mg/kg) via intraperitoneal injection. With the exception of the control group, the groups of mice received a 5 Gy quantity of X-radiation evenly over their whole body once. Changes in the peripheral hemogram, thymus and spleen indices, DNA content in the bone marrow, interleukin (IL)-2 and IL-6 levels, and the expression levels of B cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) following irradiation were assessed. The low dose of yak-activated protein significantly increased Spleen indices in mice 14 days after irradiation and the high and middle dose of yak-activated protein significantly increased Thymus indices in mice 14 days after irradiation (P<0.05) compared with the control group. In addition, hemogram results increased gradually in the low-yak-activated protein dose group and were significantly higher 7 days after irradiation compared with the radiation model group (P<0.05). The DNA content in the bone marrow was markedly increased in the yak-activated protein groups, and increased significantly in the low dose group at 7 days post-irradiation compared with the radiation model group (P<0.05). The IL-2 content was significantly increased in the yak-activated protein groups (P<0.05). Furthermore, Bcl-2 expression was increased and Bax expression was decreased (P<0.05). These results suggest that yak-activated protein exerts protective effects against radiation-induced injury in mice. The optimal effects of yak-activated protein were observed in the medium dose group 14 days after irradiation.

Effects of yak-activated protein on hematopoiesis and related cytokines in radiation-induced injury in mice

PubMed Central

Duan, Yabin; Yao, Xingchen; Zhu, Junbo; Li, Yongping; Zhang, Juanling; Zhou, Xuejiao; Qiao, Yijie; Yang, Meng; Li, Xiangyang

2017-01-01

The aim of the present study was to investigate the protective effects of yak-activated protein on hematopoiesis and cytokine function in radiation-induced injury in mice. A total of 180 Kunming mice were randomly divided into three groups (A, B and C). Of these, 60 were randomly divided into a normal control group, a radiation model group, a positive control group and 3 yak-activated protein groups (high, medium and low dose groups; 10, 5 and 2.5 mg/kg, respectively). The other 120 mice were used for the subsequent experiments on days 7 and 14 following radiation. Yak-activated protein was administered orally to mice in the treatment groups and an equal volume of saline was administered orally to mice in the normal control and radiation model groups for 14 days. The positive control group received amifostine (150 mg/kg) via intraperitoneal injection. With the exception of the control group, the groups of mice received a 5 Gy quantity of X-radiation evenly over their whole body once. Changes in the peripheral hemogram, thymus and spleen indices, DNA content in the bone marrow, interleukin (IL)-2 and IL-6 levels, and the expression levels of B cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) following irradiation were assessed. The low dose of yak-activated protein significantly increased Spleen indices in mice 14 days after irradiation and the high and middle dose of yak-activated protein significantly increased Thymus indices in mice 14 days after irradiation (P<0.05) compared with the control group. In addition, hemogram results increased gradually in the low-yak-activated protein dose group and were significantly higher 7 days after irradiation compared with the radiation model group (P<0.05). The DNA content in the bone marrow was markedly increased in the yak-activated protein groups, and increased significantly in the low dose group at 7 days post-irradiation compared with the radiation model group (P<0.05). The IL-2 content was significantly increased in the yak-activated protein groups (P<0.05). Furthermore, Bcl-2 expression was increased and Bax expression was decreased (P<0.05). These results suggest that yak-activated protein exerts protective effects against radiation-induced injury in mice. The optimal effects of yak-activated protein were observed in the medium dose group 14 days after irradiation. PMID:29285056

Dermal oncogenicity bioassays of monofunctional and multifunctional acrylates and acrylate-based oligomers.

PubMed

DePass, L R; Maronpot, R R; Weil, C S

1985-01-01

Several important components of photocurable coatings were studied for dermal tumorigenic activity by repeated application to the skin of mice. The substances tested were 2-ethylhexyl acrylate (EHA) and methylcarbamoyloxyethyl acrylate (MCEA) (monomers); neopentyl glycol diacrylate (NPGDA), esterdiol-204-diacrylate (EDDA), and pentaerythritol tri(tetra)acrylate (PETA) (cross-linkers); and three acrylated urethane oligomers. For each bioassay, 40 C3H/HeJ male mice were dosed 3 times weekly on the dorsal skin for their lifetime with the highest dose of the test agent that caused no local irritation or reduction in body weight gain. Two negative control groups received acetone (diluent) only. A positive control group received 0.2% methylcholanthrene (MC). NPGDA and EHA had significant tumorigenic activity with tumor yields of eight and six tumor-bearing mice (three and two malignancies), respectively. The MC group had 34 mice with carcinomas and 1 additional mouse with a papilloma. MCEA had no dermal tumorigenic activity but resulted in early mortality. No skin tumors in the treatment area were observed in the other groups. Additional studies will be necessary to elucidate possible relationships between structure and tumorigenic activity for the acrylates.

Preclinical safety study of a recombinant Streptococcus pyogenes vaccine formulated with aluminum adjuvant.

PubMed

HogenEsch, Harm; Dunham, Anisa; Burlet, Elodie; Lu, Fangjia; Mosley, Yung-Yi C; Morefield, Garry

2017-02-01

A recombinant vaccine composed of a fusion protein formulated with aluminum hydroxide adjuvant is under development for protection against diseases caused by Streptococcus pyogenes. The safety and local reactogenicity of the vaccine was assessed by a comprehensive series of clinical, pathologic and immunologic tests in preclinical experiments. Outbred mice received three intramuscular injections of 1/5th of the human dose (0.1 ml) and rabbits received two injections of the full human dose. Control groups received adjuvant or protein antigen. The vaccine did not cause clinical evidence of systemic toxicity in mice or rabbits. There was a transient increase of peripheral blood neutrophils after the third vaccination of mice. In addition, the concentration of acute phase proteins serum amyloid A and haptoglobin was significantly increased 1 day after injection of the vaccine in mice. There was mild transient swelling and erythema of the injection site in both mice and rabbits. Treatment-related pathology was limited to inflammation at the injection site and accumulation of adjuvant-containing macrophages in the draining lymph nodes. In conclusion, the absence of clinical toxicity in two animal species suggest that the vaccine is safe for use in a phase I human clinical trial. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Additional deleterious effects of alcohol consumption on sperm parameters and DNA integrity in diabetic mice.

PubMed

Pourentezari, M; Talebi, A R; Mangoli, E; Anvari, M; Rahimipour, M

2016-06-01

The aim of this study was to survey the impact of alcohol consumption on sperm parameters and DNA integrity in experimentally induced diabetic mice. A total of 32 adult male mice were divided into four groups: mice of group 1 served as control fed on basal diet, group 2 received streptozotocin (STZ) (200 mg kg(-1) , single dose, intraperitoneal) and basal diet, group 3 received alcohol (10 mg kg(-1) , water soluble) and basal diet, and group 4 received STZ and alcohol for 35 days. The cauda epididymidis of each mouse was dissected and placed in 1 ml of pre-warm Ham's F10 culture medium for 30 min. The swim-out spermatozoa were analysed for count, motility, morphology and viability. Sperm chromatin quality was evaluated with aniline blue, toluidine blue, acridine orange and chromomycin A3 staining. The results showed that all sperm parameters had significant differences (P < 0.05), also when sperm chromatin was assessed with cytochemical tests. There were significant differences (P < 0.001) between the groups. According to our results, alcohol and diabetes can cause abnormalities in sperm parameters and chromatin quality. In addition, alcohol consumption in diabetic mice can intensify sperm chromatin/DNA damage. © 2015 Blackwell Verlag GmbH.

Negligible Colon Cancer Risk from Food-Borne Acrylamide Exposure in Male F344 Rats and Nude (nu/nu) Mice-Bearing Human Colon Tumor Xenografts

PubMed Central

Raju, Jayadev; Roberts, Jennifer; Sondagar, Chandni; Kapal, Kamla; Aziz, Syed A.; Caldwell, Don; Mehta, Rekha

2013-01-01

Acrylamide, a possible human carcinogen, is formed in certain carbohydrate-rich foods processed at high temperature. We evaluated if dietary acrylamide, at doses (0.5, 1.0 or 2.0 mg/kg diet) reflecting upper levels found in human foods, modulated colon tumorigenesis in two rodent models. Male F344 rats were randomized to receive diets without (control) or with acrylamide. 2-weeks later, rats in each group received two weekly subcutaneous injections of either azoxymethane (AOM) or saline, and were killed 20 weeks post-injections; colons were assessed for tumors. Male athymic nude (nu/nu) mice bearing HT-29 human colon adenocarcinoma cells-derived tumor xenografts received diets without (control) or with acrylamide; tumor growth was monitored and mice were killed 4 weeks later. In the F344 rat study, no tumors were found in the colons of the saline-injected rats. However, the colon tumor incidence was 54.2% and 66.7% in the control and the 2 mg/kg acrylamide-treated AOM-injected groups, respectively. While tumor multiplicity was similar across all diet groups, tumor size and burden were higher in the 2 mg/kg acrylamide group compared to the AOM control. These results suggest that acrylamide by itself is not a “complete carcinogen”, but acts as a “co-carcinogen” by exacerbating the effects of AOM. The nude mouse study indicated no differences in the growth of human colon tumor xenografts between acrylamide-treated and control mice, suggesting that acrylamide does not aid in the progression of established tumors. Hence, food-borne acrylamide at levels comparable to those found in human foods is neither an independent carcinogen nor a tumor promoter in the colon. However, our results characterize a potential hazard of acrylamide as a colon co-carcinogen in association with known and possibly other environmental tumor initiators/promoters. PMID:24040114

Protective effects of mito-TEMPO against doxorubicin cardiotoxicity in mice.

PubMed

Rocha, Viviane Costa Junqueira; França, Luciana Souza de Aragão; de Araújo, Cintia Figueiredo; Ng, Ayling Martins; de Andrade, Candace Machado; Andrade, André Cronemberger; Santos, Emanuelle de Souza; Borges-Silva, Mariana da Cruz; Macambira, Simone Garcia; Noronha-Dutra, Alberto Augusto; Pontes-de-Carvalho, Lain Carlos

2016-03-01

Doxorubicin (DOX) is a chemotherapeutic that is widely used for the treatment of many human tumors. However, the development of cardiotoxicity has limited its use. The aim of the present study was to evaluate the possible efficacy of mito-TEMPO (mito-T) as a protective agent against DOX-induced cardiotoxicity in mice. C57BL/6 mice were treated twice with mito-T at low (5 mg/kg body weight) or high (20 mg/kg body weight) dose and once with DOX (24 mg/kg body weight) or saline (0.1 mL/20 g body weight) by means of intraperitoneal injections. The levels of malondialdehyde (MLDA), a marker of lipid peroxidation, and serum levels of creatine kinase were evaluated 48 h after the injection of DOX. DOX induced lipid peroxidation in heart mitochondria (p < 0.001), and DOX-treated mice receiving mito-T at low dose had levels of MLDA significantly lower than the mice that received only DOX (p < 0.01). Furthermore, administration of mito-T alone did not cause any significant changes from control values. Additionally, DOX-treated mice treated with mito-T at high dose showed decrease in serum levels of total CK compared to mice treated with DOX alone (p < 0.05). Our results indicate that mito-T protects mice against DOX-induced cardiotoxicity.

Acute acetaminophen toxicity in transgenic mice with elevated hepatic glutathione.

PubMed

Rzucidlo, S J; Bounous, D I; Jones, D P; Brackett, B G

2000-06-01

Previous studies demonstrated that elevation of hepatic glutathione (GSH) concentrations protect against acetaminophen (APAP) hepatotoxicity in mice. Employing transgenic mice overexpressing glutathione synthetase, this study was conducted to determine if sustained elevation of hepatic GSH concentrations could ameliorate or prevent APAP toxicity. International Cancer Research transgenic mouse males and matched (ie same strain, sex, and age) control nontransgenic mice were pretreated ip with GSH synthetase substrate gamma-glutamylcysteinyl ethyl ester (gamma-GCE) or with saline. After a 16-h fast, mice received a single dose of 500 mg APAP/kg bw in saline ip and were sacrificed 4 h later. Other mice similarly pretreated were killed without APAP challenge. The elevated GSH concentrations in transgenic mice livers did not lessen APAP hepatotoxicity. Instead higher degrees of hepatotoxicity and nephrotoxicity were observed in transgenic mice than in controls as indicated by higher serum alanine aminotransferase activity and more severe histopathological lesions in transgenic mice livers and kidneys. Pretreatment with gamma-GCE did not affect either initial or post-APAP treatment tissue GSH concentrations or observed degrees of toxicity. Detection of a higher level of serum APAP in transgenic mice and the histopathological lesions found in transgenic mice kidneys together with no observable nephrotoxicity in control mice indicated early kidney damage in transgenic mice. Our findings suggest that high levels of GSH-APAP conjugates resulting from increased GSH concentrations in the livers of transgenic mice caused rapid kidney damage. Compromised excretory ability may have caused retention of APAP, which, in effect, elicited higher hepatotoxicity than that observed in nontransgenic mice.

Prevention of Autoimmune Diabetes and Induction of β-Cell Proliferation in NOD Mice by Hyperbaric Oxygen Therapy

PubMed Central

Faleo, Gaetano; Fotino, Carmen; Bocca, Nicola; Molano, R. Damaris; Zahr-Akrawi, Elsie; Molina, Judith; Villate, Susana; Umland, Oliver; Skyler, Jay S.; Bayer, Allison L.; Ricordi, Camillo; Pileggi, Antonello

2012-01-01

We evaluated the effects of hyperbaric oxygen therapy (HOT) on autoimmune diabetes development in nonobese diabetic (NOD) mice. Animals received no treatment or daily 60-min HOT 100% oxygen (HOT-100%) at 2.0 atmospheres absolute and were monitored for diabetes onset, insulitis, infiltrating cells, immune cell function, and β-cell apoptosis and proliferation. Cyclophosphamide-induced diabetes onset was reduced from 85.3% in controls to 48% after HOT-100% (P < 0.005) and paralleled by lower insulitis. Spontaneous diabetes incidence reduced from 85% in controls to 65% in HOT-100% (P = 0.01). Prediabetic mice receiving HOT-100% showed lower insulitis scores, reduced T-cell proliferation upon stimulation in vitro (P < 0.03), increased CD62L expression in T cells (P < 0.04), reduced costimulation markers (CD40, DC80, and CD86), and reduced major histocompatibility complex class II expression in dendritic cells (DCs) (P < 0.025), compared with controls. After autoimmunity was established, HOT was less effective. HOT-100% yielded reduced apoptosis (transferase-mediated dUTP nick-end labeling-positive insulin-positive cells; P < 0.01) and increased proliferation (bromodeoxyuridine incorporation; P < 0.001) of insulin-positive cells compared with controls. HOT reduces autoimmune diabetes incidence in NOD mice via increased resting T cells and reduced activation of DCs with preservation of β-cell mass resulting from decreased apoptosis and increased proliferation. The safety profile and noninvasiveness makes HOT an appealing adjuvant therapy for diabetes prevention and intervention trials. PMID:22566533

Subcellular plasticity of the corticotropin-releasing factor receptor in dendrites of the mouse bed nucleus of the stria terminalis following chronic opiate exposure.

PubMed

Jaferi, A; Lane, D A; Pickel, V M

2009-09-29

Chronic opiate administration alters the expression levels of the stress-responsive peptide, corticotropin-releasing factor (CRF), in the bed nucleus of the stria terminalis (BNST). This brain region contains CRF receptors that drive drug-seeking behavior exacerbated by stress. We used electron microscopy to quantitatively compare immunolabeling of the corticotropin-releasing factor receptor (CRFr) and CRF in the anterolateral bed nucleus of the stria terminalis (BSTal) of mice injected with saline or morphine in escalating doses for 14 days. We also compared the results with those in non-injected control mice. The tissue was processed for CRFr immunogold and CRF immunoperoxidase labeling. The non-injected controls had a significantly lower plasmalemmal density of CRFr immunogold particles in dendrites compared with mice receiving saline, but not those receiving morphine, injections. Compared with saline, however, mice receiving chronic morphine showed a significantly lower plasmalemmal, and greater cytoplasmic, density of CRFr immunogold in dendrites. Within the cytoplasmic compartment of somata and dendrites of the BSTal, the proportion of CRFr gold particles associated with mitochondria was three times as great in mice receiving morphine compared with saline. This subcellular distribution is consistent with morphine,- and CRFr-associated modulation of intracellular calcium release or oxidative stress. The between-group changes occurred without effect on the total number of dendritic CRFr immunogold particles, suggesting that chronic morphine enhances internalization or decreases delivery of the CRFr to the plasma membrane, a trafficking effect that is also affected by the stress of daily injections. In contrast, saline and morphine treatment groups showed no significant differences in the total number of CRF-immunoreactive axon terminals, or the frequency with which these terminals contacted CRFr-containing dendrites. This suggests that morphine does not influence axonal availability of CRF in the BSTal. The results have important implications for drug-associated adaptations in brain stress systems that may contribute to the motivation to continue drug use during dependence.

Exposure to a Mycobacterial Antigen, ESAT-6, Exacerbates Granulomatous and Fibrotic Changes in a Multiwall Carbon Nanotube Model of Chronic Pulmonary Disease.

PubMed

Malur, Anagha; Barna, Barbara P; Patel, Janki; McPeek, Matthew; Wingard, Christopher J; Dobbs, Larry; Thomassen, Mary Jane

2015-12-01

Recent studies suggest additive effects of environmental pollutants and microbial antigens on respiratory disease. We established a granuloma model in which instilled multiwall carbon nanotubes (MWCNT) elicit granulomatous pathology. We hypothesized that mycobacterial antigen ESAT-6, a T cell activator associated with tuberculosis and sarcoidosis, might alter pathology. Wild-type C57Bl/6 mice received MWCNT with or without ESAT-6 peptide. Controls received vehicle (surfactant-PBS) or ESAT-6 alone. Mice were evaluated 60 days later for granulomas, fibrosis, and bronchoalveolar lavage (BAL) cell expression of inflammatory mediators (CCL2, MMP-12, and Osteopontin). Results indicated increased granulomas, fibrosis, and inflammatory mediators in mice receiving the combination of MWCNT+ESAT-6 compared to MWCNT or vehicle alone. ESAT-6 alone showed no significant effect on these pathological endpoints. However, CD3 (+) lymphocyte infiltration of lung tissue increased with MWCNT+ESAT-6 versus MWCNT alone. Findings suggest that concurrent exposure to microbial antigen and MWCNT exacerbates chronic pulmonary disease.

Progesterone neuroprotection in the Wobbler mouse, a genetic model of spinal cord motor neuron disease.

PubMed

Gonzalez Deniselle, María Claudia; López-Costa, Juan José; Saavedra, Jorge Pecci; Pietranera, Luciana; Gonzalez, Susana L; Garay, Laura; Guennoun, Rachida; Schumacher, Michael; De Nicola, Alejandro F

2002-12-01

Motor neuron degeneration characterizes the spinal cord of patients with amyotrophic lateral sclerosis and the Wobbler mouse mutant. Considering that progesterone (PROG) provides neuroprotection in experimental ischemia and injury, its potential role in neurodegeneration was studied in the murine model. Two-month-old symptomatic Wobbler mice were left untreated or received sc a 20-mg PROG implant for 15 days. Both light and electron microscopy of Wobbler mice spinal cord showed severely affected motor neurons with profuse cytoplasmic vacuolation of the endoplasmic reticulum and/or Golgi apparatus and ruptured mitochondria with damaged cristae, a profile indicative of a type II cytoplasmic form of cell death. In contrast to untreated mice, neuropathology was less severe in Wobbler mice receiving PROG; including a reduction of vacuolation and of the number of vacuolated cells and better conservation of the mitochondrial ultrastructure. In biochemical studies, we determined the mRNA for the alpha3 subunit of Na,K-ATPase, a neuronal enzyme controlling ion fluxes, neurotransmission, membrane potential, and nutrient uptake. In untreated Wobbler mice, mRNA levels in motor neurons were reduced by half compared to controls, whereas PROG treatment of Wobbler mice restored the expression of alpha3 subunit Na,K-ATPase mRNA. Therefore, PROG was able to rescue motor neurons from degeneration, based on recovery of histopathological abnormalities and of mRNA levels of the sodium pump. However, because the gene mutation in Wobbler mice is still unknown, further studies are needed to unveil the action of PROG and the mechanism of neuronal death in this genetic model of neurodegeneration.

The protective effect of royal jelly on chronic lambda-cyhalothrin toxicity: serum biochemical parameters, lipid peroxidation, and genotoxic and histopathological alterations in swiss albino mice.

PubMed

Cavuşoğlu, Kültiğin; Yapar, Kürşad; Oruç, Ertan; Yalçın, Emine

2011-10-01

The present study was undertaken to investigate the protective effect of royal jelly (RJ) against toxicity induced by a synthetic pyrethroid insecticide, lambda-cyhalothrin (LCT), in Swiss albino mice. Animals were randomly divided into six groups of six animals each. The control group received distilled water alone, whereas mice in the treatment groups received RJ alone (100 or 250 mg/kg of body weight), LCT alone (668 ppm), or RJ+LCT for 21 days. All mice (100%) survived until the end of experiment and were sacrificed at the end of 24 hours. Blood, bone marrow, and liver and kidney tissues were analyzed for aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), creatinine, malondialdehyde (MDA), and reduced glutathione (GSH) levels and micronucleus (MN) frequency, chromosomal aberrations (CAs), and pathological damages. Serum AST, ALT, BUN, and creatinine levels were elevated in mice treated with LCT alone compared with the other tested groups (P<.05). LCT-induced oxidative damage caused a significant decrease in GSH levels and a significant rise in MDA levels of liver and kidney tissues. LCT alone-treated mice presented higher frequencies (P<.05) of MNs, CAs, and abnormal metaphases compared with the controls; moreover, the mitotic index was lower than in controls (P<.05). Oral treatment with RJ significantly ameliorated the indices of hepatotoxicity, nephrotoxicity, lipid peroxidation, and genotoxicity induced by LCT. Both doses of RJ tested provided significant protection against LCT-induced toxicity, and its strongest effect was observed at the dose level of 250 mg/kg of body weight. In vivo results suggest that RJ is a potent antioxidant against LCT-induced toxicity, and its protective effect is dose dependent.

Nitrooleic Acid Attenuates Lipid Metabolic Disorders and Liver Steatosis in DOCA-Salt Hypertensive Mice

PubMed Central

Sun, Jing; Jia, Zhanjun; Yang, Tianxin; Xu, Liang; Zhao, Bing; Yu, Kezhou; Wang, Rong

2015-01-01

Nitrooleic acid (OA-NO2) is endogenous ligands for peroxisome proliferator-activated receptors. The present study was aimed at investigating the beneficial effects of OA-NO2 on the lipid metabolism and liver steatosis in deoxycorticosterone acetate- (DOCA-) salt induced hypertensive mice model. Male C57BL/6 mice were divided to receive DOCA-salt plus OA-NO2 or DOCA-salt plus vehicle and another group received neither DOCA-salt nor OA-NO2 (control group). After 3-week treatment with DOCA-salt plus 1% sodium chloride in drinking fluid, the hypertension was noted; however, OA-NO2 had no effect on the hypertension. In DOCA-salt treated mice, the plasma triglyceride and total cholesterol levels were significantly increased compared to control mice, and pretreatment with OA-NO2 significantly reduced these parameters. Further, the histopathology of liver exhibited more lipid distribution together with more serious micro- and macrovesicular steatosis after DOCA-salt treatment and that was consistent with liver tissue triglyceride and nonesterified fatty acids (NEFA) content. The mice pretreated with OA-NO2 showed reduced liver damage accompanied with low liver lipid content. Moreover, the liver TBARS, together with the expressions of gp91phox and p47phox, were parallelly decreased. These findings indicated that OA-NO2 had the protective effect on liver injury against DOCA-salt administration and the beneficial effect could be attributed to its antihyperlipidemic activities. PMID:25861250

Nitrooleic Acid Attenuates Lipid Metabolic Disorders and Liver Steatosis in DOCA-Salt Hypertensive Mice.

PubMed

Wang, Haiping; Sun, Jing; Jia, Zhanjun; Yang, Tianxin; Xu, Liang; Zhao, Bing; Yu, Kezhou; Wang, Rong

2015-01-01

Nitrooleic acid (OA-NO2) is endogenous ligands for peroxisome proliferator-activated receptors. The present study was aimed at investigating the beneficial effects of OA-NO2 on the lipid metabolism and liver steatosis in deoxycorticosterone acetate- (DOCA-) salt induced hypertensive mice model. Male C57BL/6 mice were divided to receive DOCA-salt plus OA-NO2 or DOCA-salt plus vehicle and another group received neither DOCA-salt nor OA-NO2 (control group). After 3-week treatment with DOCA-salt plus 1% sodium chloride in drinking fluid, the hypertension was noted; however, OA-NO2 had no effect on the hypertension. In DOCA-salt treated mice, the plasma triglyceride and total cholesterol levels were significantly increased compared to control mice, and pretreatment with OA-NO2 significantly reduced these parameters. Further, the histopathology of liver exhibited more lipid distribution together with more serious micro- and macrovesicular steatosis after DOCA-salt treatment and that was consistent with liver tissue triglyceride and nonesterified fatty acids (NEFA) content. The mice pretreated with OA-NO2 showed reduced liver damage accompanied with low liver lipid content. Moreover, the liver TBARS, together with the expressions of gp91phox and p47phox, were parallelly decreased. These findings indicated that OA-NO2 had the protective effect on liver injury against DOCA-salt administration and the beneficial effect could be attributed to its antihyperlipidemic activities.

Stereological estimation of ovarian oocyte volume, surface area and number: application on mice treated with nandrolone decanoate.

PubMed

Karbalay-Doust, Saied; Noorafshan, Ali

2012-07-05

Changes in the number and size of oocytes can lead to fertilization problems. The present study aimed to evaluate the number, volume, and surface area of oocytes in healthy as well as nandrolone decanoate-treated (ND) mice using stereological methods. Five control mice received vehicle, and five ND-treated mice received ND. Using the 'isotropic Cavalieri' design', the ovary was sectioned. The volume of the ovary (cortex and medulla) was estimated. The oocytes' volume and surface area were estimated using the invariator. The number of the oocytes was estimated using an optical disector. The volumes of the ovary, cortex, and medulla decreased ~50% in the ND-treated mice. The mean number (coefficient of variation) of preantral, antral, and atretic oocytes in the control ovary were 1,690 (0.29), 2,100 (0.52), and 3,900 (0.2), respectively, which decreased ~54%, ~87%, and ~91%, respectively in the ND-treated animals. The mean volume (coefficient of variation) of the preantral, antral, and atretic oocytes were 86,000 (0.27), 110,000 (0.48), and 27,000 (0.33) μm³, respectively. The mean surface area (coefficient of variation) of the three types of oocytes were 9,000 (0.24), 9,900 (0.28), and 4,700 (0.21) μm², respectively. These parameters remained unchanged in the ND-treated mice. ND induces reduction in the number of oocytes, but not in the volume or the surface area.

Vitamin E improves the in vivo efficacy of tigecycline and daptomycin in an animal model of wounds infected with meticillin-resistant Staphylococcus aureus.

PubMed

Provinciali, Mauro; Cirioni, Oscar; Orlando, Fiorenza; Pierpaoli, Elisa; Barucca, Alessandra; Silvestri, Carmela; Ghiselli, Roberto; Scalise, Alessandro; Brescini, Lucia; Guerrieri, Mario; Giacometti, Andrea

2011-12-01

A relevant bacterial load in cutaneous wounds significantly interferes with the normal process of healing. Vitamin E (VE) is a known immunomodulator and immune enhancer. Here, it was shown that administration of VE before infection was effective at increasing the antimicrobial activity of daptomycin (DAP) or tigecycline (TIG) in a mouse model of wound infection caused by meticillin-resistant Staphylococcus aureus (MRSA). A wound was established through the panniculus carnosus of mice and inoculated with MRSA. Mice were assigned to six groups: a VE pre-treated group with no antibiotics given after MRSA challenge; two VE pre-treated groups with DAP or TIG given after MRSA challenge; two groups treated with DAP or TIG only after MRSA challenge; and a control group that did not receive any treatment. Mice receiving each antibiotic alone showed a 3 log decrease in the number of c.f.u. recovered compared with the control group, mice treated with VE plus TIG had a 4 log decrease, whilst mice treated with VE plus DAP had the largest decrease in c.f.u. recovered (5 logs). The increased antimicrobial effect seen from treatment with VE plus antibiotics was associated with increased levels of natural killer cell cytotoxicity, with a more pronounced increase in leukocyte populations in mice treated with VE plus DAP. These data suggest that treatment with VE prior to infection and subsequent antibiotic treatment act in synergy. © 2011 SGM

Chronic escalating cocaine exposure, abstinence/withdrawal, and chronic re-exposure: Effects on striatal dopamine and opioid systems in C57BL/6J mice

PubMed Central

Zhang, Yong; Schlussman, Stefan D.; Rabkin, Jacqui; Butelman, Eduardo R.; Ho, Ann; Kreek, Mary Jeanne

2013-01-01

Cocaine addiction is a chronic relapsing disease with periods of chronic escalating self-exposure, separated by periods of abstinence/withdrawal of varying duration. Few studies compare such cycles in preclinical models. This study models an “addiction-like cycle” in mice to determine neurochemical/molecular alterations that underlie the chronic, relapsing nature of this disease. Groups of male C57BL/6J mice received acute cocaine exposure (14-day saline/14-day withdrawal /13-day saline + 1-day cocaine), chronic cocaine exposure (14 day cocaine) or chronic re-exposure (14-day cocaine/14-day withdrawal /14-day cocaine). Escalating-dose binge cocaine (15-30 mg/kg/injection x 3/day, i.p. at hourly intervals) or saline (14-day saline) was administered, modeling initial exposure. In “re-exposure” groups, after a 14-day injection-free period (modeling abstinence/withdrawal), mice that had received cocaine were re-injected with 14-day escalating-dose binge cocaine, whereas controls received saline. Microdialysis was conducted on the 14th day of exposure or re-exposure to determine striatal dopamine content. Messenger RNA levels of preprodynorphin (Pdyn), dopamine D1 (Drd1) and D2 (Drd2) in the caudate putamen were determined by real-time PCR. Basal striatal dopamine levels were lower in mice after 14-day escalating exposure or re-exposure than in those in the acute cocaine group and controls. Pdyn mRNA levels were higher in the cocaine groups than in controls. Long-term adaptation was observed across the stages of this addiction-like cycle, in that the effects of cocaine on dopamine levels were increased after re-exposure compared to exposure. Changes in striatal dopaminergic responses across chronic escalating cocaine exposure and re-exposure are a central feature of the neurobiology of relapsing addictive states. PMID:23164614

Preventive role of aluminosilicate clay against induction of micronuclei and chromosome aberrations in bone-marrow cells of Balb/c mice treated with Zearalenone.

PubMed

Abbès, Samir; Ouanes, Zouhour; Salah-Abbès, Jalila Ben; Abdel-Wahhab, Mosaad A; Oueslati, Ridha; Bacha, Hassen

2007-07-28

Zearalenone (ZEN) is a potent estrogenic metabolite produced by some Fusarium species. No treatment has been successfully employed to remove ZEN contamination in foods. This study was conducted to evaluate the ability of hydrated sodium calcium aluminosilicate (HSCAS) to protect Balb/c mice against cytotoxicity and genotoxicity induced by ZEN. HSCAS was given via the oral route, either alone or simultaneously with a toxic intra-gastric dose of ZEN. The experimental approach comprised treatments of seven groups of mice. The first three groups received 400, 600 or 800 mg/kg bw of HSCAS. Two experimental groups received, respectively, ZEN alone (40 mg/kg bw, representing 8% of the LD(50)) and ZEN in combination with HSCAS at 400 mg/kg bw. The two control groups received distilled water and olive oil, respectively. The positive control groups received colchicine (4 mg/kg bw) for the micronucleus assay and mitomycin C (1mg/kg bw) for the chromosome aberration test. Forty-eight hours after treatment, the femur and tibia were dissected out and analyzed. The results show that ZEN was cytotoxic and genotoxic to Balb/c mice, as indicated by the increase in the frequencies of micronucleated polychromatic erythrocytes (PCEMN) and of chromosomal aberrations in bone-marrow cells. The simultaneous intra-gastric administration of HSCAS with ZEN resulted in a reduction in the number of PCEMN and a decrease of the chromosomal aberration frequency, and an increase in the number of polychromatic erythrocytes (PCE) in bone-marrow cells, compared with those in the group treated with ZEN alone. It could be concluded that HSCAS itself was safe and efficient in the prevention of the toxic effects of ZEN in the gastrointestinal tract.

Human Parvovirus B19 NS1 Protein Aggravates Liver Injury in NZB/W F1 Mice

PubMed Central

Tsai, Chun-Chou; Chiu, Chun-Ching; Hsu, Jeng-Dong; Hsu, Huai-Sheng; Tzang, Bor-Show; Hsu, Tsai-Ching

2013-01-01

Human parvovirus B19 (B19) has been associated with a variety of diseases. However, the influence of B19 viral proteins on hepatic injury in SLE is still obscure. To elucidate the effects of B19 viral proteins on livers in SLE, recombinant B19 NS1, VP1u or VP2 proteins were injected subcutaneously into NZB/W F1 mice, respectively. Significant expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were detected in NZB/W F1 mice receiving B19 NS1 as compared to those mice receiving PBS. Markedly hepatocyte disarray and lymphocyte infiltration were observed in livers from NZB/WF 1 mice receiving B19 NS1 as compared to those mice receiving PBS. Additionally, significant increases of Tumor Necrosis Factor –α (TNF-α), TNF-α receptor, IκB kinase –α (IKK-α), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (IκB) and nuclear factor-kappa B (NF-κB) were detected in livers from NZB/W F1 mice receiving B19 NS1 as compared to those mice receiving PBS. Accordingly, significant increases of matrix metalloproteinase-9 (MMP9) and U-plasminogen activator (uPA) were also detected in livers from NZB/W F1 mice receiving B19 NS1 as compared to those mice receiving PBS. Contrarily, no significant variation on livers from NZB/W F1 mice receiving B19 VP1u or VP2 was observed as compared to those mice receiving PBS. These findings firstly demonstrated the aggravated effects of B19 NS1 but not VP1u or VP2 protein on hepatic injury and provide a clue in understanding the role of B19 NS1 on hepatic injury in SLE. PMID:23555760

Immunomodulatory effect of a formula developed from American ginseng and Chinese jujube extracts in mice.

PubMed

Yu, Zhuo-ping; Xu, Dong-dong; Lu, Lai-feng; Zheng, Xiao-dong; Chen, Wei

2016-02-01

American ginseng (Panax quinquefolius L.) and Chinese jujube (Zizyphus jujuba Mill.) are commonly used in traditional Chinese medicine to enhance immune function. The present study aimed to develop one Chinese prescription, Shenzao Cha (SZC), consisting of American ginseng and Chinese jujube, and systematically investigate its immunomodulation in healthy ICR mice. Normal ICR mice received intragastric administration of SZC (1.3, 2.6, and 5.2 g raw material/kg body weight) once daily for four weeks, while a control group received the same amount of sterile water. SZC significantly increased the spleen and thymus indices and T-lymphocyte proliferation, while the T-lymphocyte proliferation in the 5.2 g/kg group was 1.4-fold higher than that in the control. Further, 1.3 g/kg SZC could markedly improve hemolytic activity by 25.2%, and 2.6 g/kg SZC increased the NK cell activity by 78.6% relative to the control. In addition, the activities of antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase), that participated in modulating oxidative stress, were significantly increased in the liver, spleen, thymus, and serum, while the contents of malondialdehyde were dramatically decreased. SZC exhibited potent immunomodulatory effects on innate and adaptive immunity in healthy ICR mice, as well as potential antioxidant activity for prevention of oxidative stress, which was suggested to partly contribute to the immune enhancement.

The Role of Curcumin in Modulating Colonic Microbiota During Colitis and Colon Cancer Prevention.

PubMed

McFadden, Rita-Marie T; Larmonier, Claire B; Shehab, Kareem W; Midura-Kiela, Monica; Ramalingam, Rajalakshmy; Harrison, Christy A; Besselsen, David G; Chase, John H; Caporaso, J Gregory; Jobin, Christian; Ghishan, Fayez K; Kiela, Pawel R

2015-11-01

Intestinal microbiota influences the progression of colitis-associated colorectal cancer. With diet being a key determinant of the gut microbial ecology, dietary interventions are an attractive avenue for the prevention of colitis-associated colorectal cancer. Curcumin is the most active constituent of the ground rhizome of the Curcuma longa plant, which has been demonstrated to have anti-inflammatory, antioxidative, and antiproliferative properties. Il10 mice on 129/SvEv background were used as a model of colitis-associated colorectal cancer. Starting at 10 weeks of age, wild-type or Il10 mice received 6 weekly intraperitoneal injections of azoxymethane (AOM) or phosphate-buffered saline (PBS) and were started on either a control or a curcumin-supplemented diet. Stools were collected every 4 weeks for microbial community analysis. Mice were killed at 30 weeks of age. Curcumin-supplemented diet increased survival, decreased colon weight/length ratio, and, at 0.5%, entirely eliminated tumor burden. Although colonic histology indicated improvement with curcumin, no effects of mucosal immune responses have been observed in PBS/Il10 mice and limited effects were seen in AOM/Il10 mice. In wild-type and in Il10 mice, curcumin increased bacterial richness, prevented age-related decrease in alpha diversity, increased the relative abundance of Lactobacillales, and decreased Coriobacterales order. Taxonomic profile of AOM/Il10 mice receiving curcumin was more similar to those of wild-type mice than those fed control diet. In AOM/Il10 model, curcumin reduced or eliminated colonic tumor burden with limited effects on mucosal immune responses. The beneficial effect of curcumin on tumorigenesis was associated with the maintenance of a more diverse colonic microbial ecology.

The Role of Curcumin in Modulating Colonic Microbiota During Colitis and Colon Cancer Prevention

PubMed Central

McFadden, Rita-Marie T.; Larmonier, Claire B.; Shehab, Kareem W.; Midura-Kiela, Monica; Ramalingam, Rajalakshmy; Harrison, Christy A.; Besselsen, David G.; Chase, John H.; Caporaso, J. Gregory; Jobin, Christian; Ghishan, Fayez K.; Kiela, Pawel R.

2015-01-01

Background Intestinal microbiota influences the progression of colitis-associated colorectal cancer (CAC). With diet being a key determinant of the gut microbial ecology, dietary interventions are an attractive avenue for the prevention of CAC. Curcumin is the most active constituent of the ground rhizome of the Curcuma Longa plant, which has been demonstrated to have anti-inflammatory, anti-oxidative and anti-proliferative properties. Methods Il10−/− mice on 129/SvEv background were used as a model of CAC. Starting at 10 weeks of age, WT or Il10−/− mice received six weekly i.p. injections of azoxymethane (AOM) or saline, and were started on either a control or curcumin-supplemented diet. Stools were collected every 4 weeks for microbial community analysis. Mice were sacrificed at 30 weeks of age. Results Curcumin-supplemented diet increased survival, decreased colon weight/length ratio, and at 0.5%, entirely eliminated tumor burden. Although colonic histology indicated improvement with curcumin, no effects of mucosal immune responses have been observed in PBS/Il10−/− mice, and limited effects were seen in AOM/Il10−/− mice. In WT and in Il10−/− mice, curcumin increased bacterial richness, prevented age-related decrease in alpha diversity, increased the relative abundance of Lactobacillales, and decreased Coriobacterales order. Taxonomic profile of AOM/Il10−/− mice receiving curcumin was more similar to those of wild-type mice than those fed control diet. Conclusions In AOM/Il10−/− model, curcumin reduced or eliminated colonic tumor burden with limited effects on mucosal immune responses. The beneficial effect of curcumin on tumorigenesis was associated with the maintenance of a more diverse colonic microbial ecology. PMID:26218141

Tissue Fatty Acid Profile is Differently Modulated from Olive Oil and Omega-3 Polyunsaturated Fatty Acids in ApcMin/+ Mice.

PubMed

Tutino, Valeria; Caruso, Maria G; De Leonardis, Giampiero; De Nunzio, Valentina; Notarnicola, Maria

2017-11-16

Fatty acid profile can be considered an appropriate biomarker for investigating the relations between the patterns of fatty acid metabolism and specific diseases, as cancer, cardiovascular and degenerative diseases. Aim of this study was to test the effects of diets enriched with olive oil and omega-3 Polyunsaturated Fatty Acids (PUFAs) on fatty acid profile in intestinal tissue of ApcMin/+ mice. Three groups of animals were considered: control group, receiving a standard diet; olive oilgroup, receiving a standard diet enriched with olive oil; omega-3 group, receiving a standard diet enriched with salmon fish. Tissue fatty acid profile was evaluated by gas chromatography method. Olive oil and omega-3 PUFAs in the diet differently affect the tissue fatty acid profile. Compared to control group, the levels of Saturated Fatty Acids (SFAs) were lower in olive oil group, while an increase of SFAs was found in omega-3 group. Monounsaturated Fatty Acids (MUFAs) levels were enhanced after olive oil treatment, and in particular, a significant increase of oleic acid levels was detected; MUFAs levels were instead reduced in omega-3 group in line with the decrease of oleic acid levels. The total PUFAs levels were lower in olive oil respect to control group. Moreover, a significant induction of Saturation Index (SI) levels was observed after omega-3 PUFAs treatment, while its levels were reduced in mice fed with olive oil. Our data demonstrated a different effect of olive oil and omega-3 PUFAs on tissue lipid profile in APCMin/+ mice. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Prophylaxis of murine candidiasis via application of liposome-encapsulated amphotericin B and a muramyl dipeptide analog, alone and in combination.

PubMed Central

Mehta, R T; Lopez-Berestein, G; Hopfer, R L; Mehta, K; White, R A; Juliano, R L

1985-01-01

The present study was conducted to examine the effect of a lipophilic analog of muramyl dipeptide, 6-O-stearoyl-N-acetylmuramyl-L-alpha-aminobutyryl-D-isoglutamine (6-O-S-Abu-MDP), a macrophage activator, on the prophylactic activity of liposomal amphotericin B (L-AmpB) against disseminated candidiasis in mice. Multilamellar vesicles containing AmpB and (6-O-S-Abu)-MDP were prepared by using dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol (7:3 molar ratio). Hale-Stoner mice (6 to 8 weeks old) were injected with 7 X 10(5) CFU of Candida albicans 336 isolated from a patient. Groups of mice were injected intravenously with different doses of L-AmpB and L-(6-O-S-Abu)-MDP, individually or in combination, 2 days before challenge with C. albicans. The mice were injected with a fixed dose of L-AmpB (1.2 mg/kg in 400 mg of lipid per kg) and various doses of L-(6-O-S-Abu)-MDP (0.6, 1.2, 2, and 4 mg/kg in 400 mg of lipid per kg) or vice versa. Other control groups included untreated mice and those receiving empty liposomes (400 mg of lipid per kg), free AmpB (0.6 mg/kg), or free (6-O-S-Abu)-MDP (4 mg/kg). The mice receiving L-AmpB (1.2 mg/kg) plus L-(6-O-S-Abu)-MDP (0.6 to 4.0 mg/kg) survived up to 25 to 30 days as compared with those injected with L-AmpB alone (15 days) or with L-(6-O-S-Abu)-MDP alone (10 to 15 days). All the mice in other control groups died within 7 to 11 days. The kidney cultures of the mice that received L-AmpB (4 mg/kg) plus L-(6-O-S-Abu)-MDP (1.2 mg/kg) were free of C. albicans infection, unlike those injected with L-AmpB. Variance analysis of these findings indicates a synergistic activity between L-AmpB and L-(6-O-S-Abu)-MDP in the prophylaxis of candidiasis. PMID:4073873

Conditional genetic deletion of PTEN after a spinal cord injury enhances regenerative growth of CST axons and motor function recovery in mice.

PubMed

Danilov, Camelia A; Steward, Oswald

2015-04-01

Previous studies indicate that conditional genetic deletion of phosphatase and tensin homolog (PTEN) in neonatal mice enhances the ability of axons to regenerate following spinal cord injury (SCI) in adults. Here, we assessed whether deleting PTEN in adult neurons post-SCI is also effective, and whether enhanced regenerative growth is accompanied by enhanced recovery of voluntary motor function. PTEN(loxP/loxP) mice received moderate contusion injuries at cervical level 5 (C5). One group received unilateral injections of adeno-associated virus expressing CRE (AAV-CRE) into the sensorimotor cortex; controls received a vector expressing green fluorescent protein (AAV-GFP) or injuries only (no vector injections). Forelimb function was tested for 14weeks post-SCI using a grip strength meter (GSM) and a hanging task. The corticospinal tract (CST) was traced by injecting mini-ruby BDA into the sensorimotor cortex. Forelimb gripping ability was severely impaired immediately post-SCI but recovered slowly over time. The extent of recovery was significantly greater in PTEN-deleted mice in comparison to either the AAV-GFP group or the injury only group. BDA tract tracing revealed significantly higher numbers of BDA-labeled axons in caudal segments in the PTEN-deleted group compared to control groups. In addition, in the PTEN-deleted group, there were exuberant collaterals extending from the main tract rostral to the lesion and into and around the scar tissue at the injury site. These results indicate that PTEN deletion in adult mice shortly post-SCI can enhance regenerative growth of CST axons and forelimb motor function recovery. Copyright © 2015 Elsevier Inc. All rights reserved.

Sterculic Oil, a Natural SCD1 Inhibitor, Improves Glucose Tolerance in Obese ob/ob Mice

PubMed Central

Ortinau, Laura C.; Pickering, R. Taylor; Nickelson, Karen J.; Stromsdorfer, Kelly L.; Naik, Chaitasi Y.; Haynes, Rebecca A.; Bauman, Dale E.; Rector, R. Scott; Fritsche, Kevin L.; Perfield, James W.

2012-01-01

Obesity and its metabolic complications are associated with increased expression/activity of stearoyl-CoA desaturase-1 (SCD1), a major regulator of lipid metabolism. Reduction or ablation of this enzyme is associated with an improved metabolic profile and has gained attention as a target for pharmaceutical development. Sterculic oil (SO) is a known inhibitor of SCD1 and may provide a natural approach for treating obesity and/or insulin resistance. The purpose of this study was to evaluate the effects of SO consumption in leptin-deficient ob/ob mice, a model of obesity and insulin resistance. Five-week-old male mice received either an AIN-93G (control) or an AIN-93G diet containing 0.5% SO. After 9 weeks, SO supplementation did not alter food intake or body weight; however, the desaturase indices, a proxy of SCD1 activity, were reduced in liver and adipose tissue of SO-supplemented animals. This reduction was associated with improved glucose and insulin tolerance and attenuated hepatic inflammation in obese ob/ob mice, while no appreciable changes were observed in lean control mice receiving SO. Future studies are needed to better understand the mechanism(s) by which SO is functioning to improve glucose metabolism and to further explore the nutraceutical potential and health implications of SO supplementation. PMID:23209931

Spaceflight impairs antigen-specific tolerance induction in vivo and increases inflammatory cytokines.

PubMed

Chang, Tammy T; Spurlock, Sandra M; Candelario, Tara Lynne T; Grenon, S Marlene; Hughes-Fulford, Millie

2015-10-01

The health risks of a dysregulated immune response during spaceflight are important to understand as plans emerge for humans to embark on long-term space travel to Mars. In this first-of-its-kind study, we used adoptive transfer of T-cell receptor transgenic OT-II CD4 T cells to track an in vivo antigen-specific immune response that was induced during the course of spaceflight. Experimental mice destined for spaceflight and mice that remained on the ground received transferred OT-II cells and cognate peptide stimulation with ovalbumin (OVA) 323-339 plus the inflammatory adjuvant, monophosphoryl lipid A. Control mice in both flight and ground cohorts received monophosphoryl lipid A alone without additional OVA stimulation. Numbers of OT-II cells in flight mice treated with OVA were significantly increased by 2-fold compared with ground mice treated with OVA, suggesting that tolerance induction was impaired by spaceflight. Production of proinflammatory cytokines were significantly increased in flight compared with ground mice, including a 5-fold increase in IFN-γ and a 10-fold increase in IL-17. This study is the first to show that immune tolerance may be impaired in spaceflight, leading to excessive inflammatory responses. © FASEB.

Mode-of-action, efficacy, and safety of a homologous multi-epitope vaccine in a murine model for adjuvant treatment of renal cell carcinoma.

PubMed

Doehn, Christian; Esser, Norbert; Pauels, Hans-Gerd; Kiessig, Stephan T; Stelljes, Matthias; Grossmann, Armin; Jocham, Dieter; Drevs, Joachim

2009-07-01

In a phase-III trial it was recently shown that an adjuvant renal cell carcinoma (RCC) vaccine (Reniale) reduces the risk of tumour progression following nephrectomy. This clinical trial focused on efficacy and did not investigate end-points relating to mode-of-action of the vaccine. In a murine model we investigated mode-of-action, efficacy, and safety of a homologous RENCA cell-based vaccine. Six groups with 12 BALB/c mice per group received five vaccinations (lysate of 1x10(6)-1x10(7) RENCA cells, manufactured with or without prior IFN-gamma incubation) at 3-wk intervals before tumour transplantation and one vaccination 14 d afterwards. Controls (12 mice) received only solvent. All mice were sacrificed 21 d after tumour transplantation. Animal welfare, tumour growth, number of metastases, and the presence of cytotoxic T-lymphocytes as determined by a (51)chromium-release assay. Adoptive immune transfer experiments (vaccination of nine mice with the RENCA vaccine or saline and transfer of serum, spleen cells, and CD4 and/or CD8 depleted spleen cells into five recipient mice each) were carried out to demonstrate involvement of different immune mechanisms. All controls developed a renal tumour, compared to 7/72 animals (9.7%) in the vaccine groups. The mean number of lung metastases was 100 (range 3-750) in controls and 4 (range 0-196) in the vaccine groups, respectively. Tumour uptake and number of metastases were not related to the vaccine dose. The (51)chromium-release assay confirmed a significant tumour-specific cytolytic activity and marginally increased NK activity of splenocytes from vaccinated mice against RENCA cells compared to controls. Adoptive immune transfer experiments showed that the antitumoural effective immune mechanisms are cell-based. We could demonstrate the mode-of-action, efficacy, and safety of a homologous tumour vaccine in a RENCA model. These findings support the positive results from a phase-III trial with Reniale.

Effect of dietary estrogens from bovine milk on blood hormone levels and reproductive organs in mice.

PubMed

Grgurevic, N; Koracin, J; Majdic, G; Snoj, T

2016-08-01

Cows are often milked until 60 d before their next expected calving. Milk from cows in the third trimester of pregnancy contains up to 20 times more estrogens than milk from nonpregnant cows. The aim of this study was to evaluate whether exposure to known doses of estrogens from bovine milk could affect blood hormone levels in mice and influence their reproductive organs. This study was performed with 30 intact male and 30 ovariectomized female mice. Mice of each sex were randomly divided into 3 experimental groups, each with 6 animals of each sex, and a control group with 12 animals of each sex. The first experimental group received 4mL of milk each day from a pregnant cow with natural estrone (E1) and 17β-estradiol (E2) in concentrations 0.093 and 0.065ng/mL, respectively. The second experimental group received 4mL of the same milk each day, with an added 10ng/mL of both E1 and E2. The third experimental group received 4mL of the same milk each day, with an added 100ng/mL of both E1 and E2. The control group received no milk. After 8 d of treatment, mice were euthanized, blood was collected, and the uteruses, testes, and seminal vesicles were weighed. The results of our study demonstrated that consumption of native milk from a pregnant cow did not affect plasma E1 and E2 levels in either sex; uterine weight in females; or testosterone levels and testes and seminal vesicle weights in males. Similarly, we found no changes in the group that received the milk with an added 10ng/mL of E1 and E2. We did observe elevated plasma estrogens in both sexes, increased uterus weight in females, and decreased plasma testosterone levels in males from the group that received milk with an added 100ng/mL of E1 and E2. However, concentrations in the third group exceeded the physiological concentration of milk estrogens by 1,000 times, so it would be extremely unlikely to find such concentrations in native cow milk. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Allium sativum (garlic) treatment for murine transitional cell carcinoma.

PubMed

Riggs, D R; DeHaven, J I; Lamm, D L

1997-05-15

Currently, immunotherapy with Bacillus Calmette-Guerin (BCG) is the most effective treatment for superficial bladder carcinoma, but treatment-related toxicity may limit its use in some patients. Alternative treatments are needed for patients who fail to respond to BCG immunotherapy. Allium sativum (AS), or garlic, is known to have a broad range of biologic activities, including immune stimulation and reported antitumor activity. For these reasons, the authors conducted a series of experiments designed to explore the possible therapeutic effects of AS in the MBT2 murine bladder carcinoma model. C3H/HeN mice were randomized prior to initiation of each experimental protocol. Mice received 1 x 10(3) MBT2 cells in 0.1 mL RPMI-1640, administered subcutaneously into the right thigh, on Day 0 of the experiment. AS was injected at the site of tumor transplantation on Day 1 and at 2- to 7-day intervals up to Day 28. To evaluate the effects of oral AS in this model, treatment was initiated 30 days prior to tumor inoculation and continued for 30 days after tumor inoculation. Animals in all experiments were followed for tumor incidence, tumor growth, and survival. In the initial experiments, subcutaneous AS significantly reduced tumor volume compared with the saline control (P < 0.05). Unfortunately, treatment-related death was also observed, requiring reduction in the total dose of AS. Animals that received 5 weekly immunizations of AS (5 mg, 5 mg, 1 mg, 1 mg, and 1 mg; cumulative dose = 13 mg) had significantly reduced tumor incidence, tumor growth, and increased survival when compared with animals that received the saline control. No treatment-related deaths were observed with this treatment schedule. To determine whether systemic AS administration might be effective, orally administered AS was tested at doses of 5 mg, 50 mg, and 500 mg per 100 mL of drinking water. Mice that received 50 mg oral AS had significant reductions in tumor volume (P < 0.05) when compared with animals that received the saline control, and mice that received 500 mg oral AS had significant reductions in both tumor volume and mortality (P < 0.05). The significant antitumor efficacy of subcutaneous and oral AS warrants further investigation and suggests that AS may provide a new and effective form of therapy for transitional cell carcinoma of the bladder.

Reduced spatial learning in mice infected with the nematode, Heligmosomoides polygyrus.

PubMed

Kavaliers, M; Colwell, D D

1995-06-01

Parasite modification of host behaviour influences a number of critical responses, but little is known about the effects on host spatial abilities. This study examined the effects of infection with the intestinal trichostrongylid nematode, Heligmosomoides polygyrus, on spatial water maze learning by male laboratory mice, Mus musculus. In this task individual mice had to learn the spatial location of a submerged hidden platform using extramaze visual cues. Determinations of spatial performance were made on day 19 post-infection with mice that had been administered either 50 or 200 infective larvae of H. polygyrus. The infected mice displayed over 1 day of testing (6 blocks of 4 trials) significantly poorer acquisition and retention of the water maze task than either sham-infected or control mice, with mice that had received 200 infective larvae displaying significantly poorer spatial performance than individuals receiving 50 larvae. The decrease in spatial learning occurred in the absence of either any symptoms of illness and malaise, or any evident motor, visual and motivational impairments. It is suggested that in this single host system the parasitic infection-induced decrease in spatial learning arises as a side-effect of the host's immunological and neuromodulatory responses and represents a fitness cost of response to infection.

NTP Toxicology and Carcinogenesis Studies of 2,2-Bis(Bromomethyl)-1,3-Propanediol (FR-1138(R)) (CAS No. 3296-90-0) in F344 Rats and B6C3F1 Mice (Feed Studies).

PubMed

1996-05-01

2,2-Bis(bromomethyl)-1,3-propanediol is used as a fire retardant in unsaturated polyester resins, in molded products, and in rigid polyurethane foam. 2,2-Bis(bromomethyl)-1,3-propanediol was chosen for study because it is a widely used flame retardant and little toxicity and carcinogenicity data were available. Groups of male and female F344/N rats and B6C3F1 mice were exposed to technical grade 2,2-bis(bromomethyl)-1,3-propanediol (78.6% pure) in feed for 13 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, mouse bone marrow, and mouse peripheral blood. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets containing 0, 1,250, 2,500, 5,000, 10,000, or 20,000 ppm 2,2-bis(bromomethyl)- 1,3-propanediol for 13 weeks. These levels corresponded to approximately 100, 200, 400, 800, or 1,700 mg 2,2-bis(bromomethyl)-1,3-propanediol/kg body weight (males) and 100, 200, 400, 800, or 1,600 mg/kg (females). No rats died during the studies. The final mean body weights and weight gains of 5,000, 10,000, and 20,000 ppm males and females were significantly lower than those of the controls. Feed consumption by exposed animals was lower than that by controls at week 1, but was generally similar to or slightly higher than that by controls at week 13. No chemical-related clinical findings were observed. Chemical-related differences in clinical pathology parameters included increased urine volumes accompanied by decreased urine specific gravity and minimally increased protein excretion in 10,000 and 20,000 ppm males. In females, urine parameters were less affected than males. Water deprivation tests demonstrated that male and female rats were able to adequately concentrate their urine in response to decreased water intake. Serum protein and albumin concentrations in female rats exposed to 2,500 ppm and higher were slightly lower than those of the controls. Renal papillary degeneration was present in 5,000 and 10,000 ppm males, and in 20,000 ppm males and females. Hyperplasia of the urinary bladder was present in 20,000 ppm males. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were fed diets containing 0, 625, 1,250, 2,500, 5,000, or 10,000 ppm 2,2-bis(bromomethyl)-1,3-propanediol for 13 weeks. These levels corresponded to approximately 100, 200, 500, 1,300, or 3,000 mg 2,2-bis(bromomethyl)-1,3-propanediol/kg body weight (males) and 140, 300, 600, 1,200, or 2,900 mg/kg (females). One control female, two males and one female receiving 625 ppm, one female receiving 1,250 ppm, one female receiving 2,500 ppm, one female receiving 5,000 ppm, and three males receiving 10,000 ppm died during the study. The final mean body weights and body weight gains of males and females receiving 1,250, 2,500, 5,000, or 10,000 ppm and of females receiving 625 ppm were significantly lower than those of the controls. Feed consumption by exposed mice was generally higher than that by controls throughout the study. Clinical findings included abnormal posture and hypoactivity in 10,000 ppm male and female mice. Blood urea nitrogen concentrations of 5,000 ppm females and 10,000 ppm males and females were greater than those of controls. Also, urine specific gravity was lower in 10,000 ppm females. Differences in organ weights generally followed those in body weights. Papillary necrosis, renal tubule regeneration, and fibrosis were observed in the kidneys of 2,500 and 5,000 ppm males and 10,000 ppm males and females. Urinary bladder hyperplasia was observed in 5,000 and 10,000 ppm males and females. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats received 2,500, 5,000, or 10,000 ppm 2,2-bis(bromomethyl)- 1,3-propanediol in feed for 104 to 105 weeks. Groups of 70 males and 60 females received 0 ppm 2,2-bis(bromomethyl)-1,3-propanediol in feed for 104 to 105 weeks. A stop-exposure group of 70 male rats received 20,000 ppm 2,2-bis(bromomethyl)-1,3-propanediol in feed for 3 months, after which animals received undosed feed for the remainder of the 2-year styear study. Average daily doses of 2,2-bis(bromomethyl)-1,3-propanediol were 100, 200, or 430 mg/kg body weight for males and 115, 230, or 460 mg/kg for females. Stop-exposure males received an average daily dose of 800 mg/kg. Ten animals from the 0 ppm male group and the 20,000 ppm stop-exposure group were evaluated at 3 months; nine or 10 control animals and five to nine animals from each of the continuous-exposure groups were evaluated at 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Survival of 5,000 and 10,000 ppm continuous-exposure study males and females and 20,000 ppm stop-exposure males was significantly lower than that of the controls. Mean body weights of exposed male and female rats receiving 10,000 ppm and stop-exposure males receiving 20,000 ppm were lower than those of the controls throughout most of the study. In the continuous-exposure study, feed consumption by exposed rats was generally similar to that by controls throughout the study. In 20,000 ppm stop-exposure males, the feed consumption was lower than that by controls. Clinical findings included skin and/or subcutaneous masses on the face, tail, and the ventral and dorsal surfaces of exposed rats. Pathology Findings: In the 2-year continuous and stop-exposure studies in male rats, exposure to 2,2-bis(bromomethyl)-1,3-propanediol was associated with neoplastic effects in the skin, mammary gland, Zymbal's gland, oral cavity, esophagus, forestomach, small and large intestines, mesothelium, urinary bladder, lung, thyroid gland, hematopoietic system, and seminal vesicle. Nonneoplastic effects in the kidney, lung, thyroid gland, seminal vesicle, pancreas, urinary bladder, and forestomach were also observed. In females, 2-year exposure to 2,2-bis(bromomethyl)-1,3-propanediol was associated with neoplastic effects in the oral cavity, esophagus, mammary gland, and thyroid gland. Nonneoplastic effects in the kidney were also observed. These findings are outlined in the two summary tables. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female mice received 0, 312, 625, or 1,250 ppm 2,2-bis(bromomethyl)-1,3-propanediol in feed for 104 to 105 weeks. Average daily doses of 2,2-bis(bromomethyl)-1,3-propanediol were 35, 70, or 140 mg/kg (males) and 40, 80, or 170 mg/kg (females). Eight to 10 animals from each group were evaluated at 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Survival of 1,250 ppm males and females was significantly lower than that of the controls. Mean body weights of exposed male and female mice were similar to controls throughout the study. Final mean body weights were also generally similar to those of controls. Feed consumption by exposed male and female mice was similar to that by controls. Clinical findings included tissue masses involving the eye in exposed mice. Pathology Findings: Exposure of male mice to 2,2-bis(bromomethyl)-1,3-propanediol for 2 years was associated with neoplastic effects in the harderian gland, lung, and kidney. Exposure of female mice to 2,2-bis(bromomethyl)-1,3-propanediol was associated with increased incidences of neoplasms of the harderian gland, lung, and skin. Nonneoplastic effects in the lung were also observed in exposed females. These findings are outlined in the two summary tables. GENETIC TOXICOLOGY: 2,2-Bis(bromomethyl)-1,3-propanediol was mutagenic in Salmonella typhimurium strain TA100 when tested in the presence of induced 30% hamster liver S9; all other strain/activation combinations gave negative results. In cultured Chinese hamster ovary cells, 2,2-bis(bromomethyl)-1,3-propanediol induced chromosomal aberrations only in the presence of S9; no induction of sister chromatid exchanges was observed in cultured Chinese hamster ovary cells after treatment with 2,2-bis(bromomethyl)-1,3-propanediol, with or without S9. In vivo, 2,2-bis(bromomethyl)-1,3-propanediol induced significant increases in the frequencies of micronucleated erythrocytes in male and female mice. Significant increases in micronuclei were observed in peripheral blood samples from male and female mice exposed to 2,2-bis(bromomethyl)-1,3-propanediol for 13 weeks via dosed feed. Results of a bone marrow micronucleus test in male mice, where 2,2-bis(bromomethyl)-1,3-propanediol was administered by gavage, were considered to be equivocal due to inconsistent results obtained in two trials. An additional bone marrow micronucleus test was performed with male and female mice and 2,2-bis(bromomethyl)-1,3-propanediol was administered as a single intraperitoneal injection; results of this test were positive in females and negative in males. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was clear evidence of carcinogenic activity of 2,2-bis-(bromomethyl)-1,3-propanediol (FR-1138) in male F344/N rats based on increased incidences of neoplasms of the skin, subcutaneous tissue, mammary gland, Zymbal's gland, oral cavity, esophagus, forestomach, small and large intestines, mesothelium, urinary bladder, lung, thyroid gland, and seminal vesicle, and the increased incidence of mononuclear cell leukemia. There was clear evidence of carcinogenic activity of 2,2-bis(bromomethyl)-1,3-propanediol in female F344/N rats based on increased incidences of neoplasms of the oral cavity, esophagus, mammary gland, and thyroid gland. There was clear evidence of carcinogenic activity of 2,2-bis(bromomethyl)-1,3-propanediol in male B6C3F1 mice based on increased incidences of neoplasms of the harderian gland, lung, and kidney. There was clear evidence of carcinogenic activity of 2,2-bis(bromomethyl)-1,3-propanediol in female B6C3F1 mice based on increased incidences of neoplasms of the harderian gland, lung, and subcutaneous tissue. Slight increases in the incidences of neoplasms of the pancreas and kidney in male rats; forestomach in male mice; and forestomach, mammary gland, and circulatory system in female mice may have also been related to treatment. Exposure of male and female rats to 2,2-bis(bromomethyl)-1,3-propanediol was associated with alveolar/bronchiolar hyperplasia in the lung (males only); focal atrophy, papillary degeneration, transitional epithelial hyperplasia (pelvis), and papillary epithelial hyperplasia in the kidney; follicular cell hyperplasia in the thyroid gland (males only); hyperplasia in the seminal vesicle and pancreas (males only); mucosal hyperplasia in the forestomach (males only); and urinary bladder hyperplasia (males only). Exposure of mice to 2,2-bis(bromomethyl)-1,3-propanediol was associated with hyperplasia of the alveolar epithelium in females. Synonyms: 2,2-Bis(2-bromomethyl)-1,3-propanediol; 1,3-dibromo-2,2-dihydroxymethylpropane; 1,3-dibromo-2,2-dimethylolpropane; 2,2-dibromomethyl-1,3-propanediol; dibromopentaerythritol; dibromoneopentyl glycol; pentaerythritol dibromide; pentaerythritol dibromohydrin

Comparison of neurodegeneration and cognitive impairment in neonatal mice exposed to propofol or isoflurane.

PubMed

Yang, Bin; Liang, Ge; Khojasteh, Soorena; Wu, Zhen; Yang, Wenqiong; Joseph, Donald; Wei, Huafeng

2014-01-01

While previous studies have demonstrated neuronal apoptosis and associated cognitive impairment after isoflurane or propofol exposure in neonatal rodents, the effects of these two anesthetics have not been directly compared. Here, we compare and contrast the effectiveness of isoflurane and propofol to cause neurodegeneration in the developing brain and associated cognitive dysfunction. Seven-day-old mice were used. Mice in the isoflurane treatment group received 6 h of 1.5% isoflurane, while mice in propofol treatment group received one peritoneal injection (150 mg/kg), which produced persistent anesthesia with loss of righting for at least 6 h. Mice in control groups received carrying gas or a peritoneal injection of vehicle (intralipid). At 6 h after anesthetic treatment, a subset of each group was sacrificed and examined for evidence of neurodegeneration, using plasma levels of S100β, and apoptosis using caspase-3 immunohistochemistry in the cerebral cortex and hippocampus and Western blot assays of the cortex. In addition, biomarkers for inflammation (interleukin-1, interleukin-6, and tumor necrosis factor alpha) were examined with Western blot analyses of the cortex. In another subset of mice, learning and memory were assessed 32 days after the anesthetic exposures using the Morris water maze. Isoflurane significantly increased plasma S100β levels compared to controls and propofol. Both isoflurane and propofol significantly increased caspase-3 levels in the cortex and hippocampus, though isoflurane was significantly more potent than propofol. However, there were no significant differences in the inflammatory biomarkers in the cortex or in subsequent learning and memory between the experimental groups. Both isoflurane and propofol caused significant apoptosis in the mouse developing brain, with isoflurane being more potent. Isoflurane significantly increased levels of the plasma neurodegenerative biomarker, S100β. However, these neurodegenerative effects of isoflurane and propofol in the developing brain were not associated with effects on inflammation or with cognitive dysfunction in later life.

Effects of Nonpurified and Choline Supplemented or Nonsupplemented Purified Diets on Hepatic Steatosis and Methionine Metabolism in C3H Mice.

PubMed

Syed, Raisa; Shibata, Noreene M; Kharbanda, Kusum K; Su, Ruijun J; Olson, Kristin; Yokoyama, Amy; Rutledge, John C; Chmiel, Kenneth J; Kim, Kyoungmi; Halsted, Charles H; Medici, Valentina

2016-05-01

Previous studies indicated that nonpurified and purified commercially available control murine diets have different metabolic effects with potential consequences on hepatic methionine metabolism and liver histology. We compared the metabolic and histological effects of commercial nonpurified (13% calories from fat; 57% calories from carbohydrates with 38 grams/kg of sucrose) and purified control diets (12% calories from fat; 69% calories from carbohydrates with ∼500 grams/kg of sucrose) with or without choline supplementation administered to C3H mice with normal lipid and methionine metabolism. Diets were started 2 weeks before mating, continued through pregnancy and lactation, and continued in offspring until 24 weeks of age when we collected plasma and liver tissue to study methionine and lipid metabolism. Compared to mice fed nonpurified diets, the liver/body weight ratio was significantly higher in mice fed either purified diet, which was associated with hepatic steatosis and inflammation. Plasma alanine aminotransferase levels were higher in mice receiving the purified diets. The hepatic S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) ratio was higher in female mice fed purified compared to nonpurified diet (4.6 ± 2 vs. 2.8 ± 1.9; P < 0.05). Choline supplementation was associated with improvement of some parameters of lipid and methionine metabolism in mice fed purified diets. Standard nonpurified and purified diets have significantly different effects on development of steatosis in control mice. These findings can help in development of animal models of fatty liver and in choosing appropriate laboratory control diets for control animals.

Enhancement of committed hematopoietic stem cell colony formation by nandrolone decanoate after sublethal whole body irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gallicchio, V.S.; Chen, M.G.; Watts, T.D.

1984-11-01

The ability of an anabolic steroid, nandrolone decanoate, to increase committed topoietic stem cell (CFU-gm, CFU-e, and BFU-e) colony formation after sublethal irradiation was evaluated. Immediately after receiving whole body irradiation and on the next two days, each mouse was injected intraperitoneally with nandrolone decanoate (1.25 mg) in propylene glycol. Irradiated control mice received only propylene glycol. Compared to controls, drug-treated mice showed marked peripheral blood leukocytosis and more stable packed red cell volume. Drug-treated mice also demonstrated increased erythropoiesis, as CFU-e/BFU-e concentrations from both marrow (9% to 581%) and spleen (15% to 797%) were elevated. Granulopoiesis was increased similarly,more » as CFU-gm concentrations from marrow (38% to 685%) and spleen (9% to 373%) were elevated. These results demonstrate that nandrolone decanoate enhances hematopoietic stem cell recovery after sublethal whole body irradiation. This suggests that following hematopoietic suppression, nandrolone decanoate may stimulate the recovery of hematopoiesis at the stem cell level and in peripheral blood.« less

Enteral supplement enriched with glutamine, fiber, and oligosaccharide attenuates experimental colitis in mice.

PubMed

Joo, Erina; Yamane, Shunsuke; Hamasaki, Akihiro; Harada, Norio; Matsunaga, Tetsuro; Muraoka, Atsushi; Suzuki, Kazuyo; Nasteska, Daniela; Fukushima, Toru; Hayashi, Tatsuya; Tsuji, Hidemi; Shide, Kenichiro; Tsuda, Kinsuke; Inagaki, Nobuya

2013-03-01

Ulcerative colitis is a chronic recurrent disease characterized by acute inflammation of the colonic mucosa. In Japan, a dietary supplementation product enriched with glutamine, dietary fiber, and oligosaccharide (GFO) is widely applied for enteral nutrition support. These three components have been suggested to improve intestinal health. In this study, we investigated whether GFO has suppressive effects on mucosal damage in ulcerative colitis in an experimental mouse model. C57BL/6 mice received 2.5% dextran sulfate sodium in drinking water for 5 d to induce colitis. Then, they were given 0.25 mL of GFO or a 20% glucose solution twice daily for 10 d. Another set of mice receiving unaltered drinking water was used as the normal control group. The body weight loss and disease activity index were significantly lower in the GFO-treated mice compared with the glucose-treated mice (P < 0.05). The decrease in colon length induced by dextran sulfate sodium was significantly alleviated in GFO-treated mice compared with glucose-treated mice (P < 0.01). In addition, the histologic findings showed that intestinal inflammation was significantly attenuated in mice treated with GFO. Furthermore, treatment with GFO significantly inhibited the dextran sulfate sodium-induced increase in the mRNA expression of interleukin-1β. These results suggest that GFO has potential therapeutic value as an adjunct therapy for ulcerative colitis. Copyright © 2013 Elsevier Inc. All rights reserved.

Modulation of the gut microbiota by the mixture of fish oil and krill oil in high-fat diet-induced obesity mice.

PubMed

Cui, Chenxi; Li, Yanyan; Gao, Hang; Zhang, Hongyan; Han, Jiaojiao; Zhang, Dijun; Li, Ye; Zhou, Jun; Lu, Chenyang; Su, Xiurong

2017-01-01

Previous studies confirmed that dietary supplements of fish oil and krill oil can alleviate obesity in mice, but the underlying mechanism remains unclear. This study aims to discern whether oil treatment change the structure of the gut microbiota during the obesity alleviation. The ICR mice received high-fat diet (HFD) continuously for 12 weeks after two weeks of acclimatization with a standard chow diet, and the mice fed with a standard chow diet were used as the control. In the groups that received HFD with oil supplementation, the weight gains were attenuated and the liver index, total cholesterol, triglyceride and low-density lipoprotein cholesterol were reduced stepwise compared with the HFD group, and the overall structure of the gut microbiota, which was modulated in the HFD group, was shifted toward the structure found in the control group. Moreover, eighty-two altered operational taxonomic units responsive to oil treatment were identified and nineteen of them differing in one or more parameters associated with obesity. In conclusion, this study confirmed the effect of oil treatment on obesity alleviation, as well as on the microbiota structure alterations. We proposed that further researches are needed to elucidate the causal relationship between obesity alleviation and gut microbiota modulation.

Intraperitoneal Injection of Ethanol for the Euthanasia of Laboratory Mice (Mus musculus) and Rats (Rattus norvegicus)

PubMed Central

Allen-Worthington, Krystal H; Brice, Angela K; Marx, James O; Hankenson, F Claire

2015-01-01

Compassion, professional ethics, and public sensitivity require that animals are euthanized humanely and appropriately under both planned and emergent situations. According to the 2013 AVMA Guidelines for the Euthanasia of Animals, intraperitoneal injection of ethanol is “acceptable with conditions” for use in mice. Because only limited information regarding this technique is available, we sought to evaluate ethanol by using ECG and high-definition video recording. Mice (n = 85) and rats (n = 16) were treated with intraperitoneal ethanol (70% or 100%), a positive-control agent (pentobarbital–phenytoin combination [Pe/Ph]), or a negative-control agent (saline solution). After injection, animals were assessed for behavioral and physiologic responses. Pain-assessment techniques in mice demonstrated that intraperitoneal injection of ethanol was not more painful than was intraperitoneal Pe/Ph. Median time to loss of consciousness for all mice that received ethanol or Pe/Ph was 45 s. Median time to respiratory arrest was 2.75, 2.25, and 2.63 min, and time (mean ± SE) to cardiac arrest was 6.04 ± 1.3, 2.96 ± 0.6, and 4.03 ± 0.5 min for 70% ethanol, 100% ethanol, and Pe/Ph, respectively. No mouse that received ethanol or Pe/Ph regained consciousness. Although successful in mice, intraperitoneal ethanol at the doses tested (9.2 to 20.1 g/kg) was unsuitable for euthanasia of rats (age, 7 to 8 wk) because of the volume needed and prolonged time to respiratory effects. For mice, intraperitoneal injection of 70% or 100% ethanol induced rapid and irreversible loss of consciousness, followed by death, and should be considered as “acceptable with conditions.” PMID:26632787

Intraperitoneal Injection of Ethanol for the Euthanasia of Laboratory Mice (Mus musculus) and Rats (Rattus norvegicus).

PubMed

Allen-Worthington, Krystal H; Brice, Angela K; Marx, James O; Hankenson, F Claire

2015-11-01

Compassion, professional ethics, and public sensitivity require that animals are euthanized humanely and appropriately under both planned and emergent situations. According to the 2013 AVMA Guidelines for the Euthanasia of Animals, intraperitoneal injection of ethanol is "acceptable with conditions" for use in mice. Because only limited information regarding this technique is available, we sought to evaluate ethanol by using ECG and high-definition video recording. Mice (n = 85) and rats (n = 16) were treated with intraperitoneal ethanol (70% or 100%), a positive-control agent (pentobarbital-phenytoin combination [Pe/Ph]), or a negative-control agent (saline solution). After injection, animals were assessed for behavioral and physiologic responses. Pain-assessment techniques in mice demonstrated that intraperitoneal injection of ethanol was not more painful than was intraperitoneal Pe/Ph. Median time to loss of consciousness for all mice that received ethanol or Pe/Ph was 45 s. Median time to respiratory arrest was 2.75, 2.25, and 2.63 min, and time (mean ± SE) to cardiac arrest was 6.04 ± 1.3, 2.96 ± 0.6, and 4.03 ± 0.5 min for 70% ethanol, 100% ethanol, and Pe/Ph, respectively. No mouse that received ethanol or Pe/Ph regained consciousness. Although successful in mice, intraperitoneal ethanol at the doses tested (9.2 to 20.1 g/kg) was unsuitable for euthanasia of rats (age, 7 to 8 wk) because of the volume needed and prolonged time to respiratory effects. For mice, intraperitoneal injection of 70% or 100% ethanol induced rapid and irreversible loss of consciousness, followed by death, and should be considered as "acceptable with conditions."

Effect of Chorda Tympani Nerve Transection on Salt Taste Perception in Mice

PubMed Central

Ishiwatari, Yutaka; Theodorides, Maria L.; Bachmanov, Alexander A.

2011-01-01

Effects of gustatory nerve transection on salt taste have been studied extensively in rats and hamsters but have not been well explored in the mouse. We examined the effects of chorda tympani (CT) nerve transection on NaCl taste preferences and thresholds in outbred CD-1 mice using a high-throughput phenotyping method developed in our laboratory. To measure taste thresholds, mice were conditioned by oral self-administration of LiCl or NaCl and then presented with NaCl concentration series in 2-bottle preference tests. LiCl-conditioned and control NaCl-exposed mice were given bilateral transections of the CT nerve (LiCl-CTX, NaCl-CTX) or were left intact as controls (LiCl-CNT, NaCl-CNT). After recovery from surgery, mice received a concentration series of NaCl (0–300 mM) in 48-h 2-bottle tests. CT transection increased NaCl taste thresholds in LiCl-conditioned mice and eliminated avoidance of concentrated NaCl in control NaCl-exposed mice. This demonstrates that in mice, the CT nerve is important for detection and recognition of NaCl taste and is necessary for the normal avoidance of high concentrations of NaCl. The results of this experiment also show that the method of high-throughput phenotyping of salt taste thresholds is suitable for detecting changes in the taste periphery in mouse genetic studies. PMID:21743094

Nerve Growth Factor Gene Therapy Using Adeno-Associated Viral Vectors Prevents Cardiomyopathy in Type 1 Diabetic Mice

PubMed Central

Meloni, Marco; Descamps, Betty; Caporali, Andrea; Zentilin, Lorena; Floris, Ilaria; Giacca, Mauro; Emanueli, Costanza

2012-01-01

Diabetes is a cause of cardiac dysfunction, reduced myocardial perfusion, and ultimately heart failure. Nerve growth factor (NGF) exerts protective effects on the cardiovascular system. This study investigated whether NGF gene transfer can prevent diabetic cardiomyopathy in mice. We worked with mice with streptozotocin-induced type 1 diabetes and with nondiabetic control mice. After having established that diabetes reduces cardiac NGF mRNA expression, we tested NGF gene therapies with adeno-associated viral vectors (AAVs) for the capacity to protect the diabetic mouse heart. To this aim, after 2 weeks of diabetes, cardiac expression of human NGF or β-Gal (control) genes was induced by either intramyocardial injection of AAV serotype 2 (AAV2) or systemic delivery of AAV serotype 9 (AAV9). Nondiabetic mice were given AAV2–β-Gal or AAV9–β-Gal. We found that the diabetic mice receiving NGF gene transfer via either AAV2 or AAV9 were spared the progressive deterioration of cardiac function and left ventricular chamber dilatation observed in β-Gal–injected diabetic mice. Moreover, they were additionally protected from myocardial microvascular rarefaction, hypoperfusion, increased deposition of interstitial fibrosis, and increased apoptosis of endothelial cells and cardiomyocytes, which afflicted the β-Gal–injected diabetic control mice. Our data suggest therapeutic potential of NGF for the prevention of cardiomyopathy in diabetic subjects. PMID:22187379

Quercetin and rutin as inhibitors of azoxymethanol-induced colonic neoplasia.

PubMed

Deschner, E E; Ruperto, J; Wong, G; Newmark, H L

1991-07-01

Dietary quercetin (QU) and rutin (RU), phenolic flavonoids commonly found in many fruits and vegetables, were provided to CF1 female mice for 50 weeks to assess the ability of these compounds to inhibit azoxymethanol (AOM)-induced colonic neoplasia. In addition to a control group fed an AIN 76A diet, five other groups received that diet to which was added either 0.1, 0.5 or 2.0% QU and 1.0 or 4.0% RU. Acute studies revealed that, among saline controls, no alteration of any proliferative parameters of colonic epithelial cells was observed among those groups receiving any dose of QU or RU. However, among the AOM-treated mice, both 2% QU and 4% RU significantly reduced hyperproliferation and inhibited the shift of S-phase cells to the middle and upper portion of crypts. Moreover, mice fed these concentrations of QU and RU had significantly fewer AOM-induced focal areas of dysplasia (FADs) than those fed the control diet (0.2 +/- 0.4 and 0.4 +/- 0.5 versus 3.6 +/- 2.3 respectively). Tumors occurred more frequently in the distal half of the colon, regardless of treatment. Compared with controls, mice fed 2% QU had a significantly reduced tumor incidence (25.0% versus 5.9%, P = 0.03). Those fed 4% RU showed only a trend toward inhibition (25% versus 9.7%, P = 0.11). Nevertheless, both 2% QU and 4% RU suppressed tumor multiplicity, i.e. fewer tumors/animal arose in these groups than in the AOM-treated control mice (1.2 versus 2.3, P = 0.005; 1.1 versus 2.3, P = 0.003 respectively). Clearly, QU and RU exhibit significant activity in reducing AOM-induced hyperproliferation of colonic epithelial cells and FAD incidence. This behavior successfully forecast the ability of both flavonoids to suppress tumor multiplicity and ultimately tumor development.

Isoflavones in soy flour diet have different effects on whole-genome expression patterns than purified isoflavone mix in human MCF-7 breast tumors in ovariectomized athymic nude mice.

PubMed

Liu, Yunxian; Hilakivi-Clarke, Leena; Zhang, Yukun; Wang, Xiao; Pan, Yuan-Xiang; Xuan, Jianhua; Fleck, Stefanie C; Doerge, Daniel R; Helferich, William G

2015-08-01

Soy flour diet (MS) prevented isoflavones from stimulating MCF-7 tumor growth in athymic nude mice, indicating that other bioactive compounds in soy can negate the estrogenic properties of isoflavones. The underlying signal transduction pathways to explain the protective effects of soy flour consumption were studied here. Ovariectomized athymic nude mice inoculated with MCF-7 human breast cancer cells were fed either Soy flour diet (MS) or purified isoflavone mix diet (MI), both with equivalent amounts of genistein. Positive controls received estradiol pellets and negative controls received sham pellets. GeneChip Human Genome U133 Plus 2.0 Array platform was used to evaluate gene expressions, and results were analyzed using bioinformatics approaches. Tumors in MS-fed mice exhibited higher expression of tumor growth suppressing genes ATP2A3 and BLNK and lower expression of oncogene MYC. Tumors in MI-fed mice expressed a higher level of oncogene MYB and a lower level of MHC-I and MHC-II, allowing tumor cells to escape immunosurveillance. MS-induced gene expression alterations were predictive of prolonged survival among estrogen-receptor-positive breast cancer patients, whilst MI-induced gene changes were predictive of shortened survival. Our findings suggest that dietary soy flour affects gene expression differently than purified isoflavones, which may explain why soy foods prevent isoflavones-induced stimulation of MCF-7 tumor growth in athymic nude mice. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Engraftment of donor mesenchymal stem cells in chimeric BXSB includes vascular endothelial cells and hepatocytes.

PubMed

Jones, Olcay Y; Gok, Faysal; Rushing, Elisabeth J; Horkayne-Szakaly, Iren; Ahmed, Atif A

2011-01-01

Somatic tissue engraftment was studied in BXSB mice treated with mesenchymal stem cell transplantation. Hosts were conditioned with nonlethal radiation prior to introducing donor cells from major histocompatibility complex-matched green fluorescent protein transgenic mice. Transplant protocols differed for route of injection, ie, intravenous (i.v.) versus intraperitoneal (i.p.), and source of mesenchymal stem cells, ie, unfractionated bone marrow cells, ex vivo expanded mesenchymal stem cells, or bone chips. Tissue chimerism was determined after short (10-12 weeks) or long (62 weeks) posttransplant follow-up by immunohistochemistry for green fluorescent protein. Engraftment of endothelial cells was seen in several organs including liver sinusoidal cells in i.v. treated mice with ex vivo expanded mesenchymal stem cells or with unfractionated bone marrow cells. Periportal engraftment of liver hepatocytes, but not engraftment of endothelial cells, was found in mice injected i.p. with bone chips. Engraftment of adipocytes was a common denominator in both i.v. and i.p. routes and occurred during early phases post-transplant. Disease control was more robust in mice that received both i.v. bone marrow and i.p. bone chips compared to mice that received i.v. bone marrow alone. Thus, the data support potential use of mesenchymal stem cell transplant for treatment of severe lupus. Future studies are needed to optimize transplant conditions and tailor protocols that may in part be guided by fat and endothelial biomarkers. Furthermore, the role of liver chimerism in disease control and the nature of cellular communication among donor hematopoietic and mesenchymal stem cells in a chimeric host merit further investigation.

The pathophysiology underlying repetitive mild traumatic brain injury in a novel mouse model of chronic traumatic encephalopathy.

PubMed

Petraglia, Anthony L; Plog, Benjamin A; Dayawansa, Samantha; Dashnaw, Matthew L; Czerniecka, Katarzyna; Walker, Corey T; Chen, Michael; Hyrien, Ollivier; Iliff, Jeffrey J; Deane, Rashid; Huang, Jason H; Nedergaard, Maiken

2014-01-01

An animal model of chronic traumatic encephalopathy (CTE) is essential for further understanding the pathophysiological link between repetitive head injury and the development of chronic neurodegenerative disease. We previously described a model of repetitive mild traumatic brain injury (mTBI) in mice that encapsulates the neurobehavioral spectrum characteristic of patients with CTE. We aimed to study the pathophysiological mechanisms underlying this animal model. Our previously described model allows for controlled, closed head impacts to unanesthetized mice. Briefly, 12-week-old mice were divided into three groups: Control, single, and repetitive mTBI. Repetitive mTBI mice received six concussive impacts daily, for 7 days. Mice were then subsequently sacrificed for macro- and micro-histopathologic analysis at 7 days, 1 month, and 6 months after the last TBI received. Brain sections were immunostained for glial fibrillary acidic protein (GFAP) for astrocytes, CD68 for activated microglia, and AT8 for phosphorylated tau protein. Brains from single and repetitive mTBI mice lacked macroscopic tissue damage at all time-points. Single mTBI resulted in an acute rea ctive astrocytosis at 7 days and increased phospho-tau immunoreactivity that was present acutely and at 1 month, but was not persistent at 6 months. Repetitive mTBI resulted in a more marked neuroinflammatory response, with persistent and widespread astrogliosis and microglial activation, as well as significantly elevated phospho-tau immunoreactivity to 6-months. The neuropathological findings in this new model of repetitive mTBI resemble some of the histopathological hallmarks of CTE, including increased astrogliosis, microglial activation, and hyperphosphorylated tau protein accumulation.

