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Sample records for mice enhances healthy

  1. Safety assessment of inhaled xylitol in mice and healthy volunteers

    PubMed Central

    Durairaj, Lakshmi; Launspach, Janice; Watt, Janet L; Businga, Thomas R; Kline, Joel N; Thorne, Peter S; Zabner, Joseph

    2004-01-01

    Background Xylitol is a 5-carbon sugar that can lower the airway surface salt concentration, thus enhancing innate immunity. We tested the safety and tolerability of aerosolized iso-osmotic xylitol in mice and human volunteers. Methods This was a prospective cohort study of C57Bl/6 mice in an animal laboratory and healthy human volunteers at the clinical research center of a university hospital. Mice underwent a baseline methacholine challenge, exposure to either aerosolized saline or xylitol (5% solution) for 150 minutes and then a follow-up methacholine challenge. The saline and xylitol exposures were repeated after eosinophilic airway inflammation was induced by sensitization and inhalational challenge to ovalbumin. Normal human volunteers underwent exposures to aerosolized saline (10 ml) and xylitol, with spirometry performed at baseline and after inhalation of 1, 5, and 10 ml. Serum osmolarity and electrolytes were measured at baseline and after the last exposure. A respiratory symptom questionnaire was administered at baseline, after the last exposure, and five days after exposure. In another group of normal volunteers, bronchoalveolar lavage (BAL) was done 20 minutes and 3 hours after aerosolized xylitol exposure for levels of inflammatory markers. Results In naïve mice, methacholine responsiveness was unchanged after exposures to xylitol compared to inhaled saline (p = 0.49). There was no significant increase in Penh in antigen-challenged mice after xylitol exposure (p = 0.38). There was no change in airway cellular response after xylitol exposure in naïve and antigen-challenged mice. In normal volunteers, there was no change in FEV1 after xylitol exposures compared with baseline as well as normal saline exposure (p = 0.19). Safety laboratory values were also unchanged. The only adverse effect reported was stuffy nose by half of the subjects during the 10 ml xylitol exposure, which promptly resolved after exposure completion. BAL cytokine levels were

  2. Probiotic use decreases intestinal inflammation and increases bone density in healthy male but not female mice.

    PubMed

    McCabe, Laura R; Irwin, Regina; Schaefer, Laura; Britton, Robert A

    2013-08-01

    Osteoporosis can result from intestinal inflammation, as is seen with inflammatory bowel disease. Probiotics, microorganisms that provide a health benefit to the host when ingested in adequate amounts, can have anti-inflammatory properties and are currently being examined to treat inflammatory bowel disease. Here, we examined if treating healthy male mice with Lactobacillus reuteri ATCC PTA 6475 (a candidate probiotic with anti-TNFα activity) could affect intestinal TNFα levels and enhance bone density. Adult male mice were given L. reuteri 6475 orally by gavage for 3×/week for 4 weeks. Examination of jejunal and ileal RNA profiles indicates that L. reuteri suppressed basal TNFα mRNA levels in the jejunum and ileum in male mice, but surprisingly not in female mice. Next, we examined bone responses. Micro-computed tomography demonstrated that L. reuteri 6475 treatment increased male trabecular bone parameters (mineral density, bone volume fraction, trabecular number, and trabecular thickness) in the distal femur metaphyseal region as well as in the lumbar vertebrae. Cortical bone parameters were unaffected. Dynamic and static histomorphometry and serum remodeling parameters indicate that L. reuteri ingestion increases osteoblast serum markers and dynamic measures of bone formation in male mice. In contrast to male mice, L. reuteri had no effect on bone parameters in female mice. Taken together our studies indicate that femoral and vertebral bone formation increases in response to oral probiotic use, leading to increased trabecular bone volume in male mice. PMID:23389860

  3. Arctigenin Efficiently Enhanced Sedentary Mice Treadmill Endurance

    PubMed Central

    Chen, Jing; Yu, Liang; Hu, Lihong; Jiang, Hualiang; Shen, Xu

    2011-01-01

    Physical inactivity is considered as one of the potential risk factors for the development of type 2 diabetes and other metabolic diseases, while endurance exercise training could enhance fat oxidation that is associated with insulin sensitivity improvement in obesity. AMP-activated protein kinase (AMPK) as an energy sensor plays pivotal roles in the regulation of energy homeostasis, and its activation could improve glucose uptake, promote mitochondrial biogenesis and increase glycolysis. Recent research has even suggested that AMPK activation contributed to endurance enhancement without exercise. Here we report that the natural product arctigenin from the traditional herb Arctium lappa L. (Compositae) strongly increased AMPK phosphorylation and subsequently up-regulated its downstream pathway in both H9C2 and C2C12 cells. It was discovered that arctigenin phosphorylated AMPK via calmodulin-dependent protein kinase kinase (CaMKK) and serine/threonine kinase 11(LKB1)-dependent pathways. Mice treadmill based in vivo assay further indicated that administration of arctigenin improved efficiently mice endurance as reflected by the increased fatigue time and distance, and potently enhanced mitochondrial biogenesis and fatty acid oxidation (FAO) related genes expression in muscle tissues. Our results thus suggested that arctigenin might be used as a potential lead compound for the discovery of the agents with mimic exercise training effects to treat metabolic diseases. PMID:21887385

  4. MondoA deficiency enhances sprint performance in mice

    PubMed Central

    Imamura, Minako; Chang, Benny Hung-Junn; Kohjima, Motoyuki; Li, Ming; Hwang, Byounghoon; Taegtmeyer, Heinrich; Harris, Robert A.; Chan, Lawrence

    2015-01-01

    MondoA is a basic helix–loop–helix (bHLH)/leucine zipper (ZIP) transcription factor that is expressed predominantly in skeletal muscle. Studies in vitro suggest that the Max-like protein X (MondoA:Mlx) heterodimer senses the intracellular energy status and directly targets the promoter region of thioredoxin interacting protein (Txnip) and possibly glycolytic enzymes. We generated MondoA-inactivated (MondoA−/−) mice by gene targeting. MondoA−/− mice had normal body weight at birth, exhibited normal growth and appeared to be healthy. However, they exhibited unique metabolic characteristics. MondoA−/− mice built up serum lactate and alanine levels and utilized fatty acids for fuel during exercise. Gene expression and promoter analysis suggested that MondoA functionally represses peroxisome-proliferator-activated receptor γ co-activator-1α (PGC-1α)–mediated activation of pyruvate dehydrogenase kinase 4 (PDK4) transcription. PDK4 normally down-regulates the activity of pyruvate dehydrogenase, an enzyme complex that catalyses the decarboxylation of pyruvate to acetyl-CoA for entry into the Krebs cycle; in the absence of MondoA, pyruvate is diverted towards lactate and alanine, both products of glycolysis. Dynamic testing revealed that MondoA−/− mice excel in sprinting as their skeletal muscles display an enhanced glycolytic capacity. Our studies uncover a hitherto unappreciated function of MondoA in fuel selection in vivo. Lack of MondoA results in enhanced exercise capacity with sprinting. PMID:25145386

  5. Dealing with requests for pharmacological cognitive enhancement from healthy students.

    PubMed

    Chandramouleeswaran, Susmita; Edwin, Natasha Catherine; Rajaleelan, Wesley

    2016-01-01

    The use of drugs to enhance cognitive function and academic performance is clearly a global phenomenon, with the reported prevalence of stimulant use among medical students ranging from 15-20%. A multi-institution study from the USA reported a 6.9% lifetime prevalence of non-prescription use of cognitive enhancers among college students. A comprehensive systematic review indicates a 16-29% use of non-prescribed stimulants among all students for reasons that include increasing concentration and alertness. While mental health professionals and guidance counsellors anecdotally recall requests for pharmacological cognitive enhancement from otherwise healthy students, the exact magnitude of this problem in the Indian context is not clear. PMID:27474703

  6. Remote limb ischemic conditioning enhances motor learning in healthy humans.

    PubMed

    Cherry-Allen, Kendra M; Gidday, Jeff M; Lee, Jin-Moo; Hershey, Tamara; Lang, Catherine E

    2015-06-01

    Brief bouts of sublethal ischemia have been shown to protect exposed tissue (ischemic conditioning) and tissues at remote sites (remote ischemic conditioning) against subsequent ischemic challenges. Given that the mechanisms of this protective phenomenon are multifactorial and epigenetic, we postulated that remote limb ischemic conditioning (RLIC) might enhance mechanisms responsible for neural plasticity, and thereby facilitate learning. Specifically, we hypothesized that conditioning of the nervous system with RLIC, achieved through brief repetitive limb ischemia prior to training, would facilitate the neurophysiological processes of learning, thus making training more effective and more long-lasting. Eighteen healthy adults participated in this study; nine were randomly allocated to RLIC and nine to sham conditioning. All subjects underwent seven consecutive weekday sessions and 2-wk and 4-wk follow-up sessions. We found that RLIC resulted in significantly greater motor learning and longer retention of motor performance gains in healthy adults. Changes in motor performance do not appear to be due to a generalized increase in muscle activation or muscle strength and were not associated with changes in serum brain-derived neurotrophic factor (BDNF) concentration. Of note, RLIC did not enhance cognitive learning on a hippocampus-dependent task. While future research is needed to establish optimal conditioning and training parameters, this inexpensive, clinically feasible paradigm might ultimately be implemented to enhance motor learning in individuals undergoing neuromuscular rehabilitation for brain injury and other pathological conditions. PMID:25867743

  7. Remote limb ischemic conditioning enhances motor learning in healthy humans

    PubMed Central

    Cherry-Allen, Kendra M.; Gidday, Jeff M.; Lee, Jin-Moo; Hershey, Tamara

    2015-01-01

    Brief bouts of sublethal ischemia have been shown to protect exposed tissue (ischemic conditioning) and tissues at remote sites (remote ischemic conditioning) against subsequent ischemic challenges. Given that the mechanisms of this protective phenomenon are multifactorial and epigenetic, we postulated that remote limb ischemic conditioning (RLIC) might enhance mechanisms responsible for neural plasticity, and thereby facilitate learning. Specifically, we hypothesized that conditioning of the nervous system with RLIC, achieved through brief repetitive limb ischemia prior to training, would facilitate the neurophysiological processes of learning, thus making training more effective and more long-lasting. Eighteen healthy adults participated in this study; nine were randomly allocated to RLIC and nine to sham conditioning. All subjects underwent seven consecutive weekday sessions and 2-wk and 4-wk follow-up sessions. We found that RLIC resulted in significantly greater motor learning and longer retention of motor performance gains in healthy adults. Changes in motor performance do not appear to be due to a generalized increase in muscle activation or muscle strength and were not associated with changes in serum brain-derived neurotrophic factor (BDNF) concentration. Of note, RLIC did not enhance cognitive learning on a hippocampus-dependent task. While future research is needed to establish optimal conditioning and training parameters, this inexpensive, clinically feasible paradigm might ultimately be implemented to enhance motor learning in individuals undergoing neuromuscular rehabilitation for brain injury and other pathological conditions. PMID:25867743

  8. AIR PARTICULATE POLLUTION EXPOSURE INDUCES SYSTEMIC OXIDATIVE STRESS IN HEALTHY MICE

    EPA Science Inventory

    Air particulate pollution exposure induces systemic oxidative stress in healthy mice

    Elizabeth S Roberts1 and Kevin L Dreher2. 1 College or Veterinary Medicine, NC State University, Raleigh, NC , 2US Environmental Protection Agency, NHEERL, RTP, NC

    Epidemiological s...

  9. Soy Biodiesel Emissions Have Reduced Inflammatory Effects Compared to Diesel Emissions in Healthy and Allergic Mice

    EPA Science Inventory

    Toxicity of exhaust from combustion of petroleum diesel (BO), soy-based biodiesel (B100), or a 20% biodiesel/80% petrodiesel mix (B20) was compared in healthy and house dust mite (HDM)-allergic mice. Fuel emissions were diluted to target fine particulate matter (PM2.5) conrentrat...

  10. Comparative Toxicity of Soy Biodiesel and Diesel Emissions in Healthy and Allergic Mice

    EPA Science Inventory

    Toxicity from combustion of 100% soy-based biodiesel (B100) was compared to that of petrodiesel (B0) or a 20% biodiesel / 80% petrodiesel mix (B20) in healthy and house dust mite (HDM)-allergic Balb/cJ mice. Exhaust from combustion of B0, B20, or B100 was diluted to target conce...

  11. Small airway changes in healthy and ovalbumin-treated mice during quasi-static lung inflation.

    PubMed

    Sera, Toshihiro; Uesugi, Kentaro; Himeno, Ryutaro; Yagi, Naoto

    2007-06-15

    Previously, we developed a synchrotron radiation CT system to evaluate the morphometric changes (length and diameter, D) and small airway compliance (sC(aw)) of euthanized mice under quasi-static inflation [Sera, T., Uesugi, K., Yagi, N., 2005. Localized morphometric deformations of small airways and alveoli in intact mouse lungs under quasi-static inflation. Respir. Physiol. Neurobiol. 147, 51-63). Using this system, this study compared normal and asthmatic small airways. Ovalbumin-treated mice were used as an asthma model. Compared with the values at functional residual capacity, D of normal and asthmatic small airways (D<200microm) increased by 48% and 36% at the end of tidal inspiration. For larger airways (D>500microm), the increases were 23% and 20%, respectively. The ratio of the sC(aw) of asthmatic small airways to that of healthy small airways was 0.57, and the ratio was 0.70 for larger airways. The morphometric changes and sC(aw) in asthma model mice were significantly lower than those of healthy mice. The differences in sC(aw) between healthy and asthma model mice were greater for smaller airways. PMID:17174159

  12. Differential cellular responses in healthy mice and in mice with established airway inflammation when exposed to hematite nanoparticles.

    PubMed

    Gustafsson, Åsa; Bergström, Ulrika; Ågren, Lina; Österlund, Lars; Sandström, Thomas; Bucht, Anders

    2015-10-01

    The aim of this study was to investigate the inflammatory and immunological responses in airways and lung-draining lymph nodes (LDLNs), following lung exposure to iron oxide (hematite) nanoparticles (NPs). The responses to the hematite NPs were evaluated in both healthy non-sensitized mice, and in sensitized mice with an established allergic airway disease. The mice were exposed intratracheally to either hematite NPs or to vehicle (PBS) and the cellular responses were evaluated on days 1, 2, and 7, post-exposure. Exposure to hematite NPs increased the numbers of neutrophils, eosinophils, and lymphocytes in the airways of non-sensitized mice on days 1 and 2 post-exposure; at these time points the number of lymphocytes was also elevated in the LDLNs. In contrast, exposing sensitized mice to hematite NPs induced a rapid and unspecific cellular reduction in the alveolar space on day 1 post-exposure; a similar decrease of lymphocytes was also observed in the LDLN. The results indicate that cells in the airways and in the LDLN of individuals with established airway inflammation undergo cell death when exposed to hematite NPs. A possible explanation for this toxic response is the extensive generation of reactive oxygen species (ROS) in the pro-oxidative environment of inflamed airways. This study demonstrates how sensitized and non-sensitized mice respond differently to hematite NP exposure, and it highlights the importance of including individuals with respiratory disorders when evaluating health effects of inhaled nanomaterials. PMID:26163175

  13. Tolerance, fermentation, and cytokine expression in healthy aged male C57BL/6J mice fed resistant starch

    PubMed Central

    Zhou, June; Keenan, Michael J.; Keller, Jeffrey; Fernandez-Kim, Sun Ok; Pistell, Paul J.; Tulley, Richard T.; Raggio, Anne M.; Shen, Li; Zhang, Hanjie; Martin, Roy J.; Blackman, Marc R.

    2013-01-01

    Health benefits of resistant starch (RS), a dietary fermentable fiber, have been well documented in young, but not in old populations. As the essential step of more comprehensive evaluations of RS on healthy aging, we examined the effects of dietary RS on tolerance, colonic fermentation, and cytokine expression in aged mice. Healthy older (18–20 months) C57BL/6J male mice were fed control, 18% RS, or 36% RS diets for 10 weeks. Body weight gain, body composition, and fat pad weights did not differ among the three groups after 10 weeks, indicating good tolerance of the RS diet. Fermentation indicators (cecum weights, and cecal proglucagon and PYY mRNA expression) were enhanced in a RS dose dependent manner (P<0.01). Serum concentrations of soluble cytokine receptors (sTNF-Rb; sIL-4R; sIL-2Rα sVEGFR1; and sRAGE) and TNFα expression (gene and protein) in visceral fat did not differ significantly among groups. Adiponectin protein concentrations, but not gene expression, were greater in epididymal fat of the 36% RS versus control groups (P<0.05). Conclusion: in aged mice, dietary RS is well tolerated, fermented in the colon, and stimulates colonic expression of proglucagon and PYY mRNA, and adiponectin protein in visceral fat. PMID:22174009

  14. Salvia lavandulaefolia (Spanish sage) enhances memory in healthy young volunteers.

    PubMed

    Tildesley, N T J; Kennedy, D O; Perry, E K; Ballard, C G; Savelev, S; Wesnes, K A; Scholey, A B

    2003-06-01

    Sage (Salvia) has a longstanding reputation in British herbal encyclopaedias as an agent that enhances memory, although there is little evidence regarding the efficacy of sage from systematized trials. Based on known pharmacokinetic and binding properties, it was hypothesised that acute administration of sage would enhance memory in young adult volunteers. Two experiments utilised a placebo-controlled, double-blind, balanced, crossover methodology. In Trial 1, 20 participants received 50, 100 and 150 microl of a standardised essential oil extract of Salvia lavandulaefolia and placebo. In Trial 2, 24 participants received 25 and 50 microl of a standardised essential oil extract of S. lavandulaefolia and placebo. Doses were separated by a 7-day washout period with treatment order determined by Latin squares. Assessment was undertaken using the Cognitive Drug Research computerised test battery prior to treatment and 1, 2.5, 4 and 6 h thereafter. The primary outcome measures were immediate and delayed word recall. The 50 microl dose of Salvia essential oil significantly improved immediate word recall in both studies. These results represent the first systematic evidence that Salvia is capable of acute modulation of cognition in healthy young adults. PMID:12895685

  15. Pharmacokinetics of Polymersomes Composed of Poly(Butadiene-Ethylene Oxide); Healthy versus Tumor-Bearing Mice.

    PubMed

    Wang, G; de Kruijff, R M; Abou, D; Ramos, N; Mendes, E; Franken, L E; Wolterbeek, H T; Denkova, A G

    2016-02-01

    Vesicles composed of block copolymers (i.e., polymersomes) are one of the most versatile nano-carriers for medical purposes due to their tuneable physicochemical properties and the possibility to encapsulate simultaneously hydrophobic and hydrophilic substances, allowing, for instance, the combination of therapy and imaging. In cancer treatment, these vesicles need to remain long enough in the blood stream to be sufficiently taken up by tumors. Here, we have investigated the biodistribution and the pharmacokinetics of polymersomes, composed of poly(butadiene-b-ethylene oxide) having dimensions around 80 nm. The polymersomes have been radiolabeled with ¹¹¹In via the so-called active loading method achieving a loading efficiency of 92.9 ± 0.9% with radionuclide retention in mouse serum of more than 95% at 24 h. The optimized ¹¹¹In containing polymersomes have been intravenously administered in healthy and tumor bearing mice for pharmacokinetic determination using microSPECT (Single Photon Emission Computed Tomography). In healthy mice these polymersomes have been found to exhibit relatively long blood circulation (> 6 h), low liver uptake (6 ± 1.5%ID/g, 48 h p.i.) and elevated spleen uptake (188 ± 30%ID/g). The blood circulation in tumor bearing mice is dramatically reduced (< 1.5 h) most likely due to elevated splenic filtration, clearly indicating the importance of in vivo studies in diseased mice. Finally, the polymersomes have been injected subcutaneously in tumor bearing mice revealing retention of 77% in the mice, primarily accumulated at the site of injection, up to 48 hours after administration. PMID:27305765

  16. Recurrent Recruitment Manoeuvres Improve Lung Mechanics and Minimize Lung Injury during Mechanical Ventilation of Healthy Mice

    PubMed Central

    Reiss, Lucy Kathleen; Kowallik, Anke; Uhlig, Stefan

    2011-01-01

    Introduction Mechanical ventilation (MV) of mice is increasingly required in experimental studies, but the conditions that allow stable ventilation of mice over several hours have not yet been fully defined. In addition, most previous studies documented vital parameters and lung mechanics only incompletely. The aim of the present study was to establish experimental conditions that keep these parameters within their physiological range over a period of 6 h. For this purpose, we also examined the effects of frequent short recruitment manoeuvres (RM) in healthy mice. Methods Mice were ventilated at low tidal volume VT = 8 mL/kg or high tidal volume VT = 16 mL/kg and a positive end-expiratory pressure (PEEP) of 2 or 6 cmH2O. RM were performed every 5 min, 60 min or not at all. Lung mechanics were followed by the forced oscillation technique. Blood pressure (BP), electrocardiogram (ECG), heart frequency (HF), oxygen saturation and body temperature were monitored. Blood gases, neutrophil-recruitment, microvascular permeability and pro-inflammatory cytokines in bronchoalveolar lavage (BAL) and blood serum as well as histopathology of the lung were examined. Results MV with repetitive RM every 5 min resulted in stable respiratory mechanics. Ventilation without RM worsened lung mechanics due to alveolar collapse, leading to impaired gas exchange. HF and BP were affected by anaesthesia, but not by ventilation. Microvascular permeability was highest in atelectatic lungs, whereas neutrophil-recruitment and structural changes were strongest in lungs ventilated with high tidal volume. The cytokines IL-6 and KC, but neither TNF nor IP-10, were elevated in the BAL and serum of all ventilated mice and were reduced by recurrent RM. Lung mechanics, oxygenation and pulmonary inflammation were improved by increased PEEP. Conclusions Recurrent RM maintain lung mechanics in their physiological range during low tidal volume ventilation of healthy mice by preventing atelectasis and

  17. Caloric Restriction Enhances Fear Extinction Learning in Mice

    PubMed Central

    Riddle, Megan C; McKenna, Morgan C; Yoon, Yone J; Pattwell, Siobhan S; Santos, Patricia Mae G; Casey, B J; Glatt, Charles E

    2013-01-01

    Fear extinction learning, the ability to reassess a learned cue of danger as safe when it no longer predicts aversive events, is often dysregulated in anxiety disorders. Selective serotonin reuptake inhibitors (SSRI's) enhance neural plasticity and their ability to enhance fear extinction learning may explain their anxiolytic properties. Caloric restriction (CR) has SSRI-like effects on neural plasticity and anxiety-related behavior. We implemented CR in mice to determine its effects on conditioned-fear responses. Wild type and serotonin transporter (SERT) knockout mice underwent CR for 7 days leading to significant weight loss. Mice were then tested for cued fear learning and anxiety-related behavior. CR markedly enhanced fear extinction learning and its retention in adolescent female mice, and adults of both sexes. These effects of CR were absent in SERT knockout mice. Moreover, CR phenocopied behavioral and molecular effects of chronic fluoxetine, but there was no additive effect of CR in fluoxetine-treated mice. These results demonstrate that CR enhances fear extinction learning through a SERT-dependent mechanism. These results may have implications for eating disorders such as anorexia nervosa (AN), in which there is a high prevalence of anxiety before the onset of dietary restriction and support proposals that in AN, CR is a motivated effort to control dysregulated fear responses and elevated anxiety. PMID:23303073

  18. Caloric restriction enhances fear extinction learning in mice.

    PubMed

    Riddle, Megan C; McKenna, Morgan C; Yoon, Yone J; Pattwell, Siobhan S; Santos, Patricia Mae G; Casey, B J; Glatt, Charles E

    2013-05-01

    Fear extinction learning, the ability to reassess a learned cue of danger as safe when it no longer predicts aversive events, is often dysregulated in anxiety disorders. Selective serotonin reuptake inhibitors (SSRI's) enhance neural plasticity and their ability to enhance fear extinction learning may explain their anxiolytic properties. Caloric restriction (CR) has SSRI-like effects on neural plasticity and anxiety-related behavior. We implemented CR in mice to determine its effects on conditioned-fear responses. Wild type and serotonin transporter (SERT) knockout mice underwent CR for 7 days leading to significant weight loss. Mice were then tested for cued fear learning and anxiety-related behavior. CR markedly enhanced fear extinction learning and its retention in adolescent female mice, and adults of both sexes. These effects of CR were absent in SERT knockout mice. Moreover, CR phenocopied behavioral and molecular effects of chronic fluoxetine, but there was no additive effect of CR in fluoxetine-treated mice. These results demonstrate that CR enhances fear extinction learning through a SERT-dependent mechanism. These results may have implications for eating disorders such as anorexia nervosa (AN), in which there is a high prevalence of anxiety before the onset of dietary restriction and support proposals that in AN, CR is a motivated effort to control dysregulated fear responses and elevated anxiety. PMID:23303073

  19. Enhanced colonic tumorigenesis in alkaline sphingomyelinase (NPP7) knockout mice.

    PubMed

    Chen, Ying; Zhang, Ping; Xu, Shu-Chang; Yang, Liping; Voss, Ulrikke; Ekblad, Eva; Wu, Yunjin; Min, Yalan; Hertervig, Erik; Nilsson, Åke; Duan, Rui-Dong

    2015-01-01

    Intestinal alkaline sphingomyelinase (alk-SMase) generates ceramide and inactivates platelet-activating factor (PAF) and was previously suggested to have anticancer properties. The direct evidence is still lacking. We studied colonic tumorigenesis in alk-SMase knockout (KO) mice. Formation of aberrant crypt foci (ACF) was examined after azoxymethane (AOM) injection. Tumor was induced by AOM alone, a conventional AOM/dextran sulfate sodium (DSS) treatment, and an enhanced AOM/DSS method. β-Catenin was determined by immunohistochemistry, PAF levels by ELISA, and sphingomyelin metabolites by mass spectrometry. Without treatment, spontaneous tumorigenesis was not identified but the intestinal mucosa appeared thicker in KO than in wild-type (WT) littermates. AOM alone induced more ACF in KO mice but no tumors 28 weeks after injection. However, combination of AOM/DSS treatments induced colonic tumors and the incidence was significantly higher in KO than in WT mice. By the enhanced AOM/DSS method, tumor number per mouse increased 4.5 times and tumor size 1.8 times in KO compared with WT mice. Although all tumors were adenomas in WT mice, 32% were adenocarcinomas in KO mice. Compared with WT mice, cytosol expression of β-catenin was significantly increased and nuclear translocation in tumors was more pronounced in KO mice. Lipid analysis showed decreased ceramide in small intestine and increased sphingosine-1-phosphate (S1P) in both small intestine and colon in nontreated KO mice. PAF levels in feces were significantly higher in the KO mice after AOM/DSS treatment. In conclusion, lack of alk-SMase markedly increases AOM/DSS-induced colonic tumorigenesis associated with decreased ceramide and increased S1P and PAF levels. PMID:25381265

  20. Immune enhancement during chronic ethanol feeding in mice - Autoimmune phenomena

    SciTech Connect

    Honchel, R.; Rhoads, C.A.; Fitzpatrick, E.A.; McClain, C.J.; Kaplan, A.M.; Cohen, D.A. )

    1991-03-11

    Chronic alcohol abuse in humans is often associated with diminished immune reactivity and enhanced susceptibility to infections. However, many alcohol-dependent individuals display signs of autoimmunity, which has been implicated in alcohol-associated liver damage. This study demonstrates that C57Bl/6 mice placed on the Lieber-DeCarli liquid ethanol diet for up to 9 weeks displayed augmented immune reactivity as compared to mice placed on an isocaloric control diet. Spleen cells were significantly more responsive to the mitogens, LPS and ConA, as early as 3 weeks after initiation of EtOH feeding and this hyperresponsiveness persisted throughout the 9 week feeding period. Similar enhancement of the mixed lymphocyte response was also seen in EtOH fed mice. The enhancement of immune responsiveness was not related to a change in the numbers or percentages of B cells, T cells, or in the CD4/CD8 T cell ratios as determined by flow cytometry. These studies indicate that under certain conditions of ethanol feeding in mice, enhancement rather than suppression of the immune system may occur. This system may be a model to evaluate possible induction of autoimmune responses during chronic ethanol abuse. Studies are underway to measure the presence of auto-antibodies in the sera of these ethanol fed mice.

  1. Treadmill exercise enhances NMDA receptor expression in schizophrenia mice

    PubMed Central

    Park, Joon-Ki; Lee, Sam-Jun; Kim, Tae-Won

    2014-01-01

    Schizophrenia is a serious psychiatric disorder with several symptoms including cognitive dysfunction. Although the causes of schizophrenia are still unclear, there is a strong suspicion that the abnormality in N-methyl-D-aspartate (NMDA) receptor may contribute to schizophrenia symptoms. In the present study, the effect of treadmill exercise on the NMDA receptor expression was evaluated using MK-801-induced schizophrenia mice. Immunohistochemistry for expressions of NMDA receptor tyrosine hydroxylase (TH) was conducted. Western blot for brain-derived neurotrophic factor (BDNF) was also performed. In the present results, the mice in the MK-801-treated group displayed reduced NMDA receptor expression. Enhanced TH expression and suppressed BDNF expression were also observed in the MK-801-treated mice. Treadmill exercise improved NMDA receptor expression in the MK-801-induced schizophrenia mice. Treadmill exercise also suppressed TH expression and enhanced BDNF expression in the MK-801-induced schizophrenia mice. The present study showed that down-regulation of NMDA receptor demonstrated schizophrenia-like parameters, meanwhile treadmill running improved schizophrenia-related parameters through enhancing NMDA receptor expression. PMID:24678500

  2. DNA Nanocarriers for Systemic Administration: Characterization and In Vivo Bioimaging in Healthy Mice

    PubMed Central

    David, Stephanie; Passirani, Catherine; Carmoy, Nathalie; Morille, Marie; Mevel, Mathieu; Chatin, Benoit; Benoit, Jean-Pierre; Montier, Tristan; Pitard, Bruno

    2013-01-01

    We hereby present different DNA nanocarriers consisting of new multimodular systems (MMS), containing the cationic lipid dioleylaminesuccinylparomomycin (DNA MMS DOSP), or bis (guanidinium)-tren-cholesterol (DNA MMS BGTC), and DNA lipid nanocapsules (DNA LNCs). Active targeting of the asialoglycoprotein receptor (ASGP-R) using galactose as a ligand for DNA MMS (GAL DNA MMS) and passive targeting using a polyethylene glycol coating for DNA LNCs (PEG DNA LNCs) should improve the properties of these DNA nanocarriers. All systems were characterized via physicochemical methods and the DNA payload of DNA LNCs was quantified for the first time. Afterwards, their biodistribution in healthy mice was analyzed after encapsulation of a fluorescent dye via in vivo biofluorescence imaging (BFI), revealing various distribution profiles depending on the cationic lipid used and their surface characteristics. Furthermore, the two vectors with the best prolonged circulation profile were administered twice in healthy mice revealing that the new DNA MMS DOSP vectors showed no toxicity and the same distribution profile for both injections, contrary to PEG DNA LNCs which showed a rapid clearance after the second injection, certainly due to the accelerated blood clearance phenomenon. PMID:23299832

  3. Consumption of orange fermented beverage reduces cardiovascular risk factors in healthy mice.

    PubMed

    Escudero-López, Blanca; Berná, Genoveva; Ortega, Ángeles; Herrero-Martín, Griselda; Cerrillo, Isabel; Martín, Franz; Fernández-Pachón, María-Soledad

    2015-04-01

    The consumption of fruits prevents the risk of cardiovascular diseases. Alcoholic fermentation has been carried out in fruits resulting in products which provide high concentration of bioactive compounds and variable alcohol content. The aim of this study was to assess the potential beneficial effect of an orange beverage obtained by alcoholic fermentation and pasteurization of orange juice on cardiovascular risk biomarkers. For this purpose, four mice groups (n = 8) ingested orange beverage (equivalent volume to 250 mL/day in human), orange juice, alcoholic solution (at the proportional amount of orange beverage) or water during 12 weeks. The equivalent amount to double serving of orange beverage (500 mL/day) was administered to mice in a subsequent intervention, and a control group was also evaluated. Orange beverage consumption increased levels of glutathione and uric acid, improved lipid profile, decreased oxidized LDL and maintained levels of IL-6 and C-reactive protein. Synergistic effects between the bioactive compounds and the alcohol content of orange beverage may occur. The intake of double serving also increased antioxidant enzyme activities, bilirubin content and plasma antioxidant capacity. These results suggest that orange beverage may produce greater protection against cardiovascular risk factors than orange juice in healthy mice. PMID:25666657

  4. Inhibition of estrogen biosynthesis enhances lymphoma growth in mice

    PubMed Central

    Talaber, Gergely; Yakimchuk, Konstantin; Guan, Jiyu; Inzunza, Jose; Okret, Sam

    2016-01-01

    Most lymphomas show higher incidence and poorer prognosis in males compared to females. However, the endocrine contribution to this gender difference is not entirely known. Here we show that castration accelerates lymphoma growth in C57BL6 male mice grafted with murine EG7 T cell lymphoma cells. However, the androgen receptor antagonist Bicalutamide did not affect lymphoma growth, suggesting no impact of androgen receptor signaling on lymphoma progression. In contrast, inhibition of androgen-to-estrogen conversion by the aromatase inhibitor (AI) Letrozole induced faster lymphoma growth in mice, suggesting that androgens impact lymphoma growth through its conversion to estrogens. This was supported by the inability of dihydrotestosterone, which is not converted to estrogens by aromatase, to influence lymphoma growth in castrated male mice. Lymphoma growth was also stimulated in immunocompromised mice grafted with human B cell lymphoma (Granta-519) and treated with either reversible or irreversible AIs, showing that the blockage of estrogen synthesis caused enhanced growth of both murine T and human B cell lymphomas and with different AIs. Additionally, AI-treated EG7 lymphomas showed accelerated growth not only in male but also in intact female mice. Altogether, our results demonstrate that aromatase inhibition accelerates lymphoma growth but not androgens per se, highlighting a protective role of estrogens in lymphoma pathogenesis. These results also raise concern that the use of AIs in women with breast cancer might enhance lymphoma progression. PMID:26943574

  5. Generation of healthy mice from gene-corrected disease-specific induced pluripotent stem cells.

    PubMed

    Wu, Guangming; Liu, Na; Rittelmeyer, Ina; Sharma, Amar Deep; Sgodda, Malte; Zaehres, Holm; Bleidissel, Martina; Greber, Boris; Gentile, Luca; Han, Dong Wook; Rudolph, Cornelia; Steinemann, Doris; Schambach, Axel; Ott, Michael; Schöler, Hans R; Cantz, Tobias

    2011-07-01

    Using the murine model of tyrosinemia type 1 (fumarylacetoacetate hydrolase [FAH] deficiency; FAH⁻/⁻ mice) as a paradigm for orphan disorders, such as hereditary metabolic liver diseases, we evaluated fibroblast-derived FAH⁻/⁻-induced pluripotent stem cells (iPS cells) as targets for gene correction in combination with the tetraploid embryo complementation method. First, after characterizing the FAH⁻/⁻ iPS cell lines, we aggregated FAH⁻/⁻-iPS cells with tetraploid embryos and obtained entirely FAH⁻/⁻-iPS cell-derived mice that were viable and exhibited the phenotype of the founding FAH⁻/⁻ mice. Then, we transduced FAH cDNA into the FAH⁻/⁻-iPS cells using a third-generation lentiviral vector to generate gene-corrected iPS cells. We could not detect any chromosomal alterations in these cells by high-resolution array CGH analysis, and after their aggregation with tetraploid embryos, we obtained fully iPS cell-derived healthy mice with an astonishing high efficiency for full-term development of up to 63.3%. The gene correction was validated functionally by the long-term survival and expansion of FAH-positive cells of these mice after withdrawal of the rescuing drug NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione). Furthermore, our results demonstrate that both a liver-specific promoter (transthyretin, TTR)-driven FAH transgene and a strong viral promoter (from spleen focus-forming virus, SFFV)-driven FAH transgene rescued the FAH-deficiency phenotypes in the mice derived from the respective gene-corrected iPS cells. In conclusion, our data demonstrate that a lentiviral gene repair strategy does not abrogate the full pluripotent potential of fibroblast-derived iPS cells, and genetic manipulation of iPS cells in combination with tetraploid embryo aggregation provides a practical and rapid approach to evaluate the efficacy of gene correction of human diseases in mouse models. PMID:21765802

  6. Exercise training reduces inflammatory mediators in the intestinal tract of healthy older adult mice.

    PubMed

    Packer, Nicholas; Hoffman-Goetz, Laurie

    2012-06-01

    Aging is associated with increased intestinal inflammation and elevated risk of chronic diseases including inflammatory bowel diseases and colon cancer; many epidemiologic studies show that regular exercise reduces risk. This study examined the effects of long-term voluntary exercise on inflammatory mediators expressed in the intestine of older (15-16 months), healthy C57BL/6 mice. Animals were assigned to four months of freewheel running (WR; n = 20) or to a "sedentary" no wheel running (NWR; n = 20) control group. Intestinal lymphocytes were harvested and analysed for expression of (1) pro-inflammatory (TNF-α, IL-1β) and pleiotropic (IL-6) cytokines, and (2) pro-(caspase-3/-7) and anti-(Bcl-2) apoptotic proteins. Training was confirmed by skeletal muscle enzyme activity; stress was assessed by plasma 8-iso-PGF(2α) and corticosterone. The WR mice had a lower expression of TNF-α, caspase-7, and 8-isoprostanes (p < .05) compared to sedentary controls, suggesting that long-term exercise may "protect" the bowel by reducing inflammatory cytokine and apoptotic protein expression. PMID:22647663

  7. An Investigation into the Immunomodulatory Activities of Sutherlandia frutescens in Healthy Mice.

    PubMed

    Lei, Wei; Browning, Jimmy D; Eichen, Peggy A; Folk, William R; Sun, Grace Y; Lubahn, Dennis B; Fritsche, Kevin L

    2016-01-01

    Sutherlandia frutescens is a medicinal plant that has been traditionally used in southern Africa for cancers, infections, and inflammatory conditions. We recently published experiments demonstrating that an aqueous extract of S. frutescens possessed potent immune-stimulatory activity. This work was carried out with murine macrophages, an immune cell type that plays a pivotal role in host defense from infection and in shaping host inflammatory and immune responses. Here, we conducted a series of follow-up experiments to explore the impact of consuming S. frutescens on host response to bacterial challenge using healthy mice. We found that feeding mice a diet containing S. frutescens failed to significantly alter host response to systemic infection by either a gram-positive or gram-negative bacterium (i.e., L. monocytogenes and E. coli, respectively). In contrast to the in vitro observations, we found no evidence that S. frutescens consumption stimulated in vivo inflammatory responses; instead, consumption of S. frutescens tended to diminish in vivo inflammatory responses. Several possible reasons for this are discussed. PMID:27575007

  8. An Investigation into the Immunomodulatory Activities of Sutherlandia frutescens in Healthy Mice

    PubMed Central

    Lei, Wei; Browning, Jimmy D.; Eichen, Peggy A.; Folk, William R.; Sun, Grace Y.; Lubahn, Dennis B.

