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  1. Exogenous NAD(+) administration significantly protects against myocardial ischemia/reperfusion injury in rat model.

    PubMed

    Zhang, Youjun; Wang, Ban; Fu, Xingli; Guan, Shaofeng; Han, Wenzheng; Zhang, Jie; Gan, Qian; Fang, Weiyi; Ying, Weihai; Qu, Xinkai

    2016-01-01

    Acute myocardial infarction is one of the leading causes for death around the world. Although essential for successful interventional therapy, it is inevitably complicated by reperfusion injury. Thus effective approaches to reduce ischemia/reperfusion (I/R) injury are still critically needed. To test our hypothesis that intravenous administration of NAD(+) can attenuate I/R injury by reducing apoptotic damage and enhancing antioxidant capacity, we used a rat mode of myocardial I/R. Our study found that administration of 10-20 mg/kg NAD(+) can dose dependently reduce myocardial infarct induced by I/R, with an approximately 85% reduction of the infarct at the dosage of 20 mg/kg NAD(+). We further found that the injection of NAD(+) can significantly decrease I/R-induced apoptotic damage in the heart: NAD(+) administration can both decrease the TUNEL signals, Bax, cleaved caspase-3 levels and increase the Bcl-XL levels in the rats that are subjected to myocardial I/R injury. NAD(+) administration can also significantly attenuate I/R-induced decreases in SOD activity and SOD-2 protein levels in the hearts. NAD(+) can profoundly decrease myocardial I/R injury at least partially by attenuating apoptotic damage and enhancing the antioxidant capacity, thus suggesting that NAD(+) may become a promising therapeutic agent for myocardial I/R injury. PMID:27648125

  2. Exogenous NAD+ administration significantly protects against myocardial ischemia/reperfusion injury in rat model

    PubMed Central

    Zhang, Youjun; Wang, Ban; Fu, Xingli; Guan, Shaofeng; Han, Wenzheng; Zhang, Jie; Gan, Qian; Fang, Weiyi; Ying, Weihai; Qu, Xinkai

    2016-01-01

    Acute myocardial infarction is one of the leading causes for death around the world. Although essential for successful interventional therapy, it is inevitably complicated by reperfusion injury. Thus effective approaches to reduce ischemia/reperfusion (I/R) injury are still critically needed. To test our hypothesis that intravenous administration of NAD+ can attenuate I/R injury by reducing apoptotic damage and enhancing antioxidant capacity, we used a rat mode of myocardial I/R. Our study found that administration of 10-20 mg/kg NAD+ can dose dependently reduce myocardial infarct induced by I/R, with an approximately 85% reduction of the infarct at the dosage of 20 mg/kg NAD+. We further found that the injection of NAD+ can significantly decrease I/R-induced apoptotic damage in the heart: NAD+ administration can both decrease the TUNEL signals, Bax, cleaved caspase-3 levels and increase the Bcl-XL levels in the rats that are subjected to myocardial I/R injury. NAD+ administration can also significantly attenuate I/R-induced decreases in SOD activity and SOD-2 protein levels in the hearts. NAD+ can profoundly decrease myocardial I/R injury at least partially by attenuating apoptotic damage and enhancing the antioxidant capacity, thus suggesting that NAD+ may become a promising therapeutic agent for myocardial I/R injury. PMID:27648125

  3. Exogenous NAD+ administration significantly protects against myocardial ischemia/reperfusion injury in rat model

    PubMed Central

    Zhang, Youjun; Wang, Ban; Fu, Xingli; Guan, Shaofeng; Han, Wenzheng; Zhang, Jie; Gan, Qian; Fang, Weiyi; Ying, Weihai; Qu, Xinkai

    2016-01-01

    Acute myocardial infarction is one of the leading causes for death around the world. Although essential for successful interventional therapy, it is inevitably complicated by reperfusion injury. Thus effective approaches to reduce ischemia/reperfusion (I/R) injury are still critically needed. To test our hypothesis that intravenous administration of NAD+ can attenuate I/R injury by reducing apoptotic damage and enhancing antioxidant capacity, we used a rat mode of myocardial I/R. Our study found that administration of 10-20 mg/kg NAD+ can dose dependently reduce myocardial infarct induced by I/R, with an approximately 85% reduction of the infarct at the dosage of 20 mg/kg NAD+. We further found that the injection of NAD+ can significantly decrease I/R-induced apoptotic damage in the heart: NAD+ administration can both decrease the TUNEL signals, Bax, cleaved caspase-3 levels and increase the Bcl-XL levels in the rats that are subjected to myocardial I/R injury. NAD+ administration can also significantly attenuate I/R-induced decreases in SOD activity and SOD-2 protein levels in the hearts. NAD+ can profoundly decrease myocardial I/R injury at least partially by attenuating apoptotic damage and enhancing the antioxidant capacity, thus suggesting that NAD+ may become a promising therapeutic agent for myocardial I/R injury.

  4. Chronic administration of isocarbophos induces vascular cognitive impairment in rats.

    PubMed

    Li, Peng; Yin, Ya-Ling; Zhu, Mo-Li; Pan, Guo-Pin; Zhao, Fan-Rong; Lu, Jun-Xiu; Liu, Zhan; Wang, Shuang-Xi; Hu, Chang-Ping

    2016-04-01

    Vascular dementia, being the most severe form of vascular cognitive impairment (VCI), is caused by cerebrovascular disease. Whether organophosphorus causes VCI remains unknown. Isocarbophos (0.5 mg/kg per 2 days) was intragastrically administrated to rats for 16 weeks. The structure and function of cerebral arteries were assayed. The learning and memory were evaluated by serial tests of step-down, step-through and morris water maze. Long-term administration of isocarbophos reduced the hippocampal acetylcholinesterase (AChE) activity and acetylcholine (ACh) content but did not alter the plasma AChE activity, and significantly damaged the functions of learning and memory. Moreover, isocarbophos remarkably induced endothelial dysfunction in the middle cerebral artery and the expressions of ICAM-1 and VCAM-1 in the posterior cerebral artery. Morphological analysis by light microscopy and electron microscopy indicated disruptions of the hippocampus and vascular wall in the cerebral arteries from isocarbophos-treated rats. Treatment of isocarbophos injured primary neuronal and astroglial cells isolated from rats. Correlation analysis demonstrated that there was a high correlation between vascular function of cerebral artery and hippocampal AChE activity or ACh content in rats. In conclusion, chronic administration of isocarbophos induces impairments of memory and learning, which is possibly related to cerebral vascular dysfunction. PMID:26818681

  5. 21 CFR 10.70 - Documentation of significant decisions in administrative file.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 1 2010-04-01 2010-04-01 false Documentation of significant decisions in administrative file. 10.70 Section 10.70 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... appropriate employees, and show all persons to whom copies were sent; (4) Avoid defamatory...

  6. Toluene-induced ototoxicity by subcutaneous administration

    SciTech Connect

    Pryor, G.T.; Howd, R.A.

    1986-01-01

    Inhalation exposure of rats to toluene causes irreversible hearing loss (e.g., Pryor et al.). To determine whether noise emanating from the inhalation system was a major contributing factor and whether exposure by a noninhalation route would cause a similar effect, weanling, male Fischer-344 rats were injected SC twice daily in a quiet environment with PEG-300 (control) or with 1.5 or 1.7 g/kg of toluene for 7 days. After being trained to perform a multisensory conditioned avoidance response (CAR) task, tone intensity-response functions were generated at 4, 8, 12, and 20 kHz, and behavioral auditory response thresholds were estimated. Toluene caused a dose-related hearing loss at frequencies of 8 kHz and above, with no effect on performance of the CAR in response to light, nonaversive footshock, or the 4-kHz tone. The similarity of this effect to that observed following inhalation exposure indicates that noise is not a major factor in the toluene-induced hearing loss, although possible interactions between noise and toluene remain to be investigated. These results also demonstrate that direct penetration of the toluene vapors through the external ear structure, as might occur during inhalation exposure, is not a necessary condition for inducing the hearing loss.

  7. Annual committee reports on significant legislative, judicial, and administrative developments in 1981: Environmental-Quality Committee

    SciTech Connect

    Not Available

    1982-01-01

    The committee found significant developments under the National Environmental Policy Act (NEPA). There were no amendments to NEPA, but there were new rules affecting DOE defense-related nuclear facilities. Judicial developments continued a deference to agency discretion in environmental impact statement issues and conflicts with other laws. The administration's budget cuts effectively disabled the Council on Environmental Quality (CEQ). The report also outlines significant legislative, judicial, and administrative developments for the Federal Insecticide, Fungicide, and Rodenticide Act, the Endangered Species Act, and the Toxic Substances Act. 188 references. (DCK)

  8. Attenuation of methylphenidate-induced sensitization by co-administration of buspirone.

    PubMed

    Alam, Nausheen; Najam, Rahila; Naeem, Sadaf

    2016-03-01

    Methylphenidate, which inhibit dopamine transporter is effective in the treatment of ADHD (attention deficit hyperactivity disorder), but long term use of this drug is often associated with addiction and dependence. Locomotor sensitization development to psychostimulants like methylphenidate is an important contributor to drug abuse induced by psychostimulants. Different studies have shown that long term administration of drugs of abuse increases the effectiveness of 5-hydroxytryptamine (5-HT)-1A somatodendritic receptors. Repeated buspirone administration reduces the effectiveness of 5-HT1A somatodendritic receptors. This study was designed to determine that buspirone co-administration may reduce methylphenidate-induced sensitization. The motor activity was compared by using familiar and novel environments after long-term administration of methylphenidate, buspirone and their co-administration. Long term oral administration of methylphenidate at a dose of 2.0 mg/kg/day enhanced motor activity in home cage i.e. activity of familiar environment monitored at alternate day. Locomotor enhancing effects of methylphenidate were augmented on 13th day of drug administration suggesting sensitization induced by the drug. The sensitization effects were significant in home cage monitored on alternate day and also in an open field monitored weekly. Buspirone co-administration at a dose of 10 mg/kg/day prevented methylphenidate-induced sensitization. It is suggested that the sensitization development to methylphenidate may oppose by buspirone co-administration due to the reduction in the sensitivity of 5-HT1A somatodendritic receptors. These findings may help extend future therapeutics in ADHD.

  9. Early Administration of Carvedilol Protected against Doxorubicin-Induced Cardiomyopathy.

    PubMed

    Chen, Yung-Lung; Chung, Sheng-Ying; Chai, Han-Tan; Chen, Chih-Hung; Liu, Chu-Feng; Chen, Yi-Ling; Huang, Tien-Hung; Zhen, Yen-Yi; Sung, Pei-Hsun; Sun, Cheuk-Kwan; Chua, Sarah; Lu, Hung-I; Lee, Fan-Yen; Sheu, Jiunn-Jye; Yip, Hon-Kan

    2015-12-01

    This study tested for the benefits of early administration of carvedilol as protection against doxorubicin (DOX)-induced cardiomyopathy. Thirty male, adult B6 mice were categorized into group 1 (untreated control), group 2 [DOX treatment (15 mg/every other day for 2 weeks, i.p.], and group 3 [carvedilol (15 mg/kg/d, from day 7 after DOX treatment for 28 days)], and euthanized by day 35 after DOX treatment. By day 35, the left ventricular ejection fraction (LVEF) was significantly lower in group 2 than in groups 1 and 3, and significantly lower in group 3 than in group 1, whereas the left ventricular (LV) end-diastolic and LV end-systolic dimensions showed an opposite pattern to the LVEF among the three groups. The protein expressions of fibrotic (Smad3, TGF-β), apoptotic (BAX, cleaved caspase 3, PARP), DNA damage (γ-H2AX), oxidative stress (oxidized protein), mitochondrial damage (cytosolic cytochrome-C), heart failure (brain natriuretic peptide), and hypertrophic (β-MHC) biomarkers of the LV myocardium showed an opposite pattern to the LVEF among the three groups. The protein expressions of antifibrotic (BMP-2, Smad1/5), α-MHC, and phosphorylated-Akt showed an identical pattern to the LVEF among the three groups. The microscopic findings of fibrotic and collagen-deposition areas and the numbers of γ-H2AX(+) and 53BP1(+) cells in the LV myocardium exhibited an opposite pattern, whereas the numbers of endothelial cell (CD31(+), vWF(+)) markers showed an identical pattern to the LVEF among the three groups. Cardiac stem cell markers (C-kit(+) and Sca-1(+) cells) were significantly and progressively increased from group 1 to group 3. Additionally, the in vitro study showed carvedilol treatment significantly inhibited DOX-induced cardiomyoblast DNA (CD90/XRCC1(+), CD90/53BP1(+), and r-H2AX(+) cells) damage. Early carvedilol therapy protected against DOX-induced DNA damage and cardiomyopathy.

  10. Early Administration of Carvedilol Protected against Doxorubicin-Induced Cardiomyopathy.

    PubMed

    Chen, Yung-Lung; Chung, Sheng-Ying; Chai, Han-Tan; Chen, Chih-Hung; Liu, Chu-Feng; Chen, Yi-Ling; Huang, Tien-Hung; Zhen, Yen-Yi; Sung, Pei-Hsun; Sun, Cheuk-Kwan; Chua, Sarah; Lu, Hung-I; Lee, Fan-Yen; Sheu, Jiunn-Jye; Yip, Hon-Kan

    2015-12-01

    This study tested for the benefits of early administration of carvedilol as protection against doxorubicin (DOX)-induced cardiomyopathy. Thirty male, adult B6 mice were categorized into group 1 (untreated control), group 2 [DOX treatment (15 mg/every other day for 2 weeks, i.p.], and group 3 [carvedilol (15 mg/kg/d, from day 7 after DOX treatment for 28 days)], and euthanized by day 35 after DOX treatment. By day 35, the left ventricular ejection fraction (LVEF) was significantly lower in group 2 than in groups 1 and 3, and significantly lower in group 3 than in group 1, whereas the left ventricular (LV) end-diastolic and LV end-systolic dimensions showed an opposite pattern to the LVEF among the three groups. The protein expressions of fibrotic (Smad3, TGF-β), apoptotic (BAX, cleaved caspase 3, PARP), DNA damage (γ-H2AX), oxidative stress (oxidized protein), mitochondrial damage (cytosolic cytochrome-C), heart failure (brain natriuretic peptide), and hypertrophic (β-MHC) biomarkers of the LV myocardium showed an opposite pattern to the LVEF among the three groups. The protein expressions of antifibrotic (BMP-2, Smad1/5), α-MHC, and phosphorylated-Akt showed an identical pattern to the LVEF among the three groups. The microscopic findings of fibrotic and collagen-deposition areas and the numbers of γ-H2AX(+) and 53BP1(+) cells in the LV myocardium exhibited an opposite pattern, whereas the numbers of endothelial cell (CD31(+), vWF(+)) markers showed an identical pattern to the LVEF among the three groups. Cardiac stem cell markers (C-kit(+) and Sca-1(+) cells) were significantly and progressively increased from group 1 to group 3. Additionally, the in vitro study showed carvedilol treatment significantly inhibited DOX-induced cardiomyoblast DNA (CD90/XRCC1(+), CD90/53BP1(+), and r-H2AX(+) cells) damage. Early carvedilol therapy protected against DOX-induced DNA damage and cardiomyopathy. PMID:26511374

  11. Early corticosteroid administration in experimental radiation-induced heart disease

    SciTech Connect

    Reeves, W.C.; Stryker, J.A.; Abt, A.A.; Chung, C.K.; Whitesell, L.; Zelis, R.

    1980-02-01

    The ability of dexamethasone (DEX) to reduce the severity of the late stage of radiation-induced heart disease (RIHD) was assessed in 25 New Zealand white rabbits. Ten rabbits served as unirradiated controls (CONT). In Group A, seven rabbits received intravenous DEX prior to irradiation and every 24 hours for three consecutive days. DEX was not administered to the eight rabbits in Group B. At 100 days postirradiation, the severity of the late state was determined by microscopic examination (MICRO) for myocardial fibrosis and determination of myocardial hydroxyproline content (MHP). Myocardial fibrosis was evident in groups A (40%) and B (80%) while none was present in CONT by MICRO. One rabbit in Group B with no fibrosis by MICRO had abnormally increased MHP. MHP was significantly increased in Groups A and B, as compared to CONT (p < 0.01). In addition to less fibrosis by MICRO, Group A demonstrated a significant reduction of MHP when compared to Group B (p < 0.05). Determination of MHP may be superior to MICRO in the detection of the late stage of RIHD. Also, early DEX administration appears to reduce myocardial collagen content (fibrosis) in this experimental model.

  12. Chronic melatonin administration mitigates behavioral dysfunction induced by γ-irradiation.

    PubMed

    Haridas, Seenu; Kumar, Mayank; Manda, Kailash

    2012-11-01

    Melatonin, a 'hormone of darkness,' has been reported to play a role in a wide variety of physiological responses including reproduction, circadian homeostasis, sleep, retinal neuromodulation, and vasomotor responses. Our recent studies reported a prophylactic effect of exogenous melatonin against radiation-induced neurocognitive changes. However, there is no reported evidence for a mitigating effect of chronic melatonin administration against radiation-induced behavioral alterations. In the present study, C57BL/6 mice were given either whole day chronic melatonin administration (CMA) or chronic night-time melatonin administration (CNMA) by a low dose of melatonin in drinking water for a period of 2 weeks and 1 month following exposure to 6 Gy of γ-radiation. Various behavioral endpoints, such as locomotor activities, gross behavioral traits, basal anxiety level, and depressive tendencies were scored at different time points. Radiation exposure significantly impaired gross behavioral traits as observed in the open field exploratory paradigms and forced swim test. Both the CMA and CNMA significantly ameliorated the radiation-induced changes in exploratory tendencies, risk-taking behavior and gross behavior traits, such as rearing and grooming. Melatonin administration afforded anxiolytic function against radiation in terms of center exploration tendencies. The radiation-induced augmentation of immobility time in the forced swim test, indices of depression-like behavior was also inhibited by chronic melatonin administration. The results demonstrated the mitigating effect of chronic melatonin administration on radiation-induced affective disorders in mice. PMID:23026539

  13. Perampanel: a significant liver enzyme inducer in some patients?

    PubMed

    Novy, Jan; Rothuizen, Laura E; Buclin, Thierry; Rossetti, Andrea O

    2014-01-01

    Perampanel is one of the latest released antiepileptic drugs (AEDs). Early studies suggest no significant liver enzyme induction from this compound. We report on two patients with medically resistant epilepsy, who had perampanel added to their usual regimen. Both experienced a worsening of their epilepsy and presented in convulsive status epilepticus; concurrent antiepileptic drug levels (phenytoin, phenobarbital, rufinamide) were significantly decreased (<50%) in comparison with levels prior to perampanel introduction. Intravenous load and significant increase of maintenance dosages were needed to restore therapeutic drug levels. In one patient, further increase of perampanel resulted in a new drop of phenytoin level. This suggests that perampanel could, in some subjects, induce liver enzymes and interact with concomitant AEDs; monitoring levels of concomitant compounds could be useful. PMID:25227593

  14. Antibiotic Administration Routes Significantly Influence the Levels of Antibiotic Resistance in Gut Microbiota

    PubMed Central

    Zhang, Lu; Huang, Ying; Zhou, Yang; Buckley, Timothy

    2013-01-01

    This study examined the impact of oral exposure to antibiotic-resistant bacteria and antibiotic administration methods on antibiotic resistance (AR) gene pools and the profile of resistant bacteria in host gastrointestinal (GI) tracts using C57BL/6J mice with natural gut microbiota. Mice inoculated with a mixture of tet(M)-carrying Enterococcus spp. or blaCMY-2-carrying Escherichia coli were treated with different doses of tetracycline hydrochloride (Tet) or ampicillin sodium (Amp) and delivered via either feed or intravenous (i.v.) injection. Quantitative PCR assessment of mouse fecal samples revealed that (i) AR gene pools were below the detection limit in mice without prior inoculation of AR gene carriers regardless of subsequent exposure to corresponding antibiotics; (ii) oral exposure to high doses of Tet and Amp in mice inoculated with AR gene carriers led to rapid enrichment of corresponding AR gene pools in feces; (iii) significantly less or delayed development of AR in the GI tract of the AR carrier-inoculated mice was observed when the same doses of antibiotics were administered via i.v. injection rather than oral administration; and (iv) antibiotic dosage, and maybe the excretion route, affected AR in the GI tract. The shift of dominant AR bacterial populations in the gut microbiota was consistent with the dynamics of AR gene pools. The emergence of endogenous resistant bacteria in the gut microbiota corresponding to drug exposure was also observed. Together, these data suggest that oral administration of antibiotics has a prominent effect on AR amplification and development in gut microbiota, which may be minimized by alternative drug administration approaches, as illustrated by i.v. injection in this study and proper drug selection. PMID:23689712

  15. Attenuation of methylphenidate-induced sensitization by co-administration of buspirone.

    PubMed

    Alam, Nausheen; Najam, Rahila; Naeem, Sadaf

    2016-03-01

    Methylphenidate, which inhibit dopamine transporter is effective in the treatment of ADHD (attention deficit hyperactivity disorder), but long term use of this drug is often associated with addiction and dependence. Locomotor sensitization development to psychostimulants like methylphenidate is an important contributor to drug abuse induced by psychostimulants. Different studies have shown that long term administration of drugs of abuse increases the effectiveness of 5-hydroxytryptamine (5-HT)-1A somatodendritic receptors. Repeated buspirone administration reduces the effectiveness of 5-HT1A somatodendritic receptors. This study was designed to determine that buspirone co-administration may reduce methylphenidate-induced sensitization. The motor activity was compared by using familiar and novel environments after long-term administration of methylphenidate, buspirone and their co-administration. Long term oral administration of methylphenidate at a dose of 2.0 mg/kg/day enhanced motor activity in home cage i.e. activity of familiar environment monitored at alternate day. Locomotor enhancing effects of methylphenidate were augmented on 13th day of drug administration suggesting sensitization induced by the drug. The sensitization effects were significant in home cage monitored on alternate day and also in an open field monitored weekly. Buspirone co-administration at a dose of 10 mg/kg/day prevented methylphenidate-induced sensitization. It is suggested that the sensitization development to methylphenidate may oppose by buspirone co-administration due to the reduction in the sensitivity of 5-HT1A somatodendritic receptors. These findings may help extend future therapeutics in ADHD. PMID:27087081

  16. Can administrative data be used to ascertain clinically significant postoperative complications?

    PubMed

    Romano, Patrick S; Schembri, Michael E; Rainwater, Julie A

    2002-01-01

    The purpose of this study is to assess whether postoperative complications can be ascertained using administrative data. We randomly sampled 991 adults who underwent elective open diskectomies at 30 nonfederal acute care hospitals in California. Postoperative complications were specified by reviewing medical literature and by consulting clinical experts. We compared hospital-reported ICD-9-CM data and independently recoded ICD-9-CM data with complications abstracted by clinicians using detailed criteria. Recoded ICD-9-CM data were more likely than hospital-reported ICD-9-CM data to capture true complications, when they occurred, but they also mislabeled more patients who never experienced clinically significant complications. This finding was most evident for mild or ambiguous complications, such as atelectasis, posthemorrhagic anemia, and hypotension. Overall, recoded ICD-9-CM data captured 47% and 56% of all mild and severe complications, respectively, whereas hospital-reported ICD-9-CM data captured only 37% and 44%, respectively, of all mild and severe complications. These findings raise questions about the validity of using administrative data to ascertain postoperative complications, even if coders are carefully hired, trained, and supervised. ICD-9-CM complication codes are more promising as a tool to help providers identify their own adverse outcomes than as a tool for comparing performance.

  17. DHEA administration modulates stress-induced analgesia in rats.

    PubMed

    Cecconello, Ana Lúcia; Torres, Iraci L S; Oliveira, Carla; Zanini, Priscila; Niches, Gabriela; Ribeiro, Maria Flávia Marques

    2016-04-01

    An important aspect of adaptive stress response is the pain response suppression that occurs during or following stress exposure, which is often referred to as acute stress-induced analgesia. Dehydroepiandrosterone (DHEA) participates in the modulation of adaptive stress response, changing the HPA axis activity. The effect of DHEA on the HPA axis activity is dependent on the state and uses the same systems that participate in the regulation of acute stress-induced analgesia. The impact of DHEA on nociception has been studied; however, the effect of DHEA on stress-induced analgesia is not known. Thus, the aim of the present study was to evaluate the effect of DHEA on stress-induced analgesia and determine the best time for hormone administration in relation to exposure to stressor stimulus. The animals were stressed by restraint for 1h in a single exposure and received treatment with DHEA by a single injection before the stress or a single injection after the stress. Nociception was assessed with a tail-flick apparatus. Serum corticosterone levels were measured. DHEA administered before exposure to stress prolonged the acute stress-induced analgesia. This effect was not observed when the DHEA was administered after the stress. DHEA treatment in non-stressed rats did not alter the nociceptive threshold, suggesting that the DHEA effect on nociception is state-dependent. The injection of DHEA had the same effect as exposure to acute stress, with both increasing the levels of corticosterone. In conclusion, acute treatment with DHEA mimics the response to acute stress indexed by an increase in activity of the HPA axis. The treatment with DHEA before stress exposure may facilitate adaptive stress response, prolonging acute stress-induced analgesia, which may be a therapeutic strategy of interest to clinics.

  18. DHEA administration modulates stress-induced analgesia in rats.

    PubMed

    Cecconello, Ana Lúcia; Torres, Iraci L S; Oliveira, Carla; Zanini, Priscila; Niches, Gabriela; Ribeiro, Maria Flávia Marques

    2016-04-01

    An important aspect of adaptive stress response is the pain response suppression that occurs during or following stress exposure, which is often referred to as acute stress-induced analgesia. Dehydroepiandrosterone (DHEA) participates in the modulation of adaptive stress response, changing the HPA axis activity. The effect of DHEA on the HPA axis activity is dependent on the state and uses the same systems that participate in the regulation of acute stress-induced analgesia. The impact of DHEA on nociception has been studied; however, the effect of DHEA on stress-induced analgesia is not known. Thus, the aim of the present study was to evaluate the effect of DHEA on stress-induced analgesia and determine the best time for hormone administration in relation to exposure to stressor stimulus. The animals were stressed by restraint for 1h in a single exposure and received treatment with DHEA by a single injection before the stress or a single injection after the stress. Nociception was assessed with a tail-flick apparatus. Serum corticosterone levels were measured. DHEA administered before exposure to stress prolonged the acute stress-induced analgesia. This effect was not observed when the DHEA was administered after the stress. DHEA treatment in non-stressed rats did not alter the nociceptive threshold, suggesting that the DHEA effect on nociception is state-dependent. The injection of DHEA had the same effect as exposure to acute stress, with both increasing the levels of corticosterone. In conclusion, acute treatment with DHEA mimics the response to acute stress indexed by an increase in activity of the HPA axis. The treatment with DHEA before stress exposure may facilitate adaptive stress response, prolonging acute stress-induced analgesia, which may be a therapeutic strategy of interest to clinics. PMID:26852948

  19. Annual committee reports on significant legislative, judicial, and administrative developments in 1981: Water-Quality committee

    SciTech Connect

    Not Available

    1982-01-01

    This review of 1981 developments is divided into four basic parts. The first covers legislative, judicial, and administrative developments under the Clean Water Act (CWA); the second covers judicial and administrative developments under the Safe Drinking Water Act (SDWA); the third covers judicial developments respecting private rights of action and the federal common law of nuisance. 109 references.

  20. Nicotine Administration Attenuates Methamphetamine-Induced Novel Object Recognition Deficits

    PubMed Central

    Vieira-Brock, Paula L.; McFadden, Lisa M.; Nielsen, Shannon M.; Smith, Misty D.; Hanson, Glen R.

    2015-01-01

    Background: Previous studies have demonstrated that methamphetamine abuse leads to memory deficits and these are associated with relapse. Furthermore, extensive evidence indicates that nicotine prevents and/or improves memory deficits in different models of cognitive dysfunction and these nicotinic effects might be mediated by hippocampal or cortical nicotinic acetylcholine receptors. The present study investigated whether nicotine attenuates methamphetamine-induced novel object recognition deficits in rats and explored potential underlying mechanisms. Methods: Adolescent or adult male Sprague-Dawley rats received either nicotine water (10–75 μg/mL) or tap water for several weeks. Methamphetamine (4×7.5mg/kg/injection) or saline was administered either before or after chronic nicotine exposure. Novel object recognition was evaluated 6 days after methamphetamine or saline. Serotonin transporter function and density and α4β2 nicotinic acetylcholine receptor density were assessed on the following day. Results: Chronic nicotine intake via drinking water beginning during either adolescence or adulthood attenuated the novel object recognition deficits caused by a high-dose methamphetamine administration. Similarly, nicotine attenuated methamphetamine-induced deficits in novel object recognition when administered after methamphetamine treatment. However, nicotine did not attenuate the serotonergic deficits caused by methamphetamine in adults. Conversely, nicotine attenuated methamphetamine-induced deficits in α4β2 nicotinic acetylcholine receptor density in the hippocampal CA1 region. Furthermore, nicotine increased α4β2 nicotinic acetylcholine receptor density in the hippocampal CA3, dentate gyrus and perirhinal cortex in both saline- and methamphetamine-treated rats. Conclusions: Overall, these findings suggest that nicotine-induced increases in α4β2 nicotinic acetylcholine receptors in the hippocampus and perirhinal cortex might be one mechanism by which

  1. Annual committee reports on significant legislative, judicial, and administrative developments in 1982: Environmental Quality Committee

    SciTech Connect

    Not Available

    1983-01-01

    Judicial developments during 1982 dominated activities involving the National Environmental Policy Act (NEPA), the Federal Insecticide, Fungicide and Rotenticide Act, and Marine Sanctuaries, with some changes in administrative procedures and no legislative developments. The Endangered Species Act was amended to expedite changes to the lists and to alter exemption and international trade requirements. Several lawsuits challenged review standards and litigation claims. 231 references. (DCK)

  2. The significance of the erosion-induced terrestrial carbonsink

    SciTech Connect

    Berhe, A.A.; Harte, J.; Harden, J.W.; Torn, M.S.

    2006-10-10

    Estimating carbon (C) balance in erosional and depositionallandscapes is complicated by the effects of soil redistribution on bothnet primary productivity (NPP) and decomposition. Recent studies arecontradictory as to whether soil erosion does or does not constitute a Csink. Here we clarify the conceptual basis for how erosion can constitutea C sink. Specifically, the criterion for an erosional C sink is thatdynamic replacement of eroded C, and reduced decomposition rates indepositional sites, must together more than compensate for erosionallosses. This criterion is in fact met in many erosional settings, andthus erosion and deposition can make a net positive contribution to Csequestration. We show that, in a cultivated Mississippi watershed and acoastal California watershed, the magnitude of the erosion-induced C sinkis likely to be on the order of 1 percent of NPP and 16 percent of erodedC. Although soil erosion has serious environmental impacts, the annualerosion-induced C sink offsets up to 10 percent of the global fossil fuelemissions of carbon dioxide for 2005.

  3. Neurokinin B administration induces hot flushes in women.

    PubMed

    Jayasena, Channa N; Comninos, Alexander N; Stefanopoulou, Evgenia; Buckley, Adam; Narayanaswamy, Shakunthala; Izzi-Engbeaya, Chioma; Abbara, Ali; Ratnasabapathy, Risheka; Mogford, Julianne; Ng, Noel; Sarang, Zubair; Ghatei, Mohammad A; Bloom, Stephen R; Hunter, Myra S; Dhillo, Waljit S

    2015-01-01

    Neurokinin B (NKB) is a hypothalamic neuropeptide binding preferentially to the neurokinin 3 receptor. Expression of the gene encoding NKB is elevated in postmenopausal women. Furthermore, rodent studies suggest that NKB signalling may mediate menopausal hot flushes. However, the effects of NKB administration on hot flushes have not been investigated in humans. To address this, we performed a randomised, double-blinded, placebo-controlled, 2-way cross-over study. Ten healthy women were admitted to a temperature and humidity-controlled research unit. Participants received 30 minute intravenous infusions of NKB and vehicle in random order. Symptoms, heart rate, blood pressure, sweating and skin temperature were compared between NKB and vehicle in a double-blinded manner. Eight of ten participants experienced flushing during NKB infusion with none experiencing flushing during vehicle infusion (P = 0.0007). Significant elevations in heart rate (P = 0.0106 vs. pre-symptoms), and skin temperature measured using skin probe (P = 0.0258 vs. pre-symptoms) and thermal imaging (P = 0.0491 vs. pre-symptoms) characteristic of menopausal flushing were observed during hot flush episodes. Our findings provide evidence that NKB administration can cause hot flushes in women. Further studies are required to determine if pharmacological blockade of NKB signalling could inhibit hot flushes during the menopause and during treatment for sex-steroid dependent cancers. PMID:25683060

  4. Neurokinin B administration induces hot flushes in women.

    PubMed

    Jayasena, Channa N; Comninos, Alexander N; Stefanopoulou, Evgenia; Buckley, Adam; Narayanaswamy, Shakunthala; Izzi-Engbeaya, Chioma; Abbara, Ali; Ratnasabapathy, Risheka; Mogford, Julianne; Ng, Noel; Sarang, Zubair; Ghatei, Mohammad A; Bloom, Stephen R; Hunter, Myra S; Dhillo, Waljit S

    2015-01-01

    Neurokinin B (NKB) is a hypothalamic neuropeptide binding preferentially to the neurokinin 3 receptor. Expression of the gene encoding NKB is elevated in postmenopausal women. Furthermore, rodent studies suggest that NKB signalling may mediate menopausal hot flushes. However, the effects of NKB administration on hot flushes have not been investigated in humans. To address this, we performed a randomised, double-blinded, placebo-controlled, 2-way cross-over study. Ten healthy women were admitted to a temperature and humidity-controlled research unit. Participants received 30 minute intravenous infusions of NKB and vehicle in random order. Symptoms, heart rate, blood pressure, sweating and skin temperature were compared between NKB and vehicle in a double-blinded manner. Eight of ten participants experienced flushing during NKB infusion with none experiencing flushing during vehicle infusion (P = 0.0007). Significant elevations in heart rate (P = 0.0106 vs. pre-symptoms), and skin temperature measured using skin probe (P = 0.0258 vs. pre-symptoms) and thermal imaging (P = 0.0491 vs. pre-symptoms) characteristic of menopausal flushing were observed during hot flush episodes. Our findings provide evidence that NKB administration can cause hot flushes in women. Further studies are required to determine if pharmacological blockade of NKB signalling could inhibit hot flushes during the menopause and during treatment for sex-steroid dependent cancers.

  5. Neurokinin B Administration Induces Hot Flushes in Women

    PubMed Central

    Jayasena, Channa N.; Comninos, Alexander N.; Stefanopoulou, Evgenia; Buckley, Adam; Narayanaswamy, Shakunthala; Izzi-Engbeaya, Chioma; Abbara, Ali; Ratnasabapathy, Risheka; Mogford, Julianne; Ng, Noel; Sarang, Zubair; Ghatei, Mohammad A.; Bloom, Stephen R.; Hunter, Myra S.; Dhillo, Waljit S.

    2015-01-01

    Neurokinin B (NKB) is a hypothalamic neuropeptide binding preferentially to the neurokinin 3 receptor. Expression of the gene encoding NKB is elevated in postmenopausal women. Furthermore, rodent studies suggest that NKB signalling may mediate menopausal hot flushes. However, the effects of NKB administration on hot flushes have not been investigated in humans. To address this, we performed a randomised, double-blinded, placebo-controlled, 2-way cross-over study. Ten healthy women were admitted to a temperature and humidity-controlled research unit. Participants received 30 minute intravenous infusions of NKB and vehicle in random order. Symptoms, heart rate, blood pressure, sweating and skin temperature were compared between NKB and vehicle in a double-blinded manner. Eight of ten participants experienced flushing during NKB infusion with none experiencing flushing during vehicle infusion (P = 0.0007). Significant elevations in heart rate (P = 0.0106 vs. pre-symptoms), and skin temperature measured using skin probe (P = 0.0258 vs. pre-symptoms) and thermal imaging (P = 0.0491 vs. pre-symptoms) characteristic of menopausal flushing were observed during hot flush episodes. Our findings provide evidence that NKB administration can cause hot flushes in women. Further studies are required to determine if pharmacological blockade of NKB signalling could inhibit hot flushes during the menopause and during treatment for sex-steroid dependent cancers. PMID:25683060

  6. The significance of nanoparticles in particle-induced pulmonary fibrosis

    PubMed Central

    Byrne, James D; Baugh, John A

    2008-01-01

    Exposure to airborne nanoparticles contributes to many chronic pulmonary diseases. Nanoparticles, classified as anthropogenic and natural particles, and fibers of diameters less than 100 nm, have unrestricted access to most areas of the lung due to their size. Size relates to the deposition efficiency of the particle, with particles in the nano-range having the highest efficiencies. The deposition of nanoparticles in the lung can lead to chronic inflammation, epithelial injury, and further to pulmonary fibrosis. Cases of particle-induced pulmonary fibrosis, namely pneumoconiosis, are mostly occupationally influenced, and continue to be documented around the world. The tremendous growth of nanotechnology, however, has spurred fears of increased rates of pulmonary diseases, especially fibrosis. The severity of toxicological consequences warrants further examination of the effects of nanoparticles in humans, possible treatments and increased regulatory measures. PMID:18523535

  7. Significance of hair-dye base-induced sensory irritation.

    PubMed

    Fujita, F; Azuma, T; Tajiri, M; Okamoto, H; Sano, M; Tominaga, M

    2010-06-01

    Oxidation hair-dyes, which are the principal hair-dyes, sometimes induce painful sensory irritation of the scalp caused by the combination of highly reactive substances, such as hydrogen peroxide and alkali agents. Although many cases of severe facial and scalp dermatitis have been reported following the use of hair-dyes, sensory irritation caused by contact of the hair-dye with the skin has not been reported clearly. In this study, we used a self-assessment questionnaire to measure the sensory irritation in various regions of the body caused by two model hair-dye bases that contained different amounts of alkali agents without dyes. Moreover, the occipital region was found as an alternative region of the scalp to test for sensory irritation of the hair-dye bases. We used this region to evaluate the relationship of sensitivity with skin properties, such as trans-epidermal water loss (TEWL), stratum corneum water content, sebum amount, surface temperature, current perception threshold (CPT), catalase activities in tape-stripped skin and sensory irritation score with the model hair-dye bases. The hair-dye sensitive group showed higher TEWL, a lower sebum amount, a lower surface temperature and higher catalase activity than the insensitive group, and was similar to that of damaged skin. These results suggest that sensory irritation caused by hair-dye could occur easily on the damaged dry scalp, as that caused by skin cosmetics reported previously.

  8. Mechanisms and Functional Significance of Stroke-Induced Neurogenesis

    PubMed Central

    Marlier, Quentin; Verteneuil, Sebastien; Vandenbosch, Renaud; Malgrange, Brigitte

    2015-01-01

    Stroke affects one in every six people worldwide, and is the leading cause of adult disability. After stroke, some limited spontaneous recovery occurs, the mechanisms of which remain largely unknown. Multiple, parallel approaches are being investigated to develop neuroprotective, reparative and regenerative strategies for the treatment of stroke. For years, clinical studies have tried to use exogenous cell therapy as a means of brain repair, with varying success. Since the rediscovery of adult neurogenesis and the identification of adult neural stem cells in the late nineties, one promising field of investigation is focused upon triggering and stimulating this self-repair system to replace the neurons lost following brain injury. For instance, it is has been demonstrated that the adult brain has the capacity to produce large numbers of new neurons in response to stroke. The purpose of this review is to provide an updated overview of stroke-induced adult neurogenesis, from a cellular and molecular perspective, to its impact on brain repair and functional recovery. PMID:26696816

  9. Significant anthropogenic-induced changes of climate classes since 1950

    PubMed Central

    Chan, Duo; Wu, Qigang

    2015-01-01

    Anthropogenic forcings have contributed to global and regional warming in the last few decades and likely affected terrestrial precipitation. Here we examine changes in major Köppen climate classes from gridded observed data and their uncertainties due to internal climate variability using control simulations from Coupled Model Intercomparison Project 5 (CMIP5). About 5.7% of the global total land area has shifted toward warmer and drier climate types from 1950–2010, and significant changes include expansion of arid and high-latitude continental climate zones, shrinkage in polar and midlatitude continental climates, poleward shifts in temperate, continental and polar climates, and increasing average elevation of tropical and polar climates. Using CMIP5 multi-model averaged historical simulations forced by observed anthropogenic and natural, or natural only, forcing components, we find that these changes of climate types since 1950 cannot be explained as natural variations but are driven by anthropogenic factors. PMID:26316255

  10. Significant mucosal sIgA production after a single oral or parenteral administration using in vivo CD40 targeting in the chicken.

    PubMed

    Chou, Wen-Ko; Chen, Chang-Hsin; Vuong, Christine N; Abi-Ghanem, Daad; Waghela, Suryakant D; Mwangi, Waithaka; Bielke, Lisa R; Hargis, Billy M; Berghman, Luc R

    2016-10-01

    Many pathogens enter the host through mucosal surfaces and spread rapidly via the circulation. The most effective way to prevent disease is to establish mucosal and systemic immunity against the pathogen. However, current vaccination programs in poultry industry require repeated administrations of live-attenuated virus or large amounts (10 to 100μg) of antigen together with adjuvant to induce specific secretory IgA immune responses at the mucosal effector sites. In the present study, we show that a single administration of 0.4μg of oligopeptide complexed with an agonistic anti-chicken CD40 (chCD40) monoclonal antibody (Mab) effectively targets antigen-presenting cells of the bird's mucosa-associated lymphoid tissue in vivo, and induces peptide-specific secretory IgA (sIgA) in the trachea 7days post administration. Anti-chCD40 Mab-peptide complex was administered once to four-week old male Leghorns via various mucosal routes (orally, via cloacal drinking, or oculo-nasally) or via subcutaneous (s.c.) immunization. Immunization through any of the three mucosal induction routes induced significant peptide-specific mucosal sIgA responses 7 and 14days after immunization. Interestingly, s.c. injection of the complex also induced mucosal sIgA. Our data suggest in vivo targeting of CD40 as a potential adjuvant platform, particularly for the purpose of enhancing and speeding up mucosal vaccine responses in chickens, and potentially other food animals. This is the first study able to elicit specific sIgA immune responses in remote mucosal sites with a single administration of only 0.4μg of antigen. PMID:27663378

  11. Enhanced AMPA receptor activity increases operant alcohol self-administration and cue-induced reinstatement.

    PubMed

    Cannady, Reginald; Fisher, Kristen R; Durant, Brandon; Besheer, Joyce; Hodge, Clyde W

    2013-01-01

    Long-term alcohol exposure produces neuroadaptations that contribute to the progression of alcohol abuse disorders. Chronic alcohol consumption results in strengthened excitatory neurotransmission and increased α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPA) receptor signaling in animal models. However, the mechanistic role of enhanced AMPA receptor activity in alcohol-reinforcement and alcohol-seeking behavior remains unclear. This study examined the role of enhanced AMPA receptor function using the selective positive allosteric modulator, aniracetam, in modulating operant alcohol self-administration and cue-induced reinstatement. Male alcohol-preferring (P-) rats, trained to self-administer alcohol (15%, v/v) versus water were pre-treated with aniracetam to assess effects on maintenance of alcohol self-administration. To determine reinforcer specificity, P-rats were trained to self-administer sucrose (0.8%, w/v) versus water, and effects of aniracetam were tested. The role of aniracetam in modulating relapse of alcohol-seeking was assessed using a response contingent cue-induced reinstatement procedure in P-rats trained to self-administer 15% alcohol. Aniracetam pre-treatment significantly increased alcohol-reinforced responses relative to vehicle treatment. This increase was not attributed to aniracetam-induced hyperactivity as aniracetam pre-treatment did not alter locomotor activity. AMPA receptor involvement was confirmed because 6,7-dinitroquinoxaline-2,3-dione (AMPA receptor antagonist) blocked the aniracetam-induced increase in alcohol self-administration. Aniracetam did not alter sucrose-reinforced responses in sucrose-trained P-rats, suggesting that enhanced AMPA receptor activity is selective in modulating the reinforcing function of alcohol. Finally, aniracetam pre-treatment potentiated cue-induced reinstatement of alcohol-seeking behavior versus vehicle-treated P-rats. These data suggest that enhanced glutamate activity at AMPA

  12. Administration of aspartame potentiates pentylenetetrazole- and fluorothyl-induced seizures in mice.

    PubMed

    Pinto, J M; Maher, T J

    1988-01-01

    An association has recently been proposed between the incidence of seizures and prolonged consumption of the phenylalanine-containing artificial sweetener, aspartame. Since consumption of aspartame, unlike dietary protein, can elevate phenylalanine in brain, and thereby inhibit the synthesis and release of neurotransmitters known to protect against seizure activity, the effect of oral doses of aspartame on the sensitivity of mice to the proconvulsant agents, pentylenetetrazole and fluorothyl was studied. Doses of aspartame were used which increased phenylalanine more than tyrosine in brain, as occurs in humans after the consumption of any dose of aspartame. Pretreatment with aspartame significantly increased the percentage of animals convulsing after administration of pentylenetetrazole and significantly lowered the CD50 for this convulsant. The average time to onset of seizures induced by fluorothyl in control mice was 510 sec; pretreatment with oral doses of 1000, 1500 and 2000 mg/kg of aspartame 1 hr earlier significantly reduced the time required to elicit seizures (394, 381 and 339 sec, respectively). The seizure-promoting effect of aspartame could be demonstrated 30, 60 or 120 min after the 1000 mg/kg dose. The seizures induced by either convulsant were potentiated by equimolar amounts of phenylalanine, a major endogenous metabolite of aspartame, while the other metabolites, aspartic acid and methanol, were without effect. Administration together with aspartame of the large neutral amino acid valine, which competes with phenylalanine for entry into the brain, completely abolished the seizure-promoting effect of aspartame.(ABSTRACT TRUNCATED AT 250 WORDS)

  13. Alleviation of metabolic abnormalities induced by excessive fructose administration in Wistar rats by Spirulina maxima

    PubMed Central

    Jarouliya, Urmila; Anish, Zacharia J.; Kumar, Pravin; Bisen, P.S.; Prasad, G.B.K.S.

    2012-01-01

    Background & objectives: Diabetes mellitus is a metabolic disorder characterized by hyperglycaemia. Several natural products have been isolated and identified to restore the complications of diabetes. Spirulina maxima is naturally occurring fresh water cyanobacterium, enriched with proteins and essential nutrients. The aim of the study was to determine whether S. maxima could serve as a therapeutic agent to correct metabolic abnormalities induced by excessive fructose administration in Wistar rats. Methods: Oral administration of 10 per cent fructose solution to Wistar rats (n=5 in each group) for 30 days resulted in hyperglycaemia and hyperlipidaemia. Aqueous suspension of S. maxima (5 or 10%) was also administered orally once daily for 30 days. The therapeutic potential of the preparation with reference to metformin (500 mg/kg) was assessed by monitoring various biochemical parameters at 10 day intervals during the course of therapy and at the end of 30 days S. maxima administration. Results: Significant (P<0.001) reductions in blood glucose, lipid profile (triglycerides, cholesterol and LDL, VLDL) and liver function markers (SGPT and SGOT) were recorded along with elevated level of HDL-C at the end of 30 days therapy of 5 or 10 per cent S. maxima aquous extract. Co-administration of S. maxima extract (5 or 10% aqueous) with 10 per cent fructose solution offered a significant protection against fructose induced metabolic abnormalities in Wistar rats. Interpretation & Conclusions: The present findings showed that S. maxima exhibited anti-hyperglycaemic, anti-hyperlipidaemic and hepatoprotective activity in rats fed with fructose. Further studies are needed to understand the mechanisms. PMID:22561632

  14. Administration of vaccinia virus complement control protein shows significant cognitive improvement in a mild injury model.

    PubMed

    Pillay, Nirvana S; Kellaway, Laurie A; Kotwal, Girish J

    2005-11-01

    Previous studies have shown that traumatic mild brain injury in a rat model is accompanied by breakdown of the blood brain barrier and the accumulation of inflammatory cells. A therapeutic agent, vaccinia virus complement control protein (VCP), inhibits both the classic and the alternative pathways of the complement system and, in so doing, prevents cell death and inflammation. With the use of a rat mild injury model, the effects of VCP on spatial learning and memory were tested. Training in a Morris water maze consisted of a total of 16 trials over a 2-day period before rats were anesthetized and subjected to mild (1.0-1.1 atm) lateral fluid percussion injury (FPI) 3.0 mm lateral to the sagittal suture and 4.5 mm posterior to bregma. Ten microl of VCP (1.7 mg/ml) was injected into the injury site immediately after FPI. Two weeks post-FPI the rats were assessed in the Morris water maze for spatial learning and memory. Neurologic motor function tests were carried out after FPI for 14 consecutive days and again after 28 days. The Morris water maze data show that FPI plus saline-injected rats spent a significantly (P <0.05) larger amount of time in one of the incorrect quadrants than did the FPI plus VCP-injected group. Neurologic evaluations 24 hours postinjury revealed differences in sensorimotor function between groups. The results suggest that in a mild injury model, VCP influences neurologic outcome and offers some enhancement in spatial memory and learning.

  15. Systemic administration of minocycline inhibits formalin-induced inflammatory pain in rat.

    PubMed

    Cho, Ik-Hyun; Chung, Young Min; Park, Chul-Kyu; Park, Seong-Hae; Lee, Haeyeong; Li, Hai Ying; Kim, Donghoon; Piao, Zheng Gen; Choi, Se-Young; Lee, Sung Joong; Park, Kyungpyo; Kim, Joong Soo; Jung, Sung Jun; Oh, Seog Bae

    2006-02-01

    It has been demonstrated that spinal microglial activation is involved in formalin-induced pain and that minocycline, an inhibitor of microglial activation, attenuate behavioral hypersensitivity in neuropathic pain models. We investigated whether minocycline could have any anti-nociceptive effect on inflammatory pain, after intraperitonial administration of minocycline, 1 h before formalin (5%, 50 microl) injection into the plantar surface of rat hindpaw. Minocycline (15, 30, and 45 mg/kg) significantly decreased formalin-induced nociceptive behavior during phase II, but not during phase I. The enhancement in the number of c-Fos-positive cells in the L4-5 spinal dorsal horn (DH) and the magnitude of paw edema induced by formalin injection during phase II were significantly reduced by minocycline. Minocycline inhibited synaptic currents of substantia gelatinosa (SG) neurons in the spinal DH, whereas membrane electrical properties of dorsal root ganglion neurons were not affected by minocycline. Analysis with OX-42 antibody revealed the inhibitory effect of minocycline on microglial activation 3 days after formalin injection. These results demonstrate the anti-nociceptive effect of minocycline on formalin-induced inflammatory pain. In addition to the well-known inhibitory action of minocycline on microglial activation, the anti-edematous action in peripheral tissue, as well as the inhibition of synaptic transmission in SG neurons, is likely to be associated with the anti-nociceptive effect of minocycline.

  16. Maternal molecular hydrogen administration on lipopolysaccharide-induced mouse fetal brain injury

    PubMed Central

    Nakano, Tomoko; Kotani, Tomomi; Mano, Yukio; Tsuda, Hiroyuki; Imai, Kenji; Ushida, Takafumi; Li, Hua; Miki, Rika; Sumigama, Seiji; Sato, Yoshiaki; Iwase, Akira; Hirakawa, Akihiro; Asai, Masato; Toyokuni, Shinya; Kikkawa, Fumitaka

    2015-01-01

    Fetal brain injury is often related to prenatal inflammation; however, there is a lack of effective therapy. Recently, molecular hydrogen (H2), a specific antioxidant to hydroxyl radical and peroxynitrite, has been reported to have anti-inflammatory properties. The aim of this study was to investigate whether maternal H2 administration could protect the fetal brain against inflammation. Pregnant C3H/HeN mice received an intraperitoneal injection of lipopolysaccharide (LPS) on gestational day 15.5 and were provided with H2 water for 24 h prior to LPS injection. Pup brain samples were collected on gestational day 16.5, and the levels of apoptosis and oxidative damage were evaluated using immunohistochemistry. Interleukin-6 (IL-6) levels were examined using real-time PCR. The levels of apoptosis and oxidative damage, as well as the levels of IL-6 mRNA, increased significantly when the mother was injected with LPS than that in the control group. However, these levels were significantly reduced when H2 was administered prior to the LPS-injection. Our results suggest that LPS-induced apoptosis, oxidative damage and inflammation in the fetal brain were ameliorated by maternal H2 administration. Antenatal H2 administration might protect the premature brain against maternal inflammation. PMID:26566302

  17. Effects of cerebrolysin administration on oxidative stress-induced apoptosis in lymphocytes from CADASIL patients.

    PubMed

    Formichi, Patrizia; Radi, Elena; Battisti, Carla; Di Maio, Giuseppe; Dotti, Maria Teresa; Muresanu, Dafin; Federico, Antonio

    2013-04-01

    Cerebrolysin (Cere) is a peptidergic nootropic drug with neurotrophic properties which has been used to treat dementia and sequelae of stroke. Use of Cere prevents nuclear structural changes typical of apoptosis and significantly reduces the number of apoptotic cells after several apoptotic stimuli. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary disease caused by mutations of the Notch3 gene encoding the Notch3 protein. Notch3 is involved in the regulation of apoptosis, modulating Fas-Ligand (Fas-L)- induced apoptosis. The aim of this study was to evaluate the in vitro protective effects of Cere against oxidative stress-induced apoptosis in cells from CADASIL patients. We used peripheral blood lymphocytes (PBLs) from 15 CADASIL patients (age range 34-70 years); 2-deoxy-D-ribose (dRib), a highly reducing sugar, was used as paradigm pro-apoptotic stimulus. Apoptosis was analyzed by flow cytometry and fluorescence microscopy. Administration of Cere to PBLs from CADASIL patients cultured under standard conditions had no effect on the percentage of apoptotic cells. Administration of Cere to PBLs cultured with dRib caused a significant decrease in apoptosis after 48 h of culture in only 5 patients, whereas in the other 10 patients, Cere treatment was not associated with any significant difference in the percentage of apoptosis. This result showed a protective effect of Cere against oxidative stress-induced apoptosis only in 30 % of the CADASIL patients, suggesting that the Notch3 gene probably does not influence the anti-apoptotic properties of Cere in vitro.

  18. Chronic administration of galanin attenuates the TNBS-induced colitis in rats.

    PubMed

    Talero, E; Sánchez-Fidalgo, S; Calvo, J R; Motilva, V

    2007-06-01

    Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disorder considered as a consequence of an aberrant response of the immune system to luminal antigens. Numerous groups of agents are being evaluated as novel therapeutic approaches for its treatment; in this way, different peptides have emerged as potential candidates. Galanin is an active neuropeptide distributed in the central and periphery nervous systems although it has been also described having important autocrine and paracrine regulatory capacities with interesting inflammatory and immune properties. In this line, we have observed that galanin treatment has a significant preventive effect in the experimental trinitrobenzensulfonic acid (TNBS) acute model of inflammatory colitis. The aim of the present study was to investigate intensively the role played by the peptide in the evolution of the inflammatory pathology associated to IBD. Galanin (5 and 10 microg/kg/day) was administered i.p., daily, starting 24 h after TNBS instillation, and continuing for 14 and 21 days. The lesions were blindly scored according to macroscopic and histological analyses and quantified as ulcer index. The results demonstrated that chronic administration of galanin improved the colon injury than the TNBS induced. The study by Western-blotting of the expression of nitric oxide inducible enzyme (iNOS), as well as the total nitrite production (NO) assayed by Griess-reaction, showed significant reduction associated with peptide administration. The number of mast cells was also identified in histological preparations stained with toluidine blue and the results showed that samples from galanin treatment, mostly at 21 days, had increased the number of these cells and many of them had a degranulated feature. In conclusion, chronic administration of galanin is able to exert a beneficial effect in the animal model of IBD assayed improving the reparative process. Participation of nitric oxide pathways and mucosal mast cells

  19. Pretreatment with memantine prevents Alzheimer-like alterations induced by intrahippocampal okadaic acid administration in rats.

    PubMed

    Zimmer, Eduardo Rigon; Kalinine, Eduardo; Haas, Clarissa Branco; Torrez, Vitor Rocco; Souza, Diogo Onofre; Muller, Alexandre Pastoris; Portela, Luis Valmor

    2012-12-01

    Cerebral okadaic acid (OA) administration induces Alzheimer's disease (AD)-like phenotype in rats. Alterations in glutamate levels associated with hyperactivation of cyclin dependent kinase 5 (Cdk5) signaling pathway downstream Tau phosphorylation may participate in the genesis of this pathological phenotype. Here, we examined the efficacy of memantine (MN) pretreatment on reducing OA-induced AD-like phenotypes in rats. Wistar rats were given daily intraperitoneal injections of MN for 3 days and then given an intrahippocampal infusion of OA. Animals were divided into four groups: control (CO), MN, OA and MN/OA. Spontaneous locomotion and spatial memory performance were assessed by open field and Morris water maze respectively. Additionally, we measured glutamate levels in the cerebrospinal fluid (CSF) and the immunocontent of Cdk5, p35, p25 and phosphorylated Tau (pTauSer199/202) in the hippocampus. Spontaneous locomotion did not differ between groups. The OA group showed a significant decrease in spatial memory performance compared to all groups. The OA infusion also increased CSF glutamate levels and the immunocontents of Cdk5, p25 and pTauSer199/202 in the hippocampus. Conversely, pretreatment with MN prevented OA-induced spatial memory deficits and the increment of CSF glutamate level; which paralleled with normal immunocontents of Cdk5, p25 and pTau- Ser199/202 proteins. There were positive correlations between spatial memory performance and the neurochemical parameters. In summary, pretreatment with MN prevents spatial memory deficits induced by intrahippocampal OA administration in rats. The prevention of increase CSF glutamate levels, along with the reduced hippocampal phosphorylation of TauSer199/202 by Cdk5/p25 signaling pathway, are the mechanisms proposed to participate in the prophylactic effects of MN in this AD-like model.

  20. Long-Term Administration of Artesunate Induces Reproductive Toxicity in Male Rats

    PubMed Central

    Olumide, Stephen Akinsomisoye; Raji, Yinusa

    2011-01-01

    Background Artesunate is commonly used in malaria therapy. Many antimalarial drugs have been associated with male reproductive dysfunction. The effect of artesunate on male reproductive activities was studied using in–vivo and in-vitro experimental models. Methods Adult male rats (n=6) were orally given artesunate (2.9 mg/kg body weight) on daily basis for five days. Artesunate (2.9 mg/kg body weight) was administered to another group of rats daily for six weeks, while there was a recovery group of rats too. The control animals received the vehicle only. At the end of the treatment, sperm characteristics, serum follicle stimulating hormone, luteinizing hormone and testosterone levels, testicular and epididymal histology and fertility were assessed. Cultured Sertoli cells were treated with 0.3 µM to 10 µM artesunate for five days after which Sertoli cell viability, double-stranded deoxyribonucleic acid (ds-DNA) integrity and genetic expression of Glial cell line-derived neurotrophic factor (GDNF) and transferrin were assessed. The data were analyzed using Graphpad Instat Statistical software. A probability value of p <0.05 was considered significant. Results Artesunate did not cause any significant effects in short-term administration but significantly reduced the aforesaid parameters in long-term administration. There were visible lesions in the testicular and epididymal histological studies, although fertility was not significantly reduced. These changes were restored in the recovery experiment. In-vitro studies showed dose and duration dependent changes in Sertoli cell viability and ds-DNA integrity. However, transferrin and GDNF gene expressions were normal. Conclusion The results suggest that long-term administration of artesunate could induce reversible infertility in rats which may act via distortion of blood–testis barrier formed by Sertoli cells. PMID:23926511

  1. Abrupt suspension of probiotics administration may increase host pathogen susceptibility by inducing gut dysbiosis

    PubMed Central

    Liu, Zhi; Liu, Wenshu; Ran, Chao; Hu, Jun; Zhou, Zhigang

    2016-01-01

    In this study, we investigated the risk associated with suspension of probiotics administration in tilapia, an animal model that may mimic immune-compromised conditions in humans. Tilapias were fed for 14 days using a probiotics-supplemented diet, followed by a three-day suspension of probiotics treatment and a subsequent challenge by Aeromonas hydrophila. Unexpectedly, the suspension of a probiotic strain Lactobacillus plantarum JCM1149 significantly triggered susceptibility of the host to A. hydrophila. We further observed that suspension of JCM1149 resulted in host gut microbiota dysbiosis and the subsequent disorder in the intestinal metabolites (bile acids, amino acids, and glucose) and damage in the intestinal epithelium, giving rise to a condition similar to antibiotics-induced gut dysbiosis, which collectively impaired tilapia’s gut health and resistance to pathogenic challenges. Additionally, we determined that JCM1149 adhered relatively poorly to tilapia intestinal mucosa and was rapidly released from the gastrointestinal tract (GIT) after suspension, with the rapid loss of probiotic strain probably being the direct cause of gut dysbiosis. Finally, three other probiotic Lactobacillus strains with low intestinal mucosa binding activity showed similar rapid loss phenotype following administration suspension, and induced higher host susceptibility to infection, indicating that the risk is a generic phenomenon in Lactobacillus. PMID:26983596

  2. Enhanced AMPA receptor activity increases operant alcohol self-administration and cue-induced reinstatement.

    PubMed

    Cannady, Reginald; Fisher, Kristen R; Durant, Brandon; Besheer, Joyce; Hodge, Clyde W

    2013-01-01

    Long-term alcohol exposure produces neuroadaptations that contribute to the progression of alcohol abuse disorders. Chronic alcohol consumption results in strengthened excitatory neurotransmission and increased α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPA) receptor signaling in animal models. However, the mechanistic role of enhanced AMPA receptor activity in alcohol-reinforcement and alcohol-seeking behavior remains unclear. This study examined the role of enhanced AMPA receptor function using the selective positive allosteric modulator, aniracetam, in modulating operant alcohol self-administration and cue-induced reinstatement. Male alcohol-preferring (P-) rats, trained to self-administer alcohol (15%, v/v) versus water were pre-treated with aniracetam to assess effects on maintenance of alcohol self-administration. To determine reinforcer specificity, P-rats were trained to self-administer sucrose (0.8%, w/v) versus water, and effects of aniracetam were tested. The role of aniracetam in modulating relapse of alcohol-seeking was assessed using a response contingent cue-induced reinstatement procedure in P-rats trained to self-administer 15% alcohol. Aniracetam pre-treatment significantly increased alcohol-reinforced responses relative to vehicle treatment. This increase was not attributed to aniracetam-induced hyperactivity as aniracetam pre-treatment did not alter locomotor activity. AMPA receptor involvement was confirmed because 6,7-dinitroquinoxaline-2,3-dione (AMPA receptor antagonist) blocked the aniracetam-induced increase in alcohol self-administration. Aniracetam did not alter sucrose-reinforced responses in sucrose-trained P-rats, suggesting that enhanced AMPA receptor activity is selective in modulating the reinforcing function of alcohol. Finally, aniracetam pre-treatment potentiated cue-induced reinstatement of alcohol-seeking behavior versus vehicle-treated P-rats. These data suggest that enhanced glutamate activity at AMPA

  3. Inflammation induced by increased frequency of intermittent hypoxia is attenuated by tempol administration.

    PubMed

    Zhang, J; Zheng, L; Cao, J; Chen, B; Jin, D

    2015-12-01

    The levels of serum inflammatory cytokines and the activation of nuclear factor kappa B (NF-κB) and hypoxia inducible factor-1α (HIF-1α) in heart tissues in response to different frequencies of intermittent hypoxia (IH) and the antioxidant tempol were evaluated. Wistar rats (64 males, 200-220 g) were randomly divided into 6 experimental groups and 2 control groups. Four groups were exposed to IH 10, 20, 30, or 40 times/h. The other 2 experimental groups were challenged with IH (30 times/h) plus tempol, either beginning on day 0 (IH30T0) or on day 29 (IH30T29). After 6 weeks of challenge, serum levels of tumor necrosis factor (TNF)-α, intracellular adhesion molecule (ICAM)-1, and interleukin-10 were measured, and western blot analysis was used to detect NF-κB p65 and HIF-1α in myocardial tissues. Serum levels of TNF-α and ICAM-1 and myocardial expression of NF-κB p65 and HIF-1α were all significantly higher in IH rats than in controls (P<0.001). Increased IH frequency resulted in more significant changes. Administration of tempol in IH rats significantly reduced levels of TNF-α, ICAM-1, NF-κB and HIF-1α compared with the non-tempol-treated group (F=16.936, P<0.001). IH induced an inflammatory response in a frequency-dependent manner. Additionally, HIF-1α and NF-κB were increased following IH administration. Importantly, tempol treatment attenuated this effect. PMID:26397969

  4. Withdrawal from Chronic Cocaine Administration Induces Deficits in Brain Reward Function in C57BL/6J Mice

    PubMed Central

    Stoker, Astrid K.; Markou, Athina

    2011-01-01

    Anhedonia is a major symptom of cocaine withdrawal, whereas euphoria characterizes the effects of acute administration of this drug in humans. These mood states can be measured quantitatively in animals with brain reward thresholds obtained from the intracranial self-stimulation (ICSS) procedure. Studies have previously reported the reward-enhancing effects of acute cocaine administration using the ICSS procedure in mice, but the effects of chronic cocaine administration and withdrawal on brain reward thresholds have not been widely investigated in this species. Cocaine withdrawal was induced in C57BL/6J mice by removal of intraperitoneal osmotic minipumps that delivered cocaine (90 or 180 mg/kg/day, salt) for 72 h. Mice were tested in the ICSS procedure 3–100 h post-pump removal. Anxiety-like behavior was assessed in the light-dark box 24 h post-pump removal. After an 18-day washout period, tolerance and sensitization to the reward-enhancing effects of cocaine were assessed by injecting bolus cocaine intraperitoneally (0, 2.5, 5, and 10 mg/kg). The results indicated that 72 h administration of 90 and 180 mg/kg/day cocaine significantly lowered brain reward thresholds. Withdrawal from 90 and 180 mg/kg/day of cocaine administration elevated ICSS thresholds to similar extents. No anxiety-like behavior was observed in the light-dark box during withdrawal from chronic cocaine administration, although the number of transitions between compartments and locomotion in the dark compartment markedly decreased. Chronic cocaine administration did not induce tolerance or sensitization to the reward-enhancing effects of acute cocaine. In conclusion, alterations in mood states induced by cocaine administration and withdrawal in mice can be measured using the ICSS procedure. PMID:21557971

  5. Metformin administration induces hepatotoxic effects in paraoxonase-1-deficient mice.

    PubMed

    García-Heredia, Anabel; Riera-Borrull, Marta; Fort-Gallifa, Isabel; Luciano-Mateo, Fedra; Cabré, Noemí; Hernández-Aguilera, Anna; Joven, Jorge; Camps, Jordi

    2016-04-01

    Metformin is the first-line pharmacological treatment of diabetes. In these patients, metformin reduces body weight and decreases the risk of diabetes-related complications such as cardiovascular disease. However, whether metformin elicits beneficial effects on liver histology is a controversial issue and, as yet, there is no consensus. Paraoxonase-1 (PON1), an enzyme synthesized mainly by the liver, degrades lipid peroxides and reduces oxidative stress. PON1 activities are decreased in chronic liver diseases. We evaluated the effects of metformin in the liver of PON1-deficient mice which, untreated, present a mild degree of liver steatosis. Metformin administration aggravated inflammation in animals given a standard mouse chow and in those fed a high-fat diet. Also, it was associated with a higher degree of steatosis in animals fed a standard chow diet. This report is a cautionary note regarding the prescription of metformin for the treatment of diabetes in patients with concomitant liver impairment.

  6. Chronic administration of troxerutin protects mouse brain against D-galactose-induced impairment of cholinergic system.

    PubMed

    Lu, Jun; Wu, Dong-Mei; Hu, Bin; Cheng, Wei; Zheng, Yuan-Lin; Zhang, Zi-Feng; Ye, Qin; Fan, Shao-Hua; Shan, Qun; Wang, Yong-Jian

    2010-02-01

    Previous evidence showed that administration of d-galactose (d-gal) increased ROS production and resulted in impairment of cholinergic system. Troxerutin, a natural bioflavonoid, has been reported to have many benefits and medicinal properties. In this study, we evaluated the protective effect of troxerutin against d-gal-induced impairment of cholinergic system, and explored the potential mechanism of its action. Our results displayed that troxerutin administration significantly improved behavioral performance of d-gal-treated mice in step-through test and morris water maze task. One of the potential mechanisms of this action was decreased AGEs, ROS and protein carbonyl levels in the basal forebrain, hippocampus and front cortex of d-gal-treated mice. Furthermore, our results also showed that troxerutin significantly inhibited cholinesterase (AchE) activity, increased the expression of nicotinic acetylcholine receptor alpha 7 (nAchRalpha7) and enhanced interactions between nAchRalpha7 and either postsynaptic density protein 95 (PSD95) or N-methyl-d-aspartate receptors subunit 1 (NMDAR1) in the basal forebrain, hippocampus and front cortex of d-gal-treated mice, which could help restore impairment of brain function.

  7. Placental Growth Factor Administration Abolishes Placental Ischemia-Induced Hypertension.

    PubMed

    Spradley, Frank T; Tan, Adelene Y; Joo, Woo S; Daniels, Garrett; Kussie, Paul; Karumanchi, S Ananth; Granger, Joey P

    2016-04-01

    Preeclampsia is a pregnancy-specific disorder of new-onset hypertension. Unfortunately, the most effective treatment is early delivery of the fetus and placenta. Placental ischemia appears central to the pathogenesis of preeclampsia because placental ischemia/hypoxia induced in animals by reduced uterine perfusion pressure (RUPP) or in humans stimulates release of hypertensive placental factors into the maternal circulation. The anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1), which antagonizes and reduces bioavailable vascular endothelial growth factor and placental growth factor (PlGF), is elevated in RUPP rats and preeclampsia. Although PlGF and vascular endothelial growth factor are both natural ligands for sFlt-1, vascular endothelial growth factor also has high affinity to VEGFR2 (Flk-1) causing side effects like edema. PlGF is specific for sFlt-1. We tested the hypothesis that PlGF treatment reduces placental ischemia-induced hypertension by antagonizing sFlt-1 without adverse consequences to the mother or fetus. On gestational day 14, rats were randomized to 4 groups: normal pregnant or RUPP±infusion of recombinant human PlGF (180 μg/kg per day; AG31, a purified, recombinant human form of PlGF) for 5 days via intraperitoneal osmotic minipumps. On day 19, mean arterial blood pressure and plasma sFlt-1 were higher and glomerular filtration rate lower in RUPP than normal pregnant rats. Infusion of recombinant human PlGF abolished these changes seen with RUPP along with reducing oxidative stress. These data indicate that the increased sFlt-1 and reduced PlGF resulting from placental ischemia contribute to maternal hypertension. Our novel finding that recombinant human PlGF abolishes placental ischemia-induced hypertension, without major adverse consequences, suggests a strong therapeutic potential for this growth factor in preeclampsia. PMID:26831193

  8. Distinct Pathways of Humoral and Cellular Immunity Induced with the Mucosal Administration of a Nanoemulsion Adjuvant

    PubMed Central

    Makidon, Paul E.; Janczak, Katarzyna W.; Blanco, Luz P.; Swanson, Benjamin; Smith, Douglas M.; Pham, Tiffany; Szabo, Zsuzsanna; Kukowska-Latallo, Jolanta F.; Baker, James R.

    2014-01-01

    Nasal administration of an oil-in-water nanoemulsion (NE) adjuvant W805EC produces potent systemic and mucosal, Th-1– and Th-17–balanced cellular responses. However, its molecular mechanism of action has not been fully characterized and is of particular interest because NE does not contain specific ligands for innate immune receptors. In these studies, we demonstrate that W805EC NE adjuvant activates innate immunity, induces specific gene transcription, and modulates NF-κB activity via TLR2 and TLR4 by a mechanism that appears to be distinct from typical TLR agonists. Nasal immunization with NE-based vaccine showed that the TLR2, TLR4, and MyD88 pathways and IL-12 and IL-12Rβ1 expression are not required for an Ab response, but they are essential for the induction of balanced Th-1 polarization and Th-17 cellular immunity. NE adjuvant induces MHC class II, CD80, and CD86 costimulatory molecule expression and dendritic cell maturation. Further, upon immunization with NE, adjuvant mice deficient in the CD86 receptor had normal Ab responses but significantly reduced Th-1 cellular responses, whereas animals deficient in both CD80 and CD86 or lacking CD40 failed to produce either humoral or cellular immunity. Overall, our data show that intranasal administration of Ag with NE induces TLR2 and TLR4 activation along with a MyD88-independent Ab response and a MyD88-dependent Th-1 and Th-17 cell–mediated immune response. These findings suggest that the unique properties of NE adjuvant may offer novel opportunities for understanding previously unrecognized mechanisms of immune activation important for generating effective mucosal and systemic immune responses. PMID:24532579

  9. Pre-administration of curcumin prevents neonatal sevoflurane exposure-induced neurobehavioral abnormalities in mice.

    PubMed

    Ji, Mu-Huo; Qiu, Li-Li; Yang, Jiao-Jiao; Zhang, Hui; Sun, Xiao-Ru; Zhu, Si-Hai; Li, Wei-Yan; Yang, Jian-Jun

    2015-01-01

    Sevoflurane, a commonly used inhaled anesthetic, can induce neuronal apoptosis in the developing rodent brain and correlate with functional neurological impairment later in life. However, the mechanisms underlying these deleterious effects of sevoflurane remain unclear and no effective treatment is currently available. Herein, the authors investigated whether curcumin can prevent the sevoflurane anesthesia-induced cognitive impairment in mice. Six-day-old C57BL/6 mice were exposed to 3% sevoflurane 2h daily for 3 consecutive days and were treated with curcumin at the dose of 20 mg/kg or vehicle 30 min before the sevoflurane anesthesia from postnatal days 6 (P6) to P8. Cognitive functions were evaluated by open field, Morris water maze, and fear conditioning tests on P61, P63-69, and P77-78, respectively. In another separate experiment, mice were killed on day P8 or P78, and the brain tissues were harvested and then subjected to biochemistry studies. Our results showed that repeated neonatal sevoflurane exposure led to significant cognitive impairment later in life, which was associated with increased neuronal apoptosis, neuroinflammation, oxidative nitrosative stress, and decreased memory related proteins. By contrast, pre-administration of curcumin ameliorated early neuronal apoptosis, neuroinflammation, oxidative nitrosative stress, memory related proteins, and later cognitive dysfunction. In conclusion, our data suggested that curcumin pre-administration can prevent the sevoflurane exposure-induced cognitive impairment later in life, which may be partly attributed to its ability to attenuate the neural apoptosis, inflammation, and oxidative nitrosative stress in mouse brain. PMID:25447320

  10. Central Administration of Resveratrol Improves Diet-Induced Diabetes

    PubMed Central

    Ramadori, Giorgio; Gautron, Laurent; Fujikawa, Teppei; Vianna, Claudia R.; Elmquist, Joel K.; Coppari, Roberto

    2009-01-01

    Resveratrol is a natural polyphenolic compound that activates nicotinamide adenosine dinucleotide-dependent deacetylase SIRT1. Resveratrol has recently been shown to exert potent antidiabetic actions when orally delivered to animal models of type 2 diabetes. However, the tissue(s) mediating these beneficial effects is unknown. Because SIRT1 is expressed in central nervous system (CNS) neurons known to control glucose and insulin homeostasis, we hypothesized that resveratrol antidiabetic effects are mediated by the brain. Here, we report that long-term intracerebroventricular infusion of resveratrol normalizes hyperglycemia and greatly improves hyperinsulinemia in diet-induced obese and diabetic mice. It is noteworthy that these effects are independent of changes in body weight, food intake, and circulating leptin levels. In addition, CNS resveratrol delivery improves hypothalamic nuclear factor-κB inflammatory signaling by reducing acetylated-RelA/p65 and total RelA/p65 protein contents, and inhibitor of nuclear factor-κB α and IκB kinase β mRNA levels. Furthermore, this treatment leads to reduced hepatic phosphoenolpyruvate carboxykinase 1 mRNA and protein levels and ameliorates pyruvate-induced hyperglycemia in this mouse model of type 2 diabetes. Collectively, our results unveiled a previously unrecognized key role for the CNS in mediating the antidiabetic actions of resveratrol. PMID:19819963

  11. Acquisition of MDMA self-administration: pharmacokinetic factors and MDMA-induced serotonin release.

    PubMed

    Bradbury, Sarah; Bird, Judith; Colussi-Mas, Joyce; Mueller, Melanie; Ricaurte, George; Schenk, Susan

    2014-09-01

    The current study aimed to elucidate the role of pharmacokinetic (PK) parameters and neurotransmitter efflux in explaining variability in (±) 3, 4-methylenedioxymethamphetamine (MDMA) self-administration in rats. PK profiles of MDMA and its major metabolites were determined after the administration of 1.0 mg/kg MDMA (iv) prior to, and following, the acquisition of MDMA self-administration. Synaptic levels of 5-hydroxytryptamine (5HT) and dopamine (DA) in the nucleus accumbens were measured following administration of MDMA (1.0 and 3.0 mg/kg, iv) using in vivo microdialysis and compared for rats that acquired or failed to acquire MDMA self-administration. Effects of the 5HT neurotoxin, 5,7 dihydroxytryptamine (5, 7-DHT), on the acquisition of MDMA and cocaine self-administration were also determined. In keeping with previous findings, approximately 50% of rats failed to meet a criterion for acquisition of MDMA self-administration. The PK profiles of MDMA and its metabolites did not differ between rats that acquired or failed to acquire MDMA self-administration. MDMA produced more overflow of 5HT than DA. The MDMA-induced 5HT overflow was lower in rats that acquired MDMA self-administration compared with those that did not acquire self-administration. In contrast, MDMA-induced DA overflow was comparable for the two groups. Prior 5,7-DHT lesions reduced tissue levels of 5HT and markedly increased the percentage of rats that acquired MDMA self-administration and also decreased the latency to acquisition of cocaine self-administration. These data suggest that 5HT limits the initial sensitivity to the positively reinforcing effects of MDMA and delays the acquisition of reliable self-administration.

  12. Cerebrolysin administration reduces oxidative stress-induced apoptosis in lymphocytes from healthy individuals.

    PubMed

    Formichi, Patrizia; Radi, Elena; Battisti, Carla; Di Maio, Giuseppe; Muresanu, Dafin; Federico, Antonio

    2012-11-01

    Cerebrolysin is the only drug available for clinical use containing active fragments of some important neurotrophic factors obtained from purified porcine brain proteins, which has long been used for the treatment of dementia and stroke sequels. Cerebrolysin has growth factor-like activities and promotes neuronal survival and sprouting, however, its molecular mechanism still needs to be determined. It has been shown that Cerebrolysin may interact with proteolytic pathways linked to apoptosis. Administration of Cerebrolysin significantly reduces the number of apoptotic neurons after glutamate exposure. Furthermore, it has been reported that Cerebrolysin inhibits free radicals formation and lipid peroxidation. In vitro we evaluated the protective effects of Cerebrolysin towards spontaneous and induced apoptotic death in cells from healthy individuals. Peripheral blood lymphocytes (PBLs) from 10 individuals were used as cell model; 2-deoxy-D-ribose (dRib), a highly reducing sugar, was used as paradigm pro-apoptotic stimulus. Apoptosis was analysed using flow cytometry and fluorescence microscopy. Our results showed that Cerebrolysin significantly reduced the number of apoptotic PBLs after dRib treatment, although it had no significative effects on cells cultured in standard conditions. Our work showed a protective effect of Cerebrolysin on oxidative stress-induced apoptosis and suggested that PBLs can be used as an easy obtainable and handy cell model to verify Cerebrolysin effects in neurodegenerative pathologies.

  13. Attenuation of methylphenidate-induced tolerance on cognition by buspirone co-administration.

    PubMed

    Alam, Nausheen; Najam, Rahila; Khan, Saira Saeed

    2015-09-01

    Methylphenidate as a psycho stimulant drug has been prescribed in neuropsychiatric disorders to increase cognition and attention therefore is a medication of choice for attention-deficit/hyperactivity disorder however long-term administration of central nervous system stimulant produces tolerance on cognitive behavior. Previously it has been shown that long-term psychostimulant administration increases somatodendritic 5HT-1A receptors effectiveness. Repeated buspirone administration attenuates 5-HT1A soma to dendritic receptors effectiveness. This study was designed to determine that buspirone co-administration may reduce methylphenidate-induced tolerance on cognitive behavior. Cognitive effects were compared by using water maze and passive avoidance test weekly after long-term administration of methylphenidate, buspirone and their co-administration. Methylphenidate at a dose of 2.0mg/kg/day in rats initially improve memory but after long-term treatment produce tolerance on cognitive behavior this effect is more pronounce in case of spatial working memory of water maze test than passive avoidance learning memory. However oral buspirone co-administration at a dose of 10mg/kg/day prevents methylphenidate-induce tolerance on cognition. It is suggested that buspirone may oppose methylphenidate-induced cognitive tolerance by reducing the sensitivity of 5-HT 1A soma to dendritic receptors. These findings may help to extend future therapeutics in ADHD.

  14. Cisplatin-induced nephrotoxicity alters blood pressure response to angiotensin II administration in rats

    PubMed Central

    Dehghani, Aghdas; Saberi, Shadan; Nematbakhsh, Mehdi

    2016-01-01

    Background: Cisplatin (CP) is an effective chemotherapeutic drug used in the clinic, which is accompanied with nephrotoxicity. CP may also disturb hemodynamics of the circulation system. We have tested the role of CP in mean arterial pressure (MAP) response to graded angiotensin (Ang) II infusion in rats. Materials and Methods: Male and female rats were treated with CP (2.5 mg/kg/day) for a period of 1-week and compared with the vehicle-treated animals. The blood pressure response to Ang II (100–1000 ng/kg/min) was determined under the anesthesia condition. Endothelial permeability of aorta was measured according to the Evans blue uptake. The kidney tissue was also subjected to histological investigation. Results: Significant increase in serum levels of blood urea nitrogen and creatinine and pathological findings in CP-treated rats verified CP-induced nephrotoxicity. Significant difference in percentage of change in MAP response to Ang II between male and female rats was detected in vehicle-treated groups (P < 0.05) while in CP-treated animals this response difference was not observed. The groups were not significantly different with regard to the endothelial permeability of aorta while the serum level of nitrite in male rats increased significantly following administration of CP (P < 0.05). Conclusion: It seems the different response in percentage of change of MAP to graded Ang II infusion between male and female indicates the effect of CP on renin Ang system parameters. PMID:27110550

  15. Central but not systemic administration of ghrelin induces wakefulness in mice.

    PubMed

    Szentirmai, Éva

    2012-01-01

    Ghrelin is a brain-gut peptide hormone widely known for its orexigenic and growth hormone-releasing activities. Findings from our and other laboratories indicate a role of ghrelin in sleep regulation. The effects of exogenous ghrelin on sleep-wake activity in mice are, however, unknown. The aim of the present study was to determine the sleep-modulating effects of ghrelin after central and systemic administrations in mice. Sleep-wake activity after intracerebroventricular (i.c.v.) administration of 0.2, 1 and 5 µg ghrelin and intraperitoneal injections of 40, 100, and 400 µg/kg ghrelin prior to light onset were determined in C57BL/6 mice. In addition, body temperature, motor activity and 1-hour food intake was measured after the systemic injections. Sleep effects of systemic ghrelin (40 and 400 µg/kg) injected before dark onset were also determined. I.c.v. injection of ghrelin increased wakefulness and suppressed non-rapid-eye-movement sleep and electroencephalographic slow-wave activity in the first hour after injections. Rapid-eye-movement sleep was decreased for 2-4 hours after each dose of ghrelin. Sytemic administration of ghrelin did not induce changes in sleep-wake activity in mice at dark or light onset. Motor activity and body temperature remained unaltered and food intake was significantly increased after systemic injections of ghrelin given prior the light period. These findings indicate that the activation of central, but not peripheral, ghrelin-sensitive mechanisms elicits arousal in mice. The results are consistent with the hypothesis that the activation of the hypothalamic neuronal circuit formed by ghrelin, orexin, and neuropeptide Y neurons triggers behavioral sequence characterized by increased wakefulness, motor activity and feeding in nocturnal rodents.

  16. Subcutaneous Administration of Bovine Superoxide Dismutase Protects Lungs from Radiation-Induced Lung Injury

    PubMed Central

    Jackson, Isabel L.; Vujaskovic, Zeljko

    2016-01-01

    Background The objective of the present study was to determine whether single administration of the antioxidant enzyme bovine superoxide dismutase (bSOD) after radiation (RT) exposure mitigates development of pulmonary toxicity in rats. Methods Female F344 rats (n=60) were divided among six experimental groups: (1) RT, single dose of 21 Gy to the right hemithorax; (2) RT+5 mg/kg bSOD; (3) RT+15 mg/kg bSOD; (4) No RT; (5) sham RT+5mg/kg bSOD; and (6) sham RT+15mg/kg bSOD. A single subcutaneous injection of bSOD (5 or 15 mg/kg) was administered 24 hours postradiation. The effects of bSOD on radiation-induced lung injury were assessed by measurement of body weight, breathing frequency and histopathological changes. Immunohistochemistry was used to evaluate oxidative stress (8-OHdG+, NOX4+, nitrotyrosine+, 4HNE+ cells), macrophage activation (ED1+), and expression of profibrotic TGF-β in irradiated tissue. Results Radiation led to an increase in all evaluated parameters. Treatment with 15mg/kg bSOD significantly decreased levels of all evaluated parameters including tissue damage and breathing frequency starting 6 weeks post-radiation. Animals treated with 5 mg/kg bSOD trended toward a suppression of radiation-induced lung damage but did not reach statistical significance. Conclusions The single application of bSOD (15mg/kg) ameliorates radiation induced lung injury through suppression of ROS/RNS dependent tissue damage. PMID:26110460

  17. Ischemia-induced mitochondrial apoptosis is significantly attenuated by ischemic preconditioning.

    PubMed

    Racay, Peter; Chomova, Maria; Tatarkova, Zuzana; Kaplan, Peter; Hatok, Jozef; Dobrota, Dusan

    2009-09-01

    Ischemic preconditioning (IPC) represents an important adaptation of CNS to sub-lethal ischemia, which results in increased tolerance of CNS to the lethal ischemia. Ischemia-induced mitochondrial apoptosis is considered to be an important event leading to neuronal cell death after cerebral blood flow arrest. In presented study, we have determined the effect of IPC on ischemia/reperfusion-induced mitochondrial apoptosis. Global brain ischemia was induced by permanent occlusion of vertebral arteries and temporal occlusion of carotid arteries for 15 min. Rats were preconditioned by 5 min of sub-lethal ischemia and 2 days later 15 min of lethal ischemia was induced. With respect to mitochondrial apoptosis initiation, translocation of p53 to mitochondria was observed in hippocampus but not in cerebral cortex. However, level of both apoptotic bax and anti-apoptotic bcl-xl in both hippocampal and cortical mitochondria was unchanged after global brain ischemia. Detection of genomic DNA fragmentation as well as Fluoro-Jade C staining showed that ischemia induces apoptosis in vulnerable CA1 layer of rat hippocampus. IPC abolished completely ischemia-induced translocation of p53 to mitochondria and had significant protective effect on ischemia-induced DNA fragmentation. In addition, significant decrease of Fluoro-Jade C positive cells was observed as well. Our results indicate that IPC abolished almost completely both initiation and execution of mitochondrial apoptosis induced by global brain ischemia. PMID:19283470

  18. Analgesic effects of intramuscular administration of meloxicam in Hispaniolan parrots (Amazona ventralis) with experimentally induced arthritis.