Anti-miR-33 therapy does not alter the progression of atherosclerosis in low-density lipoprotein receptor-deficient mice.

PubMed

Marquart, Tyler J; Wu, Judy; Lusis, Aldons J; Baldán, Ángel

2013-03-01

To determine the efficacy of long-term anti-miR-33 therapy on the progression of atherosclerosis in high-fat, high-cholesterol-fed Ldlr(-/-) mice. Ldlr(-/-) mice received saline, or control or anti-miR-33 oligonucleotides once a week for 14 weeks. The treatment was effective, as measured by reduced levels of hepatic miR-33 and increased hepatic expression of miR-33 targets. Analysis of plasma samples revealed an initial elevation in high-density lipoprotein cholesterol after 2 weeks of treatment that was not sustained by the end of the experiment. Additionally, we found a significant increase in circulating triglycerides in anti-miR-33-treated mice, compared with controls. Finally, examination of atheromata revealed no significant changes in the size or composition of lesions between the 3 groups. Prolonged silencing of miR-33 fails to maintain elevated plasma high-density lipoprotein cholesterol and does not prevent the progression of atherosclerosis in Ldlr(-/-) mice.

Shp2 signaling in POMC neurons is important for leptin's actions on blood pressure, energy balance, and glucose regulation.

PubMed

do Carmo, Jussara M; da Silva, Alexandre A; Ebaady, Sabira E; Sessums, Price O; Abraham, Ralph S; Elmquist, Joel K; Lowell, Bradford B; Hall, John E

2014-12-15

Previous studies showed that Src homology-2 tyrosine phosphatase (Shp2) is an important regulator of body weight. In this study, we examined the impact of Shp2 deficiency specifically in proopiomelanocortin (POMC) neurons on metabolic and cardiovascular function and on chronic blood pressure (BP) and metabolic responses to leptin. Mice with Shp2 deleted in POMC neurons (Shp2/Pomc-cre) and control mice (Shp2(flox/flox)) were implanted with telemetry probes and venous catheters for measurement of mean arterial pressure (MAP) and leptin infusion. After at least 5 days of stable control measurements, mice received leptin infusion (2 μg·kg(-1)·day(-1) iv) for 7 days. Compared with Shp2(flox/flox) controls, Shp2/Pomc-cre mice at 22 wk of age were slightly heavier (34 ± 1 vs. 31 ± 1 g) but consumed a similar amount of food (3.9 ± 0.3 vs. 3.8 ± 0.2 g/day). Leptin infusion reduced food intake in Shp2(flox/flox) mice (2.6 ± 0.5 g) and Shp2/Pomc-cre mice (3.2 ± 0.3 g). Despite decreasing food intake, leptin infusion increased MAP in control mice, whereas no significant change in MAP was observed in Shp2/Pomc-cre mice. Leptin infusion also decreased plasma glucose and insulin levels in controls (12 ± 1 to 6 ± 1 μU/ml and 142 ± 12 to 81 ± 8 mg/100 ml) but not in Shp2/Pomc-cre mice. Leptin increased V̇o2 by 16 ± 2% in controls and 7 ± 1% in Shp2/Pomc-cre mice. These results indicate that Shp2 signaling in POMC neurons contributes to the long-term BP and antidiabetic actions of leptin and may play a modest role in normal regulation of body weight. Copyright © 2014 the American Physiological Society.

Flavonone treatment reverses airway inflammation and remodelling in an asthma murine model

PubMed Central

Toledo, AC; Sakoda, CPP; Perini, A; Pinheiro, NM; Magalhães, RM; Grecco, S; Tibério, IFLC; Câmara, NO; Martins, MA; Lago, JHG; Prado, CM

2013-01-01

Background and Purpose Asthma is an inflammatory disease that involves airway hyperresponsiveness and remodelling. Flavonoids have been associated to anti-inflammatory and antioxidant activities and may represent a potential therapeutic treatment of asthma. Our aim was to evaluate the effects of the sakuranetin treatment in several aspects of experimental asthma model in mice. Experimental Approach Male BALB/c mice received ovalbumin (i.p.) on days 0 and 14, and were challenged with aerolized ovalbumin 1% on days 24, 26 and 28. Ovalbumin-sensitized animals received vehicle (saline and dimethyl sulfoxide, DMSO), sakuranetin (20 mg kg–1 per mice) or dexamethasone (5 mg kg–1 per mice) daily beginning from 24th to 29th day. Control group received saline inhalation and nasal drop vehicle. On day 29, we determined the airway hyperresponsiveness, inflammation and remodelling as well as specific IgE antibody. RANTES, IL-5, IL-4, Eotaxin, IL-10, TNF-α, IFN-γ and GMC-SF content in lung homogenate was performed by Bioplex assay, and 8-isoprostane and NF-kB activations were visualized in inflammatory cells by immunohistochemistry. Key Results We have demonstrated that sakuranetin treatment attenuated airway hyperresponsiveness, inflammation and remodelling; and these effects could be attributed to Th2 pro-inflammatory cytokines and oxidative stress reduction as well as control of NF-kB activation. Conclusions and Implications These results highlighted the importance of counteracting oxidative stress by flavonoids in this asthma model and suggest sakuranetin as a potential candidate for studies of treatment of asthma. PMID:23170811

Therapeutically Targeting the Inflammasome Product in a Chimeric Model of Endometriosis-Related Surgical Adhesions.

PubMed

Stocks, Meredith M; Crispens, Marta A; Ding, Tianbing; Mokshagundam, Shilpa; Bruner-Tran, Kaylon L; Osteen, Kevin G

2017-08-01

Development of adhesions commonly occurs in association with surgery for endometriosis. Even in the absence of surgery, women with endometriosis appear to be at an enhanced risk of developing adhesions. In the current study, we utilized a chimeric mouse model of experimental endometriosis in order to examine the role of inflammasome activation in the development of postsurgical adhesions. Mice were randomized to receive peritoneal injections of human endometrial tissue fragments or endometrial tissue conditioned media (CM) from women with or without endometriosis 16 hours after ovariectomy and placement of an estradiol-releasing silastic capsule. A subset of mice receiving CM was also treated with interleukin (IL) 1 receptor antagonist (IL-1ra). Our studies demonstrate that peritoneal injection of endometrial tissue fragments near the time of surgery resulted in extensive adhesive disease regardless of tissue origin. However, adhesion scores were significantly higher in mice receiving CM from tissues acquired from patients with endometriosis compared to control tissue CM ( P = .0001). Cytokine bead array analysis of endometrial CM revealed enhanced expression of IL-1β from patients with endometriosis compared to controls ( P < .01). Finally, the ability of human tissue CM to promote adhesive disease was dramatically reduced in mice cotreated with IL-1ra ( P < .0001). Our data implicate enhanced expression of IL-1β in women with endometriosis as a potential causal factor in their increased susceptibility of developing postsurgical adhesions. Thus, targeting inflammasome activation may be an effective strategy for the prevention of surgical adhesions in patients with endometriosis.

Antitumor effect of vitamin D-binding protein-derived macrophage activating factor on Ehrlich ascites tumor-bearing mice.

PubMed

Koga, Y; Naraparaju, V R; Yamamoto, N

1999-01-01

Cancerous cells secrete alpha-N-acetylgalactosaminidase (NaGalase) into the blood stream, resulting in deglycosylation of serum vitamin D3-binding protein (known as Gc protein), which is a precursor for macrophage activating factor (MAF). Incubation of Gc protein with immobilized beta-galactosidase and sialidase generates the most potent macrophage activating factor (designated GcMAF). Administration of GcMAF to cancer-bearing hosts can bypass the inactivated MAF precursor and act directly on macrophages for efficient activation. Therapeutic effects of GcMAF on Ehrlich ascites tumor-bearing mice were assessed by survival time and serum NaGalase activity, because serum NaGalase activity was proportional to tumor burden. A single administration of GcMAF (100 pg/mouse) to eight mice on the same day after transplantation of the tumor (5 x 10(5) cells) showed a mean survival time of 21 +/- 3 days for seven mice, with one mouse surviving more than 60 days, whereas tumor-bearing controls had a mean survival time of 13 +/- 2 days. Six of the eight mice that received two GcMAF administrations, at Day 0 and Day 4 after transplantation, survived up to 31 +/- 4 days whereas, the remaining two mice survived for more than 60 days. Further, six of the eight mice that received three GcMAF administrations with 4-day intervals showed an extended survival of at least 60 days, and serum NaGalase levels were as low as those of control mice throughout the survival period. The cure with subthreshold GcMAF-treatments (administered once or twice) of tumor-bearing mice appeared to be a consequence of sustained macrophage activation by inflammation resulting from the macrophage-mediated tumoricidal process. Therefore, a protracted macrophage activation induced by a few administrations of minute amounts of GcMAF eradicated the murine ascites tumor.

A Mineral-Rich Extract from the Red Marine Algae Lithothamnion calcareum Preserves Bone Structure and Function in Female Mice on a Western-Style Diet

PubMed Central

Aslam, Muhammad Nadeem; Kreider, Jaclynn M.; Paruchuri, Tejaswi; Bhagavathula, Narasimharao; DaSilva, Marissa; Zernicke, Ronald F.; Goldstein, Steven A.; Varani, James

2010-01-01

The purpose of this study was to determine whether a mineral-rich extract derived from the red marine algae Lithothamnion calcareum could be used as a dietary supplement for prevention of bone mineral loss. Sixty C57BL/6 mice were divided into three groups based on diet: the first group received a high-fat Western-style diet (HFWD), the second group was fed the same HFWD along with the mineral-rich extract included as a dietary supplement, and the third group was used as a control and was fed a low-fat rodent chow diet (AIN76A). Mice were maintained on the respective diets for 15 months. Then, long bones (femora and tibiae) from both males and females were analyzed by three-dimensional micro-computed tomography (micro-CT) and (bones from female mice) concomitantly assessed in bone strength studies. Tartrate-resistant acid phosphatase (TRAP), osteocalcin, and N-terminal peptide of type I procollagen (PINP) were assessed in plasma samples obtained from female mice at the time of sacrifice. To summarize, female mice on the HFWD had reduced bone mineralization and reduced bone strength relative to female mice on the low-fat chow diet. The bone defects in female mice on the HFWD were overcome in the presence of the mineral-rich supplement. In fact, female mice receiving the mineral-rich supplement in the HFWD had better bone structure/function than did female mice on the low-fat chow diet. Female mice on the mineral-supplemented HFWD had higher plasma levels of TRAP than mice of the other groups. There were no differences in the other two markers. Male mice showed little diet-specific differences by micro-CT. PMID:20180099

Enhancement of Behavioral Sensitization, Anxiety-Like Behavior, and Hippocampal and Frontal Cortical CREB Levels Following Cocaine Abstinence in Mice Exposed to Cocaine during Adolescence

PubMed Central

Valzachi, Maria Cristina; Teodorov, Elizabeth; Marcourakis, Tania; Bailey, Alexis; Camarini, Rosana

2013-01-01

Adolescence has been linked to greater risk-taking and novelty-seeking behavior and a higher prevalence of drug abuse and risk of relapse. Decreases in cyclic adenosine monophosphate response element binding protein (CREB) and phosphorylated CREB (pCREB) have been reported after repeated cocaine administration in animal models. We compared the behavioral effects of cocaine and abstinence in adolescent and adult mice and investigated possible age-related differences in CREB and pCREB levels. Adolescent and adult male Swiss mice received one daily injection of saline or cocaine (10 mg/kg, i.p.) for 8 days. On day 9, the mice received a saline injection to evaluate possible environmental conditioning. After 9 days of withdrawal, the mice were tested in the elevated plus maze to evaluate anxiety-like behavior. Twelve days after the last saline/cocaine injection, the mice received a challenge injection of either cocaine or saline, and locomotor activity was assessed. One hour after the last injection, the brains were extracted, and CREB and pCREB levels were evaluated using Western blot in the prefrontal cortex (PFC) and hippocampus. The cocaine-pretreated mice during adolescence exhibited a greater magnitude of the expression of behavioral sensitization and greater cocaine withdrawal-induced anxiety-like behavior compared with the control group. Significant increases in CREB levels in the PFC and hippocampus and pCREB in the hippocampus were observed in cocaine-abstinent animals compared with the animals treated with cocaine in adulthood. Interestingly, significant negative correlations were observed between cocaine sensitization and CREB levels in both regions. These results suggest that the behavioral and neurochemical consequences of psychoactive substances in a still-developing nervous system can be more severe than in an already mature nervous system. PMID:24205196

Antitumor and immunomodulatory effects of weikangfu granule compound in tumor-bearing mice

PubMed Central

Nie, Xiaohua; Shi, Baojun; Ding, Yuting; Tao, Wenyi

2006-01-01

Background: Weikangfu granule compound (WKC) is a drug preparation based on a clinical prescription drug, Weikangfu-tang, which has been found to have therapeutic effects on gastric cancer. WKC comprises 7 components, including polysaccharides, saponin, flavonoids, and essential oil. Objective: The purpose of this study was to assess the antitumor and immunomodulatory effects of WKC in a tumor-bearing rodent model. Methods: Male and female Kuming mice weighing ∼20 g were subcutaneously implanted with sarcoma 180 (S180) tumor cells and randomly assigned to 1 of 5 treatment groups: oral WKC 175, 350, or 525 mg/kg·d, isotonic saline (negative control), or intraperitoneal cyclophosphamide 25 mg/kg·d (positive control). All treatments were administered daily for 10 days. After euthanization on day 11, the mice, tumors, and spleens were weighed. Lymphocyte proliferation and cytotoxic T lymphocyte (CTL) activity were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cellular viability assay method. Macrophage phagocytosis was identified using a yeast test. Results: Fifty mice were included in the study (10 mice were assigned to each group). The tumors of the mice administered WKC 175, 350, and 525 mg/kg·d were significantly regressed, as determined using MICs, compared with those in the negative-control group (P<0.05, P<0.01, and P<0.01, respectively), and the inhibitory rates were 30.43%, 46.72%, and 54.35%, respectively. Compared with those in the negative-control group, CTL activities and lymphocyte proliferations in the presence of concanavalin A were significantly greater in the WKC-treated groups at all doses (CTL activities: P<0.05, P<0.01, and P<0.01, respectively; lymphocyte proliferations: P<0.05, P<0.01, and P<0.01, respectively). In the groups receiving WKC 175, 350, and 525 mg/kg·d, the phagocytic rates were 1.5- to 2.0-fold those in the negative-control group (P<0.05, P<0.01, and P<0.01, respectively). In the groups receiving WKC 175, 350, and 525 mg/kg·d, the phagocytic indexes were 3.7- to 5.0-fold those in the negative-control group (all, P<0.01). In contrast, lymphocyte proliferation in the positive-control group was significantly less compared with that in the negative-control group (P<0.01), but no significant differences were found in CTL activities or macrophage phagocytosis between these 2 groups. Conclusion: The results of this study in a rodent model suggest that WKC exhibited antitumor and immunomodulatory activities in S180-bearing mice, and that WKC improved nonspecific and specific immune functions in mice, such as lymphocyte proliferation, CTL activity, and macrophage phagocytosis. PMID:24678090

Mice acquire flavor preferences during shipping.

PubMed

Tordoff, Michael G; Alarcón, Laura K; Byerly, Erica A; Doman, Samantha A

2005-11-15

Vigorous motion can cause rodents to develop flavor aversions and show other signs of malaise. We tested whether a flavor aversion could be induced by shipping mice from an animal breeder to a test site. Boxes of 12 male C57BL/6J mice were shipped approximately 950 km from Bar Harbor, ME to Philadelphia, PA by truck. For some boxes, the gel provided for hydration was flavored with almond and for others it was flavored with banana. After the journey, the mice were individually housed and allowed to recover for 5 days. They then received a choice between the two flavors of gel. Contrary to expectations, mice preferred the flavor they had previously ingested during shipping. Controls given flavored gel under similar conditions but while stationary did not show a preference. These results suggest that mice find shipping or its sequelae pleasurable. If mice are travel sick this must be inconsequential relative to other components of the shipping experience.

Exposure to a Mycobacterial Antigen, ESAT-6, Exacerbates Granulomatous and Fibrotic Changes in a Multiwall Carbon Nanotube Model of Chronic Pulmonary Disease

PubMed Central

Malur, Anagha; Barna, Barbara P; Patel, Janki; McPeek, Matthew; Wingard, Christopher J; Dobbs, Larry; Thomassen, Mary Jane

2016-01-01

Recent studies suggest additive effects of environmental pollutants and microbial antigens on respiratory disease. We established a granuloma model in which instilled multiwall carbon nanotubes (MWCNT) elicit granulomatous pathology. We hypothesized that mycobacterial antigen ESAT-6, a T cell activator associated with tuberculosis and sarcoidosis, might alter pathology. Wild-type C57Bl/6 mice received MWCNT with or without ESAT-6 peptide. Controls received vehicle (surfactant-PBS) or ESAT-6 alone. Mice were evaluated 60 days later for granulomas, fibrosis, and bronchoalveolar lavage (BAL) cell expression of inflammatory mediators (CCL2, MMP-12, and Osteopontin). Results indicated increased granulomas, fibrosis, and inflammatory mediators in mice receiving the combination of MWCNT+ESAT-6 compared to MWCNT or vehicle alone. ESAT-6 alone showed no significant effect on these pathological endpoints. However, CD3 (+) lymphocyte infiltration of lung tissue increased with MWCNT+ESAT-6 versus MWCNT alone. Findings suggest that concurrent exposure to microbial antigen and MWCNT exacerbates chronic pulmonary disease. PMID:27019768

Extending Time Profile of Morphine-Induced Analgesia Using a Chitosan-Based Molecular Imprinted Polymer Nanogel.

PubMed

Hassanzadeh, Marjan; Ghaemy, Mousa; Ahmadi, Shamseddin

2016-10-01

Chitosan-based molecular imprinted polymer (CS-MIP) nanogel is prepared in the presence of morphine template, fully characterized and used as a new vehicle to extend duration of morphine analgesic effect in Naval Medical Research Institute mice. The CS-MIP nanogel with ≈25 nm size range exhibits 98% loading efficiency, and in vitro release studies show an initial burst followed by an extended slow release of morphine. In order to study the feasibility of CS-MIP nanogel as morphine carrier, 20 mice are divided into two groups randomly and received subcutaneous injection of morphine-loaded CS-MIP and morphine (10 mg kg -1 ) dissolved in physiologic saline. Those received injection of morphine-loaded CS-MIP show slower and long lasting release of morphine with 193 min effective time of 50% (ET50) analgesia compared to 120 min ET50 in mice received morphine dissolved in physiologic saline. These results suggest that CS-MIP nanogel can be a possible strategy as morphine carrier for controlled release and extension of its analgesic efficacy. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

NTP Toxicology and Carcinogenesis Studies of 1,4-Dichlorobenzene (CAS No. 106-46-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

PubMed

1987-01-01

1,4-Dichlorobenzene is commonly used as a space deodorant in toilets and for moth control. Because of its extensive production and use and the absence of carcinogenicity data, carcinogenesis studies were conducted by administering 1,4-dichlorobenzene (greater than 99% pure) in corn oil by gavage (5 days per week) to male F344/N rats at doses of 0, 150, or 300 mg/kg and to female F344/N rats and male and female B6C3F1 mice at doses of 0, 300, or 600 mg/kg per day for 2 years (50 animals per group). Fourteen-day and 13-week studies were performed to characterize the toxicity, identify affected sites, and set doses for the 2-year studies. Clinical chemistry and hematologic studies were performed during the 13-week studies to assess the effects of 1,4-dichlorobenzene on the liver, kidney, and hematopoietic system and to assess whether the compound produced hepatic porphyria. Two 13-week studies were performed in rats. In the first study, rats were dosed with 300-1,500 mg/kg 1,4-dichlorobenzene. Because histologic changes were observed in the kidney of male rats at all doses, a second 13-week study was performed at doses of 38-600 mg/kg. In the 13-week studies, survival was decreased in groups of male rats given 1,200 or 1,500 mg/kg and in female rats given 1,500 mg/kg. Weight gain was decreased in male rats receiving doses of 300 mg/kg or more and in female rats given doses of 1,200 or 1,500 mg/kg. Doses of 1,200 or 1,500 mg/kg produced degeneration and necrosis of hepatocytes, hypoplasia of the bone marrow, lymphoid depletion of the spleen and thymus, and epithelial necrosis of the nasal turbinates in male and female rats. Renal tubular cell degeneration was observed in male rats receiving 300 mg/kg or more in the first study, but only slight changes were seen at 300 mg/kg in the second study. Liver weight to brain weight ratios were increased at 900 mg/kg or more for both male and female rats. The kidney weight to brain weight ratio was increased in male rats receiving doses of 600 mg/kg or more. Administration of 1,4-dichlorobenzene to rats for 13 weeks produced slight but statistically significant decreases in the hematocrit, red blood cell count, and hemoglobin level in all males receiving doses of 300-1,200 mg/kg. No clear hematologic changes were observed in female rats. 1,4-Dichlorobenzene produced minimal changes in clinical chemistry parameters in the 13-week studies. Serum cholesterol levels were increased by doses of 600 mg/kg or more in male rats and 900 mg/kg or more in female rats. Serum triglycerides were reduced by doses of 300 mg/kg or more in male rats. The blood urea nitrogen level was increased slightly in male rats dosed with 900 mg/kg or more. Urinary porphyrins were increased slightly in male rats administered 1,200 or 1,500 mg/kg and female rats receiving 1,200 mg/kg. However, these increases were modest and indicative of a mild porphyrinuria rather than hepatic porphyria. Liver porphyrins were not increased at any dose. Two 13-week studies were performed in mice. The doses selected for the first study were 600-1,800 mg/kg. Survival was decreased in male and female mice receiving doses of 1,500 mg/kg or more, and body weight gain was decreased at all doses. Hepatocellular degeneration was observed in both sexes at all doses, and the liver weight to brain weight ratio was increased at doses of 900 mg/kg or more. Serum cholesterol levels were increased in male mice at doses of 900 mg/kg or more, whereas serum protein and triglycerides were increased at doses of 1,500 mg/kg or more. These relatively modest clinical chemistry changes probably reflect the hepatic effects of this compound. The white blood cell count was reduced significantly in male mice receiving doses of 600 mg/kg or more and female mice receiving 1,000 mg/kg or more, but this effect was not dramatic. Hepatic porphyria was not found in mice at any dose in the 13-week study. Because hepatic effects were seen in all dose groups in the first study, a second 13-week study was performed at doses of 85-900 mg/kg. In this study, hepatocellularellular cytomegaly was observed im male and female mice at doses of 675 mg/kg or more but not at 338 mg/kg. Renal damage was not observed in mice in either 13-week study. Based on the histopathologic findings in the kidney of male rats and in the liver of both sexes of rats and mice in the 13-week studies, the doses selected for the 2-year studies were 150 and 300 mg/kg for male rats and 300 and 600 mg/kg for female rats and male and female mice. In the 2-year studies, survival of female rats and of both sexes of mice was comparable to that of the vehicle controls; survival of high dose male rats was significantly lower than that of the vehicle controls (vehicle control, 32/50; low dose, 31/50; high dose, 20/50). Mean body weights of high dose male rats were 5%-8% lower than those of vehicle controls after week 38, and those of high dose female rats were 5%-7% lower than those of vehicle controls after week 55. Mean body weights of mice dosed with 1,4-dichlorobenzene were comparable to those of vehicle controls throughout the studies. Administration of 1,4-dichlorobenzene to male rats increased the average seveity of nephropathy and caused epithelial hyperplasia of the renal pelvis (1/50; 30/50; 31/50), mineralization of the collecting tubules in the renal medulla (4/50; 46/50; 47/50), and focal hyperplasia of renal tubular epithelium (0/50; 1/50; 9/50). There were increased incidences of nephropathy in both low and high dose female rats compared with vehicle controls (21/49; 32/50; 41/49). 1,4-Dichlorobenzene produced a dose-related increase in the incidence of tubular cell adenocarcinomas of the kidney in male rats (1/50; 3/50; 7/50); one tubular cell adenoma was observed in a high dose male rat. These malignant tumors are uncommon in male F344/N rats. They have been diagnosed in only 4/1,098 (0.4%) corn oil gavage controls in previous NTP studies. There were no tubular cell tumors in dosed or vehicle control female rats. There was a marginal increase in the incidence of mononuclear cell leukemia in dosed male rats compared with that in vehicle controls (5/50; 7/50; 11/50). 1,4-Dichlorobenzene increased the incidences of nonneoplastic liver lesions in male and female mice, including alteration in cell size (cytomegaly and karyomegaly), hepatocellular degeneration, and individual cell necrosis. 1,4-Dichlorobenzene also increased the incidences of nephropathy in male mice and renal tubular regeneration in female mice. 1,4-Dichlorobenzene increased the incidences of hepatocellular carcinomas in high dose male (14/50; 11/49; 32/50) and female (5/50; 5/48; 19/50) mice and hepatocellular adenomas in dosed male (5/50; 13/49; 16/50) and high dose female (10/50; 6/48; 21/50) mice. Hepatoblastomas were observed in four high dose male mice but not in vehicle controls. This rare tumor has not occurred in 1,091 male vehicle control mice in NTP studies. An increase in thyroid gland follicular cell hyperplasia was observed in dosed male mice (1/47; 4/48; 10/47), and there was a marginal positive trend in the incidence of follicular cell adenomas of the thyroid gland in female mice (0/48; 0/45; 3/46). Pheochromocytomas (benign or malignant, combined) of the adrenal gland occurred with a positive trend in dosed male mice, and the incidence in the high dose group was significantly greater than in vehicle controls (0/47; 2/48; 4/49). The incidence of adrenal gland medullary hyperplasia in male mice was 2/47; 4/48; and 4/49. Focal hyperplasia of the adrenal gland capsule was also observed in dosed male mice (11/47;21/48; 28/49). 1,4-Dichlorobenzene was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without activation by Aroclor 1254-induced male Sprague-Dawley rat or male Syrian hamster liver S9 when tested according to a preincubational protocol at concentrations up to 100 ug/plate. 1,4-Dichlorobenzene did not induce forward mutations in the mouse lymphoma L5178Y/TK± assay in the absence of exogenous metabolic activation; however, the results were equivocal in this system in the presence of metabolic activation. 1,4-Dichlorobenzene did not produce an increase in sister-chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells in culture with or without exogenous metabolic activation. No increase in micronucleated cells was seen in erythrocytes of mice from the first 13-week studies. An audit of the experimental data was conducted for the 2-year studies of 1,4-dichlorobenzene. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, 1,4-dichlorobenzene produced clear evidence of carcinogenicity for male F344/N rats, as shown by an increased incidence of renal tubular cell adenocarcinomas. There was no evidence of carcinogenicity for female F344/N rats receiving doses of 300 or 600 mg/kg. There was clear evidence of carcinogenicity for both male and female B6C3F1 mice, as shown by increased incidences of hepatocellular carcinomas and hepatocellular adenomas. Marginal increases were observed in the incidences of pheochromocytomas of the adrenal gland in male mice. Nonneoplastic effects in the kidney of male and female rats, in the liver of male and female mice, and in the thyroid gland and adrenal gland of male mice were also associated with the administration of 1,4-dichlorobenzene. Synonyms: p-dichlorobenzene; para-dichlorobenzene; para-chlorophenyl chloride

Efficacy of albendazole:β-cyclodextrin citrate in the parenteral stage of Trichinella spiralis infection.

PubMed

Codina, Ana V; García, Agustina; Leonardi, Darío; Vasconi, María D; Di Masso, Ricardo J; Lamas, María C; Hinrichsen, Lucila I

2015-01-01

Albendazole-β-cyclodextrin citrate (ABZ:C-β-CD) inclusion complex in vivo antiparasitic activity was evaluated in the parenteral phase of Trichinella spiralis infection in mice. An equimolar complex of ABZ:C-β-CD was prepared by spray-drying and tested in CBi-IGE male mice orally infected with L1 infective larvae. Infected animals were treated with 50 or 30mg/kg albendazole, (ABZ) equivalent amounts of the ABZ:C-β-CD complex and non treated (controls). Mice received a daily dose on days 28, 29 and 30 post-infection. A week later, larval burden and percentage of encysted dead larvae were assessed in the host by counting viable and non-viable larvae in the tongue. Complexation of ABZ with C-β-CD increased the drug dissolution efficiency nearly eightfold. At 37 days p-i, the reduction percentage in muscle larval load was 35% in mice treated with 50mg/kg/day ABZ and 68% in those given the complex. Treatment with the lower dose showed a similar decrease in parasite burden. Treated animals showed a high percentage of nonviable larvae, the proportion being significantly higher in mice receiving the complex than in control animals (72-88% vs. 11%, P=0.0032). These data indicate that ABZ:C-β-CD increases bioavailability and effectiveness of ABZ against encapsulated Trichinella larvae, thus allowing the use of small doses. Copyright © 2015 Elsevier B.V. All rights reserved.

Paricalcitol modulates ACE2 shedding and renal ADAM17 in NOD mice beyond proteinuria.

PubMed

Riera, Marta; Anguiano, Lidia; Clotet, Sergi; Roca-Ho, Heleia; Rebull, Marta; Pascual, Julio; Soler, Maria Jose

2016-03-15

Circulating and renal activity of angiotensin-converting enzyme 2 (ACE2) is increased in non-obese diabetic (NOD) mice. Because paricalcitol has been reported to protect against diabetic nephropathy, we investigated the role of paricalcitol in modulating ACE2 in these mice. In addition, renal ADAM17, a metalloprotease implied in ACE2 shedding, was assessed. NOD female and non-diabetic control mice were studied for 21 days after diabetes onset and divided into various treatment groups. Diabetic animals received either vehicle; 0.4 or 0.8 μg/kg paricalcitol, aliskiren, or a combination of paricalcitol and aliskiren. We then studied the effect of paricalcitol on ACE2 expression in proximal tubular epithelial cells. Paricalcitol alone or in combination with aliskiren resulted in significantly reduced circulating ACE2 activity in NOD mice but there were no changes in urinary albumin excretion. Serum renin activity was significantly decreased in mice that received aliskiren but no effect was found when paricalcitol was used alone. Renal content of ADAM17 was significantly decreased in animals that received a high dose of paricalcitol. Renal and circulating oxidative stress (quantified by plasma H2O2 levels and immunolocalization of nitrotyrosine) were reduced in high-dose paricalcitol-treated mice compared with non-treated diabetic mice. In culture, paricalcitol incubation resulted in a significant increase in ACE2 expression compared with nontreated cells. In NOD mice with type 1 diabetes, paricalcitol modulates ACE2 activity, ADAM17, and oxidative stress renal content independently from the glycemic profile and urinary albumin excretion. In tubular cells, paricalcitol may modulate ACE2 by blocking its shedding. In the early stage of diabetic nephropathy, paricalcitol treatment counterbalances the effect of diabetes on circulating ACE2 activity. Our results suggest that additional use of paricalcitol may be beneficial in treating patients with diabetes under standard therapeutic strategies. Copyright © 2016 the American Physiological Society.

Increased acetylcholine esterase activity produced by the administration of an aqueous extract of the seed kernel of Thevetia peruviana and its role on acute and subchronic intoxication in mice

PubMed Central

Marroquín-Segura, Rubén; Calvillo-Esparza, Ricardo; Mora-Guevara, José Luis Alfredo; Tovalín-Ahumada, José Horacio; Aguilar-Contreras, Abigail; Hernández-Abad, Vicente Jesús

2014-01-01

Background: The real mechanism for Thevetia peruviana poisoning remains unclear. Cholinergic activity is important for cardiac function regulation, however, the effect of T. peruviana on cholinergic activity is not well-known. Objective: To study the effect of the acute administration of an aqueous extract of the seed kernel of T. peruviana on the acetylcholine esterase (AChE) activity in CD1 mice as well its implications in the sub-chronic toxicity of the extract. Materials and Methods: A dose of 100 mg/kg of the extract was administered to CD1 mice and after 7 days, serum was obtained for ceruloplasmin (CP) quantitation and liver function tests. Another group of mice received a 50 mg/kg dose of the extract 3 times within 1 h time interval and AChE activity was determined for those animals. Heart tissue histological preparation was obtained from a group of mice that received a daily 50 mg/kg dose of the extract by a 30-days period. Results: CP levels for the treated group were higher than those for the control group (Student's t-test, P ≤ 0.001). AChE activity in the treated group was significantly higher than the control group (Tukey test, control vs. T. peruviana, P ≤ 0.001). Heart tissue histological preparations showed leukocyte infiltrates and necrotic areas, consistent with infarcts. Conclusion: The increased levels of AChE and the hearth tissue infiltrative lesions induced by the aqueous seed kernel extract of T. peruviana explains in part the poisoning caused by this plant, which can be related to an inflammatory process. PMID:24914300

Increased acetylcholine esterase activity produced by the administration of an aqueous extract of the seed kernel of Thevetia peruviana and its role on acute and subchronic intoxication in mice.

PubMed

Marroquín-Segura, Rubén; Calvillo-Esparza, Ricardo; Mora-Guevara, José Luis Alfredo; Tovalín-Ahumada, José Horacio; Aguilar-Contreras, Abigail; Hernández-Abad, Vicente Jesús

2014-01-01

The real mechanism for Thevetia peruviana poisoning remains unclear. Cholinergic activity is important for cardiac function regulation, however, the effect of T. peruviana on cholinergic activity is not well-known. To study the effect of the acute administration of an aqueous extract of the seed kernel of T. peruviana on the acetylcholine esterase (AChE) activity in CD1 mice as well its implications in the sub-chronic toxicity of the extract. A dose of 100 mg/kg of the extract was administered to CD1 mice and after 7 days, serum was obtained for ceruloplasmin (CP) quantitation and liver function tests. Another group of mice received a 50 mg/kg dose of the extract 3 times within 1 h time interval and AChE activity was determined for those animals. Heart tissue histological preparation was obtained from a group of mice that received a daily 50 mg/kg dose of the extract by a 30-days period. CP levels for the treated group were higher than those for the control group (Student's t-test, P ≤ 0.001). AChE activity in the treated group was significantly higher than the control group (Tukey test, control vs. T. peruviana, P ≤ 0.001). Heart tissue histological preparations showed leukocyte infiltrates and necrotic areas, consistent with infarcts. The increased levels of AChE and the hearth tissue infiltrative lesions induced by the aqueous seed kernel extract of T. peruviana explains in part the poisoning caused by this plant, which can be related to an inflammatory process.

Common experience modifies the reinforcing properties of methamphetamine-injected cage mates but not morphine-injected cage mates in C57 mice.

PubMed

Watanabe, Shigeru

2015-10-01

The aim of this study was to determine whether previous exposure to a drug affects the social facilitation of conditioned place preference (CPP) for a drug-injected cage mate. Twenty-two male C57/BL6J mice received drug injections (methamphetamine or morphine) and 22 male C57/BL6J mice received saline injections. All 44 mice then received CPP training, during which one compartment of a conventional CPP apparatus was associated with a drug-injected cage mate (stimulus mouse) and the other compartment was associated with a saline-injected cage mate (stimulus mouse). The subject mice did not receive any drug injection during this CPP training. Time spent in the compartment associated with the drug-injected cage mate was measured before and after training. Subject mice that had previously received methamphetamine injections showed an increase in the time spent in the compartment associated with the methamphetamine-injected cage mate after CPP training. This effect was not observed in subject mice that had previously received saline injections. Subject mice did not show an increase in the time spent in the compartment associated with the morphine-injected cage mate irrespective of whether they had previously received morphine or saline injections. Therefore, in agreement with previous reports, common experience with methamphetamine induced reinforcing properties, but that with morphine did not.

Increased seizure latency and decreased severity of pentylenetetrazol-induced seizures in mice after essential oil administration.

PubMed

Koutroumanidou, Eleni; Kimbaris, Athanasios; Kortsaris, Alexandros; Bezirtzoglou, Eugenia; Polissiou, Moschos; Charalabopoulos, Konstantinos; Pagonopoulou, Olga

2013-01-01

The effect of pretreatment with essential oils (EOs) from eight aromatic plants on the seizure latency and severity of pentylenetetrazol- (PTZ-) induced seizures in mice was evaluated. Weight-dependent doses of Rosmarinus officinalis, Ocimum basilicum, Mentha spicata, Mentha pulegium, Lavandula angustifolia, Mentha piperita, Origanum dictamnus, and Origanum vulgare, isolated from the respective aromatic plants from NE Greece, were administered 60 minutes prior to intraperitoneal (i.p.) injection of a lethal dose of PTZ to eight respective groups of Balb-c mice. Control group received only one i.p. PTZ injection. Motor and behavioral activity of the animals after EOs administration, development of tonic-clonic seizures, seizure latency and severity, and percentage of survival after PTZ administration were determined for each group. All groups of mice treated with the EOs showed reduced activity and stability after the administration of the oil, except for those treated with O. vulgare (100% mortality after the administration of the oil). After PTZ administration, mice from the different groups showed increased latency and reduced severity of seizures (ranging from simple twitches to complete seizures). Mice who had received M. piperita demonstrated no seizures and 100% survival. The different drastic component and its concentration could account for the diversity of anticonvulsant effects.

Effects of gasoline engine emissions on preexisting allergic airway responses in mice.

PubMed

Day, Kimberly C; Reed, Matthew D; McDonald, Jacob D; Seilkop, Steven K; Barrett, Edward G

2008-10-01

Gasoline-powered vehicle emissions contribute significantly to ambient air pollution. We hypothesized that exposure to gasoline engine emissions (GEE) may exacerbate preexisting allergic airway responses. Male BALB/c mice were sensitized by injection with ovalbumin (OVA) and then received a 10-min aerosolized OVA challenge. Parallel groups were sham-sensitized with saline. Mice were exposed 6 h/day to air (control, C) or GEE containing particulate matter (PM) at low (L), medium (M), or high (H) concentrations, or to the H level with PM removed by filtration (high-filtered, HF). Immediately after GEE exposure mice received another 10-min aerosol OVA challenge (pre-OVA protocol). In a second (post-OVA) protocol, mice were similarly sensitized but only challenged to OVA before air or GEE exposure. Measurements of airway hyperresponsiveness (AHR), bronchoalveolar lavage (BAL), and blood collection were performed approximately 24 h after the last exposure. In both protocols, M, H, and HF GEE exposure significantly decreased BAL neutrophils from nonsensitized mice but had no significant effect on BAL cells from OVA-sensitized mice. In the pre-OVA protocol, GEE exposure increased OVA-specific IgG(1) but had no effect on BAL interleukin (IL)-2, IL-4, IL-13, or interferon (IFN)-gamma in OVA-sensitized mice. Nonsensitized GEE-exposed mice had increased OVA-specific IgG(2a), IgE, and IL-2, but decreased total IgE. In the post-OVA protocol, GEE exposure reduced BAL IL-4, IL-5, and IFN-gamma in nonsensitized mice but had no effect on sensitized mice. These results suggest acute exposure to the gas-vapor phase of GEE suppressed inflammatory cells and cytokines from nonsensitized mice but did not substantially exacerbate allergic responses.

Effects of intracerebroventricular injections of free fatty acids, lysophospholipids, or platelet activating factor in a mouse model of orofacial pain.

PubMed

Vahidy, Wajiha H; Ong, Wei-Yi; Farooqui, Akhlaq A; Yeo, Jin-Fei

2006-10-01

The present study was carried out to determine the effects of central nervous free fatty acids, lysophospholipids, or platelet activating factor (PAF), in a mouse facial carrageenan injection model of orofacial pain. Mice that received intracerebroventricular (I.C.V.) injection of arachidonic acid or oleic acid showed significantly reduced allodynia and behavioral responses to von Frey hair stimulation of a carrageenan-injected area of the face, at 8 h post-injection, compared to controls that received I.C.V. injection of vehicle. In contrast to free fatty acids, increased responses were observed in mice at 72 h after I.C.V. lysophosphatidic acid or lysophosphatidylcholine injection, and at 8 and 24 h after PAF injection, compared vehicle injected controls. Information regarding pro-nociceptive effect of specific brain lipids may be a useful basis for further studies to explore mechanism.

[Effect of epsilon-aminocaproic acid, cyclophosphamide and their combination on the growth of autochthonous sarcomas of mice induced by benzo(a)pyrene].

PubMed

Anikin, I V; Tyndyk, M L; Zabezhinskiĭ, M A; Popovich, I G; Anisimov, V N; Pliss, G B

2014-01-01

Antifibrinolytic drug epsilon-aminocaproic acid as a therapeutic form (5% solution in saline) was tested for antitumor activity in the autochthonous subcutaneous tumors of mice, induced by benzo (a) pyrene, in monotherapy mode (instead animals received drinking water) and in combination with cyclophosphamide, which was administered once intraperitoneally in the dose of 200 mg/kg. In the control groups, treated with drinking water and saline solution instead of water, there was no stabilization and reduction in tumor volume, while in the groups receiving epsilon-aminocaproic acid, cyclophosphamide and their combination statistically significantly in comparison with the control groups there was increased the proportion of tumors with not changed or reduced volume; epsilon-aminocaproic acid enhanced the antitumor effect of cyclophosphamide. The data obtained are for further study of the antitumor effect of epsilon-aminocaproic acid.

Effects of Nonpurified and Choline Supplemented or Nonsupplemented Purified Diets on Hepatic Steatosis and Methionine Metabolism in C3H Mice

PubMed Central

Syed, Raisa; Shibata, Noreene M.; Kharbanda, Kusum K.; Su, Ruijun J.; Olson, Kristin; Yokoyama, Amy; Rutledge, John C.; Chmiel, Kenneth J.; Kim, Kyoungmi; Halsted, Charles H.

2016-01-01

Abstract Background: Previous studies indicated that nonpurified and purified commercially available control murine diets have different metabolic effects with potential consequences on hepatic methionine metabolism and liver histology. Methods: We compared the metabolic and histological effects of commercial nonpurified (13% calories from fat; 57% calories from carbohydrates with 38 grams/kg of sucrose) and purified control diets (12% calories from fat; 69% calories from carbohydrates with ∼500 grams/kg of sucrose) with or without choline supplementation administered to C3H mice with normal lipid and methionine metabolism. Diets were started 2 weeks before mating, continued through pregnancy and lactation, and continued in offspring until 24 weeks of age when we collected plasma and liver tissue to study methionine and lipid metabolism. Results: Compared to mice fed nonpurified diets, the liver/body weight ratio was significantly higher in mice fed either purified diet, which was associated with hepatic steatosis and inflammation. Plasma alanine aminotransferase levels were higher in mice receiving the purified diets. The hepatic S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) ratio was higher in female mice fed purified compared to nonpurified diet (4.6 ± 2 vs. 2.8 ± 1.9; P < 0.05). Choline supplementation was associated with improvement of some parameters of lipid and methionine metabolism in mice fed purified diets. Conclusions: Standard nonpurified and purified diets have significantly different effects on development of steatosis in control mice. These findings can help in development of animal models of fatty liver and in choosing appropriate laboratory control diets for control animals. PMID:26881897

Nociceptive Neuropeptide Increases and Periorbital Allodynia in a Model of Traumatic Brain Injury

PubMed Central

Elliott, Melanie B.; Oshinsky, Michael L.; Amenta, Peter S.; Awe, Olatilewa O.; Jallo, Jack I.

2014-01-01

Objective This study tests the hypothesis that injury to the somatosensory cortex is associated with periorbital allodynia and increases in nociceptive neuropeptides in the brainstem in a mouse model of controlled cortical impact (CCI) injury. Methods Male C57BL/6 mice received either CCI or craniotomy-only followed by weekly periorbital von Frey (mechanical) sensory testing for up to 28 days post-injury. Mice receiving an incision only and naïve mice were included as control groups. Changes in calcitonin gene-related peptide (CGRP) and substance P (SP) within the brainstem were determined using enzyme-linked immunosorbent assay and immunohistochemistry, respectively. Activation of ionized calcium-binding adaptor molecule-1–labeled macrophages/microglia and glial fibrillary acidic protein (GFAP)-positive astrocytes were evaluated using immunohistochemistry because of their potential involvement in nociceptor sensitization. Results Incision-only control mice showed no changes from baseline periorbital von Frey mechanical thresholds. CCI significantly reduced mean periorbital von Frey thresholds (periorbital allodynia) compared with baseline and craniotomy-only at each endpoint, analysis of variance P < .0001. Craniotomy significantly reduced periorbital threshold at 14 days but not 7, 21, or 28 days compared with baseline threshold, P < .01. CCI significantly increased SP immunoreactivity in the brainstem at 7 and 14 days but not 28 days compared with craniotomy-only and controls, P < .001. CGRP levels in brainstem tissues were significantly increased in CCI groups compared with controls (incision-only and naïve mice) or craniotomy-only mice at each endpoint examined, P < .0001. There was a significant correlation between CGRP and periorbital allodynia (P < .0001, r = −0.65) but not for SP (r = 0.20). CCI significantly increased the number of macrophage/microglia in the injured cortex at each endpoint up to 28 days, although cell numbers declined over weeks post-injury, P < .001. GFAP+ immunoreactivity was significantly increased at 7 but not 14 or 28 days after CCI, P < .001. Craniotomy resulted in transient periorbital allodynia accompanied by transient increases in SP, CGRP, and GFAP immunoreactivity compared with control mice. There was no increase in the number of macrophage/microglia cells compared with controls after craniotomy. Conclusion Injury to the somatosensory cortex results in persistent periorbital allodynia and increases in brainstem nociceptive neuropeptides. Findings suggest that persistent allodynia and increased neuropeptides are maintained by mechanisms other than activation of macrophage/microglia or astrocyte in the injured somatosensory cortex. PMID:22568499

Teratogenic effects of retinoic acid on neurulation in mice embryos.

PubMed

Nobakht, M; Zirak, A; Mehdizadeh, M; Tabatabaeei, P

2006-02-21

Retinoic acids (RA) are natural chemicals that exert a hormone-like activity and a variety of biological effects on early development of mouse. In this study, the probable teratogenic effects of RA on CNS have been investigated in pregnant mice (n = 20) divided into four groups: (1) untreated controls, (2) controls which received a single dose of DMSO, (3) a group that received 40 mg/kg, and (4) a group that received 60 mg/kg of all-trans RA in DMSO, respectively on the eighth day of gestation. Embryos whose dams had received 40 and 60 mg/kg doses of RA, showed malformations and decreased size. At 40 mg/kg dosage level, 50% of the embryos had closed neural tubes while at 60 mg/kg dosage level the neural tube failed to close. The neuroblast mantle layers were disorganized in the 40 mg/kg and even more in the 60 mg/kg exposed group compared to the controls. In mitosis, the density of chromatin was increased in the 60 mg/kg dose group. Compared to controls the 40 and 60 mg/kg dose groups of RA treated dams decreases in the luminal longitudinal and internal measures were observed. Also the thickness of ventricular, mantle and marginal layers was smaller. Wide intercellular spaces due to the degenerated cells at high doses of RA as well as an accumulation of intercellular fluid were observed. Therefore, the wedge shape of neuroepithelium was abolished, preventing the elevation of the neural wall.

Alpha-ketoglutarate stabilizes redox homeostasis and improves arterial elasticity in aged mice.

PubMed

Niemiec, T; Sikorska, J; Harrison, A; Szmidt, M; Sawosz, E; Wirth-Dzieciolowska, E; Wilczak, J; Pierzynowski, S

2011-02-01

The objective of this study was to evaluate the effect of α-ketoglutarate on redox state parameters and arterial elasticity in elderly mice. Mice in the control group were fed with standard diet, while the experimental animals received the diet supplemented either with calcium (Ca-AKG) or sodium salt of α-ketoglutarate (Na-AKG). The experimental animals were divided into 4 groups with 10 individuals in each: control I (12 months old), control II (2 months old), experimental group I fed with Ca-AKG (12 months old) and experimental group II fed with Na-AKG (12 months old). Mice treated with Ca-AKG as well as the control II animals demonstrated significantly higher level of total antioxidant status (TAS), comparing to the control I animals and those treated with Ca-AKG. Thiobarbituric acid reactive substances (TBARS) level in blood plasma was found significantly lower in young and Ca-AKG treated mice. TBARS liver concentration was significantly different in each examined group. The study also demonstrates the decrease in TBARS level in Ca-AKG treated animals. Treatment with Na-AKG significantly increased glutathione peroxidase activity and decreased the activity of superoxide dismutase. The presented results suggest that Ca-AKG protects the organism against the free radicals related elderly processes. The study presents also the effect of Ca-AKG treatment on arterial elastic characteristics in elderly mice. The beneficial effect of Ca-AKG on ageing organisms was confirmed via redox state stabilization and blood vessel elasticity improvement.

Glucose concentration in the blood of intact and alloxan-treated mice after pretreatment with commercial preparations of Stevia rebaudiana (Bertoni).

PubMed

Raskovic, Aleksandar; Gavrilovic, Maja; Jakovljevic, Vida; Sabo, Jan

2004-01-01

The study was concerned with the effect of mice pretreatment with two commercial products of Stevia rebaudiana Bertoni on the blood glucose concentration. One group of mice was pretreated four days with 200 mg/kg of Stevita (Stevita Co, INC, Arlington Texas) (stevia) and the other with 20 mg/kg of Clear Steviosides liquid (Stevita Co, INC, Herbal supplement, Brazil) (stevioside), whereas the animals of control group received at the same time physiological solution. Blood glucose concentration was measured before pretreatment and four days after that. The changes in glucose level were provoked by glucose-tolerance test (500 mg/kg, p.o.) and subcutaneous injection of adrenaline (0.2 mg/kg). The same procedure of measuring blood glucose was applied on the mice with alloxan-induced diabetes mellitus (two doses of 100 mg/kg with a 24-hour interval). Blood glucose levels in mice pretreated with stevia and stevioside were lower compared with control (7.82:6.82:8.01). Also, a smaller increase in this parameter compared to control was registered with pretreated mice in the glucose-tolerance test, pretreatment with stevioside being again more effective (8.68:6.36:5.82). Pretreatment with stevioside caused no significant increase in blood glucose concentration after administering adrenaline, which was not the case with the animals pretreated with stevia and control. Pretreatment with stevia, and to a greater extent with stevioside, protected test animals from the toxic action of alloxan compared with controls.

[Effect of multi-walled carbon nanotubes on the morphofunctional state of the small intestine cells of mice].

PubMed

Beliaeva, N N; Mikhaĭlova, R I; Sycheva, L P; Savostikova, O N; Zelenkina, E A; Gasimova, Z M; Alekseeva, A V; Ryzhova, I N; Altaeva, A A

2012-01-01

The experiment was conducted in male mice SBAchS57Vl/6 and Balb/c, which consumed water, obtained from the use of carbon nanotubes. in a free drinking regimen for 2 weeks (mice SBAchS57Vl/6) and 2 months (mice Balb/c) Control group consisted of three groups of animals: intact and mice received fine coal in the same concentrations as under the impact of the nanotubes. Under exposure to the maximal of the studied concentration of carbon nanotubes a significant change in the fine structure of the villi of the small intestine was found in the form of increasing the number of unstructured villi and proliferation of epithelial cells, most pronounced in duration of exposure until 2 months.

Effect of Woody Debris abundance on daytime refuge use by cotton mice.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hinkelman, Travis, M.; Loeb, Susan, C.

Abstract - Daytime refuges are important to nocturnal rodents for protection from predators and environmental extremes. Because refuges of forest-dwelling rodents are often associated with woody debris, we examined refuge use by 37 radio-collared Peromyscus gossypinus (cotton mice) in experimental plots with different levels of woody debris. Treatment plots had six times (≈ 60 m3/ha) the volume of woody debris as control plots (≈ 10 m3/ha). Of 247 refuges, 159 were in rotting stumps (64%), 32 were in root boles (13%), 19 were in brush piles (8%), and 16 were in logs (6%); 10 refuges could not be identified. Stumpsmore » were the most common refuge type in both treatments, but the distribution of refuge types was significantly different between treatment and control plots. Root boles and brush piles were used more on treatment plots than on control plots, and logs were used more on control plots than on treatment plots. Refuge type and vegetation cover were the best predictors of refuge use by cotton mice; root bole refuges and refuges with less vegetation cover received greater-than-expected use by mice. Abundant refuges, particularly root boles, may improve habitat quality for cotton mice in southeastern pine forests.« less

Development of Ethanol Withdrawal-Related Sensitization and Relapse Drinking in Mice Selected for High or Low Ethanol Preference

PubMed Central

Lopez, Marcelo F.; Grahame, Nicholas J.; Becker, Howard C.

2010-01-01

Background Previous studies have shown that high alcohol consumption is associated with low withdrawal susceptiblility, while at the same time, other studies have shown that exposure to ethanol vapor increases alcohol drinking in rats and mice. In the present studies, we sought to shed light on this seeming contradiction by using mice selectively bred for High- (HAP) and Low- (LAP) Alcohol Preference, first, assessing these lines for differences in signs of ethanol withdrawal and second, for differences in the efficacy of intermittent alcohol vapor exposure on elevating subsequent ethanol intake. Methods Experiment 1 examined whether these lines of mice differed in ethanol withdrawal-induced CNS hyperexcitability and the development of sensitization to this effect following intermittent ethanol vapor exposure. Adult HAP and LAP lines (replicates 1 and 2), and the C3H/HeNcr inbred strain (included as a control genotype for comparison purposes) received intermittent exposure to ethanol vapor and were evaluated for ethanol withdrawal-induced seizures assessed by scoring handling-induced convulsions (HIC). Experiment 2 examined the influence of chronic intermittent ethanol exposure on voluntary ethanol drinking. Adult male and female HAP-2 and LAP-2 mice, along with male C57BL/6J (included as comparative controls) were trained to drink 10% ethanol using a limited access (2 hr/day) 2-bottle choice paradigm. After stable baseline daily intake was established, mice received chronic intermittent ethanol vapor exposure in inhalation chambers. Ethanol intake sessions resumed 72 hr after final ethanol (or air) exposure for 5 consecutive days. Results Following chronic ethanol treatment, LAP mice exhibited overall greater withdrawal seizure activity compared to HAP mice. In Experiment 2, chronic ethanol exposure/withdrawal resulted in a significant increase in ethanol intake in male C57BL/6J, and modestly elevated intake in HAP-2 male mice. Ethanol intake for male control mice did not change from baseline levels of intake. In contrast, HAP-2 females and LAP-2 mice of both sexes did not show changes in ethanol intake as a consequence of intermittent ethanol exposure. Conclusions Overall, these results indicate that the magnitude of ethanol withdrawal-related seizures is inversely related to inherited ethanol intake preference. Additionally, intermittent ethanol vapor exposure appears more likely to affect high-drinking mice (C57BL/6J and HAP-2) than low drinkers, even though these animals are less affected by ethanol withdrawal. PMID:21314693

Promotion of lung adenocarcinoma following inhalation exposure to multi-walled carbon nanotubes

PubMed Central

2014-01-01

Background Engineered carbon nanotubes are currently used in many consumer and industrial products such as paints, sunscreens, cosmetics, toiletries, electronic processes and industrial lubricants. Carbon nanotubes are among the more widely used nanoparticles and come in two major commercial forms, single-walled carbon nanotubes (SWCNT) and the more rigid, multi-walled carbon nanotubes (MWCNT). The low density and small size of these particles makes respiratory exposures likely. Many of the potential health hazards have not been investigated, including their potential for carcinogenicity. We, therefore, utilized a two stage initiation/promotion protocol to determine whether inhaled MWCNT act as a complete carcinogen and/or promote the growth of cells with existing DNA damage. Six week old, male, B6C3F1 mice received a single intraperitoneal (ip) injection of either the initiator methylcholanthrene(MCA, 10 μg/g BW, i.p.), or vehicle (corn oil). One week after i.p. injections, mice were exposed by inhalation to MWCNT (5 mg/m3, 5 hours/day, 5 days/week) or filtered air (controls) for a total of 15 days. At 17 months post-exposure, mice were euthanized and examined for lung tumor formation. Results Twenty-three percent of the filtered air controls, 26.5% of the MWCNT-exposed, and 51.9% of the MCA-exposed mice, had lung bronchiolo-alveolar adenomas and lung adenocarcinomas. The average number of tumors per mouse was 0.25, 0.81 and 0.38 respectively. By contrast, 90.5% of the mice which received MCA followed by MWCNT had bronchiolo-alveolar adenomas and adenocarcinomas with an average of 2.9 tumors per mouse 17months after exposure. Indeed, 62% of the mice exposed to MCA followed by MWCNT had bronchiolo-alveolar adenocarcinomas compared to 13% of the mice that received filtered air, 22% of the MCA-exposed, or 14% of the MWCNT-exposed. Mice with early morbidity resulting in euthanasia had the highest rate of metastatic disease. Three mice exposed to both MCA and MWCNT that were euthanized early had lung adenocarcinoma with evidence of metastasis (5.5%). Five mice (9%) exposed to MCA and MWCNT and 1 (1.6%) exposed to MCA developed serosal tumors morphologically consistent with sarcomatous mesotheliomas, whereas mice administered MWCNT or air alone did not develop similar neoplasms. Conclusions These data demonstrate that some MWCNT exposures promote the growth and neoplastic progression of initiated lung cells in B6C3F1 mice. In this study, the mouse MWCNT lung burden of 31.2 μg/mouse approximates feasible human occupational exposures. Therefore, the results of this study indicate that caution should be used to limit human exposures to MWCNT. PMID:24405760

A possible role of a cerebral energy gene in alcoholism.

PubMed

Ribeiro, A F; Correia, D; Boerngen-Lacerda, R; Brunialti-Godard, A L

2012-02-17

We examined a possible relationship between genes responsible for energy metabolism of the brain and addictive behavior in an animal model. We used non-inbred, Swiss mice exposed to a three-bottle free-choice model [water, 5% (v/v) ethanol, and 10% (v/v) ethanol] over a 16-week period, consisting of four phases: acquisition, withdrawal, reexposure, and quinine-adulteration. The mice were then behaviorally classified into three groups: loss-of-control-drinker (preference for ethanol and high levels of consumption during all phases, N = 6), heavy-drinker (preference for ethanol and high levels of consumption during acquisition and reduction during quinine-adulteration, N = 7), and light-drinker (preference for water during all phases, N = 10). Another group only received tap water (ethanol-naive control mice, N = 9). Further analysis using quantitative real-time PCR showed that in mice behaviorally classified as loss-of-control-drinkers, there was a significant inverse correlation between transcript levels of the Hadh gene and those of other energy metabolism genes in the nucleus of the amygdala, suggesting that this pathway may contribute to ethanol consumption in these mice. We conclude that cerebral energy metabolism is involved with ethanol addiction, meriting further study.

WOUND HEALING ACTIVITY OF EXTRACT FROM THYMUS DAENENSIS IN BURN WOUND MODEL: AN EXPERIMENTAL ANIMAL STUDY.

PubMed

Babaeizadeh, Simin; Heydarnejhad, Saeed; Pirbalouti, Abdollah Ghasemi; Khamesipoor, Faham; Moghtadaei-Khorasgani, Elham; Heydari-Soureshjani, Parisa

2016-11-01

Bum wound is one of the most common complications and remains a major public health issue affecting all ages groups in both developed and developing countries. This study was aimed to evaluate the extract from Thymus daenensis and silver sulfadiazine on healing bum wounds in mice. In this experimental study, the ethanol extract from the aerial parts of T. daenensis (Lamiaceae) was used. Second-degree bum wounds were induced in three groups of eight Balb/C mice each. Group-I: the animals were treated with simple cream (control), Group-II: the animals were treated with simple cream containing the herb extract, and Group-III: the animals received the standard drug (silver sulfadiazine). The experimental groups were evaluated based on wound area, epithelialization time and histopathological characteristics. There were significant differences in surface area and the period of bum wound healing between the groups, particularly among Group-II when the animals received the extract of T. daenensis in comparison with control. At the 18" day, there was no significant improvement in healing percentage of the herb treated (94.6%) in comparison to the animals receiving the standard drug (95.8%). The best results of histopathological investigation were obtained with the extract of T. daenensis, when compared to the other group as well as to the control and standard drug. The herbal cream experimentally and histopathologically revealed a bum wound healing activity probably due to the antioxidant and anti-inflammatory activity of its phytochemical contents, especially phenolic compounds. Therefore, T. daenensis accelerated wound healing in mice and thus supports its traditional use.

Beneficial effects of sarpogrelate hydrochloride, a 5-HT2A receptor antagonist, supplemented with pioglitazone on diabetic model mice.

PubMed

Iizuka, Kenji; Hamaue, Naoya; Machida, Takuji; Hirafuji, Masahiko; Tsuji, Masahiro

2009-01-01

Feeding behavior control and dietetics with consequent weight reduction can be the most efficacious and fundamental methods to normalize fasting blood glucose. However, pioglitazone treatment has been found to incrementally increase body weight. In this study, we investigated whether the combined application of a 5-HT(2A) receptor antagonist, sarpogrelate, with pioglitazone can provide a clinical benefit. Diabetic male KK-A(y) mice were randomly assigned to four groups: those receiving 10 mg/kg/day pioglitazone treatment for 30 days (pioglitazone group, n = 7), those receiving 30 mg/kg/day sarpogrelate treatment for 30 days (sarpogrelate group, n = 7), those receiving both agents for 30 days (pioglitazone + sarpogrelate group, n = 7) and those receiving no treatment (control group, n = 7). Feed intake was lower in the pioglitazone + sarpogrelate group than in the pioglitazone group. Water intake was also significantly lower in the pioglitazone, sarpogrelate and pioglitazone + sarpogrelate groups than in the control group. Combined application (pioglitazone + sarpogrelate) resulted in a 176% increase in leptin concentration compared with vehicle control. Body weight was significantly higher in the pioglitazone group, and there was a trend toward a smaller increment in body weight in the pioglitazone + sarpogrelate group. Mean values, calculated by multiplying insulin concentration and nonfasting glucose concentration, were significantly lower in the pioglitazone + sarpogrelate group than in the control group. These results suggest that the combined application of sarpogrelate with pioglitazone provides therapeutic benefits not only in preventing adverse effects but also in the treatment of diabetes.

Acute toxicity of ibogaine and noribogaine.

PubMed

Kubiliene, Asta; Marksiene, Rūta; Kazlauskas, Saulius; Sadauskiene, Ilona; Razukas, Almantas; Ivanov, Leonid

2008-01-01

To evaluate acute toxic effect of ibogaine and noribogaine on the survival of mice and determine median lethal doses of the substances mentioned. White laboratory mice were used for the experiments. Ibogaine and noribogaine were administered intragastrically to mice via a stomach tube. Control animals received the same volume of saline. The median lethal dose was calculated with the help of a standard formula. To determine the median lethal dose of ibogaine, the doses of 100, 300, 400, and 500 mg/kg were administered intragastrically to mice. The survival time of mice after the drug administration was recorded, as well as the number of survived mice in each group. Upon administration of ibogaine at a dose of 500 mg/kg, all mice in this dose group died. Three out of four mice died in the group, which received 300 mg/kg of ibogaine. No mouse deaths were observed in the group, which received 100 mg/kg of ibogaine. The determined LD(50) value of ibogaine equals to 263 mg/kg of body mass. In order to determine the median lethal dose of noribogaine, the doses of 300, 500, 700, and 900 mg/kg were administered to mice intragastrically. Noribogaine given at a dose of 500 mg/kg had no impact on the mouse survival. The increase of noribogaine dose to 700 mg/kg of mouse body mass led to the death of three out of four mice in the group. Upon administration of noribogaine at a dose of 900 mg/kg, all mice in this group died. The LD(50) value of noribogaine in mice determined on the basis of the number of dead mice and the size of the doses used equals to 630 mg/kg of mouse body mass. The behavior of mice was observed upon administration of ibogaine or noribogaine. Low doses of ibogaine and noribogaine had no impact on the mouse behavior. External effects (convulsions, nervous behaviour, limb paralysis) were observed only when substances were administrated at higher doses. It has been determined that the median lethal dose of ibogaine and noribogaine equals to 263 mg and 630 mg/kg of mouse body mass, respectively. The toxicity of ibogaine is 2.4 times higher than that of noribogaine.

Lepidium meyenii (Maca) increases litter size in normal adult female mice

PubMed Central

Ruiz-Luna, Ana C; Salazar, Stephanie; Aspajo, Norma J; Rubio, Julio; Gasco, Manuel; Gonzales, Gustavo F

2005-01-01

Background Lepidium meyenii, known as Maca, grows exclusively in the Peruvian Andes over 4000 m altitude. It has been used traditionally to increase fertility. Previous scientific studies have demonstrated that Maca increases spermatogenesis and epididymal sperm count. The present study was aimed to investigate the effects of Maca on several fertility parameters of female mice at reproductive age. Methods Adult female Balb/C mice were divided at random into three main groups: i) Reproductive indexes group, ii) Implantation sites group and iii) Assessment of uterine weight in ovariectomized mice. Animals received an aqueous extract of lyophilized Yellow Maca (1 g/Kg BW) or vehicle orally as treatment. In the fertility indexes study, animals received the treatment before, during and after gestation. The fertility index, gestation index, post-natal viability index, weaning viability index and sex ratio were calculated. Sexual maturation was evaluated in the female pups by the vaginal opening (VO) day. In the implantation study, females were checked for implantation sites at gestation day 7 and the embryos were counted. In ovariectomized mice, the uterine weight was recorded at the end of treatment. Results Implantation sites were similar in mice treated with Maca and in controls. All reproductive indexes were similar in both groups of treatment. The number of pups per dam at birth and at postnatal day 4 was significantly higher in the group treated with Maca. VO day occurred earlier as litter size was smaller. Maca did not affect VO day. In ovariectomized mice, the treatment with Maca increased significantly the uterine weights in comparison to their respective control group. Conclusion Administration of aqueous extract of Yellow Maca to adult female mice increases the litter size. Moreover, this treatment increases the uterine weight in ovariectomized animals. Our study confirms for the first time some of the traditional uses of Maca to enhance female fertility. PMID:15869705

Lepidium meyenii (Maca) increases litter size in normal adult female mice.

PubMed

Ruiz-Luna, Ana C; Salazar, Stephanie; Aspajo, Norma J; Rubio, Julio; Gasco, Manuel; Gonzales, Gustavo F

2005-05-03

Lepidium meyenii, known as Maca, grows exclusively in the Peruvian Andes over 4000 m altitude. It has been used traditionally to increase fertility. Previous scientific studies have demonstrated that Maca increases spermatogenesis and epididymal sperm count. The present study was aimed to investigate the effects of Maca on several fertility parameters of female mice at reproductive age. Adult female Balb/C mice were divided at random into three main groups: i) Reproductive indexes group, ii) Implantation sites group and iii) Assessment of uterine weight in ovariectomized mice. Animals received an aqueous extract of lyophilized Yellow Maca (1 g/Kg BW) or vehicle orally as treatment. In the fertility indexes study, animals received the treatment before, during and after gestation. The fertility index, gestation index, post-natal viability index, weaning viability index and sex ratio were calculated. Sexual maturation was evaluated in the female pups by the vaginal opening (VO) day. In the implantation study, females were checked for implantation sites at gestation day 7 and the embryos were counted. In ovariectomized mice, the uterine weight was recorded at the end of treatment. Implantation sites were similar in mice treated with Maca and in controls. All reproductive indexes were similar in both groups of treatment. The number of pups per dam at birth and at postnatal day 4 was significantly higher in the group treated with Maca. VO day occurred earlier as litter size was smaller. Maca did not affect VO day. In ovariectomized mice, the treatment with Maca increased significantly the uterine weights in comparison to their respective control group. Administration of aqueous extract of Yellow Maca to adult female mice increases the litter size. Moreover, this treatment increases the uterine weight in ovariectomized animals. Our study confirms for the first time some of the traditional uses of Maca to enhance female fertility.

Photocarcinogenesis study of aloe vera [CAS NO. 481-72-1(Aloe-emodin)] in SKH-1 mice (simulated solar light and topical application study).

PubMed

2010-09-01

The popular recognition of the Aloe barbadensis Miller (Aloe vera) plant as a therapeutic dermatologic agent has led to the widespread incorporation of Aloe vera leaf extracts in skincare products. Studies have suggested that Aloe vera in skincare preparations may enhance the induction of skin cancer by ultraviolet radiation. A 1-year study was conducted in mice to determine whether the topical application of creams containing Aloe vera plant extracts (aloe gel, whole leaf, or decolorized whole leaf) or creams containing aloe-emodin would enhance the photocarcinogenicity of simulated solar light (SSL). 1-YEAR STUDY: groups of 36 male and 36 female Crl:SKH-1 (hr -/hr -) hairless mice received topical applications of control cream or creams containing 3% or 6% (w/w) aloe gel, whole leaf, or decolorized whole leaf or 7.46 or 74.6 µg/g aloe-emodin to the dorsal skin region each weekday morning. The mice were irradiated with SSL emitted from filtered 6 kW xenon arc lamps each weekday afternoon. The topical applications of creams and irradiance exposures were conducted 5 days per week for a period of 40 weeks. A 12-week recovery/observation period followed the 40-week treatment/exposure period. Additional groups of 36 male and 36 female mice received no cream and were exposed to 0.00, 6.85, 13.70, or 20.55 mJ⋅CIE/cm2 SSL per day. Mice that received no cream treatment and were exposed to increasing levels of SSL showed significant SSL exposure-dependent decreases in survival and significant increases in the in-life observations of skin lesion onset, incidence, and multiplicity, and significant SSL exposure-dependent increases in the incidences and multiplicities of histopathology-determined squamous cell nonneoplastic skin lesions (squamous hyperplasia and focal atypical hyperplasia) and squamous cell neoplasms (papilloma, carcinoma in situ, and/or carcinoma). Squamous cell neoplasms were not detected in mice that received no SSL exposure. The topical treatment with the control cream of mice that were exposed to SSL did not impart a measurable effect when compared with comparable measurements in mice that received no cream treatment and were exposed to the same level of SSL, suggesting that the control cream used in these studies did not alter the efficiency of the SSL delivered to mice or the tolerability of mice to SSL. The application of aloe gel creams to mice had no effect on body weights, survival, or the in-life observations of skin lesion onset, incidence, or multiplicity. The administration of aloe gel creams to male mice had no effect on the incidences or multiplicities of histopathology-determined squamous cell nonneoplastic skin lesions or neoplasms. Female mice treated with aloe gel creams (3% and 6%) had significantly increased multiplicities of squamous cell neoplasms. There were no treatment-related effects on body weights, survival, or the in-life observations of skin lesion onset, incidence, or multiplicity in mice treated with the whole leaf creams. In male mice exposed to SSL and treated with the 6% whole leaf cream, a significant increase was observed in the multiplicity of squamous cell neoplasms. Female mice exposed to SSL and treated with the 3% whole leaf creams had significantly decreased multiplicity of squamous cell nonneoplastic lesions and significantly increased multiplicity of squamous cell neoplasms. Female mice exposed to SSL and treated with the 6% whole leaf cream had significantly decreased multiplicity of squamous cell nonneoplastic lesions. The application of decolorized whole leaf creams to mice had no effect on body weights, survival, or the in-life observations of skin lesion onset, incidence, or multiplicity. Male mice administered the 3% decolorized whole leaf cream had significantly increased multiplicity of squamous cell neoplasms. Female mice administered the 3% decolorized whole leaf cream had significantly decreased multiplicity of squamous cell nonneoplastic skin lesions and significantly increased multiplicity of squamous cell neoplasms. In female mice that received the 6% decolorized whole leaf cream, there was a significant increase in the multiplicity of squamous cell neoplasms. As with the Aloe vera plant extracts, the application of aloe-emodin creams to mice had no measurable effect on body weights, survival, or the in-life observations of skin lesion onset, incidence, or multiplicity. The administration of aloe-emodin creams to male mice had no effect on the incidence or multiplicity of histopathology-determined nonneoplastic skin lesions or squamous cell neoplasms. Female mice treated with the 74.6 µg/g aloe-emodin cream had significantly decreased multiplicity of histopathology-determined squamous cell nonneoplastic skin lesions and significantly increased multiplicity of squamous cell neoplasms. these experiments investigated the potential of topical application of creams containing extracts of Aloe barbadensis Miller plant (aloe gel, whole leaf, or decolorized whole leaf) or aloe-emodin to alter the photocarcinogenic activity of filtered xenon arc simulated solar light (SSL) in male and female SKH-1 hairless mice. Data on skin lesions were collected both on digital images during the in-life phase and by histopathologic evaluation at necropsy. No effects of creams upon SSL-induced skin lesions were identified from data collected during the in-life phase. ALOE GEL OR ALOE-EMODIN: under the conditions of these studies, there was a weak enhancing effect of aloe gel or aloe-emodin on the photocarcinogenic activity of SSL in female but not in male SKH-1 mice based on an increase in the multiplicity of histopathologically-determined squamous cell neoplasms. under the conditions of these studies, there was a weak enhancing effect of aloe whole leaf or decolorized whole leaf on the photocarcinogenic activity of SSL in both male and female SKH-1 mice based on an increase in the multiplicity of histopathologically-determined squamous cell neoplasms.

Testicular Busulfan Injection in Mice to Prepare Recipients for Spermatogonial Stem Cell Transplantation Is Safe and Non-Toxic.

PubMed

Qin, YuSheng; Liu, Ling; He, YaNan; Wang, Chen; Liang, MingYuan; Chen, XiaoLi; Hao, HaiSheng; Qin, Tong; Zhao, XueMing; Wang, Dong

2016-01-01

Current methods of administering busulfan to remove the endogenous germ cells cause hematopoietic toxicity, require special instruments and a narrow transplantation time. We use a direct testicular injection of busulfan method for preparing recipients for SSC transplantation. Male ICR mice (recipients) were divided into four groups, and two experimental groups were treated with a bilateral testicular injection of 4 or 6 mg/kg/side busulfan (n = 60 per concentration group). Mice received an intraperitoneal injection (i.p.) of 40 mg/kg busulfan (n = 60, positive control) and bilateral testicular injections of 50% DMSO (n = 60, negative control). Donor SSCs from RFP-transgenic C57BL/6J mice were introduced into the seminiferous tubules of each recipient testis via efferent duct injection on day 16-17 after busulfan treatment. Recipient mice mated with mature female ICR mice and the number of progeny was recorded. The index detected at day 14, 21, 28, 35 and 70 after busulfan treatment. Blood analysis shows that the toxicity of busulfan treated groups was much lower than i.p. injection groups. Fertility was restored in mice treated with busulfan and donor-derived offspring were obtained after SSC transplantation. Our study indicated that intratesticular injection busulfan for the preparation of recipients in mice is safe and feasible.

Nonalcoholic steatohepatitic (NASH) mice are protected from higher hepatotoxicity of acetaminophen upon induction of PPAR{alpha} with clofibrate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Donthamsetty, Shashikiran; Bhave, Vishakha S.; Mitra, Mayurranjan S.

2008-08-01

The objective was to investigate if the hepatotoxic sensitivity in nonalcoholic steatohepatitic mice to acetaminophen (APAP) is due to downregulation of nuclear receptor PPAR{alpha} via lower cell division and tissue repair. Male Swiss Webster mice fed methionine and choline deficient diet for 31 days exhibited NASH. On the 32nd day, a marginally toxic dose of APAP (360 mg/kg, ip) yielded 70% mortality in steatohepatitic mice, while all non steatohepatitic mice receiving the same dose survived. {sup 14}C-APAP covalent binding, CYP2E1 protein, and enzyme activity did not differ from the controls, obviating increased APAP bioactivation as the cause of amplified APAPmore » hepatotoxicity. Liver injury progressed only in steatohepatitic livers between 6 and 24 h. Cell division and tissue repair assessed by {sup 3}H-thymidine incorporation and PCNA were inhibited only in the steatohepatitic mice given APAP suggesting that higher sensitivity of NASH liver to APAP-induced hepatotoxicity was due to lower tissue repair. The hypothesis that impeded liver tissue repair in steatohepatitic mice was due to downregulation of PPAR{alpha} was tested. PPAR{alpha} was downregulated in NASH. To investigate whether downregulation of PPAR{alpha} in NASH is the critical mechanism of compromised liver tissue repair, PPAR{alpha} was induced in steatohepatitic mice with clofibrate (250 mg/kg for 3 days, ip) before injecting APAP. All clofibrate pretreated steatohepatitic mice receiving APAP exhibited lower liver injury, which did not progress and the mice survived. The protection was not due to lower bioactivation of APAP but due to higher liver tissue repair. These findings suggest that inadequate PPAR{alpha} expression in steatohepatitic mice sensitizes them to APAP hepatotoxicity.« less

Antibody hyporesponsiveness in resistant BALB/cJ mice intracorneally infected with Pseudomonas aeruginosa.

PubMed

Berk, R S; Preston, M; Montgomery, I N; Hazlett, L D; Tse, H Y

Six- to eight-week-old BALB/cJ (and BALB/cPi) mice were found able to restore corneal clarity within 3 to 4 weeks after intracorneal infection with Pseudomonas aeruginosa strain 19660. However, enzyme-linked immunosorbent assay (ELISA) for serum immunoglobulins directed specifically against P. aeruginosa indicated that the mice were initially non- or hypo-responsive for IgG and IgA over the 4-week holding period. Low IgM titers could be detected 1 week after infection, but tended to decrease with time. When the mice were re-infected by using the contralateral control eye, then the serum IgG levels began to gradually increase as the time interval following the secondary infection increased from 1 to 3 weeks. Re-infected mice did not show a significantly increased rate of corneal clarity restoration with time, when compared to the corneas of mice receiving only a primary infection despite the presence of serum antibodies specific to P. aeruginosa. When congenic mice of the BALB/c background carrying the DBA/2N Idh/Pep-3 locus found on chromosome 1 were intracorneally infected, they tended to restore corneal clarity at approximately the same rate as the BALB/cJ mice. However, the congenic mice mounted a faster and substantially greater magnitude of serum IgM and IgG response during the primary infection than BALB/cJ mice receiving either a primary and/or secondary infection. IgG subclass studies with the congenic mice indicated that serum IgG1, and IgG2a to a lesser extent, were the primary immunoglobulins produced and no major shift in subclass was noted with time during the primary infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary fish oil supplementation inhibits formation of endometriosis-associated adhesions in a chimeric mouse model.

PubMed

Herington, Jennifer L; Glore, Dana R; Lucas, John A; Osteen, Kevin G; Bruner-Tran, Kaylon L

2013-02-01

To examine whether dietary fish oil supplementation reduces development of spontaneous endometriosis-associated adhesions using an established model. Laboratory-based study. Medical center research laboratory. PATIENT(S)/ANIMAL(S): Disease-free women of reproductive age and nude mice. Women were not provided any intervention. Mice were randomized to receive fish oil supplementation or control diet. Experimental endometriosis was established in mice via injection of human endometrial tissue within 16 hours of ovariectomy. Mice were provided standard or menhaden fish oil-supplemented diets for ≥ 2 weeks before initiation of experimental endometriosis and until killing them 1 week later. At necropsy, mice were examined for the presence and extent of adhesions and endometriotic-like lesions. Tissues were excised and morphologically characterized. Adhesions/lesions were reduced in mice provided with dietary fish oil compared with control animals. Leukocytes were more numerous within the adhesions/lesions of the mice maintained on the standard diet compared with animals provided with fish oil. As indicated by staining intensity, collagen deposition was greater at adhesion sites within control mice compared with fish oil-supplemented animals. Wound-healing associated with surgery created an inflammatory peritoneal microenvironment that promoted the development of both experimental endometriosis and adhesions in a murine model. Targeting excessive inflammation with fish oil may be an effective adjuvant therapy to reduce the development of postsurgical adhesions related to endometriosis. Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Neuroprotective effect of p-coumaric acid in mice with cerebral ischemia reperfusion injuries.

PubMed

Sakamula, Romgase; Thong-Asa, Wachiryah

2018-06-01

Cerebral ischemia reperfusion (IR) is associated with neuronal death, which leads to disability and cognitive decline. The pathomechanism occurs because ischemia is exacerbated during the reperfusion period. Neuronal damage susceptibility depends on the affected brain areas and the duration of ischemia. Prevention and supplementation to neurons may help them endure during IR and further benefit them in rehabilitation. We investigated the protective effect of p-coumaric acid (PC) on cerebral IR injuries in mice. We randomly divided 30 male ICR mice into 3 groups of Sham (received vehicle and not induced IR), Control-IR (received vehicle and induced IR) and PC-IR (received 100 mg/kg PC and induced IR). We orally administered vehicle or 100 mg/kg of p-coumaric acid for 2 weeks before inducing the cerebral IR injuries by using 30 min of a bilateral common carotid artery occlusion followed by a 45-min reperfusion. We induced the IR condition in the Control-IR and PC-IR groups but not the Sham group, and only the PC-IR group received p-coumaric acid. After IR induction, we sacrificed all the mice and collected their brain tissues to evaluate their oxidative statuses, whole brain infarctions and vulnerable neuronal deaths. We studied the whole-brain infarction volume by 2, 3, 5-triethyltetrazoliumchloride staining of sections. We performed a histological investigation of the vulnerable neuronal population in the dorsal hippocampus by staining brain sections with 0.1% cresyl violet. The results indicated that IR caused significant increases in calcium and malondialdehyde (MDA) levels, whole brain infarction volume and hippocampal neuronal death. Pretreatment with p-coumaric acid significantly reduced MDA levels, whole-brain infarction volume and hippocampal neuronal death together and increased catalase and superoxide dismutase activities. We conclude here that pretreating animals with p-coumaric acid can prevent IR-induced brain oxidative stress, infarction size and neuronal vulnerability to death in cerebral IR injuries.

Treatment of Highly Virulent Extraintestinal Pathogenic Escherichia coli Pneumonia With Bacteriophages.

PubMed

Dufour, Nicolas; Debarbieux, Laurent; Fromentin, Mélanie; Ricard, Jean-Damien

2015-06-01

To study the effect of bacteriophage treatment on highly virulent extraintestinal Escherichia coli pneumonia in mice and compare it with conventional antimicrobial treatment. Animal investigation. University research laboratory. Pathogen-free 8-week-old Balb/cJRj male mice. Two bacteriophages (536_P1 and 536_P7) were isolated from sewage using strain 536, a highly virulent extraintestinal E. coli. Their in vitro and in vivo efficacy against strain 536 and a ventilator-associated pneumonia E. coli were tested. The first group of mice were infected by intranasal instillation of bioluminescent strain 536 and received 536_P1 intranasally, ceftriaxone, or control. The second group of mice was infected with the ventilator-associated pneumonia strain and received 536_P7. Adaptation of 536_P7 to this clinical isolate was also evaluated in vitro and in vivo. In vivo efficacy of bacteriophage and antibiotic treatment were assessed by recording bioluminescence for short-time periods and by recording body weight and survival of mice for longer periods. Both treatments improved survival compared with control (100% vs 0%), and in vivo bioluminescence recordings showed a similar rapid decrease of emitted light, suggesting prompt bacterial clearance. The majority of mice infected by the ventilator-associated pneumonia strain were not rescued by treatment with 536_P7; however, in vitro adaptation of this bacteriophage toward the ventilator-associated pneumonia strain led to isolate a variant which significantly improved in vivo treatment efficacy (animal survival increased from 20% to 75%). Bacteriophage treatment was as effective as antibiotherapy to provide 100% survival rate in a lethal model of highly virulent E. coli pneumonia. Adaptation of a bacteriophage is a rapid solution to improve its efficacy toward specific strains. These results suggest that phage therapy could be a promising therapeutic strategy for ventilator-associated pneumonia.

Effects of velvet antler polypeptide on sexual behavior and testosterone synthesis in aging male mice

PubMed Central

Zang, Zhi-Jun; Tang, Hong-Feng; Tuo, Ying; Xing, Wei-Jie; Ji, Su-Yun; Gao, Yong; Deng, Chun-Hua

2016-01-01

Twenty-four-month-old male C57BL/6 mice with low serum testosterone levels were used as a late-onset hypogonadism (LOH) animal model for examining the effects of velvet antler polypeptide (VAP) on sexual function and testosterone synthesis. These mice received VAP for 5 consecutive weeks by daily gavage at doses of 100, 200, or 300 mg kg−1 body weight per day (n = 10 mice per dose). Control animals (n = 10) received the same weight-based volume of vehicle. Sexual behavior and testosterone levels in serum and interstitial tissue of testis were measured after the last administration of VAP. Furthermore, to investigate the mechanisms of how VAP affects sexual behavior and testosterone synthesis in vivo, the expression of steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc), and 3β-hydroxysteroid dehydrogenase (3β-HSD) in Leydig cells was also measured by immunofluorescence staining and quantitative real-time PCR. As a result, VAP produced a significant improvement in the sexual function of these aging male mice. Serum testosterone level and intratesticular testosterone (ITT) concentration also increased in the VAP-treated groups. The expression of StAR, P450scc, and 3β-HSD was also found to be enhanced in the VAP-treated groups compared with the control group. Our results suggested that VAP was effective in improving sexual function in aging male mice. The effect of velvet antler on sexual function was due to the increased expression of several rate-limiting enzymes of testosterone synthesis (StAR, P450scc, and 3β-HSD) and the following promotion of testosterone synthesis in vivo. PMID:26608944

Effects of velvet antler polypeptide on sexual behavior and testosterone synthesis in aging male mice.

PubMed

Zang, Zhi-Jun; Tang, Hong-Feng; Tuo, Ying; Xing, Wei-Jie; Ji, Su-Yun; Gao, Yong; Deng, Chun-Hua

2016-01-01

Twenty-four-month-old male C57BL/6 mice with low serum testosterone levels were used as a late-onset hypogonadism (LOH) animal model for examining the effects of velvet antler polypeptide (VAP) on sexual function and testosterone synthesis. These mice received VAP for 5 consecutive weeks by daily gavage at doses of 100, 200, or 300 mg kg-1 body weight per day (n = 10 mice per dose). Control animals (n = 10) received the same weight-based volume of vehicle. Sexual behavior and testosterone levels in serum and interstitial tissue of testis were measured after the last administration of VAP. Furthermore, to investigate the mechanisms of how VAP affects sexual behavior and testosterone synthesis in vivo, the expression of steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc), and 3β-hydroxysteroid dehydrogenase (3β-HSD) in Leydig cells was also measured by immunofluorescence staining and quantitative real-time PCR. As a result, VAP produced a significant improvement in the sexual function of these aging male mice. Serum testosterone level and intratesticular testosterone (ITT) concentration also increased in the VAP-treated groups. The expression of StAR, P450scc, and 3β-HSD was also found to be enhanced in the VAP-treated groups compared with the control group. Our results suggested that VAP was effective in improving sexual function in aging male mice. The effect of velvet antler on sexual function was due to the increased expression of several rate-limiting enzymes of testosterone synthesis (StAR, P450scc, and 3β-HSD) and the following promotion of testosterone synthesis in vivo.