    2016-01-01

    Sutherlandia frutescens is a medicinal plant that has been traditionally used in southern Africa for cancers, infections, and inflammatory conditions. We recently published experiments demonstrating that an aqueous extract of S. frutescens possessed potent immune-stimulatory activity. This work was carried out with murine macrophages, an immune cell type that plays a pivotal role in host defense from infection and in shaping host inflammatory and immune responses. Here, we conducted a series of follow-up experiments to explore the impact of consuming S. frutescens on host response to bacterial challenge using healthy mice. We found that feeding mice a diet containing S. frutescens failed to significantly alter host response to systemic infection by either a gram-positive or gram-negative bacterium (i.e., L. monocytogenes and E. coli, respectively). In contrast to the in vitro observations, we found no evidence that S. frutescens consumption stimulated in vivo inflammatory responses; instead, consumption of S. frutescens tended to diminish in vivo inflammatory responses. Several possible reasons for this are discussed. PMID:27575007

  9. 2-Deoxy-D-Glucose Enhances Anesthethic Effects in Mice

    PubMed Central

    Wang, Hui; Xu, Zhipeng; Wu, Anshi; Dong, Yuanlin; Zhang, Yiying; Yue, Yun; Xie, Zhongcong

    2014-01-01

    Background The mechanisms of general anesthesia by volatile drugs remain largely unknown. Mitochondrial dysfunction and reduction in energy levels have been suggested to be associated with general anesthesia status. 2-Deoxy-d-glucose (2-DG), an analog of glucose, inhibits hexokinase and reduces cellular levels of adenosine triphosphate (ATP). 3-Nitropropionic acid is another compound which can deplete ATP levels. In contrast, idebenone and L-carnitine could rescue deficits of energy. We therefore sought to determine whether 2-DG and/or 3-nitropropionic acid can enhance the anesthetic effects of isoflurane, and whether idebenone and L-carnitine can reverse the actions of 2-DG. Methods C57BL/6J mice (8 months old) received different concentrations of isoflurane with and without the treatments of 2-DG, 3-nitropropionic acid, idebenone, and L-carnitine. Isoflurane-induced loss of righting reflex (LORR) was determined in the mice. ATP levels in H4 human neuroglioma cells were assessed after these treatments. Finally, 31P-magnetic resonance spectroscopy was used to determine the effects of isoflurane on brain ATP levels in the mice. Results 2-DG enhanced isoflurane-induced LORR (P = 0.002, N = 15). 3-nitropropionic acid also enhanced the anesthetic effects of isoflurane (P = 0.005, N = 15). Idebenone (Idebenone + saline versus Idebenone + 2-DG: P = 0.165, N = 15), but not L-cartinine (L-carnitine + saline versus L-carnitine + 2-DG: P < 0.0001, N = 15), inhibited the effects of 2-DG on enhancing isoflurane-induced LORR in mice, as evidenced by 2-DG not enhancing isoflurane-induced LORR in mice pretreated with idebenone. Idebenone (Idebenone + saline versus Idebenone + 2-DG: P = 0.177, N = 6), but not L-cartinine (L-carnitine + saline versus L-carnitine + 2-DG: P = 0.029, N = 6), also mitigated the effects of 2-DG on reducing ATP levels in cells, as evidenced by 2-DG not decreasing ATP levels in the cell pretreated with idebenone. Finally, isoflurane decreased ATP levels

  10. 1H-NMR METABONOMICS ANALYSIS OF SERA DIFFERENTIATES BETWEEN MAMMARY TUMOR-BEARING MICE AND HEALTHY CONTROLS

    EPA Science Inventory

    Global analysis of 1H-NMR spectra of serum is an appealing approach for the rapid detection of cancer. To evaluate the usefulness of this method in distinguishing between mammary tumor-bearing mice and healthy controls, we conducted 1H-NMR metabonomic analyses on serum samples ob...

  11. Pomelo enhances cyclosporine bioavailability in healthy male Thai volunteers.

    PubMed

    Anlamlert, Wirin; Sermsappasuk, Pakawadee; Yokubol, Dhirayudh; Jones, Sirada

    2015-04-01

    The aim of this study was to investigate the effect of pomelo pulp on the pharmacokinetics of cyclosporine in healthy male Thai volunteers. The study design was an open-label, randomized, single dose, crossover study with a 2-week washout period. A single oral dose of 2 × 100 mg cyclosporine was administered with 200 mL of water. Each subject received 250 g of pomelo pulp or 250 mL of water 1 hour before drug administration and once again 10 minutes following drug administration. Blood samples were collected over a 24 hour period. The point estimates (90% confidence intervals) of the test/control ratio using logarithmic transformed data for the area under the curve (AUC) for blood concentration from time 0 to infinity (AUC(0- ∞)) and the observed maximum concentration (C(max)) were 128.8% (120.6-137.6) and 136.1% (126.0-146.8), respectively. These 90% confidence intervals were higher than the accepted bioequivalence range defined by the European Medicines Agency guidelines for narrow therapeutic index drugs (90%-111% for AUC and 80%-125% for C(max)). However, the apparent terminal half-life (t(1/2)) was not significantly different. In conclusion, co-administration of cyclosporine and pomelo pulp increased the relative bioavailability of cyclosporine. PMID:25408261

  12. Contrast-enhanced dynamic magnetic resonance nephrography in healthy dogs.

    PubMed

    Fonseca-Matheus, J M; Pérez-García, C C; Ginja, M M D; Altónaga, J R; Orden, M A; Gonzalo-Orden, J M

    2011-09-01

    Twenty-three healthy mixed-breed male adult dogs were examined using serial magnetic resonance (MR) renograms. The images were obtained using a dynamic gradient-echo, fast SPGR, T1-weighted sequence and low doses of gadolinium chelates (0.025 mmol/kg). Time-intensity curves were obtained to assess typical urinary excretion parameters, namely, time to vascular peak (TVP), time to vascular drop (TVD), time to glomerular peak (TGP), parenchymal phase length (PPL), gradient of parenchymal phase (GPP) and pattern of excretory segment. The mean TVP, TVD, TGP and PPL were 31.6±11.8, 43.4±11.2, 154.0±36.2 and 115.2±37.7s, respectively. The GPP was 24.1±8.6% of signal intensity per min. The excretory segment was concave in all cases, and at the end of the examination, 87.1% of kidneys had shown a reduction in signal intensity of 50%. This MR nephrography protocol can provide adequate time-intensity curve parameters for the urinary system of dogs, offers excellent anatomical detail, and represents an alternative to radionuclide nephrography. PMID:20810295

  13. Dietary flaxseed modulates the colonic microenvironment in healthy C57Bl/6 male mice which may alter susceptibility to gut-associated diseases.

    PubMed

    Power, Krista A; Lepp, Dion; Zarepoor, Leila; Monk, Jennifer M; Wu, Wenqing; Tsao, Rong; Liu, Ronghua

    2016-02-01

    Understanding how dietary components alter the healthy baseline colonic microenvironment is important in determining their roles in influencing gut health and gut-associated diseases. Dietary flaxseed (FS) has demonstrated anti-colon cancer effects in numerous rodent models, however, exacerbated acute colonic mucosal injury and inflammation in a colitis model. This study investigates whether FS alters critical aspects of gut health in healthy unchallenged mice, which may help explain some of the divergent effects observed following different gut-associated disease challenges. Four-week-old C57Bl/6 male mice were fed an AIN-93G basal diet (BD) or an isocaloric BD+10% ground FS diet for 3 weeks. FS enhanced colon goblet cell density, mucus production, MUC2 mRNA expression, and cecal short chain fatty acid levels, indicative of beneficial intestinal barrier integrity responses. Additionally, FS enhanced colonic regenerating islet-derived protein 3 gamma (RegIIIγ) and reduced MUC1 and resistin-like molecule beta (RELMβ) mRNA expression which may indicate altered responses in regulating microbial defense and injury repair responses. FS diet altered the fecal microbial community structure (16S rRNA gene profiling), including a 20-fold increase in Prevotella spp. and a 30-fold reduction in Akkermansia muciniphila abundance. A 10-fold reduction in A. muciniphila abundance by FS was also demonstrated in the colon tissue-associated microbiota (quantitative PCR). Furthermore, fecal branched chain fatty acids were increased by FS, indicative of increased microbial-derived putrefactive compounds. In conclusion, consumption of a FS-supplemented diet alters the baseline colonic microenvironment of healthy mice which may modify subsequent mucosal microbial defense and injury-repair responses leading to altered susceptibility to different gut-associated diseases. PMID:26878783

  14. Caspase-2 Deficiency Enhances Aging-Related Traits in Mice

    PubMed Central

    Zhang, Yingpei; Padalecki, Susan S; Chaudhuri, Asish R; Waal, Eric De; Goins, Beth A; Grubbs, Barry; Ikeno, Yuji; Richardson, Arlan; Mundy, Gregory R; Herman, Brian

    2007-01-01

    Alteration of apoptotic activity has been observed in a number of tissues in aging mammals, but it remains unclear whether and/or how apoptosis may affect aging. Caspase-2 is a member of the cysteine protease family that plays a critical role in apoptosis. To understand the impact of compromised apoptosis function on mammalian aging, we conducted a comparative study on caspase-2 deficient mice and their wild-type littermates with a specific focus on the aging-related traits at advanced ages. We found that caspase-2 deficiency enhanced a number of traits commonly seen in premature aging animals. Loss of caspase-2 was associated with shortened maximum lifespan, impaired hair growth, increased bone loss, and reduced body fat content. In addition, we found that the livers of caspase-2 deficient mice had higher levels of oxidized proteins than those of age-matched wild-type mice, suggesting that caspase-2 deficiency compromised the animal's ability to clear oxidatively damaged cells. Collectively, these results suggest that caspase-2 deficiency affects aging in the mice. This study thus demonstrates for the first time that disruption of a key apoptotic gene has a significant impact on aging. PMID:17188333

  15. Enhanced emotional empathy after mineralocorticoid receptor stimulation in women with borderline personality disorder and healthy women.

    PubMed

    Wingenfeld, Katja; Kuehl, Linn K; Janke, Katrin; Hinkelmann, Kim; Dziobek, Isabel; Fleischer, Juliane; Otte, Christian; Roepke, Stefan

    2014-07-01

    The mineralocorticoid receptor (MR) is highly expressed in the hippocampus and prefrontal cortex. MR have an important role in appraisal processes and in modulating stress-associated emotional reactions but it is not known whether the MR affects empathy. Borderline personality disorder (BPD) is characterized by disturbed emotion regulation and alterations in empathy. In the current study, we examined whether stimulation of the MR enhances empathy in patients with BPD and healthy individuals. In a placebo-controlled study, we randomized 38 women with BPD and without psychotropic medication, and 35 healthy women to either placebo or 0.4 mg fludrocortisone, an MR agonist. Subsequently, all participants underwent two tests of social cognition, the Multifaceted Empathy Test (MET) and the Movie for the Assessment of Social Cognition (MASC), measuring cognitive and emotional facets of empathy. Eighteen BPD patients and 18 healthy women received placebo, whereas 20 BPD patients and 17 healthy women received fludrocortisone. In the MET, fludrocortisone enhanced emotional empathy across groups, whereas cognitive empathy was not affected. In the MASC, no effect of fludrocortisone could be revealed. In both tests, BPD patients and healthy women did not differ significantly in cognitive and emotional empathy and in their response to fludrocortisone. Stimulation of MR enhanced emotional empathy in healthy women and in BPD patients. Whether fludrocortisone might have a therapeutic role in psychotherapeutic processes, remains to be elucidated. PMID:24535100

  16. Impedance Alterations in Healthy and Diseased Mice During Electrically Induced Muscle Contraction.

    PubMed

    Sanchez, Benjamin; Li, Jia; Geisbush, Tom; Bardia, Ramon Bragos; Rutkove, Seward B

    2016-08-01

    Alterations in the health of muscles can be evaluated through the use of electrical impedance myography (EIM). To date, however, nearly all work in this field has relied upon the measurement of muscle at rest. To provide an insight into the contractile mechanisms of healthy and disease muscle, we evaluated the alterations in the spectroscopic impedance behavior of muscle during the active process of muscle contraction. The gastrocnemii from a total of 13 mice were studied (five wild type, four muscular dystrophy animals, and four amyotrophic lateral sclerosis animals). Muscle contraction was induced via monophasic current pulse stimulation of the sciatic nerve. Simultaneously, multisine EIM (1 kHz to 1 MHz) and force measurements of the muscle were performed. Stimulation was applied at three different rates to produce mild, moderate, and strong contractions. We identified changes in both single and multifrequency data, as assessed by the Cole impedance model parameters. The processes of contraction and relaxation were clearly identified in the impedance spectra and quantified via derivative plots. Reductions in the center frequency fc were observed during the contraction consistent with the increasing muscle fiber diameter. Different EIM stimulation rate-dependencies were also detected across the three groups of animals. PMID:24800834

  17. Differentiation of healthy brain tissue and tumors using surface-enhanced Raman scattering.

    PubMed

    Aydin, Omer; Altaş, Murat; Kahraman, Mehmet; Bayrak, Omer Faruk; Culha, Mustafa

    2009-10-01

    Surface-enhanced Raman scattering (SERS) is a powerful technique for characterization of biological samples. SERS spectra from healthy brain tissue and tumors are obtained by sudden freezing of tissue in liquid nitrogen and crashing and mixing it with a concentrated silver colloidal suspension. The acquired spectra from tissues show significant spectral differences that can be used to identify whether it is from a healthy region or tumor. The most significant change on SERS spectra from the healthy/peripheral brain tissue to tumor is the increase of the ratio of the peaks at around 723 to 655 cm(-1). In addition, the spectral changes indicate that the protein content in tumors increases compared to the peripheral/healthy tissue as observed with tumor invasion. The preliminary results show that SERS spectra can be used for a quick diagnosis due to the simplicity of the sample preparation and the speed of the spectral acquisition. PMID:19843358

  18. Mobile phone SMS messages can enhance healthy behaviour: a meta-analysis of randomised controlled trials.

    PubMed

    Orr, Jayne A; King, Robert J

    2015-01-01

    Healthy behaviour, such as smoking cessation and adherence to prescribed medications, mitigates illness risk factors but health behaviour change can be challenging. Mobile phone short-message service (SMS) messages are increasingly used to deliver interventions designed to enhance healthy behaviour. This meta-analysis used a random-effects model to synthesise 38 randomised controlled trials that investigated the efficacy of SMS messages to enhance healthy behaviour. Participants (N = 19,641) lived in developed and developing countries and were diverse with respect to age, ethnicity, socioeconomic background and health behaviours targeted for change. SMS messages had a small, positive, significant effect (g = 0.291) on a broad range of healthy behaviour. This effect was maximised when multiple SMS messages per day were used (g = 0.395) compared to using lower frequencies (daily, multiple per week and once-off) (g = 0.244). The low heterogeneity in this meta-analysis (I (2) = 38.619) supports reporting a summary effect size and implies that the effect of SMS messaging is robust, regardless of population characteristics or healthy behaviour targeted. SMS messaging is a simple, cost-effective intervention that can be automated and can reach any mobile phone owner. While the effect size is small, potential health benefits are well worth achieving. PMID:25739668

  19. Enhancing Methotrexate Tolerance with Folate Tagged Liposomes in Arthritic Mice.

    PubMed

    Nogueira, Eugénia; Lager, Franck; Le Roux, Delphine; Nogueira, Patrícia; Freitas, Jaime; Charvet, Celine; Renault, Gilles; Loureiro, Ana; Almeida, Catarina R; Ohradanova-Repic, Anna; Machacek, Christian; Bernardes, Gonçalo J L; Moreira, Alexandra; Stockinger, Hannes; Burnet, Michael; Carmo, Alexandre M; Gomes, Andreia C; Preto, Ana; Bismuth, Georges; Cavaco-Paulo, Artur

    2015-12-01

    Methotrexate is the first line of treatment of rheumatoid arthritis. Since many patients become unresponsive to methotrexate treatment, only very expensive biological therapies are effective and increased methotrexate tolerance strategies need to be identified. Here we propose the encapsulation of methotrexate in a new liposomal formulation using a hydrophobic fragment of surfactant protein conjugated to a linker and folate to enhance their tolerance and efficacy. In this study we aim to evaluate the efficiency of this system to treat rheumatoid arthritis, by targeting folate receptor β present at the surface of activated macrophages, key effector cells in this pathology. The specificity of our liposomal formulation to target folate receptor β was investigated both in vitro as in vivo using a mouse model of arthritis (collagen-induced arthritis in DBA/1J mice strain). In both systems, the liposomal constructs were shown to be highly specific and efficient in targeting folate receptor β. These liposomal formulations also significantly increase the clinical benefit of the encapsulated methotrexate in vivo in arthritic mice, together with reduced expression of CD39 and CD73 ectonucleotidases by joint-infiltrating macrophages. Thus, our formulation might be a promising cost effective way to treat rheumatoid arthritis and delay or reduce methotrexate intolerance. PMID:26510317

  20. Cordyceps militaris Enhances Cell-Mediated Immunity in Healthy Korean Men.

    PubMed

    Kang, Ho Joon; Baik, Hyun Wook; Kim, Sang Jung; Lee, Seong Gyu; Ahn, Hong Yup; Park, Ju Sang; Park, Sang Jong; Jang, Eun Jeong; Park, Sang Woon; Choi, Jin Young; Sung, Ji Hee; Lee, Seung Min

    2015-10-01

    Cordyceps militaris is a mushroom traditionally used for diverse pharmaceutical purposes in East Asia, including China, and has been found to be effective for enhancing immunity through various types of animal testing. The aim of this study is to determine the efficacy of C. militaris for enhancing cell-mediated immunity and its safety in healthy male adults. Healthy male adults were divided into the experimental group (n = 39), given 1.5 g/day of ethanol treated C. militaris in capsules, and the control group (n = 40), given the same number of identical placebo capsules filled with microcrystalline cellulose and lactose for 4 weeks from February 13 to March 14, 2012; the natural killer (NK) cell activity, lymphocyte proliferation index (PI), and T-helper cell 1 (Th1) cytokine cluster (interferon [IFN]-γ, interleukin [IL]-12, IL-2, and tumor necrosis factor [TNF]-α) were measured, along with stability test, at weeks 0, 2, and 4. The C. militaris group showed a statistically significant greater increase in NK200 (P = .0010), lymphocyte PI (P ≤ .0001), IL-2 (P = .0096), and IFN-γ (P = .0126), compared with the basal level, than the placebo group. There was no statistically significant adverse reaction. C. militaris enhanced the NK cell activity and lymphocyte proliferation and partially increased Th1 cytokine secretion. Therefore, C. militaris is safe and effective for enhancing cell-mediated immunity of healthy male adults. PMID:26284906

  1. Enhanced glucose tolerance by intravascularly administered piceatannol in freely moving healthy rats.

    PubMed

    Oritani, Yukihiro; Okitsu, Teru; Nishimura, Eisaku; Sai, Masahiko; Ito, Tatsuhiko; Takeuchi, Shoji

    2016-02-12

    Piceatannol is a phytochemical in the seeds of passion fruit that has a hypoglycemic effect when orally administered. To elucidate the contribution of intact and metabolites of piceatannol after gastro-intestinal absorption to hypoglycemic effect, we examined the influence of piceatannol and isorhapontigenin on blood glucose concentrations during fasting and glucose tolerance tests by administering them intravascularly to freely moving healthy rats. We found that intravascularly administered piceatannol reduced the blood glucose concentrations during both fasting and glucose tolerance tests, but isorhapontigenin did not during either of them. Furthermore, we found that piceatannol increased the insulinogenic index during glucose tolerance tests and that piceatannol had no influence on insulin sensitivity by performing hyperinsulinemic euglycemic clamping tests. These results suggest that piceatannol orally intaken may enhance glucose tolerance by the effect of intact piceatannol through enhanced early-phase secretion of insulin. Therefore, oral intake of piceatannol might contribute to proper control of postprandial glycemic excursions in healthy subjects. PMID:26773506

  2. MicroRNA loss enhances learning and memory in mice.

    PubMed

    Konopka, Witold; Kiryk, Anna; Novak, Martin; Herwerth, Marina; Parkitna, Jan Rodriguez; Wawrzyniak, Marcin; Kowarsch, Andreas; Michaluk, Piotr; Dzwonek, Joanna; Arnsperger, Tabea; Wilczynski, Grzegorz; Merkenschlager, Matthias; Theis, Fabian J; Köhr, Georg; Kaczmarek, Leszek; Schütz, Günther

    2010-11-01

    Dicer-dependent noncoding RNAs, including microRNAs (miRNAs), play an important role in a modulation of translation of mRNA transcripts necessary for differentiation in many cell types. In vivo experiments using cell type-specific Dicer1 gene inactivation in neurons showed its essential role for neuronal development and survival. However, little is known about the consequences of a loss of miRNAs in adult, fully differentiated neurons. To address this question, we used an inducible variant of the Cre recombinase (tamoxifen-inducible CreERT2) under control of Camk2a gene regulatory elements. After induction of Dicer1 gene deletion in adult mouse forebrain, we observed a progressive loss of a whole set of brain-specific miRNAs. Animals were tested in a battery of both aversively and appetitively motivated cognitive tasks, such as Morris water maze, IntelliCage system, or trace fear conditioning. Compatible with rather long half-life of miRNAs in hippocampal neurons, we observed an enhancement of memory strength of mutant mice 12 weeks after the Dicer1 gene mutation, before the onset of neurodegenerative process. In acute brain slices, immediately after high-frequency stimulation of the Schaffer collaterals, the efficacy at CA3-to-CA1 synapses was higher in mutant than in control mice, whereas long-term potentiation was comparable between genotypes. This phenotype was reflected at the subcellular and molecular level by the elongated filopodia-like shaped dendritic spines and an increased translation of synaptic plasticity-related proteins, such as BDNF and MMP-9 in mutant animals. The presented work shows miRNAs as key players in the learning and memory process of mammals. PMID:21048142

  3. Participatory research to enhance vision sharing for Healthy Town initiatives in Japan.

    PubMed

    Takano, Takehito; Nakamura, Keiko

    2004-09-01

    This paper presents the results of a participatory research project conducted by the Tokyo Citizens' Council for Health Promotion (Citizens' Council) to enhance vision sharing, thereby aiding the implementation of Healthy Town initiatives. The Citizens' Council conducted a survey to elucidate citizen interests and expectations regarding Healthy Towns. The project had three stages: (i) a survey; (ii) dissemination of the results; and (iii) evaluation of the impact of the survey's findings. The survey was conducted among ordinary citizens, community group members, health promotion practitioners and members of the Citizens' Council. Responses from 476 ordinary citizens, 400 community group members, 316 health promotion practitioners and 387 members of the Citizens' Council were received and analyzed. Major criteria that respondents required of a Healthy Town were: adequate sports facilities and walking/jogging trails (44.5%); easy access for senior citizens, small children and people with disabilities (42.2%); and parks, clean rivers and other natural features (33.1%). Prioritized criteria given by specific respondent groups were (i) a town with little crime and few traffic accidents (ordinary citizens: 37.2%) and (ii) a town where people help each other (health promotion practitioners: 36.7%; members of the Citizens' Council: 31.5%). Factor analysis revealed that the structure of citizen views on criteria for a Healthy Town had the following three dimensions: (i) health conducive physical living environment; (ii) social networks and mutual help; and (iii) societal discipline/rules and good access to services. The research results were disseminated to the general public, community groups and members of the Citizens' Council. The results substantiated citizen views, which were then incorporated into plans towards realizing Healthy Towns initiatives. This research effort generated a vision of the creation of Healthy Towns by the participation of citizens in a megacity

  4. Correlation of oxygenation and perfusion sensitive MRI with invasive micro probe measurements in healthy mice brain.

    PubMed

    Sedlacik, Jan; Reitz, Matthias; Bolar, Divya S; Adalsteinsson, Elfar; Schmidt, Nils O; Fiehler, Jens

    2015-03-01

    The non-invasive assessment of (patho-)physiological parameters such as, perfusion and oxygenation, is of great importance for the characterization of pathologies e.g., tumors, which may be helpful to better predict treatment response and potential outcome. To better understand the influence of physiological parameters on the investigated oxygenation and perfusion sensitive MRI methods, MRI measurements were correlated with subsequent invasive micro probe measurements during free breathing conditions of air, air+10% CO2 and 100% O2 in healthy mice brain. MRI parameters were the irreversible (R2), reversible (R2') and effective (R2*) transverse relaxation rates, venous blood oxygenation level assessed by quantitative blood oxygenation level dependent (qBOLD) method and cerebral blood flow (CBF) assessed by arterial spin labeling (ASL) using a 7 T small animal MRI scanner. One to two days after MRI, tissue perfusion and pO2 were measured by Laser-Doppler flowmetry and fluorescence quenching micro probes, respectively. The tissue pO2 values were converted to blood oxygen saturation by using the Hill equation. The animals were anesthetized by intra peritoneal injection of ketamine-xylazine-acepromazine (10-2-0.3 mg/ml · kg). Results for normal/hypercapnia/hyperoxia conditions were: R2[s(∧)-1] = 20.7/20.4/20.1, R2*[s(∧)-1] = 31.6/29.6/25.9, R2'[s-(∧)1] = 10.9/9.2/5.7, qBOLD venous blood oxygenation level = 0.43/0.51/0.56, CBF[ml · min(∧)-1 · 100 g(∧)-1] = 70.6/105.5/81.8, Laser-Doppler flowmetry[a.u.] = 89.2/120.2/90.6 and pO2[mmHg] = 6.3/32.3/46.7. All parameters were statistically significantly different with P < 0.001 between all breathing conditions. All MRI and the corresponding micro probe measurements were also statistically significantly (P ≤ 0.03) correlated with each other. However, converting the tissue pO2 to blood oxygen saturation = 0.02/0.34/0.63, showed only very limited agreement with the qBOLD venous blood oxygenation level. We found

  5. Comparative proteomics of inhaled silver nanoparticles in healthy and allergen provoked mice

    PubMed Central

    Su, Chien-Ling; Chen, Tzu-Tao; Chang, Chih-Cheng; Chuang, Kai-Jen; Wu, Cheng-Kuan; Liu, Wen-Te; Ho, Kin Fai; Lee, Kang-Yun; Ho, Shu-Chuan; Tseng, Hsiu-Er; Chuang, Hsiao-Chi; Cheng, Tsun-Jen

    2013-01-01

    Background Silver nanoparticles (AgNPs) have been associated with the exacerbation of asthma; however, the immunological basis for the adjuvant effects of AgNPs is not well understood. Objective The aim of the study reported here was to investigate the allergic effects of AgNP inhalation using proteomic approaches. Methods Allergen provoked mice were exposed to 33 nm AgNPs at 3.3 mg/m3. Following this, bronchoalveolar lavage fluid (BALF) and plasma were collected to determine protein profiles. Results In total, 106 and 79 AgNP-unique proteins were identified in the BALF of control and allergic mice, respectively. Additionally, 40 and 26 AgNP-unique proteins were found in the plasma of control and allergic mice, respectively. The BALF and plasma protein profiles suggested that metabolic, cellular, and immune system processes were associated with pulmonary exposure to AgNPs. In addition, we observed 18 proteins associated with systemic lupus erythematosus that were commonly expressed in both control and allergic mice after AgNP exposure. Significant allergy responses were observed after AgNP exposure in control and allergic mice, as determined by ovalbumin-specific immunoglobulin E. Conclusion Inhaled AgNPs may regulate immune responses in the lungs of both control and allergic mice. Our results suggest that immunology is a vital response to AgNPs. PMID:23946650

  6. Angiopoietin-1 enhances skeletal muscle regeneration in mice

    PubMed Central

    Mofarrahi, Mahroo; McClung, Joseph M.; Kontos, Christopher D.; Davis, Elaine C.; Tappuni, Bassman; Moroz, Nicolay; Pickett, Amy E.; Huck, Laurent; Harel, Sharon; Danialou, Gawiyou

    2015-01-01

    Activation of muscle progenitor cell myogenesis and endothelial cell angiogenesis is critical for the recovery of skeletal muscle from injury. Angiopoietin-1 (Ang-1), a ligand of Tie-2 receptors, enhances angiogenesis and skeletal muscle satellite cell survival; however, its role in skeletal muscle regeneration after injury is unknown. We assessed the effects of Ang-1 on fiber regeneration, myogenesis, and angiogenesis in injured skeletal muscle (tibialis anterior, TA) in mice. We also assessed endogenous Ang-1 levels and localization in intact and injured TA muscles. TA fiber injury was triggered by cardiotoxin injection. Endogenous Ang-1 mRNA levels immediately decreased in response to cardiotoxin then increased during the 2 wk. Ang-1 protein was expressed in satellite cells, both in noninjured and recovering TA muscles. Positive Ang-1 staining was present in blood vessels but not in nerve fibers. Four days after the initiation of injury, injection of adenoviral Ang-1 into injured muscles resulted in significant increases in in situ TA muscle contractility, muscle fiber regeneration, and capillary density. In cultured human skeletal myoblasts, recombinant Ang-1 protein increased survival, proliferation, migration, and differentiation into myotubes. The latter effect was associated with significant upregulation of the expression of the myogenic regulatory factors MyoD and Myogenin and certain genes involved in cell cycle regulation. We conclude that Ang-1 strongly enhances skeletal muscle regeneration in response to fiber injury and that this effect is mediated through induction of the myogenesis program in muscle progenitor cells and the angiogenesis program in endothelial cells. PMID:25608750

  7. Pharmacological cognitive enhancement: treatment of neuropsychiatric disorders and lifestyle use by healthy people.

    PubMed

    Sahakian, Barbara J; Morein-Zamir, Sharon

    2015-04-01

    Neuropsychiatric disorders typically manifest as problems with attentional biases, aberrant learning, dysfunctional reward systems, and an absence of top-down cognitive control by the prefrontal cortex. In view of the cost of common mental health disorders, in terms of distress to the individual and family in addition to the financial cost to society and governments, new developments for treatments that address cognitive dysfunction should be a priority so that all members of society can flourish. Cognitive enhancing drugs, such as cholinesterase inhibitors and methylphenidate, are used as treatments for the cognitive symptoms of Alzheimer's disease and attention deficit hyperactivity disorder. However, these drugs and others, including modafinil, are being increasingly used by healthy people for enhancement purposes. Importantly for ethical and safety reasons, the drivers for this increasing lifestyle use of so-called smart drugs by healthy people should be considered and discussions must occur about how to ensure present and future pharmacological cognitive enhancers are used for the benefit of society. PMID:26360089

  8. The role of attention in emotional memory enhancement in pathological and healthy aging.

    PubMed

    Sava, Alina-Alexandra; Paquet, Claire; Dumurgier, Julien; Hugon, Jacques; Chainay, Hanna

    2016-01-01

    After short delays between encoding and retrieval, healthy young participants have better memory performance for emotional stimuli than for neutral stimuli. Divided-attention paradigms suggest that this emotional enhancement of memory (EEM) is due to different attention mechanisms involved during encoding: automatic processing for negative stimuli, and controlled processing for positive stimuli. As far as we know, no study on the influence of these factors on EEM in Alzheimer's disease (AD) and mild cognitive impairment (MCI) patients, as compared to healthy young and older controls, has been conducted. Thus, the goal of our study was to ascertain whether the EEM in these populations depends on the attention resources available at encoding. Participants completed two encoding phases: full attention (FA) and divided attention (DA), followed by two retrieval phases (recognition tasks). There was no EEM on the discrimination accuracy, independently of group and encoding condition. Nevertheless, all participants used a more liberal response criterion for the negative and positive stimuli than for neutral ones. In AD patients, larger numbers of false recognitions for negative and positive stimuli than for neutral ones were observed after both encoding conditions. In MCI patients and in healthy older and younger controls this effect was observed only for negative stimuli, and it depended on the encoding condition. Thus, this effect was observed in young controls after both encoding conditions, in older controls after the DA encoding, and in MCI patients after the FA encoding. In conclusion, our results suggest that emotional valence does not always enhance discrimination accuracy. Nevertheless, in certain conditions related to the attention resources available at encoding, emotional valence, especially the negative one, enhances the subjective feeling of familiarity and, consequently, engenders changes in response bias. This effect seems to be sensitive to the age and

  9. EFFECT OF SEDATION ON CONTRAST-ENHANCED ULTRASONOGRAPHY OF THE SPLEEN IN HEALTHY DOGS.

    PubMed

    Rossi, Federica; Fina, Caroline; Stock, Emmelie; Vanderperren, Katrien; Duchateau, Luc; Saunders, Jimmy H

    2016-05-01

    Contrast-enhanced ultrasound of the spleen enables the dynamic assessment of the perfusion of this organ, however, both subjective and quantitative evaluation can be strongly influenced by sedative agent administration. The purpose of this prospective, experimental study was to test effects of two sedative agents on splenic perfusion during contrast-enhanced ultrasound of the spleen in a sample of healthy dogs. Contrast-enhanced ultrasound of the spleen was repeated in six healthy Beagles following a cross-over study design comparing three protocols: awake, butorphanol 0.2 mg/Kg intramuscular (IM), and dexmedetomidine 500 μg/m(2) IM. After intravenous injection of a phospholipid stabilized sulfur hexafluoride microbubble solution (SonoVue®, Bracco Imaging, Milano, Italy), the enhancement intensity and perfusion pattern of the splenic parenchyma were assessed and perfusion parameters were calculated. Normal spleen was slightly heterogeneous in the early phase, but the parenchyma was homogeneous at a later phase. Sedation with butorphanol did not modify perfusion of the spleen. Dexmedetomidine significantly reduced splenic enhancement, providing diffuse parenchymal hypoechogenicity during the entire examination. Measured parameters were significantly modified, with increased arrival time (AT; (< 0.0001) and time to peak (TTP; P < 0.0001), and decreased peak intensity (PI; P = 0.0108), wash-in (P = 0.0014), and area under the curve (AUC; P = 0.0421). Findings supported the use of butorphanol and contraindicated the use of dexmedetomidine as sedatives for splenic contrast ultrasound procedures in dogs. Short-term and diffuse heterogeneity of the spleen in the early venous phase was determined to be a normal finding. PMID:26777031

  10. The impact of neuroscience on society: cognitive enhancement in neuropsychiatric disorders and in healthy people.

    PubMed

    Sahakian, Barbara J; Bruhl, Annette B; Cook, Jennifer; Killikelly, Clare; Savulich, George; Piercy, Thomas; Hafizi, Sepehr; Perez, Jesus; Fernandez-Egea, Emilio; Suckling, John; Jones, Peter B

    2015-09-19

    In addition to causing distress and disability to the individual, neuropsychiatric disorders are also extremely expensive to society and governments. These disorders are both common and debilitating and impact on cognition, functionality and wellbeing. Cognitive enhancing drugs, such as cholinesterase inhibitors and methylphenidate, are used to treat cognitive dysfunction in Alzheimer's disease and attention deficit hyperactivity disorder, respectively. Other cognitive enhancers include specific computerized cognitive training and devices. An example of a novel form of cognitive enhancement using the technological advancement of a game on an iPad that also acts to increase motivation is presented. Cognitive enhancing drugs, such as methylphenidate and modafinil, which were developed as treatments, are increasingly being used by healthy people. Modafinil not only affects 'cold' cognition, but also improves 'hot' cognition, such as emotion recognition and task-related motivation. The lifestyle use of 'smart drugs' raises both safety concerns as well as ethical issues, including coercion and increasing disparity in society. As a society, we need to consider which forms of cognitive enhancement (e.g. pharmacological, exercise, lifelong learning) are acceptable and for which groups (e.g. military, doctors) under what conditions (e.g. war, shift work) and by what methods we would wish to improve and flourish. PMID:26240429

  11. The impact of neuroscience on society: cognitive enhancement in neuropsychiatric disorders and in healthy people

    PubMed Central

    Sahakian, Barbara J.; Bruhl, Annette B.; Cook, Jennifer; Killikelly, Clare; Savulich, George; Piercy, Thomas; Hafizi, Sepehr; Perez, Jesus; Fernandez-Egea, Emilio; Suckling, John; Jones, Peter B.

    2015-01-01

    In addition to causing distress and disability to the individual, neuropsychiatric disorders are also extremely expensive to society and governments. These disorders are both common and debilitating and impact on cognition, functionality and wellbeing. Cognitive enhancing drugs, such as cholinesterase inhibitors and methylphenidate, are used to treat cognitive dysfunction in Alzheimer's disease and attention deficit hyperactivity disorder, respectively. Other cognitive enhancers include specific computerized cognitive training and devices. An example of a novel form of cognitive enhancement using the technological advancement of a game on an iPad that also acts to increase motivation is presented. Cognitive enhancing drugs, such as methylphenidate and modafinil, which were developed as treatments, are increasingly being used by healthy people. Modafinil not only affects ‘cold’ cognition, but also improves ‘hot’ cognition, such as emotion recognition and task-related motivation. The lifestyle use of ‘smart drugs' raises both safety concerns as well as ethical issues, including coercion and increasing disparity in society. As a society, we need to consider which forms of cognitive enhancement (e.g. pharmacological, exercise, lifelong learning) are acceptable and for which groups (e.g. military, doctors) under what conditions (e.g. war, shift work) and by what methods we would wish to improve and flourish. PMID:26240429

  12. Pharmacological Cognitive Enhancement in Healthy Individuals: A Compensation for Cognitive Deficits or a Question of Personality?

    PubMed Central

    Maier, Larissa J.; Wunderli, Michael D.; Vonmoos, Matthias; Römmelt, Andreas T.; Baumgartner, Markus R.; Seifritz, Erich

    2015-01-01

    The ongoing bioethical debate on pharmacological cognitive enhancement (PCE) in healthy individuals is often legitimated by the assumption that PCE will widely spread and become desirable for the general public in the near future. This assumption was questioned as PCE is not equally save and effective in everyone. Additionally, it was supposed that the willingness to use PCE is strongly personality-dependent likely preventing a broad PCE epidemic. Thus, we investigated whether the cognitive performance and personality of healthy individuals with regular nonmedical methylphenidate (MPH) use for PCE differ from stimulant-naïve controls. Twenty-five healthy individuals using MPH for PCE were compared with 39 age-, sex-, and education-matched healthy controls regarding cognitive performance and personality assessed by a comprehensive neuropsychological test battery including social cognition, prosocial behavior, decision-making, impulsivity, and personality questionnaires. Substance use was assessed through self-report in an interview and quantitative hair and urine analyses. Recently abstinent PCE users showed no cognitive impairment but superior strategic thinking and decision-making. Furthermore, PCE users displayed higher levels of trait impulsivity, novelty seeking, and Machiavellianism combined with lower levels of social reward dependence and cognitive empathy. Finally, PCE users reported a smaller social network and exhibited less prosocial behavior in social interaction tasks. In conclusion, the assumption that PCE use will soon become epidemic is not supported by the present findings as PCE users showed a highly specific personality profile that shares a number of features with illegal stimulant users. Lastly, regular MPH use for PCE is not necessarily associated with cognitive deficits. PMID:26107846

  13. Angiography reveals novel features of the retinal vasculature in healthy and diabetic mice.

    PubMed

    McLenachan, Samuel; Magno, Aaron Len; Ramos, David; Catita, Joana; McMenamin, Paul G; Chen, Fred Kuanfu; Rakoczy, Elizabeth Piroska; Ruberte, Jesus

    2015-09-01

    The mouse retina is a commonly used animal model for the study of pathogenesis and treatment of blinding retinal vascular diseases such as diabetic retinopathy. In this study, we aimed to characterize normal and pathological variations in vascular anatomy in the mouse retina using fluorescein angiography visualized with scanning laser ophthalmoscopy and optical coherence tomography (SLO-OCT). We examined eyes from C57BL/6J wild type mice as well as the Ins2(Akita) and Akimba mouse models of diabetic retinopathy using the Heidelberg Retinal Angiography (HRA) and OCT system. Angiography was performed on three focal planes to examine distinct vascular layers. For comparison with angiographic data, ex vivo analyses, including Indian ink angiography, histology and 3D confocal scanning laser microscopy were performed in parallel. All layers of the mouse retinal vasculature could be readily visualized during fluorescein angiography by SLO-OCT. Blood vessel density was increased in the deep vascular plexus (DVP) compared with the superficial vascular plexus (SVP). Arteriolar and venular typologies were established and structural differences were observed between venular types. Unexpectedly, the hyaloid artery was found to persist in 15% of C57BL/6 mice, forming anastomoses with peripheral retinal capillaries. Fluorescein leakage was easily detected in Akimba retinae by angiography, but was not observed in Ins2(Akita) mice. Blood vessel density was increased in the DVP of 6 month old Ins2(Akita) mice, while the SVP displayed reduced branching in precapillary arterioles. In summary, we present the first comprehensive characterization of the mouse retinal vasculature by SLO-OCT fluorescein angiography. Using this clinical imaging technique, we report previously unrecognized variations in C57BL/6J vascular anatomy and novel features of vascular retinopathy in the Ins2(Akita) mouse model of diabetes. PMID:26122048

  14. Memory-enhancing effects of Cuscuta japonica Choisy via enhancement of adult hippocampal neurogenesis in mice.

    PubMed

    Moon, Minho; Jeong, Hyun Uk; Choi, Jin Gyu; Jeon, Seong Gak; Song, Eun Ji; Hong, Seon-Pyo; Oh, Myung Sook

    2016-09-15

    It is generally accepted that functional and structural changes within the hippocampus are involved in learning and memory and that adult neurogenesis in this region may modulate cognition. The extract of Cuscuta japonica Choisy (CJ) is a well-known traditional Chinese herbal medicine that has been used since ancient times as a rejuvenation remedy. The systemic effects of this herb are widely known and can be applied for the treatment of a number of physiological diseases, but there is a lack of evidence describing its effects on brain function. Thus, the present study investigated whether CJ would enhance memory function and/or increase hippocampal neurogenesis using mice orally administered with CJ water extract or vehicle for 21days. Performance on the novel object recognition and passive avoidance tests revealed that treatment with CJ dose-dependently improved the cognitive function of mice. Additionally, CJ increased the Ki-67-positive proliferating cells and the number of doublecortin-stained neuroblasts in the dentate gyrus (DG) of the hippocampus, and double labeling with 5-bromo-2-deoxyuridine and neuronal specific nuclear protein showed that CJ increased the number of mature neurons in the DG. Finally, CJ resulted in the upregulated expression of neurogenic differentiation factor, which is essential for the maturation and differentiation of granule cells in the hippocampus. Taken together, the present findings indicate that CJ stimulated neuronal cell proliferation, differentiation, and maturation, which are all processes associated with neurogenesis. Additionally, these findings suggest that CJ may improve learning and memory via the enhancement of adult hippocampal neurogenesis. PMID:27185736

  15. Substances used and prevalence rates of pharmacological cognitive enhancement among healthy subjects.

    PubMed

    Franke, Andreas G; Bagusat, Christiana; Rust, Sebastian; Engel, Alice; Lieb, Klaus

    2014-11-01

    Pharmacological "cognitive enhancement" (CE) is defined as the use of any psychoactive drug with the purpose of enhancing cognition, e.g. regarding attention, concentration or memory by healthy subjects. Substances commonly used as CE drugs can be categorized into three groups of drugs: (1) over-the-counter (OTC) drugs such as coffee, caffeinated drinks/energy drinks, caffeine tablets or Ginkgo biloba; (2) drugs being approved for the treatment of certain disorders and being misused for CE: drugs to treat attention-deficit/hyperactivity disorder (ADHD) such as the stimulants methylphenidate (MPH, e.g. Ritalin(®)) or amphetamines (AMPH, e.g. Attentin(®) or Adderall(®)), to treat sleep disorders such as modafinil or to treat Alzheimer's disease such as acetylcholinesterase inhibitors; (3) illicit drugs such as illicit AMPH, e.g. "speed", ecstasy, methamphetamine (crystal meth) or others. Evidence from randomized placebo-controlled trials shows that the abovementioned substances have limited pro-cognitive effects as demonstrated, e.g. regarding increased attention, increased cognitive speed or shortening of reaction times, but on the same time poses considerable safety risks on the consumers. Prevalence rates for the use of CE drugs among healthy subjects show a broad range from less than 1 % up to more than 20 %. The range in prevalence rates estimates results from several factors which are chosen differently in the available survey studies: type of subjects (students, pupils, special professions, etc.), degree of anonymity in the survey (online, face-to-face, etc.), definition of CE and substances used/misused for CE, which are assessed (OTC drugs, prescription, illicit drugs) as well as time periods of use (e.g. ever, during the past year/month/week, etc.). A clear and comprehensive picture of the drugs used for CE by healthy subjects and their adverse events and safety risks as well as comprehensive and comparable international data on the prevalence rates of

  16. Parkia pendula seed lectin: potential use to treat cutaneous wounds in healthy and immunocompromised mice.

    PubMed

    Coriolano, Marília Cavalcanti; de Melo, Cristiane Moutinho Lagos; Silva, Flávio de Oliveira; Schirato, Giuliana Viegas; Porto, Camila Souza; dos Santos, Paulo Jorge Parreira; Correia, Maria Tereza dos Santos; Porto, Ana Lúcia Figueiredo; Carneiro-Leão, Ana Maria dos Anjos; Coelho, Luana Cassandra Breitenbach Barroso

    2014-03-01

    Parkia pendula seed lectin was used to treat cutaneous wounds of normal and immunocompromised mice, inducing cicatrization. Methotrexate (0.8 mg/kg/week) was used as immunosuppressive drug. Wounds were produced in the dorsal region (1 cm(2)) of female albino Swiss mice (Mus musculus), health and immunocompromised. Wounds were daily topically treated with 100 μL of the following solutions: (1) control (NaCl 0.15 M), (2) control Im (0.15 M NaCl), (3) P. pendula seed lectin (100 μg/mL), and (4) P. pendula seed lectin Im (100 μg/mL). Clinical evaluation was performed during 12 days. Biopsies for histopathology analysis and microbiological examinations were carried out in the second, seventh, and 12th days. The presence of edema and hyperemia was observed in all groups during inflammatory period. The first crust was detected from the second day, only in the groups treated with P. pendula seed lectin. Microbiological analysis of wounds from day 0 to day 2 did not show bacterium at P. pendula seed lectin group; however, Staphylococcus sp. was detected every day in the other groups. The lectin markedly induced a total wound closing at P. pendula seed lectin and P. pendula seed lectin Im groups on 11th day of evolution. The present study suggests that P. pendula seed lectin is a biomaterial potential to show pharmacological effect in the repair process of cutaneous wounds. PMID:24425299

  17. Comparison of cerebral microcirculation of alloxan diabetes and healthy mice using laser speckle contrast imaging

    NASA Astrophysics Data System (ADS)

    Timoshina, Polina A.; Shi, Rui; Zhang, Yang; Zhu, Dan; Semyachkina-Glushkovskaya, Oxana V.; Tuchin, Valery V.; Luo, Qingming

    2015-03-01

    The study of blood microcirculation is one of the most important problems of the medicine. This paper presents results of experimental study of cerebral blood flow microcirculation in mice with alloxan-induced diabetes using Temporal Laser Speckle Imaging (TLSI). Additionally, a direct effect of glucose water solution (concentration 20% and 45%) on blood flow microcirculation was studied. In the research, 20 white laboratory mice weighing 20-30 g were used. The TLSI method allows one to investigate time dependent scattering from the objects with complex dynamics, since it possesses greater temporal resolution. Results show that in brain of animal diabetic group diameter of sagittal vein is increased and the speed of blood flow reduced relative to the control group. Topical application of 20%- or 45%-glucose solutions also causes increase of diameter of blood vessels and slows down blood circulation. The results obtained show that diabetes development causes changes in the cerebral microcirculatory system and TLSI techniques can be effectively used to quantify these alterations.