    PubMed

    Cole, Gretchen A; Paul-Murphy, Joanne; Krugner-Higby, Lisa; Klauer, Julia M; Medlin, Scott E; Keuler, Nicholas S; Sladky, Kurt K

    2009-12-01

    OBJECTIVE-To evaluate the analgesic efficacy of meloxicam in parrots with experimentally induced arthritis, with extent of weight bearing and rotational perch walking used as outcome measures. ANIMALS-15 adult Hispaniolan parrots (Amazona ventralis). PROCEDURES-Arthritis was experimentally induced via intra-articular injection of microcrystalline sodium urate suspension (MSU) into 1 intertarsal joint. Parrots were treated in a crossover design. Five treatments were compared as follows: meloxicam (4 dosages) at 0.05, 0.1, 0.5, and 1.0 mg/kg (IM, q 12 h, 3 times) and 0.03 mL of saline (0.9% NaCl) solution (IM, q 12 h, 3 times). The first treatment was given 6 hours following MSU administration. Lameness was assessed by use of a biomechanical perch to record weight-bearing load and a rotational perch to determine dexterity. Feces were collected to assay for occult blood. RESULTS-Parrots treated with meloxicam at 1.0 mg/kg had significantly better return to normal (baseline) weight bearing on the arthritic pelvic limb, compared with control parrots or parrots treated with meloxicam at 0.05, 0.1, and 0.5 mg/kg. All fecal samples collected from parrots following induction of arthritis and treatment with meloxicam had negative results for occult blood. CONCLUSIONS AND CLINICAL RELEVANCE-Meloxicam administered at 1.0 mg/kg, IM, every 12 hours effectively relieved arthritic pain in parrots.

  19. Acute administration of diosgenin or dioscorea improves hyperglycemia with increases muscular steroidogenesis in STZ-induced type 1 diabetic rats.

    PubMed

    Sato, K; Fujita, S; Iemitsu, M

    2014-09-01

    Acute dehydroepiandrosterone (DHEA) administration improves hyperglycemia in rats with streptozotocin (STZ)-induced type 1 diabetes mellitus. Diosgenin, a steroid structurally similar to DHEA (dehydroepiandrosterone), is contained highly levels in dioscorea; however, it is still unclear whether this natural product improves hyperglycemia in the type 1 diabetes model rats through an increase muscular GLUT4 signaling. After 1 week of STZ injection, fasting glucose level was measured in blood taken from the tail vein every 30 min for 150 min after injection of diosgenin or dioscorea (3mg/kg). On another day, muscle was resected 150 min after diosgenin or dioscorea injections. Serum DHEA level increased significantly 120 min after diosgenin or dioscorea injections; concomitantly, blood glucose level decreased significantly. Moreover, GLUT4 translocation, as well as phosphorylation of Akt and PKC ζ/λ, increased significantly by diosgenin or dioscorea administration. However, these effects of diosgenin and dioscorea were blocked by a 5α-reductase inhibitor that inhibits synthesizing dehydrotestosterone (DHT) from testosterone. Additionally, significant correlations were observed between blood glucose level, GLUT4 translocation level, and muscular sex steroid hormone level 150 min after the administrations. These results suggest that the diosgenin-induced increase in the DHEA level may contribute to the improvement of hyperglycemia by activating the muscular GLUT4 signaling pathway in type 1 diabetes model rats.

  20. Systemic Administration of Oleoylethanolamide Protects from Neuroinflammation and Anhedonia Induced by LPS in Rats

    PubMed Central

    Sayd, Aline; Antón, María; Alén, Francisco; Caso, Javier Rubén; Pavón, Javier; Leza, Juan Carlos; Rodríguez de Fonseca, Fernando

    2015-01-01

    Background: The acylethanolamides oleoylethanolamide and palmitoylethanolamide are endogenous lipid mediators with proposed neuroprotectant properties in central nervous system (CNS) pathologies. The precise mechanisms remain partly unknown, but growing evidence suggests an antiinflammatory/antioxidant profile. Methods: We tested whether oleoylethanolamide/palmitoylethanolamide (10mg/kg, i.p.) attenuate neuroinflammation and acute phase responses (hypothalamus-pituitary-adrenal (HPA) stress axis stress axis activation, thermoregulation, and anhedonia) induced by lipopolysaccharide (0.5mg/kg, i.p.) in rats. Results: Lipopolysaccharide increased mRNA levels of the proinflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interleukin-6, nuclear transcription factor-κB activity, and the expression of its inhibitory protein IκBα in cytoplasm, the inducible isoforms of nitric oxide synthase and cyclooxygenase-2, microsomal prostaglandin E2 synthase mRNA, and proinflammatory prostaglandin E2 content in frontal cortex 150 minutes after administration. As a result, the markers of nitrosative/oxidative stress nitrites (NO2 -) and malondialdehyde were increased. Pretreatment with oleoylethanolamide/ palmitoylethanolamide reduced plasma tumor necrosis factor-α levels after lipopolysaccharide, but only oleoylethanolamide significantly reduced brain tumor necrosis factor-α mRNA. Oleoylethanolamide and palmitoylethanolamide prevented lipopolysaccharide-induced nuclear transcription factor-κB (NF-κB)/IκBα upregulation in nuclear and cytosolic extracts, respectively, the expression of inducible isoforms of nitric oxide synthase, cyclooxygenase-2, and microsomal prostaglandin E2 synthase and the levels of prostaglandin E2. Additionally, both acylethanolamides reduced lipopolysaccharide-induced oxidative/nitrosative stress. Neither oleoylethanolamide nor palmitoylethanolamide modified plasma corticosterone levels after lipopolysaccharide, but both

  1. Reoxygenation of Asphyxiated Newborn Piglets: Administration of 100% Oxygen Causes Significantly Higher Apoptosis in Cortical Neurons, as Compared to 21%

    PubMed Central

    Faa, G.; Fanos, V.; Fanni, D.; Gerosa, C.; Faa, A.; Fraschini, M.; Pais, M. E.; Di Felice, E.; Papalois, A.; Varsami, M.; Xanthos, T.; Iacovidou, N.

    2014-01-01

    Objective. Evaluation of neuronal changes in an animal experimental model of normocapnic hypoxia- reoxygenation. Materials and Methods. Fifty male piglets were the study subjects; normocapnic hypoxia was induced in 40 piglets and ten were sham-operated (controls). When bradycardia and/or severe hypotension occurred, reoxygenation was initiated. Animals were allocated in 4 groups according to the oxygen concentration, they were resuscitated with 18%, 21%, 40%, and 100% O2. Persisting asystole despite 10 minutes of cardiopulmonary resuscitation and return of spontaneous circulation were the endpoints of the experiment. Surviving animals were euthanized and brain cortex samples were collected, hematoxylin and eosin-stained, and examined for apoptotic bodies observing 10 consecutive high power fields. Results. Histological examination of the control group did not show any pathological change. On the contrary, apoptosis of neurons was found in 87.5% of treated animals. When specimens were examined according to the oxygen concentration used for resuscitation, we found marked intergroup variability; a higher percentage of apoptotic neurons was observed in piglets of group 4 (100% oxygen) compared to the others (P = 0.001). Conclusions. This preliminary data shows that normocapnic hypoxia and reoxygenation in Landrace/Large White piglets resulted in significant histological changes in the brain cortex. The degree of pathological changes in cortical neurons was significantly associated with the oxygen concentration used for reoxygenation, with a higher percentage of apoptotic neurons being observed in piglets reoxygenated with 100% compared to 18% O2 and to 21% O2. PMID:24783208

  2. Tamoxifen administration routes and dosage for inducible Cre-mediated gene disruption in mouse hearts.

    PubMed

    Andersson, Kristin B; Winer, Lisbeth H; Mørk, Halvor K; Molkentin, Jeffery D; Jaisser, Frédéric

    2010-08-01

    Tissue-specific and time-dependent control of in vivo gene disruption may be achieved using conditional knockout strategies in transgenic mice. Fusion of mutant estrogen receptor ligand-binding domains to Cre recombinase (Cre-ER(T), MerCreMer) combined with cardiac-directed gene expression has been used to generate several cardiac-specific tamoxifen-inducible Cre-expressing mouse lines. Such mice have successfully been used to generate Cre-loxP-mediated gene disruption in an inducible manner in the myocardium in vivo. However, information is sparse regarding the tamoxifen dosage, the time course of gene disruption and whether different administration routes differ in efficiency in obtaining gene disruption in the myocardium. We have evaluated these parameters in Serca2 ( flox/flox ) Tg(alphaMHC-MerCreMer) transgenic mice (SERCA2 KO). Serca2 mRNA transcript abundance was used as a sensitive indicator of Cre-loxP-dependent gene disruption in the myocardium. We found that 2 i.p. injections of tamoxifen in oil (1 mg/day, approximate total dose 80 mg/kg) was sufficient for efficient gene disruption with maximal reduction of Serca2 mRNA as early as 4 days after tamoxifen induction. Moreover, a simple protocol using tamoxifen-supplemented non-pelleted dry feed p.o. was comparable to i.p. injections in inducing gene disruption. These improvements may significantly improve animal welfare and reduce the workload in the production of cardiac conditional knockout mice.

  3. Adrenal Activity during Repeated Long-Access Cocaine Self-Administration is Required for Later CRF-Induced and CRF-Dependent Stressor-Induced Reinstatement in Rats

    PubMed Central

    Graf, Evan N; Hoks, Michael A; Baumgardner, Jean; Sierra, Jose; Vranjkovic, Oliver; Bohr, Colin; Baker, David A; Mantsch, John R

    2011-01-01

    Understanding the neurobiological processes that contribute to the establishment and expression of stress-induced regulation of cocaine use in addicted individuals is important for the development of new and better treatment approaches. It has been previously shown that rats self-administering cocaine under long-access conditions (6 h daily) display heightened susceptibility to the reinstatement of extinguished cocaine seeking by a stressor, electric footshock, or i.c.v. administration of the stressor-responsive neuropeptide, corticotropin-releasing factor (CRF). This study tested the hypothesis that adrenal responsiveness during earlier long-access cocaine self-administration (SA) is necessary for the establishment of later CRF-dependent stress-induced reinstatement. Reinstatement by footshock, but not a cocaine challenge (10 mg/kg, i.p.) following long-access SA, was blocked by i.c.v. administration of the CRF receptor antagonist, α-helical CRF9−41 (10 μg). Elimination of SA-induced adrenal responses through surgical adrenalectomy and diurnal corticosterone replacement (ADX/C) before 14 days of SA under long-access conditions had minimal impact on cocaine SA, but blocked later footshock-induced reinstatement. By contrast, ADX/C after SA, but before extinction and reinstatement testing, failed to reduce footshock-induced reinstatement. Likewise, ADX/C before 14 days long-access SA prevented later reinstatement by i.c.v. CRF (0.5 or 1.0 μg). However, significant CRF-induced reinstatement was observed when rats underwent ADX/C following SA, but before extinction and reinstatement testing, although a modest but statistically nonsignificant reduction in sensitivity to CRF's reinstating effects was observed. Taken together, these findings suggest that adrenal-dependent neuroadaptations in CRF responsiveness underlie the increased susceptibility to stress-induced relapse that emerges with repeated cocaine use. PMID:21412222

  4. Voglibose administration regulates body weight and energy intake in high fat-induced obese mice.

    PubMed

    Do, Hyun Ju; Jin, Taeon; Chung, Ji Hyung; Hwang, Ji Won; Shin, Min-Jeong

    2014-01-17

    We tested whether long-term administration of voglibose (VO) prevents diet induced obesity in addition to hypoglycemic effects in high fat fed mice and further investigated the underlying mechanisms by which voglibose exerts its weight lowering effect. Male C57BL/6 mice were fed ad libitum for 12 weeks with the control diet (CTL), high-fat diet (HFD) or the HFD with VO supplementations. Blood lipid profile, plasma leptin levels and hepatic triglyceride content, as well as expressions of genes involved in appetite and mitochondrial function were examined. The results showed that VO significantly reduced body weight, fat mass and energy intakes in high fat fed mice. VO showed improved metabolic profiles including blood glucose, triglyceride and free fatty acid. Elevated levels of plasma leptin in HFD were significantly reduced with the VO, furthermore, VO modulated the hypothalamic expressions of leptin receptors and appetite related genes. VO showed the upregulated expressions of PGC-1 in the liver and epididymal adipose tissue. In conclusion, VO may exert antiobesity properties through reductions in energy intake and improvement in mitochondrial function, indicating that VO has potential therapeutic use in patients with obesity, type 2 diabetes, and related complications.

  5. Palmitate induces insulin resistance without significant intracellular triglyceride accumulation in HepG2 cells.

    PubMed

    Lee, Jin-young; Cho, Hyang-Ki; Kwon, Young Hye

    2010-07-01

    Previous studies showed that increased release of free fatty acids from adipocytes leads to insulin resistance and triglyceride (TG) accumulation in the liver, which may progress into hepatic steatohepatitis. We and other investigators have previously reported that palmitate induces endoplasmic reticulum stress-mediated toxicity in several tissues. This work investigated whether palmitate could induce insulin resistance and steatosis in HepG2 cells. We treated cells with either saturated fatty acid (palmitate) or unsaturated fatty acid (oleate), and observed that palmitate significantly activated c-jun N-terminal kinase and inactivated protein kinase B. Both 4-phenylbutyric acid and glycerol significantly activated protein kinase B, confirming the involvement of endoplasmic reticulum stress in palmitate-mediated insulin resistance. Oleate, but not palmitate, significantly induced intracellular TG deposition and activated sterol regulatory element binding protein-1. Instead, diacylglycerol level and protein kinase C epsilon activity were significantly increased by palmitate, suggesting the possible role of diacylglycerol in palmitate-mediated lipotoxicity. Therefore, the present study clearly showed that palmitate impairs insulin resistance, but does not induce significant TG accumulation in HepG2 cells. PMID:20006364

  6. Chronic Uridine Administration Induces Fatty Liver and Pre-Diabetic Conditions in Mice

    PubMed Central

    Urasaki, Yasuyo; Pizzorno, Giuseppe; Le, Thuc T.

    2016-01-01

    Uridine is a pyrimidine nucleoside that exerts restorative functions in tissues under stress. Short-term co-administration of uridine with multiple unrelated drugs prevents drug-induced liver lipid accumulation. Uridine has the ability to modulate liver metabolism; however, the precise mechanism has not been delineated. In this study, long-term effects of uridine on liver metabolism were examined in both HepG2 cell cultures and C57BL/6J mice. We report that uridine administration was associated with O-GlcNAc modification of FOXO1, increased gluconeogenesis, reduced insulin signaling activity, and reduced expression of a liver-specific fatty acid binding protein FABP1. Long-term uridine feeding induced systemic glucose intolerance and severe liver lipid accumulation in mice. Our findings suggest that the therapeutic potentials of uridine should be designed for short-term acute administration. PMID:26789264

  7. Significance of neuronal cytochrome P450 activity in opioid-mediated stress-induced analgesia.

    PubMed

    Hough, Lindsay B; Nalwalk, Julia W; Yang, Weizhu; Ding, Xinxin

    2014-08-26

    Stressful environmental changes can suppress nociceptive transmission, a phenomenon known as "stress-induced analgesia". Depending on the stressor and the subject, opioid or non-opioid mechanisms are activated. Brain μ opioid receptors mediate analgesia evoked either by exogenous agents (e.g. morphine), or by the release of endogenous opioids following stressful procedures. Recent work with morphine and neuronal cytochrome P450 (P450)-deficient mice proposed a signal transduction role for P450 enzymes in µ analgesia. Since µ opioid receptors also mediate some forms of stress-induced analgesia, the present studies assessed the significance of brain P450 activity in opioid-mediated stress-induced analgesia. Two widely-used models of opioid stress-induced analgesia (restraint and warm water swim) were studied in both sexes of wild-type control and P450-deficient (Null) mice. In control mice, both stressors evoked moderate analgesic responses which were blocked by pretreatment with the opioid antagonist naltrexone, confirming the opioid nature of these responses. Consistent with literature, sex differences (control female>control male) were seen in swim-induced, but not restraint-induced, analgesia. Null mice showed differential responses to the two stress paradigms. As compared with control subjects, Null mice showed highly attenuated restraint-induced analgesia, showing a critical role for neuronal P450s in this response. However, warm water swim-induced analgesia was unchanged in Null vs. control mice. Additional control experiments confirmed the absence of morphine analgesia in Null mice. These results are the first to show that some forms of opioid-mediated stress-induced analgesia require brain neuronal P450 activity.

  8. Intravenous Administration of Human ES-derived Neural Precursor Cells Attenuates Cuprizone-induced CNS Demyelination

    PubMed Central

    Crocker, Stephen J.; Bajpai, Ruchi; Moore, Craig S.; Frausto, Ricardo F.; Brown, Graham D.; Pagarigan, Roberto R.; Whitton, J. Lindsay; Terskikh, Alexey V.

    2011-01-01

    Aims Previous studies have demonstrated the therapeutic potential for human embryonic stem cell-derived neural precursor cells (hES-NPCs) in autoimmune and genetic animal models of demyelinating diseases. Herein, we tested whether intravenous (i.v) administration of hES-NPCs would impact central nervous system (CNS) demyelination in a cuprizone model of demyelination. Methods C57Bl/6 mice were fed cuprizone (0.2%) for two weeks and then separated into two groups that either received an i.v. injection of hES-NPCs or i.v. administration of media without these cells. After an additional two weeks of dietary cuprizone treatment, CNS tissues were analyzed for detection of transplanted cells and differences in myelination in the region of the corpus callosum (CC). Results Cuprizone-induced demyelination in the CC was significantly reduced in mice treated with hES-NPCs compared with cuprizone-treated controls that did not receive stem cells. hES-NPCs were identified within the brain tissues of treated mice and revealed migration of transplanted cells into the CNS. A limited number of human cells were found to express the mature oligodendrocyte marker, O1, or the astrocyte marker, GFAP. Reduced apoptosis and attenuated microglial and astrocytic responses were also observed in the CC of hES-NPC-treated mice. Conclusions These findings indicated that systemically-administered hES-NPCs migrated from circulation into a demyelinated lesion within the CNS and effectively reduced demyelination. Observed reductions in astrocyte and microglial responses, and (c) the benefit of hES-NPC treatment in this model of myelin injury was not obviously accountable to tissue replacement by exogenously administered cells. PMID:21276029

  9. Administration of dried Aloe vera gel powder reduced body fat mass in diet-induced obesity (DIO) rats.

    PubMed

    Misawa, Eriko; Tanaka, Miyuki; Nabeshima, Kazumi; Nomaguchi, Kouji; Yamada, Muneo; Toida, Tomohiro; Iwatsuki, Keiji

    2012-01-01

    The aim of the present study was to investigate the anti-obesity effects of Aloe vera gel administration in male Sprague-Dawley (SD) rats with diet-induced obesity (DIO). SD rats at 7 wk of age were fed either a standard diet (10 kcal% fat) (StdD) or high-fat (60 kcal% fat) diet (HFD) during the experimental period. Four weeks after of HFD-feeding, DIO rats (11 wk of age) were orally administered with two doses of Aloe vera gel powder (20 and 200 mg/kg/d) for 90 d. Body weights (g) and body fat (%) of HFD fed rats were significantly higher than those of StdD-fed rats. Although a modest decrease of body weight (g) was observed with the administration of dried Aloe vera gel powder, both subcutaneous and visceral fat weight (g) and body fat (%) were reduced significantly in Aloe vera gel-treated rats. Serum lipid parameters elevated by HFD were also improved by the Aloe vera gel treatment. The oxygen consumption (VO(2)), an index of energy expenditure, was decreased in HFD-fed rats compared with that in StdD-fed rats. Administration of Aloe vera gel reversed the change in VO(2) in the HFD-fed rats. These results suggest that intake of Aloe vera gel reduced body fat accumulation, in part, by stimulation of energy expenditure. Aloe vera gel might be beneficial for the prevention and improvement of diet-induced obesity.

  10. Sustained systemic delivery of green tea polyphenols by polymeric implants significantly diminishes benzo[a]pyrene-induced DNA adducts.

    PubMed

    Cao, Pengxiao; Vadhanam, Manicka V; Spencer, Wendy A; Cai, Jian; Gupta, Ramesh C

    2011-06-20

    The polyphenolics in green tea are believed to be the bioactive components. However, poor bioavailability following ingestion limits their efficacy in vivo. In this study, polyphenon E (poly E), a standardized green tea extract, was administered by sustained-release polycaprolactone implants (two, 2-cm implants; 20% drug load) grafted subcutaneously or via drinking water (0.8% w/v) to female S/D rats. Animals were treated with continuous low dose of benzo[a]pyrene (BP) via subcutaneous polymeric implants (2 cm; 10% load) and euthanized after 1 and 4 weeks. Analysis of lung DNA by (32)P-postlabeling resulted in a statistically significant reduction (50%; p = 0.023) of BP-induced DNA adducts in the implant group; however, only a modest (34%) but statistically insignificant reduction occurred in the drinking water group at 1 week. The implant delivery system also showed significant reduction (35%; p = 0.044) of the known BP diolepoxide-derived DNA adduct after 4 weeks. Notably, the total dose of poly E administered was >100-fold lower in the implant group than the drinking water group (15.7 versus 1,632 mg, respectively). Analysis of selected phase I, phase II, and nucleotide excision repair enzymes at both mRNA and protein levels showed no significant modulation by poly E, suggesting that the reduction in the BP-induced DNA adducts occurred presumably due to known scavenging of the antidiolepoxide of BP by the poly E catechins. In conclusion, our study demonstrated that sustained systemic delivery of poly E significantly reduced BP-induced DNA adducts in spite of its poor bioavailability following oral administration.

  11. TSPO ligand PK11195 alleviates neuroinflammation and beta-amyloid generation induced by systemic LPS administration.

    PubMed

    Ma, Li; Zhang, Hui; Liu, Na; Wang, Pei-qi; Guo, Wen-zhi; Fu, Qiang; Jiao, Lin-bo; Ma, Ya-qun; Mi, Wei-Dong

    2016-03-01

    Translocator protein 18 kDa (TSPO) is now an attractive drug target for controlling neuroinflammation. Studies applying TSPO ligands to neurodegenerative diseases, especially Alzheimer's disease (AD), were rare. Our study was aimed to evaluate the effect of PK11195, a specific TSPO ligand, in an animal model of neuroinflammation caused by systemic LPS administration. C57/BL6 mice were treated with lipopolysaccharide (LPS, 500 μg/kg, i.p.) three days after PK11195 administration (3mg/kg, i.p.). The drugs were not discontinued until the mice were sacrificed. Cognitive function was assessed by Morris water maze (MWM) seven days after LPS injection. Chronic LPS-injection in mice was characterized by cognitive dysfunction, increased expression of cyclooxygenase (COX)-2 and TSPO, elevated Aβ content with increased expression of β-site APP cleaving enzyme-1 (BACE-1) and insulin-degrading enzyme (IDE) as well as decreased brain progesterone and brain-derived neurophic factor (BDNF) level. PK11195 pretreatment protected cognitive function in LPS-injected animals and normalized the inflammatory proteins. Moreover, PK11195 pre-administration decreased elevated hippocampal Aβx-42 levels and increased brain levels of progesterone, allopregnanolone. However, LPS-induced BDNF decrease was not reversed by PK11195 administration. Our data demonstrated that PK11195 could protect cognitive deficits induced by chronic LPS administration. The underling mechanism may involve alleviated neuroinflammation, increased synthesis of neurosteroid and decreased Aβ accumulation accompanied by down-regulation of BACE-1.

  12. Neural changes induced by antipsychotic administration in adolescence: A review of studies in laboratory rodents.

    PubMed

    Moe, Aung Aung Kywe; Scott, James G; Burne, Thomas Hj; Eyles, Darryl W

    2016-08-01

    Adolescence is characterized by major remodelling processes in the brain. Use of antipsychotic drugs (APDs) in adolescents has increased dramatically in the last 20 years; however, our understanding of the neurobiological consequences of APD treatment on the adolescent brain has not kept the same pace and significant concerns have been raised. In this review, we examined currently available preclinical studies of the effects of APDs on the adolescent brain. In animal models of neuropsychiatric disorders, adolescent APD treatment appears to be protective against selected structural, behavioural and neurochemical phenotypes. In "neurodevelopmentally normal" adolescent animals, a range of short- and long-term alterations in behaviour and neurochemistry have been reported. In particular, the adolescent brain appears to be sensitive to long-term locomotor/reward effects of chronic atypical APDs in contrast with the outcomes in adults. Long-lasting changes in dopaminergic, glutamatergic and gamma-amino butyric acid-ergic systems induced by adolescent APD administration have been observed in the nucleus accumbens. A detailed examination of other potential target regions such as striatum, prefrontal cortex and ventral tegmental area is still required. Through identification of specific neural pathways targeted by adolescent APD treatment, future studies will expand the current knowledge on long-term neural outcomes which are of translational value. PMID:27413140

  13. Dopamine D(3) receptor antagonist SB-277011A inhibits methamphetamine self-administration and methamphetamine-induced reinstatement of drug-seeking in rats.

    PubMed

    Higley, Amanda E; Kiefer, Stephen W; Li, Xia; Gaál, József; Xi, Zheng-Xiong; Gardner, Eliot L

    2011-06-01

    We have previously reported that selective blockade of brain dopamine D(3) receptors by SB-277011A significantly attenuates cocaine self-administration and cocaine-induced reinstatement of drug-seeking behavior. In the present study, we investigated whether SB-277011A similarly inhibits methamphetamine self-administration and methamphetamine-induced reinstatement to drug-seeking behavior. Male Long-Evans rats were allowed to intravenously self-administer methamphetamine (0.05 mg/kg/infusion) under fixed-ratio 2 (FR2) or progressive-ratio (PR) reinforcement conditions, and some rats were tested for methamphetamine-induced reinstatement of drug-seeking behavior after extinction of self-administration. The effects of SB-277011A on each of these methamphetamine-supported behaviors were then tested. Acute intraperitoneal (i.p.) administration of SB-277011A failed to alter methamphetamine self-administration under FR2 reinforcement, but significantly lowered the break-point for methamphetamine self-administration under PR reinforcement. SB-277011A also significantly inhibited methamphetamine-triggered reinstatement of extinguished drug-seeking behavior. Overall, these data show that blockade of dopamine D(3) receptors by SB-277011A attenuates the rewarding and incentive motivational effects of methamphetamine in rats, supporting the development of selective dopamine D(3) antagonists for the treatment of methamphetamine addiction.

  14. Metformin Prevented Dopaminergic Neurotoxicity Induced by 3,4-Methylenedioxymethamphetamine Administration.

    PubMed

    Porceddu, Pier Francesca; Ishola, Ismail Ogunbayode; Contu, Liliana; Morelli, Micaela

    2016-07-01

    Metformin, a well-known antidiabetic drug, has recently been proposed to promote neurogenesis and to have a neuroprotective effect on the neurodegenerative processes induced by the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in models of Parkinson's disease. Interestingly, metformin has antioxidant properties and is involved in regulating the production of cytokines released during the neuroinflammatory process. Several studies have reported that 3,4-methylenedioxymethamphetamine (MDMA), a recreational drug mostly consumed by young adults, produces a persistent loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and caudate putamen (CPu) of mice. The aim of this study was to investigate the potential neuroprotective effect of metformin against short- and long-term neurotoxicity induced by MDMA and its role on MDMA-induced hyperthermia. Adult mice received metformin (2 × 200 mg/kg, 11-h intervals, administered orally), MDMA (4 × 20 mg/kg, 2-h interval, administered intraperitoneally), or MDMA plus metformin (2 × 200 mg/kg, 1 h before the first MDMA administration and 4 h after the last). On the second and third day, mice were treated with vehicle or metformin (1 × 200 mg/kg) and sacrificed 48 h and 7 days after the last MDMA administration. The neuroprotective effect of metformin on MDMA-induced dopaminergic damage was evaluated by dopamine transporter (DAT) and tyrosine hydroxylase (TH) immunohistochemistry in SNc and CPu. Metformin prevented the MDMA-induced loss of TH-positive neurons in the SNc and TH- and DAT-positive fibers in CPu, both at 48 h and 7 days after the last MDMA administration. These results show that metformin is neuroprotective against the short- and long-lasting dopaminergic neurodegeneration induced by MDMA. PMID:27251371

  15. Systemic administration of vitamins C and E attenuates nociception induced by chronic constriction injury of the sciatic nerve in rats.

    PubMed

    Riffel, Ana Paula K; de Souza, Jéssica A; Santos, Maria do Carmo Q; Horst, Andréa; Scheid, Taína; Kolberg, Carolina; Belló-Klein, Adriane; Partata, Wania A

    2016-03-01

    Antioxidants have been tested to treat neuropathic pain, and α-Tocopherol (vitamin E--vit. E) and ascorbic acid (vitamin C--vit. C) are potent antioxidants. We assessed the effect of intraperitoneal administration of vit. C (30 mg/kg/day) and vit. E (15 mg/kg/day), given alone or in combination, on the mechanical and thermal thresholds and the sciatic functional index (SFI) in rats with chronic constriction injury (CCI) of the sciatic nerve. We also determined the lipid hydroperoxides and total antioxidant capacity (TAC) in the injured sciatic nerve. Further, we assessed the effects of oral administration of vit. C+vit. E (vit. C+E) and of a combination of vit. C+E and gabapentin (100mg/kg/day, i.p.) on the mechanical and thermal thresholds of CCI rats. The vitamins, whether administered orally or i.p., attenuated the reductions in the mechanical and thermal thresholds induced by CCI. The antinociceptive effect was greater with a combination of vit. C+E than with each vitamin given alone. The SFI was also improved in vitamin-treated CCI rats. Co-administration of vit. C+E and gabapentin induced a greater antinociceptive effect than gabapentin alone. No significant change occurred in TAC and lipid hydroperoxide levels, but TAC increased (45%) while lipid hydroperoxides decreased (38%) in the sciatic nerve from vit. C+E-treated CCI rats. Thus, treatment with a combination of vit. C+E was more effective to treat CCI-induced neuropathic pain than vitamins alone, and the antinociceptive effect was greater with co-administration of vit. C+E and gabapentin than with gabapentin alone. PMID:26855326

  16. The effects of acute ethanol administration on ethanol withdrawal-induced anxiety-like syndrome in rats: A biochemical study.

    PubMed

    Kumar, Jaya; Hapidin, Hermizi; Get Bee, Yvonne-Tee; Ismail, Zalina

    2016-02-01

    Withdrawal from long-term ethanol consumption results in overexcitation of glutamatergic neurotransmission in the amygdala, which induces an anxiety-like syndrome. Most alcoholics that suffer from such symptoms frequently depend on habitual drinking as self-medication to alleviate their symptoms. Metabotropic glutamate receptor subtype 5 (mGlu5) and protein kinase C (PKC) epsilon have been reported to mediate acute and chronic effects of ethanol. This study explores the changes in mGlu5 and PKC epsilon in the amygdala following acute administration of ethanol during ethanol withdrawal (EW) induced anxiety. Male Wistar rats were fed a modified liquid diet containing low-fat cow milk, sucrose, and maltodextrin, with a gradual introduction of 2.4%, 4.8% and 7.2% ethanol for 20 days. Six hours into EW, the rats were intraperitoneally injected with normal saline and ethanol (2.5 g/kg, 20% v/v), and exposed to open-field and elevated plus maze tests. Then, amygdala tissue was dissected from the rat brain for Western blot and gene expression studies. EW-induced anxiety was accompanied by a significant increase in mGlu5, total PKC epsilon, and phosphorylated PKC epsilon protein levels, and also of mRNA of mGlu5 (GRM5) in the amygdala. Acute administration of ethanol significantly attenuated EW-induced anxiety as well as an EW-induced increase in GRM5. The acute challenge of ethanol to EW rats had little effect on the phosphorylated and total protein levels of PKC epsilon in the amygdala. Our results demonstrate that amygdala PKC epsilon may not be directly involved in the development of anxiety following EW.

  17. Mechanisms involved in the antinociception induced by spinal administration of inosine or guanine in mice.

    PubMed

    de Oliveira, Enderson D; Schallenberger, Cristhine; Böhmer, Ana Elisa; Hansel, Gisele; Fagundes, Aécio C; Milman, Michael; Silva, Marcos D P; Oses, Jean P; Porciúncula, Lisiane O; Portela, Luís V; Elisabetsky, Elaine; Souza, Diogo O; Schmidt, André P

    2016-02-01

    It is well known that adenine-based purines exert multiple effects on pain transmission. Recently, we have demonstrated that guanine-based purines may produce some antinociceptive effects against chemical and thermal pain in mice. The present study was designed to investigate the antinociceptive effects of intrathecal (i.t.) administration of inosine or guanine in mice. Additionally, investigation into the mechanisms of action of these purines, their general toxicity and measurements of CSF purine levels were performed. Animals received an i.t. injection of vehicle (30mN NaOH), inosine or guanine (up to 600nmol) and submitted to several pain models and behavioural paradigms. Guanine and inosine produced dose-dependent antinociceptive effects in the tail-flick, hot-plate, intraplantar (i.pl.) glutamate, i.pl. capsaicin and acetic acid pain models. Additionally, i.t. inosine inhibited the biting behaviour induced by spinal injection of capsaicin and i.t. guanine reduced the biting behaviour induced by spinal injection of glutamate or AMPA. Intrathecal administration of inosine (200nmol) induced an approximately 115-fold increase on CSF inosine levels. This study provides new evidence on the mechanism of action of extracellular guanine and inosine presenting antinociceptive effects following spinal administration. These effects seem to be related, at least partially, to the modulation of A1 adenosine receptors. PMID:26712379

  18. Significance for secure CO2 storage of earthquakes induced by fluid injection

    NASA Astrophysics Data System (ADS)

    Verdon, James P.

    2014-05-01

    The link between subsurface fluid injection and induced seismicity has gained recent significance with an increase in earthquakes associated with the disposal of oilfield waste fluids. There are obvious similarities between wastewater reinjection and proposed CO2 storage (CCS) operations. However, as well as the seismic hazard, induced seismicity during CCS operations poses additional risks, because an induced event located above the target reservoir could compromise the hydraulic integrity of the caprock. In this paper we re-examine case examples where earthquakes have been induced by wastewater injection into deep aquifers in the light of proposed future CCS operations. In particular we consider possible controls on event magnitudes, and look at the spatial distributions of events. We find that the majority of events are located below the target reservoirs. This is an encouraging observation from the perspective of caprock integrity, although it presents a challenge in terms of pre-injection characterization of deep-lying faults several kilometres below the target zone. We observe that 99% of events are found within 20 km of injection wells, suggesting a minimum radius for geomechanical characterization and monitoring. We conclude by making recommendations for modelling and monitoring strategies to be followed prior to and during commercial-scale deployment of CO2 storage projects.

  19. Light-induced morphological plasticity in the scleractinian coral Goniastrea pectinata and its functional significance

    NASA Astrophysics Data System (ADS)

    Ow, Y. X.; Todd, P. A.

    2010-09-01

    Environment-induced i.e., phenotypically plastic, changes in morphology, are potentially an important life-history component of sessile corals. Previous reciprocal transplant experiments have demonstrated depth-related responses in various coral species, but the potential adaptive significance is rarely investigated. To test for small-scale morphological plasticity in the massive coral Goniastrea pectinata Ehrenberg 1834, fragments from five colonies were reciprocally transplanted between two depths at Raffles Lighthouse (Pulau Satumu), Singapore. After 163 days, all fragments were collected, cleared of tissue, and examined. Reaction norms and multivariate analysis of variance describe light-induced changes in corallite architecture and genotype × environment interactions. In fragments transplanted to the shallow station, calices were deeper, and septa were shorter than in fragments transplanted to the deep station. To explore the functional significance of this plasticity, a two-dimensional model of corallite shape was constructed. The induced calice morphology of the shallow-water transplants was efficient at shading, possibly to protect tissue from excess radiation, whereas the calice morphology found in the deep-water transplants was more efficient at capturing light when irradiance was low.

  20. Oxygen-induced frequency shifts in hyperoxia: a significant component of BOLD signal.

    PubMed

    Song, Youngkyu; Cho, Gyunggoo; Chun, Song-I; Baek, Jin Hee; Cho, HyungJoon; Kim, Young Ro; Park, Sung Bin; Kim, Jeong Kon

    2014-07-01

    In comparison to the well-documented significance of intravascular deoxyhemoglobin (deoxyHgb), the effects of dissolved oxygen on the blood-oxygen-level-dependent (BOLD) signal have not been widely reported. Based on the fact that the prolonged inspiration of high oxygen fraction gas can result in up to a sixfold increase of the baseline tissue oxygenation, the current study focused on the influence of dissolved oxygen on the BOLD signal during hyperoxia. As results, our in vitro study revealed that the r1 and r2 (relaxivities) of the oxygen-treated serum were 0.22 mM(-1) · s(-1) and 0.19 mM(-1) · s(-1) , respectively. In an in vivo experiment, hyperoxic respiration induced negative BOLD contrast (i.e. signal decrease) in 18-42% of measured brain regions, voxels with accompanying significant decreases in both the T(*)2 (-12.1% to -19.4%) and T1 (-5.8% to -3.3%) relaxation times. In contrast, the T(*)2 relaxation time significantly increased (11.2% to 14.0%) for the voxels displaying positive BOLD contrast (in 41-50% of the measured brain), which reflected a hyperoxygenation-induced reduction in tissue deoxyHgb concentration. These data imply that hyperoxia-driven BOLD signal changes are primarily determined by the counteracting effects of extravascular oxygen and intravascular deoxyHgb. Oxygen-induced magnetic susceptibility was further demonstrated by the study of 1 min hypoxia, which induced BOLD signal changes opposite to those under hyperoxia. Vasoconstriction was more common in voxels with negative BOLD contrast than in voxels with positive contrast (% change of blood volume, -9.8% to -12.8% versus 2.0% to 2.2%), which further suggests that negative BOLD contrast is mainly evoked by an increase in extravascular oxygen concentration. Conclusively, frequency shifts, which are induced by the accumulation of oxygen molecules and associated magnetic field inhomogeneity, are a significant source of the negative BOLD contrast during hyperoxia.

  1. Olanzapine-induced suppression of cocaine self-administration in rhesus monkeys.

    PubMed

    Howell, Leonard L; Wilcox, Kristin M; Lindsey, Kimberly P; Kimmel, Heather L

    2006-03-01

    The neuropharmacological profile of the atypical antipsychotic, olanzapine, is consistent with a potentially useful medication for cocaine abuse. The present study utilized an i.v. drug self-administration paradigm in nonhuman primates to obtain definitive evidence regarding the effectiveness of olanzapine to modulate the reinforcing effects of cocaine. The effects of olanzapine were compared directly to those of the neuroleptic, haloperidol. Rhesus monkeys (n=7) were trained to self-administer cocaine (0.03-0.3 mg/kg/injection) under a second-order, fixed-interval 600-s schedule with fixed ratio 20 components. Experimental sessions comprised five consecutive fixed intervals, each followed by a 1-min timeout. In drug-interaction experiments, a single dose of olanzapine (0.03-0.3 mg/kg) or haloperidol (0.01-0.03 mg/kg) was administered i.v. 15 min presession for at least three consecutive sessions. In drug-substitution experiments, different doses of olanzapine (0.01-0.1 mg/kg/injection) were substituted for cocaine until responding stabilized. Olanzapine caused dose-related decreases in cocaine self-administration at pretreatment doses that had no overt behavioral effects indicative of sedation. A dose of 0.1 mg/kg eliminated cocaine self-administration in all subjects. In contrast, doses of haloperidol that suppressed cocaine self-administration induced marked sedation and catalepsy. Olanzapine failed to maintain self-administration behavior above saline extinction levels over a range of unit doses. In vivo microdialysis experiments in a second group of awake rhesus monkeys (n=3) confirmed previous reports in rodents that olanzapine effectively increases extracellular dopamine in ventral striatum. The dose of olanzapine that markedly suppressed cocaine self-administration behavior increased dopamine to approximately 190% of control values. Lastly, pretreatment with fluoxetine had no systematic effect on olanzapine-induced increases in striatal dopamine. The

  2. Locomotion and self-administration induced by cocaine in 129/OlaHsd mice lacking galanin

    PubMed Central

    Brabant, Christian; Kuschpel, Anna S; Picciotto, Marina R

    2010-01-01

    Previous studies have demonstrated that the galanin system modulates responses to drugs of abuse such as morphine. The current study examined whether genetic deletion of galanin could affect the locomotor and reinforcing effects of cocaine in mice. We examined spontaneous motor activity and cocaine-induced hyperactivity in wild-type (GAL-WT) and knockout mice lacking galanin (GAL-KO) maintained on the 129/OlaHsd background. Our results indicate that cocaine enhanced locomotion (defined as moving more than 5 cm) dose-dependently in GAL-WT and GAL-KO mice. However, general activity (total beam breaks) was increased by cocaine only in GAL-WT mice. An additional experiment indicated that galnon, a non-selective galanin receptor agonist, did not affect cocaine-induced hyperactivity. In a second set of experiments, mice of both genotypes were trained to self-administer cocaine under a fixed ratio schedule and tested with various doses of cocaine under different schedules of reinforcement. This set of experiments showed that cocaine self-administration did not differ markedly between genotypes. However, while GAL-WT mice acquired cocaine self-administration, a median split analysis showed that mice could be divided into large and small drug takers, whereas all GAL-KO mice were small drug takers. Our results indicate that wild-type and galanin knockout mice on a congenic 129/OlaHsd background are responsive to the locomotor effects of cocaine and can acquire i.v. cocaine self-administration. However, the phenotype observed in GAL-KO mice does not support a major role for galanin in cocaine-induced hyperlocomotion and self-administration. PMID:21038934

  3. Oral administration of dextran sodium sulphate induces a caecum-localized colitis in rabbits.

    PubMed

    Leonardi, Irina; Nicholls, Flora; Atrott, Kirstin; Cee, Alexandra; Tewes, Bernhard; Greinwald, Roland; Rogler, Gerhard; Frey-Wagner, Isabelle

    2015-06-01

    Trichuris suis ova (TSO) have shown promising results in the treatment of inflammatory bowel disease (IBD) but the mechanisms which underlies this therapeutic effect cannot be studied in mice and rats as T. suis fails to colonize the rodent intestine, whilst hatching in humans and rabbits. As a suitable rabbit IBD model is currently not available, we developed a rabbit colitis model by administration of dextran sodium sulphate (DSS). White Himalayan rabbits (n = 12) received 0.1% DSS in the daily water supply for five days. Clinical symptoms were monitored daily, and rabbits were sacrificed at different time points. A genomewide expression analysis was performed with RNA isolated from caecal lamina propria mononuclear cells (LPMC) and intestinal epithelial cells (IEC). The disease activity index of DSS rabbits increased up to 2.1 ± 0.4 (n = 6) at day 10 (controls <0.5). DSS induced a caecum-localized pathology with crypt architectural distortion, stunted villous surface and inflammatory infiltrate in the lamina propria. The histopathology score reached a peak of 14.2 ± 4.9 (n = 4) at day 10 (controls 7.7 ± 0.9, n = 5). Expression profiling revealed an enrichment of IBD-related genes in both LPMC and IEC. Innate inflammatory response, Th17 signalling and chemotaxis were among the pathways affected significantly. We describe a reproducible and reliable rabbit model of DSS colitis. Localization of the inflammation in the caecum and its similarities to IBD make this model particularly suitable to study TSO therapy in vivo.

  4. Significance of bacterial flora in abdominal irradiation-induced inhibition of lung metastases

    SciTech Connect

    Matsumoto, T.; Ando, K.; Koike, S.

    1988-06-01

    We have previously reported that abdominal irradiation prior to i.v. injection of syngeneic tumor cells reduced metastases in lung. Our report described an investigation of the significance of intestinal organisms in the radiation effect. We found that eliminating intestinal organisms with antibiotics totally abolished the radiation effect. Monoassociation of germ-free mice revealed that the radiation effect was observable only for Enterobacter cloacae, never for Streptococcus faecium, Bifidobacterium adlesentis, or Escherichia coli. After abdominal irradiation of regular mice, E. cloacae multiplied in cecal contents, adhered to mucous membranes, invaded the cecal wall, and translocated to mesenteric lymph nodes. Intravenous administration of E. cloacae in place of abdominal irradiation inhibited metastases. E. cloacae-monoassociated mice developed fewer metastases than germ-free mice, and the reduction was further enhanced by abdominal irradiation. We concluded that abdominal irradiation caused the invasion of E. cloacae from the mucous membrane of the intestine and inhibited formation of lung metastases.

  5. Space radiation does not induce a significant increase of intrachromosomal exchanges in astronauts' lymphocytes.

    PubMed

    Horstmann, M; Durante, M; Johannes, C; Pieper, R; Obe, G

    2005-12-01

    Chromosome aberration analysis in astronauts has been used to provide direct, biologically motivated estimates of equivalent doses and risk associated to cosmic radiation exposure during space flight. However, the past studies concentrated on measurements of dicentrics and translocations, while chromosome intrachanges (inversions) have never been measured in astronauts' samples. Recent data reported in the literature suggest that densely ionizing radiation can induce a large fraction of intrachanges, thus leading to the suspicion that interchanges grossly underestimate the cosmic radiation-induced cytogenetic damage in astronauts. We have analyzed peripheral blood lymphocytes from 11 astronauts involved in short- or long-term space flights in low-Earth orbit using high-resolution multicolor banding to assess the frequency of intrachromosomal exchanges in both pre- and post-flight samples. We did not detect any inversions in chromosome 5 from a total of 2800 cells in astronauts' blood. In addition, no complex type exchanges were found in a total of 3590 astronauts' lymphocytes analyzed by multifluor fluorescence in situ hybridisation. We conclude that, within the statistical power of this study, the analysis of interchanges for biological dosimetry in astronauts does not significantly underestimate the space radiation-induced cytogenetic damage, and complex-type exchanges or intrachanges have limited practical use for biodosimetry at very low doses. PMID:16217644

  6. Space radiation does not induce a significant increase of intrachromosomal exchanges in astronauts' lymphocytes.

    PubMed

    Horstmann, M; Durante, M; Johannes, C; Pieper, R; Obe, G

    2005-12-01

    Chromosome aberration analysis in astronauts has been used to provide direct, biologically motivated estimates of equivalent doses and risk associated to cosmic radiation exposure during space flight. However, the past studies concentrated on measurements of dicentrics and translocations, while chromosome intrachanges (inversions) have never been measured in astronauts' samples. Recent data reported in the literature suggest that densely ionizing radiation can induce a large fraction of intrachanges, thus leading to the suspicion that interchanges grossly underestimate the cosmic radiation-induced cytogenetic damage in astronauts. We have analyzed peripheral blood lymphocytes from 11 astronauts involved in short- or long-term space flights in low-Earth orbit using high-resolution multicolor banding to assess the frequency of intrachromosomal exchanges in both pre- and post-flight samples. We did not detect any inversions in chromosome 5 from a total of 2800 cells in astronauts' blood. In addition, no complex type exchanges were found in a total of 3590 astronauts' lymphocytes analyzed by multifluor fluorescence in situ hybridisation. We conclude that, within the statistical power of this study, the analysis of interchanges for biological dosimetry in astronauts does not significantly underestimate the space radiation-induced cytogenetic damage, and complex-type exchanges or intrachanges have limited practical use for biodosimetry at very low doses.

  7. Regulation and clinical significance of the hypoxia-induced expression of ANGPTL4 in gastric cancer

    PubMed Central

    KUBO, HIROSHI; KITAJIMA, YOSHIHIKO; KAI, KEITA; NAKAMURA, JUN; MIYAKE, SHUUSUKE; YANAGIHARA, KAZUYOSHI; MORITO, KIYOTO; TANAKA, TOMOKAZU; SHIDA, MASAAKI; NOSHIRO, HIROKAZU

    2016-01-01

    Solid tumors are often exposed to hypoxia. Hypoxia inducible factor (HIF)-1α upregulates numerous target genes associated with the malignant behavior of hypoxic cancer cells. A member of the angiopoietin family, angiopoietin-like protein 4 (ANGPTL4) is a hypoxia-inducible gene. The present study aimed to clarify whether ANGPTL4 is regulated by HIF-1α in gastric cancer cells. The study also assessed whether ANGPTL4 expression is associated with clinicopathological factors or HIF-1α expression in gastric cancer tissues. Hypoxia-induced ANGPTL4 expression was quantitatively analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in 10 gastric cancer cell lines. RT-qPCR was further employed to investigate the HIF-1α dependency of ANGPTL4 expression using HIF-1α-knockdown transfectant 58As9-KD and control 58As9-SC gastric cancer cells. The HIF-1α and ANGPTL4 expression levels were immunohistochemically analyzed in 170 gastric cancer tissue specimens and were assessed for any correlations with the clinicopathological factors and/or patient survival. Subsequently, hypoxia-induced ANGPTL4 expression was observed in 7 out of 10 gastric cancer cell lines. The hypoxic induction of ANGPTL4 was almost preserved in the 58As9-KD cells compared with that observed in the 58As9-SC cells, while the induction of known HIF-1α target gene, carbonic anhydrase 9, was completely suppressed in the 58As9-KD cells. In the gastric cancer tissues, ANGPTL4 expression was inversely correlated with the tumor depth, whereas HIF-1α expression was positively correlated with venous invasion. A survival analysis revealed that the expression of ANGPTL4 was significantly correlated with a longer survival time, whereas that of HIF-1α was correlated with a shorter survival time. In conclusion, the present findings indicate that hypoxia-induced ANGPTL4 expression is independent of HIF-1α in hypoxic gastric cancer cells. ANGPTL4 may be a favorable marker for predicting

  8. Administrators' Perceptions of Factors Related to Student Retention at Colleges with a Significant Black Student Enrollment Affiliated with the Association for Biblical Higher Education

    ERIC Educational Resources Information Center

    Wilson, Wesley B.

    2013-01-01

    This study described and explored the factors perceived as relevant to student retention by administrators at colleges and universities with significant Black student populations. The sample was 31 institutions affiliated with the Association for Biblical Higher Education (ABHE) that had Black student enrollment of 20% or more. The study sought to…

  9. 18-Methoxycoronaridine Blocks Context-induced Reinstatement Following Cocaine Self-administration in Rats

    PubMed Central

    Polston, J.E.; Pritchett, C.E.; Sell, E.M.; Glick, S.D.

    2012-01-01

    Numerous studies utilizing drug self-administration have shown the importance of conditioned cues in maintaining and reinstating addictive behaviors. However, most used simple cues that fail to replicate the complexity of cues present in human craving and addiction. We have recently shown that music can induce behavioral and neurochemical changes in rats following classical conditioning with psychostimulants. However, such effects have yet to be characterized utilizing operant self-administration procedures, particularly with regard to craving and relapse. The goal of the present study was to validate the effectiveness of music as a contextual conditioned stimulus using cocaine in an operant reinstatement model of relapse. Rats were trained to lever press for cocaine with a musical cue, and were subsequently tested during reinstatement sessions to determine how musical conditioning affected drug seeking behavior. Additionally, in vivo microdialysis was used to determine basolateral amygdala involvement during reinstatement. Lastly, tests were conducted to determine whether the putative anti-addictive agent 18-methoxycoronaridine (18-MC) could attenuate cue-induced drug seeking behavior. Our results show that music-conditioned animals exhibited increased drug seeking behaviors when compared to controls during reinstatement test sessions. Furthermore, music-conditioned subjects exhibited increased extracellular dopamine in the basolateral amygdala during reinstatement sessions. Perhaps most importantly, 18-MC blocked musical cue-induced reinstatement. Thus, music can be a powerful contextual conditioned cue in rats, capable of inducing changes in both brain neurochemistry and drug seeking behavior during abstinence. The fact that 18-MC blocked cue-induced reinstatement suggests that α3β4 nicotinic receptors may be involved in the mechanism of craving, and that 18-MC may help prevent relapse to drug addiction in humans. PMID:22885280

  10. 18-Methoxycoronaridine blocks context-induced reinstatement following cocaine self-administration in rats.

    PubMed

    Polston, J E; Pritchett, C E; Sell, E M; Glick, S D

    2012-11-01

    Numerous studies utilizing drug self-administration have shown the importance of conditioned cues in maintaining and reinstating addictive behaviors. However, most used simple cues that fail to replicate the complexity of cues present in human craving and addiction. We have recently shown that music can induce behavioral and neurochemical changes in rats following classical conditioning with psychostimulants. However, such effects have yet to be characterized utilizing operant self-administration procedures, particularly with regard to craving and relapse. The goal of the present study was to validate the effectiveness of music as a contextual conditioned stimulus using cocaine in an operant reinstatement model of relapse. Rats were trained to lever press for cocaine with a musical cue, and were subsequently tested during reinstatement sessions to determine how musical conditioning affected drug seeking behavior. Additionally, in vivo microdialysis was used to determine basolateral amygdala involvement during reinstatement. Lastly, tests were conducted to determine whether the putative anti-addictive agent 18-methoxycoronaridine (18-MC) could attenuate cue-induced drug seeking behavior. Our results show that music-conditioned animals exhibited increased drug seeking behaviors when compared to controls during reinstatement test sessions. Furthermore, music-conditioned subjects exhibited increased extracellular dopamine in the basolateral amygdala during reinstatement sessions. Perhaps most importantly, 18-MC blocked musical cue-induced reinstatement. Thus,music can be a powerful contextual conditioned cue in rats, capable of inducing changes in both brain neurochemistry and drug seeking behavior during abstinence. The fact that 18-MC blocked cue-induced reinstatement suggests that α3β4 nicotinic receptors may be involved in the mechanism of craving, and that 18-MC may help prevent relapse to drug addiction in humans. PMID:22885280

  11. 17β-Estradiol administration attenuates seawater aspiration-induced acute lung injury in rats.

    PubMed

    Fan, Qixin; Zhao, Pengtao; Li, Jiahuan; Xie, Xiaoyan; Xu, Min; Zhang, Yong; Mu, Deguang; Li, Wangping; Sun, Ruilin; Liu, Wei; Nan, Yandong; Zhang, Bo; Jin, Faguang; Li, Zhichao

    2011-12-01

    There is very little evidence on the value of administering estrogen in cases of seawater drowning which can induce acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Therefore, this study aimed to investigate whether 17β-estradiol (E2) treatment can attenuate seawater aspiration-induced ALI in rats. In the experiment, ALI was induced by endotracheal instillation of seawater (4mL/kg) and the rats were then given intraperitoneal injection of E2 (5mg/kg) 20min after seawater instillation. Finally, the changes of arterial blood gases which contained hydrogen ion concentration (pH), arterial oxygen tension (PaO(2)) and arterial carbon dioxide tension (PaCO(2)) were measured and the measurement of extravascular lung water (EVLW) was observed. The pulmonary histological changes were evaluated by hematoxylin-eosin stain. The expression of aquaporins (AQPs) 1, AQP5, and estrogen receptor-β (ERβ) was measured by western blotting and immunohistochemical methods. The results showed that compared with normal saline water, seawater aspiration induced more serious ALI in rats which was markedly alleviated by E2 treatment. Meanwhile, the ERβ in lung tissues was activated after E2 administration. The seawater aspiration group also presented with severe pulmonary edema which was paralleled with over expressed AQP1 and AQP5. However, the up-regulation of AQP1 and AQP5 was suppressed by the administration of E2, resulting in an attenuation of lung edema. In conclusion, E2 treatment could effectively attenuate seawater aspiration-induced acute lung injury in rats by the down-regulation of AQP1 and AQP5.

  12. Nicotine decreases ethanol-induced dopamine signaling and increases self-administration via stress hormones.

    PubMed

    Doyon, William M; Dong, Yu; Ostroumov, Alexey; Thomas, Alyse M; Zhang, Tao A; Dani, John A

    2013-08-01

    Tobacco smoking is a well-known risk factor for subsequent alcohol abuse, but the neural events underlying this risk remain largely unknown. Alcohol and nicotine reinforcement involve common neural circuitry, including the mesolimbic dopamine system. We demonstrate in rodents that pre-exposure to nicotine increases alcohol self-administration and decreases alcohol-induced dopamine responses. The blunted dopamine response was due to increased inhibitory synaptic transmission onto dopamine neurons. Blocking stress hormone receptors prior to nicotine exposure prevented all interactions with alcohol that we measured, including the increased inhibition onto dopamine neurons, the decreased dopamine responses, and the increased alcohol self-administration. These results indicate that nicotine recruits neuroendocrine systems to influence neurotransmission and behavior associated with alcohol reinforcement.

  13. Nicotine self-administration diminishes stress-induced norepinephrine secretion but augments adrenergic-responsiveness in the hypothalamic paraventricular nucleus and enhances adrenocorticotropic hormone and corticosterone release

    PubMed Central

    Yu, Guoliang; Sharp, Burt M.

    2010-01-01

    Chronic nicotine self-administration augments the thalamo-pituitary-adrenal (HPA) responses to stress. Altered neuropeptide expression within corticotropin-releasing factor (CRF) neurons in the hypothalamic paraventricular nucleus (PVN) contributes to this enhanced HPA response to stress. Herein, we determined the role of norepinephrine, a primary regulator of CRF neurons, in the responses to footshock during nicotine self-administration. On day 12-15 of self-administration, microdialysis showed nicotine reduced PVN norepinephrine release by footshock (<50% of saline). Yet, the reduction in footshock-induced adrenocorticotropic hormone (ACTH) and corticosterone secretion due to intra-PVN prazosin (α1 adrenergic antagonist) was significantly greater in rats self-administering nicotine (2-fold) than saline. Additionally, PVN phenylephrine (α1 agonist) stimulated ACTH and corticosterone release to a similar extent in unstressed rats self-administering nicotine or saline. Nicotine self-administration also decreased footshock-induced c-Fos expression in the nucleus of the solitary tract (NTS)-A2/C2 catecholaminergic neurons that project to the PVN. Therefore, footshock-induced NTS activation and PVN norepinephrine input are both attenuated by nicotine self-administration, yet PVN CRF neurons are more responsive to α1 stimulation, but only during stress. This plasticity in noradrenergic regulation of PVN CRF neurons provides a new mechanism contributing to the HPA sensitization to stress by nicotine self-administration and smoking. PMID:20028457

  14. From 9/11 to Recession: Historically Significant Events in America and Their Impact on Research Administration

    ERIC Educational Resources Information Center

    Minnema, Linnea

    2011-01-01

    Federally sponsored research funding sources are not stagnant programs. Many things influence the nature of research, not all of them purely scientific. Historically significant events draw public attention to causes, and in the age of immediate information those events can have a powerful and lasting impact on research funding. September 11, 2001…

  15. Alcohol-induced vascular damage of brain can be ameliorated by administration of magnesium

    SciTech Connect

    Altura, B.M.; Altura, B.T.; Gebrewold, A.

    1986-03-01

    Long-term as well as short-term administration of alcohol can cause neuronal and vascular damage in the brain. The authors have reported that acute administration of ethyl alcohol (ALC), either directly into the rat brain, IV or locally, can produce concentration-dependent spasms of cerebral arterioles, venules, arteries and veins followed by irreversible rupture of capillaries and veins followed by irreversible rupture of capillaries and venules. Several experiments have suggested that administration of magnesium ions (Mg/sup 2 +/) can modify vascular tone. Whether Mg/sup 2 +/ can exert direct actions on the intact cerebral microcirculation is not known. Using the above intact rat brain model, and TV-image intensification, the authors determine whether administration of Mg/sup 2 +/ : 1) exerts actions on cerebral (coritical) arterioles (A) and venules (V) (12-40..mu..m); 2) directly into the brain alters arterial blood pressure (BP); and 3) could ameliorate or prevent some of the detrimental cerebral-vascular actions ALC exerts in the brain. The data show that infusion of Mg/sup 7 +/ : 1) into the rat brain result in a rapid dose-dependent lowering of systolic and diastolic and BP; 2) IV or intra-arterially (IA) produces dose-dependent vaso-dilation of A and V; 3) IV or IA prevents spasms and rupture of A and V induced by 10% ALC. The cerebral vascular actions of Mg/sup 2 +/ may prove to be useful in treatment and prevention of ALC-induced brain damage.

  16. The effects of supplemental melatonin administration on the healing of bone defects in streptozotocin-induced diabetic rats

    PubMed Central

    YILDIRIMTURK, Senem; BATU, Sule; ALATLI, Canan; OLGAC, Vakur; FIRAT, Deniz; SIRIN, Yigit

    2016-01-01

    ABSTRACT Diabetes mellitus (DM) causes an increased production of free radicals that can impair bone healing. Melatonin is a hormone secreted mainly by the pineal gland, which participates in the neutralization process of free radicals. Objective The aim of this study was to investigate histologic and biochemical effects of supplemental melatonin administration on bone healing and antioxidant defense mechanism in diabetic rats. Material and Methods Eighty-six Sprague-Dawley male rats were used in this study. Diabetes mellitus was induced by intraperitoneal (i.p.) administration of 65 mg/kg streptozotocin (STZ). Surgical bone defects were prepared in the tibia of each animal. Diabetic animals and those in control groups were treated either with daily melatonin (250 μg/animal/day/i.p.) diluted in ethanol, only ethanol, or sterile saline solution. Rats were humanely killed at the 10th and 30th postoperative days. Plasma levels of Advanced Oxidation Protein Products (AOPP), Malondialdehyde (MDA), and Superoxide Dismutase (SOD) were measured. The number of osteoblasts, blood vessels and the area of new mineralized tissue formation were calculated in histologic sections. Results At the 10th day, DM+MEL (rats receiving both STZ and melatonin) group had significantly higher number of osteoblasts and blood vessels as well as larger new mineralized tissue surfaces (p<0.05 for each) when compared with DM group. At the 30th day, DM group treated with melatonin had significantly lower levels of AOPP and MDA than those of DM group (p<0.05). Conclusion Melatonin administration in STZ induced diabetic rats reduced oxidative stress related biomarkers and showed beneficial effects on bone healing at short term. PMID:27383705

  17. Oral administration of the Aureobasidium pullulans-derived β-glucan effectively prevents the development of high fat diet-induced fatty liver in mice

    PubMed Central

    Aoki, Shiho; Iwai, Atsushi; Kawata, Koji; Muramatsu, Daisuke; Uchiyama, Hirofumi; Okabe, Mitsuyasu; Ikesue, Masahiro; Maeda, Naoyoshi; Uede, Toshimitsu

    2015-01-01

    Aureobasidium pullulans-derived β-glucan (AP-PG) consisting of a β-(1,3)-linked glucose main chain and β-(1,6)-linked glucose branches is taken as a supplement to improve health. This study demonstrates that oral administration of AP-PG is effective to prevent the development of high-fat diet (HFD)-induced fatty liver in mice. Here, C57BL/6N mice were fed with a normal diet or HFD, and AP-PG diluted in drinking water was administered orally. After 16 weeks, the serological analysis showed that HFD-induced high blood cholesterol and triglyceride levels were reduced by the oral administration of AP-PG. Further, HFD induced-fatty liver was significantly reduced by the oral administration of AP-PG. The triglyceride accumulation in the liver was also significantly reduced in mice administered AP-PG. Liver injury as indicated by an increase in serum alanine aminotransferase (ALT) in the HFD-fed mice was significantly reduced in the mice administered AP-PG orally, and the gene expression of cholesterol 7 alpha-hydroxylase (CYP7A1) which is known to be involved in cholesterol degradation in the liver was significantly increased in the AP-PG administered mice. These results suggest the possibility that the oral administration of AP-PG is effective to prevent the development of non-alcoholic fatty liver disease (NAFLD). PMID:26179949

  18. Administration of orexin receptor 1 antagonist into the rostral ventromedial medulla increased swim stress-induced antinociception in rat

    PubMed Central

    Soliemani, Neda; Moslem, Alireza; Shamsizadeh, Ali; Azhdari-Zarmehri, Hassan

    2016-01-01

    Objective(s): Intracerebroventricular injection of orexin-A (hypocretin-1) antagonist has been shown to inhibit stress-induced analgesia. However the locations of central sites that may mediate these effects have not been totally demonstrated. This study was performed to investigate the role of rostral ventromedial medulla (RVM) orexin receptor 1 in stress-induced analgesia (SIA). Materials and Methods: Forced swim stress in water was employed to adult male rats (200-250 g). Nociceptive responses were measured by formalin test (50 µl injection of formalin 2% subcutaneously into hind paw) and, pain related behaviors were monitored for 90 min following intra-microinjection of SB-334867 (orexin receptor 1 antagonist) into RVM. Results: Exposure to swimming stress test after administration of SB-334867 into RVM significantly reduces the formalin-induced nociceptive behaviors in phase1, interphase, and phase 2 in rats. Conclusion: The result demonstrated the involvement of OXR1 in antinociceptive behaviors induced by swim stress in RVM. PMID:27403261

  19. Changes and significance of IL-25 in chicken collagen II-induced experimental arthritis (CIA).

    PubMed

    Kaiwen, Wang; Zhaoliang, Su; Yinxia, Zhao; Siamak, Sandoghchian Shotorbani; Zhijun, Jiao; Yuan, Xue; Heng, Yang; Dong, Zheng; Yanfang, Liu; Pei, Shen; Shengjun, Wang; Qixiang, Shao; Xinxiang, Huang; Liwei, Lu; Huaxi, Xu

    2012-08-01

    Rheumatoid arthritis (RA) is an autoimmune inflammatory disease. It is a systemic inflammatory disease, characterized by chronic, symmetrical, multi-articular synovial arthritis. IL-25 (IL-17E) is a member of the recently emerged cytokine family (IL-17s), which is expressed in Th2 cells and bone marrow-derived mast cells. Unlike the other members of this family, IL-25 is capable of inducing Th2-associated cytokines (IL-4, IL-5, and IL-13) and also promotes the release of some pro-immune factors (IL-6 and IL-8). IL-25 is also a pleiotropic factor, which constitutes a tissue-specific pathological injury and chronic inflammation. In this study, we used chicken collagen II-induced experimental arthritis (CIA) model in DBA/1 mice to investigate the relationship between IL-25 and other inflammatory factors, revealing the possible mechanism in CIA. Our results showed that the expression level of IL-25 was enhanced in the late stage of CIA, and IL-17 was increased in the early stage of the disease. It is well known that IL-17 has a crucial role in the development of RA pathogenesis, and IL-25 plays a significant role in humoral immune. For reasons given above, we suggested that the IL-25 inhibited IL-17 expression to some extent, while enhancing the production of IL-4. It was confirmed that IL-25 not only regulated the cellular immune, but also involved the humoral immune in rheumatoid arthritis.

  20. COMPLEX RESISTIVITY OF FAULT GOUGE AND ITS SIGNIFICANCE FOR EARTHQUAKE LIGHTS AND INDUCED POLARIZATION.

    USGS Publications Warehouse

    Lockner, David A.; Byerlee, James D.

    1985-01-01

    The authors measured complex resistivity of 2 water-saturated San Andreas fault gouges from 10** minus **3 to 10**6 Hz and confining pressures of 0. 2 to 200 MPa. Consistent with earlier observations of clays and common rocks, large low-frequency permittivities were observed in all cases. Comparisons were made to induced polarization (IP) measurements by inversion of the data into the time domain, where it was found that principal features of the IP response curves were due to these large low-frequency permittivities. The results also suggest that following large earthquakes, significant electrical charge could remain for many seconds and could result in a variety of reported electromagnetic effects. Refs.

  1. Antiangiogenic agents significantly improve survival in tumor-bearing mice by increasing tolerance to chemotherapy-induced toxicity

    PubMed Central

    Zhang, Danfang; Hedlund, Eva-Maria E.; Lim, Sharon; Chen, Fang; Zhang, Yin; Sun, Baocun; Cao, Yihai

    2011-01-01

    Chemotherapy-induced broad toxicities are the leading cause of the drug-induced mortality in cancer patients. Antiangiogenic drugs (ADs) in combination with chemotherapy are widely used as front-line therapy for the treatment of various human cancers. However, the beneficial mechanisms underlying combination therapy are poorly understood. Here we show that, in several murine tumor models, administration of sunitinib markedly reduced chemotherapy-induced bone marrow toxicity. Intriguingly, in a sequential treatment regimen, delivery of ADs followed by chemotherapy demonstrated superior survival benefits compared with simultaneous administration of two drugs. In murine tumor models, we show that VEGF increased chemotoxicity by synergistically suppressing bone marrow hematopoiesis with cytostatic drugs. These findings shed light on molecular mechanisms by which ADs in combination with chemotherapy produce survival benefits in cancer patients and provide conceptual information guiding future designs of clinical trials, current practice, and optimization of ADs for the treatment of cancer. PMID:21367692

  2. Chronic cocaine administration induces opposite changes in dopamine receptors in the striatum and nucleus accumbens

    SciTech Connect

    Goeders, N.E.; Kuhar, M.J.

    1987-01-01

    A variety of clinical and animal data suggest that the repeated administration of cocaine and related psychomotor stimulants may be associated with a behavioral sensitization whereby the same dose of the drug results in increasing behavioral pathology. This investigation was designed to determine the effects of chronic cocaine administration on the binding of (/sup 3/H)sulpiride, a relatively specific ligand for D2 dopaminergic receptors, in the rat brain using in vitro homogenate binding and light microscopic quantitative autoradiographic methodologies. Chronic daily injections of cocaine (10 mg/kg, i.p.) for 15 days resulted in a significant decrease in the maximum concentration of sulpiride binding sites in the striatum and a significant increase in the maximum number of these binding sites in the nucleus accumbens. No significant differences in binding affinity were observed in either brain region. These data suggest that chronic cocaine administration may result in differential effects on D2 receptors in the nigro-striatal and mesolimbic dopaminergic systems.

  3. The incidence and significance of acute kidney injury following emergent contrast administration in patients with STEMI and stroke.

    PubMed

    Marchick, Michael Robert; Allen, Brandon Russell; Weeks, Emily Cassin; Shuster, Jonathan Jacob; Elie, Marie-Carmelle

    2016-09-01

    The authors have investigated the incidence of acute kidney injury (AKI) and short-term mortality following an activated STEMI and stroke alert at a tertiary referral and academic center. A single center, retrospective chart review of STEMI and stroke activation patients from January 2010 to March 2012. Data was collected and reviewed from an institutional database following IRB-approval. Inclusion criteria were STEMI patients taken for cardiac catheterization, excluding patients receiving hemodialysis due to end-stage renal disease (ESRD). Primary outcome measures were the incidence of AKI using the RIFLE criteria and short-term mortality. 745 patients were included (488 stroke, 257 STEMI). The median age was 65, and 39 % were female. Overall inpatient mortality was 7.0 %. 5.4 % (40/745) of patients experienced some degree of AKI (8.6 % of STEMI, 3.7 % of stroke patients). Overall, 30 % of patients with AKI died during their hospitalization. AKI was associated with a 7.1-fold (95 % CI 3.4-15.1) increase in mortality in the entire cohort. Among STEMI patients, AKI was associated with a 66.6-fold (95 % CI 12.9-343.4) increase in mortality. These findings follow similar trends published among critically ill patients with AKI. The risk of death with concomitant AKI in this hospital population is significant and deserves future study. Early recognition and awareness in the emergency department is paramount to the patient's survival. Future studies should focus on modalities to improve early recognition and preventative therapies. PMID:26910240

  4. Delayed Administration of Bone Marrow Mesenchymal Stem Cell Conditioned Medium Significantly Improves Outcome After Retinal Ischemia in Rats

    PubMed Central

    Dreixler, John C.; Poston, Jacqueline N.; Balyasnikova, Irina; Shaikh, Afzhal R.; Tupper, Kelsey Y.; Conway, Sineadh; Boddapati, Venkat; Marcet, Marcus M.; Lesniak, Maciej S.; Roth, Steven

    2014-01-01

    Purpose. Delayed treatment after ischemia is often unsatisfactory. We hypothesized that injection of bone marrow stem cell (BMSC) conditioned medium after ischemia could rescue ischemic retina, and in this study we characterized the functional and histological outcomes and mechanisms of this neuroprotection. Methods. Retinal ischemia was produced in adult Wistar rats by increasing intraocular pressure for 55 minutes. Conditioned medium (CM) from rat BMSCs or unconditioned medium (uCM) was injected into the vitreous 24 hours after the end of ischemia. Recovery was assessed 7 days after ischemia using electroretinography, at which time we euthanized the animals and then prepared 4-μm-thick paraffin-embedded retinal sections. TUNEL and Western blot were used to identify apoptotic cells and apoptosis-related gene expression 24 hours after injections; that is, 48 hours after ischemia. Protein content in CM versus uCM was studied using tandem mass spectrometry, and bioinformatics methods were used to model protein interactions. Results. Intravitreal injection of CM 24 hours after ischemia significantly improved retinal function and attenuated cell loss in the retinal ganglion cell layer. CM attenuated postischemic apoptosis and apoptosis-related gene expression. By spectral counting, 19 proteins that met stringent identification criteria were increased in the CM compared to uCM; the majority were extracellular matrix proteins that mapped into an interactional network together with other proteins involved in cell growth and adhesion. Conclusions. By restoring retinal function, attenuating apoptosis, and preventing retinal cell loss after ischemia, CM is a robust means of delayed postischemic intervention. We identified some potential candidate proteins for this effect. PMID:24699381

  5. The incidence and significance of acute kidney injury following emergent contrast administration in patients with STEMI and stroke.

    PubMed

    Marchick, Michael Robert; Allen, Brandon Russell; Weeks, Emily Cassin; Shuster, Jonathan Jacob; Elie, Marie-Carmelle

    2016-09-01

    The authors have investigated the incidence of acute kidney injury (AKI) and short-term mortality following an activated STEMI and stroke alert at a tertiary referral and academic center. A single center, retrospective chart review of STEMI and stroke activation patients from January 2010 to March 2012. Data was collected and reviewed from an institutional database following IRB-approval. Inclusion criteria were STEMI patients taken for cardiac catheterization, excluding patients receiving hemodialysis due to end-stage renal disease (ESRD). Primary outcome measures were the incidence of AKI using the RIFLE criteria and short-term mortality. 745 patients were included (488 stroke, 257 STEMI). The median age was 65, and 39 % were female. Overall inpatient mortality was 7.0 %. 5.4 % (40/745) of patients experienced some degree of AKI (8.6 % of STEMI, 3.7 % of stroke patients). Overall, 30 % of patients with AKI died during their hospitalization. AKI was associated with a 7.1-fold (95 % CI 3.4-15.1) increase in mortality in the entire cohort. Among STEMI patients, AKI was associated with a 66.6-fold (95 % CI 12.9-343.4) increase in mortality. These findings follow similar trends published among critically ill patients with AKI. The risk of death with concomitant AKI in this hospital population is significant and deserves future study. Early recognition and awareness in the emergency department is paramount to the patient's survival. Future studies should focus on modalities to improve early recognition and preventative therapies.

  6. The administration of Fructus Schisandrae attenuates dexamethasone-induced muscle atrophy in mice

    PubMed Central

    KIM, JOO WAN; KU, SAE-KWANG; HAN, MIN HO; KIM, KI YOUNG; KIM, SUNG GOO; KIM, GI-YOUNG; HWANG, HYE JIN; KIM, BYUNG WOO; KIM, CHEOL MIN; CHOI, YUNG HYUN

    2015-01-01

    In the present study, we aimed to determine whether ethanol extracts of Fructus Schisandrae (FS), the dried fruit of Schizandra chinensis Baillon, mitigates the development of dexamethasone-induced muscle atrophy. Adult SPF/VAT outbred CrljOri:CD1 (ICR) mice were either treated with dexamethasone to induce muscle atrophy. Some mice were treated with various concentrations of FS or oxymetholone, a 17α-alkylated anabolic-androgenic steroid. Muscle thickness and weight, calf muscle strength, and serum creatine and creatine kinase (CK) levels were then measured. The administration of FS attenuated the decrease in calf thickness, gastrocnemius muscle thickness, muscle strength and weight, fiber diameter and serum lactate dehydrogenase levels in the gastrocnemius muscle bundles which was induced by dexamethasone in a dose-dependent manner. Treatment with FS also prevented the dexamethasone-induced increase in serum creatine and creatine kinase levels, histopathological muscle fiber microvacuolation and fibrosis, and the immunoreactivity of muscle fibers for nitrotyrosine, 4-hydroxynonenal, inducible nitric oxide synthase and myostatin. In addition, the destruction of the gastrocnemius antioxidant defense system was also inhibited by the administration of FS in a dose-dependent manner. FS downregulated the mRNA expression of atrogin-1 and muscle RING-finger protein-1 (involved in muscle protein degradation), myostatin (a potent negative regulator of muscle growth) and sirtuin 1 (a representative inhibitor of muscle regeneration), but upregulated the mRNA expression of phosphatidylinositol 3-kinase, Akt1, adenosine A1 receptor and transient receptor potential cation channel subfamily V member 4, involved in muscle growth and the activation of protein synthesis. The overall effects of treatment with 500 mg/kg FS were comparable to those observed following treatment with 50 mg/kg oxymetholone. The results from the present study support the hypothesis that FS has a favorable

  7. Effects of systemic Thalidomide and intracerebroventricular Etanercept and Infliximab administration in a Streptozotocin induced dementia model in rats.

    PubMed

    Kübra Elçioğlu, H; Kabasakal, Levent; Tufan, Fatih; Elçioğlu, Ömer H; Solakoglu, Seyhun; Kotil, Tugba; Karan, Mehmet Akif

    2015-03-01

    Tumor necrosis factor-alpha (TNF-α) upregulation enhances amyloid β (Aβ) induced neurotoxicity in Alzheimer's disease (AD). Intracerebroventricular streptozotocin (STZ) administration causes pathological changes and cognitive deficits similar to those seen in AD by causing impairment of brain glucose and energy metabolism. Recent reports indicate a protective role of Thalidomide, Etanercept, and Infliximab, all of which have anti-TNF-α activity, against cognitive and neuropathological changes in experimental and clinical studies. We aimed to investigate the protective effects of Thalidomide, Etanercept, and Infliximab in a rat model of intracerebroventricular STZ-induced dementia. Sprague-Dawley rats (250-300g) were separated to sham (n=6) and STZ (n=24) groups. The STZ group was divided into four groups (STZ, STZ-thalidomide, STZ-etanercept, and STZ-infliximab). Morris's water maze (MWM) and passive avoidance (PA) tests were performed. At the end of the third week, brain tissues were obtained. Histopathological analysis, immunohistochemistry, and electron microscopic examinations were done. The improvement performance of the STZ group was significantly reduced in the MWM test (p<0.001). Compared with the STZ, STZ-thalidomide, STZ-etanercept, and STZ-infliximab groups had significantly better performance (p<0.001, <0.05 and <0.05, respectively) in the MWM test. STZ administration caused a significant decrease in the mean escape latency in PA reflex (p<0.001). Thalidomide, Etanercept, and Infliximab were associated with better PA reflexes compared to the STZ group (p<0.001 for all). Morphological and immunohistochemical results showed increased neurodegenerative changes compared to sham group. Our findings are in line with the findings reported in the literature and encourage further studies with TNF-α antagonists, in particular Thalidomide.

  8. Profiles of Serum Cytokines in Acute Drug-Induced Liver Injury and Their Prognostic Significance

    PubMed Central

    Zhou, Jie; Parsons, Judith C.; Chalasani, Naga; Fontana, Robert J.; Watkins, Paul B.; Lee, William M.; Reddy, K. Rajender; Stolz, Andrew; Talwalkar, Jayant; Davern, Timothy; Saha, Dhanonjoy; Bell, Lauren N.; Barnhart, Huiman; Gu, Jiezhun; Serrano, Jose; Bonkovsky, Herbert L.

    2013-01-01

    Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the United-States. The aim of the study was to describe serum immune profiles associated with acute DILI, to investigate whether there are profiles associated with clinical features or types of DILI and/or with prognosis, and to assess temporal changes in levels. Twenty-seven immune analytes were measured in the sera of 78 DILI subjects in the Drug-Induced Liver Injury Network (DILIN) and compared with 40 healthy controls. Immune analytes (14 cytokines, 7 chemokines and 6 growth factors) were measured by BioPlex multiplex ELISA at DILI onset and after 6 months. A modeling process utilizing immune principles was used to select a final set of variables among 27 immune analytes and several additional clinical lab values for prediction of early death (within 6 months of DILI onset). Nineteen of the 27 immune analytes were differentially expressed among healthy control, DILI onset and 6-month cohorts. Disparate patterns of immune responses, especially innate and adaptive cellular (mostly TH17) immunity were evident. Low values of four immune analytes (IL-9, IL-17, PDGF-bb and RANTES) and serum albumin are predictive of early death [PPV = 88% (95% CI, 65%-100%), NPV = 97% (95% CI, 93%-100%), accuracy = 96% (95% CI, 92%-100%)]. Conclusions Acute DILI is associated with robust and varying immune responses. High levels of expression of cytokines associated with innate immunity are associated with a poor prognosis, whereas high levels of expression of adaptive cytokines are associated with good long-term prognosis and eventual recovery. Serum immune analyte profiles at DILI onset appear to be of prognostic, and perhaps, diagnostic significance. PMID:24386086

  9. Opposite effects of oxytocin on water intake induced by hypertonic NaCl or polyethylene glycol administration.

    PubMed

    Bernal, Antonio; Mahía, Javier; Mediavilla, Cristina; Puerto, Amadeo

    2015-03-15

    Oxytocin (OT), a neurohormone, has been related to natriuretic and diuretic effects and also to water intake and sodium appetite. The objective of the present study was to determine the effect of subcutaneous OT administration on water intake and urine-related measures induced by the administration of hypertonic NaCl (experiment 1) or polyethylene glycol (PEG) (experiment 2). Experiment 1 showed that OT administration increases the urine volume, urinary sodium concentration, and natriuresis and reduces the water intake, water and sodium balances, and estimated plasma sodium concentration induced by hypertonic NaCl administration. Conversely, experiment 2 showed that OT administration increases the water intake and the antidiuretic response induced by PEG administration. These results show that the opposite effects of OT on the water intake induced by hypertonic NaCl or PEG administration are accompanied by differential regulatory effects, enhancing a natriuretic response in the first experiment and generating an antidiuretic reaction in the second experiment. This study suggests a differential regulatory effect of OT during states of intra- and extracellular thirst.

  10. Evaluation of spatial memory and locomotor activity during hypercortisolism induced by the administration of dexamethasone in adult male rats.

    PubMed

    Yılmaz, Tevfik; Gedikli, Öznur; Yildirim, Mehmet

    2015-01-21

    In neurosurgery practice glucocorticoids are commonly used. Steroids may have central nervous system side effects affecting whole body, including steroid-induced mental agitation and psychosis. In experimental and clinical studies conducted by using dexamethasone (DEX), it has been reported that DEX adversely affects learning and memory skills. Unfortunately, there are yet no clinically accepted clinical approaches to prevent DEX-induced cognitive dysfunction. In this experimental study it was aimed to investigate the effect of chronic DEX administration on learning-memory and locomotor behaviors in adult male Sprague Dawley rats. In addition, it was also aimed to explore the potential favorable contribution of melatonin (MEL) and vitamin C (Vit C) having antioxidant and neuroprotective properties to the effects of DEX on learning-memory and locomotor behaviors. For this purpose, rats were injected 10mg/kg DEX intraperitoneally, both alone and in combination with MEL (40 mg/kg) and Vit C (100mg/kg), for 9 days, and the animals were tested using the radial arm maze and open field apparatus. The test results revealed that DEX caused a significant decrease in spatial memory and locomotor activities and MEL and Vit C failed to reverse losses in these activities. Furthermore, DEX led to a gradual weight loss that reached 30% of the initial weight at 9th day of the injection. DEX administration causes a generalized loss of behavioral activity of rats. Experimental studies devised to investigate effects of DEX should take into account this DEX-induced generalized behavioral loss when assessing the effects of DEX on learning and memory skills. This article is part of a Special Issue entitled SI: Brain and Memory.