Dermal absorption and short-term biological impact in hairless mice from sunscreens containing zinc oxide nano- or larger particles

PubMed Central

Oytam, Yalchin; Kirby, Jason K.; Gomez-Fernandez, Laura; Baxter, Brent; McCall, Maxine J.

2014-01-01

Previous studies have shown no, or very limited, skin penetration of metal oxide nanoparticles following topical application of sunscreens, yet concerns remain about their safety compared to larger particles. Here, we assessed the comparative dermal absorption of a traceable form of Zn (68Zn) from 68ZnO nano-sized and larger particles in sunscreens. Sunscreens were applied to the backs of virgin or pregnant hairless mice over four days. Control groups received topical applications of the sunscreen formulation containing no ZnO particles, or no treatment. Major organs were assessed for changes in 68Zn/64Zn ratios, 68Zn tracer and total Zn concentrations. Short-term biological impact was assessed by measuring levels of serum amyloid A in blood, and by performing whole-genome transcriptional profiling on livers from each group. Increased concentrations of 68Zn tracer were detected in internal organs of mice receiving topical applications of 68ZnO (nano-sized and larger particles), as well as in fetal livers from treated dams, compared with controls. Furthermore, concentrations of 68Zn in organs of virgin mice treated with sunscreen containing 68ZnO nanoparticles were found to be significantly higher than in mice treated with sunscreen containing larger 68ZnO particles. However, no ZnO-mediated change in total Zn concentration in any of the major organs was observed. Thus, despite 68Zn absorption, which may have been in the form of soluble 68Zn species or 68ZnO particles (not known), Zn homeostasis was largely maintained, and the presence of ZnO particles in sunscreen did not elicit an adverse biological response in the mice following short-term topical applications. PMID:24266363

Coenzyme Q10 Ameliorates Trimethyltin Chloride Neurotoxicity in Experimental Model of Injury in Dentate Gyrus of Hippocampus: A Histopathological and Behavioral Study

PubMed Central

Sakhaie, Mohammad Hassan; Soleimani, Mansoureh; Pirhajati, Vahid; Soleimani Asl, Sara; Madjd, Zahra; Mehdizadeh, Mehdi

2016-01-01

Background Coenzyme Q10 has antioxidative and free radical scavenging effects. CoQ10 supplementation is known to have neuroprotective effects in some neurodegenerative diseases, such as Parkinson’s disease and Huntington’s disease. Objectives The aim of this study was to evaluate both histopathologic and behavioral whether Coenzyme Q10 is protective against trimethyltin chloride (TMT) induced hippocampal damage. Materials and Methods This was an experimental study. Thirty-six Balb/c mice were divided into four groups, as follows: 1) control group; 2) sham group of mice that received a 100 µL intraperitoneal injection (IP) of sesame oil; 3) TMT group of mice that received a single 2.5 mg/kg/day IP injection of TMT; and 4) TMT + CoQ10 group of mice that received a 10 mg/kg IP injection of CoQ10. Body weight and Morris water maze (MWM) responses were investigated. In addition, the dentate gyrus neurons of the hippocampus were evaluated histopathologically by light and electron microscopes. Results This study revealed that the body weight scale was found to be significantly higher in the CoQ10 group (21.39 ± 2.70), compared to the TMT group (19.39 ± 2.74) (P < 0.05). In the TMT group, the animals showed body a weight loss that was significantly lower than that of the control group (22.33 ± 3.06) (P < 0.05). Our results showed that CoQ10 provided protection against MWM deficits. Furthermore, TMT impaired the ability of mice to locate the hidden platform, compared to the control group (P < 0.05). Microscopic studies showed that TMT caused histopathological changes in the dentate gyrus and increased the number of necrotic neurons (476 ± 78.51), compared to the control group (208 ± 40.84) (P < 0.001). But, CoQ10 significantly attenuated (31 9 ± 60.08) the density of necrotic neurons compared to TMT (P < 0.05). Conclusions The results of the present study indicate that Coenzyme Q10 diminished neuronal necrosis and improved learning memory. Part of its beneficial effect is due to its potential to discount oxidative stress. PMID:27781114

Mice immunized with bone marrow-derived dendritic cells stimulated with recombinant Coxiella burnetii Com1 and Mip demonstrate enhanced bacterial clearance in association with a Th1 immune response.

PubMed

Xiong, Xiaolu; Meng, Yanfen; Wang, Xile; Qi, Yong; Li, Jiaming; Duan, Changsong; Wen, Bohai

2012-11-06

The recombinant membrane-associated proteins of Coxiella burnetii, Com1, Mip and GroEL, were used in vitro to stimulate BALB/c mouse bone marrow-derived dendritic cells (BMDCs). The antigen-activated BMDCs were transferred into naïve BALB/c mice. Seven days after challenge of C. burnetii, the bacterial loads of mice receiving BMDCs activated with Com1 or Mip, but not GroEL, were significantly lower than that of mice receiving BMDCs pulsed with TrxA (Esherichia coli thioredoxin) in a quantitative polymerase chain reaction assay. After in vitro interaction with cognate antigen-pulsed BMDCs, the percentages of CD69-positive cells and TNF-α-positive cells in CD4(+) and CD8(+) T cells isolated from the spleens of mice receiving Com1-, Mip-, or GroEL-pulsed BMDCs were significantly higher than that of mice receiving mock-pulsed BMDCs in flow cytometric analysis. The percentages of IFN-γ-positive cells in CD4(+) and CD8(+) T cells from mice receiving Com1- or Mip-pulsed BMDCs were significantly greater than that of mice receiving GroEL-pulsed BMDCs. However, the percentage of IL-4-positive cells in CD4(+) T cells of mice receiving GroEL-pulsed BMDCs was obviously higher than that of mice receiving Com1- or Mip-pulsed BMDCs. Our results demonstrate that Com1 and Mip are protective antigens and strongly indicate that they favor to induce IFN-γ-producing Th1 and Tc1 cells, whereas the non-protective antigen GroEL is biased to induce a Th2 response. Therefore, Com1 and Mip are key antigens to induce a protective immune response against C. burnetii infection. Copyright © 2012 Elsevier Ltd. All rights reserved.

Attenuation of spinal cord ischemia-reperfusion injury by specific α-2a receptor activation with dexmedetomidine.

PubMed

Bell, Marshall T; Puskas, Ferenc; Smith, Phillip D; Agoston, Viktor A; Fullerton, David A; Meng, Xianzhong; Weyant, Michael J; Reece, T Brett

2012-11-01

Despite surgical adjuncts, paralysis remains a devastating complication after thoracoabdominal aortic interventions. Dexmedetomidine, a selective α-2a agonist commonly used for sedation in the critical care setting, has been shown to have protective effects against ischemia-reperfusion injuries in multiple organ systems. We hypothesized that treatment with dexmedetomidine would attenuate spinal cord ischemia-reperfusion injury via α-2a receptor activation. Adult C57BL/6 mice underwent sternotomy, followed by occlusion of the aortic arch for 4 minutes. Eight experimental mice received pretreatment with intraperitoneal dexmedetomidine (25 μg/kg) and at 12-hour intervals after reperfusion. Eight control mice received an equivalent amount of 0.9% normal saline. Five mice underwent the same procedure with dexmedetomidine (25 μg/kg) and atipamezole (250 μg/kg), an α-2a receptor antagonist. Functional analysis of the mice was obtained at 12-hour intervals and scored using the Basso Mouse Scale for Locomotion until 60 hours. All mice were euthanized at 60 hours. Their spinal cords were removed en bloc and were stained with hematoxylin and eosin to assess cytoarchitecture and neuronal viability. Mice treated with the α-2a agonist demonstrated preserved motor function compared with ischemic controls and with mice treated with the α-2a antagonist in addition to the agonist. Functional differences in the dexmedetomidine group were statistically significant from 24 hours through the remainder of the experiment (P < .05). In addition, the treated mice had preserved cytoarchitecture, decreased vacuolization, and improved neuronal viability compared with ischemic control mice and mice concurrently treated with atipamezole, the dexmedetomidine α-2a antagonist. Treatment of mice with the α-2a agonist dexmedetomidine preserves motor function and neuronal viability after aortic cross-clamping. In addition, mice exhibited almost complete reversal of the protective effect with the administration of the α-2a receptor antagonist atipamezole. Dexmedetomidine appears to attenuate spinal cord ischemia-reperfusion injury via α-2a receptor-mediated agonism. There remains a significant risk of paraplegia after thoracoabdominal aortic interventions. This complication is devastating to the patient and the health care system. Pharmacologic adjuncts to further decrease this complication have been studied; however, few viable options exist. The α-2a agonists have been shown to improve outcomes after strokes but have not been studied in spinal cord ischemia. We show that dexmedetomidine, a commonly used α-2a agonist in the operating room, can preserve neurologic function in mice after aortic cross-clamping. Although the protective mechanism of dexmedetomidine remains unknown, it might prove to be beneficial in reducing the incidence of paraplegia after aortic interventions. Copyright © 2012 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

Pravastatin reverses obesity-induced dysfunction of induced pluripotent stem cell-derived endothelial cells via a nitric oxide-dependent mechanism

PubMed Central

Gu, Mingxia; Mordwinkin, Nicholas M.; Kooreman, Nigel G.; Lee, Jaecheol; Wu, Haodi; Hu, Shijun; Churko, Jared M.; Diecke, Sebastian; Burridge, Paul W.; He, Chunjiang; Barron, Frances E.; Ong, Sang-Ging; Gold, Joseph D.; Wu, Joseph C.

2015-01-01

Aims High-fat diet-induced obesity (DIO) is a major contributor to type II diabetes and micro- and macro-vascular complications leading to peripheral vascular disease (PVD). Metabolic abnormalities of induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) from obese individuals could potentially limit their therapeutic efficacy for PVD. The aim of this study was to compare the function of iPSC-ECs from normal and DIO mice using comprehensive in vitro and in vivo assays. Methods and results Six-week-old C57Bl/6 mice were fed with a normal or high-fat diet. At 24 weeks, iPSCs were generated from tail tip fibroblasts and differentiated into iPSC-ECs using a directed monolayer approach. In vitro functional analysis revealed that iPSC-ECs from DIO mice had significantly decreased capacity to form capillary-like networks, diminished migration, and lower proliferation. Microarray and ELISA confirmed elevated apoptotic, inflammatory, and oxidative stress pathways in DIO iPSC-ECs. Following hindlimb ischaemia, mice receiving intramuscular injections of DIO iPSC-ECs had significantly decreased reperfusion compared with mice injected with control healthy iPSC-ECs. Hindlimb sections revealed increased muscle atrophy and presence of inflammatory cells in mice receiving DIO iPSC-ECs. When pravastatin was co-administered to mice receiving DIO iPSC-ECs, a significant increase in reperfusion was observed; however, this beneficial effect was blunted by co-administration of the nitric oxide synthase inhibitor, Nω-nitro-l-arginine methyl ester. Conclusion This is the first study to provide evidence that iPSC-ECs from DIO mice exhibit signs of endothelial dysfunction and have suboptimal efficacy following transplantation in a hindlimb ischaemia model. These findings may have important implications for future treatment of PVD using iPSC-ECs in the obese population. PMID:25368203

Protective effect of ethyl pyruvate on mice sperm parameters in phenylhydrazine induced hemolytic anemia.

PubMed

Mozafari, Ali Akbar; Shahrooz, Rasoul; Ahmadi, Abbas; Malekinjad, Hassan; Mardani, Karim

2016-01-01

The aim of the present study was to assess the protective effect of ethyl pyruvate (EP) on sperm quality parameters, testosterone level and malondialdehyde (MDA) in phenylhydrazine (PHZ) treated mice. For this purpose, 32 NMRI mice with the age range of 8 to 10 weeks, weight average 26.0 ± 2.0 g, were randomly divided into four equal groups. The control group (1) received normal saline (0. 1 mL per day) by intraperitoneal injection (IP). Group 2 (PHZ group) was treated with initial dose of PHZ (8 mg 100 g(-1), IP) followed by 6 mg 100 g(-1) , IP every 48 hr. Group 3, (Group PHZ+EP) received PHZ (according to the previous prescription) with EP (40 mg kg(-1), daily, IP). Ethyl pyruvate group (4) received only EP (40 mg kg(-1), daily, IP). Treatment period was 35 days. After euthanasia, sperms from caudal region of epididymis were collected and the total mean sperm count, sperm viability, motility and morphology were determined. Testis tissue MDA and serum testosterone levels of all experimental groups were also evaluated. A considerable reduction in mean percentage of number, natural morphology of sperm, sperm motility and viability and serum testosterone concentration besides DNA injury increment among mice treating with PHZ in comparison with control group were observed. However, in PHZ+EP group the above mentioned parameters were improved. This study showed that PHZ caused induction of toxicity on sperm parameters and reduction of testosterone as well as the increment of MDA level and EP as an antioxidant could reduce destructive effects of PHZ on sperm parameters, testosterone level and lipid peroxidation.

Carnosine retards tumor growth in vivo in an NIH3T3-HER2/neu mouse model.

PubMed

Renner, Christof; Zemitzsch, Nadine; Fuchs, Beate; Geiger, Kathrin D; Hermes, Matthias; Hengstler, Jan; Gebhardt, Rolf; Meixensberger, Jürgen; Gaunitz, Frank

2010-01-06

It was previously demonstrated that the dipeptide carnosine inhibits growth of cultured cells isolated from patients with malignant glioma. In the present work we investigated whether carnosine also affects tumor growth in vivo and may therefore be considered for human cancer therapy. A mouse model was used to investigate whether tumor growth in vivo can be inhibited by carnosine. Therefore, NIH3T3 fibroblasts, conditionally expressing the human epidermal growth factor receptor 2 (HER2/neu), were implanted into the dorsal skin of nude mice, and tumor growth in treated animals was compared to control mice. In two independent experiments nude mice that received tumor cells received a daily intra peritoneal injection of 500 microl of 1 M carnosine solution. Measurable tumors were detected 12 days after injection. Aggressive tumor growth in control animals, that received a daily intra peritoneal injection of NaCl solution started at day 16 whereas aggressive growth in mice treated with carnosine was delayed, starting around day 19. A significant effect of carnosine on tumor growth was observed up to day 24. Although carnosine was not able to completely prevent tumor growth, a microscopic examination of tumors revealed that those from carnosine treated animals had a significant lower number of mitosis (p < 0.0003) than untreated animals, confirming that carnosine affects proliferation in vivo. As a naturally occurring substance with a high potential to inhibit growth of malignant cells in vivo, carnosine should be considered as a potential anti-cancer drug. Further experiments should be performed in order to understand how carnosine acts at the molecular level.

TUDCA Slows Retinal Degeneration in Two Different Mouse Models of Retinitis Pigmentosa and Prevents Obesity in Bardet-Biedl Syndrome Type 1 Mice

PubMed Central

Drack, Arlene V.; Dumitrescu, Alina V.; Bhattarai, Sajag; Gratie, Daniel; Stone, Edwin M.; Mullins, Robert

2012-01-01

Purpose. To evaluate and compare the protective effect of tauroursodeoxycholic acid (TUDCA) on photoreceptor degeneration in different models of retinal degeneration (RD) in mice. Methods. BbsM390R/M390R mice were injected subcutaneously twice a week, from P40 to P120, and rd10 mice were injected every 3 days from P6 to P38 with TUDCA or vehicle (0.15 M NaHCO3). Rd1 and rd16 mice were injected daily from P6 to P30 with TUDCA or vehicle. Retinal structure and function were determined at multiple time points by electroretinography (ERG), optical coherence tomography (OCT), and histology. Results. The amplitude of ERG b-waves was significantly higher in TUDCA-treated Bbs1 and rd10 animals than in controls. Retinal thickness on OCT was slightly greater in treated Bbs1 animals than in the controls. Histologically, outer segments were preserved, and the outer nuclear layer was significantly thicker in the treated Bbs1 and rd10 mice than in the controls. Bbs1M390R/M390R mice developed less obesity than the control Bbs1M390R/M390R while receiving TUDCA. The Rd1 and rd16 mice showed no improvement with TUDCA treatment, and the rd1 mice did not have normal weight gain during treatment. Conclusions. TUDCA treatment preserved ERG b-waves and the outer nuclear layer in Bbs1M390R/M390R mice, and prevented obesity assessed at P120. TUDCA treatment preserved ERG b-waves and the outer nuclear layer in the rd10 mice to P30. TUDCA is a prime candidate for treatment of humans with retinal degeneration, especially those with Bardet-Biedl syndrome, whom it may help not only with the vision loss, but with the debilitating obesity as well. PMID:22110077

Sunitinib-ibuprofen drug interaction affects the pharmacokinetics and tissue distribution of sunitinib to brain, liver, and kidney in male and female mice differently.

PubMed

Lau, Christine Li Ling; Chan, Sook Tyng; Selvaratanam, Manimegahlai; Khoo, Hui Wen; Lim, Adeline Yi Ling; Modamio, Pilar; Mariño, Eduardo L; Segarra, Ignacio

2015-08-01

Tyrosine kinase inhibitor sunitinib (used in GIST, advanced RCC, and pancreatic neuroendocrine tumors) undergoes CYP3A4 metabolism and is an ABCB1B and ABCG2 efflux transporters substrate. We assessed the pharmacokinetic interaction with ibuprofen (an NSAID used by patients with cancer) in Balb/c male and female mice. Mice (study group) were coadministered (30 min apart) 30 mg/kg of ibuprofen and 60 mg/kg of sunitinib PO and compared with the control groups, which received sunitinib alone (60 mg/kg, PO). Sunitinib concentration in plasma, brain, kidney, and liver was measured by HPLC as scheduled and noncompartmental pharmacokinetic parameters estimated. In female control mice, sunitinib AUC0→∞ decreased in plasma (P < 0.05), was higher in liver and brain (P < 0.001), and lower in kidney (P < 0.001) vs. male control mice. After ibuprofen coadministration, female mice showed lower AUC0→∞ in plasma (P < 0.01), brain, liver, and kidney (all P < 0.001). However, in male mice, AUC0→∞ remained unchanged in plasma, increased in liver and kidney, and decreased in brain (all P < 0.001). The tissue-to-plasma AUC0→∞ ratio was similar between male and female control mice, but changed after ibuprofen coadministration: Male mice showed 1.6-fold higher liver-to-plasma ratio (P < 0.001) while remained unchanged in female mice and in kidney (male and female mice) but decreased 55% in brain (P < 0.05). The tissue-to-plasma partial AUC ratio, the drug tissue targeting index, and the tissue-plasma hysteresis-like plots also showed sex-based ibuprofen-sunitinib drug interaction differences. The results illustrate the relevance of this DDI on sunitinib pharmacokinetics and tissue uptake. These may be due to gender-based P450 and efflux/transporters differences. © 2015 Société Française de Pharmacologie et de Thérapeutique.

Modeling pulmonary fibrosis by abnormal expression of telomerase/apoptosis/collagen V in experimental usual interstitial pneumonia

PubMed Central

Parra, E.R.; Pincelli, M.S.; Teodoro, W.R.; Velosa, A.P.P.; Martins, V.; Rangel, M.P.; Barbas-Filho, J.V.; Capelozzi, V.L.

2014-01-01

Limitations on tissue proliferation capacity determined by telomerase/apoptosis balance have been implicated in pathogenesis of idiopathic pulmonary fibrosis. In addition, collagen V shows promise as an inductor of apoptosis. We evaluated the quantitative relationship between the telomerase/apoptosis index, collagen V synthesis, and epithelial/fibroblast replication in mice exposed to butylated hydroxytoluene (BHT) at high oxygen concentration. Two groups of mice were analyzed: 20 mice received BHT, and 10 control mice received corn oil. Telomerase expression, apoptosis, collagen I, III, and V fibers, and hydroxyproline were evaluated by immunohistochemistry, in situ detection of apoptosis, electron microscopy, immunofluorescence, and histomorphometry. Electron microscopy confirmed the presence of increased alveolar epithelial cells type 1 (AEC1) in apoptosis. Immunostaining showed increased nuclear expression of telomerase in AEC type 2 (AEC2) between normal and chronic scarring areas of usual interstitial pneumonia (UIP). Control lungs and normal areas from UIP lungs showed weak green birefringence of type I and III collagens in the alveolar wall and type V collagen in the basement membrane of alveolar capillaries. The increase in collagen V was greater than collagens I and III in scarring areas of UIP. A significant direct association was found between collagen V and AEC2 apoptosis. We concluded that telomerase, collagen V fiber density, and apoptosis evaluation in experimental UIP offers the potential to control reepithelization of alveolar septa and fibroblast proliferation. Strategies aimed at preventing high rates of collagen V synthesis, or local responses to high rates of cell apoptosis, may have a significant impact in pulmonary fibrosis. PMID:24919172

Oral immunization of mice with engineered Lactobacillus gasseri NM713 strain expressing Streptococcus pyogenes M6 antigen.

PubMed

Mansour, Nahla M; Abdelaziz, Sahar A

2016-08-01

The aim of this in vivo study was to evaluate the effects of a recombinant probiotic strain, Lactobacillus gasseri NM713, which expresses the conserved region of streptococcal M6 protein (CRR6), as an oral vaccine against Streptococcus pyogenes. A dose of 10(9) cells of the recombinant strain in 150 μL PBS buffer was administered orally to a group of mice. One control group received an equivalent dose of Lb. gasseri NM613 (containing the empty plasmid without insert) or and another control group received PBS buffer. Each group contained 30 mice. The immunization protocol was followed on three consecutive days, after which two booster doses were administered at two week intervals. Fecal and serum samples were collected from the mice on Days 18, 32, 46, 58 after the first immunization and Day 0 prior to immunization. Anti-CRR6 IgA and IgG concentrations were measured by ELISA in fecal and sera samples, respectively, to assess immune responses. Vaccination with the recombinant Lb. gasseri NM713 strain induced significant protection after nasal challenge with S. pyogenes, only a small percentage of this group developing streptococcal infection (10%) or dying of it (3.3%) compared with the NM613 and PBS control groups, high percentages of which developed streptococcal infection (43.3% and 46.7%, respectively) and died of it (46.7% and 53%, respectively). These results indicate that recombinant Lb. gasseri NM713 has potential as an oral delivery vaccine against streptococcus group A. © 2016 The Societies and John Wiley & Sons Australia, Ltd.

Neuromotor Activity, Anxiety and Cognitive Function in the In Vivo Model of Alimentary Hyperlipidemia and Obesity.

PubMed

Apryatin, S A; Sidorova, Yu S; Shipelin, V A; Balakina, A; Trusov, N V; Mazo, V K

2017-05-01

Behavioral indicators characterizing specific features of the pathological process of alimentary-dependent diseases were studied using in vivo model of alimentary hyperlipidemia in rats and mice. Rats and mice of the control groups received balanced semisynthetic diet for 63 days; animals of the experimental groups received a diet with high fat content (30% dry weight), balanced or high-fat diet with fructose solution instead of water, balanced cholesterol-enriched diet (0.5% dry weight), or balanced cholesterol-enriched diet with fructose solution. During the experiment, the mass of food, consumed by the animals, was monitored daily. Muscle tone was assessed by the front paw grip strength on days 33 and 54 of the experiment. Anxiety was tested in the elevated plus maze on days 36 and 57. Behavior and memory were assessed by conditioned passive avoidance reflex on days 39, 40, and 61. A significant increase in muscle tone was revealed on day 54 in rats fed with a balanced diet with fructose, and in mice, that received a similar diet, supplemented with fructose and cholesterol. Anxiety in the second test (day 57) was significantly decreased in rats fed high-fat diet and increased in mice fed high fat diet and high fat diet with fructose. In the second test, additional amount of cholesterol in the diet was the factor that significantly improved both short-term and long-term memory in both species. In mice, in contrast to rats, addition of fructose, including combination with high-fat diet, significantly worsened short-term and long-term memory. Thus, dietary factors, contributing to alimentary dyslipidemia development in rats and mice, can significantly affect the indices of neuromotor activity, anxiety level and cognitive functions, and the nature and direction of these changes are largely species-specific.

Effects of naltrexone on post-abstinence alcohol drinking in C57BL/6NCRL and DBA/2J mice.

PubMed

Tomie, Arthur; Azogu, Idu; Yu, Lei

2013-07-01

The present experiment evaluated the effects of naltrexone, a non-selective opioid receptor antagonist, on post-abstinence alcohol drinking in C57BL/6NCRL and DBA/2J male mice. Home cage 2-bottle (alcohol vs. water) free-choice procedures were employed. During the pre-abstinence period, alcohol intake was much lower for the DBA/2J mice relative to the C57BL/6NCRL mice, and this strain difference was observed for groups receiving either 3% or 10% alcohol concentrations. The four-day abstinence period effectively reduced alcohol intakes (i.e., a negative alcohol deprivation effect, negative ADE) in both groups of DBA/2J mice, but had no effect on alcohol intakes in either group of C57BL/6NCRL mice. Both groups trained with 3% alcohol received the second four-day abstinence period, where the effects of acute administration of either naltrexone or saline on post-abstinence alcohol drinking were assessed. Naltrexone was more effective in reducing post-abstinence drinking of 3% alcohol in the DBA/2J mice than in the C57BL/6NCRL mice. In the DBA/2J mice, naltrexone further reduced, relative to saline-injected controls, the low levels of post-abstinence alcohol intake. Thus, the low baseline levels of alcohol drinking in DBA/2J mice were further diminished by the four-day abstinence period (negative ADE), and this suppressed post-abstinence level of alcohol drinking was still further reduced by acute administration of naltrexone. The results indicate that naltrexone is effective in reducing further the low levels of alcohol drinking induced by the negative ADE. Copyright © 2013 Elsevier Inc. All rights reserved.

Effect of letrozole in carcinogen-plus-estrogen-induced endometrial hyperplasia in mice.

PubMed

Lara, Alessandra Cerávolo; Cândido, Eduardo Batista; Vidigal, Paula Vieira; Rocha, Ana Luiza Lunardi; Carvalho-Macedo, Alessandra Costa; Carneiro, Márcia Mendonça; Silva-Filho, Agnaldo Lopes

2016-04-01

To evaluate the effects of letrozole (Ltz) in carcinogen+estrogen-induced endometrial hyperplasia. BALB/c female mice were divided into four groups of 12 animals each receiving an intrauterine dose of N-ethyl-N-nitrosourea (ENU) and weekly subcutaneous injections of estradiol hexaidrobenzoate (EHB), except for group I(control). The groups were divided in I (control), II (ENU+EHB), III (ENU+EHB+MPA) and IV (ENU+EHB+Ltz). Group III also received intramuscular injections of MPA (medroxy progesterone acetate) every four weeks, while group IV received oral doses of Ltz daily. At the end of 16 weeks, the animals were sacrificed, and blood samples were collected for the measurement of serum estradiol and progesterone levels. Uterine histological sections were made to evaluate the presence of endometrial proliferative lesions. Differences between groups were evaluated with student's t test, ANOVA and chi-square test. Groups ENU+EHB, ENU+EHB+MPA and ENU+EHB+Ltz showed varying degrees of endometrial hyperplasia. The incidence of hyperplasia in groups ENU+EHB and ENU+EHB+Ltz was higher and more severe than in group ENU+EHB+MPA. Control group showed lower levels of serum estradiol than the other groups. There was no evidence that letrozole could act as an antiestrogenic drug in the development of endometrial proliferative lesions.

Inhibition of the cluster of differentiation 14 innate immunity pathway with IAXO-101 improves chronic microelectrode performance

NASA Astrophysics Data System (ADS)

Hermann, John K.; Ravikumar, Madhumitha; Shoffstall, Andrew J.; Ereifej, Evon S.; Kovach, Kyle M.; Chang, Jeremy; Soffer, Arielle; Wong, Chun; Srivastava, Vishnupriya; Smith, Patrick; Protasiewicz, Grace; Jiang, Jingle; Selkirk, Stephen M.; Miller, Robert H.; Sidik, Steven; Ziats, Nicholas P.; Taylor, Dawn M.; Capadona, Jeffrey R.

2018-04-01

Objective. Neuroinflammatory mechanisms are hypothesized to contribute to intracortical microelectrode failures. The cluster of differentiation 14 (CD14) molecule is an innate immunity receptor involved in the recognition of pathogens and tissue damage to promote inflammation. The goal of the study was to investigate the effect of CD14 inhibition on intracortical microelectrode recording performance and tissue integration. Approach. Mice implanted with intracortical microelectrodes in the motor cortex underwent electrophysiological characterization for 16 weeks, followed by endpoint histology. Three conditions were examined: (1) wildtype control mice, (2) knockout mice lacking CD14, and (3) wildtype control mice administered a small molecule inhibitor to CD14 called IAXO-101. Main results. The CD14 knockout mice exhibited acute but not chronic improvements in intracortical microelectrode performance without significant differences in endpoint histology. Mice receiving IAXO-101 exhibited significant improvements in recording performance over the entire 16 week duration without significant differences in endpoint histology. Significance. Full removal of CD14 is beneficial at acute time ranges, but limited CD14 signaling is beneficial at chronic time ranges. Innate immunity receptor inhibition strategies have the potential to improve long-term intracortical microelectrode performance.

Drug-primed reinstatement of cocaine seeking in mice: increased excitability of medium-sized spiny neurons in the nucleus accumbens

PubMed Central

Ma, Yao-Ying; Henley, Sandy M.; Toll, Jeff; Jentsch, James D.; Evans, Christopher J.; Levine, Michael S.; Cepeda, Carlos

2013-01-01

To examine the mechanisms of drug relapse, we first established a model for cocaine IVSA (intravenous self-administration) in mice, and subsequently examined electrophysiological alterations of MSNs (medium-sized spiny neurons) in the NAc (nucleus accumbens) before and after acute application of cocaine in slices. Three groups were included: master mice trained by AL (active lever) pressings followed by IV (intravenous) cocaine delivery, yoked mice that received passive IV cocaine administration initiated by paired master mice, and saline controls. MSNs recorded in the NAc shell in master mice exhibited higher membrane input resistances but lower frequencies and smaller amplitudes of sEPSCs (spontaneous excitatory postsynaptic currents) compared with neurons recorded from saline control mice, whereas cells in the NAc core had higher sEPSCs frequencies and larger amplitudes. Furthermore, sEPSCs in MSNs of the shell compartment displayed longer decay times, suggesting that both pre- and postsynaptic mechanisms were involved. After acute re-exposure to a low-dose of cocaine in vitro, an AP (action potential)-dependent, persistent increase in sEPSC frequency was observed in both NAc shell and core MSNs from master, but not yoked or saline control mice. Furthermore, re-exposure to cocaine induced membrane hyperpolarization, but concomitantly increased excitability of MSNs from master mice, as evidenced by increased membrane input resistance, decreased depolarizing current to generate APs, and a more negative Thr (threshold) for firing. These data demonstrate functional differences in NAc MSNs after chronic contingent versus non-contingent IV cocaine administration in mice, as well as synaptic adaptations of MSNs before and after acute re-exposure to cocaine. Reversing these functional alterations in NAc could represent a rational target for the treatment of some reward-related behaviors, including drug addiction. PMID:24000958

Elevating body temperature enhances hematopoiesis and neutrophil recovery after total body irradiation in an IL-1-, IL-17-, and G-CSF-dependent manner.

PubMed

Capitano, Maegan L; Nemeth, Michael J; Mace, Thomas A; Salisbury-Ruf, Christi; Segal, Brahm H; McCarthy, Philip L; Repasky, Elizabeth A

2012-09-27

Neutropenia is a common side effect of cytotoxic chemotherapy and radiation, increasing the risk of infection in these patients. Here we examined the impact of body temperature on neutrophil recovery in the blood and bone marrow after total body irradiation (TBI). Mice were exposed to either 3 or 6 Gy TBI followed by a mild heat treatment that temporarily raised core body temperature to approximately 39.5°C. Neutrophil recovery was then compared with control mice that received either TBI alone heat treatment alone. Mice that received both TBI and heat treatment exhibited a significant increase in the rate of neutrophil recovery in the blood and an increase in the number of marrow hematopoietic stem cells and neutrophil progenitors compared with that seen in mice that received either TBI or heat alone. The combination treatment also increased G-CSF concentrations in the serum, bone marrow, and intestinal tissue and IL-17, IL-1β, and IL-1α concentrations in the intestinal tissue after TBI. Neutralizing G-CSF or inhibiting IL-17 or IL-1 signaling significantly blocked the thermally mediated increase in neutrophil numbers. These findings suggest that a physiologically relevant increase in body temperature can accelerate recovery from neutropenia after TBI through a G-CSF-, IL-17-, and IL-1-dependent mechanism.

Elevating body temperature enhances hematopoiesis and neutrophil recovery after total body irradiation in an IL-1–, IL-17–, and G-CSF–dependent manner

PubMed Central

Capitano, Maegan L.; Nemeth, Michael J.; Mace, Thomas A.; Salisbury-Ruf, Christi; Segal, Brahm H.; McCarthy, Philip L.

2012-01-01

Neutropenia is a common side effect of cytotoxic chemotherapy and radiation, increasing the risk of infection in these patients. Here we examined the impact of body temperature on neutrophil recovery in the blood and bone marrow after total body irradiation (TBI). Mice were exposed to either 3 or 6 Gy TBI followed by a mild heat treatment that temporarily raised core body temperature to approximately 39.5°C. Neutrophil recovery was then compared with control mice that received either TBI alone heat treatment alone. Mice that received both TBI and heat treatment exhibited a significant increase in the rate of neutrophil recovery in the blood and an increase in the number of marrow hematopoietic stem cells and neutrophil progenitors compared with that seen in mice that received either TBI or heat alone. The combination treatment also increased G-CSF concentrations in the serum, bone marrow, and intestinal tissue and IL-17, IL-1β, and IL-1α concentrations in the intestinal tissue after TBI. Neutralizing G-CSF or inhibiting IL-17 or IL-1 signaling significantly blocked the thermally mediated increase in neutrophil numbers. These findings suggest that a physiologically relevant increase in body temperature can accelerate recovery from neutropenia after TBI through a G-CSF–, IL-17–, and IL-1–dependent mechanism. PMID:22806894

Impaired autophagy induces chronic atrophic pancreatitis in mice via sex- and nutrition-dependent processes.

PubMed

Diakopoulos, Kalliope N; Lesina, Marina; Wörmann, Sonja; Song, Liang; Aichler, Michaela; Schild, Lorenz; Artati, Anna; Römisch-Margl, Werner; Wartmann, Thomas; Fischer, Robert; Kabiri, Yashar; Zischka, Hans; Halangk, Walter; Demir, Ihsan Ekin; Pilsak, Claudia; Walch, Axel; Mantzoros, Christos S; Steiner, Jörg M; Erkan, Mert; Schmid, Roland M; Witt, Heiko; Adamski, Jerzy; Algül, Hana

2015-03-01

Little is known about the mechanisms of the progressive tissue destruction, inflammation, and fibrosis that occur during development of chronic pancreatitis. Autophagy is involved in multiple degenerative and inflammatory diseases, including pancreatitis, and requires the protein autophagy related 5 (ATG5). We created mice with defects in autophagy to determine its role in pancreatitis. We created mice with pancreas-specific disruption of Atg5 (Ptf1aCreex1;Atg5F/F mice) and compared them to control mice. Pancreata were collected and histology, immunohistochemistry, transcriptome, and metabolome analyses were performed. ATG5-deficient mice were placed on diets containing 25% palm oil and compared with those on a standard diet. Another set of mice received the antioxidant N-acetylcysteine. Pancreatic tissues were collected from 8 patients with chronic pancreatitis (CP) and compared with pancreata from ATG5-deficient mice. Mice with pancreas-specific disruption of Atg5 developed atrophic CP, independent of β-cell function; a greater proportion of male mice developed CP than female mice. Pancreata from ATG5-deficient mice had signs of inflammation, necrosis, acinar-to-ductal metaplasia, and acinar-cell hypertrophy; this led to tissue atrophy and degeneration. Based on transcriptome and metabolome analyses, ATG5-deficient mice produced higher levels of reactive oxygen species than control mice, and had insufficient activation of glutamate-dependent metabolism. Pancreata from these mice had reduced autophagy, increased levels of p62, and increases in endoplasmic reticulum stress and mitochondrial damage, compared with tissues from control mice; p62 signaling to Nqo1 and p53 was also activated. Dietary antioxidants, especially in combination with palm oil-derived fatty acids, blocked progression to CP and pancreatic acinar atrophy. Tissues from patients with CP had many histologic similarities to those from ATG5-deficient mice. Mice with pancreas-specific disruption of Atg5 develop a form of CP similar to that of humans. CP development appears to involve defects in autophagy, glutamate-dependent metabolism, and increased production of reactive oxygen species. These mice might be used to identify therapeutic targets for CP. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

Activation of serotonin 5-HT(2C) receptor suppresses behavioral sensitization and naloxone-precipitated withdrawal symptoms in heroin-treated mice.

PubMed

Wu, Xian; Pang, Gang; Zhang, Yong-Mei; Li, Guangwu; Xu, Shengchun; Dong, Liuyi; Stackman, Robert W; Zhang, Gongliang

2015-10-21

Abuse and dependence to heroin has evolved into a global epidemic as a significant clinical and societal problem with devastating consequences. Repeated exposure to heroin can induce long-lasting behavioral sensitization and withdrawal. Pharmacological activation of 5-HT2C receptors (5-HT2CRs) suppresses psychostimulant-induced drug-seeking and behavioral sensitization. The present study examined the effect of a selective 5-HT2CR agonist lorcaserin on behavioral sensitization and naloxone-precipitated withdrawal symptoms in heroin-treated mice. Male mice received heroin (1.0 mg/kg, s.c.) twice a day for 3 days and then drug treatment was suspended for 5 days. On day 9, a challenge dose of heroin (1.0 mg/kg) was administered to examine the expression of behavioral sensitization. Lorcaserin administered during the development, withdrawal or expression stage suppressed heroin-induced behavioral sensitization on day 9. Another cohort of mice received increasing doses of heroin over a 4.5-day period. Lorcaserin, or the positive control clonidine (an α2-adrenoceptor agonist) suppressed naloxone-precipitated withdrawal symptoms in heroin-treated mice. These findings suggest that activation of 5-HT2CRs suppresses behavioral sensitization and withdrawal in heroin-treated mice. Thus, pharmacological activation of 5-HT2CRs may represent a new avenue for the treatment of heroin addiction. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Activation of serotonin 5-HT2C receptor suppresses behavioral sensitization and naloxone-precipitated withdrawal symptoms in heroin-treated mice

PubMed Central

Li, Guangwu; Xu, Shengchun; Dong, Liuyi; Stackman, Robert W.; Zhang, Gongliang

2015-01-01

Abuse and dependence to heroin has evolved into a global epidemic as a significant clinical and societal problem with devastating consequences. Repeated exposure to heroin can induce long-lasting behavioral sensitization and withdrawal. Pharmacological activation of 5-HT2C receptors (5-HT2CRs) suppresses psychostimulant-induced drug-seeking and behavioral sensitization. The present study examined the effect of a selective 5-HT2CR agonist lorcaserin on behavioral sensitization and naloxone-precipitated withdrawal symptoms in heroin-treated mice. Male mice received heroin (1.0 mg/kg, s.c.) twice a day for 3 days and then drug treatment was suspended for 5 days. On day 9, a challenge dose of heroin (1.0 mg/kg) was administered to examine the expression of behavioral sensitization. Lorcaserin administered during the development, withdrawal or expression stage suppressed heroin-induced behavioral sensitization on day 9. Another cohort of mice received increasing doses of heroin over a 4.5-day period. Lorcaserin, or the positive control clonidine (an α2-adrenoceptor agonist) suppressed naloxone-precipitated withdrawal symptoms in heroin-treated mice. These findings suggest that activation of 5-HT2CRs suppresses behavioral sensitization and withdrawal in heroin-treated mice. Thus, pharmacological activation of 5-HT2CRs may represent a new avenue for the treatment of heroin addiction. PMID:26375926

microRNA-Based Immunotherapy for Control of Early Stage Lung Cancer

DTIC Science & Technology

2016-09-01

in NSG hosts via subcutaneously injection. A549-Luc developed tumors successfully in NSG hosts and mice bearing A549-Luc tumors were the subject...activation of NK cells from whole blood. Next we evaluated NK cells and host interaction by transferring NK cells into A549-tumor bearing NSG host via...that did not receive NK cells. 4 At day 28, we harvested tumors, blood and tissues from tumor- bearing mice to analyze for NK presence in the

Renal, hepatic, pulmonary and adrenal tumors induced by prenatal inorganic arsenic followed by dimethylarsinic acid in adulthood in CD1 mice

PubMed Central

Tokar, Erik J.; Diwan, Bhalchandra A.; Waalkes, Michael P.

2012-01-01

Inorganic arsenic, an early life carcinogen in humans and mice, can initiate lesions promotable by other agents in later life. The biomethylation product of arsenic, dimethylarsinic acid (DMA), is a multi-site tumor promoter. Thus, pregnant CD1 mice were given drinking water (0 or 85 ppm arsenic) from gestation day 8 to 18 and after weaning male offspring received DMA (0 or 200 ppm; drinking water) for up to 2 years. No renal tumors occurred in controls or DMA alone treated mice while gestational arsenic exposure plus later DMA induced a significant renal tumor incidence of 17% (primarily renal cell carcinoma). Arsenic plus DMA or arsenic alone also increased renal hyperplasia over control but DMA alone did not. Arsenic alone, DMA alone and arsenic plus DMA all induced urinary bladder hyperplasia (33–35%) versus control (2%). Compared to control (6%), arsenic alone tripled hepatocellular carcinoma (20%), and arsenic plus DMA doubled this rate again (43%), but DMA alone had no effect. DMA alone, arsenic alone, and arsenic plus DMA increased lung adenocarcinomas and adrenal adenomas versus control. Overall, DMA in adulthood promoted tumors/lesions initiated by prenatal arsenic in the kidney and liver, but acted independently in the urinary bladder, lung and adrenal. PMID:22230260

Effects of Salvia miltiorrhiza extract with supplemental liquefied calcium on osteoporosis in calcium-deficient ovariectomized mice.

PubMed

Park, Bongkyun; Song, Hae Seong; Kwon, Jeong Eun; Cho, Se Min; Jang, Seon-A; Kim, Mi Yeon; Kang, Se Chan

2017-12-20

Extracts from Salvia miltiorrhiza Bunge have been used in traditional Asian medicine to treat coronary heart disease, chronic renal failure, atherosclerosis, myocardial infraction, angina pectoris, myocardial ischemia, dysmenorrheal, neurasthenic insomnia, liver fibrosis and cirrhosis. The aim of the study was to investigate the anti-RANK signal effect of the combination of S.miltiorrhiza Bunge (SME) and liquefied calcium (LCa) supplement with ovariectomized (OVX-SML) mice, a osteoporosis animal model. Results were compared to 17β-estradiol (E 2 ) treatment. A total of 70 female ICR strain mice (7 weeks) were randomly divided into 10 groups with 7 mice in each group as follows: (1) sham-operated control mice (sham) received daily oral phosphate-buffered-saline (PBS) of equal volumes through oral administration. (2) OVX mice received a daily oral administration of PBS (OVX). (3) OVX mice treated daily with 50 mg/kg b.w./ day of SME (4) with 100 mg/kg b.w./day of SME or (5) with 200 mg/kg b.w./day of SME via oral administration. (6) OVX mice treated daily with 50 mg/kg b.w./day of SML (7) with 100 mg/kg b.w./day of SML or (8) with 200 mg/kg b.w./day of SML via oral administration. (9) OVX mice treated daily with 10 ml/kg b.w./day of LCa (10) OVX mice received i.p. injections of 17β-estradiol (E 2 ) (0.1 mg/kg b.w./day) three times per week for 12 weeks. micro-CT analysis revealed that oral administration of SML inhibited tibial bone loss, sustained trabecular bone state, and ameliorated bone biochemical markers. In addition, SML administration compared to SEM and LCa reduced serum levels of RANKL, osteocalcin and BALP through increased serum levels of OPG and E 2 in OVX mice. SML also had more beneficial effects on protection of estrogen-dependent bone loss through blocking expression of TRAF6 and NFTAc1 and produces cathepsin K and calcitonin receptor to develop osteoclast differentiation. These data suggest that S. miltiorrhiza Bunge combined with liquefied calcium supplement has an inhibitory activity in OVX mice. This result implies the possibility of a pharmacological intervention specifically directed toward a disease such as osteoporosis where decreased bone strength increases the risk of a broken bone .

Compton scattering by internal shields based on melanin-containing mushrooms provides protection of gastrointestinal tract from ionizing radiation.

PubMed

Revskaya, Ekaterina; Chu, Peter; Howell, Robertha C; Schweitzer, Andrew D; Bryan, Ruth A; Harris, Matthew; Gerfen, Gary; Jiang, Zewei; Jandl, Thomas; Kim, Kami; Ting, Li-Min; Sellers, Rani S; Dadachova, Ekaterina; Casadevall, Arturo

2012-11-01

There is a need for radioprotectors that protect normal tissues from ionizing radiation in patients receiving high doses of radiation and during nuclear emergencies. We investigated the possibility of creating an efficient oral radioprotector based on the natural pigment melanin that would act as an internal shield and protect the tissues via Compton scattering followed by free radical scavenging. CD-1 mice were fed melanin-containing black edible mushrooms Auricularia auricila-judae before 9 Gy total body irradiation. The location of the mushrooms in the body before irradiation was determined by in vivo fluorescent imaging. Black mushrooms protected 80% of mice from the lethal dose, while control mice or those given melanin-devoid mushrooms died from gastrointestinal syndrome. The crypts of mice given black mushrooms showed less apoptosis and more cell division than those in control mice, and their white blood cell and platelet counts were restored at 45 days to preradiation levels. The role of melanin in radioprotection was proven by the fact that mice given white mushrooms supplemented with melanin survived at the same rate as mice given black mushrooms. The ability of melanin-containing mushrooms to provide remarkable protection against radiation suggests that they could be developed into oral radioprotectors.

Ginseng Berry Extract Attenuates Dextran Sodium Sulfate-Induced Acute and Chronic Colitis

PubMed Central

Zhang, Wei; Xu, Li; Cho, Si-Young; Min, Kyung-Jin; Oda, Tatsuya; Zhang, LiJun; Yu, Qing; Jin, Jun-O

2016-01-01

This study investigates the in vivo functions of ginseng berry extract (GB) as a therapy for dextran sodium sulfate (DSS)-induced colitis. C57BL/6 mice were given drinking water containing DSS (3%) for eight days to induce acute colitis. At the same time, the mice received an oral dose of GB (50 mg/kg) once daily. The GB-treated mice were less susceptible to the development of acute colitis than were control mice treated with saline, as determined by weight loss, disease activity, and colon histology. The administration of GB to DSS-treated mice also reduced the numbers and inhibited the activation of colon-infiltrating T cells, neutrophils, intestinal CD103−CD11c+ dendritic cells (cDCs), and macrophages. In addition, GB treatment promoted the migration of CD103+CD11c+ cDCs and expansion of Foxp3+ regulatory T cells in the colons of DSS-treated mice. Similarly, in the DSS-induced chronic colitis model, GB treatment improved the macroscopic and histological appearance of the colon wall when compared to untreated control mice, as indicated by longer colon length and lower histological scores. This is the first report to show that oral administration of GB suppresses immune activation and protects against experimentally induced colitis. PMID:27058552

NTP Toxicology and Carcinogenesis Studies of Xylenes (Mixed) (60% m-Xylene, 14% p-Xylene, 9% o-Xylene, and 17% Ethylbenzene) (CAS No. 1330-20-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

PubMed

1986-12-01

The technical grade of xylenes (mixed) (hereafter termed xylenes) contains the three isomeric forms and ethylbenzene (percentage composition shown above). The annual production for 1985 was approximately 7.4 x 108 gallons. Xylenes is used as a solvent and a cleaning agent and as a degreaser and is a constituent of aviation and automobile fuels. Xylenes is also used in the production of benzoic acid, phthalate anhydride, and isophthalic and terephthalic acids as well as their dimethyl esters. Toxicology and carcinogenesis studies of xylenes were conducted in laboratory animals because a large number of workers are exposed and because the long- term effects of exposure to xylenes were not known. Exposure for the present studies was by gavage in corn oil. In single-administration studies, groups of five F344/N rats and B6C3F1 mice of each sex received 500, 1,000, 2,000, 4,000, or 6,000 mg/kg. Administration of xylenes caused deaths at 6,000 mg/kg in rats and mice of each sex and at 4,000 mg/kg in male rats. In rats, clinical signs observed within 24 hours of dosing at 4,000 mg/kg included prostration, muscular incoordination, and loss of hind limb movement; these effects continued through the second week of observation. Tremors, prone position, and slowed breathing were recorded for mice on day 3, but all mice appeared normal by the end of the 2- week observation period. In 14- day studies, groups of five rats of each sex were administered 0, 125, 250, 500, 1,000, or 2,000 mg/kg, and groups of five mice of each sex received 0, 250, 500, 1,000, 2,000, or 4,000 mg/kg. Chemical- related mortality occurred only at 2,000 mg/kg in rats and at 4,000 mg/kg in mice. Rats and mice exhibited shallow breathing and prostration within 48 hours following dosing at 2,000 mg/kg. These signs persisted until day 12 for rats, but no clinical signs were noted during the second week for mice. In 13- week studies, groups of 10 rats of each sex received 0, 62.5, 125, 250, 500, or 1,000 mg/kg, and groups of 10 mice of each sex received 0, 125, 250, 500, 1,000, or 2,000 mg/kg. No deaths or clinical signs of toxicity were recorded in rats. However, high dose male rats gained 15% less weight and females 8% less weight than did the vehicle controls. Two female mice died at the 2,000 mg/kg dose. Lethargy, short and shallow breathing, unsteadiness, tremors, and paresis were observed for both sexes in the 2,000 mg/kg group within 5- 10 minutes after dosing and lasted for 15- 60 minutes. Two- year toxicology and carcinogenesis studies were conducted by administering 0, 250, or 500 mg/kg xylenes in corn oil by gavage to groups of 50 F344/N rats of each sex, 5 days per week for 103 weeks. Groups of 50 B6C3F1 mice of each sex were administered 0, 500, or 1,000 mg/kg xylenes on the same schedule. Although the mortality was dose related in male rats (final survival: vehicle control, 36/50; low dose, 26/50; high dose, 20/50), many of the early deaths in the dosed males were gavage related. Body weights of the high dose male rats were 5%- 8% lower than those of the vehicle controls after week 59. The mean body weights of low dose and vehicle control male rats and those of dosed and vehicle control female rats were comparable. Survival rates of female rats and both sexes of dosed mice were not significantly different from those of the vehicle controls. The mean weights of dosed male and female mice were comparable to those of the vehicle controls. Hyperactivity lasting 5- 30 minutes was observed in high dose mice after dosing, beginning after week 4 and continuing through week 103. At no site was the incidence of nonneoplastic or neoplastic lesions in dosed rats or mice of either sex considered to be related to the administration of xylenes. Neither xylenes nor any of its components (o- xylene, m-xylene, p- xylene, or ethylbenzene) were mutagenic when tested with or without metabolic activation in Salmonella typhimurium strains TA100, TA1535, TA97, or TA98 with the preincubation protocol. In addition, ethylbenzene was tested in cytogenetic assays using cultured Cetic assays using cultured Chinese hamster ovary cells both with and without metabolic activation; neither sister- chromatid exchanges nor chromosomal aberrations were induced by ethylbenzene. An audit of the experimental data was conducted for the 2-year studies of xylenes. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenicity of xylenes (mixed) for male or female F344/N rats given 250 or 500 mg/kg or for male or female B6C3F1 mice given 500 or 1,000 mg/kg.

Hyperglycemia and hepatic tumors in ICR mice neonatally injected with streptozotocin.

PubMed

Ariza, Lorena; Zaguirre, Mireia; García, Marta; Blasco, Ester; Rabanal, Rosa Maria; Bosch, Assumpició; Otaegui, Pedro José

2014-07-01

Repeated, low-dose administration of streptozotocin (STZ) is widely used to induce insulin-dependent diabetes mellitus in mice. The authors adapted this method using neonatal mice and determined the long-term effects of STZ injection in the mice. After receiving intraperitoneal injections of STZ at postnatal day 3 (P3), P4 and P8, male and female mice were hyperglycemic by week 4. A clear sex difference was found, with blood glucose levels in STZ-treated males remaining higher than those in STZ-treated females until week 23. Whereas STZ-treated males remained hyperglycemic until week 23, STZ-treated females did not have significantly higher glucose levels than control mice after week 18. Additionally, STZ-treated mice had neoplastic lesions in their livers by week 4, with a progression in the severity of these lesions until week 24. The results confirm that, in addition to pancreatic beta cell toxicity, STZ has an oncogenic effect on the liver when administered to neonates.

Trypanosoma cruzi infection induced changes in the innervation, structure and function of the murine bladder.

PubMed

Boczko, Judd; Tar, Moses; Melman, Arnold; Jelicks, Linda A; Wittner, Murray; Factor, Stephen M; Zhao, Dazhi; Hafron, Jason; Weiss, Louis M; Tanowitz, Herbert B; Christ, George J

2005-05-01

The involvement of the lower urinary tract in chronic Chagas' disease has received little attention. Therefore, we investigated pathology and functional alterations in the bladder of Trypanosoma cruzi infected mice. CD1 mice were infected with 5 x 10 T. cruzi trypomastigotes of the Brazil strain of T. cruzi. At day 100 after infection bladder structure and function were examined by pathological evaluation, magnetic resonance imaging and cystometric studies. The bladder in infected mice weighed more and were large, dilated, deformed, friable and thin walled compared with control mice. Magnetic resonance imaging confirmed these observations. Inflammation, fibrosis and ganglionitis was observed. Cystometric studies revealed that baseline, threshold and micturition pressures were increased in infected mice. Bladder overactivity and decreased bladder compliance were also noted in infected mice. There were no detectable differences in bladder capacity, micturition volume or residual volume between infected and uninfected mice. Bladder abnormalities may be a more common clinical sequelae of T. cruzi infection than previously appreciated.

A mineral and antioxidant-rich extract from the red marine Algae Alsidium corallinum exhibits cytoprotective effects against potassium bromate-induced erythrocyte oxidative damages in mice.

PubMed

Ben Saad, Hajer; Nasri, Imen; Elwej, Awatef; Krayem, Najeh; Jarraya, Raoudha; Kallel, Choumous; Zeghal, Najiba; Amara, Ibtissem Ben

2014-07-01

The present study was carried out to investigate potassium bromate toxicity in mice and the corrective effects of marine algae Alsidium corallinum. The red algae demonstrated its rich composition in phenols, triterpenes, flavonoids, alkaloids, tropolones, sodium, potassium, calcium, magnesium, iron, copper, and zinc. To confirm its antioxidant potential, an in vivo study was performed on adult mice. The animals were divided into four groups: group I were used as controls, group II received potassium bromate (0.5 g/L) via drinking water, group III received potassium bromate (0.5 g/L) by the same route as group II and 7% of A. corallinum ethanolic extract via their diet, and group IV received only 7% of algae. The potassium bromate-treated group showed a significant decrease in erythrocyte, platelet, hemoglobin, and hematocrit values and a significant increase in total white blood cells, compared to those of controls. While, superoxide dismutase, catalase, glutathione, and vitamin C values were decreased by potassium bromate treatment, lipid peroxidation (as malondialdehyde) and erythrocyte osmotic fragility values were increased. Interestingly, potassium bromate treatment showed significant genotoxic effects, as demonstrated by DNA degradation. These changes were confirmed by blood smears histopathological observations which were marked by a necrosis and a decrease of erythrocytes number. A. corallinum extract appeared to be effective against hematotoxic and genotoxic changes induced by potassium bromate, as evidenced by the improvement of the parameters cited above.

Whole-Body Exposure to 28Si-Radiation Dose-Dependently Disrupts Dentate Gyrus Neurogenesis and Proliferation in the Short Term and New Neuron Survival and Contextual Fear Conditioning in the Long Term.

PubMed

Whoolery, Cody W; Walker, Angela K; Richardson, Devon R; Lucero, Melanie J; Reynolds, Ryan P; Beddow, David H; Clark, K Lyles; Shih, Hung-Ying; LeBlanc, Junie A; Cole, Mara G; Amaral, Wellington Z; Mukherjee, Shibani; Zhang, Shichuan; Ahn, Francisca; Bulin, Sarah E; DeCarolis, Nathan A; Rivera, Phillip D; Chen, Benjamin P C; Yun, Sanghee; Eisch, Amelia J

2017-11-01

Astronauts traveling to Mars will be exposed to chronic low doses of galactic cosmic space radiation, which contains highly charged, high-energy (HZE) particles. 56 Fe-HZE-particle exposure decreases hippocampal dentate gyrus (DG) neurogenesis and disrupts hippocampal function in young adult rodents, raising the possibility of impaired astronaut cognition and risk of mission failure. However, far less is known about how exposure to other HZE particles, such as 28 Si, influences hippocampal neurogenesis and function. To compare the influence of 28 Si exposure on indices of neurogenesis and hippocampal function with previous studies on 56 Fe exposure, 9-week-old C57BL/6J and Nestin-GFP mice (NGFP; made and maintained for 10 or more generations on a C57BL/6J background) received whole-body 28 Si-particle-radiation exposure (0, 0.2 and 1 Gy, 300 MeV/n, LET 67 KeV/μ, dose rate 1 Gy/min). For neurogenesis assessment, the NGFP mice were injected with the mitotic marker BrdU at 22 h postirradiation and brains were examined for indices of hippocampal proliferation and neurogenesis, including Ki67 + , BrdU + , BrdU + NeuN + and DCX + cell numbers at short- and long-term time points (24 h and 3 months postirradiation, respectively). In the short-term group, stereology revealed fewer Ki67 + , BrdU + and DCX + cells in 1-Gy-irradiated group relative to nonirradiated control mice, fewer Ki67 + and DCX + cells in 0.2 Gy group relative to control group and fewer BrdU + and DCX + cells in 1 Gy group relative to 0.2 Gy group. In contrast to the clearly observed radiation-induced, dose-dependent reductions in the short-term group across all markers, only a few neurogenesis indices were changed in the long-term irradiated groups. Notably, there were fewer surviving BrdU + cells in the 1 Gy group relative to 0- and 0.2-Gy-irradiated mice in the long-term group. When the short- and long-term groups were analyzed by sex, exposure to radiation had a similar effect on neurogenesis indices in male and female mice, although only male mice showed fewer surviving BrdU + cells in the long-term group. Fluorescent immunolabeling and confocal phenotypic analysis revealed that most surviving BrdU + cells in the long-term group expressed the neuronal marker NeuN, definitively confirming that exposure to 1 Gy 28 Si radiation decreased the number of surviving adult-generated neurons in male mice relative to both 0- and 0.2-Gy-irradiated mice. For hippocampal function assessment, 9-week-old male C57BL/6J mice received whole-body 28 Si-particle exposure and were then assessed long-term for performance on contextual and cued fear conditioning. In the context test the animals that received 0.2 Gy froze less relative to control animals, suggesting decreased hippocampal-dependent function. However, in the cued fear conditioning test, animals that received 1 Gy froze more during the pretone portion of the test, relative to controls and 0.2-Gy-irradiated mice, suggesting enhanced anxiety. Compared to previously reported studies, these data suggest that 28 Si-radiation exposure damages neurogenesis, but to a lesser extent than 56 Fe radiation and that low-dose 28 Si exposure induces abnormalities in hippocampal function, disrupting fear memory but also inducing anxiety-like behavior. Furthermore, exposure to 28 Si radiation decreased new neuron survival in long-term male groups but not females suggests that sex may be an important factor when performing brain health risk assessment for astronauts traveling in space.

Indomethacin Treatment of Mice with Premalignant Oral Lesions Sustains Cytokine Production and Slows Progression to Cancer.

PubMed

Johnson, Sara D; Young, M Rita I

2016-01-01

Current treatment options for head and neck squamous cell carcinoma (HNSCC) patients are often ineffective due to tumor-localized and systemic immunosuppression. Using the 4-NQO mouse model of oral carcinogenesis, this study showed that premalignant oral lesion cells produce higher levels of the immune modulator, PGE 2 , compared to HNSCC cells. Inhibiting prostaglandin production of premalignant lesion cells with the pan-cyclooxygenase inhibitor indomethacin stimulated their induction of spleen cell cytokine production. In contrast, inhibiting HNSCC prostaglandin production did not stimulate their induction of spleen cell cytokine production. Treatment of mice bearing premalignant oral lesions with indomethacin slowed progression of premalignant oral lesions to HNSCC. Flow cytometric analysis of T cells in the regional lymph nodes of lesion-bearing mice receiving indomethacin treatment showed an increase in lymph node cellularity and in the absolute number of CD8 + T cells expressing IFN-γ compared to levels in lesion-bearing mice receiving diluent control treatment. The cytokine-stimulatory effect of indomethacin treatment was not localized to regional lymph nodes but was also seen in the spleen of mice with premalignant oral lesions. Together, these data suggest that inhibiting prostaglandin production at the premalignant lesion stage boosts immune capability and improves clinical outcomes.

Transfer of in vitro expanded T lymphocytes after activation with dendritomas prolonged survival of mice challenged with EL4 tumor cells.

PubMed

Li, Jinhua; Theofanous, Leigh; Stickel, Sara; Bouton-Verville, Hilary; Burgin, Kelly E; Jakubchak, Susan; Wagner, Thomas E; Wei, Yanzhang

2007-07-01

Adoptive T cell transfer after in vitro expansion represents an attractive cancer immunotherapy. The majority of studies so far have been focusing on the expansion of tumor infiltrated lymphocytes (TIL) and some have shown very encouraging results. Recently, we have developed a unique tumor immune response activator, dendritomas, by fusion of dendritic cells and tumor cells. Animal studies and early clinical trials have shown that dendritomas are able to activate tumor specific immune responses. In this study, we hypothesized that naïve T cells can be primed with dendritomas and expanded in vitro to develop an adoptive transfer therapy for patients who do not have solid tumors, such as leukemia. T cells were isolated and purified from lymph nodes of mice. The cells were then incubated with dendritomas made from syngeneic DCs and tumor cells and expanded in vitro using Dynabeads mouse CD3/CD28 T cell expander for approximately three weeks. The in vitro primed and expanded T cells showed tumor cell specific CTL activity and increased secretion of IFN-gamma. Tumor bearing mice receiving the in vitro expanded T cells survived significantly longer than control mice. Furthermore, the depletion of regulator T cells enhanced the survival of the mice that received the adoptive transfer therapy.

Low dose radiation prevents doxorubicin-induced cardiotoxicity.

PubMed

Jiang, Xin; Hong, Yaqiong; Zhao, Di; Meng, Xinxin; Zhao, Lijing; Du, Yanwei; Wang, Zan; Zheng, Yan; Cai, Lu; Jiang, Hongyu

2018-01-02

This study aimed to develop a novel and non-invasive approach, low-dose radiation (LDR, 75 mGy X-rays), to prevent doxorubicin (DOX)-induced cardiotoxicity. BALB/c mice were randomly divided into five groups, Control, LDR (a single exposure), Sham (treated same as LDR group except for irradiation), DOX (a single intraperitoneal injection of DOX at 7.5 mg/kg), and LDR/DOX (received LDR and 72 h later received DOX). Electrocardiogram analysis displayed several kinds of abnormal ECG profiles in DOX-treated mice, but less in LDR/DOX group. Cardiotoxicity indices included histopathological changes, oxidative stress markers, and measurements of mitochondrial membrane permeability. Pretreatment of DOX group with LDR reduced oxidative damages (reactive oxygen species formation, protein nitration, and lipid peroxidation) and increased the activities of antioxidants (superoxide dismutase and glutathione peroxidase) in the heart of LDR/DOX mice compared to DOX mice. Pretreatment of DOX-treated mice with LDR also decreased DOX-induced cardiac cell apoptosis (TUNEL staining and cleaved caspase-3) and mitochondrial apoptotic pathway (increased p53, Bax, and caspase-9 expression and decreased Bcl2 expression and ΔΨm dissipation). These results suggest that LDR could induce adaptation of the heart to DOX-induced toxicity. Cardiac protection by LDR may attribute to attenuate DOX-induced cell death via suppressing mitochondrial-dependent oxidative stress and apoptosis signaling.

Proteomic CNS profile of delayed cognitive impairment in mice exposed to Gulf War agents.

PubMed

Abdullah, Laila; Crynen, Gogce; Reed, Jon; Bishop, Alex; Phillips, John; Ferguson, Scott; Mouzon, Benoit; Mullan, Myles; Mathura, Venkatarajan; Mullan, Michael; Ait-Ghezala, Ghania; Crawford, Fiona

2011-12-01

Gulf War Illness (GWI) is a chronic multisymptom condition with a central nervous system (CNS) component, for which there is no treatment available. It is now believed that the combined exposure to Gulf War (GW) agents, including pyridostigmine bromide (PB) and pesticides, such as permethrin (PER), was a key contributor to the etiology of GWI. In this study, a proteomic approach was used to characterize the biomolecular disturbances that accompany neurobehavioral and neuropathological changes associated with combined exposure to PB and PER. Mice acutely exposed to PB and PER over 10 days showed an increase in anxiety-like behavior, psychomotor problems and delayed cognitive impairment compared to control mice that received vehicle only. Proteomic analysis showed changes in proteins associated with lipid metabolism and molecular transport in the brains of GW agent-exposed mice compared to controls. Proteins associated with the endocrine and immune systems were also altered, and dysfunction of these systems is a prominent feature of GWI. The presence of astrogliosis in the GW agent-exposed mice compared to control mice further suggests an immune system imbalance, as is observed in GWI. These studies provide a broad perspective of the molecular disturbances driving the late pathology of this complex illness. Evaluation of the potential role of these biological functions in GWI will be useful in identifying molecular pathways that can be targeted for the development of novel therapeutics against GWI.

Doxycycline inhibits experimental cerebral malaria by reducing inflammatory immune reactions and tissue-degrading mediators

PubMed Central

Alferink, Judith; Hofmann, Andrea; Howland, Shanshan W.; Rénia, Laurent; Limmer, Andreas; Specht, Sabine; Hoerauf, Achim

2018-01-01

Malaria ranks among the most important infectious diseases worldwide and affects mostly people living in tropical countries. Mechanisms involved in disease progression are still not fully understood and specific treatments that might interfere with cerebral malaria (CM) are limited. Here we show that administration of doxycycline (DOX) prevented experimental CM (ECM) in Plasmodium berghei ANKA (PbA)-infected C57BL/6 wildtype (WT) mice in an IL-10-independent manner. DOX-treated mice showed an intact blood-brain barrier (BBB) and attenuated brain inflammation. Importantly, if WT mice were infected with a 20-fold increased parasite load, they could be still protected from ECM if they received DOX from day 4–6 post infection, despite similar parasitemia compared to control-infected mice that did not receive DOX and developed ECM. Infiltration of T cells and cytotoxic responses were reduced in brains of DOX-treated mice. Analysis of brain tissue by RNA-array revealed reduced expression of chemokines and tumour necrosis factor (TNF) in brains of DOX-treated mice. Furthermore, DOX-administration resulted in brains of the mice in reduced expression of matrix metalloproteinase 2 (MMP2) and granzyme B, which are both factors associated with ECM pathology. Systemic interferon gamma production was reduced and activated peripheral T cells accumulated in the spleen in DOX-treated mice. Our results suggest that DOX targeted inflammatory processes in the central nervous system (CNS) and prevented ECM by impaired brain access of effector T cells in addition to its anti-parasitic effect, thereby expanding the understanding of molecular events that underlie DOX-mediated therapeutic interventions. PMID:29438386

Doxycycline inhibits experimental cerebral malaria by reducing inflammatory immune reactions and tissue-degrading mediators.

PubMed

Schmidt, Kim E; Kuepper, Janina M; Schumak, Beatrix; Alferink, Judith; Hofmann, Andrea; Howland, Shanshan W; Rénia, Laurent; Limmer, Andreas; Specht, Sabine; Hoerauf, Achim

2018-01-01

Malaria ranks among the most important infectious diseases worldwide and affects mostly people living in tropical countries. Mechanisms involved in disease progression are still not fully understood and specific treatments that might interfere with cerebral malaria (CM) are limited. Here we show that administration of doxycycline (DOX) prevented experimental CM (ECM) in Plasmodium berghei ANKA (PbA)-infected C57BL/6 wildtype (WT) mice in an IL-10-independent manner. DOX-treated mice showed an intact blood-brain barrier (BBB) and attenuated brain inflammation. Importantly, if WT mice were infected with a 20-fold increased parasite load, they could be still protected from ECM if they received DOX from day 4-6 post infection, despite similar parasitemia compared to control-infected mice that did not receive DOX and developed ECM. Infiltration of T cells and cytotoxic responses were reduced in brains of DOX-treated mice. Analysis of brain tissue by RNA-array revealed reduced expression of chemokines and tumour necrosis factor (TNF) in brains of DOX-treated mice. Furthermore, DOX-administration resulted in brains of the mice in reduced expression of matrix metalloproteinase 2 (MMP2) and granzyme B, which are both factors associated with ECM pathology. Systemic interferon gamma production was reduced and activated peripheral T cells accumulated in the spleen in DOX-treated mice. Our results suggest that DOX targeted inflammatory processes in the central nervous system (CNS) and prevented ECM by impaired brain access of effector T cells in addition to its anti-parasitic effect, thereby expanding the understanding of molecular events that underlie DOX-mediated therapeutic interventions.

Efficacy of Tramadol as a Sole Analgesic for Postoperative Pain in Male and Female Mice

PubMed Central

Wolfe, A Marissa; Kennedy, Lucy H; Na, Jane J; Nemzek-Hamlin, Jean A

2015-01-01

Tramadol is a centrally acting weak μ opioid agonist that has few of the adverse side effects common to other opioids. Little work has been done to establish an effective analgesic dose of tramadol specific for surgical laparotomy and visceral manipulation in mice. We used general appearance parameters to score positive indicators of pain including posture, coat condition, activity, breathing, and interactions with other mice, activity events (that is, the number of times each mouse stretched up in a 3-min period) used as an indicator of decreased pain, von Frey fibers, and plasma levels of corticosterone to determine whether tramadol at 20, 40, or 80 mg/kg prevented postoperative pain in male and female C57BL/6 mice. A ventral midline laparotomy with typhlectomy was used as a model of postoperative pain. In male mice, none of the markers differed between groups that received tramadol (regardless of dose) and the saline-treated controls. However, general appearance scores and plasma corticosterone levels were lower in female mice that received 80 mg/kg tramadol compared with saline. In summary, for severe postoperative pain after laparotomy and aseptic typhlectomy, tramadol was ineffective in male C57BL/6 mice at all doses tested. Although 80 mg/kg ameliorated postoperative pain in female C57BL/6 mice, this dose is very close to the threshold reported to cause toxic side effects, such as tremors and seizures. Therefore, we do not recommend the use of tramadol as a sole analgesic in this mouse model of postoperative pain. PMID:26224442

Efficacy of Tramadol as a Sole Analgesic for Postoperative Pain in Male and Female Mice.

PubMed

Wolfe, A Marissa; Kennedy, Lucy H; Na, Jane J; Nemzek-Hamlin, Jean A

2015-07-01

Tramadol is a centrally acting weak μ opioid agonist that has few of the adverse side effects common to other opioids. Little work has been done to establish an effective analgesic dose of tramadol specific for surgical laparotomy and visceral manipulation in mice. We used general appearance parameters to score positive indicators of pain including posture, coat condition, activity, breathing, and interactions with other mice, activity events (that is, the number of times each mouse stretched up in a 3-min period) used as an indicator of decreased pain, von Frey fibers, and plasma levels of corticosterone to determine whether tramadol at 20, 40, or 80 mg/kg prevented postoperative pain in male and female C57BL/6 mice. A ventral midline laparotomy with typhlectomy was used as a model of postoperative pain. In male mice, none of the markers differed between groups that received tramadol (regardless of dose) and the saline-treated controls. However, general appearance scores and plasma corticosterone levels were lower in female mice that received 80 mg/kg tramadol compared with saline. In summary, for severe postoperative pain after laparotomy and aseptic typhlectomy, tramadol was ineffective in male C57BL/6 mice at all doses tested. Although 80 mg/kg ameliorated postoperative pain in female C57BL/6 mice, this dose is very close to the threshold reported to cause toxic side effects, such as tremors and seizures. Therefore, we do not recommend the use of tramadol as a sole analgesic in this mouse model of postoperative pain.

Xiaoyaosan Improves Depressive-Like Behaviors in Mice through Regulating Apelin-APJ System in Hypothalamus.

PubMed

Yan, Zhiyi; Jiao, Haiyan; Ding, Xiufang; Ma, Qingyu; Li, Xiaojuan; Pan, Qiuxia; Wang, Tingye; Hou, Yajing; Jiang, Youming; Liu, Yueyun; Chen, Jiaxu

2018-05-03

Background: The apelin-APJ system has been considered to play a crucial role in HPA axis function, and how the traditional Chinese compound prescription Xiaoyaosan regulates the apelin-APJ system as a supplement to treat depressive disorders. Objective: To investigate the depression-like behaviors and expression of apelin and APJ in hypothalamus of chronic unpredictable mild stress (CUMS) mice and study whether these changes related to the regulation of Xiaoyaosan. Methods: 60 adult C57BL/6J mice were randomly divided into four groups, including control group, CUMS group, Xiaoyaosan treatment group and fluoxetine treatment group. Mice in the control group and CUMS group received 0.5 mL physiological saline once a day by intragastric administration. Mice in two treatment groups received Xiaoyaosan (0.25 g/kg/d) and fluoxetine (2.6 mg/kg/d), respectively. After 21 days of modeling with CUMS, the expression of apelin and APJ in hypothalamus were measured by real-time fluorescence quantitative PCR, western blot and immunohistochemical staining. The physical condition, body weight, food intake and behavior tests such as open field test, sucrose preference test and force swimming test were measured to evaluate depressive-like behaviors. Results: In this study, significant behavioral changes were found in CUMS-induced mice, meanwhile the expressions of apelin and APJ in the hypothalamus were changed after modeling. The body weight, food-intake and depressive-like behaviors in CUMS-induced mice could be improved by Xiaoyaosan treatment which is similar with the efficacy of fluoxetine, while the expressions of apelin and APJ in hypothalamus were modified by Xiaoyaosan. Conclusions: The data suggest that apelin-APJ system changes in the hypothalamus may be a target of depressive disorders, and the beneficial effects of Chinese compound prescription Xiaoyaosan on depressive-like behaviors may be mediated by the apelin-APJ system.

Photoprotection against UV-induced damage by skin-derived precursors in hairless mice.

PubMed

Xian, Dehai; Gao, Xiaoqing; Xiong, Xia; Xu, Jixiang; Yang, Lingyu; Pan, Lun; Zhong, Jianqiao

2017-10-01

Skin photodamage is associated with UV-induced overproduction of reactive oxygen species (ROS) and the inactivation of NF-E2-related factor 2 (Nrf2). Skin-derived precursor cells (SKPs), a population of dermal stem cells, are considered to be involved in wound repair and skin regeneration through the activation of Nrf2. However, no reports concentrate on the treatment of skin photodamage with SKPs. To investigate the photoprotective role of SKPs against UV-induced damage in mice. Fifty Balb/c hairless mice were divided into five groups (n=10), namely, normal (no intervention), model, prevention, treatment, and control groups. The latter four groups were dorsally exposed to UVA+UVB irradiation over a 2-week period. Mice in the prevention group received weekly SKP injections for 2weeks the day before irradiation. Mice in the treatment and Hanks groups received a two-time injection of SKPs and Hanks, respectively, after irradiation. One week after final intervention, skin appearance, pathological alterations, and oxidative indicators were evaluated by enzyme-linked immunosorbent assay, immunohistochemical analysis, and western blotting. After irradiation, lesions were observed on the dorsal skin of mice, including erythema, edema, scales, and wrinkles; however, these were significantly ameliorated by subcutaneous SKP injection. Hyperkeratosis, acanthosis, and spongiosis in the epidermis, as well as dermal papillae edema and inflammatory cell infiltration, were observed in both model and control groups; however, these conditions resolved with either pretreatment or posttreatment with SKPs. In addition, SKPs increased Nrf2, heme oxygenase-1, glutathione peroxidase, superoxide dismutase, catalase, and gluthathione expression, while decreasing levels of ROS, MDA, and H 2 O 2 . These findings suggest that SKPs have a photoprotective role against UV-induced damage in mice, which may be associated with their ability to scavenge photo-oxidative insults and activate Nrf2. Copyright © 2017 Elsevier B.V. All rights reserved.

Effect of a high fat diet on ovary morphology, in vitro development, in vitro fertilisation rate and oocyte quality in mice.

PubMed

Sohrabi, Maryam; Roushandeh, Amaneh Mohammadi; Alizadeh, Zohreh; Vahidinia, Aliasghar; Vahabian, Mehrangiz; Hosseini, Mahnaz

2015-10-01

The aim of this study was to determine the effect of a high-fat diet (HFD) on oocyte maturation and quality in a mouse model. Female BALB/c mice were allocated to one of the following groups: (a) control group (n = 40), which received a controlled diet; or (b) HFD group (n = 40), which received an HFD for 12 weeks. Sections of the ovary were examined histologically. The number of follicles and corpora lutea were counted. In vitro maturation and in vitro fertilisation (IVF) were assessed in germinal vesicle (GV) and metaphase II (MII) oocytes, respectively. The expression of bone morphogenetic protein 15 (BMP15) and leptin receptor genes in GV and MII oocytes was evaluated using reverse transcription real-time polymerase chain reactions. In the HFD group, there was a decreased number of primordial and Graafian follicles, as well as corpora lutea (p < 0.05). The rate of oocyte development to the MII stage was also reduced (p < 0.001). Cumulus expansion was observed more frequently in the control group than the HFD group (p < 0.05). The IVF rate in the HFD group was lower than that in the control group (p < 0.05). In the HFD group, BMP15 and leptin receptor genes were upregulated in the GV stage (p > 0.05) and MII stage (p < 0.05), compared to the control group. An HFD reduces folliculogenesis in the primordial and Graafian stages, in vitro maturation and in vitro fertilisation rates, as well as oocyte quality in mice.

Immunogenicity of a Psoralen-Inactivated Dengue Virus Type 1 Vaccine Candidate in Mice

DTIC Science & Technology

2010-02-01

United States Naval Medical Research Center Detachment, Lima, Peru , 1 and United States Naval Medical Research Center, Silver Spring, Maryland2 R...and 28. The mice in group B mice received 10-ng vaccine doses on study clays 0, 14, and 28. The mice in group C received 10-ng vaccine doses on

Proper Heat Shock Pretreatment Reduces Acute Liver Injury Induced by Carbon Tetrachloride and Accelerates Liver Repair in Mice

PubMed Central

Li, San-Qiang; Wang, Dong-Mei; Shu, You-Ju; Wan, Xue-Dong; Xu, Zheng-Shun; Li, En-Zhong

2013-01-01

Whether proper heat shock preconditioning can reduce liver injury and accelerate liver repair after acute liver injury is worth study. So mice received heat shock preconditioning at 40°C for 10 minutes (min), 20 min or 30 min and recovered at room temperature for 8 hours (h) under normal feeding conditions. Then acute liver injury was induced in the heat shock-pretreated mice and unheated control mice by intraperitoneal (i.p.) injection of carbon tetrachloride (CCl4). Hematoxylin and eosin (H&E) staining, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and the expression levels of heat shock protein 70 (HSP70), cytochrome P450 1A2 (CYP1A2) and proliferating cell nuclear antigen (PCNA) were detected in the unheated control mice and heat shock-pretreated mice after CCl4 administration. Our results showed that heat shock preconditioning at 40°C for 20 min remarkably improved the mice’s survival rate (P<0.05), lowered the levels of serum AST and ALT (P<0.05), induced HSP70 (P<0.01), CYP1A2 (P<0.01) and PCNA (P<0.05) expression, effectively reduced liver injury (P<0.05) and accelerated the liver repair (P<0.05) compared with heat shock preconditioning at 40°C for 10 min or 30 min in the mice after acute liver injury induced by CCl4 when compared with the control mice. Our results may be helpful in further investigation of heat shock pretreatment as a potential clinical approach to target liver injury PMID:24526809

The mesencephalic trigeminal sensory nucleus is involved in the control of feeding and exploratory behavior in mice.

PubMed

Ishii, Toshiaki; Furuoka, Hidefumi; Itou, Takuya; Kitamura, Nobuo; Nishimura, Masakazu

2005-06-28

The mesencephalic trigeminal nucleus (Me5), which receives input from oral proprioceptors and projects to higher brain regions, is involved in mastication-induced modulation of satiation. To investigate how the Me5 is involved in the control of feeding and exploratory behavior, we examined the effect of bilateral electrolytic lesions of the Me5 on feeding and exploratory behavior in mice. Mouse feeding and exploratory behaviors were analyzed using a food-search-compulsion-apparatus (FSCA), which was designed to distinguish between the two behaviors under standard living conditions. To assess anxiety in mice in an unfamiliar environment, exploratory activity was analyzed in an automated hole-board apparatus. Mice with bilateral Me5 lesions had unique feeding and exploratory behavior profiles in the FSCA compared with sham-operated mice. Me5-lesioned mice spent more time in the food chamber during each trial in the FSCA, but the number of entries into the food chamber was decreased by 40% compared to sham-operated mice. Moreover, Me5 lesions markedly inhibited exploratory behavior, manifested as low-frequency exploration. In spite of the low-frequency exploration in the FSCA, Me5 lesions had no effect on various exploratory activities analyzed in the hole-board apparatus, i.e., total locomotor activity, frequency and duration of rearing and head-dipping, and latency to the first head-dipping. These results suggest that the Me5 is involved in the control of feeding and exploratory behavior through its ascending neuronal pathways in mice without modulating the emotional state.

Effect of inhibition of fatty acid amide hydrolase on MPTP-induced dopaminergic neuronal damage.

PubMed

Viveros-Paredes, J M; Gonzalez-Castañeda, R E; Escalante-Castañeda, A; Tejeda-Martínez, A R; Castañeda-Achutiguí, F; Flores-Soto, M E

2017-01-16

Parkinson's disease (PD) is a neurodegenerative disorder characterised by balance problems, muscle rigidity, and slow movement due to low dopamine levels and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The endocannabinoid system is known to modulate the nigrostriatal pathway through endogenous ligands such as anandamide (AEA), which is hydrolysed by fatty acid amide hydrolase (FAAH). The purpose of this study was to increase AEA levels using FAAH inhibitor URB597 to evaluate the modulatory effect of AEA on dopaminergic neuronal death induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our study included 4 experimental groups (n = 6 mice per group): a control group receiving no treatment, a group receiving URB597 (0.2mg/kg) every 3 days for 30 days, a group treated with MPTP (30mg/kg) for 5 days, and a group receiving URB597 and subsequently MPTP injections. Three days after the last dose, we conducted a series of behavioural tests (beam test, pole test, and stride length test) to compare motor coordination between groups. We subsequently analysed immunoreactivity of dopaminergic cells and microglia in the SNpc and striatum. Mice treated with URB597 plus MPTP were found to perform better on behavioural tests than mice receiving MPTP only. According to the immunohistochemistry study, mice receiving MPTP showed fewer dopaminergic cells and fibres in the SNpc and striatum. Animals treated with URB597 plus MPTP displayed increased tyrosine hydroxylase immunoreactivity compared to those treated with MPTP only. Regarding microglial immunoreactivity, the group receiving MPTP showed higher Iba1 immunoreactivity in the striatum and SNpc than did the group treated with URB597 plus MPTP. Our results show that URB597 exerts a protective effect since it inhibits dopaminergic neuronal death, decreases microglial immunoreactivity, and improves MPTP-induced motor alterations. Copyright © 2016 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Neuroprotective effects of sulforaphane on cholinergic neurons in mice with Alzheimer's disease-like lesions.

PubMed

Zhang, Rui; Zhang, Jingzhu; Fang, Lingduo; Li, Xi; Zhao, Yue; Shi, Wanying; An, Li

2014-08-18

Alzheimer's disease (AD) is a common neurodegenerative disease in elderly individuals, and effective therapies are unavailable. This study was designed to investigate the neuroprotective effects of sulforaphane (an activator of NF-E2-related factor 2) on mice with AD-like lesions induced by combined administration of aluminum and D-galactose. Step-down-type passive avoidance tests showed sulforaphane ameliorated cognitive impairment in AD-like mice. Immunohistochemistry results indicated sulforaphane attenuated cholinergic neuron loss in the medial septal and hippocampal CA1 regions in AD-like mice. However, spectrophotometry revealed no significant difference in acetylcholine level or the activity of choline acetyltransferase or acetylcholinesterase in the cerebral cortex among groups of control and AD-like mice with and without sulforaphane treatment. Sulforaphane significantly increased the numbers of 5-bromo-2'-deoxyuridine-positive neurons in the subventricular and subgranular zones in AD-like mice which were significantly augmented compared with controls. Atomic absorption spectrometry revealed significantly lower aluminum levels in the brains of sulforaphane-treated AD-like mice than in those that did not receive sulforaphane treatment. In conclusion, sulforaphane ameliorates neurobehavioral deficits by reducing cholinergic neuron loss in the brains of AD-like mice, and the mechanism may be associated with neurogenesis and aluminum load reduction. These findings suggest that phytochemical sulforaphane has potential application in AD therapeutics.