  18. Fluoxetine prevents respiratory arrest without enhancing ventilation in DBA/1 mice.

    PubMed

    Zeng, Chang; Long, Xiaoyan; Cotten, Joseph F; Forman, Stuart A; Solt, Ken; Faingold, Carl L; Feng, Hua-Jun

    2015-04-01

    Sudden unexpected death in epilepsy (SUDEP) is a fatal epileptic event. DBA/1 mice are a relevant animal model for the study of SUDEP, as these mice exhibit seizure-induced respiratory arrest (S-IRA) leading to death, which has been observed in patients with witnessed SUDEP. Fluoxetine, a selective serotonin (5-hydroxytryptamine or 5-HT) reuptake inhibitor (SSRI), reduces S-IRA in DBA/1 mice. Given that DBA/1 mice with S-IRA can be resuscitated using a ventilator, we hypothesized that breathing stimulants can prevent S-IRA and that fluoxetine prevents S-IRA by enhancing ventilation in these mice. Spontaneous respiratory function in anesthetized or awake DBA/1 mice was examined using noninvasive plethysmography before and after administering fluoxetine or breathing stimulants, doxapram, and 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (PK-THPP). The effects of these drugs on S-IRA in DBA/1 mice were tested. As reported previously, systemic administration of fluoxetine reduced S-IRA in awake DBA/1 mice, but fluoxetine in anesthetized and awake DBA/1 mice did not increase basal ventilation or the ventilatory response to 7% CO2. Both doxapram and PK-THPP increased ventilation in room air and in air+7% CO2 in anesthetized DBA/1 mice. However, neither of the breathing stimulants reduced the incidence of S-IRA. Our studies confirm that fluoxetine reduces S-IRA in DBA/1 mice without enhancing basal ventilation in the absence of seizures. Although breathing stimulants increased ventilation in the absence of seizures, they were ineffective in reducing S-IRA, indicating that drug-induced increases in ventilation are insufficient to compensate for S-IRA in DBA/1 mice. PMID:25771493

  19. Oxytocin knockout mice demonstrate enhanced intake of sweet and nonsweet carbohydrate solutions.

    PubMed

    Sclafani, Anthony; Rinaman, Linda; Vollmer, Regis R; Amico, Janet A

    2007-05-01

    Oxytocin knockout (OT KO) mice display enhanced intake of nutritive and nonnutritive sweet solutions (i.e., sucrose and saccharin) compared with wild-type (WT) mice of the same C57BL/6 background strain. The present study further investigated the differential behavioral response of OT KO and WT mice to sucrose solutions and also examined intake preferences of OT KO and WT mice for palatable but nonsweet isocaloric solutions of carbohydrate and fat. A progressive ratio operant licking procedure demonstrated that OT KO and WT mice display a similar motivational drive to consume 10% sucrose. A series of two-bottle intake tests revealed that OT KO mice consume significantly larger amounts of both sweet and nonsweet carbohydrate solutions (i.e., sucrose, Polycose, and cornstarch) compared with WT cohorts. Intake pattern analyses revealed that OT KO mice overconsume carbohydrate solutions by initiating more drinking bouts compared with WT mice; bout sizes did not differ between the genotypes. In contrast, OT KO and WT mice did not differ in their intake of Intralipid, a palatable soybean oil emulsion. These findings indicate that the absence of OT in mice does not affect their appetitive drive to consume palatable sucrose solutions. Instead, the absence of OT may increase daily intake of palatable sweet and nonsweet solutions of carbohydrate (but not fat) by selectively blunting or masking processes that contribute to postingestive satiety. PMID:17272659

  20. Male sterility and enhanced radiation sensitivity in TLS(-/-) mice.

    PubMed

    Kuroda, M; Sok, J; Webb, L; Baechtold, H; Urano, F; Yin, Y; Chung, P; de Rooij, D G; Akhmedov, A; Ashley, T; Ron, D

    2000-02-01

    TLS (also known as FUS) is an RNA-binding protein that contributes the N-terminal half of fusion oncoproteins implicated in the development of human liposarcomas and leukemias. Here we report that male mice homozygous for an induced mutation in TLS are sterile with a marked increase in the number of unpaired and mispaired chromosomal axes in pre-meiotic spermatocytes. Nuclear extracts from TLS(-/-) testes lack an activity capable of promoting pairing between homologous DNA sequences in vitro, and TLS(-/-) mice and embryonic fibroblasts exhibit increased sensitivity to ionizing irradiation. These results are consistent with a role for TLS in homologous DNA pairing and recombination. PMID:10654943

  1. Both core and F proteins of hepatitis C virus could enhance cell proliferation in transgenic mice

    SciTech Connect

    Hu, Wen-Ta; Li, Hui-Chun; Lee, Shen-Kao; Ma, Hsin-Chieh; Yang, Chee-Hing; Chen, Hung-Ling; Lo, Shih-Yen

    2013-05-24

    Highlights: •HCV core and F proteins could induce hepatocyte proliferation in the transgenic mice. •β-Catenin signaling pathway was activated by core protein in the transgenic mice. •β-Catenin signaling pathway was activated by myc-F protein in the transgenic mice. •Expression of SMA protein was enhanced by core but not myc-F protein. -- Abstract: The role of the protein encoded by the alternative open reading frame (ARF/F/core+1) of the Hepatitis C virus (HCV) genome in viral pathogenesis remains unknown. The different forms of ARF/F/core+1 protein were labile in cultured cells, a myc-tag fused at the N-terminus of the F protein made it more stable. To determine the role of core and F proteins in HCV pathogenesis, transgenic mice with either protein expression under the control of Albumin promoter were generated. Expression of core protein and F protein with myc tag (myc-F) could be detected by Western blotting analysis in the livers of these mice. The ratio of liver to body weight is increased for both core and myc-F transgenic mice compared to that of wild type mice. Indeed, the proliferating cell nuclear antigen protein, a proliferation marker, was up-regulated in the transgenic mice with core or myc-F protein. Further analyses by microarray and Western blotting suggested that β-catenin signaling pathway was activated by either core or myc-F protein in the transgenic mice. These transgenic mice were further treated with either Diethynitrosamine (a tumor initiator) or Phenobarbital (a tumor promoter). Phenobarbital but not Diethynitrosamine treatment could increase the liver/body weight ratio of these mice. However, no tumor formation was observed in these mice. In conclusion, HCV core and myc-F proteins could induce hepatocyte proliferation in the transgenic mice possibly through β-catenin signaling pathway.

  2. Enhanced Generalization of Auditory Conditioned Fear in Juvenile Mice

    ERIC Educational Resources Information Center

    Ito, Wataru; Pan, Bing-Xing; Yang, Chao; Thakur, Siddarth; Morozov, Alexei

    2009-01-01

    Increased emotionality is a characteristic of human adolescence, but its animal models are limited. Here we report that generalization of auditory conditioned fear between a conditional stimulus (CS+) and a novel auditory stimulus is stronger in 4-5-wk-old mice (juveniles) than in their 9-10-wk-old counterparts (adults), whereas nonassociative…

  3. ENHANCED PRODUCTION OF CRYPTOSPORIDIUM PARVUM OOCYSTS IN IMMUNOSUPPRESSED MICE

    EPA Science Inventory

    Recently there has been an increase in the need for fresh C. parvum oocysts for engineering and biomedical research applications. In our laboratory the emphsis has shifted from the use of dairy calves to inbred C57BL/67n mice, primarily for reasons of ease of collection and proce...

  4. Dietary chromium and nickel enhance UV-carcinogenesis in skin of hairless mice

    SciTech Connect

    Uddin, Ahmed N.; Burns, Fredric J.; Rossman, Toby G.; Chen, Haobin; Kluz, Thomas; Costa, Max . E-mail: costam01@nyu.edu

    2007-06-15

    The skin cancer enhancing effect of chromium (in male mice) and nickel in UVR-irradiated female Skh1 mice was investigated. The dietary vitamin E and selenomethionine were tested for prevention of chromium-enhanced skin carcinogenesis. The mice were exposed to UVR (1.0 kJ/m{sup 2} 3x weekly) for 26 weeks either alone, or combined with 2.5 or 5.0 ppm potassium chromate, or with 20, 100 or 500 ppm nickel chloride in drinking water. Vitamin E or selenomethionine was added to the lab chow for 29 weeks beginning 3 weeks before the start of UVR exposure. Both chromium and nickel significantly increased the UVR-induced skin cancer yield in mice. In male Skh1 mice, UVR alone induced 1.9 {+-} 0.4 cancers/mouse, and 2.5 or 5.0 ppm potassium chromate added to drinking water increased the yields to 5.9 {+-} 0.8 and 8.6 {+-} 0.9 cancers/mouse, respectively. In female Skh1 mice, UVR alone induced 1.7 {+-} 0.4 cancers/mouse, and the addition of 20, 100 or 500 ppm nickel chloride increased the yields to 2.8 {+-} 0.9, 5.6 {+-} 0.7 and 4.2 {+-} 1.0 cancers/mouse, respectively. Neither vitamin E nor selenomethionine reduced the cancer yield enhancement by chromium. These results confirm that chromium and nickel, while not good skin carcinogens per se, are enhancers of UVR-induced skin cancers in Skh1 mice. Data also suggest that the enhancement of UVR-induced skin cancers by chromate may not be oxidatively mediated since the antioxidant vitamin E as well as selenomethionine, found to prevent arsenite-enhanced skin carcinogenesis, failed to suppress enhancement by chromate.

  5. Pomegranate Juice Enhances Healthy Lifespan in Drosophila melanogaster: An Exploratory Study.

    PubMed

    Balasubramani, Subramani Paranthaman; Mohan, Jayaram; Chatterjee, Arunita; Patnaik, Esha; Kukkupuni, Subrahmanya Kumar; Nongthomba, Upendra; Venkatasubramanian, Padmavathy

    2014-01-01

    Exploring innovative ways to ensure healthy aging of populations is a pre-requisite to contain rising healthcare costs. Scientific research into the principles and practices of traditional medicines can provide new insights and simple solutions to lead a healthy life. Rasayana is a dedicated branch of Ayurveda (an Indian medicine) that deals with methods to increase vitality and delay aging through the use of diet, herbal supplements, and other lifestyle practices. The life-span and health-span enhancing actions of the fruits of pomegranate (Punica granatum L.), a well-known Rasayana, were tested on Drosophila melanogaster (fruitfly) model. Supplementation of standard corn meal with 10% (v/v) pomegranate juice (PJ) extended the life-span of male and female flies by 18 and 8%, respectively. When male and female flies were mixed and reared together, there was 19% increase in the longevity of PJ fed flies, as assessed by MSD, the median survival day (24.8). MSD for control and resveratrol (RV) groups was at 20.8 and 23.1 days, respectively. A two-fold enhancement in fecundity, improved resistance to oxidative stress (H2O2 and paraquat induced) and to Candida albicans infection were observed in PJ fed flies. Further, the flies in the PJ fed group were physically active over an extended period of time, as assessed by the climbing assay. PJ thus outperformed both control and RV groups in the life-span and health-span parameters tested. This study provides the scope to explore the potential of PJ as a nutraceutical to improve health span and lifespan in human beings. PMID:25566518

  6. Pomegranate Juice Enhances Healthy Lifespan in Drosophila melanogaster: An Exploratory Study

    PubMed Central

    Balasubramani, Subramani Paranthaman; Mohan, Jayaram; Chatterjee, Arunita; Patnaik, Esha; Kukkupuni, Subrahmanya Kumar; Nongthomba, Upendra; Venkatasubramanian, Padmavathy

    2014-01-01

    Exploring innovative ways to ensure healthy aging of populations is a pre-requisite to contain rising healthcare costs. Scientific research into the principles and practices of traditional medicines can provide new insights and simple solutions to lead a healthy life. Rasayana is a dedicated branch of Ayurveda (an Indian medicine) that deals with methods to increase vitality and delay aging through the use of diet, herbal supplements, and other lifestyle practices. The life-span and health-span enhancing actions of the fruits of pomegranate (Punica granatum L.), a well-known Rasayana, were tested on Drosophila melanogaster (fruitfly) model. Supplementation of standard corn meal with 10% (v/v) pomegranate juice (PJ) extended the life-span of male and female flies by 18 and 8%, respectively. When male and female flies were mixed and reared together, there was 19% increase in the longevity of PJ fed flies, as assessed by MSD, the median survival day (24.8). MSD for control and resveratrol (RV) groups was at 20.8 and 23.1 days, respectively. A two-fold enhancement in fecundity, improved resistance to oxidative stress (H2O2 and paraquat induced) and to Candida albicans infection were observed in PJ fed flies. Further, the flies in the PJ fed group were physically active over an extended period of time, as assessed by the climbing assay. PJ thus outperformed both control and RV groups in the life-span and health-span parameters tested. This study provides the scope to explore the potential of PJ as a nutraceutical to improve health span and lifespan in human beings. PMID:25566518

  7. DIETARY FOLATE DEFICIENCY ENHANCES ARSENIC-INDUCED MICRONUCLEUS FORMATION IN MICE

    EPA Science Inventory


    Dietary folate deficiency enhances arsenic-induced micronucleus formation in mice.

    Folate deficiency increases background levels ofDNA damage and can enhance the mutagenicity of chemical agents. Duplicate experiments were performed to investigate the effect of dietary...

  8. EXPERIMENTAL EPIDEMIOLOGY : II. EFFECT OF THE ADDITION OF HEALTHY MICE TO A POPULATION SUFFERING FROM MOUSE TYPHOID.

    PubMed

    Amoss, H L

    1922-06-30

    least of the later groups added. 5. The dying down of the epidemics and the attaining of the equilibrium do not mean the elimination of all the bacilli. Potential infection still lurks in mouse "carriers" and on the hands of the attendant. No successful method of completely removing the bacilli from the hands of the attendant was found. 6. The maintaining of the epidemic waves is dependent on the presence of new lots of mice, whether supplied from without or produced within through new births. It is the latter sources which provide the consumable material in such natural epidemics as that described by Lynch. Hence their slower movements as compared with the epidemic spreads and rise and fall of the epidemic waves in the artificially propagated instances in which new batches of mice are brought into the village in bimonthly intervals. 7. The evidence at hand is to the effect that the degree of infectivity of "mouse typhoid" bacilli is highly fluctuating, and it appears that all the bacilli which are included under that name, classed variously as Bacillus enteritidis, Gärtner's bacillus, Bacillus paratyphosus B, Bacillus suipestifer, and Bacillus pestis cavioe, infect mice in a similar, possibly indistinguishable manner, inducing self-limited outbreaks of disease reaching at times epidemic proportions. This quality of infectivity, or virulence, is one factor in the process but alone does not suffice to account for the observed facts. A second influence is not improbably quantity, or dosage, of the inciting microorganism. Attention to the manner of spread of an epidemc, as revealed graphically by the spot map, shows that it is never uniform but patchy. The supposition is, therefore, that among the new mice are certain individuals so highly susceptible as to react to small numbers of bacilli of average infectivity. Within these animals the multiplication is rapid, so that a wider spread of much larger amounts of these average, or even temporarily enhanced bacilli takes

  9. Fluoxetine Prevents Respiratory Arrest without Enhancing Ventilation in DBA/1 Mice

    PubMed Central

    Zeng, Chang; Long, Xiaoyan; Cotten, Joseph F.; Forman, Stuart A.; Solt, Ken; Faingold, Carl L.; Feng, Hua-Jun

    2015-01-01

    Sudden unexpected death in epilepsy (SUDEP) is a fatal epileptic event. The DBA/1 mouse is a relevant animal model for study of SUDEP, as these mice exhibit seizure-induced respiratory arrest (S-IRA) leading to death, which has been observed in witnessed SUDEP patients. Fluoxetine, a selective serotonin (5-hydroxytryptamine or 5-HT) reuptake inhibitor (SSRI), reduces S-IRA in DBA/1 mice. Given that DBA/1 mice with S-IRA can be resuscitated using a ventilator, we hypothesized that breathing stimulants can prevent S-IRA and that fluoxetine prevents S-IRA by enhancing ventilation in these mice. Spontaneous respiratory function in anesthetized or awake DBA/1 mice was examined using non-invasive plethysmography before and after administering fluoxetine or breathing stimulants, doxapram and 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (PK-THPP). The effects of these drugs on S-IRA in DBA/1 mice were tested. As reported previously, systemic administration of fluoxetine reduced S-IRA in awake DBA/1 mice, but fluoxetine in anesthetized and awake DBA/1 mice did not increase basal ventilation or the ventilatory response to 7% CO2. Both doxapram and PK-THPP increased ventilation in room air and in air + 7% CO2 in anesthetized DBA/1 mice. However, neither of the breathing stimulants reduced the incidence of S-IRA. Our studies confirm that fluoxetine reduces S-IRA in DBA/1 mice, but without enhancing basal ventilation in the absence of seizures. Although breathing stimulants increased ventilation in the absence of seizures, they were ineffective in reducing S-IRA, indicating that drug-induced increases in ventilation are insufficient to compensate for S-IRA in DBA/1 mice. PMID:25771493

  10. Enhanced Sympathetic Activity in Mice with Brown Adipose Tissue Transplantation (TransBATation)

    PubMed Central

    Zhu, Zheng; Spicer, Elizabeth G; Gavini, Chaitanya K; Goudjo-Ako, Ashley J; Novak, Colleen M; Shi, Haifei

    2014-01-01

    Brown adipose tissue (BAT) burns calories to produce heat, and is thus relevant to energy balance. Interscapular BAT (IBAT) of donor mice was transplanted into recipient mice (transBATation). To test whether transBATation counteracts high-fat diet (HFD)-induced obesity, some sham-operated and recipient mice were fed a HFD (HFD-sham, HFD-trans) while others remained on a standard chow (chow-sham, chow-trans). HFD-trans mice had lower body weight and fat, greater energy expenditure, but similar caloric intake compared with HFD-sham mice. We hypothesized that HFD-trans mice had elevated sympathetic activity compared with HFD-sham mice, contributing to increased energy expenditure and fuel mobilization. This was supported by findings that HFD-trans mice had greater energy expenditure during a norepinephrine challenge test and higher core temperatures after cold exposure than did HFD-sham mice, implicating enhanced whole-body metabolic response and elevated sympathetic activity. Additionally, transBATation selectively increased sympathetic drive to some, but not all, white adipose tissue depots and skeletal muscles, as well as the endogenous IBAT, heart, and liver. Collectively, transBATation confers resistance to HFD-induced obesity via increase in whole-body sympathetic activity, and differential activation of sympathetic drive to some of the tissues involved in energy expenditure and fuel mobilization. PMID:24291381

  11. Enhanced Tumor Formation in Mice Heterozygous for Blm Mutation

    NASA Astrophysics Data System (ADS)

    Heppner Goss, Kathleen; Risinger, Mary A.; Kordich, Jennifer J.; Sanz, Maureen M.; Straughen, Joel E.; Slovek, Lisa E.; Capobianco, Anthony J.; German, James; Boivin, Gregory P.; Groden, Joanna

    2002-09-01

    Persons with the autosomal recessive disorder Bloom syndrome are predisposed to cancers of many types due to loss-of-function mutations in the BLM gene, which encodes a recQ-like helicase. Here we show that mice heterozygous for a targeted null mutation of Blm, the murine homolog of BLM, develop lymphoma earlier than wild-type littermates in response to challenge with murine leukemia virus and develop twice the number of intestinal tumors when crossed with mice carrying a mutation in the Apctumor suppressor. These observations indicate that Blm is a modifier of tumor formation in the mouse and that Blm haploinsufficiency is associated with tumor predisposition, a finding with important implications for cancer risk in humans.

  12. Suppressed or enhanced antibody responses in vitro after BCG treatment of mice: importance of BCG viability.

    PubMed Central

    Brown, C A; Brown, I N; Sljivić, V S

    1979-01-01

    Mycobacterium bovis, BCG, is known to be capable of either enhancing or suppressing various immune responses. Using a standard technique and number of organisms, some of the parameters predetermining whether enhancement or supression will occur have been investigated. Dead BCG given intravenously into mice caused an enhancement of the antibody response in vitro to sheep erythrocytes. In contrast, the same number of viable organisms caused suppression if given intravenously but enhancement if given subcutaneously. The inclusion of 25% or more killed organisms in an intravenous inoculum of fully viable organisms changed suppression to enhancement. Treatment of BCG infected mice with streptomycin lessened the suppression but did not change it to enhancement. The possible causes of suppression are discussed. PMID:391696

  13. Enhancement of Microbiota in Healthy Macaques Results in Beneficial Modulation of Mucosal and Systemic Immune Function.

    PubMed

    Manuzak, Jennifer A; Hensley-McBain, Tiffany; Zevin, Alexander S; Miller, Charlene; Cubas, Rafael; Agricola, Brian; Gile, Jill; Richert-Spuhler, Laura; Patilea, Gabriela; Estes, Jacob D; Langevin, Stanley; Reeves, R Keith; Haddad, Elias K; Klatt, Nichole R

    2016-03-01

    Given the critical role of mucosal surfaces in susceptibility to infection, it is imperative that effective mucosal responses are induced when developing efficacious vaccines and prevention strategies for infection. Modulating the microbiota in the gastrointestinal (GI) tract through the use of probiotics (PBio) is a safe and well-tolerated approach to enhance mucosal and overall health. We assessed the longitudinal impact of daily treatment with the VSL#3 probiotic on cellular and humoral immunity and inflammation in healthy macaques. PBio therapy resulted in significantly increased frequencies of B cells expressing IgA in the colon and lymph node (LN), likely because of significantly increased LN T follicular helper cell frequencies and LN follicles. Increased frequencies of IL-23(+) APCs in the colon were found post-PBio treatment, which correlated with LN T follicular helper cells. Finally, VSL#3 significantly downmodulated the response of TLR2-, TLR3-, TLR4-, and TLR9-expressing HEK293 cells to stimulation with Pam3CSK4, polyinosinic-polycytidylic acid, LPS, and ODN2006, respectively. These data provide a mechanism for the beneficial impact of PBio on mucosal health and implicates the use of PBio therapy in the context of vaccination or preventative approaches to enhance protection from mucosal infection by improving immune defenses at the mucosal portal of entry. PMID:26826246

  14. Enhanced Vitreous Imaging in Healthy Eyes Using Swept Source Optical Coherence Tomography

    PubMed Central

    Liu, Jonathan J.; Witkin, Andre J.; Adhi, Mehreen; Grulkowski, Ireneusz; Kraus, Martin F.; Dhalla, Al-Hafeez; Lu, Chen D.; Hornegger, Joachim; Duker, Jay S.; Fujimoto, James G.

    2014-01-01

    Purpose To describe enhanced vitreous imaging for visualization of anatomic features and microstructures within the posterior vitreous and vitreoretinal interface in healthy eyes using swept-source optical coherence tomography (SS-OCT). The study hypothesis was that long-wavelength, high-speed, volumetric SS-OCT with software registration motion correction and vitreous window display or high-dynamic-range (HDR) display improves detection sensitivity of posterior vitreous and vitreoretinal features compared to standard OCT logarithmic scale display. Design Observational prospective cross-sectional study. Methods Multiple wide-field three-dimensional SS-OCT scans (500×500A-scans over 12×12 mm2) were obtained using a prototype instrument in 22 eyes of 22 healthy volunteers. A registration motion-correction algorithm was applied to compensate motion and generate a single volumetric dataset. Each volumetric dataset was displayed in three forms: (1) standard logarithmic scale display, enhanced vitreous imaging using (2) vitreous window display and (3) HDR display. Each dataset was reviewed independently by three readers to identify features of the posterior vitreous and vitreoretinal interface. Detection sensitivities for these features were measured for each display method. Results Features observed included the bursa premacularis (BPM), area of Martegiani, Cloquet's/BPM septum, Bergmeister papilla, posterior cortical vitreous (hyaloid) detachment, papillomacular hyaloid detachment, hyaloid attachment to retinal vessel(s), and granular opacities within vitreous cortex, Cloquet's canal, and BPM. The detection sensitivity for these features was 75.0% (95%CI: 67.8%–81.1%) using standard logarithmic scale display, 80.6% (95%CI: 73.8%–86.0%) using HDR display, and 91.9% (95%CI: 86.6%–95.2%) using vitreous window display. Conclusions SS-OCT provides non-invasive, volumetric and measurable in vivo visualization of the anatomic microstructural features of the posterior

  15. Enhanced Functional Recovery in MRL/MpJ Mice after Spinal Cord Dorsal Hemisection

    PubMed Central

    Thuret, Sandrine; Thallmair, Michaela; Horky, Laura L.; Gage, Fred H.

    2012-01-01

    Adult MRL/MpJ mice have been shown to possess unique regeneration capabilities. They are able to heal an ear-punched hole or an injured heart with normal tissue architecture and without scar formation. Here we present functional and histological evidence for enhanced recovery following spinal cord injury (SCI) in MRL/MpJ mice. A control group (C57BL/6 mice) and MRL/MpJ mice underwent a dorsal hemisection at T9 (thoracic vertebra 9). Our data show that MRL/MpJ mice recovered motor function significantly faster and more completely. We observed enhanced regeneration of the corticospinal tract (CST). Furthermore, we observed a reduced astrocytic response and fewer micro-cavities at the injury site, which appear to create a more growth-permissive environment for the injured axons. Our data suggest that the reduced astrocytic response is in part due to a lower lesion-induced increase of cell proliferation post-SCI, and a reduced astrocytic differentiation of the proliferating cells. Interestingly, we also found an increased number of proliferating microglia, which could be involved in the MRL/MpJ spinal cord repair mechanisms. Finally, to evaluate the molecular basis of faster spinal cord repair, we examined the difference in gene expression changes in MRL/MpJ and C57BL/6 mice after SCI. Our microarray data support our histological findings and reveal a transcriptional profile associated with a more efficient spinal cord repair in MRL/MpJ mice. PMID:22348029

  16. A Taenia crassiceps metacestode factor enhances ovarian follicle atresia and oocyte degeneration in female mice.

    PubMed

    Solano, S; Zepeda, N; Copitin, N; Fernandez, A M; Tato, P; Molinari, J L

    2015-01-01

    The histopathological effects of Taenia crassiceps infection or T. crassiceps metacestode factor inoculation on the mouse ovary were determined using six female mice in three groups: infected mice, mice inoculated with the metacestode factor and control mice. The control group was subcutaneously inoculated with healthy peritoneal fluid. The infected group was intraperitoneally inoculated with 40 T. crassiceps metacestodes, and the metacestode factor group was subcutaneously inoculated with T. crassiceps metacestode factor (MF). Light and electron microscopy and TUNEL (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labelling) assays revealed a significant increase in ovarian follicular atresia (predominantly in antral/preovulatory stages of development), oocyte degeneration (P< 0.05), and a decrease in the amount of corpus luteum in follicles of mice infected and inoculated with MF compared with the control group. Significant abnormalities of the granulosa cells and oocytes of the primordial, primary and secondary ovarian follicles occurred in both treated mouse groups (P< 0.05) compared with no degeneration in the control group. These pathological changes in female mice either infected with T. crassiceps metacestodes or inoculated with T. crassiceps MF may have consequences for ovulation and fertility. PMID:23962763

  17. Performance enhancement at the cost of potential brain plasticity: neural ramifications of nootropic drugs in the healthy developing brain

    PubMed Central

    Urban, Kimberly R.; Gao, Wen-Jun

    2014-01-01

    Cognitive enhancement is perhaps one of the most intriguing and controversial topics in neuroscience today. Currently, the main classes of drugs used as potential cognitive enhancers include psychostimulants (methylphenidate (MPH), amphetamine), but wakefulness-promoting agents (modafinil) and glutamate activators (ampakine) are also frequently used. Pharmacologically, substances that enhance the components of the memory/learning circuits—dopamine, glutamate (neuronal excitation), and/or norepinephrine—stand to improve brain function in healthy individuals beyond their baseline functioning. In particular, non-medical use of prescription stimulants such as MPH and illicit use of psychostimulants for cognitive enhancement have seen a recent rise among teens and young adults in schools and college campuses. However, this enhancement likely comes with a neuronal, as well as ethical, cost. Altering glutamate function via the use of psychostimulants may impair behavioral flexibility, leading to the development and/or potentiation of addictive behaviors. Furthermore, dopamine and norepinephrine do not display linear effects; instead, their modulation of cognitive and neuronal function maps on an inverted-U curve. Healthy individuals run the risk of pushing themselves beyond optimal levels into hyperdopaminergic and hypernoradrenergic states, thus vitiating the very behaviors they are striving to improve. Finally, recent studies have begun to highlight potential damaging effects of stimulant exposure in healthy juveniles. This review explains how the main classes of cognitive enhancing drugs affect the learning and memory circuits, and highlights the potential risks and concerns in healthy individuals, particularly juveniles and adolescents. We emphasize the performance enhancement at the potential cost of brain plasticity that is associated with the neural ramifications of nootropic drugs in the healthy developing brain. PMID:24860437

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

    PubMed

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

    2015-08-15

    This study investigated in mice the dose-effect of caffeine on memory retrieval in non-stress and stress conditions. C57 Bl/6 Jico mice learned two consecutive discriminations (D1 and D2) in a four-hole board which involved either distinct contextual (CSD) or similar contextual (SSD) cues. All mice received an i.p. injection of vehicle or caffeine (8, 16 or 32mg/kg) 30min before the test session. Results showed that in non-stress conditions, the 16mg/kg caffeine dose induced a significant enhancement of D1 performance in CSD but not in SSD. Hence, we studied the effect of an acute stress (electric footshocks) administered 15min before the test session on D1 performance in caffeine-treated mice. Results showed that stress significantly decreased D1 performance in vehicle-treated controls and the memory-enhancing effect induced by the 16mg/kg caffeine dose in non-stress condition is no longer observed. Interestingly, whereas caffeine-treated mice exhibited weaker concentrations of plasma corticosterone as compared to vehicles in non-stress condition, stress significantly increased plasma corticosterone concentrations in caffeine-treated mice which reached similar level to that of controls. Overall, the acute stress blocked both the endocrinological and memory retrieval enhancing effects of caffeine. PMID:25934571

  19. Dietary supplementation of milk fermented with probiotic Lactobacillus fermentum enhances systemic immune response and antioxidant capacity in aging mice.

    PubMed

    Sharma, Rohit; Kapila, Rajeev; Kapasiya, Meena; Saliganti, Vamshi; Dass, Gulshan; Kapila, Suman

    2014-11-01

    -specific antibodies and inflammatory proteins. Based on these results, it appears that LF supplementation alleviated immunosenescence, enhanced antioxidant enzyme activities, and resisted E coli infection in aging mice; thereby, signifying its potential in augmenting healthy aging. PMID:25311611

  20. Rifampin enhances cytochrome P450 (CYP) 2B6-mediated efavirenz 8-hydroxylation in healthy volunteers

    PubMed Central

    Cho, Doo-Yeoun; Shen, Joan H.Q.; Lemler, Suzanne M.; Skaar, Todd C; Li, Lang; Blievernicht, Julia; Zanger, Ulrich M.; Kim, Kwon-Bok; Shin, Jae-Gook; Flockhart, David A.; Desta, Zeruesenay

    2016-01-01

    The effect of rifampin on the in vivo metabolism of the antiretroviral drug efavirenz was evaluated in healthy volunteers. In a cross-over placebo control trial, healthy subjects (n = 20) were administered a single 600 mg oral dose of efavirenz after pretreatment with placebo or rifampin (600 mg/day for 10 days). Plasma and urine concentrations of efavirenz, 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz were measured by LC–MS/MS. Compared to placebo treatment, rifampin increased the oral clearance (by ~2.5-fold) and decreased maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC0–∞) of efavirenz (by ~1.6- and ~2.5-fold respectively) (p < 0.001). Rifampin treatment substantially increased the Cmax and AUC0–12h of 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz, metabolic ratio (AUC0–72h of metabolites to AUC0–72h efavirenz) and the amount of metabolites excreted in urine (Ae0–12hr) (all, p < 0.01). Female subjects had longer elimination half-life (1.6–2.2-fold) and larger weight-adjusted distribution volume (1.6– 1.9-fold) of efavirenz than male subjects (p < 0.05) in placebo and rifampin treated groups respectively. In conclusion, rifampin enhances CYP2B6-mediated efavirenz 8-hydroxylation in vivo. The metabolism of a single oral dose of efavirenz may be a suitable in vivo marker of CYP2B6 activity to evaluate induction drug interactions involving this enzyme. PMID:27053325

  1. Enhanced differentiation of intraepithelial lymphocytes in the intestine of polymeric immunoglobulin receptor-deficient mice.

    PubMed

    Kato-Nagaoka, Noriko; Shimada, Shin-Ichiro; Yamakawa, Yoko; Tsujibe, Satoshi; Naito, Tomoaki; Setoyama, Hiromi; Watanabe, Yohei; Shida, Kan; Matsumoto, Satoshi; Nanno, Masanobu

    2015-09-01

    To clarify the effect of secretory IgA (sIgA) deficiency on gut homeostasis, we examined intraepithelial lymphocytes (IELs) in the small intestine (SI) of polymeric immunoglobulin receptor-deficient (pIgR(-/-) ) mice. The pIgR(-/-) mice exhibited the accumulation of CD8αβ(+) T-cell receptor (TCR)-αβ(+) IELs (CD8αβ(+) αβ-IELs) after weaning, but no increase of CD8αβ(+) γδ-IELs was detected in pIgR(-/-) TCR-β(-/-) mice compared with pIgR(+/+) TCR-β(-/-) mice. When 5-bromo-2'-deoxyuridine (BrdU) was given for 14 days, the proportion of BrdU-labelled cells in SI-IELs was not different between pIgR(+/+) mice and pIgR(-/-) mice. However, the proportion of BrdU-labelled CD8αβ(+) -IELs became higher in pIgR(-/-) mice than pIgR(+/+) mice 10 days after discontinuing BrdU-labelling. Intravenously transferred splenic T cells migrated into the intraepithelial compartments of pIgR(+/+) TCR-β(-/-) mice and pIgR(-/-) TCR-β(-/-) mice to a similar extent. In contrast, in the case of injection of immature bone marrow cells, CD8αβ(+) αβ-IELs increased much more in the SI of pIgR(-/-) TCR-β(-/-) mice than pIgR(+/+) TCR-β(-/-) mice 8 weeks after the transfer. αβ-IELs from pIgR(-/-) mice could produce more interferon-γ and interleukin-17 than those of pIgR(+/+) mice, and intestinal permeability tended to increase in the SI of pIgR(-/-) mice with aging. Taken together, these results indicate that activated CD8αβ(+) αβ-IELs preferentially accumulate in pIgR(-/-) mice through the enhanced differentiation of immature haematopoietic precursor cells, which may subsequently result in the disruption of epithelial integrity. PMID:25967857

  2. Enhanced antibody responses induced by Candida albicans in mice.

    PubMed

    Cutler, J E; Lloyd, R K

    1982-12-01

    Candida albicans may immunopotentiate antibody responses in mice to antigens unrelated to the fungus. This effect occurred best with cell-associated, rather than soluble, antigens. When dead yeasts, cell walls, or a water-soluble candidal polysaccharide were used, immunopotentiation was most dramatic when the antigen and fungal materials were given concomitantly via an intraperitoneal injection. However, mice infected with viable yeasts several days before antigen administration also developed heightened responses to the antigen. The mechanism of the C. albicans-induced adjuvanticity was not defined, but the effect seemed to correlate with induction of inflammation. The presence of C. albicans or other inflammatory agents in the peritoneal cavity caused a more rapid uptake of particulate antigen by the liver. The relationship between this event and immunopotentiation is not known. These studies demonstrate that C. albicans may have profound effects on host immune responses. Because immunological aberrations are commonly found in patients with candidiasis it may be important to determine whether some of these aberrations result from, rather than precede candidiasis. PMID:6185421

  3. Effects of nanoencapsulation and PEGylation on biodistribution of indocyanine green in healthy mice: quantitative fluorescence imaging and analysis of organs

    PubMed Central

    Bahmani, Baharak; Lytle, Christian Y; Walker, Ameae M; Gupta, Sharad; Vullev, Valentine I; Anvari, Bahman

    2013-01-01

    Near-infrared nanoconstructs present a potentially effective platform for site-specific and deep tissue optical imaging and phototherapy. We have engineered a polymeric nanocapsule composed of polyallylamine hydrochloride (PAH) chains cross-linked with sodium phosphate and doped with indocyanine green (ICG) toward such endeavors. The ICG-doped nanocapsules were coated covalently with polyethylene glycol (5000 daltons) through reductive amination. We administrated the constructs by tail vein injection to healthy mice. To characterize the biodistribution of the constructs, we performed in vivo quantitative fluorescence imaging and subsequently analyzed the various extracted organs. Our results suggest that encapsulation of ICG in these PEGylated constructs is an effective approach to prolong the circulation time of ICG and delay its hepatic accumulation. Increased bioavailability of ICG, due to encapsulation, offers the potential of extending the clinical applications of ICG, which are currently limited due to rapid elimination of ICG from the vasculature. Our results also indicate that PAH and ICG-doped nanocapsules (ICG-NCs) are not cytotoxic at the levels used in this study. PMID:23637530

  4. Effects of Orally Administered Pyrroloquinoline Quinone Disodium Salt on Dry Skin Conditions in Mice and Healthy Female Subjects.