  11. Context-Dependent Effects of a Single Administration of Mirtazapine on the Expression of Methamphetamine-Induced Conditioned Place Preference

    PubMed Central

    Voigt, Robin M.; Napier, T. Celeste

    2012-01-01

    Re-exposure to cues repeatedly associated with methamphetamine (Meth) can trigger Meth-seeking and relapse in the abstinent abuser. Weakening the conditioned Meth-associated memory during cue re-exposure may provide a means for relapse-reduction pharmacotherapy. Accordingly, we sought to determine if the atypical antidepressant mirtazapine disrupted the persistence of Meth-induced conditioned place preference (CPP) when administered in conjunction with re-exposure to contextual conditioning cues, and if this effect was altered by Meth being present during cue re-exposure. First, we evaluated the effect of mirtazapine on the maintenance of Meth-induced CPP during re-exposure to either the saline- or Meth-paired chamber 12 days after conditioning. Meth-conditioned rats subsequently administered mirtazapine expressed CPP independent of re-exposure to the saline- or Meth-paired chamber; but the magnitude of CPP was significantly less for mirtazapine-treated rats re-exposed to the Meth-paired chamber. Next, we evaluated the effect of mirtazapine on a “reinforced re-exposure” to the Meth-paired context. Administration of mirtazapine vehicle and Meth, prior to re-exposure to the Meth-paired chamber did not disrupt the ability of rats to demonstrate CPP 15 days after conditioning; however, CPP was disrupted when rats were administered mirtazapine and Meth prior to re-exposure to the Meth-paired chamber. These results indicate that the capacity of mirtazapine to diminish Meth-induced CPP is promoted if mirtazapine treatment is coupled with Meth administration in the Meth-associated context and thus appears to be the consequence of disrupting processes necessary to reconsolidate CPP following activation of drug-associated memories. PMID:22347852

  12. Brown adipose tissue thermogenesis does not explain the intra-administration hyperthermic sign-reversal induced by serial administrations of 60% nitrous oxide to rats.

    PubMed

    Al-Noori, Salwa; Ramsay, Douglas S; Cimpan, Andreas; Maltzer, Zoe; Zou, Jessie; Kaiyala, Karl J

    2016-08-01

    Initial administration of ≥60% nitrous oxide (N2O) to rats promotes hypothermia primarily by increasing whole-body heat loss. We hypothesized that the drug promotes heat loss via the tail and might initially inhibit thermogenesis via brown adipose tissue (BAT), major organs of thermoregulation in rodents. Following repeated administrations, N2O inhalation evokes hyperthermia underlain by increased whole-body heat production. We hypothesized that elevated BAT thermogenesis plays a role in this thermoregulatory sign reversal. Using dual probe telemetric temperature implants and infrared (IR) thermography, we assessed the effects of nine repeated 60% N2O administrations compared to control (con) administrations on core temperature, BAT temperature, lumbar back temperature and tail temperature. Telemetric core temperature, telemetric BAT temperature, and IR BAT temperature were reduced significantly during initial 60% N2O inhalation (p≤0.001 compared to con). IR thermography revealed that acute N2O administration unexpectedly reduced tail temperature (p=0.0001) and also inhibited IR lumbar temperature (p<0.0001). In the 9th session, N2O inhalation significantly increased telemetric core temperature (p=0.007) indicative of a hyperthermic sign reversal, yet compared to control administrations, telemetric BAT temperature (p=0.86), IR BAT temperature (p=0.85) and tail temperature (p=0.47) did not differ significantly. Thus, an initial administration of 60% N2O at 21°C may promote hypothermia via reduced BAT thermogenesis accompanied by tail vasoconstriction as a compensatory mechanism to limit body heat loss. Following repeated N2O administrations rats exhibit a hyperthermic core temperature but a normalized BAT temperature, suggesting induction of a hyperthermia-promoting thermogenic adaptation of unknown origin. PMID:27503733

  13. Chronic nandrolone administration induces dysfunction of the reward pathway in rats.

    PubMed

    Zotti, Margherita; Tucci, Paolo; Colaianna, Marilena; Morgese, Maria Grazia; Mhillaj, Emanuela; Schiavone, Stefania; Scaccianoce, Sergio; Cuomo, Vincenzo; Trabace, Luigia

    2013-10-24

    Data in animal models and surveys in humans have shown psychiatric complications of long-term anabolic androgenic steroids abuse. However, neurobiochemical mechanisms behind observed behavioral changes are poorly understood. The aim of the present study was to investigate the effects of nandrolone decanoate on emotional behavior and neurochemical brain alterations in gonadally intact male rats. Behavioral reactivity to elevated plus maze and social interaction test was used to assess anxiety-related symptoms, while sucrose preference test was used to evaluate anhedonia. Dopaminergic, serotonergic and noradrenergic transmissions were also evaluated in selected brain areas. Chronic administration of nandrolone, at 5 mg kg(-1) injected for 4 weeks, induced loss of sweet taste preference, as sign of anhedonia and dysfunction of reward pathway. Behavioral outcomes were accompanied by reduction of dopamine, serotonin and noradrenaline contents in nucleus accumbens. Neither alterations in time spent in open arms nor in social interaction test were found, suggesting that nandrolone did not induce an anxiogenic profile. No differences were revealed between experimental groups in the amygdala in terms of neurotransmitters measured. Our data suggest that nandrolone-treated rats have a depressive, but not anxiogenic-like, profile, accompanied by brain region-dependent changes in dopaminergic, serotonergic and noradrenergic neurotransmission. As anabolic androgenic steroid dependence is plausibly the major form of worldwide substance dependence that remains largely unexplored, it should be underlined that our data could contribute to a better understanding of altered reward induced by nandrolone treatment and to develop appropriate treatment.

  14. Bendiocarbamate induced structural alterations in rabbit thymus after experimental peroral administration.

    PubMed

    Flesarova, Slavka; Lukac, Norbert; Danko, Jan; Massanyi, Peter

    2007-01-01

    In this study histological structure of rabbit thymus after bendiocarbamate (2,3-isopropyledene-dioxyphenyl methylcarbamate) administration was studied. Bendiocarbamate was perorally administered for 90 days. At Day 3, 10, 20, 30, 60, 90 morphometric analysis was realized. Quantitative evaluation showed that in the control group thymus cortex forms 57.94 +/- 7.10% and medulla 35.94+/- 7.38%. In almost all experimental groups significantly higher relative volume of cortex and lower relative volume of medulla was detected. Detail morphometric analysis found that the number of thymocytes per constant area and the diameter of tymocytes was decresed after bendiocarbamate administration. The number and diameter of reticular cells was not affected. Results of this study suggest negative effect of bendiocarbamate on the formation of thymus structures.

  15. Combined administration of taurine and monoisoamyl DMSA protects arsenic induced oxidative injury in rats.

    PubMed

    Flora, Swaran J S; Chouhan, Swapnila; Kannan, Gurusamy M; Mittal, Megha; Swarnkar, Harimohan

    2008-01-01

    Arsenic is a naturally occurring element that is ubiquitously present in the environment. High concentration of naturally occurring arsenic in drinking water is a major health problem in different parts of the world. Despite arsenic being a health hazard and a well documented carcinogen, no safe, effective and specific preventive or therapeutic measures are available. Among various recent strategies adopted, administration of an antioxidant has been reported to be the most effective. The present study was designed to evaluate the therapeutic efficacy of monoisoamyl dimercaptosuccinic acid (MiADMSA), administered either individually or in combination with taurine post chronic arsenic exposure in rats. Arsenic exposed male rats (25 ppm, sodium arsenite in drinking water for 24 weeks) were treated with taurine (100 mg/kg, i.p., once daily), monoisoamyl dimercaptosuccinic acid (MiADMSA) (50 mg/kg, oral, once daily) either individually or in combination for 5 consecutive days. Biochemical variables indicative of oxidative stress along-with arsenic concentration in blood, liver and kidney were measured. Arsenic exposure significantly reduced blood delta-aminolevulinic acid dehydratase (ALAD) activity, a key enzyme involved in the heme biosynthesis and enhanced zinc protoporphyrin (ZPP) level. Clinical hematological variables like white blood cells (WBC), mean cell hemoglobin (MCH), and mean cell hemoglobin concentration (MCHC) showed significant decrease with a significant elevation in platelet (PLT) count. These changes were accompanied by significant decrease in superoxide dismutase (SOD) activity and increased catalase activity. Arsenic exposure caused a significant decrease in hepatic and renal glutathione (GSH) level and an increase in oxidized glutathione (GSSG). These biochemical changes were correlated with an increased uptake of arsenic in blood, liver and kidney. Administration of taurine significantly reduced hepatic oxidative stress however co-administration

  16. Nickel-induced blood biochemistry alterations in hens after an experimental peroral administration.

    PubMed

    Kolesarova, Adriana; Capcarova, Marcela; Arpasova, Henrieta; Kalafova, Anna; Massanyi, Peter; Lukac, Norbert; Kovacik, Jaroslav; Schneidgenova, Monika

    2008-09-01

    The purpose of this study was to determine certain blood biochemical parameters in hens of Isa Brown breed (n = 20) after nickel administration. Animals were divided into four groups (K, P1, P2, P3). Experimental hens (n = 5; in each group) received nickel (NiCl2) as peroral administration in drinking water in various doses (P1 - 0.02 g NiCl2/L; P2 - 0.2 g NiCl2/L; P3 - 2.0 g NiCl2/L of drinking water) for 28 days. The last group - K (n = 5) was the control, receiving no nickel. Biochemical parameters of mineral profile (calcium; phosphorus; magnesium; sodium; potassium) and of energy and enzymatic profile [(glucose; total cholesterol; total proteins; triglycerides; alanine aminotransferase (ALT) aspartate aminotransferase (AST) gamma glutamyl transferase (GGT) and glutamatdehydrogenase (GLDH)] were analyzed in blood serum on Day 0, 7, 14, 21 and 28 of the experiment. Average levels of mineral metabolism parameters were relatively stable apart from calcium. The evaluation registered a significant decrease in calcium during the experiment mainly in the group with highest nickel concentration in drinking water. No significant differences were detected between groups in energy and enzymatic profile apart from the concentrations of ALT on Day 7. In conclusion, there were significant associations between nickel levels and calcium and ALT in blood serum of the hens. No significant differences were detected in other biochemical parameters of mineral profile (P, Mg, Na, K) and energy and enzymatic profile (glucose, total cholesterol, total proteins, triglycerides, AST, GGT and GLDH) after nickel administration. Our results may contribute to an evaluation of reference levels of analyzed parameters, to monitor the health and nutritional status of hens. In this study also the negative effect of nickel mainly on calcium metabolism was detected.

  17. Probiotic pre-administration reduces mortality in a mouse model of cecal ligation and puncture-induced sepsis

    PubMed Central

    Chen, Lufang; Xu, Keying; Gui, Qifeng; Chen, Yue; Chen, Deying; Yang, Yunmei

    2016-01-01

    A number of clinical trials have demonstrated that the use of probiotics has the potential to prevent nosocomial infections. However, the mechanism underlying probiotic-induced anti-infection and sepsis remains to be investigated. In the present study, 200 µl/day of Lactobacillus rhamnosus GG (LGG) or normal saline (control) was orally administrated to 4-week-old C57BL6 mice 4 weeks prior to cecal ligation and puncture (CLP). A number of mice were sacrificed 24 h after CLP, and the remaining mice were used for survival studies. Ileum tissues were collected to evaluate the injury on the intestine. Blood samples were also obtained to investigate the changed metabolic pattern in mice that underwent different treatments using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). In the survival studies, the mortality of CLP-induced septic mice pretreated with LGG was significantly lower compared with untreated mice (P=0.029). Ileum mucosal damage was evident in the control septic mice. Based on the data of UPLC-QTOF-MS, phosphatidylcholines were increased and lysophosphatidylcholines (LPCs) that contained polyunsaturated fatty acids were decreased in septic mice, whereas saturated fatty acid LPCs reveal no significant difference between septic and sham mice. In addition, the metabolic profile in the septic mice pretreated with LGG was much closer to that of sham mice compared with control septic mice. The results of the present study suggest that probiotic pre-administration reduces the mortality in septic mice by decreasing ileum mucosal damage, increasing the gut barrier integrity and altering global serum metabolic profiles. PMID:27588102

  18. Xanthones from Securidaca inappendiculata exert significant therapeutic efficacy on adjuvant-induced arthritis in mice.

    PubMed

    Zuo, Jian; Xia, Yan; Li, Xiang; Chen, Jian-Wei

    2014-06-01

    The study was designed to investigate effects of the xanthones from Securidaca inappendiculata on adjuvant-induced arthritis (AA) mice in vivo. Arthritis severity was evaluated by arthritic score, body weight loss, paw circumference, histological changes and hyperplasia of lymphatic tissues. Plasma samples were collected for estimation of interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-α), monocyte chemotactic protein 1 (MCP-1) and vascular endothelial growth factor (VEGF) using enzyme-linked immunosorbent assay method. The levels of glutathione (GSH), malondialdehyde (MDA), N-acetyl glucosaminidase (NAG) and sialic acid (SA) in liver were assessed by colorimetric method. Xanthones significantly ameliorated the severity of AA indicated by the physical parameters changes, and reverted the abnormal changes of MDA, GSH, NAG and SA in liver. Levels of IL-1, TNF-α, MCP-1 and VEGF reduced dramatically meanwhile. The effects of xanthones on AA were the outcome of the multitargets activities, and probably associated with NF-κB signaling pathway. PMID:24419745

  19. Significance of erosion-induced carbon fluxes in the carbon balance of a Mediterranean catchment

    NASA Astrophysics Data System (ADS)

    Nadeu, Elisabet; de Vente, Joris; Boix-Fayos, Carolina

    2014-05-01

    Large uncertainties surround our knowledge of the processes through which carbon (C) sequestration takes place in terrestrial ecosystems. Nevertheless, terrestrial ecosystems could be capturing up to one fourth of the CO2 that is emitted annually to the atmosphere from the burning of fossil fuels and land use changes. Soils are the third largest C reservoir in the C cycle, storing around 1500 Gt of C. Over the last decades, geomorphologists and soil scientists have claimed the role of soil erosion within the C cycle and its potential contribution to the terrestrial C sink. In order to assess the impact of soil erosion on the C cycle, however, an understanding and quantification of the impact of soil erosion on soil C stocks is needed. This implies quantifying lateral and vertical C fluxes associated to detachment, transport and deposition of soil and sediment at different spatial scales. As an example, we present a C budget for a mountainous catchment in south-eastern Spain for a 28 year study period during which the catchment underwent significant land use changes and hydrological correction works (i.e. check-dam construction and reforestations). We quantified lateral C fluxes induced by soil erosion processes and closed a soil/sediment C budget by combining field measurements and numerical modeling. In addition, correlation analysis was conducted between catchment properties (topographic, land use, lithology) and measured C deposition rates to understand the controlling factors on C yield (export) and C concentration in sediments. The results showed that the highest C yields (associated to high sediment yields) were found in subcatchments dominated by soft lithologies and high drainage densities. On the other hand, C concentration in deposited sediments was higher in areas dominated by forest cover, and presented high variability in those parts of the catchment with smoother slopes. Overall, we estimated that around 4000 Mg of C were mobilized from the catchment

  20. Adaptations of Presynaptic Dopamine Terminals Induced by Psychostimulant Self-Administration

    PubMed Central

    2015-01-01

    A great deal of research has focused on investigating neurobiological alterations induced by chronic psychostimulant use in an effort to describe, understand, and treat the pathology of psychostimulant addiction. It has been known for several decades that dopamine neurotransmission in the nucleus accumbens is integrally involved in the selection and execution of motivated and goal-directed behaviors, and that psychostimulants act on this system to exert many of their effects. As such, a large body of work has focused on defining the consequences of psychostimulant use on dopamine signaling in the striatum as it relates to addictive behaviors. Here, we review presynaptic dopamine terminal alterations observed following self-administration of cocaine and amphetamine, as well as possible mechanisms by which these alterations occur and their impact on the progression of addiction. PMID:25491345

  1. Combined administration of cerebrolysin and donepezil induces plastic changes in prefrontal cortex in aged mice.

    PubMed

    Alcántara-González, Faviola; Mendoza-Perez, Claudia Rebeca; Zaragoza, Néstor; Juarez, Ismael; Arroyo-García, Luis Enrique; Gamboa, Citlalli; De La Cruz, Fidel; Zamudio, Sergio; Garcia-Dolores, Fernando; Flores, Gonzalo

    2012-11-01

    Cerebrolysin (Cbl) shows neurotrophic and neuroprotective properties while donepezil (Dnp) is a potent acetylcholinesterase (AChE) inhibitor, both drugs are prescribed for Alzheimer's disease (AD) treatment. Previous studies have shown that the Dnp and Cbl administered separately, modify dendritic morphology of neurons in the prefrontal cortex and hippocampus in senile rodents. Since the deficit of neurotrophic factor activity is implicated in the degeneration of cholinergic neurons of basal forebrain, a combination therapy of Dnp and Cbl has been tested recently in Alzheimer's patients. However, the plastic changes that may underlie this combined treatment have not yet been explored. We present here the effect of the combined administration of Cbl and Dnp on dendritic morphology in brain regions related to learning and memory in aged mice. The Golgi-Cox staining protocol and Sholl analysis were used for studying dendritic changes. Cbl and Dnp were administrated daily for 2 months to 9-months-old mice. Locomotor activity was assessed, as well as the dendritic morphology of neurons in several limbic regions was analyzed. Results showed that Cbl and Dnp induced an increase in locomotor activity without synergistic effect. The Cbl or Dnp treatment modified the dendritic morphology of neurons from prefrontal cortex (PFC), dorsal hippocampus (DH), dentate gyrus (DG), and the shell of nucleus accumbens (NAcc). These changes show an increase in the total dendritic length and spine density, resulting in an improvement of dendritic arborization. Prominently, a synergistic effect of Cbl and Dnp was observed on branching order and total dendritic length of pyramidal neurons from PFC. These results suggest that Dnp and Cbl may induce plastic changes in a manner independent of each other, but could enhance their effect in target cells from PFC.

  2. Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice

    PubMed Central

    Mirsoian, Annie; Bouchlaka, Myriam N.; Sckisel, Gail D.; Chen, Mingyi; Pai, Chien-Chun Steven; Maverakis, Emanuel; Spencer, Richard G.; Fishbein, Kenneth W.; Siddiqui, Sana; Monjazeb, Arta M.; Martin, Bronwen; Maudsley, Stuart; Hesdorffer, Charles; Ferrucci, Luigi; Longo, Dan L.; Blazar, Bruce R.; Wiltrout, Robert H.; Taub, Dennis D.

    2014-01-01

    Aging is a contributing factor in cancer occurrence. We recently demonstrated that systemic immunotherapy (IT) administration in aged, but not young, mice resulted in induction of rapid and lethal cytokine storm. We found that aging was accompanied by increases in visceral fat similar to that seen in young obese (ob/ob or diet-induced obese [DIO]) mice. Yet, the effects of aging and obesity on inflammatory responses to immunotherapeutics are not well defined. We determine the effects of adiposity on systemic IT tolerance in aged compared with young obese mice. Both young ob/ob- and DIO-generated proinflammatory cytokine levels and organ pathologies are comparable to those in aged ad libitum mice after IT, culminating in lethality. Young obese mice exhibited greater ratios of M1/M2 macrophages within the peritoneal and visceral adipose tissues and higher percentages of TNF+ macrophages in response to αCD40/IL-2 as compared with young lean mice. Macrophage depletion or TNF blockade in conjunction with αCD40/IL-2 prevented cytokine storms in young obese mice and protected from lethality. Calorie-restricted aged mice contain less visceral fat and displayed reduced cytokine levels, protection from organ pathology, and protection from lethality upon αCD40/IL-2 administration. Our data demonstrate that adiposity is a critical factor in the age-associated pathological responses to systemic anti-cancer IT. PMID:25366964

  3. Leptin levels are reduced by intravenous ghrelin administration and correlated with cue-induced alcohol craving.

    PubMed

    Haass-Koffler, C L; Aoun, E G; Swift, R M; de la Monte, S M; Kenna, G A; Leggio, L

    2015-01-01

    Increasing evidence supports the role of appetite-regulating pathways, including ghrelin and leptin, in alcoholism. This study tested the hypothesis that intravenous exogenous ghrelin administration acutely decreases endogenous serum leptin levels, and that changes in leptin levels negatively correlate with alcohol craving. This was a double-blind, placebo-controlled human laboratory study. Non-treatment-seeking, alcohol-dependent, heavy drinkers (n=45) were randomized to receive intravenous ghrelin or placebo, followed by a cue-reactivity procedure, during which participants were exposed to neutral (juice) and alcohol trial cues. There was a main effect for intravenous ghrelin administration, compared with placebo, in reducing serum leptin levels (P<0.01). Post hoc analysis showed significant differences in serum leptin levels at the alcohol trial (P<0.05) that persisted at the end of the experiment (P<0.05). By contrast, there were no significant differences in serum leptin levels at the juice trial (P=not significant (NS)). The change of serum leptin level at the alcohol trial correlated with the increase in alcohol urge (P<0.05), whereas urge to drink juice was not correlated with the leptin change at the juice trial (P=NS). These findings provide preliminary evidence of ghrelin-leptin cross-talk in alcoholic individuals and suggest that their relationship may have a role in alcohol craving.

  4. Concomitant administration of Moringa oleifera seed powder in the remediation of arsenic-induced oxidative stress in mouse.

    PubMed

    Gupta, Richa; Dubey, D K; Kannan, G M; Flora, S J S

    2007-01-01

    Contamination of ground water by arsenic has become a cause of global public health concern. In West Bengal, India, almost 6 million people are endemically exposed to inorganic arsenic by drinking heavily contaminated groundwater through hand-pumped tube wells. No safe, effective and specific preventive or therapeutic measures for treating arsenic poisoning are available. We recently reported that some of the herbal extracts possess properties effective in reducing arsenic concentration and in restoring some of the toxic effects of arsenic in animal models. Moringa oleifera Lamarack (English: Horseradish-tree, Drumstick-tree, Hindi: Saijan, Sanskrit: Shigru) belongs to the Moringaceae family, is generally known in the developing world as a vegetable, a medicinal plant and a source of vegetable oil. The objective of the present study was to determine whether Moringa oleifera (M. oleifera) seed powder could restore arsenic induced oxidative stress and reduce body arsenic burden. Exposure to arsenic (2.5 mg/kg, intraperitoneally for 6weeks) led to a significant increase in the levels of tissue reactive oxygen species (ROS), metallothionein (MT) and thiobarbituric acid reactive substance (TBARS) which were accompanied by a decrease in the activities in the antioxidant enzymes such as superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) in mice. Arsenic exposed mice also exhibited liver injury as reflected by reduced acid phosphatase (ACP), alkaline phosphatase (ALP) and aspartate aminotransferase (AST) activities and altered heme synthesis pathway as shown by inhibited blood delta-aminolevulinic acid dehydratase (delta-ALAD) activity. Co-administration of M. oleifera seed powder (250 and 500 mg/kg, orally) with arsenic significantly increased the activities of SOD, catalase, GPx with elevation in reduced GSH level in tissues (liver, kidney and brain). These changes were accompanied by approximately 57%, 64% and 17% decrease in blood ROS, liver

  5. Concomitant administration of Moringa oleifera seed powder in the remediation of arsenic-induced oxidative stress in mouse.

    PubMed

    Gupta, Richa; Dubey, D K; Kannan, G M; Flora, S J S

    2007-01-01

    Contamination of ground water by arsenic has become a cause of global public health concern. In West Bengal, India, almost 6 million people are endemically exposed to inorganic arsenic by drinking heavily contaminated groundwater through hand-pumped tube wells. No safe, effective and specific preventive or therapeutic measures for treating arsenic poisoning are available. We recently reported that some of the herbal extracts possess properties effective in reducing arsenic concentration and in restoring some of the toxic effects of arsenic in animal models. Moringa oleifera Lamarack (English: Horseradish-tree, Drumstick-tree, Hindi: Saijan, Sanskrit: Shigru) belongs to the Moringaceae family, is generally known in the developing world as a vegetable, a medicinal plant and a source of vegetable oil. The objective of the present study was to determine whether Moringa oleifera (M. oleifera) seed powder could restore arsenic induced oxidative stress and reduce body arsenic burden. Exposure to arsenic (2.5 mg/kg, intraperitoneally for 6weeks) led to a significant increase in the levels of tissue reactive oxygen species (ROS), metallothionein (MT) and thiobarbituric acid reactive substance (TBARS) which were accompanied by a decrease in the activities in the antioxidant enzymes such as superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) in mice. Arsenic exposed mice also exhibited liver injury as reflected by reduced acid phosphatase (ACP), alkaline phosphatase (ALP) and aspartate aminotransferase (AST) activities and altered heme synthesis pathway as shown by inhibited blood delta-aminolevulinic acid dehydratase (delta-ALAD) activity. Co-administration of M. oleifera seed powder (250 and 500 mg/kg, orally) with arsenic significantly increased the activities of SOD, catalase, GPx with elevation in reduced GSH level in tissues (liver, kidney and brain). These changes were accompanied by approximately 57%, 64% and 17% decrease in blood ROS, liver

  6. Effects of an Oxycodone Conjugate Vaccine on Oxycodone Self-Administration and Oxycodone-Induced Brain Gene Expression in Rats

    PubMed Central

    Pravetoni, Marco; Pentel, Paul R.; Potter, David N.; Chartoff, Elena H.; Tally, Laura; LeSage, Mark G.

    2014-01-01

    Prescription opioid abuse is an increasing public health concern in the USA. A vaccine comprising a hapten (OXY) conjugated to the carrier protein keyhole limpet hemocyanin (OXY-KLH) has been shown to attenuate the antinociceptive effects of oxycodone. Here, the vaccine's ability to prevent acquisition of intravenous (i.v.) oxycodone self-administration was studied in rats. Effects of vaccination on oxycodone-induced changes in the expression of several genes within the mesolimbic system, which are regulated by chronic opiate use, were also examined. Vaccination with OXY-KLH reduced the proportion of rats acquiring i.v. self-administration of oxycodone under a fixed ratio (FR) 3 schedule of reinforcement compared to control rats immunized with the unconjugated KLH carrier protein. Vaccination significantly reduced the mean number of infusions at FR3, total number of infusions, and total oxycodone intake during the entire protocol. Compared to oxycodone self-administering control rats immunized with the carrier alone, rats vaccinated with the OXY-KLH immunogen showed increased levels of adenylate cyclase 5 (Adcy5) and decreased levels of early growth response protein 2 (Egr2) and the early immediate gene c-Fos in the striatum. These data suggest that vaccination with OXY-KLH can attenuate the reinforcing effects of oxycodone at a clinically-relevant exposure level. Analysis of mRNA expression identified some addiction-relevant markers that may be of interest in understanding oxycodone effects or the protection provided by vaccination. PMID:25025380

  7. A helicopter flight does not induce significant changes in systemic biomarker profiles.

    PubMed

    Kåsin, Jan Ivar; Kjekshus, John; Aukrust, Pål; Mollnes, Tom Eirik; Wagstaff, Anthony

    2009-01-01

    Whole-body vibration and noise are inherent characteristics of helicopter operations. The helicopter pilot is affected by vibration from both low-frequency noise and mechanical vibration sources. The way this energy is transmitted to different tissues and organs depends on intensity, frequency and resonance phenomena within the body. Whole-body vibration is known to affect the muscular and skeletal system in the lower part of the spine, but less is known about the response at the cellular level to this stimulation. In some studies, chronic pathological changes have been described in different types of tissue in people exposed to low-frequency noise and vibration. The aim of the present study was to investigate possible cellular reactions to acute exposure to low-frequency noise and vibration in a helicopter. Thirteen healthy males aged 38 (18-69) years were subjected to a 3.5 h helicopter flight in a Westland Sea King Rescue helicopter. Blood tests taken before and after the flight were analysed for more than 40 parameters, including acute phase reactants, markers of leucocyte and platelet activation, complement and hemostasis markers, as well as a broad panel of cytokines, chemokines, growth factors and cell adhesion molecules. The subjects served as their own controls. With the exception of an increase in vascular cell adhesion molecule-1 (VCAM-1) during the flight, no statistically significant changes in the biomarkers were found after controlling for diurnal variation in the control blood tests, which were observed independently of the helicopter flight. In conclusion, one helicopter flight does not induce measurable changes in systemic biomarkers.

  8. Significance of CpG methylation for solar UV-induced mutagenesis and carcinogenesis in skin.

    PubMed

    Ikehata, Hironobu; Ono, Tetsuya

    2007-01-01

    Mutations detected in the p53 gene in human nonmelanoma skin cancers show a highly UV-specific mutation pattern, a dominance of C --> T base substitutions at dipyrimidine sites plus frequent CC --> TT tandem substitutions, indicating a major involvement of solar UV in the skin carcinogenesis. These mutations also have another important characteristic of frequent occurrences at CpG dinucleotide sites, some of which actually show prominent hotspots in the p53 gene. Although mammalian solar UV-induced mutation spectra were studied intensively in the aprt gene using rodent cultured cells and the UV-specific mutation pattern was confirmed, the second characteristic of the p53 mutations in human skin cancers had not been reproduced. However, studies with transgenic mouse systems developed thereafter for mutation research, which harbor methyl CpG-abundant transgenes as mutation markers, yielded complete reproductions of the situation of the human skin cancer mutations in terms of both the UV-specific pattern and the frequent occurrence at CpG sites. In this review, we evaluate the significance of the CpG methylation for solar UV mutagenesis in the mammalian genome, which would lead to skin carcinogenesis. We propose that the UV-specific mutations at methylated CpG sites, C --> T transitions at methyl CpG-associated dipyrimidine sites, are a solar UV-specific mutation signature, and have estimated the wavelength range effective for the solar-UV-specific mutation as 310-340 nm. We also recommend the use of methyl CpG-enriched sequences as mutational targets for studies on solar-UV genotoxicity for human, rather than conventional mammalian mutational marker genes such as the aprt and hprt genes.

  9. Potential Biomarkers for Radiation-Induced Renal Toxicity following 177Lu-Octreotate Administration in Mice

    PubMed Central

    Schüler, Emil; Larsson, Maria; Parris, Toshima Z.; Johansson, Martin E.; Helou, Khalil; Forssell-Aronsson, Eva

    2015-01-01

    The kidneys are one of the main dose-limiting organs in peptide receptor radionuclide therapy and due to large inter-individual variations in renal toxicity, biomarkers are urgently needed in order to optimize therapy and reduce renal tissue damage. The aim of this study was to investigate the transcriptional, functional, and morphological effects on renal tissue after 177Lu-octreotate administration in normal mice, and to identify biomarkers for radiation induced renal toxicity. Methods C57BL/6N mice were i.v. injected with 0, 30, 60, 90, 120, or 150 MBq 177Lu-octreotate (0, 16, 29, 40, 48, and 54 Gy to the kidneys). At 4, 8, and 12 months after administration, radiation-induced effects were evaluated in relation to (a) global transcriptional variations in kidney tissues, (b) morphological changes in the kidneys, (c) changes in white and red blood cell count as well as blood levels of urea, and (d) changes in renal function using 99mTc-DTPA/99mTc-DMSA scintigraphy. Results In general, the highest number of differentially regulated transcripts was observed at 12 months after administration. The Cdkn1a, C3, Dbp, Lcn2, and Per2 genes displayed a distinct dose-dependent regulation, with increased expression level with increasing absorbed dose. Ifng, Tnf, and Il1B were identified as primary up-stream regulators of the recurrently regulated transcripts. Furthermore, previously proposed biomarkers for kidney injury and radiation damage were also observed. The functional investigation revealed reduced excretion of 99mTc-DTPA after 150 MBq, an increased uptake of 99mTc-DMSA at all dose levels compared with the controls, and markedly increased urea level in blood after 150 MBq at 12 months. Conclusion Distinct dose-response relationships were found for several of the regulated transcripts. The Cdkn1a, Dbp, Lcn2, and Per2 genes are proposed as biomarkers for 177Lu-octreotate exposure of kidney. Correlations to functional and morphological effects further confirm

  10. Effect of co-administration of Angelicae gigantis radix and Lithospermi radix on rat hepatic injury induced by carbon tetrachloride

    PubMed Central

    Lim, Chi-Yeon; Kim, Bu-Yeo; Lim, Se-Hyun; Cho, Su-In

    2015-01-01

    Background: Co-administration of Angelicae gigantis radix (AGR) and Lithospermi radix (LR) has been commonly applied to patients to treat cardiac and hepatic disorders. Individual bioactivities of these herbal medicines have been widely investigated, but the hepatoprotective effects of co-treatment of AGR and LR have yet to be clarified. Objective: The present study investigated the protective effects of extracts of AGR and LR on carbon tetrachloride (CCl4) induced hepatic injury. Materials and Methods: In this study, we measured the hepatoprotective activity of individual and co-treatment of the two herbal medicines on hepatic injury induced by CCl4 by measuring different biochemical parameters such as serum aspartate aminotransaminase (AST) and serum alanine aminotransaminase (ALT). Microarray technology also used to compare ontological difference with individual and co-treatment of these two. Results: Combined treatment with AGR and LR (AGR + LR) decreased AST and ALT level in serum which demonstrate hepatoprotective effect of the therapy. When the effect of AGR and LR according to treatment conditions was measured, co-treatment showed the most prominent effect on hepatic injury by CCl4 rather than individual treatment condition. We further defined gene set that could be the molecular target of herbal effect on hepatic injury by CCl4 using bioinformatical analysis of interaction network. Highly recovered genes by treating AGR + LR play significant roles in response to hepatic injury induced by CCl4. Conclusion: Combined treatment with AGR and LR showed synergistic protective effects on the CCl4-induced rat hepatic tissue injury. PMID:25829781

  11. Adolescent cocaine self-administration induces habit behavior in adulthood: sex differences and structural consequences.

    PubMed

    DePoy, L M; Allen, A G; Gourley, S L

    2016-01-01

    Adolescent cocaine use increases the likelihood of drug abuse and addiction in adulthood, and etiological factors may include a cocaine-induced bias towards so-called 'reward-seeking' habits. To determine whether adolescent cocaine exposure indeed impacts decision-making strategies in adulthood, we trained adolescent mice to orally self-administer cocaine. In adulthood, males with a history of escalating self-administration developed a bias towards habit-based behaviors. In contrast, escalating females did not develop habit biases; rather, low response rates were associated with later behavioral inflexibility, independent of cocaine dose. We focused the rest of our report on understanding how individual differences in young-adolescent females predicted long-term behavioral outcomes. Low, 'stable' cocaine-reinforced response rates during adolescence were associated with cocaine-conditioned object preference and enlarged dendritic spine head size in the medial (prelimbic) prefrontal cortex in adulthood. Meanwhile, cocaine resilience was associated with enlarged spine heads in deep-layer orbitofrontal cortex. Re-exposure to the cocaine-associated context in adulthood energized responding in 'stable responders', which could then be reduced by the GABAB agonist baclofen and the putative tyrosine receptor kinase B (trkB) agonist, 7,8-dihydroxyflavone. Together, our findings highlight resilience to cocaine-induced habits in females relative to males when intake escalates. However, failures in instrumental conditioning in adolescent females may precipitate reward-seeking behaviors in adulthood, particularly in the context of cocaine exposure. PMID:27576164

  12. Adolescent cocaine self-administration induces habit behavior in adulthood: sex differences and structural consequences

    PubMed Central

    DePoy, L M; Allen, A G; Gourley, S L

    2016-01-01

    Adolescent cocaine use increases the likelihood of drug abuse and addiction in adulthood, and etiological factors may include a cocaine-induced bias towards so-called ‘reward-seeking' habits. To determine whether adolescent cocaine exposure indeed impacts decision-making strategies in adulthood, we trained adolescent mice to orally self-administer cocaine. In adulthood, males with a history of escalating self-administration developed a bias towards habit-based behaviors. In contrast, escalating females did not develop habit biases; rather, low response rates were associated with later behavioral inflexibility, independent of cocaine dose. We focused the rest of our report on understanding how individual differences in young-adolescent females predicted long-term behavioral outcomes. Low, ‘stable' cocaine-reinforced response rates during adolescence were associated with cocaine-conditioned object preference and enlarged dendritic spine head size in the medial (prelimbic) prefrontal cortex in adulthood. Meanwhile, cocaine resilience was associated with enlarged spine heads in deep-layer orbitofrontal cortex. Re-exposure to the cocaine-associated context in adulthood energized responding in ‘stable responders', which could then be reduced by the GABAB agonist baclofen and the putative tyrosine receptor kinase B (trkB) agonist, 7,8-dihydroxyflavone. Together, our findings highlight resilience to cocaine-induced habits in females relative to males when intake escalates. However, failures in instrumental conditioning in adolescent females may precipitate reward-seeking behaviors in adulthood, particularly in the context of cocaine exposure. PMID:27576164

  13. Systemic Administration of the TRPV3 Ion Channel Agonist Carvacrol Induces Hypothermia in Conscious Rodents

    PubMed Central

    Feketa, Viktor V.; Marrelli, Sean P.

    2015-01-01

    Therapeutic hypothermia is a promising new strategy for neuroprotection. However, the methods for safe and effective hypothermia induction in conscious patients are lacking. The current study explored the Transient Receptor Potential Vanilloid 3 (TRPV3) channel activation by the agonist carvacrol as a potential hypothermic strategy. It was found that carvacrol lowers core temperature after intraperitoneal and intravenous administration in mice and rats. However, the hypothermic effect at safe doses was modest, while higher intravenous doses of carvacrol induced a pronounced drop in blood pressure and substantial toxicity. Experiments on the mechanism of the hypothermic effect in mice revealed that it was associated with a decrease in whole-body heat generation, but not with a change in cold-seeking behaviors. In addition, the hypothermic effect was lost at cold ambient temperature. Our findings suggest that although TRPV3 agonism induces hypothermia in rodents, it may have a limited potential as a novel pharmacological method for induction of hypothermia in conscious patients due to suboptimal effectiveness and high toxicity. PMID:26528923

  14. Significant increase of salivary testosterone levels after single therapeutic transdermal administration of testosterone: suitability as a potential screening parameter in doping control.

    PubMed

    Thieme, Detlef; Rautenberg, Claudia; Grosse, Joachim; Schoenfelder, Martin

    2013-01-01

    The legally defensible proof of the abuse of endogenous steroids in sports is currently based on carbon isotope ratio mass spectrometry (IRMS), i.e. a comparison between (13)C/(12)C ratios of diagnostic precursors and metabolites of testosterone. The application of this technique requires a chromatographic baseline separation of respective steroids prior to IRMS detection and hence laborious sample pre-processing of the urinary steroid extracts including clean up by solid-phase extraction and/or liquid chromatography. Consequently, an efficient pre-selection of suspicious control urine samples is essential for appropriate follow up confirmation by IRMS and effective doping control. Two single transdermal administration studies of testosterone (50 mg Testogel® and Testopatch® at 3.8 mg in 16 h, respectively) were conducted and resulting profiles of salivary testosterone and urinary steroid profiles and corresponding carbon isotope ratios were determined. Conventional doping control markers (testosterone/epitestosterone ratio, threshold concentrations of androsterone, etiocholanolone, or androstanediols) did not approach or exceed critical thresholds. In contrast to these moderate variations, the testosterone concentration in oral fluid increased from basal values (30-142 pg/mg) to peak concentrations above 1000 pg/mg. It is likely that this significant increase in oral fluid is due to a pulsatile elevation of free (protein unbound) circulating testosterone after transdermal administration and may be assumed to represent a more diagnostic marker for transdermal testosterone administration.

  15. Chronic nandrolone administration induces dysfunction of the reward pathway in rats.

    PubMed

    Zotti, Margherita; Tucci, Paolo; Colaianna, Marilena; Morgese, Maria Grazia; Mhillaj, Emanuela; Schiavone, Stefania; Scaccianoce, Sergio; Cuomo, Vincenzo; Trabace, Luigia

    2014-01-01

    Data in animal models and surveys in humans have revealed psychiatric complications of long-term anabolic androgenic steroid abuse. However, the neurobiochemical mechanisms behind the observed behavioral changes are poorly understood. The aim of the present study was to investigate the effects of nandrolone decanoate on emotional behavior and neurochemical brain alterations in gonadally intact male rats. The behavioral reactivity to the elevated plus maze and the social interaction test was used to assess anxiety-related symptoms, and the sucrose preference test was used to evaluate anhedonia. Dopaminergic, serotonergic and noradrenergic transmissions were also evaluated in selected brain areas. The chronic administration of nandrolone, at 5 mg kg(-1) injected daily for 4 weeks, induced the loss of sweet taste preference, a sign of anhedonia and dysfunction of the reward pathway. The behavioral outcomes were accompanied by reductions in the dopamine, serotonin and noradrenaline contents in the nucleus accumbens. Alterations in the time spent in the open arms and in the social interaction test were not found, suggesting that nandrolone did not induce an anxiogenic profile. No differences were revealed between the experimental groups in the amygdala in terms of the neurotransmitters measured. Our data suggest that nandrolone-treated rats have a depressive, but not anxiogenic-like, profile, accompanied by brain region-dependent changes in dopaminergic, serotonergic and noradrenergic neurotransmission. As anabolic androgenic steroid dependence is plausibly the major form of worldwide substance dependence that remains largely unexplored, it should be highlighted that our data could contribute to a better understanding of the altered rewards induced by nandrolone treatment and to the development of appropriate treatments.

  16. Intratracheal Administration of Prostacyclin Analogue–incorporated Nanoparticles Ameliorates the Development of Monocrotaline and Sugen-Hypoxia-induced Pulmonary Arterial Hypertension

    PubMed Central

    Matsubara, Hiromi; Kondo, Megumi; Miura, Daiji; Matoba, Tetsuya; Egashira, Kensuke; Ito, Hiroshi

    2016-01-01

    Abstract: Nanoparticles (NPs) have been used as novel drug delivery systems. Drug-incorporated NPs for local delivery might optimize the efficacy and minimize the side effects of drugs. Intravenous prostacyclin improves long-term survival in patients with pulmonary arterial hypertension (PAH), but it causes serious side effects such as catheter-related infections. We investigated the efficacy and safety of intratracheal administration of a prostacyclin analogue, beraprost (BPS), incorporated NPs in Sugen-hypoxia-normoxia and monocrotaline rat models of PAH and in human PAH pulmonary arterial smooth muscle cells (PASMCs). After a single administration, BPS NPs significantly decreased right ventricular pressure, right ventricular hypertrophy, and pulmonary artery muscularization in the 2 rat models. BPS NPs significantly improved the survival rate in the monocrotaline rat model. No infiltration of inflammatory cells, hemorrhage, or fibrosis was found in the liver, kidney, spleen, and heart after the administration of BPS NPs. No liver or kidney dysfunction was found in the blood examinations. BPS and BPS NPs significantly inhibited the proliferation of human PAH PASMCs after 24 hours of treatment. BPS NPs significantly continued to inhibit the proliferation of human PAH PASMCs at 24 hours after the removal of BPS NPs. BPS NPs significantly induced apoptosis in PAH PASMCs compared to that in non-PAH PASMCs. Intratracheal administration of BPS NPs ameliorates pulmonary hypertension in PAH rat models by a sustained antiproliferative effect and a proapoptotic effect on PAH PASMCs. PMID:26745002

  17. Repeated administration of aripiprazole produces a sensitization effect in the suppression of avoidance responding and phencyclidine-induced hyperlocomotion and increases D2 receptor-mediated behavioral function.

    PubMed

    Gao, Jun; Qin, Rongyin; Li, Ming

    2015-04-01

    The present study investigated how repeated administration of aripiprazole (a novel antipsychotic drug) alters its behavioral effects in two behavioral tests of antipsychotic activity and whether this alteration is correlated with an increase in dopamine D2 receptor function. Male adult Sprague-Dawley rats were first repeatedly tested with aripiprazole (3, 10 and 30 mg/kg, subcutaneously (sc)) or vehicle in a conditioned avoidance response (CAR) test or a phencyclidine (PCP) (3.20 mg/kg, sc)-induced hyperlocomotion test daily for five consecutive days. After 2-3 days of drug-free retraining or resting, all rats were then challenged with aripiprazole (1.5 or 3.0 mg/kg, sc). Repeated administration of aripiprazole progressively increased its inhibition of avoidance responding and PCP-induced hyperlocomotion. More importantly, rats previously treated with aripiprazole showed significantly lower avoidance response and lower PCP-induced hyperlocomotion than those previously treated with vehicle in the challenge tests. An increased sensitivity to quinpirole (a selective D2/3 agonist) in prior aripiprazole-treated rats was also found in the quinpirole-induced hyperlocomotion test, suggesting an enhanced D2/3-mediated function. These findings suggest that aripiprazole, despite its distinct receptor mechanisms of action, induces a sensitization effect similar to those induced by other antipsychotic drugs and this effect may be partially mediated by brain plasticity involving D2/3 receptor systems.

  18. Efficacy of preanesthetic intramuscular administration of ephedrine for prevention of anesthesia-induced hypotension in cats and dogs.

    PubMed

    Egger, Christine; McCrackin, Mary-Ann; Hofmeister, Erik; Touzot-Jourde, Gwenola; Rohrbach, Bart

    2009-02-01

    To determine if the preanesthetic administration of ephedrine would prevent anesthesia-induced hypotension in dogs and cats, 10 cats were anesthetized with acepromazine, butorphanol, ketamine, and isoflurane, and 8 dogs were anesthetized with acepromazine, morphine, propofol, and halothane. Cats received ephedrine or saline 10 minutes after premedication. Dogs received ephedrine or saline at the time of premedication. Systolic arterial blood pressure, respiratory rate, heart rate, end-tidal CO2, O2 saturation, cardiac rhythm, and rectal temperature were recorded.The systolic arterial pressure in cats receiving saline was significantly lower than baseline at 10 minutes after premedication, and systolic arterial pressure was < 80 mmHg for the duration of anesthesia. In cats receiving ephedrine, the systolic arterial pressure was significantly lower than baseline for the duration of anesthesia, but systolic arterial pressure was not < 80 mmHg until 25 min after induction. In dogs, systolic arterial pressure was significantly lower than baseline by 5 and 40 min after pre-medication in dogs receiving saline and ephedrine, respectively. There was no difference in heart rate, respiratory rate, end-tidal CO2, rectal temperature, O2 saturation, or cardiac rhythm among treatment groups. Prophylactic ephedrine delayed, but did not prevent, the onset of hypotension.

  19. Attenuation of Biochemical Parameters in Streptozotocin-induced Diabetic Rats by Oral Administration of Extracts and Fractions of Cephalotaxus sinensis

    PubMed Central

    Saeed, Muhammad K.; Deng, Yulin; Dai, Rongji

    2008-01-01

    Cephalotaxus sinensis (C. sinensis) large size, evergreen tree common in China and utilized for numerous effective pharmacological applications in Chinese traditional medicine. The hepato-renal effects of C. sinensis were evaluated in vivo using Streptozotocin (STZ)-induced diabetic rats as an tentative model. Animals were orally treated with 80% EtOH extract (aq.EE), H2O extract (WtE) and ethylacetate (EaF)/butanol fractions (BtF) of C. sinensis (200 mg/kg, b.w.) for 28 days whereas control received vehicle merely. The degree of fortification was measured by using biochemical parameters like serum transaminases (ALT and AST), alkaline phosphatase (ALP), creatinine, urea and urine sugar. Meanwhile, the histopathological studies were conducted out to support the above parameters. Administration of C. sinensis aq.EE/BtF (p<0.05) and EaF (p<0.01) patently prevented STZ-induced elevation levels of serum ALT, AST, ALP, creatinine, urea, urine sugar and increase body weight respectively, which were comparable with the standard drug tolbutamide, while WtE did not show any significant effect (p>0.05). Phytochemical studies revealed the presence of saponins, terpenes, sterols and flavonoids in C. sinensis which could be responsible for the possible hepato-renal protective action. The results sustain the fact that the extract/fractions of C. sinensis have an immense potential to be developed further into a phytomedicine. PMID:18231626

  20. Lack of aldehyde dehydrogenase ameliorates oxidative stress induced by single-dose ethanol administration in mouse liver.

    PubMed

    Matsumoto, Akiko; Ichiba, Masayoshi; Horita, Mikako; Yamashita, Zenko; Takahashi, Tatsuya; Isse, Toyohi; Oyama, Tsunehiro; Kawamoto, Toshihiro; Tomokuni, Katsumaro

    2007-02-01

    Polymorphism of aldehyde dehydrogenase 2 (ALDH2), denoted ALDH2*2, is far more common in East Asian countries. Acetaldehyde, an intermediate metabolite of ethanol, is metabolized very slowly in people who have ALDH2*2, as the mutated ALDH2 lacks acetaldehyde metabolizing activity. On the other hand, it is well established that metabolism of ethanol causes oxidative stress in liver tissue. To examine the consequences of this polymorphism on ethanol-induced oxidative stress in liver tissue, we conducted a study using Aldh2 knockout mice. Aldh2+/+ and Aldh2-/- mice were orally administered ethanol at a dose of 5g/kg body weight. Levels of malondialdehyde, an indicator of oxidative stress, and glutathione, a key antioxidant, in liver tissue were analyzed 0-24h after administration. Levels of malondialdehyde were significantly lower in Aldh2-/- mice than in Aldh2+/+ mice at 12h after injection, while levels of glutathione were higher in Aldh2-/- mice than in Aldh2+/+ mice at 6 and 12h after injection. Our results suggest that a lack of ALDH ameliorates ethanol-induced oxidative stress in liver tissue. PMID:17452299

  1. Chronic administration of troxerutin protects mouse kidney against D-galactose-induced oxidative DNA damage.

    PubMed

    Liu, Chan-Min; Ma, Jie-Qiong; Lou, Yao

    2010-10-01

    Troxerutin, a natural bioflavonoid, has been reported to have many benefits and medicinal properties. In this study, we evaluated the protective effect of troxerutin against D-gal-induced oxidative DNA damage in mouse kidney, and explored the potential mechanism of its action. Our data showed that troxerutin significantly decreased levels of urea, uric acid and creatinine in serum and the renal histological injury in D-gal-treated mice. Troxerutin markedly restored Cu/Zn-SOD, CAT and GPx activities in the kidney of D-gal-treated mouse. Furthermore, the increase of 8-hydroxydeoxyguanosine (a marker of oxidative DNA damage) induced by d-gal was effectively suppressed by troxerutin. Internucleosomal DNA ladder fragmentation and the number of terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end-labeling (TUNEL)-positive cells in D-gal-treated mice were inhibited by troxerutin, which might be attributed to its antioxidant property by decreasing activities of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) and levels of reactive oxygen species (ROS). In conclusion, these results suggested that troxerutin could protect the mouse kidney against D-gal-induced injury by improving renal function, attenuating histopathologic changes, reducing ROS production, renewing the activities of antioxidant enzymes and decreasing DNA oxidative damage. This study provided novel insights into the protective mechanisms of troxerutin in D-gal-induced kidney injury.

  2. Significant response to lacosamide in a patient with severe chemotherapy-induced peripheral neuropathy.

    PubMed

    Ibrahim, Samar A; Albany, Zhanna; Albany, Constantine

    2015-05-01

    Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting toxicity of potentially curative cancer therapy regimens. Cisplatin is the class of chemotherapy agent that has a broad spectrum of activity against several solid tumors, but it induces sensory neuropathy of upper and lower extremities. Cisplatin-induced peripheral neuropathy is usually in a "gloves and socks" distribution that can persist for months or years after completion of chemotherapy treatment. If the pain is severe, it affects the patient's long-term quality of life and can potentially result in chemotherapy dose reduction or treatment discontinuation. The mechanism of CIPN is not well understood, and a number of pathophysiological mechanisms have been proposed to explain the phenomenon. Although many therapies have been investigated for the prevention or treatment of CIPN, there is currently no accepted proven therapy. Here we report a case in which lacosamide alleviated painful CIPN symptoms. Lacosamide is an anticonvulsant drug that blocks the voltage-gated sodium channels in the neurons and may also be a promising novel candidate for the prevention and treatment of chemotherapy-induced peripheral neuropathy. Preclinical data support the role of lacosamide protective effect in a rat model of chemotherapy-induced neuropathy, randomized clinical trial is needed.

  3. Acute Morphine Administration Reduces Cell-Mediated Immunity and Induces Reactivation of Latent Herpes Simplex Virus Type 1 in BALB/c Mice

    PubMed Central

    Mojadadi, Shafi; Jamali, Abbas; Khansarinejad, Behzad; Soleimanjahi, Hoorieh; Bamdad, Taravat

    2009-01-01

    Acute morphine administration is known to alter the course of herpes simplex virus infection. In this study, the effect of acute morphine administration on the reactivation of latent herpes was investigated in a mouse model. Because of the important role of cytolytic T lymphocyte (CTL) activity in the inhibition of herpes simplex virus type 1 (HSV-1) reactivation, the effect of acute morphine administration on CTL responses was also evaluated. Furthermore, lymphocyte proliferation and IFN-γ production were evaluated for their roles in the induction of the CTL response. The findings showed that acute morphine administration significantly reduced CTL responses, lymphocyte proliferation, and IFN-γ production. Furthermore, acute morphine administration has been shown to reactivate latent HSV-1. Previous studies have shown that cellular immune responses have important roles in the inhibition of HSV reactivation. These findings suggest that suppression of a portion of the cellular immune response after acute morphine administration may constitute one part of the mechanism that induces HSV reactivation. PMID:19403060

  4. Damage of vascular endothelial barrier induced by explosive blast and its clinical significance.

    PubMed

    Wang, Jian-Min; Chen, Jing

    2016-06-01

    In recent years, injuries induced by explosive blast have got more and more attention owing to weapon development and frequent terrorist activities. Tear, bleeding and edema of tissues and organs are the main manifestations of blast shock wave damage. Vascular endothelial barrier is the main defense of tissues and organs' integrity. This article aims to discuss possible mechanisms of endothelial barrier damage induced by explosive blast and main manifestations of blood brain barrier, bloodeair barrier, and intestinal vascular barrier impairments. In addition, the main regulatory factors of vascular permeability are also summarized so as to provide theoretical basis for prevention and cure of vascular endothelial barrier damage resulting from explosive blast. PMID:27321288

  5. Damage of vascular endothelial barrier induced by explosive blast and its clinical significance.

    PubMed

    Wang, Jian-Min; Chen, Jing

    2016-06-01

    In recent years, injuries induced by explosive blast have got more and more attention owing to weapon development and frequent terrorist activities. Tear, bleeding and edema of tissues and organs are the main manifestations of blast shock wave damage. Vascular endothelial barrier is the main defense of tissues and organs' integrity. This article aims to discuss possible mechanisms of endothelial barrier damage induced by explosive blast and main manifestations of blood brain barrier, bloodeair barrier, and intestinal vascular barrier impairments. In addition, the main regulatory factors of vascular permeability are also summarized so as to provide theoretical basis for prevention and cure of vascular endothelial barrier damage resulting from explosive blast.

  6. Chronic administration of THC prevents the behavioral effects of intermittent adolescent MDMA administration and attenuates MDMA-induced hyperthermia and neurotoxicity in rats.

    PubMed

    Shen, Erica Y; Ali, Syed F; Meyer, Jerrold S

    2011-12-01

    Most recreational users of 3, 4-methylenedioxymethamphetamine (MDMA or "ecstasy") also take cannabis, in part because cannabis can reduce the dysphoric symptoms of the ecstasy come-down such as agitation and insomnia. Although previous animal studies have examined the acute effects of co-administering MDMA and Δ(9)-tetrahydrocannabinol (THC), which is the major psychoactive ingredient in cannabis, research on chronic exposure to this drug combination is lacking. Therefore, the present study was conducted to investigate the effects of chronic adolescent administration of both THC and MDMA on behavior and on regional serotonin transporter (SERT) binding and serotonin (5-HT) concentrations as indices of serotonergic system integrity. Male Sprague-Dawley rats were divided into four drug administration groups: (1) MDMA alone, (2) THC alone, (3) MDMA plus THC, and (4) vehicle controls. MDMA (2 × 10 mg/kg × 4 h) was administered every fifth day from postnatal day (PD) 35 to 60 to simulate intermittent recreational ecstasy use, whereas THC (5mg/kg) was given once daily over the same time period to simulate heavy cannabis use. THC unexpectedly produced a modest hyperthermic effect when administered alone, but in animals co-treated with both THC and MDMA, there was an attenuation of MDMA-induced hyperthermia on dosing days. Subsequent testing conducted after a drug washout period revealed that THC reduced MDMA-related behavioral changes in the emergence and social interaction tests of anxiety-like behavior and also blunted the MDMA-induced decrease in exploratory behavior in the hole-board test. THC additionally attenuated MDMA -induced decreases in 5-HT levels and in SERT binding in the frontal cortex, parietal cortex, and striatum, but not in the hippocampus. These results suggest that chronic co-administration of THC during adolescence can provide some protection against various adverse physiological, behavioral, and neurochemical effects produced by MDMA. PMID

  7. Dopamine dynamics associated with, and resulting from, schedule-induced alcohol self-administration: Analyses in dopamine transporter knockout mice

    PubMed Central

    Mittleman, Guy; Call, Stanford B.; Cockroft, Jody L.; Goldowitz, Dan; Matthews, Douglas B.; Blaha, Charles D.

    2011-01-01

    Preclinical and clinical evidence suggest an association between alcoholism and the primary regulator of extracellular dopamine concentrations, the dopamine transporter (DAT). However, the nature of this association is unclear. We determined if ten days of voluntary alcohol self-administration followed by withdrawal could directly alter DAT function, or if genetically-mediated changes in DAT function and/or availability could influence vulnerability to alcohol abuse. Heterozygous (DAT+/-) and homozygous mutant (DAT-/-) and wildtype (DAT+/+) mice were allowed to consume 5% alcohol in a schedule-induced polydipsia (SIP) task. In vivo fixed potential amperometry in anesthetized mice was used to (1) identify functional characteristics of mesoaccumbens dopamine neurons related to genotype, including dopamine autoreceptor (DAR) sensitivity, DAT efficiency, and DAT capacity, (2) determine if any of these characteristics correlated with alcohol drinking observed in DAT+/+ and DAT+/- animals, and (3) determine if SIP-alcohol self-administration altered DAR sensitivity, DAT efficiency, and DAT capacity by comparing these characteristics in wildtype (DAT+/+) mice that were SIP-alcohol naïve, with those that had undergone SIP-alcohol testing. DAT-/- mice consumed significantly less alcohol during testing and this behavioral difference was related to significant differences in DAR sensitivity, DAT efficiency, and DAT capacity. These functional characteristics were correlated to varying degrees with g/kg alcohol consumption in DAT+/+ and DAT+/- mice. DAR sensitivity was consistently reduced and DAT efficiency was enhanced in SIP-alcohol experienced DAT+/+ mice in comparison to naïve animals. These results indicate that DAR sensitivity is reduced by SIP-alcohol consumption and that DAT efficiency is modified by genotype as well as SIP-alcohol exposure. DAT capacity appeared to be strictly associated with SIP-alcohol consumption. PMID:21354763

  8. Mechanism of nephrotoxicity induced by repeated administration of cadmium chloride in rats

    SciTech Connect

    Sudo, Jun-ichi; Hayashi, Taiji; Kimura, Shin-ichi

    1996-07-01

    To explore the mechanism of Cd nephrotoxicity, CdCl{sub 2} was subcutaneously injected to rats, at 3 mg Cd/kg body weight once a day, for 8 d. In the liver, Cd bound to metallothioneins (MTs-Cd) rose from d 1 after the initiation of CdCl{sub 2} administration, and reached a plateau after the administration ceased. In the plasma, MTs-Cd rose from d 4, peaked on d 8, and gradually fell thereafter. In the kidney`s leucine aminopeptidase (LAP) and N-acetyl {beta}-D-glucosaminidase (NAG) fell during d 6-20, and Cd bound to cellular membranes (Mem-Cd) rose from d 1 and reached a plateau during d 6-20. The Mem-Cd levels were significantly correlated with the reduction in the LAP and NAG activity; the values of MTs-Cd plus Mem-Cd were almost equivalent to those of total Cd. These findings showed that the hepatic synthesis of MTs-Cd occurred followed by its release into plasma; the extent of renal injury was aggravated as the plasma level of MTs-Cd rose; and a greater part of the renal Cd distributed intracellularly as the MTs-binding form, while the residual Cd distributed as the cellular membrane-binding form. Also, it was suggested that Cd that occurred as the cullular membrane-binding form in the kidneys was involved in manifestation of renal injury. 29 refs., 9 figs., 1 tab.

  9. Endomembrane Ca2+ -ATPases play significant role in virus-induced adaptation to oxidative stress

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In our recently published paper (Plant Cell Environ 34: 406-417) we have reported a phenomenon of Potato Virus X (PVX) - induced cross tolerance to oxidative stress in Nicotiana benthamiana plants and showed a critical role of plasma membrane Ca2+/H+ exchangers in this process. The current study fol...

  10. Adaptive significance of gall formation for a gall-inducing aphids on Japanese elm trees.

    PubMed

    Takei, Mami; Yoshida, Sayaka; Kawai, Takashi; Hasegawa, Morifumi; Suzuki, Yoshihito

    2015-01-01

    Insect galls are abnormal plant tissues induced by external stimuli from parasitizing insects. It has been suggested that the stimuli include phytohormones such as auxin and cytokinins produced by the insects. In our study on the role of hormones in gall induction by the aphid Tetraneura nigriabdominalis, it was found that feedback regulation related to auxin and cytokinin activity is absent in gall tissues, even though the aphids contain higher concentrations of those phytohormones than do plant tissues. Moreover, jasmonic acid signaling appears to be compromised in gall tissue, and consequently, the production of volatile organic compounds, which are a typical defense response of host plants to herbivory, is diminished. These findings suggest that these traits of the gall tissue benefit aphids, because the gall tissue is highly sensitive to auxin and cytokinin, which induce and maintain it. The induced defenses against aphid feeding are also compromised. The abnormal responsiveness to phytohormones is regarded as a new type of extended phenotype of gall-inducing insects. PMID:25437243

  11. Adaptive significance of gall formation for a gall-inducing aphids on Japanese elm trees.

    PubMed

    Takei, Mami; Yoshida, Sayaka; Kawai, Takashi; Hasegawa, Morifumi; Suzuki, Yoshihito

    2015-01-01

    Insect galls are abnormal plant tissues induced by external stimuli from parasitizing insects. It has been suggested that the stimuli include phytohormones such as auxin and cytokinins produced by the insects. In our study on the role of hormones in gall induction by the aphid Tetraneura nigriabdominalis, it was found that feedback regulation related to auxin and cytokinin activity is absent in gall tissues, even though the aphids contain higher concentrations of those phytohormones than do plant tissues. Moreover, jasmonic acid signaling appears to be compromised in gall tissue, and consequently, the production of volatile organic compounds, which are a typical defense response of host plants to herbivory, is diminished. These findings suggest that these traits of the gall tissue benefit aphids, because the gall tissue is highly sensitive to auxin and cytokinin, which induce and maintain it. The induced defenses against aphid feeding are also compromised. The abnormal responsiveness to phytohormones is regarded as a new type of extended phenotype of gall-inducing insects.

  12. Voluntary exercise does not ameliorate spatial learning and memory deficits induced by chronic administration of nandrolone decanoate in rats.

    PubMed

    Tanehkar, Fatemeh; Rashidy-Pour, Ali; Vafaei, Abbas Ali; Sameni, Hamid Reza; Haghighi, Saeed; Miladi-Gorji, Hossien; Motamedi, Fereshteh; Akhavan, Maziar Mohammad; Bavarsad, Kowsar

    2013-01-01

    Chronic exposure to the anabolic androgenic steroids (AAS) nandrolone decanoate (ND) in supra-physiological doses is associated with learning and memory impairments. Given the well-known beneficial effects of voluntary exercise on cognitive functions, we examined whether voluntary exercise would improve the cognitive deficits induced by chronic administration of ND. We also investigated the effects of ND and voluntary exercise on hippocampal BDNF levels. The rats were randomly distributed into 4 experimental groups: the vehicle-sedentary group, the ND-sedentary group, the vehicle-exercise group, and the ND-exercise group. The vehicle-exercise and the ND-exercise groups were allowed to freely exercise in a running wheel for 15 days. The vehicle-sedentary and the ND-sedentary groups were kept sedentary for the same period. Vehicle or ND injections were started 14 days prior to the voluntary exercise and continued throughout the 15 days of voluntary exercise. After the 15-day period, the rats were trained and tested on a water maze spatial task using four trials per day for 5 consecutive days followed by a probe trial two days later. Exercise significantly improved performance during both the training and retention of the water maze task, and enhanced hippocampal BDNF. ND impaired spatial learning and memory, and this effect was not rescued by exercise. ND also potentiated the exercise-induced increase in hippocampal BDNF levels. These results seem to indicate that voluntary exercise is unable to improve the disruption of cognitive functions by chronic ND. Moreover, increased levels of BDNF may play a role in ND-induced impairments in learning and memory. The harmful effects of ND and other AAS on learning and memory should be taken into account when athletes decide to use AAS for performance or body image improvement.

  13. Intrahippocampal Administration of Ibotenic Acid Induced Cholinergic Dysfunction via NR2A/NR2B Expression: Implications of Resveratrol against Alzheimer Disease Pathophysiology

    PubMed Central

    Karthick, Chennakesavan; Periyasamy, Sabapathy; Jayachandran, Kesavan S.; Anusuyadevi, Muthuswamy

    2016-01-01

    Although several drugs revealed moderate amelioration of symptoms, none of them have sufficient potency to prevent or reverse the progression toward Alzheimer's disease (AD) pathology. Resveratrol (RSV), a polyphenolic compound has shown an outstanding therapeutic effect on a broad spectrum of diseases like age-associated neurodegeneration, inflammation etc. The present study was thus conducted to assess the therapeutic efficacy of RSV in ameliorating the deleterious effects of Ibotenic acid (IBO) in male Wistar rats. Stereotactic intrahippocampal administration of IBO (5 μg/μl) lesioned rats impairs cholinergic transmission, learning and memory performance that is rather related to AD and thus chosen as a suitable model to understand the drug efficacy in preventing AD pathophysiology. Since IBO is an agonist of glutamate, it is expected to exhibit an excitotoxic effect by altering glutamatergic receptors like NMDA receptor. The current study displayed significant alterations in the mRNA expression of NR2A and NR2B subunits of NMDA receptors, and further it is surprising to note that cholinergic receptors decreased in expression particularly α7-nAChR with increased m1AChR. RSV administration (20 mg/kg body weight, i.p.) significantly reduced these changes in IBO induced rats. Glutamatergic and cholinergic receptor alterations were associated with significant changes in the behavioral parameters of rats induced by IBO. While RSV improved spatial learning performance, attenuated immobility, and improvised open field activity in IBO induced rats. NR2B activation in the present study might mediate cell death through oxidative stress that form the basis of abnormal behavioral pattern in IBO induced rats. Interestingly, RSV that could efficiently encounter oxidative stress have significantly decreased stress markers viz., nitrite, PCO, and MDA levels by enhancing antioxidant status. Histopathological analysis displayed significant reduction in the hippocampal

  14. Effects of Administration of Amlodipine and Lacidipine on Inflammation-Induced Bone Loss in the Ovariectomized Rat.

    PubMed

    Karakus, Emre; Halici, Zekai; Albayrak, Abdulmecit; Bayir, Yasin; Demirci, Elif; Aydin, Ali; Ozturk-Karagoz, Berna; Cadirci, Elif; Ayan, Arif Kursat; Sahin, Ali; Unal, Deniz

    2016-02-01

    This study was performed to evaluate the possible protective effect of two calcium channel blocker's "lacidipine (LAC) and amlodipine (AML)" on bone metabolism in an experimental ovariectomized and inflammation-induced osteoporosis rat model (OVXinf). For the purpose of this study, the rats were divided into eight groups, each containing eight rats: sham-operated control (group 1, SH), sham + inflammation (group 2, SHinf), ovariectomy (group 3, OVX), ovariectomy + inflammation (group 4, OVXinf), ovariectomy + LAC 4 mg/kg (group 5, OVX + LAC), ovariectomy + inflammation + LAC 4 mg/kg (group 6, OVXinf + LAC), ovariectomy + AML 5 mg/kg (group 7, OVX + AML), ovariectomy + inflammation + AML 5 mg/kg (group 8, OVXinf + AML). The levels of osteocalcin and osteopontin decreased in OVXinf + LAC and OVXinf + AML groups. The serum levels of TNF-α, IL-1β, and IL-6 were increased significantly in the OVXinf rats compared with the SH group. Gene expression levels of the osteogenic factor runt-related transcription factor 2 (Runx2) and type I collagen 1A1 (Col1A1) significantly decreased in the OVXinf group, when compared with the control group. AML or LAC administrations increased the levels of Runx2 and Col1A1. These results suggest that amlodipine and lacidipine may be a novel therapeutic target for radical osteoporosis treatment in hypertensive patients.

  15. Brief report: the effect of suggestion on unpleasant dreams induced by ketamine administration.

    PubMed

    Cheong, Soon Ho; Lee, Kun Moo; Lim, Se Hun; Cho, Kwang Rae; Kim, Myoung Hun; Ko, Myoung Jin; Shim, Joo Cheol; Oh, Min Kyung; Kim, Yong Han; Lee, Sang Eun

    2011-05-01

    The use of ketamine may be associated with the recall of unpleasant dreams after sedation. We hypothesized that a positive suggestion before sedation could reduce the incidence of ketamine-induced unpleasant dreams. To test this hypothesis, we randomized 100 patients receiving sedation with ketamine for their procedure into 2 groups with 1 group having an anesthesiologist provide a mood-elevating suggestion to the patient before ketamine administration (suggestion group), whereas in the control group no suggestion was provided. Patients were provided with a pleasantness/unpleasantness scale to rate "the overall mood of the dream" as very unpleasant (grade 1), quite unpleasant (grade 2), neither or mixed (grade 3), quite pleasant (grade 4), and very pleasant (grade 5). In those patients who lost consciousness, the frequencies of grades 1, 2, 3, 4, and 5 were 0%, 0%, 46%, 24%, and 30% in the suggestion group and were 6%, 2%, 70%, 12%, and 10%, respectively, in the control group (P=0.01). In the intent-to-treat population the overall frequency between groups was very similar. This study implies that when administering ketamine as part of a sedation regimen, positive suggestion may help reduce the recall of unpleasant dreaming.

  16. Bacteriophage administration significantly reduces Shigella colonization and shedding by Shigella-challenged mice without deleterious side effects and distortions in the gut microbiota

    PubMed Central

    Mai, Volker; Ukhanova, Maria; Reinhard, Mary K; Li, Manrong; Sulakvelidze, Alexander

    2015-01-01

    We used a mouse model to establish safety and efficacy of a bacteriophage cocktail, ShigActive™, in reducing fecal Shigella counts after oral challenge with a susceptible strain. Groups of inbred C57BL/6J mice challenged with Shigella sonnei strain S43-NalAcR were treated with a phage cocktail (ShigActive™) composed of 5 lytic Shigella bacteriophages and ampicillin. The treatments were administered (i) 1 h after, (ii) 3 h after, (iii) 1 h before and after, and (iv) 1 h before bacterial challenge. The treatment regimens elicited a 10- to 100-fold reduction in the CFU's of the challenge strain in fecal and cecum specimens compared to untreated control mice, (P < 0.05). ShigActiveTM treatment was at least as effective as treatment with ampicillin but had a significantly less impact on the gut microbiota. Long-term safety studies did not identify any side effects or distortions in overall gut microbiota associated with bacteriophage administration. Shigella phages may be therapeutically effective in a “classical phage therapy” approach, at least during the early stages after Shigella ingestion. Oral prophylactic “phagebiotic” administration of lytic bacteriophages may help to maintain a healthy gut microbiota by killing specifically targeted bacterial pathogens in the GI tract, without deleterious side effects and without altering the normal gut microbiota. PMID:26909243

  17. Topical Administration of Manuka Oil Prevents UV-B Irradiation-Induced Cutaneous Photoaging in Mice

    PubMed Central

    Kwon, Oh Sook; Yang, Beom Seok

    2013-01-01

    Manuka tree is indigenous to New Zealand, and its essential oil has been used as a traditional medicine to treat wounds, fever, and pain. Although there is a growing interest in the use of manuka oil for antiaging skin care products, little is known about its bioactivity. Solar ultraviolet (UV) radiation is the primary environmental factor causing skin damage and consequently premature aging. Therefore, we evaluated manuka oil for its effects against photoaging in UV-B-irradiated hairless mice. Topical application of manuka oil suppressed the UV-B-induced increase in skin thickness and wrinkle grading in a dose-dependent manner. Application of 10% manuka oil reduced the average length, depth, and % area of wrinkles significantly, and this was correlated with inhibition of loss of collagen fiber content and epidermal hyperplasia. Furthermore, we observed that manuka oil could suppress UV-B-induced skin inflammation by inhibiting the production of inflammatory cytokines. Taken together, this study provides evidence that manuka oil indeed possesses antiphotoaging activity, and this is associated with its inhibitory activity against skin inflammation induced by UV irradiation. PMID:23762170

  18. Effects of combined administration of captopril and DMSA on arsenite induced oxidative stress and blood and tissue arsenic concentration in rats.

    PubMed

    Kalia, Kiran; Narula, Gagan Deep; Kannan, G M; Flora, S J S

    2007-01-01

    We compared the therapeutic efficacy of captopril and a thiol chelating agent, meso 2,3-dimercaptosuccinic acid (DMSA) either individually or in combination against arsenite induced oxidative stress and mobilization of metal in rats. Animals were exposed to 100 ppm arsenite as sodium arsenite in drinking water for six weeks followed by treatment with DMSA (50 mg/kg, orally), captopril (50 mg/kg, intraperitoneally) either alone or in combination, once daily for 5 consecutive days. Arsenite exposure led to a significant depletion of blood delta-aminolevulinic acid dehydratase (ALAD) activity, glutathione and platelet levels while significantly increased the level of reactive oxygen species (in RBCs). Hepatic reduced glutathione (GSH) level showed a significant decrease while, thiobarbituric acid reactive substances (TBARS) levels increased on arsenite exposure indicating arsenite induced hepatic oxidative stress. Kidney GSH, GSSG, catalase and TBARS remained unchanged on arsenite exposure. Treatment with DMSA was effective in increasing ALAD activity while, captopril was ineffective when given alone. Captopril when co-administered with DMSA also provided no additional beneficial effect on blood ALAD activity but significant brought altered platelet counts back to the normal value. In contrast, administration of captopril alone provided significant beneficial effects on hepatic oxidative stress, and in combination with DMSA provided a more pronounced recovery in the TBARS level compared to the individual effect of DMSA and captopril. Renal biochemical variables remained insensitive to arsenite and any of the treatments. Interestingly, combined administration of captopril with DMSA had a remarkable effect in depleting total arsenic concentration from blood and soft tissues. These results lead us to conclude that captopril administration during chelation treatment had some beneficial effects particularly on the protection of inhibited blood ALAD activity, and depletion

  19. Thymoquinone ameliorates testicular tissue inflammation induced by chronic administration of oral sodium nitrite.

    PubMed

    Alyoussef, A; Al-Gayyar, M M H

    2016-06-01

    Although sodium nitrite has been widely used as food preservative, building bases of scientific evidence about nitrite continues to oppose the general safety in human health. Moreover, thymoquinone (TQ) has therapeutic potential as antioxidant, anti-inflammatory, antibacterial and anticancer. Therefore, we investigated the effects of both sodium nitrite and TQ on testicular tissues of rats. Forty adult male Sprague Dawley rats were used. They received either 80 mg kg(-1) sodium nitrite or 50 mg kg(-1) TQ daily for twelve weeks. Serum testosterone was measured. Testis were weighed and the testicular tissue homogenates were used for measurements of tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-4, IL-6, IL10, caspase-3, caspase-8 and caspase-9. Sodium nitrite resulted in significant reduction in serum testosterone concentration and elevation in testis weight and Gonado-Somatic Index. We found significant reduction in testicular tissues levels of IL-4 and IL-10 associated with elevated levels of TNF-α, IL-1β, IL-6, caspase-3, caspase-8 and caspase-9. In conclusion, chronic oral sodium nitrite induced changes in the weight of rat testis accompanied by elevation in the testicular tissue level of oxidative stress markers and inflammatory cytokines. TQ attenuated sodium nitrite-induced testicular tissue damage through blocking oxidative stress, restoration of normal inflammatory cytokines balance and blocking of apoptosis.

  20. Vertical administration of vanadium through lactation induces behavioural and neuromorphological changes: protective role of vitamin E.

    PubMed

    Olopade, J O; Fatola, I O; Olopade, F E

    2011-11-23

    The work investigated the protective role of vitamin E on vanadium induced neurotoxicity. Three adult female rats were divided into three groups, A-C with each dam and her pups forming a group. Group A served as control. The dam in Group B was given 3mg/kg b.w./day of vanadium from PND 1 while the Group C dam were given 3mg/kg b.w./day of vanadium, for 14 days and 500mg/kg b.w. of vitamin E 72 hourly in the same time frame. The results showed that pups from Group B, exhibited behavioural deficits in most tests, a significant reduction in body weight gain and absolute brain weight; in addition immunohistochemistry showed reactive astrogliosis induced by vanadium exposure. All these findings were however attenuated in pups whose dam was exposed to vanadium and vitamin E depicting the significant protective effects of this antioxidant against vanadium. This study is novel in that both vanadium and vitamin E were introduced through the lactation route. We conclude that though caution remains essential in the posology of vitamin E, the management of lactating mothers who have been exposed to vanadium occupationally, environmentally or therapeutically with supplementation of this antioxidant may be beneficial at least in the short term to both mother and offspring.

  1. Alternative method of oral administration by peanut butter pellet formulation results in target engagement of BACE1 and attenuation of gavage-induced stress responses in mice.

    PubMed

    Gonzales, C; Zaleska, M M; Riddell, D R; Atchison, K P; Robshaw, A; Zhou, H; Sukoff Rizzo, S J

    2014-11-01

    Development of novel therapeutic agents aimed at treating neurodegenerative disorders such as Alzheimer's and Parkinson's diseases require chronic and preferentially oral dosing in appropriate preclinical rodent models. Since many of these disease models involve transgenic mice that are frequently aged and fragile, the commonly used oro-gastric gavage method of drug administration often confounds measured outcomes due to repeated stress and high attrition rates caused by esophageal complications. We employed a novel drug formulation in a peanut butter (PB) pellet readily consumed by mice and compared the stress response as measured by plasma corticosterone levels relative to oral administration via traditional gavage. Acute gavage produced significant elevations in plasma corticosterone comparable to those observed in mice subjected to stress-induced hyperthermia. In contrast, corticosterone levels following consumption of PB pellets were similar to levels in naive mice and significantly lower than in mice subjected to traditional gavage. Following sub-chronic administration, corticosterone levels remained significantly higher in mice subjected to gavage, relative to mice administered PB pellets or naive controls. Furthermore, chronic 30day dosing of a BACE inhibitor administered via PB pellets to PSAPP mice resulted in expected plasma drug exposure and Aβ40 lowering consistent with drug treatment demonstrating target engagement. Taken together, this alternative method of oral administration by drug formulated in PB pellets results in the expected pharmacokinetics and pharmacodynamics with attenuated stress levels, and is devoid of the detrimental effects of repetitive oral gavage. PMID:25242810

  2. Ameliorating Adriamycin-Induced Chronic Kidney Disease in Rats by Orally Administrated Cardiotoxin from Naja naja atra Venom.

    PubMed

    Ding, Zhi-Hui; Xu, Li-Min; Wang, Shu-Zhi; Kou, Jian-Qun; Xu, Yin-Li; Chen, Cao-Xin; Yu, Hong-Pei; Qin, Zheng-Hong; Xie, Yan

    2014-01-01

    Previous studies reported the oral administration of Naja naja atra venom (NNAV) reduced adriamycin-induced chronic kidney damage. This study investigated the effects of intragastric administrated cardiotoxin from Naja naja atra venom on chronic kidney disease in rats. Wistar rats were injected with adriamycin (ADR; 6 mg/kg body weight) via the tail vein to induce chronic kidney disease. The cardiotoxin was administrated daily by intragastric injection at doses of 45, 90, and 180  μ g/kg body weight until the end of the protocol. The rats were placed in metabolic cages for 24 hours to collect urine, for determination of proteinuria, once a week. After 6 weeks, the rats were sacrificed to determine serum profiles relevant to chronic kidney disease, including albumin, total cholesterol, phosphorus, blood urea nitrogen, and serum creatinine. Kidney histology was examined with hematoxylin and eosin, periodic acid-Schiff, and Masson's trichrome staining. The levels of kidney podocin were analyzed by Western blot analysis and immunofluorescence. We found that cardiotoxin reduced proteinuria and can improve biological parameters in the adriamycin-induced kidney disease model. Cardiotoxin also reduced adriamycin-induced kidney pathology, suggesting that cardiotoxin is an active component of NNAV for ameliorating adriamycin-induced kidney damage and may have a potential therapeutic value on chronic kidney disease.

  3. Administration of the peroxisomal proliferator-activated receptor {gamma} agonist pioglitazone during fractionated brain irradiation prevents radiation-induced cognitive impairment

    SciTech Connect

    Zhao Weiling; Payne, Valerie; Tommasi, Ellen; Diz, Debra I.; Hsu, F.-C.; Robbins, Mike E. . E-mail: mrobbins@wfubmc.edu

    2007-01-01

    Purpose: We hypothesized that administration of the anti-inflammatory peroxisomal proliferator-activated receptor {gamma} (PPAR{gamma}) agonist pioglitazone (Pio) to adult male rats would inhibit radiation-induced cognitive impairment. Methods and Materials: Young adult male F344 rats received one of the following: (1) fractionated whole brain irradiation (WBI); 40 or 45 Gy {gamma}-rays in 4 or 4.5 weeks, respectively, two fractions per week and normal diet; (2) sham-irradiation and normal diet; (3) WBI plus Pio (120 ppm) before, during, and for 4 or 54 weeks postirradiation; (4) sham-irradiation plus Pio; or (5) WBI plus Pio starting 24h after completion of WBI. Results: Administration of Pio before, during, and for 4 or 54 weeks after WBI prevented Radiation-induced cognitive impairment. Administration of Pio for 54 weeks starting after completion of fractionated WBI substantially but not significantly reduced Radiation-induced cognitive impairment. Conclusions: These findings offer the promise of improving the quality of life and increasing the therapeutic window for brain tumor patients.

  4. Zinc administration modulates radiation-induced oxidative injury in lens of rat

    PubMed Central

    Taysi, Seyithan; Okumus, Seydi; Akyuz, Mehmet; Uzun, Naim; Aksoy, Adnan; Demir, Elif; Orkmez, Mustafa; Tarakcioglu, Mehmet; Adli, Mustafa

    2012-01-01

    Background: The aim of this study was to evaluate the antioxidant role of zinc (Zn) against radiation-induced cataract in the rat lens after total cranial irradiation with a single 5 Gray (Gy) dose of gamma irradiation. Materials and Methods: Twenty-one Sprague-Dawley rats were used for the experiment. The control group did not receive Zn or irradiation but received 1-ml saline orally plus sham-irradiation. The irradiation (IR) group received 5 Gy gamma irradiation to the total cranium as a single dose plus 0.1 ml physiological saline intraperitoneally. The IR plus Zn group received irradiation to total cranium plus 10 mg/kg/day Zn intraperitoneally. Biochemical parameters measured in rat lenses were carried out using spectrophotometric techniques. Results: Lens total (enzymatic plus non-enzymatic) superoxide scavenger activity (TSSA), glutathione reductase (GRD), and glutathione-S-transferase (GST) activities significantly increased in the IR plus Zn groups when compared with the IR group. However, TSSA, GRD and GST activities were significantly lower in the IR group when compared with the control group. Lens non-enzymatic superoxide scavenger activity (NSSA) in the IR plus Zn group was significantly increased compared to that of the IR group. Lens xanthine oxidase (XO) activity in the IR group significantly increased compared to that of both the control and IR plus Zn groups. Conclusion: Zn has clear antioxidant properties and prevented oxidative stress by scavenging free radicals generated by ionizing radiation in rat lenses. PMID:24082625

  5. Peripheral Administration of a Long-Acting Peptide Oxytocin Receptor Agonist Inhibits Fear-Induced Freezing

    PubMed Central

    Modi, Meera E.; Majchrzak, Mark J.; Fonseca, Kari R.; Doran, Angela; Osgood, Sarah; Vanase-Frawley, Michelle; Feyfant, Eric; McInnes, Heather; Darvari, Ramin; Buhl, Derek L.

    2016-01-01

    Oxytocin (OT) modulates the expression of social and emotional behaviors and consequently has been proposed as a pharmacologic treatment of psychiatric diseases, including autism spectrum disorders and schizophrenia; however, endogenous OT has a short half-life in plasma and poor permeability across the blood-brain barrier. Recent efforts have focused on the development of novel drug delivery methods to enhance brain penetration, but few efforts have aimed at improving its half-life. To explore the behavioral efficacy of an OT analog with enhanced plasma stability, we developed PF-06655075 (PF1), a novel non–brain-penetrant OT receptor agonist with increased selectivity for the OT receptor and significantly increased pharmacokinetic stability. PF-06478939 was generated with only increased stability to disambiguate changes to selectivity versus stability. The efficacy of these compounds in evoking behavioral effects was tested in a conditioned fear paradigm. Both central and peripheral administration of PF1 inhibited freezing in response to a conditioned fear stimulus. Peripheral administration of PF1 resulted in a sustained level of plasma concentrations for greater than 20 hours but no detectable accumulation in brain tissue, suggesting that plasma or cerebrospinal fluid exposure was sufficient to evoke behavioral effects. Behavioral efficacy of peripherally administered OT receptor agonists on conditioned fear response opens the door to potential peripheral mechanisms in other behavioral paradigms, whether they are mediated by direct peripheral activation or feed-forward responses. Compound PF1 is freely available as a tool compound to further explore the role of peripheral OT in behavioral response. PMID:27217590

  6. A single dose of dexamethasone encapsulated in polyethylene glycol-coated polylactic acid nanoparticles attenuates cisplatin-induced hearing loss following round window membrane administration.