Testicular Busulfan Injection in Mice to Prepare Recipients for Spermatogonial Stem Cell Transplantation Is Safe and Non-Toxic

PubMed Central

Qin, YuSheng; Liu, Ling; He, YaNan; Wang, Chen; Liang, MingYuan; Chen, XiaoLi; Hao, HaiSheng; Qin, Tong; Zhao, XueMing; Wang, Dong

2016-01-01

Current methods of administering busulfan to remove the endogenous germ cells cause hematopoietic toxicity, require special instruments and a narrow transplantation time. We use a direct testicular injection of busulfan method for preparing recipients for SSC transplantation. Male ICR mice (recipients) were divided into four groups, and two experimental groups were treated with a bilateral testicular injection of 4 or 6 mg/kg/side busulfan (n = 60 per concentration group). Mice received an intraperitoneal injection (i.p.) of 40 mg/kg busulfan (n = 60, positive control) and bilateral testicular injections of 50% DMSO (n = 60, negative control). Donor SSCs from RFP-transgenic C57BL/6J mice were introduced into the seminiferous tubules of each recipient testis via efferent duct injection on day 16–17 after busulfan treatment. Recipient mice mated with mature female ICR mice and the number of progeny was recorded. The index detected at day 14, 21, 28, 35 and 70 after busulfan treatment. Blood analysis shows that the toxicity of busulfan treated groups was much lower than i.p. injection groups. Fertility was restored in mice treated with busulfan and donor-derived offspring were obtained after SSC transplantation. Our study indicated that intratesticular injection busulfan for the preparation of recipients in mice is safe and feasible. PMID:26871566

Effects of Postchallenge Administration of ST-246 on Dissemination of IHD-J-Luc Vaccinia Virus in Normal Mice and in Immune-Deficient Mice Reconstituted with T Cells

PubMed Central

Shotwell, Elisabeth; Scott, John; Cruz, Stephanie; King, Lisa R.; Manischewitz, Jody; Diaz, Claudia G.; Jordan, Robert A.; Grosenbach, Douglas W.; Golding, Hana

2013-01-01

Whole-body bioimaging was used to study dissemination of vaccinia virus (VACV) in normal and in immune deficient (nu−/nu−) mice protected from lethality by postchallenge administration of ST-246. Total fluxes were recorded in the liver, spleen, lungs, and nasal cavities of live mice after intranasal infection with a recombinant IHD-J-Luc VACV expressing luciferase. Areas under the flux curve were calculated for individual mice to assess viral loads. Treatment for 2 to 5 days of normal BALB/c mice with ST-246 at 100 mg/kg starting 24 h postchallenge conferred 100% protection and reduced viral loads in four organs compared to control mice. Mice also survived after 5 days of treatment with ST-246 at 30 mg/kg, and yet the viral loads and poxes were higher in these mice compared to 100-mg/kg treatment group. Nude mice were not protected by ST-246 alone or by 10 million adoptively transferred T cells. In contrast, nude mice that received T cells and 7-day treatment with ST-246 survived infection and exhibited reduced viral loads compared to nonreconstituted and ST-246-treated mice after ST-246 was stopped. Similar protection of nude mice was achieved using adoptively transferred 1.0 and 0.1 million, but not 0.01 million, purified T cells or CD4+ or CD8+ T cells in conjunction with ST-246 treatment. These data suggest that ST-246 protects immunocompetent mice from lethality and reduces viral dissemination in internal organs and poxvirus lesions. Furthermore, immune-deficient animals with partial T cell reconstitution can control virus replication after a course of ST-246 and survive lethal vaccinia virus challenge. PMID:23468500

Effects of concomitant diabetes mellitus and hyperthyroidism on testicular and epididymal histoarchitecture and steroidogenesis in male animals*

PubMed Central

Korejo, Nazar Ali; Wei, Quan-wei; Shah, Atta Hussain; Shi, Fang-xiong

2016-01-01

This study evaluated the effects of comorbid disorders of diabetes and hyperthyroidism in the adult male mice. In total, 32 ICR strain mice were equally distributed into four groups: control (C), diabetic (D), diabetic-plus-hyperthyroid (DH), and hyperthyroid (H). Mice allocated for diabetes received a single intraperitoneal injection of streptozotocin (STZ) at 200 mg/kg body weight. At the onset of diabetes, one group of mice was concomitantly injected levothyroxine (LT4; 0.3 mg/kg body weight) and the other set of animals received the same treatment independently on a daily basis. The body weight, as well as the testicular and epididymal weights, was reduced markedly in D and DH mice. Higher trends of blood glucose levels were seen in the DH group, in comparison to euthyroid diabetic mice. Thyroid hormones could exert a transient effect on blood glucose homeostasis by altering the serum blood glucose level in diabetic patients. Histomorphometric analysis showed increased luminal sizes of seminiferous tubules, along with decreased epithelial height and atrophic changes in germinal stem cells in the testis of DH and H mice. Caput epididymis of DH mice showed extensive compaction of principal cells, loss of stereocilia, lipid vacuolization, and inflammatory infiltrations; however, damaged tubular integrity, packed clear cells, exfoliated cells, and round spermatids were profoundly noticed in the cauda epididymis. Hyperthyroidism elevated the serum testosterone levels in H and DH mice and produced critical damages to the histoarchitecture of the epididymis. Collectively, this experiment endeavored to mimic the polyglandular autoimmune syndrome, which will be helpful to better understand the reasons for male infertility in diabetic-cum-hyperthyroid patients. PMID:27819132

Effects of concomitant diabetes mellitus and hyperthyroidism on testicular and epididymal histoarchitecture and steroidogenesis in male animals.

PubMed

Korejo, Nazar Ali; Wei, Quan-Wei; Shah, Atta Hussain; Shi, Fang-Xiong

This study evaluated the effects of comorbid disorders of diabetes and hyperthyroidism in the adult male mice. In total, 32 ICR strain mice were equally distributed into four groups: control (C), diabetic (D), diabetic-plus-hyperthyroid (DH), and hyperthyroid (H). Mice allocated for diabetes received a single intraperitoneal injection of streptozotocin (STZ) at 200 mg/kg body weight. At the onset of diabetes, one group of mice was concomitantly injected levothyroxine (LT4; 0.3 mg/kg body weight) and the other set of animals received the same treatment independently on a daily basis. The body weight, as well as the testicular and epididymal weights, was reduced markedly in D and DH mice. Higher trends of blood glucose levels were seen in the DH group, in comparison to euthyroid diabetic mice. Thyroid hormones could exert a transient effect on blood glucose homeostasis by altering the serum blood glucose level in diabetic patients. Histomorphometric analysis showed increased luminal sizes of seminiferous tubules, along with decreased epithelial height and atrophic changes in germinal stem cells in the testis of DH and H mice. Caput epididymis of DH mice showed extensive compaction of principal cells, loss of stereocilia, lipid vacuolization, and inflammatory infiltrations; however, damaged tubular integrity, packed clear cells, exfoliated cells, and round spermatids were profoundly noticed in the cauda epididymis. Hyperthyroidism elevated the serum testosterone levels in H and DH mice and produced critical damages to the histoarchitecture of the epididymis. Collectively, this experiment endeavored to mimic the polyglandular autoimmune syndrome, which will be helpful to better understand the reasons for male infertility in diabetic-cum-hyperthyroid patients.

Administration of kefir-fermented milk protects mice against Giardia intestinalis infection.

PubMed

Franco, Mariana Correa; Golowczyc, Marina A; De Antoni, Graciela L; Pérez, Pablo F; Humen, Martín; Serradell, María de los Angeles

2013-12-01

Giardiasis, caused by the protozoan Giardia intestinalis, is one of the most common intestinal diseases worldwide and constitutes an important problem for the public health systems of various countries. Kefir is a probiotic drink obtained by fermenting milk with 'kefir grains', which consist mainly of bacteria and yeasts that coexist in a complex symbiotic association. In this work, we studied the ability of kefir to protect mice from G. intestinalis infection, and characterized the host immune response to this probiotic in the context of the intestinal infection. Six- to 8-week-old C75BL/6 mice were separated into four groups: controls, kefir mice (receiving 1 : 100 dilution of kefir in drinking water for 14 days), Giardia mice (infected orally with 4×10(7) trophozoites of G. intestinalis at day 7) and Giardia-kefir mice (kefir-treated G. intestinalis-infected mice), and killed at 2 or 7 days post-infection. Kefir administration was able to significantly reduce the intensity of Giardia infection at 7 days post-infection. An increase in the percentage of CD4(+) T cells at 2 days post-infection was observed in the Peyer's patches (PP) of mice belonging to the Giardia group compared with the control and kefir groups, while the percentage of CD4(+) T cells in PP in the Giardia-kefir group was similar to that of controls. At 2 days post-infection, a reduction in the percentage of B220-positive major histocompatibility complex class II medium cells in PP was observed in infected mice compared with the other groups. At 7 days post-infection, Giardia-infected mice showed a reduction in RcFcε-positive cells compared with the control group, suggesting a downregulation of the inflammatory response. However, the percentages of RcFcε-positive cells did not differ from controls in the kefir and Giardia-kefir groups. An increase in IgA-positive cells was observed in the lamina propria of the kefir group compared with controls at 2 days post-infection. Interestingly, the diminished number of IgA-positive cells registered in the Giardia group at 7 days post-infection was restored by kefir feeding, although the increase in IgA-positive cells was no longer observed in the kefir group at that time. No significant differences in CXCL10 expression were registered between groups, in concordance with the absence of inflammation in small-intestinal tissue. Interestingly, a slight reduction in CCL20 expression was observed in the Giardia group, suggesting that G. intestinalis might downregulate its expression as a way of evading the inflammatory immune response. On the other hand, a trend towards an increase in TNF-α expression was observed in the kefir group, while the Giardia-kefir group showed a significant increase in TNF-α expression. Moreover, kefir-receiving mice (kefir and Giardia-kefir groups) showed an increase in the expression of IFN-γ, the most relevant Th1 cytokine, at 2 days post-infection. Our results demonstrate that feeding mice with kefir reduces G. intestinalis infection and promotes the activation of different mechanisms of humoral and cellular immunity that are downregulated by parasitic infection, thus contributing to protection.

Protective Effect of Lycium ruthenicum Murr. Against Radiation Injury in Mice

PubMed Central

Duan, Yabin; Chen, Fan; Yao, Xingchen; Zhu, Junbo; Wang, Cai; Zhang, Juanling; Li, Xiangyang

2015-01-01

The protective effect of Lycium ruthenicum Murr. against radiation injury was examined in mice. Kunming mice were randomly divided into a control group, model group, positive drug group and L. ruthenicum high dose (8 g/kg), L. ruthenicum middle dose (4 g/kg), L. ruthenicum low dose (2 g/kg) treatment groups, for which doses were administered the third day, seventh day and 14th day after irradiation. L. ruthenicum extract was administered orally to the mice in the three treatment groups and normal saline was administered orally to the mice in the control group and model group for 14 days. The positive group was treated with amifostine (WR-2721) at 30 min before irradiation. Except for the control group, the groups of mice received a 5 Gy quantity of X-radiation evenly over their whole body at one time. Body weight, hemogram, thymus and spleen index, DNA, caspase-3, caspase-6, and P53 contents were observed at the third day, seventh day, and 14th day after irradiation. L. ruthenicum could significantly increase the total red blood cell count, hemoglobin count and DNA contents (p < 0.05). The spleen index recovered significantly by the third day and 14th day after irradiation (p < 0.05). L. ruthenicum low dose group showed a significant reduction in caspase-3 and caspase-6 of serum in mice at the third day, seventh day, and 14th day after irradiation and L. ruthenicum middle dose group experienced a reduction in caspase-6 of serum in mice by the seventh day after irradiation. L. ruthenicum could decrease the expression of P53. The results showed that L. ruthenicum had protective effects against radiation injury in mice. PMID:26193298

Leptin Signaling Is Not Required for Anorexigenic Estradiol Effects in Female Mice.

PubMed

Kim, Joon S; Rizwan, Mohammed Z; Clegg, Deborah J; Anderson, Greg M

2016-05-01

Estradiol and leptin are critical hormones in the regulation of body weight. The aim of this study was to determine whether this cross talk between leptin receptor (LepRb) and estrogen receptor-α (ERα) signaling is critical for estradiol's anorexigenic effects. Leprb-Cre mice were crossed with Cre-dependent Tau-green fluorescent protein (GFP) reporter, Stat3-flox or Erα-flox mice to generate female mice with GFP expression, signal transducer and activator of transcription 3 (STAT3) knockout (KO), or ERα KO, specifically in LepRb-expressing cells. The proportion of Leprb-GFP cells colocalizing ERα was high (∼80%) in the preoptic area but low (∼10%) in the mediobasal hypothalamus, suggesting that intracellular cross talk between these receptors is minimal for metabolic regulation. To test whether estradiol enhanced arcuate leptin sensitivity, ovarectomized mice received varying levels of estradiol replacement. Increasing estrogenic states did not increase the degree of leptin-induced STAT3 phosphorylation. LepRb-specific STAT3 KO mice and controls were ovarectomized and given either chronic estradiol or vehicle treatment to test whether STAT3 is required for estrogen-induced body weight suppression. Both groups of estradiol-treated mice showed an equivalent reduction in body weight and fat content compared with vehicle controls. Finally, mice lacking ERα specifically in LepRb-expressing neurons also showed no increase in body weight or impairments in metabolic function compared with controls, indicating that estradiol acts independently of leptin-responsive cells to regulate body weight. However, fecundity was impaired in in Leprb-ERα KO females. Contrary to the current dogma, we report that estradiol has minimal direct actions on LepRb cells in the mediodasal hypothalamus and that its anorexigenic effects can occur entirely independently of LepRb-STAT3 signaling in female mice.

DSS-induced acute colitis in C57BL/6 mice is mitigated by sulforaphane pre-treatment.

PubMed

Wagner, Anika E; Will, Olga; Sturm, Christine; Lipinski, Simone; Rosenstiel, Philip; Rimbach, Gerald

2013-12-01

The Brassica-derived isothiocyanate sulforaphane (SFN) is known to induce factor erythroid 2-related factor 2 (Nrf2), a transcription factor centrally involved in chemoprevention. Furthermore, SFN exhibits anti-inflammatory properties in vitro and in vivo. However, little is known regarding the anti-inflammatory properties of SFN in severe inflammatory phenotypes. In the present study, we tested if pre-treatment with SFN protects mice from dextran sodium sulphate (DSS)-induced colitis. C57BL/6 mice received either phosphate-buffered saline (control) or 25 mg/kg body weight (BW) SFN per os for 7 days. Subsequently, acute colitis was induced by administering 4% DSS via drinking water for 5 days and BWs, stool consistency and faecal blood loss were recorded. Following endoscopic colonoscopy, mice were sacrificed, the organs excised and spleen weights and colon lengths measured. For histopathological analysis, distal colon samples were fixed in 4% para-formaldehyde, sectioned and stained with hematoxylin/eosin. Inflammatory biomarkers were also measured in distal colon. Treatment with SFN prior to colitis induction significantly minimised both BW loss and the disease activity index compared to control mice. Furthermore, colon lengths in SFN pre-treated mice were significantly longer than in control mice. Both macroscopic and microscopic analysis of the colon revealed attenuated inflammation in SFN pre-treated animals. mRNA analysis of distal colon samples confirmed reduced expression of inflammatory markers and increased expression of Nrf2-dependent genes in SFN pre-treated mice. Our results indicate that pre-treating mice with SFN confers protection from DSS-induced colitis. These protective effects were corroborated macroscopically, microscopically and at the molecular level. © 2013.

Hypertension Is a Conditional Factor for the Development of Cardiac Hypertrophy in Type 2 Diabetic Mice

PubMed Central

Brouwers, Olaf; Janssen, Ben J. A.; Derks, Wouter J. A.; Brouns, Agnieszka E.; Munts, Chantal; Schalkwijk, Casper G.; van der Vusse, Ger J.; van Nieuwenhoven, Frans A.

2014-01-01

Background Type 2 diabetes is frequently associated with co-morbidities, including hypertension. Here we investigated if hypertension is a critical factor in myocardial remodeling and the development of cardiac dysfunction in type 2 diabetic db/db mice. Methods Thereto, 14-wks-old male db/db mice and non-diabetic db/+ mice received vehicle or angiotensin II (AngII) for 4 wks to induce mild hypertension (n = 9–10 per group). Left ventricular (LV) function was assessed by serial echocardiography and during a dobutamine stress test. LV tissue was subjected to molecular and (immuno)histochemical analysis to assess effects on hypertrophy, fibrosis and inflammation. Results Vehicle-treated diabetic mice neither displayed marked myocardial structural remodeling nor cardiac dysfunction. AngII-treatment did not affect body weight and fasting glucose levels, and induced a comparable increase in blood pressure in diabetic and control mice. Nonetheless, AngII-induced LV hypertrophy was significantly more pronounced in diabetic than in control mice as assessed by LV mass (increase +51% and +34%, respectively, p<0.01) and cardiomyocyte size (+53% and +31%, p<0.001). This was associated with enhanced LV mRNA expression of markers of hypertrophy and fibrosis and reduced activation of AMP-activated protein kinase (AMPK), while accumulation of Advanced Glycation End products (AGEs) and the expression levels of markers of inflammation were not altered. Moreover, AngII-treatment reduced LV fractional shortening and contractility in diabetic mice, but not in control mice. Conclusions Collectively, the present findings indicate that type 2 diabetes in its early stage is not yet associated with adverse cardiac structural changes, but already renders the heart more susceptible to hypertension-induced hypertrophic remodeling. PMID:24416343

Protective effect of royal jelly on the sperm parameters and testosterone level and lipid peroxidation in adult mice treated with oxymetholone.

PubMed

Zahmatkesh, Ensieh; Najafi, Gholamreza; Nejati, Vahid; Heidari, Reza

2014-01-01

Objectives : The aim of the present study was to evaluate protective effect of royal jelly on sperm parameters, testosterone level, and malondialdehyde (MDA) production in mice. Thirty-two adult male NMRI mice weighing 30±2 g were used. All the animals were divided into 4 groups. received saline 0.1 ml/mouse/day orally for 30 days. Royal jelly group (RJ): received royal jelly at dose of 100 mg/kg daily for 30 days orally. Oxymetholone group: the received Oxymetholone (OX) at dose of 5 mg/kg daily for 30 days orally. Royal jelly+Oxymetholone group: received royal jelly at dose of 100 mg/kg/day orally concomitant with OX administration. Sperm count, sperm motility, viability, maturity, and DNA integrity were analyzed. Furthermore, serum testosterone and MDA concentrations were determined. In Oxymetholone group, sperm count, motility as well as testosterone concentration reduced significantly (p<0.05), while significant (p<0.05) increases in immature sperm, sperm with DNA damaged, and MDA concentration were announced in Oxymetholone group in comparison with control group and Royal jelly+Oxymetholone group. RJ caused partially amelioration in all of the above- mentioned parameters in Royal Jelly+Oxymetholone group. In conclusion, RJ may be used in combination with OX to improve OX-induced oxidative stress and male infertility.

Dietary olive oil induces cannabinoid CB2 receptor expression in adipose tissue of ApcMin/+ transgenic mice

PubMed Central

Notarnicola, Maria; Tutino, Valeria; Tafaro, Angela; Bianco, Giusy; Guglielmi, Emilia; Caruso, Maria Gabriella

2016-01-01

BACKGROUND: Cannabinoid- 2 (CB2) receptor is known for its anti-obesity effects silencing the activated immune cells that are key drivers of metabolic syndrome and inflammation. Nutritional interventions in experimental models of carcinogenesis have been demonstrated to modulate tissue inflammation state and proliferation. OBJECTIVE: Aim of this study was to test, in ApcMin/+ mice, whether a diet enriched with olive oil, omega- 3 and omega-6- PUFAs affects the adipose tissue inflammation status. METHODS: Four groups of animal were studied: ST group, receiving a standard diet; OO group, receiving the standard diet in which soybean oil (source of fats) was replaced with olive oil; OM-3 group, receiving the standard diet in which soybean oil was replaced with salmon oil; OM-6 group, receiving the standard diet in which soybean oil was replaced with oenothera oil. Gene and protein expression, in adipose tissue, were evaluated by RT-PCR and Western Blotting, respectively. Enzymatic activities were assayed by fluorescent and radiometric method, where appropriated. RESULTS: The diet enriched with olive oil significantly induced CB2 receptor expression and it was able to control inflammatory and proliferative activity of mice adipose tissue. CONCLUSIONS: The present findings open opportunities for developing novel nutritional strategies considering olive oil a key ingredient of a healthy dietary pattern. PMID:28035344

Protective effect of humus extract against Trypanosoma brucei infection in mice.

PubMed

Kodama, Hiroshi; Denso; Okazaki, Fumi; Ishida, Saeko

2008-11-01

Humic substances are formed during the decomposition of organic matter in humus, and are found in many natural environments in which organic materials and microorganisms are present. Oral administration of humus extract to mice successfully induced effective protection against experimental challenge by the two subspecies, Trypanosoma brucei brucei and T. brucei gambiense. Mortality was most reduced among mice who received a 3% humus extract for 21 days in drinking water ad libitum. Spleen cells from humus-administered mice exhibited significant non-specific cytotoxic activity against L1210 mouse leukemia target cells. Also, spleen cells produced significantly higher amounts of Interferon-gamma when stimulated in vitro with Concanavalin A than cells from normal controls. These results clearly show that administration to mice of humus extract induced effective resistance against Trypanosoma infection. Enhancement of the innate immune system may be involved in host defense against trypanosomiasis.

Subchronic Oral Bromocriptine Methanesulfonate Enhances Open Field Novelty-Induced Behavior and Spatial Memory in Male Swiss Albino Mice.

PubMed

Onaolapo, Olakunle James; Onaolapo, Adejoke Yetunde

2013-01-01

This study set out to assess the neurobehavioral effects of subchronic, oral bromocriptine methanesulfonate using the open field and the Y-maze in healthy male mice. Sixty adult Swiss albino mice were assigned into three groups. Controls received normal saline, while test groups received bromocriptine methanesulfonate at 2.5 and 5 mg/kg/day, respectively, for a period of 21 days. Neurobehavioral tests were carried out on days 1 and 21 after administration. Open field assessment on day 1 after administration revealed significant increase in grooming at 2.5 and 5 mg/kg, while horizontal and vertical locomotion showed no significant changes. Day 1 also showed no significant changes in Y-maze alternation. On day 21, horizontal locomotion, rearing, and grooming were increased significantly at 2.5 and 5 mg/kg doses after administration; also, spatial memory was significantly enhanced at 2.5 mg/kg. In conclusion, the study demonstrates the ability of oral bromocriptine to affect neurobehavior in normal mice. It also suggests that there is a cumulative effect of oral bromocriptine on the behaviors studied with more changes being seen after subchronic administration rather than after a single oral dose.

The Effect of Different Doses of Cigarette Smoke in a Mouse Lung Tumor Model

PubMed Central

Santiago, Ludmilla Nadir; de Camargo Fenley, Juliana; Braga, Lúcia Campanario; Cordeiro, José Antônio; Cury, Patrícia M.

2009-01-01

Few studies have used Balb/c mice as an animal model for lung carcinogenesis. In this study, we investigated the effect of different doses of cigarette smoking in the urethane-induced Balb/c mouse lung cancer model. After injection of 3mg/kg urethane intraperitoneally, the mice were then exposed to tobacco smoke once or twice a day, five times a week, in a closed chamber. The animals were randomly divided into four groups. The control group (G0) received urethane only. The experimental groups (G1, G2 and G3) received urethane and exposure to the smoke of 3 cigarettes for 10 minutes once a day, 3 cigarettes for 10 minutes twice a day, and 6 cigarettes for 10 minutes twice a day, respectively. The mice were sacrificed after 16 weeks of exposure, and the number of nodules and hyperplasia in the lungs was counted. The results showed no statistically significant difference in the mean number of nodules and hyperplasia among the different groups, suggesting that the Balb/c mice are not suitable to study the pathogenesis of tobacco smoking-induced tumor progression in the lungs. PMID:19079653

Neurotoxic effects of ivermectin administration in genetically engineered mice with targeted insertion of the mutated canine ABCB1 gene.

PubMed

Orzechowski, Krystyna L; Swain, Marla D; Robl, Martin G; Tinaza, Constante A; Swaim, Heidi L; Jones, Yolanda L; Myers, Michael J; Yancy, Haile F

2012-09-01

To develop in genetically engineered mice an alternative screening method for evaluation of P-glycoprotein substrate toxicosis in ivermectin-sensitive Collies. 14 wild-type C57BL/6J mice (controls) and 21 genetically engineered mice in which the abcb1a and abcb1b genes were disrupted and the mutated canine ABCB1 gene was inserted. Mice were allocated to receive 10 mg of ivermectin/kg via SC injection (n = 30) or a vehicle-only formulation of propylene glycol and glycerol formal (5). Each was observed for clinical signs of toxic effects from 0 to 7 hours following drug administration. After ivermectin administration, considerable differences were observed in drug sensitivity between the 2 types of mice. The genetically engineered mice with the mutated canine ABCB1 gene had signs of severe sensitivity to ivermectin, characterized by progressive lethargy, ataxia, and tremors, whereas the wild-type control mice developed no remarkable effects related to the ivermectin. The ivermectin sensitivity modeled in the transgenic mice closely resembled the lethargy, stupor, disorientation, and loss of coordination observed in ivermectin-sensitive Collies with the ABCB1-1Δ mutation. As such, the model has the potential to facilitate toxicity assessments of certain drugs for dogs that are P-glycoprotein substrates, and it may serve to reduce the use of dogs in avermectin derivative safety studies that are part of the new animal drug approval process.

Anxiolytic effect of BPC-157, a gastric pentadecapeptide: shock probe/burying test and light/dark test.

PubMed

Sikiric, P; Jelovac, N; Jelovac-Gjeldum, A; Dodig, G; Staresinic, M; Anic, T; Zoricic, I; Ferovic, D; Aralica, G; Buljat, G; Prkacin, I; Lovric-Bencic, M; Separovic, J; Seiwerth, S; Rucman, R; Petek, M; Turkovic, B; Ziger, T

2001-03-01

To study anxiolytic effect of a gastric pentadecapeptide, BPC-157. In shock probe/burying test, pentadecapeptide BPC-157 (10 microg/kg, 10 ng/kg, ip), diazepam (0.075, 0.0375 mg/kg, ip), and an equivolume of saline (5 mL/kg, ip) were given at 30 min prior test. In light/dark test, the same dosage of diazepam, BPC-157, and saline were given at 45 min prior procedure. Shock probe/burying test: rats treated with either diazepam or pentadecapeptide BPC-157 were much less afraid after the shock: almost not burying and the total time spent in burying was clearly less than in controls. However, while in the diazepam treated rats the number of shocks received increased over control values, in pentadecapeptide BPC-157 treated groups the number of shocks remained not modified compared with the control values. Light/dark test: after exposure to the intense light, diazepam treated mice had longer latencies of crossing to the dark compartment, a greater number of crossing and a greater number of exploratory rearing, and spent longer time in the light compartment, as compared to the control mice, while BPC-157 mice had a similar behavior to that of the control mice. In contrast with the effect in light area, in dark zone diazepam produced no change with respect to controls, while BPC-157 (10 microg/kg) mice had a greater number of crossing and a greater number of exploratory rearing. Both diazepam and BPC-157 displayed a bidirectional effect, but the activity of pentadecapeptide BPC-157 was particular, and different from diazepam.

Human HLA-A*02:01/CHM1+ allo-restricted T cell receptor transgenic CD8+ T Cells specifically inhibit Ewing sarcoma growth in vitro and in vivo

PubMed Central

Kirschner, Andreas; Thiede, Melanie; Rubio, Rebeca Alba; Schirmer, David; Kirchner, Thomas; Richter, Gunther H.S.; Mall, Sabine; Klar, Richard; Riddell, Stanley; Busch, Dirk H.; Krackhardt, Angela; Grunewald, Thomas G.P.; Burdach, Stefan

2016-01-01

The endochondral bone protein Chondromodulin-I (CHM1) provides oncogene addiction in Ewing sarcoma (ES). We pre-clinically tested the targetability of CHM1 by TCR transgenic, allo-restricted, peptide specific T cells to treat ES. We previously generated allo-restricted wildtype CD8+ T cells directed against the ES specific antigen CHM1319 causing specific responses against ES. However, utilization of these cells in current therapy protocols is hampered due to high complexity in production, relatively low cell numbers, and rapid T cell exhaustion. In order to provide off-the-shelf products in the future, we successfully generated HLA-A*02:01-restricted T cell receptor (TCR) transgenic T cells directed against CHM1319 by retroviral transduction. After short-term expansion a 100% purified CHM1319-TCR-transgenic T cell population expressed a CD62L+/CD45RO and CD62L+/CD45RA+ phenotype. These cells displayed specific in vitro IFNg and granzyme B release in co-culture with HLA-A*02:01+ ES cell lines expressing CHM1. When co-injected with ES cells in Rag2−/−ɣc−/− mice, CHM1-specific TCR-transgenic T cells significantly inhibited the formation of lung and liver metastases in contrast to control mice. Lungs and livers of representative mice displayed CD8+ T cell infiltration in the presence (control group treated with unspecific T cells) and in the absence (study group) of metastatic disease, respectively. Furthermore, mice receiving unspecific T cells showed signs of graft-versus-host-disease in contrast to all mice, receiving CHM1319-TCR-transgenic T cells. CHM1319 specific TCR-transgenic T cells were successfully generated causing anti-ES responses in vitro and in vivo. In the future, CHM1319-TCR-transgenic T cells may control minimal residual disease rendering donor lymphocyte infusions more efficacious and less toxic. PMID:27281613

A dopamine receptor d2-type agonist attenuates the ability of stress to alter sleep in mice.

PubMed

Jefferson, F; Ehlen, J C; Williams, N S; Montemarano, J J; Paul, K N

2014-11-01

Although sleep disruptions that accompany stress reduce quality of life and deteriorate health, the mechanisms through which stress alters sleep remain obscure. Psychological stress can alter sleep in a variety of ways, but it has been shown to be particularly influential on rapid eye movement (REM) sleep. Prolactin (PRL), a sexually dimorphic, stress-sensitive hormone whose basal levels are higher in females, has somnogenic effects on REM sleep. In the current study, we examined the relationship between PRL secretion and REM sleep after restraint stress to determine whether: 1) the ability of stress to increase REM sleep is PRL-dependent, and 2) fluctuating PRL levels underlie sex differences in sleep responses to stress. Because dopamine D2 receptors in the pituitary gland are the primary regulator of PRL secretion, D2 receptor agonist, 1-[(6-allylergolin-8β-yl)-carbonyl]-1-[3-(dimethylamino) propyl]-3-ethylurea (cabergoline), was used to attenuate PRL levels in mice before 1 hour of restraint stress. Mice were implanted with electroencephalographic/electromyographic recording electrodes and received an ip injection of either 0.3-mg/kg cabergoline or vehicle before a control procedure of 1 hour of sleep deprivation by gentle handling during the light phase. Six days after the control procedure, mice received cabergoline or vehicle 15 minutes before 1 hour of restraint stress. Cabergoline blocked the ability of restraint stress to increase REM sleep amount in males but did not alter REM sleep amount after stress in females even though it reduced basal REM sleep amount in female controls. These data provide evidence that the ability for restraint stress to increase REM sleep is dependent on PRL and that sex differences in REM sleep amount may be driven by PRL.

Effects of topical sphingosine-1-phosphate 1 receptor agonist on corneal allograft in mice.

PubMed

Jia, Liang; Liu, Yong; Wang, Liqiang; Zhu, Jing; Huang, Yifei

2014-04-01

The aim of this study was to compare the antirejection effects of topical selective sphingosine-1-phosphate 1 receptor (S1P1) agonist and cyclosporine A (CsA) on the acceptance of a transplanted, allogeneic cornea graft in a murine animal model. Fifty-six BALB/c mice were randomly divided into 4 groups. All the mice received corneal grafts from 28 C57BL/6 donors. Experimental recipients were treated with 0.25%, 0.5% S1P1 agonist suspension eye drops or 1% CsA eye drops 4 times a day after the corneal graft was performed. Controls received no treatment. The corneal grafts were imaged and evaluated with clinical scoring. The excised corneal sections 14 days after transplantation were stained using hematoxylin-eosin for histopathological evaluation. CD86+ and MHC-II+ dendritic cells in corneal samples were identified by immunohistochemical staining. The expression of mRNA in the cornea was evaluated using real-time quantitative PCR for interleukin-2, interferon-gamma, and cytotoxic T-lymphocyte antigen 4. Corneal graft survival was prolonged by treatment with 0.5% S1P1 agonist and 1% CsA (P < 0.01, respectively) when compared with that in the control in clinical scoring. In addition, topical application of 0.5% S1P1 increased the cytotoxic T-lymphocyte antigen 4 mRNA expression of the corneal grafts. There were significant differences observed with 0.5% S1P1 and agonist 1% CsA (P < 0.01, respectively) when compared with the values of the control group in histology scoring. Topical 0.5% S1P1 agonist is as effective as 1% CsA, and both can effectively prolong the survival of corneal allografts in mice.

Modafinil improves methamphetamine-induced object recognition deficits and restores prefrontal cortex ERK signaling in mice.

PubMed

González, Betina; Raineri, Mariana; Cadet, Jean Lud; García-Rill, Edgar; Urbano, Francisco J; Bisagno, Veronica

2014-12-01

Chronic use of methamphetamine (METH) leads to long-lasting cognitive dysfunction in humans and in animal models. Modafinil is a wake-promoting compound approved for the treatment of sleeping disorders. It is also prescribed off label to treat METH dependence. In the present study, we investigated whether modafinil could improve cognitive deficits induced by sub-chronic METH treatment in mice by measuring visual retention in a Novel Object Recognition (NOR) task. After sub-chronic METH treatment (1 mg/kg, once a day for 7 days), mice performed the NOR task, which consisted of habituation to the object recognition arena (5 min a day, 3 consecutive days), training session (2 equal objects, 10 min, day 4), and a retention session (1 novel object, 5 min, day 5). One hour before the training session, mice were given a single dose of modafinil (30 or 90 mg/kg). METH-treated mice showed impairments in visual memory retention, evidenced by equal preference of familiar and novel objects during the retention session. The lower dose of modafinil (30 mg/kg) had no effect on visual retention scores in METH-treated mice, while the higher dose (90 mg/kg) rescued visual memory retention to control values. We also measured extracellular signal-regulated kinase (ERK) phosphorylation in medial prefrontal cortex (mPFC), hippocampus, and nucleus accumbens (NAc) of METH- and vehicle-treated mice that received modafinil 1 h before exposure to novel objects in the training session, compared to mice placed in the arena without objects. Elevated ERK phosphorylation was found in the mPFC of vehicle-treated mice, but not in METH-treated mice, exposed to objects. The lower dose of modafinil had no effect on ERK phosphorylation in METH-treated mice, while 90 mg/kg modafinil treatment restored the ERK phosphorylation induced by novelty in METH-treated mice to values comparable to controls. We found neither a novelty nor treatment effect on ERK phosphorylation in hippocampus or NAc of vehicle- and METH-treated mice receiving acute 90 mg/kg modafinil treatment. Our results showed a palliative role of modafinil against METH-induced visual cognitive impairments, possibly by normalizing ERK signaling pathways in mPFC. Modafinil may be a valuable pharmacological tool for the treatment of cognitive deficits observed in human METH abusers as well as in other neuropsychiatric conditions. This article is part of the Special Issue entitled 'CNS Stimulants'. Copyright © 2014 Elsevier Ltd. All rights reserved.

Evaluation of propolis, honey, and royal jelly in amelioration of peripheral blood leukocytes and lung inflammation in mouse conalbumin-induced asthma model

PubMed Central

El-Aidy, Waleed K.; Ebeid, Ahmad A.; Sallam, Abd El-Raouf M.; Muhammad, Ibrahim E.; Abbas, Ayman T.; Kamal, M.A.; Sohrab, Sayed Sartaj

2014-01-01

Bee products have been used since ancient times to treat many diseases, including respiratory ailments. The present study aimed to examine the modulatory effect of honey, royal jelly, and propolis extract on peripheral blood leukocytes and lung inflammation in a mouse conalbumin-induced asthma model. The mice in group I were not sensitised or treated; they were kept as controls. The mice in group II were sensitised and challenged with conalbumin. Twenty-four hours after the first challenge with antigen, the mice in group III received 0.5 mg/kg of dexamethasone intraperitoneally per day for 18 consecutive days and kept as positive controls. The mice in groups IV, V, and VI received 650, 1000, and 30 mg/kg of honey, royal jelly, and propolis (aqueous and ethanolic extract), respectively, once per day for 18 consecutive days. Blood was collected from all of the mice for white blood cell differentiation, and the lungs were removed for histopathological studies. The groups treated with propolis extract exhibited considerable ameliorative effects against asthma, which might be explained by the flavonoids and phenolics found in propolis, which might have antioxidative effects. Otherwise, the sensitised and honey- or royal jelly-treated groups exhibited an increased incidence of asthma cascade events due to increased inflammatory cells. These results might be due to the immunostimulatory and vasodilatory effects of royal jelly and honey, which are antagonistic to bronchial asthma cases. Histopathological examination revealed that the sensitised treated propolis extract groups had significant decreases in inflammatory scores compared with other treatments and the sensitised untreated group. These results confirmed the previous data of peripheral blood cells. PMID:26587007

[The Impact of Electroacupuncture Intervention on Expression of 5-HTR 1 B/2 C Genes in Mice under Radiation Stimulation from Mobile Phone].

PubMed

Dai, Jian-yu; Chen, Yi-guo; Zhang, Xiao-qing

2015-08-01

To observe the effect of electroacupuncture (EA) stimulation of "Yifen" (TE 17), "Shenshu" (BL 23) on the expression of 5-hydroxytryptamine receptor 1 B (5-HTR 1 B) mRNA and 5-hydroxytryptamine receptor 2 C (5-HTR 2 C) mRNA in the cochlear nucleus tissue in mice experiencing radiation from mobile phone, so as to explore its mechanisms underlying improvement of tinnitus. Thirty Kunming mice were randomly divided into control group (n = 6) and modeling group (n = 24). The tinnitus model was established by giving the mice with mobile phone-radiation for 1 h in the morning and 1 h in the afternoon, continuously for 40 days. EA stimulation was applied to "Yifeng" (TE 17) group (n = 6) and "Shenshu" (BL 23) group (n = 6) for 20 min, once a day for 7 days. The expression of 5-THR 1 B/2 C mRNA in the cochlear nucleus was assayed by fluorescence quantitative polymerase chain reaction (real time-PCR). The expression level of 5-HTR 1 B was significantly lower in the model group than in the control group (P < 0.05), while that of 5-HTR 2 C mRNA significantly increased (P < 0.01). TE 17 group received a significant acupoint intervention effect (P < 0.01). Compared with TE 17 group, BL 23 group received a weaker effect (P < 0.05). EA of TE 17 can up-regulate expression level of 5-HTR 1 B and down-regulate expression level of 5-HTR 2 C in the cochlear nucleus in mice experiencing mobile-phone radiation.

Evaluation of propolis, honey, and royal jelly in amelioration of peripheral blood leukocytes and lung inflammation in mouse conalbumin-induced asthma model.

PubMed

El-Aidy, Waleed K; Ebeid, Ahmad A; Sallam, Abd El-Raouf M; Muhammad, Ibrahim E; Abbas, Ayman T; Kamal, M A; Sohrab, Sayed Sartaj

2015-11-01

Bee products have been used since ancient times to treat many diseases, including respiratory ailments. The present study aimed to examine the modulatory effect of honey, royal jelly, and propolis extract on peripheral blood leukocytes and lung inflammation in a mouse conalbumin-induced asthma model. The mice in group I were not sensitised or treated; they were kept as controls. The mice in group II were sensitised and challenged with conalbumin. Twenty-four hours after the first challenge with antigen, the mice in group III received 0.5 mg/kg of dexamethasone intraperitoneally per day for 18 consecutive days and kept as positive controls. The mice in groups IV, V, and VI received 650, 1000, and 30 mg/kg of honey, royal jelly, and propolis (aqueous and ethanolic extract), respectively, once per day for 18 consecutive days. Blood was collected from all of the mice for white blood cell differentiation, and the lungs were removed for histopathological studies. The groups treated with propolis extract exhibited considerable ameliorative effects against asthma, which might be explained by the flavonoids and phenolics found in propolis, which might have antioxidative effects. Otherwise, the sensitised and honey- or royal jelly-treated groups exhibited an increased incidence of asthma cascade events due to increased inflammatory cells. These results might be due to the immunostimulatory and vasodilatory effects of royal jelly and honey, which are antagonistic to bronchial asthma cases. Histopathological examination revealed that the sensitised treated propolis extract groups had significant decreases in inflammatory scores compared with other treatments and the sensitised untreated group. These results confirmed the previous data of peripheral blood cells.

Optimal timing and frequency of bone marrow soup therapy for functional restoration of salivary glands injured by single-dose or fractionated irradiation.

PubMed

Fang, Dongdong; Shang, Sixia; Liu, Younan; Bakkar, Mohammed; Sumita, Yoshinori; Seuntjens, Jan; Tran, Simon D

2018-02-01

Injections of bone marrow (BM) cell extract, known as 'BM soup', were previously reported to mitigate ionizing radiation (IR) injury to salivary glands (SGs). However, the optimal starting time and frequency to maintain BM soup therapeutic efficacy remains unknown. This study tested the optimal starting time and frequency of BM soup injections in mice radiated with either a single dose or a fractionated dose. First, BM soup treatment was started at 1, 3 or 7 weeks post-IR; positive (non-IR) and negative (IR) control mice received injections of saline (vehicle control). Second, BM soup-treated mice received injections at different frequencies (1, 2, 3 and 5 weekly injections). Third, a 'fractionated-dose radiation' model to injure mouse SGs was developed (5 Gy × 5 days) and compared with the single high dose radiation model. All mice (n = 65) were followed for 16 weeks post-IR. The results showed that starting injections of BM soup between 1 and 3 weeks mitigated the effect of IR-induced injury to SGs and improved the restoration of salivary function. Although the therapeutic effect of BM soup lessens after 8 weeks, it can be sustained by increasing the frequency of weekly injections. Moreover, both single-dose and fractionated-dose radiation models are efficient and comparable in inducing SG injury and BM soup treatments are effective in restoring salivary function in both radiation models. In conclusion, starting injections of BM soup within 3 weeks post-radiation, with 5 weekly injections, maintains 90-100% of saliva flow in radiated mice. Copyright © 2017 John Wiley & Sons, Ltd.

[EFFECT OF α-LIPOIC ACID IN INHIBITING OXIDATIVE STRESS AND PROMOTING DIABETIC WOUND HEALING BY SUPPRESSING EXPRESSION OF miR-29b IN MICE].

PubMed

Wu, Jun; Tang, Huiqin; Liu, Qun; Gan, Dingyun; Zhou, Man

2016-08-08

To investigate the effect of α-lipoic acid on the oxidative stress of wound tissues and diabetic wound healing in mice with diabetic feet. Sixty male C57BL/6J mice weighting 200-300 g were randomly divided into model group (control group, n =15), α-lipoic acid-treated model group ( n =15), miR-29b mimic group ( n =15), and miR-29b mimic negative control group (NC group, n =15). All animals received intraperitoneal injection of streptozocin to establish the diabetic model. Then, a full thickness wound of 5 mm×2 mm in size was created at 4 weeks after modeling. All mice were administrated with high-sugar-fat-diet. At the same day after modeling, α-lipoic acid-treated model group was continuously given intravenous injection of 100 mg/(kg·d) α-lipoic acid for 14 days; miR-29b mimic group and NC group received the tail intravenous injection of lentiviral vector for miR-29b mimic and miR-29b mimic negative control (a total of 2×10 7 TU), respectively, with the treatment of α-lipoic acid. The wound healing was observed and wound area was measured at 7 and 14 days. The wound tissues were harvested to detect the levels of superoxide dismutase (SOD) and glutathione (GSH) using xanthine oxidase method and 5, 5-dithiobis-2-nitrobenzoic acid staining method at 14 days. At the same day, 7, and 14 days after modeling, the relative miR-29b expression in wound tissues from control and α-lipoic acid-treated model groups was detected by real-time fluorescence quantitative PCR. All mice survived to the experiment end. The wound healing was faster in α-lipoic acid-treated group than control group. At 7 and 14 days, the relative wound area and miR-29b expression level were significantly lower, while the contents of SOD and GSH were significantly higher in α-lipoic acid-treated group than control group ( P <0.05). In addition, miR-29b mimic group had significantly increased relative wound area and significantly decreased the contents of SOD and GSH when compared with NC group at 7 and 14 days ( P <0.05). α-lipoic acid could inhibit oxidative stress and promote diabetic wound healing by suppressing expression of miR-29b in mice.

Therapeutic effects of dl-3-n-butylphthalide in a transgenic mouse model of amyotrophic lateral sclerosis.

PubMed

Feng, Xin-Hong; Yuan, Wei; Peng, Ying; Liu, Ming-Sheng; Cui, Li-Ying

2012-05-01

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive death of the upper and lower motor neurons. Transgenic mice over-expressing a mutant form of the human SOD1 gene develop an ALS-like phenotype. Currently, there is no effective treatment or drug for the fatal disease. Previous studies reported potent efficacy of dl-3-n-butylphthalide (DL-NBP) for several neurodegenerative disorders and cerebral ischemia. SOD1-G93A mice are a mouse model of ALS. In this study, we investigated the efficacy of DL-NBP on this ALS mouse model. Sixty SOD1-G93A female mice were divided into four groups. The vehicle control group received 0 mg×kg(-1)×d(-1) DL-NBP. The experimental groups received DL-NBP with doses of 30, 60 or 120 mg×kg(-1)×d(-1), respectively. For measurement of motor activity, the hanging wire test and rotarod test were performed. Survival statistics were analyzed by Kaplan-Meier survival curves. The body weight of each mouse was recorded twice per week. The statistical motor unit number estimation (MUNE) technique was used to estimate the number of functioning motor units in gastrocnemius muscle. Muscle morphology was evaluated by hematoxylin and eosin staining. Motor neuron quantitation was performed by Nissl staining and microglia activation was observed by immunohistochemistry. Oral administration of 60 mg×kg(-1)×d(-1)1 DL-NBP significantly prolonged survival ((164.78 ± 16.67) days) of SOD1-G93A mice compared with vehicle control ((140.00 ± 16.89) days). Treating mice with DL-NBP (60 mg×kg(-1)×d(-1)) significantly decreased the progression rate of motor deficits and suppressed body weight reduction. Furthermore, we found that treating SOD1-G93A mice with DL-NBP (60 mg×kg(-1)×d(-1)) slowed the rate of MUNE reduction (P < 0.01). Motor neurons were remarkably preserved in the anterior horns in mice treated with DL-NBP (60 mg×kg(-1)×d(-1)) at the stage of 19 weeks (P < 0.01). Treating mice with DL-NBP (60 mg×kg(-1)×d(-1)) significantly reduced CD11b immunoreactivity compared with vehicle control mice (P < 0.05). No significant effect was observed in mice treated with DL-NBP of 30 or 120 mg×kg(-1)×d(-1). The post-disease-onset administration of DL-NBP significantly prolonged survival and improved motor performance in SOD1-G93A mice. DL-NBP may be a potential therapeutic agent for ALS.

Assessment of carprofen and buprenorphine on recovery of mice after surgical removal of the mammary fat pad.

PubMed

Adamson, Trinka W; Kendall, Lon V; Goss, Sherri; Grayson, Kevin; Touma, Chadi; Palme, Rupert; Chen, Jane Q; Borowsky, Alexander D

2010-09-01

The purpose of this study was to determine the level of pain elicited by mammary fat pad removal surgery and the effects of postoperative analgesics on recovery. Female FVB mice were anesthetized, and mammary fat pad removal was performed. After surgery, mice received carprofen, buprenorphine, a combination of carprofen and buprenorphine, or saline treatment. Additional mice received anesthesia but no surgery or treatment. Food and water intake, body weight, wheel running activity, and a visual assessment score were recorded daily for 4 d after surgery and compared with presurgical findings. Corticosterone metabolites in fecal samples were analyzed at 12 and 24 h postsurgically and compared with baseline values. All surgical groups had significantly decreased food intake at 24 h, with a return to baseline by 48 h. The combination treatment resulted in a significantly decreased water intake and body weight at 24 h. All surgical groups had significantly decreased wheel running activity at 24 h only. The visual assessment scores indicated mild pain for all surgical groups, with the buprenorphine treated mice showing the highest pain index scores, as compared with nonsurgical controls. Fecal corticosterone metabolite levels did not differ significantly between any of the groups or across time. The parameters used in this study did not indicate that administration of these analgesic regimens improved recovery as compared with that of saline-treated mice. Care should be taken when using visual assessment scores to evaluate pain in mice, given that analgesics may have side effects that inadvertently elevate the score.

Assessment of Carprofen and Buprenorphine on Recovery of Mice after Surgical Removal of the Mammary Fat Pad

PubMed Central

Adamson, Trinka W; Kendall, Lon V; Goss, Sherri; Grayson, Kevin; Touma, Chadi; Palme, Rupert; Chen, Jane Q; Borowsky, Alexander D

2010-01-01

The purpose of this study was to determine the level of pain elicited by mammary fat pad removal surgery and the effects of postoperative analgesics on recovery. Female FVB mice were anesthetized, and mammary fat pad removal was performed. After surgery, mice received carprofen, buprenorphine, a combination of carprofen and buprenorphine, or saline treatment. Additional mice received anesthesia but no surgery or treatment. Food and water intake, body weight, wheel running activity, and a visual assessment score were recorded daily for 4 d after surgery and compared with presurgical findings. Corticosterone metabolites in fecal samples were analyzed at 12 and 24 h postsurgically and compared with baseline values. All surgical groups had significantly decreased food intake at 24 h, with a return to baseline by 48 h. The combination treatment resulted in a significantly decreased water intake and body weight at 24 h. All surgical groups had significantly decreased wheel running activity at 24 h only. The visual assessment scores indicated mild pain for all surgical groups, with the buprenorphine treated mice showing the highest pain index scores, as compared with nonsurgical controls. Fecal corticosterone metabolite levels did not differ significantly between any of the groups or across time. The parameters used in this study did not indicate that administration of these analgesic regimens improved recovery as compared with that of saline-treated mice. Care should be taken when using visual assessment scores to evaluate pain in mice, given that analgesics may have side effects that inadvertently elevate the score. PMID:20858363

Protective Effects of Flax Seed (Linum Usitatissimum) Hydroalcoholic Extract on Fetus Brain in Aged and Young Mice.

PubMed

Kamali, Mahsa; Bahmanpour, Soghra

2016-05-01

One of the major problems of the aged women or older than 35 is getting pregnant in the late fertility life. Fertility rates begin to decline gradually at the age of 30, more so at 35, and markedly at 40. Even with fertility treatments such as in vitro fertilization, women have more difficulty in getting pregnant or may deliver abnormal fetus. The purpose of this study was to assess the effects of flax seed hydroalcoholic extract on the fetal brain of aged mice and its comparison with young mice. In this experimental study, 32 aged and 32 young mice were divided into 4 groups. Controls received no special treatment. The experimental mice groups, 3 weeks before mating, were fed with flax seed hydroalcoholic extract by oral gavages. After giving birth, the brains of the fetus were removed. Data analysis was performed by statistical test ANOVA using SPSS version 18 (P<0.05). The mean fetus brain weight of aged mother groups compared to the control group was increased significantly (P<0.05). This study showed that flax seed hydroalcoholic extract could improve fetal brain weights in the aged groups.

Differential neurotoxic effects of in utero and lactational exposure to hydroxylated polychlorinated biphenyl (OH-PCB 106) on spontaneous locomotor activity and motor coordination in young adult male mice.

PubMed

Haijima, Asahi; Lesmana, Ronny; Shimokawa, Noriaki; Amano, Izuki; Takatsuru, Yusuke; Koibuchi, Noriyuki

2017-01-01

We investigated whether in utero or lactational exposure to 4-hydroxy-2',3,3',4',5'-pentachlorobiphenyl (OH-PCB 106) affects spontaneous locomotor activity and motor coordination in young adult male mice. For in utero exposure, pregnant C57BL/6J mice received 0.05 or 0.5 mg/kg body weight of OH-PCB 106 or corn oil vehicle via gavage every second day from gestational day 10 to 18. For lactational exposure, the different groups of dams received 0.05 or 0.5 mg/kg body weight of OH-PCB 106 or corn oil vehicle via gavage every second day from postpartum day 3 to 13. At 6-7 weeks of age, the spontaneous locomotor activities of male offspring were evaluated for a 24-hr continuous session in a home cage and in an open field for 30-min. Motor coordination function on an accelerating rotarod was also measured. Mice exposed prenatally to OH-PCB 106 showed increased spontaneous locomotor activities during the dark phase in the home cage and during the first 10-min in the open field compared with control mice. Mice exposed lactationally to OH-PCB 106, however, did not show a time-dependent decrease in locomotor activity in the open field. Instead, their locomotor activity increased significantly during the second 10-min block. In addition, mice exposed lactationally to OH-PCB 106 displayed impairments in motor coordination in the rotarod test. These results suggest that perinatal exposure to OH-PCB 106 affects motor behaviors in young adult male mice. Depending on the period of exposure, OH-PCB 106 may have different effects on neurobehavioral development.

Testosterone suppresses the expression of regulatory enzymes of fatty acid synthesis and protects against hepatic steatosis in cholesterol-fed androgen deficient mice.

PubMed

Kelly, Daniel M; Nettleship, Joanne E; Akhtar, Samia; Muraleedharan, Vakkat; Sellers, Donna J; Brooke, Jonathan C; McLaren, David S; Channer, Kevin S; Jones, T Hugh

2014-07-30

Non-alcoholic fatty liver disease and its precursor hepatic steatosis is common in obesity and type-2 diabetes and is associated with cardiovascular disease (CVD). Men with type-2 diabetes and/or CVD have a high prevalence of testosterone deficiency. Testosterone replacement improves key cardiovascular risk factors. The effects of testosterone on hepatic steatosis are not fully understood. Testicular feminised (Tfm) mice, which have a non-functional androgen receptor (AR) and very low serum testosterone levels, were used to investigate testosterone effects on high-cholesterol diet-induced hepatic steatosis. Hepatic lipid deposition was increased in Tfm mice and orchidectomised wild-type littermates versus intact wild-type littermate controls with normal androgen physiology. Lipid deposition was reduced in Tfm mice receiving testosterone treatment compared to placebo. Oestrogen receptor blockade significantly, but only partially, reduced the beneficial effects of testosterone treatment on hepatic lipid accumulation. Expression of key regulatory enzymes of fatty acid synthesis, acetyl-CoA carboxylase alpha (ACACA) and fatty acid synthase (FASN) were elevated in placebo-treated Tfm mice versus placebo-treated littermates and Tfm mice receiving testosterone treatment. Tfm mice on normal diet had increased lipid accumulation compared to littermates but significantly less than cholesterol-fed Tfm mice and demonstrated increased gene expression of hormone sensitive lipase, stearyl-CoA desaturase-1 and peroxisome proliferator-activated receptor-gamma but FASN and ACACA were not altered. An action of testosterone on hepatic lipid deposition which is independent of the classic AR is implicated. Testosterone may act in part via an effect on the key regulatory lipogenic enzymes to protect against hepatic steatosis. Copyright © 2014 Elsevier Inc. All rights reserved.

Role of A1 and A2A adenosine receptor agonists in adipose tissue inflammation induced by obesity in mice.

PubMed

DeOliveira, Caroline Candida; Paiva Caria, Cintia Rabelo E; Ferreira Gotardo, Erica Martins; Ribeiro, Marcelo Lima; Gambero, Alessandra

2017-03-15

Adenosine receptors are expressed in adipose tissue and control physiological and pathological events such as lipolysis and inflammation. The aim of this study was to evaluate the activity of N 6 -cyclopentyladenosine (CPA), a potent and selective A 1 adenosine receptor agonist; 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxyamidoadenosine hydrochloride (CGS-21680), an A 2A adenosine receptor agonist; and 5'-N-ethylcarboxamidoadenosine (NECA), a potent non-selective adenosine receptor agonist on adipose tissue inflammatory alterations induced by obesity in mice. Swiss mice were fed with a high-fat diet for 12 weeks and agonists were administered in the last two weeks. Body weight, adiposity and glucose homeostasis were evaluated. Inflammation in adipose tissue was assessed by evaluation of adipokine production and macrophage infiltration. Adenosine receptor signaling in adipose tissue was also evaluated. Mice that received CGS21680 presented an improvement in glucose homeostasis in association with systemically reduced inflammatory markers (TNF-α, PAI-1) and in the visceral adipose tissue (TNF-α, MCP-1, macrophage infiltration). Activation of p38 signaling was found in adipose tissue of this group of mice. NECA-treated mice presented some improvements in glucose homeostasis associated with an observed weight loss. Mice that received CPA presented only a reduction in the ex vivo basal lipolysis rate measured within visceral adipose tissue. In conclusion, administration of the A 2A receptor agonist to obese mice resulted in improvements in glucose homeostasis and adipose tissue inflammation, corroborating the idea that new therapeutics to treat obesity could emerge from these compounds. Copyright © 2017 Elsevier B.V. All rights reserved.

Prophylactic fenbendazole therapy does not affect the incidence and onset of type 1 diabetes in non-obese diabetic mice.

PubMed

Franke, Deanna D H; Shirwan, Haval

2006-03-01

Fenbendazole (FBZ) is a common, highly efficacious broad-spectrum anthelmintic drug used to treat and limit rodent pinworm infections. However, the effect of its prophylactic use on the immune response of rodents is largely undefined. The non-obese diabetic (NOD) mouse is a model commonly used to study type 1 diabetes (T1D). Parasitic infections will inhibit diabetes development in NOD mice; thus, in the presence of contamination, prophylactic treatment with anthelmintics must be considered to maintain experimental research. Herein, we investigated the prophylactic use of FBZ in NOD mice to determine its effect on the incidence and onset of diabetes, lymphocyte sub-populations and T cell proliferative responses. NOD mice were separated into control and treatment groups. The treatment group received a diet containing FBZ. Animals were monitored for the incidence and onset of T1D. At matched time points, diabetic and non-diabetic mice were killed and splenic lymphocytes analyzed for various cell sub-populations and mitogen-induced proliferative responses using flow cytometry. Treated and control mice were monitored >23 weeks with no detectable effects on the incidence or onset of diabetes. Moreover, no significant differences were detected in lymphocyte sub-populations and mitogen-induced CD4(+) and CD8(+) proliferative responses between control and treatment groups. These results suggest that prophylactic FBZ treatment does not significantly alter the incidence or onset of diabetes in NOD mice. The prophylactic use of FBZ, therefore, presents a viable approach for the prevention of pinworm infection in precious experimental animals with substantial scientific and economic benefits.

Activity of ergoferon against lethal influenza A (H3N2) virus infection in mice.

PubMed

Skarnovich, Maria A; Emelyanova, Alexandra G; Petrova, Nataliia V; Borshcheva, Alena A; Gorbunov, Evgeniy A; Mazurkov, Oleg Yu; Skarnovich, Maksim O; Tarasov, Sergey A; Shishkina, Larisa N; Epstein, Oleg I

2017-01-01

The influenza A virus accounts for serious annual viral upper respiratory tract infections. It is constantly able to modify its antigenic structure, thus evading host defence mechanisms. Moreover, currently available anti-influenza agents have a rather limited application, emphasizing the further need for new effective treatments. One of them is ergoferon, a drug containing combined polyclonal antibodies - anti-interferon gamma, anti-CD4 receptor and anti-histamine - in released-active form. The purpose of the study was to assess ergoferon antiviral efficacy in mice challenged with the A/Aichi/2/68 (H3N2) influenza virus. The virus was inoculated intranasally at a 90% lethal dose. Ergoferon was administered at 0.4 ml/day per os in a preventive and therapeutic regimen - daily for 5 days prior to and for 16 days after the challenge. The reference product, Tamiflu (oseltamivir), was used as a positive control treatment - at 20 mg/kg/day for 5 days after the challenge. Mice in the negative control group received distilled water which had been utilized for test sample preparation; untreated control animals received no treatment. Antiviral efficacy was assessed by an increase in survival rate, average life expectancy and virus titre reduction in the challenged mouse lungs. Survival rate and average life expectancy values were increased significantly in groups treated with ergoferon and Tamiflu, as compared with controls. Lung virus titres were reduced in these groups as observed on days 2 and 4 post-inoculation. Ergoferon demonstrated antiviral activity by reducing the severity and duration of the major signs of induced influenza infection.

Acute stress blocks the caffeine-induced enhancement of contextual memory retrieval in mice.

PubMed

Pierard, Chistophe; Krazem, Ali; Henkous, Nadia; Decorte, Laurence; Béracochéa, Daniel

2015-08-15

This study investigated in mice the dose-effect of caffeine on memory retrieval in non-stress and stress conditions. C57 Bl/6 Jico mice learned two consecutive discriminations (D1 and D2) in a four-hole board which involved either distinct contextual (CSD) or similar contextual (SSD) cues. All mice received an i.p. injection of vehicle or caffeine (8, 16 or 32mg/kg) 30min before the test session. Results showed that in non-stress conditions, the 16mg/kg caffeine dose induced a significant enhancement of D1 performance in CSD but not in SSD. Hence, we studied the effect of an acute stress (electric footshocks) administered 15min before the test session on D1 performance in caffeine-treated mice. Results showed that stress significantly decreased D1 performance in vehicle-treated controls and the memory-enhancing effect induced by the 16mg/kg caffeine dose in non-stress condition is no longer observed. Interestingly, whereas caffeine-treated mice exhibited weaker concentrations of plasma corticosterone as compared to vehicles in non-stress condition, stress significantly increased plasma corticosterone concentrations in caffeine-treated mice which reached similar level to that of controls. Overall, the acute stress blocked both the endocrinological and memory retrieval enhancing effects of caffeine. Copyright © 2015 Elsevier B.V. All rights reserved.

Changes of neuronal acetylcholine receptor alpha 7 of peritoneal macrophage in experimental acute pancreatitis treated by Chaiqin Chengqi Decoction ().

PubMed

Xue, Ping; Guo, Jia; Yang, Xiao-nan; Huang, Wei; Xia, Qing

2014-10-01

To investigate effect of Chaiqin Chengqi Decoction (, CQCQD) on changes of neuronal acetylcholine receptor alpha 7 (nAChRα7) of peritoneal macrophages in acute pancreatitis (AP). Eighteen Kunming mice were equally randomized into the control group, AP group and CQCQD treatment group. AP was induced by two intraperitoneal injections of 4 g/kg L-arginine at 1 h apart, while control mice received saline injections. At 72 h after the first injection of L-arginine, mice in the treatment group were intragastrically administered 0.1 mL/10 g CQCQD every 2 h for 3 times, whilst mice in the other two groups received the same amount of saline feeding. Mice were sacrificed by cervical dislocation 2 h after the last feeding of either CQCQD or saline. Peritoneal macrophages were collected for determination of nAChRα7 mRNA and protein expression. Serum was collected for detection of interleukin-6 (IL-6), IL-10 and acetylcholine (ACh) levels, and pancreas was for histopathology analysis. The CQCQD treatment significantly ameliorated the severity of AP as evidenced by reducing the pancreatic histopathology score (4.5±0.5 vs. 6.2±1.7, P<0.05) and the serum IL-6 levels (1228.3±419.2 pg/mL vs. 1589.6±337.3 pg/mL, P<0.05). The mRNA and protein expression of nAChRα7 of the peritoneal macrophages in the AP group were similar to the control group (P>0.05), but were significantly up-regulated after the CQCQD treatment (P<0.05). The serum ACh levels in the AP group were significantly lower than those in the control group (3.1±0.6 μg/mL vs 4.8±0.7 μg/mL P<0.05), but were significantly increased after the CQCQD treatment (5.6±1.5 μg/mL vs 3.1±0.6 μg/mL, P<0.05). CQCQD is protective against L-arginine-induced AP through mechanisms involving nAChRα7 of peritoneal macrophages.

Interleukin-12 induces a Th1-like response to Burkholderia mallei and limited protection in BALB/c mice.

PubMed

Amemiya, Kei; Meyers, Jennifer L; Trevino, Sylvia R; Chanh, Tran C; Norris, Sarah L; Waag, David M

2006-02-27

We evaluated the effect of interleukin (IL)-12 on the immune response to Burkholderia mallei in BALB/c mice. Mice were vaccinated with non-viable B. mallei cells with or without IL-12. There was a seven- to nine-fold increase in IgG2a levels, and a significant increase in the proliferative response and interferon (IFN)-gamma production by splenocytes from mice that received B. mallei and IL-12. We saw an increase in survivors in the groups of mice that received B. mallei and IL-12 when challenged, compared to mice that received only B. mallei or IL-12. The results suggest that IL-12 can enhance the Th1-like immune response to B. mallei and mediate limited protection from a lethal challenge.

Regulation of food intake and body weight by recombinant proghrelin.

PubMed

Zhang, Weizhen; Majumder, Arundhati; Wu, Xiaobin; Mulholland, Michael W

2009-12-01

Ghrelin is a 28-amino-acid hormone derived from the endoproteolytic processing of its prehormone proghrelin. Although ghrelin has been reported to regulate food intake and body weight, it is still unknown whether proghrelin exercises any biological function. Here we show that recombinant proghrelin alters food intake and energy metabolism in mice. After intraperitoneal administration of recombinant proghrelin (100 nmol/kg body wt), cumulative food intake was significantly increased at days 1, 2, and 3 (6 +/- 0.3, 13 +/- 0.5, and 20 +/- 0.8 g vs. 5 +/- 0.2, 10 +/- 0.2, and 16 +/- 0.3 g of the control mice receiving normal saline, respectively, n = 6, P < 0.05). Twelve-hour cumulative food intake in the light photo period in mice treated with proghrelin increased significantly relative to the control (2.1 +/- 0.04 vs. 1.3 +/- 0.2 g, n = 6, P < 0.05). No change in 12-h cumulative food intake in the dark photo period was observed between mice treated with proghrelin and vehicle (4.2 +/- 0.6 vs. 4.3 +/- 0.6 g, n = 6, P > 0.05). This is associated with a decrease in body weight (0.42 +/- 0.04 g) for mice treated with proghrelin, whereas control animals gained body weight (0.31 +/- 0.04 g). Mice treated with proghrelin demonstrate a significant decrease in respiratory quotient, indicating an increase in fat consumption. Recombinant proghrelin is functionally active with effects on food intake and energy metabolism.

Supplementation with α-Lipoic Acid, CoQ10, and Vitamin E Augments Running Performance and Mitochondrial Function in Female Mice

PubMed Central

Abadi, Arkan; Crane, Justin D.; Ogborn, Daniel; Hettinga, Bart; Akhtar, Mahmood; Stokl, Andrew; MacNeil, Lauren; Safdar, Adeel; Tarnopolsky, Mark

2013-01-01

Antioxidant supplements are widely consumed by the general public; however, their effects of on exercise performance are controversial. The aim of this study was to examine the effects of an antioxidant cocktail (α-lipoic acid, vitamin E and coenzyme Q10) on exercise performance, muscle function and training adaptations in mice. C57Bl/J6 mice were placed on antioxidant supplement or placebo-control diets (n = 36/group) and divided into trained (8 wks treadmill running) (n = 12/group) and untrained groups (n = 24/group). Antioxidant supplementation had no effect on the running performance of trained mice nor did it affect training adaptations; however, untrained female mice that received antioxidants performed significantly better than placebo-control mice (p ≤ 0.05). Furthermore, antioxidant-supplemented females (untrained) showed elevated respiratory capacity in freshly excised muscle fibers (quadriceps femoris) (p ≤ 0.05), reduced oxidative damage to muscle proteins (p ≤ 0.05), and increased expression of mitochondrial proteins (p ≤ 0.05) compared to placebo-controls. These changes were attributed to increased expression of proliferator-activated receptor gamma coactivator 1α (PGC-1α) (p ≤ 0.05) via activation of AMP-activated protein kinase (AMPK) (p ≤ 0.05) by antioxidant supplementation. Overall, these results indicate that this antioxidant supplement exerts gender specific effects; augmenting performance and mitochondrial function in untrained females, but does not attenuate training adaptations. PMID:23565271

Therapeutic efficacy induced by the oral administration of Agaricus blazei Murill against Leishmania amazonensis.

PubMed

Valadares, Diogo G; Duarte, Mariana C; Ramírez, Laura; Chávez-Fumagalli, Miguel A; Lage, Paula S; Martins, Vivian T; Costa, Lourena E; Ribeiro, Tatiana G; Régis, Wiliam C B; Soto, Manuel; Fernandes, Ana Paula; Tavares, Carlos A P; Coelho, Eduardo A F

2012-10-01

The development of therapeutic alternatives to treat leishmaniasis has received considerable attention. The present study aimed to investigate the efficacy of the Agaricus blazei Murill water extract (AbM) to treat BALB/c mice infected with Leishmania amazonensis. First, a dose-titration curve was performed. The most well-defined concentration able to induce the most effective results in the infected animals, considering a daily administration of the product, was that of 100 mg kg(-1) day(-1). In this context, the AbM was administered orally, beginning on day 0 up to 20 days postinfection. Additional animals were treated with amphotericin B (AmpB, 5 mg kg(-1) day(-1)) by peritoneal route for the same period of time, while the control group received distilled water. The animals were evaluated at 14 weeks post-infection, at which time the parasitological and immunological parameters were analyzed. Mice treated with the AbM presented a 60% reduction in the inflammation of infected footpads as compared to untreated control-infected mice. Moreover, in the treated mice, as compared to the untreated controls, approximately 60 and 66% reductions could be observed in the parasite burdens of the footpad and draining lymph nodes, respectively. In addition, no parasites could be detected in the spleen of treated mice at week 14 postinfection. These treated animals produced significantly higher levels of interferon gamma (IFN-γ) and nitric oxide (NO), higher levels of parasite-specific IgG2a isotype antibodies, and lower levels of interleukin (IL)-4, and IL-10 in the spleen and lymph node cell cultures than did the controls. Differences could be observed by comparing animals treated with AbM to those treated with AmpB, as indicated by a significant reduction in tissue parasitism, higher levels of IFN-γ and NO, and lower levels of IL-4 and IL-10, as well as by a decreased hepatic toxicity. In conclusion, the present study's data show that the A. blazei Murill water extract presents a high potential for the treatment of leishmaniasis, although additional studies on mice, as well as on other mammal hosts, are warranted in an attempt to determine this extract's true efficacy as compared to other known therapeutic products.

Inhibitory effect of interferon-α-2b on expression of cyclooxygenase-2 and vascular endothelial growth factor in human hepatocellular carcinoma inoculated in nude mice

PubMed Central

Cao, Bin; Chen, Xiao-Ping; Zhu, Peng; Ding, Lei; Guan, Jian; Shi, Zuo-Liang

2008-01-01

AIM: To evaluate the effects of interferon-α-2b (IFN-α-2b) on expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) in human hepatocellular carcinoma (HCC) inoculated in nude mice and to study the underlying mechanism of IFN-α-2b against HCC growth. METHODS: Thirty-two nude mice bearing human HCC were randomly divided into four groups (n = 8). On the 10th day after implantation of HCC cells, the mice in test groups (groups A, B and C) received IFN-α-2b at a serial dose (10 000 IU for group A, 20 000 IU for group B, 40 000 IU for group C sc daily) for 35 d. The mice in control group received normal saline (NS). The growth conditions of transplanted tumors were observed. Both genes and proteins of COX-2 and VEGF were detected by RT-PCR and Western blot. Apoptosis of tumor cells in nude mice was detected by TUNEL assay after treatment with IFN-α-2b. RESULTS: Tumors were significantly smaller and had a lower weight in the IFN-α-2b treatment groups than those in the control group (P < 0.01), and the tumor growth inhibition rate in groups A, B and C was 27.78%, 65.22% and 49.64%, respectively. The expression levels of both genes and proteins of COX-2 and VEGF were much lower in the IFN-α-2b treatment groups than in the control group (P < 0.01). The apoptosis index (AI) of tumor cells in the IFN-α-2b treatment groups was markedly higher than that in the control group (P < 0.01). Group B had a higher inhibition rate of tumor growth, a lower expression level of COX-2 and VEGF and a higher AI than groups A and C (P < 0.05), but there was no significant difference between groups A and C. CONCLUSION: The inhibitory effects of IFN-α-2b on implanted tumor growth and apoptosis may be associated with the down-regulation of COX-2 and VEGF expression. There is a dose-effect relationship. The medium dose of IFN-α-2b for inhibiting tumor growth is 20 000 IU/d. PMID:19058305

Protective effects of apigenin and myricetin against cisplatin-induced nephrotoxicity in mice.

PubMed

Hassan, Samar M; Khalaf, Marwa M; Sadek, Sawsan A; Abo-Youssef, Amira M

2017-12-01

Currently, the outcomes of the use of cisplatin in cancer therapy is limited by nephrotoxicity. This study aims to investigate the nephroprotective role of apigenin and myricetin against cisplatin-induced nephrotoxicity in mice. Adult female Wistar Albino mice were divided into eight groups (n = 8). Group I served as normal control. Groups II, III and IV received apigenin (3 mg/kg, i.p.), myricetin (3 mg/kg, i.p.) or their combination respectively, for seven days. Group V served as positive control group, received vehicles for seven days and cisplatin (7.5 mg/kg, i.p.) for three days starting at day five. Groups VI, VII and VIII received apigenin, myricetin or their combination, respectively for seven days as well as cisplatin injection for three days starting at day five. by the end of the experimental period, a biochemical study involving, nephrotoxicity markers [serum creatinine (Cr) and blood urea nitrogen (BUN)], apoptotic marker [caspase 3], inflammatory mediators [tumour necrosis factor alpha (TNF-α), interleukin 6 (IL-6), cyclooxygenase I and II (COXI, COXII)] and oxidative stress biomarkers [malondialdehyde (MDA), reduced glutathione (GSH) and catalase] was conducted. In addition, renal histopathological alterations were evaluated. Apigenin, myricetin and their combination significantly reduced blood BUN, serum Cr, caspase-3TNF-α, IL-6, COXI and COXII, MDA levels and significantly increased GSH level and catalase activity parallel to, histopathological improvement in kidney tissues. Apigenin and myricetin exhibited a protective and promising preventive strategy against cisplatin-induced nephrotoxicity due to their antioxidant and anti-inflammatory effects.

Evaluation of cutaneous wound healing activity of Malva sylvestris aqueous extract in BALB/c mice

PubMed Central

Afshar, Mohammad; Ravarian, Behdad; Zardast, Mahmoud; Moallem, Seyed Adel; Fard, Mohammad Hasanpour; Valavi, Masoomeh

2015-01-01

Objective(s): The aim of this study was to evaluate the effects of Malva sylvestris aqueous extract on cutaneous wound healing in BALB/c mice. Materials and Methods: Twenty seven male BALB/c mice (2.5 months of age) were used. A cut wound (superficial fascia depth) was made locally. The mice were then divided into three groups: the first, second and third groups received topical administration of M. sylvestris 1% aqueous extract, silver sulfadiazine topical cream and cold cream (positive and negative control groups), respectively. On days 4, 7 and 10 excisional biopsies were performed and wound healing was evaluated histopathologically. The data were analyzed by the ANOVA and Tukey statistical tests. Results: On days 4 and 7, the numbers of inflammatory cells in the silver sulfadiazine and M. sylvestris-treated groups were significantly lower than the control group and keratinization at the edges of the wound in both groups was significantly higher than the control group. On the tenth day of the study, the Malva-treated mice showed better healing features and less fibrosis and scar formation, and also fewer hair follicles were damaged in this group. On the tenth day of the study, the numbers of inflammatory cells in M. sylvestris and silver sulfadiazine-treated groups were significantly lower than the control group. Conclusion: The present study supports the beneficial effects of M. sylvestris on the wound healing process and suggests a potential clinical application. PMID:26221487

Effect of Variable Doses of Zinc Oxide Nanoparticles on Male Albino Mice Behavior.

PubMed

Zahra, Javeria; Iqbal, Shahid; Zahra, Kiran; Javed, Zulha; Shad, Muhammad Aslam; Akbar, Atif; Ashiq, Muhammad Naeem; Iqbal, Furhan

2017-02-01

Zinc oxide nanoparticles (ZnO NPs) have diverse utility these days ranging from being part of nanosensors to be ingredient of cosmetics. Present study was designed to report the effect of variable doses of ZnO NPs on selected aspects of male albino mice behavior. Nano particles were synthesized by sol-gel auto-combustion method (Data not shown here). 10 week old male albino mice were divided into four experimental groups; group A, B and C were orally supplemented with 50 (low dose), 300 (medium dose) and 600 mg/ml solvent/kg body weight (high dose) of ZnO NPs for 4 days. Group D (control) orally received 0.2 M sodium phosphate buffer (solvent for ZnO NPs) for the same duration. A series of neurological tests (Rota rod, open field, novel object and light-dark box test) were conducted in all groups and performance was compared between ZnO NPs treated and control group. Muscular functioning during rota rod test was significantly improved in all ZnO NPs treated mice as compared to control group. While no significant differences in open field, novel object and light-dark box test performance were observed when data from studied parameters of specific ZnO NPs treatment were compared with the control group indicating that applied doses of ZnO NPs did not affect the exploratory, anxiolytic behavior and object recognition capability of adult male albino mice.

Epidermal growth factor receptor VIII peptide vaccination is efficacious against established intracerebral tumors.

PubMed

Heimberger, Amy B; Crotty, Laura E; Archer, Gary E; Hess, Kenneth R; Wikstrand, Carol J; Friedman, Allan H; Friedman, Henry S; Bigner, Darell D; Sampson, John H

2003-09-15

The epidermal growth factor receptor (EGFR) is often amplified and structurally rearranged in malignant gliomas and other tumors such as breast and lung, with the most common mutation being EGFRvIII. In the study described here, we tested in mouse models a vaccine consisting of a peptide encompassing the tumor-specific mutated segment of EGFRvIII (PEP-3) conjugated to keyhole limpet hemocyanin [KLH (PEP-3-KLH)]. C57BL/6J or C3H mice were vaccinated with PEP-3-KLH and subsequently challenged either s.c. or intracerebrally with a syngeneic melanoma cell line stably transfected with a murine homologue of EGFRvIII. Control mice were vaccinated with KLH. To test its effect on established tumors, C3H mice were also challenged intracerebrally and subsequently vaccinated with PEP-3-KLH. S.c. tumors developed in all of the C57BL/6J mice vaccinated with KLH in Freund's adjuvant, and there were no long-term survivors. Palpable tumors never developed in 70% of the PEP-3-KLH-vaccinated mice. In the C57BL/6J mice receiving the PEP-3-KLH vaccine, the tumors that did develop were significantly smaller than those in the control group (P < 0.05). PEP-3-KLH vaccination did not result in significant cytotoxic responses in standard cytotoxicity assays; however, antibody titers against PEP-3 were enhanced. The passive transfer of sera from the immunized mice to nonimmunized mice protected 31% of the mice from tumor development (P < 0.05). In vivo depletion studies showed that the effector cell population was natural killer and CD8+ T cells, and in vitro assays showed that macrophages could lyse target tumor cells with serum from the PEP-3-KLH-vaccinated mice. Peptide vaccination was also sufficiently potent to have marked efficacy against intracerebral tumors, resulting in a >173% increase in median survival time, with 80% of the C3H mice achieving long-term survival (P = 0.014). In addition, C3H mice with established intracerebral tumor that received a single treatment of PEP-3-KLH showed a 26% increase in median survival time, with 40% long-term survival (P = 0.007). Vaccination with an EGFRvIII-specific peptide is efficacious against both s.c. and established intracerebral tumors. The therapeutic effect of peptide vaccination may be mediated, in part, by antibody-dependent cellular cytotoxicity.

Brief pup exposure induces Fos expression in the lateral habenula and serotonergic caudal dorsal raphe nucleus of paternally experienced male California mice (Peromyscus californicus).

PubMed

de Jong, T R; Measor, K R; Chauke, M; Harris, B N; Saltzman, W

2010-09-01

Fathers play a substantial role in infant care in a small but significant number of mammalian species, including humans. However, the neural circuitry controlling paternal behavior is much less understood than its female counterpart. In order to characterize brain areas activated by paternal care, male California mice were separated from their female mate and litter for 3 h and then exposed to a pup or a control object (a glass pebble with the approximate size and oblong shape of a newborn pup) for 10 min. All males receiving a pup showed a strong paternal response towards it, whereas males receiving a pebble interacted with it only occasionally. Despite the clear behavioral differences, exposure to a pup did not increase Fos-like immunoreactivity (Fos-LIR) compared to a pebble in brain areas previously found to be associated with parental care, including the medial preoptic nucleus and medial bed nucleus of the stria terminalis. Pup exposure did, however, significantly increase Fos-LIR in the lateral habenula (LHb) and in predominantly serotonergic neurons in the caudal dorsal raphe nucleus (DRC), as compared to pebble exposure. Both the LHb and DRC are known to be involved in the behavioral responses to strong emotional stimuli; therefore, these areas might play a role in controlling parental behavior in male California mice. Copyright (c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Cathinone, an active principle of Catha edulis, accelerates oxidative stress in the limbic area of swiss albino mice.

PubMed

Safhi, Mohammed M; Alam, Mohammad Firoz; Hussain, Sohail; Hakeem Siddiqui, Mohammed Abdul; Khuwaja, Gulrana; Jubran Khardali, Ibrahim Abdu; Al-Sanosi, Rashad Mohammed; Islam, Fakhrul

2014-10-28

Cathinone hydrochloride is an active principle of the khat plant (Catha edulis) that produces pleasurable and stimulating effects in khat chewers. To the best of our knowledge no data of cathinone on oxidative stress in limbic areas of mice is available. This is the first study of cathinone on oxidative stress in limbic areas of the brain in Swiss albino male mice. The animals were divided into four groups. Group-I was the control group and received vehicle, while groups-II to IV received (-)-cathinone hydrochloride (0.125, 0.25 and 0.5 mg/kg body wt., i.p.) once daily for 15 days. The level of lipid peroxidation (LPO) was elevated dose-dependently and was significant (p<0.05, p<0.01) with doses of 0.25 and 0.5mg/kg body wt. of cathinone as compared to control group. In contrast, the content of reduced glutathione (GSH) was decreased significantly (p<0.01, p<0.001) with doses of 0.25 and 0.5mg/kg body wt. of cathinone as compared to control group. The activity of antioxidant enzymes (GPx, GR, GST, CAT, and SOD) was also decreased dose-dependently: the decreased activity of GPx, GR, catalase and SOD was significant with doses of 0.25 and 0.5 mg of cathinone as compared to control group, while the activity of GST was decreased dose-dependently and was significant with 0.5mg of cathinone as compared to control group. The results indicate that the cathinone generated oxidative stress hampered antioxidant enzymes, glutathione and lipid peroxidation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Sonic hedgehog signaling regulates amygdalar neurogenesis and extinction of fear memory.

PubMed

Hung, Hui-Chi; Hsiao, Ya-Hsin; Gean, Po-Wu

2015-10-01

It is now recognized that neurogenesis occurs throughout life predominantly in the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ) of the lateral ventricle. In the present study, we investigated the relationship between neurogenesis in the amygdala and extinction of fear memory. Mice received 15 tone-footshock pairings. Twenty-four hours after training, the mice were given 15 tone-alone trials (extinction training) once per day for 7 days. Two hours before extinction training, the mice were injected intraperitoneally with 5-bromo-3-deoxyuridine (BrdU). BrdU-positive and NeuN-positive cells were analyzed 52 days after the training. A group of mice that received tone-footshock pairings but no extinction training served as controls (FC+No-Ext). The number of BrdU(+)/NeuN(+) cells was significantly higher in the extinction (FC+Ext) than in the FC+No-Ext mice. Proliferation inhibitor methylazoxymethanol acetate (MAM) or DNA synthesis inhibitor cytosine arabinoside (Ara-C) reduced neurogenesis and retarded extinction. Silencing Sonic hedgehog (Shh) gene with short hairpin interfering RNA (shRNA) by means of a retrovirus expression system to knockdown Shh specifically in the mitotic neurons reduced neurogenesis and retarded extinction. By contrast, over-expression of Shh increased neurogenesis and facilitated extinction. These results suggest that amygdala neurogenesis and Shh signaling are involved in the extinction of fear memory. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Induction of colonic aberrant crypts in mice by feeding apparent N-nitroso compounds derived from hot dogs

PubMed Central

Davis, Michael E; Lisowyj, Michal P; Zhou, Lin; Wisecarver, James L; Gulizia, James M; Shostrom, Valerie K; Naud, Nathalie; Corpet, Denis E; Mirvish, Sidney S

2012-01-01

Nitrite-preserved meats (e.g., hot dogs) may help cause colon cancer because they contain N-nitroso compounds. We tested whether purified hot-dog-derived total apparent N-nitroso compounds (ANC) could induce colonic aberrant crypts, which are putative precursors of colon cancer. We purified ANC precursors in hot dogs and nitrosated them to produce ANC. In preliminary tests, CF1 mice received 1 or 3 i.p. injections of 5mg azoxymethane (AOM)/kg. In Experiments 1 and 2, female A/J mice received ANC in diet. In Experiment 1, ANC dose initially dropped sharply because the ANC precursors had mostly decomposed but, later in Experiment 1 and throughout Experiment 2, ANC remained at 85 nmol/g diet. Mice were killed after 8 (AOM tests) or 17–34 (ANC tests) wk. Median numbers of aberrant crypts in the distal 2 cm of the colon for 1 and 3 AOM injections, CF1 controls, ANC (Experiment 1), ANC (Experiment 2),and untreated A/J mice were 31, 74, 12, 20, 12, and 5–6, with P < 0.01 for both ANC tests. Experiment 2 showed somewhat increased numbers of colonic mucin-depleted foci in the ANC-treated group. We conclude that hot-dog-derived ANC induced significant numbers of aberrant crypts in the mouse colon. PMID:22293095

Low dose radiation prevents doxorubicin-induced cardiotoxicity

PubMed Central

Jiang, Xin; Hong, Yaqiong; Zhao, Di; Meng, Xinxin; Zhao, Lijing; Du, Yanwei; Wang, Zan; Zheng, Yan; Cai, Lu; Jiang, Hongyu

2018-01-01

This study aimed to develop a novel and non-invasive approach, low-dose radiation (LDR, 75 mGy X-rays), to prevent doxorubicin (DOX)-induced cardiotoxicity. BALB/c mice were randomly divided into five groups, Control, LDR (a single exposure), Sham (treated same as LDR group except for irradiation), DOX (a single intraperitoneal injection of DOX at 7.5 mg/kg), and LDR/DOX (received LDR and 72 h later received DOX). Electrocardiogram analysis displayed several kinds of abnormal ECG profiles in DOX-treated mice, but less in LDR/DOX group. Cardiotoxicity indices included histopathological changes, oxidative stress markers, and measurements of mitochondrial membrane permeability. Pretreatment of DOX group with LDR reduced oxidative damages (reactive oxygen species formation, protein nitration, and lipid peroxidation) and increased the activities of antioxidants (superoxide dismutase and glutathione peroxidase) in the heart of LDR/DOX mice compared to DOX mice. Pretreatment of DOX-treated mice with LDR also decreased DOX-induced cardiac cell apoptosis (TUNEL staining and cleaved caspase-3) and mitochondrial apoptotic pathway (increased p53, Bax, and caspase-9 expression and decreased Bcl2 expression and ΔΨm dissipation). These results suggest that LDR could induce adaptation of the heart to DOX-induced toxicity. Cardiac protection by LDR may attribute to attenuate DOX-induced cell death via suppressing mitochondrial-dependent oxidative stress and apoptosis signaling. PMID:29416617

Evaluation of Sub-acute Oral Toxicity of Lithium Carbonate Microemulsion (Nano Size) on Liver and Kidney of Mice

PubMed Central

Kalantari, Heibatullah; Salimi, Anayatollah; Rezaie, Anahita; Jazayeri Shushtari, Fereshteh; Goudarzi, Mehdi

2015-01-01

Background: The development of drug delivery systems has improved the therapeutic and toxic properties of existing drugs in therapy. Microemulsion systems are novel vehicles for drug delivery, which have been developed in recent years. These systems are currently of interest to the pharmaceutical scientist because of their considerable potential to act as drug delivery vehicles by incorporating into a wide range of drug molecules. Although these systems improved solubility and bioavailability of drugs, they may have potential toxic effects on the body organs. Objectives: The purpose of this study was to examine a possible hepatotoxic and nephrotoxic effect of lithium carbonate microemulsion (LCME) in a mice model. Materials and Methods: Eighty male Swiss albino mice were randomly allocated to eight experimental groups, as follows: Group 1, as negative control group were treated orally with normal saline (0.9% NaCl); Group 2, received microemulsion base without drug as control group; Groups 3 to 5, received lithium carbonate (LC) solution in doses of 50, 100, and 200 mg/kg, respectively; Groups 6 to 8, received LCME orally in doses of 50, 100, and 200 mg/kg, respectively. All drugs were administered orally for ten consecutive days. Serum glutamate pyruvate aminotransferase (SGPT), serum glutamate oxaloacetate aminotransferase (SGOT), alkaline phosphatase (ALP), blood urea nitrogen (BUN), and plasma creatinine (Cr), as markers of liver and kidney toxicity in treated mice, were measured. Furthermore, the changes of tissue were assessed by histopathologic examination. Results: The findings showed that serum activity of ALP, SGOT, and SGPT and the levels of BUN and Cr in microemulsion base group was greater than normal saline group. However, this difference was not significant. Administration of LC and LCME in all doses resulted in a significant increase in the levels of BUN and serum activity of SGOT and SGPT in comparison to normal saline group (P < 0.05). Histopathological changes were observed in mice treated with LC or LCME. Conclusions: This study showed that subacute oral administration of different doses of LCME with severe toxicity in comparison to the same dose of LC. PMID:25866723

A multiagent filovirus DNA vaccine delivered by intramuscular electroporation completely protects mice from ebola and Marburg virus challenge.