    PubMed

    Nakano, Masahiko; Kamimura, Ayako; Watanabe, Fumiko; Kamiya, Toshikazu; Watanabe, Daisuke; Yamamoto, Etsushi; Fukagawa, Mitsuhiko; Hasumi, Keiji; Suzuki, Eriko

    2015-01-01

    Pyrroloquinoline quinone (PQQ) is a coenzyme involved in the redox-cycling system. The supplemental use of PQQ has been examined based on its properties as an antioxidant and redox modulator. Although an animal study on deficiency of PQQ suggested that PQQ contributes to skin conditions, its efficacy in humans has not been reported. The present study aimed to investigate the effects of orally administered PQQ on skin moisture, viscoelasticity, and transepidermal water loss (TEWL) both in dry skin mouse models and in healthy female subjects with a subjective symptom of dry skin. In our dry skin mouse model study, oral intake of PQQ (0.0089%, w/w, in the diet for 6 wk) significantly decreased the number of mast cells in the dermis and the number of CD3⁺ T-cells in the epidermis. In our human study, oral intake of PQQ (20 mg/d for 8 wk) significantly inhibited the increase in TEWL on the forearm. Finally, subject questionnaires showed positive impressions for the improvement of skin conditions. These results suggest that oral intake of PQQ improves skin conditions both in female subjects with dry skin and in mice with a compromised skin barrier function. PMID:26226961

  5. Clemastine Enhances Myelination in the Prefrontal Cortex and Rescues Behavioral Changes in Socially Isolated Mice.

    PubMed

    Liu, Jia; Dupree, Jeffrey L; Gacias, Mar; Frawley, Rebecca; Sikder, Tamjeed; Naik, Payal; Casaccia, Patrizia

    2016-01-20

    Altered myelin structure and oligodendrocyte function have been shown to correlate with cognitive and motor dysfunction and deficits in social behavior. We and others have previously demonstrated that social isolation in mice induced behavioral, transcriptional, and ultrastructural changes in oligodendrocytes of the prefrontal cortex (PFC). However, whether enhancing myelination and oligodendrocyte differentiation could be beneficial in reversing such changes remains unexplored. To test this hypothesis, we orally administered clemastine, an antimuscarinic compound that has been shown to enhance oligodendrocyte differentiation and myelination in vitro, for 2 weeks in adult mice following social isolation. Clemastine successfully reversed social avoidance behavior in mice undergoing prolonged social isolation. Impaired myelination was rescued by oral clemastine treatment, and was associated with enhanced oligodendrocyte progenitor differentiation and epigenetic changes. Clemastine induced higher levels of repressive histone methylation (H3K9me3), a marker for heterochromatin, in oligodendrocytes, but not neurons, of the PFC. This was consistent with the capability of clemastine in elevating H3K9 histone methyltransferases activity in cultured primary mouse oligodendrocytes, an effect that could be antagonized by cotreatment with muscarine. Our data suggest that promoting adult myelination is a potential strategy for reversing depressive-like social behavior. Significance statement: Oligodendrocyte development and myelination are highly dynamic processes influenced by experience and neuronal activity. However, whether enhancing myelination and oligodendrocyte differentiation is beneficial to treat depressive-like behavior has been unexplored. Mice undergoing prolonged social isolation display impaired myelination in the prefrontal cortex. Clemastine, a Food and Drug Administration-approved antimuscarinic compound that has been shown to enhance myelination under

  6. Clemastine Enhances Myelination in the Prefrontal Cortex and Rescues Behavioral Changes in Socially Isolated Mice

    PubMed Central

    Dupree, Jeffrey L.; Gacias, Mar; Frawley, Rebecca; Sikder, Tamjeed; Naik, Payal; Casaccia, Patrizia

    2016-01-01

    Altered myelin structure and oligodendrocyte function have been shown to correlate with cognitive and motor dysfunction and deficits in social behavior. We and others have previously demonstrated that social isolation in mice induced behavioral, transcriptional, and ultrastructural changes in oligodendrocytes of the prefrontal cortex (PFC). However, whether enhancing myelination and oligodendrocyte differentiation could be beneficial in reversing such changes remains unexplored. To test this hypothesis, we orally administered clemastine, an antimuscarinic compound that has been shown to enhance oligodendrocyte differentiation and myelination in vitro, for 2 weeks in adult mice following social isolation. Clemastine successfully reversed social avoidance behavior in mice undergoing prolonged social isolation. Impaired myelination was rescued by oral clemastine treatment, and was associated with enhanced oligodendrocyte progenitor differentiation and epigenetic changes. Clemastine induced higher levels of repressive histone methylation (H3K9me3), a marker for heterochromatin, in oligodendrocytes, but not neurons, of the PFC. This was consistent with the capability of clemastine in elevating H3K9 histone methyltransferases activity in cultured primary mouse oligodendrocytes, an effect that could be antagonized by cotreatment with muscarine. Our data suggest that promoting adult myelination is a potential strategy for reversing depressive-like social behavior. SIGNIFICANCE STATEMENT Oligodendrocyte development and myelination are highly dynamic processes influenced by experience and neuronal activity. However, whether enhancing myelination and oligodendrocyte differentiation is beneficial to treat depressive-like behavior has been unexplored. Mice undergoing prolonged social isolation display impaired myelination in the prefrontal cortex. Clemastine, a Food and Drug Administration-approved antimuscarinic compound that has been shown to enhance myelination under

  7. Functional beverage of Garcinia mangostana (mangosteen) enhances plasma antioxidant capacity in healthy adults.

    PubMed

    Xie, Zhuohong; Sintara, Marsha; Chang, Tony; Ou, Boxin

    2015-01-01

    This study was to investigate the absorption and antioxidant effect of a mangosteen-based functional beverage in humans. The beverage contained mangosteen, aloe vera, green tea, and multivitamins. A randomized, double-blind, placebo-controlled clinical trial was conducted with generally healthy male and female subjects between 18 and 60 years of age. Ten men and 10 women participated in this study. Participants were randomly divided into two groups, treatment and placebo group. Participants received either a daily single dose (245 mL) of the beverage or a placebo. Blood samples were collected from each participant at time points 0, 1, 2, 4, and 6 h. The plasma samples were analyzed by LC/MS for α-mangostin and vitamins B2 and B5. Results indicated that the three analytes were bioavailable, with observed C max at around 1 h. The antioxidant capacity measured with the oxygen radical absorbance capacity (ORAC) assay was increased with a maximum effect of 60% after 1 h, and the elevated antioxidant level lasted at least 6 h. This study demonstrated the bioavailability of α-mangostin and B vitamins from a xanthone-rich beverage and the mechanisms of the increase in plasma antioxidant may be direct effects from antioxidants, enhancement of endogenous antioxidant activity through activation of Nrf2 pathway, and synergism of the antioxidants. PMID:25649891

  8. Functional beverage of Garcinia mangostana (mangosteen) enhances plasma antioxidant capacity in healthy adults

    PubMed Central

    Xie, Zhuohong; Sintara, Marsha; Chang, Tony; Ou, Boxin

    2015-01-01

    This study was to investigate the absorption and antioxidant effect of a mangosteen-based functional beverage in humans. The beverage contained mangosteen, aloe vera, green tea, and multivitamins. A randomized, double-blind, placebo-controlled clinical trial was conducted with generally healthy male and female subjects between 18 and 60 years of age. Ten men and 10 women participated in this study. Participants were randomly divided into two groups, treatment and placebo group. Participants received either a daily single dose (245 mL) of the beverage or a placebo. Blood samples were collected from each participant at time points 0, 1, 2, 4, and 6 h. The plasma samples were analyzed by LC/MS for α-mangostin and vitamins B2 and B5. Results indicated that the three analytes were bioavailable, with observed Cmax at around 1 h. The antioxidant capacity measured with the oxygen radical absorbance capacity (ORAC) assay was increased with a maximum effect of 60% after 1 h, and the elevated antioxidant level lasted at least 6 h. This study demonstrated the bioavailability of α-mangostin and B vitamins from a xanthone-rich beverage and the mechanisms of the increase in plasma antioxidant may be direct effects from antioxidants, enhancement of endogenous antioxidant activity through activation of Nrf2 pathway, and synergism of the antioxidants. PMID:25649891

  9. Glucose enhancement of memory is modulated by trait anxiety in healthy adolescent males.

    PubMed

    Smith, Michael A; Hii, Hilary L; Foster, Jonathan K; van Eekelen, J A M

    2011-01-01

    Glucose administration is associated with memory enhancement in healthy young individuals under conditions of divided attention at encoding. While the specific neurocognitive mechanisms underlying this 'glucose memory facilitation effect' are currently uncertain, it is thought that individual differences in glucoregulatory efficiency may alter an individual's sensitivity to the glucose memory facilitation effect. In the present study, we sought to investigate whether basal hypothalamic-pituitary-adrenal axis function (itself a modulator of glucoregulatory efficiency), baseline self-reported stress and trait anxiety influence the glucose memory facilitation effect. Adolescent males (age range = 14-17 years) were administered glucose and placebo prior to completing a verbal episodic memory task on two separate testing days in a counter-balanced, within-subjects design. Glucose ingestion improved verbal episodic memory performance when memory recall was tested (i) within an hour of glucose ingestion and encoding, and (ii) one week subsequent to glucose ingestion and encoding. Basal hypothalamic-pituitary-adrenal axis function did not appear to influence the glucose memory facilitation effect; however, glucose ingestion only improved memory in participants reporting relatively higher trait anxiety. These findings suggest that the glucose memory facilitation effect may be mediated by biological mechanisms associated with trait anxiety. PMID:19939878

  10. Simple coating with fibronectin fragment enhances stainless steel screw osseointegration in healthy and osteoporotic rats.

    PubMed

    Agarwal, Rachit; González-García, Cristina; Torstrick, Brennan; Guldberg, Robert E; Salmerón-Sánchez, Manuel; García, Andrés J

    2015-09-01

    Metal implants are widely used to provide structural support and stability in current surgical treatments for bone fractures, spinal fusions, and joint arthroplasties as well as craniofacial and dental applications. Early implant-bone mechanical fixation is an important requirement for the successful performance of such implants. However, adequate osseointegration has been difficult to achieve especially in challenging disease states like osteoporosis due to reduced bone mass and strength. Here, we present a simple coating strategy based on passive adsorption of FN7-10, a recombinant fragment of human fibronectin encompassing the major cell adhesive, integrin-binding site, onto 316-grade stainless steel (SS). FN7-10 coating on SS surfaces promoted α5β1 integrin-dependent adhesion and osteogenic differentiation of human mesenchymal stem cells. FN7-10-coated SS screws increased bone-implant mechanical fixation compared to uncoated screws by 30% and 45% at 1 and 3 months, respectively, in healthy rats. Importantly, FN7-10 coating significantly enhanced bone-screw fixation by 57% and 32% at 1 and 3 months, respectively, and bone-implant ingrowth by 30% at 3 months compared to uncoated screws in osteoporotic rats. These coatings are easy to apply intra-operatively, even to implants with complex geometries and structures, facilitating the potential for rapid translation to clinical settings. PMID:26100343

  11. Enhancing Quality Interventions Promoting Healthy Sexuality (EQUIPS): A novel application of translational research methods

    PubMed Central

    Chinman, Matthew; Acosta, Joie; Ebener, Patricia; Driver, Jennifer; Keith, Jamie; Peebles, Dana

    2013-01-01

    Translational research is expanding, in part, because Evidence-Based Programs or Practices (EBPs) are not adopted in many medical domains. However, little translational research exists on EBPs that are prevention programs delivered in non-clinical, community-based settings. These organizations often have low capacity, which undermines implementation quality and outcomes. Rigorous translational research is needed in these settings so within a single study, capacity, implementation quality, and outcomes are measured and links between them tested. This paper overviews the study Enhancing Quality Interventions Promoting Healthy Sexuality (EQUIPS), which tests how well a community-based setting (Boys & Girls Clubs) conducts an EBP called Making Proud Choices that aims to prevent teen pregnancy and sexually transmitted infections, with and without an implementation support intervention called Getting To Outcomes®. The study design is novel as it assesses: Getting To Outcomes’ impact on capacity, implementation quality, and outcomes simultaneously and in both study conditions; will assess sustainability by measuring capacity and fidelity a year after the Getting To Outcomes support ends; and will operate on a large scale similar to many national initiatives. Many studies have not incorporated all these elements and thus EQUIPS could serve as a model for translational research in many domains. PMID:23751031

  12. Enhanced resistance to acute infection with Trypanosoma cruzi in mice treated with an interferon inducer.

    PubMed Central

    James, S L; Kipnis, T L; Sher, A; Hoff, R

    1982-01-01

    For an exploration of the effects of interferon-inducible resistance mechanisms in acute American trypanosomiasis, the synthetic interferon inducer tilerone hydrochloride was administered to mice of the C57BL/6J strain, which is highly resistant to Trypanosoma cruzi, 18 to 24 h before infection with a potentially lethal dose of bloodstream trypomastigotes. Although all of the control mice died within 30 days of the acute infection, approximately 50% of the tilerone-treated animals were able to survive indefinitely (P less than 0.05). The tilerone-treated mice demonstrated significant levels of serum interferon and splenic natural killer cells at the time of infection. Macrophages isolated from the peritoneal cavities of tilerone-treated C57BL/6J mice appeared to kill significant numbers of trypanosomes during 2 to 3 days of in vitro culture, indicating that activated macrophages may contribute to the enhanced resistance to T. cruzi infection in these mice. Beige mice treated with tilerone did not survive T. cruzi infection as well as tilerone-treated heterozygotes did, suggesting a role for natural killer cells in interferon-induced resistance. These results suggest that interferon or effector mechanisms enhanced by interferon induction can play a significant role in influencing resistance to T. cruzi infection. PMID:6173326

  13. Cognitive-enhancing effects of hydrolysate of polygalasaponin in SAMP8 mice*

    PubMed Central

    Xu, Pan; Xu, Shu-ping; Wang, Ke-zhu; Lu, Cong; Zhang, Hong-xia; Pan, Rui-le; Qi, Chang; Yang, Yan-yan; Li, Ying-hui; Liu, Xin-min

    2016-01-01

    Objectives: The aim of the study is to evaluate the cognitive-enhancing effects of hydrolysate of polygalasaponin (HPS) on senescence accelerate mouse P8 (SAMP8) mice, an effective Alzheimer’s disease (AD) model, and to research the relevant mechanisms. Methods: The cognitive-enhancing effects of HPS on SAMP8 mice were assessed using Morris water maze (MWM) and step-through passive avoidance tests. Then N-methyl-D-aspartate (NMDA) receptor subunit expression for both the cortex and hippocampus of mice was observed using Western blotting. Results: HPS (25 and 50 mg/kg) improved the escape rate and decreased the escape latency and time spent in the target quadrant for the SAMP8 mice in the MWM after oral administration of HPS for 10 d. Moreover, it decreased error times in the passive avoidance tests. Western blotting showed that HPS was able to reverse the levels of NMDAR1 and NMDAR2B expression in the cortex or hippocampus of model mice. Conclusions: The present study suggested that HPS can improve cognitive deficits in SAMP8 mice, and this mechanism might be associated with NMDA receptor (NMDAR)-related pathways. PMID:27381727

  14. Memory-Enhancing Effects of the Crude Extract of Polygala tenuifolia on Aged Mice.

    PubMed

    Li, Zongyang; Liu, Yamin; Wang, Liwei; Liu, Xinmin; Chang, Qi; Guo, Zhi; Liao, Yonghong; Pan, Ruile; Fan, Tai-Ping

    2014-01-01

    Learning and memory disorders arise from distinct age-associated processes, and aging animals are often used as a model of memory impairment. The root of Polygala tenuifolia has been commonly used in some Asian countries as memory enhancer and its memory improvement has been reported in various animal models. However, there is less research to verify its effect on memory functions in aged animals. Herein, the memory-enhancing effects of the crude extract of Polygala tenuifolia (EPT) on normal aged mice were assessed by Morris water maze (MWM) and step-down passive avoidance tests. In MWM tests, the impaired spatial memory of the aged mice was partly reversed by EPT (100 and 200 mg/kg; P < 0.05) as compared with the aged control mice. In step-down tests, the nonspatial memory of the aged mice was improved by EPT (100 and 200 mg/kg; P < 0.05). Additionally, EPT could increase superoxide dismutase (SOD) and catalase (CAT) activities, inhibit monoamine oxidase (MAO) and acetyl cholinesterase (AChE) activities, and decrease the levels of malondialdehyde (MDA) in the brain tissue of the aged mice. The results showed that EPT improved memory functions of the aged mice probably via its antioxidant properties and via decreasing the activities of MAO and AChE. PMID:24744810

  15. Memory-Enhancing Effects of the Crude Extract of Polygala tenuifolia on Aged Mice

    PubMed Central

    Li, Zongyang; Liu, Yamin; Wang, Liwei; Liu, Xinmin; Chang, Qi; Guo, Zhi; Liao, Yonghong; Pan, Ruile; Fan, Tai-Ping

    2014-01-01

    Learning and memory disorders arise from distinct age-associated processes, and aging animals are often used as a model of memory impairment. The root of Polygala tenuifolia has been commonly used in some Asian countries as memory enhancer and its memory improvement has been reported in various animal models. However, there is less research to verify its effect on memory functions in aged animals. Herein, the memory-enhancing effects of the crude extract of Polygala tenuifolia (EPT) on normal aged mice were assessed by Morris water maze (MWM) and step-down passive avoidance tests. In MWM tests, the impaired spatial memory of the aged mice was partly reversed by EPT (100 and 200 mg/kg; P < 0.05) as compared with the aged control mice. In step-down tests, the nonspatial memory of the aged mice was improved by EPT (100 and 200 mg/kg; P < 0.05). Additionally, EPT could increase superoxide dismutase (SOD) and catalase (CAT) activities, inhibit monoamine oxidase (MAO) and acetyl cholinesterase (AChE) activities, and decrease the levels of malondialdehyde (MDA) in the brain tissue of the aged mice. The results showed that EPT improved memory functions of the aged mice probably via its antioxidant properties and via decreasing the activities of MAO and AChE. PMID:24744810

  16. Environmental enrichment improves novel object recognition and enhances agonistic behavior in male mice.

    PubMed

    Mesa-Gresa, Patricia; Pérez-Martinez, Asunción; Redolat, Rosa

    2013-01-01

    Environmental enrichment (EE) is an experimental paradigm in which rodents are housed in complex environments containing objects that provide stimulation, the effects of which are expected to improve the welfare of these subjects. EE has been shown to considerably improve learning and memory in rodents. However, knowledge about the effects of EE on social interaction is generally limited and rather controversial. Thus, our aim was to evaluate both novel object recognition and agonistic behavior in NMRI mice receiving EE, hypothesizing enhanced cognition and slightly enhanced agonistic interaction upon EE rearing. During a 4-week period half the mice (n = 16) were exposed to EE and the other half (n = 16) remained in a standard environment (SE). On PND 56-57, animals performed the object recognition test, in which recognition memory was measured using a discrimination index. The social interaction test consisted of an encounter between an experimental animal and a standard opponent. Results indicated that EE mice explored the new object for longer periods than SE animals (P < .05). During social encounters, EE mice devoted more time to sociability and agonistic behavior (P < .05) than their non-EE counterparts. In conclusion, EE has been shown to improve object recognition and increase agonistic behavior in adolescent/early adulthood mice. In the future we intend to extend this study on a longitudinal basis in order to assess in more depth the effect of EE and the consistency of the above-mentioned observations in NMRI mice. PMID:23588702

  17. Enhanced Susceptibility to Pulmonary Infection with Burkholderia cepacia in Cftr−/− Mice

    PubMed Central

    Sajjan, Uma; Thanassoulis, George; Cherapanov, Vera; Lu, Annie; Sjolin, Carola; Steer, Brent; Wu, Yi Jun; Rotstein, Ori D.; Kent, Geraldine; McKerlie, Colin; Forstner, Janet; Downey, Gregory P.

    2001-01-01

    Progressive pulmonary infection is the dominant clinical feature of cystic fibrosis (CF), but the molecular basis for this susceptibility remains incompletely understood. To study this problem, we developed a model of chronic pneumonia by repeated instillation of a clinical isolate of Burkholderia cepacia (genomovar III, ET12 strain), an opportunistic gram-negative bacterium, from a case of CF into the lungs of Cftr m1unc−/− (Cftr−/−) and congenic Cftr+/+ controls. Nine days after the last instillation, the CF transmembrane regulator knockout mice showed persistence of viable bacteria with chronic severe bronchopneumonia while wild-type mice remained healthy. The histopathological changes in the lungs of the susceptible Cftr−/− mice were characterized by infiltration of a mixed inflammatory-cell population into the peribronchiolar and perivascular spaces, Clara cell hyperplasia, mucus hypersecretion in airways, and exudation into alveolar airspaces by a mixed population of macrophages and neutrophils. An increased proportion of neutrophils was observed in bronchoalveolar lavage fluid from the Cftr−/− mice, which, despite an increased bacterial load, demonstrated minimal evidence of activation. Alveolar macrophages from Cftr−/− mice also demonstrated suboptimal activation. These observations suggest that the pulmonary host defenses are compromised in lungs from animals with CF, as manifested by increased susceptibility to bacterial infection and lung injury. This murine model of chronic pneumonia thus reflects, in part, the situation in human patients and may help elucidate the mechanisms leading to defective host defense in CF. PMID:11447196

  18. Reconciling depressed Ca2+ sparks occurrence with enhanced RyR2 activity in failing mice cardiomyocytes.

    PubMed

    Ruiz-Hurtado, Gema; Li, Linwei; Fernández-Velasco, María; Rueda, Angélica; Lefebvre, Florence; Wang, Yueyi; Mateo, Philippe; Cassan, Cécile; Gellen, Barnabas; Benitah, Jean Pierre; Gómez, Ana María

    2015-10-01

    Abnormalities in cardiomyocyte Ca2+ handling contribute to impaired contractile function in heart failure (HF). Experiments on single ryanodine receptors (RyRs) incorporated into lipid bilayers have indicated that RyRs from failing hearts are more active than those from healthy hearts. Here, we analyzed spontaneous Ca2+ sparks (brief, localized increased in [Ca2+]i) to evaluate RyR cluster activity in situ in a mouse post-myocardial infarction (PMI) model of HF. The cardiac ejection fraction of PMI mice was reduced to ∼30% of that of sham-operated (sham) mice, and their cardiomyocytes were hypertrophied. The [Ca2+]i transient amplitude and sarcoplasmic reticulum (SR) Ca2+ load were decreased in intact PMI cardiomyocytes compared with those from sham mice, and spontaneous Ca2+ sparks were less frequent, whereas the fractional release and the frequency of Ca2+ waves were both increased, suggesting higher RyR activity. In permeabilized cardiomyocytes, in which the internal solution can be controlled, Ca2+ sparks were more frequent in PMI cells (under conditions of similar SR Ca2+ load), confirming the enhanced RyR activity. However, in intact cells from PMI mice, the Ca2+ sparks frequency normalized by the SR Ca2+ load in that cell were reduced compared with those in sham mice, indicating that the cytosolic environment in intact cells contributes to the decrease in Ca2+ spark frequency. Indeed, using an internal "failing solution" with less ATP (as found in HF), we observed a dramatic decrease in Ca2+ spark frequency in permeabilized PMI and sham myocytes. In conclusion, our data show that, even if isolated RyR channels show more activity in HF, concomitant alterations in intracellular media composition and SR Ca2+ load may mask these effects at the Ca2+ spark level in intact cells. Nonetheless, in this scenario, the probability of arrhythmogenic Ca2+ waves is enhanced, and they play a potential role in the increase in arrhythmia events in HF patients. PMID:26371209

  19. Reconciling depressed Ca2+ sparks occurrence with enhanced RyR2 activity in failing mice cardiomyocytes

    PubMed Central

    Li, Linwei; Fernández-Velasco, María; Rueda, Angélica; Lefebvre, Florence; Wang, Yueyi; Mateo, Philippe; Cassan, Cécile; Gellen, Barnabas; Benitah, Jean Pierre

    2015-01-01

    Abnormalities in cardiomyocyte Ca2+ handling contribute to impaired contractile function in heart failure (HF). Experiments on single ryanodine receptors (RyRs) incorporated into lipid bilayers have indicated that RyRs from failing hearts are more active than those from healthy hearts. Here, we analyzed spontaneous Ca2+ sparks (brief, localized increased in [Ca2+]i) to evaluate RyR cluster activity in situ in a mouse post-myocardial infarction (PMI) model of HF. The cardiac ejection fraction of PMI mice was reduced to ∼30% of that of sham-operated (sham) mice, and their cardiomyocytes were hypertrophied. The [Ca2+]i transient amplitude and sarcoplasmic reticulum (SR) Ca2+ load were decreased in intact PMI cardiomyocytes compared with those from sham mice, and spontaneous Ca2+ sparks were less frequent, whereas the fractional release and the frequency of Ca2+ waves were both increased, suggesting higher RyR activity. In permeabilized cardiomyocytes, in which the internal solution can be controlled, Ca2+ sparks were more frequent in PMI cells (under conditions of similar SR Ca2+ load), confirming the enhanced RyR activity. However, in intact cells from PMI mice, the Ca2+ sparks frequency normalized by the SR Ca2+ load in that cell were reduced compared with those in sham mice, indicating that the cytosolic environment in intact cells contributes to the decrease in Ca2+ spark frequency. Indeed, using an internal “failing solution” with less ATP (as found in HF), we observed a dramatic decrease in Ca2+ spark frequency in permeabilized PMI and sham myocytes. In conclusion, our data show that, even if isolated RyR channels show more activity in HF, concomitant alterations in intracellular media composition and SR Ca2+ load may mask these effects at the Ca2+ spark level in intact cells. Nonetheless, in this scenario, the probability of arrhythmogenic Ca2+ waves is enhanced, and they play a potential role in the increase in arrhythmia events in HF patients. PMID

  20. FOLATE DEFICIENCY ENHANCES ARSENIC-INDUCED GENOTOXICITY IN MICE

    EPA Science Inventory

    Folate deficiency increases background levels of DNA damage and can enhance the mutagenicity of chemical agents. Duplicate experiments were performed to investigate the effect of dietary folate deficiency on arsenic induction of micronuclei (MN) in peripheral blood cells. Male C5...

  1. Lymphocytes from wasted mice express enhanced spontaneous and {gamma}-ray-induced apoptosis

    SciTech Connect

    Woloschak, G.E. |; Chang-Liu, Chin-Mei; Chung, Jen; Libertin, C.R.

    1993-09-01

    Mice bearing the autosomal recessive mutation wasted (wst/wst) display a disease pattern including faulty repair of DNA damage in lymphocytes after radiation exposure, neurologic abnormalities, and immunodeficiency. Many of the features of this mouse model have suggested a premature or increased spontaneous frequency of apoptosis in thymocytes; past work has shown an inability to establish cultured T cell lines, an abnormally high death rate of stimulated T cells in culture, and an increased sensitivity of T cells to the killing effects of ionizing radiations in wst/wst mice relative to controls. The experiments reported here were designed to examine splenic and thymic lymphocytes from wasted and control mice for signs of early apoptosis. Our results revealed enhanced expression of Rp-8 mRNA (associated with apoptosis) in thymic lymphocytes and reduced expression in splenic lymphocytes of wst/wst mice relative to controls; expression of Rp-2 and Td-30 mRNA (induced during apoptosis) were not detectable in spleen or thymus. Higher spontaneous DNA fragmentation was observed in wasted mice than in controls; however, {gamma}-ray-induced DNA fragmentation peaked at a lower dose and occurred to a greater extent in wasted mice relative to controls. These results provide evidence for high spontaneous and {gamma}-ray-induced apoptosis in T cells of wasted mice as a mechanism underlying the observed lymphocyte and DNA repair abnormalities.

  2. Resistance to Malaria by Enhanced Phagocytosis of Erythrocytes in LMP7-deficient Mice

    PubMed Central

    Duan, Xuefeng; Imai, Takashi; Chou, Bin; Tu, Liping; Himeno, Kunisuke; Suzue, Kazutomo; Hirai, Makoto; Taniguchi, Tomoyo; Okada, Hiroko; Shimokawa, Chikako; Hisaeda, Hajime

    2013-01-01

    General cellular functions of proteasomes occur through protein degradation, whereas the specific function of immunoproteasomes is the optimization of antigen processing associated with MHC class I. We and others previously reported that deficiency in subunits of immunoproteasomes impaired the activation of antigen-specific CD8+ T cells, resulting in higher susceptibility to tumor and infections. We demonstrated that CD8+ T cells contributed to protection against malaria parasites. In this study, we evaluated the role of immunoproteasomes in the course of infection with rodent malaria parasites. Unexpectedly, Plasmodium yoelii infection of mice deficient in LMP7, a catalytic subunit of immunoproteasomes, showed lower parasite growth in the early phase of infection and lower lethality compared with control mice. The protective characteristics of LMP7-deficient mice were not associated with enhanced immune responses, as the mutant mice showed comparable or diminished activation of innate and acquired immunity. The remarkable difference was observed in erythrocytes instead of immune responses. Parasitized red blood cells (pRBCs) purified from LMP7-deficient mice were more susceptible to phagocytosis by macrophages compared with those from wild-type mice. The susceptibility of pRBC to phagocytosis appeared to correlate with deformity of the membrane structures that were only observed after infection. Our results suggest that RBCs of LMP7-deficient mice were more likely to deform in response to infection with malaria parasites, presumably resulting in higher susceptibility to phagocytosis and in the partial resistance to malaria. PMID:23527234

  3. F. novicida-Infected A. castellanii Does Not Enhance Bacterial Virulence in Mice

    PubMed Central

    Ozanic, Mateja; Gobin, Ivana; Brezovec, Martin; Marecic, Valentina; Trobonjaca, Zlatko; Abu Kwaik, Yousef; Santic, Marina

    2016-01-01

    Francisella tularensis is a facultative intracellular bacterium that causes tularemia in humans and animals. Epidemiology of tularemia worldwide is often associated with water-borne transmission, which includes mosquitoes and amoebae as the potential host reservoirs of the bacteria in water environment. In vitro studies showed intracellular replication of F. tularensis within Acanthamoeba castellanii and Hartmanella vermiformis cells. While infection of amoeba by Legionella pneumophila has been shown to enhance infectivity of L. pneumophila the role of F. tularensis-infected protozoa in the pathogenesis of tularemia is not known. We used 6 h coculture of A. castellanii and F. novicida for investigation of the effect of inhaled amoeba on the pathogenesis of tularemia on in vivo model. Balb/c mice were infected intratracheally with F. novicida or with F. novicida-infected A. castellanii. Surprisingly, infection with F. novicida-infected A. castellanii did not lead to bronchopneumonia in Balb/c mice, and Francisella did not disseminate into the liver and spleen. Upon inhalation, F. novicida infects a variety of host cells, though neutrophils are the predominant cells early during infection in the lung infiltrates of pulmonary tularemia. The numbers of neutrophils in the lungs of Balb/c mice were significantly lower in the infection of mice with F. novicida-infected A. castellanii in comparison to group of mice infected only with F. novicida. These results demonstrate that following inoculation of mice with F. novicida-infected A. castellanii, mice did not develop tularemia. PMID:27242974

  4. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP.

    PubMed

    Lewis, J; Dickson, D W; Lin, W L; Chisholm, L; Corral, A; Jones, G; Yen, S H; Sahara, N; Skipper, L; Yager, D; Eckman, C; Hardy, J; Hutton, M; McGowan, E

    2001-08-24

    JNPL3 transgenic mice expressing a mutant tau protein, which develop neurofibrillary tangles and progressive motor disturbance, were crossed with Tg2576 transgenic mice expressing mutant beta-amyloid precursor protein (APP), thus modulating the APP-Abeta (beta-amyloid peptide) environment. The resulting double mutant (tau/APP) progeny and the Tg2576 parental strain developed Abeta deposits at the same age; however, relative to JNPL3 mice, the double mutants exhibited neurofibrillary tangle pathology that was substantially enhanced in the limbic system and olfactory cortex. These results indicate that either APP or Abeta influences the formation of neurofibrillary tangles. The interaction between Abeta and tau pathologies in these mice supports the hypothesis that a similar interaction occurs in Alzheimer's disease. PMID:11520987

  5. Ursolic acid enhances pentobarbital-induced sleeping behaviors via GABAergic neurotransmission in mice.

    PubMed

    Jeon, Se Jin; Park, Ho Jae; Gao, Qingtao; Pena, Irene Joy Dela; Park, Se Jin; Lee, Hyung Eun; Woo, Hyun; Kim, Hee Jin; Cheong, Jae Hoon; Hong, Eunyoung; Ryu, Jong Hoon

    2015-09-01

    Prunella vulgaris is widely used as a herbal medicine for cancers, inflammatory diseases, and other infections. Although it has long been used, few studies have examined its effects on central nervous system function. Here, we first observed that ethanolic extracts of P. vulgaris (EEPV) prolonged pentobarbital-induced sleep duration in mice. It is known that EEPV consists of many active components including triterpenoid (ursolic acid and oleanolic acid), which have many biological activities. Therefore, we evaluated which EEPV components induced sleep extension in pentobarbital-mediated sleeping model in mice. Surprisingly, despite their structural similarity and other common functions such as anti-inflammation, anti-cancer, and tissue protection, only ursolic acid enhanced sleep duration in pentobarbital-treated mice. These results were attenuated by bicuculline treatment, which is a GABAA receptor antagonist. The present results suggest that ursolic acid from P. vulgaris enhances sleep duration through GABAA receptor activation and could be a therapeutic candidate for insomnia treatment. PMID:26102564

  6. ENHANCED MORTALITY AND LIVER DAMAGE IN VIRUS-INFECTED MICE EXPOSED TO PARAXYLENE

    EPA Science Inventory

    This study assessed effects of p-xylene exposure on mice concurrently infected with murine cytomegalovirus (MCMV). ossible effects included: enhanced infection due to p-xylene induced immune suppression; increased p-xylene toxicity due to viral suppression of cytochrome P-450 (P-...

  7. SYNTHETIC PARTICLES ENHANCE AIRWAY RESPONSES TO OVALBUMIN ANTIGEN IN BALB/C MICE

    EPA Science Inventory

    SYNTHETIC PARTICLES ENHANCE AIRWAY RESPONSES TO OVALBUMIN ANTIGEN IN BALB/CJ MICE. S H Gavett, N Haykal-Coates, and M I Gilmour. Experimental Toxicology Division, NHEERL, ORD, USEPA, Research Triangle Park, NC

    Levels of airborne particulate matter (PM) are positively c...

  8. HemoHIM enhances the therapeutic efficacy of ionizing radiation treatment in tumor-bearing mice.

    PubMed

    Park, Hae-Ran; Ju, Eun-Jin; Jo, Sung-Kee; Jung, Uhee; Kim, Sung-Ho

    2010-02-01

    Although radiotherapy is commonly used for a variety of cancers, radiotherapy alone does not achieve a satisfactory therapeutic outcome. In this study, we examined the possibility that HemoHIM can enhance the anticancer effects of ionizing radiation (IR) in melanoma-bearing mice. The HemoHIM was prepared by adding the ethanol-insoluble fraction to the total water extract of a mixture of three edible herbs-Angelica Radix, Cnidium Rhizoma, and Paeonia Radix. Anticancer effects of HemoHIM were evaluated in melanoma-bearing mice exposed to IR. IR treatment (5 Gy at 7 days after melanoma cell injection) reduced the weight of the solid tumors, and HemoHIM supplementation with IR enhanced the decreases in tumor weight (P < .03). In the melanoma-bearing mice treated with IR, HemoHIM administration also increased the activity of natural killer cells and cytotoxic T cells, although the proportions of these cells in spleen were not different. In addition, HemoHIM administration increased the interleukin-2 and tumor necrosis factor-alpha secretion from lymphocytes stimulated with concanavalin A, which seemed to contribute to the enhanced efficacy of HemoHIM in tumor-bearing mice treated with IR. In conclusion, HemoHIM may be a beneficial supplement during radiotherapy for enhancing the antitumor efficacy. PMID:20136435

  9. SYNTHETIC COPPER-CONTAINING PARTICLES ENHANCE ALLERGIC AIRWAY RESPONSES IN MICE

    EPA Science Inventory

    SYNTHETIC COPPER-CONTAINING PARTICLES ENHANCE ALLERGIC AIRWAY RESPONSES IN MICE. SH Gavett, MI Gilmour, and N Haykal-Coates. National Health and Environ Effects Research Lab, USEPA, Res Triangle Park, NC USA
    Respiratory morbidity and mortality associated with increases in ...

  10. Systemic inflammation enhances surgery-induced cognitive dysfunction in mice.

    PubMed

    Fidalgo, António Rei; Cibelli, Mario; White, John P M; Nagy, Istvan; Maze, Mervyn; Ma, Daqing

    2011-07-01

    The activation of the immune system, by either lipopolysaccharide (LPS) administration or surgical trauma, has been shown to be capable of affecting hippocampal function, causing memory impairment. Here, we examined the extent to which LPS-induced infection may aggravate impairment of memory function following orthopaedic surgery. Hippocampal memory function impairment was assessed using fear-conditioning tasks, while IL-1β levels in plasma and hippocampus were measured using ELISA. LPS-induced inflammation disrupted hippocampal memory consolidation as evidenced by reduced contextual freezing time exhibited by infected mice. Likewise, surgery caused hippocampal-dependent memory impairment, which was associated with increased levels of IL-1β both in plasma and hippocampus. However, a sub-pyrogenic dose of LPS alone failed to impair memory function. This dose of LPS, when administered prior to surgery, exacerbated surgery-induced cognitive dysfunction as evidenced by further reduction of contextual freezing time. Also, it caused a concomitant additional increase in the levels of IL-1β in both plasma and hippocampus of those animals. Our data suggest that sub-clinical infection may sensitise the immune system augmenting the severity of post-operative cognitive dysfunction. PMID:21575676

  11. Basal Bone Phenotype and Increased Anabolic Responses to Intermittent Parathyroid Hormone in Healthy Male COX-2 Knockout Mice

    PubMed Central

    Xu, Manshan; Choudhary, Shilpa; Voznesensky, Olga; Gao, Qi; Adams, Douglas; Diaz-Doran, Vilmaris; Wu, Qian; Goltzman, David; Raisz, Lawrence G.; Pilbeam, Carol C.

    2011-01-01

    Cyclooxygenase-2 (COX-2) knockout (KO) mice in inbred strains can have renal dysfunction with secondary hyperparathyroidism (HPTH), making direct effects of COX-2 KO on bone difficult to assess. COX-2 KO mice in an outbred CD-1 background did not have renal dysfunction but still had two-fold elevated PTH compared to wild type (WT) mice. Compared to WT mice, KO mice had increased serum markers of bone turnover, decreased femoral bone mineral density (BMD) and cortical bone thickness, but no differences in trabecular bone volume by μCT or dynamic histomorphometry. Because PTH is a potent inducer of COX-2 and prostaglandin (PG) production, we examined effects of COX-2 KO on bone responses after three weeks of intermittent PTH. Intermittent PTH increased femoral BMD and cortical bone area more in KO mice than in WT mice and increased trabecular bone volume in the distal femur in both WT and KO mice. Although not statistically significant, PTH-stimulated increases in trabecular bone tended to be greater in KO mice than in WT mice. PTH increased serum markers of bone formation and resorption more in KO than in WT mice but increased the ratio of osteoblastic surface to osteoclastic surface only in KO mice. PTH also increased femoral mineral apposition rates and bone formation rates in KO mice more than in WT mice. Acute mRNA responses to PTH of genes that might mediate some anabolic and catabolic effects of PTH tended to be greater in KO than WT mice. We conclude that (1) the basal bone phenotype in male COX-2 KO mice might reflect HPTH, COX-2 deficiency or both, and (2) increased responses to intermittent PTH in COX-2 KO mice, despite the presence of chronic HPTH, suggest that absence of COX-2 increased sensitivity to PTH. It is possible that manipulation of endogenous PGs could have important clinical implications for anabolic therapy with PTH. PMID:20471507

  12. Combined administration of (L)-cystine and (L)-theanine enhances immune functions and protects against influenza virus infection in aged mice.