    PubMed

    Sun, Changling; Wang, Xueling; Zheng, Zhaozhu; Chen, Dongye; Wang, Xiaoqin; Shi, Fuxin; Yu, Dehong; Wu, Hao

    2015-01-01

    This study aimed to investigate the sustained drug release properties and hearing protection effect of polyethylene glycol-coated polylactic acid (PEG-PLA) stealth nanoparticles loaded with dexamethasone (DEX). DEX was fabricated into PEG-PLA nanoparticles using an emulsion and evaporation technique, as previously reported. The DEX-loaded PEG-PLA nanoparticles (DEX-NPs) had a hydrodynamic diameter of 130±4.78 nm, and a zeta potential of -26.13±3.28 mV. The in vitro release of DEX from DEX-NPs lasted 24 days in phosphate buffered saline (pH 7.4), 5 days in artificial perilymph (pH 7.4), and 1 day in rat plasma. Coumarin 6-labeled NPs placed onto the round window membrane (RWM) of guinea pigs penetrated RWM quickly and accumulated to the organs of Corti, stria vascularis, and spiral ganglion cells after 1 hour of administration. The DEX-NPs locally applied onto the RWM of guinea pigs by a single-dose administration continuously released DEX in 48 hours, which was significantly longer than the free DEX that was cleared out within 12 hours after administration at the same dose. Further functional studies showed that locally administrated single-dose DEX-NPs effectively preserved outer hair cells in guinea pigs after cisplatin insult and thus significantly attenuated hearing loss at 4 kHz and 8 kHz frequencies when compared to the control of free DEX formulation. Histological analyses indicated that the administration of DEX-NPs did not induce local inflammatory responses. Therefore, prolonged delivery of DEX by PEG-PLA nanoparticles through local RWM diffusion (administration) significantly protected the hair cells and auditory function in guinea pigs from cisplatin toxicity, as determined at both histological and functional levels, suggesting the potential therapeutic benefits in clinical applications.

  7. Shock wave lithotripsy (SWL) induces significant structural and functional changes in the kidney

    NASA Astrophysics Data System (ADS)

    Evan, Andrew P.; Willis, Lynn R.; Lingeman, James E.

    2003-10-01

    The foundation for understanding SWL-injury has been well-controlled renal structural and functional studies in pigs, a model that closely mimics the human kidney. A clinical dose (2000 shocks at 24 kV) of SWL administered by the Dornier HM3 induces a predictable, unique vascular injury at F2 that is associated with transient renal vasoconstriction, seen as a reduction in renal plasma flow, in both treated and untreated kidneys. Unilateral renal denervation studies links the fall in blood flow in untreated kidneys to autonomic nerve activity in the treated kidney. SWL-induced trauma is associated with an acute inflammatory process, termed Lithotripsy Nephritis and tubular damage at the site of damage that leads to a focal region of scar. Lesion size increases with shock number and kV level. In addition, risk factors like kidney size and pre-existing renal disease (e.g., pyelonephritis), can exaggerate the predicted level of renal impairment. Our new protection data show that lesion size can be greatly reduced by a pretreatment session with low kV and shock number. The mechanisms of soft tissue injury probably involves shear stress followed by acoustic cavitation. Because of the perceived enhanced level of bioeffects from 3rd generation lithotripters, these observations are more relevant than ever.

  8. Helping the heart grow fonder during absence: Daydreaming about significant others replenishes connectedness after induced loneliness.

    PubMed

    Poerio, Giulia L; Totterdell, Peter; Emerson, Lisa-Marie; Miles, Eleanor

    2016-09-01

    People are known to engage in behaviours aimed at replenishing social connectedness after their sense of belonging is threatened. We explored whether the mental strategy of daydreaming about significant others could have similar effects by acting as an imaginary substitute when loved ones are unavailable. Following a loneliness induction, participants (N = 126) were asked to either daydream about a significant other, daydream about a non-social scenario or complete a control task. Social daydreamers showed significantly increased feelings of connection, love and belonging compared to non-social daydreamers and control participants. Consistent with the proposition that social daydreaming replenished connectedness, social daydreamers also behaved more pro-socially and expressed less of a desire to interact with others after daydreaming. These findings demonstrate that through imagination, social daydreaming can replenish connectedness providing a potential strategy for enhancing socio-emotional well-being.

  9. Helping the heart grow fonder during absence: Daydreaming about significant others replenishes connectedness after induced loneliness.

    PubMed

    Poerio, Giulia L; Totterdell, Peter; Emerson, Lisa-Marie; Miles, Eleanor

    2016-09-01

    People are known to engage in behaviours aimed at replenishing social connectedness after their sense of belonging is threatened. We explored whether the mental strategy of daydreaming about significant others could have similar effects by acting as an imaginary substitute when loved ones are unavailable. Following a loneliness induction, participants (N = 126) were asked to either daydream about a significant other, daydream about a non-social scenario or complete a control task. Social daydreamers showed significantly increased feelings of connection, love and belonging compared to non-social daydreamers and control participants. Consistent with the proposition that social daydreaming replenished connectedness, social daydreamers also behaved more pro-socially and expressed less of a desire to interact with others after daydreaming. These findings demonstrate that through imagination, social daydreaming can replenish connectedness providing a potential strategy for enhancing socio-emotional well-being. PMID:26192399

  10. Changes in brain oxidative metabolism induced by inhibitory avoidance learning and acute administration of amitriptyline.

    PubMed

    González-Pardo, Héctor; Conejo, Nélida M; Arias, Jorge L; Monleón, Santiago; Vinader-Caerols, Concepción; Parra, Andrés

    2008-05-01

    The effects of antidepressant drugs on memory have been somewhat ignored, having been considered a mere side effect of these compounds. However, the memory impairment caused by several antidepressants could be considered to form part of their therapeutic effects. Amitriptyline is currently one of the most prescribed tricyclic antidepressants, and exerts marked anticholinergic and antihistaminergic effects. In this study, we evaluated the effects of inhibitory avoidance (IA) learning and acute administration of amitriptyline on brain oxidative metabolism. Brain oxidative metabolism was measured in several limbic regions using cytochrome oxidase (CO) quantitative histochemistry. Amitriptyline produced a clear impairment in the IA task. In animals exposed only to the apparatus, amitriptyline decreased CO activity in nine brain regions, without affecting the remaining regions. In animals that underwent the IA training phase, amitriptyline reduced CO activity in only three of these nine regions. In animals treated with saline, IA acquisition increased CO activity in the medial prefrontal cortex, the prelimbic cortex, and the medial mammillary body, and diminished it in the medial septum and the nucleus basalis of Meynert with respect to animals exposed only to the IA apparatus. In animals treated with amitriptyline, IA acquisition did not modify CO activity in any of these regions, but increased it in the anteromedial nucleus of the thalamus, the diagonal band of Broca, and the dentate gyrus. The results reveal a pattern of changes in brain oxidative metabolism induced by IA training in saline-treated animals that was clearly absent in animals submitted to the same behavioural training but treated with amitriptyline. PMID:18313125

  11. Repeated dose (28-day) administration of silver nanoparticles of varied size and coating does not significantly alter the indigenous murine gut microbiome.

    PubMed

    Wilding, Laura A; Bassis, Christine M; Walacavage, Kim; Hashway, Sara; Leroueil, Pascale R; Morishita, Masako; Maynard, Andrew D; Philbert, Martin A; Bergin, Ingrid L

    2016-01-01

    Silver nanoparticles (AgNPs) have been used as antimicrobials in a number of applications, including topical wound dressings and coatings for consumer products and biomedical devices. Ingestion is a relevant route of exposure for AgNPs, whether occurring unintentionally via Ag dissolution from consumer products, or intentionally from dietary supplements. AgNP have also been proposed as substitutes for antibiotics in animal feeds. While oral antibiotics are known to have significant effects on gut bacteria, the antimicrobial effects of ingested AgNPs on the indigenous microbiome or on gut pathogens are unknown. In addition, AgNP size and coating have been postulated as significantly influential towards their biochemical properties and the influence of these properties on antimicrobial efficacy is unknown. We evaluated murine gut microbial communities using culture-independent sequencing of 16S rRNA gene fragments following 28 days of repeated oral dosing of well-characterized AgNPs of two different sizes (20 and 110 nm) and coatings (PVP and Citrate). Irrespective of size or coating, oral administration of AgNPs at 10 mg/kg body weight/day did not alter the membership, structure or diversity of the murine gut microbiome. Thus, in contrast to effects of broad-spectrum antibiotics, repeat dosing of AgNP, at doses equivalent to 2000 times the oral reference dose and 100-400 times the effective in vitro anti-microbial concentration, does not affect the indigenous murine gut microbiome.

  12. Altered mineral metabolism in glucocorticoid-induced osteopenia. Effect of 25-hydroxyvitamin D administration.

    PubMed Central

    Hahn, T J; Halstead, L R; Teitelbaum, S L; Hahn, B H

    1979-01-01

    Parameters of mineral and bone metabolism were studied in 17 patients treated chronically with supraphysiologic doses of glucocorticoids. When compared to 15 matched normal subjects, the patient group exhibited similar serum 25-hydroxyvitamin D (25-OHD) levels, decreased intestinal 47Ca absorption, increased serum immunoreactive parathyroid hormone, and decreased forearm bone mass. Iliac crest bone biopsies revealed a decreased bone formation rate and increased osteoclast number. Treatment with 25-OHD (mean dose 4.03 micrograms/d) and calcium (500 mg/d) in nine patients produced a 46% increase in 47Ca absorption (P less than 0.001) and a 54% decrease in serum immunoreactive parathyroid hormone (P less than 0.001) by 3 mo. In addition, by 12 mo the treatment group exhibited (a) a 13.2 +/- 5.1% increase in metaphyseal (P less than 0.001) and a 2.1 +/- 0.4% increase in diaphyseal (P less than 0.05) forearm bone mass, and (b) significant decreases in cortical and endosteal osteoclast number. Biochemical and bone mass changes persisted through 18 mo. No significant changes in any parameter occurred in eight control patients administered calcium 100 mg/d. It is concluded that treatment with 25-OHD and calcium can significantly improve parameters of mineral and bone metabolism in patients with glucocorticoid-induced osteopenia. PMID:457875

  13. Subchronic administration of riparin III induces antidepressive-like effects and increases BDNF levels in the mouse hippocampus.

    PubMed

    Vasconcelos, Auriana S; Oliveira, Iris C M; Vidal, Laura T M; Rodrigues, Gabriel C; Gutierrez, Stanley J C; Barbosa-Filho, José M; Vasconcelos, Silvânia M M; de França Fonteles, Marta M; Gaspar, Danielle M; de Sousa, Francisca C F

    2015-08-01

    Riparin III (Rip III) is an alcamide isolated from Aniba riparia that has presented effects of antidepressant and anxiolytic activities in acute stress behavioral models. The trial's goal was to investigate the activity of Rip III in mice exposed to corticosterone-induced chronic depression model. Swiss female mice, 22-25 g, were distributed in following experimental groups: control group (vehicle1: saline containing 0.1% dimethyl sulfoxide and 0.1% Tween-80, SC+ vehicle 2: distilled water emulsified with 2% Tween-80, PO); stressed group (corticosterone, 20 mg/kg, SC, + vehicle 2, orally); Rip III group (50 mg/kg, orally); and fluvoxamine (Flu) group (50 mg/kg, orally). The mice were exposed to the behavioral tests, and posteriorly, Brain-derived neurotrophic factor protein levels were assessed in hippocampal samples. Statistical analysis of the data was performed by one-way anova, followed by Newman-Keuls test. Both administrations of Rip III and Flu significantly reduced the immobility time in tail suspension and forced swimming tests after 21 days without affecting locomotor function. There was also an increase in BDNF protein levels in the mice hippocampus. These findings further support the hypothesis that Rip III could be a new pharmacological target for the treatment of mood disorders.

  14. Red cabbage (Brassica oleracea L.) mediates redox-sensitive amelioration of dyslipidemia and hepatic injury induced by exogenous cholesterol administration.

    PubMed

    Al-Dosari, Mohammed S

    2014-01-01

    The widely used culinary vegetable, red cabbage (Brassica oleracea L. Var. capitata f. rubra), of the Brassicaceae family contains biologically potent anthocyanins and a myriad of antioxidants. Previous studies have shown that the pharmacological effects of red cabbage in vivo are redox-sensitive. The present study explored whether red cabbage modulates various histopathological and biochemical parameters in rats administered with a cholesterol-rich diet (CRD). To this end, prolonged administration of a lyophilized-aqueous extract of red cabbage (250 and 500 mg/kg body weight) significantly blunted the imbalances in lipids, liver enzymes and renal osmolytes induced by the CRD. The effects of red cabbage were compared to simvastatin (30 mg/kg body weight) treated rats. Estimation of malondialdehyde and non-protein sulfhydryls revealed robust antioxidant properties of red cabbage. Histopathological analysis of livers from rats administered with red cabbage showed marked inhibition in inflammatory and necrotic changes triggered by CRD. Similarly, in vitro studies using a 2',7'-Dichlorofluorescein-based assay showed that red cabbage conferred cytoprotective effects in cultured HepG2 cells. In conclusion, the present study discloses the potential therapeutic effects of red cabbage in dyslipidemia as well as hepatic injury, that is at least, partly mediated by its antioxidant properties.

  15. Red cabbage (Brassica oleracea L.) mediates redox-sensitive amelioration of dyslipidemia and hepatic injury induced by exogenous cholesterol administration.

    PubMed

    Al-Dosari, Mohammed S

    2014-01-01

    The widely used culinary vegetable, red cabbage (Brassica oleracea L. Var. capitata f. rubra), of the Brassicaceae family contains biologically potent anthocyanins and a myriad of antioxidants. Previous studies have shown that the pharmacological effects of red cabbage in vivo are redox-sensitive. The present study explored whether red cabbage modulates various histopathological and biochemical parameters in rats administered with a cholesterol-rich diet (CRD). To this end, prolonged administration of a lyophilized-aqueous extract of red cabbage (250 and 500 mg/kg body weight) significantly blunted the imbalances in lipids, liver enzymes and renal osmolytes induced by the CRD. The effects of red cabbage were compared to simvastatin (30 mg/kg body weight) treated rats. Estimation of malondialdehyde and non-protein sulfhydryls revealed robust antioxidant properties of red cabbage. Histopathological analysis of livers from rats administered with red cabbage showed marked inhibition in inflammatory and necrotic changes triggered by CRD. Similarly, in vitro studies using a 2',7'-Dichlorofluorescein-based assay showed that red cabbage conferred cytoprotective effects in cultured HepG2 cells. In conclusion, the present study discloses the potential therapeutic effects of red cabbage in dyslipidemia as well as hepatic injury, that is at least, partly mediated by its antioxidant properties. PMID:24467544

  16. Pathological Significance of a Panel of Urinary Biomarkers in Patients with Drug-Induced Tubulointerstitial Nephritis

    PubMed Central

    Wu, Yu; Yang, Li; Su, Tao; Wang, Chen; Liu, Gang

    2010-01-01

    Background and objectives: Although a renal biopsy is indispensable for depicting the severity of pathologic lesions in drug-induced tubulointerstitial nephritis (DTIN), it is not acceptable in some cases and cannot be performed serially because of its invasive nature. Therefore, the discovery of noninvasive markers that are closely related to the pathology of DTIN is of great value. Design, setting, participants, & measurements: In this study, the urinary levels of monocyte chemotactic peptide-1 (MCP-1), neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-β-d-glucosaminidase, and α1-microglobulin were measured in 40 DTIN subjects, and the performances of these parameters for distinguishing different pathologic lesions were compared. Results: Linear correlation and receiver operating characteristic curve analyses showed that urinary MCP-1 levels were able to identify serious interstitial edema and inflammatory infiltration with greater accuracy than the other biomarkers (r = 0.501, P < 0.001 and r = 0.768, P < 0.001, respectively), whereas urinary NGAL levels showed the highest correlation coefficient with tubular atrophy (r = 0.692, P < 0.001). Conclusions: These results suggest that these biomarker levels were higher in patients with DTIN than in controls. Urinary MCP-1 levels correlated and were predictive of the gradated severity of acute lesions in DTIN, whereas the roles of NGAL and α1-microglobulin in chronic alterations require further study. PMID:20813857

  17. Significant modulation of the hepatic proteome induced by exposure to low temperature in Xenopus laevis

    PubMed Central

    Nagasawa, Kazumichi; Tanizaki, Yuta; Okui, Takehito; Watarai, Atsuko; Ueda, Shinobu; Kato, Takashi

    2013-01-01

    Summary The African clawed frog, Xenopus laevis, is an ectothermic vertebrate that can survive at low environmental temperatures. To gain insight into the molecular events induced by low body temperature, liver proteins were evaluated at the standard laboratory rearing temperature (22°C, control) and a low environmental temperature (5°C, cold exposure). Using nano-flow liquid chromatography coupled with tandem mass spectrometry, we identified 58 proteins that differed in abundance. A subsequent Gene Ontology analysis revealed that the tyrosine and phenylalanine catabolic processes were modulated by cold exposure, which resulted in decreases in hepatic tyrosine and phenylalanine, respectively. Similarly, levels of pyruvate kinase and enolase, which are involved in glycolysis and glycogen synthesis, were also decreased, whereas levels of glycogen phosphorylase, which participates in glycogenolysis, were increased. Therefore, we measured metabolites in the respective pathways and found that levels of hepatic glycogen and glucose were decreased. Although the liver was under oxidative stress because of iron accumulation caused by hepatic erythrocyte destruction, the hepatic NADPH/NADP ratio was not changed. Thus, glycogen is probably utilized mainly for NADPH supply rather than for energy or glucose production. In conclusion, X. laevis responds to low body temperature by modulating its hepatic proteome, which results in altered carbohydrate metabolism. PMID:24167716

  18. Analysis and significance of gravity-induced asymmetric growth in the grass leaf-sheath pulvinus

    NASA Technical Reports Server (NTRS)

    Dayanandan, P.; Kaufman, P. B.

    1984-01-01

    The negative gravitropic response in the grass leaf-sheath pulvinus is a consequence of cell elongation involving all cells except those of the uppermost region of the upper flank of an horizontally oriented pulvinus. The lowermost layer of cells elongate maximally, and the regions in between elongate to intermediate extents. The resulting curvatures of a responding pulvinus can be expressed mathematically by relating the angle of curvature (theta) to the original length (L0) and the maximal length of the lower surface (L1) and the diameter of the organ (D), using the equation, theta = (L1-L0)/D, where theta is in radians. The elongation response (S) of any individual cells within the pulvinus can be expressed by the equation, S = 0.5 - r cos theta, where r is the radius of the pulvinus and theta is in degrees. Microscopic measurement of cell lengths in different regions of the pulvinus supports the mathematical predictions. Indirect support is also obtained from the use of colchicine, coumarin, dichlorobenzonitrile (DCBN) and isopropyl N-chlorophenyl carbamate which exaggerate the inherent asymmetry during gravitropic response. Coumarin and DCBN also induce thickenings in the radial walls which appear first in the statenchyma, and later, in cells located towards the outer periphery of the pulvinus. The distribution patterns of these thickenings suggest that the asymmetric growth response of the pulvinus may be due to a differential and radial, centrifugal transport of growth promotors from the central statenchyma region.

  19. Drug-induced sleep endoscopy changes snoring management plan very significantly compared to standard clinical evaluation.

    PubMed

    Pilaete, Karen; De Medts, Joris; Delsupehe, Kathelijne Godelieve

    2014-05-01

    Drug-induced sleep endoscopy (DISE) is a new tool in the work-up of patients with sleep-disordered breathing (SDB). We assessed the impact of DISE on the treatment plan of snoring patients. This is a single institution prospective longitudinal clinical trial. The setting is a private teaching hospital. A consecutive series of 100 snoring patients prospectively underwent a standardised questionnaire, clinical examination, rhinomanometry, allergy skin prick testing, DISE and polysomnography. Management plan before and after DISE evaluation was compared. In 61 patients (excluding 16 patients sent for continuous positive airway pressure, three patients refused sleep endoscopy and 20 were lost to follow-up), we compared the treatment plans. DISE showed single level airway collapse in 13 and multilevel collapse in 48 patients. The site of flutter did not add additional information as compared to the pattern and the location of the collapse. After DISE, the initial management plan changed in 41% of patients irrespective of the type of initial management plan. The only somewhat accurate initial treatment plan was uvulopalatopharyngoplasty (unchanged in 11/13 patients). Excluding moderate to severe obstructive sleep apnea patients DISE is an indispensable tool in treatment decision in all SDB patients. We suggest to simplify the protocol for DISE reporting.

  20. Xenobiotic-induced apoptosis: significance and potential application as a general biomarker of response

    USGS Publications Warehouse

    Sweet, Leonard I.; Passino-Reader, Dora R.; Meier, Peter G.; Omann, Geneva M.

    1999-01-01

    The process of apoptosis, often coined programmed cell death, involves cell injury induced by a variety of stimuli including xenobiotics and is morphologically, biochemically, and physiologically distinct from necrosis. Apoptotic death is characterized by cellular changes such as cytoplasm shrinkage, chromatin condensation, and plasma membrane asymmetry. This form of cell suicide is appealing as a general biomarker of response in that it is expressed in multiple cell systems (e.g. immune, neuronal, hepatal, intestinal, dermal, reproductive), is conserved phylogenetically (e.g. fish, rodents, birds, sheep, amphibians, roundworms, plants, humans), is modulated by environmentally relevant levels of chemical contaminants, and indicates a state of stress of the organism. Further, apoptosis is useful as a biomarker as it serves as a molecular control point and hence may provide mechanistic information on xenobiotic stress. Studies reviewed here suggest that apoptosis is a sensitive and early indicator of acute and chronic chemical stress, loss of cellular function and structure, and organismal health. Examples are provided of the application of this methodology in studies of health of lake trout (Salvelinus namaycush) in the Laurentian Great Lakes.

  1. Significant modulation of the hepatic proteome induced by exposure to low temperature in Xenopus laevis.

    PubMed

    Nagasawa, Kazumichi; Tanizaki, Yuta; Okui, Takehito; Watarai, Atsuko; Ueda, Shinobu; Kato, Takashi

    2013-01-01

    The African clawed frog, Xenopus laevis, is an ectothermic vertebrate that can survive at low environmental temperatures. To gain insight into the molecular events induced by low body temperature, liver proteins were evaluated at the standard laboratory rearing temperature (22°C, control) and a low environmental temperature (5°C, cold exposure). Using nano-flow liquid chromatography coupled with tandem mass spectrometry, we identified 58 proteins that differed in abundance. A subsequent Gene Ontology analysis revealed that the tyrosine and phenylalanine catabolic processes were modulated by cold exposure, which resulted in decreases in hepatic tyrosine and phenylalanine, respectively. Similarly, levels of pyruvate kinase and enolase, which are involved in glycolysis and glycogen synthesis, were also decreased, whereas levels of glycogen phosphorylase, which participates in glycogenolysis, were increased. Therefore, we measured metabolites in the respective pathways and found that levels of hepatic glycogen and glucose were decreased. Although the liver was under oxidative stress because of iron accumulation caused by hepatic erythrocyte destruction, the hepatic NADPH/NADP ratio was not changed. Thus, glycogen is probably utilized mainly for NADPH supply rather than for energy or glucose production. In conclusion, X. laevis responds to low body temperature by modulating its hepatic proteome, which results in altered carbohydrate metabolism.

  2. Low-intensity electrical muscle stimulation induces significant increases in muscle strength and cardiorespiratory fitness.

    PubMed

    Miyamoto, Toshiaki; Kamada, Hiroyuki; Tamaki, Akira; Moritani, Toshio

    2016-11-01

    The aim of this study was to investigate the effect of low-intensity exercise training using belt electrode skeletal muscle electrical stimulation on muscle strength and cardiorespiratory fitness in healthy subjects. Nineteen healthy subjects were allocated into control or intervention groups; in both groups the participants kept regular physical activity while the intervention group underwent 30 min B-SES training at 3-4 METs for four weeks. Knee extensor muscle strength and cardiorespiratory endurance during incremental exercise test were measured at baseline and after four weeks for all participants. The relative change of knee extensor muscle strength in the intervention group was significantly higher than control group (p < .05). Also, oxygen uptake at ventilator threshold and peak oxygen uptake during incremental exercise test significantly increased in the intervention group when compared with control group (p < .05). This study showed that prolonged low-intensity B-SES training resulted in significant increases in muscle strength and cardiorespiratory fitness in healthy subjects. Our present work suggested that B-SES training could assist patients who might have difficulty performing adequate voluntary exercise because of excessive obesity, orthopaedic problems and chronic diseases such as cardiovascular disease and type 2 diabetes. An intervention study conducted for such patients is strongly recommended.

  3. Systemic amitriptyline administration does not prevent the increased thermal response induced by paradoxical sleep deprivation.

    PubMed

    Damasceno, Fabio; Skinner, Gabriela O; Gomes, Aline; Araújo, Paulo C; de Almeida, Olga M M S

    2009-11-01

    Sleep deprivation has been associated with hyperalgesia in humans and in animal models. The tricyclic antidepressant amitriptyline is used as an analgesic drug in patients and in animal models of chronic pain, including that associated with spinal nerve injury. Pain hypersensitivity following paradoxical sleep deprivation (PSD) and that following peripheral nerve injury seem to share common spinal mechanisms. Accordingly, we evaluated the effects of amitriptyline (acutely and chronically administered) on the increased thermal response observed in PSD rats (72 or 96 h). Rats were evaluated for thermal sensitivity using a hot plate (52 degrees C or 46 degrees C) at 1 or 24 h after the last administration of the drug. Following the hot plate test, motor behavior was analyzed in an open field arena for a period of 5 min. Paw withdrawal latency response to temperatures of 46 degrees C and 52 degrees C was significantly lower in PSD and in 24-hour post-PSD rats than in controls and it was not modified by amitriptyline (3, 10 and 30 mg/kg). Analgesic effects and reduced motor behavior were only observed in control groups. Overall, these findings indicate that a period of PSD can influence pain modulatory mechanisms, and that amitriptyline action is insufficient to reduce PSD-enhanced thermal sensitivity.

  4. Administration of a Sigma Receptor Agonist Delays MCAO-Induced Neurodegeneration and White Matter Injury

    PubMed Central

    Leonardo, Christopher C.; Hall, Aaron A.; Collier, Lisa A.; Green, Suzanne M.; Willing, Alison E.; Pennypacker, Keith R.

    2010-01-01

    Many pharmacological treatments for stroke have afforded protection in rodent models but failed to show efficacy in clinical trials. This discrepancy may be due to the lack of long-term functional studies. Previously, delayed administration of the sigma receptor agonist 1,3-di-o-tolylguanidine (DTG) reduced infarct volume after middle cerebral artery occlusion (MCAO) in rats. The present study was conducted to determine whether the protective effects of DTG lead to improvements in behavioral functioning. Rats were subjected to MCAO and administered 7.5, 1.5, or 0.75 mg/kg DTG beginning 24 h post-surgery. Histological outcomes (96 h, 2 weeks, and 5 weeks) were compared with performance on a series of behavioral tests (2 and 4 weeks). Fluoro-Jade staining and immunohistochemistry were used to assess infarct volume and immune cell recruitment. All doses significantly reduced infarct volume and perturbation of striatal white matter tracts at 96 h. These reductions were associated with decreased numbers of CD11b-positive amoeboid microglia/macrophages. Despite short-term efficacy, DTG failed to improve behavioral outcomes or reduce infarct volumes after 96 h. While DTG may prove beneficial as a short-term therapy, these data highlight the importance of long-term functional recovery when evaluating novel therapies to treat stroke. PMID:20563232

  5. Cortisol administration induces sex change from ovary to testis in the protogynous Wrasse, Halichoeres trimaculatus.

    PubMed

    Nozu, Ryo; Nakamura, Masaru

    2015-01-01

    Steroid hormones have been shown to play important roles in triggering sex change. However, the upstream mechanism that regulates the secretion of sex steroid hormones controlling sex change is not yet known. Cortisol, the primary glucocorticoid in teleost fish, is known to exhibit anti-stress action and is involved in many physiological functions, including regulation of steroidogenesis. Therefore, cortisol could be one of the candidate factors involved in the onset of sex change. In this study, we investigated the role of cortisol in sex change in the three-spot wrasse, Halichoeres trimaculatus, by prolonged administration of cortisol. Our results showed that gonads of all individuals treated with cortisol (1,000 µg/g diet) for 6 weeks contained spermatogenic germ cells. One of them exhibited matured testes with an ovarian cavity, indicating sex change. Additionally, the plasma estradiol-17β level in the cortisol treatment group was significantly lower than in the control group suggesting that cortisol plays a direct and/or indirect role in the regulation of estrogen production. These data imply that cortisol might be involved in the regulation of steroidogenesis by causing a decrease in the estrogen level, leading to the onset of sex change.

  6. Histopathological findings of the pancreas, liver, and carbohydrate metabolizing enzymes in STZ-induced diabetic rats improved by administration of myrtenal.

    PubMed

    Rathinam, Ayyasamy; Pari, Leelavinothan; Chandramohan, Ramasamy; Sheikh, Bashir Ahmad

    2014-12-01

    This study aims to evaluate the efficacy of myrtenal, a natural monoterpene, for its antihyperglycemic effects and β cell protective properties in streptozotocin (STZ)-induced diabetic rats. Oral administration of myrtenal at doses of 20, 40, and 80 mg/kg body weight to diabetic rats for 28 days resulted in a significant reduction (P < 0.05) in the levels of plasma glucose, glycosylated hemoglobin (HbA1c), and an increase in the levels of insulin and hemoglobin (Hb). Protection of body weight loss of diabetic rats by myrtenal was noted. The altered activities of the key metabolic enzymes involved in carbohydrate metabolism such as hexokinase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, and hepatic enzymes AST, ALT, and ALP levels of diabetic rats were significantly improved by the administration of myrtenal in STZ-induced diabetic rats. Moreover, myrtenal treatment improved hepatic and muscle glycogen content in diabetic rats. Histopathological studies further revealed that the reduced islet cells were restored to near-normal conditions on treatment with myrtenal in STZ-induced diabetic rats. An alteration in liver architecture was also prevented by myrtenal treatment. Our results suggest that myrtenal possess antihyperglycemic and β cell protective effects. Hence, myrtenal could be considered as a potent phytochemical for development as a new antidiabetic agent.

  7. Tick-induced allergies: mammalian meat allergy, tick anaphylaxis and their significance

    PubMed Central

    2015-01-01

    Serious tick-induced allergies comprise mammalian meat allergy following tick bites and tick anaphylaxis. Mammalian meat allergy is an emergent allergy, increasingly prevalent in tick-endemic areas of Australia and the United States, occurring worldwide where ticks are endemic. Sensitisation to galactose-α-1,3-galactose (α-Gal) has been shown to be the mechanism of allergic reaction in mammalian meat allergy following tick bite. Whilst other carbohydrate allergens have been identified, this allergen is unique amongst carbohydrate food allergens in provoking anaphylaxis. Treatment of mammalian meat anaphylaxis involves avoidance of mammalian meat and mammalian derived products in those who also react to gelatine and mammalian milks. Before initiating treatment with certain therapeutic agents (e.g., cetuximab, gelatine-containing substances), a careful assessment of the risk of anaphylaxis, including serological analysis for α-Gal specific-IgE, should be undertaken in any individual who works, lives, volunteers or recreates in a tick endemic area. Prevention of tick bites may ameliorate mammalian meat allergy. Tick anaphylaxis is rare in countries other than Australia. Tick anaphylaxis is secondarily preventable by prevention and appropriate management of tick bites. Analysis of tick removal techniques in tick anaphylaxis sufferers offers insights into primary prevention of both tick and mammalian meat anaphylaxis. Recognition of the association between mammalian meat allergy and tick bites has established a novel cause and effect relationship between an environmental exposure and subsequent development of a food allergy, directing us towards examining environmental exposures as provoking factors pivotal to the development of other food allergies and refocusing our attention upon causation of allergy in general. PMID:25653915

  8. Tick-induced allergies: mammalian meat allergy, tick anaphylaxis and their significance.

    PubMed

    van Nunen, Sheryl

    2015-01-01

    Serious tick-induced allergies comprise mammalian meat allergy following tick bites and tick anaphylaxis. Mammalian meat allergy is an emergent allergy, increasingly prevalent in tick-endemic areas of Australia and the United States, occurring worldwide where ticks are endemic. Sensitisation to galactose-α-1,3-galactose (α-Gal) has been shown to be the mechanism of allergic reaction in mammalian meat allergy following tick bite. Whilst other carbohydrate allergens have been identified, this allergen is unique amongst carbohydrate food allergens in provoking anaphylaxis. Treatment of mammalian meat anaphylaxis involves avoidance of mammalian meat and mammalian derived products in those who also react to gelatine and mammalian milks. Before initiating treatment with certain therapeutic agents (e.g., cetuximab, gelatine-containing substances), a careful assessment of the risk of anaphylaxis, including serological analysis for α-Gal specific-IgE, should be undertaken in any individual who works, lives, volunteers or recreates in a tick endemic area. Prevention of tick bites may ameliorate mammalian meat allergy. Tick anaphylaxis is rare in countries other than Australia. Tick anaphylaxis is secondarily preventable by prevention and appropriate management of tick bites. Analysis of tick removal techniques in tick anaphylaxis sufferers offers insights into primary prevention of both tick and mammalian meat anaphylaxis. Recognition of the association between mammalian meat allergy and tick bites has established a novel cause and effect relationship between an environmental exposure and subsequent development of a food allergy, directing us towards examining environmental exposures as provoking factors pivotal to the development of other food allergies and refocusing our attention upon causation of allergy in general. PMID:25653915

  9. Character, distribution, and ecological significance of storm wave-induced scour in Rhode Island Sound, USA

    USGS Publications Warehouse

    McMullen, Katherine Y.; Poppe, Lawrence J.; Parker, Castle E.

    2015-01-01

    Multibeam bathymetry, collected during NOAA hydrographic surveys in 2008 and 2009, is coupled with USGS data from sampling and photographic stations to map the seabed morphology and composition of Rhode Island Sound along the US Atlantic coast, and to provide information on sediment transport and benthic habitats. Patchworks of scour depressions cover large areas on seaward-facing slopes and bathymetric highs in the sound. These depressions average 0.5-0.8 m deep and occur in water depths reaching as much as 42 m. They have relatively steep well-defined sides and coarser-grained floors, and vary strongly in shape, size, and configuration. Some individual scour depressions have apparently expanded to combine with adjacent depressions, forming larger eroded areas that commonly contain outliers of the original seafloor sediments. Where cobbles and scattered boulders are present on the depression floors, the muddy Holocene sands have been completely removed and the winnowed relict Pleistocene deposits exposed. Low tidal-current velocities and the lack of obstacle marks suggest that bidirectional tidal currents alone are not capable of forming these features. These depressions are formed and maintained under high-energy shelf conditions owing to repetitive cyclic loading imposed by high-amplitude, long-period, storm-driven waves that reduce the effective shear strength of the sediment, cause resuspension, and expose the suspended sediments to erosion by wind-driven and tidal currents. Because epifauna dominate on gravel floors of the depressions and infauna are prevalent in the finer-grained Holocene deposits, it is concluded that the resultant close juxtaposition of silty sand-, sand-, and gravel-dependent communities promotes regional faunal complexity. These findings expand on earlier interpretations, documenting how storm wave-induced scour produces sorted bedforms that control much of the benthic geologic and biologic diversity in Rhode Island Sound.

  10. Character, distribution, and ecological significance of storm wave-induced scour in Rhode Island Sound, USA

    NASA Astrophysics Data System (ADS)

    McMullen, Katherine Y.; Poppe, Lawrence J.; Parker, Castle E.

    2015-04-01

    Multibeam bathymetry, collected during NOAA hydrographic surveys in 2008 and 2009, is coupled with USGS data from sampling and photographic stations to map the seabed morphology and composition of Rhode Island Sound along the US Atlantic coast, and to provide information on sediment transport and benthic habitats. Patchworks of scour depressions cover large areas on seaward-facing slopes and bathymetric highs in the sound. These depressions average 0.5-0.8 m deep and occur in water depths reaching as much as 42 m. They have relatively steep well-defined sides and coarser-grained floors, and vary strongly in shape, size, and configuration. Some individual scour depressions have apparently expanded to combine with adjacent depressions, forming larger eroded areas that commonly contain outliers of the original seafloor sediments. Where cobbles and scattered boulders are present on the depression floors, the muddy Holocene sands have been completely removed and the winnowed relict Pleistocene deposits exposed. Low tidal-current velocities and the lack of obstacle marks suggest that bidirectional tidal currents alone are not capable of forming these features. These depressions are formed and maintained under high-energy shelf conditions owing to repetitive cyclic loading imposed by high-amplitude, long-period, storm-driven waves that reduce the effective shear strength of the sediment, cause resuspension, and expose the suspended sediments to erosion by wind-driven and tidal currents. Because epifauna dominate on gravel floors of the depressions and infauna are prevalent in the finer-grained Holocene deposits, it is concluded that the resultant close juxtaposition of silty sand-, sand-, and gravel-dependent communities promotes regional faunal complexity. These findings expand on earlier interpretations, documenting how storm wave-induced scour produces sorted bedforms that control much of the benthic geologic and biologic diversity in Rhode Island Sound.

  11. Reversal of an aluminium induced alteration in redox status in different regions of rat brain by administration of centrophenoxine.

    PubMed

    Nehru, Bimla; Bhalla, Punita

    2006-10-01

    Aluminium is one of the most studied neurotoxin, and its effects on nervous system are both structural and functional, involving various regions of brain. Aluminium toxicity is known to have multiple mechanisms of action in the central nervous system. Affinity of aluminium for thiol substrates is considered a possible molecular mechanism involved in aluminium neurotoxicity. The reduced glutathione (GSH) is especially important for cellular defence against aluminium toxicity. This study pertains to the modulatory action of centrophenoxine on GSH status in aluminium exposed different brain regions of the female rats. Aluminium was administered orally at a dose of 40 mg/Kg x b x wt x /day for a period of eight weeks whereas, centrophenoxine was administered intraperitoneally at a dose of 100 mg/Kg x b x wt x /day for a period of six weeks. The study was carried out in different regions of brain namely cerebrum, cerebellum, medulla oblongata and hypothalamus. Animals exposed to aluminum, registered a significant decrease in the levels of reduced glutathione, and oxidized glutathione as well as in the activity of glutathione reductase in all the different regions studied when compared to normal control animals. Post-treatment with centrophenoxine, showed a significant improvement in the thiol levels in different regions. Centrophenoxine when administered alone also had a profound effect on the levels of reduced glutathione as well as on the activity of glutathione reductase. From the present results, it can be stated that centrophenoxine administration, as a thiol-antioxidant, arrests the aluminium induced cellular damage by improving the thiol status in brain regions.

  12. Systemic administration of antigen-pulsed dendritic cells induces experimental allergic asthma in mice upon aerosol antigen rechallenge.

    PubMed

    Graffi, Sebastian J; Dekan, Gerhard; Stingl, Georg; Epstein, Michelle M

    2002-05-01

    Antigen-pulsed dendritic cells (DCs) have been used extensively as cellular vaccines to induce a myriad of protective immune responses. Adoptive transfer of antigen-pulsed DCs is especially effective at generating Th1 and CD8 immune responses. However, recently this strategy has been shown to induce Th2 cells when DCs are administered locally into the respiratory tract. We sought to address whether systemic rather than local antigen-pulsed DC administration could induce Th2 experimental allergic asthma. We found that OVA-pulsed splenic DCs injected intraperitoneally induced polarized Th2 allergic lung disease upon secondary OVA aerosol challenge. Disease was characterized by eosinophilic lung inflammation, excess mucus production, airway hyperresponsiveness, and OVA-specific IgG1 and IgE. In addition, unusual pathology characterized by macrophage alveolitis and multinucleated giant cells was observed. These data show that systemic administration of antigen-pulsed DCs and subsequent aeroantigen challenge induces Th2 immunity. These findings have important implications for the development of DC-based vaccines.

  13. Chronic Administration of Bacopa Monniera Increases BDNF Protein and mRNA Expressions: A Study in Chronic Unpredictable Stress Induced Animal Model of Depression

    PubMed Central

    Banerjee, Ritabrata; Hazra, Somoday; Ghosh, Anup Kumar

    2014-01-01

    Objective The present study aimed to investigate whether graded doses of Bacopa Monniera (BM) extract could produce antidepressant-like effects in chronic unpredictable stress (CUS) induced depression in rats and its possible mechanism(s). Methods Rats were subjected to an experimental setting of CUS. The effect of BM extract treatment in CUS-induced depression was examined using behavioral tests including the sucrose consumption, open field test and shuttle box escape test. The mechanism underlying the antidepressant-like action of BM extract was examined by measuring brain-derived neurotrophic factor (BDNF) protein and mRNA expression in brain tissues of CUS-exposed rats. Results Exposure to CUS for 4 weeks caused depression-like behavior in rats, as indicated by significant decreases in sucrose consumption, locomotor activity and escape latency. In addition, it was found that BDNF protein and mRNA levels in the hippocampus and frontal cortex were lower in CUS-treated rats, as compared to controls. Daily administration of the graded doses of BM extract during the 4-week period of CUS significantly suppressed behavioral changes and attenuated the CUS-induced decrease in BDNF protein and mRNA levels in the hippocampus and frontal cortex. Conclusion The results suggest that BM extract alleviates depression induced by CUS. Present study also confirms that 80-120 mg/kg doses of BM extract have significantly higher antidepressant-like activity. PMID:25110503

  14. Mass Administration of Ivermectin for the Elimination of Onchocerciasis Significantly Reduced and Maintained Low the Prevalence of Strongyloides stercoralis in Esmeraldas, Ecuador

    PubMed Central

    Anselmi, Mariella; Buonfrate, Dora; Guevara Espinoza, Angel; Prandi, Rosanna; Marquez, Monica; Gobbo, Maria; Montresor, Antonio; Albonico, Marco; Racines Orbe, Marcia; Bisoffi, Zeno

    2015-01-01

    Objectives To evaluate the effect of ivermectin mass drug administration on strongyloidiasis and other soil transmitted helminthiases. Methods We conducted a retrospective analysis of data collected in Esmeraldas (Ecuador) during surveys conducted in areas where ivermectin was annually administered to the entire population for the control of onchocerciasis. Data from 5 surveys, conducted between 1990 (before the start of the distribution of ivermectin) and 2013 (six years after the interruption of the intervention) were analyzed. The surveys also comprised areas where ivermectin was not distributed because onchocerciasis was not endemic. Different laboratory techniques were used in the different surveys (direct fecal smear, formol-ether concentration, IFAT and IVD ELISA for Strongyloides stercoralis). Results In the areas where ivermectin was distributed the strongyloidiasis prevalence fell from 6.8% in 1990 to zero in 1996 and 1999. In 2013 prevalence in children was zero with stool examination and 1.3% with serology, in adult 0.7% and 2.7%. In areas not covered by ivermectin distribution the prevalence was 23.5% and 16.1% in 1996 and 1999, respectively. In 2013 the prevalence was 0.6% with fecal exam and 9.3% with serology in children and 2.3% and 17.9% in adults. Regarding other soil transmitted helminthiases: in areas where ivermectin was distributed the prevalence of T. trichiura was significantly reduced, while A. lumbricoides and hookworms were seemingly unaffected. Conclusions Periodic mass distribution of ivermectin had a significant impact on the prevalence of strongyloidiasis, less on trichuriasis and apparently no effect on ascariasis and hookworm infections. PMID:26540412

  15. A novel topical formulation containing strontium chloride significantly reduces the intensity and duration of cowhage-induced itch.

    PubMed

    Papoiu, Alexandru D P; Valdes-Rodriguez, Rodrigo; Nattkemper, Leigh A; Chan, Yiong-Huak; Hahn, Gary S; Yosipovitch, Gil

    2013-09-01

    The aim of this double-blinded, vehicle-controlled study was to test the antipruritic efficacy of topical strontium to relieve a nonhistaminergic form of itch that would be clinically relevant for chronic pruritic diseases. Itch induced with cowhage is mediated by PAR2 receptors which are considered to play a major role in itch of atopic dermatitis and possibly other acute and chronic pruritic conditions. The topical strontium hydrogel formulation (TriCalm®) was tested in a head-to-head comparison with 2 common topical formulations marketed as antipruritics: hydrocortisone and diphenhydramine, for their ability to relieve cowhage-induced itch. Topically-applied strontium salts were previously found to be effective for reducing histamine-induced and IgE-mediated itch in humans. However, histamine is not considered the critical mediator in the majority of skin diseases presenting with chronic pruritus. The current study enrolled 32 healthy subjects in which itch was induced with cowhage before and after skin treatment with a gel containing 4% SrCl2, control vehicle, topical 1% hydrocortisone and topical 2% diphenhydramine. Strontium significantly reduced the peak intensity and duration of cowhage-induced itch when compared to the control itch curve, and was significantly superior to the other two over-the-counter antipruritic agents and its own vehicle in antipruritic effect. We hereby show that a 4% topical strontium formulation has a robust antipruritic effect, not only against histamine-mediated itch, but also for non-histaminergic pruritus induced via the PAR2 pathway, using cowhage. PMID:23474847

  16. [Analysis of type 2 diabetes-induced late effects based on administrative data of social insurance in Austria and implications for the evaluation of the DMP diabetes mellitus].

    PubMed

    Großschädl, Franziska; Freidl, Wolfgang; Stronegger, Willibald J; Burkert, Nathalie T; Muckenhuber, Johanna; Rásky, Éva

    2014-08-01

    The present study analyses administrative data of medical services related to the distribution of diabetes mellitus type 2-induced late effects. Pseudonymous statutory health insurance data of all Austrian social security institutions for the years 2006/2007 in outpatient and inpatient (performance and diagnostic data) setting were used. Type 2 diabetics have been identified by prescribed medication. The specific late effects were defined as endpoints and the respective diagnoses and health performances were extracted. The study population included 7,945,774 insured. The percentage of the defined late effects was significantly higher in diabetics than in persons from the general population, with exception for kidney transplantation. The risk of a late effect was greatest among diabetics for an amputation. The results of this study can be used as a baseline for the evaluation of DMP diabetes. The administrative data used are limited for answering the defined research questions. Anyway, the data quality must be improved and unified in Austria.

  17. Inhalation administration of all-trans-retinoic acid for treatment of elastase-induced pulmonary emphysema in Fischer 344 rats.

    PubMed

    March, Thomas H; Cossey, Patricia Y; Esparza, Dolores C; Dix, Kelly J; McDonald, Jacob D; Bowen, Larry E

    2004-01-01

    A past study demonstrated that all-trans-retinoic acid (ATRA) treatment by intraperitoneal injection in a rat model of elastase-induced emphysema caused tissue regeneration as evidenced by a decrease in alveolar size and lung volume and an increase in alveolar number. We postulated that treatment with this retinoid by nose-only inhalation exposure would be a more efficient means of targeting damaged lung tissue. Emphysema was induced in male Fischer 344 rats by intratracheal instillation of pancreatic elastase (0.5 IU/g body weight). Four weeks after elastase instillation, animals were treated once daily, 4 days/week, for 3 weeks by exposing them nose-only to aerosolized ATRA (target concentration-time of 3000 or 15,000 mg-min/m3) or by injecting them intraperitoneally with ATRA in cottonseed oil (0.5 or 2.5 mg/kg). Based on estimates of particle deposition in the respiratory tract, inhalation doses were chosen to be consistent with injected doses. Lungs were fixed by inflation with formalin (constant pressure for 6 hours followed by >48 hours of immersion) and were embedded in paraffin. Sections were evaluated by histopathology and stereology. Inhalation exposure to ATRA at both aerosol concentrations caused significant elevations of ATRA in the lung, whereas only the high-dose injection treatment was associated with an elevation of lung ATRA. The mean ATRA concentration from lungs of rats in the high-dose inhalation exposure groups as measured by liquid chromatography--mass spectrometry was approximately 12-fold greater than that of high-dose injection-treated rats. Elastase instillation caused increased lung volumes, irregular alveolar air space enlargement, and fragmentation and attenuation of alveolar septa. Neither inhaled nor injected ATRA reduced the enlarged lung volumes associated with this emphysema model. Stereology demonstrated that alveolar air space enlargement in ATRA-treated rats was similar to that in sham-treated emphysematous animals. Thus

  18. Tactile cues significantly modulate the perception of sweat-induced skin wetness independently of the level of physical skin wetness.

    PubMed

    Filingeri, Davide; Fournet, Damien; Hodder, Simon; Havenith, George

    2015-06-01

    Humans sense the wetness of a wet surface through the somatosensory integration of thermal and tactile inputs generated by the interaction between skin and moisture. However, little is known on how wetness is sensed when moisture is produced via sweating. We tested the hypothesis that, in the absence of skin cooling, intermittent tactile cues, as coded by low-threshold skin mechanoreceptors, modulate the perception of sweat-induced skin wetness, independently of the level of physical wetness. Ten males (22 yr old) performed an incremental exercise protocol during two trials designed to induce the same physical skin wetness but to induce lower (TIGHT-FIT) and higher (LOOSE-FIT) wetness perception. In the TIGHT-FIT, a tight-fitting clothing ensemble limited intermittent skin-sweat-clothing tactile interactions. In the LOOSE-FIT, a loose-fitting ensemble allowed free skin-sweat-clothing interactions. Heart rate, core and skin temperature, galvanic skin conductance (GSC), and physical (w(body)) and perceived skin wetness were recorded. Exercise-induced sweat production and physical wetness increased significantly [GSC: 3.1 μS, SD 0.3 to 18.8 μS, SD 1.3, P < 0.01; w(body): 0.26 no-dimension units (nd), SD 0.02, to 0.92 nd, SD 0.01, P < 0.01], with no differences between TIGHT-FIT and LOOSE-FIT (P > 0.05). However, the limited intermittent tactile inputs generated by the TIGHT-FIT ensemble reduced significantly whole-body and regional wetness perception (P < 0.01). This reduction was more pronounced when between 40 and 80% of the body was covered in sweat. We conclude that the central integration of intermittent mechanical interactions between skin, sweat, and clothing, as coded by low-threshold skin mechanoreceptors, significantly contributes to the ability to sense sweat-induced skin wetness.

  19. Transfusion of murine RBCs expressing the human KEL glycoprotein induces clinically significant alloantibodies

    PubMed Central

    Stowell, Sean R.; Girard-Pierce, Kathryn R.; Smith, Nicole H.; Henry, Kate L.; Arthur, C. Maridith; Zimring, James C.; Hendrickson, Jeanne E.

    2013-01-01

    Background Red blood cell (RBC) alloantibodies to non-self antigens may develop following transfusion or pregnancy, leading to morbidity and mortality in the form of hemolytic transfusion reactions or hemolytic disease of the newborn. A better understanding of the mechanisms of RBC alloantibody induction, or strategies to mitigate the consequences of such antibodies, may ultimately improve transfusion safety. However, such studies are inherently difficult in humans. Study Design and Methods We recently generated transgenic mice with RBC specific expression of the human KEL glycoprotein, with the KEL2 or KEL1 antigens. Herein, we investigate recipient alloimmune responses to transfused RBCs in this system. Results Transfusion of RBCs from KEL2 donors into wild type recipients (lacking the human KEL protein but expressing the murine KEL orthologue) resulted in dose dependent anti-KEL glycoprotein IgM and IgG antibody responses, enhanced by recipient inflammation with poly (I:C). Boostable responses were evident upon repeat transfusion, with morbid appearing alloimmunized recipients experiencing rapid clearance of transfused KEL2 but not control RBCs. Although KEL1 RBCs were also immunogenic following transfusion into wild type recipients, transfusion of KEL1 RBCs into KEL2 recipients or vice versa failed to lead to detectable anti-KEL1 or anti-KEL2 responses. Conclusions This murine model, with reproducible and clinically significant KEL glycoprotein alloantibody responses, provides a platform for future mechanistic studies of RBC alloantibody induction and consequences. Long term translational goals of these studies include improving transfusion safety for at risk patients. PMID:23621760

  20. Percutaneous Perineal Electrostimulation Induces Erection: Clinical Significance in Patients With Spinal Cord Injury and Erectile Dysfunction

    PubMed Central

    Shafik, Ahmed; Shafik, Ali A; Shafik, Ismail A; Sibai, Olfat El

    2008-01-01

    Objectives: Approximately one third to one half of the penis is embedded in the pelvis and can be felt through the scrotum and in the perineum. The main arteries and nerves enter the penis through this perineal part of the penis, which seems to represent a highly sensitive area. We investigated the hypothesis that percutaneous perineal stimulation evokes erection in patients with neurogenic erectile dysfunction. Methods: Percutaneous electrostimulation of the perineum (PESP) with synchronous intracorporeal pressure (ICP) recording was performed in 28 healthy volunteers (age 36.3 ± 7.4 y) and 18 patients (age 36.6 ± 6.8 y) with complete neurogenic erectile dysfunction (NED). Current was delivered in a sine wave summation fashion. Average maximal voltages and number of stimulations delivered per session were 15 to 18 volts and 15 to 25 stimulations, respectively. Results: PESP of healthy volunteers effected an ICP increase (P < 0.0001), which returned to the basal value upon stimulation cessation. The latent period recorded was 2.5 ± 0.2 seconds. Results were reproducible on repeated PESP in the same subject but with an increase of the latent period. Patients with NED recorded an ICP increase that was lower (P < 0.05) and a latent period that was longer (P < 0.0001) than those of healthy volunteers. Conclusion: PESP effected ICP increase in the healthy volunteers and patients with NED. The ICP was significantly higher and latent period shorter in the healthy volunteers than in the NED patients. PESP may be of value in the treatment of patients with NED, provided that further studies are performed to reproduce these results. PMID:18533410

  1. Oral Administration of Achyranthis radix Extract Prevents TMA-induced Allergic Contact Dermatitis by Regulating Th2 Cytokine and Chemokine Production in Vivo.

    PubMed

    Jung, Sung Keun; Choi, Dae Woon; Kwon, Da-Ae; Kim, Min Jung; Seong, Ki Seung; Shon, Dong-Hwa

    2015-12-03

    Allergic contact dermatitis (ACD) remains a major skin disease in many countries, necessitating the discovery of novel and effective anti-ACD agents. In this study, we investigated the preventive effects of Achyranthis radix extract (AcRE) on trimellitic anhydride (TMA)-induced dermatitis and the potential mechanism of action involved. Oral administration of AcRE and prednisolone (PS) significantly suppressed TMA-induced increases in ear and epidermal thickness, and IgE expression. In addition, abnormal expression of IL-1β and TNF-α protein and mRNA was also significantly attenuated by oral administration of AcRE. Treatment with AcRE also significantly suppressed TMA-induced IL-4 and IL-13 cytokines and mRNA expression in vivo. Moreover, AcRE strongly suppressed TMA-induced IL-4 and IL-5 production in draining lymph nodes, as well as OVA-induced IL-4 and IL-5 expression in primary cultured splenocytes. Interestingly, AcRE suppressed IL-4-induced STAT6 phosphorylation in both primary cultured splenocytes and HaCaT cells, and TMA-induced GATA3 mRNA expression ex vivo. AcRE also suppressed TMA-mediated CCL11 and IL-4-induced CCL26 mRNA expression and infiltration of CCR3 positive cells. The major compounds from AcRE were identified as gentisic acid (0.64 ± 0.2 μg/g dry weight of AcRE), protocatechuic acid (2.69 ± 0.1 μg/g dry weight of AcRE), 4-hydroxybenzoic acid (5.59 ± 0.3 μg/g dry weight of AcRE), caffeic acid (4.21 ± 0.1 μg/g dry weight of AcRE), and ferulic acid (14.78 ± 0.4 ± 0.3 μg/g dry weight of AcRE). Taken together, these results suggest that AcRE has potential for development as an agent to prevent and treat allergic contact dermatitis.

  2. Administration of α-Galactosylceramide Improves Adenine-Induced Renal Injury

    PubMed Central

    Aguiar, Cristhiane Favero; Naffah-de-Souza, Cristiane; Castoldi, Angela; Corrêa-Costa, Matheus; Braga, Tárcio T; Naka, Érika L; Amano, Mariane T; Abate, Débora T R S; Hiyane, Meire I; Cenedeze, Marcos A; Filho, Alvaro Pacheco e Silva; Câmara, Niels O S

    2015-01-01

    Natural killer T (NKT) cells are a subset of lymphocytes that reacts to glycolipids presented by CD1d. Invariant NKT cells (iNKT) correspond to >90% of the total population of NKTs and reacts to α-galactosylceramide (αGalCer). αGalCer promotes a complex mixture of Th1 and Th2 cytokines, as interferon (IFN)-γ and interleukin (IL)-4. NKT cells and IFN-γ are known to participate in some models of renal diseases, but further studies are still necessary to elucidate their mechanisms. The aim of our study was to analyze the participation of iNKT cells in an experimental model of tubule-interstitial nephritis. We used 8-wk-old C57BL/6j, Jα18KO and IFN-γKO mice. They were fed a 0.25% adenine diet for 10 d. Both adenine-fed wild-type (WT) and Jα18KO mice exhibited renal dysfunction, but adenine-fed Jα18KO mice presented higher expression of kidney injury molecule-1 (KIM-1), tumor necrosis factor (TNF)-α and type I collagen. To analyze the role of activated iNKT cells in our model, we administered αGalCer in WT mice during adenine ingestion. After αGalCer injection, we observed a significant reduction in serum creatinine, proinflammatory cytokines and renal fibrosis. However, this improvement in renal function was not observed in IFN-γKO mice after αGalCer treatment and adenine feeding, illustrating that this cytokine plays a role in our model. Our findings may suggest that IFN-γ production is one of the factors contributing to improved renal function after αGalCer administration. PMID:26101952

  3. Single rapamycin administration induces prolonged downward shift in defended body weight in rats.

    PubMed

    Hebert, Mark; Licursi, Maria; Jensen, Brittany; Baker, Ashley; Milway, Steve; Malsbury, Charles; Grant, Virginia L; Adamec, Robert; Hirasawa, Michiru; Blundell, Jacqueline

    2014-01-01

    Manipulation of body weight set point may be an effective weight loss and maintenance strategy as the homeostatic mechanism governing energy balance remains intact even in obese conditions and counters the effort to lose weight. However, how the set point is determined is not well understood. We show that a single injection of rapamycin (RAP), an mTOR inhibitor, is sufficient to shift the set point in rats. Intraperitoneal RAP decreased food intake and daily weight gain for several days, but surprisingly, there was also a long-term reduction in body weight which lasted at least 10 weeks without additional RAP injection. These effects were not due to malaise or glucose intolerance. Two RAP administrations with a two-week interval had additive effects on body weight without desensitization and significantly reduced the white adipose tissue weight. When challenged with food deprivation, vehicle and RAP-treated rats responded with rebound hyperphagia, suggesting that RAP was not inhibiting compensatory responses to weight loss. Instead, RAP animals defended a lower body weight achieved after RAP treatment. Decreased food intake and body weight were also seen with intracerebroventricular injection of RAP, indicating that the RAP effect is at least partially mediated by the brain. In summary, we found a novel effect of RAP that maintains lower body weight by shifting the set point long-term. Thus, RAP and related compounds may be unique tools to investigate the mechanisms by which the defended level of body weight is determined; such compounds may also be used to complement weight loss strategy.

  4. Oral Administration of Herbal Mixture Extract Inhibits 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis in BALB/c Mice

    PubMed Central

    Kim, Soon Re; Choi, Han-Seok; Seo, Hye Sook; Ku, Jin Mo; Hong, Se Hyang; Shin, Yong Cheol; Ko, Seong-Gyu

    2014-01-01

    CP001 is four traditional herbal medicine mixtures with anti-inflammatory properties. In this study, we investigated the effect of oral administration of CP001 ethanol extract on the 2,4-dinitrochlorobenzene- (DNCB-) induced AD mouse models. For that purpose, we observed the effects of oral administration of CP001 on skin inflammatory cell infiltration, skin mast cells, production of serum IgE, and expression of Th2 cytokine mRNA in the AD skin lesions of DNCB treated BALB/c mice. Histological analyses demonstrated that CP001 decreased dermis and epidermis thickening as well as dermal infiltration induced by inflammatory cells. In addition, CP001 decreased mast cell infiltration in count as well as dermal infiltration induced by inflammatory cells. In the skin lesions, mRNA expression of interleukin- (IL-) 4 and IL-13 was inhibited by CP001. CP001 also reduced the production of IgE level in mouse plasma. In addition, we investigated the effect of CP001 on the inflammatory allergic reaction using human mast cells (HMC-1). In HMC-1, cytokine production and mRNA levels of IL-4, IL-13, IL-6, and IL-8 were suppressed by CP001. Taken together, our results showed that oral administration of CP001 exerts beneficial effects in AD symptoms, suggesting that CP001 might be a useful candidate for the treatment of AD. PMID:25132731

  5. The site of administration influences both the type and the magnitude of the immune response induced by DNA vaccine electroporation.

    PubMed

    Vandermeulen, Gaëlle; Vanvarenberg, Kevin; De Beuckelaer, Ans; De Koker, Stefaan; Lambricht, Laure; Uyttenhove, Catherine; Reschner, Anca; Vanderplasschen, Alain; Grooten, Johan; Préat, Véronique

    2015-06-22

    We investigated the influence of the site of administration of DNA vaccine on the induced immune response. DNA vaccines were administered by electroporation at three different sites: tibial cranial muscle, abdominal skin and ear pinna. Aiming to draw general conclusions about DNA vaccine delivery, we successively used several plasmids encoding either luciferase and ovalbumin as models or gp160 and P1A as vaccines against HIV and P815 mastocytoma, respectively. Low levels and duration of luciferase transgene expression were observed after electroporation of the abdominal skin, partly explaining its lower immunogenic performance as compared to the other sites of administration. Analyses of OT-I CD8+ and OT-II CD4+ T cell responses highlighted the differential impact of the delivery site on the elicited immune response. Muscle electroporation induced the strongest humoral immune response and both muscle and ear pinna sites induced cellular immunity against gp160. Ear pinna delivery generated the highest level of CTL responses against P1A but electroporation of muscle and ear pinna were equally efficient in delaying P815 growth and improving mice survival. The present study demonstrated that the site of administration is a key factor to be tested in the development of DNA vaccine.

  6. Candidatus Liberibacter americanus induces significant reprogramming of the transcriptome of the susceptible citrus genotype

    PubMed Central

    2013-01-01

    symptomatic and asymptomatic leaves infected with CaLam or CaLas. Conclusions Many gene transcripts and biological processes are significantly altered upon CaLam infection. Some of them had been identified in response to CaLas infection, while others had not been previously reported. These data will be useful for selecting target genes for genetic engineering to control HLB. PMID:23586643

  7. Administration of antioxidant peptide SS-31 attenuates transverse aortic constriction-induced pulmonary arterial hypertension in mice

    PubMed Central

    Lu, Hung-i; Huang, Tien-hung; Sung, Pei-hsun; Chen, Yung-lung; Chua, Sarah; Chai, Han-yan; Chung, Sheng-ying; Liu, Chu-feng; Sun, Cheuk-kwan; Chang, Hsueh-wen; Zhen, Yen-yi; Lee, Fan-yen; Yip, Hon-kan

    2016-01-01

    Aim: Antioxidant peptide SS-31 is a class of cell-permeable small peptides, which selectively resides on the inner mitochondrial membrane and possesses intrinsic mitochondrial protective capacities. In this study we investigated the therapeutic effects of antioxidant peptide SS-31 on transverse aortic constriction (TAC)-induced pulmonary arterial hypertension (PAH) in a murine model. Methods: Adult male mice were divided into 3 groups: sham-operated mice, TAC mice, and TAC+SS-31 mice that underwent TAC surgery and received SS-31 (2 mg/d, ip) for 60 d. The right ventricular systolic blood pressure (RVSBP) was measured on d 60 prior to sacrificing the mice; then their right heart and lung tissues were collected for histological and biochemical examinations. Lung injury scores were defined by the increased crowded area and decreased number of alveolar sacs. Results: TAC mice showed significantly higher RVSBP compared with sham-operated mice, the elevation was substantially suppressed in TAC+SS-31 mice. The same pattern of changes was found in pulmonary levels of oxidative stress proteins (NOX-1/NOX-2/oxidized proteins), cytosolic cytochrome c, biomarkers related to inflammation (MMP-9/TNF-α/iNOS), calcium overload index (TRPC1, 2, 4, 6), apoptosis (mitochondrial BAX, cleaved caspase 3/PARP), fibrosis (Smad3/TGF-β), hypoxic (HIF-1α), DNA damage (γ-H2AX) and endothelial function (eNOS/ET-1R), as well as in lung injury score, number of muscularized vessels in lungs, number of TRPC1+ and HIF-1α+ cells in pulmonary artery, and number of γ-H2AX+ and Ki-67+ cells in lung parenchyma. An opposite pattern of changes was observed in pulmonary anti-fibrotic markers (Smad1/5, BMP-2), number of small vessels, and number of alveolar sacs. In contrast, the levels of antioxidant proteins (HO-1/NQO-1/GR/GPx) in lung parenchyma were progressively and significantly increased from sham-operated mice, TAC mice to TAC+SS-31 mice. Conclusion: Antioxidant peptide SS-31 administration

  8. Tocilizumab's effect on cognitive deficits induced by intracerebroventricular administration of streptozotocin in Alzheimer's model.

    PubMed

    Elcioğlu, H Kübra; Aslan, Ersin; Ahmad, Sarfraz; Alan, Saadet; Salva, Emine; Elcioglu, Ö Haluk; Kabasakal, Levent

    2016-09-01

    Neuroinflammation plays pivotal roles in the pathogenesis of Alzheimer's disease (AD). IL-6 is pleiotropic cytokine which plays significant pathological role in inflammatory diseases and causes prolonged inflammation. Additionally, IL-6 activates microglia cells and enhances the accumulation of amyloid-β peptides. Moreover, IL-6 signal transduction is mediated by membrane-bound and soluble IL-6 receptors. Tocilizumab which is a humanized anti-human IL-6 receptor (IL-6R) monoclonal antibody binds to both of these receptors and inhibits IL-6 signaling by this route. The objective was to investigate tocilizumab's potential effects in the treatment of AD. Male Sprague-Dawley rats were divided into three groups: sham (control), streptozotocin (STZ), and tocilizumab-STZ. We used a single dose of intracerebroventricular (ICV) tocilizumab, beginning 1 h prior to injection of STZ for 3 weeks. The rats in STZ and tocilizumab-STZ groups were given ICV-STZ (3 mg/kg). Behavioral parameters were evaluated on days 17-20 and the rats were sacrificed on day-21 to examine histopathological changes. STZ injection caused significant decrease in the mean escape latency in passive avoidance and also declined the performance improvement in Morris water maze tests. Tocilizumab-STZ group significantly improved learning and spatial memory functions by increasing RLT in the passive avoidance and by shortening escape latency in reaching the platform in the Morris water maze. Histopathological changes were examined using hematoxylin and eosin and immunohistochemical (IHC) stainings. IHC analysis revealed that while protein expressions of amyloid-ß (3.5 ± 0.2) and IL-6 (2.9 ± 0.4) showed intense immune-positivity in STZ group, amyloid-ß (1.3 ± 0.1) and IL-6 (1.5 ± 0.2) immunoreactivities were substantially decreased in tocilizumab treatment group. We conclude that tocilizumab treatment attenuated significantly STZ-induced cognitive impairment and histopathological changes

  9. 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. PMID:23819045

  10. Prophylactic Administration of Silybin Ameliorates L-Arginine-Induced Acute Pancreatitis

    PubMed Central

    Uçmak, Feyzullah; Ekin, Nazım; İbiloğlu, İbrahim; Arslan, Serkan; Kaplan, İbrahim; Şenateş, Ebubekir

    2016-01-01

    Background Oxidative stress have been shown to play a role in the pathogenesis of acute pancreatitis. The aim of this study was to investigate the potential effect of silybin, a potent antioxidant, on L-arginine-induced acute pancreatitis in an experimental rat model. Material/Methods Forty female Wistar Albino rats were divided into 5 groups as follows: Group 1 (C): control group (n=8), Group 2 (SL): silybin group (n=8), Group 3 (LA): acute pancreatitis group (n=8), Group 4 (SLLA): prophylaxis group (n=8), and Group 5 (LASL): treatment group (n=8). Group C (control) received 2 intraperitoneal (i.p.) injections of physiological saline at an interval of 1 h. Group SL received only a single i.p. injection of silybin. The SLLA group received a single i.p. injection of silybin before the induction of acute pancreatitis with L-arginine, whereas the LASL group received the same injection after the induction of acute pancreatitis with L-arginine. Pancreatic tissues were histopathologically examined. Levels of amylase and oxidative stress markers (total oxidant status and total anti-oxidant status) were determined in the blood samples. Oxidative stress index was calculated. Results In comparison to the LA, the prophylaxis and treatment groups showed significant improvements in serum oxidative stress parameters (p=0.001 and p=0.005, respectively). Histopathological analysis showed that the treatment group had significant improvements in edema scores only (p=0.006), whereas the prophylaxis group had the same improvements in inflammation and necrosis scores as well as in total scores (p=0.004, 0.006, and 0.004, respectively). Conclusions When used for prophylactic rather than therapeutic purposes, silybin ameliorates serum oxidative stress parameters and improves histopathological results via its antioxidant and anti-inflammatory properties. PMID:27725627

  11. Chronic and acute alcohol administration induced neurochemical changes in the brain: comparison of distinct zebrafish populations.

    PubMed

    Chatterjee, Diptendu; Shams, Soaleha; Gerlai, Robert

    2014-04-01

    The zebrafish is increasingly utilized in the analysis of the effects of ethanol (alcohol) on brain function and behavior. We have shown significant population-dependent alcohol-induced changes in zebrafish behavior and have started to analyze alterations in dopaminergic and serotoninergic responses. Here, we analyze the effects of alcohol on levels of selected neurochemicals using a 2 × 3 (chronic × acute) between-subject alcohol exposure paradigm randomized for two zebrafish populations, AB and SF. Each fish first received the particular chronic treatment (0 or 0.5 vol/vol% alcohol) and subsequently the acute exposure (0, 0.5 or 1.0% alcohol). We report changes in levels of dopamine, DOPAC, serotonin, 5HIAA, glutamate, GABA, aspartate, glycine and taurine as quantified from whole brain extracts using HPLC. We also analyze monoamine oxidase and tyrosine hydroxylase enzymatic activity. The results demonstrate that compared to SF, AB is more responsive to both acute alcohol exposure and acute alcohol withdrawal at the level of neurochemistry, a finding that correlates well with prior behavioral observations and one which suggests the involvement of genes in the observed alcohol effects. We discuss correlations between the current results and prior behavioral findings, and stress the importance of characterization of zebrafish strains for future behavior genetic and psychopharmacology studies.

  12. Subchronic steroid administration induces long lasting changes in neurochemical and behavioral response to cocaine in rats.

    PubMed

    Kailanto, Sanna; Kankaanpää, Aino; Seppälä, Timo

    2011-11-01

    The abuse of anabolic androgenic steroids (AASs), such as nandrolone, is not only a problem in the world of sports but is associated with the polydrug use of non-athletes. Among other adverse effects, AAS abuse has been associated with long term or even persistent psychiatric problems. We have previously found that nandrolone decanoate treatment could produce prolonged changes in rats' brain reward circuits associated to drug dependence. The aim in this study was to evaluate whether AAS-induced neurochemical and behavioral changes are reversible. The increases in extracellular dopamine (DA) and serotonin (5-HT) concentration, as well as stereotyped behavior and locomotor activity (LMA) evoked by cocaine were attenuated by pretreatment with nandrolone. The recovery period, which was needed for the DA system to return back to the basic level, was fairly long compared to the dosing period of the steroid. In the 5-HT system, the time that system needed to return back to the basal level, was even longer than in the DA system. The attenuation was still seen though there were no detectable traces of nandrolone in the blood samples. Given that accumbal outflow of DA and 5-HT, as well as LMA and stereotyped behavior are all related to reward of stimulant drugs, this study suggests that nandrolone decanoate has significant, long-lasting but reversible effects on the rewarding properties of cocaine.

  13. Amelioration of alcohol-induced hepatotoxicity by the administration of ethanolic extract of Sida cordifolia Linn.

    PubMed

    Rejitha, S; Prathibha, P; Indira, M

    2012-10-01

    Sida cordifolia Linn. (Malvaceae) is a plant used in folk medicine for the treatment of the inflammation of oral mucosa, asthmatic bronchitis, nasal congestion and rheumatism. We studied the hepatoprotective activity of 50 % ethanolic extract of S. cordifolia Linn. against alcohol intoxication. The duration of the experiment was 90 d. The substantially elevated levels of toxicity markers such as alanine aminotransferase, aspartate aminotransferase and γ-glutamyl transferase due to the alcohol treatment were significantly lowered in the extract-treated groups. The activity of antioxidant enzymes and glutathione content, which was lowered due to alcohol toxicity, was increased to a near-normal level in the co-administered group. Lipid peroxidation products, protein carbonyls, total collagen and hydroxyproline, which were increased in the alcohol-treated group, were reduced in the co-administered group. The mRNA levels of cytochrome P450 2E1, NF-κB, TNF-α and transforming growth factor-β1 were found to be increased in the alcohol-treated rats, and their expressions were found to be decreased in the co-administered group. These observations were reinforced by histopathological analysis. Thus, the present study clearly indicates that 50 % ethanolic extract of the roots of S. cordifolia Linn. has a potent hepatoprotective action against alcohol-induced toxicity, which was mediated by lowering oxidative stress and by down-regulating the transcription factors.

  14. [Risk Factors for Oxaliplatin-Induced Phlebitis and Venous Pain, and Evaluation of the Preventive Effect of Preheating with a Hot Compress for Administration of Oxaliplatin].

    PubMed

    Nakauchi, Kana; Kawazoe, Hitoshi; Miyajima, Risa; Waizumi, Chieko; Rokkaku, Yuki; Tsuneoka, Kikue; Higuchi, Noriko; Fujiwara, Mitsuko; Kojima, Yoh; Yakushijin, Yoshihiro

    2015-11-01

    Venous pain induced by oxaliplatin(L-OHP)is a clinical issue related to adherence to the Cape OX regimen. To prevent LOHP- induced venous pain, we provided nursing care to outpatients who were administered a preheated L -OHP diluted solution using a hot compress. We retrospectively evaluated the risk factors for colorectal cancer patients who had L -OHP induced phlebitis and venous pain. Furthermore, the preventive effect of nursing care was compared between inpatients and outpatients from January 2010 to March 2012. At the L-OHP administration site, any symptoms were defined as phlebitis, whereas pain was defined as venous pain. A total of 132 treatment courses among 31 patients were evaluated. Multivariate logistic regression analysis revealed that both phlebitis and venous pain were significantly more common in female patients (adjusted odds ratio, 2.357; 95%CI: 1.053-5.418; and adjusted odds ratio, 5.754; 95%CI: 2.119-18.567, respectively). The prevalence of phlebitis and venous pain did not differ between inpatients and outpatients (phlebitis, 61.3% vs 67.7%; venous pain, 29.0%vs 19.4%). These results suggest that administration of L-OHP via a central venous route should be considered in female patients.

  15. How Much Calcium Is in Your Drinking Water? A Survey of Calcium Concentrations in Bottled and Tap Water and Their Significance for Medical Treatment and Drug Administration

    PubMed Central

    Morr, Simon; Cuartas, Esteban; Alwattar, Basil

    2006-01-01

    Introduction Different forms of water vary in calcium content. High divalent ion (i.e., Ca2+, Mg2+, etc.) concentration is deleterious to the absorption and efficacy of the bisphosphonate group of drugs in osteoporosis treatment. Water with high calcium concentration may also present an alternate pathway of calcium administration. In either case, knowing the actual concentration is critical. Hypothesis The current paper is a surveillance study. We hypothesize that there is considerable variation in the calcium concentrations in the various water sources: tap water from US and Canadian cities of different regions and purified, spring, and mineral bottled waters. In addition, we hypothesize that the water filter removes a significant amount of minerals including calcium from the water. Methodology Calcium concentrations in various city tap waters, as well as an assorted number of bottled waters, were determined through the direct inspection of scientific data. The effect of filtering was also determined by mineral analysis of mineral water directly before and after filtration. Result The calcium concentration of water varies from 1 to 135 mg/L across the USA and Canada. Most spring waters were found to have a relatively low calcium concentration, with an average of 21.8 mg/L. Purified waters contain a negligible calcium concentration. Mineral waters, on the other hand, were generally found to contain higher calcium concentrations, an average of 208 mg/L of calcium. Filtration was found to remove a considerable amount of calcium from the water, removing 89% on average. Conclusion Calcium concentration in water varied substantially from different sources in the USA and Canada. Bottled waters presented with concentrations of calcium covering a very large range. Certain tap and bottled waters present with concentrations of calcium sufficient to exhibit a deleterious effect on bisphosphonate treatment. Alternatively, certain waters may be used as a source of calcium

  16. Cocaine Self-Administration Experience Induces Pathological Phasic Accumbens Dopamine Signals and Abnormal Incentive Behaviors in Drug-Abstinent Rats

    PubMed Central

    Wang, Xuefei; Sugam, Jonathan A.; Carelli, Regina M.

    2016-01-01

    Chronic exposure to drugs of abuse is linked to long-lasting alterations in the function of limbic system structures, including the nucleus accumbens (NAc). Although cocaine acts via dopaminergic mechanisms within the NAc, less is known about whether phasic dopamine (DA) signaling in the NAc is altered in animals with cocaine self-administration experience or if these animals learn and interact normally with stimuli in their environment. Here, separate groups of rats self-administered either intravenous cocaine or water to a receptacle (controls), followed by 30 d of enforced abstinence. Next, all rats learned an appetitive Pavlovian discrimination and voltammetric recordings of real-time DA release were taken in either the NAc core or shell of cocaine and control subjects. Cocaine experience differentially impaired DA signaling in the core and shell relative to controls. Although phasic DA signals in the shell were essentially abolished for all stimuli, in the core, DA did not distinguish between cues and was abnormally biased toward reward delivery. Further, cocaine rats were unable to learn higher-order associations and even altered simple conditioned approach behaviors, displaying enhanced preoccupation with cue-associated stimuli (sign-tracking; ST) but diminished time at the food cup awaiting reward delivery (goal-tracking). Critically, whereas control DA signaling correlated with ST behaviors, cocaine experience abolished this relationship. These findings show that cocaine has persistent, differential, and pathological effects on both DA signaling and DA-dependent behaviors and suggest that psychostimulant experience may remodel the very circuits that bias organisms toward repeated relapse. SIGNIFICANCE STATEMENT Relapsing to drug abuse despite periods of abstinence and sincere attempts to quit is one of the most pernicious facets of addiction. Unfortunately, little is known about how the dopamine (DA) system functions after periods of drug abstinence

  17. Opioid-induced hyperalgesia and rapid opioid detoxification after tacrolimus administration.

    PubMed

    Siniscalchi, Antonio; Piraccini, Emanuele; Miklosova, Zuzana; Taddei, Stefania; Faenza, Stefano; Martinelli, Gerardo

    2008-02-01

    Opioids can induce central sensitization and hyperalgesia, referred to as "opioid-induced hyperalgesia." Our report describes a patient who underwent intestinal transplant followed by immunosuppressant-related neuropathic pain. Her pain was treated with limited success over the course of 3 yr with different therapies, including i.v. morphine. She developed opioid-induced hyperalgesia, which was successfully treated with rapid detoxification under general anesthesia. Detoxification improved her quality of life, including the ability to resume physiotherapy. Six months after treatment, she remained opioid free. Our experience suggests that rapid detoxification under general anesthesia may be an effective treatment for opioid-induced hyperalgesia and merits comparison to traditional detoxification methods.

  18. Withdrawal from repeated administration of morphine alters histamine-induced anxiogenic effects produced by intra-ventral hippocampal microinjection.

    PubMed

    Zarrindast, Mohammad-Reza; Khodarahmi, Parvin; Rezayof, Ameneh; Oryan, Shahrbano

    2010-06-01

    In the present study, the influence of withdrawal from repeated administration of morphine on intra-ventral hippocampal microinjection of histamine-induced anxiety-like behavior was investigated in male Wistar rats. Three days subcutaneous administration of morphine (5-10 mg/kg) followed by five days free of the drug decreased the percentage open arm time and the percentage open arm entries. Intra-ventral hippocampal administration of histamine (2.5-7.5 microg/rat) decreased percentage open arm time and percentage open arm entries. Intra-ventral hippocampal histamine-induced anxiogenic effect was reversed in animals that had previously received the three days morphine (7.5 mg/kg) followed by five days free of the drug. Intra-ventral hippocampal administration of pyrilamine (5-20 microg/rat) or ranitidine (10-40 microg/rat) decreased percentage open arm time and percentage open arm entries. Pyrilamine- or ranitidine-induced anxiogenic effect was not changed in animals that had previously received the three days morphine (7.5 mg/kg) followed by five days free of the drug. Intra-ventral hippocampal injections of clobenpropit increased percentage open arm time. The percentage open arm time and percentage open arm entries were decreased in the morphine-treated animals compared with non-morphine-treated controls. Percentage open arm entries and locomotor activity was reduced with some doses of clobenpropit. It can be concluded that the histamine system is involved in anxiety-like behavior, and repeated injections of morphine followed by five days free of the drugs interact with histamine receptor mechanism.

  19. Experimentally-induced immune activation in natural hosts of SIV induces significant increases in viral replication and CD4+ T cell depletion

    SciTech Connect

    Ribeiro, Ruy M

    2008-01-01

    Chronically SIVagm-infected African green monkeys (AGMs) have a remarkably stable non-pathogenic disease course, with levels of immune activation in chronic SIVagm infection similar to those observed in uninfected monkeys and stable viral loads (VLs) for long periods of time. In vivo administration of lipopolysaccharide (LPS) or an IL-2/diphtheria toxin fusion protein (Ontak) to chronically SIVagm-infected AGMs triggered increases in immune activation and subsequently of viral replication and depletion of intestinal CD4{sup +} T cells. Our study indicates that circulating microbial products can increase viral replication by inducing immune activation and increasing the number of viral target cells, thus demonstrating that immune activation and T cell prolifeation are key factors in AIDS pathogenesis.

  20. Enhancement of ovalbumin-induced pulmonary eosinophilia by intranasal administration of alpha1-proteinase inhibitor type 2 antisense oligonucleotides.

    PubMed

    Sung, Ha-Na; Jeon, Chang-Hwan; Gill, Byoung-Chul; Kim, Hye-Rin; Cheong, Sun-Woo; Park, Joo-Hung

    2009-01-29

    To identify asthma-susceptibility genes, we did proteome analyses of the lung from control and ovalbumin-sensitized BALB/c mice. Among the 6 up-regulated proteins is alpha(1)-protease inhibitor (alpha(1)-PI) type 2, which is a member of the serine protease inhibitor superfamily of protease inhibitors that participate in a variety of physiological functions, including extracellular matrix remodeling and inflammation. The up-regulated expression of alpha(1)-PI type 2 was confirmed by real-time PCR. Then we examined mRNA expression of five members of the alpha(1)-PI family genes (alpha(1)-PI types 1-5) in several organs of BALB/c mice and found that in addition to the liver, all the organs tested also expressed different isoforms of alpha(1)-PI in a tissue-specific manner, albeit to a lesser extent compared with the liver. When a similar study was performed with C57BL/6 mice, which have been shown to be more susceptible to ovalbumin-induced asthma than BALB/c mice, a pair of remarkable differences between the mouse strains were revealed: (1) the magnitude of alpha(1)-PI type 2 mRNA in all the organs was much higher in BALB/c than in C57BL/6 mice and (2) alpha(1)-PI type 2 is the only isoform expressed in the lung of BALB/c, but not of C57BL/c mice. Using the antisense oligonucleotide technology to specifically down-regulate expression of alpha(1)-PI type 2, we demonstrated that pulmonary infiltration of eosinophils was significantly increased by intranasal administration of alpha(1)-PI type 2 antisense oligonucleotides in OVA-sensitized mice, suggesting that alpha(1)-PI type 2 may suppress the progress of asthma, probably by acting on neutrophil elastase, which can produce many of the pathological features of asthma.

  1. Effect of prenatal forced-swim stress and morphine co-administration on pentylentetrazol-induced epileptic behaviors in infant and prepubertal rats.

    PubMed

    Ebrahimi, Loghman; Saboory, Ehsan; Roshan-Milani, Shiva; Hashemi, Paria

    2014-09-01

    Prenatal exposure to stress and morphine has complicated effects on epileptic seizure. Many reports have shown an interaction between morphine- and stress-induced behavioral changes in adult rats. In the present study, effect of prenatal forced-swim stress and morphine co-administration on pentylentetrazole (PTZ)-induced epileptic behaviors was investigated in rat offspring to address effect of the interaction between morphine and stress. Pregnant rats were divided to four groups of control-saline, control-morphine, stressed-saline and stressed-morphine. In the stressed group, the rats were placed in 25 °C water on 17-19 days of pregnancy. In the morphine/saline group, the rats received morphine/saline on the same days. In the morphine/saline-stressed group, they were exposed to stress and received morphine/saline simultaneously. On postnatal day 15 (P15), blood samples were collected to determine corticosterone (COS) level. On P15 and P25, PTZ was injected to the rest of pups to induce seizure. Then, epileptic behaviors of each rat were individually observed. Latency of tonic-colonic seizures decreased in control-morphine and stressed-saline groups while increasing in stressed-morphine rats compared to control-saline group on P15. Duration of tonic-colonic seizures significantly increased in control-morphine and stressed-saline rats compared to stressed-morphine and control-saline rats on P15, but not P25. COS levels increased in stressed-saline group but decreased in control-morphine group compared to control-saline rats. Body weight was significantly higher in morphine groups than saline treated rats. Prenatal exposure to forced-swim stress potentiated PTZ-induced seizure in the offspring rats. Co-administration of morphine attenuated effect of stress on body weight, COS levels, and epileptic behaviors.

  2. Levo-tetrahydropalmatine, a natural, mixed dopamine receptor antagonist, inhibits methamphetamine self-administration and methamphetamine-induced reinstatement.