PubMed

Grant-Klein, Rebecca J; Van Deusen, Nicole M; Badger, Catherine V; Hannaman, Drew; Dupuy, Lesley C; Schmaljohn, Connie S

2012-11-01

We evaluated the immunogenicity and protective efficacy of DNA vaccines expressing the codon-optimized envelope glycoprotein genes of Zaire ebolavirus, Sudan ebolavirus, and Marburg marburgvirus (Musoke and Ravn). Intramuscular or intradermal delivery of the vaccines in BALB/c mice was performed using the TriGrid™ electroporation device. Mice that received DNA vaccines against the individual viruses developed robust glycoprotein-specific antibody titers as determined by ELISA and survived lethal viral challenge with no display of clinical signs of infection. Survival curve analysis revealed there was a statistically significant increase in survival compared to the control groups for both the Ebola and Ravn virus challenges. These data suggest that further analysis of the immune responses generated in the mice and additional protection studies in nonhuman primates are warranted.

Isoflurane produces sustained cardiac protection after ischemia-reperfusion injury in mice.

PubMed

Tsutsumi, Yasuo M; Patel, Hemal H; Lai, N Chin; Takahashi, Toshiyuki; Head, Brian P; Roth, David M

2006-03-01

Isoflurane reduces myocardial ischemia-reperfusion injury within hours to days of reperfusion. Whether isoflurane produces sustained cardiac protection has never been examined. The authors studied isoflurane-induced cardiac protection in the intact mouse after 2 h and 2 weeks of reperfusion and determined the dependence of this protection on adenosine triphosphate-dependent potassium channels and the relevance of this protection to myocardial function and apoptosis. Mice were randomly assigned to receive oxygen or isoflurane for 30 min with 15 min of washout. Some mice received mitochondrial (5-hydroxydecanoic acid) or sarcolemmal (HMR-1098) adenosine triphosphate-dependent potassium channel blockers with or without isoflurane. Mice were then subjected to a 30-min coronary artery occlusion followed by 2 h or 2 weeks of reperfusion. Infarct size was determined at 2 h and 2 weeks of reperfusion. Cardiac function and apoptosis were determined 2 weeks after reperfusion. Isoflurane did not change hemodynamics. Isoflurane reduced infarct size after reperfusion when compared with the control groups (27.7 +/- 6.3 vs. 41.7 +/- 6.4% at 2 h and 19.6 +/- 5.9 vs. 28.8 +/- 9.0% at 2 weeks). Previous administration of 5-hydroxydecanoic acid, but not HMR-1098, abolished isoflurane-induced cardiac protection. At 2 weeks, left ventricular end-diastolic diameter was decreased significantly and end-systolic pressure and maximum and minimum dP/dt were improved by isoflurane. Isoflurane-treated mice subjected to ischemia and 2 weeks of reperfusion showed less expression of proapoptotic genes, significantly decreased expression of cleaved caspase-3, and significantly decreased deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling-positive nuclei compared with the control group. Cardiac protection induced by isoflurane against necrotic and apoptotic cell death is associated with an acute memory period that is sustained and functionally relevant 2 weeks after ischemia-reperfusion injury in mice in vivo.

High-energy proton irradiation of C57Bl6 mice under hindlimb unloading

NASA Astrophysics Data System (ADS)

Mendonca, Marc; Todd, Paul; Orschell, Christie; Chin-Sinex, Helen; Farr, Jonathan; Klein, Susan; Sokol, Paul

2012-07-01

Solar proton events (SPEs) pose substantial risk for crewmembers on deep space missions. It has been shown that low gravity and ionizing radiation both produce transient anemia and immunodeficiencies. We utilized the C57Bl/6 based hindlimb suspension model to investigate the consequences of hindlimb-unloading induced immune suppression on the sensitivity to whole body irradiation with modulated 208 MeV protons. Eight-week old C57Bl/6 female mice were conditioned by hindlimb-unloading. Serial CBC and hematocrit assays by HEMAVET were accumulated for the hindlimb-unloaded mice and parallel control animals subjected to identical conditions without unloading. One week of hindlimb-unloading resulted in a persistent, statistically significant 10% reduction in RBC count and a persistent, statistically significant 35% drop in lymphocyte count. This inhibition is consistent with published observations of low Earth orbit flown mice and with crewmember blood analyses. In our experiments the cell count suppression was sustained for the entire six-week period of observation and persisted for at least 7 days beyond the period of active hindlimb-unloading. C57Bl/6 mice were also irradiated with 208 MeV Spread Out Bragg Peak (SOBP) protons at the Midwest Proton Radiotherapy Institute at the Indiana University Cyclotron Facility. We found that at 8.5 Gy hindlimb-unloaded mice were significantly more radiation sensitive with 35 lethalities out of 51 mice versus 15 out of 45 control (non-suspended) mice within 30 days of receiving 8.5 Gy of SOBP protons (p =0.001). Both control and hindlimb-unloaded stocktickerCBC analyses of 8.5 Gy proton irradiated and control mice by HEMAVET demonstrated severe reductions in WBC counts (Lymphocytes and PMNs) by day 2 post-irradiation, followed a week to ten days later by reductions in platelets, and then reductions in RBCs about 2 weeks post-irradiation. Recovery of all blood components commenced by three weeks post-irradiation. CBC analyses of 8.5 Gy proton irradiated hindlimb-unloaded mice indicated that the recovery of the WBC counts appeared delayed compared to 8.5 Gy irradiated controls. However, stocktickerRBC recovery appeared similar in both sets of irradiated mice. Our data indicate that hindlimb-unloaded mice are more radiation sensitive compared to irradiated controls. We thank Brian Allen and Rick Jessup for valuable assistance with dosimetry and physical arrangements at the IU Cyclotron Facility and Midwest Proton Radiotherapy Institute and Alan Constance for design of hindlimb-unloading cages. Research supported in part by NASA Grant NNJ06HE95A.

Anterior Cingulate Cortex Contributes to Alcohol Withdrawal- Induced and Socially Transferred Hyperalgesia.

PubMed

Smith, Monique L; Walcott, Andre T; Heinricher, Mary M; Ryabinin, Andrey E

2017-01-01

Pain is often described as a "biopsychosocial" process, yet social influences on pain and underlying neural mechanisms are only now receiving significant experimental attention. Expression of pain by one individual can be communicated to nearby individuals by auditory, visual, and olfactory cues. Conversely, the perception of another's pain can lead to physiological and behavioral changes in the observer, which can include induction of hyperalgesia in "bystanders" exposed to "primary" conspecifics in which hyperalgesia has been induced directly. The current studies were designed to investigate the neural mechanisms responsible for the social transfer of hyperalgesia in bystander mice housed and tested with primary mice in which hyperalgesia was induced using withdrawal (WD) from voluntary alcohol consumption. Male C57BL/6J mice undergoing WD from a two-bottle choice voluntary alcohol-drinking procedure served as the primary mice. Mice housed in the same room served as bystanders. Naïve, water-drinking controls were housed in a separate room. Immunohistochemical mapping identified significantly enhanced Fos immunoreactivity (Fos-ir) in the anterior cingulate cortex (ACC) and insula (INS) of bystander mice compared to naïve controls, and in the dorsal medial hypothalamus (DMH) of primary mice. Chemogenetic inactivation of the ACC but not primary somatosensory cortex reversed the expression of hyperalgesia in both primary and bystander mice. These studies point to an overlapping neural substrate for expression of socially transferred hyperalgesia and that expressed during alcohol WD.

Immunological mechanism of low-dose priming radiation resistance in walker-256 tumor model mice

PubMed Central

Feng, Li; Qin, Ling; Guo, Dan; Deng, Daping; Lu, Feng; Li, Hailiang; Bao, Narisu; Yang, Xiting; Ding, Hongyu; Li, Jianguo

2017-01-01

The aim of the present study was to investigate whether low-dose priming radiation induces antitumor immunity that can be augmented by the modulation of natural killer (NK) cell and cytokine activity using a mouse tumor model. Walker-256 cells were injected into the right flank of male BALB/c mice. At 7 days after inoculation, mice were divided into three groups, including group 1,2,3. In group 1 the mice were without radiation, in group 2 the mice were received 2 Gy radiation only, and in group 3 the mice were radiated with a priming dose of 75 mGy followed by 2 Gy radiation after 24 h. On day 21 following the radiation, the tumors were removed and the tumor index (tumor weight as a percentage of body weight) was calculated. At 1, 7, 14 and 21 days following the 2 Gy radiation, mouse splenocytes were isolated to analyze the NK activity and measure the production of the cytokines interleukin-1β, interferon-γ and tumor necrosis factor-α by ELISA. Apoptosis was also measured by flow cytometry. The results demonstrated that priming radiation significantly delayed the tumor growth and prolonged the median survival time to 38 days compared with the 31-day survival in the 2 Gy radiation group. The percentage of apoptotic cells was significantly higher in the mice that received 75 mGy + 2 Gy radiation compared with that in the mice that received 2 Gy alone; by contrast, mice that were not irradiated exhibited a relatively low level of apoptosis. The primed mice had a higher level of NK activity as compared with the mice exposed to 2 Gy radiation only or mice that were not irradiated. Furthermore, cytokine expression remained at a higher level in mice receiving priming dose of radiation compared that in the mice receiving only 2 Gy radiation. In conclusion, the results indicated that low-dose priming X-ray radiation may enhance the NK activity and the levels of cytokines, and that the immune response serves an important role in anticancer therapy, including radiotherapy. PMID:29042994

Mixed Tocotrienols Inhibit Prostate Carcinogenesis in TRAMP Mice

PubMed Central

Barve, Avantika; Khor, Tin Oo; Reuhl, Kenneth; Reddy, Bandaru; Newmark, Harold; Kong, Ah-Ng

2015-01-01

The biological activities of tocotrienols are receiving increasing attention. Herein, we report the efficacy of a mixed-tocotrienol diet against prostate tumorigenesis in the transgenic adenocarcinoma mouse prostate (TRAMP) mouse model. Male TRAMP mice, 8 wk old, were fed 0.1%, 0.3%, or 1% mixed tocotrienols in AIN-76A diet up to 24 wk old. Likewise, a positive control group consisting of male TRAMP mice and a negative control group consisting of wild-type nontransgenic mice were fed regular AIN-76A diet up to 24 wk old. Our results show that mixed-tocotrienol-fed groups had a lower incidence of tumor formation along with a significant reduction in the average wet weight of genitourinary apparatus. Furthermore, mixed tocotrienols significantly reduced the levels of high-grade neoplastic lesions as compared to the positive controls. This decrease in levels of high-grade neoplastic lesions was found to be associated with increased expression of proapoptotic proteins BAD (Bcl2 antagonist of cell death) and cleaved caspase-3 and cell cycle regulatory proteins cyclin dependent kinase inhibitors p21 and p27. In contrast, the expression of cyclins A and E were found to be decreased in mixed-tocotrienol groups. Taken together, our results show that by modulating cell cycle regulatory proteins and increasing expression of proapoptotic proteins, mixed tocotrienols suppress prostate tumorigenesis in the TRAMP mice. PMID:20661828

Acemannan-containing wound dressing gel reduces radiation-induced skin reactions in C3H mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Roberts, D.B.; Travis, E.L.

To determine (a) whether a wound dressing gel that contains acemannan extracted from aloe leaves affects the severity of radiation-induced acute skin reactions in C3H mice; (b) if so, whether other commercially available gels such as a personal lubricating jelly and a healing ointment have similar effects; and (c) when the wound dressing gel should be applied for maximum effect. Male C3H mice received graded single doses of gamma radiation ranging from 30 to 47.5 Gy to the right leg. In most experiments, the gel was applied daily beginning immediately after irradiation. Dose-response curves were obtained by plotting the percentagemore » of mice that reached or exceeded a given peak skin reaction as a function of dose. Curves were fitted by logit analysis and ED{sub 50} values, and 95% confidence limits were obtained. The average peak skin reactions of the wound dressing gel-treated mice were lower than those of the untreated mice at all radiation doses tested. The ED{sub 50} values for skin reactions of 2.0-2.75 were approximately 7 Gy higher in the wound dressing gel-treated mice. The average peak skin reactions and the ED{sub 50} values for mice treated with personal lubricating jelly or healing ointment were similar to irradiated control values. Reduction in the percentage of mice with skin reactions of 2.5 or more was greatest in the groups that received wound dressing gel for at least 2 weeks beginning immediately after irradiation. There was no effect if gel was applied only before irradiation or beginning 1 week after irradiation. Wound dressing gel, but not personal lubricating jelly or healing ointment, reduces acute radiation-induced skin reactions in C3H mice if applied daily for at least 2 weeks beginning immediately after irradiation. 31 refs., 4 figs., 1 tab.« less

NADPH oxidase 4 induces cardiac fibrosis and hypertrophy through activating Akt/mTOR and NFκB signaling pathways.

PubMed

Zhao, Qingwei David; Viswanadhapalli, Suryavathi; Williams, Paul; Shi, Qian; Tan, Chunyan; Yi, Xiaolan; Bhandari, Basant; Abboud, Hanna E

2015-02-17

NADPH oxidase 4 (Nox4) has been implicated in cardiac remodeling, but its precise role in cardiac injury remains controversial. Furthermore, little is known about the downstream effector signaling pathways activated by Nox4-derived reactive oxygen species in the myocardium. We investigated the role of Nox4 and Nox4-associated signaling pathways in the development of cardiac remodeling. Cardiac-specific human Nox4 transgenic mice (c-hNox4Tg) were generated. Four groups of mice were studied: (1) control mice, littermates that are negative for hNox4 transgene but Cre positive; (2) c-hNox4 Tg mice; (3) angiotensin II (AngII)-infused control mice; and (4) c-hNox4Tg mice infused with AngII. The c-hNox4Tg mice exhibited an ≈10-fold increase in Nox4 protein expression and an 8-fold increase in the production of reactive oxygen species, and manifested cardiac interstitial fibrosis. AngII infusion to control mice increased cardiac Nox4 expression and induced fibrosis and hypertrophy. The Tg mice receiving AngII exhibited more advanced cardiac remodeling and robust elevation in Nox4 expression, indicating that AngII worsens cardiac injury, at least in part by enhancing Nox4 expression. Moreover, hNox4 transgene and AngII infusion induced the expression of cardiac fetal genes and activated the Akt-mTOR and NFκB signaling pathways. Treatment of AngII-infused c-hNox4Tg mice with GKT137831, a Nox4/Nox1 inhibitor, abolished the increase in oxidative stress, suppressed the Akt-mTOR and NFκB signaling pathways, and attenuated cardiac remodeling. Upregulation of Nox4 in the myocardium causes cardiac remodeling through activating Akt-mTOR and NFκB signaling pathways. Inhibition of Nox4 has therapeutic potential to treat cardiac remodeling. © 2015 American Heart Association, Inc.

L-arginine supplementation prevents increases in intestinal permeability and bacterial translocation in male Swiss mice subjected to physical exercise under environmental heat stress.

PubMed

Costa, Kátia Anunciação; Soares, Anne Danieli Nascimento; Wanner, Samuel Penna; Santos, Rosana das Graças Carvalho dos; Fernandes, Simone Odília Antunes; Martins, Flaviano dos Santos; Nicoli, Jacques Robert; Coimbra, Cândido Celso; Cardoso, Valbert Nascimento

2014-02-01

Dietary supplementation with l-arginine has been shown to improve the intestinal barrier in many experimental models. This study investigated the effects of arginine supplementation on the intestinal permeability and bacterial translocation (BT) induced by prolonged physical exercise under heat stress. Under anesthesia, male Swiss mice (5-wk-old) were implanted with an abdominal sensor to record their core body temperature (T(core)). After recovering from surgery, the mice were divided into 3 groups: a non-supplemented group that was fed the standard diet formulated by the American Institute of Nutrition (AIN-93G; control), a non-supplemented group that was fed the AIN-93G diet and subjected to exertional hyperthermia (H-NS), and a group supplemented with l-arginine at 2% and subjected to exertional hyperthermia (H-Arg). After 7 d of treatment, the H-NS and H-Arg mice were forced to run on a treadmill (60 min, 8 m/min) in a warm environment (34°C). The control mice remained at 24°C. Thirty min before the exercise or control trials, the mice received a diethylenetriamine pentaacetic acid (DTPA) solution labeled with technetium-99m ((99m)Tc-DTPA) or (99m)Tc-Escherichia coli by gavage to assess intestinal permeability and BT, respectively. The H-NS mice terminated the exercise with T(core) values of ∼40°C, and, 4 h later, presented a 12-fold increase in the blood uptake of (99m)Tc-DTPA and higher bacterial contents in the blood and liver than the control mice. Although supplementation with arginine did not change the exercise-induced increase in T(core), it prevented the increases in intestinal permeability and BT caused by exertional hyperthermia. Our results indicate that dietary l-arginine supplementation preserves the integrity of the intestinal epithelium during exercise under heat stress, acting through mechanisms that are independent of T(core) regulation.

Potent Antitumor Effects of Combination Therapy With IFNs and Monocytes in Mouse Models of Established Human Ovarian and Melanoma Tumors

PubMed Central

Nakashima, Hideyuki; Miyake, Kotaro; Clark, Christopher R; Bekisz, Joseph; Finbloom, Joel; Husain, Syed R.; Baron, Samuel; Puri, Raj K.; Zoon, Kathryn C.

2012-01-01

Interferon-activated monocytes are known to exert cytocidal activity against tumor cells in vitro. Here, we have examined whether a combination of IFN-α2a and IFN-γ and human monocytes mediate significant antitumor effects against human ovarian and melanoma tumor xenografts in mouse models. OVCAR-3 tumors were treated i.t. with monocytes alone, IFN-α2a and IFN-γ alone or combination of all three on day 0, 15 or 30 post-tumor implantation. Mice receiving combination therapy beginning day 15 showed significantly reduced tumor growth and prolonged survival including complete regression in 40% mice., Tumor volumes measured on day 80 in mice receiving combination therapy (206 mm3) were significantly smaller than those of mice receiving the IFNs alone (1041 mm3), monocytes alone (1111 mm3) or untreated controls (1728 mm3). Similarly, combination therapy with monocytes and IFNs of much larger tumor also inhibited OVCAR-3 tumor growth. Immunohistochemistry studies showed a large number of activated macrophages (CD31+/CD68+) infiltrating into OVCAR-3 tumors and higher densities of IL-12, IP10 and NOS2, markers of M1 (classical) macrophages in tumors treated with combination therapy compared to the controls. Interestingly, IFNs activated macrophages induced apoptosis of OVCAR-3 tumor cells as monocytes alone or IFNs alone did not mediate significant apoptosis. Similar antitumor activity was observed in the LOX melanoma mouse model, but not as profound as seen with the OVCAR-3 tumors. Administration of either mixture of monocytes and IFN-α2a or monocytes and IFN-γ did not inhibit Lox melanoma growth; however a significant inhibition was observed when tumors were treated with a mixture of monocytes, IFN-α2a and IFN-γ. These results indicate that monocytes and both IFN-α2a and IFN-γ may be required to mediate profound antitumor effect against human ovarian and melanoma tumors in mouse models. PMID:22159517

Physical exercise reduces pyruvate carboxylase (PCB) and contributes to hyperglycemia reduction in obese mice.

PubMed

Muñoz, Vitor Rosetto; Gaspar, Rafael Calais; Crisol, Barbara Moreira; Formigari, Guilherme Pedron; Sant'Ana, Marcella Ramos; Botezelli, José Diego; Gaspar, Rodrigo Stellzer; da Silva, Adelino S R; Cintra, Dennys Esper; de Moura, Leandro Pereira; Ropelle, Eduardo Rochete; Pauli, José Rodrigo

2018-07-01

The present study evaluated the effects of exercise training on pyruvate carboxylase protein (PCB) levels in hepatic tissue and glucose homeostasis control in obese mice. Swiss mice were distributed into three groups: control mice (CTL), fed a standard rodent chow; diet-induced obesity (DIO), fed an obesity-inducing diet; and a third group, which also received an obesity-inducing diet, but was subjected to an exercise training protocol (DIO + EXE). Protocol training was carried out for 1 h/d, 5 d/wk, for 8 weeks, performed at an intensity of 60% of exhaustion velocity. An insulin tolerance test (ITT) was performed in the last experimental week. Twenty-four hours after the last physical exercise session, the animals were euthanized and the liver was harvested for molecular analysis. Firstly, DIO mice showed increased epididymal fat and serum glucose and these results were accompanied by increased PCB and decreased p-Akt in hepatic tissue. On the other hand, physical exercise was able to increase the performance of the mice and attenuate PCB levels and hyperglycemia in DIO + EXE mice. The above findings show that physical exercise seems to be able to regulate hyperglycemia in obese mice, suggesting the participation of PCB, which was enhanced in the obese condition and attenuated after a treadmill running protocol. This is the first study to be aimed at the role of exercise training in hepatic PCB levels, which may be a novel mechanism that can collaborate to reduce the development of hyperglycemia and type 2 diabetes in DIO mice.

Regulation of Blood Pressure, Appetite, and Glucose by Leptin After Inactivation of Insulin Receptor Substrate 2 Signaling in the Entire Brain or in Proopiomelanocortin Neurons.

PubMed

do Carmo, Jussara M; da Silva, Alexandre A; Wang, Zhen; Freeman, Nathan J; Alsheik, Ammar J; Adi, Ahmad; Hall, John E

2016-02-01

Insulin receptor substrate 2 (IRS2) is one of the 3 major leptin receptor signaling pathways, but its role in mediating the chronic effects of leptin on blood pressure, food intake, and glucose regulation is unclear. We tested whether genetic inactivation of IRS2 in the entire brain (IRS2/Nestin-cre mice) or specifically in proopiomelanocortin (POMC) neurons (IRS2/POMC-cre mice) attenuates the chronic cardiovascular, metabolic, and antidiabetic effects of leptin. Mice were instrumented with telemetry probes for measurement of blood pressure and heart rate and with venous catheters for intravenous infusions. After a 5-day control period, mice received leptin infusion (2 μg/kg per minute) for 7 days. Compared with control IRS2(flox/flox) mice, IRS2/POMC-cre mice had similar body weight and food intake (33±1 versus 35±1 g and 3.6±0.5 versus 3.8±0.2 g per day) but higher mean arterial pressure (MAP) and heart rate (110±2 versus 102±2 mm Hg and 641±9 versus 616±5 bpm). IRS2/Nestin-cre mice were heavier (38±2 g), slightly hyperphagic (4.5±1.0 g per day), and had higher MAP and heart rate (108±2 mm Hg and 659±9 bpm) compared with control mice. Leptin infusion gradually increased MAP despite decreasing food intake by 31% in IRS2(flox/flox) and in Nestin-cre control mice. In contrast, leptin infusion did not change MAP in IRS2/Nestin-cre or IRS2/POMC-cre mice. The anorexic and antidiabetic effects of leptin, however, were similar in all 3 groups. These results indicate that IRS2 signaling in the central nervous system, and particularly in POMC neurons, is essential for the chronic actions of leptin to raise MAP but not for its anorexic or antidiabetic effects. © 2015 American Heart Association, Inc.

Post-sensitization administration of non-digestible oligosaccharides and Bifidobacterium breve M-16V reduces allergic symptoms in mice.

PubMed

van Esch, Betty C A M; Abbring, Suzanne; Diks, Mara A P; Dingjan, Gemma M; Harthoorn, Lucien F; Vos, A Paul; Garssen, Johan

2016-06-01

To support dietary management of severe cow's milk allergic infants, a synbiotic mixture of non-digestible oligosaccharides and Bifidobacterium breve M-16V ( B. breve ) was designed from source materials that are completely cow's milk-free. It was investigated whether this specific synbiotic concept can reduce an established food allergic response in a research model for hen's egg allergy. Mice were orally sensitized once a week for 5 weeks to ovalbumin (OVA) using cholera toxin (CT) as an adjuvant. Non-sensitized mice received CT in PBS only. Sensitized mice were fed a control diet or a diet enriched with short-chain- (scFOS) and long-chain fructo-oligosaccharides (lcFOS), B. breve or scFOSlcFOS +  B. breve for 3 weeks starting after the last sensitization. Non-sensitized mice received the control diet. Anaphylactic shock symptoms, acute allergic skin responses and serum specific IgE, mMCP-1 and galectin-9 were measured upon OVA challenge. Activated Th2-, Th1-cells and regulatory T-cells were quantified in spleen and mesenteric lymph nodes (MLN) and cytokine profiles were analyzed. Short chain fatty acids (SCFA) were measured in ceacal samples. The acute allergic skin response was reduced in mice fed the scFOSlcFOS +  B. breve diet compared to mice fed any of the other diets. A reduction in mast cell degranulation (mMCP-1) and anaphylactic shock symptoms was also observed in these mice. Unstimulated splenocyte cultures produced increased levels of IL10 and IFNg in mice fed the scFOSlcFOS +  B. breve diet. Correspondingly, increased percentages of activated Th1 cells were observed in the spleen. Allergen-specific re-stimulation of splenocytes showed a decrease in IL5 production. In summary; post-sensitization administration of scFOSlcFOS +  B. breve was effective in reducing allergic symptoms after allergen challenge. These effects coincided with changes in regulatory and effector T-cell subsets and increases in the SCFA propionic acid. These results suggest immune modulatory benefits of dietary intervention with a unique combination of scFOSlcFOS +  B. breve in established food allergy. Whether these effects translate to human applications is subject for ongoing clinical studies.

Characterization of the Burkholderia mallei tonB Mutant and Its Potential as a Backbone Strain for Vaccine Development

PubMed Central

Mott, Tiffany M.; Vijayakumar, Sudhamathi; Sbrana, Elena; Endsley, Janice J.; Torres, Alfredo G.

2015-01-01

Background In this study, a Burkholderia mallei tonB mutant (TMM001) deficient in iron acquisition was constructed, characterized, and evaluated for its protective properties in acute inhalational infection models of murine glanders and melioidosis. Methodology/Principal Findings Compared to the wild-type, TMM001 exhibits slower growth kinetics, siderophore hyper-secretion and the inability to utilize heme-containing proteins as iron sources. A series of animal challenge studies showed an inverse correlation between the percentage of survival in BALB/c mice and iron-dependent TMM001 growth. Upon evaluation of TMM001 as a potential protective strain against infection, we found 100% survival following B. mallei CSM001 challenge of mice previously receiving 1.5 x 104 CFU of TMM001. At 21 days post-immunization, TMM001-treated animals showed significantly higher levels of B. mallei-specific IgG1, IgG2a and IgM when compared to PBS-treated controls. At 48 h post-challenge, PBS-treated controls exhibited higher levels of serum inflammatory cytokines and more severe pathological damage to target organs compared to animals receiving TMM001. In a cross-protection study of acute inhalational melioidosis with B. pseudomallei, TMM001-treated mice were significantly protected. While wild type was cleared in all B. mallei challenge studies, mice failed to clear TMM001. Conclusions/Significance Although further work is needed to prevent chronic infection by TMM001 while maintaining immunogenicity, our attenuated strain demonstrates great potential as a backbone strain for future vaccine development against both glanders and melioidosis. PMID:26114445

Characterization of the Burkholderia mallei tonB Mutant and Its Potential as a Backbone Strain for Vaccine Development.

PubMed

Mott, Tiffany M; Vijayakumar, Sudhamathi; Sbrana, Elena; Endsley, Janice J; Torres, Alfredo G

2015-01-01

In this study, a Burkholderia mallei tonB mutant (TMM001) deficient in iron acquisition was constructed, characterized, and evaluated for its protective properties in acute inhalational infection models of murine glanders and melioidosis. Compared to the wild-type, TMM001 exhibits slower growth kinetics, siderophore hyper-secretion and the inability to utilize heme-containing proteins as iron sources. A series of animal challenge studies showed an inverse correlation between the percentage of survival in BALB/c mice and iron-dependent TMM001 growth. Upon evaluation of TMM001 as a potential protective strain against infection, we found 100% survival following B. mallei CSM001 challenge of mice previously receiving 1.5 x 10(4) CFU of TMM001. At 21 days post-immunization, TMM001-treated animals showed significantly higher levels of B. mallei-specific IgG1, IgG2a and IgM when compared to PBS-treated controls. At 48 h post-challenge, PBS-treated controls exhibited higher levels of serum inflammatory cytokines and more severe pathological damage to target organs compared to animals receiving TMM001. In a cross-protection study of acute inhalational melioidosis with B. pseudomallei, TMM001-treated mice were significantly protected. While wild type was cleared in all B. mallei challenge studies, mice failed to clear TMM001. Although further work is needed to prevent chronic infection by TMM001 while maintaining immunogenicity, our attenuated strain demonstrates great potential as a backbone strain for future vaccine development against both glanders and melioidosis.

From the Cover: Adipose tissue mass can be regulated through the vasculature

NASA Astrophysics Data System (ADS)

Rupnick, Maria A.; Panigrahy, Dipak; Zhang, Chen-Yu; Dallabrida, Susan M.; Lowell, Bradford B.; Langer, Robert; Judah Folkman, M.

2002-08-01

Tumor growth is angiogenesis dependent. We hypothesized that nonneoplastic tissue growth also depends on neovascularization. We chose adipose tissue as an experimental system because of its remodeling capacity. Mice from different obesity models received anti-angiogenic agents. Treatment resulted in dose-dependent, reversible weight reduction and adipose tissue loss. Marked vascular remodeling was evident in adipose tissue sections, which revealed decreased endothelial proliferation and increased apoptosis in treated mice compared with controls. Continuous treatment maintained mice near normal body weights for age without adverse effects. Metabolic adaptations in food intake, metabolic rate, and energy substrate utilization were associated with anti-angiogenic weight loss. We conclude that adipose tissue mass is sensitive to angiogenesis inhibitors and can be regulated by its vasculature.

Effects of acute social stress on the conditioned place preference induced by MDMA in adolescent and adult mice.

PubMed

García-Pardo, Maria P; Rodríguez-Arias, Marta; Maldonado, Concepcion; Manzanedo, Carmen; Miñarro, Jose; Aguilar, Maria A

2014-09-01

Exposure to social defeat stress increases the rewarding effects of psychostimulants in animal models, but its effect on 3,4-methylenedioxymethylamphetamine (MDMA) reward has received little attention. In the present study, we evaluated the influence of social defeat on the rewarding effects of MDMA in adolescent [postnatal day (PND) 29-40] and adult (PND 50-61) male mice using the conditioned place preference paradigm. Experimental mice were exposed to social defeat in an agonistic encounter before each session of conditioning with 1.25 or 10 mg/kg of MDMA. The effects of social defeat on corticosterone levels and the motor or the anxiogenic effects of MDMA were also evaluated. Mice exposed to social defeat during adulthood did not show conditioned place preference after conditioning with either dose of MDMA. Conversely, social defeat did not affect the anxiogenic and motor effects of MDMA. Adult mice exposed to social defeat showed higher levels of corticosterone than their controls and adolescent mice. Social stress did not induce behavioural effects in adolescent mice. Our results show that stress induced by social defeat decreases the sensitivity of adult mice to the rewarding effects of MDMA.

Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity.

PubMed

Chen, Zhongyi; Guo, Lilu; Zhang, Yongqin; Walzem, Rosemary L; Pendergast, Julie S; Printz, Richard L; Morris, Lindsey C; Matafonova, Elena; Stien, Xavier; Kang, Li; Coulon, Denis; McGuinness, Owen P; Niswender, Kevin D; Davies, Sean S

2014-08-01

Metabolic disorders, including obesity, diabetes, and cardiovascular disease, are widespread in Westernized nations. Gut microbiota composition is a contributing factor to the susceptibility of an individual to the development of these disorders; therefore, altering a person's microbiota may ameliorate disease. One potential microbiome-altering strategy is the incorporation of modified bacteria that express therapeutic factors into the gut microbiota. For example, N-acylphosphatidylethanolamines (NAPEs) are precursors to the N-acylethanolamide (NAE) family of lipids, which are synthesized in the small intestine in response to feeding and reduce food intake and obesity. Here, we demonstrated that administration of engineered NAPE-expressing E. coli Nissle 1917 bacteria in drinking water for 8 weeks reduced the levels of obesity in mice fed a high-fat diet. Mice that received modified bacteria had dramatically lower food intake, adiposity, insulin resistance, and hepatosteatosis compared with mice receiving standard water or control bacteria. The protective effects conferred by NAPE-expressing bacteria persisted for at least 4 weeks after their removal from the drinking water. Moreover, administration of NAPE-expressing bacteria to TallyHo mice, a polygenic mouse model of obesity, inhibited weight gain. Our results demonstrate that incorporation of appropriately modified bacteria into the gut microbiota has potential as an effective strategy to inhibit the development of metabolic disorders.

Immunomodulatory effect of gelatin-coated silver nanoparticles in mice: Ultrastructural evaluation.

PubMed

Ahmed, Omar Bauomy; Mahmoud, Usama Taha; Elganady, Sara; Nafady, Allam Mohamed; Afifi, Salah Mohamed Hassan

2016-01-01

Silver nanoparticles (SNP) are used in many pharmaceutical, cosmetic, and industrial products already available in the market. Although they are considered relatively safe, many toxic and pathological alterations in different organs including immune organs were reported after SNP administration. In this study, 10-week-old male mice (n = 20) were divided into two groups. Ten mice received greenly synthesized gelatin-coated silver nanoparticles in a dose of 10 mg/kg body weight for five consecutive days while the other 10 received 0.5 ml of distilled water daily for 5 days and kept as control. At the sixth day, all mice were sacrificed; blood and tissue samples were collected and prepared for pathological analysis. Liver and kidney lesions were in the form of degenerative and inflammatory changes. Interestingly, the immune organs were drastically affected by SNP treatment. Severe hyperplasia of the Peyer's patches was noticed in the intestines of intoxicated animals both in gross and microscopic examination. Spleen was enlarged and showed large number of megakaryocytes. The particles were encountered in membrane-bound phagosomes inside macrophages in different organs like lungs and spleen. Blood picture complied to morphological findings with an increase in monocytes and eosinophils accompanied by drop in the platelets count in the intoxicated animals.

Effects of Multimodal Analgesia on the Success of Mouse Embryo Transfer Surgery

PubMed Central

Parker, John M.; Austin, Jamie; Wilkerson, James; Carbone, Larry

2011-01-01

Multimodal analgesia is promoted as the best practice pain management for invasive animal research procedures. Universal acceptance and incorporation of multimodal analgesia requires assessing potential effects on study outcome. The focus of this study was to assess effects on embryo survival after multimodal analgesia comprising an opioid and nonsteroidal antiinflammatory drug (NSAID) compared with opioid-only analgesia during embryo transfer procedures in transgenic mouse production. Mice were assigned to receive either carprofen (5 mg/kg) with buprenorphine (0.1 mg/kg; CB) or vehicle with buprenorphine (0.1 mg/kg; VB) in a prospective, double-blinded placebo controlled clinical trial. Data were analyzed in surgical sets of 1 to 3 female mice receiving embryos chimeric for a shared targeted embryonic stem-cell clone and host blastocyst cells. A total of 99 surgical sets were analyzed, comprising 199 Crl:CD1 female mice and their 996 offspring. Neither yield (pups weaned per embryo implanted in the surgical set) nor birth rate (average number of pups weaned per dam in the set) differed significantly between the CB and VB conditions. Multimodal opioid–NSAID analgesia appears to have no significant positive or negative effect on the success of producing novel lines of transgenic mice by blastocyst transfer. PMID:21838973

Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity

PubMed Central

Chen, Zhongyi; Guo, Lilu; Zhang, Yongqin; L. Walzem, Rosemary; Pendergast, Julie S.; Printz, Richard L.; Morris, Lindsey C.; Matafonova, Elena; Stien, Xavier; Kang, Li; Coulon, Denis; McGuinness, Owen P.; Niswender, Kevin D.; Davies, Sean S.

2014-01-01

Metabolic disorders, including obesity, diabetes, and cardiovascular disease, are widespread in Westernized nations. Gut microbiota composition is a contributing factor to the susceptibility of an individual to the development of these disorders; therefore, altering a person’s microbiota may ameliorate disease. One potential microbiome-altering strategy is the incorporation of modified bacteria that express therapeutic factors into the gut microbiota. For example, N-acylphosphatidylethanolamines (NAPEs) are precursors to the N-acylethanolamide (NAE) family of lipids, which are synthesized in the small intestine in response to feeding and reduce food intake and obesity. Here, we demonstrated that administration of engineered NAPE-expressing E. coli Nissle 1917 bacteria in drinking water for 8 weeks reduced the levels of obesity in mice fed a high-fat diet. Mice that received modified bacteria had dramatically lower food intake, adiposity, insulin resistance, and hepatosteatosis compared with mice receiving standard water or control bacteria. The protective effects conferred by NAPE-expressing bacteria persisted for at least 4 weeks after their removal from the drinking water. Moreover, administration of NAPE-expressing bacteria to TallyHo mice, a polygenic mouse model of obesity, inhibited weight gain. Our results demonstrate that incorporation of appropriately modified bacteria into the gut microbiota has potential as an effective strategy to inhibit the development of metabolic disorders. PMID:24960158

Effects of leptin treatment and Western diet on wheel running in selectively bred high runner mice.

PubMed

Meek, Thomas H; Dlugosz, Elizabeth M; Vu, Kim T; Garland, Theodore

2012-05-15

The role of leptin in regulating physical activity is varied. The behavioral effects of leptin signaling depend on the type of activity and the animal's physiological state. We used mice from lines selectively bred for high voluntary wheel running to further study how leptin regulates volitional exercise. Mice from four replicate high runner (HR) lines typically run ~3-fold more revolutions per day than those from four non-selected control (C) lines. HR mice have altered dopamine function and differences from C in brain regions known to be important in leptin-mediated behavior. Furthermore, male HR mice have been found to dramatically increase running when administered Western diet, an effect possibly mediated through leptin signaling. Male mice from generation 61 (representing three HR lines and one C line) were allowed wheel access at 24 days of age and given either Western diet (high in fat and with added sucrose) or standard chow. After four weeks, Western diet significantly increased circulating leptin, insulin, C-peptide, gastric inhibitory polypeptide, and inflammatory hormone resistin concentrations in HR mice (C mice not measured). Western diet increased running in HR mice, but did not significantly affect running in C mice. During the fifth week, all mice received two days of intra-peritoneal sham injections (physiological saline) followed by three days of murine recombinant leptin injections, and then another six days of sham injections. Leptin treatment significantly decreased caloric intake (adjusted for body mass) and body mass in all groups. Wheel running significantly increased with leptin injections in HR mice (fed Western or standard diet), but was unaffected in C mice. Whether Western diet and leptin treatment stimulate wheel running in HR mice through the same physiological pathways awaits future study. These results have implications for understanding the neural and endocrine systems that control locomotor activity, food consumption, and body weight, and how they may vary with genetic background. Copyright © 2012 Elsevier Inc. All rights reserved.

Dietary L-glutamine supplementation improves pregnancy outcome in mice infected with type-2 porcine circovirus.

PubMed

Ren, Wenkai; Luo, Wei; Wu, Miaomiao; Liu, Gang; Yu, Xinglong; Fang, Jun; Li, Teijun; Yin, Yulong; Wu, Guoyao

2013-09-01

Porcine circovirus type 2 (PCV2) causes reproductive failure in swine. As glutamine can enhance immune function in animals, this study was conducted with mice to test the hypothesis that dietary glutamine supplementation will improve pregnancy outcome in PCV2-infected dams. Beginning on day 0 of gestation, mice were fed a standard diet supplemented with 1.0% L-glutamine or 1.22% L-alanine (isonitrogenous control). All mice were infected with PCV2 (2000 TCID50) on day 10 of gestation. On day 17 of gestation, six mice from each group were euthanized to obtain maternal tissues and fetuses for hematology and histopathology tests. The remaining mice continued to receive their respective diets supplemented with 1.0% L-glutamine or 1.22% L-alanine through lactation. The PCV2 virus was present in maternal samples (serum and lung) of most mice in the control group but was not detected in the glutamine-supplemented mice. Dietary glutamine supplementation reduced abortion, decreased fetal deaths, and enhanced neonatal survival. The glutamine treatment also reduced concentrations of interleukin-6, while increasing concentrations of tumor necrosis factor-α and C-reactive protein, in the maternal serum of mice. Furthermore, glutamine supplementation attenuated microscopic lesions in maternal tissues (lung, spleen, and liver). Collectively, these results indicate that dietary glutamine supplementation is beneficial for ameliorating reproductive failure in virus-infected mice. The findings support the notion that gestating dams require adequate amounts of dietary glutamine for the optimal survival and growth of embryos, fetuses, and neonates, and have important implications for nutritional support of mammals (including swine and humans) during gestation and lactation.

Extra virgin olive oil improves learning and memory in SAMP8 mice.

PubMed

Farr, Susan A; Price, Tulin O; Dominguez, Ligia J; Motisi, Antonio; Saiano, Filippo; Niehoff, Michael L; Morley, John E; Banks, William A; Ercal, Nuran; Barbagallo, Mario

2012-01-01

Polyphenols are potent antioxidants found in extra virgin olive oil (EVOO); antioxidants have been shown to reverse age- and disease-related learning and memory deficits. We examined the effects of EVOO on learning and memory in SAMP8 mice, an age-related learning/memory impairment model associated with increased amyloid-β protein and brain oxidative damage. We administered EVOO, coconut oil, or butter to 11 month old SAMP8 mice for 6 weeks. Mice were tested in T-maze foot shock avoidance and one-trial novel object recognition with a 24 h delay. Mice which received EVOO had improved acquisition in the T-maze and spent more time with the novel object in one-trial novel object recognition versus mice which received coconut oil or butter. Mice that received EVOO had improve T-maze retention compared to the mice that received butter. EVOO increased brain glutathione levels suggesting reduced oxidative stress as a possible mechanism. These effects plus increased glutathione reductase activity, superoxide dismutase activity, and decreased tissue levels of 4-hydroxynoneal and 3-nitrotyrosine were enhanced with enriched EVOO (3 × and 5 × polyphenols concentration). Our findings suggest that EVOO has beneficial effects on learning and memory deficits found in aging and diseases, such as those related to the overproduction of amyloid-β protein, by reversing oxidative damage in the brain, effects that are augmented with increasing concentrations of polyphenols in EVOO.

Aliskiren Attenuates Steatohepatitis and Increases Turnover of Hepatic Fat in Mice Fed with a Methionine and Choline Deficient Diet

PubMed Central

Lee, Kuei-Chuan; Chan, Che-Chang; Yang, Ying-Ying; Hsieh, Yun-Cheng; Huang, Yi-Hsiang; Lin, Han-Chieh

2013-01-01

Background & Aims Activation of the renin-angiotensin-system is known to play a role in nonalcoholic steatohepatitis. Renin knockout mice manifest decreased hepatic steatosis. Aliskiren is the first direct renin inhibitor to be approved for clinical use. Our study aims to evaluate the possible therapeutic effects and mechanism of the chronic administration of aliskiren in a dietary steatohepatitis murine model. Methods Male C57BL/6 mice were fed with a methionine and choline-deficient (MCD) diet to induce steatohepatitis. After 8 weeks of feeding, the injured mice were randomly assigned to receive aliskiren (50 mg·kg-1 per day) or vehicle administration for 4 weeks. Normal controls were also administered aliskiren (50 mg·kg-1 per day) or a vehicle for 4 weeks. Results In the MCD mice, aliskiren attenuated hepatic steatosis, inflammation and fibrosis. Aliskiren did not change expression of lipogenic genes but increase turnover of hepatic fat by up-regulating peroxisome proliferator-activated receptor α, carnitine palmitoyltransferase 1a, cytochrome P450-4A14 and phosphorylated AMP-activated protein kinase. Furthermore, aliskiren decreased the hepatic expression of angiotensin II and nuclear factor κB. The levels of oxidative stress, hepatocyte apoptosis, activation of Kupffer cells and hepatic stellate cells, and pro-fibrotic markers were also reduced in the livers of the MCD mice receiving aliskiren. Conclusions Aliskiren attenuates steatohepatitis and fibrosis in mice fed with a MCD diet. Thus, the noted therapeutic effects might come from not only the reduction of angiotensin II but also the up-regulation of fatty acid oxidation-related genes. PMID:24204981

Effect of crude extracts of Moringa stenopetala and Artemisia absinthium on parasitaemia of mice infected with Trypanosoma congolense

PubMed Central

2014-01-01

Background Treatment of trypanosomosis is currently facing a number of problems including toxicity of trypanocidal drugs and development of resistance by the parasites. These limitations have prompted the search for alternative active substances (such as of natural origin). The purpose of the study was to investigate the effect of extracts of Moringa stenopetala and Artemisia absinthium on Trypanosoma congolense in mice. Methods Swiss white male mice aged 8–12 weeks were divided into six experimental groups of six animals. Water and methanol extracts of the two plants were prepared. T. congolense was isolated from cattle at Ghibe valley (Ethiopia). All experimental mice received approximately 1 x 105 trypanosomes in 0.2 ml of blood. Plant extracts were given orally to four groups (2 plant species and two extraction methods) at 400 mg/kg body weight for seven consecutive days. One group remained as distilled water treated control and the other as diminzene aceturate treated control. The effect of the extracts on levels of parasitaemia, body weight, packed cell volume (PCV) and mice survival was monitored for 25 days. Results All treatments have significantly reduced parasitaemia and helped improve body weight, PCV and survival of mice compared to the water-treated control (P < 0.01 in all cases). These effects were comparable to that with diminazene aceturate. No significant difference was observed in the reduction of parasitaemia between plant extract treatment groups. However, mice with extracts of A. absinthium had significantly higher body weight than those with extracts of M. stenopetala (P < 0.05). Conclusions The two plants have antitrypanosomal potential against T. congolense by reducing the levels of parasitaemia, maintaining good PCV and body weight, and prolonging the lives of infected animals. PMID:24962241

Effect of crude extracts of Moringa stenopetala and Artemisia absinthium on parasitaemia of mice infected with Trypanosoma congolense.

PubMed

Kifleyohannes, Tsegabirhan; Terefe, Getachew; Tolossa, Yacob H; Giday, Mirutse; Kebede, Nigatu

2014-06-24

Treatment of trypanosomosis is currently facing a number of problems including toxicity of trypanocidal drugs and development of resistance by the parasites. These limitations have prompted the search for alternative active substances (such as of natural origin). The purpose of the study was to investigate the effect of extracts of Moringa stenopetala and Artemisia absinthium on Trypanosoma congolense in mice. Swiss white male mice aged 8-12 weeks were divided into six experimental groups of six animals. Water and methanol extracts of the two plants were prepared. T. congolense was isolated from cattle at Ghibe valley (Ethiopia). All experimental mice received approximately 1 x 10(5) trypanosomes in 0.2 ml of blood. Plant extracts were given orally to four groups (2 plant species and two extraction methods) at 400 mg/kg body weight for seven consecutive days. One group remained as distilled water treated control and the other as diminzene aceturate treated control. The effect of the extracts on levels of parasitaemia, body weight, packed cell volume (PCV) and mice survival was monitored for 25 days. All treatments have significantly reduced parasitaemia and helped improve body weight, PCV and survival of mice compared to the water-treated control (P < 0.01 in all cases). These effects were comparable to that with diminazene aceturate. No significant difference was observed in the reduction of parasitaemia between plant extract treatment groups. However, mice with extracts of A. absinthium had significantly higher body weight than those with extracts of M. stenopetala (P < 0.05). The two plants have antitrypanosomal potential against T. congolense by reducing the levels of parasitaemia, maintaining good PCV and body weight, and prolonging the lives of infected animals.

Increased Radioresistance to Lethal Doses of Gamma Rays in Mice and Rats after Exposure to Microwave Radiation Emitted by a GSM Mobile Phone Simulator

PubMed Central

Mortazavi, SMJ; Mosleh-Shirazi, MA; Tavassoli, AR; Taheri, M; Mehdizadeh, AR; Namazi, SAS; Jamali, A; Ghalandari, R; Bonyadi, S; Haghani, M; Shafie, M

2013-01-01

The aim of this study was to investigate the effect of pre-irradiation with microwaves on the induction of radioadaptive response. In the 1st phase of the study, 110 male mice were divided into 8 groups. The animals in these groups were exposed/sham-exposed to microwave, low dose rate gamma or both for 5 days. On day six, the animals were exposed to a lethal dose (LD). In the 2nd phase, 30 male rats were divided into 2 groups of 15 animals. The 1st group received microwave exposure. The 2nd group (controls) received the same LD but there was no treatment before the LD. On day 5, all animals were whole-body irradiated with the LD. Statistically significant differences between the survival rate of the mice only exposed to lethal dose of gamma radiation before irradiation with a lethal dose of gamma radiation with those of the animals pre-exposed to either microwave (p=0.02), low dose rate gamma (p=0.001) or both of these physical adapting doses (p=0.003) were observed. Likewise, a statistically significant difference between survival rates of the rats in control and test groups was observed. Altogether, these experiments showed that exposure to microwave radiation may induce a significant survival adaptive response. PMID:23930107

Blockade of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling for therapy of metastatic human pancreatic cancer.

PubMed

Baker, Cheryl H; Solorzano, Carmen C; Fidler, Isaiah J

2002-04-01

We determined whether concurrent blockage of vascular endothelial growth factor (VEGF) receptor and epidermal growth factor (EGF) receptor signaling by two novel tyrosine kinase inhibitors, PTK 787 and PKI 166, respectively, can inhibit angiogenesis and, hence, the growth and metastasis of human pancreatic carcinoma in nude mice. Highly metastatic human pancreatic carcinoma L3.6pl cells were injected into the pancreas of nude mice. Seven days later, groups of mice began receiving oral doses of PTK 787 and PKI 166 three times weekly. Some groups of mice also received i.p. injections of gemcitabine twice a week. The mice were necropsied when the control mice became moribund. Treatment with PTK 787 and PKI 166, with gemcitabine alone, or with the combination of PTK 787, PKI 166, and gemcitabine produced 69, 50, and 97% reduction in the volume of pancreatic tumors, respectively. Administration of protein tyrosine kinase inhibitors and gemcitabine also significantly decreased the incidence of lymph node and liver metastasis. The therapeutic efficacy directly correlated with a decrease in circulating proangiogenic molecules (VEGF, interleukin-8), a decrease in microvessel density, a decrease in proliferating cell nuclear antigen staining, and an increase in apoptosis of tumor cells and endothelial cells. Therapies produced by combining gemcitabine with either PKI 166 or PTK 787 were similar to those produced by combining gemcitabine with both PKI 166 and PTK 787. These results suggest that blockade of either epidermal growth factor receptor or VEGF receptor signaling combined with chemotherapy provides an effective approach to the therapy of pancreatic cancer.

Effects of High Estrogen Levels on Monocyte Chemoattractant Protein-1 and Wound Healing

PubMed Central

Plackett, Timothy P.; Gregory, Meredith S.; Kovacs, Elizabeth J.

2015-01-01

Objective: Herein, we tested the effects of high levels of supplemental estrogen treatment on cutaneous wound healing. Approach: Female mice were implanted with a 17β-estradiol (E2) secreting pellet or placebo before receiving a full-thickness dermal excisional wound. Mice receiving the E2 pellet attained hormone levels that are comparable to those achieved during pregnancy. At 1, 3, and 5 days after injury, the dermal excision wound was examined for their histologic appearance, rate of closure, and chemokine levels. Results: Wound closure, assessed by percent reepithelialization, was slower in E2-treated mice relative to placebo (42.6%±6.6% vs. 70.0%±5.3%, respectively, 3 days after injury). In addition, there was a marked reduction in the subepithelial inflammatory infiltrate and granulation tissue in E2-treated mice relative to placebo. Wound levels of monocyte chemoattractant protein-1 (MCP-1) were increased by 3 days after injury and continued to rise at 5 days after injury in placebo-treated mice (p<0.01). By contrast, MCP-1 levels were significantly reduced at 3 and 5 days after injury in E2-treated mice relative to placebo-treated controls (p<0.01). This attenuation could be reversed by treatment with an estrogen receptor antagonist. Innovation: High levels of estrogen are able to suppress normal wound closure. Conclusion: Dermal wound healing can be altered by manipulating the gonadal steroid hormone levels. In particular, high levels of estrogen can be utilized to slow down the rate of wound healing through a reduction in the inflammatory response. PMID:25713751

Calpastatin overexpression impairs postinfarct scar healing in mice by compromising reparative immune cell recruitment and activation.

PubMed

Wan, Feng; Letavernier, Emmanuel; Le Saux, Claude Jourdan; Houssaini, Amal; Abid, Shariq; Czibik, Gabor; Sawaki, Daigo; Marcos, Elisabeth; Dubois-Rande, Jean-Luc; Baud, Laurent; Adnot, Serge; Derumeaux, Geneviève; Gellen, Barnabas

2015-12-01

The activation of the calpain system is involved in the repair process following myocardial infarction (MI). However, the impact of the inhibition of calpain by calpastatin, its natural inhibitor, on scar healing and left ventricular (LV) remodeling is elusive. Male mice ubiquitously overexpressing calpastatin (TG) and wild-type (WT) controls were subjected to an anterior coronary artery ligation. Mortality at 6 wk was higher in TG mice (24% in WT vs. 44% in TG, P < 0.05) driven by a significantly higher incidence of cardiac rupture during the first week post-MI, despite comparable infarct size and LV dysfunction and dilatation. Calpain activation post-MI was blunted in TG myocardium. In TG mice, inflammatory cell infiltration and activation were reduced in the infarct zone (IZ), particularly affecting M2 macrophages and CD4(+) T cells, which are crucial for scar healing. To elucidate the role of calpastatin overexpression in macrophages, we stimulated peritoneal macrophages obtained from TG and WT mice in vitro with IL-4, yielding an abrogated M2 polarization in TG but not in WT cells. Lymphopenic Rag1(-/-) mice receiving TG splenocytes before MI demonstrated decreased T-cell recruitment and M2 macrophage activation in the IZ day 5 after MI compared with those receiving WT splenocytes. Calpastatin overexpression prevented the activation of the calpain system after MI. It also impaired scar healing, promoted LV rupture, and increased mortality. Defective scar formation was associated with blunted CD4(+) T-cell and M2-macrophage recruitment. Copyright © 2015 the American Physiological Society.

Effect of yogurt containing deep sea water on health-related serum parameters and intestinal microbiota in mice.

PubMed

Kang, Sun Moon; Jhoo, Jin Woo; Pak, Jae In; Kwon, Ill Kyoung; Lee, Sung Ki; Kim, Gur Yoo

2015-09-01

Deep sea water (DSW) has health benefits and is widely used as food supplement; however, its effect in fermented products has not been explored. Here, we investigated the effect of DSW-containing yogurt on health-related serum parameters and intestinal microbiota in mice. Animals were assigned to 3 feeding groups, which received water (control), normal yogurt (N-yogurt), or DSW-containing yogurt (DSW-yogurt) with a basal diet. Mice were killed at wk 4 or 8 of feeding and analyzed for serum parameters and microbial population in the small intestine. Both yogurt groups demonstrated increased populations of intestinal lactic acid bacteria compared with the control group. The activity of serum aspartate aminotransferase and alanine aminotransferase was markedly decreased in the DSW-yogurt and N-yogurt groups, and triglyceride level tended to be lower in the DSW-yogurt group compared with that in the control mice. Furthermore, the DSW-yogurt group showed a more significant decrease in the ratio of total cholesterol to high-density lipoprotein-cholesterol than did the N-yogurt group. These findings suggest that DSW supplementation of yogurt can increase its beneficial effects on lipid metabolism. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Asparagus cochinchinensis stimulates release of nerve growth factor and abrogates oxidative stress in the Tg2576 model for Alzheimer's disease.

PubMed

Lee, Hyun Ah; Kim, Ji Eun; Sung, Ji Eun; Yun, Woo Bin; Kim, Dong Seob; Lee, Hee Seob; Hong, Jin Tae; Hwang, Dae Youn

2018-04-06

Use of multifunctional drugs with neurotrophic supporting and oxidative stress suppressing activity may be considered a therapeutic strategy to protect or repair cellular damage caused during the progression of Alzheimer's disease (AD). In this study, we investigated the therapeutic effects of aqueous extract of A. cochinchinesis root (AEAC), particularly its role as a nerve growth factor (NGF) stimulator and anti-oxidant in Tg2576 mice showing AD phenotypes of human. Tg2576 mice were received 100 mg/kg/day AEAC via oral administration, while mice in the Vehicle treated group received dH 2 O for 4 weeks. Non-Tg littermates were used as a control group. Following AEAC treatment for 4 weeks, NGF function, anti-oxidantive status, Aβ-42 peptide level, γ-secretase expression and neuronal cell functions were analyzed in the brain of Tg2576 mice. AEAC containing flavonoids, phenols, saponins and protodioscin induced enhancement of NGF secretion and decreased intracellular ROS in the neuronal and microglial cell line. These effects as well as enhanced SOD levels were also detected in AEAC treated Tg2576 mice. The expression of p-Akt among downstream effectors of the high affinity NGF receptor was dramatically recovered in AEAC treated Tg2576 mice, while the expression of p75 NTR was slightly recovered in the same group. Significant recovery on the level of Aβ-42 peptides and the expression of γ-secretase members including PS-2, APH-1 and NCT were detected in AEAC treated Tg2576 mice. Furthermore, AEAC treated Tg2576 mice showed decreased numbers of dead cells and suppressed acetyl choline esterase (AChE) activity. These results suggest that AEAC contribute to improving the deposition of Aβ-42 peptides and neuronal cell injuries during the pathological progression stage of AD in the brain of Tg2576 mice through increased NGF secretion and suppressed oxidative stress.

WHOLE BODY VIBRATION IMPROVES ATTENTION AND MOTOR PERFORMANCE IN MICE DEPENDING ON THE DURATION OF THE WHOLE-BODY VIBRATION SESSION.

PubMed

Keijser, Jan N; van Heuvelen, Marieke J G; Nyakas, Csaba; Tóth, Kata; Schoemaker, Regien G; Zeinstra, Edzard; van der Zee, Eddy A

2017-01-01

Whole body vibration (WBV) is a form of physical stimulation via mechanical vibrations transmitted to a subject. It is assumed that WBV induces sensory stimulation in cortical brain regions through the activation of skin and muscle receptors responding to the vibration. The effects of WBV on muscle strength are well described. However, little is known about the impact of WBV on the brain. Recently, it was shown in humans that WBV improves attention in an acute WBV protocol. Preclinical research is needed to unravel the underlying brain mechanism. As a first step, we examined whether chronic WBV improves attention in mice. A custom made vibrating platform for mice with low intensity vibrations was used. Male CD1 mice (3 months of age) received five weeks WBV (30 Hz; 1.9 G), five days a week with sessions of five (n=12) or 30 (n=10) minutes. Control mice (pseudo-WBV; n=12 and 10 for the five and 30 minute sessions, respectively) were treated in a similar way, but did not receive the actual vibration. Object recognition tasks were used as an attention test (novel and spatial object recognition - the primary outcome measure). A Balance beam was used for motor performance, serving as a secondary outcome measure. WBV sessions of five (but not WBV sessions of 30 minutes) improved balance beam performance (mice gained 28% in time needed to cross the beam) and novel object recognition (mice paid significantly more attention to the novel object) as compared to pseudo WBV, but no change was found for spatial object performance (mice did not notice the relocation). Although 30 minutes WBV sessions were not beneficial, it did not impair either attention or motor performance. These results show that brief sessions of WBV improve, next to motor performance, attention for object recognition, but not spatial cues of the objects. The selective improvement of attention in mice opens the avenue to unravel the underlying brain mechanisms.

Pyridostigmine but not 3,4-diaminopyridine exacerbates ACh receptor loss and myasthenia induced in mice by muscle-specific kinase autoantibody

PubMed Central

Morsch, Marco; Reddel, Stephen W; Ghazanfari, Nazanin; Toyka, Klaus V; Phillips, William D

2013-01-01

In myasthenia gravis, the neuromuscular junction is impaired by the antibody-mediated loss of postsynaptic acetylcholine receptors (AChRs). Muscle weakness can be improved upon treatment with pyridostigmine, a cholinesterase inhibitor, or with 3,4-diaminopyridine, which increases the release of ACh quanta. The clinical efficacy of pyridostigmine is in doubt for certain forms of myasthenia. Here we formally examined the effects of these compounds in the antibody-induced mouse model of anti-muscle-specific kinase (MuSK) myasthenia gravis. Mice received 14 daily injections of IgG from patients with anti-MuSK myasthenia gravis. This caused reductions in postsynaptic AChR densities and in endplate potential amplitudes. Systemic delivery of pyridostigmine at therapeutically relevant levels from days 7 to 14 exacerbated the anti-MuSK-induced structural alterations and functional impairment at motor endplates in the diaphragm muscle. No such effect of pyridostigmine was found in mice receiving control human IgG. Mice receiving smaller amounts of MuSK autoantibodies did not display overt weakness, but 9 days of pyridostigmine treatment precipitated generalised muscle weakness. In contrast, one week of treatment with 3,4-diaminopyridine enhanced neuromuscular transmission in the diaphragm muscle. Both pyridostigmine and 3,4-diaminopyridine increase ACh in the synaptic cleft yet only pyridostigmine potentiated the anti-MuSK-induced decline in endplate ACh receptor density. These results thus suggest that ongoing pyridostigmine treatment potentiates anti-MuSK-induced AChR loss by prolonging the activity of ACh in the synaptic cleft. PMID:23440963

Pyridostigmine but not 3,4-diaminopyridine exacerbates ACh receptor loss and myasthenia induced in mice by muscle-specific kinase autoantibody.

PubMed

Morsch, Marco; Reddel, Stephen W; Ghazanfari, Nazanin; Toyka, Klaus V; Phillips, William D

2013-05-15

In myasthenia gravis, the neuromuscular junction is impaired by the antibody-mediated loss of postsynaptic acetylcholine receptors (AChRs). Muscle weakness can be improved upon treatment with pyridostigmine, a cholinesterase inhibitor, or with 3,4-diaminopyridine, which increases the release of ACh quanta. The clinical efficacy of pyridostigmine is in doubt for certain forms of myasthenia. Here we formally examined the effects of these compounds in the antibody-induced mouse model of anti-muscle-specific kinase (MuSK) myasthenia gravis. Mice received 14 daily injections of IgG from patients with anti-MuSK myasthenia gravis. This caused reductions in postsynaptic AChR densities and in endplate potential amplitudes. Systemic delivery of pyridostigmine at therapeutically relevant levels from days 7 to 14 exacerbated the anti-MuSK-induced structural alterations and functional impairment at motor endplates in the diaphragm muscle. No such effect of pyridostigmine was found in mice receiving control human IgG. Mice receiving smaller amounts of MuSK autoantibodies did not display overt weakness, but 9 days of pyridostigmine treatment precipitated generalised muscle weakness. In contrast, one week of treatment with 3,4-diaminopyridine enhanced neuromuscular transmission in the diaphragm muscle. Both pyridostigmine and 3,4-diaminopyridine increase ACh in the synaptic cleft yet only pyridostigmine potentiated the anti-MuSK-induced decline in endplate ACh receptor density. These results thus suggest that ongoing pyridostigmine treatment potentiates anti-MuSK-induced AChR loss by prolonging the activity of ACh in the synaptic cleft.

Effect of Hochu-ekki-to (TJ-41), a Japanese Herbal Medicine, on Daily Activity in a Murine Model of Chronic Fatigue Syndrome

PubMed Central

2004-01-01

We aimed to evaluate the effect of a Japanese herbal medicine, Hochu-ekki-to (TJ-41), on daily activity in a murine model of chronic fatigue syndrome (CFS). CFS was induced by repeated injection of Brucella abortus (BA) antigen every 2 weeks. TJ-41 was orally administered to mice in a dose of 500 mg/kg/day for 1 week before injecting BA and for 4 weeks thereafter. We evaluated daily running activity in mice receiving TJ-41 as compared with that in untreated mice. Survival of both mouse groups was also monitored during the observation period. Body weight (BW), spleen weight (SW), SW/ BW ratio and expression levels of interleukin-10 (IL-10) mRNA in spleen were determined in both groups at the time of sacrifice. The daily activity was significantly higher in the treated group than in the control. Two mice in the untreated group died 2 days after the second injection of BA, whereas no mice in the group treated with TJ-41 died. The SW and SW/BW ratio were significantly lower in the treated mice than in the control. Suppressed IL-10 mRNA levels were observed in the spleens of the mice treated with TJ-41. Our data suggest that Hochu-ekki-to might possess an inhibitory effect on the marked decrease in running activity following BA injection. PMID:15480446

L-arginine prevents xanthoma development and inhibits atherosclerosis in LDL receptor knockout mice.

PubMed

Aji, W; Ravalli, S; Szabolcs, M; Jiang, X C; Sciacca, R R; Michler, R E; Cannon, P J

1997-01-21

The potential antiatherosclerotic actions of NO were investigated in four groups of mice (n = 10 per group) lacking functional LDL receptor genes, an animal model of familial hypercholesterolemia. Group 1 was fed a regular chow diet. Groups 2 through 4 were fed a 1.25% high-cholesterol diet. In addition, group 3 received supplemental L-arginine and group 4 received L-arginine and N omega-nitro-L-arginine (L-NA), an inhibitor of NO synthase (NOS). Animals were killed at 6 months; aortas were stained with oil red O for planimetry and with antibodies against constitutive and inducible NOSs. Plasma cholesterol was markedly increased in the animals receiving the high-cholesterol diet. Xanthomas appeared in all mice fed the high-cholesterol diet alone but not in those receiving L-arginine. Aortic atherosclerosis was present in all mice on the high-cholesterol diet. The mean atherosclerotic lesion area was reduced significantly (P < .01) in the cholesterol-fed mice given L-arginine compared with those receiving the high-cholesterol diet alone. The mean atherosclerotic lesion area was significantly larger (P < .01) in cholesterol-fed mice receiving L-arginine + L-NA than in those on the high-cholesterol diet alone. Within the atherosclerotic plaques, endothelial cells immunoreacted for endothelial cell NOS; macrophages, foam cells, and smooth muscle cells immunostained strongly for inducible NOS and nitrotyrosine residues. The data indicate that L-arginine prevents xanthoma formation and reduces atherosclerosis in LDL receptor knockout mice fed a high-cholesterol diet. The abrogation of the beneficial effects of L-arginine by L-NA suggests that the antiatherosclerotic actions of L-arginine are mediated by NOS. The data suggest that L-arginine may be beneficial in familial hypercholesterolemia.

Effects of hydroalcoholic extract of Rhus coriaria seed on glucose and insulin related biomarkers, lipid profile, and hepatic enzymes in nicotinamide-streptozotocin-induced type II diabetic male mice.

PubMed

Ahangarpour, Akram; Heidari, Hamid; Junghani, Majid Salehizade; Absari, Reza; Khoogar, Mehdi; Ghaedi, Ehsan

2017-10-01

Type 2 diabetes often leads to dislipidemia and abnormal activity of hepatic enzymes. The purpose of this study was to evaluate the antidiabetic and hypolipidemic properties of Rhus coriaria ( R. coriaria ) seed extrac on nicotinamide-streptozotocin induced type 2 diabetic mice. In this experimental study, 56 male Naval Medical Research Institute mice (30-35 g) were randomly separated into seven groups: control, diabetic group, diabetic mice treated with glibenclamide (0.25 mg/kg, as standard antidiabetic drug) or R. coriaria seed extract in doses of 200 and 300 mg/kg, and control groups received these two doses of extract orally for 28 days. Induction of diabetes was done by intraperitoneal injection of nicotinamide and streptozotocin. Ultimately, body weight of mice, blood levels of glucose, insulin, hepatic enzymes, leptin, and lipid profile were assayed. After induction of type 2 diabetes, level of glucose, cholesterol, low density lipoprotein, serum glutamic oxaloacetic transaminase, and serum glutamic pyruvic transaminase increased and level of insulin and high density lipoprotein decreased remarkably. Administration of both doses of extract decreased level of glucose and cholesterol significantly in diabetic mice. LDL level decreased in treated group with dose of 300 mg/kg of the extract. Although usage of the extract improved level of other lipid profiles, insulin and hepatic enzymes, changes weren't significant. This study showed R. coriaria seeds administration has a favorable effect in controlling some blood parameters in type 2 diabetes. Therefore it may be beneficial in the treatment of diabetes.

Human bone marrow mesenchymal stem cells for retinal vascular injury.

PubMed

Wang, Jin-Da; An, Ying; Zhang, Jing-Shang; Wan, Xiu-Hua; Jonas, Jost B; Xu, Liang; Zhang, Wei

2017-09-01

To examine the potential of intravitreally implanted human bone marrow-derived mesenchymal stem cells (BMSCs) to affect vascular repair and the blood-retina barrier in mice and rats with oxygen-induced retinopathy, diabetic retinopathy or retinal ischaemia-reperfusion damage. Three study groups (oxygen-induced retinopathy group: 18 C57BL/6J mice; diabetic retinopathy group: 15 rats; retinal ischaemia-reperfusion model: 18 rats) received BMSCs injected intravitreally. Control groups (oxygen-induced retinopathy group: 12 C57BL/6J mice; diabetic retinopathy group: 15 rats; retinal ischaemia-reperfusion model: 18 rats) received an intravitreal injection of phosphate-buffered saline. We applied immunohistological techniques to measure retinal vascularization, spectroscopic measurements of intraretinally extravasated fluorescein-conjugated dextran to quantify the blood-retina barrier breakdown, and histomorphometry to assess retinal thickness and retinal ganglion cell count. In the oxygen-induced retinopathy model, the study group with intravitreally injected BMSCs as compared with the control group showed a significantly (p = 0.001) smaller area of retinal neovascularization. In the diabetic retinopathy model, study group and control group did not differ significantly in the amount of intraretinally extravasated dextran. In the retinal ischaemia-reperfusion model, on the 7th day after retina injury, the retina was significantly thicker in the study group than in the control group (p = 0.02), with no significant difference in the retinal ganglion cell count (p = 0.36). Intravitreally implanted human BMSCs were associated with a reduced retinal neovascularization in the oxygen-induced retinopathy model and with a potentially cell preserving effect in the retinal ischaemia-reperfusion model. Intravitreal BMSCs may be of potential interest for the therapy of retinal vascular disorders. © 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Inhibitory Effects of North American Wild Rice on Monocyte Adhesion and Inflammatory Modulators in Low-Density Lipoprotein Receptor-Knockout Mice.

PubMed

Moghadasian, Mohammed H; Zhao, Ruozhi; Ghazawwi, Nora; Le, Khuong; Apea-Bah, Franklin B; Beta, Trust; Shen, Garry X

2017-10-18

The present study examined the effects of wild rice on monocyte adhesion, inflammatory and fibrinolytic mediators in low-density lipoprotein receptor-knockout (LDLr-KO) mice. Male LDLr-KO mice received a cholesterol (0.06%, w/w)-supplemented diet with or without white or wild rice (60%, w/w) for 20 weeks. White rice significantly increased monocyte adhesion and abundances of monocyte chemoattractant protein-1, tissue necrosis factor-α, intracellular cell adhesion molecule-1, plasminogen activator inhibitor-1, urokinase plasminogen activator (uPA), and uPA receptor in aortae and hearts of LDLr-KO mice compared to the control diet. Wild rice inhibited monocyte adhesion to the aorta, atherosclerosis, and abundances of the inflammatory and fibrinolytic regulators in the cardiovascular tissue of LDLr-KO mice compared to white rice. White or wild rice did not significantly alter the levels of cholesterol, triglycerides, or antioxidant enzymes in plasma. The anti-atherosclerotic effect of wild rice may result from its inhibition on monocyte adhesion and inflammatory modulators in LDLr-KO mice.

Trichoderma virens as a biocontrol of Toxocara canis: In vivo evaluation.

PubMed

de Souza Maia Filho, Fernando; da Silva Fonseca, Anelise Oliveira; Persici, Beatriz Maroneze; de Souza Silveira, Julia; Braga, Caroline Quintana; Pötter, Luciana; de Avila Botton, Sônia; Brayer Pereira, Daniela Isabel

Microorganisms have been widely studied as biological control agents of parasites of medical and veterinary importance. Coprophagous arthropods, bacteria and fungi are among the different organisms evaluated as potential biological control agents. Nematophagous fungi capture and digest the free forms of nematodes in the soil. Due to its zoonotic potential, Toxocara canis have been brought to the attention of researchers. The aim of the present study was to determine whether the administration of embryonated T. canis eggs exposed to the nematophagous fungus Trichoderma virens reduces parasite infection in experimental animals. Embryonated T. canis eggs were exposed to T. virens mycelium for 15 days at 25°C. Subsequently, 100 fungus-exposed eggs were orally administered to 20 Swiss mice. As a positive control, another 20 mice received 100 embryonated eggs that were not exposed to the fungus. After 48h, the animals were killed, and heart, lungs and liver were harvested for the recovery of larvae. The organs of the animals that received embryonated T. canis eggs exposed to the fungus showed a lower mean larval recovery when compared with the animals that received embryonated eggs without fungus exposure (p<0.05). The exposure of T. canis eggs to T. virens reduces the experimental infection, demonstrating the potential of this nematophagous fungus as a biocontrol agent. Copyright © 2016 Asociación Española de Micología. Publicado por Elsevier España, S.L.U. All rights reserved.

Administration of midazolam in infancy does not affect learning and memory of adult mice.

PubMed

Xu, Hua; Liu, Zhi-Qiang; Liu, Yi; Zhang, Wei-Shi; Xu, Bo; Xiong, Yuan-Chang; Deng, Xiao-Ming

2009-12-01

1. Midazolam is a common fast-acting GABA(A) receptor agonist. Recent data suggest that exposure to midazolam in early life may cause long-term effects on brain function through stable epigenetic reprogramming. The aim of the present study was to determine whether the administration of midazolam to infant mice would affect their learning and memory in adulthood. 2. An open-field test was conducted before and then 3, 24, 48 and 72 h after administration of midazolam (50 mg/kg, i.p.) to infant mice. Saline control mice received an equal volume of saline i.p. 3 h before the open-field test. Total movements, total movement time, total movement distance and velocity were analysed. Novel object recognition (NOR), Morris water-maze and passive avoidance tests were performed when the treated mice grew to adulthood (105 days of age). 3. The results of open-field test showed that midazolam significantly reduced locomotor activity (total movements, total movement time, total movement distance and velocity) in infant mice 3 and 24 h after drug administration and that these effects had disappeared by 72 h after drug administration. The results of the water-maze, NOR and passive avoidance tests in adulthood (at 105 days of age) indicated that administration of midazolam in infancy had no long-term effects on the learning and memory behaviours of adult mice compared with the saline control. 4. Acute midazolam administration to infant mice affected spontaneous locomotor activity for approximately 2 days, but did not seem to have any significant impact on cognitive functioning that lasted into adulthood.

Adaptation and immunogenicity of Cryptosporidium parvum to immunocompetent mice.

PubMed

Matsuo, Tomohide; Tsuge, Yasuko; Umemiya-Shirafuji, Rika; Fujino, Takashi; Matsui, Toshihiro

2014-03-01

The adaptation and immunogenisity of Cryptosporidium parvum isolated from Siberian chipmunks (SC1 strain) in immunocompetent (ICR) mice were examined. The oocysts were received to the severe combined immunodeficiency (SCID) mice by repeated passage. The oocysts collected from the 18th SCID mice were inoculated to 5 ICR mice. The mice began to shed oocysts from 6 days after inoculation, the patency was 5 days, and the maximum oocysts per gram of feces (OPG) value was 10(4). The maximum of OPG value was gradually increased by successive passage, and finally that in the 22nd mice reached 10(6) (patency: 11 days). It is considered that these results indicate completion of their adaptation to ICR mice. To examine the immunogenicity of C. parvum to ICR mice, 8 groups of 5 mice each were inoculated with 1.3 × 10(6) oocysts of SC1 strain, which were collected after adaptation to SCID mice. All groups shed oocysts from 6th day, and their patency was from 8 to 12 days. On the 21st day after the primary infection, these mice were challenged with 1.3 × 10(6) oocysts. No oocysts shed from any groups, although 2 control groups shed oocysts from the 6th day, and their OPG values were more than 10(6). These results suggest that this strain has strong immunogenicity against ICR mice. Therefore, the immunological healthy mice were considered a useful experimental model to investigate immunological and drug treatments in the strain of C. parvum.

TEMPOL increases NAD(+) and improves redox imbalance in obese mice.

PubMed

Yamato, Mayumi; Kawano, Kimika; Yamanaka, Yuki; Saiga, Misako; Yamada, Ken-Ichi

2016-08-01

Continuous energy conversion is controlled by reduction-oxidation (redox) processes. NAD(+) and NADH represent an important redox couple in energy metabolism. 4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPOL) is a redox-cycling nitroxide that promotes the scavenging of several reactive oxygen species (ROS) and is reduced to hydroxylamine by NADH. TEMPOL is also involved in NAD(+) production in the ascorbic acid-glutathione redox cycle. We utilized the chemical properties of TEMPOL to investigate the effects of antioxidants and NAD(+)/NADH modulators on the metabolic imbalance in obese mice. Increases in the NAD(+)/NADH ratio by TEMPOL ameliorated the metabolic imbalance when combined with a dietary intervention, changing from a high-fat diet to a normal diet. Plasma levels of the superoxide marker dihydroethidium were higher in mice receiving the dietary intervention compared with a control diet, but were normalized with TEMPOL consumption. These findings provide novel insights into redox regulation in obesity. Copyright © 2016. Published by Elsevier B.V.

A study on effects of glutathione s-transferase from silkworm on CCL4-induced mouse liver injury.

PubMed

Yan, Hui; Gui, Zhongzheng; Wang, Bochu

2011-01-01

To assess the hepatoprotective activity of Glutathione S-transferase(GSTsw), extracted and purified from silkworm, in experimental acute mice liver injury and explore mechanisms. Mice were divided into five groups: control group, carbon tetrachloride (CCl4) group, and three treatment groups that received CCl4 and GSTsw at doses of 0.083 mg•g(-1), 0.0415 mg•g(-1) and 0.0207 mg•g(-1) for 3 days. ALT in serum, GST, SOD and T-AOC in liver tissue homogenate, and changes in liver pathology in the five groups were studied. CCl4 administration led to pathological and biochemical evidence of liver injury as compared to untreated controls. GSTsw administration led to significant protection against CCl4-induced changes in liver pathology. It was also associatedwith significantly lower serum ALT levels, higher GST-SOD and T-AOC level in live tissue homogenate. Thus, GSTsw showed protective activity against CCl4-induced hepatotoxicity in mice.

Δ9-tetrahydrocannabinol (Δ9-THC) administration after neonatal exposure to phencyclidine potentiates schizophrenia-related behavioral phenotypes in mice.

PubMed

Rodríguez, Guadalupe; Neugebauer, Nichole M; Yao, Katherine Lan; Meltzer, Herbert Y; Csernansky, John G; Dong, Hongxin

2017-08-01

The clinical onset of schizophrenia often coincides with cannabis use in adolescents and young adults. However, the neurobiological consequences of this co-morbidity are not well understood. In this study, we examined the effects of Δ9-THC exposure during early adulthood on schizophrenia-related behaviors using a developmental mouse model of schizophrenia. Phencyclidine (PCP) or saline was administered once in neonatal mice (at P7; 10mg/kg). In turn, Δ9-THC or saline was administered sub-acutely later in life to cohorts of animals who had received either PCP or saline (P55-80, 5mg/kg). Mice who were administered PCP alone displayed behavioral changes in the Morris water waze (MWM) and pre-pulse inhibition (PPI) task paradigm that were consistent with schizophrenia-related phenotypes, but not in the locomotor activity or novel object recognition (NOR) task paradigms. Mice who were administered PCP and then received Δ9-THC later in life displayed behavioral changes in the locomotor activity paradigm (p<0.001) that was consistent with a schizophrenia-related phenotype, as well as potentiated changes in the NOR (p<0.01) and MWM (p<0.05) paradigms as compared to mice that received PCP alone. Decreased cortical receptor expression of NMDA receptor 1 subunit (NR1) was observed in mice that received PCP and PCP+Δ9-THC, while mice that received Δ9-THC and PCP+Δ9-THC displayed decreases in CB1 receptor expression. These findings suggest that administration of Δ9-THC during the early adulthood can potentiate the development of schizophrenia-related behavioral phenotypes induced by neonatal exposure to PCP in mice. Copyright © 2017 Elsevier Inc. All rights reserved.

Persistent escalation of alcohol consumption by mice exposed to brief episodes of social defeat stress: suppression by CRF-R1 antagonism.

PubMed

Newman, Emily L; Albrechet-Souza, Lucas; Andrew, Peter M; Auld, John G; Burk, Kelly C; Hwa, Lara S; Zhang, Eric Y; DeBold, Joseph F; Miczek, Klaus A

2018-06-01

Episodic bouts of social stress can precede the initiation, escalation, or relapse to disordered alcohol intake. Social stress may engender neuroadaptations in the hypothalamic-pituitary-adrenal (HPA) axis and in extrahypothalamic stress circuitry to promote the escalation of alcohol intake. We aimed to (1) confirm a pattern of escalated drinking in socially defeated mice and to (2) test drugs that target distinct aspects of the HPA axis and extrahypothalamic neural substrates for their effectiveness in reducing murine, stress-escalated drinking. Male C57BL/6J (B6) mice were socially defeated by resident Swiss-derived males for ten consecutive days receiving 30 bites/day. Ten days after the final defeat, cohorts of B6 mice received continuous or intermittent access to 20% EtOH (w/v) and water. After 4 weeks of drinking, mice were injected with weekly, systemic doses of the CRF-R1 antagonist, CP376395; the glucocorticoid receptor antagonist, mifepristone; the 11-beta-hydroxylase inhibitor, metyrapone; or the 5-alpha-reductase inhibitor, finasteride. Prior to drug treatments, defeated mice reliably consumed more EtOH than non-defeated controls, and mice given alcohol intermittently consumed more EtOH than those with continuous access. CP376395 (17-30 mg/kg) reduced continuous, but not intermittent EtOH intake (g/kg) in socially defeated mice. Mifepristone (100 mg/kg), however, increased drinking by defeated mice with intermittent access to alcohol while reducing drinking during continuous access. When administered finasteride (100 mg/kg) or metyrapone (50 mg/kg), all mice reduced their EtOH intake while increasing their water consumption. Mice with a history of episodic social defeat stress were selectively sensitive to the effects of CRF-R1 antagonism, suggesting that CRF-R1 may be a potential target for treating alcohol use disorders in individuals who escalate their drinking after exposure to repeated bouts of psychosocial stress. Future studies will clarify how social defeat stress may alter the expression of extrahypothalamic CRF-R1 and glucocorticoid receptors.

Methamphetamine-induced hyperthermia and dopaminergic neurotoxicity in mice: pharmacological profile of protective and nonprotective agents.

PubMed

Albers, D S; Sonsalla, P K

1995-12-01

Neurotoxic doses of methamphetamine (METH) can cause hyperthermia in experimental animals. Damage sustained to dopaminergic nerve terminals by this stimulant can be reduced by environmental cooling or by pharmacological manipulation which attenuates the hyperthermia. Many pharmacological agents with very diverse actions protect against METH-induced neuropathology. Several of these compounds, as well as drugs which do not protect, were investigated to determine if there was a relationship between protection and METH-induced hyperthermia. Mice received METH with or without concurrent administration of other drugs and core (i.e., colonic) temperature was monitored during treatment. The animals were sacrificed > or = 5 days later and neostriatal tyrosine hydroxylase activity and dopamine were measured. Core temperature was significantly elevated (> or = 2 degrees C) in mice treated with doses of METH which produced > or = 90% losses in striatal dopamine but not in mice less severally affected (only 50% loss of dopamine). Concurrent treatment of mice with METH and pharmacological agents which protected partially or completely from METH-induced toxicity also prevented the hyperthermic response (i.e., dopamine receptor antagonists, fenfluramine, dizocilpine, alpha-methyl-p-tyrosine, phenytoin, aminooxyacetic acid and propranol). These findings are consistent with the hypothesis that the hyperthermia produced by METH contributes to its neuropathology. However, studies with reserpine, a compound which dramatically lowers core temperature, demonstrated that hyperthermia per se is not a requirement for METH-induced neurotoxicity. Although core temperature was elevated in reserpinized mice treated with METH as compared with reserpinized control mice, their temperatures remained significantly lower than in nonreserpinized control mice. However, the hypothermic state produced in the reserpinized mice did not provide protection from METH-induced toxicity. These data demonstrate that hyperthermia per se contributes to but is not solely responsible for the METH-induced neuropathology.

Loss of long term protection with the inclusion of HIV pol to a DNA vaccine encoding gag.