    PubMed

    Takagi, Yasuhiro; Kurihara, Shigekazu; Higashi, Natsumi; Morikawa, Saeko; Kase, Tetsuo; Maeda, Akiko; Arisaka, Harumi; Shibahara, Susumu; Akiyama, Yukio

    2010-02-01

    Cell-mediated and humoral immune responses are attenuated with aging. Intracellular glutathione (GSH) levels also decrease with aging. Previously, we have reported that combined administration of (L)-cystine and (L)-theanine enhances antigen-specific IgG production, partly through augmentation of GSH levels and T helper 2-mediated responses in 12-week-old mice. These findings suggest that combined administration of (L)-cystine and (L)-theanine to aged mice improves immune responses via increase of GSH synthesis. Here, we examined the effects of combined administration of (L)-cystine and (L)-theanine on antigen-specific antibody production and influenza virus infection in aged mice. Combined administration of these amino acids for 14 days before primary immunization significantly enhanced the serum antigen-specific IgM and IgG levels in 24-month-old mice. Furthermore, 13-month-old mice co-treated with these amino acids orally for 10 days had significantly lower lung viral titers than controls at 6 days after influenza virus infection. In addition, this co-treatment also significantly prevented the weight loss associated with infection. Enhancement of anti-influenza-virus IgG antibodies by combined administration of (L)-cystine and (L)-theanine was seen 10 days after infection. The significantly elevated serum interleukin-10/interferon-gamma ratio and gamma-glutamylcysteine synthetase mRNA expression, which is the rate-limiting enzyme of GSH synthesis, in the spleen 3 days after infection may have contributed to the observed beneficial effects. These results suggest that combined administration of (L)-cystine and (L)-theanine enhances immune function and GSH synthesis which are compromised with advanced age, and may become a useful strategy in healthy aging. PMID:19940390

  13. Enhanced antitumor efficacy of cisplatin in combination with HemoHIM in tumor-bearing mice

    PubMed Central

    2009-01-01

    Background Although cisplatin is one of the most effective chemotherapeutic agents, cisplatin alone does not achieve a satisfactory therapeutic outcome. Also cisplatin accumulation shows toxicity to normal tissues. In this study, we examined the possibility of HemoHIM both to enhance anticancer effect with cisplatin and to reduce the side effects of cisplatin in melanoma-bearing mice. Methods HemoHIM was prepared by adding the ethanol-insoluble fraction to the total water extract of a mixture of 3 edible herbs, Angelica Radix, Cnidium Rhizoma and Paeonia Radix. Anticancer effects of HemoHIM with cisplatin were evaluated in melanoma-bearing mice. We used a Cr51-release assay to measure the activity of NK/Tc cell and ELISA to evaluate the production of cytokines. Results In melanoma-bearing mice, cisplatin (4 mg/kg B.W.) reduced the size and weight of the solid tumors, and HemoHIM supplementation with cisplatin enhanced the decrease of both the tumor size (p < 0.1) and weight (p < 0.1). HemoHIM itself did not inhibit melanoma cell growth in vitro, and did not disturb the effects of cisplatin in vitro. However HemoHIM administration enhanced both NK cell and Tc cell activity in mice. Interestingly, HemoHIM increased the proportion of NK cells in the spleen. In melanoma-bearing mice treated with cisplatin, HemoHIM administration also increased the activity of NK cells and Tc cells and the IL-2 and IFN-γ secretion from splenocytes, which seemed to contribute to the enhanced efficacy of cisplatin by HemoHIM. Also, HemoHIM reduced nephrotoxicity as seen by tubular cell of kidney destruction. Conclusion HemoHIM may be a beneficial supplement during cisplatin chemotherapy for enhancing the anti-tumor efficacy and reducing the toxicity of cisplatin. PMID:19292900

  14. Enhanced UV-Induced Skin Carcinogenesis in Transgenic Mice Overexpressing Proprotein Convertases1

    PubMed Central

    Fu, Jian; Bassi, Daniel E; Zhang, Jirong; Li, Tianyu; Cai, Kathy Q; Testa, Courtney Lyons; Nicolas, Emmanuelle; Klein-Szanto, Andres J

    2013-01-01

    The proprotein convertases (PCs) furin and PACE4 process numerous substrates involved in tumor growth, invasion, and metastasis. We have previously shown that PCs increase the susceptibility to chemical skin carcinogenesis. Because of the human relevancy of UV radiation in the etiopathogenesis of human skin cancer, we investigated whether or not transgenic mice overexpressing either furin alone or both furin and PACE4 show increased susceptibility to UV carcinogenesis. After backcrossing our previously described furin and PACE4 transgenic lines, targeted to the epidermis, into a SKH-1 background, we exposed both single and double transgenic mice to UV radiation for 34 weeks. The results showed an increase in squamous cell carcinoma (SCC) multiplicity of approximately 70% in the single furin transgenic mouse line SF47 (P < .002) and a 30% increase in the other single transgenic line SF49 when compared to wild-type (WT) SKH-1 mice. Interestingly, there was also an increase in the percentage of high histologic grade SCCs in the transgenic lines compared to the WT mice, i.e., WT = 9%, SF47 = 15%, and SF49 = 26% (P < .02). Targeting both furin and PACE4 to the epidermis in double transgenic mice did not have an additive effect on tumor incidence/multiplicity but did enhance the tumor histopathologic grade, i.e., a significant increase in higher grade SCCs was seen in the bigenic mouse line SPF47 (P < .02). Thus, we observed an increased susceptibility to UV in single furin transgenic mice that was not substantially enhanced in the double furin/PACE4 transgenic mice. PMID:23441131

  15. Loss of Blm enhances basal cell carcinoma and rhabdomyosarcoma tumorigenesis in Ptch1+/- mice.

    PubMed

    Davari, Parastoo; Hebert, Jennifer L; Albertson, Donna G; Huey, Bing; Roy, Ritu; Mancianti, Maria L; Horvai, Andrew E; McDaniel, Lisa D; Schultz, Roger A; Epstein, Ervin H

    2010-06-01

    Basal cell carcinomas (BCCs) have relative genomic stability and relatively benign clinical behavior but whether these two are related causally is unknown. To investigate the effects of introducing genomic instability into murine BCCs, we have compared ionizing radiation-induced tumorigenesis in Ptch1(+/-) mice versus that in Ptch1(+/-) mice carrying mutant Blm alleles. We found that BCCs in Ptch1(+/-) Blm(tm3Brd/tm3Brd) mice had a trend toward greater genomic instability as measured by array comprehensive genomic hybridization and that these mice developed significantly more microscopic BCCs than did Ptch1(+/-) Blm(+/tm3Brd) or Ptch1(+/-) Blm(+/+) mice. The mutant Blm alleles also markedly enhanced the formation of rhabdomyosarcomas (RMSs), another cancer to which Ptch1(+/)(-) mice and PTCH1(+/)(-) (basal cell nevus syndrome) patients are susceptible. Highly recurrent but different copy number changes were associated with the two tumor types and included losses of chromosomes 4 and 10 in all BCCs and gain of chromosome 10 in 80% of RMSs. Loss of chromosome 11 and 13, including the Trp53 and Ptch1 loci, respectively, occurred frequently in BCCs, suggesting tissue-specific selection for genes or pathways that collaborate with Ptch deficiency in tumorigenesis. Despite the quantitative differences, there was no dramatic qualititative difference in the BCC or RMS tumors associated with the mutant Blm genotype. PMID:19995795

  16. Systemic administration of rhIGF-I enhanced regeneration after sciatic nerve crush in mice.

    PubMed

    Contreras, P C; Steffler, C; Yu, E; Callison, K; Stong, D; Vaught, J L

    1995-09-01

    Despite numerous reports suggesting that insulin-like growth factor-I (IGF-I) may be involved in the survival and regeneration of damaged neurons in vitro and after local administration in vivo, there have been few studies on the effect of IGF-I administered systemically on regeneration of damaged nerves in vivo and the functional consequences of enhanced regeneration. In an earlier study, recombinant human IGF-I (rhIGF-I) administered systemically enhanced the rate of regeneration after a sciatic crush as measured by the number of nerve fibers/muscle section. The purpose of this study was to follow up this finding by evaluating whether rhIGF-I administered peripherally enhances the rate of functional recovery. In this study following nerve injury, mice lost the ability to grip a wire screen with their hind paws and to walk normally as indicated by a decrease in toe spread, internal toe spread and an increase in the angle between hind feet. The ability of injured mice treated with rhIGF-I to grip an inverted screen returned to control levels significantly faster than that of vehicle-treated mice (day 12 vs. day 15, respectively). Similarly, rhIGF-I treatment of injured mice resulted in toe spread, internal toe spread and angle values that were significantly better than that of vehicle-treated mice and returned to control levels faster than vehicle-treated injured mice. There was a parallel loss of innervation after sciatic nerve crush as measured by a loss in choline acetyltransferase activity in the soleus and gastrocnemius muscles.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7562520

  17. Hexose enhances oligonucleotide delivery and exon skipping in dystrophin-deficient mdx mice

    PubMed Central

    Han, Gang; Gu, Ben; Cao, Limin; Gao, Xianjun; Wang, Qingsong; Seow, Yiqi; Zhang, Ning; Wood, Matthew J. A.; Yin, HaiFang

    2016-01-01

    Carbohydrate-based infusion solutions are widely used in the clinic. Here we show that co-administration of phosphorodiamidate morpholino oligomers (PMOs) with glucose enhances exon-skipping activity in Duchenne muscular dystrophy (DMD) mdx mice. We identify a glucose–fructose (GF) formulation that potentiates PMO activity, completely corrects aberrant Dmd transcripts, restores dystrophin levels in skeletal muscles and achieves functional rescue without detectable toxicity. This activity is attributed to enhancement of GF-mediated PMO uptake in the muscle. We demonstrate that PMO cellular uptake is energy dependent, and that ATP from GF metabolism contributes to enhanced cellular uptake of PMO in the muscle. Collectively, we show that GF potentiates PMO activity by replenishing cellular energy stores under energy-deficient conditions in mdx mice. Our findings provide mechanistic insight into hexose-mediated oligonucleotide delivery and have important implications for the development of DMD exon-skipping therapy. PMID:26964641

  18. Hexose enhances oligonucleotide delivery and exon skipping in dystrophin-deficient mdx mice.

    PubMed

    Han, Gang; Gu, Ben; Cao, Limin; Gao, Xianjun; Wang, Qingsong; Seow, Yiqi; Zhang, Ning; Wood, Matthew J A; Yin, HaiFang

    2016-01-01

    Carbohydrate-based infusion solutions are widely used in the clinic. Here we show that co-administration of phosphorodiamidate morpholino oligomers (PMOs) with glucose enhances exon-skipping activity in Duchenne muscular dystrophy (DMD) mdx mice. We identify a glucose-fructose (GF) formulation that potentiates PMO activity, completely corrects aberrant Dmd transcripts, restores dystrophin levels in skeletal muscles and achieves functional rescue without detectable toxicity. This activity is attributed to enhancement of GF-mediated PMO uptake in the muscle. We demonstrate that PMO cellular uptake is energy dependent, and that ATP from GF metabolism contributes to enhanced cellular uptake of PMO in the muscle. Collectively, we show that GF potentiates PMO activity by replenishing cellular energy stores under energy-deficient conditions in mdx mice. Our findings provide mechanistic insight into hexose-mediated oligonucleotide delivery and have important implications for the development of DMD exon-skipping therapy. PMID:26964641

  19. Self-Exposure to the Male Pheromone ESP1 Enhances Male Aggressiveness in Mice.

    PubMed

    Hattori, Tatsuya; Osakada, Takuya; Matsumoto, Ayaka; Matsuo, Naoki; Haga-Yamanaka, Sachiko; Nishida, Takaya; Mori, Yuji; Mogi, Kazutaka; Touhara, Kazushige; Kikusui, Takefumi

    2016-05-01

    Exocrine gland-secreting peptide 1 (ESP1) released into male tear fluids is a male pheromone that stimulates sexually receptive behavior in female mice via the vomeronasal sensory system. ESP1 also induces c-Fos expression in male brain regions distinct from those in females. However, behavior in males following ESP1 exposure has not been examined. In the present study, we show that ESP1, in conjunction with unfamiliar male urine, enhances male aggression via the specific vomeronasal receptor V2Rp5. In addition, male mice that secrete ESP1 but lack V2Rp5 exhibit a lower level of aggressiveness than do mice that express V2Rp5. These results suggest that ESP1 not only acts as a male pheromone in both sexes but also serves as an auto-stimulatory factor that enhances male aggressiveness by self-exposure. Finally, re-activation of ESP1-induced c-Fos-positive neurons by using the designer receptor exclusively activated by designer drug (DREADD) approach resulted in enhancement of sexual and aggressive behaviors in female and male mice, respectively, indicating that sexually dimorphic activation in the brain is a neural basis for the sex-specific behavioral responses to ESP1. PMID:27151664

  20. Correlation between the enhancement of flunitrazepam binding by GABA and seizure susceptibility in mice

    SciTech Connect

    Marley, R.J.; Wehner, J.M.

    1987-06-08

    Various populations of mice exhibit differential sensitivity to seizure-inducing agents. The relationship of seizure susceptibility to alterations in the GABA receptor complex was investigated in six different populations of mice consisting of four inbred strains (C57BL, DBA, C3H, and BALB) and two selected lines (long sleep and short sleep). Seizure activity was induced by intraperitoneal administration of the GAD inhibitor, 3-mercaptopropionic acid, and latencies to seizure onset and tonus were measured. In naive mice of the same populations, GABA enhancement of TH-flunitrazepam binding was measured in extensively washed whole brain membranes at several GABA concentrations. Both differential seizure sensitivity to 3-mercaptopropionic acid and differential enhancement of TH-flunitrazepam binding by GABA were observed in these six populations of mice. Correlational analyses indicated a positive correlation between the degree of GABA enhancement of TH-flunitrazepam binding and resistance to the seizure-inducing properties of 3-mercaptopropionic acid. These data suggest that genetic differences in sensitivity to seizure-inducing agents that disrupt the GABAergic system may be related to differences in coupling between the various receptors associated with the GABA receptor complex.

  1. Gastric carcinogenesis by N-Methyl-N-nitrosourea is enhanced in db/db diabetic mice.

    PubMed

    Yoshizawa, Nao; Yamaguchi, Hirokazu; Yamamoto, Masami; Shimizu, Nobuyuki; Furihata, Chie; Tatematsu, Masae; Seto, Yasuyuki; Kaminishi, Michio

    2009-07-01

    In 2005, a Japanese epidemiological study showed that increase in plasma glucose levels is a risk factor for gastric cancer. However, no animal model has hitherto shown any association between diabetes mellitus and neoplasia in the stomach. Diabetic (db/db) mice have obese and diabetic phenotypes, including hyperglycemia, because of disruption of the leptin receptor. In the present study, effects of hyperglycemia and/or hyperinsulinemia on the development of proliferative lesions were therefore examined in db/db mice given N-methyl-N-nitrosourea (MNU). A total of 120 mice were assigned to four groups: Group A, 40 db/db mice with MNU; Group B, 40 + /db mice with MNU; Group C, 30 misty (wild-type) mice with MNU; Group D, 10 db/db mice without MNU. MNU was given at 60 ppm in drinking water for 20 weeks. Subgroups of animals were sacrificed at weeks 21 and 30 and blood samples were collected to measure glucose, insulin, leptin, and adiponectin concentrations. The removed stomachs were fixed in formalin, and embedded in paraffin for histological examination and immunohistochemistry. At week 30 in Groups A, B, C and D, hyperplasia was observed in 100, 79, 57, and 0%, and dysplasia in 91, 43, 71, and 0%, respectively. Adenocarcinomas and pepsinogen-altered pyloric glands (PAPG), putative preneoplastic lesions, were observed only in Group A, at an incidence of 45%. The serum levels of insulin and leptin were also elevated in Group A. Gastric carcinogenesis by MNU was enhanced in db/db mice, possibly in association with hyperinsulinemia and hyperleptinemia. PMID:19432903

  2. Enhanced spontaneous locomotor activity in bovine GH transgenic mice involves peripheral mechanisms.

    PubMed

    Bohlooly-Y, M; Olsson, B; Gritli-Linde, A; Brusehed, O; Isaksson, O G; Ohlsson, C; Söderpalm, B; Törnell, J; Ola, B

    2001-10-01

    Clinical and experimental studies indicate a role for GH in mechanisms related to anhedonia/hedonia, psychic energy, and reward. Recently we showed that transgenic mice with general overexpression of bovine GH display increased spontaneous locomotor activity. In the present study, we investigated whether this behavioral change is owing to a direct action of GH in the central nervous system or to peripheral GH actions. A transgenic construct, containing the glial fibrillary acidic protein promoter directing specific expression of bovine GH to the central nervous system, was designed. The central nervous system-specific expression of bovine GH in the glial fibrillary acidic protein-bovine GH transgenic mice was confirmed, but no effect on spontaneous locomotor activity was observed. Serum bovine GH levels were increased in glial fibrillary acidic protein-bovine GH transgenic mice but clearly lower than in transgenic mice with general overexpression of bovine GH. In contrast to the transgenic mice with general overexpression of bovine GH, glial fibrillary acidic protein-bovine GH mice did not display any difference in serum IGF-I levels. The levels of free T(3) and the conversion of the free T(4) to free T(3) were only increased in transgenic mice with general overexpression of bovine GH, but serum corticosterone levels were similarly increased in both transgenic models. These results suggest that free T(3) and/or IGF-I, affecting dopamine and serotonin systems in the central nervous system, may mediate the enhanced locomotor activity observed in transgenic mice with general overexpression of bovine GH. PMID:11564723

  3. Dietary trans fats enhance doxorubicin-induced cardiotoxicity in mice.

    PubMed

    Mong, Mei-chin; Hsia, Te-chun; Yin, Mei-chin

    2013-10-01

    This study investigated the combined effects of trans fat diet (TFD) and doxorubicin upon cardiac oxidative, inflammatory, and coagulatory stress. TFD increased trans fatty acid deposit in heart (P < 0.05), and decreased protein C and antithrombin-III activities in circulation (P < 0.05). TFD plus doxorubicin treatment elevated activities of plasminogen activator inhibitor-1, lactate dehydrogenase, and creatine phosphokinase (P < 0.05). This combination also raised xanthine oxidase activity, and enhanced cardiac levels of reactive oxygen species, interleukin (IL)-6, IL-10, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 than TFD or doxorubicin treatment alone (P < 0.05). TFD alone increased cardiac nuclear factor kappa B (NF-κB) activity (P < 0.05), but failed to affect expression of NF-κB and mitogen-activated protein kinase (MAPK) (P > 0.05). Doxorubicin treatment alone augmented cardiac activity, mRNA expression, and protein production of NF-κB and MAPK (P < 0.05). TFD plus doxorubicin treatment further upregulated cardiac expression of NF-κB p65, p-p38, and p-ERK1/2 (P < 0.05). These findings suggest that TFD exacerbates doxorubicin-induced cardiotoxicity. PMID:24024564

  4. Maternal Antibody-Mediated Disease Enhancement in Type I Interferon-Deficient Mice Leads to Lethal Disease Associated with Liver Damage

    PubMed Central

    Lam, Jian Hang; Binte Aman, Siti Amanlina; Libau, Eshele Anak; Lee, Pei Xuan; St. John, Ashley L.; Alonso, Sylvie

    2016-01-01

    Epidemiological studies have reported that most of the severe dengue cases occur upon a secondary heterologous infection. Furthermore, babies born to dengue immune mothers are at greater risk of developing severe disease upon primary infection with a heterologous or homologous dengue virus (DENV) serotype when maternal antibodies reach sub-neutralizing concentrations. These observations have been explained by the antibody mediated disease enhancement (ADE) phenomenon whereby heterologous antibodies or sub-neutralizing homologous antibodies bind to but fail to neutralize DENV particles, allowing Fc-receptor mediated entry of the virus-antibody complexes into host cells. This eventually results in enhanced viral replication and heightened inflammatory responses. In an attempt to replicate this ADE phenomenon in a mouse model, we previously reported that upon DENV2 infection 5-week old type I and II interferon (IFN) receptors-deficient mice (AG129) born to DENV1-immune mothers displayed enhancement of disease severity characterized by increased virus titers and extensive vascular leakage which eventually led to the animals’ death. However, as dengue occurs in immune competent individuals, we sought to reproduce this mouse model in a less immunocompromised background. Here, we report an ADE model that is mediated by maternal antibodies in type I IFN receptor-deficient A129 mice. We show that 5-week old A129 mice born to DENV1-immune mothers succumbed to a DENV2 infection within 4 days that was sub-lethal in mice born to naïve mothers. Clinical manifestations included extensive hepatocyte vacuolation, moderate vascular leakage, lymphopenia, and thrombocytopenia. Anti-TNFα therapy totally protected the mice and correlated with healthy hepatocytes. In contrast, blocking IL-6 did not impact the virus titers or disease outcome. This A129 mouse model of ADE may help dissecting the mechanisms involved in dengue pathogenesis and evaluate the efficacy of vaccine and

  5. Gomafu lncRNA knockout mice exhibit mild hyperactivity with enhanced responsiveness to the psychostimulant methamphetamine

    PubMed Central

    Ip, Joanna Y.; Sone, Masamitsu; Nashiki, Chieko; Pan, Qun; Kitaichi, Kiyoyuki; Yanaka, Kaori; Abe, Takaya; Takao, Keizo; Miyakawa, Tsuyoshi; Blencowe, Benjamin J.; Nakagawa, Shinichi

    2016-01-01

    The long noncoding RNA Gomafu/MIAT/Rncr2 is thought to function in retinal cell specification, stem cell differentiation and the control of alternative splicing. To further investigate physiological functions of Gomafu, we created mouse knockout (KO) model that completely lacks the Gomafu gene. The KO mice did not exhibit any developmental deficits. However, behavioral tests revealed that the KO mice are hyperactive. This hyperactive behavior was enhanced when the KO mice were treated with the psychostimulant methamphetamine, which was associated with an increase in dopamine release in the nucleus accumbens. RNA sequencing analyses identified a small number of genes affected by the deficiency of Gomafu, a subset of which are known to have important neurobiological functions. These observations suggest that Gomafu modifies mouse behavior thorough a mild modulation of gene expression and/or alternative splicing of target genes. PMID:27251103

  6. Gomafu lncRNA knockout mice exhibit mild hyperactivity with enhanced responsiveness to the psychostimulant methamphetamine.

    PubMed

    Ip, Joanna Y; Sone, Masamitsu; Nashiki, Chieko; Pan, Qun; Kitaichi, Kiyoyuki; Yanaka, Kaori; Abe, Takaya; Takao, Keizo; Miyakawa, Tsuyoshi; Blencowe, Benjamin J; Nakagawa, Shinichi

    2016-01-01

    The long noncoding RNA Gomafu/MIAT/Rncr2 is thought to function in retinal cell specification, stem cell differentiation and the control of alternative splicing. To further investigate physiological functions of Gomafu, we created mouse knockout (KO) model that completely lacks the Gomafu gene. The KO mice did not exhibit any developmental deficits. However, behavioral tests revealed that the KO mice are hyperactive. This hyperactive behavior was enhanced when the KO mice were treated with the psychostimulant methamphetamine, which was associated with an increase in dopamine release in the nucleus accumbens. RNA sequencing analyses identified a small number of genes affected by the deficiency of Gomafu, a subset of which are known to have important neurobiological functions. These observations suggest that Gomafu modifies mouse behavior thorough a mild modulation of gene expression and/or alternative splicing of target genes. PMID:27251103

  7. The disorganized visual cortex in reelin-deficient mice is functional and allows for enhanced plasticity.

    PubMed

    Pielecka-Fortuna, Justyna; Wagener, Robin Jan; Martens, Ann-Kristin; Goetze, Bianka; Schmidt, Karl-Friedrich; Staiger, Jochen F; Löwel, Siegrid

    2015-11-01

    A hallmark of neocortical circuits is the segregation of processing streams into six distinct layers. The importance of this layered organization for cortical processing and plasticity is little understood. We investigated the structure, function and plasticity of primary visual cortex (V1) of adult mice deficient for the glycoprotein reelin and their wild-type littermates. In V1 of rl-/- mice, cells with different laminar fates are present at all cortical depths. Surprisingly, the (vertically) disorganized cortex maintains a precise retinotopic (horizontal) organization. Rl-/- mice have normal basic visual capabilities, but are compromised in more challenging perceptual tasks, such as orientation discrimination. Additionally, rl-/- animals learn and memorize a visual task as well as their wild-type littermates. Interestingly, reelin deficiency enhances visual cortical plasticity: juvenile-like ocular dominance plasticity is preserved into late adulthood. The present data offer an important insight into the capabilities of a disorganized cortical system to maintain basic functional properties. PMID:25119525

  8. Constitutive adipocyte mTORC1 activation enhances mitochondrial activity and reduces visceral adiposity in mice.

    PubMed

    Magdalon, Juliana; Chimin, Patricia; Belchior, Thiago; Neves, Rodrigo X; Vieira-Lara, Marcel A; Andrade, Maynara L; Farias, Talita S; Bolsoni-Lopes, Andressa; Paschoal, Vivian A; Yamashita, Alex S; Kowaltowski, Alicia J; Festuccia, William T

    2016-05-01

    Mechanistic target of rapamycin complex 1 (mTORC1) loss of function reduces adiposity whereas partial mTORC1 inhibition enhances fat deposition. Herein we evaluated how constitutive mTORC1 activation in adipocytes modulates adiposity in vivo. Mice with constitutive mTORC1 activation in adipocytes induced by tuberous sclerosis complex (Tsc)1 deletion and littermate controls were evaluated for body mass, energy expenditure, glucose and fatty acid metabolism, mitochondrial function, mRNA and protein contents. Adipocyte-specific Tsc1 deletion reduced visceral, but not subcutaneous, fat mass, as well as adipocyte number and diameter, phenotypes that were associated with increased lipolysis, UCP-1 content (browning) and mRNA levels of pro-browning transcriptional factors C/EBPβ and ERRα. Adipocyte Tsc1 deletion enhanced mitochondrial oxidative activity, fatty acid oxidation and the expression of PGC-1α and PPARα in both visceral and subcutaneous fat. In brown adipocytes, however, Tsc1 deletion did not affect UCP-1 content and basal respiration. Adipocyte Tsc1 deletion also reduced visceral adiposity and enhanced glucose tolerance, liver and muscle insulin signaling and adiponectin secretion in mice fed with purified low- or high-fat diet. In conclusion, adipocyte-specific Tsc1 deletion enhances mitochondrial activity, induces browning and reduces visceral adiposity in mice. PMID:26923434

  9. Intestinal barrier analysis by assessment of mucins, tight junctions, and α-defensins in healthy C57BL/6J and BALB/cJ mice.

    PubMed

    Volynets, Valentina; Rings, Andreas; Bárdos, Gyöngyi; Ostaff, Maureen J; Wehkamp, Jan; Bischoff, Stephan C

    2016-01-01

    The intestinal barrier is gaining increasing attention because it is related to intestinal homeostasis and disease. Different parameters have been used in the past to assess intestinal barrier functions in experimental studies; however most of them are poorly defined in healthy mice. Here, we compared a number of barrier markers in healthy mice, established normal values and correlations. In 48 mice (24 C57BL/6J, 24 BALB/cJ background), we measured mucus thickness, and expression of mucin-2, α-defensin-1 and -4, zonula occludens-1, occludin, junctional adhesion molecule-A, claudin-1, 2 and -5. We also analyzed claudin-3 and fatty acid binding protein-2 in urine and plasma, respectively. A higher expression of mucin-2 protein was found in the colon compared to the ileum. In contrast, the α-defensins-1 and -4 were expressed almost exclusively in the ileum. The protein expression of the tight junction molecules claudin-1, occludin and zonula occludens-1 did not differ between colon and ileum, although some differences occurred at the mRNA level. No age- or gender-related differences were found. Differences between C57BL/6J and BALB/cJ mice were found for α-defensin-1 and -4 mRNA expression, and for urine and plasma marker concentrations. The α-defensin-1 mRNA correlated with claudin-5 mRNA, whereas α-defensin-4 mRNA correlated with claudin-3 concentrations in urine. In conclusion, we identified a number of murine intestinal barrier markers requiring tissue analyses or measurable in urine or plasma. We provide normal values for these markers in mice of different genetic background. Such data might be helpful for future animal studies in which the intestinal barrier is of interest. PMID:27583194

  10. Enhanced growth and experimental metastasis of chemically induced tumor in ultraviolet irradiated syngeneic mice.

    PubMed

    Gensler, H L; Chen, H

    1991-05-01

    Recent studies have shown that ultraviolet (UV) irradiation induces a systemic effect which enhances subsequent tumor induction by benzo[a]pyrene in a manner which is dependent on the dose of benzo[a]pyrene. The present study was designed to test whether UV-B irradiation renders mice susceptible to subcutaneous or intravenous injection of a regressor tumor induced by benzo[a]pyrene. The sources of UV-B irradiation were banks of 6 Westinghouse FS-40 sunlamps, situated 20 cm above the mouse cages. Female BALB/cAnNHsd received five 30-min dorsal UV-B radiation treatments per week for 12 weeks, resulting in a total dose of approx. 6.4 x 10(5) J m-2. Two to seven days after termination of UV treatments, syngeneic regressor tumor cells (BP2) induced by benzo[a]pyrene were injected subcutaneously or intravenously into irradiated mice and unirradiated controls. By 38 days post subcutaneous implantation, 24/30 and 3/30 BP2 implants were detectable in the irradiated and unirradiated mice, respectively. Ultraviolet irradiated mice were also unable to reject lung colonies resulting from intravenous administration of BP2 cells, although they were rejected by unirradiated mice. The mean number of lung colonies per mouse was 16- to 35-fold greater in UV irradiated mice than in unirradiated controls, at 14 to 17 days post injection. Thus, UV irradiation rendered mice, with no known exposure to benzo[a]pyrene, susceptible to a subcutaneous or intravenous injection of a regressor tumor induced by benzo[a]pyrene. PMID:1881963

  11. Enhanced Susceptibility of Ago1/3 Double-Null Mice to Influenza A Virus Infection

    PubMed Central

    Van Stry, Melanie; Oguin, Thomas H.; Cheloufi, Sihem; Vogel, Peter; Watanabe, Makiko; Pillai, Meenu R.; Dash, Pradyot; Thomas, Paul G.; Hannon, Gregory J.

    2012-01-01

    RNA interference (RNAi) is a critical component of many cellular antiviral responses in plants, invertebrates, and mammals. However, its in vivo role in host protection from the negative-sense RNA virus influenza virus type A (flu) is unclear. Here we have examined the role of RNAi in host defense to flu by analyzing Argonaute 1 and 3 double-knockout mice deficient in components of the RNA-induced silencing complex. Compared to littermate controls, flu-infected double-knockout mice exhibited increased mortality, consistent with more severe alveolitis and pneumonitis. These data indicate that optimal resistance to flu requires Argonaute 1 and/or 3. Enhanced mortality of double-knockout mice was not associated either with increased viral replication or with differential pulmonary recruitment or function of innate and adaptive immune cells. Given the absence of detectable immune defects, our results support the notion that the enhanced flu susceptibility of double-knockout mice arises from an intrinsic impairment in the ability of lung cells to tolerate flu-elicited inflammation. PMID:22318144

  12. Enhanced susceptibility of Ago1/3 double-null mice to influenza A virus infection.

    PubMed

    Van Stry, Melanie; Oguin, Thomas H; Cheloufi, Sihem; Vogel, Peter; Watanabe, Makiko; Pillai, Meenu R; Dash, Pradyot; Thomas, Paul G; Hannon, Gregory J; Bix, Mark

    2012-04-01

    RNA interference (RNAi) is a critical component of many cellular antiviral responses in plants, invertebrates, and mammals. However, its in vivo role in host protection from the negative-sense RNA virus influenza virus type A (flu) is unclear. Here we have examined the role of RNAi in host defense to flu by analyzing Argonaute 1 and 3 double-knockout mice deficient in components of the RNA-induced silencing complex. Compared to littermate controls, flu-infected double-knockout mice exhibited increased mortality, consistent with more severe alveolitis and pneumonitis. These data indicate that optimal resistance to flu requires Argonaute 1 and/or 3. Enhanced mortality of double-knockout mice was not associated either with increased viral replication or with differential pulmonary recruitment or function of innate and adaptive immune cells. Given the absence of detectable immune defects, our results support the notion that the enhanced flu susceptibility of double-knockout mice arises from an intrinsic impairment in the ability of lung cells to tolerate flu-elicited inflammation. PMID:22318144

  13. Enhanced penetration of exogenous EPCs into brains of APP/PS1 transgenic mice.

    PubMed

    Yuan, Xiaoyang; Mei, Bin; Zhang, Le; Zhang, Cuntai; Zheng, Miao; Liang, Huifang; Wang, Wei; Zheng, Jie; Ding, Ling; Zheng, Kai

    2016-01-01

    The aim of this study was to investigate the repair function of exogenous Endothelial progenitor cells (EPCs) for brain microvascular damage of the APP/PS1 transgenic mouse model of Alzheimer's disease (AD). This study used a density-gradient centrifugation method to isolate mononuclear cells (MNCs) from mouse bone marrow, which were subsequently seeded and cultured. Cells were characterized by morphology and detection of the surface markers CD34 and CD133 at different time points by immunofluorescence (IF) and flow cytometry (FCM). Then, EPCs were transfected with GFP adenoviral vectors (GFP-EPCs). Wild-type (WT) and APP/PS1 transgenic mice both received GFP-EPCs injection through the tail vein, and using a PBS buffer injection as the control. Seven days later, the animals' brain tissue was isolated. Expression of GFP was detected by quantitative polymerase chain reaction (qPCR) and western-blot (WB), while the fluorescence of GFP within the brains of mice was observed under a fluorescence microscope. Higher mRNA and protein expression of GFP, accompanied with increased green fluorescence, were detected in the brain of GFP-EPCs-injected APP/PS1 mice, as compared with GFP-EPCs-injected WT mice. The results show that the APP/PS1 transgenic mouse model of AD exhibited enhanced penetration of exogenous EPCs into brains than the WT mice. PMID:27186272

  14. Enhanced penetration of exogenous EPCs into brains of APP/PS1 transgenic mice

    PubMed Central

    Yuan, Xiaoyang; Mei, Bin; Zhang, Le; Zhang, Cuntai; Zheng, Miao; Liang, Huifang; Wang, Wei; Zheng, Jie; Ding, Ling; Zheng, Kai

    2016-01-01

    The aim of this study was to investigate the repair function of exogenous Endothelial progenitor cells (EPCs) for brain microvascular damage of the APP/PS1 transgenic mouse model of Alzheimer’s disease (AD). This study used a density-gradient centrifugation method to isolate mononuclear cells (MNCs) from mouse bone marrow, which were subsequently seeded and cultured. Cells were characterized by morphology and detection of the surface markers CD34 and CD133 at different time points by immunofluorescence (IF) and flow cytometry (FCM). Then, EPCs were transfected with GFP adenoviral vectors (GFP-EPCs). Wild-type (WT) and APP/PS1 transgenic mice both received GFP-EPCs injection through the tail vein, and using a PBS buffer injection as the control. Seven days later, the animals’ brain tissue was isolated. Expression of GFP was detected by quantitative polymerase chain reaction (qPCR) and western-blot (WB), while the fluorescence of GFP within the brains of mice was observed under a fluorescence microscope. Higher mRNA and protein expression of GFP, accompanied with increased green fluorescence, were detected in the brain of GFP-EPCs-injected APP/PS1 mice, as compared with GFP-EPCs-injected WT mice. The results show that the APP/PS1 transgenic mouse model of AD exhibited enhanced penetration of exogenous EPCs into brains than the WT mice. PMID:27186272

  15. Apoptosis inhibitor of macrophage protein enhances intraluminal debris clearance and ameliorates acute kidney injury in mice.

    PubMed

    Arai, Satoko; Kitada, Kento; Yamazaki, Tomoko; Takai, Ryosuke; Zhang, Xizhong; Tsugawa, Yoji; Sugisawa, Ryoichi; Matsumoto, Ayaka; Mori, Mayumi; Yoshihara, Yasunori; Doi, Kent; Maehara, Natsumi; Kusunoki, Shunsuke; Takahata, Akiko; Noiri, Eisei; Suzuki, Yusuke; Yahagi, Naoki; Nishiyama, Akira; Gunaratnam, Lakshman; Takano, Tomoko; Miyazaki, Toru

    2016-02-01

    Acute kidney injury (AKI) is associated with prolonged hospitalization and high mortality, and it predisposes individuals to chronic kidney disease. To date, no effective AKI treatments have been established. Here we show that the apoptosis inhibitor of macrophage (AIM) protein on intraluminal debris interacts with kidney injury molecule (KIM)-1 and promotes recovery from AKI. During AKI, the concentration of AIM increases in the urine, and AIM accumulates on necrotic cell debris within the kidney proximal tubules. The AIM present in this cellular debris binds to KIM-1, which is expressed on injured tubular epithelial cells, and enhances the phagocytic removal of the debris by the epithelial cells, thus contributing to kidney tissue repair. When subjected to ischemia-reperfusion (IR)-induced AKI, AIM-deficient mice exhibited abrogated debris clearance and persistent renal inflammation, resulting in higher mortality than wild-type (WT) mice due to progressive renal dysfunction. Treatment of mice with IR-induced AKI using recombinant AIM resulted in the removal of the debris, thereby ameliorating renal pathology. We observed this effect in both AIM-deficient and WT mice, but not in KIM-1-deficient mice. Our findings provide a basis for the development of potentially novel therapies for AKI. PMID:26726878

  16. Enhanced photodynamic efficacy of PLGA-encapsulated 5-ALA nanoparticles in mice bearing Ehrlich ascites carcinoma

    NASA Astrophysics Data System (ADS)

    Shaker, Maryam N.; Ramadan, Heba S.; Mohamed, Moustafa M.; El khatib, Ahmed M.; Roston, Gamal D.

    2014-10-01

    Nanoparticles (NPs) fabricated from the biodegradable copolymer poly(lactic- co-glycolic acid) (PLGA) were investigated as a drug delivery system to enhance the photodynamic efficacy of 5-aminolevulinic acid (5-ALA) in mice bearing Ehrlich ascites carcinoma. The PLGA-encapsulated 5-ALA NPs were prepared using binary organic solvent diffusion method and characterized in terms of shape and particle size. The in vivo photodynamic efficiency in Ehrlich ascites-bearing mice was studied. The obtained particles were uniform in size with spherical shape of mean size of 249.5 nm as obtained by particle size analyzer and the in vitro release studies demonstrated a controlled release profile of 5-ALA. Tumor-bearing mice injected with PLGA-encapsulated 5-ALA NPs exhibited significantly smaller mean tumor volume, increased tumor growth delay compared with the control group and the group injected with free 5-ALA during the time course of the experiment. Histopathological examination of tumor from mice treated with PLGA-encapsulated 5-ALA NPs showed regression of tumor cells, in contrast to those obtained from mice treated with free 5-ALA. The results indicate that PLGA-encapsulated 5-ALA NPs are a successful delivery system for improving photodynamic activity in the target tissue.

  17. Meta-chlorophenylpiperazine enhances leptin sensitivity in diet-induced obese mice

    PubMed Central

    Yan, Chunling; Yang, Yongjie; Saito, Kenji; Xu, Pingwen; Wang, Chunmei; Hinton Jr, Antentor Othrell; Yan, Xiaofeng; Wu, Qi; Tong, Qingchun; Elmquist, Joel K; Fukuda, Makoto; Xu, Yong

    2015-01-01

    Background and Purpose Most forms of human obesity are characterized by impaired leptin sensitivity and, therefore, the effectiveness of anti-obesity leptin therapy in these leptin-resistant obese patients is marginal. Hence, the development of strategies to increase leptin sensitivity is of high priority in the field of obesity research. Experimental Approach We first examined the effects of co-administration of leptin and meta-chlorophenylpiperazine (mCPP), an agonist of 5-HT2C and 5-HT1B receptors, on energy balance in leptin-resistant diet-induced obese (DIO) mice. We further assessed leptin-induced phosphorylation of the STAT-3 (pSTAT3) in various brain regions of DIO mice pretreated with mCPP or in mice genetically lacking 5-HT2C receptors. Results Co-administration of mCPP with leptin had an additive effect on reducing body weight in DIO mice. Furthermore, mCPP pretreatment in DIO mice enhanced leptin-induced pSTAT3 in the arcuate nucleus, the ventromedial hypothalamic nucleus, and the ventral premammillary nucleus. Finally, deletion of 5-HT2C receptors significantly blunted leptin-induced pSTAT3 in these same hypothalamic regions. Conclusions and Implications Our study provides evidence that drugs, which activate 5-HT2C receptors, could function as leptin sensitizers and be used in combination with leptin to provide additional weight loss in DIO. PMID:25817043

  18. Enhanced Interleukin (IL)-13 Responses in Mice Lacking IL-13 Receptor α 2

    PubMed Central

    Wood, Nancy; Whitters, Matthew J.; Jacobson, Bruce A.; Witek, JoAnn; Sypek, Joseph P.; Kasaian, Marion; Eppihimer, Michael J.; Unger, Michelle; Tanaka, Takashi; Goldman, Samuel J.; Collins, Mary; Donaldson, Debra D.; Grusby, Michael J.