    PubMed

    Gong, Xiaokang; Yue, Kai; Ma, Baomiao; Xing, Junqiao; Gan, Yongping; Wang, Daisong; Jin, Guozhang; Li, Chaoying

    2016-05-01

    Despite the high prevalence of methamphetamine (METH) use, no FDA-approved pharmacological treatment is currently available for individuals with a METH addiction. Levo-tetrahydropalmatine (l-THP) is an alkaloid substance derived from corydalis and stephania that has been used in traditional Asian medicine for its analgesic, sedative and hypnotic properties. Previous pharmacological studies of l-THP indicated that it not only binds to D1 and D2 receptors but also has a low affinity for D3 receptors and may function as an antagonist. The unique pharmacological profile of l-THP suggests that it may have potential therapeutic effects on drug addiction; however, the effects of l-THP in individuals with METH addictions are largely unknown. In this study, we investigated the effects of l-THP on METH self-administration and METH-induced reinstatement. In our experiments, l-THP (1.25, 2.50 and 5.00 mg/kg, i.p.) decreased METH self-administration under the fixed-ratio 1 schedule. l-THP (2.50 and 5.00 mg/kg, i.p) also prevented the METH-induced reinstatement of METH-seeking behaviors. Interestingly, l-THP (1.25 and 2.50mg/kg, i.p) did not affect locomotor activity following METH injection (1mg/kg) suggesting that the observed effects of l-THP (2.50mg/kg) on METH-induced reinstatement were not due to motor impairments. Thus, l-THP (a natural, mixed dopamine (DA) receptor antagonist) attenuates METH self-administration and METH-induced reinstatement. PMID:26806555

  3. Hibiscus sabdariffa ethanolic extract protects against dyslipidemia and oxidative stress induced by chronic cholesterol administration in rabbits.

    PubMed

    Ekor, M; Adesanoye, O A; Udo, I E; Adegoke, O A; Raji, J; Farombi, E O

    2010-12-01

    Excessive intake of cholesterol (CHOL) and induction of free radical production play a critical role in the pathophysiology of several human diseases. Dietary therapy with plant products rich in flavonoids has been shown to provide benefits without the adverse effects of agents used in clinical practice. Hibiscus sabdariffa (HS) has been used for various purposes due to myriads of flavonoids present in it. In this study, the chemopreventive property of HS ethanolic extract (HSE) was investigated in dyslipidemia and oxidant stress associated with prolonged CHOL administration in rabbits. Twenty-five (25) adult male rabbits weighing between 1.5 and 1.7 kg were used and randomly divided into five groups of five rabbits per group. The CHOL-fed rabbits received 1 g/kg/day of CHOL suspended in 1 ml of corn oil for 8 weeks. Group 1 received 1 ml of corn oil and served as control. Group 2 was fed with CHOL only while groups 3, 4 and 5 received daily doses ofcholestyramine (questran, 260 mg/kg), HSE 200 mg/kg and HSE 300 mg/kg respectively along with CHOL. Animals were sacrificed by cervical dislocation 24-hours after last dose. Enzymic and non-enzymic markers of oxidative stress and lipid profile were analysed in serum, liver, kidney and heart of rabbits. HSE significantly attenuated the alteration in lipid levels and antioxidant status induced by high CHOL intake in rabbits in this study. Both serum and tissue levels of low density lipoprotein-CHOL, triglycerides, phospholipids, and total CHOL decreased with increase in high density lipoprotein-CHOL except in the heart, following treatment with HSE in CHOL-fed rabbits when compared with the untreated group (p<0.05). Similarly, HSE prevented CHOL-induced depletion of enzymic (superoxide dismutase, catalase) and non-enzymic (reduced glutathione, vitamin C) antioxidants with the attendant increases in lipid peroxidation and xanthine oxidase activity in these animals. The effectiveness of HSE in this condition was comparable

  4. Effects of environmental enrichment on ERK1/2 phosphorylation in the rat prefrontal cortex following nicotine-induced sensitization or nicotine self-administration.

    PubMed

    Gomez, Adrian M; Sun, Wei-Lun; Midde, Narasimha M; Harrod, Steven B; Zhu, Jun

    2015-01-01

    Rats raised in an enriched condition (EC) exhibit alterations in the neurobiological and behavioral response to nicotine compared with rats reared in an impoverished condition (IC) or a standard condition (SC). The current study determined whether environmental enrichment differentially regulates extracellular signal-regulated kinase1/2 (ERK1/2) activity in the prefrontal cortex in rats following nicotine sensitization or nicotine self-administration. Under the saline control condition, EC rats displayed diminished baseline activity and greater sensitization to repeated administration of nicotine compared with IC and SC rats. After repeated saline injections, the basal levels of phosphorylated ERK1/2 (pERK1/2) were higher in EC compared with IC and SC rats, which was negatively correlated with their respective baseline activities. Repeated nicotine (0.35 mg/kg) injections induced pERK1/2 to similar levels in SC and IC rats; however, the induction of pERK1/2 in EC rats by nicotine was not significantly different from saline controls, owing to their high baseline. In the self-administration paradigm, EC rats self-administered less nicotine (0.03 mg/kg/infusion) relative to IC or SC rats on a fixed ratio-1 schedule of reinforcement. Accordingly, no differences in pERK1/2 were found between EC and IC rats self-administering saline, whereas nicotine self-administration resulted in an increase in pERK1/2 in IC rats but not in EC rats. Furthermore, the levels of pERK1/2 in EC and IC rats were positively correlated with their respective total number of nicotine infusions. Thus, these findings suggest that environmental enrichment alters the basal and nicotine-mediated pERK1/2, which may contribute to enrichment-induced behavioral alterations in response to nicotine.

  5. Effects of environmental enrichment on ERK1/2 phosphorylation in the rat prefrontal cortex following nicotine-induced sensitization or nicotine self-administration

    PubMed Central

    Gomez, Adrian M.; Sun, Wei-Lun; Midde, Narasimha M.; Harrod, Steven B.; Zhu, Jun

    2014-01-01

    Rats raised in an enriched condition (EC) exhibit alterations in the neurobiological and behavioral response to nicotine compared to rats reared in an impoverished condition (IC) or a standard condition (SC). The current study determined whether environmental enrichment differentially regulates extracellular signal-regulated kinase1/2 (ERK1/2) activity in the prefrontal cortex (PFC) in rats following nicotine sensitization or nicotine self-administration. Under the saline control condition, EC rats displayed diminished baseline activity, and greater sensitization to repeated administration of nicotine compared to IC and SC rats. After repeated saline injections, the basal levels of phosphorylated ERK1/2 (pERK1/2) were higher in EC compared to IC and SC rats, which was negatively correlated with their respective baseline activities. Repeated nicotine (0.35 mg/kg) injections induced pERK1/2 to similar levels in SC and IC rats; however, the induction of pERK1/2 in EC rats by nicotine was not significantly different from saline controls, owing to their high baseline. In the self-administration paradigm, EC rats self-administered less nicotine (0.03 mg/kg/infusion) relative to IC or SC rats on a fixed ratio-1 schedule of reinforcement. Accordingly, no differences in pERK1/2 were found between EC and IC rats self-administering saline, whereas nicotine self-administration resulted in an increase in pERK1/2 in IC rats but not in EC rats. Furthermore, the levels of pERK1/2 in EC and IC rats were positively correlated with their respective total number of nicotine infusions. Thus, these findings suggest that environmental enrichment alters the basal and nicotine-mediated pERK1/2, which may contribute to enrichment-induced behavioral alterations in response to nicotine. PMID:25328101

  6. Neuregulin-1 Administration Protocols Sufficient for Stimulating Cardiac Regeneration in Young Mice Do Not Induce Somatic, Organ, or Neoplastic Growth

    PubMed Central

    Ganapathy, Balakrishnan; Nandhagopal, Nikitha; Polizzotti, Brian D.; Bennett, David; Asan, Alparslan; Wu, Yijen; Kühn, Bernhard

    2016-01-01

    Background We previously developed and validated a strategy for stimulating heart regeneration by administration of recombinant neuregulin (rNRG1), a growth factor, in mice. rNRG1 stimulated proliferation of heart muscle cells, cardiomyocytes, and was most effective when administration began during the neonatal period. Our results suggested the use of rNRG1 to treat pediatric patients with heart failure. However, administration in this age group may stimulate growth outside of the heart. Methods NRG1 and ErbB receptor expression was determined by RT-PCR. rNRG1 concentrations in serum were quantified by ELISA. Mice that received protocols of recombinant neuregulin1-β1 administration (rNRG1, 100 ng/g body weight, daily subcutaneous injection for the first month of life), previously shown to induce cardiac regeneration, were examined at pre-determined intervals. Somatic growth was quantified by weighing. Organ growth was quantified by MRI and by weighing. Neoplastic growth was examined by MRI, visual inspection, and histopathological analyses. Phospho-ERK1/2 and S6 kinase were analyzed with Western blot and ELISA, respectively. Results Lung, spleen, liver, kidney, brain, and breast gland exhibited variable expression of the NRG1 receptors ErbB2, ErbB3, ErbB4, and NRG1. Body weight and tibia length were not altered in mice receiving rNRG1. MRI showed that administration of rNRG1 did not alter the volume of the lungs, liver, kidneys, brain, or spinal cord. Administration of rNRG1 did not alter the weight of the lungs, spleen, liver, kidneys, or brain. MRI, visual inspection, and histopathological analyses showed no neoplastic growth. Follow-up for 6 months showed no alteration of somatic or organ growth. rNRG1 treatment increased the levels of phospho-ERK1/2, but not phospho-S6 kinase. Conclusions Administration protocols of rNRG1 for stimulating cardiac regeneration in mice during the first month of life did not induce unwanted growth effects. Further studies may be

  7. A Tetravalent Sub-unit Dengue Vaccine Formulated with Ionizable Cationic Lipid Nanoparticle induces Significant Immune Responses in Rodents and Non-Human Primates

    PubMed Central

    Swaminathan, Gokul; Thoryk, Elizabeth A.; Cox, Kara S.; Smith, Jeffrey S.; Wolf, Jayanthi J.; Gindy, Marian E.; Casimiro, Danilo R.; Bett, Andrew J.

    2016-01-01

    Dengue virus has emerged as an important arboviral infection worldwide. As a complex pathogen, with four distinct serotypes, the development of a successful Dengue virus vaccine has proven to be challenging. Here, we describe a novel Dengue vaccine candidate that contains truncated, recombinant, Dengue virus envelope protein from all four Dengue virus serotypes (DEN-80E) formulated with ionizable cationic lipid nanoparticles (LNPs). Immunization studies in mice, Guinea pigs, and in Rhesus macaques, revealed that LNPs induced high titers of Dengue virus neutralizing antibodies, with or without co-administration or encapsulation of a Toll-Like Receptor 9 agonist. Importantly, LNPs were also able to boost DEN-80E specific CD4+ and CD8+ T cell responses. Cytokine and chemokine profiling revealed that LNPs induced strong chemokine responses without significant induction of inflammatory cytokines. In addition to being highly efficacious, the vaccine formulation proved to be well-tolerated, demonstrating no elevation in any of the safety parameters evaluated. Notably, reduction in cationic lipid content of the nanoparticle dramatically reduced the LNP’s ability to boost DEN-80E specific immune responses, highlighting the crucial role for the charge of the LNP. Overall, our novel studies, across multiple species, reveal a promising tetravalent Dengue virus sub-unit vaccine candidate. PMID:27703172

  8. Sucrose administration to partially hepatectomized rats: a possible model to study ethanol-induced inhibition of liver regeneration.

    PubMed

    Gutiérrez-Salinas, J; Aranda-Fraustro, A; Paredes-Díaz, R; Hernández-Muñoz, R

    1996-09-01

    Although acute ethanol treatment drastically inhibits liver regeneration after partial hepatectomy, the exact mechanisms involved remain obscure. On the other hand, it is known that early carbohydrate administration promotes a more successful restoration of the liver mass. Therefore, carbohydrate administration could be an experimental approach for studying ethanol action on the regenerating liver. In rats subjected to two-thirds partial hepatectomy, ethanol was administered alone or in combination with a variety of carbohydrates (glucose, fructose, glucose plus fructose, sucrose and maltose). In liver samples, regeneration parameters and histological assessment were performed. Blood ethanol and metabolites reflecting liver function were assayed. Ethanol intake strongly decreased the incorporation of [3H]thymidine into liver DNA, the concentration of DNA/g of tissue, and thymidine kinase activity. In this group, severe alterations in cell structure (i.e. abundant fat droplets and abnormal mitochondria) were found. Carbohydrates readily improved the survival rate of ethanol-intoxicated hepatectomized rats. Sucrose was effective in reverting the ethanol-induced alterations in liver structure and the parameters of liver regeneration, and partially blocked the ethanol-induced alterations in serum levels of albumin, triacylglycerols and ammonia without modifying the blood levels and clearance of ethanol. Data suggest that the beneficial action of sucrose might be related to an adequate supply of energetic sources at early times of liver regeneration, rather than altering ethanol bioavailability. Thus, the present model could be an experimental approach for studying the metabolic alterations involved in the ethanol-induced inhibition of the liver regeneration.

  9. Oral Administration of Linoleic Acid Induces New Vessel Formation and Improves Skin Wound Healing in Diabetic Rats

    PubMed Central

    Rodrigues, Hosana G.; Vinolo, Marco A. R.; Sato, Fabio T.; Magdalon, Juliana; Kuhl, Carolina M. C.; Yamagata, Ana S.; Pessoa, Ana Flávia M.; Malheiros, Gabriella; dos Santos, Marinilce F.; Lima, Camila; Farsky, Sandra H.; Camara, Niels O. S.; Williner, Maria R.; Bernal, Claudio A.; Calder, Philip C.; Curi, Rui

    2016-01-01

    Introduction Impaired wound healing has been widely reported in diabetes. Linoleic acid (LA) accelerates the skin wound healing process in non-diabetic rats. However, LA has not been tested in diabetic animals. Objectives We investigated whether oral administration of pure LA improves wound healing in streptozotocin-induced diabetic rats. Methods Dorsal wounds were induced in streptozotocin-induced type-1 diabetic rats treated or not with LA (0.22 g/kg b.w.) for 10 days. Wound closure was daily assessed for two weeks. Wound tissues were collected at specific time-points and used to measure fatty acid composition, and contents of cytokines, growth factors and eicosanoids. Histological and qPCR analyses were employed to examine the dynamics of cell migration during the healing process. Results LA reduced the wound area 14 days after wound induction. LA also increased the concentrations of cytokine-induced neutrophil chemotaxis (CINC-2αβ), tumor necrosis factor-α (TNF-α) and leukotriene B4 (LTB4), and reduced the expression of macrophage chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1 (MIP-1). These results together with the histological analysis, which showed accumulation of leukocytes in the wound early in the healing process, indicate that LA brought forward the inflammatory phase and improved wound healing in diabetic rats. Angiogenesis was induced by LA through elevation in tissue content of key mediators of this process: vascular-endothelial growth factor (VEGF) and angiopoietin-2 (ANGPT-2). Conclusions Oral administration of LA hastened wound closure in diabetic rats by improving the inflammatory phase and angiogenesis. PMID:27764229

  10. Tolerance to the locomotor-activating effects of 3,4-methylenedioxymethamphetamine (MDMA) predicts escalation of MDMA self-administration and cue-induced reinstatement of MDMA seeking in rats.

    PubMed

    Ball, Kevin T; Slane, Mylissa

    2014-11-01

    Pre-clinical studies of individual differences in addiction vulnerability have been increasing over recent years, but the amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) has received relatively little attention in this regard. Previously, we reported large individual differences both in rats' initial behavioral response to experimenter-administered MDMA and their degree of behavioral sensitization to repeated administration. To determine whether these differences could predict subsequent patterns of MDMA-taking or -seeking behaviors we used the self-administration-extinction-reinstatement model to examine addiction-like behavior (i.e., escalation of MDMA self-administration and cue-induced reinstatement of MDMA seeking) in rats a priori characterized for either locomotor sensitization or tolerance to MDMA. Rats that developed tolerance to the locomotor-activating effects of MDMA had a significantly larger locomotor response to the first MDMA injection relative to rats that developed sensitization. Importantly, rats that developed tolerance subsequently displayed an escalation of MDMA self-administration over days, as well as clear cue-induced reinstatement of MDMA seeking following extinction. Conversely, rats that developed locomotor sensitization to MDMA subsequently maintained relatively stable levels of MDMA self-administration over days and showed no cue-induced reinstatement of MDMA seeking. These results show that differences in the level of psychomotor activation following acute and repeated MDMA administration can reliably predict two important addiction-like behaviors in rats, which may have implications in the prediction of compulsive MDMA use in humans.

  11. Administration of activated glial condition medium in the nucleus accumbens extended extinction and intensified reinstatement of methamphetamine-induced conditioned place preference.

    PubMed

    Arezoomandan, Reza; Moradi, Marzieh; Attarzadeh-Yazdi, Ghassem; Tomaz, Carlos; Haghparast, Abbas

    2016-07-01

    Methamphetamine (METH) is a psychostimulant drug with significant abuse potential and neurotoxic effects. A high percentage of users relapse to use after detoxification and no effective medication has been developed for treatment of METH addiction. Developing evidences indicated the role of glial cells in drugs abused related phenomena. However, little is known about the role of these cells in the maintenance and reinstatement of METH-seeking behaviors. Therefore, the current study was conducted to clarify the role of glial cells in the maintenance and reinstatement of METH-induced conditioned place preference (CPP) in rats. Astrocyte condition medium (ACM) and neuroglia conditioned medium (NCM) are liquid mediums prepared from primary astrocyte and neuroglia cells. These mediums seem to contain many factors that release by glia cells. CPP was induced by systemic administration of METH (1mg/kg for 5days, s.c.). Following the establishment of CPP, the rats were given daily bilateral injections (0.5μl/side) of either vehicle, ACM or NCM into the nucleus accumbens (NAc) and then were tested for the maintenance and reinstatement. Intra-NAc administration of ACM treated with METH, could extend the extinction period and also, intensified the magnitude of METH reinstatement. Furthermore, intra-accumbal administration of NCM treated with METH notably delayed the extinction period by four days and significantly increased the magnitude of CPP score in the reinstatement phase compared to the post-test phase. Collectively, these findings suggested that activation of glial cells may be involved in the maintenance and reinstatement of METH-seeking behaviors. It provides new evidence that glia cells might be considered as a potential target for the treatment of METH addiction. PMID:27346277

  12. Oral administration of Aloe vera gel powder prevents UVB-induced decrease in skin elasticity via suppression of overexpression of MMPs in hairless mice.

    PubMed

    Saito, Marie; Tanaka, Miyuki; Misawa, Eriko; Yao, Ruiquing; Nabeshima, Kazumi; Yamauchi, Kouji; Abe, Fumiaki; Yamamoto, Yuki; Furukawa, Fukumi

    2016-07-01

    This study reports the effects of oral Aloe vera gel powder (AVGP) containing Aloe sterols on skin elasticity and the extracellular matrix in ultraviolet B (UVB)-irradiated hairless mice. Ten-week-old hairless mice were fed diets containing 0.3% AVGP for 8 weeks and irradiated UVB for 6 weeks. Mice treated with AVGP showed significant prevention of the UVB-induced decrease in skin elasticity. To investigate the mechanism underlying this suppression of skin elasticity loss, we measured the expression of matrix metalloproteinase (MMP)-2, -9, and -13. AVGP prevented both the UVB-induced increases in MMPs expressions. Moreover, we investigated hyaluronic acid (HA) content of mice dorsal skin and gene expression of HA synthase-2 (Has2). In the results, AVGP oral administration prevented UVB-induced decreasing in skin HA content and Has2 expression and attenuates the UVB-induced decrease in serum adiponectin, which promotes Has2 expression. These results suggested that AVGP has the ability to prevent the skin photoaging. PMID:27045316

  13. Prevention of haloperidol-induced alterations in brain acetylcholinesterase activity by vitamins B co-administration in a rodent model of tardive dyskinesia.

    PubMed

    de Oliveira, Gersilene Valente; Gomes, Patrícia Xavier Lima; de Araújo, Fernanda Yvelize Ramos; Vasconcelos, Silvânia Maria Mendes; Júnior, Hélio Vitoriano Nobre; de Sousa, Francisca Cléa Florenço; de Lucena, David F; Hyphantis, Thomas N; Carvalho, André Férrer; Macêdo, Danielle Silveira

    2013-03-01

    Tardive dyskinesia (TD) is an iatrogenic syndrome being a significant adverse outcome of typical and atypical antipsychotic therapy. Recently we demonstrated that vitamins B (B1, B6, B12 alone or in combination) were able to prevent haloperidol-induced orofacial dyskinesia (OD) possibly by their antioxidant activity in the striatum, using a well-established model of TD. Here, based on the fact that alterations in cholinergic neurotransmission are related to TD pathophysiology and that vitamins B seems to influence brain cholinergic neurotransmission, we decided to investigate the effects of vitamins B1, B6, B12 and their association, vitamin B cocktail in haloperidol-induced cholinergic alterations, evaluated by alterations in acetylcholinesterase (AChE) activity, in striatum, prefrontal cortex and hippocampus, as a way to determine the participation of cholinergic neurotransmission, in these vitamins antidyskinetic mechanism. Haloperidol 1 mg/kg i.p. daily administration during 21 days to Wistar rats caused OD while decreased AChE activity in all brain areas studied. Vitamins B administration (B1:B6:B12 at 60:60:0.6 mg/kg, s.c) alone and vitamin B cocktail co-administered with haloperidol prevented OD development and increased AChE activity in all brain areas studied, with the maximum activity increment observed in the hippocampus of the animals co-treated with vitamin B12 and vitamin B cocktail. The antidyskinetic drug, clozapine did not induce OD and increased AChE activity similarly to the groups coadministered with vitamin B and HAL. The present data suggest that vitamins B can prevent haloperidol-induced alterations in AChE activity what can be related to the mechanism underlying their antidyskinetic effect.

  14. Intravenous Administration of Bone Marrow-Derived Mesenchymal Stem Cells Induces a Switch from Classical to Atypical Symptoms in Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Kurte, Mónica; Bravo-Alegría, Javiera; Torres, Alexander; Carrasco, Vania; Ibáñez, Cristina; Vega-Letter, Ana María; Fernández-O'Ryan, Catalina; Irarrázabal, Carlos E.; Figueroa, Fernando E.; Fuentealba, Rodrigo A.; Riedel, Claudia; Carrión, Flavio

    2015-01-01

    Potent immunosuppressive and regenerative properties of mesenchymal stem cells (MSCs) position them as a novel therapy for autoimmune diseases. This research examines the therapeutic effect of MSCs administration at different disease stages in experimental autoimmune encephalomyelitis (EAE). Classical and atypical scores of EAE, associated with Th1 and Th17 response, respectively, and also Treg lymphocytes, were evaluated. MSCs administration at the onset (EAE+MSConset) induced an important amelioration of the clinical signs and less lasting effect at the peak of EAE (EAE+MSCpeak). No effect was observed when MSCs were applied after EAE stabilization (EAE+MSClate). Surprisingly, EAE atypical signs were detected in EAE+MSCpeak and EAE+MSClate mice. However, no correlation was found in Th17/Th1 ratio. Interestingly, regardless of time administration, MSCs significantly reduced IL-6 and also T-bet, RORγT, and Foxp3 mRNA levels in brain samples of EAE mice. The downregulation of IL-6 could restore the well-functioning of the blood-brain barrier of EAE mice, correlated with a decreased number of brain infiltrating leukocytes. These results suggest that the inflammatory status is important to be considered for administering MSCs in autoimmune pathologies, leading to a further research to clarify the effect of MSCs for multiple sclerosis. PMID:25838828

  15. Oral administration of diphenylarsinic acid, a degradation product of chemical warfare agents, induces oxidative and nitrosative stress in cerebellar Purkinje cells.

    PubMed

    Kato, Koichi; Mizoi, Mutsumi; An, Yan; Nakano, Masayuki; Wanibuchi, Hideki; Endo, Ginji; Endo, Yoko; Hoshino, Mikio; Okada, Shoji; Yamanaka, Kenzo

    2007-11-10

    A new clinical syndrome with prominent cerebellar symptoms in patients living in Kamisu City, Ibaraki Prefecture, Japan, is described. Since the patients ingested drinking water containing diphenylarsinic acid (DPA), a stable degradation product of both diphenylcyanoarsine and diphenylchloroarsine, which were developed for use as chemical weapons and cause severe vomiting and sneezing, DPA was suspected of being responsible for the clinical syndrome. The purpose of the present study was to elucidate prominent cerebellar symptoms due to DPA. The aim of the study was to determine if single (15 mg/kg) or continuous (5 mg/kg/day for 5 weeks) oral administration of DPA to ICR-strain mice induced oxidative and/or nitrosative stress in their brain. Significantly positive staining with malondialdehyde (MDA) and 3-nitrotyrosine (3-NT) was observed in the cerebellar Purkinje cells by repeated administration (5 mg/kg/day) with DPA for 5 weeks that led to the cerebellar symptoms from a behavioral pharmacology standpoint and by single administration of DPA (15 mg/kg). Furthermore, it is possible that the production of 3-NT was not caused by peroxynitrite formation. The present results suggest the possibility that arsenic-associated novel active species may be a factor underlying the oxidative and nitrosative stress in Purkinje cells due to exposure to DPA, and that the damage may lead to the cerebellar symptoms.

  16. Administration of caffeine inhibited adenosine receptor agonist-induced decreases in motor performance, thermoregulation, and brain neurotransmitter release in exercising rats.

    PubMed

    Zheng, Xinyan; Hasegawa, Hiroshi

    2016-01-01

    We examined the effects of an adenosine receptor agonist on caffeine-induced changes in thermoregulation, neurotransmitter release in the preoptic area and anterior hypothalamus, and endurance exercise performance in rats. One hour before the start of exercise, rats were intraperitoneally injected with either saline alone (SAL), 10 mg kg(-1) caffeine and saline (CAF), a non-selective adenosine receptor agonist (5'-N-ethylcarboxamidoadenosine [NECA]: 0.5 mg kg(-1)) and saline (NECA), or the combination of caffeine and NECA (CAF+NECA). Rats ran until fatigue on the treadmill with a 5% grade at a speed of 18 m min(-1) at 23 °C. Compared to the SAL group, the run time to fatigue (RTTF) was significantly increased by 52% following caffeine administration and significantly decreased by 65% following NECA injection (SAL: 91 ± 14.1 min; CAF: 137 ± 25.8 min; NECA: 31 ± 13.7 min; CAF+NECA: 85 ± 11.8 min; p<0.05). NECA decreased the core body temperature (Tcore), oxygen consumption, which is an index of heat production, tail skin temperature, which is an index of heat loss, and extracellular dopamine (DA) release at rest and during exercise. Furthermore, caffeine injection inhibited the NECA-induced decreases in the RTTF, Tcore, heat production, heat loss, and extracellular DA release. Neither caffeine nor NECA affected extracellular noradrenaline or serotonin release. These results support the findings of previous studies showing improved endurance performance and overrides in body limitations after caffeine administration, and imply that the ergogenic effects of caffeine may be associated with the adenosine receptor blockade-induced increases in brain DA release.

  17. Administration of caffeine inhibited adenosine receptor agonist-induced decreases in motor performance, thermoregulation, and brain neurotransmitter release in exercising rats.

    PubMed

    Zheng, Xinyan; Hasegawa, Hiroshi

    2016-01-01

    We examined the effects of an adenosine receptor agonist on caffeine-induced changes in thermoregulation, neurotransmitter release in the preoptic area and anterior hypothalamus, and endurance exercise performance in rats. One hour before the start of exercise, rats were intraperitoneally injected with either saline alone (SAL), 10 mg kg(-1) caffeine and saline (CAF), a non-selective adenosine receptor agonist (5'-N-ethylcarboxamidoadenosine [NECA]: 0.5 mg kg(-1)) and saline (NECA), or the combination of caffeine and NECA (CAF+NECA). Rats ran until fatigue on the treadmill with a 5% grade at a speed of 18 m min(-1) at 23 °C. Compared to the SAL group, the run time to fatigue (RTTF) was significantly increased by 52% following caffeine administration and significantly decreased by 65% following NECA injection (SAL: 91 ± 14.1 min; CAF: 137 ± 25.8 min; NECA: 31 ± 13.7 min; CAF+NECA: 85 ± 11.8 min; p<0.05). NECA decreased the core body temperature (Tcore), oxygen consumption, which is an index of heat production, tail skin temperature, which is an index of heat loss, and extracellular dopamine (DA) release at rest and during exercise. Furthermore, caffeine injection inhibited the NECA-induced decreases in the RTTF, Tcore, heat production, heat loss, and extracellular DA release. Neither caffeine nor NECA affected extracellular noradrenaline or serotonin release. These results support the findings of previous studies showing improved endurance performance and overrides in body limitations after caffeine administration, and imply that the ergogenic effects of caffeine may be associated with the adenosine receptor blockade-induced increases in brain DA release. PMID:26604076

  18. [Preventive trial of preheating administration of oxaliplatin-diluted solution in combination with a hot compress for oxaliplatin-induced venous pain].

    PubMed

    Miyajima, Risa; Kawazoe, Hitoshi; Tsuneoka, Kikue; Fujiwara, Mitsuko; Kojima, Yoh; Yakushijin, Yoshihiro

    2013-04-01

    Venous pain induced by oxaliplatin (L-OHP) is a clinical problem in relation to adherence in the CapeOX regimen. We investigated the preventive effect of nursing care preheating administration of L-OHP a hot compress for colorectal cancer patients who received L-OHP via the peripheral venous route between January 2010 and January 2011. L-OHP was diluted in 500 mL of 5% glucose and administered by 2 hours. We evaluated a total of 64 courses among fifteen patients. The presence of any symptoms, any pain with or without touch, and some symptoms of numbness at the L-OHP-administered arm were defined as phlebitis, venous pain, and acute peripheral neuropathy, respectively. The prevalence of phlebitis, venous pain, and acute peripheral neuropathy in the nursing care group was 56.5%, 32.6%, and 25.8%, respectively, which was not significantly less in comparison with the control group (72.2%, 38.9%, and 54.5%, respectively). These results suggest that both types of nursing care, preheating administration and a hot compress, may be effective for the relief of acute peripheral neuropathy induced by L-OHP.

  19. Sublingual administration of bacteria-expressed influenza virus hemagglutinin 1 (HA1) induces protection against infection with 2009 pandemic H1N1 influenza virus.

    PubMed

    Shim, Byoung-Shik; Choi, Jung-Ah; Song, Ho-Hyun; Park, Sung-Moo; Cheon, In Su; Jang, Ji-Eun; Woo, Sun Je; Cho, Chung Hwan; Song, Min-Suk; Kim, Hyemi; Song, Kyung Joo; Lee, Jae Myun; Kim, Suhng Wook; Song, Dae Sub; Choi, Young Ki; Kim, Jae-Ouk; Nguyen, Huan Huu; Kim, Dong Wook; Bahk, Young Yil; Yun, Cheol-Heui; Song, Man Ki

    2013-02-01

    Influenza viruses are respiratory pathogens that continue to pose a significantly high risk of morbidity and mortality of humans worldwide. Vaccination is one of the most effective strategies for minimizing damages by influenza outbreaks. In addition, rapid development and production of efficient vaccine with convenient administration is required in case of influenza pandemic. In this study, we generated recombinant influenza virus hemagglutinin protein 1 (sHA1) of 2009 pandemic influenza virus as a vaccine candidate using a well-established bacterial expression system and administered it into mice via sublingual (s.l.) route. We found that s.l. immunization with the recombinant sHA1 plus cholera toxin (CT) induced mucosal antibodies as well as systemic antibodies including neutralizing Abs and provided complete protection against infection with pandemic influenza virus A/CA/04/09 (H1N1) in mice. Indeed, the protection efficacy was comparable with that induced by intramuscular (i.m.) immunization route utilized as general administration route of influenza vaccine. These results suggest that s.l. vaccination with the recombinant non-glycosylated HA1 protein offers an alternative strategy to control influenza outbreaks including pandemics. PMID:23456722

  20. An oral DNA vaccine against infectious haematopoietic necrosis virus (IHNV) encapsulated in alginate microspheres induces dose-dependent immune responses and significant protection in rainbow trout (Oncorrhynchus mykiss).

    PubMed

    Ballesteros, Natalia A; Alonso, Marta; Saint-Jean, Sylvia Rodríguez; Perez-Prieto, Sara I

    2015-08-01

    Administered by intramuscular injection, a DNA vaccine (pIRF1A-G) containing the promoter regions upstream of the rainbow trout interferon regulatory factor 1A gene (IRF1A) driven the expression of the infectious hematopoietic necrosis virus (IHNV) glycoprotein (G) elicited protective immune responses in rainbow trout (Oncorhynchus mykiss). However, less laborious and cost-effective routes of DNA vaccine delivery are required to vaccinate large numbers of susceptible farmed fish. In this study, the pIRF1A-G vaccine was encapsulated into alginate microspheres and orally administered to rainbow trout. At 1, 3, 5, and 7 d post-vaccination, IHNV G transcripts were detected by quantitative real-time PCR in gills, spleen, kidney and intestinal tissues of vaccinated fish. This result suggested that the encapsulation of pIRF1A-G in alginate microparticles protected the DNA vaccine from degradation in the fish stomach and ensured vaccine early delivery to the hindgut, vaccine passage through the intestinal mucosa and its distribution thought internal and external organs of vaccinated fish. We also observed that the oral route required approximately 20-fold more plasmid DNA than the injection route to induce the expression of significant levels of IHNV G transcripts in kidney and spleen of vaccinated fish. Despite this limitation, increased IFN-1, TLR-7 and IgM gene expression was detected by qRT-PCR in kidney of vaccinated fish when a 10 μg dose of the oral pIRF1A-G vaccine was administered. In contrast, significant Mx-1, Vig-1, Vig-2, TLR-3 and TLR-8 gene expression was only detected when higher doses of pIRF1A-G (50 and 100 μg) were orally administered. The pIRF1A-G vaccine also induced the expression of several markers of the adaptive immune response (CD4, CD8, IgM and IgT) in kidney and spleen of immunized fish in a dose-dependent manner. When vaccinated fish were challenged by immersion with live IHNV, evidence of a dose-response effect of the oral vaccine could also

  1. Spinal tumors induced by neonatal administration of N-ethyl-N-nitrosourea in Wistar rats.

    PubMed

    Naito, M; Naito, Y; Ito, A

    1981-02-01

    The carcinogenic effect of N-ethyl-N-nitrosourea (ENU) administered by single neonatal injection (40 mg/kg) was examined in wistar rats. By 2 months after ENU administration, 30% of the examined animals had spinal cord tumors. After months all rats had neurogenic tumors, and the incidence of spinal tumor was as high as 86%. Spinal cord tumors were observed at all levels of the white matter of the spinal cord without any predilection site, though spinal root tumors were located exclusively on lumbosacral plexuses. Most of the spinal cord tumors were oligodedrogliomas or glioependymomas, whereas all the spinal root tumors were anaplastic schwannomas.

  2. Significance of Cystatin C for Early Diagnosis of Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography.

    PubMed

    Wang, Mian; Zhang, Li; Yue, Rongzheng; You, Guiying; Zeng, Rui

    2016-01-01

    BACKGROUND Contrast-induced nephropathy is acute kidney injury caused by contrast medium exposure. Serum creatinine is the clinical diagnostic standard, but it does not yield quick results. The serum level of cystatin C is stable and it can reflect renal function sensitively. The study aimed to assess the usefulness of cystatin C for early diagnosis of contrast-induced nephropathy in patients undergoing coronary angiography. MATERIAL AND METHODS We included 300 patients who underwent CAG. According to the sCr at 48 h, patients were divided into 2 groups: CIN group and non-CIN group. Their demographics and basal renal function were recorded. Changes in sCr, Cys C, and e GFR were compared at the same time. ROC analysis was used to assess the sensitivity and specificity of Cys C in the early diagnosis of CIN. RESULTS Comparison of basal renal function and serum level of Cys C showed no significant differences between the 2 groups. Serum level of Cys C increased significantly at 24 h (p<0.001), and sCr increased significantly at 48 h. ROC analysis showed that the AUC of the change in Cys C between baseline and 24 h was 0.936 (95% CI: 0.879-0.992, p=0.000) and the optimum cut-off level was 0.26 mg/L (sensitivity=89.7% and specificity=95.6%). CONCLUSIONS The concentration change of Cys C is better than sCr as a biomarker in the early detection of CIN. PMID:27548357

  3. Significance of Cystatin C for Early Diagnosis of Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography

    PubMed Central

    Wang, Mian; Zhang, Li; Yue, Rongzheng; You, Guiying; Zeng, Rui

    2016-01-01

    Background Contrast-induced nephropathy is acute kidney injury caused by contrast medium exposure. Serum creatinine is the clinical diagnostic standard, but it does not yield quick results. The serum level of cystatin C is stable and it can reflect renal function sensitively. The study aimed to assess the usefulness of cystatin C for early diagnosis of contrast-induced nephropathy in patients undergoing coronary angiography. Material/Methods We included 300 patients who underwent CAG. According to the sCr at 48 h, patients were divided into 2 groups: CIN group and non-CIN group. Their demographics and basal renal function were recorded. Changes in sCr, Cys C, and e GFR were compared at the same time. ROC analysis was used to assess the sensitivity and specificity of Cys C in the early diagnosis of CIN. Results Comparison of basal renal function and serum level of Cys C showed no significant differences between the 2 groups. Serum level of Cys C increased significantly at 24 h (p<0.001), and sCr increased significantly at 48 h. ROC analysis showed that the AUC of the change in Cys C between baseline and 24 h was 0.936 (95% CI: 0.879–0.992, p=0.000) and the optimum cut-off level was 0.26 mg/L (sensitivity=89.7% and specificity=95.6%). Conclusions The concentration change of Cys C is better than sCr as a biomarker in the early detection of CIN. PMID:27548357

  4. Differential antagonism of cocaine self-administration and cocaine-induced disruptions of learning by haloperidol in rhesus monkeys.

    PubMed

    Winsauer, Peter J; Moerschbaecher, Joseph M; Roussell, Alison M

    2008-03-01

    Six rhesus monkeys responding under a three-component multiple schedule were administered haloperidol to determine its effects on cocaine self-administration and on cocaine's disruptive effects on the repeated acquisition and performance of response chains. In the absence of haloperidol, 0.0032-0.032 mg/kg/infusion of cocaine increased response rate and the number of infusions in the self-administration component when compared to saline administration, whereas 0.1-0.32 mg/kg/infusion decreased response rate and the number of infusions. When compared to saline administration, the two lowest infusion doses of cocaine had little or no effect on responding in the acquisition and performance components; however, higher infusion doses of cocaine dose-dependently decreased response rate in these components. In addition, the higher doses of cocaine also increased the percentage of errors in the acquisition and performance components. Pretreatment with haloperidol (0.0032 or 0.01 mg/kg, i.m.) antagonized the effects of low doses of cocaine on the number of infusions in the self-administration component, whereas only the 0.01-mg/kg dose antagonized the effects of high doses of cocaine on the number of infusions. Neither dose of haloperidol antagonized the rate-decreasing effects of cocaine on responding in the acquisition and performance components significantly; the highest dose of haloperidol alone decreased rates of responding in each component. Antagonism of cocaine's error-increasing effects by haloperidol was only evident at one dose of cocaine (0.032 mg/kg/infusion), and was more complete in the performance components than in the acquisition components. Together, these data show the limited suitability of haloperidol for selectively antagonizing cocaine self-administration in the context of a multiple schedule involving transition behavior, and show the lack of uniform antagonism across operant behaviors. PMID:18422020

  5. Differential Antagonism of Cocaine Self-Administration and Cocaine-Induced Disruptions of Learning by Haloperidol in Rhesus Monkeys

    PubMed Central

    Winsauer, Peter J; Moerschbaecher, Joseph M; Roussell, Alison M

    2008-01-01

    Six rhesus monkeys responding under a three-component multiple schedule were administered haloperidol to determine its effects on cocaine self-administration and on cocaine's disruptive effects on the repeated acquisition and performance of response chains. In the absence of haloperidol, 0.0032–0.032 mg/kg/infusion of cocaine increased response rate and the number of infusions in the self-administration component when compared to saline administration, whereas 0.1–0.32 mg/kg/infusion decreased response rate and the number of infusions. When compared to saline administration, the two lowest infusion doses of cocaine had little or no effect on responding in the acquisition and performance components; however, higher infusion doses of cocaine dose-dependently decreased response rate in these components. In addition, the higher doses of cocaine also increased the percentage of errors in the acquisition and performance components. Pretreatment with haloperidol (0.0032 or 0.01 mg/kg, i.m.) antagonized the effects of low doses of cocaine on the number of infusions in the self-administration component, whereas only the 0.01-mg/kg dose antagonized the effects of high doses of cocaine on the number of infusions. Neither dose of haloperidol antagonized the rate-decreasing effects of cocaine on responding in the acquisition and performance components significantly; the highest dose of haloperidol alone decreased rates of responding in each component. Antagonism of cocaine's error-increasing effects by haloperidol was only evident at one dose of cocaine (0.032 mg/kg/infusion), and was more complete in the performance components than in the acquisition components. Together, these data show the limited suitability of haloperidol for selectively antagonizing cocaine self-administration in the context of a multiple schedule involving transition behavior, and show the lack of uniform antagonism across operant behaviors. PMID:18422020

  6. Stimulatory effect of oral administration of tea, coffee or caffeine on UVB-induced apoptosis in the epidermis of SKH-1 mice

    SciTech Connect

    Conney, Allan H. Zhou, Sherry; Lee Maojung; Xie Jianguo; Yang, Chung S.; Lou Yourong; Lu Yaoping

    2007-11-01

    Oral administration of green tea or a caffeine solution, but not decaffeinated green tea, inhibits UVB-induced complete carcinogenesis in SKH-1 mice. Oral administration of green tea, coffee or a caffeine solution for 2 weeks enhanced UVB-induced increases in apoptosis in the epidermis, but these treatments had no effect in non-UVB treated normal epidermis. Our results suggest that administration of green tea, coffee and caffeine may inhibit UVB-induced carcinogenesis - at least in part - by enhancing UVB-induced apoptosis. Plasma levels of caffeine observed after its oral administration at cancer-preventive dose levels were within the range observed in moderate coffee drinkers. Topical applications of caffeine to mice previously treated with UVB for 20 weeks (high risk mice without tumors) inhibited the formation of tumors and stimulated apoptosis in the tumors but not in areas of the epidermis away from tumors. The selective effects of caffeine administration to stimulate UVB-induced apoptosis or apoptosis in tumors but not in normal epidermis or in areas of the epidermis away from tumors is of considerable interest, but the reasons for the selective effects of caffeine on apoptosis in DNA damaged tissues are unknown. Further studies are needed to determine mechanisms of these effects of caffeine and to determine the effects of caffeine administration on sunlight-induced actinic keratoses and squamous cell carcinomas in humans.

  7. Stimulatory effect of oral administration of tea, coffee or caffeine on UVB-induced apoptosis in the epidermis of SKH-1 mice.

    PubMed

    Conney, Allan H; Zhou, Sherry; Lee, Mao-Jung; Xie, Jian Guo; Yang, Chung S; Lou, You Rong; Lu, YaoPing

    2007-11-01

    Oral administration of green tea or a caffeine solution, but not decaffeinated green tea, inhibits UVB-induced complete carcinogenesis in SKH-1 mice. Oral administration of green tea, coffee or a caffeine solution for 2 weeks enhanced UVB-induced increases in apoptosis in the epidermis, but these treatments had no effect in non-UVB treated normal epidermis. Our results suggest that administration of green tea, coffee and caffeine may inhibit UVB-induced carcinogenesis--at least in part--by enhancing UVB-induced apoptosis. Plasma levels of caffeine observed after its oral administration at cancer-preventive dose levels were within the range observed in moderate coffee drinkers. Topical applications of caffeine to mice previously treated with UVB for 20 weeks (high risk mice without tumors) inhibited the formation of tumors and stimulated apoptosis in the tumors but not in areas of the epidermis away from tumors. The selective effects of caffeine administration to stimulate UVB-induced apoptosis or apoptosis in tumors but not in normal epidermis or in areas of the epidermis away from tumors is of considerable interest, but the reasons for the selective effects of caffeine on apoptosis in DNA damaged tissues are unknown. Further studies are needed to determine mechanisms of these effects of caffeine and to determine the effects of caffeine administration on sunlight-induced actinic keratoses and squamous cell carcinomas in humans.

  8. Estradiol administration to ovariectomized rats potentiates mephedrone-induced disruptions of nonspatial learning.

    PubMed

    Weed, Peter F; Leonard, Stuart T; Sankaranarayanan, Ananthakrishnan; Winsauer, Peter J

    2014-03-01

    Mephedrone (4-methylmethcathinone) has been found in several over-the-counter products that are abused by humans, but very little is known about its behavioral effects and abuse liability. The present study examined the effects of mephedrone (1-10 mg/kg) on learning in female rats, as well as its interaction with the ovarian hormone estradiol. More specifically, female rats were trained to respond under a multiple schedule of repeated acquisition and performance of response sequences and then ovariectomized. Following ovariectomy, mephedrone dose-effect curves were obtained during periods of 17β-estradiol administration and periods without estradiol administration. Unlike mephedrone, which was administered acutely (i.p.) before the experimental sessions, 17β-estradiol was administered via subcutaneous Silastic capsules containing 25% 17β-estradiol and 75% cholesterol. In general, mephedrone produced dose-dependent rate-decreasing and error-increasing effects in the acquisition and performance components of the schedule in all subjects. However, when estradiol was present, three of the four rats were more sensitive to the rate-decreasing effects of mephedrone, and all of the subjects were more sensitive to its error-increasing effects. These data indicate that estradiol can potentiate the disruptive effects of mephedrone on both the acquisition and performance of complex behavior in female rats.

  9. Thermal conditions influence changes in body temperature induced by intragastric administration of capsaicin in mice.

    PubMed

    Mori, Noriyuki; Urata, Tomomi; Fukuwatari, Tsutomu

    2016-08-01

    Capsaicin has been reported to have unique thermoregulatory actions. However, changes in core temperature after the administration of capsaicin are a controversial point. Therefore, we investigated the effects of environmental thermal conditions on changes in body temperature caused by capsaicin in mice. We showed that intragastric administration of 10 and 15 mg/kg capsaicin increased tail temperature and decreased colonic temperatures in the core temperature (CT)-constant and CT-decreasing conditions. In the CT-increasing condition, 15 mg/kg capsaicin increased tail temperature and decreased colonic temperature. However, 10 mg/kg capsaicin increased colonic temperature. Furthermore, the amount of increase in tail temperature was greater in the CT-decreasing condition and lower in the CT-increasing condition, compared with that of the CT-constant condition. These findings suggest that the changes in core temperature were affected by the environmental thermal conditions and that preliminary thermoregulation state might be more important than the constancy of temperature to evaluate the effects of heat diffusion and thermogensis.

  10. Effect of perioperative somatostatin administration of sphincteroplasty-induced increase of amylase.

    PubMed

    Roncoroni, L; De Bernardinis, M; Violi, V; Montanari, M; Peracchia, A

    1986-06-01

    Twenty patients undergoing sphincteroplasty for cholelithiasis were randomly divided into two groups of 10. The former (T) were treated with a 4-h somatostatin intravenous drip (250 micrograms/h), started at the beginning of operation, while the latter (C) made up the control group. Serum and urine amylase, amylase creatinine clearance ratio, and liver function tests were assessed for 2 days before surgery, after the operation and for a period of 5 postoperative days. Homogeneity between the two series was verified in experimental conditions. Statistical differences occurred postoperatively in amylase creatinine clearance ratio, which proved higher in C group, and gamma-GT, which was higher in T group. Short-term somatostatin administration proved effective in reducing the postoperative amylase creatinine clearance ratio, although more evident results are reported after long-term administration. Cholestasis or any serious impairment in liver function did not occur, suggesting the suitability of somatostatin use even in patients with jaundice. Since a relationship between postoperative amylase levels and risk of pancreatitis has not yet been proved, the value of somatostatin in the prevention of postoperative pancreatitis after sphincteroplasty needs to be further verified.

  11. Nicotine self-administration induces CB1-dependent LTP in the bed nucleus of the stria terminalis.

    PubMed

    Reisiger, Anne-Ruth; Kaufling, Jennifer; Manzoni, Olivier; Cador, Martine; Georges, François; Caillé, Stephanie

    2014-03-19

    Nicotine addiction is characterized by repetitive drug taking and drug seeking, both tightly controlled by cannabinoid CB1 receptors. The responsiveness of neurons of the bed nucleus of the stria terminalis (BNST) to infralimbic cortex (ILCx) excitatory inputs is increased in rats with active, but not passive, nicotine taking. Therefore, we hypothesize that acquisition of the learned association between nicotine infusion and a paired cue light permits the strengthening of the ILCx-BNST synapses after ILCx tetanic stimulation. We exposed rats to intravenous nicotine self-administration for 2 months. Using a combination of in vivo protocols (electrical stimulations, extracellular recordings, and pharmacological manipulations), we characterized the effects of 10 Hz stimulation of the ILCx on BNST excitatory responses, under different conditions of exposure to nicotine. In addition, we tested whether the effects of the stimulation were CB1 receptor-dependent. The results show that nicotine self-administration supports the induction of evoked spike potentiation in the BNST in response to 10 Hz stimulation of ILCx afferents. Although not altered by nicotine abstinence, this cellular adaptation was blocked by CB1 receptor antagonism. Moreover, blockade of BNST CB1 receptors prevented increases in time-out responding subsequent to ILCx stimulation and decreased cue-induced reinstatement. Thus, the synaptic potentiation within the BNST in response to ILCx stimulation seems to contribute to the cue-elicited responding associated with nicotine self-administration and is tightly controlled by CB1 receptors.

  12. Benefits of Preventive Administration of Chlorella sp. on Visceral Pain and Cystitis Induced by a Single Administration of Cyclophosphamide in Female Wistar Rat.

    PubMed

    Hidalgo-Lucas, Sophie; Rozan, Pascale; Guérin-Deremaux, Laetitia; Baert, Blandine; Violle, Nicolas; Saniez-Degrave, Marie-Hélène; Bisson, Jean-François

    2016-05-01

    Chlorella sp. is a green microalgae containing nutrients, vitamins, minerals, and chlorophyll. In some communities, Chlorella sp. is a traditional medicinal plant used for the management of inflammation-related diseases. In a rat model, ROQUETTE Chlorella sp. (RCs) benefits were investigated on visceral pain and associated inflammatory parameters related to cystitis both induced by cyclophosphamide (CYP). RCs was orally administered every day from day 1-16 (250 and 500 mg/kg body weight). Six hours after an intraperitoneal injection of 200 mg/kg body weight of CYP, body temperature, general behavior, food intake, and body weight were recorded. Twenty-four hours after CYP injection, rats were tested in two behavioral tests, an open field and the aversive light stimulus avoidance conditioning test, to evaluate the influence of pain on general activity and learning ability of rats. After euthanasia, bladders were weighed, their thickness was scored, and the urinary hemoglobin was measured. RCs orally administered at the two dosages significantly reduced visceral pain and associated inflammatory parameters related to cystitis both induced by CYP injection, and improved rat behavior. To conclude, RCs demonstrated beneficial effects against visceral pain and cystitis. PMID:27152976

  13. Oral administration of Lactobacillus paracasei alleviates clinical symptoms of colitis induced by dextran sulphate sodium salt in BALB/c mice.

    PubMed

    Pan, T; Guo, H Y; Zhang, H; Liu, A P; Wang, X X; Ren, F Z

    2014-09-01

    The aim of this study was to investigate the alleviating effect of Lactobacillus paracasei subsp. paracasei LC-01 (LC-01) on the murine model of colitis induced by dextran sulphate sodium (DSS). 50 pathogen-free, 6-week-old male BALB/c mice were divided randomly into 5 groups, including a control group and four DSS-LC-01-treated groups (DSS, DSS-106, DSS-108, and DSS-1010 with 0, 1×106, 1×108 and 1×1010 cfu/ml LC-01, respectively). To test the effectiveness of LC-01 as a prophylactic it was administered for 7 days before the onset of the disease in DSS-LC-01-treated mice. After 7 days, colitis was induced by administration of 2.5% (w/v) DSS in drinking water for a further 7 days. The disease activity index (DAI), histological score, myeloperoxidase (MPO) activity and the level of the pro-inflammatory cytokines interleukin-1β (IL-1β) and tumour necrosis factor α (TNF-α) were measured. DAI, histological scores and MPO activity of mice treated with a medium or high dose of LC-01 were significantly lower compared to a low-dose of LC-01 and DSS treatment alone (P<0.05). Colon length shortening could be prevented with increasing dose of LC-01. In addition, the levels of IL-1β and TNF-α were suppressed significantly by treatment with a medium and high dose of LC-01. However, no significant difference in the indices mentioned above were observed between a low dose of LC-01 and treatment with DSS alone (P≯0.05). An appropriate dose of LC-01 can prevent intestinal damage in mice with DSS-induced colitis. The expression of inflammatory cytokines related to pathogenesis of DSS-induced colitis decreased following treatment with LC-01. PMID:24889889

  14. Sex-Dependent Depression-Like Behavior Induced by Respiratory Administration of Aluminum Oxide Nanoparticles.

    PubMed

    Zhang, Xin; Xu, Yan; Zhou, Lian; Zhang, Chengcheng; Meng, Qingtao; Wu, Shenshen; Wang, Shizhi; Ding, Zhen; Chen, Xiaodong; Li, Xiaobo; Chen, Rui

    2015-12-09

    Ultrafine aluminum oxide, which are abundant in ambient and involved occupational environments, are associated with neurobehavioral alterations. However, few studies have focused on the effect of sex differences following exposure to environmental Al₂O₃ ultrafine particles. In the present study, male and female mice were exposed to Al₂O₃ nanoparticles (NPs) through a respiratory route. Only the female mice showed depression-like behavior. Although no obvious pathological changes were observed in mice brain tissues, the neurotransmitter and voltage-gated ion channel related gene expression, as well as the small molecule metabolites in the cerebral cortex, were differentially modulated between male and female mice. Both mental disorder-involved gene expression levels and metabolomics analysis results strongly suggested that glutamate pathways were implicated in sex differentiation induced by Al₂O₃ NPs. Results demonstrated the potential mechanism of environmental ultrafine particle-induced depression-like behavior and the importance of sex dimorphism in the toxic research of environmental chemicals.

  15. Trace administration of vitamin E can retrieve and prevent UV-irradiation- and metal exposure-induced memory deficits in nematode Caenorhabditis elegans.

    PubMed

    Ye, Huayue; Ye, Boping; Wang, Dayong

    2008-07-01

    Vitamin E (alpha-tocopherol), a lipid-soluble anti-oxidant, prevents the uncontrolled propagation of lipid peroxidation by free radicals. Nevertheless, there is weak or no evidence of a protective effect of previous vitamin E intake on cognitive function in humans. In the present study, we explored the thermosensation model to investigate the possible effects of vitamin E administration on memory behaviors in Caenorhabditis elegans. Administration of 100 and 200microg/mL of vitamin E had no significant effects on the memory for different time intervals, whereas relatively high concentration (400microg/mL) of vitamin E exposure shortened the extinction period of the association paradigm (food at 20 degrees C). Following the UV-irradiation, post-treatment with 200microg/mL of vitamin E not only retrieved the UV-irradiation-induced memory deficits, but also enhanced the memory functions in UV-irradiating animals. Post-treatment with trace vitamin E could also ameliorate the memory deficits in metal (Al or Pb) exposed worms. In addition, pre-treatment with 200microg/mL of vitamin E could effectively prevent the occurrence of memory deficits induced by metal exposure and UV-irradiation. Therefore, the close association may exist between trace dietary vitamin E intake and memory behaviors, and a specific response mechanism may be activated after the administration of vitamin E in stress-exposed animals. Moreover, treatment with 200microg/mL of vitamin E could restore the memory deficits formed in the ncs-1 mutant worms, suggesting that exogenous treatment with trace vitamin E can largely mimic the function of NCS-1 in regulating the memory for thermosensation.

  16. Oral Administration of P. gingivalis Induces Dysbiosis of Gut Microbiota and Impaired Barrier Function Leading to Dissemination of Enterobacteria to the Liver

    PubMed Central

    Nakajima, Mayuka; Arimatsu, Kei; Kato, Tamotsu; Matsuda, Yumi; Minagawa, Takayoshi; Takahashi, Naoki; Ohno, Hiroshi; Yamazaki, Kazuhisa

    2015-01-01

    Although periodontitis has been implicated as a risk factor for various systemic diseases, the precise mechanisms by which periodontitis induces systemic disease remain to be elucidated. We have previously revealed that repeated oral administration of Porphyromonas gingivalis elicits endotoxemia via changes in the gut microbiota of the ileum, and thereby induces systemic inflammation and insulin resistance. However, it is not clear to what extent a single administration of P. gingivalis could affect gut microbiota composition, gut barrier function, and subsequent influx of gut microbiota into the liver. Therefore, in the present study, C57BL/6 mice were orally administered P. gingivalis (strain W83) once and compared to sham-inoculated mice. The phylogenetic structure and diversity of microbial communities in the gut and liver were analyzed by pyrosequencing the 16S ribosomal RNA genes. Serum endotoxin activity was determined by a Limulus amebocyte lysate test. Gene expression in the intestine and expression of 16S rRNA genes in the blood and liver were examined by quantitative polymerase chain reaction. Administration of P. gingivalis significantly altered gut microbiota, with an increased proportion of phylum Bacteroidetes, a decreased proportion of phylum Firmicutes, and increased serum endotoxin levels. In the intestinal tissues, gene expression of tjp-1 and occludin, which are involved in intestinal permeability, were downregulated. Higher amounts of bacterial DNA were detected in the liver of infected mice. Importantly, changes in gut microbiota preceded systemic inflammatory changes. These results further support the idea that disturbance of the gut microbiota composition by orally derived periodontopathic bacteria may be a causal mechanism linking periodontitis and systemic disease. PMID:26218067

  17. Oral Administration of P. gingivalis Induces Dysbiosis of Gut Microbiota and Impaired Barrier Function Leading to Dissemination of Enterobacteria to the Liver.

    PubMed

    Nakajima, Mayuka; Arimatsu, Kei; Kato, Tamotsu; Matsuda, Yumi; Minagawa, Takayoshi; Takahashi, Naoki; Ohno, Hiroshi; Yamazaki, Kazuhisa

    2015-01-01

    Although periodontitis has been implicated as a risk factor for various systemic diseases, the precise mechanisms by which periodontitis induces systemic disease remain to be elucidated. We have previously revealed that repeated oral administration of Porphyromonas gingivalis elicits endotoxemia via changes in the gut microbiota of the ileum, and thereby induces systemic inflammation and insulin resistance. However, it is not clear to what extent a single administration of P. gingivalis could affect gut microbiota composition, gut barrier function, and subsequent influx of gut microbiota into the liver. Therefore, in the present study, C57BL/6 mice were orally administered P. gingivalis (strain W83) once and compared to sham-inoculated mice. The phylogenetic structure and diversity of microbial communities in the gut and liver were analyzed by pyrosequencing the 16S ribosomal RNA genes. Serum endotoxin activity was determined by a Limulus amebocyte lysate test. Gene expression in the intestine and expression of 16S rRNA genes in the blood and liver were examined by quantitative polymerase chain reaction. Administration of P. gingivalis significantly altered gut microbiota, with an increased proportion of phylum Bacteroidetes, a decreased proportion of phylum Firmicutes, and increased serum endotoxin levels. In the intestinal tissues, gene expression of tjp-1 and occludin, which are involved in intestinal permeability, were downregulated. Higher amounts of bacterial DNA were detected in the liver of infected mice. Importantly, changes in gut microbiota preceded systemic inflammatory changes. These results further support the idea that disturbance of the gut microbiota composition by orally derived periodontopathic bacteria may be a causal mechanism linking periodontitis and systemic disease. PMID:26218067

  18. The dopamine receptor antagonist levo-tetrahydropalmatine attenuates heroin self-administration and heroin-induced reinstatement in rats.

    PubMed

    Yue, Kai; Ma, Baomiao; Ru, Qin; Chen, Lin; Gan, Yongping; Wang, Daisong; Jin, Guozhang; Li, Chaoying

    2012-07-01

    Opiate addiction is a chronic recrudescent disorder characterized by a high rate of relapse. Levo-tetrahydropalmatine (l-THP) is an alkaloid substance extracted from Corydalis and Stephania and is contained in a number of traditional Chinese herbal preparations. Compared to other dopamine receptor antagonists, l-THP has lower affinity for D2 receptors than for D1 receptors, and a recent study showed that l-THP also binds to D3 receptors, possibly functioning as an antagonist. The unique pharmacological profile of l-THP suggests that l-THP may be effective for the treatment of opiate addiction. In this study, we investigated the effects of l-THP on heroin self-administration and reinstatement triggered by a priming injection of heroin in abstinent rats trained to stably self-administer heroin under an extinction/reinstatement protocol, and found that l-THP (2.5 and 5 mg/kg, i.p.) decreased heroin self-administration on the fixed-ratio 1 schedule and dose-dependently (1.25, 2.5 and 5 mg/kg, i.p.) inhibited heroin-induced reinstatement of heroin-seeking behavior. Importantly, l-THP (1.25 and 2.5 mg/kg, i.p.) did not affect locomotion, indicating that the observed effects of l-THP on reinstatement do not appear to be due to motor impairments. The present results demonstrated that dopamine receptor antagonist l-THP attenuates heroin self-administration and heroin-induced reinstatement. PMID:22741173

  19. Myocardial infarction induced by coronary vasospasm after self-administration of epinephrine.

    PubMed

    Saff, R; Nahhas, A; Fink, J N

    1993-05-01

    A case of a 30-year-old man who developed a myocardial infarction after self-administering an Epi-Pen for an episode of idiopathic anaphylaxis is reported. The patient had numerous risk factors for coronary artery disease, and it was suspected that epinephrine-induced coronary spasm caused the infarct. The Epi-Pen Junior may be indicated in such adults with numerous risk factors for coronary artery disease who are at risk for recurrent anaphylaxis. PMID:8498731

  20. Co-administration of Grape Seed Extract and Exercise Training Improves Endothelial Dysfunction of Coronary Vascular Bed of STZ-Induced Diabetic Rats

    PubMed Central

    Badavi, Mohammad; Abedi, Hassan Ali; Sarkaki, Ali Reza; Dianat, Mahin

    2013-01-01

    Background One of the known complications of diabetes mellitus is vascular dysfunction. Inability of the coronary vascular response to cardiac hyperactivity might cause a higher incidence of ischemic heart disease in diabetic subjects. It has been indicated that regular exercise training and antioxidants could prevent diabetic cardiovascular problems enhanced by vascular damage. Objectives The aim of this study was to determine the effects of grape seed extract (as antioxidant), with and without exercise training on coronary vascular function in streptozotocin induced diabetic rats. Materials and Methods Fifty male Wistar rats weighing 200 – 232 grams were randomly divided into five groups of 10 rats each: sedentary control, sedentary diabetic, trained diabetic, grape seed extract (200 mg/kg) treated sedentary diabetic and, grape seed extract treated trained diabetic. Diabetes was induced by one intraperitoneal injection of streptozotocin. After eight weeks, coronary vascular responses to vasoactive agents were determined. Results The endothelium dependent vasorelaxation to acetylcholine was reduced significantly in diabetic animals; exercise training or grape seed extract administration partially improves this response. However, exercise training in combination with grape seed extract restores endothelial function completely. The endothelium independent vasorelaxation to sodium nitroprusside was improved by combination of exercise training and grape seed extract. On the other hand, the basal perfusion pressure and vasoconstrictive response to phenylephrine did not change significantly. Conclusions The data indicated that co-administration of grape seed extract and exercise training had more significant effects than exercise training or grape seed extract alone; this may constitute a convenient and inexpensive therapeutic approach to diabetic vascular complications. PMID:24693368

  1. Levofloxacin‐Induced QTc Prolongation Depends on the Time of Drug Administration

    PubMed Central

    Kervezee, L; Gotta, V; Stevens, J; Birkhoff, W; Kamerling, IMC; Danhof, M; Meijer, JH

    2016-01-01

    Understanding the factors influencing a drug's potential to prolong the QTc interval on an electrocardiogram is essential for the correct evaluation of its safety profile. To explore the effect of dosing time on drug‐induced QTc prolongation, a randomized, crossover, clinical trial was conducted in which 12 healthy male subjects received levofloxacin at 02:00, 06:00, 10:00, 14:00, 18:00, and 22:00. Using a pharmacokinetic‐pharmacodynamic (PK‐PD) modeling approach to account for variations in PKs, heart rate, and daily variation in baseline QT, we find that the concentration‐QT relationship shows a 24‐hour sinusoidal rhythm. Simulations show that the extent of levofloxacin‐induced QT prolongation depends on dosing time, with the largest effect at 14:00 (1.73 (95% prediction interval: 1.56–1.90) ms per mg/L) and the smallest effect at 06:00 (−0.04 (−0.19 to 0.12) ms per mg/L). These results suggest that a 24‐hour variation in the concentration‐QT relationship could be a potentially confounding factor in the assessment of drug‐induced QTc prolongation. PMID:27479699

  2. Effect of tyrosine administration on duodenal ulcer induced by cysteamine in the rat

    SciTech Connect

    Oishi, T.; Szabo, S.

    1987-03-01

    Duodenal ulcers were produced by administering cysteamine to rats. Pretreatment with the catecholamine precursor, L-tyrosine (40 mg/100 g i.p. for 5 days), decreased the intensity of duodenal ulcers induced by cysteamine. Equimolar doses of tyrosine methyl ester (51.2 mg/100 g i.p. or s.c.) were equally effective in reducing ulcer intensity. Other amino acids (i.e., alanine, aspartic acid, glutamic acid, glycine, leucine, lysine, tryptophan and valine) did not prevent experimental duodenal ulcers. Coadministration of other large neutral amino acids (e.g., leucine and valine) that compete with tyrosine for uptake into the brain did not inhibit the effect of tyrosine on duodenal ulcers induced by cysteamine. Gastric, duodenal and brain dopamine concentrations were increased 1 hr after the injection of tyrosine methyl ester (25.6 mg/100 g s.c.). These results suggest that the effect of tyrosine on duodenal ulcer induced by cysteamine may be mediated by changes in gastrointestinal dopamine metabolism.

  3. Combined administration of oxalic acid, succimer and its analogue for the reversal of gallium arsenide-induced oxidative stress in rats.

    PubMed

    Flora, Swaran J S; Kannan, Gurusamy M; Pant, Bhagwat P; Jaiswal, Devendra K

    2002-06-01

    Gallium arsenide (GaAs), a group III-VA intermetallic semiconductor, possesses superior electronic and optical properties and has a wide application in the electronics industry. Exposure to GaAs in the semiconductor industry is a potential occupational hazard because cleaning and slicing GaAs ingots to yield the desired wafer could generate GaAs particles. The ability of GaAs to induce oxidative stress has not yet been reported. The present study reports the role of oxidative stress in GaAs-induced haematological and liver disorders and its possible reversal overturn by administration of meso-2,3-dimercaptosuccinic acid (DMSA) and one of its analogue, monoisoamyl DMSA (MiADMSA), either individually or in combination with oxalic acid. While DMSA and MiADMSA are potential arsenic chelators, oxalic acid is reported to be an effective gallium chelator. Male rats were exposed to 10 mg/kg GaAs orally, 5 days a week for 8 weeks. GaAs exposure was then stopped and rats were given a 0.5 mmol/kg dose of succimers (DMSA or MiADMSA), oxalic acid or a combination of the two, intraperitoneally once daily for 5 consecutive days. We found a significant fall in blood delta-aminolevulinic acid dehydratase (ALAD) activity and blood glutathione (GSH) level, and an increased urinary excretion of delta-aminolevulinic acid (ALA) and an increased malondialdehyde (MDA) level in erythrocytes of rats exposed to GaAs. Hepatic GSH levels decreased, whereas there was an increase in GSSG and MDA levels. The results suggest a role of oxidative stress in GaAs-induced haematological and hepatic damage. Administration of DMSA and MiADMSA produced effective recovery in most of the above variables. However, a greater effectiveness of the chelation treatment (i.e. removal of both gallium and arsenic from body organs) could be achieved by combined administration of succimer (DMSA) with oxalic acid since, after MiADMSA administration, a marked loss of essential metals (copper and zinc) is of concern.

  4. Stress- and pharmacologically-induced behavioral sensitization increases vulnerability to acquisition of amphetamine self-administration.

    PubMed

    Piazza, P V; Deminiere, J M; le Moal, M; Simon, H

    1990-04-23

    Individual vulnerability to drug addiction may be an important factor in the prognosis of this pathological behavior in man. However, experimental investigations have largely neglected the psychobiological substrate of predisposition to addiction. In this study, we show using a self-administration (SA) acquisition paradigm that previous repeated exposure to a stressful experience (tail-pinch) or to amphetamine, increase the locomotor response to this drug (behavioral sensitization) and enhance vulnerability to acquire amphetamine SA. These results show that vulnerability to develop amphetamine SA may be influenced by stressful experiences, and that previous contact with the drug may enhance a predisposition to amphetamine-taking behavior. As tail-pinch and amphetamine sensitization affect both the dopamine (DA) neural system and the propensity to self-administer amphetamine (behavior also modulated by DA activity), stress may influence SA via an action on the DA system. PMID:2357527

  5. Hypoxis hemerocallidea Significantly Reduced Hyperglycaemia and Hyperglycaemic-Induced Oxidative Stress in the Liver and Kidney Tissues of Streptozotocin-Induced Diabetic Male Wistar Rats.

    PubMed

    Oguntibeju, Oluwafemi O; Meyer, Samantha; Aboua, Yapo G; Goboza, Mediline

    2016-01-01

    Background. Hypoxis hemerocallidea is a native plant that grows in the Southern African regions and is well known for its beneficial medicinal effects in the treatment of diabetes, cancer, and high blood pressure. Aim. This study evaluated the effects of Hypoxis hemerocallidea on oxidative stress biomarkers, hepatic injury, and other selected biomarkers in the liver and kidneys of healthy nondiabetic and streptozotocin- (STZ-) induced diabetic male Wistar rats. Materials and Methods. Rats were injected intraperitoneally with 50 mg/kg of STZ to induce diabetes. The plant extract-Hypoxis hemerocallidea (200 mg/kg or 800 mg/kg) aqueous solution was administered (daily) orally for 6 weeks. Antioxidant activities were analysed using a Multiskan Spectrum plate reader while other serum biomarkers were measured using the RANDOX chemistry analyser. Results. Both dosages (200 mg/kg and 800 mg/kg) of Hypoxis hemerocallidea significantly reduced the blood glucose levels in STZ-induced diabetic groups. Activities of liver enzymes were increased in the diabetic control and in the diabetic group treated with 800 mg/kg, whereas the 200 mg/kg dosage ameliorated hepatic injury. In the hepatic tissue, the oxygen radical absorbance capacity (ORAC), ferric reducing antioxidant power (FRAP), catalase, and total glutathione were reduced in the diabetic control group. However treatment with both doses improved the antioxidant status. The FRAP and the catalase activities in the kidney were elevated in the STZ-induced diabetic group treated with 800 mg/kg of the extract possibly due to compensatory responses. Conclusion. Hypoxis hemerocallidea demonstrated antihyperglycemic and antioxidant effects especially in the liver tissue. PMID:27403200

  6. Hypoxis hemerocallidea Significantly Reduced Hyperglycaemia and Hyperglycaemic-Induced Oxidative Stress in the Liver and Kidney Tissues of Streptozotocin-Induced Diabetic Male Wistar Rats

    PubMed Central

    Oguntibeju, Oluwafemi O.; Meyer, Samantha; Aboua, Yapo G.; Goboza, Mediline

    2016-01-01

    Background. Hypoxis hemerocallidea is a native plant that grows in the Southern African regions and is well known for its beneficial medicinal effects in the treatment of diabetes, cancer, and high blood pressure. Aim. This study evaluated the effects of Hypoxis hemerocallidea on oxidative stress biomarkers, hepatic injury, and other selected biomarkers in the liver and kidneys of healthy nondiabetic and streptozotocin- (STZ-) induced diabetic male Wistar rats. Materials and Methods. Rats were injected intraperitoneally with 50 mg/kg of STZ to induce diabetes. The plant extract-Hypoxis hemerocallidea (200 mg/kg or 800 mg/kg) aqueous solution was administered (daily) orally for 6 weeks. Antioxidant activities were analysed using a Multiskan Spectrum plate reader while other serum biomarkers were measured using the RANDOX chemistry analyser. Results. Both dosages (200 mg/kg and 800 mg/kg) of Hypoxis hemerocallidea significantly reduced the blood glucose levels in STZ-induced diabetic groups. Activities of liver enzymes were increased in the diabetic control and in the diabetic group treated with 800 mg/kg, whereas the 200 mg/kg dosage ameliorated hepatic injury. In the hepatic tissue, the oxygen radical absorbance capacity (ORAC), ferric reducing antioxidant power (FRAP), catalase, and total glutathione were reduced in the diabetic control group. However treatment with both doses improved the antioxidant status. The FRAP and the catalase activities in the kidney were elevated in the STZ-induced diabetic group treated with 800 mg/kg of the extract possibly due to compensatory responses. Conclusion. Hypoxis hemerocallidea demonstrated antihyperglycemic and antioxidant effects especially in the liver tissue. PMID:27403200

  7. Heme biosynthesis modulation via δ-aminolevulinic acid administration attenuates chronic hypoxia-induced pulmonary hypertension

    PubMed Central

    Alhawaj, Raed; Patel, Dhara; Kelly, Melissa R.; Sun, Dong

    2015-01-01

    This study examines how heme biosynthesis modulation with δ-aminolevulinic acid (ALA) potentially functions to prevent 21-day hypoxia (10% oxygen)-induced pulmonary hypertension in mice and the effects of 24-h organoid culture with bovine pulmonary arteries (BPA) with the hypoxia and pulmonary hypertension mediator endothelin-1 (ET-1), with a focus on changes in superoxide and regulation of micro-RNA 204 (miR204) expression by src kinase phosphorylation of signal transducer and activator of transcription-3 (STAT3). The treatment of mice with ALA attenuated pulmonary hypertension (assessed through echo Doppler flow of the pulmonary valve, and direct measurements of right ventricular systolic pressure and right ventricular hypertrophy), increases in pulmonary arterial superoxide (detected by lucigenin), and decreases in lung miR204 and mitochondrial superoxide dismutase (SOD2) expression. ALA treatment of BPA attenuated ET-1-induced increases in mitochondrial superoxide (detected by MitoSox), STAT3 phosphorylation, and decreases in miR204 and SOD2 expression. Because ALA increases BPA protoporphyrin IX (a stimulator of guanylate cyclase) and cGMP-mediated protein kinase G (PKG) activity, the effects of the PKG activator 8-bromo-cGMP were examined and found to also attenuate the ET-1-induced increase in superoxide. ET-1 increased superoxide production and the detection of protoporphyrin IX fluorescence, suggesting oxidant conditions might impair heme biosynthesis by ferrochelatase. However, chronic hypoxia actually increased ferrochelatase activity in mouse pulmonary arteries. Thus, a reversal of factors increasing mitochondrial superoxide and oxidant effects that potentially influence remodeling signaling related to miR204 expression and perhaps iron availability needed for the biosynthesis of heme by the ferrochelatase reaction could be factors in the beneficial actions of ALA in pulmonary hypertension. PMID:25659899

  8. Administration of interleukin-6 stimulates multilineage hematopoiesis and accelerates recovery from radiation-induced hematopoietic depression

    SciTech Connect

    Patchen, M.L.; MacVittie, T.J.; Williams, J.L.; Schwartz, G.N.; Souza, L.M. )

    1991-02-01

    Hematopoietic depression and subsequent susceptibility to potentially lethal opportunistic infections are well-documented phenomena following radiotherapy. Methods to therapeutically mitigate radiation-induced myelosuppression could offer great clinical value. In vivo studies have demonstrated that interleukin-6 (IL-6) stimulates pluripotent hematopoietic stem cell (CFU-s), granulocyte-macrophage progenitor cell (GM-CFC), and erythroid progenitor cell (CFU-e) proliferation in normal mice. Based on these results, the ability of IL-6 to stimulate hematopoietic regeneration following radiation-induced hematopoietic injury was also evaluated. C3H/HeN female mice were exposed to 6.5 Gy 60Co radiation and subcutaneously administered either saline or IL-6 on days 1 through 3 or 1 through 6 postexposure. On days 7, 10, 14, 17, and 22, femoral and splenic CFU-s, GM-CFC, and CFU-e contents and peripheral blood white cell, red cell, and platelet counts were determined. Compared with saline treatment, both 3-day and 6-day IL-6 treatments accelerated hematopoietic recovery; 6-day treatment produced the greater effects. For example, compared with normal control values (N), femoral and splenic CFU-s numbers in IL-6-treated mice 17 days postirradiation were 27% N and 136% N versus 2% N and 10% N in saline-treated mice. At the same time, bone marrow and splenic GM-CFC values were 58% N and 473% N versus 6% N and 196% N in saline-treated mice; bone marrow and splenic CFU-e numbers were 91% N and 250% N versus 31% N and 130% N in saline-treated mice; and peripheral blood white cell, red cell, and platelet values were 210% N, 60% N, and 24% N versus 18% N, 39% N, and 7% N in saline-treated mice. These studies demonstrate that therapeutically administered IL-6 can effectively accelerate multilineage hematopoietic recovery following radiation-induced hematopoietic injury.

  9. Cadmium induced testicular damage and its response to administration of succimer and diphenyl diselenide in mice.

    PubMed

    Santos, Francielli W; Oro, Tatiana; Zeni, Gilson; Rocha, João B T; do Nascimento, Paulo C; Nogueira, Cristina W

    2004-09-25

    Acute effects of cadmium in mice testes were evaluated. Animals received a single dose of CdCl2 (2.5 mg/kg or 5 mg/kg, intraperitoneally) and a number of toxicological parameters in mice testes were examined such as delta-aminolevulinic acid dehydratase (delta-ALA-D) activity, lipid peroxidation, hemoglobin content and components of the antioxidant defenses (superoxide dismutase (SOD) activity and ascorbic acid concentration). Furthermore, a possible protective effect of meso-2,3-dimercaptosuccinic acid (DMSA) and diphenyl diselenide (PhSe)2 are studied. The results demonstrated inhibition of delta-ALA-D and SOD activities, reduction in ascorbic acid, increase of lipid peroxidation induced by cadmium, indicating testes damage. DMSA (400 micromol/Kg) and (PhSe)2 (100 micromol/Kg) protected inhibitory effect of 2.5 mg/kg CdCl2 on delta-ALA-D and restored the increase of TBARS levels. Otherwise, (PhSe)2 treatment was effective in reducing the increase of TBARS levels induced by 5 mg/kg CdCl2, whereas DMSA and (PhSe)2, in combination, were ineffective in reducing TBARS level. However, these compounds alone or in combination, were unable to protect SOD activity and to improve ascorbic acid levels near to the normal value. The use of combined therapy (DMSA plus (PhSe)2) not proved be better than the monotherapy, in improving toxicological parameters evaluated in this model of testicular damage induced by cadmium. PMID:15331134

  10. Prognostic Significance of Tumor Hypoxia Inducible Factor-1{alpha} Expression for Outcome After Radiotherapy in Oropharyngeal Cancer

    SciTech Connect

    Silva, Priyamal; Slevin, Nick J.; Sloan, Philip; Valentine, Helen; Cresswell, Jo; Ryder, David; Price, Patricia; Homer, Jarrod J.; West, Catharine

    2008-12-01

    Purpose: Head-and-neck squamous cell carcinoma (HNSCC) represents a heterogeneous group of patients in terms of subsite, treatment, and biology. Currently most management decisions are based on clinical parameters with little appreciation of patient differences in underlying tumor biology. We investigated the prognostic significance of clinicopathologic features and tumor hypoxia-inducible factor-1{alpha} (HIF-1{alpha}) expression in a homogeneous series of patients who underwent radiotherapy. Methods and Materials: An audit identified 133 consecutive patients with histologically proven squamous cell carcinoma of the tonsil or tongue base. All patients received primary radiotherapy between 1996 and 2001. Tumor HIF-1{alpha} expression was examined in 79 patients. Results: Features associated with poor locoregional control were low Hb level (p = 0.05) and advancing T (p = 0.008), N (p = 0.03), and disease (p = 0.008) stage. HIF-1{alpha} expression was a more significant adverse prognostic factor in the tonsil (hazard ratio [HR], 23.1; 95% confidence interval [CI]. 3.04-176.7) than the tongue-base tumor (HR, 2.86; 95% CI, 1.14-7.19) group (p = 0.03, test for interaction). High tumor HIF-1{alpha} expression was associated with low blood Hb levels (p = 0.03). In a multivariate analysis HIF-1{alpha} expression retained prognostic significance for locoregional control (HR, 7.10; 95% CI, 3.07-16.43) and cancer-specific survival (HR, 9.19; 95% CI, 3.90-21.6). Conclusions: There are significant differences in radiation therapy outcome within a homogeneous subsite of the oropharynx related to molecular marker expression. The work highlights the importance of studying homogeneous groups of patients in HNSCC, and the complex interrelationships between tumor biology and clinicopathologic factors. The establishment of tumor-type specific markers would represent a major advance in this area.

  11. Intrathecal administration of rapamycin inhibits the phosphorylation of DRG Nav1.8 and attenuates STZ-induced painful diabetic neuropathy in rats.

    PubMed

    He, Wan-You; Zhang, Bin; Xiong, Qing-Ming; Yang, Cheng-Xiang; Zhao, Wei-Cheng; He, Jian; Zhou, Jun; Wang, Han-Bing

    2016-04-21

    The mammalian target of rapamycin (mTOR) is a key regulator of mRNA translation and protein synthesis, and it is specifically inhibited by rapamycin. In chronic pain conditions, mTOR-mediated local protein synthesis is crucial for neuronal hyperexcitability and synaptic plasticity. The tetrodotoxin-resistant (TTX-R) sodium channel Nav1.8 plays a major role in action potential initiation and propagation and cellular excitability in DRG (dorsal root ganglion) neurons. In this study, we investigated if mTOR modulates the phosphorylation of Nav1.8 that is associated with neuronal hyperexcitability and behavioral hypersensitivity in STZ-induced diabetic rats. Painful diabetic neuropathy (PDN) was induced in Sprague-Dawley rats by intraperitoneal injection with streptozotocin (STZ) at 60mg/kg. After the onset of PDN, the rats received daily intrathecal administrations of rapamycin (1μg, 3μg, or 10μg/day) for 7 days; other diabetic rats received the same volumes of dimethyl sulfoxide (DMSO). Herein, we demonstrate a marked increase in protein expression of total mTOR and phospho-mTOR (p-mTOR) together with the up-regulation of phosphor-Nav1.8 (p-Nav1.8) prior to the mechanical withdrawal threshold reaching a significant reduction in dorsal root ganglions (DRGs). Furthermore, the intrathecal administration of rapamycin, inhibiting the activity of mTOR, suppressed the phosphorylation of DRG Nav1.8, reduced the TTX-R current density, heightened the voltage threshold for activation and lowered the voltage threshold for inactivation and relieved mechanical hypersensitivity in diabetic rats. An intrathecal injection (i.t.) of rapamycin inhibited the phosphorylation and enhanced the functional availability of DRG Nav1.8 attenuated STZ-induced hyperalgesia. These results suggest that rapamycin is a potential therapeutic intervention for clinical PDN. PMID:26946108

  12. Renoprotective effect of sitagliptin against hypertensive nephropathy induced by chronic administration of L-NAME in rats: role of GLP-1 and GLP-1 receptor.

    PubMed

    Abd El Motteleb, Dalia M; Elshazly, Shimaa M

    2013-11-15

    The present study was undertaken to assess the possible protective effects of sitagliptin, a dipeptidyl peptidase 4-inhibitor (DPP4), against Nω-nitro-L-arginine methyl ester (L-NAME) induced hypertensive nephropathy in rats. Hypertension was induced in adult rats by administration of L-NAME for 6 weeks. Rats were treated with sitagliptin (10mg/kg/day or 30 mg/kg/day) for six weeks. Chronic L-NAME administration resulted in depletion of serum nitric oxide (NO) associated with elevation in the mean arterial pressure. When compared with the control group; serum urea, serum creatinine, albuminuria, urinary N-acetyl-ß-d-glucosaminidase (NAG) level and renal tissue malondialdhyde (MDA) content were significantly elevated, while creatinine clearance, serum level of glucagon like peptide-1 (GLP-1) as well as renal tissue superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were signifcantly decreased in L-NAME treated group. Renal expression of mRNA for eNOS and GLP-1 receptors were reduced in the L-NAME treated group as compared with the control group. Treatment with sitagliptin (10mg/kg or 30 mg/kg) successfully ameliorated the deleterious effects of L-NAME on the all tested parameters. Our study indicates a novel protective effect of sitagliptin against L-NAME induced hypertensive nephropathy. An effect which is mediated through, increasing serum level of GLP-1, upregulation of GLP-1 receptors, which in turn, lead to induction of expression eNOS, increased serum NO level, tandem with decreased lipid perodixation and restore the antioxidant defense mechanisms. It is worth mentioning that the effects produced by sitaglipin (30 mg/kg) were superior to the effects obtained by the lower dose.

  13. Successive Administration of Streptococcus Type 5 Group A Antigens and S. typhimurium Antigenic Complex Corrects Elevation of Serum Cytokine Concentration and Number of Bone Marrow Stromal Pluripotent Cells in CBA Mice Induced by Each Antigen Separately.