PubMed

Garrod, Tamsin J; Gargett, Tessa; Yu, Wenbo; Major, Lee; Burrell, Christopher J; Wesselingh, Steven; Suhrbier, Andreas; Grubor-Bauk, Branka; Gowans, Eric J

2014-11-04

Traditional vaccine strategies that induce antibody responses have failed to protect against HIV infection in clinical trials, and thus cell-mediated immunity is now an additional criterion. Recent clinical trials that aimed to induce strong T cell responses failed to do so. Therefore, to enhance induction of protective T cell responses, it is crucial that the optimum antigen combination is chosen. Limited research has been performed into the number of antigens selected for an HIV vaccine. This study aimed to compare DNA vaccines encoding either a single HIV antigen or a combination of two antigens, using intradermal vaccination of C57BL/6 mice. Immune assays were performed on splenocytes, and in vivo protection was examined by challenge with a chimeric virus, EcoHIV, able to infect mouse but not human leukocytes, at 10 days (short term) and 60 days (long term) post final vaccination. At 60 days there was significantly lower frequency of induced antigen-specific CD8(+) T cells in the spleens of pCMVgag-pol-vaccinated mice compared with mice which received pCMVgag only. Most importantly, short term viral control of EcoHIV was similar for pCMVgag and pCMVgag-pol-vaccinated mice at day 10, but only the pCMVgag-vaccinated significantly controlled EcoHIV at day 60 compared with pCMV-vaccinated mice, showing that control was reduced with the inclusion of the HIV pol gene. Copyright © 2014 Elsevier B.V. All rights reserved.

High-Fat Diet During Mouse Pregnancy and Lactation Targets GIP-Regulated Metabolic Pathways in Adult Male Offspring.

PubMed

Kruse, Michael; Keyhani-Nejad, Farnaz; Isken, Frank; Nitz, Barbara; Kretschmer, Anja; Reischl, Eva; de las Heras Gala, Tonia; Osterhoff, Martin A; Grallert, Harald; Pfeiffer, Andreas F H

2016-03-01

Maternal obesity is a worldwide problem associated with increased risk of metabolic diseases in the offspring. Genetic deletion of the gastric inhibitory polypeptide (GIP) receptor (GIPR) prevents high-fat diet (HFD)-induced obesity in mice due to specific changes in energy and fat cell metabolism. We investigated whether GIP-associated pathways may be targeted by fetal programming and mimicked the situation by exposing pregnant mice to control or HFD during pregnancy (intrauterine [IU]) and lactation (L). Male wild-type (WT) and Gipr(-/-) offspring received control chow until 25 weeks of age followed by 20 weeks of HFD. Gipr(-/-) offspring of mice exposed to HFD during IU/L became insulin resistant and obese and exhibited increased adipose tissue inflammation and decreased peripheral tissue substrate utilization after being reintroduced to HFD, similar to WT mice on regular chow during IU/L. They showed decreased hypothalamic insulin sensitivity compared with Gipr(-/-) mice on control diet during IU/L. DNA methylation analysis revealed increased methylation of CpG dinucleotides and differential transcription factor binding of promoter regions of genes involved in lipid oxidation in the muscle of Gipr(-/-) offspring on HFD during IU/L, which were inversely correlated with gene expression levels. Our data identify GIP-regulated metabolic pathways that are targeted by fetal programming. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Pravastatin Effects on Placental Prosurvival Molecular Pathways in a Mouse Model of Preeclampsia.

PubMed

Saad, Antonio F; Diken, Zaid M; Kechichian, Talar B; Clark, Shannon M; Olson, Gayle L; Saade, George R; Costantine, Maged M

2016-11-01

Using an animal model of preeclampsia induced by overexpression of soluble fms-like tyrosine kinase 1 (sFlt-1), we previously showed that pravastatin prevents the development of a preeclampsia phenotype. Our objective is to determine whether pravastatin treatment may be explained by its effects on apoptotic/survival pathways in the placenta. Pregnant CD1 mice at day 8 of gestation (length of gestation 19 days) were randomly allocated to injection via tail vein with either adenovirus carrying sFlt-1 or adenovirus carrying the murine immunoglobulin G2α Fc fragment (mFc virus control group). Mice from the sFlt group were randomly assigned to receive pravastatin (5 mg/kg/d) in their drinking water from day 9 until killing (sFlt-1 + Pravastatin) or water (sFlt-1). The mFc control received water only. Mice were killed on day 18, and the placentas were collected. Protein mitogen-activated protein kinase (MAPK) pathway substrates were assayed using Bioplex Multiplex Immunoassay (Bio-Rad, Hercules, California). Data are reported as mean  ±  standard error of the mean or median (interquartile range) when appropriate. One-way analysis of variance followed by post hoc analysis was performed. Two-sided P value < .05 was considered statistically significant. The sFlt-1 + Pravastatin mice had significantly higher placental protein concentrations of prosurvival/ antiapoptotic factors (activating transcription factor 2, pp38, phosphorylated c-jun N-terminal kinase, and phosphorylated extracellular signal-regulated kinase) and of heat-shock protein 27 and signal transducer and activator of transcription 3, 2 factors crucial for embryonic and placental development during oxidative stress, compared to sFlt-1 mice (P  <  .05) and similar to the mFc control group. No differences were noted in substrates of the proapoptotic pp53 pathway. Pravastatin ability to prevent preeclampsia phenotype may be mediated through pleiotropic mechanisms involving a prosurvival/ antiapoptotic MAPK pathway in the placenta. Our results further support continued research in the role for statins in the prevention of preeclampsia. © The Author(s) 2016.

Liposomal 64Cu-PET Imaging of Anti-VEGF Drug Effects on Liposomal Delivery to Colon Cancer Xenografts.

PubMed

Blocker, Stephanie J; Douglas, Kirk A; Polin, Lisa Anne; Lee, Helen; Hendriks, Bart S; Lalo, Enxhi; Chen, Wei; Shields, Anthony F

2017-01-01

Liposomes (LP) deliver drug to tumors due to enhanced permeability and retention (EPR). LP were labeled with 64 Cu for positron emission tomography (PET) to image tumor localization. Bevacizumab (bev), a VEGF targeted antibody, may modify LP delivery by altering tumor EPR and this change can also be imaged. Objective : Assess the utility of 64 Cu-labeled LP for PET in measuring altered LP delivery early after treatment with bev. Methods: HT-29 human colorectal adenocarcinoma tumors were grown subcutaneously in SCID mice. Empty LP MM-DX-929 (Merrimack Pharmaceuticals, Inc. Cambridge, MA) were labeled with 64 CuCl 2 chelated with 4-DEAP-ATSC. Tumor-bearing mice received ~200-300 μCi of 64 Cu-MM-DX-929 and imaged with microPET. All mice were scanned before and after the treatment period, in which half of the mice received bev for one week. Scans were compared for changes in LP accumulation during this time. Initially, tissues were collected after the second PET for biodistribution measurements and histological analysis. Subsequent groups were divided for further treatment. Tumor growth following bev treatment, with or without LP-I, was assessed compared to untreated controls. Results : PET scans of untreated mice showed increased uptake of 64 Cu-MM-DX-929, with a mean change in tumor SUV max of 43.9%±6.6% (n=10) after 7 days. Conversely, images of treated mice showed that liposome delivery did not increase, with changes in SUV max of 7.6%±4.8% (n=12). Changes in tumor SUV max were significantly different between both groups (p=0.0003). Histology of tumor tissues indicated that short-term bev was able to alter vessel size. Therapeutically, while bev monotherapy, LP-I monotherapy, and treatment with bev followed by LP-I all slowed HT-29 tumor growth compared to controls, combination provided no therapeutic benefit. Conclusions: PET with tracer LP 64 Cu-MM-DX-929 can detect significant differences in LP delivery to colon tumors treated with bev when compared to untreated controls. Imaging with 64 Cu-MM-DX-929 is sensitive enough to measure drug-induced changes in LP localization which can have an effect on outcomes of treatment with LP.

Extract of Irish potatoes (Solanum tuberosum L.) decreases body weight gain and adiposity and improves glucose control in the mouse model of diet-induced obesity.

PubMed

Kubow, Stan; Hobson, Luc; Iskandar, Michèle M; Sabally, Kebba; Donnelly, Danielle J; Agellon, Luis B

2014-11-01

Both sexes of mice were fed a high fat diet (HFD) for 10 weeks without and with polyphenolic-rich potato extracts (PRPE) of cultivars Onaway and Russet Burbank. PRPE attenuated weight gain in male and female mice by as much as 63.2%, which was associated mostly with a reduction in adiposity. Mice receiving PRPE showed enhanced capacity for blood glucose clearance. Sex differences regarding the impact of HFD and PRPE on plasma levels of insulin, ghrelin, leptin, gastric inhibitory peptide, and resistin were noted. PRPE may serve as part of a preventative dietary strategy against the development of obesity and type 2 diabetes. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Fear Conditioning Increases NREM Sleep

PubMed Central

Hellman, Kevin; Abel, Ted

2010-01-01

To understand the role that sleep may play in memory storage, the authors investigated how fear conditioning affects sleep–wake states by performing electroencephalographic (EEG) and electromyographic recordings of C57BL/6J mice receiving fear conditioning, exposure to conditioning stimuli, or immediate shock treatment. This experimental design allowed us to examine the effects of associative learning, presentation of the conditioning stimuli, and presentation of the unconditioned stimuli on sleep–wake states. During the 24 hr after training, fear-conditioned mice had approximately 1 hr more of nonrapid-eye-movement (NREM) sleep and less wakefulness than mice receiving exposure to conditioning stimuli or immediate shock treatment. Mice receiving conditioning stimuli had more delta power during NREM sleep, whereas mice receiving fear conditioning had less theta power during rapid-eye-movement sleep. These results demonstrate that a single trial of fear conditioning alters sleep–wake states and EEG oscillations over a 24-hr period, supporting the idea that sleep is modified by experience and that such changes in sleep–wake states and EEG oscillations may play a role in memory consolidation. PMID:17469920

Protective Effects of Apigenin Against Paraquat-Induced Acute Lung Injury in Mice.

PubMed

Luan, Rui-Ling; Meng, Xiang-Xi; Jiang, Wei

2016-04-01

This study aimed to investigate the protective effects of apigenin against paraquat (PQ)-induced acute lung injury (ALI) in mice. Male Kunming mice were randomly divided into five groups: group 1 (control), group 2 (PQ), group 3 (PQ + apigenin 25 mg/kg), group 4 (PQ + apigenin 50 mg/kg), and group 5 (PQ + apigenin 100 mg/kg). The PQ + apigenin group received apigenin by gavage daily for consecutive 7 days, respectively, while the mice in control and PQ groups were given an equivalent volume of saline. We detected the lung wet/dry weight ratios and the histopathology of the lung. The levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were determined using enzyme-linked immunosorbent assay (ELISA) kits. The activity of nuclear factor (NF)-κB was also determined. The results indicated that apigenin administration decreased biochemical parameters of inflammation and oxidative stress, and improved oxygenation and lung edema in a dose-dependent manner. These protective effects of apigenin were associated with inhibition of NF-κB. In conclusion, apigenin reduces PQ-induced ALI by inhibition of inflammation and oxidative stress.

Evaluation of anxiolytic activity of aqueous extract of Coriandrum sativum Linn. in mice: A preliminary experimental study

PubMed Central

Latha, K.; Rammohan, B.; Sunanda, B. P. V.; Maheswari, M. S. Uma; Mohan, Surapaneni Krishna

2015-01-01

Objectives: To evaluate the anxiolytic effect of Coriandrum sativum (CS) aqueous extract in mice. To compare the antianxiety activity of CS against standard drug diazepam (3 mg/kg). Materials and Methods: After obtaining Institutional Animal Ethics Committee approval, Swiss albino mice (18–25 g) of either sex were randomly divided into five groups of six animals each. Dried powder of CS leaves was boiled with distilled water, cooled, filtered, placed on a hotplate for complete evaporation, finally weighed and stored. The control group, test group, and standard drugs group received saline, CS extract (50, 100, and 200 mg/kg), diazepam (3 mg/kg), respectively, by oral feeding. The antianxiety effect was assessed by elevated plus maze (EPM) in mice. Results: In EPM, it implied that CS 50 mg/kg (Group III), 100 mg/kg (Group IV), and 200 mg/kg (Group V) significantly (P < 0.001) increases the number of entries in open arms compared to control. The time spent in open arms also increased in all the doses of CS extract significantly. Conclusion: The current study demonstrates statistically significant dose-dependent antianxiety activity of CS leaves. PMID:26109787

tPA-MMP-9 Axis Plays a Pivotal Role in Mobilization of Endothelial Progenitor Cells from Bone Marrow to Circulation and Ischemic Region for Angiogenesis

PubMed Central

Day, Yuan-Ji

2016-01-01

We examined the role of tissue plasminogen activator- (tPA-) matrix metalloproteinase- (MMP-) 9 in mobilizing endothelial progenitor cells (EPCs) from bone marrow to circulation and critical limb ischemia (CLI) region. Male C57BL/6J mice having been irradiated were categorized into wild-type mice (WT) receiving WT bone marrow cell (BMC) transfusion (group 1), WT mice receiving MMP-9 knockout (MMP-9−/−) BMC (group 2), MMP-9−/− receiving MMP-9−/− BMC (group 3), and MMP-9−/− receiving WT BMC (group 4), each of which was subdivided into sham control (SC), CLI, SC-tPA, and CLI-tPA. In groups 1 and 4, by post-CLI 18 h and day 14, circulating EPC (C-kit+/CD31+, Sca-1+/KDR+) levels were highest in CLI-tPA subgroup. In groups 2 and 3, EPC levels did not differ among all subgroups. The EPC levels in bone marrow were higher in groups 2 and 3 than those in groups 1 and 4. By day 14, in animals with CLI, expression levels of proangiogenic factors (CXCR4, SDF-1α, and VEGF) showed similar trends as circulating EPC levels. Moreover, the number of infiltrated neutrophils and macrophages in quadriceps was higher in groups 1 and 4 than groups in 2 and 3. In conclusion, tPA-MMP-9 axis plays a crucial role in EPC mobilization and angiogenesis in experimental CLI. PMID:27610138

Assessment of post-laparotomy pain in laboratory mice by telemetric recording of heart rate and heart rate variability

PubMed Central

Arras, Margarete; Rettich, Andreas; Cinelli, Paolo; Kasermann, Hans P; Burki, Kurt

2007-01-01

Background Pain of mild to moderate grade is difficult to detect in laboratory mice because mice are prey animals that attempt to elude predators or man by hiding signs of weakness, injury or pain. In this study, we investigated the use of telemetry to identify indicators of mild-to-moderate post-laparotomy pain. Results Adult mice were subjected to laparotomy, either combined with pain treatment (carprofen or flunixin, 5 mg/kg s/c bid, for 1 day) or without pain relief. Controls received anesthesia and analgesics or vehicle only. Telemetrically measured locomotor activity was undisturbed in all animals, thus confirming that any pain experienced was of the intended mild level. No symptoms of pain were registered in any of the groups by scoring the animals' outer appearance or spontaneous and provoked behavior. In contrast, the group receiving no analgesic treatment after laparotomy demonstrated significant changes in telemetry electrocardiogram recordings: increased heart rate and decreased heart rate variability parameters pointed to sympathetic activation and pain lasting for 24 hours. In addition, core body temperature was elevated. Body weight and food intake were reduced for 3 and 2 days, respectively. Moreover, unstructured cage territory and destroyed nests appeared for 1–2 days in an increased number of animals in this group only. In controls these parameters were not affected. Conclusion In conclusion, real-time telemetric recordings of heart rate and heart rate variability were indicative of mild-to-moderate post-laparotomy pain and could define its duration in our mouse model. This level of pain cannot easily be detected by direct observation. PMID:17683523

Trehalose protects against ocular surface disorders in experimental murine dry eye through suppression of apoptosis.

PubMed

Chen, Wei; Zhang, Xiaobo; Liu, Mimi; Zhang, Jingna; Ye, Ya; Lin, Ying; Luyckx, Jacques; Qu, Jia

2009-09-01

The disaccharide trehalose is a key element involved in anhydrobiosis (the capability of surviving almost complete dehydration) in many organisms. Its presence also confers resistance to desiccation and high osmolarity in bacterial and human cells by protecting proteins and membranes from denaturation. The present study used a novel murine dry eye model induced by controlled low-humidity air velocity to determine whether topically applied trehalose could heal ocular surface epithelial disorders caused by ocular surface desiccation. In addition, the efficacy of 87.6 mM trehalose eyedrops was compared with that of 20% serum, the efficacy of which has been well documented. Mice ocular surface epithelial disorders were induced by exposure of murine eyes to continuous controlled low-humidity air velocity in an intelligently controlled environmental system (ICES) for 21 days, which accelerated the tear evaporation. The mice were then randomized into three groups: the control group received PBS (0.01 M) treatment; a second group received 87.6 mM trehalose eyedrops treatment; and the third group received mice serum eyedrops treatment. Each treatment was administered as a 10 microl dose every 6 h for 14 days. The resultant changes in corneal barrier function and histopathologic examination of cornea and conjunctiva were analyzed and the level of apoptosis on the ocular surface was assessed using active caspase-3. After 14 days of treatment, the corneal fluorescein staining area, the ruffling and desquamating cells on the apical corneal epithelium, as well as the apoptotic cells on ocular surface epithelium had significantly reduced in eyes treated with trehalose compared with those treated with serum and PBS. In contrast, after 14 days of treatment, improvements in the thickness of the corneal epithelium, the squamous metaplasia in conjunctival epithelium and the number of goblet cells of the conjunctiva were less marked in eyes treated with trehalose compared with serum. These results demonstrated that trehalose could improve the appearance of ocular surface epithelial disorders due to desiccation through suppression of apoptosis. Trehalose produces some of the same responses as serum upon topical application and can maintain corneal health.

Evaluation of Protective Immune Responses Induced by Recombinant TrxLp and ENO2 Proteins against Toxoplasma gondii Infection in BALB/c Mice

PubMed Central

Wang, Meng; Yang, Xiao-Yu; Zhang, De-Lin

2016-01-01

Toxoplasma gondii is an obligate intracellular parasitic protozoan that can infect almost all species of warm-blooded animals. As any chemical-based drugs could not act against the tissue cyst stage of T. gondii, vaccination may be one of the ideal control strategies. In the present study, two new vaccine candidates, named TgENO2 and TgTrxLp, were purified from Escherichia coli with pET-30a(+) expression system and then were injected into BALB/c mice to evaluate the protective efficacy against acute and chronic toxoplasmosis. The results showed that both the recombinant proteins, either alone or in combination, could elicit strong humoral and cellular immune responses with a higher level of IgG antibodies, IFN-γ, IL-2, CD4+, and CD8+ T cells as compared to those in mice from control groups. After acute challenge with tachyzoites of the GJS strain, mice immunized with rTgTrxLp (8 ± 2.77 d), rTgENO2 (7.4 ± 1.81 d), and rTgTrxLp + rTgENO2 (8.38 ± 4.57 d) proteins showed significantly longer survival time than those that received Freund's adjuvant (6.78 ± 2.08 d) and PBS (6.38 ± 4.65 d) (χ 2 = 9.687, df = 4, P = 0.046). The protective immunity of rTgTrxLp, rTgENO2, and rTgTrxLp + rTgENO2 proteins against chronic T. gondii infection showed 69.77%, 58.14%, and 20.93% brain cyst reduction as compared to mice that received PBS. The present study suggested that both TgENO2 and TgTrxLp were potential candidates for the development of multicomponent vaccines against toxoplasmosis. PMID:27803923

Effect of the Egyptian propolis on the hepatic antioxidant defense and pro-apoptotic p53 and anti-apoptotic bcl2 expressions in aflatoxin B1 treated male mice.

PubMed

Alm-Eldeen, Abeer A; Basyony, Mohammed A; Elfiky, Nabil K; Ghalwash, Mohamed M

2017-03-01

Aflatoxins are potent hepatotoxic due to their role in producing reactive oxygen species and consequently peroxidative damage. Propolis is a honey bee product known for its antioxidant capacity. The aim of this study was to verify the antioxidant effect of the Egyptian propolis extract (EPE) against aflatoxin B1 (AFB1)-induced hepatotoxicity in mice. Forty eight male mice were divided: first, second and third groups were used as control receiving saline, olive oil and EPE respectively, fourth was AFB1 group, fifth and sixth received EPE post or pre AFB1 treatment, respectively. EPE was given as (0.2mg/kg) 3 times a week. AFB1 was given as a single dose (0.25μg/kg). After 2 weeks, the mice were scarified and biochemical, histopathological and immunohistochemical investigations were assessed. EPE has a high content of total phenolics and alkaloids. The inhibitory concentration 50 (IC50) value for DPPH radical scavenging was 1353.8μg/mL. Pretreatment with EPE improved AFB1-induced hepatotoxicity represented in lowering alanine transaminase, aspartate aminotransferase, alkaline phosphatase, cholesterol, triglycerides, lipid peroxidation and pro-apoptotic p53 expression to 33.48±1.98 IU/ml, 53.00±2.37 IU/ml, 123.50±2.02 IU/ml, 76.50±2.66mg/dl, 54.00±3.03mg/dl, 2.22±0.14 nmol/g and 4.31±2.1 cells/field and raising the reduced glutathione, catalase, superoxide dismutase and anti-apoptotic bcl2 expression to 3.37±1.65 nmol/g, 4.92±0.25 nmol/g, 57±0.91UI/g and 39.7±5.9 cells/field which all had non-significant differences with the control, respectively. In conclusion, EPE can attenuate aflatoxin B1-induced hepatotoxicity in mice. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Experimental re-evaluation of flunarizine as add-on antiepileptic therapy.

PubMed

Thakur, Anamika; Sahai, A K; Thakur, J S

2011-04-01

Experimental studies have found several calcium channel blockers with anticonvulsant property. Flunarizine is one of the most potent calcium channel blockers, which has shown anticonvulsant effect against pentylenetetrazole (PTZ) and maximal electroshock (MES)-induced seizures. However, further experimental and clinical trials have shown varied results. We conducted a PTZ model experimental study to re-evaluate the potential of flunarizine for add-on therapy in the management of refractory epilepsy. Experiments were conducted in PTZ model involving Swiss strain mice. Doses producing seizures in 50% and 99% mice, i.e. CD(50) and CD(99) values of PTZ were obtained from the dose-response study. Animals received graded, single dose of sodium valproate (100-300 mg/kg), lamotrigine (3-12 mg/kg) and flunarizine (5-20 mg/kg), and then each group of mice was injected with CD(99) dose of PTZ (65mg/kg i.p.). Another group of mice received single ED(50) dose (dose producing seizure protection in 50% mice) of sodium valproate and flunarizine separately in left and right side of abdomen. Results were analysed by Kruskal-Wallis ANOVA on Ranks test. As compared to control, sodium valproate at 250 mg/kg and 300 mg/kg produced statistical significant seizure protection. At none of the pre-treatment dose levels of lamotrigine, the seizure score with PTZ differed significantly from that observed in the vehicle-treated group. Pre-treatment with flunarizine demonstrated dose-dependent decrease in the seizure score to PTZ administration. As compared to control group, flunarizine at 20 mg/kg produced statistical significant seizure protection. As combined use of sodium valproate and flunarizine has shown significant seizure protection in PTZ model, flunarizine has a potential for add-on therapy in refractory cases of partial seizures. It is therefore, we conclude that further experimental studies and multicenter clinical trials involving large sample size are needed to establish flunarizine as add-on therapy in refractory epilepsy.

Dietary supplementation with fresh pineapple juice decreases inflammation and colonic neoplasia in IL-10-deficient mice with colitis.

PubMed

Hale, Laura P; Chichlowski, Maciej; Trinh, Chau T; Greer, Paula K

2010-12-01

Bromelain, a mixture of proteolytic enzymes typically derived from pineapple stem, decreases production of proinflammatory cytokines and leukocyte homing to sites of inflammation. We previously showed that short-term oral treatment with bromelain purified from pineapple stem decreased the severity of colonic inflammation in C57BL/6 Il10(-/-) mice with chronic colitis. Since fresh pineapple fruit contains similar bromelain enzymes but at different proportions, this study aimed to determine whether long-term dietary supplementation with pineapple (supplied as juice) could decrease colon inflammation and neoplasia in Il10(-/-) mice with chronic colitis as compared with bromelain derived from stem. Colitis was triggered in Il10(-/-) mice by exposure to the non-steroidal anti-inflammatory drug piroxicam. Mice with colitis were supplemented with fresh vs. boiled pineapple juice or bromelain purified from stem for up to 6 months. Experimental mice readily consumed fresh pineapple juice at a level that generated mean stool proteolytic activities equivalent to 14 mg bromelain purified from stem, while control mice received boiled juice with inactive enzymes. Survival was increased in the group supplemented with fresh rather than boiled juice (P = 0.01). Mice that received fresh juice also had decreased histologic colon inflammation scores and a lower incidence of inflammation-associated colonic neoplasia (35% versus 66%; P < 0.02), with fewer neoplastic lesions/colon (P = 0.05). Flow cytometric analysis of murine splenocytes exposed to fresh pineapple juice in vitro demonstrated proteolytic removal of cell surface molecules that can affect leukocyte trafficking and activation. These results demonstrate that long-term dietary supplementation with fresh or unpasteurized frozen pineapple juice with proteolytically active bromelain enzymes is safe and decreases inflammation severity and the incidence and multiplicity of inflammation-associated colonic neoplasia in this commonly used murine model of inflammatory bowel disease. Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.

A Subtype of Olfactory Bulb Interneurons Is Required for Odor Detection and Discrimination Behaviors.

PubMed

Takahashi, Hiroo; Ogawa, Yoichi; Yoshihara, Sei-Ichi; Asahina, Ryo; Kinoshita, Masahito; Kitano, Tatsuro; Kitsuki, Michiko; Tatsumi, Kana; Okuda, Mamiko; Tatsumi, Kouko; Wanaka, Akio; Hirai, Hirokazu; Stern, Peter L; Tsuboi, Akio

2016-08-03

Neural circuits that undergo reorganization by newborn interneurons in the olfactory bulb (OB) are necessary for odor detection and discrimination, olfactory memory, and innate olfactory responses, including predator avoidance and sexual behaviors. The OB possesses many interneurons, including various types of granule cells (GCs); however, the contribution that each type of interneuron makes to olfactory behavioral control remains unknown. Here, we investigated the in vivo functional role of oncofetal trophoblast glycoprotein 5T4, a regulator for dendritic arborization of 5T4-expressing GCs (5T4 GCs), the level of which is reduced in the OB of 5T4 knock-out (KO) mice. Electrophysiological recordings with acute OB slices indicated that external tufted cells (ETCs) can be divided into two types, bursting and nonbursting. Optogenetic stimulation of 5T4 GCs revealed their connection to both bursting and nonbursting ETCs, as well as to mitral cells (MCs). Interestingly, nonbursting ETCs received fewer inhibitory inputs from GCs in 5T4 KO mice than from those in wild-type (WT) mice, whereas bursting ETCs and MCs received similar inputs in both mice. Furthermore, 5T4 GCs received significantly fewer excitatory inputs in 5T4 KO mice. Remarkably, in olfactory behavior tests, 5T4 KO mice had higher odor detection thresholds than the WT, as well as defects in odor discrimination learning. Therefore, the loss of 5T4 attenuates inhibitory inputs from 5T4 GCs to nonbursting ETCs and excitatory inputs to 5T4 GCs, contributing to disturbances in olfactory behavior. Our novel findings suggest that, among the various types of OB interneurons, the 5T4 GC subtype is required for odor detection and discrimination behaviors. Neuronal circuits in the brain include glutamatergic principal neurons and GABAergic interneurons. Although the latter is a minority cell type, they are vital for normal brain function because they regulate the activity of principal neurons. If interneuron function is impaired, brain function may be damaged, leading to behavior disorder. The olfactory bulb (OB) possesses various types of interneurons, including granule cells (GCs); however, the contribution that each type of interneuron makes to the control of olfactory behavior remains unknown. Here, we analyzed electrophysiologically and behaviorally the function of oncofetal trophoblast glycoprotein 5T4, a regulator for dendritic branching in OB GCs. We found that, among the various types of OB interneuron, the 5T4 GC subtype is required for odor detection and odor discrimination behaviors. Copyright © 2016 the authors 0270-6474/16/368211-18$15.00/0.

Effects of Lepidium meyenii Walp and Jatropha macrantha on blood levels of estradiol-17 beta, progesterone, testosterone and the rate of embryo implantation in mice.

PubMed

Oshima, Masami; Gu, Yeunhwa; Tsukada, Sekihito

2003-10-01

The effects of two Peruvian folk medicines, Lepidium meyenii Walp and Jatropha macrantha, on mouse sex steroid hormones and embryo implantation were investigated. Progesterone levels increased significantly in mice that received L. meyenii Walp, while testosterone levels increased significantly in mice that received L. meyenii Walp as well as in those that received both L. meyenii Walp and J. macrantha. However, there were no marked changes in blood levels of estradiol-17beta or the rate of embryo implantation.

A cytokine-delivering polymer is effective in reducing tumor burden in a head and neck squamous cell carcinoma murine model.

PubMed

Lin, Yuan; Luo, Jie; Zhu, Weichao Eric; Srivastava, Minu; Schaue, Dorthe; Elashoff, David A; Dubinett, Steven M; Sharma, Sherven; Wu, Benjamin; St John, Maie A

2014-09-01

This study aimed to evaluate the therapeutic efficacy of a novel polymer platform delivering cisplatin and cytokines in the treatment of head and neck squamous cell carcinoma (HNSCC). In vivo study. Academic research laboratory. Mice were randomized to receive implantation of (1) no polymer, (2) plain polymer, (3) plain polymer with local cisplatin injection, or (4) cisplatin polymer. The 2 groups of mice implanted with cisplatin polymer or no polymer were further randomized to receive (1) 4 Grays external beam radiation for 4 days or (2) no radiation. For cytokine studies, mice were grouped into (1) no polymer, (2) plain polymer, (3) plain polymer with intratumoral injection of recombinant CCL21 twice a week, (4) polymer containing parental dendritic cells, or (5) polymer containing dendritic cells secreting CCL21 (DC-CCL21). The cisplatin-secreting polymer effectively reduced tumors in the mice by more than 16-fold (P < .01). We also observed a statistically significant lower tumor weight among mice treated with cisplatin polymer and concomitant radiation compared to control groups. The DC-CCL21 polymer reduced SCCVII/SF tumors in the C3H/HeJ mice by more than 41% (P < .01). Herein, we demonstrate the efficacy of a novel polymer platform in delivering cisplatin and cytokines. We also demonstrate that we can effectively grow dendritic cells in the polymer that can actively secrete CCL21 for a minimum of 5 days. This polymer may represent a new therapeutic modality for patients with HNSCC. Once this polymer platform is optimized, we will plan to pursue prospective trials in patients with HNSCC. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2014.

Differential Sensitivity to Ethanol-Induced Circadian Rhythm Disruption in Adolescent and Adult Mice

PubMed Central

Ruby, Christina L.; Palmer, Kaitlyn N.; Zhang, Jiawen; Risinger, Megan O.; Butkowski, Melissa A.; Swartzwelder, H. Scott

2016-01-01

Background Growing evidence supports a central role for the circadian system in alcohol use disorders, but few studies have examined this relationship during adolescence. In mammals, circadian rhythms are regulated by the suprachiasmatic nucleus (SCN), a biological clock whose timing is synchronized (reset) to the environment primarily by light (photic) input. Alcohol (ethanol) disrupts circadian timing in part by attenuating photic phase-resetting responses in adult rodents. However, circadian rhythms change throughout life and it is not yet known whether ethanol has similar effects on circadian regulation during adolescence. Methods General circadian locomotor activity was monitored in male C57BL6/J mice beginning in adolescence (P27) or adulthood (P61) in a 12 h light, 12 h dark photocycle for ~2 weeks to establish baseline circadian activity measures. On the day of the experiment, mice received an acute injection of ethanol (1.5 g/kg, i.p.) or equal volume saline 15 min prior to a 30-min light pulse at Zeitgeber Time 14 (2 h into the dark phase), then were released into constant darkness (DD) for ~2 weeks to assess phase-resetting responses. Control mice of each age group received injections but no light pulse prior to DD. Results While adults showed the expected decrease in photic phase-delays induced by acute ethanol, this effect was absent in adolescent mice. Adolescents also showed baseline differences in circadian rhythmicity compared to adults, including advanced photocycle entrainment, larger photic phase-delays, a shorter free-running (endogenous) circadian period, and greater circadian rhythm amplitude. Conclusions Collectively, our results indicate that adolescent mice are less sensitive to the effect of ethanol on circadian photic phase-resetting and that their daily activity rhythms are markedly different than those of adults. PMID:27997028

Rosemary tea consumption results to anxiolytic- and anti-depressant-like behavior of adult male mice and inhibits all cerebral area and liver cholinesterase activity; phytochemical investigation and in silico studies.

PubMed

Ferlemi, Anastasia-Varvara; Katsikoudi, Antigoni; Kontogianni, Vassiliki G; Kellici, Tahsin F; Iatrou, Grigoris; Lamari, Fotini N; Tzakos, Andreas G; Margarity, Marigoula

2015-07-25

Our aim was to investigate the possible effects of regular drinking of Rosmarinus officinalis L. leaf infusion on behavior and on AChE activity of mice. Rosemary tea (2% w/w) phytochemical profile was investigated through LC/DAD/ESI-MS(n). Adult male mice were randomly divided into two groups: "Rosemary-treated" that received orally the rosemary tea for 4weeks and "control" that received drinking water. The effects of regular drinking of rosemary tea on behavioral parameters were assessed by passive avoidance, elevated plus maze and forced swimming tests. Moreover, its effects on cerebral and liver cholinesterase (ChE) isoforms activity were examined colorimetricaly. Phytochemical analysis revealed the presence of diterpenes, flavonoids and hydroxycinnamic derivatives in rosemary tea; the major compounds were quantitatively determined. Its consumption rigorously affected anxiety/fear and depression-like behavior of mice, though memory/learning was unaffected. ChE isoforms activity was significantly decreased in brain and liver of "rosemary treated" mice. In order to explain the tissue ChE inhibition, principal component analysis, pharmacophore alignment and molecular docking were used to explore a possible relationship between main identified compounds of rosemary tea, i.e. rosmarinic acid, luteolin-7-O-glucuronide, caffeic acid and known AChE inhibitors. Results revealed potential common pharmacophores of the phenolic components with the inhibitors. Our findings suggest that rosemary tea administration exerts anxiolytic and antidepressant effects on mice and inhibits ChE activity; its main phytochemicals may function in a similar way as inhibitors. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Dietary Supplementation with Fresh Pineapple Juice Decreases Inflammation and Colonic Neoplasia in IL-10-deficient Mice with Colitis

PubMed Central

Hale, Laura P.; Chichlowski, Maciej; Trinh, Chau T.; Greer, Paula K.

2010-01-01

Background Bromelain, a mixture of proteolytic enzymes typically derived from pineapple stem, decreases production of pro-inflammatory cytokines and leukocyte homing to sites of inflammation. We previously showed that short-term oral treatment with bromelain purified from pineapple stem decreased the severity of colonic inflammation in C57BL/6 Il10−/− mice with chronic colitis. Since fresh pineapple fruit contains similar bromelain enzymes but at different proportions, this study aimed to determine whether long-term dietary supplementation with pineapple (supplied as juice) could decrease colon inflammation and neoplasia in Il10−/− mice with chronic colitis as compared with bromelain derived from stem. Results Experimental mice readily consumed fresh pineapple juice at a level that generated mean stool proteolytic activities equivalent to 16 mg bromelain purified from stem, while control mice received boiled juice with inactive enzymes. Survival was increased in the group supplemented with fresh rather than boiled juice (p = 0.01). Mice that received fresh juice also had decreased histologic colon inflammation scores and a lower incidence of inflammation-associated colonic neoplasia (35% vs. 66%; p< 0.02), with fewer neoplastic lesions/colon (p = 0.05). Flow cytometric analysis of murine splenocytes exposed to fresh pineapple juice in vitro demonstrated proteolytic removal of cell surface molecules that can affect leukocyte trafficking and activation. Conclusions These results demonstrate that long-term dietary supplementation with fresh or unpasteurized frozen pineapple juice with proteolytically active bromelain enzymes is safe and decreases inflammation severity and the incidence and multiplicity of inflammation-associated colonic neoplasia in this commonly used murine model of inflammatory bowel disease. PMID:20848493

Effects of Berberine Against Radiation-Induced Intestinal Injury in Mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li Guanghui; Zhang Yaping; Tang Jinliang

2010-08-01

Purpose: Radiation-induced intestinal injury is a significant clinical problem in patients undergoing abdominal radiotherapy (RT). Berberine has been used as an antimicrobial, anti-inflammatory, and antimotility agent. The present study investigated the protective effect of berberine against radiation-induced intestinal injury. Methods and Materials: The mice were administrated berberine or distilled water. A total of 144 mice underwent 0, 3, 6, 12, or 16 Gy single session whole-abdominal RT and 16 mice underwent 3 Gy/fraction/d for four fractions of fractionated abdominal RT. Tumor necrosis factor-{alpha}, interleukin-10, diamine oxidase, intestinal fatty acid-binding protein, malonaldehyde, and apoptosis were assayed in the mice after RT.more » The body weight and food intake of the mice receiving fractionated RT were recorded. Another 72 mice who had undergone 12, 16, or 20 Gy abdominal RT were monitored for mortality every 12 h. Results: The body weight and food intake of the mice administered with distilled water decreased significantly compared with before RT. After the same dose of abdominal RT, tumor necrosis factor-{alpha}, diamine oxidase, intestinal fatty acid-binding protein in plasma and malonalhehyde and apoptosis of the intestine were significantly greater in the control group than in the mice administered berberine (p < .05-.01). In contrast, interleukin-10 in the mice with berberine treatment was significantly greater than in the control group (p < .01). A similar result was found in the fractionated RT experiment and at different points after 16 Gy abdominal RT (p < .05-.01). Berberine treatment significantly delayed the point of death after 20 Gy, but not 16 Gy, abdominal RT (p < .01). Conclusion: Treatment with berberine can delay mortality and attenuated intestinal injury in mice undergoing whole abdominal RT. These findings could provide a useful therapeutic strategy for radiation-induced intestinal injury.« less

Naringenin attenuates behavioral derangements induced by social defeat stress in mice via inhibition of acetylcholinesterase activity, oxidative stress and release of pro-inflammatory cytokines.

PubMed

Umukoro, Solomon; Kalejaye, Hassanat Adeola; Ben-Azu, Benneth; Ajayi, Abayomi M

2018-06-12

The effects of naringenin; a dietary flavonoid, with potent anti-oxidant and anti-inflammatory activities on social defeat stress (SDS)-induced neurobehavioral and biochemical changes were evaluated in mice using resident-intruder paradigm. The intruder male mice were distributed into 6 groups (n = 6). Mice in group 1 (control) received vehicle (3% DMSO, i.p), group 2 (SDS-control) were also given vehicle, groups 3-5 received naringenin (10, 25 and 50 mg/kg, i.p.) while group 6 had ginseng (50 mg/kg, i.p) daily for 14 days. However, 30 min after treatment on day 7, mice in groups 2-6 were exposed to SDS for a period of 10 min confrontation with aggressive counterparts for 7 consecutive days. Neurobehavioral phenotypes: spontaneous motor activity (SMA), memory, anxiety and depression were then evaluated on day 14. Malondialdehyde (MDA), glutathione (GSH), catalase and superoxide dismutase (SOD) were then estimated in the brain tissues. Acetylcholinesterase (AChE) activity and the concentrations of tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) were also determined. SDS-induced neurobehavioral deficits were significantly (p < 0.05) attenuated by naringenin. The increased brain level of MDA (13.00 ± 0.63 μmol/g tissue) relative to vehicle-control (6.50 ± 0.43 μmol/g tissue) was significantly (p < 0.05) reduced to 5.50 ± 0.22 μmol/g tissue by naringenin (50 mg/kg). Mice exposed to SDS had decreased brain GSH level (5.17 ± 0.40 μmol/g tissue) relative to control (11.67 ± 0.84 μmol/g tissue). However, naringenin (50 mg/kg) significantly (p < 0.05) elevated GSH content (13.33 ± 0.88 μmol/g tissue) in the brains of SDS-mice. Moreover, 50 mg/Kg of naringenin (38.13 ± 2.38 ρg/mL) attenuated (p < 0.05) increased TNF-α level when compared with SDS (49.69 ± 2.81 ρg/mL). SDS-induced increase in brain level of IL-1β (236.5 ± 6.92 ρg/mL) was significantly (p < 0.05) reduced by naringenin (219.90 ± 15.25 ρg/mL). Naringenin also elevated antioxidant enzymes and decreased AChE activity in the brains of mice exposed to SDS (p < 0.05). These findings suggest that naringenin attenuates SDS-induced neurobehavioral deficits through inhibition of acetylcholinesterase activity, oxidative stress and release of pro-inflammatory cytokines. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Modulating Effects of Spirulina platensis against Tilmicosin-Induced Cardiotoxicity in Mice.

PubMed

Ibrahim, Abdelaziz E; Abdel-Daim, Mohamed Mohamed

2015-01-01

Tilmicosin (TIL) is a long-acting macrolide antibiotic used to treat cattle for pathogens that cause bovine respiratory disease. However, overdoses of this medication have been reported to induce cardiac damage. Our experimental objective was to evaluate the protective effects of Spirulina platensis (SP) administration against TIL-induced cardiotoxicity in mice. Our experimental in vivo animal study used 40 male albino mice that were divided into five groups of eight mice per group. The first group served as a control group and was injected with saline. The second group received SP at dose of 1000 mg/kg body weight for five days. The third group received a single dose of TIL (75 mg/kg, subcutaneously). Groups 4 and 5 were given SP at doses of 500 and 1000 mg/kg body weight for five consecutive days just before administration of TIL at the same dose and regimen used for group 3. TIL treated animals showed a significant increase in serum cardiac injury biomarkers as well as cardiac lipid peroxidation, however they had evidence of an inhibition in antioxidant biomarkers. SP normalized elevated serum levels of lactate dehydrogenase (LDH), creatine kinase (CK), and CK-MB. Furthermore, SP reduced TIL-induced lipid peroxidation and oxidative stress in a dose-dependent manner. Administration of SP minimized the toxic effects of TIL by its free radicalscavenging and potent antioxidant activity.

Modulating Effects of Spirulina platensis against Tilmicosin-Induced Cardiotoxicity in Mice

PubMed Central

Ibrahim, Abdelaziz E.; Abdel-Daim, Mohamed Mohamed

2015-01-01

Objective Tilmicosin (TIL) is a long-acting macrolide antibiotic used to treat cattle for pathogens that cause bovine respiratory disease. However, overdoses of this medication have been reported to induce cardiac damage. Our experimental objective was to evaluate the protective effects of Spirulina platensis (SP) administration against TIL-induced cardiotoxicity in mice. Materials and Methods Our experimental in vivo animal study used 40 male albino mice that were divided into five groups of eight mice per group. The first group served as a control group and was injected with saline. The second group received SP at dose of 1000 mg/kg body weight for five days. The third group received a single dose of TIL (75 mg/kg, subcutaneously). Groups 4 and 5 were given SP at doses of 500 and 1000 mg/kg body weight for five consecutive days just before administration of TIL at the same dose and regimen used for group 3. Results TIL treated animals showed a significant increase in serum cardiac injury biomarkers as well as cardiac lipid peroxidation, however they had evidence of an inhibition in antioxidant biomarkers. SP normalized elevated serum levels of lactate dehydrogenase (LDH), creatine kinase (CK), and CK-MB. Furthermore, SP reduced TIL-induced lipid peroxidation and oxidative stress in a dose-dependent manner. Conclusion Administration of SP minimized the toxic effects of TIL by its free radicalscavenging and potent antioxidant activity. PMID:25870843

Effects of dietary fat profile on gut permeability and microbiota and their relationships with metabolic changes in mice.

PubMed

Lam, Yan Y; Ha, Connie W Y; Hoffmann, Jenny M A; Oscarsson, Jan; Dinudom, Anuwat; Mather, Thomas J; Cook, David I; Hunt, Nicholas H; Caterson, Ian D; Holmes, Andrew J; Storlien, Len H

2015-07-01

To distinguish the effects of dietary fat profile on gut parameters and their relationships with metabolic changes and to determine the capacity of n-3 fatty acids to modify gut variables in the context of diet-induced metabolic dysfunctions. Mice received control or high-fat diets emphasizing saturated (HFD-sat), n-6 (HFD-n6), or n-3 (HFD-n3) fatty acids for 8 weeks. In another cohort, mice that were maintained on HFD-sat received n-3-rich fish oil or resolvin D1 supplementation. HFD-sat and HFD-n6 induced similar weight gain, but only HFD-sat increased index of insulin resistance (HOMA-IR), colonic permeability, and mesenteric fat inflammation. Hydrogen sulfide-producing bacteria were one of the major groups driving the diet-specific changes in gut microbiome, with the overall microbial profile being associated with changes in body weight, HOMA-IR, and gut permeability. In mice maintained on HFD-sat, fish oil and resolvin D1 restored barrier function and reduced inflammation in the colon but were unable to normalize HOMA-IR. Different dietary fat profiles led to distinct intestinal and metabolic outcomes that are independent of obesity. Interventions targeting inflammation successfully restored gut health but did not reverse systemic aspects of diet-induced metabolic dysfunction, implicating separation between gut dysfunctions and disease-initiating and/or -maintaining processes. © 2015 The Obesity Society.

Dietary Broccoli Lessens Development of Fatty Liver and Liver Cancer in Mice Given Diethylnitrosamine and Fed a Western or Control Diet123

PubMed Central

Chen, Yung-Ju; Wallig, Matthew A; Jeffery, Elizabeth H

2016-01-01

Background: The high-fat and high-sugar Westernized diet that is popular worldwide is associated with increased body fat accumulation, which has been related to the development of nonalcoholic fatty liver disease (NAFLD). Without treatment, NAFLD may progress to hepatocellular carcinoma (HCC), a cancer with a high mortality rate. The consumption of broccoli in the United States has greatly increased in the last 2 decades. Epidemiologic studies show that incorporating brassica vegetables into the daily diet lowers the risk of several cancers, although, to our knowledge, this is the first study to evaluate HCC prevention through dietary broccoli. Objective: We aimed to determine the impact of dietary broccoli on hepatic lipid metabolism and the progression of NAFLD to HCC. Our hypothesis was that broccoli decreases both hepatic lipidosis and the development of HCC in a mouse model of Western diet–enhanced liver cancer. Methods: Adult 5-wk-old male B6C3F1 mice received a control diet (AIN-93M) or a Western diet (high in lard and sucrose, 19% and 31%, wt:wt, respectively), with or without freeze-dried broccoli (10%, wt:wt). Starting the following week, mice were treated once per week with diethylnitrosamine (DEN; 45 mg/kg body weight intraperitoneally at ages 6, 7, 8, 10, 11, and 12 wk). Hepatic gene expression, lipidosis, and tumor outcomes were analyzed 6 mo later, when mice were 9 mo old. Results: Mice receiving broccoli exhibited lower hepatic triglycerides (P < 0.001) and NAFLD scores (P < 0.0001), decreased plasma alanine aminotransferase (P < 0.0001), suppressed activation of hepatic CD68+ macrophages (P < 0.0001), and slowed initiation and progression of hepatic neoplasm. Hepatic Cd36 was downregulated by broccoli feeding (P = 0.006), whereas microsomal triglyceride transfer protein was upregulated (P = 0.045), supporting the finding that dietary broccoli decreased hepatic triglycerides. Conclusion: Long-term consumption of whole broccoli countered both NAFLD development enhanced by a Western diet and hepatic tumorigenesis induced by DEN in male B6C3F1 mice. PMID:26865652

Dietary Broccoli Lessens Development of Fatty Liver and Liver Cancer in Mice Given Diethylnitrosamine and Fed a Western or Control Diet.

PubMed

Chen, Yung-Ju; Wallig, Matthew A; Jeffery, Elizabeth H

2016-03-01

The high-fat and high-sugar Westernized diet that is popular worldwide is associated with increased body fat accumulation, which has been related to the development of nonalcoholic fatty liver disease (NAFLD). Without treatment, NAFLD may progress to hepatocellular carcinoma (HCC), a cancer with a high mortality rate. The consumption of broccoli in the United States has greatly increased in the last 2 decades. Epidemiologic studies show that incorporating brassica vegetables into the daily diet lowers the risk of several cancers, although, to our knowledge, this is the first study to evaluate HCC prevention through dietary broccoli. We aimed to determine the impact of dietary broccoli on hepatic lipid metabolism and the progression of NAFLD to HCC. Our hypothesis was that broccoli decreases both hepatic lipidosis and the development of HCC in a mouse model of Western diet-enhanced liver cancer. Adult 5-wk-old male B6C3F1 mice received a control diet (AIN-93M) or a Western diet (high in lard and sucrose, 19% and 31%, wt:wt, respectively), with or without freeze-dried broccoli (10%, wt:wt). Starting the following week, mice were treated once per week with diethylnitrosamine (DEN; 45 mg/kg body weight intraperitoneally at ages 6, 7, 8, 10, 11, and 12 wk). Hepatic gene expression, lipidosis, and tumor outcomes were analyzed 6 mo later, when mice were 9 mo old. Mice receiving broccoli exhibited lower hepatic triglycerides (P < 0.001) and NAFLD scores (P < 0.0001), decreased plasma alanine aminotransferase (P < 0.0001), suppressed activation of hepatic CD68(+) macrophages (P < 0.0001), and slowed initiation and progression of hepatic neoplasm. Hepatic Cd36 was downregulated by broccoli feeding (P = 0.006), whereas microsomal triglyceride transfer protein was upregulated (P = 0.045), supporting the finding that dietary broccoli decreased hepatic triglycerides. Long-term consumption of whole broccoli countered both NAFLD development enhanced by a Western diet and hepatic tumorigenesis induced by DEN in male B6C3F1 mice. © 2016 American Society for Nutrition.

Curcumin protects against acetaminophen-induced apoptosis in hepatic injury

PubMed Central

Li, Gang; Chen, Jun-Bao; Wang, Chao; Xu, Zhi; Nie, Hao; Qin, Xiao-Yan; Chen, Xiao-Mei; Gong, Quan

2013-01-01

AIM: To explore the effects of curcumin (CMN) on hepatic injury induced by acetaminophen (APAP) in vivo. METHODS: Male mice were randomly divided into three groups: group I (control) mice received the equivalent volumes of phosphate-buffered saline (PBS) intraperitoneally (ip); Group II [APAP + carboxymethylcellulose (CMC)] mice received 1% CMC (vehicle) 2 h before APAP injection; Group III (APAP + CMN) mice received curcumin (10 or 20 mg/kg, ip) 2 h before before or after APAP challenge. In Groups II and III, APAP was dissolved in pyrogen-free PBS and injected at a single dose of 300 mg/kg. CMN was dissolved in 1% CMC. Mice were sacrificed 16 h after the APAP injection to determine alanine aminotransferase (ALT) levels in serum and malondialdehyde (MDA) accumulation, superoxide dismutase (SOD) activity and hepatocyte apoptosis in liver tissues. RESULTS: Both pre- and post-treatment with curcumin resulted in a significant decrease in serum ALT compared with APAP treatment group (10 mg/kg: 801.46 ± 661.34 U/L; 20 mg/kg: 99.68 ± 86.48 U/L vs 5406.80 ± 1785.75 U/L, P < 0.001, respectively). The incidence of liver necrosis was significantly lowered in CMN treated animals. MDA contents were significantly reduced in 20 mg/kg CMN pretreatment group, but increased in APAP treated group (10.96 ± 0.87 nmol/mg protein vs 16.03 ± 2.58 nmol/mg protein, P < 0.05). The decrease of SOD activity in APAP treatment group and the increase of SOD in 20 mg/kg CMN pretreatment group were also detected (24.54 ± 4.95 U/mg protein vs 50.21 ± 1.93 U/mg protein, P < 0.05). Furthermore, CMN treatment efficiently protected against APAP-induced apoptosis via increasing Bcl-2/Bax ratio. CONCLUSION: CMN has significant therapeutic potential in both APAP-induced hepatotoxicity and other types of liver diseases. PMID:24259976

Iron-deficient erythropoiesis in blood donors and red blood cell recovery after transfusion: initial studies with a mouse model

PubMed Central

Bandyopadhyay, Sheila; Brittenham, Gary M.; Francis, Richard O.; Zimring, James C.; Hod, Eldad A.; Spitalnik, Steven L.

2017-01-01

Background Most frequent red cell (RBC) donors and many first-time donors are iron deficient, but meet haemoglobin standards. However, the effects of donation-induced iron deficiency on RBC storage quality are unknown. Thus, we used a mouse model to determine if donor iron deficiency reduced post-transfusion RBC recovery. Methods Weanling mice received a control diet or an iron-deficient diet. A third group receiving the iron-deficient diet was also phlebotomised weekly. This provided 3 groups of mice with different iron status: (1) iron replete, (2) mild iron deficiency with iron-deficient erythropoiesis, and (3) iron-deficiency anaemia. At ten weeks of age, blood was collected, leucoreduced, and stored at 4 ºC. After 12 days of storage, 24-hour (h) post-transfusion RBC recovery was quantified in recipients by flow cytometry. Results Before blood collection, mean haemoglobin concentrations in the iron-replete, iron-deficient, and iron-deficiency anaemia donor mice were 16.5±0.4, 11.5±0.4, and 7.0±1.4 [g/dL± 1 standard deviation (SD)], respectively (p<0.01 for all comparisons between groups). The 24-h post-transfusion RBC recoveries in recipients receiving transfusions from these three cohorts were 77.1±13.2, 66.5±10.9, and 46.7±15.9 (% ±1 SD), respectively (p<0.05 for all comparisons between groups). Discussion In summary, donor iron deficiency significantly reduced 24-h post-transfusion RBC recovery in recipient mice. RBCs from mice with mild iron deficiency and iron-deficient erythropoiesis, with haemoglobin levels similar to those used for human autologous blood donation, had intermediate post-transfusion RBC recovery, as compared to iron-replete donors and those with iron-deficiency anaemia. This suggests that, in addition to the effects of iron deficiency on donor health, frequent blood donation, leading to iron-deficient erythropoiesis, may also have adverse effects for transfusion recipients. PMID:28263174

[Effects of intrasplenic transplantation of IL-18 gene-modified fetal hepatocytes on mouse immune function

PubMed

Yao, Hang-Ping; Zhang, Li-Huang; Sun, Wen-Ji; Leng, Jian-Hang

2002-04-01

OBJECTIVE: To investigate the effects of IL-18 gene-modified fetal hepatocytes (AdmIL-18/MNL.CL2) intrasplenic transplantation on mouse immune function. METHODS: Forty mice were evenly divided into 4 groups of 10. Each group received an intrasplenic transplantation one of the following: AdmIL-18/BNL.CL2, Ad-LacZ/BNL.CL2 (virus control), BNL.CL2 (cell control) and PBS (blank control). After two weeks, the mice were sacrificed. Serum cytokine levels, Mpsi and splenic cell culture supernatant and liver tissue extracts supernatants were measured using ELISA. Hepatic cytokines mRNA expression were determined by RT-PCR. THe cytotoxicity of peritoneal Mpsi and NK activity of spienocytes were detected by LDH release assay. The proliferation of splenic lymphocytes was determined by MTT assay. RESULTS: The IL-18, IL-2,IFN-gamma, TNF-alpha levels of serum, Mpsi and splenocyte culture supernatant, liver tissue extracts supernatants in mice transplanted with AdmIL-18/BNL.CL2 were higher and the IL-4, IL-10 levels were lower compared to their levels in other 3 groups. The highest IL-18, IL-2, IFN-gamma, TNF-alpha and the lowest IL-4, IL-10 mRNA expressions in the liver were observed in mice transplanted with AdmIL-18/BNL.CL2. The mice transplanted with AdmIL-18/BNL.Cl2 showed significantly increases cytotoxicity of Mpsi, NK activity and splenic cell proliferation compared with the other 3 groups. CONCLUSION: AdmIL-18 can be effectively transfected into mice fetal heptocytes which subsequently IL-18. Intransplenic transplantation of IL-18 gene-modified fetal hepatocytes may augment mouse immune function and provide an useful basis for targeted gene therapy of liver disease.

Low-dose recombinant properdin provides substantial protection against Streptococcus pneumoniae and Neisseria meningitidis infection.

PubMed

Ali, Youssif Mohammed; Hayat, Azam; Saeed, Bayad Mawlood; Haleem, Kashif S; Alshamrani, Saleh; Kenawy, Hany I; Ferreira, Viviana P; Saggu, Gurpanna; Buchberger, Anna; Lachmann, Peter J; Sim, Robert B; Goundis, Dimitrios; Andrew, Peter W; Lynch, Nicholas J; Schwaeble, Wilhelm J

2014-04-08

Modern medicine has established three central antimicrobial therapeutic concepts: vaccination, antibiotics, and, recently, the use of active immunotherapy to enhance the immune response toward specific pathogens. The efficacy of vaccination and antibiotics is limited by the emergence of new pathogen strains and the increased incidence of antibiotic resistance. To date, immunotherapy development has focused mainly on cytokines. Here we report the successful therapeutic application of a complement component, a recombinant form of properdin (Pn), with significantly higher activity than native properdin, which promotes complement activation via the alternative pathway, affording protection against N. menigitidis and S. pneumoniae. In a mouse model of infection, we challenged C57BL/6 WT mice with N. menigitidis B-MC58 6 h after i.p. administration of Pn (100 µg/mouse) or buffer alone. Twelve hours later, all control mice showed clear symptoms of infectious disease while the Pn treated group looked healthy. After 16 hours, all control mice developed sepsis and had to be culled, while only 10% of Pn treated mice presented with sepsis and recoverable levels of live Meningococci. In a parallel experiment, mice were challenged intranasally with a lethal dose of S. pneumoniae D39. Mice that received a single i.p. dose of Pn at the time of infection showed no signs of bacteremia at 12 h postinfection and had prolonged survival times compared with the saline-treated control group (P < 0.0001). Our findings show a significant therapeutic benefit of Pn administration and suggest that its antimicrobial activity could open new avenues for fighting infections caused by multidrug-resistant neisserial or streptococcal strains.

Low-dose recombinant properdin provides substantial protection against Streptococcus pneumoniae and Neisseria meningitidis infection

PubMed Central

Ali, Youssif Mohammed; Hayat, Azam; Saeed, Bayad Mawlood; Haleem, Kashif S.; Alshamrani, Saleh; Kenawy, Hany I.; Ferreira, Viviana P.; Saggu, Gurpanna; Buchberger, Anna; Lachmann, Peter J.; Sim, Robert B.; Goundis, Dimitrios; Andrew, Peter W.; Lynch, Nicholas J.; Schwaeble, Wilhelm J.

2014-01-01

Modern medicine has established three central antimicrobial therapeutic concepts: vaccination, antibiotics, and, recently, the use of active immunotherapy to enhance the immune response toward specific pathogens. The efficacy of vaccination and antibiotics is limited by the emergence of new pathogen strains and the increased incidence of antibiotic resistance. To date, immunotherapy development has focused mainly on cytokines. Here we report the successful therapeutic application of a complement component, a recombinant form of properdin (Pn), with significantly higher activity than native properdin, which promotes complement activation via the alternative pathway, affording protection against N. menigitidis and S. pneumoniae. In a mouse model of infection, we challenged C57BL/6 WT mice with N. menigitidis B-MC58 6 h after i.p. administration of Pn (100 µg/mouse) or buffer alone. Twelve hours later, all control mice showed clear symptoms of infectious disease while the Pn treated group looked healthy. After 16 hours, all control mice developed sepsis and had to be culled, while only 10% of Pn treated mice presented with sepsis and recoverable levels of live Meningococci. In a parallel experiment, mice were challenged intranasally with a lethal dose of S. pneumoniae D39. Mice that received a single i.p. dose of Pn at the time of infection showed no signs of bacteremia at 12 h postinfection and had prolonged survival times compared with the saline-treated control group (P < 0.0001). Our findings show a significant therapeutic benefit of Pn administration and suggest that its antimicrobial activity could open new avenues for fighting infections caused by multidrug-resistant neisserial or streptococcal strains. PMID:24706855

The Dietary Supplement Protandim Decreases Plasma Osteopontin and Improves Markers of Oxidative Stress in Muscular Dystrophy Mdx Mice.

PubMed

Qureshi, Muhammad Muddasir; McClure, Warren C; Arevalo, Nicole L; Rabon, Rick E; Mohr, Benjamin; Bose, Swapan K; McCord, Joe M; Tseng, Brian S

2010-06-01

Therapeutic options for Duchenne muscular dystrophy (DMD), the most common and lethal neuromuscular disorder in children, remain elusive. Oxidative damage is implicated as a pertinent factor involved in its pathogenesis. Protandim((R)) is an over-the-counter supplement with the ability to induce antioxidant enzymes. In this study we investigated whether Protandim((R)) provided benefit using surrogate markers and functional measures in the dystrophin-deficient (mdx)mouse model of DMD. Male 3-week-old mdx mice were randomized into two treatment groups: control (receiving standard rodent chow) and Protandim((R))-supplemented standard rodent chow. The diets were continued for 6-week and 6-month studies. The endpoints included the oxidative stress marker thiobarbituric acid-reactive substances (TBARS), plasma osteopontin (OPN), plasma paraoxonase (PON1) activity, H&E histology, gadolinium-enhanced magnetic resonance imaging (MRI) of leg muscle and motor functional measurements. The Protandim((R)) chow diet in mdx mice for 6 months was safe and well tolerated. After 6 months of Protandim((R)), a 48% average decrease in plasma TBARS was seen; 0.92 nmol/mg protein in controls versus 0.48 nmol/mg protein in the Protandim((R)) group (p = .006). At 6 months, plasma OPN was decreased by 57% (p = .001) in the Protandim((R))-treated mice. Protandim((R)) increased the plasma antioxidant enzyme PON1 activity by 35% (p = .018). After 6 months, the mdx mice with Protandim((R)) showed 38% less MRI signal abnormality (p = .07) than mice on control diet. In this 6-month mdx mouse study, Protandim((R)) did not significantly alter motor function nor histological criteria.

Beneficial Effect of Brewers' Yeast Extract on Daily Activity in a Murine Model of Chronic Fatigue Syndrome

PubMed Central

Takahashi, Takashi; Yu, Fei; Zhu, Shi-jie; Moriya, Junji; Sumino, Hiroyuki; Morimoto, Shigeto; Yamaguchi, Nobuo; Kanda, Tsugiyasu

2006-01-01

The aim of this study was to assess the effect of Brewers' yeast extract (BYE) on daily activity in a mouse model of chronic fatigue syndrome (CFS). CFS was induced by repeated injection of Brucella abortus (BA) antigen every 2 weeks. BYE was orally administered to mice in a dose of 2 g per kg per day for 2 weeks before injecting BA and for 4 weeks thereafter. We evaluated daily running activity in mice receiving BYE as compared with that in untreated mice. Weekly variation of body weight (BW) and survival in both groups was monitored during the observation period. Spleen weight (SW), SW/BW ratio, percent splenic follicular area and expression levels of interferon-γ (IFN-γ) and interleukin-10 (IL-10) mRNA in spleen were determined in both groups at the time of sacrifice. The daily activity during 2 weeks after the second BA injection was significantly higher in the treated group than in the control. There was no difference in BW between both groups through the experimental course. Two mice in the control died 2 and 7 days after the second injection, whereas no mice in the treated group died. Significantly decreased SW and SW/BW ratio were observed in the treated mice together with elevation of splenic follicular area. There were suppressed IFN-γ and IL-10 mRNA levels in spleens from the treated mice. Our results suggest that BYE might have a protective effect on the marked reduction in activity following repeated BA injection via normalization of host immune responses. PMID:16550231

Effects of female steroid hormones on A-type K+ currents in murine colon.

PubMed

Beckett, Elizabeth A H; McCloskey, Conor; O'Kane, Neil; Sanders, Kenton M; Koh, Sang Don

2006-06-01

Idiopathic constipation is higher in women of reproductive age than postmenopausal women or men, suggesting that female steroid hormones influence gastrointestinal motility. How female hormones affect motility is unclear. Colonic motility is regulated by ion channels in colonic myocytes. Voltage-dependent K(+) channels serve to set the excitability of colonic muscles. We investigated regulation of Kv 4.3 channel expression in response to acute or chronic changes in female hormones. Patch clamp experiments and quantitative PCR were used to compare outward currents and transcript expression in colonic myocytes from male, non-pregnant, pregnant and ovariectomized mice. Groups of ovariectomized mice received injections of oestrogen or progesterone to investigate the effects of hormone replacement. The capacitance of colonic myocytes from non-pregnant females was larger than in males. Net outward current density in male and ovariectomized mice was higher than in non-pregnant females and oestrogen-treated ovariectomized mice. Current densities in late pregnancy were lower than in female controls. Progesterone had no effect on outward currents. A-type currents were decreased in non-pregnant females compared with ovariectomized mice, and were further decreased by pregnancy or oestrogen replacement. Kv 4.3 transcripts did not differ significantly between groups; however, expression of the potassium channel interacting protein KChIP1 was elevated in ovariectomized mice compared with female controls and oestrogen-treated ovariectomized mice. Delayed rectifier currents were not affected by oestrogen. In the mouse colon, oestrogen suppresses A-type currents, which are important for regulating excitability. These observations suggest a possible link between female hormones and altered colonic motility associated with menses, pregnancy and menopause.

Morin hydrate mitigates rapid eye movement sleep deprivation-induced neurobehavioural impairments and loss of viable neurons in the hippocampus of mice.

PubMed

Olonode, Elizabeth T; Aderibigbe, Adegbuyi O; Adeoluwa, Olusegun A; Eduviere, Anthony T; Ben-Azu, Benneth

2017-12-25

Rapid eye movement sleep deprivation distorts the body's homeostasis and results in oxidative breakdown which may be responsible for a variety of neurological disorders. Some naturally occurring compounds of plant origin with antioxidant and neuroprotective properties are known to attenuate the detrimental effects of REM sleep deprivation. Morin hydrate, a flavonoid from Mulberry has demonstrated antioxidant and neuroprotective activities but its effect in sleep disturbed mice is unknown. The study was designed to explore the neuroprotective effect of Morin hydrate on 48 h. REM sleep deprivation-induced behavioural impairments and neuronal damage in mice. Mice were allotted into six treatment groups (n = 6): groups 1 and 2 received vehicle (10 ml/kg normal saline), groups 3-5 received Morin hydrate (5, 10, 20 mg/kg i.p) while group 6 received ginseng (25 mg/kg) which served as the reference drug. Treatment was performed daily for 5 days and animals were sleep-deprived on the last 48 h. Various behavioural tests (Elevated plus maze, Y-maze, locomotor activity) followed by oxidative parameters (malondialdehyde, nitric oxide, reduced glutathione) and histolopathological changes in the Cornu ammonis 1 (CA1) region of the hippocampus were assessed. Data were analysed using ANOVA at α 0.05 . Morin hydrate (5, 10, 20 mg/kg) significantly enhanced memory performance, improves anxiolytic-like behaviour, reverses hyperlocomotion, restored depleted reduced glutathione, attenuated raised malondialdehyde and nitric oxide levels as compared to control animals and protects against loss of hippocampal neurons. Results of this present study suggest that Morin hydrate possess neuroprotective effects against sleep deprivation-induced behavioural impairments, oxidative stress and neuronal damage. Copyright © 2017 Elsevier B.V. All rights reserved.

Preliminary in vivo evaluation of [131I]-2-iodo-D-phenylalanine as a potential radionuclide therapeutic agent in R1M-fluc rhabdomyosarcoma tumor-bearing NuNu mice using bioluminescent imaging.

PubMed

Bauwens, Matthias; Wimana, Lena; Keyaerts, Marleen; Peleman, Cindy; Lahoutte, Tony; Kersemans, Ken; Snykers, Sarah; Vinken, Mathieu; Mertens, John; Bossuyt, Axel

2010-04-01

Carrier-added [(123)I]-2-iodo-D-phenylalanine (CA [(123)I]-2-I-D-Phe) was previously found to have a preferential retention in tumors with a high tumor background contrast in animal models. A previous human dosimetry study demonstrated a favorable biodistribution and radiation burden in human subjects. The aim of this study was to investigate the potential of CA [(131)I]-2-I-D-Phe as an agent for radionuclide therapy. Sixty (60) nude athymic mice were inoculated subcutaneously with firefly luciferase-transduced R1M rhabdomyosarcoma cells. The mice in the therapy group were injected intravenously (i.v.) with 148 MBq [(131)I]-2-I-D-Phe (432 GBq/mmol) in kit solution. Controls were injected with kit solution without radioactivity, with physiological saline, or with 148 MBq [(131)I](-) in physiological saline. Tumor growth was quantified using bioluminescent imaging and caliper measurements. [(131)I]-2-I-D-Phe clearly reduced tumor growth in the treated mice compared with the control groups. A tumor growth-rate reduction of at least 33% was found for mice receiving a therapeutic dose. There were no serious adverse side-effects of the therapy. In conclusion, i.v. injection of CA 148 MBq [(131)I]-2-I-D-Phe specifically reduces tumor growth in athymic nude mice without relevant side-effects on the animals' health.

Differential effects of human interferon alpha and interferon gamma on xenografted human thyroid tissue in severe combined immunodeficient mice and nude mice.

PubMed

Kawai, K; Enomoto, T; Fornasier, V; Resetkova, E; Volpé, R

1997-03-01

We have studied the in vivo effects of human interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma) administration on human thyroid tissue xenografted into two mouse strains: severe combined immunodeficient (SCID) mice and nude mice. Human lymphocytes survive in SCID mice but are lysed in nude mice. Thyroid tissues from Graves' disease or Hashimoto's thyroiditis, or paranodular [normal, (N)] tissue was xenografted into SCID mice (0.8 g/mouse) pretreated with anti-asialo GM-1 antiserum and radiation and also into nude mice. One week after xenografting, SCID and nude mice were divided into three groups. Group A was treated with IFN-alpha intraperitoneally (2,000 units/mouse) three times weekly; group B was treated with IFN-gamma similarly; group C was treated with phosphate buffered saline (PBS) only (control). Autologous human peripheral blood mononuclear cells (PBMCs) were added to mice receiving N xenografts. Blood was taken every 2 weeks for levels of IgG and thyroid antibodies (TAb). After 6 weeks of treatment, mice were sacrificed, and xenograft thyrocyte histocompatibility leukocyte antigen (HLA-DR) and intercellular adhesion molecule (ICAM-1) expression were measured. In addition, thyrocyte cultures were stimulated in vitro with 200 units/ml of either IFN-alpha or IFN-gamma or PBS (control). SCID mice xenografted with autoimmune thyroid disease (AITD) in group A showed a significantly higher TAb production than group C, whereas in group B, TAb production was not statistically increased compared to control (group C). SCID mice xenografted with N did not produce TAb in any group, nor did nude mice xenografted with AITD. Thyrocyte HLA-DR expression was markedly increased in group A and B in SCID mice xenografted with Graves' disease, Hashimoto's thyroiditis, and N tissue compared to group C. In contrast, only group B (IFN-gamma) showed an increase in thyrocyte HLA-DR in nude mice. In the in vitro studies, only IFN-gamma (not IFN-alpha) stimulated thyrocyte HLA-DR and ICAM-1 expression in Graves' disease, Hashimoto's thyroiditis, and N tissues. We concluded that in SCID mice, IFN-alpha causes TAB production in AITD xenografts but not in N xenografts, while increasing thyrocyte HLA-DR expression in both. Also, IFN-gamma does not cause a statistically increased TAb in AITD xenografts in SCID mice, despite a sharp rise in thyrocyte HLA-DR expression. In addition, because IFN-alpha has no effect in nude mice or in vitro on thyrocyte HLA-DR expression, its effects in SCID mice must be mediated via local infiltrating lymphocytes. Finally, IFN-gamma has a direct effect on thyrocytes to increase HLA-DR expression (and, in vitro, ICAM-1 expression) but may not stimulate TAb production.

Preclinical Colorectal Cancer Chemopreventive Efficacy and p53-Modulating Activity of 3′,4′,5′-Trimethoxyflavonol, a Quercetin Analog

PubMed Central

Howells, Lynne M; Britton, Robert G; Mazzoletti, Marco; Greaves, Peter; Broggini, Massimo; Brown, Karen; Steward, William P; Gescher, Andreas J; Sale, Stewart

2010-01-01

Some naturally occurring flavonols, exemplified by quercetin, appear to possess experimental cancer chemopreventive efficacy. Modulation of p53 is a mechanism thought to contribute to their activity. The hypothesis was tested that a synthetic flavonol, 3′,4′,5′-trimethoxyflavonol (TMFol), can interfere with tumor development and p53 expression in two models of colorectal carcinogenesis, ApcMin mice and human-derived HCT116 adenocarcinoma-bearing nude mice. Mice received TMFol with their diet (0.2%) from weaning to week 16 in the case of ApcMin, or from either day 7 prior to (“TMFol early”) or day 7 after (“TMFol late”) tumor inoculation in HCT116 mice. The ability of TMFol to affect tumor proliferation or apoptosis, as reflected by staining for Ki-67 or cleaved caspase 3, respectively, was studied in HCT116 tumors. TMFol tumor levels were measured by HPLC. Consumption of TMFol reduced small intestinal adenoma burden in ApcMin mice by 47%, compared to control mice (P<0.002). The TMFol early regimen approximately halved HCT116 tumor size (P<0.05), decreased tumor proliferation and increased apoptosis, whilst the TMFol late regimen had no significant effect, when compared to controls. In tumor tissues from mice, in which TMFol reduced tumor development, p53 expression was increased, 3-fold in ApcMin and 1.5-fold in HCT116 tumor-bearing mice (P=0.02). TMFol increased p53 also in cells derived from these tumors. TMFol was detected in HCT116 tumors, but levels did not correlate to tumor burden. TMFol was not mutagenic in the Ames test. The results suggest that chemical modification of the flavonol structure may generate safe and efficacious cancer chemopreventive agents. PMID:20628003

The Ethanolic Extracts The Gorgonian Isis hippuris Inhibited the Induced Mammary Carcinoma Growth In C3H Mice

NASA Astrophysics Data System (ADS)

Trianto, Agus; Andriyas, Yogi; Ridlo, Ali; Sedjati, Sri; Susilaningsih, Neni; Murwani, Retno

2018-02-01

The gorgonian Isis hippuris contains secondary metabolites gorgosterol and hippuristanol which are capable of inhibiting cancer cells. However, in vivo test of the gorgonian Isis hippuris extract as the anticancer drug has not been conducted. The research to study of the effect of ethanolic extract of the gorgonian on the induced tumor growth in C3H mice. The I. hippuris was obtained from Karimunjawa water in Jepara. The extract was prepared by maceration using ethanol. A total 20, 8-10 moths old of C3H mice with an initial weight of 20-25 gram were assigned into control, Ih-1, Ih-2, and Ih-3 groups. Control, Ih-1, Ih-2, and Ih-3 groups each received 0, 0.15, 1.5, and 15 mg extract per mouse per day respectively for two weeks. Cancer cells were introduced to all groups from a donor cancer mouse by injection via left or right axilla and allowed to grow. The cancer mass was removed and processed for histological examination, and cancer growth was determined according to Elston and Ellis criteria. The result showed that histological grade of cancer mass from the control group was in grade 2 or differentiated moderately. The histological grade of cancer mass from Ih-1, Ih-2, and Ih-3 groups were in grade 1 (low grade) or similar to a normal cell. Statistical analysis by Kruskal-Wallis test showed a significant difference (p<0,05) between control and treated mice. Mann-Whitney test found no significant differences among Ih-1, Ih-2, and Ih-3 treated mice. The results indicated the potential of active substances in the ethanol extract of I. hippuris as an anti-cancer drug.

A Small Molecule β2 Integrin Agonist Improves Chronic Kidney Allograft Survival by Reducing Leukocyte Recruitment and Accompanying Vasculopathy

PubMed Central

Khan, Samia Q.; Guo, Lingling; Cimbaluk, David J.; Elshabrawy, Hatem; Faridi, Mohd Hafeez; Jolly, Meenakshi; George, James F.; Agarwal, Anupam; Gupta, Vineet

2014-01-01

Kidney allograft rejection is associated with infiltration of inflammatory CD11b+ leukocytes. A CD11b agonist leukadherin-1 (LA1) increases leukocyte adhesion, preventing their transmigration and tissue recruitment in vivo. Here, we test the extent to which LA1-mediated activation of CD11b/CD18 enhances kidney allograft survival in a mouse model of fully MHC-mismatched orthotopic kidney transplantation, where C57BL/6J (H-2b) recipients received kidney allografts from Balb/c mice (H-2d). Isograft control recipients received a kidney from a littermate. Control isograft and allograft recipients were treated daily with cyclosporine (CsA) for 2 weeks, while the test group received CsA therapy and daily LA1 injections during week 1 and alternate days during weeks 2–8. LA1 treatment reduced interstitial leukocyte infiltration in the allograft, reduced neointimal hyperplasia and glomerular damage, and prolonged graft survival from 48.5% (CsA only) to 100% (CsA and LA1) on day 60. Serum creatinine levels showed significantly improved kidney function in LA1-treated mice compared to CsA-treated allograft controls [0.52 ± 0.18 mg/dL vs 0.24 ± 0.07 mg/dL (n = 5), respectively]. Furthermore, combination therapy reduced macrophage infiltration and increased the frequency of FoxP3 + Tregs in the allograft. These findings indicate a crucial role for CD11b/CD18 in the control of leukocyte migration to the transplanted kidney and identify integrin agonist LA1 as a novel potential therapeutic agent for kidney transplantation. PMID:25593918

Immunotherapy by targeting of VGKC complex for seizure control and prevention of cognitive impairment in a mouse model of epilepsy.

PubMed

Fan, Zhiliang; Feng, Xiaojuan; Fan, Zhigang; Zhu, Xingyuan; Yin, Shaohua

2018-05-09

Epilepsy is a type of refractory neurologic disorder mental disease, which is associated with cognitive impairments and memory dysfunction. However, the potential mechanisms of epilepsy are not well understood. Previous evidence has identified the voltage gated potassium channel complex (VGKC) as a target in various cohorts of patients with epilepsy. In the present study, the efficacy of an antibody against VGKC (anti‑VGKC) for the treatment of epilepsy in mice was investigated. A mouse model of lithium‑pilocarpine temporal lobe epilepsy was established and anti‑VGKC treatment was administered for 30 days. Memory impairment, anxiety, visual attention, inhibitory control and neuronal loss were measured in the mouse model of lithium‑pilocarpine temporal lobe epilepsy. The results revealed that epileptic mice treated with anti‑VGKC were able to learn the task and presented attention impairment, even a tendency toward impulsivity and compulsivity. It was also exhibited that anti‑VGKC treatment decreased neuronal loss in structures classically associated with attentional performance in hippocampus. Mice who received Anti‑VGKC treatment had inhibited motor seizures and hippocampal damage as compared with control mice. In conclusion, these results indicated that anti‑VGKC treatment may present benefits for improvements of the condition of motor attention impairment and cognitive competence, which suggests that VGKC may be a potential target for the treatment of epilepsy.

Estrogen deficiency heterogeneously affects tissue specific stem cells in mice

PubMed Central

Kitajima, Yuriko; Doi, Hanako; Ono, Yusuke; Urata, Yoshishige; Goto, Shinji; Kitajima, Michio; Miura, Kiyonori; Li, Tao-Sheng; Masuzaki, Hideaki

2015-01-01

Postmenopausal disorders are frequently observed in various organs, but their relationship with estrogen deficiency and mechanisms remain unclear. As tissue-specific stem cells have been found to express estrogen receptors, we examined the hypothesis that estrogen deficiency impairs stem cells, which consequently contributes to postmenopausal disorders. Six-week-old C57BL/6 female mice were ovariectomized, following which they received 17β-estradiol replacement or vehicle (control). Sham-operated mice were used as healthy controls. All mice were killed for evaluation 2 months after treatments. Compared with the healthy control, ovariectomy significantly decreased uterine weight, which was partially recovered by 17β-estradiol replacement. Ovariectomy significantly increased the numbers of c-kit-positive hematopoietic stem/progenitor cells in bone marrow, but impaired their capacity to grow mixed cell-type colonies in vitro. Estrogen replacement further increased the numbers of c-kit-positive hematopoietic stem/progenitor cells in bone marrow, without significantly affecting colony growth in vitro. The number of CD105-positive mesenchymal stem cells in bone marrow also significantly decreased after ovariectomy, but completely recovered following estrogen replacement. Otherwise, neither ovariectomy nor estrogen replacement changed the number of Pax7-positive satellite cells, which are a skeletal muscle-type stem cell. Estrogen deficiency heterogeneously affected tissue-specific stem cells, suggesting a likely and direct relationship with postmenopausal disorders. PMID:26245252

Infectivity and egg production of Nematospiroides dubius as affected by space flight and ultraviolet irradiation

NASA Technical Reports Server (NTRS)

Long, R. A.; Ellis, W. L.; Taylor, G. R.

1973-01-01

Nematospiroides dubius was tested to determine the infective potential of the third stage larvae and the egg-production and egg-viability rates of the resulting adults after they are exposed to space flight and solar ultraviolet irradiation. The results are indicative that space-flown larvae exposed to solar ultraviolet irradiation were rendered noninfective in C57 mice, whereas flight control larvae that received no solar ultraviolet irradiation matured at the same rate as the ground control larvae. However, depressed egg viability was evident in the flight control larvae.

T cell leukemia control via Ras-Raf pathway inhibition with peptides.

PubMed

Marin, G H; Rebollo, A; Bruzzoni-Giovanelli, H; Schinella, G; Piazzon, I; Duarte, A; Errecalde, J

2017-01-01

RAS-RAF-MEK-ERK pathway has been considered a promising target for anticancer therapy. However, tumor cells may develop resistance against such drugs via hyperactivation of N-Ras, which explains why novel therapeut-ic approaches. In this sense, the Institute Curie- Université Pierre et Marie Curie (Paris 6) designed peptides in order to disturb Ras/Raf interaction which showed pro-apoptotic properties. These peptides were patented as WO2015001045 A2 (PCT/EP2014/064243)5. In order to check the anti-tumoral action of WO2015001045 A2 peptides in a very aggressive BALB/c mice spontaneous leukemia called LB, we performed the present study. 50 BALB/c mice inoculated with 106 LB tumor cells were randomly assigned either to control (placebo) or treatment group (that daily received 3 mg of peptide per kg of mice) during 30 days. By day 15 only 24% of the control group was alive vs. 100% of the treatment group. The average survival in treated group was 20,27 days while in control group the mean survival was 15,48 days. Either bone marrow, spleen or axillary nodes demonstrated a higher level of malignant T cell presence compare with treated group (89,78% ; 95,64% & 77,68% versus 72,45%, 80,23% & 63.44% respectively for each organ inspected. Our study demonstrated an improvement in survival curves in mice model affected by spontaneous T lymphoid leukemia when peptides WO2015001045 A2 were used. These peptides might be a valid option to become part of the therapeutic armory for malignant lymphoproliferative diseases control.

Wnt Signaling in Form Deprivation Myopia of the Mice Retina

PubMed Central

Ma, Mingming; Zhang, Zhengwei; Du, Ergang; Zheng, Wenjing; Gu, Qing; Xu, Xun; Ke, Bilian

2014-01-01

Background The canonical Wnt signaling pathway plays important roles in cellular proliferation and differentiation, axonal outgrowth, cellular maintenance in retinas. Here we test the hypothesis that elements of the Wnt signaling pathway are involved in the regulation of eye growth and prevention of myopia, in the mouse form-deprivation myopia model. Methodology/Principal Findings (1) One hundred twenty-five C57BL/6 mice were randomly distributed into form-deprivation myopia and control groups. Form-deprivation myopia (FDM) was induced by suturing the right eyelid, while the control group received no treatment. After 1, 2, and 4 weeks of treatment, eyes were assessed in vivo by cycloplegic retinoscopic refraction and axial length measurement by photography or A-scan ultrasonography. Levels of retinal Wnt2b, Fzd5 and β-catenin mRNA and protein were evaluated using RT-PCR and western blotting, respectively. (2) Another 96 mice were divided into three groups: control, drugs-only, and drugs+FDM (by diffuser). Experimentally treated eyes in the last two groups received intravitreal injections of vehicle or the proteins, DKK-1 (Wnt-pathway antagonist) or Norrin (Wnt-pathway agonist), once every three days, for 4 injections total. Axial length and retinoscopic refraction were measured on the 14th day of form deprivation. Following form-deprivation for 1, 2, and 4 weeks, FDM eyes had a relatively myopic refractive error, compared with contralateral eyes. There were no significant differences in refractive error between right and left eye in control group. The amounts of Wnt2b, Fzd5 and β-catenin mRNA and protein were significantly greater in form-deprived myopia eyes than in control eyes.DKK-1 (antagonist) reduced the myopic shift in refractive error and increase in axial elongation, whereas Norrin had the opposite effect in FDM eyes. Conclusions/Significance Our studies provide the first evidence that the Wnt2b signaling pathway may play a role in the development and progression of form-deprivation myopia, in a mammalian model. PMID:24755605

Wnt signaling in form deprivation myopia of the mice retina.

PubMed

Ma, Mingming; Zhang, Zhengwei; Du, Ergang; Zheng, Wenjing; Gu, Qing; Xu, Xun; Ke, Bilian

2014-01-01

The canonical Wnt signaling pathway plays important roles in cellular proliferation and differentiation, axonal outgrowth, cellular maintenance in retinas. Here we test the hypothesis that elements of the Wnt signaling pathway are involved in the regulation of eye growth and prevention of myopia, in the mouse form-deprivation myopia model. (1) One hundred twenty-five C57BL/6 mice were randomly distributed into form-deprivation myopia and control groups. Form-deprivation myopia (FDM) was induced by suturing the right eyelid, while the control group received no treatment. After 1, 2, and 4 weeks of treatment, eyes were assessed in vivo by cycloplegic retinoscopic refraction and axial length measurement by photography or A-scan ultrasonography. Levels of retinal Wnt2b, Fzd5 and β-catenin mRNA and protein were evaluated using RT-PCR and western blotting, respectively. (2) Another 96 mice were divided into three groups: control, drugs-only, and drugs+FDM (by diffuser). Experimentally treated eyes in the last two groups received intravitreal injections of vehicle or the proteins, DKK-1 (Wnt-pathway antagonist) or Norrin (Wnt-pathway agonist), once every three days, for 4 injections total. Axial length and retinoscopic refraction were measured on the 14th day of form deprivation. Following form-deprivation for 1, 2, and 4 weeks, FDM eyes had a relatively myopic refractive error, compared with contralateral eyes. There were no significant differences in refractive error between right and left eye in control group. The amounts of Wnt2b, Fzd5 and β-catenin mRNA and protein were significantly greater in form-deprived myopia eyes than in control eyes.DKK-1 (antagonist) reduced the myopic shift in refractive error and increase in axial elongation, whereas Norrin had the opposite effect in FDM eyes. Our studies provide the first evidence that the Wnt2b signaling pathway may play a role in the development and progression of form-deprivation myopia, in a mammalian model.