    2003-01-01

    Interleukin (IL)-13 has recently been shown to play important and unique roles in asthma, parasite immunity, and tumor recurrence. At least two distinct receptor components, IL-4 receptor (R)α and IL-13Rα1, mediate the diverse actions of IL-13. We have recently described an additional high affinity receptor for IL-13, IL-13Rα2, whose function in IL-13 signaling is unknown. To better appreciate the functional importance of IL-13Rα2, mice deficient in IL-13Rα2 were generated by gene targeting. Serum immunoglobulin E levels were increased in IL-13Rα2−/− mice despite the fact that serum IL-13 was absent and immune interferon γ production increased compared with wild-type mice. IL-13Rα2–deficient mice display increased bone marrow macrophage progenitor frequency and decreased tissue macrophage nitric oxide and IL-12 production in response to lipopolysaccharide. These results are consistent with a phenotype of enhanced IL-13 responsiveness and demonstrate a role for endogenous IL-13 and IL-13Rα2 in regulating immune responses in wild-type mice. PMID:12642602

  19. Enhanced head-twitch response to 5-HT-related agonists in thiamine-deficient mice.

    PubMed

    Nakagawasai, O; Murata, A; Arai, Y; Ohba, A; Wakui, K; Mitazaki, S; Niijima, F; Tan-No, K; Tadano, T

    2007-01-01

    While many studies suggest an involvement of brain serotonergic systems in neuro-psychiatric disorders such as schizophrenia and depression, their role in Wernicke-Korsakoff syndrome (WKS) remains unclear. Since dietary thiamine deficiency (TD) in mice is considered as a putative model of WKS, it was used in the present study to investigate the function of serotonergic neurons in this disorder. After 20 days of TD feeding, the intensity of tryptophan hydroxylase immunofluorescence was found to be significantly decreased in the dorsal and medial raphe nuclei. In addition, the head-twitch response (HTR) elicited by the intracerebroventricular administration of the 5-HT(2A) agonist 2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) was significantly increased in TD versus control mice, whereas the injection of ketanserin, a 5-HT(2A) receptor antagonist, prevented this enhancement. A single injection of thiamine HCl on the 19th day of TD feeding did not reduce the enhanced DOI-induced HTR. On the other hand, the administration of d-fenfluramine, a 5-HT releaser, did not enhance the HTR in TD mice. Together, our results indicate that TD causes a super-sensitivity of 5-HT(2A) receptors by reducing presynaptic 5-HT synthesis derived from degenerating neurons projecting from the raphe nucleus. PMID:17372673

  20. Nck2 Deficiency in Mice Results in Increased Adiposity Associated With Adipocyte Hypertrophy and Enhanced Adipogenesis.

    PubMed

    Dusseault, Julie; Li, Bing; Haider, Nida; Goyette, Marie-Anne; Côté, Jean-François; Larose, Louise

    2016-09-01

    Obesity results from an excessive expansion of white adipose tissue (WAT) from hypertrophy of preexisting adipocytes and enhancement of precursor differentiation into mature adipocytes. We report that Nck2-deficient mice display progressive increased adiposity associated with adipocyte hypertrophy. A negative relationship between the expression of Nck2 and WAT expansion was recapitulated in humans such that reduced Nck2 protein and mRNA levels in human visceral WAT significantly correlate with the degree of obesity. Accordingly, Nck2 deficiency promotes an adipogenic program that not only enhances adipocyte differentiation and lipid droplet formation but also results in dysfunctional elevated lipogenesis and lipolysis activities in mouse WAT as well as in stromal vascular fraction and 3T3-L1 preadipocytes. We provide strong evidence to support that through a mechanism involving primed PERK activation and signaling, Nck2 deficiency in adipocyte precursors is associated with enhanced adipogenesis in vitro and adiposity in vivo. Finally, in agreement with elevated circulating lipids, Nck2-deficient mice develop glucose intolerance, insulin resistance, and hepatic steatosis. Taken together, these findings reveal that Nck2 is a novel regulator of adiposity and suggest that Nck2 is important in limiting WAT expansion and dysfunction in mice and humans. PMID:27325288

  1. Healthy Pokes: After-School Education and Mentoring to Enhance Child Health

    ERIC Educational Resources Information Center

    Gaudreault, Karen Lux; Shiver, Victoria; Kinder, Christopher; Guseman, Emily

    2016-01-01

    Childhood obesity and related health consequences are currently considered some of the most important health challenges in our nation today. Early intervention programs designed to teach healthy lifestyle choices and behaviors are imperative to addressing this issue. Evidence suggests that intervention programs offered at an earlier age may reduce…

  2. Improving the classification of brain tumors in mice with perturbation enhanced (PE)-MRSI.

    PubMed

    Simões, Rui Vasco; Ortega-Martorell, Sandra; Delgado-Goñi, Teresa; Le Fur, Yann; Pumarola, Martí; Candiota, Ana Paula; Martín, Juana; Stoyanova, Radka; Cozzone, Patrick J; Julià-Sapé, Margarida; Arús, Carles

    2012-02-01

    Classifiers based on statistical pattern recognition analysis of MRSI data are becoming important tools for the non-invasive diagnosis of human brain tumors. Here we investigate the potential interest of perturbation-enhanced MRSI (PE-MRSI), in this case acute hyperglycemia, for improving the discrimination between mouse brain MRS patterns of glioblastoma multiforme (GBM), oligodendroglioma (ODG), and non-tumor brain parenchyma (NT). Six GBM-bearing mice and three ODG-bearing mice were scanned at 7 Tesla by PRESS-MRSI with 12 and 136 ms echo-time, during euglycemia (Eug) and also during induced acute hyperglycemia (Hyp), generating altogether four datasets per animal (echo time + glycemic condition): 12Eug, 136Eug, 12Hyp, and 136Hyp. For classifier development all spectral vectors (spv) selected from the MRSI matrix were unit length normalized (UL2) and used either as a training set (76 GBM spv, four mice; 70 ODG spv, two mice; 54 NT spv) or as an independent testing set (61 GBM spv, two mice; 31 ODG, one mouse; 23 NT spv). All Fisher's LDA classifiers obtained were evaluated as far as their descriptive performance-correctly classified cases of the training set (bootstrapping)-and predictive accuracy-balanced error rate of independent testing set classification. MRSI-based classifiers at 12Hyp were consistently more efficient in separating GBM, ODG, and NT regions, with overall accuracies always >80% and up to 95-96%; remaining classifiers were within the 48-85% range. This was also confirmed by user-independent selection of training and testing sets, using leave-one-out (LOO). This highlights the potential interest of perturbation-enhanced MRSI protocols for improving the non-invasive characterization of preclinical brain tumors. PMID:22193155

  3. Dietary energy restriction reduces high-fat diet-enhanced metastasis of Lewis lung carcinoma in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Obesity is a risk factor for cancer. The objective of this study was to determine the effects of dietary energy restriction on high-fat diet-enhanced spontaneous metastasis of Lewis lung carcinoma (LLC) in mice. Male C57BL/6 mice were fed an AIN93G diet or a high-fat diet (16% or 45% of energy fro...

  4. Chronic caffeine treatment enhances the resilience to social defeat stress in mice.

    PubMed

    Yin, Yong-Qin; Zhang, Chun; Wang, Jian-Xin; Hou, Jia; Yang, Xu; Qin, Jing

    2015-02-01

    Strong evidence has shown that caffeine exerts antidepressant-like effects in chronic stress situations by increasing dopamine levels. However, whether caffeine mediates the dopaminergic system and interferes with the resilience to social defeat stress in mice is unknown. The aim of this study is to investigate the role of caffeine in the behavioral responses to social defeat stress and the possible regulatory role of the dopaminergic system. Mice experienced chronic social defeat stress for 10 days. Caffeine was administered intraperitoneally before, during and after social defeat stress. The time spent in interaction zone, social interaction ratio and sucrose preference test was used to measure the social avoidance and anhedonia in mice. The results showed that chronic pretreatment with caffeine for 14 days and for 10 days during stress reversed the avoidance of social behavior and anhedonia induced by social defeat stress in mice, suggesting the enhancement of the resilience to social defeat stress induced by caffeine. However, neither the treatment with caffeine only during the social defeat stress for 10 days nor the treatment with acute caffeine after defeat stress altered the resilience to stress. Furthermore, chronic caffeine treatment did not affect the normal locomotor activity and the desperate behavior in naïve mice. Moreover, the antagonism of dopamine D1 receptor and not D2 receptor reversed the effect of caffeine on the social avoidance and depressive-like behavior. Finally, pretreatment with higher doses of caffeine did not affect the behavioral response to social defeat stress. Taken together, our findings provide new insight into the effects of caffeine on social avoidance and anhedonia in mice. In addition, our results illustrated the value of measuring changes in depressive-like behavior before and after social defeat stress to determine the potential treatment of caffeine on depression through the regulation of dopaminergic system. PMID

  5. 2-deoxy-D-glucose-induced metabolic stress enhances resistance to Listeria monocytogenes infection in mice

    NASA Technical Reports Server (NTRS)

    Miller, E. S.; Bates, R. A.; Koebel, D. A.; Fuchs, B. B.; Sonnenfeld, G.

    1998-01-01

    Exposure to different forms of psychological and physiological stress can elicit a host stress response, which alters normal parameters of neuroendocrine homeostasis. The present study evaluated the influence of the metabolic stressor 2-deoxy-D-glucose (2-DG; a glucose analog, which when administered to rodents, induces acute periods of metabolic stress) on the capacity of mice to resist infection with the facultative intracellular bacterial pathogen Listeria monocytogenes. Female BDF1 mice were injected with 2-DG (500 mg/kg b. wt.) once every 48 h prior to, concurrent with, or after the onset of a sublethal dose of virulent L. monocytogenes. Kinetics of bacterial growth in mice were not altered if 2-DG was applied concurrently or after the start of the infection. In contrast, mice exposed to 2-DG prior to infection demonstrated an enhanced resistance to the listeria challenge. The enhanced bacterial clearance in vivo could not be explained by 2-DG exerting a toxic effect on the listeria, based on the results of two experiments. First, 2-DG did not inhibit listeria replication in trypticase soy broth. Second, replication of L. monocytogenes was not inhibited in bone marrow-derived macrophage cultures exposed to 2-DG. Production of neopterin and lysozyme, indicators of macrophage activation, were enhanced following exposure to 2-DG, which correlated with the increased resistance to L. monocytogenes. These results support the contention that the host response to 2-DG-induced metabolic stress can influence the capacity of the immune system to resist infection by certain classes of microbial pathogens.

  6. Mechanism of Selenium-Induced Inhibition of Arsenic-Enhanced UVR Carcinogenesis in Mice

    PubMed Central

    Burns, Fredric J.; Rossman, Toby; Vega, Katherine; Uddin, Ahmed; Vogt, Stefan; Lai, Barry; Reeder, Richard J.

    2008-01-01

    Background Hairless mice that ingested arsenite in drinking water exhibited more than a 5-fold enhancement of ultraviolet radiation (UVR) carcinogenesis, whereas arsenite alone was carcinogenically inactive. Dietary organoselenium blocked the cancer enhancement effect of arsenic but not cancer induction by UVR. Objective In this study we sought to explain selenium blockage of As enhancement by establishing the extent that As and Se tissue distributions are coincident or divergent. Methods We used the X-ray fluorescence microprobe at the Advanced Photon Source (Argonne National Laboratory) to probe sections of skin and liver from hairless mice exposed to a) UVR, b) UVR + As, c) UVR + organoselenium, or d) UVR + As + organoselenium. Results We found elevated levels of As in the skin epithelium (hair follicles and epidermis) and diffusely in the liver of mice exposed to UVR + As. Arsenic was entirely absent in skin in mice exposed to UVR + As + organoselenium, but a diffuse low level was seen in the liver. As and Se locations were consistently divergent in skin; As was more diffusely distributed, whereas Se was strongly associated with membranes. X-ray absorption near-edge spectra are consistent with the presence of the seleno-bis(S-glutathionyl) arsinium ion in the liver. Conclusions Supplemental Se was uncommonly effective at preventing even a trace of As in skin at 14 or 196 days of continuous exposure to As in drinking water. Traces of the seleno-bis(S-glutathionyl) arsinium ion in the liver suggested that formation of this compound was more likely to be responsible for the As-blocking effect of Se than was a mechanism based on antioxidation. PMID:18560523

  7. Dietary wolfberry supplementation enhances the protective effect of flu vaccine against influenza challenge in aged mice.

    PubMed

    Du, Xiaogang; Wang, Junpeng; Niu, Xinli; Smith, Donald; Wu, Dayong; Meydani, Simin Nikbin

    2014-02-01

    Current vaccines for influenza do not fully protect the aged against influenza infection. Although wolfberry (goji berry) has been shown to improve immune response, including enhanced antibody production, after vaccination in the aged, it is not known if this effect would translate to better protection after influenza infection, nor is its underlying mechanism well understood. To address these issues, we conducted a study using a 2 × 2 design in which aged male mice (20-22 mo) were fed a control or a 5% wolfberry diet for 30 d, then immunized with an influenza vaccine or saline (control) on days 31 and 52 of the dietary intervention, and finally challenged with influenza A/Puerto Rico/8/34 virus. Mice fed wolfberry had higher influenza antibody titers and improved symptoms (less postinfection weight loss) compared with the mice treated by vaccine alone. Furthermore, an in vitro mechanistic study showed that wolfberry supplementation enhanced maturation and activity of antigen-presenting dendritic cells (DCs) in aged mice, as indicated by phenotypic change in expression of DC activation markers major histocompatibility complex class II, cluster of differentiation (CD) 40, CD80, and CD86, and functional change in DC production of cytokines interleukin-12 and tumor necrosis factor-α as well as DC endocytosis. Also, adoptive transfer of wolfberry-treated bone marrow DCs (loaded with ovalbumin(323-339)-peptide) promoted antigen-specific T cell proliferation as well as interleukin-4 and interferon-γ production in CD4(+) T cells. In summary, our data indicate that dietary wolfberry enhances the efficacy of influenza vaccination, resulting in better host protection to prevent subsequent influenza infection; this effect may be partly attributed to improved DC function. PMID:24336457

  8. Enhanced glucose tolerance in pancreatic-derived factor (PANDER) knockout C57BL/6 mice.

    PubMed

    Moak, Shari L; Dougan, Grace C; MarElia, Catherine B; Danse, Whitney A; Fernandez, Amanda M; Kuehl, Melanie N; Athanason, Mark G; Burkhardt, Brant R

    2014-11-01

    Pancreatic-derived factor (PANDER; also known as FAM3B) is a uniquely structured protein strongly expressed within and secreted from the endocrine pancreas. PANDER has been hypothesized to regulate fasting and fed glucose homeostasis, hepatic lipogenesis and insulin signaling, and to serve a potential role in the onset or progression of type 2 diabetes (T2D). Despite having potentially pivotal pleiotropic roles in glycemic regulation and T2D, there has been limited generation of stable animal models for the investigation of PANDER function, and there are no models on well-established genetic murine backgrounds for T2D. Our aim was to generate an enhanced murine model to further elucidate the biological function of PANDER. Therefore, a pure-bred PANDER knockout C57BL/6 (PANKO-C57) model was created and phenotypically characterized with respect to glycemic regulation and hepatic insulin signaling. The PANKO-C57 model exhibited an enhanced metabolic phenotype, particularly with regard to enhanced glucose tolerance. Male PANKO-C57 mice displayed decreased fasting plasma insulin and C-peptide levels, whereas leptin levels were increased as compared with matched C57BL/6J wild-type mice. Despite similar peripheral insulin sensitivity between both groups, hepatic insulin signaling was significantly increased during fasting conditions, as demonstrated by increased phosphorylation of hepatic PKB/Akt and AMPK, along with mature SREBP-1 expression. Insulin stimulation of PANKO-C57 mice resulted in increased hepatic triglyceride and glycogen content as compared with wild-type C57BL/6 mice. In summary, the PANKO-C57 mouse represents a suitable model for the investigation of PANDER in multiple metabolic states and provides an additional tool to elucidate the biological function and potential role in T2D. PMID:25217499

  9. Enhanced glucose tolerance in pancreatic-derived factor (PANDER) knockout C57BL/6 mice

    PubMed Central

    Moak, Shari L.; Dougan, Grace C.; MarElia, Catherine B.; Danse, Whitney A.; Fernandez, Amanda M.; Kuehl, Melanie N.; Athanason, Mark G.; Burkhardt, Brant R.

    2014-01-01

    Pancreatic-derived factor (PANDER; also known as FAM3B) is a uniquely structured protein strongly expressed within and secreted from the endocrine pancreas. PANDER has been hypothesized to regulate fasting and fed glucose homeostasis, hepatic lipogenesis and insulin signaling, and to serve a potential role in the onset or progression of type 2 diabetes (T2D). Despite having potentially pivotal pleiotropic roles in glycemic regulation and T2D, there has been limited generation of stable animal models for the investigation of PANDER function, and there are no models on well-established genetic murine backgrounds for T2D. Our aim was to generate an enhanced murine model to further elucidate the biological function of PANDER. Therefore, a pure-bred PANDER knockout C57BL/6 (PANKO-C57) model was created and phenotypically characterized with respect to glycemic regulation and hepatic insulin signaling. The PANKO-C57 model exhibited an enhanced metabolic phenotype, particularly with regard to enhanced glucose tolerance. Male PANKO-C57 mice displayed decreased fasting plasma insulin and C-peptide levels, whereas leptin levels were increased as compared with matched C57BL/6J wild-type mice. Despite similar peripheral insulin sensitivity between both groups, hepatic insulin signaling was significantly increased during fasting conditions, as demonstrated by increased phosphorylation of hepatic PKB/Akt and AMPK, along with mature SREBP-1 expression. Insulin stimulation of PANKO-C57 mice resulted in increased hepatic triglyceride and glycogen content as compared with wild-type C57BL/6 mice. In summary, the PANKO-C57 mouse represents a suitable model for the investigation of PANDER in multiple metabolic states and provides an additional tool to elucidate the biological function and potential role in T2D. PMID:25217499

  10. Engineered silica nanoparticles act as adjuvants to enhance allergic airway disease in mice

    PubMed Central

    2013-01-01

    Background With the increase in production and use of engineered nanoparticles (NP; ≤ 100 nm), safety concerns have risen about the potential health effects of occupational or environmental NP exposure. Results of animal toxicology studies suggest that inhalation of NP may cause pulmonary injury with subsequent acute or chronic inflammation. People with chronic respiratory diseases like asthma or allergic rhinitis may be even more susceptible to toxic effects of inhaled NP. Few studies, however, have investigated adverse effects of inhaled NP that may enhance the development of allergic airway disease. Methods We investigated the potential of polyethylene glycol coated amorphous silica NP (SNP; 90 nm diameter) to promote allergic airway disease when co-exposed during sensitization with an allergen. BALB/c mice were sensitized by intranasal instillation with 0.02% ovalbumin (OVA; allergen) or saline (control), and co-exposed to 0, 10, 100, or 400 μg of SNP. OVA-sensitized mice were then challenged intranasally with 0.5% OVA 14 and 15 days after sensitization, and all animals were sacrificed a day after the last OVA challenge. Blood and bronchoalveolar lavage fluid (BALF) were collected, and pulmonary tissue was processed for histopathology and biochemical and molecular analyses. Results Co-exposure to SNP during OVA sensitization caused a dose-dependent enhancement of allergic airway disease upon challenge with OVA alone. This adjuvant-like effect was manifested by significantly greater OVA-specific serum IgE, airway eosinophil infiltration, mucous cell metaplasia, and Th2 and Th17 cytokine gene and protein expression, as compared to mice that were sensitized to OVA without SNP. In saline controls, SNP exposure did cause a moderate increase in airway neutrophils at the highest doses. Conclusions These results suggest that airway exposure to engineered SNP could enhance allergen sensitization and foster greater manifestation of allergic airway disease upon

  11. (16)Oxygen irradiation enhances cued fear memory in B6D2F1 mice.

    PubMed

    Raber, Jacob; Marzulla, Tessa; Kronenberg, Amy; Turker, Mitchell S

    2015-11-01

    The space radiation environment includes energetic charged particles that may impact cognitive performance. We assessed the effects of (16)O ion irradiation on cognitive performance of C57BL/6J × DBA/2J F1 (B6D2F1) mice at OHSU (Portland, OR) one month following irradiation at Brookhaven National Laboratory (BNL, Upton, NY). Hippocampus-dependent contextual fear memory and hippocampus-independent cued fear memory of B6D2F1 mice were tested. (16)O ion exposure enhanced cued fear memory. This effect showed a bell-shaped dose response curve. Cued fear memory was significantly stronger in mice irradiated with (16)O ions at a dose of 0.4 or 0.8 Gy than in sham-irradiated mice or following irradiation at 1.6 Gy. In contrast to cued fear memory, contextual fear memory was not affected following (16)O ion irradiation at the doses used in this study. These data indicate that the amygdala might be particularly susceptible to effects of (16)O ion exposure. PMID:26553639

  12. PMC-12, a traditional herbal medicine, enhances learning memory and hippocampal neurogenesis in mice.

    PubMed

    Park, Hee Ra; Kim, Ju Yeon; Lee, Yujeong; Chun, Hye Jeong; Choi, Young Whan; Shin, Hwa Kyoung; Choi, Byung Tae; Kim, Cheol Min; Lee, Jaewon

    2016-03-23

    The beneficial effects of traditional Korean medicine are recognized during the treatment of neurodegenerative conditions, such as, Alzheimer's disease and neurocognitive dysfunction, and recently, hippocampal neurogenesis has been reported to be associated with memory function. In this study, the authors investigated the beneficial effects of polygonum multiflorum Thunberg complex composition-12 (PMC-12), which is a mixture of four medicinal herbs, that is, Polygonum multiflorum, Polygala tenuifolia, Rehmannia glutinosa, and Acorus gramineus, on hippocampal neurogenesis, learning, and memory in mice. PMC-12 was orally administered to male C57BL/6 mice (5 weeks old) at 100 or 500 mg/kg daily for 2 weeks. PMC-12 administration significantly was found to increase the proliferation of neural progenitor cells and the survival of newly-generated cells in the dentate gyrus. In the Morris water maze test, the latency times of PMC-12 treated mice (100 or 500 mg/kg) were shorter than those of vehicle-control mice. In addition, PMC-12 increased the levels of BDNF, p-CREB, and synaptophysin, which are known to be associated with neural plasticity and hippocampal neurogenesis. These findings suggest PMC-12 enhances hippocampal neurogenesis and neurocognitive function and imply that PMC-12 ameliorates memory impairment and cognitive deficits. PMID:26917101

  13. 2-Phenylethynyl-butyltellurium enhances learning and memory impaired by scopolamine in mice.

    PubMed

    Souza, Ana Cristina G; Bruning, César A; Acker, Carmine I; Neto, José S S; Nogueira, Cristina W

    2013-08-01

    Taking into account the memory-enhancing properties of 2-phenylethynyl-butyltellurium (PEBT) and the constant search for drugs that improve cognitive performance, the present study was designed to investigate the effect of PEBT on cognitive impairment induced by scopolamine in mice. PEBT (10 mg/kg, gavage) was administered to mice 1 h before the probe trial in the Morris water maze task. Memory impairment was induced by scopolamine (1 mg/kg, intraperitoneally) 30 min before the probe trial. PEBT significantly ameliorated the scopolamine-induced impairment of long-term memory, as indicated by a decrease in escape latency and an increase in the number of crossings of the platform location when compared with the amnesic mice. To evaluate the effect of PEBT on different phases of memory (acquisition, consolidation, and retrieval) impaired by scopolamine, the step-down inhibitory avoidance task was used. Scopolamine was administered 30 min before training (acquisition), test (retrieval), or immediately after training (consolidation). PEBT, administered 30 min before scopolamine, increased step-down latency in memory-impaired mice, improving the consolidation and retrieval stages, but not acquisition. No significant alterations in locomotor or exploratory behaviors were found in animals treated with PEBT and/or scopolamine. PEBT improved memory deficits during consolidation and retrieval induced by scopolamine. PMID:23751517

  14. Enhanced susceptibility of mice with streptozotocin-induced diabetes to type II group B streptococcal infection.

    PubMed Central

    Edwards, M S; Fuselier, P A

    1983-01-01

    Since diabetes mellitus predisposes adults to group B streptococcal (GBS) bacteremia, a murine model of streptozotocin-induced diabetes and type II GBS bacteremia was developed to assess certain immune factors which might influence susceptibility to infection. In diabetic mice, the 50% lethal dose for two strains of type II GBS was significantly lower (greater than 1 log10 decrease in CFU per milliliter) than in control animals. This enhanced virulence of GBS for diabetic animals was associated with prolonged bacteremia, persistent sequestration of organisms in the splanchnic reticuloendothelial system, and a shift from splenic to hepatic clearance. Although immunization of control and diabetic animals resulted in high concentrations of type-specific serum antibody, it had no effect on late reticuloendothelial system sequestration in diabetics. In contrast, depletion of complement by treatment of mice with cobra venom factor blocked reticuloendothelial system clearance and resulted in fatal infection in both diabetic and control mice. These results indicate that neither type-specific antibody nor an intact complement system is adequate for effective clearance of type II GBS bacteremia in mice with experimentally induced diabetes. This clearance deficit could be the result of a defect in hepatocyte membrane receptors necessary for removal of this encapsulated microorganism. PMID:6339383

  15. Immuno-enhancement effects of Lycium ruthenicum Murr. polysaccharide on cyclophosphamide-induced immunosuppression in mice

    PubMed Central

    Gong, Yuan; Wu, Jin; Li, Shi-Tong

    2015-01-01

    Lycium ruthenicum Murr. is commonly used in traditional Tibetan medicine, and the fruits of Lycium ruthenicum Murr. contain an immunologically active pectin which improves immune function against chronic diseases. The present study was performed to evaluate the immunomodulatory effects of Lycium ruthenicum Murr. polysaccharide 3 (LRGP3) in cyclophosphamide (Cy)-induced immunosuppressed mice. Mice were injected intraperitoneally once daily with low-dose (25 mg/kg), intermediate-dose (50 mg/kg), high-dose (100 mg/kg) of LRGP3 for 10 consecutive days, respectively. Compared with Cy group, LRGP3 accelerated recovery of spleen and thymus indices, enhanced T cell and B cell proliferation responses, as well as peritoneal macrophage phagocytosis. In addition, LRGP3 treatment restored the levels of interleukin-2 (IL-2), IL-6 and tumor necrosis factor-α (TNF-α) in the serum of Cy-treated mice. These results indicate that LRGP3 plays an important role in the protection against immunosuppression in Cy-treated mice and could be a potential immunomodulatory agent. PMID:26884983

  16. Enhancement of chemical carcinogenesis in mice by systemic effects of ultraviolet irradiation.

    PubMed

    Gensler, H L

    1988-02-01

    The present study was designed to determine the systemic influence of ultraviolet (UVB) irradiation upon subsequent carcinogenesis induced by benzo(a)pyrene. The source of UV irradiation consisted of six Westinghouse FS-40 fluorescent sunlamps. Female BALB/c mice received five 30-min dorsal UVB radiation treatments per week for 13 wk. At the end of 13 wk, irradiated and unirradiated mice received ventral applications of 0.1 or 1.0 mg of benzo(a)pyrene twice weekly for 20 or 10 wk, respectively. At 18 wk after the first benzo(a)pyrene treatment, mice receiving 0-, 0.1-, or 1.0-mg benzo(a)pyrene treatments bore 0, 12, or 29 tumors per group of 18 mice, respectively. Tumor-free survival was significantly shortened in the UV-irradiated hosts as compared with unirradiated hosts, as analyzed by the Kaplan-Meier method of survival analysis. Therefore, ultraviolet irradiation induced a systemic effect which enhanced subsequent tumor induction by benzo(a)pyrene in a manner which was dependent on the dose of benzo(a)pyrene. PMID:3335024

  17. Vaccine adjuvant ginsenoside Rg1 enhances immune responses against hepatitis B surface antigen in mice.

    PubMed

    Yuan, Ding; Yuan, Qin; Cui, Qianqian; Liu, Chaoqi; Zhou, Zhiyong; Zhao, Haixia; Dun, Yaoyan; Wang, Ting; Zhang, Changcheng

    2016-06-01

    The adjuvant effect of ginsenoside Rg1 on immune responses against hepatitis B surface antigen (HBsAg) in mice was investigated. Female BALB/c mice were subcutaneously injected with saline or HBsAg antigen with or without Rg1 on days 7 and 21. Samples were collected 2 weeks after the boosting for the detection of anti-HBsAg immunoglobulin G (IgG) isotypes in sera and gamma interferon (IFN-γ) and interleukin-4 (IL-4) produced in splenocytes. The innate and adaptive immune responses were measured in mice immunized as described above. The results showed that ginsenoside Rg1 had adjuvant properties in stimulating IgG, splenocyte proliferation, and mRNA expression of cytokines IFN-γ and IL-4, as well as the expression of cell surface marker TLR4 in the HBsAg-immunized mice. These results indicate that Rg1 enhances both Th1 (IgG2b and IFN-γ) and Th2 (IgG1 and IL-4) responses. In addition, the TLR4 signaling pathway is involved in the adjuvant activities of ginsenoside Rg1. PMID:27095502

  18. 16Oxygen irradiation enhances cued fear memory in B6D2F1 mice

    NASA Astrophysics Data System (ADS)

    Raber, Jacob; Marzulla, Tessa; Kronenberg, Amy; Turker, Mitchell S.

    2015-11-01

    The space radiation environment includes energetic charged particles that may impact cognitive performance. We assessed the effects of 16O ion irradiation on cognitive performance of C57BL/6J × DBA/2J F1 (B6D2F1) mice at OHSU (Portland, OR) one month following irradiation at Brookhaven National Laboratory (BNL, Upton, NY). Hippocampus-dependent contextual fear memory and hippocampus-independent cued fear memory of B6D2F1 mice were tested. 16O ion exposure enhanced cued fear memory. This effect showed a bell-shaped dose response curve. Cued fear memory was significantly stronger in mice irradiated with 16O ions at a dose of 0.4 or 0.8 Gy than in sham-irradiated mice or following irradiation at 1.6 Gy. In contrast to cued fear memory, contextual fear memory was not affected following 16O ion irradiation at the doses used in this study. These data indicate that the amygdala might be particularly susceptible to effects of 16O ion exposure.

  19. Pglyrp-Regulated Gut Microflora Prevotella falsenii, Parabacteroides distasonis and Bacteroides eggerthii Enhance and Alistipes finegoldii Attenuates Colitis in Mice

    PubMed Central

    Dziarski, Roman; Dowd, Scot E.; Gupta, Dipika

    2016-01-01

    Dysbiosis is a hallmark of inflammatory bowel disease (IBD), but it is unclear which specific intestinal bacteria predispose to and which protect from IBD and how they are regulated. Peptidoglycan recognition proteins (Pglyrps) are antibacterial, participate in maintaining intestinal microflora, and modulate inflammatory responses. Mice deficient in any one of the four Pglyrp genes are more sensitive to dextran sulfate sodium (DSS)-induced colitis, and stools from Pglyrp-deficient mice transferred to wild type (WT) germ-free mice predispose them to much more severe colitis than stools from WT mice. However, the identities of these Pglyrp-regulated bacteria that predispose Pglyrp-deficient mice to colitis or protect WT mice from colitis are not known. Here we identified significant changes in β-diversity of stool bacteria in Pglyrp-deficient mice compared with WT mice. The most consistent changes in microbiome in all Pglyrp-deficient mice were in Bacteroidales, from which we selected four species, two with increased abundance (Prevotella falsenii and Parabacteroides distasonis) and two with decreased abundance (Bacteroides eggerthii and Alistipes finegoldii). We then gavaged WT mice with stock type strains of these species to test the hypothesis that they predispose to or protect from DSS-induced colitis. P. falsenii, P. distasonis, and B. eggerthii all enhanced DSS-induced colitis in both WT mice with otherwise undisturbed intestinal microflora and in WT mice with antibiotic-depleted intestinal microflora. By contrast, A. finegoldii (which is the most abundant species in WT mice) attenuated DSS-induced colitis both in WT mice with otherwise undisturbed intestinal microflora and in WT mice with antibiotic-depleted intestinal microflora, similar to the colitis protective effect of the entire normal microflora. These results identify P. falsenii, P. distasonis, and B. eggerthii as colitis-promoting species and A. finegoldii as colitis-protective species. PMID

  20. Pglyrp-Regulated Gut Microflora Prevotella falsenii, Parabacteroides distasonis and Bacteroides eggerthii Enhance and Alistipes finegoldii Attenuates Colitis in Mice.

    PubMed

    Dziarski, Roman; Park, Shin Yong; Kashyap, Des Raj; Dowd, Scot E; Gupta, Dipika

    2016-01-01

    Dysbiosis is a hallmark of inflammatory bowel disease (IBD), but it is unclear which specific intestinal bacteria predispose to and which protect from IBD and how they are regulated. Peptidoglycan recognition proteins (Pglyrps) are antibacterial, participate in maintaining intestinal microflora, and modulate inflammatory responses. Mice deficient in any one of the four Pglyrp genes are more sensitive to dextran sulfate sodium (DSS)-induced colitis, and stools from Pglyrp-deficient mice transferred to wild type (WT) germ-free mice predispose them to much more severe colitis than stools from WT mice. However, the identities of these Pglyrp-regulated bacteria that predispose Pglyrp-deficient mice to colitis or protect WT mice from colitis are not known. Here we identified significant changes in β-diversity of stool bacteria in Pglyrp-deficient mice compared with WT mice. The most consistent changes in microbiome in all Pglyrp-deficient mice were in Bacteroidales, from which we selected four species, two with increased abundance (Prevotella falsenii and Parabacteroides distasonis) and two with decreased abundance (Bacteroides eggerthii and Alistipes finegoldii). We then gavaged WT mice with stock type strains of these species to test the hypothesis that they predispose to or protect from DSS-induced colitis. P. falsenii, P. distasonis, and B. eggerthii all enhanced DSS-induced colitis in both WT mice with otherwise undisturbed intestinal microflora and in WT mice with antibiotic-depleted intestinal microflora. By contrast, A. finegoldii (which is the most abundant species in WT mice) attenuated DSS-induced colitis both in WT mice with otherwise undisturbed intestinal microflora and in WT mice with antibiotic-depleted intestinal microflora, similar to the colitis protective effect of the entire normal microflora. These results identify P. falsenii, P. distasonis, and B. eggerthii as colitis-promoting species and A. finegoldii as colitis-protective species. PMID

  1. Absence of Cx43 selectively from osteocytes enhances responsiveness to mechanical force in mice.

    PubMed

    Bivi, Nicoletta; Pacheco-Costa, Rafael; Brun, Lucas R; Murphy, Thomas R; Farlow, Nathan R; Robling, Alexander G; Bellido, Teresita; Plotkin, Lilian I

    2013-07-01

    The osteocyte network is crucial for the response of bone to mechanical force. Within this network, connexin43 (Cx43) is thought to mediate the communication of osteocytes and osteoblasts among themselves and the exchange of small molecules with the extracellular milieu. Despite recent advances in understanding Cx43 role for the response of bone cells to mechanical stimulation, the contribution of Cx43 specifically in osteocytes to mechanotransduction in vivo is not well-known. We examined the anabolic response to ulnar axial loading of mice lacking Cx43 in osteocytes (Cx43(ΔOt)). Loading induced a greater increase in periosteal bone formation rate in Cx43(ΔOt) mice compared to control littermates, resulting from higher mineralizing surface and enhanced mineral apposition rate. Expression of β-catenin protein, a molecule implicated in mechanotransduction, was higher in bones from Cx43(ΔOt) mice, compared to littermate controls. In addition, MLO-Y4 osteocytic cells knocked-down for Cx43 exhibited higher β-catenin protein expression and enhanced response to mechanical stimulation. These findings suggest that osteocytes lacking Cx43 are "primed" to respond to mechanical stimulation and that absence of Cx43 in osteocytes unleashes bone formation, by a mechanism that might involve accumulation of β-catenin. PMID:23483620

  2. Life Extension Factor Klotho Prevents Mortality and Enhances Cognition in hAPP Transgenic Mice

    PubMed Central

    Zhu, Lei; Sanchez, Pascal E.; Worden, Kurtresha; Broestl, Lauren; Johnson, Erik; Ho, Kaitlyn; Yu, Gui-Qiu; Kim, Daniel; Betourne, Alexander; Kuro-o, Makoto; Masliah, Eliezer; Abraham, Carmela R.

    2015-01-01

    Aging is the principal demographic risk factor for Alzheimer disease (AD), the most common neurodegenerative disorder. Klotho is a key modulator of the aging process and, when overexpressed, extends mammalian lifespan, increases synaptic plasticity, and enhances cognition. Whether klotho can counteract deficits related to neurodegenerative diseases, such as AD, is unknown. Here we show that elevating klotho expression decreases premature mortality and network dysfunction in human amyloid precursor protein (hAPP) transgenic mice, which simulate key aspects of AD. Increasing klotho levels prevented depletion of NMDA receptor (NMDAR) subunits in the hippocampus and enhanced spatial learning and memory in hAPP mice. Klotho elevation in hAPP mice increased the abundance of the GluN2B subunit of NMDAR in postsynaptic densities and NMDAR-dependent long-term potentiation, which is critical for learning and memory. Thus, increasing wild-type klotho levels or activities improves synaptic and cognitive functions, and may be of therapeutic benefit in AD and other cognitive disorders. PMID:25673831

  3. Life extension factor klotho prevents mortality and enhances cognition in hAPP transgenic mice.

    PubMed

    Dubal, Dena B; Zhu, Lei; Sanchez, Pascal E; Worden, Kurtresha; Broestl, Lauren; Johnson, Erik; Ho, Kaitlyn; Yu, Gui-Qiu; Kim, Daniel; Betourne, Alexander; Kuro-O, Makoto; Masliah, Eliezer; Abraham, Carmela R; Mucke, Lennart

    2015-02-11

    Aging is the principal demographic risk factor for Alzheimer disease (AD), the most common neurodegenerative disorder. Klotho is a key modulator of the aging process and, when overexpressed, extends mammalian lifespan, increases synaptic plasticity, and enhances cognition. Whether klotho can counteract deficits related to neurodegenerative diseases, such as AD, is unknown. Here we show that elevating klotho expression decreases premature mortality and network dysfunction in human amyloid precursor protein (hAPP) transgenic mice, which simulate key aspects of AD. Increasing klotho levels prevented depletion of NMDA receptor (NMDAR) subunits in the hippocampus and enhanced spatial learning and memory in hAPP mice. Klotho elevation in hAPP mice increased the abundance of the GluN2B subunit of NMDAR in postsynaptic densities and NMDAR-dependent long-term potentiation, which is critical for learning and memory. Thus, increasing wild-type klotho levels or activities improves synaptic and cognitive functions, and may be of therapeutic benefit in AD and other cognitive disorders. PMID:25673831

  4. Pleurotus nebrodensis polysaccharide (PN-S) enhances the immunity of immunosuppressed mice.

    PubMed

    Cui, Hai-Yan; Wang, Chang-Lu; Wang, Yu-Rong; Li, Zhen-Jing; Chen, Mian-Hua; Li, Feng-Juan; Sun, Yan-Ping

    2015-10-01

    In the present study, the effects of Pleurotus nebrodensis polysaccharide (PN-S) on the immune functions of immunosuppressed mice were determined. The immunosuppressed mouse model was established by treating the mice with cyclophosphamide (40 mg/kg/2d, CY) through intraperitoneal injection. The results showed that PN-S administration significantly reversed the CY-induced weight loss, increased the thymic and splenic indices, and promoted proliferation of T lymphocyte, B lymphocyte, and macrophages. PN-S also enhanced the activity of natural killer cells and increased the immunoglobulin M (IgM) and immunoglobulin G (IgG) levels in the serum. In addition, PN-S treatment significantly increased the phagocytic activity of mouse peritoneal macrophages. PN-S also increased the levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interferon-γ (INF-γ), and nitric oxide (NOS) in splenocytes. qRT-PCR results also indicated that PN-S increased the mRNA expression of IL-6, TNF-α, INF-γ, and nitric oxide synthase (iNOS) in the splenocytes. These results suggest that PN-S treatment enhances the immune function of immunosuppressed mice. This study may provide a basis for the application of this fungus in adjacent immunopotentiating therapy against cancer and in the treatment of chemotherapy-induced immunosuppression. PMID:26481376

  5. Megavoltage X-ray Dose Enhancement with Gold Nanoparticles in Tumor Bearing Mice

    PubMed Central

    Mousavie Anijdan, Sayyed Hossein; Mahdavi, Seyyed Rabi; Shirazi, Alireza; Zarrinfard, Mohammad Ali; Hajati, Jamshid

    2013-01-01

    One of the applications of gold nanoparticles (GNPs) in medicine is radiation dose-enhancing effect. Although there are many simulations, in vitro and in vivo evidence that GNPs can enhance significantly the radiation dose effect of orthovoltage beams. These beams compared with megavoltage (MV) beams, have limited applications in radiotherapy. In order to evaluate GNPs radiosensitization performance with MV beams in-vivo, we used two most clinically used X-ray beams (6 and 18 MV) with the dose of 20 Gy for each mouse. Intratumoral injection of 50 nm GNPs with the concentration of 5 mg ml-1 was applied to melanoma tumor growing in the left leg of 7 to 8 mice in 4 control and treatment groups of C57BL/6 mice. Albeit, using 10 cm plexiglass jig phantom in the beam path improved the radiation - treatments, the statistical differences between groups were not significant. According to the results, it is concluded that mice can be treated with smaller tumors and higher concentrations of GNPs in MV radiation beams. PMID:24551801

  6. C/EBPε mediates nicotinamide-enhanced clearance of Staphylococcus aureus in mice

    PubMed Central

    Kyme, Pierre; Thoennissen, Nils H.; Tseng, Ching Wen; Thoennissen, Gabriela B.; Wolf, Andrea J.; Shimada, Kenichi; Krug, Utz O.; Lee, Kunik; Müller-Tidow, Carsten; Berdel, Wolfgang E.; Hardy, W. David; Gombart, Adrian F.; Koeffler, H. Phillip; Liu, George Y.