    PubMed

    Gorskaya, Yu F; Danilova, T A; Grabko, V I; Nesterenko, V G

    2015-12-01

    Administration of bacterial antigens to CBA mice induced an increase in serum concentration of virtually all cytokines with a peak in 4 h after administration of S. typhimurium antigens and in 7 h after administration of streptococcus antigens. In 20 h, cytokine concentrations returned to the control level or were slightly below it. In 4 h after administration of S. typhimurium antigens preceded 3 h before by administration of streptococcus antigens, we observed a significant decrease in serum concentrations of IFN-γ, IL-10, GM-CSF, IL-12, and TNF-α, in comparison with injection S. typhimurium antigens alone and IL-5, IL-10, GM-CSF, and TNF-α in comparison with injection of streptococcus antigens alone; the concentrations of IL-2 and IFN-γ, in contrast, increased by 1.5 times in this case. In 20 h after administration of S. typhimurium antigens, the number of multipotential stromal cells (MSC) in the bone marrow and their cloning efficiency (ECF-MSC) increased by 4.8 and 4.4 times, respectively, in comparison with the control, while after administration of streptococcus antigens by 2.6 and 2.4 times, respectively. In 20 h after administration of S. typhimurium antigens preceded 3 h before by administration of streptococcus antigens, these parameters increased by 3.2 and 2.9 times, respectively, in comparison with the control, i.e. the observed increase in the level of MSC count and ECF-MSC is more consistent with the response of the stromal tissue to streptococcus antigens. Thus, successive administration of two bacterial antigens corrected both serum cytokine profiles and MSC response to administration of each antigen separately, which indicates changeability of the stromal tissue in response to changes in the immune response.

  14. Mucosal Administration of Collagen V Ameliorates the Atherosclerotic Plaque Burden by Inducing Interleukin 35-dependent Tolerance.

    PubMed

    Park, Arick C; Huang, Guorui; Jankowska-Gan, Ewa; Massoudi, Dawiyat; Kernien, John F; Vignali, Dario A; Sullivan, Jeremy A; Wilkes, David S; Burlingham, William J; Greenspan, Daniel S

    2016-02-12

    We have shown previously that collagen V (col(V)) autoimmunity is a consistent feature of atherosclerosis in human coronary artery disease and in the Apoe(-/-) mouse model. We have also shown sensitization of Apoe(-/-) mice with col(V) to markedly increase the atherosclerotic burden, providing evidence of a causative role for col(V) autoimmunity in atherosclerotic pathogenesis. Here we sought to determine whether induction of immune tolerance to col(V) might ameliorate atherosclerosis, providing further evidence for a causal role for col(V) autoimmunity in atherogenesis and providing insights into the potential for immunomodulatory therapeutic interventions. Mucosal inoculation successfully induced immune tolerance to col(V) with an accompanying reduction in plaque burden in Ldlr(-/-) mice on a high-cholesterol diet. The results therefore demonstrate that inoculation with col(V) can successfully ameliorate the atherosclerotic burden, suggesting novel approaches for therapeutic interventions. Surprisingly, tolerance and reduced atherosclerotic burden were both dependent on the recently described IL-35 and not on IL-10, the immunosuppressive cytokine usually studied in the context of induced tolerance and amelioration of atherosclerotic symptoms. In addition to the above, using recombinant protein fragments, we were able to localize two epitopes of the α1(V) chain involved in col(V) autoimmunity in atherosclerotic Ldlr(-/-) mice, suggesting future courses of experimentation for the characterization of such epitopes.

  15. Sex-Dependent Depression-Like Behavior Induced by Respiratory Administration of Aluminum Oxide Nanoparticles

    PubMed Central

    Zhang, Xin; Xu, Yan; Zhou, Lian; Zhang, Chengcheng; Meng, Qingtao; Wu, Shenshen; Wang, Shizhi; Ding, Zhen; Chen, Xiaodong; Li, Xiaobo; Chen, Rui

    2015-01-01

    Ultrafine aluminum oxide, which are abundant in ambient and involved occupational environments, are associated with neurobehavioral alterations. However, few studies have focused on the effect of sex differences following exposure to environmental Al2O3 ultrafine particles. In the present study, male and female mice were exposed to Al2O3 nanoparticles (NPs) through a respiratory route. Only the female mice showed depression-like behavior. Although no obvious pathological changes were observed in mice brain tissues, the neurotransmitter and voltage-gated ion channel related gene expression, as well as the small molecule metabolites in the cerebral cortex, were differentially modulated between male and female mice. Both mental disorder-involved gene expression levels and metabolomics analysis results strongly suggested that glutamate pathways were implicated in sex differentiation induced by Al2O3 NPs. Results demonstrated the potential mechanism of environmental ultrafine particle-induced depression-like behavior and the importance of sex dimorphism in the toxic research of environmental chemicals. PMID:26690197

  16. Sex-Dependent Depression-Like Behavior Induced by Respiratory Administration of Aluminum Oxide Nanoparticles.

    PubMed

    Zhang, Xin; Xu, Yan; Zhou, Lian; Zhang, Chengcheng; Meng, Qingtao; Wu, Shenshen; Wang, Shizhi; Ding, Zhen; Chen, Xiaodong; Li, Xiaobo; Chen, Rui

    2015-12-01

    Ultrafine aluminum oxide, which are abundant in ambient and involved occupational environments, are associated with neurobehavioral alterations. However, few studies have focused on the effect of sex differences following exposure to environmental Al₂O₃ ultrafine particles. In the present study, male and female mice were exposed to Al₂O₃ nanoparticles (NPs) through a respiratory route. Only the female mice showed depression-like behavior. Although no obvious pathological changes were observed in mice brain tissues, the neurotransmitter and voltage-gated ion channel related gene expression, as well as the small molecule metabolites in the cerebral cortex, were differentially modulated between male and female mice. Both mental disorder-involved gene expression levels and metabolomics analysis results strongly suggested that glutamate pathways were implicated in sex differentiation induced by Al₂O₃ NPs. Results demonstrated the potential mechanism of environmental ultrafine particle-induced depression-like behavior and the importance of sex dimorphism in the toxic research of environmental chemicals. PMID:26690197

  17. Intracerebral Administration of BDNF Protects Rat Brain Against Oxidative Stress Induced by Ouabain in an Animal Model of Mania.

    PubMed

    Valvassori, Samira S; Arent, Camila O; Steckert, Amanda V; Varela, Roger B; Jornada, Luciano K; Tonin, Paula T; Budni, Josiane; Mariot, Edemilson; Kapczinski, Flávio; Quevedo, João

    2015-08-01

    Several studies have suggested that alterations in brain-derived neurotrophic factor (BDNF) and increased oxidative stress have a central role in bipolar disorder (BD). Intracerebroventricular (ICV) injection of ouabain (OUA) in rats alters oxidative stress parameters and decreases BDNF levels in the brain. In this context, the present study aims to investigate the effects of BDNF ICV administration on BDNF levels and oxidative stress parameters in brains of rats submitted to animal model of mania induced by OUA. Wistar rats received an ICV injection of OUA, artificial cerebrospinal fluid (ACSF), OUA plus BDNF, or ACSF plus BDNF. Locomotor activity and risk-taking behavior in the rats were measured using the open-field test. In addition, we analyzed the BDNF levels and oxidative stress parameters (TBARS, Carbonyl, CAT, SOD, GR, and GPx) in the frontal cortex and hippocampus of rats. The BDNF was unable to reverse the ouabain-induced hyperactivity and risk-taking behavior. Nevertheless, BDNF treatment increased BDNF levels, modulated the antioxidant enzymes, and protected the OUA-induced oxidative damage in the brain of rats. These results suggest that BDNF alteration observed in BD patients may be associated with oxidative damage, both seen in this disorder. PMID:25164569

  18. Central administration of neuropeptide Y induces precocious puberty in female rats.

    PubMed

    Minami, S; Sarkar, D K

    1992-12-01

    To examine the role of neuropeptide Y (NPY) in the regulation of puberty, the effects of various doses of NPY or saline injected into the 3rd ventricle of peripubertal female rats were determined. A single injection of NPY at a dose range of 10-20 micrograms into the 3rd ventricle of 30-day-old female rats advanced the time of vaginal opening (VO) and first ovulation by 4 days, as compared to saline-treated controls. Ova number and ovarian, adrenal and uterine weights at first estrous were similar in all animals regardless of treatment. The NPY-treated precocious animals showed lower body weight than did the VO-matched controls, but showed similar body weight as that of age-matched controls. Determination of plasma luteinizing hormone (LH) levels in the peripubertal female rats revealed that plasma LH was increased transiently immediately after NPY administration. Also, NPY-treated rats which had precocious puberty showed elevated pituitary and plasma LH levels on the day of VO. These results suggest that NPY can activate the hypothalamic-pituitary-gonadal axis to precociously initiate puberty.

  19. Cre-inducible human CD59 mediates rapid cell ablation after intermedilysin administration

    PubMed Central

    Feng, Dechun; Dai, Shen; Liu, Fengming; Ohtake, Yosuke; Zhou, Zhou; Wang, Hua; Zhang, Yonggang; Kearns, Alison; Peng, Xiao; Zhu, Faliang; Hayat, Umar; Li, Man; He, Yong; Xu, Mingjiang; Zhao, Chunling; Cheng, Min; Zhang, Lining; Wang, Hong; Yang, Xiaofeng; Ju, Cynthia; Bryda, Elizabeth C.; Gordon, Jennifer; Khalili, Kamel; Hu, Wenhui; Li, Shuxin; Qin, Xuebin

    2016-01-01

    Cell ablation is a powerful tool for studying cell lineage and/or function; however, current cell-ablation models have limitations. Intermedilysin (ILY), a cytolytic pore-forming toxin that is secreted by Streptococcus intermedius, lyses human cells exclusively by binding to the human complement regulator CD59 (hCD59), but does not react with CD59 from nonprimates. Here, we took advantage of this feature of ILY and developed a model of conditional and targeted cell ablation by generating floxed STOP-CD59 knockin mice (ihCD59), in which expression of human CD59 only occurs after Cre-mediated recombination. The administration of ILY to ihCD59+ mice crossed with various Cre-driver lines resulted in the rapid and specific ablation of immune, epithelial, or neural cells without off-target effects. ILY had a large pharmacological window, which allowed us to perform dose-dependent studies. Finally, the ILY/ihCD59-mediated cell-ablation method was tested in several disease models to study immune cell functionalities, hepatocyte and/or biliary epithelial damage and regeneration, and neural cell damage. Together, the results of this study demonstrate the utility of the ihCD59 mouse model for studying the effects of cell ablation in specific organ systems in a variety of developmental and disease states. PMID:27159394

  20. Methamphetamine administration targets multiple immune subsets and induces phenotypic alterations suggestive of immunosuppression.

    PubMed

    Harms, Robert; Morsey, Brenda; Boyer, Craig W; Fox, Howard S; Sarvetnick, Nora

    2012-01-01

    Methamphetamine (Meth) is a widely abused stimulant and its users are at increased risk for multiple infectious diseases. To determine the impact of meth on the immune system, we utilized a murine model that simulates the process of meth consumption in a typical addict. Our phenotypic analysis of leukocytes from this dose escalation model revealed that meth affected key immune subsets. Meth administration led to a decrease in abundance of natural killer (NK) cells and the remaining NK cells possessed a phenotype suggesting reduced responsiveness. Dendritic cells (DCs) and Gr-1(high) monocytes/macrophages were also decreased in abundance while Gr-1(low) monocytes/macrophages appear to show signs of perturbation. CD4 and CD8 T cell subsets were affected by methamphetamine, both showing a reduction in antigen-experienced subsets. CD4 T cells also exhibited signs of activation, with increased expression of CD150 on CD226-expressing cells and an expansion of KLRG1(+), FoxP3(-) cells. These results exhibit that meth has the ability to disrupt immune homeostasis and impact key subsets of leukocytes which may leave users more vulnerable to pathogens.

  1. Dityrosine administration induces novel object recognition deficits in young adulthood mice.

    PubMed

    Ran, Yumei; Yan, Biao; Li, Zhuqing; Ding, Yinyi; Shi, Yonghui; Le, Guowei

    2016-10-01

    Dietary modifications have been shown to contribute to the physical and mental diseases. Oxidative modifications of protein can be easily found in protein-rich food such as meat and milk products. Previous studies mainly focus on the consequences of lipid oxidation products intake in vivo, but the effects of protein oxidation products consumption have been largely neglected. Oxidants have been shown to play an important role in aging and neurodegenerative diseases. Dityrosine is the oxidated product of tyrosine residues in protein which is considered as a biomarker for oxidative stress, but the potential deleterious effects of dityrosine are unknown. In the present study, we explored the effects of dityrosine administration on the behavioral aspect. We found that dityrosine-ingested mice displayed impaired memory during novel object recognition test, but no influence to the spatial memory in Morris water maze compared with the saline group. Other aspects of neurobehavioral function such as locomotor activity, anxiety and social behavior were not affected by dityrosine ingestion. Furthermore, we found that dityrosine-ingested mice showed decreased expression level of NMDA receptor subunits Nr1, Nr2a, Nr2b as well as Bdnf, Trkb. Our study suggests that dityrosine exposure impairs hippocampus-dependent nonspatial memory accompanied by modulation of NMDA receptor subunits and Bdnf expression. PMID:27317839

  2. Intranasal Administration of Recombinant Mycobacterium smegmatis Inducing IL-17A Autoantibody Attenuates Airway Inflammation in a Murine Model of Allergic Asthma.

    PubMed

    Xu, Wanting; Chen, Ling; Guo, Sheng; Wu, Liangxia; Zhang, Jianhua

    2016-01-01

    Asthma is a chronic inflammatory disorder, previous studies have shown that IL-17A contributes to the development of asthma, and there is a positive correlation between the level of IL-17A and the severity of disease. Here, we constructed recombinant Mycobacterium smegmatis expressing fusion protein Ag85A-IL-17A (rMS-Ag85a-IL-17a) and evaluated whether it could attenuate allergic airway inflammation, and further investigated the underlying mechanism. In this work, the murine model of asthma was established with ovalbumin, and mice were intranasally vaccinated with rMS-Ag85a-IL-17a. Autoantibody of IL-17A in sera was detected, and the airway inflammatory cells infiltration, the local cytokines and chemokines production and the histopathological changes of lung tissue were investigated. We found that the administration of rMS-Ag85a-IL-17a induced the autoantibody of IL-17A in sera. The vaccination of rMS-Ag85a-IL-17a remarkably reduced the infiltration of inflammatory cells and the secretion of mucus in lung tissue and significantly decreased the numbers of the total cells, eosinophils and neutrophils in BALF. Th1 cells count in spleen, Th1 cytokine levels in BALF and supernatant of splenocytes and mediastinal lymph nodes, and T-bet mRNA in lung tissue were significantly increased with rMS-Ag85a-IL-17a administration. Meanwhile, rMS-Ag85a-IL-17a vaccination markedly decreased Th2 cells count, Th2 cytokine and Th17 cytokine levels in BALF and supernatant of splenocytes and mediastinal lymph nodes, and chemokines mRNA expression in lung tissue. These data confirmed that recombinant Mycobacterium smegmatis in vivo could induce autoantibody of IL-17A, which attenuated asthmatic airway inflammation.

  3. Intranasal Administration of Recombinant Mycobacterium smegmatis Inducing IL-17A Autoantibody Attenuates Airway Inflammation in a Murine Model of Allergic Asthma.

    PubMed

    Xu, Wanting; Chen, Ling; Guo, Sheng; Wu, Liangxia; Zhang, Jianhua

    2016-01-01

    Asthma is a chronic inflammatory disorder, previous studies have shown that IL-17A contributes to the development of asthma, and there is a positive correlation between the level of IL-17A and the severity of disease. Here, we constructed recombinant Mycobacterium smegmatis expressing fusion protein Ag85A-IL-17A (rMS-Ag85a-IL-17a) and evaluated whether it could attenuate allergic airway inflammation, and further investigated the underlying mechanism. In this work, the murine model of asthma was established with ovalbumin, and mice were intranasally vaccinated with rMS-Ag85a-IL-17a. Autoantibody of IL-17A in sera was detected, and the airway inflammatory cells infiltration, the local cytokines and chemokines production and the histopathological changes of lung tissue were investigated. We found that the administration of rMS-Ag85a-IL-17a induced the autoantibody of IL-17A in sera. The vaccination of rMS-Ag85a-IL-17a remarkably reduced the infiltration of inflammatory cells and the secretion of mucus in lung tissue and significantly decreased the numbers of the total cells, eosinophils and neutrophils in BALF. Th1 cells count in spleen, Th1 cytokine levels in BALF and supernatant of splenocytes and mediastinal lymph nodes, and T-bet mRNA in lung tissue were significantly increased with rMS-Ag85a-IL-17a administration. Meanwhile, rMS-Ag85a-IL-17a vaccination markedly decreased Th2 cells count, Th2 cytokine and Th17 cytokine levels in BALF and supernatant of splenocytes and mediastinal lymph nodes, and chemokines mRNA expression in lung tissue. These data confirmed that recombinant Mycobacterium smegmatis in vivo could induce autoantibody of IL-17A, which attenuated asthmatic airway inflammation. PMID:26974537

  4. Modulation of innate immunity in chickens induced by in vivo administration of baculovirus.

    PubMed

    Chimeno Zoth, Silvina; Carballeda, Juan Manuel; Gómez, Evangelina; Gravisaco, María José; Carrillo, Elisa; Berinstein, Analía

    2012-01-15

    Baculoviruses stimulate cytokine production in mammalian cells. They induce a strong innate immune response in animals and have adjuvant properties. The purpose of this work was to study the in vivo effect of baculovirus on chicken innate immune response. SPF chickens were inoculated intravenously with Autographa californica nuclear polyhedrosis virus (BV). Three hours later, chickens were bled, euthanized and their spleen, duodenum and cecal tonsils were excised in order to take samples for RNA extraction and real time PCR, and to isolate lymphocytes, which were stained and analyzed by flow cytometry. The results obtained showed that baculovirus inoculation up-regulates the expression of IFN-γ, IL-6 and LITAF in spleen cells. This result (IFN-γ) correlated with that obtained by ELISA which showed a very strong increase of IFN-γ in chicken plasma. Flow cytometry analysis revealed that BV inoculation induced in spleen an increase in the percentage of monocyte/macrophage population together with an increase in CD3(+)CD4(+) T lymphocytes. On the other hand, BV inoculation decreased the percentage of CD3(+)CD4(+) T lymphocytes and increased the percentage of NK cells in cecal tonsils. However, intraepithelial lymphocytes of the gut did not show differences between BV and control treated animals. Even though further studies in order to understand the mechanisms by which BVs affect the avian immune response are needed, results obtained in the present work demonstrate the ability of BVs to stimulate the innate immunity in chickens, modifying the expression pattern of related genes and the profile of the immune cells involved. PMID:22142984

  5. Response of thymus lymphocytes to streptozotocin-induced diabetes and exogenous vitamin C administration in rats.

    PubMed

    Ozerkan, Dilşad; Ozsoy, Nesrin; Cebesoy, Suna

    2014-12-01

    Diabetes causes oxidative stress, which in turn generates excessive free radicals resulting in cellular damage. Vitamin C is an antioxidant that protects tissues and organs from oxidative stress. The thymus is one of the most important lymphoid organs, which regulates T-lymphocyte proliferation and maturation. The aim of this study is to investigate the protective effects of vitamin C on the thymus of streptozotocin (STZ)-induced diabetic rats. The mitotic activity and cell integrity of thymic lymphocytes were explored. Wistar Albino rats were divided into three groups: control (Group 1), STZ-diabetes (Group 2) and vitamin C-treated STZ-diabetics (Group 3). Rats received a single intraperitoneal injection of 45 mg/kg STZ to induce diabetes. Vitamin C (20 mg/kg) was administered intragastrically. Semithin and ultrathin sections were examined under a light or an electron microscope, respectively. Considerable numbers of mitotic lymphocytes were observed in the thymus of control rats. In the diabetic rats, however, numbers of mitotic lymphocytes decreased to ∼57% of controls, and cell division abnormalities were observed. Additionally, diabetic rats showed degeneration in the structure of the thymus including trabecular thickening, accumulation of lipid vacuoles, heterochromatic nuclei and loss of mitochondrial cristae. Degradation of medullar and cortical integrity was also detected. In the vitamin C-treated STZ-diabetic group, the structure of the thymus and mitotic activity of the lymphocytes were similar to the control group. These results suggest that vitamin C protects the thymus against injury caused by diabetes and restores thymocyte mitotic activity. PMID:25145646

  6. Response of thymus lymphocytes to streptozotocin-induced diabetes and exogenous vitamin C administration in rats.

    PubMed

    Ozerkan, Dilşad; Ozsoy, Nesrin; Cebesoy, Suna

    2014-12-01

    Diabetes causes oxidative stress, which in turn generates excessive free radicals resulting in cellular damage. Vitamin C is an antioxidant that protects tissues and organs from oxidative stress. The thymus is one of the most important lymphoid organs, which regulates T-lymphocyte proliferation and maturation. The aim of this study is to investigate the protective effects of vitamin C on the thymus of streptozotocin (STZ)-induced diabetic rats. The mitotic activity and cell integrity of thymic lymphocytes were explored. Wistar Albino rats were divided into three groups: control (Group 1), STZ-diabetes (Group 2) and vitamin C-treated STZ-diabetics (Group 3). Rats received a single intraperitoneal injection of 45 mg/kg STZ to induce diabetes. Vitamin C (20 mg/kg) was administered intragastrically. Semithin and ultrathin sections were examined under a light or an electron microscope, respectively. Considerable numbers of mitotic lymphocytes were observed in the thymus of control rats. In the diabetic rats, however, numbers of mitotic lymphocytes decreased to ∼57% of controls, and cell division abnormalities were observed. Additionally, diabetic rats showed degeneration in the structure of the thymus including trabecular thickening, accumulation of lipid vacuoles, heterochromatic nuclei and loss of mitochondrial cristae. Degradation of medullar and cortical integrity was also detected. In the vitamin C-treated STZ-diabetic group, the structure of the thymus and mitotic activity of the lymphocytes were similar to the control group. These results suggest that vitamin C protects the thymus against injury caused by diabetes and restores thymocyte mitotic activity.

  7. Administration of PPARβ/δ agonist reduces copper-induced liver damage in mice: possible implications in clinical practice.

    PubMed

    Sanchez-Siles, Alvaro A; Ishimura, Norihisa; Rumi, Mohammad A K; Tamagawa, Yuji; Ito, Satoko; Ishihara, Shunji; Nabika, Toru; Kinoshita, Yoshikazu

    2011-07-01

    In this study we investigated if peroxisome proliferator-activated receptor β/δ activation protects from copper-induced acute liver damage. Mice treated with copper had significant body weight loss, serum alanine aminotransferase increase, modest changes in liver histology, increase of tumor necrosis factor α and macrophage inflammatory protein 2 mRNA and 8-hydroxy-2'-deoxyguanosine. Mice treated with copper and peroxisome proliferator-activated receptor β/δ agonist GW0742 had significantly less body weight loss, less serum alanine aminotransferase increase, less tumor necrosis factor α, macrophage inflammatory protein-2 and 8-hydroxy-2'-deoxyguanosine upregulation than copper treated mice. The opposite effect was observed in mice treated with copper and peroxisome proliferator-activated receptor β/δ antagonist GSK0660. In vitro, copper induced reactive oxygen species, which was lower in cells treated with GW0742 or transfected with peroxisome proliferator-activated receptor β/δ expression vector; together, transfection and GW0742 had an additive reactive oxygen species-reducing effect. Copper also upregulated Fas ligand and Caspase 3/7 activity, effects that were significantly lower in cells also treated with GW0742. In conclusion, peroxisome proliferator-activated receptor β/δ activation reduced copper-induced reactive oxygen species, pro-inflammatory and acute phase reaction cytokines in mice liver. Peroxisome proliferator-activated receptor β/δ agonists could become useful in the management of copper-induced liver damage.

  8. BZYX, a novel acetylcholinesterase inhibitor, significantly improved chemicals-induced learning and memory impairments on rodents and protected PC12 cells from apoptosis induced by hydrogen peroxide.

    PubMed

    Zhang, Jing; Zhu, Difeng; Sheng, Rong; Wu, Honghai; Hu, Yongzhou; Wang, Feng; Cai, Tianyu; Yang, Bo; He, Qiaojun

    2009-06-24

    BZYX was designed as a dual-binding-site acetylcholinesterase (AChE) inhibitor and selected from series of indanone derivatives. The present study was designed to examine the cognition-enhanced, anti-cholinesterase, and neuroprotective effects of BZYX. In the passive avoidance performance and radial arm maze, BZYX showed a comparable effect to donepezil and rivastigmine on memory deficits in different stages induced by scopolamine, NaNO(2) and ethanol, respectively. Ellman's assay indicated BZYX exhibited high inhibition on AChE activity. IC(50) values for BZYX: 0.058+/-0.022 microM; donepezil: 0.019+/-0.004 microM; rivastigmine: 3.81+/-2.81 microM; glantamine: 3.01+/-1.85 microM and huperzine A: 0.053+/-0.016 microM. BZYX also presented great neuroprotecive function from apoptosis induced by hydrogen peroxide(H(2)O(2)) in PC12 cells. MTT assay and Annexin V-FITC Apoptosis Detection showed the viability of PC12 cells remarkably decreased with 400 microM H(2)O(2), while it significantly increased when the cells were pretreated with 0.1-1.0 microM BZYX. BZYX pretreatment remarkably reversed the loss of mitochondria membrane potential (DeltaPsim), scavenged reactive oxygen species formation induced by H(2)O(2) and resulted in up-regulation of procaspase3 and xIAP protein level and down-regulation of phosphorylated JNK protein, p53 protein level and cleavage of caspase 3. It is speculated that the mitochondrial pathway, mediated by Bcl-2 family and Mitogen-Activated Protein Kinases (MAPKs), might involved in the neuroprotection of BZYX. These results first demonstrated that BZYX had neuroprotective effects as well as cognition enhancement and acetylcholinesterase inhibition. It is hopeful that BZYX becomes a potential candidate for use in the intervention for neurodegenerative diseases. PMID:19345205

  9. Development of a Risk Index for Serious Prescription Opioid‐Induced Respiratory Depression or Overdose in Veterans’ Health Administration Patients

    PubMed Central

    Xie, Lin; Wang, Li; Joyce, Andrew; Vick, Catherine; Brigham, Janet; Kariburyo, Furaha; Baser, Onur; Murrelle, Lenn

    2015-01-01

    Abstract Objective Develop a risk index to estimate the likelihood of life‐threatening respiratory depression or overdose among medical users of prescription opioids. Subjects, Design, and Methods A case‐control analysis of administrative health care data from the Veterans’ Health Administration identified 1,877,841 patients with a pharmacy record for an opioid prescription between October 1, 2010 and September 30, 2012. Overdose or serious opioid‐induced respiratory depression (OSORD) occurred in 817. Ten controls were selected per case (n = 8,170). Items for an OSORD risk index (RIOSORD) were selected through logistic regression modeling, with point values assigned to each predictor. Modeling of risk index scores produced predicted probabilities of OSORD; risk classes were defined by the predicted probability distribution. Results Fifteen variables most highly associated with OSORD were retained as items, including mental health disorders and pharmacotherapy; impaired drug metabolism or excretion; pulmonary disorders; specific opioid characteristics; and recent hospital visits. The average predicted probability of experiencing OSORD ranged from 3% in the lowest risk decile to 94% in the highest, with excellent agreement between predicted and observed incidence across risk classes. The model's C‐statistic was 0.88 and Hosmer–Lemeshow goodness‐of‐fit statistic 10.8 (P > 0.05). Conclusion RIOSORD performed well in identifying medical users of prescription opioids within the Veterans’ Health Administration at elevated risk of overdose or life‐threatening respiratory depression, those most likely to benefit from preventive interventions. This novel, clinically practical, risk index is intended to provide clinical decision support for safer pain management. It should be assessed, and refined as necessary, in a more generalizable population, and prospectively evaluated. PMID:26077738

  10. Administration of NaHS Attenuates Footshock-Induced Pathologies and Emotional and Cognitive Dysfunction in Triple Transgenic Alzheimer's Mice.

    PubMed

    Huang, Hei-Jen; Chen, Shu-Ling; Hsieh-Li, Hsiu Mei

    2015-01-01

    Alzheimer's disease (AD) is characterized by progressive cognitive decline and neuropsychiatric symptoms. Increasing evidence indicates that environmental risk factors in young adults may accelerate cognitive loss in AD and that Hydrogen Sulfide (H2S) may represent an innovative treatment to slow the progression of AD. Therefore, the aim of this study was to evaluate the effects of NaHS, an H2S donor, in a triple transgenic AD mouse model (3×Tg-AD) under footshock with situational reminders (SRs). Inescapable footshock with SRs induced anxiety and cognitive dysfunction as well as a decrease in the levels of plasma H2S and GSH and an increase in IL-6 levels in 3×Tg-AD mice. Under footshock with SR stimulus, amyloid deposition, tau protein hyperphosphorylation, and microgliosis were highly increased in the stress-responsive brain structures, including the hippocampus and amygdala, of the AD mice. Oxidative stress, inflammatory response, and β-site APP cleaving enzyme 1 (BACE1) levels were also increased, and the level of inactivated glycogen synthase kinase-3β (GSK3β) (pSer9) was decreased in the hippocampi of AD mice subjected to footshock with SRs. Furthermore, the numbers of cholinergic neurons in the medial septum/diagonal band of Broca (MS/DB) and noradrenergic neurons in the locus coeruleus (LC) were also decreased in the 3×Tg-AD mice under footshock with SRs. These biochemical hallmarks and pathological presentations were all alleviated by the semi-acute administration of NaHS in the AD mice. Together, these findings suggest that footshock with SRs induces the impairment of spatial cognition and emotion, which involve pathological changes in the peripheral and central systems, including the hippocampus, MS/DB, LC, and BLA, and that the administration of NaHS may be a candidate strategy to ameliorate the progression of neurodegeneration. PMID:26635562

  11. d-galactose administration induces memory loss and energy metabolism disturbance in mice: protective effects of catalpol.

    PubMed

    Zhang, Xiu-Li; An, Li-Jia; Bao, Yong-Ming; Wang, Jing-Yun; Jiang, Bo

    2008-08-01

    The neuroprotective effects of catalpol, an iridoid glycoside isolated from the fresh rehmannia roots, on the behavior and brain energy metabolism in senescent mice induced by d-galactose were assessed. Except control group, mice were subcutaneously injected with d-galactose (150 mg/kg body weight) for 6 weeks. From the fifth week, drug group mice were treated with catalpol (2.5, 5, 10 mg/kg body weight) and piracetam (300 mg/kg body weight) for the last 2 weeks. Behavioral changes including open field test and passive avoidance were examined after drug administration. To determine the brain damage, pathological alterations were measured by hematoxylin and eosin (HE) staining. The activities of lactate dehydrogenase (LDH), glutathione S-transferase (GSH-ST), glutamine synthetase (GS), creatine kinase (CK) in brain cortex and hippocampus were determined using different biochemical methods. Consistent with the cognition deficits, the activities of GSH-ST, GS and CK decreased while the activity of LDH increased in aging mice brain. Administration of catalpol for 2-weeks not only ameliorated cognition deficit, but also reversed the biochemical markers mentioned above and reduced the histological lesions in mouse brain. These results suggest that catalpol has protective effects on memory damage and energy metabolism failure in aging model mice and is worth testing for further preclinical study aimed for senescence or neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD).

  12. Exogenous midkine administration prevents cardiac remodeling in pacing-induced congestive heart failure of rabbits.

    PubMed

    Harada, Masahide; Hojo, Mayumi; Kamiya, Kaichiro; Kadomatsu, Kenji; Murohara, Toyoaki; Kodama, Itsuo; Horiba, Mitsuru

    2016-01-01

    Midkine (MK), a heparin-binding growth factor, has been shown to prevent cardiac remodeling after ischemic injury through its anti-apoptotic effect. Cell apoptosis is central to the pathophysiology of cardiac remodeling in congestive heart failure (CHF) of ischemic as well as non-ischemic origin. We hypothesized that MK exerts the anti-apoptotic cardioprotective effect in CHF of non-ischemic etiology. MK protein or vehicle (normal saline) was subcutaneously administered in tachycardia-induced CHF rabbits (right ventricular pacing, 350 beats/min, 4 weeks). The vehicle-treated rabbits (n = 19, control) demonstrated severe CHF and high mortality rate, whereas MK (n = 16) demonstrated a well-compensated state and a lower mortality rate. In echocardiography, left ventricular (LV) end-diastolic dimension decreased in MK versus control, whereas LV systolic function increased. In histological analysis (picrosirius red staining), MK decreased collagen deposition area compared with control. TUNEL staining showed that MK prevented cell apoptosis and minimized myocyte loss in the CHF rabbit ventricle, associated with activation of PI3-K/Akt signaling, producing a parallel decrease of Bax/Bcl-2 ratio. MK prevented progression of cardiac remodeling in the CHF rabbit, likely by activation of anti-apoptotic signaling. Exogenous MK application might be a novel therapeutic strategy for CHF due to non-ischemic origin.

  13. Shoshin Beriberi Induced by Long-Term Administration of Diuretics: A Case Report

    PubMed Central

    Misumida, Naoki; Umeda, Hisashi; Iwase, Mitsunori

    2014-01-01

    Previous studies have suggested that diuretic therapy for heart failure may lead to thiamine deficiency due to the increased urinary thiamine excretion. Herein, we present the case of a 61-year-old man with shoshin beriberi, a fulminant form of wet beriberi, induced by long-term diuretic therapy. The patient had a history of heart failure with preserved ejection fraction and was receiving furosemide and trichlormethiazide therapy. He presented with worsening exertional dyspnea and was admitted for heart failure exacerbation. His condition failed to improve even after intensive treatment. A hemodynamic evaluation with the Swan-Ganz catheter revealed high-output heart failure with low peripheral vascular resistance. Thiamine was administered for suspected shoshin beriberi; his hemodynamic status improved dramatically within the next six hours. The serum thiamine level was below the normal range; the patient was therefore diagnosed with shoshin beriberi. The common causes of thiamine deficiency were not identified. Long-term diuretic therapy with furosemide and thiazide was thought to have played a major role in the development of thiamine deficiency. This case illustrates the importance of considering wet beriberi as a possible cause of heart failure exacerbation in patients taking diuretics, even when the common thiamine deficiency causes are not identified with history-taking. PMID:25105030

  14. Choice of study endpoint significantly impacts the results of breast cancer trials evaluating chemotherapy-induced nausea and vomiting.

    PubMed

    Ng, Terry; Mazzarello, Sasha; Wang, Zhou; Hutton, Brian; Dranitsaris, George; Vandermeer, Lisa; Smith, Stephanie; Clemons, Mark

    2016-01-01

    Multiple endpoints can be used to evaluate chemotherapy-induced nausea and vomiting (CINV). These endpoints reflect the various combinations of vomiting, nausea and rescue antiemetic use in the acute (0-24 h), delayed (>24-120 h) and overall (0-120 h) periods after chemotherapy. As the choice of outcome measure could potentially change the interpretation of clinical trial results, we evaluated CINV rates using different endpoints on a single dataset from a prospective cohort. Data from 177 breast cancer patients receiving anthracycline and cyclophosphamide-based chemotherapy was used to calculate CINV control rates using the 15 most commonly reported CINV endpoints. As nausea remains such a significant symptom, we explored the frequency at which pharmaceutical and non-pharmaceutical company-funded studies included measures of nausea in their primary study endpoint. CINV control rates ranged from 12.5 %, 95 % (CI 7.6-17.4 %) for total control (no vomiting, no nausea and no rescue medication) in the overall period to 77.4 %, 95 % (CI 71.2-83.6 %) for no vomiting in the overall period. Similar differences were found in the acute and delayed periods. Non-pharmaceutical company-funded trials were more likely to include a measure of nausea in the primary study outcome (9/18, 50 %) than pharmaceutical-funded trials (1/12, 8.3 %). The choice of trial endpoint has an important impact on reported CINV control rates and could significantly impact on interpretation of the results. Primary endpoints of studies, including those mandated by regulatory bodies, should account for nausea to reflect patient experience. Reporting of endpoints should be more comprehensive to allow for cross-trial comparisons.

  15. Ozone-Induced Dissociation of Conjugated Lipids Reveals Significant Reaction Rate Enhancements and Characteristic Odd-Electron Product Ions

    NASA Astrophysics Data System (ADS)

    Pham, Huong T.; Maccarone, Alan T.; Campbell, J. Larry; Mitchell, Todd W.; Blanksby, Stephen J.

    2013-02-01

    Ozone-induced dissociation (OzID) is an alternative ion activation method that relies on the gas phase ion-molecule reaction between a mass-selected target ion and ozone in an ion trap mass spectrometer. Herein, we evaluated the performance of OzID for both the structural elucidation and selective detection of conjugated carbon-carbon double bond motifs within lipids. The relative reactivity trends for [M + X]+ ions (where X = Li, Na, K) formed via electrospray ionization (ESI) of conjugated versus nonconjugated fatty acid methyl esters (FAMEs) were examined using two different OzID-enabled linear ion-trap mass spectrometers. Compared with nonconjugated analogues, FAMEs derived from conjugated linoleic acids were found to react up to 200 times faster and to yield characteristic radical cations. The significantly enhanced reactivity of conjugated isomers means that OzID product ions can be observed without invoking a reaction delay in the experimental sequence (i.e., trapping of ions in the presence of ozone is not required). This possibility has been exploited to undertake neutral-loss scans on a triple quadrupole mass spectrometer targeting characteristic OzID transitions. Such analyses reveal the presence of conjugated double bonds in lipids extracted from selected foodstuffs. Finally, by benchmarking of the absolute ozone concentration inside the ion trap, second order rate constants for the gas phase reactions between unsaturated organic ions and ozone were obtained. These results demonstrate a significant influence of the adducting metal on reaction rate constants in the fashion Li > Na > K.

  16. Ozone-induced dissociation of conjugated lipids reveals significant reaction rate enhancements and characteristic odd-electron product ions.

    PubMed

    Pham, Huong T; Maccarone, Alan T; Campbell, J Larry; Mitchell, Todd W; Blanksby, Stephen J

    2013-02-01

    Ozone-induced dissociation (OzID) is an alternative ion activation method that relies on the gas phase ion-molecule reaction between a mass-selected target ion and ozone in an ion trap mass spectrometer. Herein, we evaluated the performance of OzID for both the structural elucidation and selective detection of conjugated carbon-carbon double bond motifs within lipids. The relative reactivity trends for [M + X](+) ions (where X = Li, Na, K) formed via electrospray ionization (ESI) of conjugated versus nonconjugated fatty acid methyl esters (FAMEs) were examined using two different OzID-enabled linear ion-trap mass spectrometers. Compared with nonconjugated analogues, FAMEs derived from conjugated linoleic acids were found to react up to 200 times faster and to yield characteristic radical cations. The significantly enhanced reactivity of conjugated isomers means that OzID product ions can be observed without invoking a reaction delay in the experimental sequence (i.e., trapping of ions in the presence of ozone is not required). This possibility has been exploited to undertake neutral-loss scans on a triple quadrupole mass spectrometer targeting characteristic OzID transitions. Such analyses reveal the presence of conjugated double bonds in lipids extracted from selected foodstuffs. Finally, by benchmarking of the absolute ozone concentration inside the ion trap, second order rate constants for the gas phase reactions between unsaturated organic ions and ozone were obtained. These results demonstrate a significant influence of the adducting metal on reaction rate constants in the fashion Li > Na > K.

  17. Improvement in γ-hydroxybutyrate-induced contextual fear memory deficit by systemic administration of NCS-382

    PubMed Central

    Ishiwari, Keita

    2016-01-01

    Low, nonsedative doses of γ-hydroxybutyric acid (GHB) produce short-term anterograde amnesia in humans and memory impairments in experimental animals. We have previously shown that acute systemic treatment of GHB in adolescent female rats impairs the acquisition, but not the expression, of contextual fear memory while sparing both the acquisition and the expression of auditory cued fear memory. In the brain, GHB binds to specific GHB-binding sites as well as to γ-aminobutyric acid type B (GABAB) receptors. Although many of the behavioral effects of GHB at high doses have been attributed to its effects on the GABAB receptor, it is unclear which receptor mediates its relatively low-dose memory-impairing effects. The present study examined the ability of the putative GHB receptor antagonist NCS-382 to block the disrupting effects of GHB on fear memory in adolescent rat. Groups of rats received either a single dose of NCS-382 (3–10 mg/kg, intraperitoneally) or vehicle, followed by an injection of either GHB (100 mg/kg, intraperitoneally) or saline. All rats were trained in the fear paradigm, and tested for contextual fear memory and auditory cued fear memory. NCS-382 dose-dependently reversed deficits in the acquisition of contextual fear memory induced by GHB in adolescent rats, with 5 mg/kg of NCS-382 maximally increasing freezing to the context compared with the group administered GHB alone. When animals were tested for cued fear memory, treatment groups did not differ in freezing responses to the tone. These results suggest that low-dose amnesic effects of GHB are mediated by GHB receptors. PMID:27105320

  18. Improvement in γ-hydroxybutyrate-induced contextual fear memory deficit by systemic administration of NCS-382.

    PubMed

    Ishiwari, Keita; Sircar, Ratna

    2016-06-15

    Low, nonsedative doses of γ-hydroxybutyric acid (GHB) produce short-term anterograde amnesia in humans and memory impairments in experimental animals. We have previously shown that acute systemic treatment of GHB in adolescent female rats impairs the acquisition, but not the expression, of contextual fear memory while sparing both the acquisition and the expression of auditory cued fear memory. In the brain, GHB binds to specific GHB-binding sites as well as to γ-aminobutyric acid type B (GABAB) receptors. Although many of the behavioral effects of GHB at high doses have been attributed to its effects on the GABAB receptor, it is unclear which receptor mediates its relatively low-dose memory-impairing effects. The present study examined the ability of the putative GHB receptor antagonist NCS-382 to block the disrupting effects of GHB on fear memory in adolescent rat. Groups of rats received either a single dose of NCS-382 (3-10 mg/kg, intraperitoneally) or vehicle, followed by an injection of either GHB (100 mg/kg, intraperitoneally) or saline. All rats were trained in the fear paradigm, and tested for contextual fear memory and auditory cued fear memory. NCS-382 dose-dependently reversed deficits in the acquisition of contextual fear memory induced by GHB in adolescent rats, with 5 mg/kg of NCS-382 maximally increasing freezing to the context compared with the group administered GHB alone. When animals were tested for cued fear memory, treatment groups did not differ in freezing responses to the tone. These results suggest that low-dose amnesic effects of GHB are mediated by GHB receptors. PMID:27105320

  19. Regulated hypothermia in the hypothyroid rat induced by administration of propylthiouracil.

    PubMed

    Yang, Y; Gordon, C J

    1997-05-01

    Propylthiouracil (PTU), an antithyroidal drug that reduces serum L-thyroxine (T4) and 3,5,3'-triiodothyronine (T3), is presumed to lower core temperature (T0) by impairing metabolic thermogenesis. However, it is not understood why PTU-treated animals cannot use behavioral and other thermoeffectors to maintain normal Tc. Male rats were administered PTU in drinking water (0.05 mg/ml) while the following parameters were measured: 1) Tc and motor activity (MA) recorded by radiotelemetry for 24 h at ambient temperatures (Ta) of 10-30 degrees C; 2) selected Ta, MA, and Tc in a temperature gradient; and 3) Tc, MA, and grooming behavior during exposure to heat stress (TH = 34.5 degrees C) for 2 h. PTU reduced serum levels of T4, and T3 by 95 and 60%, respectively. Tc decreased after 3 days of PTU treatment; a 0.5 degree C decrease in Tc persisted throughout the PTU treatment. PTU rats exposed to Ta of 10-30 degrees C maintained a consistent hypothermic Tc during the light phase; however, a deficit in the stability of Tc at night was noted during exposure to 10 degrees C. In the temperature gradient, PTU rats selected warmer Ta, but their Tc was maintained at the same hypothermic levels as observed at fixed Ta values of 15-30 degrees C. Heat stress caused Tc of control rats to increase to 39 degrees C, whereas Tc of the PTU rats was maintained below 38 degrees C. The regulation of Tc at hypothermic levels over a wide range of Ta values and when rats were housed in a temperature gradient indicates that chronic PTU induces a state of regulated hypothermia. PMID:9176328

  20. Effect of plantar subcutaneous administration of bergamot essential oil and linalool on formalin-induced nociceptive behavior in mice.

    PubMed

    Katsuyama, Soh; Otowa, Akira; Kamio, Satomi; Sato, Kazuma; Yagi, Tomomi; Kishikawa, Yukinaga; Komatsu, Takaaki; Bagetta, Giacinto; Sakurada, Tsukasa; Nakamura, Hitoshi

    2015-01-01

    This study investigated the effect of bergamot essential oil (BEO) or linalool, a major volatile component of BEO, on the nociceptive response to formalin. Plantar subcutaneous injection of BEO or linalool into the ipsilateral hindpaw reduced both the first and late phases of the formalin-induced licking and biting responses in mice. Plantar subcutaneous injection of BEO or linalool into the contralateral hindpaw did not yield an antinociceptive effect, suggesting that the antinociceptive effect of BEO or linalool in the formalin test occurred peripherally. Intraperitoneal and plantar subcutaneous injection pretreatment with naloxone hydrochloride, an opioid receptor antagonist, significantly attenuated both BEO- and linalool-induced antinociception. Pretreatment with naloxone methiodide, a peripherally acting opioid receptor antagonists, also significantly antagonized the antinociceptive effects of BEO and linalool. Our results provide evidence for the involvement of peripheral opioids in antinociception induced by BEO and linalool. These results suggest that activation of peripheral opioid receptors may play an important role in reducing formalin-induced nociception.

  1. Protection against Rift Valley fever virus infection in mice upon administration of interferon-inducing RNA transcripts from the FMDV genome.

    PubMed

    Lorenzo, Gema; Rodríguez-Pulido, Miguel; López-Gil, Elena; Sobrino, Francisco; Borrego, Belén; Sáiz, Margarita; Brun, Alejandro

    2014-09-01

    In this work we have addressed the effect of synthetic, non-infectious, RNA transcripts, mimicking structural domains of the non-coding regions (NCRs) of the foot-and-mouth disease virus (FMDV) genome on the infection of mice with Rift Valley fever virus (RVFV). Groups of 5 mice were inoculated intraperitoneally (i.p.) with 200 μg of synthetic RNA resembling the 5'-terminal S region, the internal ribosome entry site (IRES) or the 3'-NCR of the FMDV genome. RNA inoculation was performed 24h before (-24 h), 24 h after (+24 h) or simultaneously to the challenge with a lethal dose of RVFV. Administration of the IRES RNA afforded higher survival rates than administration of S or 3'NCR transcripts either at -24h or +24h after challenge. In contrast, when RNA inoculation and viral challenge were performed simultaneously, all mice survived in both IRES- and 3'NCR-inoculated groups, with an 80% survival in mice receiving the S RNA. Among survivors, a complete correlation between significant anti-RVFV circulating antibody titers and resistance to a second lethal challenge with the virus was observed, supporting a limited viral replication in the RNA-inoculated animals upon the first challenge. All three RNA transcripts were able to induce the production of systemic antiviral and pro-inflammatory cytokines. These data show that triggering of intracellular pathogen sensing pathways constitutes a promising approach towards development of novel RVF preventive or therapeutic strategies. PMID:24973761

  2. Administration of the TrkB receptor agonist 7,8-dihydroxyflavone prevents traumatic stress-induced spatial memory deficits and changes in synaptic plasticity.

    PubMed

    Sanz-García, Ancor; Knafo, Shira; Pereda-Pérez, Inmaculada; Esteban, José A; Venero, César; Armario, Antonio

    2016-09-01

    Post-traumatic stress disorder (PTSD) occurs after exposure to traumatic situations and it is characterized by cognitive deficits that include impaired explicit memory. The neurobiological bases of such PTSD-associated memory alterations are yet to be elucidated and no satisfactory treatment for them exists. To address this issue, we first studied whether a single exposure of young adult rats (60 days) to immobilization on boards (IMO), a putative model of PTSD, produces long-term behavioral effects (2-8 days) similar to those found in PTSD patients. Subsequently, we investigated whether the administration of the TrkB agonist 7,8-dihydroxyflavone (DHF) 8 h after stress (therapeutic window) ameliorated the PTSD-like effect of IMO and the associated changes in synaptic plasticity. A single IMO exposure induced a spatial memory impairment similar to that found in other animal models of PTSD or in PTSD patients. IMO also increased spine density and long-term potentiation (LTP) in the CA3-CA1 pathway. Significantly, DHF reverted both spatial memory impairment and the increase in LTP, while it produced no effect in the controls. These data provide novel insights into the possible neurobiological substrate for explicit memory impairment in PTSD patients, supporting the idea that the activation of the BDNF/TrkB pathway fulfils a protective role after severe stress. Administration of DHF in the aftermath of a traumatic experience might be relevant to prevent its long-term consequences. © 2016 Wiley Periodicals, Inc.

  3. Administration of the TrkB receptor agonist 7,8-dihydroxyflavone prevents traumatic stress-induced spatial memory deficits and changes in synaptic plasticity.

    PubMed

    Sanz-García, Ancor; Knafo, Shira; Pereda-Pérez, Inmaculada; Esteban, José A; Venero, César; Armario, Antonio

    2016-09-01

    Post-traumatic stress disorder (PTSD) occurs after exposure to traumatic situations and it is characterized by cognitive deficits that include impaired explicit memory. The neurobiological bases of such PTSD-associated memory alterations are yet to be elucidated and no satisfactory treatment for them exists. To address this issue, we first studied whether a single exposure of young adult rats (60 days) to immobilization on boards (IMO), a putative model of PTSD, produces long-term behavioral effects (2-8 days) similar to those found in PTSD patients. Subsequently, we investigated whether the administration of the TrkB agonist 7,8-dihydroxyflavone (DHF) 8 h after stress (therapeutic window) ameliorated the PTSD-like effect of IMO and the associated changes in synaptic plasticity. A single IMO exposure induced a spatial memory impairment similar to that found in other animal models of PTSD or in PTSD patients. IMO also increased spine density and long-term potentiation (LTP) in the CA3-CA1 pathway. Significantly, DHF reverted both spatial memory impairment and the increase in LTP, while it produced no effect in the controls. These data provide novel insights into the possible neurobiological substrate for explicit memory impairment in PTSD patients, supporting the idea that the activation of the BDNF/TrkB pathway fulfils a protective role after severe stress. Administration of DHF in the aftermath of a traumatic experience might be relevant to prevent its long-term consequences. © 2016 Wiley Periodicals, Inc. PMID:27068341

  4. Impairment of Electron Transfer Chain Induced by Acute Carnosine Administration in Skeletal Muscle of Young Rats

    PubMed Central

    Macarini, José Roberto; Maravai, Soliany Grassi; Cararo, José Henrique; Dimer, Nádia Webber; Gonçalves, Cinara Ludvig; Kist, Luiza Wilges; Bogo, Mauricio Reis; Schuck, Patrícia Fernanda; Streck, Emilio Luiz; Ferreira, Gustavo Costa

    2014-01-01

    Serum carnosinase deficiency is an inherited disorder that leads to an accumulation of carnosine in the brain tissue, cerebrospinal fluid, skeletal muscle, and other tissues of affected patients. Considering that high levels of carnosine are associated with neurological dysfunction and that the pathophysiological mechanisms involved in serum carnosinase deficiency remain poorly understood, we investigated the in vivo effects of carnosine on bioenergetics parameters, namely, respiratory chain complexes (I–III, II, and II-III), malate dehydrogenase, succinate dehydrogenase, and creatine kinase activities and the expression of mitochondrial-specific transcription factors (NRF-1, PGC-1α, and TFAM) in skeletal muscle of young Wistar rats. We observed a significant decrease of complexes I–III and II activities in animals receiving carnosine acutely, as compared to control group. However, no significant alterations in respiratory chain complexes, citric acid cycle enzymes, and creatine kinase activities were found between rats receiving carnosine chronically and control group animals. As compared to control group, mRNA levels of NRF-1, PGC-1α, and TFAM were unchanged. The present findings indicate that electron transfer through the respiratory chain is impaired in skeletal muscle of rats receiving carnosine acutely. In case these findings are confirmed by further studies and ATP depletion is also observed, impairment of bioenergetics could be considered a putative mechanism responsible for the muscle damage observed in serum carnosinase-deficient patients. PMID:24877122

  5. Impairment of electron transfer chain induced by acute carnosine administration in skeletal muscle of young rats.

    PubMed

    Macarini, José Roberto; Maravai, Soliany Grassi; Cararo, José Henrique; Dimer, Nádia Webber; Gonçalves, Cinara Ludvig; Kist, Luiza Wilges; Bogo, Mauricio Reis; Schuck, Patrícia Fernanda; Streck, Emilio Luiz; Ferreira, Gustavo Costa

    2014-01-01

    Serum carnosinase deficiency is an inherited disorder that leads to an accumulation of carnosine in the brain tissue, cerebrospinal fluid, skeletal muscle, and other tissues of affected patients. Considering that high levels of carnosine are associated with neurological dysfunction and that the pathophysiological mechanisms involved in serum carnosinase deficiency remain poorly understood, we investigated the in vivo effects of carnosine on bioenergetics parameters, namely, respiratory chain complexes (I-III, II, and II-III), malate dehydrogenase, succinate dehydrogenase, and creatine kinase activities and the expression of mitochondrial-specific transcription factors (NRF-1, PGC-1α , and TFAM) in skeletal muscle of young Wistar rats. We observed a significant decrease of complexes I-III and II activities in animals receiving carnosine acutely, as compared to control group. However, no significant alterations in respiratory chain complexes, citric acid cycle enzymes, and creatine kinase activities were found between rats receiving carnosine chronically and control group animals. As compared to control group, mRNA levels of NRF-1, PGC-1α , and TFAM were unchanged. The present findings indicate that electron transfer through the respiratory chain is impaired in skeletal muscle of rats receiving carnosine acutely. In case these findings are confirmed by further studies and ATP depletion is also observed, impairment of bioenergetics could be considered a putative mechanism responsible for the muscle damage observed in serum carnosinase-deficient patients. PMID:24877122

  6. Parietal cell hyperplasia induced by long-term administration of antacids to rats.

    PubMed Central

    Mazzacca, G; Cascione, F; Budillon, G; D'Agostino, L; Cimino, L; Femiano, C

    1978-01-01

    Suspension of magnesium and aluminum hydroxide (30--60 mEq/24h) or a comparable volme of water was orally administered by gastric intubation to two groups of 20 male Wistar rats each over 60 days. The antacid treatment led to a significant increase in the height (0.464 +/- 0.02 mm v. 0.318 +/- 0.06) and in the volume (472 +/- 32 mm3v.328 +/- 45) of the fundic mucosa of the stomach, in the average count of parietal cells per unit area of the mucosa (32.37 +/- 1.8 v. 22.3 +/- 1.6), and in the total parietal cell population of the stomach (53.6 +/- 3.5 x 10(6) v. 43.2 +/- 3.7 x 10(6)). Furthermore fasting serum gastrin concentration was significantly higher in the antacid treated rats (81.2 +/- 7.4 pg/ml) than in control animals (56.9 +/- 6.9 pg/ml). PMID:710969

  7. Response of arsenic-induced oxidative stress, DNA damage, and metal imbalance to combined administration of DMSA and monoisoamyl-DMSA during chronic arsenic poisoning in rats.

    PubMed

    Bhadauria, S; Flora, S J S

    2007-03-01

    -exposed rats compared to that of normal animals. These changes were accompanied by a significant elevation in blood and soft-tissue arsenic concentration. Co-administration of DMSA and MiADMSA at lower dose (0.15 mmol/kg) was most effective not only in reducing arsenic-induced oxidative stress but also in depleting arsenic from blood and soft tissues compared to other treatments. This combination was also able to repair DNA damage caused following arsenic exposure. We thus recommend combined administration of DMSA and MiADMSA for achieving optimum effects of chelation therapy.

  8. Oral and Intraperitoneal Administration of Quercetin Decreased Lymphocyte DNA Damage and Plasma Lipid Peroxidation Induced by TSA In Vivo

    PubMed Central

    Chan, Shu-Ting; Shiau, Rong-Jen; Liao, Jiunn-Wang; Yeh, Shu-Lan

    2014-01-01

    Our previous study showed that quercetin enhances the anticancer effect of trichostatin A (TSA) in xenograft mice given quercetin intraperitoneally (10 mg/kg, 3 times/week). Herein, we investigate whether quercetin administered orally exerts such an effect and prevents the cytotoxic side effects of TSA. We found that quercetin given orally (20 and 100 mg/kg, 3 times/week) failed to enhance the antitumor effect of TSA although it increased the total quercetin concentration more than quercetin administered intraperitoneally in the plasma. The compound quercetin-3-glucuronide (Q3G) increased the most. However, quercetin administered intraperitoneally increased the total quercetin level in tumor tissues more than oral quercetin. Oral and intraperitoneal administration of quercetin similarly decreased lymphocyte DNA damage and plasma lipid peroxidation level induced by TSA. Furthermore, we found that the enhancing effect of Q3G on the antitumor effect of TSA and the incorporation of Q3G was less than that of quercetin in A549 cells. However, we found that A549 cells possessed the ability to convert Q3G to quercetin. In conclusion, different from quercetin administered intraperitoneally, quercetin administered orally failed to enhance the antitumor effect of TSA because of its metabolic conversion. However, it prevented TSA-induced DNA damage and lipid peroxidation. PMID:24868531

  9. Protective effects of vitamins (C and E) and melatonin co-administration on hematological and hepatic functions and oxidative stress in alloxan-induced diabetic rats.

    PubMed

    Allagui, Mohamed Salah; Feriani, Anouer; Bouoni, Zouhour; Alimi, Hichem; Murat, Jean Claud; El Feki, Abdelfattah

    2014-09-01

    The present study aimed to investigate the potential effects of vitamins (C and E)/melatonin co-administration on the hematologic and hepatic functions and oxidative stress in alloxan-induced diabetic rats. The intraperitoneal injection of alloxan (120 mg/kg b.w. for 2 days) induced a significant increase of blood glucose levels (hyperglycemia) associated with serious hematologic disorders (P < 0.01) evidenced by the decrease in the levels of red blood cell count (RBC) (-18%), hematocrit (Ht) (-18%), hemoglobin content (Hb) (-36%), mean corpuscular hemoglobin (MCH) (-17%), and mean corpuscular hemoglobin concentration (MCHC) (-16%). The activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and the plasmatic levels of total cholesterol and triglyceride contents of diabetic rats were, however, noted to undergo significant increases by 42% (P < 0.01), 134% (P < 0.001), 27.5% (P < 0.01), 147% (P < 0.001), and 67% (P < 0.01), respectively, as compared to the control animals. Furthermore, a significant increase in malondialdehyde (MDA) content and a significant decrease in superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities were observed in the plasma and hepatic tissues of diabetic rats when compared to the controls. Interestingly, the treatment with vitamins (C, E) in combination with melatonin was noted to reduce the plasma levels of glucose, lower the MDA levels, and restore the hematologic parameters and biochemical and antioxidant levels of diabetic rats back to normal values, alleviating diabetes metabolic disorders in rats. PMID:24919717

  10. A single intravenous administration of zoledronic acid prevents the bone loss and mechanical compromise induced by aromatase inhibition in rats.

    PubMed

    Gasser, Jürg A; Green, Jonathan R; Shen, Victor; Ingold, Peter; Rebmann, Andrea; Bhatnagar, Ajay S; Evans, Dean B

    2006-10-01

    Recent evidence has demonstrated that long-term estrogen deprivation using aromatase inhibitor therapy in postmenopausal women with breast cancer results in bone loss and increased fracture risk. Bisphosphonates are potent inhibitors of bone resorption and have demonstrated efficacy in preventing bone loss in postmenopausal women with low bone mineral density (BMD) and in patients with breast cancer receiving estrogen deprivation therapy. Therefore, this study investigated the effects of the bisphosphonate zoledronic acid on BMD and bone strength in rats treated with the aromatase inhibitor, letrozole. Peripheral quantitative computed tomography demonstrated that treatment of rats with daily oral letrozole (1 mg/kg) induced significant bone loss and cortical thinning compared with control animals (P < 0.01). A single prior intravenous dose of zoledronic acid dose dependently protected against letrozole-induced bone loss and cortical thinning, with the highest evaluated dose (20 microg/kg) resulting in BMD values that were not significantly different from controls over the 24 weeks of letrozole treatment. Furthermore, biomechanical testing of the distal femoral metaphysis demonstrated that zoledronic acid (20 microg/kg) significantly prevented the decrease in stiffness and elastic modulus induced by letrozole treatment. Taken together, these data support the use of zoledronic acid for the prevention of bone loss in women with breast cancer receiving aromatase inhibitor therapy.

  11. Administration of microparticles from blood of the lipopolysaccharide-treated rats serves to induce pathologic changes of acute respiratory distress syndrome

    PubMed Central

    Li, Hongxia; Meng, Xiangyu; Liang, Xiaoyan; Gao, Yue

    2015-01-01

    This study was conducted to investigate the effect of intratracheal and intravenous administration of microparticles (MPs) on developing acute respiratory distress syndrome (ARDS). The blood MPs from lipopolysaccharide-treated rats were collected and examined by transmission electron microscopy (TEM). Cellular source of the MPs was identified by fluorescent-labeled antibodies after the circulating MPs were delivered to naïve rats. Levels of myeloperoxidase (MPO), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-10 productions in bronchoalveolar lavage fluid (BALF) and plasma were determined 24 h after the rats received intratracheal and intravenous administration of the MPs. Histopathologic examination of lungs was performed by light microscope. A TEM image of MPs showed spherical particles at a variable diameter from 0.1 to 0.5 µm. Endothelial- and leukocyte-derived vesicles were abundant in the investigated samples. Treatment with MPs may lead to significant increases in MPO, TNF-α, IL-1β, and IL-10 productions in BALF and plasma of the rats (all P < 0.001). Morphological observation indicated that alveolar structures were destroyed with a large amount of neutrophil infiltration in the lungs of the MP-treated rats. Perivascular and/or intra-alveolar hemorrhage were serious and hyaline membrane formed in the alveoli. Intratracheal and intravenous approaches to delivery of the circulating MPs to naïve recipient rats may induce ARDS. This presents an inducer of the onset of ARDS and provides potential therapeutic targets for attenuating lung injury. PMID:26088862

  12. Mycophenolate mofetil administration reduces renal inflammation, oxidative stress, and arterial pressure in rats with lead-induced hypertension.

    PubMed

    Bravo, Yanauri; Quiroz, Yasmir; Ferrebuz, Atilio; Vaziri, Nosratola D; Rodríguez-Iturbe, Bernardo

    2007-08-01

    Hypertension is a likely consequence of chronic lead exposure in humans, especially in association with reduced renal function and in high risk populations. Numerous studies have demonstrated that oxidative stress plays an important role in the pathogenesis of experimental lead-induced hypertension and we have shown recently that tubulointerstitial immune cell infiltration is a feature of chronic low-dose lead exposure. Since oxidative stress, renal inflammation, and angiotensin activity are closely linked characteristics in experimental models of hypertension, we decided to investigate whether lead-induced hypertension would be ameliorated by suppressing renal inflammation with the immunosuppressive drug mycophenolate mofetil (MMF). We studied rats exposed for 14 wk to lead acetate (100 ppm in the drinking water) that, in addition, received either MMF, 20 mg.kg(-1).day(-1) by gastric gavage (Pb.MMF group, n = 12) or vehicle (Pb group, n = 12). Control rats received MMF alone (n = 5) or neither lead nor MMF (n = 6). All rats were killed at the end of the experiment. Low-dose lead exposure resulted in mild to moderate tubular cell damage and a progressive increment in blood pressure, oxidative stress, interstitial accumulation of lymphocytes and macrophages, NF-kappaB activation, and increased renal angiotensin II level. The administration of MMF suppressed the tubulointerstitial accumulation of lymphocytes and macrophages and prevented the hypertension, oxidative stress, and NF-kappaB activation and reduced the heightened renal angiotensin content associated with chronic lead exposure. We conclude that interstitial inflammation plays an important role in lead-induced hypertension.

  13. Recombinant AAV9-TLK1B Administration Ameliorates Fractionated Radiation-Induced Xerostomia

    PubMed Central

    Shanmugam, Prakash Srinivasan Timiri; Dayton, Robert D.; Palaniyandi, Senthilnathan; Abreo, Fleurette; Caldito, Gloria; Klein, Ronald L.

    2013-01-01

    Abstract Salivary glands are highly susceptible to radiation, and patients with head and neck cancer treated with radiotherapy invariably suffer from its distressing side effect, salivary hypofunction. The reduction in saliva disrupts oral functions, and significantly impairs oral health. Previously, we demonstrated that adenoviral-mediated expression of Tousled-like kinase 1B (TLK1B) in rat submandibular glands preserves salivary function after single-dose ionizing radiation. To achieve long-term transgene expression for protection of salivary gland function against fractionated radiation, this study examines the usefulness of recombinant adeno-associated viral vector for TLK1B delivery. Lactated Ringers or AAV2/9 with either TLK1B or GFP expression cassette were retroductally delivered to rat submandibular salivary glands (1011 vg/gland), and animals were exposed, or not, to 20 Gy in eight fractions of 2.5 Gy/day. AAV2/9 transduced predominantly the ductal cells, including the convoluted granular tubules of the submandibular glands. Transgene expression after virus delivery could be detected within 5 weeks, and stable gene expression was observed till the end of study. Pilocarpine-stimulated saliva output measured at 8 weeks after completion of radiation demonstrated >10-fold reduction in salivary flow in saline- and AAV2/9-GFP-treated animals compared with the respective nonirradiated groups (90.8% and 92.5% reduction in salivary flow, respectively). Importantly, there was no decrease in stimulated salivary output after irradiation in animals that were pretreated with AAV2/9-TLK1B (121.5% increase in salivary flow; p<0.01). Salivary gland histology was better preserved after irradiation in TLK1B-treated group, though not significantly, compared with control groups. Single preemptive delivery of AAV2/9-TLK1B averts salivary dysfunction resulting from fractionated radiation. Although AAV2/9 transduces mostly the ductal cells of the gland, their protection

  14. Intrathecal [6]-gingerol administration alleviates peripherally induced neuropathic pain in male Sprague-Dawley rats.

    PubMed

    Gauthier, Marie-Lou; Beaudry, Francis; Vachon, Pascal

    2013-08-01

    [6]-Gingerol, a structural analog of capsaicin, is an agonist of the transient receptor potential vanilloid 1 channel, which is known to have therapeutic properties for the treatment of pain and inflammation. The main objective of this study was to determine the central effect of [6]-gingerol on neuropathic pain when injected intrathecally at the level of the lumbar spinal cord. [6]-Gingerol distribution was evaluated following a 40 mg/kg intraperitoneal injection, and the brain-to-plasma and spinal cord-to-plasma ratios (0.73 and 1.7, respectively) suggest that [6]-gingerol penetrates well the central nervous system of rats. Induction of pain was performed using the sciatic nerve ligation model on rats, and a 10-µg intrathecal injections of [6]-gingerol was performed to evaluate its central effect. The results suggest a significant decrease of secondary mechanical allodynia after 30 min, 2 h and 4 h (p < 0.05, p < 0.01 and p < 0.001) and thermal hyperalgesia after 30 min, 2 h and 4 h (p < 0.05, p < 0.01 and p < 0.01). These promising results illustrate that [6]-gingerol could alleviate neuropathic pain by acting centrally at the level of the spinal cord.

  15. Aluminum-induced oxidative stress in rat brain: response to combined administration of citric acid and HEDTA.

    PubMed

    Flora, Swaran J S; Mehta, Ashish; Satsangi, Kiran; Kannan, Gurusamy M; Gupta, Manju

    2003-03-01

    Aluminum, a known neurotoxic substance, has been suggested as a contributing factor in the pathogenesis of Alzheimer's disease. Therapeutic efficacy of combined administration of citric acid (CA) and N-(2-hydroxyethyl) ethylenediaminetriacetic acid (HEDTA) was evaluated in decreasing blood and brain aluminum concentration and parameters indicative of hematological disorders and brain oxidative stress. Adult male wistar rats were exposed to drinking water containing 0.2% aluminum nitrate for 8 months and treated once daily for 5 consecutive days with CA (50 mg/kg, orally) or HEDTA (50 mg/kg, intraperitoneally) either individually or in combination. Aluminum exposure significantly inhibited blood delta-aminolevulinic acid dehydratase while increased zinc protoporphyrin confirming changed heme biosynthesis. Significant decrease in the level of glutathione S-transferase in various brain regions and an increase in whole brain thiobarbituric acid reactive substance, and oxidized glutathione (GSSG) levels were also observed. Glutathione peroxidase activity showed a significant increase in cerebellum of aluminum exposed rats. Most of the above parameters responded moderately to the individual treatment with CA and HEDTA, but significantly reduced blood and brain aluminum burden. However, more pronounced beneficial effects on some of the above described parameters were observed when CA and HEDTA were administered concomitantly. Blood and brain aluminum concentration however, showed no further decline on combined treatment over the individual effect with HEDTA or CA. We conclude that in order to achieve an optimum effect of chelation, combined administration of CA and HEDTA might be preferred. However, further work is needed before a final recommendation could be made.

  16. Clinical significance of the administration of cytarabine or thiotepa in addition to total body irradiation and cyclophosphamide for allogeneic hematopoietic cell transplantation in patients with acute leukemia.

    PubMed

    Tachibana, Takayoshi; Tanaka, Masatsugu; Hagihara, Maki; Kawasaki, Rika; Yamazaki, Etsuko; Koharazawa, Hideyuki; Taguchi, Jun; Tomita, Naoto; Fujimaki, Katsumichi; Sakai, Rika; Fujita, Hiroyuki; Fujisawa, Shin; Maruta, Atsuo; Ishigatsubo, Yoshiaki; Kanamori, Heiwa

    2015-10-01

    A multicenter retrospective study was performed to determine the significance of adding cytarabine (CA) or thiotepa (TT) in the context of total body irradiation (TBI) and cyclophosphamide (CY). A total of 322 patients who underwent allogeneic hematopoietic cell transplantation (HCT) were distributed to the following three groups: TBI/CY (n = 75), TBI/CY/CA (n = 77), and TBI/CY/TT (n = 170). In the TBI/CY/TT group, 164 of patients (96 %) received HCT during the previous year (2000-2005). Multivariate analysis revealed that the TBI/CY/TT group demonstrated a trend of poorer survival rate than the TBI/CY group, [hazard ratio (HR) = 1.49, 95 % confidence interval (CI) 0.99-2.24, P = 0.055] with a higher non-relapse mortality (NRM) (HR = 2.34, 95 % CI 1.35-4.06, P = 0.002) rates, while TBI/CY/CA group demonstrated similar outcomes. Even in the subgroup analyses of disease type or disease risk, the outcomes with intensified conditioning regimens were not superior to those with TBI/CY. In conclusion, although the significant bias has to be carefully considered, the clinical benefit of adding CA or TT to the TBI/CY regimen was not demonstrated.

  17. Effect of oral administration of kefir on serum proinflammatory cytokines on 5-FU induced oral mucositis in patients with colorectal cancer.

    PubMed

    Topuz, E; Derin, D; Can, G; Kürklü, E; Cinar, S; Aykan, F; Cevikbaş, A; Dişçi, R; Durna, Z; Sakar, B; Saglam, S; Tanyeri, H; Deniz, G; Gürer, U; Taş, F; Guney, N; Aydiner, A

    2008-12-01

    In order to investigate the effect of kefir consumption on mucositis induced by 5-FU based chemotherapy (CT), we monitored the systemic immune response by measurement of the serum proinflammatory cytokine levels and we evaluated the anti-microbial effect of kefir with an agar diffusion method. Forty patients with colorectal cancer were included in this randomized prospective study. On the first 5 days of each CT cycle, the study group received oral lavage with kefir and then swallowed 250 ml of kefir while control group received oral lavage with 0.09% NaCl twice a day. Before and after every cycle of CT, the oral mucosa was assessed. Serum proinflammatory cytokine levels were evaluated before the initiation and after the third and the sixth cycle. Kefir was administered in 99 out of 205 courses. Mucositis developed in 27.3% of the courses given with kefir administration and in 21.7% of the courses given with 0.9% NaCl oral rinses. The difference between the two groups was not statistically significant (p > 0.05). When we compared the serum proinflammatory cytokine levels of the two groups at the baseline and following the third and the sixth cycles, we again found no statistically significant difference (p > 0.05). Kefir consumption at the mentioned doses made no statistically significant effect on serum proinflammatory cytokine levels and on the incidence of mucositis development in cancer patients. Under in vitro conditions, kefir inhibits only Staphylococcus epidermidis.

  18. Effect of oral administration of kefir on serum proinflammatory cytokines on 5-FU induced oral mucositis in patients with colorectal cancer.

    PubMed

    Topuz, E; Derin, D; Can, G; Kürklü, E; Cinar, S; Aykan, F; Cevikbaş, A; Dişçi, R; Durna, Z; Sakar, B; Saglam, S; Tanyeri, H; Deniz, G; Gürer, U; Taş, F; Guney, N; Aydiner, A

    2008-12-01

    In order to investigate the effect of kefir consumption on mucositis induced by 5-FU based chemotherapy (CT), we monitored the systemic immune response by measurement of the serum proinflammatory cytokine levels and we evaluated the anti-microbial effect of kefir with an agar diffusion method. Forty patients with colorectal cancer were included in this randomized prospective study. On the first 5 days of each CT cycle, the study group received oral lavage with kefir and then swallowed 250 ml of kefir while control group received oral lavage with 0.09% NaCl twice a day. Before and after every cycle of CT, the oral mucosa was assessed. Serum proinflammatory cytokine levels were evaluated before the initiation and after the third and the sixth cycle. Kefir was administered in 99 out of 205 courses. Mucositis developed in 27.3% of the courses given with kefir administration and in 21.7% of the courses given with 0.9% NaCl oral rinses. The difference between the two groups was not statistically significant (p > 0.05). When we compared the serum proinflammatory cytokine levels of the two groups at the baseline and following the third and the sixth cycles, we again found no statistically significant difference (p > 0.05). Kefir consumption at the mentioned doses made no statistically significant effect on serum proinflammatory cytokine levels and on the incidence of mucositis development in cancer patients. Under in vitro conditions, kefir inhibits only Staphylococcus epidermidis. PMID:18762864

  19. Systemic administration of [6]-gingerol, a pungent constituent of ginger, induces hypothermia in rats via an inhibitory effect on metabolic rate.

    PubMed

    Ueki, Shiori; Miyoshi, Michio; Shido, Osamu; Hasegawa, Junichi; Watanabe, Tatsuo

    2008-04-14

    We investigated the effects of systemic administrations of ginger (Zingiber officinale Roscoe, Zingiberaceae) or its pungent constituent, [6]-gingerol, on resting body temperature in rats. Rats given ginger-containing rat chow for 5 days showed no changes in their day-night cycle of body temperature or physical activity. However, a single intraperitoneal (i.p.) injection of [6]-gingerol (2.5 or 25 mg/kg) induced a rapid, marked drop in body temperature in a dose-related manner, with no change in physical activity. A significant decrease in metabolic rate was observed immediately after an i.p. injection of [6]-gingerol (25 mg/kg), although heat-loss responses underwent no alteration (versus vehicle). These results suggest that in rats: (a) a decrease in metabolic rate is responsible for the [6]-gingerol-induced hypothermia, and (b) [6]-gingerol modulates or interferes with the mechanisms underlying body temperature regulation, while other bioactive constituents of ginger may counteract the hypothermic effect of [6]-gingerol. PMID:18295202

  20. Comparative study on toxic effects induced by oral or intravascular administration of commonly used disinfectants and surfactants in rats.

    PubMed

    Xue, Yuying; Zhang, Shanshan; Tang, Meng; Zhang, Ting; Wang, Yiqing; Hieda, Yoko; Takeshita, Haruo

    2012-07-01

    Accidental ingestion or injection of household products sometimes occurs due to their accessibility, but the toxic manifestations have not been well characterized when they are internally administered. The aim of this study was to investigate the toxic effects induced by ingestion or injection of different ionic surfactants and disinfectants in rats. The test drugs involved benzalkonium and benzethonium (BZK and BZT, both cationic surfactants used as disinfectants), alkyldiaminoethylglycine (AEG, an amphoteric surfactant used as a disinfectant), linear alkylbenzenesulfonate (LAS, an anionic surfactant), polyoxyethylene cetylether (PEC, a nonionic surfactant), chlorhexidine (CHX, not a surfactant but a disinfectant) and saline (control). Male Sprague-Dawley rats were administered one of the test drugs orally (p.o.), intravenously (i.v.) or intraarterially (i.a.). The fatal effects appeared rapidly (<30 min) in i.v.-administered rats, while taking hours (>5 h) in i.a./p.o.-administered rats after a dose of around LD(50) , although the progress and degree of toxic effects varied among the drugs tested. In intravascular administration, BZK and BZT were fatal at doses of 15-20 mg kg(-1) . Higher concentrations in lung and kidney than in blood were determined. CHX showed a high toxic effect compared with cationic surfactants. The rats administered anionic (LAS) or amphoteric (AEG) surfactant died in less than 24 h at doses over 100 mg kg(-1) . In p.o. administration, the toxic effects were concentration/dose-dependent, and all rats administered high doses of surfactants except for PEC died at 5-20 h. The overall toxic ranks could be: cationic surfactant/CHX> anionic/amphoteric surfactant > nonionic surfactant.

  1. Effects of methiothepin on changes in brain serotonin release induced by repeated administration of high doses of anorectic serotoninergic drugs

    NASA Technical Reports Server (NTRS)

    Gardier, A. M.; Kaakkola, S.; Erfurth, A.; Wurtman, R. J.

    1992-01-01

    We previously observed, using in vivo microdialysis, that the potassium-evoked release of frontocortical serotonin (5-HT) is suppressed after rats receive high doses (30 mg/kg, i.p., daily for 3 days) of fluoxetine, a selective blocker of 5-HT reuptake. We now describe similar impairments in 5-HT release after repeated administration of two other 5-HT uptake blockers, zimelidine and sertraline (both at 20 mg/kg, i.p. for 3 days) as well as after dexfenfluramine (7.5 mg/kg, i.p. daily for 3 days), a drug which both releases 5-HT and blocks its reuptake. Doses of these indirect serotonin agonists were about 4-6 times the drug's ED50 in producing anorexia, a serotonin-related behavior. In addition, methiothepin (20 microM), a non-selective receptor antagonist, locally perfused through the dialysis probe 24 h after the last drug injection, enhanced K(+)-evoked release of 5-HT at serotoninergic nerve terminals markedly in control rats and slightly in rats treated with high doses of dexfenfluramine or fluoxetine. On the other hand, pretreatment with methiothepin (10 mg/kg, i.p.) one hour before each of the daily doses of fluoxetine or dexfenfluramine given for 3 days, totally prevented the decrease in basal and K(+)-evoked release of 5-HT. Finally, when methiothepin was injected systemically the day before the first of 3 daily injections of dexfenfluramine, it partially attenuated the long-term depletion of brain 5-HT and 5-HIAA levels induced by repeated administration of high doses of dexfenfluramine. These data suggest that drugs which bring about the prolonged blockade of 5-HT reuptake - such as dexfenfluramine and fluoxetine - can, by causing prolonged increases in intrasynaptic 5-HT levels as measured by in vivo microdialysis, produce receptor-mediated long-term changes in the processes controlling serotonin levels and dynamics.

  2. [A case of advanced hepatocellular carcinoma successfully treated by liver resection after complete response induced by sorafenib administration].

    PubMed

    Kim, Yongkook; Hosoda, Yohei; Kakita, Naruyasu; Yamada, Yukinori; Yamasaki, Masaru; Nishino, Masaya; Okano, Miho; Nagai, Kenichi; Yasui, Masayoshi; Tsujinaka, Toshimasa

    2014-11-01

    A 50-year-old man presented to our hospital with the chief complaint of right hypochondriac pain and a palpable tumor. Advanced hepatocellular carcinoma (HCC) and chronic hepatitis B infection were diagnosed and treated by twice-repeated transcatheterarterial chemoembolization (TACE) followed by administration of entecavir. Two months after the last TACE, alpha-fetoprotein(AFP)and protein induced by vitamin K absence or antagonistII (PIVKA-II) levels had elevated, and multiple small early enhancing nodules were detected on computed tomography(CT)scan. Based on his age and liver function (Child-Pugh score A5), a full dose of sorafenib (800 mg/day) was administered. The sorafenib dose was decreased after one month to 400mg/day because of hand-foot syndrome. Following sorafenib administration, the lesions shrank markedly, and complete response (CR) according to modified Response Evaluation Criteria In Solid Tumors(mRECIST)was achieved within 4 months. Six months after sorafenib treatment was begun, recurrent HCC was detected in segment 6, near the previously treated lesion. The decreased size of the main tumor and normalization of AFP levels allowed curative surgical resection. The patient was discharged 5 days after surgery and is currently treated with a half dose of sorafenib. Thirteen months after surgery, a small early enhancing lesion is visible on postoperative CT scan, but AFP and PIVKA-II levels are still keeping in a normal range. This case demonstrates that if sorafenib treatment is effective, then subsequent surgical treatment can be reconsidered in patients with advanced HCC responding to this combined therapy. PMID:25731444

  3. Intermittent Administration of Parathyroid Hormone [1–34] Prevents Particle-Induced Periprosthetic Osteolysis in a Rat Model

    PubMed Central

    Bi, Fanggang; Shi, Zhongli; Zhou, Chenhe; Liu, An; Shen, Yue; Yan, Shigui

    2015-01-01

    We examined whether intermittent administration of parathyroid hormone [1–34] (PTH[1–34]; 60 μg/kg/day) can prevent the negative effects of titanium (Ti) particles on implant fixation and periprosthetic osteolysis in a rat model. Eighteen adult male rats (12 weeks old, bones still growing) received intramedullary Ti implants in their bilateral femurs; 6 rats from the blank group received vehicle injections, and 12 rats from the control group and PTH treatment group received Ti particle injections at the time of operation and intra-articular injections 2 and 4 weeks postoperatively. Six of the rats that received Ti particles from the PTH group also received PTH[1–34] treatment. Six weeks postoperatively, all specimens were collected for assessment by X-ray, micro-CT, biomechanical, scanning electron microscopy (SEM), and dynamic histomorphometry. A lower BMD, BV/TV, Tb.N, maximal fixation strength, and mineral apposition rate were observed in the control group compared to the blank group, demonstrating that a periprosthetic osteolysis model had been successfully established. Administration of PTH[1–34] significantly increased the bone mineral density of the distal femur, BV/TV, Tb.N, Tb.Th, Tb.Sp, Con.D, SMI, and maximal fixation strength in the PTH group compared to that in the control group. SEM revealed higher bone–implant contact, thicker lamellar bone, and larger trabecular bone area in the PTH group than in the control group. A higher mineral apposition rate was observed in the PTH group compared to both the blank and control groups. These findings imply that intermittent administration of PTH[1–34] prevents periprosthetic osteolysis by promoting bone formation. The effects of PTH[1–34] were evaluated at a suprapharmacological dosage to the human equivalent in rats; therefore, additional studies are required to demonstrate its therapeutic potential in periprosthetic osteolysis. PMID:26441073

  4. Intermittent Administration of Parathyroid Hormone [1-34] Prevents Particle-Induced Periprosthetic Osteolysis in a Rat Model.

    PubMed

    Bi, Fanggang; Shi, Zhongli; Zhou, Chenhe; Liu, An; Shen, Yue; Yan, Shigui

    2015-01-01

    We examined whether intermittent administration of parathyroid hormone [1-34] (PTH[1-34]; 60 μg/kg/day) can prevent the negative effects of titanium (Ti) particles on implant fixation and periprosthetic osteolysis in a rat model. Eighteen adult male rats (12 weeks old, bones still growing) received intramedullary Ti implants in their bilateral femurs; 6 rats from the blank group received vehicle injections, and 12 rats from the control group and PTH treatment group received Ti particle injections at the time of operation and intra-articular injections 2 and 4 weeks postoperatively. Six of the rats that received Ti particles from the PTH group also received PTH[1-34] treatment. Six weeks postoperatively, all specimens were collected for assessment by X-ray, micro-CT, biomechanical, scanning electron microscopy (SEM), and dynamic histomorphometry. A lower BMD, BV/TV, Tb.N, maximal fixation strength, and mineral apposition rate were observed in the control group compared to the blank group, demonstrating that a periprosthetic osteolysis model had been successfully established. Administration of PTH[1-34] significantly increased the bone mineral density of the distal femur, BV/TV, Tb.N, Tb.Th, Tb.Sp, Con.D, SMI, and maximal fixation strength in the PTH group compared to that in the control group. SEM revealed higher bone-implant contact, thicker lamellar bone, and larger trabecular bone area in the PTH group than in the control group. A higher mineral apposition rate was observed in the PTH group compared to both the blank and control groups. These findings imply that intermittent administration of PTH[1-34] prevents periprosthetic osteolysis by promoting bone formation. The effects of PTH[1-34] were evaluated at a suprapharmacological dosage to the human equivalent in rats; therefore, additional studies are required to demonstrate its therapeutic potential in periprosthetic osteolysis. PMID:26441073

  5. Significance of vascular endothelial growth factor expression and its correlation with inducible nitric oxide synthase in gastric cancer

    PubMed Central

    Song, Zhen-Ya; Wen, Shu-Qun; Peng, Jia-Ping; Huang, Xuan; Qian, Ke-Da

    2004-01-01

    AIM: To investigate the clinical significance of the expression of VEGF165mRNA and the correlation with vascular endothelial growth factor (VEGF) protein and inducible nitric oxide synthase (iNO) in human gastric cancer. METHODS: We tested VEGF165mRNA expression in 31 cases of resected gastric cancer specimens and normal paired gastric mucosae by RT-PCR. Total RNA was extracted with TRIzol reagents, transcribed into cDNA with oligo (dT15) priming, inner controlled with β-actin expression and agarose gel isolated after PCR. VEGF expression was quantitated with IS1000 imaging system. Meanwhile we also examined expression levels of VEGF protein and iNOS in 85 cases of gastric cancer. All paraffin-embedded samples were immunohistochemically stained by streptavidin-peroxidase method (SP). RESULTS: The mean expression of VEGF165mRNA in gastric cancer was 1.125 ± 0.356, significantly higher than that of normal paired mucosae, which was 0.760 ± 0.278. The data indicated that the expression level of VEGF165mRNA was well related to lymph node metastasis and TNM stages of UICC. The expression levels in patients with lymph node metastasis and without lymph node metastasis were 1.219 ± 0.377 and 0.927 ± 0.205 respectively (P < 0.05). The expression in stages I, II, III, IV was 0.934 ± 0.194, 1.262 ± 0.386 respectively (P < 0.01). Further analysis showed the lymph node metastasis rate in the group with over-expression of VEGF was higher than that in the group with low expression of VEGF (83.3% vs 46.2%), and the ratio of stage III+IV in the group with over-expression of VEGF was also higher than that in the group with low expression with VEGF (77.8% vs 33.8%) (P < 0.05). The positive rates of expression of VEGF protein and iNOS in 85 cases of gastric cancer were 75.4% and 58.8% respectively, and 50.1% of the patients showed positive staining both for iNOS and VEGF, the correlation with the two factors was significant (P = 0.018). But more intensive analysis showed the

  6. Chronic Administration of Δ9-Tetrahydrocannabinol Induces Intestinal Anti-Inflammatory MicroRNA Expression during Acute Simian Immunodeficiency Virus Infection of Rhesus Macaques

    PubMed Central

    Chandra, Lawrance C.; Kumar, Vinay; Torben, Workineh; Stouwe, Curtis Vande; Winsauer, Peter; Amedee, Angela; Molina, Patricia E.