[Role of acetylcholine in gelsenicine-induced death in mice].

PubMed

Lai, Zhou-Yi; Wang, Hai-Bo; Lv, Rui-Ling; Tan, Qiu-Chan; Deng, Zhi-Qin; Wang, Yuan; Sun, Xiao-Xue; Wu, Jia-Bao; Zhu, Lin-Yan; Wang, Lei; Chen, Li-Xin; Ye, Wen-Cai; Wang, Li-Wei

2016-06-25

The aim of this study was to investigate the relationship between the acetylcholine concentration in the blood and gelsenicine-induced death in mice. Kunming mice were given intraperitoneal injections of normal saline, gelsenicine or different doses of acetylcholine chloride. Atropine was given to the mice which received gelsenicine or medium dose acetylcholine chloride injection. The blood was sampled immediately when the mice died or survived for 20 min after injection. The acetylcholine concentration and acetylcholinesterase activity in the blood were measured by the testing kits, and the mortality was calculated and analyzed. The results showed that half lethal dose of gelsenicine (0.15 mg/kg) reduced the acetylcholinesterase activity and increased the blood acetylcholine concentration. The blood acetylcholine concentration of the dead mice in the gelsenicine group was increased to 43.0 μg/mL (from 31.1 μg/mL in the control), which was lower than that (53.9 μg/mL) of the dead mice in the medium dose acetylcholine chloride group, but almost equal to that (42.7 μg/mL) of the survival mice in the medium dose acetylcholine chloride group. Atropine could successfully rescue the mice from acetylcholine poisoning, but its efficiency of rescuing the mice from gelsenicine intoxication was weak. These results suggest that gelsenicine can inhibit acetylcholinesterase activity and increase blood acetylcholine concentration, but the accumulation of acetylcholine may not be the only or main cause of the death induced by gelsenicine in mice.

Critical role of IFN-gamma in CFA-mediated protection of NOD mice from diabetes development.

PubMed

Mori, Yoshiko; Kodaka, Tetsuro; Kato, Takako; Kanagawa, Edith M; Kanagawa, Osami

2009-11-01

IFN-gamma signaling-deficient non-obese diabetic (NOD) mice develop diabetes with similar kinetics to those of wild-type NOD mice. However, the immunization of IFN-gamma signaling-deficient NOD mice with CFA failed to induce long-term protection, whereas wild-type NOD mice receiving CFA remained diabetes-free. CFA also failed to protect IFN-gamma receptor-deficient (IFN-gammaR(-/-)) NOD mice from the autoimmune rejection of transplanted islets, as it does in diabetic NOD mice, and from disease transfer by spleen cells from diabetic NOD mice. These data clearly show that the pro-inflammatory cytokine IFN-gamma is necessary for the CFA-mediated protection of NOD mice from diabetes. There is no difference in the T(h)1/T(h)17 balance between IFN-gammaR(-/-) NOD and wild-type NOD mice. There is also no difference in the total numbers and percentages of regulatory T (Treg) cells in the lymph node CD4(+) T-cell populations between IFN-gammaR(-/-) NOD and wild-type NOD mice. However, pathogenic T cells lacking IFN-gammaR are resistant to the suppressive effect of Treg cells, both in vivo and in vitro. Therefore, it is likely that CFA-mediated protection against diabetes development depends on a change in the balance between Treg cells and pathogenic T cells, and IFN-gamma signaling seems to control the susceptibility of pathogenic T cells to the inhibitory activity of Treg cells.

An Immune-Modulating Diet in Combination with Chemotherapy Prevents Cancer Cachexia by Attenuating Systemic Inflammation in Colon 26 Tumor-Bearing Mice.

PubMed

Nakamura, Kentaro; Sasayama, Akina; Takahashi, Takeshi; Yamaji, Taketo

2015-01-01

Cancer cachexia is characterized by muscle wasting caused partly by systemic inflammation. We previously demonstrated an immune-modulating diet (IMD), an enteral diet enriched with immunonutrition and whey-hydrolyzed peptides, to have antiinflammatory effects in some experimental models. Here, we investigated whether the IMD in combination with chemotherapy could prevent cancer cachexia in colon 26 tumor-bearing mice. Forty tumor-bearing mice were randomized into 5 groups: tumor-bearing control (TB), low dose 5-fluorouracil (5-FU) and standard diet (LF/ST), low dose 5-FU and IMD (LF/IMD), high dose 5-FU and standard diet (HF/ST) and high dose 5-FU and IMD (HF/IMD). The ST and IMD mice received a standard diet or the IMD ad libitum for 21 days. Muscle mass in the IMD mice was significantly higher than that in the ST mice. The LF/IMD in addition to the HF/ST and HF/IMD mice preserved their body and carcass weights. Plasma prostaglandin E2 levels were significantly lower in the IMD mice than in the ST mice. A combined effect was also observed in plasma interleukin-6, glucose, and vascular endothelial growth factor levels. Tumor weight was not affected by different diets. In conclusion, the IMD in combination with chemotherapy prevented cancer cachexia without suppressing chemotherapeutic efficacy.

Torticollis in Mice Intravenously Infected with Mycobacterium tuberculosis

PubMed Central

Magden, Elizabeth R; Weiner, Cristina M; Gilliland, Janet C; DeGroote, Mary Ann; Lenaerts, Anne J; Kendall, Lon V

2011-01-01

Female BALB/cAnNCrl (n = 170; age, 6 to 9 wk) mice were infected by intravenous inoculation of 5 × 106 cfu Mycobacterium tuberculosis strain Erdman (ATCC 35801). Between day 52 and 5 mo after infection, 10 of the 170 mice infected according to this protocol developed torticollis, including mice in treatment groups that received combination antibiotic therapy of rifampin–pyrazinamide or moxifloxacin–rifampin–pyrazinamide. Torticollis did not develop in mice receiving isoniazid–rifampin–pyrazinamide therapy, nor was it present in the cohort of aerogenically infected mice. Affected mice were euthanized, and complete necropsy evaluation was performed on 4 mice. Gross necropsy evaluation revealed typical tuberculosis lesions in lungs of infected mice. Histologic evaluation of tissues revealed granulomatous otitis media with intralesional acid-fast bacilli consistent with Mycobacterium tuberculosis. These cases represent an unusual finding specific to the intravenous mouse model of Mycobacterium tuberculosis and may represent a model of a similar condition in humans that is known as tuberculous otitis media. PMID:21439219

Torticollis in mice intravenously infected with Mycobacterium tuberculosis.

PubMed

Magden, Elizabeth R; Weiner, Cristina M; Gilliland, Janet C; DeGroote, Mary Ann; Lenaerts, Anne J; Kendall, Lon V

2011-03-01

Female BALB/cAnNCrl (n = 170; age, 6 to 9 wk) mice were infected by intravenous inoculation of 5 × 10(6) cfu Mycobacterium tuberculosis strain Erdman (ATCC 35801). Between day 52 and 5 mo after infection, 10 of the 170 mice infected according to this protocol developed torticollis, including mice in treatment groups that received combination antibiotic therapy of rifampin-pyrazinamide or moxifloxacin-rifampin-pyrazinamide. Torticollis did not develop in mice receiving isoniazid- rifampin-pyrazinamide therapy, nor was it present in the cohort of aerogenically infected mice. Affected mice were euthanized, and complete necropsy evaluation was performed on 4 mice. Gross necropsy evaluation revealed typical tuberculosis lesions in lungs of infected mice. Histologic evaluation of tissues revealed granulomatous otitis media with intralesional acid-fast bacilli consistent with Mycobacterium tuberculosis. These cases represent an unusual finding specific to the intravenous mouse model of Mycobacterium tuberculosis and may represent a model of a similar condition in humans that is known as tuberculous otitis media.

Papain-induced experimental pulmonary emphysema in male and female mice.

PubMed

Machado, Mariana Nascimento; Figueirôa, Silviane Fernandes da Silva; Mazzoli-Rocha, Flavia; Valença, Samuel dos Santos; Zin, Walter Araújo

2014-08-15

In papain-induced models of emphysema, despite the existing extensive description of the cellular and molecular aspects therein involved, sexual hormones may play a complex and still not fully understood role. Hence, we aimed at exploring the putative gender-related differences in lung mechanics, histology and oxidative stress in papain-exposed mice. Thirty adult BALB/c mice received intratracheally either saline (50 μL) or papain (10 U/50 μL saline) once a week for 2 weeks. In males papain increased lung resistive and viscoelastic/inhomogeneous pressures, static elastance, and viscoelastic component of elastance, while females showed higher static elastance and resistive pressure only. Both genders presented similar higher parenchymal cellularity and mean alveolar diameter, and less collagen-elastic fiber content and body weight gain than their respective controls. Increased functional residual capacity was more prominent in males. Female papain-treated mice were more susceptible to oxidative stress. Thus, male and female papain-exposed mice respond differently, which should be carefully considered to avoid confounding results. Copyright © 2014 Elsevier B.V. All rights reserved.

Effect of aminoguanidine and albendazole on inducible nitric oxide synthase (iNOS) activity in T. spiralis-infected mice muscles.

PubMed

Zeromski, Jan; Boczoń, Krystyna; Wandurska-Nowak, Elzbieta; Mozer-Lisewska, Iwona

2005-01-01

The aim of this study was to provide evidence for the expression of iNOS in the cells of inflammatory infiltrates around larvae in skeletal muscles of T. spiralis infected mice. The BALB/c mice (n = 8) divided into subgroups, received either aminoguanidine (AMG)--a specific iNOS inhibitor or albendazole (ALB)--an antiparasitic drug of choice in trichinellosis treatment. Control animals (n = 2 in each subgroup) were either uninfected and treated or uninfected and untreated. Frozen sections of hind leg muscles from mice sacrificed at various time intervals after infection were cut and subjected to immunohistochemistry, using monoclonal anti-iNOS antibody. The ALB-treated mice revealed stronger iNOS staining in the infiltrating cells around larvae than the infected and untreated animals. On the contrary, in the AMG-treated animals, the infiltrating cells did not show any specific iNOS reaction. These data confirm the specificity of iNOS staining in the cellular infiltrates around T. spiralis larvae and shed some light on the role of nitric oxide during ALB treatment in experimental trichinellosis.

Evaluation of the ameliorative effects of immunosuppressants on crescentic glomerulonephritis in SCG/Kj mice.

PubMed

Saiga, Kan; Yoshida, Minako; Nakamura, Iwao; Toyoda, Eriko; Tokunaka, Kazuhiro; Morohashi, Hirohisa; Abe, Fuminori; Nemoto, Kyuichi; Nose, Masato

2008-09-01

The therapeutic efficacy of immunosuppressants for treating rapidly progressive glomerulonephritis (RPGN) with crescent formation remains controversial. SCG/Kj mice spontaneously develop RPGN-like symptoms, characteristic of crescentic glomerulonephritis and systemic small vessel vasculitis, associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). We evaluated the "ameliorative", not prophylactic, effects of immunosuppressive agents, deoxyspergualin (DSG), cyclophosphamide (CYC) and prednisolone (PDN), on RPGN in these mice. DSG at intraperitoneal doses of 3 and 6 mg/kg, CYC at an oral dose of 12 mg/kg, or PDN at an intraperitoneal dose of 120 mg/kg was administered once a day for 21 days to female mice "at the onset of hematuria". A set of control SCG/Kj mice received only saline injections. DSG and CYC significantly prolonged survival, improved the proteinuria, hematuria and hyperuremia, and decreased the serum level of myeloperoxidase-ANCA. Moreover, DSG significantly suppressed the formation of crescents in glomeruli. PDN failed to affect any of the parameters. DSG might be useful for inducing remission in crescentic glomerulonephritis involved in RPGN.

Protective effect of Withania somnifera roots extract on hematoserological profiles against lead nitrate-induced toxicity in mice.

PubMed

Sharma, Veena; Sharma, Sadhana; Pracheta

2012-12-01

The in vivo protective role of hydro-methanolic root extract of Withania somnifera (WS) was evaluated in alleviating lead nitrate (LN)-induced toxicity in male Swiss albino mice by measuring hematoserological profiles. The lead-treated (20 mg/kg body wt, p.o.) albino mice (25-30 g) concurrently received the root extract (200 and 500 mg/kg body wt, p.o.) once daily for the duration of six weeks. Animals exposed to LN showed significant (P < 0.001) decline in haemoglobin content, red blood cell count, white blood cell count, packed cell volume and insignificant decrease in mean corpuscular haemoglobin and mean corpuscular haemoglobin content, while mean corpuscular volume and platelet count were increased. A significant elevation (P < 0.001) in serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, alkaline phosphatase, acid phosphatase and total cholesterol were also observed, when compared with control mice. Thus, the study demonstrated that the concurrent daily administration of root extract of WS protected the adverse effects of LN intoxication in mice.

Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice.

PubMed

Le Roy, Tiphaine; Llopis, Marta; Lepage, Patricia; Bruneau, Aurélia; Rabot, Sylvie; Bevilacqua, Claudia; Martin, Patrice; Philippe, Catherine; Walker, Francine; Bado, André; Perlemuter, Gabriel; Cassard-Doulcier, Anne-Marie; Gérard, Philippe

2013-12-01

Non-alcoholic fatty liver disease (NAFLD) is prevalent among obese people and is considered the hepatic manifestation of metabolic syndrome. However, not all obese individuals develop NAFLD. Our objective was to demonstrate the role of the gut microbiota in NAFLD development using transplantation experiments in mice. Two donor C57BL/6J mice were selected on the basis of their responses to a high-fat diet (HFD). Although both mice displayed similar body weight gain, one mouse, called the 'responder', developed hyperglycaemia and had a high plasma concentration of pro-inflammatory cytokines. The other, called a 'non-responder', was normoglycaemic and had a lower level of systemic inflammation. Germ-free mice were colonised with intestinal microbiota from either the responder or the non-responder and then fed the same HFD. Mice that received microbiota from different donors developed comparable obesity on the HFD. The responder-receiver (RR) group developed fasting hyperglycaemia and insulinaemia, whereas the non-responder-receiver (NRR) group remained normoglycaemic. In contrast to NRR mice, RR mice developed hepatic macrovesicular steatosis, which was confirmed by a higher liver concentration of triglycerides and increased expression of genes involved in de-novo lipogenesis. Pyrosequencing of the 16S ribosomal RNA genes revealed that RR and NRR mice had distinct gut microbiota including differences at the phylum, genera and species levels. Differences in microbiota composition can determine response to a HFD in mice. These results further demonstrate that the gut microbiota contributes to the development of NAFLD independently of obesity.

Impaired extinction of fear and maintained amygdala-hippocampal theta synchrony in a mouse model of temporal lobe epilepsy.

PubMed

Lesting, Jörg; Geiger, Matthias; Narayanan, Rajeevan T; Pape, Hans-Christian; Seidenbecher, Thomas

2011-02-01

The relationship between epilepsy and fear has received much attention. However, seizure-modulated fear and physiologic or structural correlates have not been examined systematically, and the underlying basics of network levels remain unclear to date. Therefore, this project was set up to characterize the neurophysiologic basis of seizure-related fear and the contribution of the amygdala-hippocampus system. The experimental strategy was composed of the following steps: (1) use of the mouse pilocarpine model of temporal lobe epilepsy (TLE); (2) behavioral analyses of anxiety states in the elevated plus maze test, light-dark avoidance test, and Pavlovian fear conditioning; and (3) probing neurophysiologic activity patterns in amygdala-hippocampal circuits in freely behaving mice. Our results displayed no significant differences in basic anxiety levels comparing mice that developed spontaneous recurrent seizures (SRS) and controls. Furthermore, conditioned fear memory retrieval was not influenced in SRS mice. However, during fear memory extinction, SRS mice showed an extended freezing behavior and a maintained amygdala-hippocampal theta frequency synchronization compared to controls. These results indicate specific alterations in conditioned fear behavior and related neurophysiologic activities in the amygdala-hippocampal network contributing to impaired fear memory extinction in mice with TLE. Clinically, the nonextinguished fear memories may well contribute to the experience of fear in patients with TLE. Wiley Periodicals, Inc. © 2010 International League Against Epilepsy.

Crocin Improves Damage Induced by Nicotine on A Number of Reproductive Parameters in Male Mice

PubMed Central

Salahshoor, Mohammad Reza; Khazaei, Mozafar; Jalili, Cyrus; Keivan, Mona

2016-01-01

Background Crocin, a carotenoid isolated from Crocus sativus L. (saffron), is a pharmacologically active component of saffron. Nicotine consumption can decrease fertility in males through induction of oxidative stress and DNA damage. The aim of this study is to determine the effects of crocin on reproductive parameter damages in male mice exposed to nicotine. Materials and Methods In this experimental study, we divided 48 mice into 8 groups (n=6 per group): control (normal saline), nicotine (2.5 mg/kg), crocin (12.5, 25 and 50 mg/kg) and crocin (12.5, 25 and 50 mg/kg)+nicotine (2.5 mg/kg). Mice received once daily intraperitoneal injections of crocin, nicotine and crocin+nicotine for 4 weeks. Sperm parameters (count, motility, and viability), testis weight, seminiferous tube diameters, testosterone, and serum nitric oxide levels were analyzed and compared. Results Nicotine administration significantly decreased testosterone level; sperm count, viability, and motility; testis weight and seminiferous tubule diameters compared to the control group (P<0.05). However, increasing the dose of crocin in the crocin and crocin+nicotine groups significantly boosted sperm motility and viability; seminiferous tubule diameters; testis weight; and testosterone levels in all groups compared to the nicotine group (P<0.05). Conclusion Crocin improves nicotine-induced adverse effects on reproductive parameters in male mice. PMID:27123203

THC inhibits the expression of ethanol-induced locomotor sensitization in mice.

PubMed

Filev, Renato; Engelke, Douglas S; Da Silveira, Dartiu X; Mello, Luiz E; Santos-Junior, Jair G

2017-12-01

The motivational circuit activated by ethanol leads to behavioral changes that recruit the endocannabinoid system (ECS). Case reports and observational studies suggest that the use of Cannabis sp. mitigates problematic ethanol consumption in humans. Here, we verified the effects of the two main phytocannabinoid compounds of Cannabis sp., cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), in the expression of ethanol-induced locomotor sensitization in mice. Male adult DBA/2 mice were exposed to locomotor sensitization by daily intraperitoneal injections of ethanol (2.5 g/kg) for 12 days; control groups received saline. After the acquisition phase, animals were treated with cannabinoids: CBD (2.5 mg/kg); THC (2.5 mg/kg); CBD + THC (1:1 ratio), or vehicle for 4 days with no access to ethanol during this period. One day after the last cannabinoid injection, all animals were challenged with ethanol (2.0 g/kg) to evaluate the expression of the locomotor sensitization. Mice treated with THC alone or THC + CBD showed reduced expression of locomotor sensitization, compared to the vehicle control group. No effects were observed with CBD treatment alone. Our findings showing that phytocannabinoid treatment prevents the expression of behavioral sensitization in mice provide insight into the potential therapeutic use of phytocannabinoids in alcohol-related problems. Copyright © 2017 Elsevier Inc. All rights reserved.

Use of Fenbendazole-Containing Therapeutic Diets for Mice in Experimental Cancer Therapy Studies

PubMed Central

Duan, Qiwen; Liu, Yanfeng; Booth, Carmen J; Rockwell, Sara

2012-01-01

Pinworm infection (oxyuriasis) is a common problem in rodent colonies. Facility-wide prophylactic treatment of all mice with a diet containing therapeutic levels of fenbendazole for several weeks is often used to control pinworm outbreaks. We examined the effect of feeding a therapeutic diet containing 150 ppm fenbendazole on the growth of EMT6 mouse mammary tumors implanted into BALB/c Rw mice. Mice were randomized to receive either a fenbendazole-containing or control diet for 1 wk before tumor cells were injected intradermally in the flanks and throughout tumor growth. Tumor growth was monitored by serial measurements of tumor diameters from the time tumors became palpable until they reached 1000 mm3. The medicated diet did not alter tumor growth, invasion, or metastasis. When tumors reached volumes of approximately 100 mm3, some were irradiated locally with 10 Gy of X-rays. Irradiation significantly delayed tumor growth; fenbendazole did not alter the radiation-induced growth delay. However, cell culture studies showed that fenbendazole concentrations not far above those expected in the tissues of mice on this diet altered the growth of the tumor cells in culture. Recent data from other laboratories also have demonstrated effects of fenbendazole that could complicate experiments. Care should therefore be exercised in deciding whether chow containing fenbendazole should be administered to mouse colonies being used in cancer research. PMID:22776123

Use of fenbendazole-containing therapeutic diets for mice in experimental cancer therapy studies.

PubMed

Duan, Qiwen; Liu, Yanfeng; Booth, Carmen J; Rockwell, Sara

2012-03-01

Pinworm infection (oxyuriasis) is a common problem in rodent colonies. Facility-wide prophylactic treatment of all mice with a diet containing therapeutic levels of fenbendazole for several weeks is often used to control pinworm outbreaks. We examined the effect of feeding a therapeutic diet containing 150 ppm fenbendazole on the growth of EMT6 mouse mammary tumors implanted into BALB/c Rw mice. Mice were randomized to receive either a fenbendazole-containing or control diet for 1 wk before tumor cells were injected intradermally in the flanks and throughout tumor growth. Tumor growth was monitored by serial measurements of tumor diameters from the time tumors became palpable until they reached 1000 mm3. The medicated diet did not alter tumor growth, invasion, or metastasis. When tumors reached volumes of approximately 100 mm3, some were irradiated locally with 10 Gy of X-rays. Irradiation significantly delayed tumor growth; fenbendazole did not alter the radiation-induced growth delay. However, cell culture studies showed that fenbendazole concentrations not far above those expected in the tissues of mice on this diet altered the growth of the tumor cells in culture. Recent data from other laboratories also have demonstrated effects of fenbendazole that could complicate experiments. Care should therefore be exercised in deciding whether chow containing fenbendazole should be administered to mouse colonies being used in cancer research.

4-Hydroxydocosahexaenoic acid, a potent peroxisome proliferator-activated receptor {gamma} agonist alleviates the symptoms of DSS-induced colitis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yamamoto, Keiko; Ninomiya, Yuichi; Iseki, Mioko

2008-03-14

(5E,7Z,10Z,13Z,16Z,19Z)-4-Hydroxy-5,7,10,13,16,19-docosahexaenoic acid (4-OHDHA) is a potential agonist of peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) and antidiabetic agent as has been previously reported. As PPAR{gamma} agonists may also have anti-inflammatory functions, in this study, we investigated whether 4-OHDHA has an inhibitory effect on expression of inflammatory genes in vitro and whether 4-OHDHA could relieve the symptoms of dextran sodium sulfate (DSS)-induced colitis in a murine model of inflammatory bowel disease. 4-OHDHA inhibited production of nitric oxide and expression of a subset of inflammatory genes including inducible nitric oxide synthase (Nos2/iNOS) and interleukin 6 (Il6) by lipopolysaccharide (LPS)-activated macrophages. In addition, 4-OHDHA-treated mice whenmore » compared to control mice not receiving treatment recovered better from the weight loss caused by DSS-induced colitis. Changes in disease activity index (DAI) of 4-OHDHA-treated mice were also more favorable than for control mice and were comparable with mice treated with a typical anti-inflammatory-drug, 5-aminosalichylic acid (5-ASA). These results suggest that 4-OHDHA has potentially clinically useful anti-inflammatory effects mediated by suppression of inflammatory gene expression.« less

Increased adult hippocampal neurogenesis is not necessary for wheel running to abolish conditioned place preference for cocaine in mice.

PubMed

Mustroph, M L; Merritt, J R; Holloway, A L; Pinardo, H; Miller, D S; Kilby, C N; Bucko, P; Wyer, A; Rhodes, J S

2015-01-01

Recent evidence suggests that wheel running can abolish conditioned place preference (CPP) for cocaine in mice. Running significantly increases the number of new neurons in the hippocampus, and new neurons have been hypothesised to enhance plasticity and behavioral flexibility. Therefore, we tested the hypothesis that increased neurogenesis was necessary for exercise to abolish cocaine CPP. Male nestin-thymidine kinase transgenic mice were conditioned with cocaine, and then housed with or without running wheels for 32 days. Half of the mice were fed chow containing valganciclovir to induce apoptosis in newly divided neurons, and the other half were fed standard chow. For the first 10 days, mice received daily injections of bromodeoxyuridine (BrdU) to label dividing cells. On the last 4 days, mice were tested for CPP, and then euthanized for measurement of adult hippocampal neurogenesis by counting the number of BrdU-positive neurons in the dentate gyrus. Levels of running were similar in mice fed valganciclovir-containing chow and normal chow. Valganciclovir significantly reduced the numbers of neurons (BrdU-positive/NeuN-positive) in the dentate gyrus of both sedentary mice and runner mice. Valganciclovir-fed runner mice showed similar levels of neurogenesis as sedentary, normal-fed controls. However, valganciclovir-fed runner mice showed the same abolishment of CPP as runner mice with intact neurogenesis. The results demonstrate that elevated adult hippocampal neurogenesis resulting from running is not necessary for running to abolish cocaine CPP in mice. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Effect of tocopherol-monoglucoside (TMG), a water-soluble glycosylated derivate of vitamin E, on hematopoietic recovery in irradiated mice.

PubMed

Cherdyntseva, Nadezda; Shishkina, Anna; Butorin, Ivan; Murase, Hironobu; Gervas, Polina; Kagiya, Tsutomu V

2005-03-01

A preparation of alpha-tocopherol monoglucoside (TMG) administered i.p. at a dose of 600 mg/kg immediately after whole body gamma irradiation was examined for its radioprotective efficacy towards bone marrow and peripheral blood nucleated cells. When mice received X-rays at a dose of 5,6 Gy, a marked decrease in bone marrow karyocytes and a reduction of peripheral leukocytes within the early post-irradiated period were observed. However these changes were attenuated in TMG-treated mice. Significant protection of blood lymphocytes was found for the TMG group of mice. The return to normal value of the reduced blood leukocyte count starting from the 8th day was more rapid in TMG-treated mice than in untreated irradiated mice. TMG administration was found to enhance hematopoietic recovery, as measured by the exceeded nucleated bone marrow cell count due to elevated amount of both lymphoid and granulocytic elements in the TMG-group, in comparison with that of both control irradiated and non-irradiated animals. These findings indicate that the radioprotective effect of TMG is apparently realized through its influence on hematopoietic system.

Anti-fatigue activities of polysaccharides extracted from Hericium erinaceus.

PubMed

Liu, Jianqing; DU, Congxin; Wang, Yifei; Yu, Zhihua

2015-02-01

Hericium erinaceus (HEP) is a notable medicinal fungus grown in China and other oriental countries. Polysaccharides from HEP have recently attracted considerable attention due to their numerous physiological activities. The objective of this study was to evaluate the anti-fatigue activity of HEP in a mouse model. After one week of acclimation, mice were randomly divided into four groups: a control group, a low-dose HEP-treated group, a moderate-dose HEP-treated group, and a high-dose HEP-treated group. The treated groups received HEP (50, 100 and 200 mg/kg, ig), while the control group received saline solution. Following treatment for 28 days, the mice performed a forced swimming test until they were exhausted, then the exhaustive swimming time was recorded along with certain biochemical parameters related to fatigue, including blood lactic acid (BLA), serum urea nitrogen (SUN), tissue glycogen, superoxide dismutase (SOD), glutathione peroxidase (GPx) and malondialdehyde (MDA). These results suggested that HEP has significant anti-fatigue activity by decreasing BLA, SUN and MDA content, as well as increasing tissue glycogen content and antioxidant enzyme activity. Based on these results, this study provided theoretical support for the application of HEP in the field of sports nutrition.

Anti-fatigue activities of polysaccharides extracted from Hericium erinaceus

PubMed Central

LIU, JIANQING; DU, CONGXIN; WANG, YIFEI; YU, ZHIHUA

2015-01-01

Hericium erinaceus (HEP) is a notable medicinal fungus grown in China and other oriental countries. Polysaccharides from HEP have recently attracted considerable attention due to their numerous physiological activities. The objective of this study was to evaluate the anti-fatigue activity of HEP in a mouse model. After one week of acclimation, mice were randomly divided into four groups: a control group, a low-dose HEP-treated group, a moderate-dose HEP-treated group, and a high-dose HEP-treated group. The treated groups received HEP (50, 100 and 200 mg/kg, ig), while the control group received saline solution. Following treatment for 28 days, the mice performed a forced swimming test until they were exhausted, then the exhaustive swimming time was recorded along with certain biochemical parameters related to fatigue, including blood lactic acid (BLA), serum urea nitrogen (SUN), tissue glycogen, superoxide dismutase (SOD), glutathione peroxidase (GPx) and malondialdehyde (MDA). These results suggested that HEP has significant anti-fatigue activity by decreasing BLA, SUN and MDA content, as well as increasing tissue glycogen content and antioxidant enzyme activity. Based on these results, this study provided theoretical support for the application of HEP in the field of sports nutrition. PMID:25574220

Experimental approach to IGF-1 therapy in CCl4-induced acute liver damage in healthy controls and mice with partial IGF-1 deficiency.

PubMed

Morales-Garza, Luis A; Puche, Juan E; Aguirre, Gabriel A; Muñoz, Úrsula; García-Magariño, Mariano; De la Garza, Rocío G; Castilla-Cortazar, Inma

2017-05-04

Cell necrosis, oxidative damage, and fibrogenesis are involved in cirrhosis development, a condition in which insulin-like growth factor 1 (IGF-1) levels are diminished. This study evaluates whether the exogenous administration of low doses of IGF-1 can induce hepatoprotection in acute carbon tetrachloride (CCl 4 )-induced liver damage compared to healthy controls (Wt Igf +/+ ). Additionally, the impact of IGF-1 deficiency on a damaged liver was investigated in mice with a partial deficit of this hormone (Hz Igf1 +/- ). Three groups of 25 ± 5-week-old healthy male mice (Wt Igf +/+ ) were included in the protocol: untreated controls (Wt). Controls that received CCl 4 (Wt + CCl 4 ) and Wt + CCl 4 were treated subcutaneously with IGF-1 (2 µg/100 g body weight/day) for 10 days (Wt + CCl 4  + IGF1). In parallel, three IGF-1-deficient mice (Hz Igf1 +/- ) groups were studied: untreated Hz, Hz + CCl 4 , and Hz + CCl 4  + IGF-1. Microarray and real-time quantitative polymerase chain reaction (RT-qPCR) analyses, serum aminotransferases levels, liver histology, and malondialdehyde (MDA) levels were assessed at the end of the treatment in all groups. All data represent mean ± SEM. An altered gene coding expression pattern for proteins of the extracellular matrix, fibrosis, and cellular protection were found, as compared to healthy controls, in which IGF-1 therapy normalized in the series including healthy mice. Liver histology showed that Wt + CCl 4  + IGF1 mice had less oxidative damage, fibrosis, lymphocytic infiltrate, and cellular changes when compared to the Wt + CCl 4 . Moreover, there was a correlation between MDA levels and the histological damage score (Pearson's r = 0.858). In the IGF-1-deficient mice series, similar findings were identified, denoting a much more vulnerable hepatic parenchyma. IGF1 treatment improved the biochemistry, histology, and genetic expression of pro-regenerative and cytoprotective factors in both series (healthy and IGF-1-deficient mice) with acute liver damage, suggesting that low doses of IGF-1, in acute liver damage, could be a feasible therapeutic option.

Analgesic duration and kinetics of liposomal bupivacaine after subcutaneous injection in mice.

PubMed

Grant, G J; Piskoun, B; Bansinath, M

2003-12-01

1. The objective of the present study was to assess the time-course profile of analgesia and bupivacaine concentrations at the site of injection after subcutaneous administration of a single dose of standard bupivacaine or a novel controlled-release liposomal bupivacaine formulation. 2. Groups of mice were injected subcutaneously with 0.2 mL of 0.5% standard bupivacaine or 0.5, 1 or 2% liposomal bupivacaine. 3. A prolonged duration of analgesia occurred in mice receiving liposomal bupivacaine. In the liposomal groups, the bupivacaine remained at the injection site for more than 96 h, compared with approximately 8 h in groups injected with standard bupivacaine. 4. These results confirm that the prolonged analgesia observed after injection of the liposomal formulation is associated with sustained higher levels of bupivacaine at the site of injection.

The effect of nandrolone, an anabolic steroid on putrescine metabolism in the mouse.

PubMed Central

Henningsson, S; Rosengren, E

1976-01-01

1 The catabolism of injected 14 C-putrescine was studied in mice treated with nandrolone phenpropionate, an anabolic steroid. 2 The putrescine was rapidly metabolized; almost 50% of the injected radioactivity was recovered within 2 h as 14 CO2 in the expired air. 3 Considerable amounts of radioactive gamma-aminobutyric acid (GABA) and an unidentified compound were found in the kidney and in the urine in addition to radioactive putrescine, spermidine and spermine both in controls and nandrolone-treated mice. 4 Nandrolone elevated the concentration of endogenous putrescine in the kidney and urine, eightfold and twentyfold, respectively, and the concentrations of spermidine and spermine were also increased 5 after the injection of 14C-putrescine the incorporation of 14C into spermidine was significantly increased in the kidney of mice receiving nandrolone. PMID:990594

Ultra-low Doses of Follicle Stimulating Hormone and Progesterone Attenuate the Severity of Polycystic Ovary Syndrome Features in a Hyperandrogenized Mouse Model

PubMed Central

Tessaro, Irene; Modina, Silvia; Lodde, Valentina; Sivelli, Giulia; Franciosi, Federica; Terzaghi, Laura; Luchini, Patrizia; Rumio, Cristiano; Luciano, Alberto Maria

2017-01-01

Background: Polycystic-ovary syndrome (PCOS) is a reproductive illness characterized by hyperandrogenism and anovulation. Using hyperandrogenized mice, it was demonstrated that the oral administration of incremental dose of follicle stimulating hormone (FSH) attenuated some of PCOS characteristics. This work aimed to study the effect of ultra-low doses of combined FSH and progesterone orally administered on PCOS murine model. Moreover, the effect of sequential kinetic activation of administered hormones was tested. Methods: Thirty-two female mice were used as animal model (four groups of eight animals each). Mice were hyperandrogenized by injection of dehyidroepiandrosterone diluted in sesame oil. Control group received only oil. Simultaneously, each animal daily received per os an activated or a not-activated combination of FSH (0.44 pg) plus progesterone (0.44 pg) or saline solution as control. Serum testosterone, estradiol, progesterone and luteinizing hormone were analyzed as endocrine markers and a morphological study of antral follicle was conducted. Data were analyzed by one-way ANOVA, followed by multiple comparison test. The p<0.05 was considered significant. Results: Dehyidroepiandrosterone treatment increased both estradiol and progesterone serum levels, besides testosterone, while reduced luteinizing hormone (p<0.05); histological examination revealed an increase of cystic follicles (p<0.05). Irrespective of activation, the combined FSH and progesterone treatments restored estradiol level (p>0.05 vs. control group) and reduced cystic signs in the follicles (p<0.05 vs. dehyidroepiandrosterone treatment). Conclusion: This study indicate that ultra-low doses of FSH and progesterone orally administrated can reduce the sternness of PCOS in the mouse model and open a route for the study of innovative approaches for PCOS treatment. PMID:29062793

Single-Dose and Fractionated Irradiation Promote Initiation and Progression of Atherosclerosis and Induce an Inflammatory Plaque Phenotype in ApoE{sup -/-} Mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hoving, Saske; Heeneman, Sylvia; Gijbels, Marion J.J.

2008-07-01

Purpose: Increased risk of atherosclerosis and stroke has been demonstrated in patients receiving radiotherapy for Hodgkin's lymphoma and head-and-neck cancer. We previously showed that 14 Gy to the carotid arteries of hypercholesterolemic ApoE{sup -/-} mice resulted in accelerated development of macrophage-rich, inflammatory atherosclerotic lesions. Here we investigate whether clinically relevant fractionated irradiation schedules and lower single doses also predispose to an inflammatory plaque phenotype. Methods and Materials: ApoE{sup -/-} mice were given 8 or 14 Gy, or 20 x 2.0 Gy in 4 weeks to the neck, and the carotid arteries were subsequently examinated for presence of atherosclerotic lesions, plaquemore » size, and phenotype. Results: At 4 weeks, early atherosclerotic lesions were found in 44% of the mice after single doses of 14 Gy but not in age-matched controls. At 22 to 30 weeks after irradiation there was a twofold increase in the mean number of carotid lesions (8-14 Gy and 20 x 2.0 Gy) and total plaque burden (single doses only), compared with age-matched controls. The majority of lesions seen at 30 to 34 weeks after fractionated irradiation or 14-Gy single doses were granulocyte rich (100% and 63%, respectively), with thrombotic features (90% and 88%), whereas these phenotypes were much less common in age-matched controls or after a single dose of 8 Gy. Conclusions: We showed that fractionated irradiation accelerated the development of atherosclerosis in ApoE{sup -/-} mice and predisposed to the formation of an inflammatory, thrombotic plaque phenotype.« less

Ghrelin did not change coronary angiogenesis in diet-induced obese mice.

PubMed

Khazaei, M; Tahergorabi, Z

2017-02-28

Ghrelin is a 28 amino acids peptide that initially was recognized as an endogenous ligand for growth hormone secretagogue receptor (GHSR). Recently, a number of studies demonstrated that ghrelin is a cardiovascular hormone with a series cardiovascular effect. The main objective of this study was to investigate the effect of systemic ghrelin administration on angiogenesis in the heart and its correlation with serum leptin levels in normal and diet-induced obese mice. 24 male C57BL/6 mice were randomly divided into four groups: normal diet (ND) or control, ND+ghrelin, high-fat-diet (HFD) or obese and HFD+ghrelin (n=6/group). Obese and control groups received HFD or ND, respectively, for 14 weeks. Then, the ghrelin was injected subcutaneously 100µg/kg twice daily. After 10 days, the animals were sacrificed, blood samples were taken and the hearts were removed. The angiogenic response in the heart was assessed by immunohisochemical staining. HFD significantly increased angiogenesis in the heart expressed as the number of CD31 positive cells than standard diet. Ghrelin did not alter angiogenesis in the heart in both obese and control groups, however, it reduced serum nitric oxide (NO) and leptin levels in obese mice. There was a strong positive correlation between the number of CD31 positive cells and serum leptin concentration (r=0.74). Leptin as an angiogenic factor has a positive correlation with angiogenesis in the heart. Although systemic administration of ghrelin reduced serum leptin and NO levels in obese mice, however, it could not alter coronary angiogenesis.

Sub-chronic administration of the 11beta-HSD1 inhibitor, carbenoxolone, improves glucose tolerance and insulin sensitivity in mice with diet-induced obesity.

PubMed

Taylor, Ashley; Irwin, Nigel; McKillop, Aine M; Flatt, Peter R; Gault, Victor A

2008-04-01

We have examined the metabolic effects of daily administration of carbenoxolone (CBX), a naturally occurring 11beta-hydroxysteroid dehydrogenase (11beta-HSD1) inhibitor, in mice with high fat diet-induced insulin resistance and obesity. Eight-week-old male Swiss TO mice placed on a synthetic high fat diet received daily intraperitoneal injections of either saline vehicle or CBX over a 16-day period. Daily administration of CBX had no effect on food intake, but significantly lowered body weight (1.1- to 1.2-fold) compared to saline-treated controls. Non-fasting plasma glucose levels were significantly decreased (1.6-fold) by CBX treatment on day 4 and remained lower throughout the treatment period. Circulating plasma corticosterone levels were not significantly altered by CBX treatment. Plasma glucose concentrations of CBX-treated mice were significantly reduced (1.4-fold) following an intraperitoneal glucose load compared with saline controls. Similarly, after 16-day treatment with CBX, exogenous insulin evoked a significantly greater reduction in glucose concentrations (1.4- to 1.8-fold). 11beta-HSD1 gene expression was significantly down-regulated in liver, whereas glucocorticoid receptor gene expression was increased in both liver and adipose tissue following CBX treatment. The reduced body weight and improved metabolic control in mice with high fat diet-induced obesity upon daily CBX administration highlights the potential value of selective 11beta-HSD1 inhibition as a new route for the treatment of type 2 diabetes and obesity.

Multigenerational effects of bisphenol A or ethinyl estradiol exposure on F2 California mice (Peromyscus californicus) pup vocalizations

PubMed Central

Johnson, Sarah A.; Farrington, Michelle J.; Murphy, Claire R.; McAllister, Leif A.; Kaur, Sarabjit; Chun, Catherine; Ortega, Madison T.; Marshall, Brittney L.; Hoffmann, Frauke; Ellersieck, Mark R.; Schenk, A. Katrin

2018-01-01

Rodent pups use vocalizations to communicate with one or both parents in biparental species, such as California mice (Peromyscus californicus). Previous studies have shown California mice developmentally exposed to endocrine disrupting chemicals, bisphenol A (BPA) or ethinyl estradiol (EE), demonstrate later compromised parental behaviors. Reductions in F1 parental behaviors might also be due to decreased emissions of F2 pup vocalizations. Thus, vocalizations of F2 male and female California mice pups born to F1 parents developmentally exposed to BPA, EE, or controls were examined. Postnatal days (PND) 2–4 were considered early postnatal period, PND 7 and 14 were defined as mid-postnatal period, and PND 21 and 28 were classified as late postnatal period. EE pups showed increased latency to emit the first syllable compared to controls. BPA female pups had decreased syllable duration compared to control and EE female pups during the early postnatal period but enhanced responses compared to controls at late postnatal period; whereas, male BPA and EE pups showed greater syllable duration compared to controls during early postnatal period. In mid-postnatal period, F2 BPA and EE pups emitted greater number of phrases than F2 control pups. Results indicate aspects of vocalizations were disrupted in F2 pups born to F1 parents developmentally exposed to BPA or EE, but their responses were not always identical, suggesting BPA might not activate estrogen receptors to the same extent as EE. Changes in vocalization patterns by F2 pups may be due to multigenerational exposure to BPA or EE and/or reduced parental care received. PMID:29912934

Effects of Early Training and Nicotine Treatment on the Performance of Male NMRI Mice in the Water Maze

PubMed Central

Vicens, Paloma; Carrasco, M. Carmen; Redolat, Rosa

2003-01-01

This research aimed to evaluate the effect of nicotine treatment and prior training on a spatial learning task in differently aged NMRI male mice. In a longitudinal study, mice were randomly assigned to one of 14 experimental groups receiving different combinations of chronically injected nicotine (0.35 mg/kg) administered for 10 days (5 days before and during 5 days acquisition of task) or control treatments and training in the water maze at different ages. The mice displayed shorter escape latencies when evaluated at 6 and 10 months than when tested in this task at 2 months for the first time, demonstrating that early training preserves performance in the water maze up to 8 months after the initial experience. Nicotine treatment did not significantly change performance in the water maze at any age tested. Early practice in a spatial reference memory task appears to have lasting consequences and can potentially contribute to preventing some age-related spatial learning deficits. PMID:15152984

Importance of functional and metabolic impairments in the characterization of the C-26 murine model of cancer cachexia

PubMed Central

Murphy, Kate T.; Chee, Annabel; Trieu, Jennifer; Naim, Timur; Lynch, Gordon S.

2012-01-01

SUMMARY Cancer cachexia describes the progressive skeletal muscle wasting and weakness that is associated with many cancers. It impairs quality of life and accounts for >20% of all cancer-related deaths. The main outcome that affects quality of life and mortality is loss of skeletal muscle function and so preclinical models should exhibit similar functional impairments in order to maximize translational outcomes. Mice bearing colon-26 (C-26) tumors are commonly used in cancer cachexia studies but few studies have provided comprehensive assessments of physiological and metabolic impairment, especially those factors that impact quality of life. Our aim was to characterize functional impairments in mildly and severely affected cachectic mice, and determine the suitability of these mice as a preclinical model. Metabolic abnormalities are also evident in cachectic patients and we investigated whether C-26-tumor-bearing mice had similar metabolic aberrations. Twelve-week-old CD2F1 mice received a subcutaneous injection of PBS (control) or C-26 tumor cells. After 18–20 days, assessments were made of grip strength, rotarod performance, locomotor activity, whole body metabolism, and contractile properties of tibialis anterior (TA) muscles (in situ) and diaphragm muscle strips (in vitro). Injection of C-26 cells reduced body and muscle mass, and epididymal fat mass. C-26-tumor-bearing mice exhibited lower grip strength and rotarod performance. Locomotor activity was impaired following C-26 injection, with reductions in movement distance, duration and speed compared with controls. TA muscles from C-26-tumor-bearing mice had lower maximum force (−27%) and were more susceptible to fatigue. Maximum specific (normalized) force of diaphragm muscle strips was reduced (−10%) with C-26 injection, and force during fatiguing stimulation was also lower. C-26-tumor-bearing mice had reduced carbohydrate oxidation and increased fat oxidation compared with controls. The range and consistency of functional and metabolic impairments in C-26-tumor-bearing mice confirm their suitability as a preclinical model for cancer cachexia. We recommend the use of these comprehensive functional assessments to maximize the translation of findings to more accurately identify effective treatments for cancer cachexia. PMID:22563056

Anakinra reduces blood pressure and renal fibrosis in one kidney/DOCA/salt-induced hypertension.

PubMed

Ling, Yeong Hann; Krishnan, Shalini M; Chan, Christopher T; Diep, Henry; Ferens, Dorota; Chin-Dusting, Jaye; Kemp-Harper, Barbara K; Samuel, Chrishan S; Hewitson, Timothy D; Latz, Eicke; Mansell, Ashley; Sobey, Christopher G; Drummond, Grant R

2017-02-01

To determine whether a clinically-utilised IL-1 receptor antagonist, anakinra, reduces renal inflammation, structural damage and blood pressure (BP) in mice with established hypertension. Hypertension was induced in male mice by uninephrectomy, deoxycorticosterone acetate (2.4mg/d,s.c.) and replacement of drinking water with saline (1K/DOCA/salt). Control mice received uninephrectomy, a placebo pellet and normal drinking water. 10days post-surgery, mice commenced treatment with anakinra (75mg/kg/d, i.p.) or vehicle (0.9% saline, i.p.) for 11days. Systolic BP was measured by tail cuff while qPCR, immunohistochemistry and flow cytometry were used to measure inflammatory markers, collagen and immune cell infiltration in the kidneys. By 10days post-surgery, 1K/DOCA/salt-treated mice displayed elevated systolic BP (148.3±2.4mmHg) compared to control mice (121.7±2.7mmHg; n=18, P<0.0001). The intervention with anakinra reduced BP in 1K/DOCA/salt-treated mice by ∼20mmHg (n=16, P<0.05), but had no effect in controls. In 1K/DOCA/salt-treated mice, anakinra modestly reduced (∼30%) renal expression of some (CCL5, CCL2; n=7-8; P<0.05) but not all (ICAM-1, IL-6) inflammatory markers, and had no effect on immune cell infiltration (n=7-8, P>0.05). Anakinra reduced renal collagen content (n=6, P<0.01) but paradoxically appeared to exacerbate the renal and glomerular hypertrophy (n=8-9, P<0.001) that accompanied 1K/DOCA/salt-induced hypertension. Despite its anti-hypertensive and renal anti-fibrotic actions, anakinra had minimal effects on inflammation and leukocyte infiltration in mice with 1K/DOCA/salt-induced hypertension. Future studies will assess whether the anti-hypertensive actions of anakinra are mediated by protective actions in other BP-regulating or salt-handling organs such as the arteries, skin and brain. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

High fat diet drives obesity regardless the composition of gut microbiota in mice

PubMed Central

Rabot, Sylvie; Membrez, Mathieu; Blancher, Florence; Berger, Bernard; Moine, Déborah; Krause, Lutz; Bibiloni, Rodrigo; Bruneau, Aurélia; Gérard, Philippe; Siddharth, Jay; Lauber, Christian L.; Chou, Chieh Jason

2016-01-01

The gut microbiota is involved in many aspects of host physiology but its role in body weight and glucose metabolism remains unclear. Here we studied the compositional changes of gut microbiota in diet-induced obesity mice that were conventionally raised or received microbiota transplantation. In conventional mice, the diversity of the faecal microbiota was weakly associated with 1st week weight gain but transferring the microbiota of mice with contrasting weight gain to germfree mice did not change obesity development or feed efficiency of recipients regardless whether the microbiota was taken before or after 10 weeks high fat (HF) feeding. Interestingly, HF-induced glucose intolerance was influenced by microbiota inoculation and improved glucose tolerance was associated with a low Firmicutes to Bacteroidetes ratio. Transplantation of Bacteroidetes rich microbiota compared to a control microbiota ameliorated glucose intolerance caused by HF feeding. Altogether, our results demonstrate that gut microbiota is involved in the regulation of glucose metabolism and the abundance of Bacteroidetes significantly modulates HF-induced glucose intolerance but has limited impact on obesity in mice. Our results suggest that gut microbiota is a part of complex aetiology of insulin resistance syndrome, individual microbiota composition may cause phenotypic variation associated with HF feeding in mice. PMID:27577172

Evaluation of the cancer chemopreventive efficacy of rice bran in genetic mouse models of breast, prostate and intestinal carcinogenesis.

PubMed

Verschoyle, R D; Greaves, P; Cai, H; Edwards, R E; Steward, W P; Gescher, A J

2007-01-29

Brown rice is a staple dietary constituent in Asia, whereas rice consumed in the Western world is generally white, obtained from brown rice by removal of the bran. We tested the hypothesis that rice bran interferes with development of tumours in TAg, TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) or Apc(Min) mice, genetic models of mammary, prostate and intestinal carcinogenesis, respectively. Mice received rice bran (30%) in AIN-93G diet throughout their post-weaning lifespan. In TAg and TRAMP mice, rice bran did not affect carcinoma development. In TRAMP or wild-type C57Bl6/J mice, dietary rice bran increased kidney weight by 18 and 20%, respectively. Consumption of rice bran reduced numbers of intestinal adenomas in Apc(Min) mice by 51% (P<0.01), compared to mice on control diet. In parallel, dietary rice bran decreased intestinal haemorrhage in these mice, as reflected by increased haematocrit. At 10% in the diet, rice bran did not significantly retard Apc(Min) adenoma development. Likewise, low-fibre rice bran (30% in the diet) did not affect intestinal carcinogenesis, suggesting that the fibrous constituents of the bran mediate chemopreventive efficacy. The results suggest that rice bran might be beneficially evaluated as a putative chemopreventive intervention in humans with intestinal polyps.

High fat diet drives obesity regardless the composition of gut microbiota in mice.

PubMed

Rabot, Sylvie; Membrez, Mathieu; Blancher, Florence; Berger, Bernard; Moine, Déborah; Krause, Lutz; Bibiloni, Rodrigo; Bruneau, Aurélia; Gérard, Philippe; Siddharth, Jay; Lauber, Christian L; Chou, Chieh Jason

2016-08-31

The gut microbiota is involved in many aspects of host physiology but its role in body weight and glucose metabolism remains unclear. Here we studied the compositional changes of gut microbiota in diet-induced obesity mice that were conventionally raised or received microbiota transplantation. In conventional mice, the diversity of the faecal microbiota was weakly associated with 1(st) week weight gain but transferring the microbiota of mice with contrasting weight gain to germfree mice did not change obesity development or feed efficiency of recipients regardless whether the microbiota was taken before or after 10 weeks high fat (HF) feeding. Interestingly, HF-induced glucose intolerance was influenced by microbiota inoculation and improved glucose tolerance was associated with a low Firmicutes to Bacteroidetes ratio. Transplantation of Bacteroidetes rich microbiota compared to a control microbiota ameliorated glucose intolerance caused by HF feeding. Altogether, our results demonstrate that gut microbiota is involved in the regulation of glucose metabolism and the abundance of Bacteroidetes significantly modulates HF-induced glucose intolerance but has limited impact on obesity in mice. Our results suggest that gut microbiota is a part of complex aetiology of insulin resistance syndrome, individual microbiota composition may cause phenotypic variation associated with HF feeding in mice.

Mast Cell Activation Protects Cornea by Promoting Neutrophil Infiltration via Stimulating ICAM-1 and Vascular Dilation in Fungal Keratitis.

PubMed

Xie, Yanting; Zhang, Hongmin; Liu, Susu; Chen, Guoming; He, Siyu; Li, Zhijie; Wang, Liya

2018-05-30

The role of mast cells (MCs) in fungal infection is largely unknown. This study was to explore a protective role and mechanism of MCs in fungal keratitis. Experimental fungal keratitis (FK) mouse model was developed. Mice untreated (UT) or receiving corneal wound without fungal infection (Mock) were used as controls. Large number of connective tissue MCs was found in normal mice. MC activation with degranulation was largely observed, and the percentage of degranulated/total cells was high in FK. Dilated limbal vasculature with increased permeability, as well as largely infiltrated neutrophils with stimulated ICAM-1 protein levels were observed in corneas of FK mice, when compared with Mock and UT mice. Interestingly, pretreatment with cromolyn sodium (Block) significantly blocked MC degranulation, dramatically suppressed vascular dilation and permeability, and markedly reduced neutrophil infiltration with lower ICAM-1 levels in FK mice at 6-24 hours. Furthermore, the Block mice manifested prolonged disease course, increased pathological damage, and vigorous fungus growth, with much higher corneal perforation rate than FK mice at 72 h. These findings reveal a novel phenomenon that MCs play a vital role in protecting cornea against fungal infection through degranulation that promotes neutrophil infiltration via stimulating ICAM-1 production and limbal vascular dilation and permeability.

Light microscopic study of the effect of new antischistosmal drug (myrrh extract) on the liver of mice.

PubMed

Massoud, Ahmed M A; el Ebiary, Faika H; Ibrahim, Suzi H

2005-12-01

The efficacy of purified oleo-resin extract of myrrh derived from Commiphora molmol tree, (known as Mirazid) was studied against an Egyptian strain of Schistosoma mansoni in mice. Seventy adult male mice were used in this study. They were divided into 4 groups: G.I: consisted of control noninfected nontreated mice. G.II: comprised the noninfected treated mice and was subdivided into two subgroups, subgroup II-A: included mice which received Myrrh extract dissolved in cremophore EL and subgroup II-B: included mice which were treated with cremophore EL. G.III: consisted of the infected nontreated animals and G.IV: included infected mice which were treated with myrrh extract. The drug was given 8 weeks post infection in a dose of 500 mg/kg body weight/day for 5 successive days. All animals were sacrificed after 12 weeks from the beginning of the experiment. Liver paraffin sections were prepared and stained with H&E, Masson's Trichrome stain, PAS stain and Wilder's technique. A morphometric study was performed for the mean number and perimeter of the granulomas. Area percentage of the total collagen content around central veins as well as in portal areas was also estimated. The livers of the animals in G.II which received either myrrh extract (subgroup II-A) or cremophore EL (subgroup II-B) showed a more or less normal histological profile when compared to G.I (noninfected-nontreated group). G.IV (Infected treated G.) showed complete preservation of the hepatic architecture. Most of the hepatocytes appeared almost normal. The reticular network in the central part of the granulomas as well as in the portal tracts appeared rarefied. The hepatic reticular network was preserved. A significant decrease in the number and size of granulomas with significant reduction in the collagen content deposition in portal tracts and around central veins was detected when compared to G.III (infected nontreated mice). The data of this study proved the efficacy of myrrh as a promising antischistosomal drug.

Adolescent mice are less sensitive to the effects of acute nicotine on context pre-exposure than adults.

PubMed

Kutlu, Munir Gunes; Braak, David C; Tumolo, Jessica M; Gould, Thomas J

2016-07-01

Adolescence is a critical developmental period associated with both increased vulnerability to substance abuse and maturation of certain brain regions important for learning and memory such as the hippocampus. In this study, we employed a hippocampus-dependent learning context pre-exposure facilitation effect (CPFE) paradigm in order to test the effects of acute nicotine on contextual processing during adolescence (post-natal day (PND) 38) and adulthood (PND 53). In Experiment 1, adolescent or adult C57BL6/J mice received either saline or one of three nicotine doses (0.09, 0.18, and 0.36mg/kg) prior to contextual pre-exposure and testing. Our results demonstrated that both adolescent and adult mice showed CPFE in the saline groups. However, adolescent mice only showed acute nicotine enhancement of CPFE with the highest nicotine dose whereas adult mice showed the enhancing effects of acute nicotine with all three doses. In Experiment 2, to determine if the lack of nicotine's effects on CPFE shown by adolescent mice is specific to the age when they are tested, mice were either given contextual pre-exposure during adolescence or adulthood and received immediate shock and testing during adulthood after a 15day delay. We found that both adolescent and adult mice showed CPFE in the saline groups when tested during adulthood. However, like Experiment 1, mice that received contextual pre-exposure during adolescence did not show acute nicotine enhancement except at the highest dose (0.36mg/kg) whereas both low (0.09mg/kg) and high (0.36mg/kg) doses enhanced CPFE in adult mice. Finally, we showed that the enhanced freezing response found with 0.36mg/kg nicotine in the 15-day experiment may be a result of decreased locomotor activity as mice that received this dose of nicotine traveled shorter distances in an open field paradigm. Overall, our results indicate that while adolescent mice showed normal contextual processing when tested both during adolescence and adulthood, they are less sensitive to the enhancing effects of nicotine on contextual processing. Copyright © 2016 Elsevier B.V. All rights reserved.

A BCR-ABL Kinase Activity-Independent Signaling Pathway in Chronic Myelogenous Leukemia

DTIC Science & Technology

2008-02-01

myeloproliferative disease in mice receiving P210 bcr/abl-transduced bone marrow. Blood. 1998;92:3780-3792. 17. Zhang X, Ren R. Bcr-Abl efficiently induces a... myeloproliferative disease and production of excess interleukin-3 and granulocyte-macrophage colony-stimulating factor in mice: a novel model for chronic...Xu L, et al. Efficient and rapid induction of a chronic myelogenous leukemia-like myeloproliferative disease in mice receiving P210 bcr/abl-transduced

Gene therapy/bone marrow transplantation in ADA-deficient mice: roles of enzyme-replacement therapy and cytoreduction.

PubMed

Carbonaro, Denise A; Jin, Xiangyang; Wang, Xingchao; Yu, Xiao-Jin; Rozengurt, Nora; Kaufman, Michael L; Wang, Xiaoyan; Gjertson, David; Zhou, Yang; Blackburn, Michael R; Kohn, Donald B

2012-11-01

Gene therapy (GT) for adenosine deaminase-deficient severe combined immune deficiency (ADA-SCID) can provide significant long-term benefit when patients are given nonmyeloablative conditioning and ADA enzyme-replacement therapy (ERT) is withheld before autologous transplantation of γ-retroviral vector-transduced BM CD34+ cells. To determine the contributions of conditioning and discontinuation of ERT to the therapeutic effects, we analyzed these factors in Ada gene knockout mice (Ada(-/-)). Mice were transplanted with ADA-deficient marrow transduced with an ADA-expressing γ-retroviral vector without preconditioning or after 200 cGy or 900 cGy total-body irradiation and evaluated after 4 months. In all tissues analyzed, vector copy numbers (VCNs) were 100- to 1000-fold greater in mice receiving 900 cGy compared with 200 cGy (P < .05). In mice receiving 200 cGy, VCN was similar whether ERT was stopped or given for 1 or 4 months after GT. In unconditioned mice, there was decreased survival with and without ERT, and VCN was very low to undetectable. When recipients were conditioned with 200 cGy and received transduced lineage-depleted marrow, only recipients receiving ERT (1 or 4 months) had detectable vector sequences in thymocytes. In conclusion, cytoreduction is important for the engraftment of gene-transduced HSC, and short-term ERT after GT did not diminish the capacity of gene-corrected cells to engraft and persist.

Lung tumor induction in strain A mice with benzotrichloride.

PubMed

Stoner, G D; You, M; Morgan, M A; Superczynski, M J

1986-11-01

Benzotrichloride (BTC) is used in the synthesis of benzoyl chloride and benzoyl peroxide. Epidemiological data suggest that BTC is a human lung carcinogen. In the present study, BTC was evaluated for its ability to induce lung adenomas in strain A/J mice. Four groups of 15 male and 15 female A/J mice were injected i.p. with either tricaprylin or BTC in tricaprylin three times a week for 8 weeks. BTC groups received doses totaling 1440 mg/kg, 719 mg/kg or 287 mg/kg. The mean number of lung tumors per mouse was 127 87 +/- 5.81, 43 +/- 2.44, and 17.73 +/- 1.09 in the groups treated with either 1440 mg/kg, 719 mg/kg, or 287 mg/kg, respectively. Tricaprylin-vehicle controls had a mean number of 0.46 +/- 0.15 lung tumors per mouse. Therefore, BTC produced a significant (P less than 0.001) and dose-related increase in the lung tumor response when compared to tricaprylin controls and is a potent carcinogen in the strain A mouse lung tumor bioassay.

A Comparative Study on the Life-Saving Radioprotective Effects of Vitamins A, E, C and Over-the-Counter Multivitamins.

PubMed

Mortazavi, S M J; Rahimi, S; Mosleh-Shirazi, M A; Arjomandi, M; Soleimani, A; Koohi Hossein-Abadi, O; Haghani, M; Alavi, M

2015-06-01

Oral intake of vitamins which present antioxidant characteristics can protect living organisms against oxidative damage caused by exposure to ionizing radiation. It was previously reported that administration of high levels of vitamin C can lead to increased DNA damage through production of hydroxyl radicals from hydrogen peroxide by the Fenton reaction. However, our early experiments did not confirm this hypothesis. The main goal of this study was to determine if high doses of Vit C can show life-saving radioprotective effects. Phase I: Seventy two male Balb/c mice weighing 20-25g were randomly divided into six groups of 12 animals each. Group I; Vit E for five days, Groups II and III; Vit C and Vit A. Group 4; all three vitamins. Group V; an over-the-counter multivitamin. Group VI; none of the above. Phase II: 120 male BALB/c mice weighing 20-25g were randomly divided into 12 groups of 10 each. Group I; Vit A for five days. Groups II-IV; Vit C 200 mg/kg, 400 mg/kg, 800 mg/kg, respectively. Group V-VII; Vit E at daily doses of 200 iu/kg, 400 iu/kg, 800 iu/kg, respectively. Group VIII and IX; all three vitamins at low and high doses, respectively. Group X; an over-the-counter multivitamin. Group XI; controls group and Group XII; received pure olive oil. All animals (Phases I and II) were exposed to a lethal dose of gamma rays and the survival rates of the animals were monitored and recorded continuously for 16 days after exposure. Phase I: 14 days after irradiation the survival rate for control group was 33.33%, while the survival rates for the 1st to 5th groups were 45.45%, 81.81%, 50%, 57.14%, and 9.09% , respectively. Phase II: The survival rates in the control group and the group that only received pure olive oil, were 50% and 60%, respectively. Survival rate in the animals received Vit C at daily doses of 200 mg/kg, 400 mg/kg, 800 mg/kg, were 90%, 90% and 90%, respectively. Log rank (Mantel-Cox) test showed statistically significant differences between the survival rates in control irradiated mice (no vitamins) and mice received Vit C at daily doses of 200 mg/kg (P=0.042), 400 mg/kg (P=0.042) and 800 mg/kg (P=0.042). Altogether, findings of this study showed that even high doses of Vit C can show life-saving radioprotective effects. The significant radioprotective effect of Vit C at doses used in this study, opens new horizons in developing non-toxic, cost effective, easily available radioprotectors in life-threatening situations such as exposure to lethal doses of ionizing radiation.  The radioprotective effect of Vit A and Vit E seem to be less efficient compared to that of Vit C.

Synergy between cilofungin and amphotericin B in a murine model of candidiasis.

PubMed Central

Hanson, L H; Perlman, A M; Clemons, K V; Stevens, D A

1991-01-01

The efficacies of cilofungin and amphotericin B separately and together in mice with disseminated candidiasis were studied. Male CD-1 mice (age, 5 weeks) were infected intravenously with 3 X 10(5) CFU of Candida albicans. At 4 days postinfection, intraperitoneal therapy was initiated and was continued for 14 days. Therapy groups included those given cilofungin at 6.25 or 62.5 mg/kg/day (given twice daily), amphotericin B at 0.625 mg/kg/day (given once daily), cilofungin at 6.25 mg/kg/day plus amphotericin B, and cilofungin at 62.5 mg/kg/day plus amphotericin B. Mice were observed through 30 days postinfection. All infected untreated mice died of infection between days 6 and 18. Eighty-five percent of mice receiving cilofungin at 6.25 mg/kg/day died between days 13 and 30. All other mice survived. Quantitative determination of the number of CFU of C. albicans in the spleens and kidneys of all survivors revealed that mice that had received both drugs had lower residual burdens of C. albicans. All mice treated with cilofungin at 62.5 mg/kg/day plus amphotericin B had sterile spleens, whereas 42 to 58% of mice given cilofungin or amphotericin B monotherapy had sterile spleens. All kidneys were infected in mice which had received cilofungin at 62.5 mg/kg/day or amphotericin B. Neither organ was infected in 17% of each group receiving combination therapy with cilofungin and amphotericin B. The number of CFU in the kidneys of mice treated with cilofungin at 62.5 mg/kg/day plus amphotericin B was lower than those cultured from mice treated with cilofungin at 62.5 mg/kg/day (P less than 0.001, Mann-Whitney) or amhotericin B (P less than 0.05). Modest synergy was noted in inhibition of the C. albicans isolate in vitro. Pharmacokinetic studies showed elevated levels of cilofungin but not amphotericin B in sera of mice treated with combined therapy compared with those in mice given monotherapy. No overt toxicity was evident with any regimen. The mechanism of increased efficacy may be altered cilofungin distribution, excretion, or metabolism; antifungal synergy; or both. These results indicate that concurrent cilofungin-amphotericin B therapy has synergistic or additive efficacy in vivo. PMID:1929290

Fucosylation Deficiency in Mice Leads to Colitis and Adenocarcinoma.

PubMed

Wang, Yiwei; Huang, Dan; Chen, Kai-Yuan; Cui, Min; Wang, Weihuan; Huang, Xiaoran; Awadellah, Amad; Li, Qing; Friedman, Ann; Xin, William W; Di Martino, Luca; Cominelli, Fabio; Miron, Alex; Chan, Ricky; Fox, James G; Xu, Yan; Shen, Xiling; Kalady, Mathew F; Markowitz, Sanford; Maillard, Ivan; Lowe, John B; Xin, Wei; Zhou, Lan

2017-01-01

De novo synthesis of guanosine diphosphate (GDP)-fucose, a substrate for fucosylglycans, requires sequential reactions mediated by GDP-mannose 4,6-dehydratase (GMDS) and GDP-4-keto-6-deoxymannose 3,5-epimerase-4-reductase (FX or tissue specific transplantation antigen P35B [TSTA3]). GMDS deletions and mutations are found in 6%-13% of colorectal cancers; these mostly affect the ascending and transverse colon. We investigated whether a lack of fucosylation consequent to loss of GDP-fucose synthesis contributes to colon carcinogenesis. FX deficiency and GMDS deletion produce the same biochemical phenotype of GDP-fucose deficiency. We studied a mouse model of fucosylation deficiency (Fx-/- mice) and mice with the full-length Fx gene (controls). Mice were placed on standard chow or fucose-containing diet (equivalent to a control fucosylglycan phenotype). Colon tissues were collected and analyzed histologically or by enzyme-linked immunosorbent assays to measure cytokine levels; T cells also were collected and analyzed. Fecal samples were analyzed by 16s ribosomal RNA sequencing. Mucosal barrier function was measured by uptake of fluorescent dextran. We transplanted bone marrow cells from Fx-/- or control mice (Ly5.2) into irradiated 8-week-old Fx-/- or control mice (Ly5.1). We performed immunohistochemical analyses for expression of Notch and the hes family bHLH transcription factor (HES1) in colon tissues from mice and a panel of 60 human colorectal cancer specimens (27 left-sided, 33 right-sided). Fx-/- mice developed colitis and serrated-like lesions. The intestinal pathology of Fx-/- mice was reversed by addition of fucose to the diet, which restored fucosylation via a salvage pathway. In the absence of fucosylation, dysplasia appeared and progressed to adenocarcinoma in up to 40% of mice, affecting mainly the right colon and cecum. Notch was not activated in Fx-/- mice fed standard chow, leading to decreased expression of its target Hes1. Fucosylation deficiency altered the composition of the fecal microbiota, reduced mucosal barrier function, and altered epithelial proliferation marked by Ki67. Fx-/- mice receiving control bone marrow cells had intestinal inflammation and dysplasia, and reduced expression of cytokines produced by cytotoxic T cells. Human sessile serrated adenomas and right-sided colorectal tumors with epigenetic loss of MutL homolog 1 (MLH1) had lost or had lower levels of HES1 than other colorectal tumor types or nontumor tissues. In mice, fucosylation deficiency leads to colitis and adenocarcinoma, loss of Notch activation, and down-regulation of Hes1. HES1 loss correlates with the development of human right-sided colorectal tumors with epigenetic loss of MLH1. These findings indicate that carcinogenesis in a subset of colon cancer is consequent to a molecular mechanism driven by fucosylation deficiency and/or HES1-loss. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

The gut microbiota contributes to a mouse model of spontaneous bile duct inflammation.

PubMed

Schrumpf, Elisabeth; Kummen, Martin; Valestrand, Laura; Greiner, Thomas U; Holm, Kristian; Arulampalam, Velmurugesan; Reims, Henrik M; Baines, John; Bäckhed, Fredrik; Karlsen, Tom H; Blumberg, Richard S; Hov, Johannes R; Melum, Espen

2017-02-01

A strong association between human inflammatory biliary diseases and gut inflammation has led to the hypothesis that gut microbes and lymphocytes activated in the intestine play a role in biliary inflammation. The NOD.c3c4 mouse model develops spontaneous biliary inflammation in extra- and intrahepatic bile ducts. We aimed to clarify the role of the gut microbiota in the biliary disease of NOD.c3c4 mice. We sampled cecal content and mucosa from conventionally raised (CONV-R) NOD.c3c4 and NOD control mice, extracted DNA and performed 16S rRNA sequencing. NOD.c3c4 mice were rederived into a germ free (GF) facility and compared with CONV-R NOD.c3c4 mice. NOD.c3c4 mice were also co-housed with NOD mice and received antibiotics from weaning. The gut microbial profiles of mice with and without biliary disease were different both before and after rederivation (unweighted UniFrac-distance). GF NOD.c3c4 mice had less distended extra-hepatic bile ducts than CONV-R NOD.c3c4 mice, while antibiotic treated mice showed reduction of biliary infarcts. GF animals also showed a reduction in liver weight compared with CONV-R NOD.c3c4 mice, and this was also observed in antibiotic treated NOD.c3c4 mice. Co-housing of NOD and NOD.c3c4 mice indicated that the biliary phenotype was neither transmissible nor treatable by co-housing with healthy mice. NOD.c3c4 and NOD control mice show marked differences in the gut microbiota. GF NOD.c3c4 mice develop a milder biliary affection compared with conventionally raised NOD.c3c4 mice. Our findings suggest that the intestinal microbiota contributes to disease in this murine model of biliary inflammation. Mice with liver disease have a gut microflora (microbiota) that differs substantially from normal mice. In a normal environment, these mice spontaneously develop disease in their bile ducts. However, when these mice, are raised in an environment devoid of bacteria, the disease in the bile ducts diminishes. Overall this clearly indicates that the bacteria in the gut (the gut microbiota) influences the liver disease in these mice. Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

[Circadian rhythm in susceptibility of mice to the anti-tumor drug carboplatin].

PubMed

Lu, X H; Yin, L J

1994-12-01

The platinum-containing compounds has become a major chemical agent in the treatment of cancer. A circadian rhythm in the susceptibility of rodents and human being to cisplatin has been demonstrated, the maximal tolerance being found in the animal's active phase. Carboplatin is a second generation analog. Two studies were performed on mice with carboplatin under 12:12 light dark cycle to study its chronotoxicity and chronoeffectiveness. In study I, single intraperitoneal injection of 192mg/kg (LD50) carboplatin was given to four groups of mice at four different circadian stage. It was found that at 50% the overall mortality of mice, there was a mortality difference of 28% for mice receiving the drug at 9 a.m. to 71% for mice receiving drug at 9 p.m. It demonstrated that carboplatin was better tolerated in the animal's early sleep phase. In study II, S180 tumor-bearing mice were treated with 50mg/kg of carboplatin. The longest mean survival time and the lowest marrow toxicity occurred in the group which received the drug at the beginning of the sleep phase. It showed that the susceptibility of mice to carboplatin is circadian stage dependent. These data clearly demonstrate that, by timing the administration of drugs according to body rhythms, such as the host susceptibility-resistance rhythm to a drug, one can gain a therapeutic advantage over an approach which ignores such rhythms.

Mouse Model of Halogenated Platinum Salt Hypersensitivity ...

EPA Pesticide Factsheets

Occupational exposure to halogenated platinum salts can trigger the development of asthma. Concern for increased asthma risk exists for the general population due to the use of platinum (Pt) in catalytic converters and its emerging use as a diesel fuel additive. To investigate airway responses to Pt, we developed a mouse model of Pt hypersensitivity. Previously, we confirmed the dermal sensitizing potency of ammonium hexachloroplatinate (AHCP) using an ex vivo [3H]methyl thymidine labeling version of the local lymph node assay in BALB/c mice. Here, we investigated the ability of AHCP to induce airway responses in mice sensitized by the dermal route. Mice were sensitized through application of 100 µL 1% AHCP in DMSO to the shaved back on days 0, 5 and 19, and 25 µl to each ear on days 10, 11 and 12. Unsensitized mice received vehicle. On day 24, mice were challenged by oropharyngeal aspiration (OPA) with 0 or 100 µg AHCP in saline. Before and immediately after challenge, airway responses were assessed using whole body plethysmography (WBP). On day 26, changes in ventilatory responses to methacholine (Mch) aerosol were assessed by WBP; dose-dependent increases in Mch responsiveness occurred in sensitized mice. Bronchoalveolar lavage fluid harvested from sensitized mice contained an average of 7.5% eosinophils compared to less than 0.5% in control mice (p < 0.05). This model will be useful for assessing both relative sensitizing potency and cross-reacti

Evaluation of acute toxicity, genotoxicity and inhibitory effect on acute inflammation of an ethanol extract of Morus alba L. (Moraceae) in mice.

PubMed

Oliveira, Alisson Macário de; Nascimento, Matheus Ferreira do; Ferreira, Magda Rhayanny Assunção; Moura, Danielle Feijó de; Souza, Talita Giselly Dos Santos; Silva, Gabriela Cavalcante da; Ramos, Eduardo Henrique da Silva; Paiva, Patrícia Maria Guedes; Medeiros, Paloma Lys de; Silva, Teresinha Gonçalves da; Soares, Luiz Alberto Lira; Chagas, Cristiano Aparecido; Souza, Ivone Antônia de; Napoleão, Thiago Henrique

2016-12-24

Morus alba L. (white mulberry) is used in traditional medicine worldwide, including Brazil. The leaves of this plant are used to treat inflammatory disorders. Universal interest in this plant necessitates studies on the toxicological safety and scientific substantiation of the medicinal properties of M. alba. In previous work, we investigated the acute toxicity of orally administered M. alba ethanol extract in mice. This work was designed to investigate the ethanol extract obtained from M. alba leaves for acute toxicity when intraperitoneally administered, in vivo genotoxicity, and potential to reduce acute inflammation. In order to further investigate the constituents of the extract, we also obtained the high-performance liquid chromatography (HPLC) fingerprint of the extract. Phytochemical analysis by thin layer chromatography (TLC) was performed and the results were used to obtain the HPLC fingerprint. Acute toxicity of 300 and 2000mg/kg b.w. i.p. doses administered to mice for 14 days was evaluated. Genotoxicity was evaluated by counting the number of micronucleated polychromatic erythrocytes in the blood of mice that either received or did not receive the extract at 75, 150 and 300mg/kg b.w. per os. The anti-inflammatory effect of the same doses administered per os was investigated using the carrageenan air pouch model. The TLC analysis of the extract revealed the presence of a remarkable amount of flavonoids and cinnamic acids. The HPLC fingerprint showed the presence of one major peak corresponding to chlorogenic acid and two smaller peaks corresponding to flavonoids. In the toxicity assays, there were no deaths or deviations in behavior of treated mice as compared to the control at any dose. However, biochemical, hematological, and histological analyses showed that intraperitoneal injection caused several forms of damage to the mice, which were not observed in case of oral administration, studied in our previous work. Oral administration of the extract did not result in genotoxicity and considerably reduced (58.6-65.6% inhibition) leukocyte migration in all doses evaluated, in comparison with the negative control. The ethanol extract from M. alba leaves administered intraperitoneally possesses a greater degree of toxicity in mice when compared to per os administration. The extract was not genotoxic when ingested by mice and exhibited a highly inhibitory effect against acute inflammation, which is probably linked to the presence of chlorogenic acid and flavonoids in the composition. This work contributes to the determination of safety of the medicinal use of M. alba leaves. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Possible carcinogenic potential of dimethyl dimethoxy biphenyl dicarboxylate in experimental animals

PubMed Central

Botros, Sanaa Sabet; El-Lakkany, Naglaa Mohamed; Hammam, Olfat Ali; Sabra, Abdel-Naser Abdel-Aal; Taha, Alaa Awad

2016-01-01

Dimethyl dimethoxy biphenyl dicarboxylate (DDB) has been extensively used in the treatment of liver diseases accounting for 1–6% of the global disease burden. Cell replication, DNA synthesis, and proliferation, providing significant information about behavior of cells were examined in mice exposed to subchronic administration with DDB. Conventional liver functions specifically gamma-glutamyltransferase (γ-GT), a marker expressing liver canceration was also investigated. Normal mice were allocated into two groups each of 10 mice. The 1st and 2nd groups were treated with DDB in a dose of 50 mg/kg/day, 5 days/week for 1 month and 3 months, respectively. Comparable groups of normal mice were left without treatment as controls. Compared to normal control group, animals receiving DDB for 3 months showed marked elevations of both alanine aminotransferase and γ-GT, significant inhibition in cytochrome P450, a significant increase in the mean ploidy and 4C with moderate to marked increase in S-phase populations and the number of proliferating cell nuclear antigen-positive cells. In conclusion, this is the first report on the potential relationship between the subchronic administration of DDB and the increase in the hepatocyte proliferation, cell replication and DNA synthesis that may raise an alarm regarding possible DDB insult on the biological behavior of cells. PMID:27144153

Impact of N-acetylcysteine and sesame oil on lipid metabolism and hypothalamic-pituitary-adrenal axis homeostasis in middle-aged hypercholesterolemic mice

PubMed Central

Korou, Laskarina-Maria; Agrogiannis, George; Koros, Christos; Kitraki, Efthimia; Vlachos, Ioannis S.; Tzanetakou, Irene; Karatzas, Theodore; Pergialiotis, Vasilios; Dimitroulis, Dimitrios; Perrea, Despina N.

2014-01-01

Hyperlipidemia and stress are important factors affecting cardiovascular health in middle-aged individuals. We investigated the effects of N-acetylcysteine (NAC) and sesame oil on the lipidemic status, liver architecture and the hypothalamic-pituitary-adrenal (HPA) axis of middle-aged mice fed a cholesterol-enriched diet. We randomized 36 middle-aged C57bl/6 mice into 6 groups: a control group, a cholesterol/cholic acid diet group, a cholesterol/cholic acid diet group with NAC supplementation, a cholesterol/cholic acid diet enriched with 10% sesame oil and two groups receiving a control diet enriched with NAC or sesame oil. NAC administration prevented the onset of the disturbed lipid profile, exhibiting decreased lipid peroxidation and alkaline phosphatase (ALP) levels, restored nitric oxide bioavailability and reduced hepatic damage, compared to non-supplemented groups. High-cholesterol feeding resulted in increased hypothalamic glucocorticoid receptors (GR) levels, while NAC supplementation prevented this effect. NAC supplementation presented significant antioxidant capacity by means of preventing serum lipid status alterations, hepatic damage, and HPA axis disturbance due to high-cholesterol feeding in middle-aged mice. These findings suggest a beneficial preventive action of plant-derived antioxidants, such as NAC, on lipid metabolism and on the HPA axis. PMID:25348324

Ginseng ameliorates chronic histopathologic changes in a murine model of asthma.

PubMed

Babayigit, Arzu; Olmez, Duygu; Karaman, Ozkan; Bagriyanik, H Alper; Yilmaz, Osman; Kivcak, Bijen; Erbil, Guven; Uzuner, Nevin

2008-01-01

Currently, asthma therapies are effective in reducing inflammation but airway remodeling is poorly responsive to these agents. New therapeutic options that have fewer side effects and reverse chronic changes in the lungs are essential. This study aimed to determine the efficacy of oral administration of ginseng on lung histopathology in a murine model of chronic asthma. BALB/c mice were divided into four groups: control, placebo, ginseng, and dexamethasone. All mice except those in the control group were sensitized and challenged with ovalbumin. Then, mice in the ginseng group were given 2 gr/kg per day of ginseng and mice in the dexamethasone group received 1 mg/kg per day of dexamethasone via orogastic gavage once daily for 1 week. Lung histopathology was evaluated by using light and electron microscopy in all groups. All of the chronic changes of airways in the ginseng group were significantly ameliorated when compared with the placebo group. When compared with the dexamethasone group, the ginseng group had significantly lower numbers of mast cell count. Thicknesses of basement membrane, epithelium, and subepithelial smooth muscle were not statistically different between the ginseng and dexamethasone groups. Goblet cell numbers were much more reduced in the dexamethasone group. Ginseng is effective in resolving the established chronic histopathological changes of the lungs in the murine model of asthma.

Role of lipocalin 2 in intraventricular haemoglobin-induced brain injury

PubMed Central

Shishido, Hajime; Toyota, Yasunori; Hua, Ya; Keep, Richard F; Xi, Guohua

2016-01-01

Objective Our recent studies have shown that blood components, including haemoglobin and iron, contribute to hydrocephalus development and brain injury after intraventricular haemorrhage (IVH). The current study investigated the role of lipocalin 2 (LCN2), a protein involved in iron handling, in the ventricular dilation and neuroinflammation caused by brain injury in a mouse model of IVH. Design Female wild-type (WT) C57BL/6 mice and LCN2-deficient (LCN2−/−) mice had an intraventricular injection of haemoglobin, and control mice received an equivalent amount of saline. MRI was performed presurgery and postsurgery to measure ventricular volume and the brains were used for either immunohistochemistry or western blot. Results Ventricular dilation was observed in WT mice at 24 h after haemoglobin (25 mg/mL, 20 µL) injection (12.5±2.4 vs 8.6±1.5 mm3 in the control, p<0.01). Western blotting showed that LCN2 was significantly upregulated in the periventricular area (p<0.01). LCN2 was mainly expressed in astrocytes, whereas the LCN2 receptor was detected in astrocytes, microglia/macrophages and neurons. Haemoglobin-induced ventricle dilation and glia activation were less in LCN2−/− mice (p<0.01). Injection of high-dose haemoglobin (50 mg/mL) resulted in lower mortality in LCN2−/− mice (27% vs 86% in WT; p<0.05). Conclusions Intraventricular haemoglobin caused LCN2 upregulation and ventricular dilation. Haemoglobin resulted in lower mortality and less ventricular dilation in LCN2−/− mice. These results suggest that LCN2 has a role in haemoglobin-induced brain injury and may be a therapeutic target for IVH. PMID:28959462

Evaluating The Effect of Melatonin on HAS2, and PGR expression, as well as Cumulus Expansion, and Fertility Potential in Mice.

PubMed

Ezzati, Maryam; Roshangar, Leila; Soleimani Rad, Jafar; Karimian, Nahid

2018-04-01

Infertility is a worldwide health problem which affects approximately 15% of sexually active couples. One of the factors influencing the fertility is melatonin. Also, protection of oocytes and embryos from oxidative stress inducing chemicals in the culture medium is important. The aim of the present study was to investigate if melatonin could regulate hyaluronan synthase-2 (HAS2) and Progesterone receptor (PGR) expressions in the cumulus cells of mice oocytes and provide an in vitro fertilization (IVF) approach. In this experimental study, for this purpose, 30 adult female mice and 15 adult male mice were used. The female mice were superovulated using 10 U of pregnant mare serum gonadotropin (PMSG) and 24 hours later, 10 U of human chorionic gonadotropin (hCG) were injected. Next, cumulus oocyte complexes (COCs) were collected from the oviducts of the female mice by using a matrix-flushing method. The cumulus cells were cultured with melatonin 10 μM for 6 hours and for real-time reverse transcription-polymerase chain reaction (RT-PCR) was used for evaluation of HAS2 and PGR expression levels. The fertilization rate was evaluated through IVF. All the data were analyzed using a t test. The results of this study showed that HAS2 and PGR expressions in the cumulus cells of the mice receiving melatonin increased in comparison to the control groups. Also, IVF results revealed an enhancement in fertilization rate in the experimental groups compared to the control groups. To improve the oocyte quality and provide new approaches for infertility treatment, administration of melatonin as an antioxidant, showed promising results. Thus, it is concluded that fertility outcomes can be improved by melatonin it enhances PGR. Copyright© by Royan Institute. All rights reserved.

Parvalbumin Gene Transfer Impairs Skeletal Muscle Contractility in Old Mice

PubMed Central

Murphy, Kate T.; Ham, Daniel J.; Church, Jarrod E.; Naim, Timur; Trieu, Jennifer; Williams, David A.