    2012-01-01

    The myeloid-specific transcription factor, CCAAT/enhancer-binding protein ε (C/EBPε) is a critical mediator of myelopoiesis. Mutation of this gene is responsible for neutrophil-specific granule deficiency in humans, a condition that confers susceptibility to Staphylococcus aureus infection. We found that C/EBPε-deficient mice are severely affected by infection with S. aureus, and C/EBPε deficiency in neutrophils contributes to the infectious phenotype. Conversely, exposure to the epigenetic modulator nicotinamide (vitamin B3) increased expression of C/EBPε in WT myeloid cells. Further, nicotinamide increased the activity of C/EBPε and select downstream antimicrobial targets, particularly in neutrophils. In a systemic murine infection model as well as in murine and human peripheral blood, nicotinamide enhanced killing of S. aureus by up to 1,000 fold but had no effect when administered to either C/EBPε-deficient mice or mice depleted of neutrophils. Nicotinamide was efficacious in both prophylactic and therapeutic settings. Our findings suggest that C/EBPε is an important target to boost killing of bacteria by the innate immune system. PMID:22922257

  7. Identification of hypothalamic arcuate nucleus-specific enhancer region of Kiss1 gene in mice.

    PubMed

    Goto, Teppei; Tomikawa, Junko; Ikegami, Kana; Minabe, Shiori; Abe, Hitomi; Fukanuma, Tatsuya; Imamura, Takuya; Takase, Kenji; Sanbo, Makoto; Tomita, Koichi; Hirabayashi, Masumi; Maeda, Kei-ichiro; Tsukamura, Hiroko; Uenoyama, Yoshihisa

    2015-01-01

    Pulsatile secretion of GnRH plays a pivotal role in follicular development via stimulating tonic gonadotropin secretion in mammals. Kisspeptin neurons, located in the arcuate nucleus (ARC), are considered to be an intrinsic source of the GnRH pulse generator. The present study aimed to determine ARC-specific enhancer(s) of the Kiss1 gene by an in vivo reporter assay. Three green fluorescent protein (GFP) reporter constructs (long, medium length, and short) were generated by insertion of GFP cDNA at the Kiss1 locus. Transgenic female mice bearing the long and medium-length constructs showed apparent GFP signals in kisspeptin-immunoreactive cells in both the ARC and anteroventral periventricular nucleus, in which another population of kisspeptin neurons are located. On the other hand, transgenic mice bearing 5'-truncated short construct showed few GFP signals in the ARC kisspeptin-immunoreactive cells, whereas they showed colocalization of GFP- and kisspeptin-immunoreactivities in the anteroventral periventricular nucleus. In addition, chromatin immunoprecipitation and chromosome conformation capture assays revealed recruitment of unoccupied estrogen receptor-α in the 5'-upstream region and intricate chromatin loop formation between the 5'-upstream and promoter regions of Kiss1 locus in the ARC. Taken together, the present results indicate that 5'-upstream region of Kiss1 locus plays a critical role in Kiss1 gene expression in an ARC-specific manner and that the recruitment of estrogen receptor-α and formation of a chromatin loop between the Kiss1 promoter and the 5' enhancer region may be required for the induction of ARC-specific Kiss1 gene expression. These results suggest that the 5'-upstream region of Kiss1 locus functions as an enhancer for ARC Kiss1 gene expression in mice. PMID:25486239

  8. Enhanced resistance against Listeria monocytogenes at an early phase of primary infection in pregnant mice: activation of macrophages during pregnancy.

    PubMed Central

    Watanabe, Y; Mitsuyama, M; Sano, M; Nakano, H; Nomoto, K

    1986-01-01

    We investigated the pregnancy-induced changes in macrophage activity which are important in the expression of host defense against infections. Several macrophage functions were examined by using Listeria monocytogenes. In pregnant mice, prolonged survival and enhanced in vivo elimination of bacteria were observed in the early phase of primary infection. Functions of peritoneal macrophages, including in vitro phagocytosis intracellular killing, glucose consumption, generation of superoxide anion, and intracellular beta-glucuronidase activity were shown to be enhanced in pregnant mice. These findings indicate that pregnancy enhances macrophage functions qualitatively. Possible mechanisms for this enhancement and the significance of macrophage activation for pregnant hosts are discussed. PMID:3011673

  9. Enhancement of Neuromuscular Activity by Natural Specimens and Cultured Mycelia of Cordyceps sinensis in Mice.

    PubMed

    Singh, K P; Meena, H S; Negi, P S

    2014-09-01

    The present study was aimed to evaluate the effect of natural specimen and laboratory cultured mycelia of Cordyceps sinensis on neuromuscular activity in mice. The powder of natural specimen and laboratory cultured Cordyceps sinensis was orally administered at the dose rate of 100, 300 and 500 mg/kg for 30 days. Natural specimen and in vitro propagated Cordyceps sinensis showed significant (P<0.05) enhancement in neuromuscular endurance and antidepressant activity at 300 and 500 mg/kg as compared to the control group. However, the fungus did not proved to be as effective as fluoxetine in exhibiting antidepressant action. Muscular endurance was determined on a Rota rod apparatus while antidepressant (mood elevating) activity was measured on a photoactometer in Swiss albino mice. The effects produced by both natural specimens and laboratory cultured Cordyceps sinensis were comparable and showed almost equal potency. PMID:25425763

  10. Enhancement in fecal excretion of dioxin isomer in mice by several dietary fibers.

    PubMed

    Aozasa, O; Ohta, S; Nakao, T; Miyata, H; Nomura, T

    2001-10-01

    The effect of increased nutrients (protein, lipid, vitamins and minerals) on dioxin-induced toxic manifestations such as immune suppression, hepatic hypertrophy, splenic atrophy and enzyme induction was investigated in mice after oral administration of 1,2,3,4,7,8-HxCDD (HxCDD) as one of a representative compound of dioxin isomers. Consequently, it appeared that increased minerals and vitamins in the diet prevented immune suppression by HxCDD. In addition, to clarify the additive effect of nutrients and the ability to hasten the excretion of dioxins by dietary fiber, the adsorbing of dioxins by 16 dietary fibers was investigated by in vitro experiment. Among 16 dietary fibers, locust bean gum, pectin, alginic acid, guar gum, chitin and cellulose were effective in binding dioxin isomers. These dietary fibers also enhanced the fecal excretion of HxCDD in mice. PMID:11572611

  11. Overexpression of motor protein KIF17 enhances spatial and working memory in transgenic mice.

    PubMed

    Wong, Richard Wing-Chuen; Setou, Mitsutoshi; Teng, Junlin; Takei, Yosuke; Hirokawa, Nobutaka

    2002-10-29

    The kinesin superfamily proteins (KIFs) play essential roles in receptor transportation along the microtubules. KIF17 transports the N-methyl-d-aspartate receptor NR2B subunit in vitro, but its role in vivo is unknown. To clarify this role, we generated transgenic mice overexpressing KIF17 tagged with GFP. The KIF17 transgenic mice exhibited enhanced learning and memory in a series of behavioral tasks, up-regulated NR2B expression with the potential involvement of a transcriptional factor, the cAMP-dependent response element-binding protein, and increased phosphorylation of the cAMP-dependent response element-binding protein. Our results suggest that the motor protein KIF17 contributes to neuronal events required for learning and memory by trafficking fundamental N-methyl-d-aspartate-type glutamate receptors. PMID:12391294

  12. Leucine supplementation does not affect protein turnover and impairs the beneficial effects of endurance training on glucose homeostasis in healthy mice.

    PubMed

    Costa Júnior, José M; Rosa, Morgana R; Protzek, André O; de Paula, Flávia M; Ferreira, Sandra M; Rezende, Luiz F; Vanzela, Emerielle C; Zoppi, Cláudio C; Silveira, Leonardo R; Kettelhut, Isis C; Boschero, Antonio C; de Oliveira, Camila A M; Carneiro, Everardo M

    2015-04-01

    Endurance exercise training as well as leucine supplementation modulates glucose homeostasis and protein turnover in mammals. Here, we analyze whether leucine supplementation alters the effects of endurance exercise on these parameters in healthy mice. Mice were distributed into sedentary (C) and exercise (T) groups. The exercise group performed a 12-week swimming protocol. Half of the C and T mice, designated as the CL and TL groups, were supplemented with leucine (1.5 % dissolved in the drinking water) throughout the experiment. As well known, endurance exercise training reduced body weight and the retroperitoneal fat pad, increased soleus mass, increased VO2max, decreased muscle proteolysis, and ameliorated peripheral insulin sensitivity. Leucine supplementation had no effect on any of these parameters and worsened glucose tolerance in both CL and TL mice. In the soleus muscle of the T group, AS-160(Thr-642) (AKT substrate of 160 kDa) and AMPK(Thr-172) (AMP-Activated Protein Kinase) phosphorylation was increased by exercise in both basal and insulin-stimulated conditions, but it was reduced in TL mice with insulin stimulation compared with the T group. Akt phosphorylation was not affected by exercise but was lower in the CL group compared with the other groups. Leucine supplementation increased mTOR phosphorylation at basal conditions, whereas exercise reduced it in the presence of insulin, despite no alterations in protein synthesis. In trained groups, the total FoxO3a protein content and the mRNA for the specific isoforms E2 and E3 ligases were reduced. In conclusion, leucine supplementation did not potentiate the effects of endurance training on protein turnover, and it also reduced its positive effects on glucose homeostasis. PMID:25575490

  13. In vivo Imaging of Optic Nerve Fiber Integrity by Contrast-Enhanced MRI in Mice

    PubMed Central

    Herrmann, Karl-Heinz; Reichenbach, Jürgen R.; Witte, Otto W.; Weih, Falk; Kretz, Alexandra; Haenold, Ronny

    2014-01-01

    The rodent visual system encompasses retinal ganglion cells and their axons that form the optic nerve to enter thalamic and midbrain centers, and postsynaptic projections to the visual cortex. Based on its distinct anatomical structure and convenient accessibility, it has become the favored structure for studies on neuronal survival, axonal regeneration, and synaptic plasticity. Recent advancements in MR imaging have enabled the in vivo visualization of the retino-tectal part of this projection using manganese mediated contrast enhancement (MEMRI). Here, we present a MEMRI protocol for illustration of the visual projection in mice, by which resolutions of (200 µm)3 can be achieved using common 3 Tesla scanners. We demonstrate how intravitreal injection of a single dosage of 15 nmol MnCl2 leads to a saturated enhancement of the intact projection within 24 hr. With exception of the retina, changes in signal intensity are independent of coincided visual stimulation or physiological aging. We further apply this technique to longitudinally monitor axonal degeneration in response to acute optic nerve injury, a paradigm by which Mn2+ transport completely arrests at the lesion site. Conversely, active Mn2+ transport is quantitatively proportionate to the viability, number, and electrical activity of axon fibers. For such an analysis, we exemplify Mn2+ transport kinetics along the visual path in a transgenic mouse model (NF-κB p50KO) displaying spontaneous atrophy of sensory, including visual, projections. In these mice, MEMRI indicates reduced but not delayed Mn2+ transport as compared to wild type mice, thus revealing signs of structural and/or functional impairments by NF-κB mutations. In summary, MEMRI conveniently bridges in vivo assays and post mortem histology for the characterization of nerve fiber integrity and activity. It is highly useful for longitudinal studies on axonal degeneration and regeneration, and investigations of mutant mice for genuine or

  14. Role of oxidative stress on diesel-enhanced influenza infection in mice

    PubMed Central

    2010-01-01

    Numerous studies have shown that air pollutants, including diesel exhaust (DE), reduce host defenses, resulting in decreased resistance to respiratory infections. This study sought to determine if DE exposure could affect the severity of an ongoing influenza infection in mice, and examine if this could be modulated with antioxidants. BALB/c mice were treated by oropharyngeal aspiration with 50 plaque forming units of influenza A/HongKong/8/68 and immediately exposed to air or 0.5 mg/m3 DE (4 hrs/day, 14 days). Mice were necropsied on days 1, 4, 8 and 14 post-infection and lungs were assessed for virus titers, lung inflammation, immune cytokine expression and pulmonary responsiveness (PR) to inhaled methacholine. Exposure to DE during the course of infection caused an increase in viral titers at days 4 and 8 post-infection, which was associated with increased neutrophils and protein in the BAL, and an early increase in PR. Increased virus load was not caused by decreased interferon levels, since IFN-β levels were enhanced in these mice. Expression and production of IL-4 was significantly increased on day 1 and 4 p.i. while expression of the Th1 cytokines, IFN-γ and IL-12p40 was decreased. Treatment with the antioxidant N-acetylcysteine did not affect diesel-enhanced virus titers but blocked the DE-induced changes in cytokine profiles and lung inflammation. We conclude that exposure to DE during an influenza infection polarizes the local immune responses to an IL-4 dominated profile in association with increased viral disease, and some aspects of this effect can be reversed with antioxidants. PMID:21092162

  15. Muscle-specific transgenic expression of porcine myostatin propeptide enhances muscle growth in mice.

    PubMed

    Wang, Kaiyun; Li, Zicong; Li, Yang; Zeng, Jinyong; He, Chang; Yang, Jinzeng; Liu, Dewu; Wu, Zhenfang

    2013-10-01

    Myostatin is a well-known negative regulator of skeletal muscle growth. Inhibition of myostatin activity results in increased muscle mass. Myostatin propeptide, as a myostatin antagonist, could be applied to promote meat production in livestock such as pigs. In this study, we generated a transgenic mouse model expressing porcine myostatin propeptide under the control of muscle-specific regulatory elements. The mean body weight of transgenic mice from a line expressing the highest level of porcine myostatin propeptide was increased by 5.4 % (P = 0.023) and 3.2 % (P = 0.031) in males and females, respectively, at 8 weeks of age. Weight of carcass, fore limb and hind limb was respectively increased by 6.0 % (P = 0.038), 9.0 % (P = 0.014), 8.7 % (P = 0.036) in transgenic male mice, compared to wild-type male controls at the age of 9 weeks. Similarly, carcass, fore limb and hind limb of transgenic female mice was 11.4 % (P = 0.002), 14.5 % (P = 0.006) and 14.5 % (P = 0.03) respectively heavier than that of wild-type female mice. The mean cross-section area of muscle fiber was increased by 17 % (P = 0.002) in transgenic mice, in comparison with wild-type controls. These results demonstrated that porcine myostatin propeptide is effective in enhancement of muscle growth. The present study provided useful information for future study on generation of transgenic pigs overexpressing porcine myostatin propeptide for improvement of muscle mass. PMID:23543410

  16. Genetically Determined Susceptibility to Tuberculosis in Mice Causally Involves Accelerated and Enhanced Recruitment of Granulocytes

    PubMed Central

    Keller, Christine; Hoffmann, Reinhard; Lang, Roland; Brandau, Sven; Hermann, Corinna; Ehlers, Stefan

    2006-01-01

    Classical twin studies and recent linkage analyses of African populations have revealed a potential involvement of host genetic factors in susceptibility or resistance to Mycobacterium tuberculosis infection. In order to identify the candidate genes involved and test their causal implication, we capitalized on the mouse model of tuberculosis, since inbred mouse strains also differ substantially in their susceptibility to infection. Two susceptible and two resistant mouse strains were aerogenically infected with 1,000 CFU of M. tuberculosis, and the regulation of gene expression was examined by Affymetrix GeneChip U74A array with total lung RNA 2 and 4 weeks postinfection. Four weeks after infection, 96 genes, many of which are involved in inflammatory cell recruitment and activation, were regulated in common. One hundred seven genes were differentially regulated in susceptible mouse strains, whereas 43 genes were differentially expressed only in resistant mice. Data mining revealed a bias towards the expression of genes involved in granulocyte pathophysiology in susceptible mice, such as an upregulation of those for the neutrophil chemoattractant LIX (CXCL5), interleukin 17 receptor, phosphoinositide kinase 3 delta, or gamma interferon-inducible protein 10. Following M. tuberculosis challenge in both airways or peritoneum, granulocytes were recruited significantly faster and at higher numbers in susceptible than in resistant mice. When granulocytes were efficiently depleted by either of two regimens at the onset of infection, only susceptible mice survived aerosol challenge with M. tuberculosis significantly longer than control mice. We conclude that initially enhanced recruitment of granulocytes contributes to susceptibility to tuberculosis. PMID:16790804

  17. Artemisia extracts activate PPARγ, promote adipogenesis, and enhance insulin sensitivity in adipose tissue of obese mice

    PubMed Central

    Richard, Allison J.; Burris, Thomas P.; Sanchez-Infantes, David; Wang, Yongjun; Ribnicky, David M.; Stephens, Jacqueline M.

    2014-01-01

    Objective Studies have shown that the inability of adipose tissue to properly expand during the obese state or respond to insulin can lead to metabolic dysfunction. Artemisia is a diverse group of plants that has a history of medicinal use. This study examines the ability of ethanolic extracts of Artemisia scoparia (SCO) and Artemisia santolinifolia (SAN) to modulate adipocyte development in cultured adipocytes and white adipose tissue (WAT) function in vivo using a mouse model of diet-induced obesity. Research Design & Procedures Adipogenesis was assessed using Oil Red O staining and immunoblotting. A nuclear receptor specificity assay was used to examine the specificity of SCO- and SAN-induced PPARγ activation. C57BL/6J mice, fed a high-fat diet, were gavaged with saline, SCO, or SAN for 2 weeks. Whole-body insulin sensitivity was examined using insulin tolerance tests. WAT depots were assessed via immunoblotting for markers of insulin action and adipokine production. Results We established that SCO and SAN were highly specific activators of PPARγ and did not activate other nuclear receptors. After a one-week daily gavage, SCO- and SAN-treated mice had lower insulin-induced glucose disposal rates than control mice. At the end of the 2-week treatment period, SCO- and SAN-treated mice had enhanced insulin-responsive Akt serine-473 phosphorylation and significantly decreased MCP-1 levels in visceral WAT relative to control mice; these differences were depot specific. Moreover, plasma adiponectin levels were increased following SCO treatment. Conclusion Overall, these studies demonstrate that extracts from two Artemisia species can have metabolically favorable effects on adipocytes and WAT. PMID:24985103

  18. Impaired neutrophil function in 24p3 null mice contributes to enhanced susceptibility to bacterial infections

    PubMed Central

    Liu, Zhuoming; Petersen, Robert; Devireddy, L.

    2013-01-01

    Lipocalin 24p3 (24p3) is a neutrophil secondary granule protein. 24p3 is also a siderocalin, which binds several bacterial siderophores. It was therefore proposed that synthesis and secretion of 24p3 by stimulated macrophages or release of 24p3 upon neutrophil degranulation sequesters iron-laden siderophores to attenuate bacterial growth. Accordingly, 24p3-deficient mice are susceptible to bacterial pathogens whose siderophores would normally be chelated by 24p3. Specific granule deficiency (SGD) is a rare congenital disorder characterized by complete absence of proteins in secondary granules. Neutrophils from SGD patients, who are prone to bacterial infections, lack normal functions but the potential role of 24p3 in neutrophil dysfunction in SGD is not known. Here we show that neutrophils from 24p3−/− mice are defective in many neutrophil functions. Specifically, neutrophils in 24p3−/− mice do not extravasate to sites of infection and are defective for chemotaxis. A transcriptome analysis revealed that genes that control cytoskeletal reorganization are selectively suppressed in 24p3−/− neutrophils. Additionally, small regulatory RNAs (miRNAs) that control upstream regulators of cytoskeletal proteins are also increased in 24p3−/− neutrophils. Further, 24p3−/− neutrophils failed to phagocytose bacteria, which may account for the enhanced sensitivity of 24p3−/− mice to both intracellular (Listeria monocytogenes) and extracellular (Candida albicans, Staphylococcus aureus) pathogens. Listeria does not secrete siderophores and additionally, the siderophore secreted by Candida is not sequestered by 24p3. Therefore, the heightened sensitivity of 24p3−/− mice to these pathogens is not due to sequestration of siderophores limiting iron availability, but is a consequence of impaired neutrophil function. PMID:23543755

  19. Improved muscle healing through enhanced regeneration and reduced fibrosis in myostatin-null mice.

    PubMed

    McCroskery, Seumas; Thomas, Mark; Platt, Leanne; Hennebry, Alex; Nishimura, Takanori; McLeay, Lance; Sharma, Mridula; Kambadur, Ravi

    2005-08-01

    Numerous stimulatory growth factors that can influence muscle regeneration are known. Recently, it has been demonstrated that neutralization of muscle growth inhibitory factors, such as myostatin (Mstn; also known as growth differentiation factor 8, Gdf8), also leads to increased muscle regeneration in mdx mice that are known to have cycles of degeneration. However, the precise mechanism by which Mstn regulates muscle regeneration has not yet been fully determined. To investigate the role of Mstn in adult skeletal muscle regeneration, wild-type and myostatin-null (Mstn-/-) mice were injured with notexin. Forty-eight hours after injury, accelerated migration and enhanced accretion of myogenic cells (MyoD1+) and macrophages (Mac-1+) was observed at the site of regeneration in Mstn-/- muscle as compared with wild-type muscle. Inflammatory cell numbers decreased more rapidly in the Mstn-/- muscle, indicating that the whole process of inflammatory cell response is accelerated in Mstn-/- mice. Consistent with this result, the addition of recombinant Mstn reduced the activation of satellite cells (SCs) and chemotactic movements of both myoblasts and macrophages ex vivo. Examination of regenerated muscle (28 days after injury) also revealed that Mstn-/- mice showed increased expression of decorin mRNA, reduced fibrosis and improved healing as compared with wild-type mice. On the basis of these results, we propose that Mstn negatively regulates muscle regeneration not only by controlling SC activation but also by regulating the migration of myoblasts and macrophages to the site of injury. Thus, antagonists of Mstn could potentially be useful as pharmacological agents for the treatment of disorders of overt degeneration and regeneration. PMID:16079293

  20. Environmental enrichment alters splenic immune cell composition and enhances secondary influenza vaccine responses in mice.

    PubMed

    Gurfein, Blake T; Davidenko, Olga; Premenko-Lanier, Mary; Milush, Jeffrey M; Acree, Michael; Dallman, Mary F; Touma, Chadi; Palme, Rupert; York, Vanessa A; Fromentin, Gilles; Darcel, Nicolas; Nixon, Douglas F; Hecht, Frederick M

    2014-01-01

    Chronic stress has deleterious effects on immune function, which can lead to adverse health outcomes. However, studies investigating the impact of stress reduction interventions on immunity in clinical research have yielded divergent results, potentially stemming from differences in study design and genetic heterogeneity, among other clinical research challenges. To test the hypothesis that reducing glucocorticoid levels enhances certain immune functions, we administered influenza vaccine once (prime) or twice (boost) to mice housed in either standard control caging or environmental enrichment (EE) caging. We have shown that this approach reduces mouse corticosterone production. Compared with controls, EE mice had significantly lower levels of fecal corticosterone metabolites (FCMs) and increased splenic B and T lymphocyte numbers. Corticosterone levels were negatively associated with the numbers of CD19(+) (r(2) = 0.43, p = 0.0017), CD4(+) (r(2) = 0.28, p = 0.0154) and CD8(+) cells (r(2) = 0.20, p = 0.0503). Vaccinated mice showed nonsignificant differences in immunoglobulin G (IgG) titer between caging groups, although EE mice tended to exhibit larger increases in titer from prime to boost than controls; the interaction between the caging group (control versus EE) and vaccine group (prime versus boost) showed a strong statistical trend (cage-group*vaccine-group, F = 4.27, p = 0.0555), suggesting that there may be distinct effects of EE caging on primary versus secondary IgG vaccine responses. Vaccine-stimulated splenocytes from boosted EE mice had a significantly greater frequency of interleukin 5 (IL-5)-secreting cells than boosted controls (mean difference 7.7, IL-5 spot-forming units/10(6) splenocytes, 95% confidence interval 0.24-135.1, p = 0.0493) and showed a greater increase in the frequency of IL-5-secreting cells from prime to boost. Our results suggest that corticosterone reduction via EE caging was associated with enhanced secondary vaccine responses

  1. Environmental Enrichment Alters Splenic Immune Cell Composition and Enhances Secondary Influenza Vaccine Responses in Mice

    PubMed Central

    Gurfein, Blake T; Davidenko, Olga; Premenko-Lanier, Mary; Milush, Jeffrey M; Acree, Michael; Dallman, Mary F; Touma, Chadi; Palme, Rupert; York, Vanessa A; Fromentin, Gilles; Darcel, Nicolas; Nixon, Douglas F; Hecht, Frederick M

    2014-01-01

    Chronic stress has deleterious effects on immune function, which can lead to adverse health outcomes. However, studies investigating the impact of stress reduction interventions on immunity in clinical research have yielded divergent results, potentially stemming from differences in study design and genetic heterogeneity, among other clinical research challenges. To test the hypothesis that reducing glucocorticoid levels enhances certain immune functions, we administered influenza vaccine once (prime) or twice (boost) to mice housed in either standard control caging or environmental enrichment (EE) caging. We have shown that this approach reduces mouse corticosterone production. Compared with controls, EE mice had significantly lower levels of fecal corticosterone metabolites (FCMs) and increased splenic B and T lymphocyte numbers. Corticosterone levels were negatively associated with the numbers of CD19+ (r2 = 0.43, p = 0.0017), CD4+ (r2 = 0.28, p = 0.0154) and CD8+ cells (r2 = 0.20, p = 0.0503). Vaccinated mice showed nonsignificant differences in immunoglobulin G (IgG) titer between caging groups, although EE mice tended to exhibit larger increases in titer from prime to boost than controls; the interaction between the caging group (control versus EE) and vaccine group (prime versus boost) showed a strong statistical trend (cage-group*vaccine-group, F = 4.27, p = 0.0555), suggesting that there may be distinct effects of EE caging on primary versus secondary IgG vaccine responses. Vaccine-stimulated splenocytes from boosted EE mice had a significantly greater frequency of interleukin 5 (IL-5)-secreting cells than boosted controls (mean difference 7.7, IL-5 spot-forming units/106 splenocytes, 95% confidence interval 0.24–135.1, p = 0.0493) and showed a greater increase in the frequency of IL-5–secreting cells from prime to boost. Our results suggest that corticosterone reduction via EE caging was associated with enhanced secondary vaccine responses, but had

  2. The memory-enhancing effect of erucic acid on scopolamine-induced cognitive impairment in mice.

    PubMed

    Kim, Eunji; Ko, Hae Ju; Jeon, Se Jin; Lee, Sunhee; Lee, Hyung Eun; Kim, Ha Neul; Woo, Eun-Rhan; Ryu, Jong Hoon

    2016-03-01

    Erucic acid is a monounsaturated omega-9 fatty acid isolated from the seed of Raphanus sativus L. that is known to normalize the accumulation of very long chain fatty acids in the brains of patients suffering from X-linked adrenoleukodystrophy. Here, we investigated whether erucic acid enhanced cognitive function or ameliorated scopolamine-induced memory impairment using the passive avoidance, Y-maze and Morris water maze tasks. Erucic acid (3mg/kg, p.o.) enhanced memory performance in normal naïve mice. In addition, erucic acid (3mg/kg, p.o.) ameliorated scopolamine-induced memory impairment, as assessed via the behavioral tasks. We then investigated the underlying mechanism of the memory-enhancing effect of erucic acid. The administration of erucic acid increased the phosphorylation levels of phosphatidylinositide 3-kinase (PI3K), protein kinase C zeta (PKCζ), extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB) and additional protein kinase B (Akt) in the hippocampus. These results suggest that erucic acid has an ameliorative effect in mice with scopolamine-induced memory deficits and that the effect of erucic acid is partially due to the activation of PI3K-PKCζ-ERK-CREB signaling as well as an increase in phosphorylated Akt in the hippocampus. Therefore, erucic acid may be a novel therapeutic agent for diseases associated with cognitive deficits, such as Alzheimer's disease. PMID:26780350

  3. Tenuigenin treatment improves behavioral Y-maze learning by enhancing synaptic plasticity in mice.

    PubMed

    Huang, Jun-ni; Wang, Chun-yang; Wang, Xiu-li; Wu, Bo-zhi; Gu, Xing-yang; Liu, Wen-xiao; Gong, Liang-wei; Xiao, Peng; Li, Chu-hua

    2013-06-01

    Polygala tenuifolia root has been used to improve memory and cognitive function in Traditional Chinese Medicine for more than 2000 years. Since tenuigenin (TEN) is one of the most utilized P. tenuifolia root extracts, it is surprising there is no evidence for the effects of TEN on learning and memory so far. In the present study, we investigated the effects of TEN on learning and memory with Y-maze test in mice. We found that oral administration of 4mg/kg TEN significantly improved learning and memory in Y-maze task. Treatment with 4mg/kg TEN markedly reduced the acetylcholinesterase (AChE) activity and malondialdehyde (MDA) level, and increased superoxide dismutase (SOD) activity in hippocampus. In the electrophysiological test of hippocampal brain slice, 2μg/ml TEN perfusion substantially enhanced field excitatory postsynaptic potential (fEPSP) amplitude both in basic synaptic transmission and after high frequency stimulation (HFS) in Schaffer to CA1 pathway (Scha-CA1). These results indicate that TEN enhancing learning and memory may result from inhibiting AChE activity, improving antioxidation and enhancing synaptic plasticity in mice. Therefore, TEN shows promise as a potential nootropic product in improving learning and memory. PMID:23499702

  4. Maitake beta-glucan enhances therapeutic effect and reduces myelosupression and nephrotoxicity of cisplatin in mice.

    PubMed

    Masuda, Yuki; Inoue, Munechika; Miyata, Ayu; Mizuno, Shigeto; Nanba, Hiroaki

    2009-05-01

    Cisplatin is broadly used clinically as an anticancer drug. Despite its significant anticancer activity, cisplatin-induced nephrotoxicity and myelosuppression limit its use. MD-Fraction is glucan purified from maitake (Grifola frondosa), which has beta-1, 6-main chain with beta-1, 3-branches, has been reported to exhibit antitumor and antimetastatic activities by enhancing the immune system. In this study, we demonstrate that MD-Fraction in combination with cisplatin significantly enhanced antitumor and antimetastatic activity compared to cisplatin alone. MD-Fraction reduced decreases in body weight, spleen weight and the number of immunocompetent cells such as macrophages, DCs and NK cells in cisplatin-treated mice. MD-Fraction also induced IL-12p70 production by splenocytes, resulting in increased NK cell activity in cisplatin-treated mice. MD-Fraction significantly increased the mRNA expression of GM-CSF, G-CSF, M-CSF, IFN-gamma, IL-12 p40 in splenocytes and reduced the decrease in the number of CFU-GM colonies in cisplatin-treated bone marrow. These facts suggest that MD-Fraction can reduce cisplatin-induced myelosuppression. Moreover, treatment with MD-Fraction significantly reduced cisplatin-induced nephrotoxicity accompanied by increases in serum creatinine level, necrosis and apoptosis of renal tubular cells. These results suggest that MD-Fraction in combination with cisplatin cannot only enhance antitumor and antimentastatic acitivity, but also reduce cisplatin-induced myelotoxicity and nephrotoxicity. PMID:19249389

  5. Thromboxane prostanoid receptors enhance contractions, endothelin-1 and oxidative stress in microvessels from mice with CKD

    PubMed Central

    Wang, Cheng; Luo, Zaiming; Kohan, Donald; Wellstein, Anton; Jose, Pedro A.; Welch, William J.; Wilcox, Christopher S.; Wang, Dan

    2015-01-01

    Cardiovascular disease (CVD) is frequent in chronic kidney disease (CKD) and has been related to angiotensin II (ANG II), endothelin-1 (ET-1), thromboxane A2 (TxA2) and reactive oxygen species (ROS). Since activation of thromboxane prostanoid receptors (TP-Rs) can generate ROS which can generate ET-1, we tested the hypothesis that CKD induces cyclooxygenase (COX)-2 whose products activate TP-Rs to enhance ET-1 and ROS generation and contractions. Mesenteric resistance arterioles were isolated from C57/BL6, or TP-R +/+ and TP-R −/− mice 3 months after SHAM-operation (SHAM) or surgical reduced renal mass (RRM, n=6/group). Microvascular contractions were studied on a wire myograph. Cellular (ethidium: dihydroethidium) and mitochondrial (mitoSOX) ROS were measured by fluorescence microscopy. Mice with RRM had increased excretion of markers of oxidative stress, thromboxane, and microalbumin, increased plasma ET-1 and increased microvascular expression of p22phox, COX-2, TP-Rs, preproendothelin and endothelin-A receptors and increased arteriolar remodeling. They had increased contractions to U-46,619 (118±3 vs. 87±6, P<0.05) and ET-1 (108±5 vs. 89±4, P<0.05), which were dependent on cellular and mitochondrial ROS, COX-2, and TP-Rs. RRM doubled the ET-1-induced cellular and mitochondrial ROS generation (P<0.05). TP-R −/− mice with RRM lacked these abnormal structural and functional microvascular responses and lacked the increased systemic and the increased microvascular oxidative stress and circulating ET-1. In conclusion, RRM leads to microvascular remodeling and enhanced ET-1-induced cellular and mitochondrial ROS and contractions that are mediated by COX-2 products activating TP-Rs. Thus, TP-Rs can be upstream from enhanced ROS, ET-1, microvascular remodeling and contractility and may thereby coordinate vascular dysfunction in CKD. PMID:25733239

  6. Citalopram Enhances Neurovascular Regeneration and Sensorimotor Functional Recovery after Ischemic Stroke in Mice

    PubMed Central

    Espinera, Alyssa R.; Ogle, Molly E.; Gu, Xiaohuan; Wei, Ling

    2013-01-01

    Recent clinical trials have demonstrated that treatment with selective serotonin reuptake inhibitors (SSRIs) after stroke enhances motor functional recovery; however, the underlying mechanisms remain to be further elucidated. We hypothesized that daily administration of the clinical drug citalopram would produce these functional benefits via enhancing neurovascular repair in the ischemic peri-infarct region. To test this hypothesis, focal ischemic stroke was induced in male C57/B6 mice by permanent ligation of distal branches of the middle cerebral artery to the barrel cortex and 7-min occlusion of the bilateral common carotid arteries. Citalopram (10 mg/kg, i.p.) was injected 24 hrs after stroke and daily thereafter. To label proliferating cells, bromo-deoxyuridine was injected daily beginning 3 days after stroke. Immunohistochemical and functional assays were performed to elucidate citalopram-mediated cellular and sensorimotor changes after stroke. Citalopram treatment had no significant effect on infarct formation or edema 3 days after stroke; however, citalopram-treated mice had better functional recovery than saline-treated controls 3 and 14 days after stroke in the adhesive removal test. Increased expression of brain derived neurotrophic factor was detected in the peri-infarct region 7 days after stroke in citalopram-treated animals. The number of proliferating neural progenitor cells and the distance of neuroblast migration from the sub-ventricular zone towards the ischemic cortex were significantly greater in citalopram-treated mice at 7 days after stroke. Immunohistochemical staining and co-localization analysis showed that citalopram-treated animals generated more new neurons and microvessels in the peri-infarct region 21 and 28 days after stroke. Taken together, these results suggest that citalopram promotes post-stroke sensorimotor recovery likely via enhancing neurogenesis, neural cell migration and the microvessel support in the peri-infarct region of

  7. Simvastatin enhances hippocampal long-term potentiation in C57BL/6 mice

    PubMed Central

    Mans, Robert A.; Chowdhury, Nazma; Cao, Dongfeng; McMahon, Lori L.; Li, Ling

    2010-01-01

    Statins inhibit 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA), the rate-limiting enzyme in the cholesterol biosynthetic pathway, and they are widely used to control plasma cholesterol levels and prevent cardiovascular disease. However, emerging evidence indicates that the beneficial effects of statins extend to the central nervous system. Statins have been shown to improve the outcome of stroke and traumatic brain injury, and statin use has been associated with a reduced prevalence of Alzheimer’s disease (AD) and dementia. However, prospective studies with statins in AD have produced mixed results. Recently, we reported that simvastatin, a widely used statin in humans, enhances learning and memory in non-transgenic mice as well as in transgenic mice with AD-like pathology on a mixed genetic background. However, the cellular and molecular mechanisms underlying the beneficial effects of simvastatin on learning and memory remain elusive. The present study was undertaken to investigate the effect of acute simvastatin treatment on hippocampal long-term potentiation (LTP), a cellular model of learning and memory, in brain slices from C57BL/6 mice. Our results demonstrate that a prolonged in vitro simvastatin treatment for 2-4 hrs, but not a short-term 20-min exposure, significantly increases the magnitude of LTP at CA3-CA1 synapses without altering basal synaptic transmission or the paired-pulse facilitation ratio in hippocampal slices. Furthermore, we show that phosphorylation of Akt (protein kinase B) is increased significantly in the CA1 region following 2-hour treatment with simvastatin, and that inhibition of Akt phosphorylation suppresses the simvastatin-induced enhancement of LTP. These findings suggest activation of Akt as a molecular pathway for augmented hippocampal LTP by simvastatin treatment, and implicate enhancement of hippocampal LTP as a potential cellular mechanism underlying the beneficial effects of simvastatin on cognitive function. PMID

  8. Traumatic brain injury enhances neuroinflammation and lesion volume in caveolin deficient mice

    PubMed Central

    2014-01-01

    Background Traumatic brain injury (TBI) enhances pro-inflammatory responses, neuronal loss and long-term behavioral deficits. Caveolins (Cavs) are regulators of neuronal and glial survival signaling. Previously we showed that astrocyte and microglial activation is increased in Cav-1 knock-out (KO) mice and that Cav-1 and Cav-3 modulate microglial morphology. We hypothesized that Cavs may regulate cytokine production after TBI. Methods Controlled cortical impact (CCI) model of TBI (3 m/second; 1.0 mm depth; parietal cortex) was performed on wild-type (WT; C57Bl/6), Cav-1 KO, and Cav-3 KO mice. Histology and immunofluorescence microscopy (lesion volume, glia activation), behavioral tests (open field, balance beam, wire grip, T-maze), electrophysiology, electron paramagnetic resonance, membrane fractionation, and multiplex assays were performed. Data were analyzed by unpaired t tests or analysis of variance (ANOVA) with post-hoc Bonferroni’s multiple comparison. Results CCI increased cortical and hippocampal injury and decreased expression of MLR-localized synaptic proteins (24 hours), enhanced NADPH oxidase (Nox) activity (24 hours and 1 week), enhanced polysynaptic responses (1 week), and caused hippocampal-dependent learning deficits (3 months). CCI increased brain lesion volume in both Cav-3 and Cav-1 KO mice after 24 hours (P < 0.0001, n = 4; one-way ANOVA). Multiplex array revealed a significant increase in expression of IL-1β, IL-9, IL-10, KC (keratinocyte chemoattractant), and monocyte chemoattractant protein 1 (MCP-1) in ipsilateral hemisphere and IL-9, IL-10, IL-17, and macrophage inflammatory protein 1 alpha (MIP-1α) in contralateral hemisphere of WT mice after 4 hours. CCI increased IL-2, IL-6, KC and MCP-1 in ipsilateral and IL-6, IL-9, IL-17 and KC in contralateral hemispheres in Cav-1 KO and increased all 10 cytokines/chemokines in both hemispheres except for IL-17 (ipsilateral) and MIP-1α (contralateral) in Cav-3 KO (versus WT CCI). Cav-3 KO CCI

  9. Chronic subhepatotoxic exposure to arsenic enhances hepatic injury caused by high fat diet in mice

    SciTech Connect

    Tan, Min; Schmidt, Robin H.; Beier, Juliane I.; Watson, Walter H.; Zhong, Hai; States, J. Christopher; Arteel, Gavin E.