    2014-01-01

    ABSTRACT Recreational and medical use of cannabis among human immunodeficiency virus (HIV)-infected individuals has increased in recent years. In simian immunodeficiency virus (SIV)-infected macaques, chronic administration of Δ9-tetrahydrocannabinol (Δ9-THC) inhibited viral replication and intestinal inflammation and slowed disease progression. Persistent gastrointestinal disease/inflammation has been proposed to facilitate microbial translocation and systemic immune activation and promote disease progression. Cannabinoids including Δ9-THC attenuated intestinal inflammation in mouse colitis models and SIV-infected rhesus macaques. To determine if the anti-inflammatory effects of Δ9-THC involved differential microRNA (miRNA) modulation, we profiled miRNA expression at 14, 30, and 60 days postinfection (days p.i.) in the intestine of uninfected macaques receiving Δ9-THC (n = 3) and SIV-infected macaques administered either vehicle (VEH/SIV; n = 4) or THC (THC/SIV; n = 4). Chronic Δ9-THC administration to uninfected macaques significantly and positively modulated intestinal miRNA expression by increasing the total number of differentially expressed miRNAs from 14 to 60 days p.i. At 60 days p.i., ∼28% of miRNAs showed decreased expression in the VEH/SIV group compared to none showing decrease in the THC/SIV group. Furthermore, compared to the VEH/SIV group, THC selectively upregulated the expression of miR-10a, miR-24, miR-99b, miR-145, miR-149, and miR-187, previously been shown to target proinflammatory molecules. NOX4, a potent reactive oxygen species generator, was confirmed as a direct miR-99b target. A significant increase in NOX4+ crypt epithelial cells was detected in VEH/SIV macaques compared to the THC/SIV group. We speculate that miR-99b-mediated NOX4 downregulation may protect the intestinal epithelium from oxidative stress-induced damage. These results support a role for differential miRNA induction in THC-mediated suppression of intestinal

  7. Lack of effect of ethanol on cocaine prime-induced reinstatement of extinguished cocaine self-administration in rhesus monkeys.

    PubMed

    Czoty, Paul W

    2016-10-01

    Cocaine and alcohol are commonly co-abused for reasons that are incompletely understood. Laboratory animal studies have suggested that, although the reinforcing effects of low cocaine doses are increased following chronic ethanol (EtOH) consumption, acute EtOH administration does not consistently alter cocaine self-administration. The present study examined whether EtOH influences another abuse-related effect of cocaine: reinstatement of extinguished responding. Rhesus monkeys that had previously consumed EtOH for 8 weeks (2.0 g/kg over 1 h, 5 days/week) self-administered up to 10 injections per day of 0.1 mg/kg cocaine under a fixed-interval 300-s schedule. After responding had been extinguished by substituting saline for cocaine, a pre-session infusion of saline or EtOH (0.5 or 1.0 g/kg, intravenously over 10 min) was followed by a 'priming' injection of saline or cocaine (intravenously). Responding was increased significantly by priming injections of cocaine, but not saline. EtOH infusions neither reinstated behavior when administered before a saline prime nor altered the priming effect of cocaine. The inability of EtOH to alter the response-reinstating ability of cocaine provides further evidence for a lack of acute behavioral interactions between cocaine and EtOH. PMID:27509315

  8. Evidence that lipid lateral phase separation induces functionally significant structural changes in the Ca+2ATPase of the sarcoplasmic reticulum.

    PubMed Central

    Asturias, F J; Pascolini, D; Blasie, J K

    1990-01-01

    We have studied lipid lateral phase separation (LPS) in the intact sarcoplasmic reticulum (SR) membrane and in bilayers of isolated SR membrane lipids as a function of temperature, [Mg+2], and degree of hydration. Lipid LPS was observed in both the intact membrane and in the bilayers of isolated SR lipids, and the LPS behavior of both systems was found to be qualitatively similar. Namely, lipid LPS occurs only at relatively low temperature and water content, independently of the [Mg+2], and the upper characteristic temperature (th) for lipid LPS for both the membrane and bilayers of its isolated lipids coincide to within a few degrees. However, at similar temperatures, isolated lipids show more LPS than the lipids in the intact membrane. Lipid LPS in the intact membrane and in bilayers of the isolated lipids is fully reversible, and more extensive for samples partially dehydrated at temperatures below th. Our previous x-ray diffraction studies established the existence of a temperature-induced transition in the profile structure of the sarcoplasmic reticulum Ca+2ATPase which occurs at a temperature corresponding to the [Mg+2]-dependent upper characteristic temperature for lipid LPS in the SR membrane. Furthermore, the functionality of the ATPase, and in particular the lifetime of the first phosphorylated enzyme conformation (E1 approximately P) in the Ca+2 transport cycle, were also found to be linked to the occurrence of this structural transition. The hysterisis observed in lipid LPS behavior as a function of temperature and water content provides a possible explanation for the more efficient transient trapping of the enzyme in the E1 approximately P conformation observed in SR membranes partially dehydrated at temperatures below th. The observation that LPS behavior for the intact SR membrane and bilayers of isolated SR lipids (no protein present) are qualitatively similar strongly suggests that the LPS behavior of the SR membrane lipids is responsible for the

  9. Multiple-dose therapy with bovine colostrum confers significant protection against diarrhea in a mouse model of human rotavirus-induced gastrointestinal disease.

    PubMed

    Inagaki, M; Yamamoto, M; Cairangzhuoma; Xijier; Yabe, T; Uchida, K; Kawasaki, M; Nakagomi, T; Nakagomi, O; Minamoto, N; Kanamaru, Y

    2013-02-01

    Rotavirus is the most important etiologic agent of severe gastroenteritis. Previously, we reported that skimmed and concentrated bovine late colostrum (SCBLC) obtained from normal unimmunized cows at 6 to 7d after parturition effectively prevented against human rotavirus (HRV)-induced severe gastroenteritis in vivo, when administered as a single dose 60 min before viral inoculation. In the present study, we examined the efficacy of multiple administrations of SCBLC at smaller dosages after viral inoculation in vivo. We demonstrate that multiple administrations within 24h after virus inoculation resulted in earlier recovery from diarrheal symptoms, in an administration frequency-dependent manner. Furthermore, we investigated whether isolated IgG anti-HRV activity in SCBLC was equivalent to that of IgG isolated from bovine mature milk as measured by in vitro activity assays. We found that IgG-containing fractions from SCBLC and mature milk exhibited approximately the same level of anti-HRV activity. We concluded that the SCBLC contains a high level of IgG against HRV-induced severe gastroenteritis, which will be possible to use in protective effects in immunocompromised hosts, such as children and the elderly. Multiple doses of SCBLC during the early stages of infection or lower dosage of SCBLC given as a single dose both resulted in relief of diarrheal symptoms. PMID:23200479

  10. Myocardial hydroxyproline reduced by early administration of methylprednisolone or ibuprofen to rabbits with radiation-induced heart disease

    SciTech Connect

    Reeves, W.C.; Cunningham, D.; Schwiter, E.J.; Abt, A.; Skarlatos, S.; Wood, M.A.; Whitesell, L.

    1982-05-01

    The ability of methylprednisolone (MP) and ibuprofen (IB) to reduce the severity of the late state of radiation-induced heart disease was assessed in 57 New Zealand white rabbits. Before and shortly after cardiac irradiation, 15 rabbits received i.v. MP, 30 mg/kg twice daily for 3 days, and 15 others received IB, 12.5 mg/kg twice daily for 2 days. No drug was administered to 14 irradiated rabbits, and neither irradiation nor drugs were administered to 13 rabbits that served as controls, All 15 rabbits treated with MP and 13 of the 15 treated with IB lived for 100 days. Only seven of the untreated, irradiated rabbits lived that long. Longevity of each treated group of rabbits was better (p less than 0.01 and 0.05) than that of the untreated, irradiated rabbits. Surviving rabbits were killed 100 days after irradiation. Pericarditis (p less than 0.05) and pericardial effusion (p less than 0.01) were less frequent in the treated, irradiated groups than in the untreated, irradiated rabbits. At least some rabbits in each irradiated group had microscopic evidence of myocardial fibrosis. The fibrosis was quantitated by determination of myocardial hydroxyproline concentrations (MHP). MHP concentration in the untreated, irradiated rabbits was greater than in those treated with MP (p less than 0.05) or IB (p less than 0.01) and in the untreated, unirradiated rabbits (p less than 0.01). Early administration of MP or IB retarded the development of myocardial fibrosis, pericarditis and pericardial effusion, and improved survival in this experimental model of radiation-induced heart disease.

  11. Effect of the oral thrombin inhibitor dabigatran on allergic lung inflammation induced by repeated house dust mite administration in mice.

    PubMed

    de Boer, Johannes D; Berkhout, Lea C; de Stoppelaar, Sacha F; Yang, Jack; Ottenhoff, Roelof; Meijers, Joost C M; Roelofs, Joris J T H; van't Veer, Cornelis; van der Poll, Tom

    2015-10-15

    Asthma is a chronic disease of the airways; asthma patients are hampered by recurrent symptoms of dyspnoea and wheezing caused by bronchial obstruction. Most asthma patients suffer from chronic allergic lung inflammation triggered by allergens such as house dust mite (HDM). Coagulation activation in the pulmonary compartment is currently recognized as a feature of allergic lung inflammation, and data suggest that coagulation proteases further drive inflammatory mechanisms. Here, we tested whether treatment with the oral thrombin inhibitor dabigatran attenuates allergic lung inflammation in a recently developed HDM-based murine asthma model. Mice were fed dabigatran (10 mg/g) or placebo chow during a 3-wk HDM airway exposure model. Dabigatran treatment caused systemic thrombin inhibitory activity corresponding with dabigatran levels reported in human trials. Surprisingly, dabigatran did not lead to inhibition of HDM-evoked coagulation activation in the lung as measured by levels of thrombin-antithrombin complexes and D-dimer. Repeated HDM administration caused an influx of eosinophils and neutrophils into the lungs, mucus production in the airways, and a T helper 2 response, as reflected by a rise in bronchoalveolar IL-4 and IL-5 levels and a systemic rise in IgE and HDM-IgG1. Dabigatran modestly improved HDM-induced lung pathology (P < 0.05) and decreased IL-4 levels (P < 0.01), without influencing other HDM-induced responses. Considering the limited effects of dabigatran in spite of adequate plasma levels, these results argue against clinical evaluation of dabigatran in patients with asthma.

  12. Myocardial hydroxyproline reduced by early administration of methylprednisolone or ibuprofen to rabbits with radiation-induced heart disease

    SciTech Connect

    Reeves, W.C.; Cunningham, D.; Schwiter, E.J.; Abt, A.; Skarlatos, S.; Wood, M.A.; Whitesell, L.

    1982-05-01

    The ability of methylprednisolone (MP) and ibuprofen (IB) to reduce the severity of the late state of radiation-induced heart disease was assessed in 57 New Zealand white rabbits. Before and shortly after cardiac irradiation, 15 rabbits received i.v. MP, 30 mg/kg twice daily for 3 days, and 15 others received IB, 12.5 mg/kg twice daily for 2 days. No drug administered to 14 irradiated rabbits, and neither irradiation nor drugs were administered to 13 rabbits that served as controls. All 15 rabbits treated with MP and 13 of the 15 treated with IB lived for 100 days. Only seven of the untreated, irradiated rabbits lived that long. Longevity of each treated group of rabbits was better (p < 0.01 and 0.05) than that of the untreated, irradiated rabbits. Surviving rabbits were killed 100 days after irradiation. Pericarditis (p < 0.05) and pericardial effusion (p < 0.01) were less frequent in the treated, irradiated groups than in the untreated, irradiated rabbits. At least some rabbits in each irradiated group had microscopic evidence of myocardial fibrosis. The fibrosis was quantitated by determination of myocardial hydroxyproline concentrations (MHP). MHP concentration in the untreated, irradiated rabbits was greater than in those treated with MP (p < 0.05) or IB (p < 0.01) and in the untreated, unirradiated rabbits (p < 0.01). Early administrative of MP or IB retarded the development of myocardial fibrosis, pericarditis and pericardial effusin, and improved survival in this experimental model of radiation-induced heart disease.

  13. Delayed Anaphylaxis with Methimazole: Nicolau Syndrome After Oxytocin Intramuscular Administration Anastrazole-Induced Autoimmune Hepatitis Amoxicillin- and Cephalexin-Induced Eosinophilic Colitis Docetaxel-Induced Supravenous Erythematous Eruption.

    PubMed

    Mancano, Michael A

    2016-07-01

    The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration's (FDA's) MedWatch program (800-FDA-1088). If you have reported an interesting, preventable ADR to MedWatch, please consider sharing the account with our readers. Write to Dr. Mancano at ISMP, 200 Lakeside Drive, Suite 200, Horsham, PA 19044 (phone: 215-707-4936; e-mail: mmancano@temple.edu). Your report will be published anonymously unless otherwise requested. This feature is provided by the Institute for Safe Medication Practices (ISMP) in cooperation with the FDA's MedWatch program and Temple University School of Pharmacy. ISMP is an FDA MedWatch partner. PMID:27559184

  14. The effect of parenteral iron administration on the development of Staphylococcus aureus-induced experimental pyelonephritis in rats.

    PubMed Central

    Anğ, O.; Güngör, M.; Aricioğlu, F.; Inanç, D.; Sağduyu, H.; Uysal, V.; Küçüker, M.

    1990-01-01

    The first of the three groups of rats was taken as a control and the other two groups were injected with high (15 mg/kg) and low (5 mg/kg) doses of ferric ammonium citrate given intramuscularly twice daily for 5 days. Pyelonephritis was produced in all groups by intravenous inoculation with Staphylococcus aureus. Serum and urine of each rat was collected periodically and their iron content was determined. The severity of pyelonephritis was evaluated by determination of bacterial growth and pathological lesions in kidneys after 10 days of bacterial inoculation. The results showed that parenteral iron administration markedly aggravated pyelonephritis development in rats. But there was no significant difference in the severity of pyelonephritis between rats treated with high or low iron doses. Images Fig. 2 PMID:2400738

  15. Amelioration of Prallethrin-Induced Oxidative Stress and Hepatotoxicity in Rat by the Administration of Origanum majorana Essential Oil

    PubMed Central

    Mossa, Abdel-Tawab H.; Refaie, Amel A.; Ramadan, Amal; Bouajila, Jalloul

    2013-01-01

    This study was carried out to evaluate the adverse effects of exposure to prallethrin on oxidant/antioxidant status and liver dysfunction biomarkers and the protective role of Origanum majorana essential oil (EO) in rat. Male rats were divided into 4 groups: (i) received only olive oil (ii) treated with 64.0 mg/kg body weight prallethrin (1/10 LD50) in olive oil via oral route daily for 28 days, (iii) treated with 64.0 mg/kg body weight prallethrin (1/10 LD50) and EO (160 μL/kg b.wt.) in olive oil and (iv) received EO (160 μL/kg b.wt.) in olive oil via oral route twice daily for 28 days. Prallethrin treatment caused decrease in body weight gain and increase in relative liver weight. There was a significant increase in the activity of serum marker enzymes, aspartate transaminase, alanine transaminase, and alkaline phosphatase. It caused increase in thiobarbituric acid reactive substances and reduction in the activities of superoxide dismutase, catalase, and glutathione-S-transferase in liver. Consistent histological changes were found in the liver of prallethrin treatment. EO showed significant protection with the depletion of serum marker enzymes and replenishment of antioxidant status and brought all the values to near normal, indicating the protective effect of EO. We can conclude that prallethrin caused oxidative damage and liver injury in male rat and co-administration of EO attenuated the toxic effect of prallethrin. These results demonstrate that administration of EO may be useful, easy, and economical to protect human against pyrethroids toxic effects. PMID:24381944

  16. Effects of Single Drug and Combined Short-term Administration of Sildenafil, Pimobendan, and Nicorandil on Right Ventricular Function in Rats With Monocrotaline-induced Pulmonary Hypertension

    PubMed Central

    Tanaka, Ryou; Yoshiyuki, Rieko; Fukayama, Toshiharu; Goya, Seijiro; Fukushima, Ryuji

    2015-01-01

    Abstract: This study was designed to assess the progression of pulmonary arterial hypertension (PAH) and the effectiveness of therapy using recently investigated echocardiographic parameters. PAH is characterized by the progressive elevation of pulmonary artery pressure and right ventricular hypertrophy and dysfunction, which ultimately results in right-sided heart failure and death. Echocardiography results and invasive measurements of right and left ventricular systolic pressures were compared after 3-week administrations of sildenafil (S group), pimobendan (P group), nicorandil (N group), and their combinations (SP and SPN groups) in male rats with monocrotaline (MCT)-induced pulmonary hypertension (M group) and without this condition (C group). The groups that received pimobendan alone and in combinations (SP and SPN groups) showed improvement in their echocardiographic parameters of systolic function. A significant improvement of diastolic function was achieved in the SPN group. Invasive measurements showed the most significant decreases of right ventricular systolic pressure in the N and SPN groups, and the use of pimobendan resulted in a comparatively low risk of adverse hemodynamic effects (left ventricular systolic pressure). Although our results suggested the attenuation of PAH severity in all treatment groups, PAH could not be reversed. PMID:25806612

  17. Effects of Single Drug and Combined Short-term Administration of Sildenafil, Pimobendan, and Nicorandil on Right Ventricular Function in Rats With Monocrotaline-induced Pulmonary Hypertension.

    PubMed

    Nakata, Telma M; Tanaka, Ryou; Yoshiyuki, Rieko; Fukayama, Toshiharu; Goya, Seijiro; Fukushima, Ryuji

    2015-06-01

    This study was designed to assess the progression of pulmonary arterial hypertension (PAH) and the effectiveness of therapy using recently investigated echocardiographic parameters. PAH is characterized by the progressive elevation of pulmonary artery pressure and right ventricular hypertrophy and dysfunction, which ultimately results in right-sided heart failure and death. Echocardiography results and invasive measurements of right and left ventricular systolic pressures were compared after 3-week administrations of sildenafil (S group), pimobendan (P group), nicorandil (N group), and their combinations (SP and SPN groups) in male rats with monocrotaline (MCT)-induced pulmonary hypertension (M group) and without this condition (C group). The groups that received pimobendan alone and in combinations (SP and SPN groups) showed improvement in their echocardiographic parameters of systolic function. A significant improvement of diastolic function was achieved in the SPN group. Invasive measurements showed the most significant decreases of right ventricular systolic pressure in the N and SPN groups, and the use of pimobendan resulted in a comparatively low risk of adverse hemodynamic effects (left ventricular systolic pressure). Although our results suggested the attenuation of PAH severity in all treatment groups, PAH could not be reversed.

  18. Abrogation of attenuated lentivirus-induced protection in rhesus macaques by administration of depo-provera before intravaginal challenge with simian immunodeficiency virus mac239.

    PubMed

    Abel, Kristina; Rourke, Tracy; Lu, Ding; Bost, Kristen; McChesney, Michael B; Miller, Christopher J

    2004-11-01

    In nonhuman primate models of acquired immunodeficiency syndrome, live attenuated lentiviruses provide the most reliable protection from systemic and mucosal challenge with pathogenic simian immunodeficiency virus (SIV). Although live attenuated lentiviruses may never be used in humans because of safety concerns, understanding the nature of the protective immune mechanisms induced by live attenuated vaccines in primate models will be useful for developing other vaccine approaches. Approximately 60% of rhesus macaques immunized with nonpathogenic simian-human immunodeficiency virus (SHIV) strain 89.6 are protected from infection or clinical disease after intravaginal (IVAG) challenge with pathogenic SIVmac239. The goal of the present study was to determine whether administration of Depo-Provera before IVAG challenge with SIV decreases the protective efficacy of infection with SHIV89.6. The rate of protection after IVAG challenge with SIVmac239 was significantly lower (P<.05), and the acute postchallenge plasma viral RNA levels were significantly higher (P<.006), in Depo-Provera-treated, SHIV89.6-immunized macaques than in Depo-Provera-naive, SHIV89.6-immunized macaques. In the primate model of sexual transmission of human immunodeficiency virus, treatment with progesterone before IVAG challenge with a pathogenic virus can decrease the efficacy of a model "vaccine."

  19. Mesenchymal stem cells can prevent alterations in behavior and neurogenesis induced by Aß25-35 administration.

    PubMed

    Hamisha, Keren Nicole; Tfilin, Matanel; Yanai, Joseph; Turgeman, Gadi

    2015-04-01

    Mesenchymal stem cells (MSCs) are known to enhance neurogenesis in the dentate gyrus, as well as to modulate immune cell activity and inflammation. Easily obtained and expanded from the bone marrow and other tissues, MSCs have been proposed as candidates for stem cell therapy in various neurodegenerartive diseases. In the present study, we sought to explore these therapeutic properties of MSC on Aß25-35-induced pathology when coadministered together. Apparently, coadministration of MSC prevented mild cognitive deficits observed following Aß administration alone, by promoting microglial activation and rapid clearance of injected Aß aggregates. Surprisingly, increased hippocampal neurogenesis was observed in the Aß-injected animals and was normal in MSC-coadministered animals just as in control animals. The observed increase in neurogenesis can be explained as a compensating mechanism responsible for the mild and temporary cognitive deficits observed in the Morris water maze assay in Aß-injected animals. Interestingly, MSC engrafted not only to the hippocampus but were also detected in the choroid plexus. We thus conclude that MSC may act in multiple pathways to protect the CNS from Aß pathology, while neurogenesis is a possible compensating mechanism; it is not always activated by MSC, which in turn may interact with local immune cells to regulate Aß accumulation.

  20. The administration of demethyl fruticulin A from Salvia corrugata to mammalian cells lines induces "anoikis", a special form of apoptosis.

    PubMed

    Giannoni, Paolo; Narcisi, Roberto; De Totero, Daniela; Romussi, Giovanni; Quarto, Rodolfo; Bisio, Angela

    2010-05-01

    Recently demethyl fruticulin A was identified as the major diterpenoid component of the exudates produced by the trichomes of Salvia corrugata leafs. Given the documented apoptotic effects of some of the other known components of the exudates from Salvia species, we assessed if demethyl fruticulin A, once administered to mammalian cells, was involved in the onset of apoptosis and if its biological effects were exerted through the participation of a scavenger membrane receptor, CD36. Three model cell lines were chosen, one of which lacking CD36 expression. Functional availability of the receptor, or its transcriptional rate, were blocked/reduced with a specific antibody or by the administration of vitamin E. Immunodetection of cell cytoskeletal components and tunel analysis revealed that demethyl fruticulin A triggers the onset of anoikis, a special form of apoptosis induced by cell detachment from the substrate. Impairment of CD36 availability/transcription confirmed the receptor partial involvement in the intake of the substance and in anoikis, as also sustained by FACS analysis and by the downregulation of p95, a marker of anoikis, upon blockade of CD36 transcription. However, experiments with CD36-deficient cells suggested that alternate pathways, still to be determined, may take part in the biological effects exerted by demethyl fruticulin A.

  1. Rhenium-coated glass beads for intracolonic administration attenuate TNBS-induced colitis in mice: Proof-of-Concept Study.

    PubMed

    Siczek, Krzysztof; Zatorski, Hubert; Pawlak, Wojciech; Fichna, Jakub

    2015-01-01

    In search for novel effective treatments in inflammatory bowel diseases, a new strategy employing glass beads coated with rhenium nanolayer has been developed and validated in the mouse model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Briefly, mice were randomly divided into 5 experimental groups: control (vehicle alone, Group 1); control treated with rhenium-coated glass beads (Group 2); TNBS (Group 3); TNBS treated with rhenium-coated glass beads (Group 4); and TNBS treated with uncoated glass beads (Group 5). Mice from Group 2, 4 and 5 were treated with respective beads (once daily, 5 beads / animal, i.c.) between D3-D6 post-TNBS/vehicle and evaluation of colonic damage was performed on D7, based on macroscopic scoring and clinical parameters. Severe colonic inflammation developed in post-TNBS mice (Group 3) [P <0.001 vs. control (Group 1) for macroscopic score], which was significantly attenuated by treatment with rhenium-coated glass beads (Group 4) [P <0.01 vs. TNBS (Group 3), for macroscopic score]. Neither rhenium-coated glass beads had any effect in control animals (Group 2), nor uncoated glass beads influenced TNBS-induced colitis (Group 5). In conclusion, a novel and attractive strategy for the treatment of colonic inflammation has been proposed; therapy with rhenium-coated glass beads already proved effective in the mouse model of TNBS-induced colitis, now requires further characterization in clinical conditions.

  2. Rhenium-coated glass beads for intracolonic administration attenuate TNBS-induced colitis in mice: Proof-of-Concept Study.

    PubMed

    Siczek, Krzysztof; Zatorski, Hubert; Pawlak, Wojciech; Fichna, Jakub

    2015-01-01

    In search for novel effective treatments in inflammatory bowel diseases, a new strategy employing glass beads coated with rhenium nanolayer has been developed and validated in the mouse model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Briefly, mice were randomly divided into 5 experimental groups: control (vehicle alone, Group 1); control treated with rhenium-coated glass beads (Group 2); TNBS (Group 3); TNBS treated with rhenium-coated glass beads (Group 4); and TNBS treated with uncoated glass beads (Group 5). Mice from Group 2, 4 and 5 were treated with respective beads (once daily, 5 beads / animal, i.c.) between D3-D6 post-TNBS/vehicle and evaluation of colonic damage was performed on D7, based on macroscopic scoring and clinical parameters. Severe colonic inflammation developed in post-TNBS mice (Group 3) [P <0.001 vs. control (Group 1) for macroscopic score], which was significantly attenuated by treatment with rhenium-coated glass beads (Group 4) [P <0.01 vs. TNBS (Group 3), for macroscopic score]. Neither rhenium-coated glass beads had any effect in control animals (Group 2), nor uncoated glass beads influenced TNBS-induced colitis (Group 5). In conclusion, a novel and attractive strategy for the treatment of colonic inflammation has been proposed; therapy with rhenium-coated glass beads already proved effective in the mouse model of TNBS-induced colitis, now requires further characterization in clinical conditions. PMID:26867119

  3. Lead induced oxidative stress and its recovery following co-administration of melatonin or N-acetylcysteine during chelation with succimer in male rats.

    PubMed

    Flora, S J S; Pande, M; Kannan, G M; Mehta, A

    2004-01-01

    Lead is a ubiquitous element in the environment causing oxidative burst in the exposed individuals leading to tissue damage. Antioxidants have long been known to reduce the free radical-mediated oxidative stress while, thiol chelators have been used to treat arsenic toxicity. The therapeutic efficacy of melatonin or N-acetylcysteine (NAC) was studied in the present study, both individually and in combination with a potent thiol-chelating agent, meso 2,3-dimercaptosuccinic acid (DMSA), in reducing lead concentration in blood and other soft tissues. Their ability to restore altered haematopoietic, hepatic and other biochemical variables indicative of tissue oxidative stress in male rats was also investigated. Administration of melatonin and NAC individually, provided significant protection to lead induced disturbed antioxidant defense that may significantly compromise normal cellular function. Administration of melatonin and NAC also provided a significant protection to thiobarbituric acid reactive substances (TBARS) levels, reduced glutathione (GSH) and oxidized glutathione (GSSG) contents in tissues, suggesting their ability to act as a free radical scavenger and in protecting cells against toxic insult. NAC, a thiol containing antioxidant, has been used under several clinical conditions with few adverse side effects. It has a high toxicity threshold and its wide therapeutic window enhances its utility. The antioxidant action of NAC is due to its ability to interact with reactive oxygen species (ROS) or its ability to stimulate endogenous glutathione (GSH) synthesis. DMSA, on the other hand when given alone, provided significant recovery in restoring the altered lead sensitive biochemical indices like blood delta-aminolevulinic acid dehydratase (ALAD), urinary delta-aminolevulinic acid (ALA), beside increasing urinary lead excretion and decreasing lead concentration in blood and soft tissues. Interestingly, combined treatment of DMSA and NAC provided more

  4. Paternal dapoxetine administration induced deterioration in reproductive performance, fetal outcome, sexual behavior and biochemistry of male rats.

    PubMed

    ElMazoudy, R; AbdelHameed, N; ElMasry, A

    2015-01-01

    Dapoxetine, a selective serotonin reuptake inhibitor, is considered an antidepressant drug and has been developed for the treatment of premature ejaculation. Hence the objective was to assess whether dapoxetine administration to male rats adversely affect sexual behavior and pregnancy outcomes after mating with untreated female rats. Proven fertile male rats were gavaged with 0, 2.0, 4.0 and 8.0 mg dapoxetine per kg body weight (bw) per day (DC, DI, DII and DIII groups, respectively) for 70 days prior to mating with untreated female rats. Weight gain, organ weights and feed consumption were decreased significantly in the DII and DIII groups. A significant decline in the number of spermatozoa in the DII and DIII groups is attributed to a significant decrease in testosterone, luteinizing hormone and follicle-stimulating hormone. Levels of prolactin were significantly increased in the DII and DIII groups. Rats treated with a high dose of dapoxetine (8.0 mg kg(-1)) showed a significant inhibition in sperm motility and increment in sperm abnormalities. There was a pronounced decrease in fertility index in females mated with males treated chronically with 4.0 and 8.0 mg per kg bw dapoxetine. In addition, the treatment markedly increased the number of fetal resorptions in female rats impregnated by males in the DII and DIII groups reflecting their infertility. The number of implantation sites and the number of viable fetuses were also notably decreased in female rats impregnated by males given 4.0 or 8.0 mg kg(-1) dapoxetine. These findings suggest that the long-term dapoxetine at high dosages causes failure of the fertilization or successful impregnation of the females mated with dapoxetine-treated male rats, which were clearly able to copulate. A detrimental effect of dapoxetine on fertility parameters was also revealed.

  5. Systemic Administration of Human Bone Marrow-Derived Mesenchymal Stromal Cell Extracellular Vesicles Ameliorates Aspergillus Hyphal Extract-Induced Allergic Airway Inflammation in Immunocompetent Mice

    PubMed Central

    Cruz, Fernanda F.; Borg, Zachary D.; Goodwin, Meagan; Sokocevic, Dino; Wagner, Darcy E.; Coffey, Amy; Antunes, Mariana; Robinson, Kristen L.; Mitsialis, S. Alex; Kourembanas, Stella; Thane, Kristen; Hoffman, Andrew M.; McKenna, David H.; Rocco, Patricia R.M.

    2015-01-01

    An increasing number of studies demonstrate that administration of either conditioned media (CM) or extracellular vesicles (EVs) released by mesenchymal stromal cells (MSCs) derived from bone marrow and other sources are as effective as the MSCs themselves in mitigating inflammation and injury. The goal of the current study was to determine whether xenogeneic administration of CM or EVs from human bone marrow-derived MSCs would be effective in a model of mixed Th2/Th17, neutrophilic-mediated allergic airway inflammation, reflective of severe refractory asthma, induced by repeated mucosal exposure to Aspergillus hyphal extract (AHE) in immunocompetent C57Bl/6 mice. Systemic administration of both CM and EVs isolated from human and murine MSCs, but not human lung fibroblasts, at the onset of antigen challenge in previously sensitized mice significantly ameliorated the AHE-provoked increases in airway hyperreactivity (AHR), lung inflammation, and the antigen-specific CD4 T-cell Th2 and Th17 phenotype. Notably, both CM and EVs from human MSCs (hMSCs) were generally more potent than those from mouse MSCs (mMSCs) in most of the outcome measures. The weak cross-linking agent 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride was found to inhibit release of both soluble mediators and EVs, fully negating effects of systemically administered hMSCs but only partly inhibited the ameliorating effects of mMSCs. These results demonstrate potent xenogeneic effects of CM and EVs from hMSCs in an immunocompetent mouse model of allergic airway inflammation and they also show differences in mechanisms of action of hMSCs versus mMSCs to mitigate AHR and lung inflammation in this model. Significance There is a growing experience demonstrating benefit of mesenchymal stromal cell (MSC)-based cell therapies in preclinical models of asthma. In the current study, conditioned media (CM) and, in particular, the extracellular vesicle fraction obtained from the CM were as potent as the

  6. Histamine h3 receptor antagonists potentiate methamphetamine self-administration and methamphetamine-induced accumbal dopamine release.

    PubMed

    Munzar, Patrik; Tanda, Gianluigi; Justinova, Zuzana; Goldberg, Steven R

    2004-04-01

    Methamphetamine administration increases brain levels of histamine and neuronal histamine attenuates several of methamphetamine's behavioral effects. The role of different subtypes of histamine receptors in this negative feedback, however, remains unclear. There is some evidence on possible involvement of histamine H3 receptors in these actions of methamphetamine. The aim of the present study was to evaluate the effects of two histamine H3 receptor antagonists, clobenpropit and thioperamide, on rewarding and neurochemical effects of methamphetamine utilizing three in vivo methodologies, drug self-administration, drug discrimination, and microdialysis in Sprague-Dawley rats. In rats self-administering methamphetamine intravenously under a fixed-ratio schedule, presession treatment with thioperamide (1.0-3.0 mg/kg, subcutaneous, s.c.) or clobenpropit (1.0-3.0 mg/kg, s.c.) potentiated the reinforcing effects of methamphetamine, as indicated by a dose-dependent increase in responding for a low 0.03 mg/kg dose of methamphetamine, that by itself failed to maintain responding above saline substitution levels, and a decrease in responding for a higher 0.06 mg/kg training dose of methamphetamine. In contrast, neither thioperamide nor clobenpropit treatment increased responding during saline substitution. In other rats trained to discriminate intraperitoneal (i.p.) injection of 1.0 mg/kg methamphetamine from i.p. injection of saline, both thioperamide and clobenpropit (0.3-3.0 mg/kg, s.c.) dose dependently increased methamphetamine-appropriate responding when administered with a low 0.3 mg/kg i.p. dose of methamphetamine, which by itself produced predominantly saline-appropriate responding. However, thioperamide and clobenpropit produced only saline-appropriate responding when administered with saline vehicle. Finally, thioperamide and clobenpropit potentiated methamphetamine-induced elevations in extracellular dopamine levels in the shell of the nucleus accumbens, but did

  7. Protective effect of systemic L-kynurenine and probenecid administration on behavioural and morphological alterations induced by toxic soluble amyloid beta (25-35) in rat hippocampus.

    PubMed

    Carrillo-Mora, Paul; Méndez-Cuesta, Luis A; Pérez-De La Cruz, Verónica; Fortoul-van Der Goes, Teresa I; Santamaría, Abel

    2010-07-11

    Amyloid beta (Abeta) peptide exerts different toxic effects at a cellular level, including over-activation of N-methyl-D-aspartate receptor (NMDAr) and excitotoxicity, synaptic dysfunction and neuronal death. Kynurenic acid (KYNA) is an endogenous antagonist of NMDAr and alpha7 nicotinic receptors. Systemic administrations of both the immediate metabolic precursor of KYNA, L-kynurenine (L-KYN), and a proved inhibitor of KYNA's brain transport, probenecid (PROB), have shown to produce neuroprotective effects in a considerable number of experimental toxic conditions; however, this strategy has not been tested in the toxic model Abeta peptide so far. In this study we evaluated the effects of systemic administration of PROB (50 mg/kg/day for 7 days), L-KYN (75 mg/kg/day for 7 days) and their combination, on behavioural (locomotor activity and spatial memory) and morphological alterations induced by an intrahippocampal infusion of Abeta 25-35 to rats. An additional group was administered with the potent NMDAr antagonist dizocilpine (MK-801, 0.8 mg/kg/day for 7 days) for comparative purposes. A significant improvement of spatial memory was evident in Abeta-lesioned rats since post-lesion day 21 with all treatments tested and this effect was correlated with a reduction of cell damage and a decrease in reactive gliosis in hippocampal CA1 area. Neither L-KYN, nor PROB, or their combination, produced major alterations in motor function when given alone to rats. These results suggest that modulation of NMDAr activity by mean of therapeutic strategies designed to enhance KYNA in the brain may help to counteract neurodegenerative events coursing with Abeta toxicity and excitotoxic patterns.

  8. Growth performance and oxidative damage in kidney induced by oral administration of Cr(III) in chicken.

    PubMed

    Liu, Yanhan; Liu, Cun; Cheng, Jia; Fan, Wentao; Zhang, Xiao; Liu, Jianzhu

    2015-11-01

    This study aimed to evaluate the effects of adding chromic chloride (CrCl3) in the drinking water of chickens. Hyland brown male chickens were randomly divided into four groups. Three groups orally received 1/2 LD50, 1/4 LD50, and 1/8 LD50 CrCl3mgkg(-1) body weight daily for 42d. The fourth group was treated with water. The chickens were sacrificed at 14, 28, and 42d post-treatment. The renal injury was examined through histological analysis, and kidney mass was determined. The effects on growth performance were assessed by measuring the weight of the body, chest muscles, and leg muscles. Oxidative damage was evaluated by determining the antioxidant defense levels in kidney homogenates. The body weight and the weight of tissues gained time-dependently, but significantly decreased compared with those in the control group (P<0.05) at the same exposure time. Administering Cr(3+) significantly increased the levels of malondialdehyde, glutathione, and hydrogen peroxide in the kidney compared with those in the control groups. Whereas, administering Cr(3+) reduced the activities of superoxide dismutase, catalase, glutathione peroxidase, and total an-tioxidant capacity compared with those in the control group (P<0.05) in a dose- and time-dependent manner. In conclusion, oral administration of CrCl3 decreases the growth performance of chickens, leads to the pathological lesions and affects nephritic antioxidant capacity in the kidney dose- and time-dependently.

  9. Intranasal Administration of Mycobacterium bovis BCG Induces Superior Protection against Aerosol Infection with Mycobacterium tuberculosis in Mice

    PubMed Central

    Kolibab, Kristopher; Yang, Amy; Morris, Sheldon L.

    2014-01-01

    Despite the widespread use of Mycobacterium bovis BCG, the only licensed vaccine against tuberculosis (TB), TB remains a global epidemic. To assess whether more direct targeting of the lung mucosa by respiratory immunization would enhance the potency and longevity of BCG-induced anti-TB protective immunity, the long-term impact of intranasal (i.n.) BCG vaccination was compared to conventional subcutaneous (s.c.) immunization by using a mouse model of pulmonary tuberculosis. Although significantly improved protection in the lung was seen at early time points (2 and 4 months postvaccination) in i.n. BCG-immunized mice, no differences in pulmonary protection were seen 8 and 10 months postvaccination. In contrast, in all of the study periods, i.n. BCG vaccination induced significantly elevated protective splenic responses relative to s.c. immunization. At five of nine time points, we observed a splenic protective response exceeding 1.9 log10 protection relative to the s.c. route. Furthermore, higher frequencies of CD4 T cells expressing gamma interferon (IFN-γ) and IFN-γ/tumor necrosis factor alpha, as well as CD8 T cells expressing IFN-γ, were detected in the spleens of i.n. vaccinated mice. Using PCR arrays, significantly elevated levels of IFN-γ, interleukin-9 (IL-9), IL-11, and IL-21 expression were also seen in the spleen at 8 months after respiratory BCG immunization. Overall, while i.n. BCG vaccination provided short-term enhancement of protection in the lung relative to s.c. immunization, potent and extremely persistent splenic protective responses were seen for at least 10 months following respiratory immunization. PMID:25143340

  10. Antiproliferative effects on colon adenocarcinoma cells induced by co-administration of vitamin K1 and Lactobacillus rhamnosus GG.

    PubMed

    Orlando, Antonella; Linsalata, Michele; Russo, Francesco

    2016-06-01

    Vitamin K (VK), an essential nutrient associated with the clotting cascade, has also been demonstrated to have anticancer properties in various cancer cells including colon cancer cells. Also probiotics have gained interest as potential anticancer agents. Among them, Lactobacillus rhamnosus GG (L.GG) has been shown to inhibit cell proliferation and polyamine biosynthesis as well as to induce apoptosis in different human gastrointestinal cancer cells. Nevertheless, the exact mechanisms involved in these actions are not completely elucidated. Therefore, the aims of the present study were to evaluate in three differently graded human colon cancer cells (namely Caco-2, HT-29 and SW480) the effects of increasing VK1 concentrations, administered alone or in combination with viable L.GG, on the cell proliferation evaluated by MTT test, apoptosis investigated by Bax/Bcl-2 ratio and the percentage of the apoptotic cells, and the cell cycle evaluated by MUSE cell analyzer. Both VK1 and L.GG administered alone up to 72 h, caused inhibition of proliferation, induction of apoptosis and the cell cycle arrest in all the tested colon cancer cells. When VK1 and L.GG were co-administered, the addition of increasing VK1 concentrations potentiated the probiotic antiproliferative effect in a dose-dependent manner, being also related to the individual features of each cell line. The effect was more evident in Caco-2 and HT-29 cells compared to the less differentiated SW480. The enhanced antiproliferative efficacy due to co-administration of L.GG and VK1 could represent a suitable option in a functional food strategy for cancer growth inhibition and chemoprevention.

  11. Antinociceptive action of diphenyl diselenide in the nociception induced by neonatal administration of monosodium glutamate in rats.

    PubMed

    Rosa, Suzan G; Quines, Caroline B; da Rocha, Juliana T; Bortolatto, Cristiani F; Duarte, Thiago; Nogueira, Cristina W

    2015-07-01

    Monosodium glutamate (MSG) is a neuroexcitatory amino acid commonly used as flavoring of foods. MSG neonatal administration to animals leads to behavioral and physiological disorders in adulthood, including increased pain sensitivity. This study aimed to investigate the effect of diphenyl diselenide (PhSe)2, an organoselenium compound with pharmacological properties already documented, on nociception induced by MSG. Newborn Wistar rats received 10 subcutaneous injections of MSG at a dose of 4.0g/kg or saline (once daily). At the 60th day of life, the rats were daily treated with (PhSe)2 (1mg/kg) or vehicle (canola oil) by the intragastric route for 7 days. The behavioral tests (locomotor activity, hot plate, tail-immersion and mechanical allodynia) were carried out. Ex vivo assays were performed in samples of hippocampus to determine Na(+), K(+)-ATPase and Ca(2+)-ATPase activities, cytokine levels and [(3)H]glutamate uptake. The results demonstrated that MSG increased nociception in the hot plate test and in the mechanical allodynia stimulated by Von-Frey hair but did not alter the tail immersion test. (PhSe)2 reversed all nociceptive behaviors altered by MSG. MSG caused an increase in Na(+),K(+)-ATPase and Ca(2+)-ATPase activities and in pro-inflammatory cytokine levels and a decrease in the anti-inflammatory cytokine and in the [(3)H]glutamate uptake. (PhSe)2 was effective in reversing all alterations caused by MSG. The results indicate that (PhSe)2 had a potential antinociceptive and anti-inflammatory action in the MSG model.

  12. Antiproliferative effects on colon adenocarcinoma cells induced by co-administration of vitamin K1 and Lactobacillus rhamnosus GG.

    PubMed

    Orlando, Antonella; Linsalata, Michele; Russo, Francesco

    2016-06-01

    Vitamin K (VK), an essential nutrient associated with the clotting cascade, has also been demonstrated to have anticancer properties in various cancer cells including colon cancer cells. Also probiotics have gained interest as potential anticancer agents. Among them, Lactobacillus rhamnosus GG (L.GG) has been shown to inhibit cell proliferation and polyamine biosynthesis as well as to induce apoptosis in different human gastrointestinal cancer cells. Nevertheless, the exact mechanisms involved in these actions are not completely elucidated. Therefore, the aims of the present study were to evaluate in three differently graded human colon cancer cells (namely Caco-2, HT-29 and SW480) the effects of increasing VK1 concentrations, administered alone or in combination with viable L.GG, on the cell proliferation evaluated by MTT test, apoptosis investigated by Bax/Bcl-2 ratio and the percentage of the apoptotic cells, and the cell cycle evaluated by MUSE cell analyzer. Both VK1 and L.GG administered alone up to 72 h, caused inhibition of proliferation, induction of apoptosis and the cell cycle arrest in all the tested colon cancer cells. When VK1 and L.GG were co-administered, the addition of increasing VK1 concentrations potentiated the probiotic antiproliferative effect in a dose-dependent manner, being also related to the individual features of each cell line. The effect was more evident in Caco-2 and HT-29 cells compared to the less differentiated SW480. The enhanced antiproliferative efficacy due to co-administration of L.GG and VK1 could represent a suitable option in a functional food strategy for cancer growth inhibition and chemoprevention. PMID:27035094

  13. Aggression behaviour induced by oral administration of the Janus-kinase inhibitor tofacitinib, but not oclacitinib, under stressful conditions.

    PubMed

    Fukuyama, Tomoki; Tschernig, Thomas; Qi, Yulin; Volmer, Dietrich A; Bäumer, Wolfgang

    2015-10-01

    Janus kinase (JAK) inhibitors have recently been developed for allergic diseases. We focused on the 2 different JAK inhibitors, tofacitinib (selective for JAK3) and oclacitinib (selective for JAK1 and 2), to clarify the mechanism of anti-inflammatory and anti-itching potency of these drugs. In the process of detecting anti-itching potency, we observed that tofacitinib treated mice showed aggression behaviour. The objective of the study reported here was to investigate the aggressive behaviour induced by tofacitinib by using a mouse model of allergic dermatitis and the resident-intruder test. For the allergic dermatitis model, female BALB/c mice were sensitised and challenged topically with toluene-2,4-diisocyanate (TDI). Vehicle, tofacitinib or oclacitinib, was administered orally 30 min before TDI challenge. Scratching, aggression and standing behaviours were monitored in the 60 min period immediately following challenge of TDI. Another group of male BALB/c mice treated with vehicle, tofacitinib or oclacitinib was evaluated in the resident-intruder test and brains were obtained to determine blood brain barrier penetration. In the allergic dermatitis model, a significant increase in aggression and standing behaviour was only obvious in the tofacitinib treatment group. There was no effect in non-sensitised mice, but similar aggression was also induced by tofacitinib in male resident-intruder test. Penetration of blood-brain barrier was observed both in tofacitinib and oclacitinib treated mice. These results suggest that aggression was induced by tofacitinib under some kind of stressful environment. This study indicates a possible role of the JAK-STAT pathway in modulation of aggression behaviour.

  14. Administration of ascorbic acid to prevent bleaching-induced tooth sensitivity: a randomized triple-blind clinical trial.

    PubMed

    de Paula, E A; Kossatz, S; Fernandes, D; Loguercio, A D; Reis, A

    2014-01-01

    This study evaluated the effect of ascorbic acid, 500 mg every eight hours, on bleaching-induced tooth sensitivity. A triple-blind, parallel design, and placebo-controlled randomized clinical trial was conducted on 39 adults. The pills (placebo or ascorbic acid) were administered three times per day for 48 hours; the first dose was given one hour prior to each bleaching session. Two bleaching sessions with 35% hydrogen peroxide gel were performed with a one-week interval. Tooth sensitivity was recorded up to 48 hours after bleaching. The color evaluation was performed before and 30 days after bleaching. The absolute risk and intensity of tooth sensitivity were evaluated by Fisher exact and Mann-Whitney U-tests, respectively. Color changes were evaluated by unpaired t-test (α=0.05). There were no significant differences in the absolute risk and intensity of tooth sensitivity and color change between the groups. Both groups showed a similar risk of tooth sensitivity (p>0.05). The perioperative use of an antioxidant, such as ascorbic acid (500 mg, three times daily) perorally, was not able to prevent bleaching-induced tooth sensitivity or reduce its intensity. PMID:23802640

  15. Noisy galvanic vestibular stimulation enhances spatial memory in cognitive impairment-induced by intracerebroventricular-streptozotocin administration.

    PubMed

    Adel Ghahraman, Mansoureh; Zahmatkesh, Maryam; Pourbakht, Akram; Seifi, Behjat; Jalaie, Shohreh; Adeli, Soheila; Niknami, Zohreh

    2016-04-01

    There are several anatomical connections between vestibular system and brain areas construct spatial memory. Since subliminal noisy galvanic vestibular stimulation (GVS) has been demonstrated to enhance some types of memory, we speculated that application of noisy GVS may improve spatial memory in a rat model of intracerebroventricular streptozotocin (ICV-STZ)-induced cognitive impairment. Moreover, we attempted to determine the effect of repeated exposure to GVS on spatial memory performance. The spatial memory was assessed using Morris water maze test. The groups received 1 (ICV-STZ/GVS-I) or 5 (ICV-STZ/GVS-II) sessions, each lasting 30 min, of low amplitude noisy GVS, or no GVS at all (Control, ICV-saline, ICV-STZ/noGVS). Hippocampal morphological changes investigated with cresyl violet staining and the immediate early gene product c-Fos, as a neuronal activity marker, was measured. Hippocampal c-Fos positive cells increased in both GVS stimulated groups. We observed significantly improved spatial performance only in ICV-STZ/GVS-II group. Histological evaluation showed normal density in ICV-STZ/GVS-II group whereas degeneration observed in ICV-STZ/GVS-I group similar to ICV-STZ/noGVS. The results showed the improvement of memory impairment after repeated exposure to GVS. This effect may be due in part to frequent activation of the vestibular neurons and the hippocampal regions connected to them. Our current study suggests the potential role of GVS as a practical method to combat cognitive decline induced by sporadic Alzheimer disease.

  16. Impaired recovery of brain muscarinic receptor sites following an adaptive down-regulation induced by repeated administration of diisopropyl fluorophosphate in aged rats

    SciTech Connect

    Pintor, A.; Fortuna, S.; De Angelis, S.; Michalek, H. )

    1990-01-01

    Potential age-related differences in the recovery rate of brain cholinesterase activity (ChE) and muscarinic acetylcholine receptor binding sites (mAChRs) following reduction induced by repeated treatment with diisopropyl fluorophosphate (DFP) were evaluated in Sprague-Dawley rats. Male 3- and 24-month old rats were s.c. injected with DFP on alternate days for 2 weeks and killed 48 hr and 7, 14, 21, 28 and 35 days after the last treatment. In the hippocampus and striatum, but not in the cerebral cortex, of control rats there as a significant age-related decline of ChE activity and maximal density of 3H-QNB binding sites (Bmax). The repeated administration of DFP during the first week caused a syndrome of cholinergic stimulation both in aged and young rats. The syndrome was more pronounced, in terms of intensity and duration in aged than in young animals resulting in 40 and 12% mortality, respectively; during the second week the syndrome attenuated in the two age-groups. The percentage inhibition of brain ChE at the end of DFP treatment did not differ between young and surviving aged rats. The down-regulation of mACRs was present in the three brain regions of both young and age rats (from 20 to 40%). Factorial analysis of variance showed significant differences for age, recovery rate, and significant interaction between age and recovery rate, both for ChE and mAChRs in young rats the three brain areas.

  17. Intranasal Administration of Type V Collagen Reduces Lung Carcinogenesis through Increasing Endothelial and Epithelial Apoptosis in a Urethane-Induced Lung Tumor Model.

    PubMed

    Parra, Edwin Roger; Alveno, Renata Antunes; Faustino, Carolina Brito; Corrêa, Paula Yume Sato Serzedello; Vargas, Camilla Mutai; de Morais, Jymenez; Rangel, Maristela Peres; Velosa, Ana Paula Pereira; Fabro, Alexandre Todorovic; Teodoro, Walcy Rosolia; Capelozzi, Vera Luiza

    2016-08-01

    Type V collagen (Col V) is a "minor" component of normal lung extracellular matrix, which is subjected to decreased and abnormal synthesis in human lung infiltrating adenocarcinoma. We previously reported that a direct link between low amounts of Col V and decreased cell apoptosis may favor cancer cell growth in the mouse lung after chemical carcinogenesis. Moreover, this collagen species was able to trigger DNA fragmentation and impair survival of neoplastic cells. In this study, we have extended our investigation with the aim to obtain further evidence that the death induced by Col V-treatment is of the caspase-9 apoptotic type. We used (1) optical and electron microscopy, (2) quantitation of TUNEL-labeled cells and (3) analysis of the expression levels of Col V and selected genes coding for apoptosis-linked factors, by conventional RT-PCR. BALB/c mice were injected intraperitoneally with 1.5 g/kg body weight of urethane. After urethane injection, the animals received intranasal administration of 20 µg/20 µl of Col V every day during 2 months. We report here that Col V treatment was able to determine significant increase in Col V protein and gene expression and in the percentage of TUNEL-positive cells, to up-regulate caspase-9, resulting in low growth of tumor cells. Our data validate chemical carcinogenesis as a suitable "in vivo" model for further and more detailed studies on the molecular mechanisms of the death response induced by Col V in lung infiltrating adenocarcinoma opening new strategies for treatment.

  18. Treatment of chemotherapy-induced neutropenia in a rat model by using multiple daily doses of oral administration of G-CSF-containing nanoparticles.

    PubMed

    Su, Fang-Yi; Chuang, Er-Yuan; Lin, Po-Yen; Chou, Yi-Chun; Chen, Chiung-Tong; Mi, Fwu-Long; Wey, Shiaw-Pyng; Yen, Tzu-Chen; Lin, Kun-Ju; Sung, Hsing-Wen

    2014-04-01

    Chemotherapy-induced neutropenia often increases the likelihood of life-threatening infections. In this study, a nanoparticle (NP) system composed of chitosan and poly(γ-glutamic acid) conjugated with diethylene triamine pentaacetic acid (γPGA-DTPA) was prepared for oral delivery of granulocyte colony-stimulating factor (G-CSF), a hematopoietic growth factor. The therapeutic potential of this NP system for daily administration of G-CSF to treat neutropenia associated with chemotherapy was evaluated in a rat model. In vitro results indicate that the procedures of NP loading and release preserved the structural integrity and bioactivity of the G-CSF molecules adequately. Those results further demonstrated the enzymatic inhibition activity of γPGA-DTPA towards G-CSF against intestinal proteases. Additionally, the in vivo biodistribution study clearly identified accumulations of G-CSF in the heart, liver, bone marrow, and urinary bladder, an indication of systemic absorption of G-CSF; its relative bioavailability was approximately 13.6%. Moreover, significant glucose uptake was observed in bone marrow during G-CSF treatment, suggesting increased bone marrow metabolism and neutrophil production. Consequently, neutrophil count in the blood increased in a sustained manner; this fact may help a patient's immune system recover from the side effects of chemotherapy.

  19. Protection against bovine tuberculosis induced by oral vaccination of cattle with Mycobacterium bovis BCG is not enhanced by co-administration of mycobacterial protein vaccines.

    PubMed

    Wedlock, D Neil; Aldwell, Frank E; Vordermeier, H Martin; Hewinson, R Glyn; Buddle, Bryce M

    2011-12-15

    Mycobacterium bovis bacille Calmette-Guérin (BCG) delivered to calves by the oral route in a formulated lipid matrix has been previously shown to induce protection against bovine tuberculosis. A study was conducted in cattle to determine if a combination of a low dose of oral BCG and a protein vaccine could induce protective immunity to tuberculosis while not sensitising animals to tuberculin. Groups of calves (10 per group) were vaccinated by administering 2 × 10(7)colony forming units (CFU) of BCG orally or a combination of 2 × 10(7)CFU oral BCG and a protein vaccine comprised of M. bovis culture filtrate proteins (CFP) formulated with the adjuvants Chitin and Gel 01 and delivered by the intranasal route, or CFP formulated with Emulsigen and the TLR2 agonist Pam(3)CSK(4) and administered by the subcutaneous (s.c.) route. Two further groups were vaccinated with the CFP/Chitin/Gel 01 or CFP/Emulsigen/Pam(3)CSK(4) vaccines alone. Positive control groups were given 10(8)CFU oral BCG or 10(6)CFU s.c. BCG while a negative control group was non-vaccinated. All animals were challenged with M. bovis 15 weeks after vaccination and euthanized and necropsied at 16 weeks following challenge. Groups of cattle vaccinated with s.c. BCG, 10(8)CFU or 2 × 10(7)CFU oral BCG showed significant reductions in seven, three and four pathological or microbiological disease parameters, respectively, compared to the results for the non-vaccinated group. There was no evidence of protection in calves vaccinated with the combination of oral BCG and CFP/Emulsigen/Pam(3)CSK(4) or oral BCG and CFP/Chitin/Gel 01 or vaccinated with the protein vaccines alone. Positive responses in the comparative cervical skin test at 12 weeks after vaccination were only observed in animals vaccinated with s.c. BCG, 10(8)CFU oral BCG or a combination of 2 × 10(7)CFU oral BCG and CFP/Chitin/Gel 01. In conclusion, co-administration of a protein vaccine, administered by either systemic or mucosal routes with oral

  20. Significant Traumatic Intracranial Hemorrhage in the Setting of Massive Bee Venom-Induced Coagulopathy: A Case Report.

    PubMed

    Stack, Kelsey; Pryor, Lindsey

    2016-09-01

    Bees and wasps of the Hymenoptera order are encountered on a daily basis throughout the world. Some encounters prove harmless, while others can have significant morbidity and mortality. Hymenoptera venom is thought to contain an enzyme that can cleave phospholipids and cause significant coagulation abnormalities. This toxin and others can lead to reactions ranging from local inflammation to anaphylaxis. We report a single case of a previously healthy man who presented to the emergency department with altered mental status and anaphylaxis after a massive honeybee envenomation that caused a fall from standing resulting in significant head injury. He was found to have significant coagulopathy and subdural bleeding that progressed to near brain herniation requiring emergent decompression. Trauma can easily occur to individuals escaping swarms of hymenoptera. Closer attention must be paid to potential bleeding sources in these patients and in patients with massive bee envenomation.

  1. Significant Traumatic Intracranial Hemorrhage in the Setting of Massive Bee Venom-Induced Coagulopathy: A Case Report.

    PubMed

    Stack, Kelsey; Pryor, Lindsey

    2016-09-01

    Bees and wasps of the Hymenoptera order are encountered on a daily basis throughout the world. Some encounters prove harmless, while others can have significant morbidity and mortality. Hymenoptera venom is thought to contain an enzyme that can cleave phospholipids and cause significant coagulation abnormalities. This toxin and others can lead to reactions ranging from local inflammation to anaphylaxis. We report a single case of a previously healthy man who presented to the emergency department with altered mental status and anaphylaxis after a massive honeybee envenomation that caused a fall from standing resulting in significant head injury. He was found to have significant coagulopathy and subdural bleeding that progressed to near brain herniation requiring emergent decompression. Trauma can easily occur to individuals escaping swarms of hymenoptera. Closer attention must be paid to potential bleeding sources in these patients and in patients with massive bee envenomation. PMID:27427329

  2. Clinical significance of exercise-induced left ventricular wall motion abnormality occurring at a low heart rate

    SciTech Connect

    Kimchi, A.; Rozanski, A.; Fletcher, C.; Maddahi, J.; Swan, H.J.; Berman, D.S.

    1987-10-01

    We studied the relationship between the heart rate at the time of onset of exercise-induced wall motion abnormality and the severity of coronary artery disease in 89 patients who underwent exercise equilibrium radionuclide ventriculography as part of their evaluation for coronary artery disease. Segmental wall motion was scored with a five-point system (3 = normal; -1 = dyskinesis); a decrease of one score defined the onset of wall motion abnormality. The onset of wall motion abnormality at less than or equal to 70% of maximal predicted heart rate had 100% predictive accuracy for coronary artery disease and higher sensitivity than the onset of ischemic ST segment depression at similar heart rate during exercise: 36% (25 of 69 patients with coronary disease) vs 19% (13 of 69 patients), p = 0.01. Wall motion abnormality occurring at less than or equal to 70% of maximal predicted heart rate was present in 49% of patients (23 of 47) with critical stenosis (greater than or equal to 90% luminal diameter narrowing), and in only 5% of patients (2 of 42) without such severe stenosis, p less than 0.001. The sensitivity of exercise-induced wall motion abnormality occurring at a low heart rate for the presence of severe coronary artery disease was similar to that of a deterioration in wall motion by more than two scores during exercise (49% vs 53%) or an absolute decrease of greater than or equal to 5% in exercise left ventricular ejection fraction (49% vs 45%).

  3. Effect of oral administration of ethanolic extract of Vitex negundo on thioacetamide-induced nephrotoxicity in rats

    PubMed Central

    2013-01-01

    Background Oxidative stress due to abnormal induction of reactive oxygen species (ROS) molecules is believed to be involved in the etiology of many diseases. Evidences suggest that ROS is involved in nephrotoxicity through frequent exposure to industrial toxic agents such as thioacetamide (TAA). The current investigation was designed to explore the possible protective effects of the leaves of Vitex negundo(VN) extract against TAA-induced nephrotoxicity in rats. Methods Twenty four Sprague Dawleyrats were divided into four groups: (A) Normal control, (B) TAA (0.03% w/v in drinking water), (C) VN100 (VN 100 mg/kg + TAA) and (D) VN300 (VN 300 mg/kg + TAA). Blood urea and serum creatinine levels were measured,supraoxide dismutase (SOD), catalase (CAT) and malondialdehyde (MDA) levels of renal tissue were assayed. Histopathological analysis together with the oxidative stress nicotinamide adenine dinucleotide phosphate (NADPH) oxidase p22phox in kidney sections were examined in all experimental groups. Results Blood urea and serum creatinine levels were increased in TAA group as a result of the nephrotoxicity compared to the VN100 and VN300 groups where, the levels were significantly decreased (p < 0.05). Renal MDA level was significantly decreased (p < 0.05) in the VN-treated groups with increased CAT and SOD activities compared to the TAA group. Light microscopic examination of renal tissues stained by H&E stain and Masson’s Trichrome for TAA-treated groups revealed severe histopathological changes, whereas specimens obtained from VN-treated groups showed only mild changes. These findings were supported by immunohistochemical results. Conclusions VN extract acts as a natural potent antioxidant to prevent ongoing TAA-induced nephrotoxicity in rats, both biochemically and morphologically. PMID:24499255

  4. Herbal tea extract combined with light-induced significant in vitro cytotoxicity of human bladder cancer cells

    NASA Astrophysics Data System (ADS)

    Nseyo, Unyime; Kim, Albert; Stavropoulos, Nicholas E.; Skalkos, Dimitris; Nseyo, U. U.; Chung, Theodore D.

    2005-04-01

    The anti-inflammatory, anti-microbial, antiviral, and antidepressant activities of the Greek herb, Hypericum Perforatum L, HP L, have been attributed to the total extract or single constituents. We investigated the use of the extract,specifically of the polar methanolic fraction (PMF) of Epirus"HPL in photodynamic therapy (PDT) alone and in combination with recombinant Interferon-a2b (IFN) and gemcitabine (GCB) in the treatment of human bladder cancer cells. The PMF was extracted from the dry herb with methanol, followed by liquid-liquid extraction with petroleum ether. T-24 bladder cancer cells were plated (105 cells/well) and placed in the incubator (370 C, 5%CO) for 24 hours prior to addition of drugs. PMF 60ug/ml was added and incubation continued. After 24 hours, the cells were subjected to laser light (630nm) treatment with 0, 1, 4 and 8 Joules. After reincubation for 24 hours, IFN, (50,000 IU) or GCB, (2ug/ml) was added to the PDT-treated cells. After this incubation cell survival was assessed by the MTT assay. PMF-PDT alone-induced percent cell kill of 0%, 8%, 44% and 80% versus 31%, 64 and 86 % for PMF-PDT and IFN, versus 63%, 80% and 88% for MPF-PDT plus GCB at 1, 2, 4 and 8 Joules respectively. IFN and GCB induced 20% and 53% cell kill respectively. Our data suggest that MPF may be an effective agent for in vitro photodynamic therapy. PMF-PDT combined with Intron A, or gemcitabine achieved improved kill of cultured bladder cancer cells. Confirmation of these results in preclinical studies may lead to clinical trials.

  5. Prevalence and prognostic significance of exercise-induced silent myocardial ischemia detected by thallium scintigraphy and electrocardiography in asymptomatic volunteers

    SciTech Connect

    Fleg, J.L.; Gerstenblith, G.; Zonderman, A.B.; Becker, L.C.; Weisfeldt, M.L.; Costa, P.T. Jr.; Lakatta, E.G. )

    1990-02-01

    Although a silent ischemic electrocardiographic response to treadmill exercise in clinically healthy populations is associated with an increased likelihood of future coronary events (i.e., angina pectoris, myocardial infarction, or cardiac death), such a response has a low predictive value for future events because of the low prevalence of disease in asymptomatic populations. To examine whether detection of reduced regional perfusion by thallium scintigraphy improved the predictive value of exercise-induced ST segment depression, we performed maximal treadmill exercise electrocardiography (ECG) and thallium scintigraphy (201Tl) in 407 asymptomatic volunteers 40-96 years of age (mean = 60) from the Baltimore Longitudinal Study on Aging. The prevalence of exercise-induced silent ischemia, defined by concordant ST segment depression and a thallium perfusion defect, increased more than sevenfold from 2% in the fifth and sixth decades to 15% in the ninth decade. Over a mean follow-up period of 4.6 years, cardiac events developed in 9.8% of subjects and consisted of 20 cases of new angina pectoris, 13 myocardial infarctions, and seven deaths. Events occurred in 7% of individuals with both negative 201Tl and ECG, 8% of those with either test positive, and 48% of those in whom both tests were positive (p less than 0.001). By proportional hazards analysis, age, hypertension, exercise duration, and a concordant positive ECG and 201Tl result were independent predictors of coronary events. Furthermore, those with positive ECG and 201Tl had a 3.6-fold relative risk for subsequent coronary events, independent of conventional risk factors.

  6. Significance of the Melanocortin 1 and Endothelin B Receptors in Melanocyte Homeostasis and Prevention of Sun-Induced Genotoxicity

    PubMed Central

    Swope, Viki B.; Abdel-Malek, Zalfa A.

    2016-01-01

    The membrane bound melanocortin 1 receptor (MC1R), and the endothelin B receptor (ENDBR) are two G-protein coupled receptors that play important roles in constitutive regulation of melanocytes and their response to ultraviolet radiation (UVR), the main etiological factor for melanoma. The human MC1R is a Gs protein-coupled receptor, which is activated by its agonists α-melanocyte stimulating hormone (α-melanocortin; α-MSH) and adrenocorticotropic hormone (ACTH). The ENDBR is a Gq coupled-receptor, which is activated by Endothelin (ET)-3 during embryonic development, and ET-1 postnatally. Pigmentation and the DNA repair capacity are two major factors that determine the risk for melanoma. Activation of the MC1R by its agonists stimulates the synthesis of eumelanin, the dark brown photoprotective pigment. In vitro studies showed that α-MSH and ET-1 interact synergistically in the presence of basic fibroblast growth factor to stimulate human melanocyte proliferation and melanogenesis, and to inhibit UVR-induced apoptosis. An important function of the MC1R is reduction of oxidative stress and activation of DNA repair pathways. The human MC1R is highly polymorphic, and MC1R variants, particularly those that cause loss of function of the expressed receptor, are associated with increased melanoma risk independently of pigmentation. These variants compromise the DNA repair and antioxidant capacities of human melanocytes. Recently, activation of ENDBR by ET-1 was reported to reduce the induction and enhance the repair of UVR-induced DNA photoproducts. We conclude that α-MSH and ET-1 and their cognate receptors MC1R and ENDBR reduce the risk for melanoma by maintaining genomic stability of melanocytes via modulating the DNA damage response to solar UVR. Elucidating the response of melanocytes to UVR should improve our understanding of the process of melanomagenesis, and lead to effective melanoma chemoprevention, as well as therapeutic strategies. PMID:27582758

  7. Significance of the Melanocortin 1 and Endothelin B Receptors in Melanocyte Homeostasis and Prevention of Sun-Induced Genotoxicity.

    PubMed

    Swope, Viki B; Abdel-Malek, Zalfa A

    2016-01-01

    The membrane bound melanocortin 1 receptor (MC1R), and the endothelin B receptor (ENDBR) are two G-protein coupled receptors that play important roles in constitutive regulation of melanocytes and their response to ultraviolet radiation (UVR), the main etiological factor for melanoma. The human MC1R is a Gs protein-coupled receptor, which is activated by its agonists α-melanocyte stimulating hormone (α-melanocortin; α-MSH) and adrenocorticotropic hormone (ACTH). The ENDBR is a Gq coupled-receptor, which is activated by Endothelin (ET)-3 during embryonic development, and ET-1 postnatally. Pigmentation and the DNA repair capacity are two major factors that determine the risk for melanoma. Activation of the MC1R by its agonists stimulates the synthesis of eumelanin, the dark brown photoprotective pigment. In vitro studies showed that α-MSH and ET-1 interact synergistically in the presence of basic fibroblast growth factor to stimulate human melanocyte proliferation and melanogenesis, and to inhibit UVR-induced apoptosis. An important function of the MC1R is reduction of oxidative stress and activation of DNA repair pathways. The human MC1R is highly polymorphic, and MC1R variants, particularly those that cause loss of function of the expressed receptor, are associated with increased melanoma risk independently of pigmentation. These variants compromise the DNA repair and antioxidant capacities of human melanocytes. Recently, activation of ENDBR by ET-1 was reported to reduce the induction and enhance the repair of UVR-induced DNA photoproducts. We conclude that α-MSH and ET-1 and their cognate receptors MC1R and ENDBR reduce the risk for melanoma by maintaining genomic stability of melanocytes via modulating the DNA damage response to solar UVR. Elucidating the response of melanocytes to UVR should improve our understanding of the process of melanomagenesis, and lead to effective melanoma chemoprevention, as well as therapeutic strategies. PMID:27582758

  8. Systemic administration of micro-dystrophin restores cardiac geometry and prevents dobutamine-induced cardiac pump failure.

    PubMed

    Townsend, DeWayne; Blankinship, Michael J; Allen, James M; Gregorevic, Paul; Chamberlain, Jeffrey S; Metzger, Joseph M

    2007-06-01

    Duchenne muscular dystrophy (DMD) is a fatal disease of striated muscle deterioration resulting from the loss of the cytoskeletal protein dystrophin. Most patients develop significant cardiomyopathy, with heart failure being the second leading cause of death in DMD. Compared with the extensive studies on skeletal muscle defects and potential therapy in DMD, very little attention has been directed at the increasing incidence of heart failure in DMD. Here we show that a single systemic injection of recombinant adeno-associated virus (rAAV2/6) harboring micro-dystrophin leads to extensive cardiac transduction, with micro-dystrophin correctly localized at the periphery of the cardiac myocytes and functionally associated with the sarcolemmal membrane. Significantly, micro-dystrophin gene transfer corrected the baseline end-diastolic volume defect in the mdx mouse heart and prevented cardiac pump failure induced by dobutamine stress testing in vivo, although several parameters of systolic function were not corrected. These results demonstrate that systemic gene delivery of micro-dystrophin can restore ventricular distensibility and protect the mdx myocardium from pump dysfunction during adrenergic stimulation in vivo.

  9. Long-term dysregulation of circadian and 17-beta estradiol-induced LH, prolactin and corticosterone secretion after dimethylbenz (a) anthracene administration in the Sprague-Dawley female rat.

    PubMed

    Yon de Jonage-Canonico, M Beau; Lenoir, V; Scholler, R; Kerdelhué, B

    2005-07-01

    A single intragastric administration of 7,12-dimethylbenz (a) anthracene (DMBA) has been shown, when given at 55-60 days of age, to induce mammary tumors in young cycling female Sprague-Dawley rats. The appearance of the tumors is preceded by a series of neuroendocrine disturbances of the hypothalamo-pituitary-gonadal (HPG) axis, including attenuation of the preovulatory Luteinizing Hormone (LH) and Gonadotropin-Releasing Hormone (GnRH) release and amplification of the preovulatory 17beta-Estradiol (E(2)) surge. In this study, we examined the hypothesis that a single administration of DMBA could also, in the long range, induce disturbances of others neuroendocrine axis, like the Hypothalamic-Pituitary-Adrenal (HPA) axis and/or the Lactotroph axis. Sprague-Dawley rats, 55-60 days of age, received, on the day of Estrous of the Estrous cycle, a single administration of 15 mg of DMBA delivered by intragastric intubation. Then, they were ovariectomized 5 days later. One month later, (1) Two groups of animal were sacrificed by decapitation at 09:00 a.m. and 05:00 p.m. to record the circadian rhythm of plasma LH, Prolactin (PRL) and corticosterone, (2) Three other groups of animal were sacrificed by decapitation at three different times after a morning subcutaneous administration of 50 microg/kg of Estradiol Benzoate (EB), to induce a negative and positive feed-back of the secretion of LH. Then, plasma LH, PRL and corticosterone concentrations were measured. After DMBA administration, (1) the negative--but not the positive--LH feed-back was seen, (2) the PRL circadian rhythm was blunted and the corticosterone circadian rhythm was almost absent, (3) the increase in PRL or Corticosterone plasma concentration was significantly reduced. In conclusion, a single administration of DMBA provokes a long-term dysregulation of not only the HPG axis but also of the lactotroph and HPA axis. These dysregulations, along with the already evidenced long-term inhibition of DMBA upon

  10. Noisy galvanic vestibular stimulation enhances spatial memory in cognitive impairment-induced by intracerebroventricular-streptozotocin administration.

    PubMed

    Adel Ghahraman, Mansoureh; Zahmatkesh, Maryam; Pourbakht, Akram; Seifi, Behjat; Jalaie, Shohreh; Adeli, Soheila; Niknami, Zohreh

    2016-04-01

    There are several anatomical connections between vestibular system and brain areas construct spatial memory. Since subliminal noisy galvanic vestibular stimulation (GVS) has been demonstrated to enhance some types of memory, we speculated that application of noisy GVS may improve spatial memory in a rat model of intracerebroventricular streptozotocin (ICV-STZ)-induced cognitive impairment. Moreover, we attempted to determine the effect of repeated exposure to GVS on spatial memory performance. The spatial memory was assessed using Morris water maze test. The groups received 1 (ICV-STZ/GVS-I) or 5 (ICV-STZ/GVS-II) sessions, each lasting 30 min, of low amplitude noisy GVS, or no GVS at all (Control, ICV-saline, ICV-STZ/noGVS). Hippocampal morphological changes investigated with cresyl violet staining and the immediate early gene product c-Fos, as a neuronal activity marker, was measured. Hippocampal c-Fos positive cells increased in both GVS stimulated groups. We observed significantly improved spatial performance only in ICV-STZ/GVS-II group. Histological evaluation showed normal density in ICV-STZ/GVS-II group whereas degeneration observed in ICV-STZ/GVS-I group similar to ICV-STZ/noGVS. The results showed the improvement of memory impairment after repeated exposure to GVS. This effect may be due in part to frequent activation of the vestibular neurons and the hippocampal regions connected to them. Our current study suggests the potential role of GVS as a practical method to combat cognitive decline induced by sporadic Alzheimer disease. PMID:26892259

  11. Involvement of oxidative stress in the impairment in biliary secretory function induced by intraperitoneal administration of aluminum to rats.

    PubMed

    Gonzalez, Marcela A; Alvarez, Maria Del Lujan; Pisani, Gerardo B; Bernal, Claudio A; Roma, Marcelo G; Carrillo, María C

    2007-06-01

    We have shown that aluminum (Al) induces cholestasis associated with multiple alterations in hepatocellular transporters involved in bile secretory function, like Mrp2. This work aims to investigate whether these harmful effects are mediated by the oxidative stress caused by the metal. For this purpose, the capability of the antioxidant agent, vitamin E, to counteract these alterations was studied in male Wistar rats. Aluminum hydroxide (or saline in controls) was administered ip (27 mg/kg body weight, three times a week, for 90 d). Vitamin E (600 mg/kg body weight) was coadministered, sc. Al increased lipid peroxidation (+50%) and decreased hepatic glutation levels (-43%) and the activity of glutation peroxidase (-50%) and catalase (-88%). Vitamin E counteracted these effects total or partially. Both plasma and hepatic Al levels reached at the end of the treatment were significantly reduced by vitamin E (-40% and -44%, respectively; p<0.05). Al increased 4 times the hepatic apoptotic index, and this effect was fully counteracted by vitamin E. Bile flow was decreased in Altreated rats (-37%) and restored to normality by vitamin E. The antioxidant normalized the hepatic handling of the Mrp2 substrates, rose bengal, and dinitrophenyl-S-glutathione, which was causally associated with restoration of Mrp2 expression. Our data indicate that oxidative stress has a crucial role in cholestasis, apoptotic/necrotic hepatocellular damage, and the impairment in liver transport function induced by Al and that vitamin E counteracts these harmful effects not only by preventing free-radical formation but also by favoring Al disposal. PMID:17709913

  12. Involvement of oxidative stress in the impairment in biliary secretory function induced by intraperitoneal administration of aluminum to rats.

    PubMed

    Gonzalez, Marcela A; Alvarez, Maria Del Lujan; Pisani, Gerardo B; Bernal, Claudio A; Roma, Marcelo G; Carrillo, María C

    2007-06-01

    We have shown that aluminum (Al) induces cholestasis associated with multiple alterations in hepatocellular transporters involved in bile secretory function, like Mrp2. This work aims to investigate whether these harmful effects are mediated by the oxidative stress caused by the metal. For this purpose, the capability of the antioxidant agent, vitamin E, to counteract these alterations was studied in male Wistar rats. Aluminum hydroxide (or saline in controls) was administered ip (27 mg/kg body weight, three times a week, for 90 d). Vitamin E (600 mg/kg body weight) was coadministered, sc. Al increased lipid peroxidation (+50%) and decreased hepatic glutation levels (-43%) and the activity of glutation peroxidase (-50%) and catalase (-88%). Vitamin E counteracted these effects total or partially. Both plasma and hepatic Al levels reached at the end of the treatment were significantly reduced by vitamin E (-40% and -44%, respectively; p<0.05). Al increased 4 times the hepatic apoptotic index, and this effect was fully counteracted by vitamin E. Bile flow was decreased in Altreated rats (-37%) and restored to normality by vitamin E. The antioxidant normalized the hepatic handling of the Mrp2 substrates, rose bengal, and dinitrophenyl-S-glutathione, which was causally associated with restoration of Mrp2 expression. Our data indicate that oxidative stress has a crucial role in cholestasis, apoptotic/necrotic hepatocellular damage, and the impairment in liver transport function induced by Al and that vitamin E counteracts these harmful effects not only by preventing free-radical formation but also by favoring Al disposal.

  13. Exogenous administration of thiosulfate, a donor of hydrogen sulfide, attenuates angiotensin II-induced hypertensive heart disease in rats

    PubMed Central

    Snijder, P M; Frenay, A R; de Boer, R A; Pasch, A; Hillebrands, J L; Leuvenink, H G D; van Goor, H

    2015-01-01

    Background and Purpose Hypertension is an important mediator of cardiac damage and remodelling. Hydrogen sulfide (H2S) is an endogenously produced gasotransmitter with cardioprotective properties. However, it is not yet in clinical use. We, therefore, investigated the protective effects of sodium thiosulfate (STS), a clinically applicable H2S donor substance, in angiotensin II (Ang II)-induced hypertensive cardiac disease in rats. Experimental Approach Male Sprague Dawley rats were infused with Ang II (435 ng kg min−1) or saline (control) for 3 weeks via s.c. placed osmotic minipumps. During these 3 weeks, rats received i.p. injections of either STS, NaHS or vehicle (0.9% NaCl). Key Results Compared with controls, Ang II infusion caused an increase in systolic and diastolic BP with associated cardiac damage as evidenced by cardiac hypertrophy, an increase in atrial natriuretic peptide (ANP) mRNA, cardiac fibrosis and increased oxidative stress. Treatment with NaHS and STS prevented the development of hypertension and the increase in ANP mRNA levels. Furthermore, the degree of cardiac hypertrophy, the extent of histological fibrosis in combination with the expression of profibrotic genes and the levels of oxidative stress were all significantly decreased. Conclusions and Implications Ang II-induced hypertensive cardiac disease can be attenuated by treatment with STS and NaHS. Although BP regulation is the most plausible mechanism of cardiac protection, the antifibrotic and antioxidant properties of released sulfide may also contribute to their effects. Our data show that H2S might be a valuable addition to the already existing antihypertensive and cardioprotective therapies. Linked Articles This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-6 PMID:24962324

  14. Enhancement of hippocampal long-term potentiation induced by cocaine self-administration is maintained during the extinction of this behavior.

    PubMed

    del Olmo, Nuria; Miguéns, Miguel; Higuera-Matas, Alejandro; Torres, Isabel; García-Lecumberri, Carmen; Solís, José María; Ambrosio, Emilio

    2006-10-20

    Drug addiction may involve learning and memory processes requiring the participation of hippocampal formation. One of the best studied examples of hippocampal synaptic plasticity is the long-term potentiation (LTP) which usually occurs when hippocampal synapses are stimulated with high-frequency stimulation. The aim of this work has been to study the effect of extinction of cocaine self-administration behavior on synaptic plasticity in rat hippocampal slices. LTP was induced using a tetanization paradigm consisting of a single train of high-frequency (100 Hz) stimulation for one second. This tetanization protocol evoked a greater and more perdurable LTP in slices obtained after 10 days of extinction of cocaine self-administration (1 mg/kg/injection) than that elicited in slices from saline self-administering (0.9% NaCl) animals. In addition, this LTP facilitation in animals which have followed the cocaine self-administration extinction protocol was very similar to that obtained in slices from cocaine self-administering animals. These results suggest that chronic cocaine self-administration induces enduring neuroadaptive changes in hippocampal synaptic plasticity which last even after the extinction of this behavior and that they may be involved in cocaine dependence.

  15. Sub-chronic Administration of Methanolic Whole Fruit Extract of Lagenaria breviflora (Benth.) Roberty Induces Mild Toxicity in Rats

    PubMed Central

    Olorunnisola, Olubukola Sinbad; Afolayan, Anthony Jide; Adetutu, Adewale

    2015-01-01

    Background: The effect of the methanolic whole fruit extract from Lagenaria breviflora on vital organs and antioxidant enzymes was investigated in this study. Materials and Methods: L. breviflora (250, 500 and 1000 mg/kg/b.w.t./day/rat) was fed orally with the cannula to male albino rats for 28 days. At the end of the treatment, the rats were sacrificed and the effect of the extract on histology of the liver, heart, lipid peroxidation, tissue and serum antioxidant enzymes (superoxide dismutase, catalase, glutathione-s-transferase, glutathione peroxidase) activities, glutathione, myocardial marker enzymes (creatine kinase [CK], lactate dehydrogenase [LDH], alanine transaminase [ALT], and aspartate transaminase [AST]) in serum, and heart homogenate were assessed. Results: The extract demonstrated mild organ doses dependent (500 and 1000 mg/kg) pathological alterations in the architectural section of the liver and heart. At 250 mg/kg/b.w.t., the extract caused a significant (P < 0.05) increase in the level of thiobarbituric reacting acids substance and antioxidant enzyme activities, but causes (P < 0.05) decrease in serum and tissue antioxidant capacity at 500 and 1000 mg/kg/b.w.t., respectively. Also on these two doses, a significant (P < 0.05) increase in serum activity of CK, LDH, ALT, and AST and concomitantly decrease (P < 0.05) in heart homogenate were also observed. Conclusion: The results suggested that the Fruit of L. breviflora may contain phytotoxic Substances(s) which may be hepatotoxic, cardiotoxic or able to induce oxidative stress at high concentration. Hence, the consumption of the plant should be taken with caution. SUMMARY Methanolic whole fruit extract from Lagenaria breviflora demonstrate dose dependent mild toxicity on vital organs (Heart and liver) and anti-oxidant enzymes. The fruit of Lagenaria breviflora may contain Phyto-toxic substance (s) which may be hepatotoxic, Cardio-toxic or able to induce oxidative stress at high concentration. Hence

  16. Co-administration of α-lipoic acid and cyclosporine aggravates colon ulceration of acetic acid-induced ulcerative colitis via facilitation of NO/COX-2/miR-210 cascade.

    PubMed

    El-Gowelli, Hanan M; Saad, Evan I; Abdel-Galil, Abdel-Galil A; Ibrahim, Einas R

    2015-11-01

    In this work, α-lipoic acid and cyclosporine demonstrated significant protection against acetic acid-induced ulcerative colitis in rats. We proposed that α-lipoic acid and cyclosporine co-administration might modulate their individual effects. Induction of ulcerative colitis in rats was performed by intra-rectal acetic acid (5% v/v) administration for 3 consecutive days. Effects of individual or combined used of α-lipoic acid (35 mg/kg ip) or cyclosporine (5mg/kg sc) for 6 days starting 2 days prior to acetic acid were assessed. Acetic acid caused colon ulceration, bloody diarrhea and weight loss. Histologically, there was mucosal atrophy and inflammatory cells infiltration in submucosa, associated with depletion of colon reduced glutathione, superoxide dismutase and catalase activities and elevated colon malondialdehyde, serum C-reactive protein (C-RP) and tumor necrosis factor-α (TNF-α). Colon gene expression of cyclooxygenase-2 and miR-210 was also elevated. These devastating effects of acetic acid were abolished upon concurrent administration of α-lipoic acid. Alternatively, cyclosporine caused partial protection against acetic acid-induced ulcerative colitis. Cyclosporine did not restore colon reduced glutathione, catalase activity, serum C-RP or TNF-α. Unexpectedly, co-administration of α-lipoic acid and cyclosporine aggravated colon ulceration. Concomitant use of α-lipoic acid and cyclosporine significantly increased nitric oxide production, cyclooxygenase-2 and miR-210 gene expression compared to all other studied groups. The current findings suggest that facilitation of nitric oxide/cyclooxygenase-2/miR-210 cascade constitutes, at least partially, the cellular mechanism by which concurrent use of α-lipoic acid and cyclosporine aggravates colon damage. Collectively, the present work highlights the probable risk of using α-lipoic acid/cyclosporine combination in ulcerative colitis patients.