2012-01-01

Abstract Sarcopenia is the progressive age-related loss of skeletal muscle mass associated with functional impairments that reduce mobility and quality of life. Overt muscle wasting with sarcopenia is usually preceded by a slowing of the rate of relaxation and a reduction in maximum force production. Parvalbumin (PV) is a cytosolic Ca2+ buffer thought to facilitate relaxation in muscle. We tested the hypothesis that restoration of PV levels in muscles of old mice would increase the magnitude and hasten relaxation of submaximal and maximal force responses. The tibialis anterior (TA) muscles of young (6 month), adult (13 month), and old (26 month) C57BL/6 mice received electroporation-assisted gene transfer of plasmid encoding PV or empty plasmid (pcDNA3.1). Contractile properties of TA muscles were assessed in situ 14 days after transfer. In old mice, muscles with increased PV expression had a 40% slower rate of tetanic force development (p<0.01), and maximum twitch and tetanic force were 22% and 16% lower than control values, respectively (p<0.05). Muscles with increased PV expression from old mice had an 18% lower maximum specific (normalized) force than controls, and absolute force was ∼26% lower at higher stimulation frequencies (150–300 Hz, p<0.05). In contrast, there was no effect of increased PV expression on TA muscle contractile properties in young and adult mice. The impairments in skeletal muscle function in old mice argue against PV overexpression as a therapeutic strategy for ameliorating aspects of contractile dysfunction with sarcopenia and help clarify directions for therapeutic interventions for age-related changes in skeletal muscle structure and function. PMID:22455364

Consumption of Goats’ Milk Protects Mice From Carbon Tetrachloride-Induced Acute Hepatic Injury and Improves the Associated Gut Microbiota Imbalance

PubMed Central

Zhang, Jiachao; Wang, Zhaoxia; Huo, Dongxue; Shao, Yuyu

2018-01-01

Drugs used to treat liver diseases have serious side effects; it is important to search for safe functional foods with hepatoprotective functions and few side effects. In this study, potential hepatoprotective effects of goats’ milk and cows’ milk on mice with CCl4-induced acute hepatic injury were evaluated. We also elucidated the role of goats’ and cows’ milk on the regulation of CCl4-induced gut microbiota imbalance. In mice with liver damage induced by CCl4, administration of goats’ milk for 7 days prior to injection of CCl4 had beneficial effects on the indicators of liver damage within 1 day: the area of liver necrosis was small; activity of alanine transaminase (ALT) and aspartate transaminase (AST) and expression of the genes CYP2E1 and TNF-α were lower than that of model group of mice. By 7 days after CCl4 injection, there were no significant differences in liver damage indicators (ALT, AST, malondialdehyde, superoxide dismutase, and glutathione) between the goats’ milk group, which continued to receive goats’ milk, and the untreated control group of mice showing that goats’ milk continued to protect against liver damage. Throughout the entire experiment, the community of gut microbes from mice in the goats’ milk treatment was more similar to the untreated control group than to the cows’ milk group and the model group, indicating that intake of goats’ milk prior and post-CCl4 injection effectively prevented and alleviated the intestinal microbial disorder that caused by CCl4 in mice. Our research suggests that goats’ milk could be developed as a potential functional food to prevent/protect against liver injury. PMID:29867999

In vivo near-infrared imaging of fibrin deposition in thromboembolic stroke in mice.

PubMed

Zhang, Yi; Fan, Shufeng; Yao, Yuyu; Ding, Jie; Wang, Yu; Zhao, Zhen; Liao, Lei; Li, Peicheng; Zang, Fengchao; Teng, Gao-Jun

2012-01-01

Thrombus and secondary thrombosis plays a key role in stroke. Recent molecular imaging provides in vivo imaging of activated factor XIII (FXIIIa), an important mediator of thrombosis or fibrinolytic resistance. The present study was to investigate the fibrin deposition in a thromboembolic stroke mice model by FXIIIa-targeted near-infrared fluorescence (NIRF) imaging. The experimental protocol was approved by our institutional animal use committee. Seventy-six C57B/6J mice were subjected to thromboembolic middle cerebral artery occlusion or sham operation. Mice were either intravenously injected with the FXIIIa-targeted probe or control probe. In vivo and ex vivo NIRF imaging were performed thereafter. Probe distribution was assessed with fluorescence microscopy by spectral imaging and quantification system. MR scans were performed to measure lesion volumes in vivo, which were correlated with histology after animal euthanasia. In vivo significant higher fluorescence intensity over the ischemia-affected hemisphere, compared to the contralateral side, was detected in mice that received FXIIIa-targeted probe, but not in the controlled mice. Significantly NIRF signals showed time-dependent processes from 8 to 96 hours after injection of FXIIIa-targeted probes. Ex vivo NIRF image showed an intense fluorescence within the ischemic territory only in mice injected with FXIIIa-targeted probe. The fluorescence microscopy demonstrated distribution of FXIIIa-targeted probe in the ischemic region and nearby micro-vessels, and FXIIIa-targeted probe signals showed good overlap with immune-fluorescent fibrin staining images. There was a significant correlation between total targeted signal from in vivo or ex vivo NIRF images and lesion volume. Non-invasive detection of fibrin deposition in ischemic mouse brain using NIRF imaging is feasible and this technique may provide an in vivo experimental tool in studying the role of fibrin in stroke.

In Vivo Near-Infrared Imaging of Fibrin Deposition in Thromboembolic Stroke in Mice

PubMed Central

Zhang, Yi; Fan, Shufeng; Yao, Yuyu; Ding, Jie; Wang, Yu; Zhao, Zhen; Liao, Lei; Li, Peicheng; Zang, Fengchao; Teng, Gao-Jun

2012-01-01

Objectives Thrombus and secondary thrombosis plays a key role in stroke. Recent molecular imaging provides in vivo imaging of activated factor XIII (FXIIIa), an important mediator of thrombosis or fibrinolytic resistance. The present study was to investigate the fibrin deposition in a thromboembolic stroke mice model by FXIIIa–targeted near-infrared fluorescence (NIRF) imaging. Materials and Methods The experimental protocol was approved by our institutional animal use committee. Seventy-six C57B/6J mice were subjected to thromboembolic middle cerebral artery occlusion or sham operation. Mice were either intravenously injected with the FXIIIa-targeted probe or control probe. In vivo and ex vivo NIRF imaging were performed thereafter. Probe distribution was assessed with fluorescence microscopy by spectral imaging and quantification system. MR scans were performed to measure lesion volumes in vivo, which were correlated with histology after animal euthanasia. Results In vivo significant higher fluorescence intensity over the ischemia-affected hemisphere, compared to the contralateral side, was detected in mice that received FXIIIa-targeted probe, but not in the controlled mice. Significantly NIRF signals showed time-dependent processes from 8 to 96 hours after injection of FXIIIa-targeted probes. Ex vivo NIRF image showed an intense fluorescence within the ischemic territory only in mice injected with FXIIIa-targeted probe. The fluorescence microscopy demonstrated distribution of FXIIIa-targeted probe in the ischemic region and nearby micro-vessels, and FXIIIa-targeted probe signals showed good overlap with immune-fluorescent fibrin staining images. There was a significant correlation between total targeted signal from in vivo or ex vivo NIRF images and lesion volume. Conclusion Non-invasive detection of fibrin deposition in ischemic mouse brain using NIRF imaging is feasible and this technique may provide an in vivo experimental tool in studying the role of fibrin in stroke. PMID:22272319

Twenty-six-week oral carcinogenicity study of 3-monochloropropane-1,2-diol in CB6F1-rasH2 transgenic mice.

PubMed

Lee, Byoung-Seok; Park, Sang-Jin; Kim, Yong-Bum; Han, Ji-Seok; Jeong, Eun Ju; Son, Hwa-Young; Moon, Kyoung-Sik

2017-01-01

The carcinogenic potential of 3-monochloro-1,2-propanediol (3-MCPD) was evaluated in a short-term carcinogenicity testing study using CB6F1 rasH2-Tg (rasH2-Tg) mice. 3-MCPD is found in many foods and food ingredients as a result of storage or processing and is regarded as a carcinogen since it is known to induce Leydig cell and kidney tumors in rats. Male and female rasH2-Tg mice were administered 3-MCPD once daily by oral gavage at doses of 0, 10, 20, and 40 mg/kg body weight (bw) per day for 26 weeks. As a positive control, N-methyl-N-nitrosourea (MNU) was administered as a single intraperitoneal injection (75 mg/kg). In 3-MCPD-treated mice, there was no increase in the incidence of neoplastic lesions compared to the incidence in vehicle control mice. However, 3-MCPD treatment resulted in an increased incidence of tubular basophilia in the kidneys and germ cell degeneration in the testes, with degenerative germ cell debris in the epididymides of males at 20 and 40 mg/kg bw per day. In 3-MCPD-treated females, vacuolation of the brain and spinal cord was observed at 40 mg/kg bw per day; however, only one incidence of vacuolation was observed in males. Forestomach and cutaneous papilloma and/or carcinoma and lymphoma were observed in most rasH2 mice receiving MNU treatment. We concluded that 3-MCPD did not show carcinogenic potential in the present study using rasH2-Tg mice. The findings of this study suggest that the carcinogenic potential of 3-MCPD is species specific.

Role of Muscarinic Acetylcholine Receptors in Serial Feature-Positive Discrimination Task during Eyeblink Conditioning in Mice

PubMed Central

Rahman, Md. Ashrafur; Tanaka, Norifumi; Usui, Koji; Kawahara, Shigenori

2016-01-01

We investigated the role of muscarinic acetylcholine receptors (mAChRs) in eyeblink serial feature-positive discrimination learning in mice using the mAChR antagonist. A 2-s light cue was delivered 5 or 6 s before the presentation of a 350-ms tone paired with a 100-ms periorbital electrical shock (cued trial) but not before the tone-alone presentation (non-cued trial). Mice received 30 cued and 30 non-cued trials each day in a random order. We found that saline-injected control mice were successfully discriminating between cued and non-cued trials within a few days of conditioning. The mice responded more frequently to the tone in cued trials than in non-cued trials. Analysis of conditioned response (CR) dynamics revealed that the CR onset latency was shorter in cued trials than in non-cued trials, despite the CR peak amplitude not differing significantly between the two conditions. In contrast, scopolamine-injected mice developed an equal number of CRs with similar temporal patterns irrespective of the presence of the cue during the 7 days of conditioning, indicating in a failure to acquire conditional discrimination. In addition, the scopolamine administration to the control mice after they had successfully acquired discrimination did not impair the conditional discrimination and expression of pre-acquired CR. These results suggest that mAChRs may play a pivotal role in memory formation in the conditional brain state associated with the feature cue; however they are unlikely to be involved in the development of discrimination after conditional memory had formed in the serial feature-positive discrimination task during eyeblink conditioning. PMID:26808980

An extract from the Atlantic brown algae Saccorhiza polyschides counteracts diet-induced obesity in mice via a gut related multi-factorial mechanisms.

PubMed

Huebbe, Patricia; Nikolai, Sibylle; Schloesser, Anke; Herebian, Diran; Campbell, Graeme; Glüer, Claus-Christian; Zeyner, Annette; Demetrowitsch, Tobias; Schwarz, Karin; Metges, Cornelia C; Roeder, Thomas; Schultheiss, Gerhard; Ipharraguerre, Ignacio R; Rimbach, Gerald

2017-09-26

In this study we addressed the questions whether an Atlantic brown algae extract (BAE) affects diet induced obesity in mice and which would be the primary targets and underlying key mechanisms. Male C57 BL/6 mice were fed a hypercaloric diet, referred to as high fat diet (HFD), supplemented with a freeze-dried aqueous BAE from Saccorhiza polyschides (5 %) for 8 months. Compared to the control group, dietary BAE supplementation significantly attenuated increase in body weight and fat mass. We observed apparent metabolic improvement including normalization of blood glucose, reduced plasma leptin, reduced fecal bile salt hydrolase activity with lower microbial production of toxic bile acid metabolites in the gut and increased systemic bile acid circulation in BAE-fed mice counteracting adverse effects of long term HFD feeding. Survival of mice receiving dietary BAE supplementation appeared slightly enhanced; however, median and maximal life spans as well as hepatic mTOR activation were not significantly different between BAE and control mice. We suggest that the beneficial metabolic effects of our BAE are at least partly mediated by alterations in gut microbiota associated with fermentation of indigestible polysaccharides that are major components of brown algae such as alginates and fucoidans. We moreover propose a multi-factorial mechanism that involves profound alterations in bile acid homeostasis, changes in intestinal and systemic glucose metabolism likely including increased intestinal gluconeogenesis, increased activity of the intestinally derived hormone GLP-1 contributing to promote systemic insulin sensitivity, and inhibition of α-amylase activity, which expectably limits dietary carbohydrate digestion and glucose release.

Contrasting effects of Bifidobacterium breve NCIMB 702258 and Bifidobacterium breve DPC 6330 on the composition of murine brain fatty acids and gut microbiota.

PubMed

Wall, Rebecca; Marques, Tatiana M; O'Sullivan, Orla; Ross, R Paul; Shanahan, Fergus; Quigley, Eamonn M; Dinan, Timothy G; Kiely, Barry; Fitzgerald, Gerald F; Cotter, Paul D; Fouhy, Fiona; Stanton, Catherine

2012-05-01

We previously showed that microbial metabolism in the gut influences the composition of bioactive fatty acids in host adipose tissue. This study compared the effect of dietary supplementation for 8 wk with human-derived Bifidobacterium breve strains on fat distribution and composition and the composition of the gut microbiota in mice. C57BL/6 mice (n = 8 per group) received B. breve DPC 6330 or B. breve NCIMB 702258 (10(9) microorganisms) daily for 8 wk or no supplement (controls). Tissue fatty acid composition was assessed by gas-liquid chromatography while 16S rRNA pyrosequencing was used to investigate microbiota composition. Visceral fat mass and brain stearic acid, arachidonic acid, and DHA were higher in mice supplemented with B. breve NCIMB 702258 than in mice in the other 2 groups (P < 0.05). In addition, both B. breve DPC 6330 and B. breve NCIMB 702258 supplementation resulted in higher propionate concentrations in the cecum than did no supplementation (P < 0.05). Compositional sequencing of the gut microbiota showed a tendency for greater proportions of Clostridiaceae (25%, 12%, and 18%; P = 0.08) and lower proportions of Eubacteriaceae (3%, 12%, and 13%; P = 0.06) in mice supplemented with B. breve DPC 6330 than in mice supplemented with B. breve NCIMB 702258 and unsupplemented controls, respectively. The response of fatty acid metabolism to administration of bifidobacteria is strain-dependent, and strain-strain differences are important factors that influence modulation of the gut microbial community by ingested microorganisms.

Mangiferin induces islet regeneration in aged mice through regulating p16INK4a

PubMed Central

Liu, Yilong; Huai, Guoli; Sun, Minghan; Deng, Shaoping; Yang, Hongji; Tong, Rongsheng; Wang, Yi

2018-01-01

Previous studies by our group on mangiferin demonstrated that it exerts an antihyperglycemic effect through the regulation of cell cycle proteins in 3-month-old, partially pancreatectomized (PPx) mice. However, β-cell proliferation is known to become severely restricted with advanced age. Therefore, it is unknown whether mangiferin is able to reverse the diabetic condition and retain β-cell regeneration capability in aged mice. In the present study, 12-month-old C57BL/6J mice that had undergone PPx were subjected to mangiferin treatment (90 mg/kg) for 28 days. Mangiferin-treated aged mice exhibited decreased blood glucose levels and increased glucose tolerance, which was accompanied with higher serum insulin levels when compared with those in untreated PPx control mice. In addition, islet hyperplasia, elevated β-cell proliferation and reduced β-cell apoptosis were also identified in the mice that received mangiferin treatment. Further studies on the mRNA transcript and protein expression levels indicated comparatively increased levels of cyclins D1 and D2 and cyclin-dependent kinase 4 in mangiferin-treated mice, while the levels of p27Kip1 and p16INK4a were decreased relative to those in the untreated PPx controls. Of note, mangiferin treatment improved the proliferation rate of islet β-cells in adult mice overexpressing p16INK4a, suggesting that mangiferin induced β-cell proliferation via the regulation of p16INK4a. In addition, the mRNA transcription levels of critical genes associated with insulin secretion, including pancreatic and duodenal homeobox 1, glucose transporter 2 and glucokinase, were observed to be upregulated after mangiferin treatment. Taken together, it was indicated that mangiferin treatment significantly induced β-cell proliferation and inhibited β-cell apoptosis by regulating cell cycle checkpoint proteins. Furthermore, mangiferin was also demonstrated to regulate genes associated with insulin secretion. Collectively these, results suggest the therapeutic potential of mangiferin in the treatment of diabetes in aged individuals. PMID:29512742

Secretoglobin Superfamily Protein SCGB3A2 Alleviates House Dust Mite-Induced Allergic Airway Inflammation in Mice.

PubMed

Yoneda, Mitsuhiro; Xu, Lei; Kajiyama, Hiroaki; Kawabe, Shuko; Paiz, Jorge; Ward, Jerrold M; Kimura, Shioko

2016-01-01

Secretoglobin (SCGB) 3A2, a novel, lung-enriched, cytokine-like, secreted protein of small molecular weight, was demonstrated to exhibit various biological functions including anti-inflammatory, antifibrotic and growth-factor activities. Anti-inflammatory activity was uncovered using the ovalbumin-induced allergic airway inflammation model. However, further validation of this activity using knockout mice in a different allergic inflammation model is necessary in order to establish the antiallergic inflammatory role for this protein. Scgb3a2-null (Scgb3a2-/-) mice were subjected to nasal inhalation of Dermatophagoides pteronyssinus extract for 5 days/week for 5 consecutive weeks; control mice received nasal inhalation of saline as a comparator. Airway inflammation was assessed by histological analysis, the number of inflammatory cells and various Th2-type cytokine levels in the lungs and bronchoalveolar lavage fluids by qRT-PCR and ELISA, respectively. Exacerbated inflammation was found in the airway of Scgb3a2-/- mice subjected to house dust mite (HDM)-induced allergic airway inflammation compared with saline-treated control groups. All the inflammation end points were increased in the Scgb3a2-/- mice. The Ccr4 and Ccl17 mRNA levels were higher in HDM-treated lungs of Scgb3a2-/- mice than wild-type mice or saline-treated Scgb3a2-/- mice, whereas no changes were observed for Ccr3 and Ccl11 mRNA levels. These results demonstrate that SCGB3A2 has an anti-inflammatory activity in the HDM-induced allergic airway inflammation model, in which SCGB3A2 may modulate the CCR4-CCL17 pathway. SCGB3A2 may provide a useful tool to treat allergic airway inflammation, and further studies on the levels and function of SCGB3A2 in asthmatic patients are warranted. © 2016 S. Karger AG, Basel.

Rhythmic brain stimulation reduces anxiety-related behavior in a mouse model based on meditation training.

PubMed

Weible, Aldis P; Piscopo, Denise M; Rothbart, Mary K; Posner, Michael I; Niell, Cristopher M

2017-03-07

Meditation training induces changes at both the behavioral and neural levels. A month of meditation training can reduce self-reported anxiety and other dimensions of negative affect. It also can change white matter as measured by diffusion tensor imaging and increase resting-state midline frontal theta activity. The current study tests the hypothesis that imposing rhythms in the mouse anterior cingulate cortex (ACC), by using optogenetics to induce oscillations in activity, can produce behavioral changes. Mice were randomly assigned to groups and were given twenty 30-min sessions of light pulses delivered at 1, 8, or 40 Hz over 4 wk or were assigned to a no-laser control condition. Before and after the month all mice were administered a battery of behavioral tests. In the light/dark box, mice receiving cortical stimulation had more light-side entries, spent more time in the light, and made more vertical rears than mice receiving rhythmic cortical suppression or no manipulation. These effects on light/dark box exploratory behaviors are associated with reduced anxiety and were most pronounced following stimulation at 1 and 8 Hz. No effects were seen related to basic motor behavior or exploration during tests of novel object and location recognition. These data support a relationship between lower-frequency oscillations in the mouse ACC and the expression of anxiety-related behaviors, potentially analogous to effects seen with human practitioners of some forms of meditation.

Regulatory T cells and liver pathology in a murine graft versus host response model.

PubMed

Miyazaki, Teruo; Doy, Mikio; Unno, Rie; Honda, Akira; Ikegami, Tadashi; Itoh, Shinichi; Bouscarel, Bernard; Matsuzaki, Yasushi

2009-06-01

We have previously reported in mice the hepatic inflammatory in graft versus host response (GVHR) model due to the disparity of major histocompatibility complex class-II. The regulatory T (Treg) cells have been reported to control excessive immune response and prevent immune-related diseases. This study aimed to investigate the pathogenesis profiles of chronic GVHR progression, focusing on the Treg cells. GVHR mice induced by parental spleen CD4(+) T cell injection were sacrificed after 0, 2, 4, and 8 weeks (G0, G2, G4, G8). Further, one GVHR group received anti-IL-10 antibody in advance and were maintained for 2 weeks. Pathologic profiles of hepatic infiltrating inflammatory cells were evaluated by haematoxylin and eosin and immunohistochemistry staining with surface markers including Treg cell markers. Remarkable hepatic inflammatory in G2 significantly and gradually improved over time up to G8. In immunohistochemical staining, the increased IL-10 receptor beta(+) Tr1 cells in G2 were maintained through to G8; although other inflammatory cells decreased from G2 to G8. By contrast, in the anti-IL-10 antibody received-GVHR mice, the Tr1 cells were not detectable with significant inflammatory aggravation, while FoxP3(+) Treg cells significantly enhanced. These findings in the GVHR mice suggest that the expression and activity of Treg cells, especially the Tr1 cells, might be key factors for pathologic alteration in immune-related liver disease.

Analgesic and anti-inflammatory activities of 80% methanol root extract of Jasminum abyssinicum Hochst. ex. Dc. (Oleaceae) in mice.

PubMed

Tadiwos, Yohannes; Nedi, Teshome; Engidawork, Ephrem

2017-04-18

Pain and inflammation are associated with the pathophysiology of various clinical conditions. Most analgesic and anti-inflammatory drugs available in the market present a wide range of problems. The current study was aimed at investigating the analgesic and anti-inflammatory activity of 80% methanol extract of J. abyssinicum root. The analgesic activity was determined using tail-flick test and acetic acid induced writhing, whereas anti-inflammatory activity was determined by carrageenan induced paw edema and formalin induced pedal edema, carried out in vivo. The test group received three different doses of the extract (50mg/kg, 100mg/kg and 200mg/kg) orally. The positive control group received diclofenac (10mg/kg), aspirin (100mg/kg or 150mg/kg) or morphine (20mg/kg) orally. The negative control group received vehicle (2% Tween 80, 10ml/kg) orally. Furthermore, preliminary phytochemical screening was carried out. Oral administration of J. abbysinicum 80% methanol extract (at all doses) significantly (p<0.001) inhibit pain sensation in the pain models. Similarly, the extract demonstrated anti-inflammatory effect in the inflammation models in mice. Preliminary phytochemical screening showed the presence of saponins, flavonoids, terpenoids, triterpenens and glycosides. The data obtained from the present study indicates that the extract possessed a significant analgesic and anti-inflammatory activity, upholding the folkloric use of the plant. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

The effect of DNA priming-protein boosting on enhancing humoral immunity and protecting mice against lethal HSV infections.

PubMed

Soleimanjahi, Hoorieh; Roostaee, Mohammad Hassan; Rasaee, Mohammad Javad; Mahboudi, Fereidoon; Kazemnejad, Anooshirvan; Bamdad, Taravat; Zandi, Keivan

2006-02-01

Herpes simplex virus produces primary and latent infections with periodic recurrency. The prime-boost immunization strategies were studied using a DNA vaccine carrying the full-length glycoprotein D-1 gene and a baculovirus-derived recombinant glycoprotein D, both expressing herpes simplex virus glycoprotein D-1 protein. Immunization with recombinant DNAs encoding antigenic proteins could induce cellular and humoral responses by providing antigen expression in vivo. Higher immune response, however, occurred when the recombinant proteins followed DNA inoculation. While all groups of the immunized mice and positive control group could resist virus challenge, a higher virus neutralizing antibody level was detected in the animals receiving recombinant protein following DNA vaccination.

Excretory-secretory antigens: a suitable candidate for immunization against ocular toxoplasmosis in a murine model.

PubMed

Norouzpour Deilami, Kiumars; Daryani, Ahmad; Ahmadpour, Ehsan; Sharif, Mehdi; Dadimoghaddam, Yousef; Sarvi, Shahabeddin; Alizadeh, Ahad

2014-12-01

Toxoplasmosis, responsible for ocular impairment, is caused by Toxoplasma gondii. We investigated the effect of Toxoplasma excretory-secretory antigens (ESA) on parasite load and distribution in the eye tissue of a murine model. Case and control groups were immunized with ESA and PBS, respectively. Two weeks after the second immunization, the mice were challenged intraperitoneally with virulent RH strain of Toxoplasma; eye tissue samples of both groups were collected daily (days 1, 2, 3, and the last day before death). Parasite load was determined using real-time quantitative PCR targeted at the B1 gene. Compared to the control group, infected mice that received ESA vaccine presented a considerable decrease in parasite load in the eye tissue, demonstrating the effect of ESA on parasite load and distribution. Diminution of parasite load in mouse eye tissue indicated that ESA might help control disease-related complications and could be a valuable immunization candidate against ocular toxoplasmosis. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effectiveness of Changing the Application of Japanese Honey to a Hydrocolloid Dressing in Between the Inflammatory and Proliferative Phases on Cutaneous Wound Healing in Male Mice.

PubMed

Mukai, Kanae; Komatsu, Emi; Yamanishi, Misa; Hutakuchi, Misako; Kanzaka, Kayo; Uno, Yuka; Yamazaki, Shizuka; Kato, Shizuka; Yamamoto, Tomomi; Hattori, Mayumi; Nakajima, Yukari; Urai, Tamae; Asano, Kimi; Murakado, Naoko; Okuwa, Mayumi; Nakatani, Toshio

2017-01-01

The aim of this study was to investigate the effects of changing the application of Japanese honey to a hydrocolloid dressing (HCD) in between the inflammatory and proliferative phases on cutaneous wound healing in 8-week-old, BALB/cCrSlc male mice. Mice were divided into 4 groups: acacia honey followed by a HCD, buckwheat flour honey followed by a HCD, Chinese milk vetch honey followed by a HCD, and a HCD alone (control group). All mice received 2 full-thickness wounds on both sides of the dorsum using a Disposable Biopsy Punch. The wounds of the control group were covered with a HCD, whereas wounds in the other groups were treated with 0.1 mL of the relevant type of honey until day 3 post-wound and then were covered with a HCD from days 4 to 14. In the experimental groups, the wound area ratio was significantly smaller in the inflammatory phase but significantly larger in the proliferative phase. Reepithelialization, collagen deposition, and wound contraction were significantly delayed compared with those in the control group. The re-expansion of the wounds in the proliferative phase could not be prevented, and reepithelialization, collagen deposition, and wound contraction were delayed compared with those upon the use of a HCD. The study's authors concluded that these methods do not promote cutaneous wound healing better than the use of a HCD alone.

Is there a role for Serratia marcescens in male infertility: An experimental study?

PubMed

Rana, Kalpana; Thaper, Deepali; Prabha, Vijay

2017-04-01

Establishment of a male BALB/c mouse model to study the role of sperm impairing S. marcescens on mouse reproductive potential. The current study can add to use of reliable animal models to provide a noteworthy evidence for the microbial cause of infertility. The mice in the test groups II, III, IV were intraperitoneally administered with different doses (10 4 , 10 6 or 10 8  cfu) of S. marcescens whereas, group I serving as control, received PBS, for 10 consecutive days. The groups were evaluated for any change in body weight, tissue somatic index (%), seminal parameters and histology. Confirmation of S. marcescens from reproductive organs was done by reisolating the same by cultural characteristics and biochemical tests. The results showed that weight gain was evident only in mice receiving PBS (group I), whereas a decrease was recorded in the test groups (group II, III and IV). Only testes of test groups showed significant changes in TSI values whereas, no change in TSI was observed in any reproductive organ of any test group. Seminal parameters viz. sperm count, motility and viability were found to decrease in test groups II, III and IV as compared to control group I. Interestingly, the number of pus cells and percent decapitation was more prominent in test groups which received higher doses (i.e. group III and group IV). The histopathological examination revealed mild to dense inflammation in vas deferens and caudal epididymis in all test groups except hypospermatogenesis which was observed only in test group III and IV. However, in group I, neither adverse changes nor any sign of inflammation were observed. Intraperitoneal inoculation of S. marcescens could lead to alteration of semen parameters, induction of decapitation in spermatozoa and histopathological changes, thereby decreasing the reproductive potential of male mice. Copyright © 2017 Elsevier Ltd. All rights reserved.

Add-On Aliskiren Elicits Stronger Renoprotection Than High-Dose Valsartan in Type 2 Diabetic KKAy Mice That Do Not Respond to Low-Dose Valsartan

PubMed Central

Lei, Bai; Nakano, Daisuke; Fan, Yu-Yan; Kitada, Kento; Hitomi, Hirofumi; Kobori, Hiroyuki; Mori, Hirohito; Masaki, Tsutomu; Nishiyama, Akira

2012-01-01

We hypothesized that aliskiren provides renoprotection in diabetic animals that did not receive sufficient renoprotection by AT1-receptor antagonist treatment. Type 2 diabetic KKAy mice were treated with group 1: vehicle or group 2: valsartan (15 mg/kg per day) from 12 to 16 weeks of age. The mice were subsequently divided into 4 groups and treated with the following combinations of drugs for another 6 weeks: 1: group 1 kept receiving vehicle, 2: group 2 continuously received 15 mg/kg per day of valsartan (Val-Val15), 3: group 2 received 50 mg/kg per day of valsartan (Val-Val50), 4: group 2 continuously received 15 mg/kg per day of valsartan with 25 mg/kg per day of aliskiren (Val-Val+Ali). Aliskiren exerted significant anti-albuminuric effects, whereas valsartan failed to ameliorate the albuminuria in the first four weeks. Surprisingly, the increasing dosage of valsartan in the Val-Val50 group showed non-significant tendencies to attenuate the albuminuria compared with vehicle infusion. Val-Val+Ali significantly suppressed the development of albuminuria and podocyte injury. Val-Val50 and Val-Val+Ali showed similar suppression of angiotensin II contents in the kidney of KKAy mice. In conclusion, the anti-albuminuric effect that was observed in the type 2 diabetic mice showing no anti-albuminuric effect by valsartan can be attributed to the add-on aliskiren. PMID:22673148

Use of Ronidazole and Limited Culling To Eliminate Tritrichomonas muris from Laboratory Mice.

PubMed

Steiner, Jörg M; Schwamberger, Sabine; Pantchev, Nikola; Balzer, Hans-Jörg; Vrhovec, Majda Globokar; Lesina, Marina; Algül, Hana

2016-01-01

Tritrichomonas muris is occasionally identified during routine fecal screening of laboratory mice. Frequently, entire racks are affected, and because no effective treatment is available, culling of affected mice and rederivation by embryo transfer have been suggested. The current study evaluated whether treatment with ronidazole, a nitroimidazole efficacious against T. fetus infections in cats, combined with limited culling was effective against T. muris in laboratory mice (Mus musculus). A subset (n = 39) of mice were treated with ronidazole (400 mg/L in drinking water) for 15 d, after which 6 of the mice still shed T. muris. Consequently all mice in the affected rack received ronidazole (500 mg /L in drinking water) for 25 d. All mice were retested by using pooled samples, and those positive for T. muris (except for a valuable breeding pair) were culled. The remaining mice continued to receive ronidazole for another 17 d. At the end of the treatment period, all mice were tested (days 60 and 81) and were shown to be negative for T. muris. Over the following year, sentinel mice from the rack were tested every 3 mo and remained negative for tritrichomonads by fecal smear. Thus, a combination of limited culling and treatment with ronidazole in the drinking water successfully cleared research mice of infection with T. muris.

The effects of green Ocimum basilicum hydroalcoholic extract on retention and retrieval of memory in mice

PubMed Central

Sarahroodi, Shadi; Esmaeili, Somayyeh; Mikaili, Peyman; Hemmati, Zahra; Saberi, Yousof

2012-01-01

The purpose of this study was evaluation of green Ocimum basilicum (sweet basil) hydroalcoholic extract on memory retention and retrieval of mice by using passive avoidance apparatus. For this purpose, after weighting, coding and classifying the mice, they were grouped (n = 8) as follow as: test groups (electric shock plus sweet basil extract by doses: 100, 200, 400 and 800 mg/kg, i.p.), control group (Only electric shock) and blank group (electric shock plus normal saline). In all mentioned groups delay time of leaving the platform for both retention and retrieval test of memory was measured. In retention test, sweet basil extract was administered immediately after receiving electric shock and in retrieval test it was administered 24 hours after receiving electric shock. The results indicated that hydroalcoholic extract of green Ocimum basilicum significantly (P < 0.05) increased memory retention. The best response was achieved with 400 mg/Kg of the extract. Also, results showed that sweet basil extract significantly (P < 0.05) increased memory retrieval and the best result was achieved with 400 mg/Kg too. It can be concluded that memory enhancing effects of green Ocimum basilicum is because of antioxidant activity of flavonoids, tannins and terpenoids. PMID:23661866

Gene therapy/bone marrow transplantation in ADA-deficient mice: roles of enzyme-replacement therapy and cytoreduction

PubMed Central

Jin, Xiangyang; Wang, Xingchao; Yu, Xiao-Jin; Rozengurt, Nora; Kaufman, Michael L.; Wang, Xiaoyan; Gjertson, David; Zhou, Yang; Blackburn, Michael R.; Kohn, Donald B.

2012-01-01

Gene therapy (GT) for adenosine deaminase–deficient severe combined immune deficiency (ADA-SCID) can provide significant long-term benefit when patients are given nonmyeloablative conditioning and ADA enzyme-replacement therapy (ERT) is withheld before autologous transplantation of γ-retroviral vector-transduced BM CD34+ cells. To determine the contributions of conditioning and discontinuation of ERT to the therapeutic effects, we analyzed these factors in Ada gene knockout mice (Ada−/−). Mice were transplanted with ADA-deficient marrow transduced with an ADA-expressing γ-retroviral vector without preconditioning or after 200 cGy or 900 cGy total-body irradiation and evaluated after 4 months. In all tissues analyzed, vector copy numbers (VCNs) were 100- to 1000-fold greater in mice receiving 900 cGy compared with 200 cGy (P < .05). In mice receiving 200 cGy, VCN was similar whether ERT was stopped or given for 1 or 4 months after GT. In unconditioned mice, there was decreased survival with and without ERT, and VCN was very low to undetectable. When recipients were conditioned with 200 cGy and received transduced lineage-depleted marrow, only recipients receiving ERT (1 or 4 months) had detectable vector sequences in thymocytes. In conclusion, cytoreduction is important for the engraftment of gene-transduced HSC, and short-term ERT after GT did not diminish the capacity of gene-corrected cells to engraft and persist. PMID:22833548

Influence of early stress on memory reconsolidation: Implications for post-traumatic stress disorder treatment

PubMed Central

Birmes, Philippe; Ferry, Barbara

2018-01-01

Post-traumatic stress disorder (PTSD) is a common consequence of exposure to a life-threatening event. Currently, pharmacological treatments are limited by high rates of relapse, and novel treatment approaches are needed. We have recently demonstrated that propranolol, a β-adrenergic antagonist, inhibited aversive memory reconsolidation in animals. Following this, in an open-label study 70% of patients with PTSD treated with propranolol during reactivation of traumatic memory exhibited full remission. However, the reason why 30% of these patients did not respond positively to propranolol treatment is still unclear. One of the major candidates as factor of treatment resistance is the patient's early-life traumatic history. To test the role of this factor, mice with pre- or postnatal stress are being tested in fear conditioning and in a new behavioral task, the "city-like", specifically designed as a mouse model of PTSD. After reactivation of the traumatic event, mice received propranolol injection to block the noradrenergic system during memory reconsolidation. Results show that, in the “city-like” test, control mice strongly avoided the shock compartment but also the compartments containing cues associated with the electric shocks. Injection of propranolol after reactivation greatly reduced the memory of the traumatic event, but this effect was not present when mice had received pre- or postnatal stress. Moreover, propranolol produced only a very weak effect in the fear conditioning test, and never changed the corticosterone level whatever the behavioral experiment. Taken together our results suggest that our new behavioural paradigm is well adapted to PTSD study in mice, and that early stress exposure may have an impact on propranolol PTSD treatment outcome. These data are critical to understanding the effect of propranolol treatment, in order to improve the therapeutic protocol currently used in humans. PMID:29352277

Low dose dietary nitrate improves endothelial dysfunction and plaque stability in the ApoE-/- mouse fed a high fat diet.

PubMed

Bakker, J R; Bondonno, N P; Gaspari, T A; Kemp-Harper, B K; McCashney, A J; Hodgson, J M; Croft, K D; Ward, N C

2016-10-01

Nitric oxide (NO) is an important vascular signalling molecule. NO is synthesised endogenously by endothelial nitric oxide synthase (eNOS). An alternate pathway is exogenous dietary nitrate, which can be converted to nitrite and then stored or further converted to NO and used immediately. Atherosclerosis is associated with endothelial dysfunction and subsequent lesion formation. This is thought to arise due to a reduction in the bioavailability and/or bioactivity of endogenous NO. To determine if dietary nitrate can protect against endothelial dysfunction and lesion formation in the ApoE -/- mouse fed a high fat diet (HFD). ApoE -/- fed a HFD were randomized to receive (i) high nitrate (10mmol/kg/day, n=12), (ii) moderate nitrate (1mmol/kg/day, n=8), (iii) low nitrate (0.1mmol/kg/day, n=8), or (iv) sodium chloride supplemented drinking water (control, n=10) for 10 weeks. A group of C57BL6 mice (n=6) received regular water and served as a healthy reference group. At 10 weeks, ACh-induced vessel relaxation was significantly impaired in ApoE -/- mice versus C57BL6. Mice supplemented with low or moderate nitrate showed significant improvements in ACh-induced vessel relaxation compared to ApoE -/- mice given the high nitrate or sodium chloride. Plaque collagen expression was increased and lipid deposition reduced following supplementation with low or moderate nitrate compared to sodium chloride, reflecting increased plaque stability with nitrate supplementation. Plasma nitrate and nitrite levels were significantly increased in all three groups fed the nitrate-supplemented water. Low and moderate dose nitrate significantly improved endothelial function and atherosclerotic plaque composition in ApoE -/- mice fed a HFD. Copyright © 2016 Elsevier Inc. All rights reserved.

L-threo-dihydroxyphenylserine corrects neurochemical abnormalities in a Menkes disease mouse model.

PubMed

Donsante, Anthony; Sullivan, Patricia; Goldstein, David S; Brinster, Lauren R; Kaler, Stephen G

2013-02-01

Menkes disease is a lethal neurodegenerative disorder of infancy caused by mutations in a copper-transporting adenosine triphosphatase gene, ATP7A. Among its multiple cellular tasks, ATP7A transfers copper to dopamine beta hydroxylase (DBH) within the lumen of the Golgi network or secretory granules, catalyzing the conversion of dopamine to norepinephrine. In a well-established mouse model of Menkes disease, mottled-brindled (mo-br), we tested whether systemic administration of L-threo-dihydroxyphenylserine (L-DOPS), a drug used successfully to treat autosomal recessive norepinephrine deficiency, would improve brain neurochemical abnormalities and neuropathology. At 8, 10, and 12 days of age, wild-type and mo-br mice received intraperitoneal injections of 200μg/g body weight of L-DOPS, or mock solution. Five hours after the final injection, the mice were euthanized, and brains were removed. We measured catecholamine metabolites affected by DBH via high-performance liquid chromatography with electrochemical detection, and assessed brain histopathology. Compared to mock-treated controls, mo-br mice that received intraperitoneal L-DOPS showed significant increases in brain norepinephrine (p < 0.001) and its deaminated metabolite, dihydroxyphenylglycol (p < 0.05). The ratio of a non-beta-hydroxylated metabolite in the catecholamine biosynthetic pathway, dihydroxyphenylacetic acid, to the beta-hydroxylated metabolite, dihydroxyphenylglycol, improved equivalently to results obtained previously with brain-directed ATP7A gene therapy (p < 0.01). However, L-DOPS treatment did not arrest global brain pathology or improve somatic growth, as gene therapy had. We conclude that (1) L-DOPS crosses the blood-brain barrier in mo-br mice and corrects brain neurochemical abnormalities, (2) norepinephrine deficiency is not the cause of neurodegeneration in mo-br mice, and (3) L-DOPS treatment may ameliorate noradrenergic hypofunction in Menkes disease. Copyright © 2012 American Neurological Association.

L-DOPS corrects neurochemical abnormalities in a Menkes disease mouse model

PubMed Central

Donsante, Anthony; Sullivan, Patricia; Goldstein, David S.; Brinster, Lauren R.; Kaler, Stephen G.

2012-01-01

Objective Menkes disease is a lethal neurodegenerative disorder of infancy caused by mutations in a copper-transporting ATPase gene, ATP7A. Among its multiple cellular tasks, ATP7A transfers copper to dopamine-beta-hydroxylase (DBH) within the lumen of the Golgi network or secretory granules, catalyzing the conversion of dopamine to norepinephrine. In a well-established mouse model of Menkes disease, mottled-brindled, we tested whether systemic administration of L-threo-dihydroxyphenylserine (L-DOPS), a drug used successfully to treat autosomal recessive norepinephrine deficiency, would improve brain neurochemical abnormalities and neuropathology. Methods At 8, 10, and 12 days of age, wild type and mo-br mice received intraperi-toneal injections of 200μg/g body weight of L-DOPS, or mock solution. Five hours after the final injection, the mice were euthanized and brains removed. We measured catecholamine metabolites affected by DBH via high-performance liquid chromatography with electrochemical detection, and assessed brain histopathology. Results Compared to mock-treated controls, mo-br mice that received intraperitoneal L-DOPS showed significant increases in brain norepinephrine (P<0.001) and its deaminated metabolite, dihydroxyphenylglycol (DHPG, P<0.05). The ratio of a non-beta-hydroxylated metabolite in the catecholamine biosynthetic pathway, dihydroxyphenylacetic acid, to the beta-hydroxylated metabolite, dihydroxyphenylglycol, improved equivalently to results obtained previously with brain-directed ATP7A gene therapy (P<0.01). However, L-DOPS treatment did not arrest global brain pathology or improve somatic growth, as gene therapy had. Interpretation We conclude that 1) L-DOPS crosses the blood-brain barrier in mo-br mice and corrects brain neurochemical abnormalities, 2) norepinephrine deficiency is not the cause of neurodegeneration in mo-br mice, and 3) L-DOPS treatment may ameliorate noradrenergic hypofunction in Menkes disease. PMID:23224983

Influence of early stress on memory reconsolidation: Implications for post-traumatic stress disorder treatment.

PubMed

Villain, Hélène; Benkahoul, Aïcha; Birmes, Philippe; Ferry, Barbara; Roullet, Pascal

2018-01-01

Post-traumatic stress disorder (PTSD) is a common consequence of exposure to a life-threatening event. Currently, pharmacological treatments are limited by high rates of relapse, and novel treatment approaches are needed. We have recently demonstrated that propranolol, a β-adrenergic antagonist, inhibited aversive memory reconsolidation in animals. Following this, in an open-label study 70% of patients with PTSD treated with propranolol during reactivation of traumatic memory exhibited full remission. However, the reason why 30% of these patients did not respond positively to propranolol treatment is still unclear. One of the major candidates as factor of treatment resistance is the patient's early-life traumatic history. To test the role of this factor, mice with pre- or postnatal stress are being tested in fear conditioning and in a new behavioral task, the "city-like", specifically designed as a mouse model of PTSD. After reactivation of the traumatic event, mice received propranolol injection to block the noradrenergic system during memory reconsolidation. Results show that, in the "city-like" test, control mice strongly avoided the shock compartment but also the compartments containing cues associated with the electric shocks. Injection of propranolol after reactivation greatly reduced the memory of the traumatic event, but this effect was not present when mice had received pre- or postnatal stress. Moreover, propranolol produced only a very weak effect in the fear conditioning test, and never changed the corticosterone level whatever the behavioral experiment. Taken together our results suggest that our new behavioural paradigm is well adapted to PTSD study in mice, and that early stress exposure may have an impact on propranolol PTSD treatment outcome. These data are critical to understanding the effect of propranolol treatment, in order to improve the therapeutic protocol currently used in humans.

Improved diagnosis of pulmonary emphysema using in vivo dark-field radiography.

PubMed

Meinel, Felix G; Yaroshenko, Andre; Hellbach, Katharina; Bech, Martin; Müller, Mark; Velroyen, Astrid; Bamberg, Fabian; Eickelberg, Oliver; Nikolaou, Konstantin; Reiser, Maximilian F; Pfeiffer, Franz; Yildirim, Ali Ö

2014-10-01

The purpose of this study was to assess whether the recently developed method of grating-based x-ray dark-field radiography can improve the diagnosis of pulmonary emphysema in vivo. Pulmonary emphysema was induced in female C57BL/6N mice using endotracheal instillation of porcine pancreatic elastase and confirmed by in vivo pulmonary function tests, histopathology, and quantitative morphometry. The mice were anesthetized but breathing freely during imaging. Experiments were performed using a prototype small-animal x-ray dark-field scanner that was operated at 35 kilovolt (peak) with an exposure time of 5 seconds for each of the 10 grating steps. Images were compared visually. For quantitative comparison of signal characteristics, regions of interest were placed in the upper, middle, and lower zones of each lung. Receiver-operating-characteristic statistics were performed to compare the effectiveness of transmission and dark-field signal intensities and the combined parameter "normalized scatter" to differentiate between healthy and emphysematous lungs. A clear visual difference between healthy and emphysematous mice was found for the dark-field images. Quantitative measurements of x-ray dark-field signal and normalized scatter were significantly different between the mice with pulmonary emphysema and the control mice and showed good agreement with pulmonary function tests and quantitative histology. The normalized scatter showed a significantly higher discriminatory power (area under the receiver-operating-characteristic curve [AUC], 0.99) than dark-field (AUC, 0.90; P = 0.01) or transmission signal (AUC, 0.69; P < 0.001) alone did, allowing for an excellent discrimination of healthy and emphysematous lung regions. In a murine model, x-ray dark-field radiography is technically feasible in vivo and represents a substantial improvement over conventional transmission-based x-ray imaging for the diagnosis of pulmonary emphysema.

Coffee consumption in aged mice increases energy production and decreases hepatic mTOR levels.

PubMed

Takahashi, Keita; Yanai, Shuichi; Shimokado, Kentaro; Ishigami, Akihito

2017-06-01

Coffee, one of the world's most consumed beverages, has many benefits. Some studies have reported the effects of coffee on aging. The aim of this study was to investigate the locomotor activity, energy metabolism, and lipid metabolism of aged (20-mo-old) mice given coffee. Aged C57 BL/6 NCr mice were divided into three groups: controls that were not given coffee (n = 9), a group that received 0.1% caffeinated coffee (n = 9), and a group that received 0.1% decaffeinated coffee (n = 9). This regimen continued for 17 wk until mice reached the age of 24 mo. Regular and decaffeinated coffee consumption decreased plasma-free fatty acid levels, increased hepatic adenosine triphosphate content, and decreased total mammalian target of rapamycin (mTOR) and phosphorylated mTOR (p-mTOR) protein content in the liver. However, no differences were found in the protein or activity levels of Akt, adenosine monophosphate-activated protein kinase (AMPK), p70 S6 kinase, or sterol regulatory element-binding protein 1, proteins that are upstream or downstream of the mTOR complex 1 (mTORC1)-related pathways. Regular coffee consumption increased food and water intake, locomotor activity, the volume of carbon dioxide production, and the respiration exchange ratio. Regular and decaffeinated coffee consumption decreased hepatic total mTOR and p-mTOR levels independently of Akt and AMPK pathways in aged mice. Because decreased mTORC1 activity is known to have antiaging effects, coffee consumption during old age may retard aging. Moreover, coffee consumption by the aged population had a positive effect on behavioral energy and lipid metabolism. Copyright © 2017 Elsevier Inc. All rights reserved.

DDDAS Design of Drug Interventions for the Treatment of Dyslipidemia in ApoE−/− Mice

PubMed Central

Metts, Brittney; Thatcher, Sean; Lewis, Eboni; Karounos, Mike; Cassis, Lisa; Smith, Rebecca; Lodder, Robert A

2014-01-01

Computational models of complex systems, such as signaling networks and biological systems, can be used to explain the behavior of such systems under various conditions. The large number of integrated processes and variables, and the nonlinearities inherent in the fundamental processes, make it difficult for scientists unassisted by computer simulations to effectively predict the consequences of a particular intervention. For this reason, computer simulation has become an important tool for generating hypotheses about the behavior of these systems that can then be tested in the laboratory and clinic. A dynamic data-driven application simulation (DDDAS) was designed by Biospherics to model complex metabolic disease pathways by testing potential binary therapies in simulations at various combinations of two points in the pathways. Since DDDAS chooses the most effective pair-wise combinations, this data-driven system allows for the implementation of real-time data to model or predict a measurement or event. By incorporating data dynamically rather than statically, the predictions and measurements become more reliable. Dyslipidemia, a common precursor to atherosclerosis, can be manifested by high triglycerides, increased apolipoprotein (Apo) B, high levels of LDL, and low levels of HDL. SPX106 and D-tagatose is a combination drug therapy composed of a carbohydrate (D-tagatose) and SPX106. D-tagatose has been studied for the treatment of diabetes for several years, and has the ability to lower blood insulin levels and to decrease glycogen formation. SPX106 is a natural substance that accelerates lipid catabolism and inhibits dyslipidemia. In apolipoprotein E knockout mice (ApoE−/−), this drug combination has been shown to significantly lower both the amount of atherosclerosis and blood cholesterol levels. This study used 26 male ApoE−/− mice (n=13 in each group, control and treated). The control group received the normal “Western” diet (Harlan TD88137) and the treatment group received a modified version in which the sucrose was replaced with D-tagatose and 1g of SPX106 was added for every kilogram of chow. Mice were fed the diet for 8 weeks and then sacrificed via cardiac puncture. Blood serum was analyzed for cholesterol concentration. A significant difference was observed between the control and treated groups for total cholesterol levels. FPLC separations were done on fractions from both control and treated groups. A significant difference between VLDL and HDL levels was found between the treated and control mice (p<0.05 for both). Aortas were also taken and preserved in formalin to be quantified for atherosclerosis. Aortic sinuses were frozen in OCT and sectioned using a cryostat and then quantified for atherosclerosis. Treated mice showed statistically significant reduction in atherosclerosis in the aortic arch (p<0.01), the thoracic aorta (p<0.05), and the aortic sinus (p<0.05) as well as a reduction of cholesterol (p<0.05). PMID:25866829

Fennel induces cytotoxic effects against testicular germ cells in mice; evidences for suppressed pre-implantation embryo development.

PubMed

Minas, Aram; Najafi, Gholamreza; Jalali, Ali Shalizar; Razi, Mazdak

2018-05-15

Foeniculum vulgare (FVE; fennel) is an aromatic plant belonging to Umbelliferae family, which is widely used in traditional societies because of its different pharmaceutical properties. To uncover the fennel-derived essential oil (FVEO)-induced effects on male reproductive potential, 24 mature male albino mice were divided into, control, 0.37, 0.75, and 1.5 mg kg -1 FVEO-received groups. Following 35 days, the animals were euthanized and the testicular tissue and sperm samples were collected. The histological alterations, tubular differentiation (TDI), spermiogenesis (SPI) indices, apoptosis ratio, and RNA damage of germinal cells were analyzed. Moreover, the sperm count, motility, viability, chromatin condensation, and DNA fragmentation were assessed. Finally, the pre-implantation embryo development including; the percentage of zygote, 2-cell embryos and blastocysts were assessed. Observations showed that the FVEO, dose dependently, increased histological damages, resulted in germ cells dissociation, depletion, nuclear shrinkage and significantly (P < .05) decreased tubular differentiation and spermiogenesis ratios. Moreover, the FVEO-received animals (more significantly in 1.5 mg kg -1 -received group) exhibited decreased sperm count, viability, and motility and represented enhanced percentage of sperms with decondensed chromatin and DNA fragmentation. Finally, the animals in FVEO-received group showed diminished zygote formation and represented decreased pre-implantation embryo development compared to control animals. In conclusion, our data showed that, FVEO albeit at higher doses, is able to adversely affect cellular DNA and RNA contents, which in turn is able to negatively affect the sperm count and morphology. All these impairments are able to negatively affect the fertilization potential as well as pre-implantation embryo development. © 2018 Wiley Periodicals, Inc.

Effects of artificial sweeteners on body weight, food and drink intake.

PubMed

Polyák, Eva; Gombos, K; Hajnal, B; Bonyár-Müller, K; Szabó, Sz; Gubicskó-Kisbenedek, A; Marton, K; Ember, I

2010-12-01

Artificial sweeteners are widely used all over the world. They may assist in weight management, prevention of dental caries, control of blood glucose of diabetics, and also can be used to replace sugar in foods. In the animal experimentation mice were given oral doses of water solutions of table top artificial sweeteners (saccharin, cyclamate based, acesulfame-K based, and aspartame) the amount of maximum Acceptable Daily Intake (ADI) ad libitum. The controls received only tap water with the same drinking conditions as the treated groups. The mice were fed chow ad libitum.We measured food intake and body weight once a week, water and solutions of artificial sweeteners intake twice a week. The data were analysed by statistical methods (T-probe, regression analysis).Consumption of sweeteners resulted in significantly increased body weight; however, the food intake did not change.These results question the effect of non-caloric artificial sweeteners on weight-maintenance or body weight decrease.

Wirelessly powered, fully internal optogenetics for brain, spinal and peripheral circuits in mice

PubMed Central

Montgomery, Kate L; Yeh, Alexander J; Ho, John S; Tsao, Vivien; Iyer, Shrivats Mohan; Grosenick, Logan; Ferenczi, Emily A; Tanabe, Yuji; Deisseroth, Karl; Delp, Scott L; Poon, Ada S Y

2017-01-01

To enable sophisticated optogenetic manipulation of neural circuits throughout the nervous system with limited disruption of animal behavior, light-delivery systems beyond fiber optic tethering and large, head-mounted wireless receivers are desirable. We report the development of an easy-to-construct, implantable wireless optogenetic device. Our smallest version (20 mg, 10 mm3) is two orders of magnitude smaller than previously reported wireless optogenetic systems, allowing the entire device to be implanted subcutaneously. With a radio-frequency (RF) power source and controller, this implant produces sufficient light power for optogenetic stimulation with minimal tissue heating (<1 °C). We show how three adaptations of the implant allow for untethered optogenetic control throughout the nervous system (brain, spinal cord and peripheral nerve endings) of behaving mice. This technology opens the door for optogenetic experiments in which animals are able to behave naturally with optogenetic manipulation of both central and peripheral targets. PMID:26280330

Antisense oligonucleotide therapy rescues disruptions in organization of exploratory movements associated with Usher syndrome type 1C in mice.

PubMed

Donaldson, Tia N; Jennings, Kelsey T; Cherep, Lucia A; McNeela, Adam M; Depreux, Frederic F; Jodelka, Francine M; Hastings, Michelle L; Wallace, Douglas G

2018-02-15

Usher syndrome, Type 1C (USH1C) is an autosomal recessive inherited disorder in which a mutation in the gene encoding harmonin is associated with multi-sensory deficits (i.e., auditory, vestibular, and visual). USH1C (Usher) mice, engineered with a human USH1C mutation, exhibit these multi-sensory deficits by circling behavior and lack of response to sound. Administration of an antisense oligonucleotide (ASO) therapeutic that corrects expression of the mutated USH1C gene, has been shown to increase harmonin levels, reduce circling behavior, and improve vestibular and auditory function. The current study evaluates the organization of exploratory movements to assess spatial organization in Usher mice and determine the efficacy of ASO therapy in attenuating any such deficits. Usher and heterozygous mice received the therapeutic ASO, ASO-29, or a control, non-specific ASO treatment at postnatal day five. Organization of exploratory movements was assessed under dark and light conditions at two and six-months of age. Disruptions in exploratory movement organization observed in control-treated Usher mice were consistent with impaired use of self-movement and environmental cues. In general, ASO-29 treatment rescued organization of exploratory movements at two and six-month testing points. These observations are consistent with ASO-29 rescuing processing of multiple sources of information and demonstrate the potential of ASO therapies to ameliorate topographical disorientation associated with other genetic disorders. Copyright © 2017 Elsevier B.V. All rights reserved.

Prenatal and lactational exposure to low-doses of bisphenol A alters adult mice behavior.

PubMed

Nakamura, Keiko; Itoh, Kyoko; Dai, Hongmei; Han, Longzhe; Wang, Xiaohang; Kato, Shingo; Sugimoto, Tohru; Fushiki, Shinji

2012-01-01

Bisphenol A (BPA) is an endocrine-disrupting chemical, widely used in dentistry and various industries. We previously reported that BPA affected murine neocortical development by accelerating neuronal differentiation/migration, resulting in abnormal neocortical architecture as well as aberrant thalamocortical connections in the brains of adult mice. The aim of this study was to investigate whether prenatal and lactational BPA exposure affected behavior in adult mice. Pregnant mice were injected subcutaneously with 20μg/kg of BPA daily from embryonic day 0 (E0) until postnatal day 21 (P21). Control animals received a vehicle alone. Behavioral tests (n=15-20) were conducted at postnatal 3weeks (P3W) and P10-15W. After an open-field test, an elevated plus maze and Morris water maze tests were performed. The total distance in the elevated plus maze test at P3W and in the open-field test at P10W was significantly decreased in the BPA-exposed group, compared with the control group. Significant sex differences were observed in the time spent in the central area in the open-field test at P3W and in the total distance in the elevated plus maze test at P11W. These results indicated that prenatal and lactational BPA exposure disturbed the murine behavior in the postnatal development period and the adult mice. Copyright © 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Imipramine attenuates neuroinflammatory signaling and reverses stress-induced social avoidance.

PubMed

Ramirez, Karol; Shea, Daniel T; McKim, Daniel B; Reader, Brenda F; Sheridan, John F

2015-05-01

Psychosocial stress is associated with altered immunity, anxiety and depression. Previously we showed that repeated social defeat (RSD) promoted microglia activation and social avoidance behavior that persisted for 24days after cessation of RSD. The aim of the present study was to determine if imipramine (a tricyclic antidepressant) would reverse RSD-inducedsocial avoidance and ameliorate neuroinflammatory responses. To test this, C57BL/6 mice were divided into treatment groups. One group from RSD and controls received daily injections of imipramine for 24days, following 6 cycles of RSD. Two other groups were treated with saline. RSD mice spent significantly less time in the interaction zone when an aggressor was present in the cage. Administration of imipramine reversed social avoidance behavior, significantly increasing the interaction time, so that it was similar to that of control mice. Moreover, 24days of imipramine treatment in RSD mice significantly decreased stress-induced mRNA levels for IL-6 in brain microglia. Following ex vivo LPS stimulation, microglia from mice exposed to RSD, had higher mRNA expression of IL-6, TNF-α, and IL-1β, and this was reversed by imipramine treatment. In a second experiment, imipramine was added to drinking water confirming the reversal of social avoidant behavior and decrease in mRNA expression of IL-6 in microglia. These data suggest that the antidepressant imipramine may exert its effect, in part, by down-regulating microglial activation. Copyright © 2015 Elsevier Inc. All rights reserved.

Imipramine attenuates neuroinflammatory signaling and reverses stress-induced social avoidance

PubMed Central

Ramirez, Karol; Shea, Daniel T.; McKim, Daniel B.; B.F., Reader; Sheridan, John F.

2015-01-01

Psychosocial stress is associated with altered immunity, anxiety and depression. Previously we showed that repeated social defeat (RSD) promoted microglia activation and social avoidance behavior that persisted for 24 days after cessation of RSD. The aim of the present study was to determine if imipramine (a tricyclic antidepressant) would reverse RSD-induced social avoidance and ameliorate neuroinflammatory responses. To test this, C57BL/6 mice were divided into treatment groups. One group from RSD and controls received daily injections of imipramine for 24 days, following 6 cycles of RSD. Two other groups were treated with saline. RSD mice spent significantly less time in the interaction zone when an aggressor was present in the cage. Administration of imipramine reversed social avoidance behavior, significantly increasing the interaction time, so that it was similar to that of control mice. Moreover, 24 days of imipramine treatment in RSD mice significantly decreased stress-induced mRNA levels for IL-6 in brain microglia. Following ex vivo LPS stimulation, microglia from mice exposed to RSD, had higher mRNA expression of IL-6, TNF-α, and IL-1β, and this was reversed by imipramine treatment. In a second experiment, imipramine was added to drinking water confirming the reversal of social avoidant behavior and decrease in mRNA expression of IL-6 in microglia. These data suggest that the antidepressant imipramine may exert its effect, in part, by down-regulating microglial activation. PMID:25701613

Early Disruption of Extracellular Pleiotrophin Distribution Alters Cerebellar Neuronal Circuit Development and Function.

PubMed

Hamza, M M; Rey, S A; Hilber, P; Arabo, A; Collin, T; Vaudry, D; Burel, D

2016-10-01

The cerebellum is a structure of the central nervous system involved in balance, motor coordination, and voluntary movements. The elementary circuit implicated in the control of locomotion involves Purkinje cells, which receive excitatory inputs from parallel and climbing fibers, and are regulated by cerebellar interneurons. In mice as in human, the cerebellar cortex completes its development mainly after birth with the migration, differentiation, and synaptogenesis of granule cells. These cellular events are under the control of numerous extracellular matrix molecules including pleiotrophin (PTN). This cytokine has been shown to regulate the morphogenesis of Purkinje cells ex vivo and in vivo via its receptor PTPζ. Since Purkinje cells are the unique output of the cerebellar cortex, we explored the consequences of their PTN-induced atrophy on the function of the cerebellar neuronal circuit in mice. Behavioral experiments revealed that, despite a normal overall development, PTN-treated mice present a delay in the maturation of their flexion reflex. Moreover, patch clamp recording of Purkinje cells revealed a significant increase in the frequency of spontaneous excitatory postsynaptic currents in PTN-treated mice, associated with a decrease of climbing fiber innervations and an abnormal perisomatic localization of the parallel fiber contacts. At adulthood, PTN-treated mice exhibit coordination impairment on the rotarod test associated with an alteration of the synchronization gait. Altogether these histological, electrophysiological, and behavior data reveal that an early ECM disruption of PTN composition induces short- and long-term defaults in the establishment of proper functional cerebellar circuit.

Preclinical evaluation of 18F-ML-10 to determine timing of apoptotic response to chemotherapy in solid tumors

DOE PAGES

Demirci, Emre; Ahmed, Rafay; Ocak, Meltem; ...

2017-01-10

Here, we investigated 2-(5-fluoro-pentyl)-2-methyl-malonic acid ( 18F-ML-10) positron emission tomography (PET) imaging of apoptosis posttherapy to determine optimal timing for predicting chemotherapy response in a mouse head/neck xenograft cancer model. BALB/c nude mice (4-8 weeks old) were implanted with UM-SCC-22B tumors. The treatment group received 2 doses of doxorubicin (10 mg/kg, days 0, 2). Small animal 18F-ML-10 PET/computed tomography was performed before and on days 1, 3, and 7 postchemotherapy. Using regions of interest around tumors, 18F-ML-10 uptake change was measured as %ID/g and uptake relative to liver. Terminal Uridine Nick-End Labeling (TUNEL) immunohistochemistry assay was performed using tumor samplesmore » of baseline and on days 1, 3, and 7 posttreatment. As a result, treated mice demonstrated increased 18F-ML-10 uptake compared to baseline and controls, and 10 of 13 mice showed tumor volume decreases. All control mice showed tumor volume increases. Tumor-to-liver (T/L) ratios from the control group mice did not show significant change from baseline ( P > .05); however, T/L ratios of the treatment group showed significant 18F-ML-10 uptake differences from baseline compared to days 3 and 7 posttreatment ( P < .05), but no significant difference at 1 day posttreatment. In conclusion, 2-(5-Fluoro-pentyl)-2-methyl-malonic acid PET imaging has the potential for early assessment of treatment-induced apoptosis. Timing and image analysis strategies may require optimization, depending on the type of tumor and cancer treatment.« less

Preclinical evaluation of 18F-ML-10 to determine timing of apoptotic response to chemotherapy in solid tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Demirci, Emre; Ahmed, Rafay; Ocak, Meltem

Here, we investigated 2-(5-fluoro-pentyl)-2-methyl-malonic acid ( 18F-ML-10) positron emission tomography (PET) imaging of apoptosis posttherapy to determine optimal timing for predicting chemotherapy response in a mouse head/neck xenograft cancer model. BALB/c nude mice (4-8 weeks old) were implanted with UM-SCC-22B tumors. The treatment group received 2 doses of doxorubicin (10 mg/kg, days 0, 2). Small animal 18F-ML-10 PET/computed tomography was performed before and on days 1, 3, and 7 postchemotherapy. Using regions of interest around tumors, 18F-ML-10 uptake change was measured as %ID/g and uptake relative to liver. Terminal Uridine Nick-End Labeling (TUNEL) immunohistochemistry assay was performed using tumor samplesmore » of baseline and on days 1, 3, and 7 posttreatment. As a result, treated mice demonstrated increased 18F-ML-10 uptake compared to baseline and controls, and 10 of 13 mice showed tumor volume decreases. All control mice showed tumor volume increases. Tumor-to-liver (T/L) ratios from the control group mice did not show significant change from baseline ( P > .05); however, T/L ratios of the treatment group showed significant 18F-ML-10 uptake differences from baseline compared to days 3 and 7 posttreatment ( P < .05), but no significant difference at 1 day posttreatment. In conclusion, 2-(5-Fluoro-pentyl)-2-methyl-malonic acid PET imaging has the potential for early assessment of treatment-induced apoptosis. Timing and image analysis strategies may require optimization, depending on the type of tumor and cancer treatment.« less

Effects of Pfaffia paniculata (Brazilian ginseng) extract on macrophage activity.

PubMed

Pinello, Kátia Cristina; Fonseca, Evelise de S M; Akisue, Gokithi; Silva, Ana Paula; Salgado Oloris, Silvia Catarina; Sakai, Mônica; Matsuzaki, Patrícia; Nagamine, Márcia Kazumi; Palermo Neto, João; Dagli, Maria Lúcia Zaidan

2006-02-16

The roots of Pfaffia paniculata (Brazilian ginseng) have been indicated for the treatment of several diseases and as an analgesic and antiinflamatory drug. Treatment of mice with 200 mg/kg of the powdered root of P. paniculata reduced the Ehrlich ascitic volume [Matsuzaki, P., Akisue, G., Salgado Oloris, S.C., Gorniak, S.L., Zaidan Dagli, M.L., 2003. Effect of Pffafia paniculata (Brazilian ginseng) on the Ehrlich tumor on its ascitic form. Life Sciences, Dec 19; 74 (5), 573-579.]. One of the putative means to control the Ehrlich tumor growth is by increasing macrophage activity [Kleeb, S.R., Xavier, J.G., Frussa-Filho, R., Dagli, M.L.Z., 1997. Effect of haloperidol on the development of the solid Ehrlich tumor in mice. Life Sciences, 60 (4/5), 69-742.]. The aim of this study was to investigate experimentally the effects of the methanolic extract of P. paniculata roots on macrophage activity. Male mice received, by gavage, once a day, different doses (100, 250, or 500 mg/kg) of the methanolic extract of P. paniculata or filtered water, as control, for 10 days. Macrophage activity was evaluated through the phagocytosis index (PI), spreading index (SI), production of peroxide oxigen and nitric oxide. The peritoneal cells were activated with ip inoculation of Ehrlich ascitic cells, 24 h before the macrophage harvesting. The methanolic extract raised significantly the SI of mice from group of 500 mg/kg in comparison with the control group and group of 100 mg/kg. This raise of SI possibly induced the higher phagocytic activity observed in the experimental situation. Increased macrophage activity may be one of the effects contributing to inhibition of the Ehrlich ascitic tumor growth in mice.

Systemic effects in naïve mice injected with immunomodulatory lectin ArtinM

PubMed Central

Oliveira Brito, Patrícia Kellen Martins; Gonçalves, Thiago Eleutério; Fernandes, Fabrício Freitas; Miguel, Camila Botelho; Rodrigues, Wellington Francisco; Lazo Chica, Javier Emílio; Roque-Barreira, Maria Cristina

2017-01-01

Toll-like receptors (TLR) contain N-glycans, which are important glycotargets for plant lectins, to induce immunomodulation. The lectin ArtinM obtained from Artocarpus heterophyllus interacts with TLR2 N-glycans to stimulate IL-12 production by antigen-presenting cells and to drive the immune response toward the Th1 axis, conferring resistance against intracellular pathogens. This immunomodulatory effect was demonstrated by subcutaneously injecting (s.c.) ArtinM (0.5 μg) in infected mice. In this study, we evaluated the systemic implications of ArtinM administration in naïve BALB/c mice. The mice were s.c. injected twice (7 days interval) with ArtinM (0.5, 1.0, 2.5, or 5.0 μg), LPS (positive control), or PBS (negative control) and euthanized after three days. None of the ArtinM-injected mice exhibited change in body weight, whereas the relative mass of the heart and lungs diminished in mice injected with the highest ArtinM dose (5.0 μg). Few and discrete inflammatory foci were detected in the heart, lung, and liver of mice receiving ArtinM at doses ≥2.5 μg. Moreover, the highest dose of ArtinM was associated with increased serum levels of creatine kinase MB isoenzyme (CK-MB) and globulins as well as an augmented presence of neutrophils in the heart and lung. IL-12, IFN-γ, TNF-α, and IL-10 measurements in the liver, kidney, spleen, heart, and lung homogenates revealed decreased IL-10 level in the heart and lung of mice injected with 5.0 μg ArtinM. We also found an augmented frequency of T helper and B cells in the spleen of all ArtinM-injected naïve mice, whereas the relative expressions of T-bet, GATA-3, and ROR-γt were similar to those in PBS-injected animals. Our study demonstrates that s.c. injection of high doses of ArtinM in naïve mice promotes mild inflammatory lesions and that a low immunomodulatory dose is innocuous to naïve mice. PMID:29084277

A hand-held apparatus for "nose-only" exposure of mice to inhalable microparticles as a dry powder inhalation targeting lung and airway macrophages.

PubMed

Kaur, Jatinder; Muttil, Pavan; Verma, Rahul Kumar; Kumar, Kaushlendra; Yadav, Awadh Bihari; Sharma, Rolee; Misra, Amit

2008-05-10

Microparticles containing isoniazid and rifabutin were aerosolised using a simple apparatus fabricated from a 15-ml centrifuge tube. The dose available for inhalation by rodents was determined by collecting microparticles emitted at the delivery port. The dose available for inhalation was proportional to durations of exposure ranging from 10 to 90 s (10.5-13.5 CV%) and the weight of powder taken for fluidization (10-50 mg, r2=0.982). The apparatus was then used to administer inhalations of microparticles to mice. Other groups of mice received free rifabutin orally, or by i.v. injection. Rifabutin was estimated in serum and tissues of dosed mice by HPLC. When approximately 20 mg of microparticles were loaded in the apparatus, approximately 2.5 mg were collected at the delivery port in 30 s of operation. Mice inhaled approximately 300 microg of the 2.5 mg emitted at the delivery port. Airway and lung macrophages of mice receiving inhalations for 30 s accumulated 0.38 microg of rifabutin, while the amount in blood serum of these mice was 0.62 microg. In mice receiving 83 microg rifabutin i.v. or orally, the intracellular amounts were 0.06 and 0.07 microg respectively, while the amounts in serum were 1.02 and 0.80 microg. These observations confirmed that inhalation of microparticles targeted airway and lung macrophages.

Assessment of Traumatic Brain Injury by Increased 64Cu Uptake on 64CuCl2 PET/CT

PubMed Central

Peng, Fangyu; Muzik, Otto; Gatson, Joshua; Kernie, Steven G.; Diaz-Arrastia, Ramon

2015-01-01

Copper is a nutritional trace element required for cell proliferation and wound repair. Methods To explore increased copper uptake as a biomarker for noninvasive assessment of traumatic brain injury (TBI), experimental TBI in C57BL/6 mice was induced by controlled cortical impact, and 64Cu uptake in the injured cortex was assessed with 64CuCl2 PET/CT. Results At 24 h after intravenous injection of the tracer, uptake was significantly higher in the injured cortex of TBI mice (1.15 ± 0.53 percentage injected dose per gram of tissue [%ID/g]) than in the uninjured cortex of mice without TBI (0.53 ± 0.07 %ID/g, P = 0.027) or the cortex of mice that received an intracortical injection of zymosan A (0.62 ± 0.22 %ID/g, P = 0.025). Furthermore, uptake in the traumatized cortex of untreated TBI mice (1.15 ± 0.53 %ID/g) did not significantly differ from that in minocycline-treated TBI mice (0.93 ± 0.30 %ID/g, P = 0.33). Conclusion Overall, the data suggest that increased 64Cu uptake in traumatized brain tissues holds potential as a new biomarker for noninvasive assessment of TBI with 64CuCl2 PET/CT. PMID:26112025

Expression of macrophage migration inhibitory factor and CD74 in the inner ear and middle ear in lipopolysaccharide-induced otitis media.

PubMed

Ishihara, Hisashi; Kariya, Shin; Okano, Mitsuhiro; Zhao, Pengfei; Maeda, Yukihide; Nishizaki, Kazunori

2016-10-01

Significant expression of macrophage migration inhibitory factor and its receptor (CD74) was observed in both the middle ear and inner ear in experimental otitis media in mice. Modulation of macrophage migration inhibitory factor and its signaling pathway might be useful in the management of inner ear inflammation due to otitis media. Inner ear dysfunction secondary to otitis media has been reported. However, the specific mechanisms involved are not clearly understood. The aim of this study is to investigate the expression of macrophage migration inhibitory factor and CD74 in the middle ear and inner ear in lipopolysaccharide-induced otitis media. BALB/c mice received a transtympanic injection of either lipopolysaccharide or phosphate-buffered saline (PBS). The mice were sacrificed 24 h after injection, and temporal bones were processed for polymerase chain reaction (PCR) analysis, histologic examination, and immunohistochemistry. PCR examination revealed that the lipopolysaccharide-injected mice showed a significant up-regulation of macrophage migration inhibitory factor in both the middle ear and inner ear as compared with the PBS-injected control mice. The immunohistochemical study showed positive reactions for macrophage migration inhibitory factor and CD74 in infiltrating inflammatory cells, middle ear mucosa, and inner ear in the lipopolysaccharide-injected mice.

Protective Effects of Lactobacillus plantarum CCFM8246 against Copper Toxicity in Mice

PubMed Central

Li, Xiaoxiao; Zhai, Qixiao; Wang, Gang; Zhang, Qiuxiang; Zhang, Hao; Chen, Wei

2015-01-01

Lactobacillus plantarum CCFM8246, which has a relatively strong copper binding capacity and tolerance to copper ions, was obtained by screening from 16 lactic acid bacteria in vitro. The selected strain was then applied to a mouse model to evaluate its protective function against copper intoxication in vivo. The experimental mice were divided into an intervention group and a therapy group; mice in the intervention group received co-administration of CCFM8246 and a copper ion solution by gavage, while mice in the therapy group were treated with CCFM8246 after 4 weeks of copper exposure. In both two groups, mice treated with copper alone and that treated with neither CCFM8246 nor copper served as positive and negative controls, respectively. At the end of the experimental period, the copper content in feces and tissues, the activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum, and oxidation stress indices in liver and kidney tissue were determined. Learning and memory ability was evaluated by Morris water maze experiments. The results indicated that treatment with CCFM8246 significantly increased the copper content in feces to promote copper excretion, reduce the accumulation of copper in tissues, reverse oxidative stress induced by copper exposure, recover the ALT and AST in serum and improve the spatial memory of mice. PMID:26605944

A mouse model for Chlamydia suis genital infection.

PubMed

Donati, Manuela; Di Paolo, Maria; Favaroni, Alison; Aldini, Rita; Di Francesco, Antonietta; Ostanello, Fabio; Biondi, Roberta; Cremonini, Eleonora; Ginocchietti, Laura; Cevenini, Roberto

2015-02-01

A mouse model for Chlamydia suis genital infection was developed. Ninety-nine mice were randomly divided into three groups and intravaginally inoculated with chlamydia: 45 mice (group 1) received C. suis purified elementary bodies (EBs), 27 (group 2) were inoculated with C. trachomatis genotype E EBs and 27 mice (group 3) with C. trachomatis genotype F EBs. Additionally, 10 mice were used as a negative control. At seven days post-infection (dpi) secretory anti-C. suis IgA were recovered from vaginal swabs of all C. suis inoculated mice. Chlamydia suis was isolated from 93, 84, 71 and 33% vaginal swabs at 3, 5, 7 and 12 dpi. Chlamydia trachomatis genotype E and F were isolated from 100% vaginal swabs up to 7 dpi and from 61 and 72%, respectively, at 12 dpi. Viable C. suis and C. trachomatis organisms were isolated from uterus and tubes up to 16 and 28 dpi, respectively. The results of the present study show the susceptibility of mice to intravaginal inoculation with C. suis. A more rapid course and resolution of C. suis infection, in comparison to C. trachomatis, was highlighted. The mouse model could be useful for comparative investigations involving C. suis and C. trachomatis species. © FEMS 2014. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Pre-training in a radial arm maze abolished anxiety and impaired habituation in C57BL6/J mice treated with dizocilpine.

PubMed

Abuhamdah, R M; Hussain, M D; Chazot, P L; Ennaceur, A

2016-10-01

Familiarity can imply a reduction of fear and anxiety, which may render learning and memory performance insensitive to NMDA receptor antagonism. Our previous study indicates that MK-801 (dizocilpine), NMDA antagonist, increased anxiety and prevented the acquisition of a spatial memory task. Here, we examined whether MK-801 will produce anxiety in mice that were familiar with the test environment. Male C57BL/6J mice were exposed, one session a day for 7days, to a 3D maze, which consisted of nine arms attached to upward inclined bridges radiating from a nonagonal platform. In this maze, high anxiety mice avoid the arms in the first sessions. One group of mice received saline (SAL) while a second group received MK-801 (MKD1), both on day one. A third group received saline in the first 3 sessions, and MK 801 in subsequent sessions (MKD4). Saline and MK-801 (0.1mg/kg) were administered intraperitoneally 30min before the test. MKD4 mice demonstrated an increase in bridge and arm visits, and reached arm/bridge entries ratio close to 1 in session 5. SAL mice also crossed frequently onto the arms, and reached a comparable ratio, but this was achieved with a lower number of arm visits. MKD1 mice demonstrated a reduced number of arm visits in each session compared to SAL and MKD4 mice. Dizocilpine produced anxiety in mice treated from day 1 of the test, but not in those treated from day 4. It also impaired habituation in animals familiar with the test environment; it produced sustained non-habituating hyperactivity. Copyright © 2016 Elsevier Inc. All rights reserved.

Environmentally toxicant exposures induced intragenerational transmission of liver abnormalities in mice

PubMed Central

Al-Griw, Mohamed A.; Treesh, Soad A.; Alghazeer, Rabia O.; Regeai, Sassia O.

2017-01-01

Environmental toxicants such as chemicals, heavy metals, and pesticides have been shown to promote transgenerational inheritance of abnormal phenotypes and/or diseases to multiple subsequent generations following parental and/or ancestral exposures. This study was designed to examine the potential transgenerational action of the environmental toxicant trichloroethane (TCE) on transmission of liver abnormality, and to elucidate the molecular etiology of hepatocyte cell damage. A total of thirty two healthy immature female albino mice were randomly divided into three equal groups as follows: a sham group, which did not receive any treatment; a vehicle group, which received corn oil alone, and TCE treated group (3 weeks, 100 μg/kg i.p., every 4th day). The F0 and F1 generation control and TCE populations were sacrificed at the age of four months, and various abnormalities histpathologically investigated. Cell death and oxidative stress indices were also measured. The present study provides experimental evidence for the inheritance of environmentally induced liver abnormalities in mice. The results of this study show that exposure to the TCE promoted adult onset liver abnormalities in F0 female mice as well as unexposed F1 generation offspring. It is the first study to report a transgenerational liver abnormalities in the F1 generation mice through maternal line prior to gestation. This finding was based on careful evaluation of liver histopathological abnormalities, apoptosis of hepatocytes, and measurements of oxidative stress biomarkers (lipid peroxidation, protein carbonylation, and nitric oxide) in control and TCE populations. There was an increase in liver histopathological abnormalities, cell death, and oxidative lipid damage in F0 and F1 hepatic tissues of TCE treated group. In conclusion, this study showed that the biological and health impacts of environmental toxicant TCE do not end in maternal adults, but are passed on to offspring generations. Hence, linking observed liver abnormality in the offspring to environmental exposure of their parental line. This study also illustrated that oxidative stress and apoptosis appear to be a molecular component of the hepatocyte cell injury. PMID:28884077

Distinct effects of calorie restriction on adipose tissue cytokine and angiogenesis profiles in obese and lean mice

PubMed Central

2012-01-01

Background Obesity associates with low-grade inflammation and adipose tissue remodeling. Using sensitive high-throughput protein arrays we here investigated adipose tissue cytokine and angiogenesis-related protein profiles from obese and lean mice, and in particular, the influence of calorie restriction (CR). Methods Tissue samples from visceral fat were harvested from obese mice fed with a high-fat diet (60% of energy), lean controls receiving low-fat control diet as well as from obese and lean mice kept under CR (energy intake 70% of ad libitum intake) for 50 days. Protein profiles were analyzed using mouse cytokine and angiogenesis protein array kits. Results In obese and lean mice, CR was associated with 11.3% and 15.6% reductions in body weight, as well as with 4.0% and 4.6% reductions in body fat percentage, respectively. Obesity induced adipose tissue cytokine expressions, the most highly upregulated cytokines being IL-1ra, IL-2, IL-16, MCP-1, MIG, RANTES, C5a, sICAM-1 and TIMP-1. CR increased sICAM-1 and TIMP-1 expression both in obese and lean mice. Overall, CR showed distinct effects on cytokine expressions; in obese mice CR largely decreased but in lean mice increased adipose tissue cytokine expressions. Obesity was also associated with increased expressions of angiogenesis-related proteins, in particular, angiogenin, endoglin, endostatin, endothelin-1, IGFBP-3, leptin, MMP-3, PAI-1, TIMP-4, CXCL16, platelet factor 4, DPPIV and coagulation factor III. CR increased endoglin, endostatin and platelet factor 4 expressions, and decreased IGFBP-3, NOV, MMP-9, CXCL16 and osteopontin expressions both in obese and lean mice. Interestingly, in obese mice, CR decreased leptin and TIMP-4 expressions, whereas in lean mice their expressions were increased. CR decreased MMP-3 and PAI-1 only in obese mice, whereas CR decreased FGF acidic, FGF basic and coagulation factor III, and increased angiogenin and DPPIV expression only in lean mice. Conclusions CR exerts distinct effects on adipocyte cytokine and angiogenesis profiles in obese and lean mice. Our study also underscores the importance of angiogenesis-related proteins and cytokines in adipose tissue remodeling and development of obesity. PMID:22748184

Induction of periimplantitis in dental implants.

PubMed

Becker, Stephan T; Föge, Marc; Beck-Broichsitter, Benedicta E; Gavrilova, Olga; Bolte, Hendrik; Rosenstiel, Philipp; Wiltfang, Jörg

2013-01-01

Development, progression, and therapy of periimplantitis are nonresolved emerging problems. The aim of this pilot study was to establish a model for periimplantitis in mice to have a base for tests with immune-deficient knockout organisms to improve the knowledge about development and progression of periimplantitis and to develop further therapeutic options.In 8 mice, titanium implants were inserted in the median of the palate. Four of these implants had ligatures (periimplantitis group). After 2 weeks, the animals received a special diet enriched with sugar and flavor. After 9 weeks, micro-computed tomography (micro-CT) examinations to evaluate the periimplant tissue and histologies were performed.Dental implant insertions within the oral cavity are possible in living mice. Implants with ligatures showed significantly larger periimplant bone defects than controls. The radiologic findings were confirmed by histology. At the end of the observation period, the portion of implants lost was higher in the ligature group.This is the first publication to describe the insertion of dental implants in living mice. In addition, it is the first time that periimplant infection could be induced in that species. This model will pave the way to study knockout mice with reduced or even enhanced resistance to periimplantitis.

In Vivo Zinc Finger Nuclease-mediated Targeted Integration of a Glucose-6-phosphatase Transgene Promotes Survival in Mice With Glycogen Storage Disease Type IA

PubMed Central

Landau, Dustin J; Brooks, Elizabeth Drake; Perez-Pinera, Pablo; Amarasekara, Hiruni; Mefferd, Adam; Li, Songtao; Bird, Andrew; Gersbach, Charles A; Koeberl, Dwight D

2016-01-01

Glycogen storage disease type Ia (GSD Ia) is caused by glucose-6-phosphatase (G6Pase) deficiency in association with severe, life-threatening hypoglycemia that necessitates lifelong dietary therapy. Here we show that use of a zinc-finger nuclease (ZFN) targeted to the ROSA26 safe harbor locus and a ROSA26-targeting vector containing a G6PC donor transgene, both delivered with adeno-associated virus (AAV) vectors, markedly improved survival of G6Pase knockout (G6Pase-KO) mice compared with mice receiving the donor vector alone (P < 0.04). Furthermore, transgene integration has been confirmed by sequencing in the majority of the mice treated with both vectors. Targeted alleles were 4.6-fold more common in livers of mice with GSD Ia, as compared with normal littermates, at 8 months following vector administration (P < 0.02). This suggests a selective advantage for vector-transduced hepatocytes following ZFN-mediated integration of the G6Pase vector. A short-term experiment also showed that 3-month-old mice receiving the ZFN had significantly-improved biochemical correction, in comparison with mice that received the donor vector alone. These data suggest that the use of ZFNs to drive integration of G6Pase at a safe harbor locus might improve vector persistence and efficacy, and lower mortality in GSD Ia. PMID:26865405

Effect of human milk on blood and bone marrow cells in a malnourished mice model; comparative study with cow milk.

PubMed

García, Isabel; Salva, Susana; Zelaya, Hortensia; Villena, Julio; Agüero, Graciela

2013-11-01

It has been demonstrated that the alterations caused by nutrient deficiency can be reverted by adequate nutritional repletion. To perform comparative studies between human and cow milks in order to evaluate the impact of both milks on the recovery of blood and bone marrow cells affected in malnourished mice. Weaned mice were malnourished after consuming a protein free diet for 21 days. Malnourished mice received cow or human milk (CM or HM) for 7 or 14 consecutive days. During the period of administration of milk, the mice consumed the protein free diet ad libitum. The malnourished control (MNC) group received only protein free diet whereas the wellnourished control (WNC) mice consumed the balanced conventional diet. Both milks normalized serum albumin levels and improved thymus weight. Human milk was less effective than cow milk to increase body weight and serum transferrin levels. In contrast, human milk was more effective than cow milk to increase the number of leukocytes (WNC: 6.90 ± 1.60a; MNC: 2.80 ± 0.90b; CM 7d: 3.74 ± 1.10b; HM 7d: 7.16 ± 1.90a; CM 14d: 4.35 ± 1.20b; HM 14d: 6.75 ± 1.20a (109/L); p < 0.05) and lymphocytes (WNC: 5.80 ± 0.36a; MNC: 1.80 ± 0.40b; CM 7d: 2.50 ± 0.30b; HM 7d: 4.20 ± 0.50c; CM 14d: 3.30 ± 0.31d; HM 14d: 4.70 ± 0.28c (109/L); p < 0.05) in peripheral blood. Both milks induced an increment in mitotic pool cells in bone marrow and α-naphthyl butyrate esterase positive cells in peripheral blood. They also normalized phagocytic function in blood neutrophils and oxidative burst in peritoneal cells. Both milks were equally effective to exert favorable effects on the number of the bone marrow cells and the functions of the blood and peritoneal cells involved in immune response. However, only human milk normalized the number of leukocytes and increased the number of neutrophils in peripheral blood. Copyright AULA MEDICA EDICIONES 2013. Published by AULA MEDICA. All rights reserved.