  17. Clinical significance of exercise-induced ST segment elevation. Correlative angiographic study in patients with ischaemic heart disease.

    PubMed Central

    de Feyter, P J; Majid, P A; van Eenige, M J; Wardeh, R; Wempe, F N; Roos, J P

    1981-01-01

    We have examined the relation between electrocardiographic ST elevation during treadmill exercise (greater than or equal to 1 mm, using the conventional 12 leads), the severity of coronary artery disease, and left ventricular wall motion abnormalities in 680 patients. They were divided into three groups: (1) 218 patients with clinically significant coronary artery disease, (2) 178 patients with clinically significant coronary artery disease, and (3) 284 patients with clinically significant coronary artery disease and previous myocardial infarction. ST elevation during exercise (predominantly in lead V2) was seen in two patients (1%) in group 1, three patients (2%) in group 2, and 147 patients (52%) in group 3. Coronary artery disease (number of vessels involved and severity of stenoses) was comparable in groups 2 and 3. All the patients in group 1 showed a normal left ventricular contraction pattern; 64% of the patients in group 2 showed wall motion abnormalities (predominantly hypokinesia) and 95% of group 3 (mainly akinesia, dyskinesia, or aneurysm). A strongly positive correlation was seen between the ST elevation and left ventricular dysfunction in patients belonging to group 3. The overall sensitivity and the specificity of the stress test in detecting wall motion abnormalities was 55% and 100% respectively. The sensitivity increased with deterioration in left ventricular function, reaching 81% and 90% in patients with dyskinesia and aneurysm, respectively. Maximal ST elevation (greater than or equal to 3 mm) was confined to the patients with dyskinesia or aneurysm. The incidence of ST elevation during exercise was also related to the location of previous infarction, showing a positive response in 85% of patients with anterior myocardial infarction and in only 33% with inferior myocardial infarction. We conclude that ST segment elevation during exercise in patients with previous myocardial infarction is a sensitive and a specific indicator of advanced left

  18. Chronic administration of Liu Wei Dihuang protects rat's brain against D-galactose-induced impairment of cholinergic system.

    PubMed

    Zhang, Wei-Wei; Sun, Qi-Xin; Liu, Yin-Hui; Gao, Wei; Li, Yan-Hai; Lu, Kun; Wang, Zhuo

    2011-06-25

    This study was aimed to investigate the protective effect of Liu Wei Dihuang (LWDH) against D-galactose (D-gal)-induced brain injury in rats and the existence of sex-dependent differences in LWDH protection. Sixty-four rats evenly composed of males and females were randomly assigned into 4 groups (n = 8): normal saline (NS) + NS (N + N), NS + LWDH (N + L), D-gal + NS (D + N) and D-gal + LWDH (D + L) groups. Rats in D + N and D + L groups received daily injection of D-gal (100 mg/kg, s.c.) for six weeks to establish the aging model, while rats in N + N and N + L groups were injected with the same volume of NS. From the third week, rats in N + L and D + L groups were orally administered with a decoction of LWDH for subsequent six weeks. Rats in N + N and D + N groups were orally administered just with the same volume of NS simultaneously. Morris water maze test was employed to evaluate the ability of learning and memory of the rats in all the groups. Acetylcholine (ACh) content, activities of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) in visual cortex were assayed. Hematoxylin and eosin (HE) staining were used to observe the morphologic injury in hippocampus and visual cortex, and immunohistochemistry was performed to evaluate ChAT and AChE expression levels in the visual cortex. The results showed that the rats in D + N groups exhibited a longer escape latency to platform, lower swimming speed, less percent of target quadrant search time and platform crossings, compared with N + N groups, suggesting the establishment of aging model, while LWDH improved these indexes in D-gal-treated rats. Compared with D + N groups, LWDH increased ACh content and ChAT activity, and decreased AChE activity in visual cortex. Remarkable loss of neurons was found in hippocampus and visual cortex of aging rats, and the injury was significantly attenuated by LWDH. Immunohistochemistry showed D-gal-induced decreases of ChAT and AChE expressions were restored by LWDH

  19. The chronic administration of cerebrolysin induces plastic changes in the prefrontal cortex and dentate gyrus in aged mice.

    PubMed

    Juárez, Ismael; González, Deniss Janeth; Mena, Raúl; Flores, Gonzalo

    2011-11-01

    Cerebrolysin (Cbl) is a mixture of neuropeptides with effects similar to the endogenous neurotrophic factors and is considered one of the best drugs used in the treatment of dementias such as Alzheimer's disease (AD). In brains with AD, morphological changes in the dendrites of pyramidal neurons of the prefrontal cortex (PFC) and hippocampus have been reported. These changes are reflected particularly in the decrement of both the dendritic tree and spine density. Here we evaluated the effect of this drug on the dendrites of pyramidal neurons of the PFC and CA1 dorsal hippocampus and granule cells from the dentate gyrus (DG) and medium spiny neurons of the nucleus accumbens (NAcc) of aged mice. Cbl (5 ml kg(-1) , i.p.) was administered daily for 60 days to 6-month-old mice. Dendritic morphology was studied by the Golgi-Cox stain procedure followed by Sholl analysis at 8 months ages. In all Cbl-treated mice a significant increase in dendritic spine density and dendritic length in pyramidal neurons of the PFC and granule cells of the DG was observed. Interestingly, the enhancement in dendritic length was close to the soma in pyramidal neurons of the PFC whereas in granule neurons of the DG the increase in dendritic length was further from the soma. Our results suggest that Cbl induces plastic modifications of dendritic morphology in the PFC and DG. These changes may explain the therapeutic effect seen in AD patients treated with Cbl.

  20. The significance of T cells, B cells, antibodies and macrophages against encephalomyocarditis (EMC)-D virus-induced diabetes in mice.

    PubMed

    Kounoue, Etsushi; Izumi, Ken-ichi; Ogawa, Shuichiro; Kondo, Shiori; Katsuta, Hitoshi; Akashi, Tomoyuki; Niho, Yoshiyuki; Harada, Mine; Tamiya, Sadafumi; Kurisaki, Hironori; Nagafuchi, Seiho

    2008-01-01

    In order to clarify the significance of protective mechanisms against encephalomyocarditis (EMC) virus-induced diabetes in mice, we studied the relative importance of T cells, B cells, antibodies and macrophages in the prevention of virus-induced diabetes. Neither T cell-deficient athymic nude mice nor B cell-deficient microMT/microMT mice showed an enhanced clinical course of EMC-D virus-induced diabetes, indicating that neither T cells nor B cells played a major role in the protection against EMC-D-virus-induced diabetes. Transfer of a large amount of antiserum to EMC-D-virus-infected mice protected the development of diabetes only when transferred within 36 h of infection, the timing of which was earlier than that for the production of natural neutralizing antibodied. Since pretreatment of mice with the macrophage-activating immunopotentiator Corynebacterium parvum (CP) completely prevented the development of diabetes, we studied the clinical outcome of EMC-D-virus-infected mice pretreated with CP. Mice treated with CP showed reduced proliferation of EMC-D virus in the affected organs, including the pancreas, while the levels of development of neutralizing antibody and serum interferon were not enhanced compared with the controls. Finally, we studied the macrophages derived from mice pretreated with CP and found that they inhibited the growth of EMC-D virus in vitro more than those derived from non-treated and thioglycolate-treated mice. Taken together, it can be suggested that neither T cells nor B cells, which have to do with adaptive immunity, play a significant role in the pathogenesis of EMC-D-virus-induced diabetes, while innate immunity, which is dependent on activated macrophages, contributes to in vivo resistance against EMC-D-virus-induced diabetes. PMID:18500429

  1. The significance of the pre-challenge immune status of mice for development of retrovirus-induced immunodeficiency syndrome (MAIDS).

    PubMed Central

    Pavlovitch, J H; Rizk-Rabin, M; Picard, F; Marussig, M; Halbreich, A

    1994-01-01

    The effects of vaccination with RNA-free viral pseudoparticles, preinfection with non-pathogenic ecotropic virus, and induction of tolerance to viral proteins in newborns on the outcome of murine immunodeficiency syndrome (MAIDS) were studied. The parameters used to follow disease progression were: lymphopenia, circulating B and T8 cells, serum IgG and IgM levels, lymphoproliferation and skin graft rejection. Immunization with RNA-free viral pseudoparticles had no effect on any of these parameters. Preinfection of adults with ecotropic virus and the induction of tolerance in newborns to virus antigens both attenuated the early symptoms of viral infection and delayed the onset of immunodeficiency and lymphoproliferation in some mice, but did not significantly alter the number of deaths due to MAIDS. Failure of immune-based therapy to produce successful protection against MAIDS suggests that immune destruction caused by the persistent virus rather than hyperimmune activity is the main pathogenic factor in this disease. Images Fig. 1 PMID:8149668

  2. Significantly elevated dielectric permittivity of Si-based semiconductor/polymer 2-2 composites induced by high polarity polymers

    NASA Astrophysics Data System (ADS)

    Feng, Yefeng; Gong, Honghong; Xie, Yunchuan; Wei, Xiaoyong; Zhang, Zhicheng

    2016-02-01

    To disclose the essential influence of polymer polarity on dielectric properties of polymer composites filled with semiconductive fillers, a series of Si-based semiconductor/polymer 2-2 composites in a series model was fabricated. The dielectric permittivity of composites is highly dependant on the polarity of polymer layers as well as the electron mobility in Si-based semiconductive sheets. The huge dielectric permittivity achieved in Si-based semiconductive sheets after being coated with high polarity polymer layers is inferred to originate from the strong induction of high polarity polymers. The increased mobility of the electrons in Si-based semiconductive sheets coated by high polarity polymer layers should be responsible for the significantly enhanced dielectric properties of composites. This could be facilely achieved by either increasing the polarity of polymer layers or reducing the percolative electric field of Si-based semiconductive sheets. The most promising 2-2 dielectric composite was found to be made of α-SiC with strong electron mobility and poly(vinyl alcohol) (PVA) with high polarity, and its highest permittivity was obtained as 372 at 100 Hz although the permittivity of α-SiC and PVA is 3-5 and 15, respectively. This work may help in the fabrication of high dielectric constant (high-k) composites by tailoring the induction effect of high polarity polymers to semiconductors.

  3. Higher and longer stress-induced increase in dopamine concentrations in the nucleus accumbens of animals predisposed to amphetamine self-administration. A microdialysis study.

    PubMed

    Rougé-Pont, F; Piazza, P V; Kharouby, M; Le Moal, M; Simon, H

    1993-01-29

    Individual vulnerability to the reinforcing effects of drugs appears to be a crucial factor in the development of addiction in humans. In the rat, individuals at risk for psychostimulant self-administration (SA) may be identified from their locomotor reactivity to a stress situation such as exposure to a novel environment. Animals with high locomotor responses to novelty (high responders, HR) acquire amphetamine SA, while animals with low responses (low responders, LR) do not. In this study we examined by microdialysis whether stress-induced extracellular dopamine (DA) concentrations in the nucleus accumbens differed between these two groups of animals. This neurotransmitter was studied because it is thought to be involved in the reinforcing effects of psychostimulants. Furthermore, previous studies have shown that HR animals have a higher basal DOPAC/DA ratio in the nucleus accumbens and higher extracellular concentrations of dopamine in this structure in response to cocaine. The stress procedure used in this experiment consisted of a 10 min tail-pinch. HR animals displayed a higher and longer stress-induced changes in DA concentrations than the LR group. Regression analysis showed that stress-induced changes in DA levels accounted for 75% of the variance observed in the locomotor response to a novel environment. Since higher DA activity in the nucleus accumbens has been reported in animals in which the propensity to psychostimulant SA is induced by brain lesions or life events, this biochemical modification may be one neurobiological substrate of the predisposition to acquire psychostimulant self-administration. PMID:8448654

  4. Study of the Effect of Route of Administration of Mesenchymal Stem Cells on Cisplatin-Induced Acute Kidney Injury in Sprague Dawley Rats

    PubMed Central

    Moustafa, Fatma E; Sobh, Mohamed-A; Abouelkheir, Mohamed; Khater, Youmna; Mahmoud, Khalid; Saad, Mohamed-Ahdy; Sobh, Mohamed A

    2016-01-01

    Background and Objectives Mesenchymal stem cells (MSCs) have been shown to ameliorate cisplatin-induced acute kidney injury (AKI). The present study compares the efficacy of different routes of MSCs administration on kidney damage and regeneration after cisplatin-induced AKI. Methods A single intraperitoneal injection of cisplatin (5 mg/kg) was used to induce AKI in 160 rats. MSCs (5×106) were given by either intravenous, intra-arterial or kidney sub capsular injection one day after cisplatin injection. Suitable control groups were included. Rats were sacrificed at 4, 7, 11 and 30 days after cisplatin injection. Kidney function parameters, kidney tissue oxidative stress markers, and scoring for renal tissue injury, regeneration and chronicity were all determined. Results MSCs by any routes were able to ameliorate kidney function deterioration and renal tissue damage induced by cisplatin. The overall results of the three routes were equal. Differences between the different routes in one parameter were transient and inconsistent with other parameters. Conclusions Changing the route of MSCs injection does not have a major influence on the outcome. Future evaluation should focus on differences between the routes of administration considering the long term safety. PMID:27426089

  5. Does virus-induced lysis contribute significantly to bacterial mortality in the oxygenated sediment layer of shallow oxbow lakes?

    PubMed

    Fischer, Ulrike R; Wieltschnig, Claudia; Kirschner, Alexander K T; Velimirov, Branko

    2003-09-01

    Despite the recognition that viruses are ubiquitous components of aquatic ecosystems, the number of studies on viral abundance and the ecological role of viruses in sediments is scarce. In this investigation, the interactions between viruses and bacteria were studied in the oxygenated silty sediment layer of a mesotrophic oxbow lake. A long-term study (13 months) and a diel study revealed that viruses are a numerically important and dynamic component of the microbial community. The abundance and decay rates ranged from 4.3 x 10(9) to 7.2 x 10(9) particles ml of wet sediment(-1) and from undetectable to 22.2 x 10(7) particles ml(-1) h(-1), respectively, and on average the values were 2 orders of magnitude higher than the values for the overlying water. In contrast to our expectations, viruses did not contribute significantly to the bacterial mortality in the sediment, since on average only 6% (range, 0 to 25%) of the bacterial secondary production was controlled by viruses. The low impact of viruses on the bacterial community may be associated with the quantitatively low viral burden that benthic bacteria have to cope with compared to the viral burden with which bacterial assemblages in the water column are confronted. The virus-to-bacterium ratio of the sediment varied between 0.9 and 3.2, compared to a range of 5.0 to 12.4 obtained for the water column. We speculate that despite high numbers of potential hosts, the possibility of encountering a host cell is limited by the physical conditions in the sediment, which is therefore not a favorable environment for viral proliferation. Our data suggest that viruses do not play an important role in the processing and transfer of bacterial carbon in the oxygenated sediment layer of the environment investigated. PMID:12957915

  6. Repeated methylphenidate administration during lactation reduces maternal behavior, induces maternal tolerance, and increases anxiety-like behavior in pups in adulthood.

    PubMed

    Ponchio, R A; Teodorov, E; Kirsten, T B; Coelho, C P; Oshiro, A; Florio, J C; Bernardi, M M

    2015-01-01

    Methylphenidate (MPD) is a dopamine uptake inhibitor and the most commonly prescribed drug for the treatment of attention-deficit/hyperactivity disorder in children. Several studies have shown that such stimulants as cocaine and amphetamine that are administered during gestation and lactation may disrupt maternal behavior. Also, MPD is used in lactation. Repeated MPD administration can induce either sensitization or tolerance. The aim of the present study was to investigate whether repeated MPD administration alters maternal behavior and promotes tolerance or sensitization in these females. The effects in adult offspring were also examined in models of anxiety. Methylphenidate (5mg/kg) was administered from lactation day 2 to 4, and maternal pup retrieval behavior was assessed. This treatment was continued until lactation day 7. At weaning, the dams received a challenge dose of MPD, and general activity was evaluated in the open field. Striatal monoamine and metabolite levels were also measured to determine whether this treatment promotes behavioral or biochemical plasticity. The long-term behavioral effects of MPD exposure were evaluated in pups in adulthood. The results showed an increase in the latency to retrieve the first, second, and third pups and a decrease in the number of dams that retrieved all pups. After a challenge dose of MPD, the dams exhibited a decrease in locomotion frequency, an increase in immobility duration in the open field, and a decrease in striatal serotonin levels. In pups, anxiety-like behavior increased in the light/dark box test. These results indicate that repeated MPD administration during early lactation impairs maternal behavior, likely by decreasing maternal motivation. Repeated MPD administration induced maternal tolerance at weaning after a challenge dose of MPD, suggesting the development of central nervous system plasticity. In pups, maternal exposure to MPD during early lactation induced long-term effects and increased

  7. Repeated methylphenidate administration during lactation reduces maternal behavior, induces maternal tolerance, and increases anxiety-like behavior in pups in adulthood.

    PubMed

    Ponchio, R A; Teodorov, E; Kirsten, T B; Coelho, C P; Oshiro, A; Florio, J C; Bernardi, M M

    2015-01-01

    Methylphenidate (MPD) is a dopamine uptake inhibitor and the most commonly prescribed drug for the treatment of attention-deficit/hyperactivity disorder in children. Several studies have shown that such stimulants as cocaine and amphetamine that are administered during gestation and lactation may disrupt maternal behavior. Also, MPD is used in lactation. Repeated MPD administration can induce either sensitization or tolerance. The aim of the present study was to investigate whether repeated MPD administration alters maternal behavior and promotes tolerance or sensitization in these females. The effects in adult offspring were also examined in models of anxiety. Methylphenidate (5mg/kg) was administered from lactation day 2 to 4, and maternal pup retrieval behavior was assessed. This treatment was continued until lactation day 7. At weaning, the dams received a challenge dose of MPD, and general activity was evaluated in the open field. Striatal monoamine and metabolite levels were also measured to determine whether this treatment promotes behavioral or biochemical plasticity. The long-term behavioral effects of MPD exposure were evaluated in pups in adulthood. The results showed an increase in the latency to retrieve the first, second, and third pups and a decrease in the number of dams that retrieved all pups. After a challenge dose of MPD, the dams exhibited a decrease in locomotion frequency, an increase in immobility duration in the open field, and a decrease in striatal serotonin levels. In pups, anxiety-like behavior increased in the light/dark box test. These results indicate that repeated MPD administration during early lactation impairs maternal behavior, likely by decreasing maternal motivation. Repeated MPD administration induced maternal tolerance at weaning after a challenge dose of MPD, suggesting the development of central nervous system plasticity. In pups, maternal exposure to MPD during early lactation induced long-term effects and increased

  8. Subchronic administration of atomoxetine causes an enduring reduction in context-induced relapse to cocaine seeking without affecting impulsive decision making.

    PubMed

    Broos, Nienke; Loonstra, Rhianne; van Mourik, Yvar; Schetters, Dustin; Schoffelmeer, Anton N M; Pattij, Tommy; De Vries, Taco J

    2015-07-01

    Previous work has established a robust relationship between impulsivity and addiction, and revealed that impulsive decision making predisposes the vulnerability to cocaine-seeking behavior in rats. An important next step is to assess whether elevated relapse vulnerability can be treated via the reduction of impulsive decision making. Therefore, this study explored whether subchronic atomoxetine treatment can reduce relapse vulnerability by reducing impulsive decision making. Rats were trained in the delayed reward task and were subjected to 3 weeks of cocaine self-administration. Following drug self-administration, animals were divided to different experimental groups and received the noradrenaline transporter inhibitor and attention-deficit/hyperactivity disorder drug atomoxetine or vehicle subchronically for 20 days. On days 1 and 10 after treatment cessation, a context-induced reinstatement test was performed. Throughout the entire experiment, changes in impulsive decision making were continuously monitored. Subchronic treatment with atomoxetine reduced context-induced reinstatement both 1 and 10 days after treatment cessation, only in animals receiving no extinction training. Interestingly, neither subchronic nor acute atomoxetine treatments affected impulsive decision making. Our data indicate that the enduring reduction in relapse sensitivity by atomoxetine occurred independent of a reduction in impulsive decision making. Nonetheless, repeated atomoxetine administration seems a promising pharmacotherapeutical strategy to prevent relapse to cocaine seeking in abstinent drug-dependent subjects.

  9. Subchronic administration of atomoxetine causes an enduring reduction in context-induced relapse to cocaine seeking without affecting impulsive decision making.

    PubMed

    Broos, Nienke; Loonstra, Rhianne; van Mourik, Yvar; Schetters, Dustin; Schoffelmeer, Anton N M; Pattij, Tommy; De Vries, Taco J

    2015-07-01

    Previous work has established a robust relationship between impulsivity and addiction, and revealed that impulsive decision making predisposes the vulnerability to cocaine-seeking behavior in rats. An important next step is to assess whether elevated relapse vulnerability can be treated via the reduction of impulsive decision making. Therefore, this study explored whether subchronic atomoxetine treatment can reduce relapse vulnerability by reducing impulsive decision making. Rats were trained in the delayed reward task and were subjected to 3 weeks of cocaine self-administration. Following drug self-administration, animals were divided to different experimental groups and received the noradrenaline transporter inhibitor and attention-deficit/hyperactivity disorder drug atomoxetine or vehicle subchronically for 20 days. On days 1 and 10 after treatment cessation, a context-induced reinstatement test was performed. Throughout the entire experiment, changes in impulsive decision making were continuously monitored. Subchronic treatment with atomoxetine reduced context-induced reinstatement both 1 and 10 days after treatment cessation, only in animals receiving no extinction training. Interestingly, neither subchronic nor acute atomoxetine treatments affected impulsive decision making. Our data indicate that the enduring reduction in relapse sensitivity by atomoxetine occurred independent of a reduction in impulsive decision making. Nonetheless, repeated atomoxetine administration seems a promising pharmacotherapeutical strategy to prevent relapse to cocaine seeking in abstinent drug-dependent subjects. PMID:25056833

  10. Differential Antagonism of Cocaine Self-Administration and Cocaine-Induced Disruptions of Learning by Haloperidol in Rhesus Monkeys

    ERIC Educational Resources Information Center

    Winsauer, Peter J.; Moerschbaecher, Joseph M.; Roussell, Alison M.

    2008-01-01

    Six rhesus monkeys responding under a three-component multiple schedule were administered haloperidol to determine its effects on cocaine self-administration and on cocaine's disruptive effects on the repeated acquisition and performance of response chains. In the absence of haloperidol, 0.0032 - 0.032 mg/kg/infusion of cocaine increased response…

  11. High Fat Diet-Induced Skeletal Muscle Wasting Is Decreased by Mesenchymal Stem Cells Administration: Implications on Oxidative Stress, Ubiquitin Proteasome Pathway Activation, and Myonuclear Apoptosis.

    PubMed

    Abrigo, Johanna; Rivera, Juan Carlos; Aravena, Javier; Cabrera, Daniel; Simon, Felipe; Ezquer, Fernando; Ezquer, Marcelo; Cabello-Verrugio, Claudio

    2016-01-01

    Obesity can lead to skeletal muscle atrophy, a pathological condition characterized by the loss of strength and muscle mass. A feature of muscle atrophy is a decrease of myofibrillar proteins as a result of ubiquitin proteasome pathway overactivation, as evidenced by increased expression of the muscle-specific ubiquitin ligases atrogin-1 and MuRF-1. Additionally, other mechanisms are related to muscle wasting, including oxidative stress, myonuclear apoptosis, and autophagy. Stem cells are an emerging therapy in the treatment of chronic diseases such as high fat diet-induced obesity. Mesenchymal stem cells (MSCs) are a population of self-renewable and undifferentiated cells present in the bone marrow and other mesenchymal tissues of adult individuals. The present study is the first to analyze the effects of systemic MSC administration on high fat diet-induced skeletal muscle atrophy in the tibialis anterior of mice. Treatment with MSCs reduced losses of muscle strength and mass, decreases of fiber diameter and myosin heavy chain protein levels, and fiber type transitions. Underlying these antiatrophic effects, MSC administration also decreased ubiquitin proteasome pathway activation, oxidative stress, and myonuclear apoptosis. These results are the first to indicate that systemically administered MSCs could prevent muscle wasting associated with high fat diet-induced obesity and diabetes. PMID:27579157

  12. High Fat Diet-Induced Skeletal Muscle Wasting Is Decreased by Mesenchymal Stem Cells Administration: Implications on Oxidative Stress, Ubiquitin Proteasome Pathway Activation, and Myonuclear Apoptosis.

    PubMed

    Abrigo, Johanna; Rivera, Juan Carlos; Aravena, Javier; Cabrera, Daniel; Simon, Felipe; Ezquer, Fernando; Ezquer, Marcelo; Cabello-Verrugio, Claudio

    2016-01-01

    Obesity can lead to skeletal muscle atrophy, a pathological condition characterized by the loss of strength and muscle mass. A feature of muscle atrophy is a decrease of myofibrillar proteins as a result of ubiquitin proteasome pathway overactivation, as evidenced by increased expression of the muscle-specific ubiquitin ligases atrogin-1 and MuRF-1. Additionally, other mechanisms are related to muscle wasting, including oxidative stress, myonuclear apoptosis, and autophagy. Stem cells are an emerging therapy in the treatment of chronic diseases such as high fat diet-induced obesity. Mesenchymal stem cells (MSCs) are a population of self-renewable and undifferentiated cells present in the bone marrow and other mesenchymal tissues of adult individuals. The present study is the first to analyze the effects of systemic MSC administration on high fat diet-induced skeletal muscle atrophy in the tibialis anterior of mice. Treatment with MSCs reduced losses of muscle strength and mass, decreases of fiber diameter and myosin heavy chain protein levels, and fiber type transitions. Underlying these antiatrophic effects, MSC administration also decreased ubiquitin proteasome pathway activation, oxidative stress, and myonuclear apoptosis. These results are the first to indicate that systemically administered MSCs could prevent muscle wasting associated with high fat diet-induced obesity and diabetes.

  13. High Fat Diet-Induced Skeletal Muscle Wasting Is Decreased by Mesenchymal Stem Cells Administration: Implications on Oxidative Stress, Ubiquitin Proteasome Pathway Activation, and Myonuclear Apoptosis

    PubMed Central

    Aravena, Javier; Cabrera, Daniel; Simon, Felipe; Ezquer, Fernando

    2016-01-01

    Obesity can lead to skeletal muscle atrophy, a pathological condition characterized by the loss of strength and muscle mass. A feature of muscle atrophy is a decrease of myofibrillar proteins as a result of ubiquitin proteasome pathway overactivation, as evidenced by increased expression of the muscle-specific ubiquitin ligases atrogin-1 and MuRF-1. Additionally, other mechanisms are related to muscle wasting, including oxidative stress, myonuclear apoptosis, and autophagy. Stem cells are an emerging therapy in the treatment of chronic diseases such as high fat diet-induced obesity. Mesenchymal stem cells (MSCs) are a population of self-renewable and undifferentiated cells present in the bone marrow and other mesenchymal tissues of adult individuals. The present study is the first to analyze the effects of systemic MSC administration on high fat diet-induced skeletal muscle atrophy in the tibialis anterior of mice. Treatment with MSCs reduced losses of muscle strength and mass, decreases of fiber diameter and myosin heavy chain protein levels, and fiber type transitions. Underlying these antiatrophic effects, MSC administration also decreased ubiquitin proteasome pathway activation, oxidative stress, and myonuclear apoptosis. These results are the first to indicate that systemically administered MSCs could prevent muscle wasting associated with high fat diet-induced obesity and diabetes. PMID:27579157

  14. Omega-3 fatty acid ethyl-eicosapentaenoate, but not soybean oil, attenuates memory impairment induced by central IL-1beta administration.

    PubMed

    Song, Cai; Horrobin, David

    2004-06-01

    Proinflammatory cytokine interleukin (IL)-1beta can cause cognitive impairment, activate the hypothalamic-pituitary-adrenal axis and impair monoaminergic neurotransmission in the rat. IL-1beta has also been shown to increase the concentration of the inflammatory mediator prostaglandin E2 (PGE2) in the blood. Omega (n)-3 fatty acids, such as eicosapentaenoic acid (EPA), which are components of fish oil, have been shown to reduce both the proinflammatory cytokines and the synthesis of PGE2. The purpose of this study was to determine whether dietary supplements of EPA would attenuate the inflammation-induced impairment of spatial memory by centrally administered IL-1beta. Rats were fed with a diet of coconut oil (contained a negligible quantity of fatty acids), soybean oil (contained mainly n-6 fatty acids), or a diet of coconut oil enriched with ethyl-EPA (E-EPA). The rats were then injected intracerebroventricularly with IL-1beta or saline. The results of this study demonstrated that the IL-1-induced deficit in spatial memory was correlated with an impairment of central noradrenergic and serotonergic (but not dopaminergic) function and an increase in the serum corticosterone concentration. IL-1beta also caused an increase in the hippocampal PGE2 concentration. These effects of IL-1 were attenuated by the chronic administration of E-EPA. By contrast, rats fed with the soybean oil diet showed no effect on the changes induced by the IL-1 administration.

  15. Interventions delivered in clinical settings are effective in reducing risk of HIV transmission among people living with HIV: results from the Health Resources and Services Administration (HRSA)'s Special Projects of National Significance initiative.

    PubMed

    Myers, Janet J; Shade, Starley B; Rose, Carol Dawson; Koester, Kimberly; Maiorana, Andre; Malitz, Faye E; Bie, Jennifer; Kang-Dufour, Mi-Suk; Morin, Stephen F

    2010-06-01

    To support expanded prevention services for people living with HIV, the US Health Resources and Services Administration (HRSA) sponsored a 5-year initiative to test whether interventions delivered in clinical settings were effective in reducing HIV transmission risk among HIV-infected patients. Across 13 demonstration sites, patients were randomized to one of four conditions. All interventions were associated with reduced unprotected vaginal and/or anal intercourse with persons of HIV-uninfected or unknown status among the 3,556 participating patients. Compared to the standard of care, patients assigned to receive interventions from medical care providers reported a significant decrease in risk after 12 months of participation. Patients receiving prevention services from health educators, social workers or paraprofessional HIV-infected peers reported significant reduction in risk at 6 months, but not at 12 months. While clinics have a choice of effective models for implementing prevention programs for their HIV-infected patients, medical provider-delivered methods are comparatively robust.

  16. Intranasal guanosine administration presents a wide therapeutic time window to reduce brain damage induced by permanent ischemia in rats.

    PubMed

    Ramos, Denise Barbosa; Muller, Gabriel Cardozo; Rocha, Guilherme Botter Maio; Dellavia, Gustavo Hirata; Almeida, Roberto Farina; Pettenuzzo, Leticia Ferreira; Loureiro, Samanta Oliveira; Hansel, Gisele; Horn, Ângelo Cássio Magalhães; Souza, Diogo Onofre; Ganzella, Marcelo

    2016-03-01

    In addition to its intracellular roles, the nucleoside guanosine (GUO) also has extracellular effects that identify it as a putative neuromodulator signaling molecule in the central nervous system. Indeed, GUO can modulate glutamatergic neurotransmission, and it can promote neuroprotective effects in animal models involving glutamate neurotoxicity, which is the case in brain ischemia. In the present study, we aimed to investigate a new in vivo GUO administration route (intranasal, IN) to determine putative improvement of GUO neuroprotective effects against an experimental model of permanent focal cerebral ischemia. Initially, we demonstrated that IN [(3)H] GUO administration reached the brain in a dose-dependent and saturable pattern in as few as 5 min, presenting a higher cerebrospinal GUO level compared with systemic administration. IN GUO treatment started immediately or even 3 h after ischemia onset prevented behavior impairment. The behavior recovery was not correlated to decreased brain infarct volume, but it was correlated to reduced mitochondrial dysfunction in the penumbra area. Therefore, we showed that the IN route is an efficient way to promptly deliver GUO to the CNS and that IN GUO treatment prevented behavioral and brain impairment caused by ischemia in a therapeutically wide time window.

  17. Systemic administration of the apocarotenoid bixin protects skin against solar UV-induced damage through activation of NRF2.

    PubMed

    Tao, Shasha; Park, Sophia L; Rojo de la Vega, Montserrat; Zhang, Donna D; Wondrak, Georg T

    2015-12-01

    Exposure to solar ultraviolet (UV) radiation is a causative factor in skin photodamage and carcinogenesis, and an urgent need exists for improved molecular photoprotective strategies different from (or synergistic with) photon absorption. Recent studies suggest a photoprotective role of cutaneous gene expression orchestrated by the transcription factor NRF2 (nuclear factor-E2-related factor 2). Here we have explored the molecular mechanism underlying carotenoid-based systemic skin photoprotection in SKH-1 mice and provide genetic evidence that photoprotection achieved by the FDA-approved apocarotenoid and food additive bixin depends on NRF2 activation. Bixin activates NRF2 through the critical Cys-151 sensor residue in KEAP1, orchestrating a broad cytoprotective response in cultured human keratinocytes as revealed by antioxidant gene expression array analysis. Following dose optimization studies for cutaneous NRF2 activation by systemic administration of bixin, feasibility of bixin-based suppression of acute cutaneous photodamage from solar UV exposure was investigated in Nrf2(+/+) versus Nrf2(-/-) SKH-1 mice. Systemic administration of bixin suppressed skin photodamage, attenuating epidermal oxidative DNA damage and inflammatory responses in Nrf2(+/+) but not in Nrf2(-/-) mice, confirming the NRF2-dependence of bixin-based cytoprotection. Taken together, these data demonstrate feasibility of achieving NRF2-dependent cutaneous photoprotection by systemic administration of the apocarotenoid bixin, a natural food additive consumed worldwide.

  18. Effect of the anti-oestrogen tamoxifen on the development of renal cortical necrosis induced by oestrone + vasopressin administration in rats.

    PubMed Central

    Kocsis, J.; Karácsony, G.; Karcsú, S.; László, F. A.

    1988-01-01

    Bilateral renal cortical necrosis was observed after vasopressin administration in rats pretreated with oestrone acetate. Histochemical (succinic dehydrogenase, trichrome, periodic acid Schiff) and electronmicroscopic methods were used to examine how the anti-oestrogen, Tamoxifen, influences the development of this renal cortical necrosis. The experiments revealed that in most rats vasopressin did not induce renal tubular necrosis if the anti-oestrogen was administered simultaneously, even during oestrogen pretreatment. The results suggest that oestrogen receptors in the kidney are involved in the induction of renal cortical necrosis by vasopressin. Images Fig. 5 Fig. 5 Fig. 3 Fig. 4 Fig. 1 Fig. 2 PMID:3377960

  19. The Stereotypy-Inducing Effects of N-Substituted Benztropine Analogs Alone and in Combination with Cocaine Do Not Account for Their Blockade of Cocaine Self-Administration

    PubMed Central

    Li, Libin; Hiranita, Takato; Hayashi, Shuichiro; Newman, Amy H.; Katz, Jonathan L.

    2015-01-01

    Rationale Previous studies have demonstrated that several N-substituted 4′,4″-diF-benztropine (BZT) analogs with high dopamine transporter affinity selectively decreased cocaine self-administration without affecting food-maintained behavior in rats. Objectives The present study examined if the decreases in cocaine self-administration are due to competition from excess behavioral activity (hyperlocomotion or stereotypy) induced by the BZT analogs alone or in combination with cocaine. Results Pretreatments with the typical dopamine uptake inhibitor methylphenidate (1.0, 3.2 and 10 mg/kg, i.p.) dose-dependently shifted the cocaine self-administration dose-effect curve (0, 0.032, 0.1, 0.32 1.0 mg/kg/injection) leftward. The shift in the dose-effect curve was obtained at doses of methylphenidate that, when administered alone, also decreased food-maintained behavior and increased locomotor activity and stereotypy. In contrast, the N-substituted BZT analogs, JHW 007 (1.0, 3.2 and 10 mg/kg, i.p.), AHN 1-055 (10 mg/kg), and, AHN 2-005 (10 mg/kg), as previously reported, decreased the maximum for the cocaine self-administration dose-effect curve, and did so at doses that were virtually without effects on food-maintained behavior. Further, the BZT analogs alone had minimal effects on locomotor activity and stereotypies and did not appreciably change the effects of cocaine on these measures when administered in combination with cocaine. Conclusions The present results suggest that the decrease in cocaine self-administration produced by the N-substituted BZT analogs is due to an antagonism of the reinforcing effects of cocaine rather than due to interference from competing behavioral overstimulation, and further supports the development of N-substituted BZT analogs as medications to treat cocaine abuse. PMID:22975727

  20. Conditions supporting repair of potentially lethal damage cause a significant reduction of ultraviolet light-induced division delay in synchronized and plateau-phase Ehrlich ascites tumor cells

    SciTech Connect

    Iliakis, G.; Nusse, M.

    1982-09-01

    Repair of potentially lethal damage (PLD) induced by uv light in synchronized and in plateau-phase cultures of Ehrlich ascites tumor cells was studied by measuring cell survival. In particlar the influence of conditions supporting repair of PLD on growth kinetics was investigated. In synchronized G/sub 1/, S, or G/sub 2/ + M cells as well as in plateau-phase cells, uv light induced, almost exclusively, delay in the next S phase. A significant decrease of this delay was observed when the cells were incubated for 24 hr in balanced salt solution. Repair of PLD after uv irradiation was found to occur in plateau-phase cells and in cells in different phases of the cell cycle provided that after irradiation these were kept under conditions inhibiting cell multiplication (incubation in balanced salt solution or in conditioned medium). The repair time constant t/sub 50/ was significantly higher than those found for X irradiation (5-10 hr compared to 2 hr), and repair was not significantly inhibited by either 20 ..mu..g/ml cycloheximide or 2 mM caffeine in 24 hr.

  1. Intrathecal Administration of Tempol Reduces Chronic Constriction Injury-Induced Neuropathic Pain in Rats by Increasing SOD Activity and Inhibiting NGF Expression.

    PubMed

    Zhao, Baisong; Pan, Yongying; Wang, Zixin; Tan, Yonghong; Song, Xingrong

    2016-08-01

    We investigate the antinociceptive effect of intrathecal and intraperitoneal tempol administration in a rat model of chronic constriction injury (CCI)-induced neuropathic pain and explore the underlying antinociceptive mechanisms of tempol. Rats were randomly assigned to four groups (n = 8 per group): sham group, CCI group, Tem1 group (intrathecal injection of tempol), and Tem2 group (intraperitoneal injection of tempol). Neuropathic pain was induced by CCI of the sciatic nerve. Tempol was intrathecally or intraperitoneally administered daily for 7 days beginning on postoperative day one. The mechanical withdrawal threshold and thermal withdrawal latency were tested on preoperative day 3 and postoperative days 1, 3, 5, 7, 10, 14, and 21. Structural changes were examined by hematoxylin and eosin staining, toluidine blue staining, and electron microscopy. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels were determined using the thiobarbituric acid and nitroblue tetrazolium methods, respectively. Nerve growth factor (NGF) expression levels were determined by immunohistochemistry and Western blot. Intrathecal, but not intraperitoneal, injection of tempol produced a persistent antinociceptive effect. Intraperitoneal injection of tempol did not result in high enough concentration of tempol in the cerebrospinal fluid. Intrathecal, but not intraperitoneal, injection of tempol inhibited CCI-induced structural damage in the spinal cord reduced MDA levels, and increased SOD activities in the spinal cord. Furthermore, intrathecal, but not intraperitoneal, injection of tempol further downregulated the expression of NGF in the spinal cord following CCI, and this effect was blocked by p38MAPK inhibitor. Intrathecal injection of tempol produces antinociceptive effects and reduces CCI-induced structural damage in the spinal cord by increasing SOD activities and downregulating the expression of NGF via the p38MAPK pathway. Intraperitoneal administration of tempol does

  2. Acute administration of a small molecule p75NTR ligand does not prevent hippocampal neuron loss nor development of spontaneous seizures after pilocarpine-induced status epilepticus

    PubMed Central

    Grabenstatter, H.L.; Carlsen, J.; Raol, Y.H.; Yang, T.; Hund, D.; Del Angel, Y. Cruz; White, A.M.; Gonzalez, M.I.; Longo, F.M.; Russek, S.J.; Brooks-Kayal, A.R.

    2014-01-01

    Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are initially expressed in a precursor form (e.g., proBDNF) and cleaved to form mature BDNF (mBDNF). Following pilocarpine-induced status epilepticus (SE), increases in neurotrophins regulate a wide variety of cell signaling pathways including pro-survival and cell-death machinery in a receptor-specific manner. ProBDNF preferentially binds to the p75 neurotrophin receptor (p75NTR), while mBDNF is the major ligand of the tropomyosin related kinase receptor (TrkB). To elucidate a potential role of p75NTR in acute stages of epileptogenesis, rats were injected prior to and at onset of SE with LM11A-31, a small molecule ligand that binds to p75NTR to promote survival signaling and inhibit neuronal cell death. Modulation of early p75NTR signaling and its effects on (1) electrographic SE, (2) SE-induced neurodegeneration, and (3) subsequent spontaneous seizures were examined following LM11A-31 administration. Despite an established neuroprotective effect of LM11A-31 in several animal models of neurodegenerative disorders (e.g., Alzheimer’s disease, traumatic brain injury, and spinal cord injury), high-dose LM11A-31 administration prior to and at onset of SE did not reduce the intensity of electrographic SE, prevent SE-induced neuronal cell injury, nor inhibit the progression of epileptogenesis. Further studies are required to understand the role of p75NTR activation during epileptogenesis and in seizure-induced cell injury in the hippocampus among other potential cellular pathologies contributing to the onset of spontaneous seizures. Additional studies utilizing more prolonged treatment with LM11A-31 are required to reach a definite conclusion on its potential neuroprotective role in epilepsy. PMID:24801281

  3. Social defeat stress-induced sensitization and escalated cocaine self-administration: The role of ERK signaling in the rat ventral tegmental area

    PubMed Central

    Yap, Jasmine J.; Chartoff, Elena H.; Holly, Elizabeth N.; Potter, David N.; Carlezon, William A.; Miczek, Klaus A.

    2015-01-01

    Rationale Intermittent social defeat stress can induce neuroadaptations that promote compulsive drug taking. Within the mesocorticolimbic circuit, repeated cocaine administration activates extracellular signal-regulated kinase (ERK). Objective The present experiments examine whether changes in ERK phosphorylation are necessary for the behavioral and neural adaptations that occur as a consequence of intermittent defeat stress. Materials and methods Rats were exposed to four brief intermittent defeats over the course of 10 days. Ten days after the last defeat, rats were challenged with cocaine (10 mg/kg, i.p.) or saline, and ERK activity was examined in mesocorticolimbic regions. To determine the role of ERK in defeat stress-induced behavioral sensitization, we bilaterally microinjected the MAPK/ERK kinase inhibitor U0126 (1 μg/side) or vehicle (20% DMSO) into the ventral tegmental area (VTA) prior to each of 4 defeats. Ten days following the last defeat, locomotor activity was assessed for the expression of behavioral cross-sensitization to cocaine (10 mg/kg, i.p.). Thereafter, rats self-administered cocaine under fixed and progressive ratio schedules of reinforcement, including a 24-h continuous access “binge” (0.3 mg/kg/infusion). Results We found that repeated defeat stress increased ERK phosphorylation in the VTA. Inhibition of VTA ERK prior to each social defeat attenuated the development of stress-induced sensitization and prevented stress-induced enhancement of cocaine self-administration during a continuous access binge. Conclusions These results suggest that enhanced activation of ERK in the VTA due to brief defeats is critical in the induction of sensitization and escalated cocaine taking. PMID:25373870

  4. Beneficial effect of spironolactone administration on ethynylestradiol-induced cholestasis in the rat: involvement of up-regulation of multidrug resistance-associated protein 2.

    PubMed

    Ruiz, María L; Villanueva, Silvina S M; Luquita, Marcelo G; Ikushiro, Shin-ichi; Mottino, Aldo D; Catania, Viviana A

    2007-11-01

    The effect of spironolactone (SL) administration on 17alpha-ethynylestradiol (EE)-induced cholestasis was studied, with emphasis on expression and activity of Mrps. Adult male Wistar rats were divided into the following groups: EE (5 mg/kg daily for 5 days, s.c.), SL (200 micromol/kg daily for 3 days, i.p.), EE+SL (same doses, SL administered the last 3 days of EE treatment), and controls. SL prevented the decrease in bile salt-independent fraction of bile flow induced by EE, in association with normalization of biliary excretion of glutathione. Western blot studies indicate that EE decreased the expression of multidrug resistance-associated protein 2 (Mrp2) by 41% and increased that of Mrp3 by 200%, whereas SL only affected Mrp2 expression (+60%) with respect to controls. The EE+SL group showed increased levels of Mrp2 and Mrp3 to the same extent as that registered for the individual treatments. Real-time polymerase chain reaction studies indicated that up-regulation of Mrp2 and Mrp3 by SL and EE, respectively, was at the transcriptional level. To estimate Mrp2 and Mrp3 activities, apical and basolateral excretion of acetaminophen glucuronide (APAP-glu), a common substrate for both transporters, was measured in the recirculating isolated perfused liver model. Biliary/perfusate excretion ratio was decreased in EE (-88%) and increased in SL (+36%) with respect to controls. Coadministration of rats with SL partially prevented (-53%) impairment induced by EE in this ratio. In conclusion, SL administration to EE-induced cholestatic rats counteracted the decrease in bile flow and biliary excretion of glutathione and APAP-glu, a model Mrp substrate, findings associated with up-regulation of Mrp2 expression. PMID:17686906

  5. Effect of N-acetylcysteine route of administration on chemoprotection against cisplatin-induced toxicity in rat models

    PubMed Central

    Dickey, D. Thomas; Muldoon, Leslie L.; Doolittle, Nancy D.; Peterson, Darryl R.; Kraemer, Dale F.; Neuwelt, Edward A.

    2009-01-01

    Dosing and route of administration of N-acetylcysteine (NAC) for protection against cisplatin (CDDP) nephrotoxicity was investigated in rats. Two models of toxicity were tested: a single high dose of CDDP (10 mg/kg intraperitoneally (IP)), and multiple low dose treatments (1 mg/kg IP twice a day for 4 days, 10 days rest, then repeated). NAC (50–1,200 mg/kg) was given to the rats by IP, oral (PO), intravenous (IV) and intra-arterial (IA) routes. Renal toxicity was determined by blood urea nitrogen (BUN) and creatinine (CR) levels 3 days after treatment. Blood collected 15 min after NAC was analyzed for total NAC. Both models of CDDP administration produced renal toxicity. In the single dose CDDP model, NAC 400 mg/kg given IP and PO produced no renal protection as measured by BUN (131.8 ± 8.2 and 123.3 ± 8.2, respectively) or CR (2.3 ± 0.38 and 1.77 ± 0.21, respectively). IV NAC reduced nephrotoxicity, (BUN 26.3 ± 6.8, CR 0.47 ± 0.15). NAC 50 mg/kg IA gave better protection than IV. In the repeated-dose CDDP model, nephrotoxicity was blocked by 800 mg/kg NAC given IV but not IP. Blood concentrations of total NAC showed a dose response after IV NAC, but high dose NAC (1,200 mg/kg) by the PO route gave very low levels of NAC. Thus the protective properties of NAC are aVected by the dose and route of administration. PMID:17909806

  6. Effect of repeated oral administration of Bifidobacterium longum BB536 on apomorphine-induced rearing behavior in mice.

    PubMed

    Orikasa, Shuzo; Nabeshima, Kazumi; Iwabuchi, Noriyuki; Xiao, Jin-Zhong

    2016-01-01

    Schizophrenia is a chronic psychiatric illness. Disruption of the dopaminergic system has been suggested to be the pathogenic cause of this disease. The effect of Bifidobacterium longum BB536 (BB536) on schizophrenic behavior was investigated in an animal model. Daily administration of BB536 (10(9) CFU/mouse, p.o. for 2 weeks) was found to reduce rearing behavior augmented by the dopamine receptor agonist apomorphine and to decrease the resting level of plasma corticosterone and the ratio of kynurenine to tryptophan. These results suggest the potential of BB536 for supplemental treatment of the symptoms of schizophrenia.

  7. Effect of repeated oral administration of Bifidobacterium longum BB536 on apomorphine-induced rearing behavior in mice

    PubMed Central

    ORIKASA, Shuzo; NABESHIMA, Kazumi; IWABUCHI, Noriyuki; XIAO, Jin-Zhong

    2016-01-01

    Schizophrenia is a chronic psychiatric illness. Disruption of the dopaminergic system has been suggested to be the pathogenic cause of this disease. The effect of Bifidobacterium longum BB536 (BB536) on schizophrenic behavior was investigated in an animal model. Daily administration of BB536 (109 CFU/mouse, p.o. for 2 weeks) was found to reduce rearing behavior augmented by the dopamine receptor agonist apomorphine and to decrease the resting level of plasma corticosterone and the ratio of kynurenine to tryptophan. These results suggest the potential of BB536 for supplemental treatment of the symptoms of schizophrenia. PMID:27508116

  8. Effects of morning compared with evening bright light administration to ameliorate short-photoperiod induced depression- and anxiety-like behaviors in a diurnal rodent model.

    PubMed

    Krivisky, Katy; Einat, Haim; Kronfeld-Schor, Noga

    2012-10-01

    The lack of appropriate animal models for affective disorders is a major factor hindering better understanding of the underlying pathologies and the development of more efficacious treatments. Because circadian rhythms play an important role in affective disorders, we recently suggested that diurnal rodents can be advantageous as model animals. We found that in diurnal rodents, short photoperiod induces depression- and anxiety-like behaviors, with similarities to human seasonal affective disorder. In a pilot study we also found that these behaviors are ameliorated by morning bright light administration. In the present study we further evaluated the effects of morning and evening bright light administration on short photoperiod-induced depression- and anxiety-like behaviors in diurnal fat sand rats. Animals were maintained under short (5L:19D) or neutral (12L:12D) photoperiod and treated with morning or evening bright light or red dim light as control. Morning bright light ameliorated the behavioral deficits in the elevated plus maze and social interaction tests whereas evening bright light was effective only in the social interaction test. This is the first detailed presentation of the effects of bright light treatment in an animal model and a clear demonstration to the advantages of utilizing diurnal rodents to study interactions between circadian rhythms and affect.

  9. Intravenous administration of equine-derived whole IgG antivenom does not induce early adverse reactions in non-envenomed horses and cows.

    PubMed

    Estrada, Ricardo; Herrera, María; Segura, Alvaro; Araya, Javier; Boschini, Carlos; Gutiérrez, José María; León, Guillermo

    2010-11-01

    Administration of antivenoms to treat snakebite envenomings has the potential risk of inducing early adverse reactions. The mechanisms involved in these reactions are unclear. In this study, polyspecific antivenom consisting of whole IgG purified from equine plasma by caprylic acid precipitation was administered intravenously to non-envenomed horses (n = 47) and cows (n = 20) at a dose of 0.4 mL/kg. It has been reported that, in humans, this formulation (administered at a dose of 0.4 mL/kg) induces mild noticeable early adverse reactions, such as fever, vomiting, diarrhea, urticaria, generalized rash, tachypnea or tachycardia, in about 15-20% of the patients. Unexpectedly, none of the animals receiving antivenom in our study showed any evidence of early adverse reaction. Moreover, no late adverse reactions, i.e. serum sickness, were observed during 40 days after antivenom administration. Unlike studies performed in envenomed humans, our present results were obtained in a group of non-envenomed individuals. It is concluded that, in addition to the physicochemical characteristics of the formulation, other unknown factors must determine the occurrence of adverse reactions in snakebite envenomed humans treated with equine-derived antivenoms.

  10. Effect of the administration of Solanum nigrum fruit on blood glucose, lipid profiles, and sensitivity of the vascular mesenteric bed to phenylephrine in streptozotocin-induced diabetic rats

    PubMed Central

    Sohrabipour, Shahla; Kharazmi, Fatemah; Soltani, Nepton; Kamalinejad, Mohammad

    2013-01-01

    Background Solanum nigrum fruit is traditionally used in Asia to manage, control, and treat diabetes but there is no scientific evidence of the efficacy of Solanum nigrum fruit in treatment of diabetes. We designed this study to investigate the effect of the administration of oral doses of aqueous extract from Solanum nigrum fruit on plasma glucose, lipid profiles, and the sensitivity of the vascular mesenteric bed to Phenylephrine in diabetic and non-diabetic rats. Material/Methods Animals were divided into 5 groups (n=10): 2 groups served as non-diabetic controls (NDC), and the other groups had diabetes induced with a single injection of streptozotocin (STZ). Solanum nigrum-treated chronic diabetic (CD-SNE) and Solanum nigrum-treated controls (ND-SNE) received 1g/l of Solanum nigrum added to drinking water for 8 weeks. The mesenteric vascular beds were prepared using the McGregor method. Results Administration of Solanum nigrum caused Ca/Mg ratio, plasma glucose, high-density lipoprotein (HDL), low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), total cholesterol, and triglyceride concentrations to return to normal levels, and was shown to decrease alteration in vascular reactivity to vasoconstrictor agents. Conclusions Our results support the hypothesis that Solanum nigrum could play a role in the management of diabetes and the prevention of vascular complications in STZ-induced diabetic rats. PMID:23660828

  11. TriCalm® hydrogel is significantly superior to 2% diphenhydramine and 1% hydrocortisone in reducing the peak intensity, duration, and overall magnitude of cowhage-induced itch

    PubMed Central

    Papoiu, Alexandru DP; Chaudhry, Hunza; Hayes, Erin C; Chan, Yiong-Huak; Herbst, Kenneth D

    2015-01-01

    Background Itch is one of the most frequent skin complaints and its treatment is challenging. From a neurophysiological perspective, two distinct peripheral and spinothalamic pathways have been described for itch transmission: a histaminergic pathway and a nonhistaminergic pathway mediated by protease-activated receptors (PAR)2 and 4. The nonhistaminergic itch pathway can be activated exogenously by spicules of cowhage, a tropical plant that releases a cysteine protease named mucunain that binds to and activates PAR2 and PAR4. Purpose This study was conducted to assess the antipruritic effect of a novel over-the-counter (OTC) steroid-free topical hydrogel formulation, TriCalm®, in reducing itch intensity and duration, when itch was induced with cowhage, and compared it with two other commonly used OTC anti-itch drugs. Study participants and methods This double-blinded, vehicle-controlled, randomized, crossover study recorded itch intensity and duration in 48 healthy subjects before and after skin treatment with TriCalm hydrogel, 2% diphenhydramine, 1% hydrocortisone, and hydrogel vehicle, used as a vehicle control. Results TriCalm hydrogel significantly reduced the peak intensity and duration of cowhage-induced itch when compared to the control itch curve, and was significantly superior to the two other OTC antipruritic agents and its own vehicle in antipruritic effect. TriCalm hydrogel was eight times more effective than 1% hydrocortisone and almost six times more effective than 2% diphenhydramine in antipruritic action, as evaluated by the reduction of area under the curve. Conclusion TriCalm hydrogel has a robust antipruritic effect against nonhistaminergic pruritus induced via the PAR2 pathway, and therefore it could represent a promising treatment option for itch. PMID:25941445

  12. The effects of long-term administration of tadalafil on STZ-induced diabetic rats with erectile dysfunction via a local antioxidative mechanism

    PubMed Central

    Chen, Yun; Li, Xiao-Xin; Lin, Hao-Cheng; Qiu, Xue-Feng; Gao, Jing; Dai, Yu-Tian; Wang, Run

    2012-01-01

    Type 5 phosphodiesterase inhibitors (PDE5Is) are well known being effective via the nitric oxide and cyclic guanosine monophosphate (NO–cGMP) pathway and are widely used in the treatment of diabetic erectile dysfunction (ED). However, it is unclear whether other pathways may be involved in the treatment of diabetic ED with PDE5Is. The purpose of this study was to clarify the role of antioxidants in diabetic ED treatment through the long-term administration of PDE5Is. Three groups of Sprague–Dawley rats were utilized: Group N, the normal control; Group D, streptozotocin (STZ)-induced diabetic rats as a control; and Group D+T, STZ-induced diabetic rats who received oral administration of tadalafil for 8 weeks. Erectile function was assessed by intracavernous pressure (ICP) and mean arterial pressure (MAP) during electrical stimulation of the cavernous nerve before euthanasia. The levels of malondialdehyde (MDA), superoxide dismutase (SOD) and mitochondrial membrane potential (MMP) of cavernous tissue were assessed by biochemical analysis. The morphology of mitochondria was observed by electron microscopy. The ICP/MAP ratio was higher in Group D+T than in Group D (P<0.05). The levels of MDA decreased and the activities of SOD increased in Group D+T in comparison with Group D (P<0.05). The mitochondrial membrane potential level of cavernous tissue in diabetic rats was partially recovered by tadalafil treatment for 8 weeks. The morphology changes of mitochondria were also remarkably ameliorated in Group D+T. Collectively, the long-term administration of tadalafil in diabetic rats partially reduced oxidative stress lesions of the penis via a local antioxidative stress pathway. Long-term dosages of tadalafil given once daily beginning soon after the onset of diabetes may aid in preventing rats from developing diabetic ED. PMID:22504870

  13. Chronic administration of recombinant IL-6 upregulates lipogenic enzyme expression and aggravates high-fat-diet-induced steatosis in IL-6-deficient mice.

    PubMed

    Vida, Margarita; Gavito, Ana Luisa; Pavón, Francisco Javier; Bautista, Dolores; Serrano, Antonia; Suarez, Juan; Arrabal, Sergio; Decara, Juan; Romero-Cuevas, Miguel; Rodríguez de Fonseca, Fernando; Baixeras, Elena

    2015-07-01

    Interleukin-6 (IL-6) has emerged as an important mediator of fatty acid metabolism with paradoxical effects in the liver. Administration of IL-6 has been reported to confer protection against steatosis, but plasma and tissue IL-6 concentrations are elevated in chronic liver diseases, including fatty liver diseases associated with obesity and alcoholic ingestion. In this study, we further investigated the role of IL-6 on steatosis induced through a high-fat diet (HFD) in wild-type (WT) and IL-6-deficient (IL-6(-/-)) mice. Additionally, HFD-fed IL-6(-/-) mice were also chronically treated with recombinant IL-6 (rIL-6). Obesity in WT mice fed a HFD associated with elevated serum IL-6 levels, fatty liver, upregulation of carnitine palmitoyltransferase 1 (CPT1) and signal transducer and activator of transcription-3 (STAT3), increased AMP kinase phosphorylation (p-AMPK), and downregulation of the hepatic lipogenic enzymes fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1). The HFD-fed IL-6(-/-) mice showed severe steatosis, no changes in CPT1 levels or AMPK activity, no increase in STAT3 amounts, inactivated STAT3, and marked downregulation of the expression of acetyl-CoA carboxylase (ACCα/β), FAS and SCD1. The IL-6 chronic replacement in HFD-fed IL-6 -/-: mice restored hepatic STAT3 and AMPK activation but also increased the expression of the lipogenic enzymes ACCα/β, FAS and SCD1. Furthermore, rIL-6 administration was associated with aggravated steatosis and elevated fat content in the liver. We conclude that, in the context of HFD-induced obesity, the administration of rIL-6 might contribute to the aggravation of fatty liver disease through increasing lipogenesis.

  14. Chronic administration of recombinant IL-6 upregulates lipogenic enzyme expression and aggravates high-fat-diet-induced steatosis in IL-6-deficient mice

    PubMed Central

    Vida, Margarita; Gavito, Ana Luisa; Pavón, Francisco Javier; Bautista, Dolores; Serrano, Antonia; Suarez, Juan; Arrabal, Sergio; Decara, Juan; Romero-Cuevas, Miguel; Rodríguez de Fonseca, Fernando; Baixeras, Elena

    2015-01-01

    ABSTRACT Interleukin-6 (IL-6) has emerged as an important mediator of fatty acid metabolism with paradoxical effects in the liver. Administration of IL-6 has been reported to confer protection against steatosis, but plasma and tissue IL-6 concentrations are elevated in chronic liver diseases, including fatty liver diseases associated with obesity and alcoholic ingestion. In this study, we further investigated the role of IL-6 on steatosis induced through a high-fat diet (HFD) in wild-type (WT) and IL-6-deficient (IL-6−/−) mice. Additionally, HFD-fed IL-6−/− mice were also chronically treated with recombinant IL-6 (rIL-6). Obesity in WT mice fed a HFD associated with elevated serum IL-6 levels, fatty liver, upregulation of carnitine palmitoyltransferase 1 (CPT1) and signal transducer and activator of transcription-3 (STAT3), increased AMP kinase phosphorylation (p-AMPK), and downregulation of the hepatic lipogenic enzymes fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1). The HFD-fed IL-6−/− mice showed severe steatosis, no changes in CPT1 levels or AMPK activity, no increase in STAT3 amounts, inactivated STAT3, and marked downregulation of the expression of acetyl-CoA carboxylase (ACCα/β), FAS and SCD1. The IL-6 chronic replacement in HFD-fed IL-6−/− mice restored hepatic STAT3 and AMPK activation but also increased the expression of the lipogenic enzymes ACCα/β, FAS and SCD1. Furthermore, rIL-6 administration was associated with aggravated steatosis and elevated fat content in the liver. We conclude that, in the context of HFD-induced obesity, the administration of rIL-6 might contribute to the aggravation of fatty liver disease through increasing lipogenesis. PMID:26035386

  15. Nasal administration of interleukin-33 induces airways angiogenesis and expression of multiple angiogenic factors in a murine asthma surrogate.

    PubMed

    Shan, Shan; Li, Yan; Wang, Jingjing; Lv, Zhe; Yi, Dawei; Huang, Qiong; Corrigan, Chris J; Wang, Wei; Quangeng, Zhang; Ying, Sun

    2016-05-01

    The T-helper cell type 2-promoting cytokine interleukin-33 (IL-33) has been implicated in asthma pathogenesis. Angiogenesis is a feature of airways remodelling in asthma. We hypothesized that IL-33 induces airways angiogenesis and expression of angiogenic factors in an established murine surrogate of asthma. In the present study, BALB/c mice were subjected to serial intranasal challenge with IL-33 alone for up to 70 days. In parallel, ovalbumin (OVA) -sensitized mice were subjected to serial intranasal challenge with OVA or normal saline to serve as positive and negative controls, respectively. Immunohistochemical analysis of expression of von Willebrand factor and erythroblast transformation-specific-related gene, both blood vessel markers, and angiogenic factors angiogenin, insulin-like growth factor-1, endothelin-1, epidermal growth factor and amphiregulin was performed in lung sections ex vivo. An established in-house assay was used to test whether IL-33 was able to induce microvessel formation by human vascular endothelial cells. Results showed that serial intranasal challenge of mice with IL-33 or OVA resulted in proliferation of peribronchial von Willebrand factor-positive blood vessels to a degree closely related to the total expression of the angiogenic factors amphiregulin, angiogenin, endothelin-1, epidermal growth factor and insulin-like growth factor-1. IL-33 also induced microvessel formation by human endothelial cells in a concentration-dependent fashion in vitro. Our data are consistent with the hypothesis that IL-33 has the capacity to induce angiogenesis at least partly by increasing local expression of multiple angiogenic factors in an allergen-independent murine asthma surrogate, and consequently that IL-33 or its receptor is a potential novel molecular target for asthma therapy.

  16. Moderate ethanol administration accentuates cardiomyocyte contractile dysfunction and mitochondrial injury in high fat diet-induced obesity.

    PubMed

    Yuan, Fang; Lei, Yonghong; Wang, Qiurong; Esberg, Lucy B; Huang, Zaixing; Scott, Glenda I; Li, Xue; Ren, Jun

    2015-03-18

    Light to moderate drinking confers cardioprotection although it remains unclear with regards to the role of moderate drinking on cardiac function in obesity. This study was designed to examine the impact of moderate ethanol intake on myocardial function in high fat diet intake-induced obesity and the mechanism(s) involved with a focus on mitochondrial integrity. C57BL/6 mice were fed low or high fat diet for 16 weeks prior to ethanol challenge (1g/kg/d for 3 days). Cardiac contractile function, intracellular Ca(2+) homeostasis, myocardial histology, and mitochondrial integrity [aconitase activity and the mitochondrial proteins SOD1, UCP-2 and PPARγ coactivator 1α (PGC-1α)] were assessed 24h after the final ethanol challenge. Fat diet intake compromised cardiomyocyte contractile and intracellular Ca(2+) properties (depressed peak shortening and maximal velocities of shortening/relengthening, prolonged duration of relengthening, dampened intracellular Ca(2+) rise and clearance without affecting duration of shortening). Although moderate ethanol challenge failed to alter cardiomyocyte mechanical property under low fat diet intake, it accentuated high fat diet intake-induced changes in cardiomyocyte contractile function and intracellular Ca(2+) handling. Moderate ethanol challenge failed to affect fat diet intake-induced cardiac hypertrophy as evidenced by H&E staining. High fat diet intake reduced myocardial aconitase activity, downregulated levels of mitochondrial protein UCP-2, PGC-1α, SOD1 and interrupted intracellular Ca(2+) regulatory proteins, the effect of which was augmented by moderate ethanol challenge. Neither high fat diet intake nor moderate ethanol challenge affected protein or mRNA levels as well as phosphorylation of Akt and GSK3β in mouse hearts. Taken together, our data revealed that moderate ethanol challenge accentuated high fat diet-induced cardiac contractile and intracellular Ca(2+) anomalies as well as mitochondrial injury.

  17. Reversal of high dietary fructose-induced PPARalpha suppression by oral administration of lipoxygenase/cyclooxygenase inhibitors.

    PubMed

    Kelley, Glen L; Azhar, Salman

    2005-08-01

    High fructose feeding causes diet-induced alterations of lipid metabolism and decreased insulin sensitivity, hallmark of which is a rapid and profound hypertriglyceridemia. One of the mechanisms that contribute to serum hypertriglyceridemia in this model is suppression of hepatic PPARalpha. HMG-CoA inhibitors, which reduce serum triglycerides in these animals, also elevate/restore hepatic PPARalpha. Previously we demonstrated that two known lipoxygenase/cyclooxygenase inhibitors reversed diet-induced hypertriglyceridemia in this model and that reversal of certain inflammatory markers in the liver correlated with the metabolic benefit. In this paper we extended these studies by examining the impact of these compounds on expression of PPARalpha, both at the level of transcription and expression. Our data show that diet-induced suppression of hepaic PPARalpha is reversed upon treatment with lipoxygenase/cyclooxygenase compounds. We then tested one of these compounds, BW-755c, over a range of doses from 10 mg/kg to 100 mg/kg to establish a dose-response relationship with the reduction of serum hypertriglyceridemia in this model. These experiments support the concept of using anti-inflammatory medications as one method to correct metabolic dysfunction. PMID:16091142

  18. Prednisone-induced leukocytosis. Influence of dosage, method and duration of administration on the degree of leukocytosis.

    PubMed

    Shoenfeld, Y; Gurewich, Y; Gallant, L A; Pinkhas, J

    1981-11-01

    The long-term pattern of prednisone-induced leukocytosis was examined in 80 patients. Our results disclosed an extremely variable leukocytic responses, in which the white blood cell count surpassed 20,000/mm3 as early as the first day of treatment, an increase that persisted for the duration of therapy. Although the degree of leukocytosis was related to the dosage administered, it did appear sooner with higher doses. Leukocytosis reached maximal values within two weeks in most cases, after which the white blood cell count decreased, albeit not to pretreatment levels. The leukocytosis was attributed predominantly to a rise in the polymorphonuclear white blood cells, a phenomenon that coincided with monocytosis, eosinopenia and a variable degree of lymphopenia. It can be concluded that even small doses of prednisone, administered over a prolonged period of time, can induce extreme and persistent leukocytosis. This observation is of consequence especially when infection is suspected, particularly in an immunocompromised host. However, a shift to the left in the peripheral white blood cells, i.e., more than 6 percent band forms, and the appearance of toxic granulation may assist in the differential diagnosis between infection, in which the latter are observed, and corticosteroid-induced leukocytosis, in which they are rare.

  19. Heroin self-administration: II. CNS gene expression following withdrawal and cue-induced drug-seeking behavior.

    PubMed

    Kuntz, Kara L; Patel, Kruti M; Grigson, Patricia S; Freeman, Willard M; Vrana, Kent E

    2008-09-01

    In the accompanying paper, we described incubation of heroin-seeking behavior in rats following 14 days of abstinence. To gain an understanding of genomic changes that accompany this behavioral observation, we measured the expression of genes previously reported to respond to drugs of abuse. Specifically, after 1 or 14 days of abstinence, mRNA expression was measured for 11 genes in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) immediately following a single 90 min extinction session. Additionally, the role of contingency was examined in control rats that received yoked, response-independent heroin administration. Gene expression was quantified by real-time quantitative PCR. Expression of five genes (Arc, EGR1, EGR2, Fos, and Homer1b/c) was changed in the mPFC. EGR1 and EGR2 expression was increased following the 90 min extinction session in a contingency-specific manner and this increase persisted through the 14 days of abstinence. Fos expression was also increased after 1 and 14 days of abstinence, but at 14 days this increase was response-independent (i.e., it occurred in both the rats with a history of heroin self-administration and in the yoked controls). Arc expression increased following the extinction session only in rats with a history of heroin self-administration and only when tested following 1, but not 14, days of abstinence. Homer 1 b/c decreased after 14 days of enforced abstinence in rats that received non-contingent heroin. Expression of only a single gene (EGR2) was increased in the NAc. These data demonstrate that behavioral incubation is coincident with altered levels of specific transcripts and that this response is contingently-specific. Moreover, EGR1 and EGR2 are specifically upregulated in self-administering rats following extinction and this finding persists through 14 days of abstinence, suggesting that these genes are particularly associated with the incubation phenomenon. These latter observations of persistent changes

  20. Repeated Neonatal Propofol Administration Induces Sex-Dependent Long-Term Impairments on Spatial and Recognition Memory in Rats

    PubMed Central

    Gonzales, Edson Luck T.; Yang, Sung Min; Choi, Chang Soon; Mabunga, Darine Froy N.; Kim, Hee Jin; Cheong, Jae Hoon; Ryu, Jong Hoon; Koo, Bon-Nyeo; Shin, Chan Young

    2015-01-01

    Propofol is an anesthetic agent that gained wide use because of its fast induction of anesthesia and rapid recovery post-anesthesia. However, previous studies have reported immediate neurodegeneration and long-term impairment in spatial learning and memory from repeated neonatal propofol administration in animals. Yet, none of those studies has explored the sex-specific long-term physical changes and behavioral alterations such as social (sociability and social preference), emotional (anxiety), and other cognitive functions (spatial working, recognition, and avoidance memory) after neonatal propofol treatment. Seven-day-old Wistar-Kyoto (WKY) rats underwent repeated daily intraperitoneal injections of propofol or normal saline for 7 days. Starting fourth week of age and onwards, rats were subjected to behavior tests including open-field, elevated-plus-maze, Y-maze, 3-chamber social interaction, novel-object-recognition, passive-avoidance, and rotarod. Rats were sacrificed at 9 weeks and hippocampal protein expressions were analyzed by Western blot. Results revealed long-term body weight gain alterations in the growing rats and sex-specific impairments in spatial (female) and recognition (male) learning and memory paradigms. A markedly decreased expression of hippocampal NMDA receptor GluN1 subunit in female- and increased expression of AMPA GluR1 subunit protein expression in male rats were also found. Other aspects of behaviors such as locomotor activity and coordination, anxiety, sociability, social preference and avoidance learning and memory were not generally affected. These results suggest that neonatal repeated propofol administration disrupts normal growth and some aspects of neurodevelopment in rats in a sex-specific manner. PMID:25995824

  1. Biochemical and cognitive impairments observed in animal models of schizophrenia induced by prenatal stress paradigm or methylazoxymethanol acetate administration.

    PubMed

    Ratajczak, Piotr; Kus, Krzysztof; Murawiecka, Patrycja; Słodzińska, Iwona; Giermaziak, Wojciech; Nowakowska, Elżbieta

    2015-01-01

    The aim of the study was to find whether spatial memory impairment and disruption in locomotor activity were found in prenatally stressed rats (PSG) or prenatally methylazoxymethanol acetate-treated rats (MAMG). In addition to this, we examined basal plasma corticosterone level as well as brain-derived neurothropic factor (BDNF) in the PSG and MAMG rats. The effect of prenatal stress (stress paradigm between 14 and 21 day of gestation) and methylazoxymethanol acetate (MAM) administration (17 day of gestation) to the female Wistar rats were studied on the male offspring in the Morris Water Maze (spatial memory) and locomotor activity test. Through Morris Water Maze rats were injected with saline 4 times (on 1, 7, 14 and 21 day of testing) while in locomotor activity test saline was injected only once. Corticosterone level was measured using ELISA Kit while BDNF levels were assessed using ELISA Chemikine TM BDNF kit. Results indicate that both PSG and MAMG rats deteriorate spatial memory as well as increase locomotor activity compared to the control group. Biochemical studies indicate that basal plasma corticosterone level increased in both PSG and MAMG rats compared to the control group. Analyses of the BDNF level, on the other hand, have shown decrease of the neurothropin level in both hippocampus and prefrontal cortex (PFC) in both PSG and MAMG groups of rats. As shown by the obtained results, both the prenatal stress model and prenatal MAM administration model generate a number of behavioural (e.g. spatial memory disorders, increased locomotor activity) and biochemical (e.g. increased corticosterone and decreased BDNF levels) changes in the examined offspring, Thus, these models can be successfully used in the efficacy analysis of the pharmacotherapy applied. PMID:26581387

  2. Reversal of apixaban induced alterations in hemostasis by different coagulation factor concentrates: significance of studies in vitro with circulating human blood.

    PubMed

    Escolar, Gines; Fernandez-Gallego, Victor; Arellano-Rodrigo, Eduardo; Roquer, Jaume; Reverter, Joan Carles; Sanz, Victoria Veronica; Molina, Patricia; Lopez-Vilchez, Irene; Diaz-Ricart, Maribel; Galan, Ana Maria

    2013-01-01

    Apixaban is a new oral anticoagulant with a specific inhibitory action on FXa. No information is available on the reversal of the antihemostatic action of apixaban in experimental or clinical settings. We have evaluated the effectiveness of different factor concentrates at reversing modifications of hemostatic mechanisms induced by moderately elevated concentrations of apixaban (200 ng/ml) added in vitro to blood from healthy donors (n = 10). Effects on thrombin generation (TG) and thromboelastometry (TEM) parameters were assessed. Modifications in platelet adhesive, aggregating and procoagulant activities were evaluated in studies with blood circulating through damaged vascular surfaces, at a shear rate of 600 s(-1). The potential of prothrombin complex concentrates (PCCs; 50 IU/kg), activated prothrombin complex concentrates (aPCCs; 75 IU/kg), or activated recombinant factor VII (rFVIIa; 270 μg/kg), at reversing the antihemostatic actions of apixaban, were investigated. Apixaban interfered with TG kinetics. Delayed lag phase, prolonged time to peak and reduced peak values, were improved by the different concentrates, though modifications in TG patterns were diversely affected depending on the activating reagents. Apixaban significantly prolonged clotting times (CTs) in TEM studies. Prolongations in CTs were corrected by the different concentrates with variable efficacies (rFVIIa≥aPCC>PCC). Apixaban significantly reduced fibrin and platelet interactions with damaged vascular surfaces in perfusion studies (p<0.05 and p<0.01, respectively). Impairments in fibrin formation were normalized by the different concentrates. Only rFVIIa significantly restored levels of platelet deposition. Alterations in hemostasis induced by apixaban were variably compensated by the different factor concentrates investigated. However, effects of these concentrates were not homogeneous in all the tests, with PCCs showing more efficacy in TG, and rFVIIa being more effective on TEM

  3. Intradermal administration of ATP augments methacholine-induced cutaneous vasodilation but not sweating in young males and females.

    PubMed

    Fujii, Naoto; Halili, Lyra; Singh, Maya Sarah; Meade, Robert D; Kenny, Glen P

    2015-10-15

    Acetylcholine released from cholinergic nerves is a key neurotransmitter contributing to heat stress-induced cutaneous vasodilation and sweating. Given that sympathetic cholinergic nerves also release ATP, ATP may play an important role in modulating cholinergic cutaneous vasodilation and sweating. However, the pattern of response may differ between males and females given reports of sex-related differences in the peripheral mechanisms governing these heat loss responses. Cutaneous vascular conductance (CVC, laser-Doppler perfusion units/mean arterial pressure) and sweat rate (ventilated capsule) were evaluated in 17 young adults (8 males, 9 females) at four intradermal microdialysis skin sites continuously perfused with: 1) lactated Ringer (Control), 2) 0.3 mM ATP, 3) 3 mM ATP, or 4) 30 mM ATP. At all skin sites, methacholine was coadministered in a concentration-dependent manner (0.0125, 0.25, 5, 100, 2,000 mM, each for 25 min). In both males and females, CVC was elevated with the lone infusion of 30 mM ATP (both P < 0.05), but not with 0.3 and 3 mM ATP compared with control (all P >0.27). However, 0.3 mM ATP induced a greater increase in CVC compared with control in response to 100 mM methacholine infusion in males (P < 0.05). In females, 0.3 mM ATP infusion resulted in a lower concentration of methacholine required to elicit a half-maximal response (EC50) (P < 0.05). In both males and females, methacholine-induced sweating was unaffected by any concentration of ATP (all P > 0.44). We demonstrate that ATP enhances cholinergic cutaneous vasodilation albeit the pattern of response differs between males and females. Furthermore, we show that ATP does not modulate cholinergic sweating. PMID:26290105

  4. Dermal Lipogenesis Inhibits Adiponectin Production in Human Dermal Fibroblasts while Exogenous Adiponectin Administration Prevents against UVA-Induced Dermal Matrix Degradation in Human Skin

    PubMed Central

    Fang, Chien-Liang; Huang, Ling-Hung; Tsai, Hung-Yueh; Chang, Hsin-I

    2016-01-01

    Adiponectin is one of the most abundant adipokines from the subcutaneous fat, and regulates multiple activities through endocrine, paracrine, or autocrine mechanisms. However, its expression in adipogenic induced fibroblasts, and the potential role in photoaging has not been determined. Here, human dermal fibroblasts, Hs68, were presented as a cell model of dermal lipogenesis through stimulation of adipogenic differentiation medium (ADM). Similar to other studies in murine pre-adipocyte models (i.e., 3T3-L1), Hs68 fibroblasts showed a tendency to lipogenesis based on lipid accumulation, triglyceride formation, and the expressions of PPAR-γ, lipoprotein lipase (LPL), and FABP4 mRNA. As expected, ADM-treated fibroblasts displayed a reduction on adiponectin expression. Next, we emphasized the photoprotective effects of adiponectin against UVA-induced damage in Hs68 fibroblasts. UVA radiation can downregulate cell adhesion strength and elastic modulus of Hs68 fibroblasts. Moreover, UVA radiation could induce the mRNA expressions of epidermal growth factor receptor (EGFR), adiponectin receptor 1 (AdipoR1), matrix metalloproteinase-1 (MMP-1), MMP-3, and cyclooxygenase-2 (COX-2), but downregulate the mRNA expressions of type I and type III collagen. On the other hand, post-treatment of adiponectin can partially overcome UVA-induced reduction in the cell adhesion strength of Hs68 fibroblasts through the activation of AdipoR1 and the suppression of EGF-R. In addition, post-treatment of adiponectin indicated the increase of type III collagen and elastin mRNA expression and the decrease of MMP-1 and MMP-3 mRNA expression, but a limited degree of recovery of elastic modulus on UVA-irradiated Hs68 fibroblasts. Overall, these results suggest that dermal lipogenesis may inhibit the expression of adiponectin while exogenous adiponectin administration prevents against UVA-induced dermal matrix degradation in Hs68 fibroblasts. PMID:27428951

  5. Dermal Lipogenesis Inhibits Adiponectin Production in Human Dermal Fibroblasts while Exogenous Adiponectin Administration Prevents against UVA-Induced Dermal Matrix Degradation in Human Skin.

    PubMed

    Fang, Chien-Liang; Huang, Ling-Hung; Tsai, Hung-Yueh; Chang, Hsin-I

    2016-01-01

    Adiponectin is one of the most abundant adipokines from the subcutaneous fat, and regulates multiple activities through endocrine, paracrine, or autocrine mechanisms. However, its expression in adipogenic induced fibroblasts, and the potential role in photoaging has not been determined. Here, human dermal fibroblasts, Hs68, were presented as a cell model of dermal lipogenesis through stimulation of adipogenic differentiation medium (ADM). Similar to other studies in murine pre-adipocyte models (i.e., 3T3-L1), Hs68 fibroblasts showed a tendency to lipogenesis based on lipid accumulation, triglyceride formation, and the expressions of PPAR-γ, lipoprotein lipase (LPL), and FABP4 mRNA. As expected, ADM-treated fibroblasts displayed a reduction on adiponectin expression. Next, we emphasized the photoprotective effects of adiponectin against UVA-induced damage in Hs68 fibroblasts. UVA radiation can downregulate cell adhesion strength and elastic modulus of Hs68 fibroblasts. Moreover, UVA radiation could induce the mRNA expressions of epidermal growth factor receptor (EGFR), adiponectin receptor 1 (AdipoR1), matrix metalloproteinase-1 (MMP-1), MMP-3, and cyclooxygenase-2 (COX-2), but downregulate the mRNA expressions of type I and type III collagen. On the other hand, post-treatment of adiponectin can partially overcome UVA-induced reduction in the cell adhesion strength of Hs68 fibroblasts through the activation of AdipoR1 and the suppression of EGF-R. In addition, post-treatment of adiponectin indicated the increase of type III collagen and elastin mRNA expression and the decrease of MMP-1 and MMP-3 mRNA expression, but a limited degree of recovery of elastic modulus on UVA-irradiated Hs68 fibroblasts. Overall, these results suggest that dermal lipogenesis may inhibit the expression of adiponectin while exogenous adiponectin administration prevents against UVA-induced dermal matrix degradation in Hs68 fibroblasts. PMID:27428951

  6. Enhanced transcription of pancreatic peptide YY by 1α-hydroxyvitamin D3 administration in streptozotocin-induced diabetic mice.

    PubMed

    Ozeki, Jun; Choi, Mihwa; Endo-Umeda, Kaori; Sakurai, Kenichi; Amano, Sadao; Makishima, Makoto

    2013-10-01

    Peptide YY (PYY) is a peptide hormone secreted from L cells in the intestine in response to food intake that regulates appetite and gastrointestinal function. PYY is also produced in the pancreatic islets. The vitamin D receptor (VDR) is a nuclear receptor for the active form of vitamin D3 that regulates numerous physiological processes. VDR is expressed in the pancreatic islets and pharmacological VDR activation increases PYY expression in mouse peripheral islet cells. Although VDR is present in insulin-producing β cells as well as non-β cells, the role of β cell VDR in Pyy transcription remains unknown. We treated mice with streptozotocin to ablate β cells in the pancreas. Pancreatic Vdr mRNA expression was decreased in streptozotocin-induced diabetic mice. Interestingly, streptozotocin-treated mice exhibited increased basal Pyy expression and 1α-hydroxyvitamin D3 treatment further increased expression. Moreover, 1α-hydroxyvitamin D3 increased mRNA expression of pancreatic polypeptide and decreased that of neuropeptide Y in streptozotocin-induced diabetic mice but not in control mice. 1α-Hydroxyvitamin D3 slightly increased mRNA expression of insulin but transcript levels were nearly undetectable in the pancreas of streptozotocin-treated mice. Thus, VDR in non-β islet cells is involved in Pyy expression in the mouse pancreas. The findings from this β cell ablation study suggest a hormone transcription regulatory network composed of β cells and non-β cells.

  7. Artificial cytokine storm combined with hyperthermia induces significant anti-tumor effect in mice inoculated with lewis lung carcinoma and B16 melanoma cells.

    PubMed

    Kushida, Shigeki; Ohmae, Hiroshi; Kamma, Hiroshi; Totsuka, Rumiko; Matsumura, Masayuki; Takeuchi, Akira; Saiki, Ikuo; Yanagawa, Toru; Onizawa, Kojiro; Ishii, Tetsuro; Ohn, Tadao

    2006-12-01

    In cancer immunotherapies combined with hyperthermia, one or two cytokines have been tested to augment the anti-tumor effect. However, the therapies have not shown sufficient improvement. The aim of this study is to find a new potent tumor immunotherapy in order to augment antitumor effect of hyperthermia by the cytokine cocktails in vivo. We used a combination therapy of local hyperthermia (LH) and various cytokine cocktails composed of IFNs (IFN-alpha, -beta, and -gamma), Thl cytokines (IL-2, -12, -15, and -18), a Th2 cytokine (IL-4), inflammatory cytokines (IL-lalpha and TNF-alpha), and dendritic cell-inducible cytokines (IL-3 and GM-CSF). These cytokines in a proper combination augmented the anti-tumor effect of LH and prolonged survival time in Lewis lung carcinoma or B16 melanoma significantly. Moreover, the 12-cytokine cocktail suppressed B 16 metastasis to the lung and lymph nodes, and complete regression of the tumors without regrowth occurred in 3 of 5 mice. In the cured three B16 mice, there was hyperplasia of lymphatic organs with many CD3-positive T lymphocytes. The most effective cytokine combination should be able to augment the anti-tumor effect of other therapies besides hyperthermia that induce the necrosis of tumor cells.

  8. The administration of atomoxetine during alcohol deprivation induces a time-limited increase in alcohol consumption after relapse.

    PubMed

    Alén, Francisco; Serrano, Antonia; Gorriti, Miguel Ángel; Pavón, Francisc