    2011-12-15

    Arsenic is a ubiquitous contaminant in drinking water. Whereas arsenic can be directly hepatotoxic, the concentrations/doses required are generally higher than present in the US water supply. However, physiological/biochemical changes that are alone pathologically inert can enhance the hepatotoxic response to a subsequent stimulus. Such a '2-hit' paradigm is best exemplified in chronic fatty liver diseases. Here, the hypothesis that low arsenic exposure sensitizes liver to hepatotoxicity in a mouse model of non-alcoholic fatty liver disease was tested. Accordingly, male C57Bl/6J mice were exposed to low fat diet (LFD; 13% calories as fat) or high fat diet (HFD; 42% calories as fat) and tap water or arsenic (4.9 ppm as sodium arsenite) for ten weeks. Biochemical and histologic indices of liver damage were determined. High fat diet ({+-} arsenic) significantly increased body weight gain in mice compared with low-fat controls. HFD significantly increased liver to body weight ratios; this variable was unaffected by arsenic exposure. HFD caused steatohepatitis, as indicated by histological assessment and by increases in plasma ALT and AST. Although arsenic exposure had no effect on indices of liver damage in LFD-fed animals, it significantly increased the liver damage caused by HFD. This effect of arsenic correlated with enhanced inflammation and fibrin extracellular matrix (ECM) deposition. These data indicate that subhepatotoxic arsenic exposure enhances the toxicity of HFD. These results also suggest that arsenic exposure might be a risk factor for the development of fatty liver disease in human populations. -- Highlights: Black-Right-Pointing-Pointer Characterizes a mouse model of arsenic enhanced NAFLD. Black-Right-Pointing-Pointer Arsenic synergistically enhances experimental fatty liver disease at concentrations that cause no overt hepatotoxicity alone. Black-Right-Pointing-Pointer This effect is associated with increased inflammation.

  10. Performance enhancement in the workplace: why and when healthy individuals should disclose their reliance on pharmaceutical cognitive enhancers.

    PubMed

    Garasic, Mirko D; Lavazza, Andrea

    2015-01-01

    The use of pharmaceuticals cognitive enhancers (PCE) has been stirring growing interest, not only in the scientific domain but also in the popular media, and has probably had some increase recently in academic, professional and military quarters. So this phenomenon is deemed as a normal procedure aimed at improving the performance of an individual as well as the overall standards of an organization. Although the vast majority of countries have some kind of restrictions to reduce the wide non-medical usage of PCE, these can be overcome quite easily. In arguing for our explicit claim that, in many contexts, the use of cognitive enhancers should be disclosed-as a moral and socially relevant duty-we maintain that PCE present typical, or at least not rare, properties. The features are the following: (a) the enhancer has acute and/or chronic effects. In the first case, shortly after taking the drug the performance is significantly better than average; in the second case, there is a growing or lasting effect, which, however, is poised to diminish when one stops taking the drug; (b) those effects are significant (there is a difference in the outcome considered between taking and not taking the drug) and sometimes dramatic; and (c) a third feature, not directly related to enhancers as such, is their varying safety, availability, and legal permissibility, which might either induce people to take them or refrain them from doing so. We will consider the issue of fairness due to "unenhanced" people as well as the potentially dysfunctional social consequences of an undisclosed PCE use. PMID:25762902

  11. Performance enhancement in the workplace: why and when healthy individuals should disclose their reliance on pharmaceutical cognitive enhancers

    PubMed Central

    Garasic, Mirko D.; Lavazza, Andrea

    2015-01-01

    The use of pharmaceuticals cognitive enhancers (PCE) has been stirring growing interest, not only in the scientific domain but also in the popular media, and has probably had some increase recently in academic, professional and military quarters. So this phenomenon is deemed as a normal procedure aimed at improving the performance of an individual as well as the overall standards of an organization. Although the vast majority of countries have some kind of restrictions to reduce the wide non-medical usage of PCE, these can be overcome quite easily. In arguing for our explicit claim that, in many contexts, the use of cognitive enhancers should be disclosed—as a moral and socially relevant duty—we maintain that PCE present typical, or at least not rare, properties. The features are the following: (a) the enhancer has acute and/or chronic effects. In the first case, shortly after taking the drug the performance is significantly better than average; in the second case, there is a growing or lasting effect, which, however, is poised to diminish when one stops taking the drug; (b) those effects are significant (there is a difference in the outcome considered between taking and not taking the drug) and sometimes dramatic; and (c) a third feature, not directly related to enhancers as such, is their varying safety, availability, and legal permissibility, which might either induce people to take them or refrain them from doing so. We will consider the issue of fairness due to “unenhanced” people as well as the potentially dysfunctional social consequences of an undisclosed PCE use. PMID:25762902

  12. Cognitive-Enhancing Effect of Aronia melanocarpa Extract against Memory Impairment Induced by Scopolamine in Mice.

    PubMed

    Lee, Hyeon Yong; Weon, Jin Bae; Jung, Youn Sik; Kim, Nam Young; Kim, Myong Ki; Ma, Choong Je

    2016-01-01

    Aronia melanocarpa (A. melanocarpa) berries are a fruit with a marked antioxidant effect. The objective of this study was to confirm the effect of A. melanocarpa berries extract against scopolamine-induced memory impairment in mice using the Morris water maze and passive avoidance test. Moreover, we determined a possible mechanism of the cognitive-enhancing effect involving AChE activity and BDNF and p-CREB expression in the hippocampus of mice. A. melanocarpa berries extract attenuated the learning and memory impairment induced by scopolamine in the Morris water maze (79.3 ± 0.8 s of 200 mg/kg and 64.4 ± 10.7 s of 400 mg/kg on day 4) and passive avoidance tests (46.0 ± 41.1 s of 200 mg/kg and 25.6 ± 18.7 s of 400 mg/kg). A. melanocarpa berries extract reduced the acetylcholinesterase level in the hippocampus of scopolamine-injected mice and increased BDNF and p-CREB expression in the hippocampus. The major compound, cyanidin-3-O-galactoside, also reversed memory impairment. These results showed that A. melanocarpa berries extract improved memory impairment by inhibiting AChE and increasing BDNF and p-CREB expression, and cyanidin-3-O-galactoside may be responsible for the effect of A. melanocarpa berries extract. PMID:27239211

  13. Cognitive-Enhancing Effect of Aronia melanocarpa Extract against Memory Impairment Induced by Scopolamine in Mice

    PubMed Central

    Lee, Hyeon Yong; Weon, Jin Bae; Jung, Youn Sik; Kim, Nam Young; Kim, Myong Ki; Ma, Choong Je

    2016-01-01

    Aronia melanocarpa (A. melanocarpa) berries are a fruit with a marked antioxidant effect. The objective of this study was to confirm the effect of A. melanocarpa berries extract against scopolamine-induced memory impairment in mice using the Morris water maze and passive avoidance test. Moreover, we determined a possible mechanism of the cognitive-enhancing effect involving AChE activity and BDNF and p-CREB expression in the hippocampus of mice. A. melanocarpa berries extract attenuated the learning and memory impairment induced by scopolamine in the Morris water maze (79.3 ± 0.8 s of 200 mg/kg and 64.4 ± 10.7 s of 400 mg/kg on day 4) and passive avoidance tests (46.0 ± 41.1 s of 200 mg/kg and 25.6 ± 18.7 s of 400 mg/kg). A. melanocarpa berries extract reduced the acetylcholinesterase level in the hippocampus of scopolamine-injected mice and increased BDNF and p-CREB expression in the hippocampus. The major compound, cyanidin-3-O-galactoside, also reversed memory impairment. These results showed that A. melanocarpa berries extract improved memory impairment by inhibiting AChE and increasing BDNF and p-CREB expression, and cyanidin-3-O-galactoside may be responsible for the effect of A. melanocarpa berries extract. PMID:27239211

  14. Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin

    PubMed Central

    Kessenbrock, Kai; Fröhlich, Leopold; Sixt, Michael; Lämmermann, Tim; Pfister, Heiko; Bateman, Andrew; Belaaouaj, Azzaq; Ring, Johannes; Ollert, Markus; Fässler, Reinhard; Jenne, Dieter E.

    2008-01-01

    Neutrophil granulocytes form the body’s first line of antibacterial defense, but they also contribute to tissue injury and noninfectious, chronic inflammation. Proteinase 3 (PR3) and neutrophil elastase (NE) are 2 abundant neutrophil serine proteases implicated in antimicrobial defense with overlapping and potentially redundant substrate specificity. Here, we unraveled a cooperative role for PR3 and NE in neutrophil activation and noninfectious inflammation in vivo, which we believe to be novel. Mice lacking both PR3 and NE demonstrated strongly diminished immune complex–mediated (IC-mediated) neutrophil infiltration in vivo as well as reduced activation of isolated neutrophils by ICs in vitro. In contrast, in mice lacking just NE, neutrophil recruitment to ICs was only marginally impaired. The defects in mice lacking both PR3 and NE were directly linked to the accumulation of antiinflammatory progranulin (PGRN). Both PR3 and NE cleaved PGRN in vitro and during neutrophil activation and inflammation in vivo. Local administration of recombinant PGRN potently inhibited neutrophilic inflammation in vivo, demonstrating that PGRN represents a crucial inflammation-suppressing mediator. We conclude that PR3 and NE enhance neutrophil-dependent inflammation by eliminating the local antiinflammatory activity of PGRN. Our results support the use of serine protease inhibitors as antiinflammatory agents. PMID:18568075

  15. Amyloid-β immunization enhances neurogenesis and cognitive ability in neonatal mice

    PubMed Central

    Chen, Hongguang; Wang, Min; Jiao, Aihong; Tang, Guotai; Zhu, Wei; Zou, Peng; Li, Tuo; Cui, Guangqiang; Gong, Peiyou

    2015-01-01

    Whether Aβ actually has a physiological as well as a pathological role is not known. In order to investigate the effect of endogenous Aβ, wild type C57BL/6 mice were immunized with human or mouse derived Aβ1-42. The anti-Aβ antibody concentrations were increased in both treated groups. Compared to the human Aβ1-42 treated group, level of serum Aβ significantly decreased in mouse Aβ1-42 treated group. Western blot results revealed that these two derived Aβ1-42 had no cross-reaction. The new dentate granule survival cells increased in Aβ1-42 immunization groups, indicated by more BrdU+/NeuN+ and BrdU+/DCX+ cells as compared to PBS-treated group, accompanied by behavioral performance improving in a hippocampus-dependent learning task. Immunohistochemical analysis showed that BrdU+/Iba1+ cells also increased, however new born astrocytes (BrdU+/GFAP+) were unaffected in all treated mice. Interestingly, according the results of ELISA analysis both vaccines up-regulated IL-4 and IFN-γ levels in the brains and sera, but the TNF-α level did not changed. Of note, human Aβ1-42 immunization in neonatal mice enhanced neurogenesis and cognitive ability, might via Aβ immune response rather than cleaning endogenous Aβ. PMID:26131110

  16. Enhancement of thermal response of normal and malignant tissues by Corynebacterium parvum. [Mice

    SciTech Connect

    Urano, M.; Yamashita, T.; Suit, H.D.; Gerweck, L.E.

    1984-06-01

    Further studies were carried out on the combined effects of Corynebacterium parvum and hyperthermia on animal tissues and cultured Chinese hamster ovary cells. Experimental animals were C3Hf/Sed mice derived from a defined flora mouse colony. Tumors were eighth-generation isotransplants of a spontaneous fibrosarcoma, FSa-II. Hyperthermia was given by immersing the mouse foot or culture flasks in the constant temperature water bath. Present experiments include thermal enhancement of C. parvum at different temperatures, effect of the agent on the kinetics of thermal resistance, and the mechanism of the thermal enhancement. The thermal enhancement by C. parvum was independent of temperature in a range between 42.5 and 46.5 degrees, and it increased with decreasing temperature. The analysis of the Arrhenius plot suggested a comparable activation energy for combined treatments and for heat alone between 42.5 and 46.5 degrees. The thermal resistance developed very rapidly in both normal and tumor tissues. Systemic administration of C. parvum failed to modify the kinetics of thermal resistance. Several experiments were attempted in order to disclose the mechanism. A single injection of C. parvum-induced macrophages failed to enhance thermal response of the mouse foot, while 3 daily injections of the macrophages enhanced the response, indicating that the enhancement by C. parvum is at least partly attributed to the C. parvum-induced macrophages. Whole-body irradiation of 6 Gy and/or administration of anti-mouse T-cell serum and histamine failed to inhibit the C. parvum enhancement of thermal response. No thermal enhancement was observed for Chinese hamster ovary cells treated at 43.0 degrees in vitro with C. parvum or thiomersalate, a preservative supplemented in C. parvum, although cytotoxic effect was shown at a high concentration of thiomersalate.

  17. Selective X-ray contrast enhancement of the spleen of living mice mediated by gold nanorods.

    PubMed

    Wathen, Connor A; Caldwell, Chuck; Chanda, Nripen; Upendran, Anandhi; Zambre, Ajit; Afrasiabi, Zahra; Chapaman, Sarah E; Foje, Nathan; Leevy, W Matthew; Kannan, Raghuraman

    2015-01-01

    Gold nanomaterials (AuNPs) represent a promising new class of contrast agents for X-ray computed tomographic (CT) imaging in both research and clinical settings. These materials exhibit superior X-ray absorption properties compared with other iodinated agents, and thus require lower injection doses. Gold is nonimmunogenic and therefore contributes to safety profile in living specimens. Unfortunately, most reports on the use of AuNPs as X-ray CT enhancers only demonstrate marginal enhancement of the intended anatomical structure. In this study, we demonstrate the dramatic properties of gold nanorods (GNR) to serve as robust X-ray CT contrast-enhancing agent for selective imaging of the spleen. These organ-specific uptake properties were delineated by performing longitudinal CT imaging of living mice that were dosed with GNR at 2 day intervals. Rapid uptake in spleen was noted within 12 h of first systemic administration with a change in contrast enhancement of 90 Hounsfield units (ΔHU = 90) and with two subsequent injections a total contrast enhancement of over 200 HU was observed. The resulting images provide excellent contrast that will enable the detailed anatomical visualization and study of a range of pre-clinical models of spleen disease including infection and cancer. PMID:25169942

  18. A myostatin and activin decoy receptor enhances bone formation in mice.

    PubMed

    Bialek, P; Parkington, J; Li, X; Gavin, D; Wallace, C; Zhang, J; Root, A; Yan, G; Warner, L; Seeherman, H J; Yaworsky, P J

    2014-03-01

    Myostatin is a member of the bone morphogenetic protein/transforming growth factor-β (BMP/TGFβ) super-family of secreted differentiation factors. Myostatin is a negative regulator of muscle mass as shown by increased muscle mass in myostatin deficient mice. Interestingly, these mice also exhibit increased bone mass suggesting that myostatin may also play a role in regulating bone mass. To investigate the role of myostatin in bone, young adult mice were administered with either a myostatin neutralizing antibody (Mstn-mAb), a soluble myostatin decoy receptor (ActRIIB-Fc) or vehicle. While both myostatin inhibitors increased muscle mass, only ActRIIB-Fc increased bone mass. Bone volume fraction (BV/TV), as determined by microCT, was increased by 132% and 27% in the distal femur and lumbar vertebrae, respectively. Histological evaluation demonstrated that increased BV/TV in both locations was attributed to increased trabecular thickness, trabecular number and bone formation rate. Increased BV/TV resulted in enhanced vertebral maximum compressive force compared to untreated animals. The fact that ActRIIB-Fc, but not Mstn-mAb, increased bone volume suggested that this soluble decoy receptor may be binding a ligand other than myostatin, that plays a role in regulating bone mass. This was confirmed by the significant increase in BV/TV in myostatin deficient mice treated with ActRIIB-Fc. Of the other known ActRIIB-Fc ligands, BMP3 has been identified as a negative regulator of bone mass. However, BMP3 deficient mice treated with ActRIIB-Fc showed similar increases in BV/TV as wild type (WT) littermates treated with ActRIIB-Fc. This result suggests that BMP3 neutralization is not the mechanism responsible for increased bone mass. The results of this study demonstrate that ActRIIB-Fc increases both muscle and bone mass in mice. Therefore, a therapeutic that has this dual activity represents a potential approach for the treatment of frailty. PMID:24333131

  19. Improving introspection to inform free will regarding the choice by healthy individuals to use or not use cognitive enhancing drugs

    PubMed Central

    Thaler, David S

    2009-01-01

    A commentary in Nature entitled "Towards responsible use of cognitive-enhancing drugs by the healthy" (Greely et al 2008 Nature 456: 702–705) offers an opportunity to move toward a humane societal appreciation of mind-altering drugs. Using cognitive enhancing drugs as an exemplar, this article presents a series of hypotheses concerning how an individual might learn optimal use. The essence of the proposal is that individuals can cultivate sensitivity to the effects of ever-smaller amounts of psychoactive drugs thereby making harm less likely and benign effects more probable. Four interrelated hypotheses are presented and briefly discussed. 1. Humans can learn to discriminate ever-smaller doses of at least some mind-altering drugs; a learning program can be designed or discovered that will have this outcome. 2. The skill to discriminate drugs and dose can be generalized, i.e. if learned with one drug a second one is easier and so on. 3. Cultivating this skill/knack would be beneficial in leading to choices informed by a more accurate sense of mind-body interactions. 4. From a philosophical point of view learning the effects of ever-smaller doses of psychoactive agents offers a novel path into and to transcend the objective/subjective barrier and the mind/body problem. Whatever the fate of these specific hypotheses, discussion of cognitive enhancing drugs for healthy individuals has the potential to inspire innovative educational and public policy initiatives toward all types of mind-altering drugs and the people who use them. PMID:19531231

  20. Enhanced Energy Expenditure, Glucose Utilization, and Insulin Sensitivity in VAMP8 Null Mice

    PubMed Central

    Zong, Haihong; Wang, Cheng-Chun; Vaitheesvaran, Bhavapriya; Kurland, Irwin J.; Hong, Wanjin; Pessin, Jeffrey E.

    2011-01-01

    OBJECTIVE Previous studies have demonstrated that the VAMP8 protein plays a complex role in the control of granule secretion, transport vesicle trafficking, phagocytosis, and endocytosis. The present study was aimed to investigate the role of VAMP8 in mediating GLUT4 trafficking and therefore insulin action in mice. RESEARCH DESIGN AND METHODS Physiological parameters were measured using Oxymax indirect calorimetry system in 12-week-old VAMP8 null mice. Dynamic analysis of glucose homeostasis was assessed using euglycemic–hyperinsulinemic clamp coupled with tracer radioactively labeled 2-deoxyglucose. Insulin stimulated GLUT4 protein expressions on muscle cell surface were examined by immunofluorescence microscopy. RESULTS VAMP8 null mice display reduced adiposity with increased energy expenditure despite normal food intake and reduced spontaneous locomotor activity. In parallel, the VAMP8 null mice also had fasting hypoglycemia (84 ± 11 vs. 115 ± 4) and enhanced glucose tolerance with increased insulin sensitivity due to increases in both basal and insulin-stimulated glucose uptake in skeletal muscle (0.19 ± 0.04 vs. 0.09 ± 0.01 mmol/kg/min during basal, 0.6 ± 0.04 vs. 0.31 ± 0.06 mmol/kg/min during clamp in red-gastrocnemius muscle, P < 0.05). Consistent with a role for VAMP8 in the endocytosis of the insulin-responsive GLUT4, sarcolemma GLUT4 protein levels were increased in both the basal and insulin-stimulated states without any significant change in the total amount of GLUT4 protein or related facilitative glucose transporters present in skeletal muscle, GLUT1, GLUT3, and GLUT11. CONCLUSIONS These data demonstrate that, in the absence of VAMP8, the relative subcellular distribution of GLUT4 is altered, resulting in increased sarcolemma levels that can account for increased glucose clearance and insulin sensitivity. PMID:20876717

  1. Estradiol enhances retention but not organization of hippocampus-dependent memory in intact male mice.

    PubMed

    Al Abed, Alice Shaam; Sellami, Azza; Brayda-Bruno, Laurent; Lamothe, Valérie; Noguès, Xavier; Potier, Mylène; Bennetau-Pelissero, Catherine; Marighetto, Aline

    2016-07-01

    Because estrogens have mostly been studied in gonadectomized females, effects of chronic exposure to environmental estrogens in the general population are underestimated. Estrogens can enhance hippocampus-dependent memory through the modulation of information storage. However, declarative memory, the hippocampus-dependent memory of facts and events, demands more than abilities to retain information. Specifically, memory of repetitive events of everyday life such as "where I parked" requires abilities to organize/update memories to prevent proactive interference from similar memories of previous "parking events". Whether such organizational processes are estrogen-sensitive is unknown. We here studied, in intact young and aged adult mice, drinking-water (1μM) estradiol effects on both retention and organizational components of hippocampus-dependent memory, using a radial-maze task of everyday-like memory. Demand on retention vs organization was manipulated by varying the time-interval separating repetitions of similar events. Estradiol increased performance in young and aged mice under minimized organizational demand, but failed to improve the age-associated memory impairment and diminished performance in young mice under high organizational demand. In fact, estradiol prolonged mnemonic retention of successive events without improving organization abilities, hence resulted in more proactive interference from irrelevant memories. c-Fos imaging of testing-induced brain activations showed that the deterioration of young memory was associated with dentate gyrus dysconnectivity, reminiscent of that seen in aged mice. Our findings support the view that estradiol is promnesic but also reveal that such property can paradoxically impair memory. These findings have important outcomes regarding health issues relative to the impact of environmental estrogens in the general population. PMID:27038677

  2. Enhancement of leptin receptor signaling by SOCS3 deficiency induces development of gastric tumors in mice.

    PubMed

    Inagaki-Ohara, K; Mayuzumi, H; Kato, S; Minokoshi, Y; Otsubo, T; Kawamura, Y I; Dohi, T; Matsuzaki, G; Yoshimura, A

    2014-01-01

    Leptin acts on its receptor (ObR) in the hypothalamus to inhibit food intake and energy expenditure. Leptin and ObR are also expressed in the gastrointestinal tract; however, the physiological significance of leptin signaling in the gut remains uncertain. Suppressor of cytokine signaling 3 (SOCS3) is a key negative feedback regulator of ObR-mediated signaling in the hypothalamus. We now show that gastrointestinal epithelial cell-specific SOCS3 conditional knockout (T3b-SOCS3 cKO) mice developed gastric tumors by enhancing leptin production and the ObRb/signal transducer and activator of transcription 3 (STAT3) signaling pathway. All T3b-SOCS3 cKO mice developed tumors in the stomach but not in the bowels by 2 months of age, even though the SOCS3 deletion occurred in both the epithelium of stomach and bowels. The tumors developed in the absence of the inflammatory response and all cKO mice died within 6 months. These tumors displayed pathology and molecular alterations, such as an increase in MUC2 (Mucin 2, oligomeric mucus/gel-forming) and TFF3 (trefoil factor 3), resembling human intestinal-type gastric tumors. Administration of antileptin antibody to T3b-SOCS3 cKO mice reduced hyperplasia of gastric mucosa, which is the step of the initiation of gastric tumor. These data suggest that SOCS3 is an antigastric tumor gene that suppresses leptin overexpression and ObRb/STAT3 hyperactivation, supporting the hypothesis that the leptin/ObRb/STAT3 axis accelerates tumorigenesis and that it may represent a new therapeutic target for the treatment of gastric cancer. PMID:23178499

  3. Hematopoietic Stem Cell Regeneration Enhanced by Ectopic Expression of ROS-detoxifying Enzymes in Transplant Mice

    PubMed Central

    Miao, Weimin; XuFeng, Richard; Park, Moo-Rim; Gu, Haihui; Hu, Linping; Kang, Jin Wook; Ma, Shihui; Liang, Paulina H; Li, Yanxin; Cheng, Haizi; Yu, Hui; Epperly, Michael; Greenberger, Joel; Cheng, Tao

    2013-01-01

    High levels of reactive oxygen species (ROS) can exhaust hematopoietic stem cells (HSCs). Thus, maintaining a low state of redox in HSCs by modulating ROS-detoxifying enzymes may augment the regeneration potential of HSCs. Our results show that basal expression of manganese superoxide dismutase (MnSOD) and catalase were at low levels in long-term and short-term repopulating HSCs, and administration of a MnSOD plasmid and lipofectin complex (MnSOD-PL) conferred radiation protection on irradiated recipient mice. To assess the intrinsic role of elevated MnSOD or catalase in HSCs and hematopoietic progenitor cells, the MnSOD or catalase gene was overexpressed in mouse hematopoietic cells via retroviral transduction. The impact of MnSOD and catalase on hematopoietic progenitor cells was mild, as measured by colony-forming units (CFUs). However, overexpressed catalase had a significant beneficial effect on long-term engraftment of transplanted HSCs, and this effect was further enhanced after an insult of low-dose γ-irradiation in the transplant mice. In contrast, overexpressed MnSOD exhibited an insignificant effect on long-term engraftment of transplanted HSCs, but had a significant beneficial effect after an insult of sublethal irradiation. Taken together, these results demonstrate that HSC function can be enhanced by ectopic expression of ROS-detoxifying enzymes, especially after radiation exposure in vivo. PMID:23295952

  4. Hematopoietic stem cell regeneration enhanced by ectopic expression of ROS-detoxifying enzymes in transplant mice.

    PubMed

    Miao, Weimin; Xufeng, Richard; Park, Moo-Rim; Gu, Haihui; Hu, Linping; Kang, Jin Wook; Ma, Shihui; Liang, Paulina H; Li, Yanxin; Cheng, Haizi; Yu, Hui; Epperly, Michael; Greenberger, Joel; Cheng, Tao

    2013-02-01

    High levels of reactive oxygen species (ROS) can exhaust hematopoietic stem cells (HSCs). Thus, maintaining a low state of redox in HSCs by modulating ROS-detoxifying enzymes may augment the regeneration potential of HSCs. Our results show that basal expression of manganese superoxide dismutase (MnSOD) and catalase were at low levels in long-term and short-term repopulating HSCs, and administration of a MnSOD plasmid and lipofectin complex (MnSOD-PL) conferred radiation protection on irradiated recipient mice. To assess the intrinsic role of elevated MnSOD or catalase in HSCs and hematopoietic progenitor cells, the MnSOD or catalase gene was overexpressed in mouse hematopoietic cells via retroviral transduction. The impact of MnSOD and catalase on hematopoietic progenitor cells was mild, as measured by colony-forming units (CFUs). However, overexpressed catalase had a significant beneficial effect on long-term engraftment of transplanted HSCs, and this effect was further enhanced after an insult of low-dose γ-irradiation in the transplant mice. In contrast, overexpressed MnSOD exhibited an insignificant effect on long-term engraftment of transplanted HSCs, but had a significant beneficial effect after an insult of sublethal irradiation. Taken together, these results demonstrate that HSC function can be enhanced by ectopic expression of ROS-detoxifying enzymes, especially after radiation exposure in vivo. PMID:23295952

  5. Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice.

    PubMed

    Rangasamy, Tirumalai; Guo, Jia; Mitzner, Wayne A; Roman, Jessica; Singh, Anju; Fryer, Allison D; Yamamoto, Masayuki; Kensler, Thomas W; Tuder, Rubin M; Georas, Steve N; Biswal, Shyam

    2005-07-01

    Oxidative stress has been postulated to play an important role in the pathogenesis of asthma; although a defect in antioxidant responses has been speculated to exacerbate asthma severity, this has been difficult to demonstrate with certainty. Nuclear erythroid 2 p45-related factor 2 (Nrf2) is a redox-sensitive basic leucine zipper transcription factor that is involved in the transcriptional regulation of many antioxidant genes. We show that disruption of the Nrf2 gene leads to severe allergen-driven airway inflammation and hyperresponsiveness in mice. Enhanced asthmatic response as a result of ovalbumin sensitization and challenge in Nrf2-disrupted mice was associated with more pronounced mucus cell hyperplasia and infiltration of eosinophils into the lungs than seen in wild-type littermates. Nrf2 disruption resulted in an increased expression of the T helper type 2 cytokines interleukin (IL)-4 and IL-13 in bronchoalveolar lavage fluid and in splenocytes after allergen challenge. The enhanced severity of the asthmatic response from disruption of the Nrf2 pathway was a result of a lowered antioxidant status of the lungs caused by lower basal expression, as well as marked attenuation, of the transcriptional induction of multiple antioxidant genes. Our studies suggest that the responsiveness of Nrf2-directed antioxidant pathways may act as a major determinant of susceptibility to allergen-mediated asthma. PMID:15998787

  6. Prenatal bupropion exposure enhances the cocaine reward and stress susceptibility in adult mice.

    PubMed

    Hsiao, S Y; Cherng, C F G; Yang, Y K; Yeh, T L; Yu, L

    2005-12-31

    Although a growing body of evidence supports the notion that certain antidepressant treatments in pregnancy produce earlier delivery and minor behavioral teratogenesis in infants, the long-term effects of such treatments in adulthood remain ill-defined. Recently, postnatal exposure to psychotropic drugs was found to affect the emotional development and susceptibility to abused drugs. Thus, this study aimed to examine whether prenatal exposure of four frequently-used antidepressants, bupropion, fluvoxamine, citalopram, and trazodone, altered the responsiveness to stress and cocaine in the adulthood. Dams received daily injection of bupropion (25 or 12.5 mg/kg), citalopram (5 mg/kg), fluvoxamine (10 mg/kg), trazodone (20 mg/kg) or saline throughout their third trimester of gestation, and several birth outcome indices were then examined. Locomotor activity, naive anxiety levels, and the sensitivity to the cocaine reinforcing effects were observed in pups at their day 56-60 post partum. We found that trazodone treatment produced a high mortality rate in pups after weaning. Mice, prenatally treated with bupropion at 25 mg/kg, exhibited lower rearing numbers and ambulatory activity as compared to the saline-treated mice. More importantly, such treatment enhanced the mouse sensitivity to the reinforcing effects of cocaine. Taken together, these results suggest that use of bupropion in the late pregnancy may run a risk of enhancing the offspring's susceptibility to stress and cocaine reward in adulthood. PMID:16548425

  7. Increased microvascular density and enhanced leukocyte rolling and adhesion in the skin of VEGF transgenic mice.

    PubMed

    Detmar, M; Brown, L F; Schön, M P; Elicker, B M; Velasco, P; Richard, L; Fukumura, D; Monsky, W; Claffey, K P; Jain, R K

    1998-07-01

    Vascular endothelial growth factor (VEGF) has been implicated in the pathologic angiogenesis observed in psoriasis and other chronic inflammatory skin diseases that are characterized by enhanced expression of VEGF by epidermal keratinocytes and of VEGF receptors by tortuous microvessels in the upper dermis. To investigate the functional importance of chronic VEGF overexpression in vivo, we used a keratin 14 promoter expression cassette containing the gene for murine VEGF164 to selectively target VEGF expression to basal epidermal keratinocytes in transgenic mice. These mice demonstrated an increased density of tortuous cutaneous blood capillaries with elevated expression levels of the high affinity VEGF receptors, VEGFR-1 and VEGFR-2, most prominently during the neonatal period. In contrast, no abnormalities of lymphatic vessels were detected. In addition, the number of mast cells in the upper dermis was significantly increased in transgenic skin. Intravital fluorescence microscopy revealed highly increased leukocyte rolling and adhesion in postcapillary skin venules that were both inhibited after injection of blocking antibodies against E- and P-selectin. Combined blocking antibodies against intercellular adhesion molecule-1 and lymphocyte function-associated antigen-1 were without effect, whereas an anti-vascular cell adhesion molecule-1/VLA-4 antibody combination almost completely normalized the enhanced leukocyte adhesion in transgenic mice. This study reveals VEGF as a growth factor specific for blood vessels, but not lymphatic vessels, and demonstrates that chronic orthotopic overexpression of VEGF in the epidermis is sufficient to induce cardinal features of chronic skin inflammation, providing a molecular link between angiogenesis, mast cell accumulation, and leukocyte recruitment to sites of inflammation. PMID:9665379

  8. Passport to health: an innovative tool to enhance healthy lifestyle choices.

    PubMed

    Vaczy, Elizabeth; Seaman, Brenda; Peterson-Sweeney, Kathleen; Hondorf, Carol

    2011-01-01

    Obesity in children and adolescents has become an epidemic in the United States. The ramifications of obesity at a young age are longstanding and affect physical health, emotional health, and the economics of the health care industry. The Strong Pediatric Practice at Golisano Children's Hospital is a large inner-city practice serving more than 14,000 urban children and adolescents, the majority living below the poverty level. The Obesity Task Force, which comprises four nurse practitioners, two nurses, a nutritionist, and one physician, developed and implemented the "Passport to Health" tool in an attempt to encourage providers to assess and work with families around the issues of weight and activity, a need that was identified through chart audits. The Passport to Health supports the policy statements on prevention of overweight and obesity by the Centers for Disease Control and Prevention, National Association of Pediatric Nurse Practitioners, and American Academy of Pediatrics. Quality assurance standards for managed care that mandate body mass index (BMI) assessment and nutrition counseling in all children and adolescents also is supported by this tool. The Passport to Health also provides the same message as a current community initiative in the Rochester area that has received widespread media coverage. This tool includes a visual color-coded indicator of the child's BMI status and a synopsis of specific healthy eating and activity goals, and it permits an individualized goal to be established. The Passport to Health translates information that the provider knows about the BMI status into information that the family and child can embrace and understand. Chart audits as well as exit interviews have demonstrated that use of the Passport to Health has increased the assessment, identification, and counseling by providers in relation to healthy eating and activity. Chart audits found that nurse practitioners embraced this practice change more readily than did

  9. Fluoxetine Protection in Decompression Sickness in Mice is Enhanced by Blocking TREK-1 Potassium Channel with the "spadin" Antidepressant.

    PubMed

    Vallée, Nicolas; Lambrechts, Kate; De Maistre, Sébastien; Royal, Perrine; Mazella, Jean; Borsotto, Marc; Heurteaux, Catherine; Abraini, Jacques; Risso, Jean-Jacques; Blatteau, Jean-Eric

    2016-01-01

    In mice, disseminated coagulation, inflammation, and ischemia induce neurological damage that can lead to death. These symptoms result from circulating bubbles generated by a pathogenic decompression. Acute fluoxetine treatment or the presence of the TREK-1 potassium channel increases the survival rate when mice are subjected to an experimental dive/decompression protocol. This is a paradox because fluoxetine is a blocker of TREK-1 channels. First, we studied the effects of an acute dose of fluoxetine (50 mg/kg) in wild-type (WT) and TREK-1 deficient mice (knockout homozygous KO and heterozygous HET). Then, we combined the same fluoxetine treatment with a 5-day treatment protocol with spadin, in order to specifically block TREK-1 activity (KO-like mice). KO and KO-like mice were regarded as antidepressed models. In total, 167 mice (45 WTcont 46 WTflux 30 HETflux and 46 KOflux) constituting the flux-pool and 113 supplementary mice (27 KO-like 24 WTflux2 24 KO-likeflux 21 WTcont2 17 WTno dive) constituting the spad-pool were included in this study. Only 7% of KO-TREK-1 treated with fluoxetine (KOflux) and 4% of mice treated with both spadin and fluoxetine (KO-likeflux) died from decompression sickness (DCS) symptoms. These values are much lower than those of WT control (62%) or KO-like mice (41%). After the decompression protocol, mice showed significant consumption of their circulating platelets and leukocytes. Spadin antidepressed mice were more likely to exhibit DCS. Nevertheless, mice which had both blocked TREK-1 channels and fluoxetine treatment were better protected against DCS. We conclude that the protective effect of such an acute dose of fluoxetine is enhanced when TREK-1 is inhibited. We confirmed that antidepressed models may have worse DCS outcomes, but concomitant fluoxetine treatment not only decreased DCS severity but increased the survival rate. PMID:26909044

  10. Application of SPECT/CT imaging system and radiochemical analysis for investigation of blood kinetics and tissue distribution of radiolabeled plumbagin in healthy and Plasmodium berghei-infected mice.

    PubMed

    Sumsakul, W; Karbwang, J; Na-Bangchang, K

    2016-02-01

    Plumbagin is a derivative of napthoquinone which is isolated from the roots of plants in several families. These compound exhibits a wide range of biological and pharmacological activities including antimalarial, antibacterial, antifungal, and anticancer activities. The aim of the study was to investigate blood kinetics and tissue distribution of plumbagin in healthy and Plasmodium berghei-infected mice using Single-Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) and radiochemical analysis by gamma counter. Plumbagin was labeled with (99m)technetium and the reducing agent stannous chloride dihydrate (50 μg/ml) at pH 6.5. Blood kinetics and tissue distribution of the radiolabeled plumbagin were investigated in healthy and P. berghei-infected mice (2 males and 2 females for each experimental group). In vitro and in vivo stability of plumbagin complex suggested satisfactory stability profiles of (99m)Tc-plumbagin complex in plasma and normal saline (92.21-95.47%) within 24 h. Significant difference in blood kinetics parameters (Cmax, AUC, t1/2, MRT, Vd, and CL) were observed between P. berghei-infected and healthy mice. The labeled complex distributed to all organs of both healthy and infected mice but with high intensity in liver, followed by lung, stomach, large intestine and kidney. Accumulation in spleen was markedly noticeable in the infected mice. Plumbagin-labeled complex was rapidly cleared from blood and major routes of excretion were hepatobiliary and pulmonary routes. In P. berghei-infected mice, t1/2 was significantly decreased, while Vd and CL were increased compared with healthy mice. Result suggests that malaria disease state influenced the pharmacokinetics and disposition of plumbagin. SPECT/CT imaging with radiolabeled (99m)Tc is a viable non-invasive technique that can be applied for investigation of kinetics and biodistribution of plumbagin in animal models. PMID:26713669

  11. Pathological Type-2 Immune Response, Enhanced Tumor Growth, and Glucose Intolerance in Retnlβ (RELMβ) Null Mice: A Model of Intestinal Immune System Dysfunction in Disease Susceptibility.

    PubMed

    Wernstedt Asterholm, Ingrid; Kim-Muller, Ja Young; Rutkowski, Joseph M; Crewe, Clair; Tao, Caroline; Scherer, Philipp E

    2016-09-01

    Resistin, and its closely related homologs, the resistin-like molecules (RELMs) have been implicated in metabolic dysregulation, inflammation, and cancer. Specifically, RELMβ, expressed predominantly in the goblet cells in the colon, is released both apically and basolaterally, and is hence found in both the intestinal lumen in the mucosal layer as well as in the circulation. RELMβ has been linked to both the pathogenesis of colon cancer and type 2 diabetes. RELMβ plays a complex role in immune system regulation, and the impact of loss of function of RELMβ on colon cancer and metabolic regulation has not been fully elucidated. We therefore tested whether Retnlβ (mouse ortholog of human RETNLβ) null mice have an enhanced or reduced susceptibility for colon cancer as well as metabolic dysfunction. We found that the lack of RELMβ leads to increased colonic expression of T helper cell type-2 cytokines and IL-17, associated with a reduced ability to maintain intestinal homeostasis. This defect leads to an enhanced susceptibility to the development of inflammation, colorectal cancer, and glucose intolerance. In conclusion, the phenotype of the Retnlβ null mice unravels new aspects of inflammation-mediated diseases and strengthens the notion that a proper intestinal barrier function is essential to sustain a healthy phenotype. PMID:27397737

  12. Oral lipid-based nanoformulation of tafenoquine enhanced bioavailability and blood stage antimalarial efficacy and led to a reduction in human red blood cell loss in mice

    PubMed Central

    Melariri, Paula; Kalombo, Lonji; Nkuna, Patric; Dube, Admire; Hayeshi, Rose; Ogutu, Benhards; Gibhard, Liezl; deKock, Carmen; Smith, Peter; Wiesner, Lubbe; Swai, Hulda

    2015-01-01

    Tafenoquine (TQ), a new synthetic analog of primaquine, has relatively poor bioavailability and associated toxicity in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. A microemulsion formulation of TQ (MTQ) with sizes <20 nm improved the solubility of TQ and enhanced the oral bioavailability from 55% to 99% in healthy mice (area under the curve 0 to infinity: 11,368±1,232 and 23,842±872 min·μmol/L) for reference TQ and MTQ, respectively. Average parasitemia in Plasmodium berghei-infected mice was four- to tenfold lower in the MTQ-treated group. In vitro antiplasmodial activities against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum indicated no change in half maximal inhibitory concentration, suggesting that the microemulsion did not affect the inherent activity of TQ. In a humanized mouse model of G6PD deficiency, we observed reduction in toxicity of TQ as delivered by MTQ at low but efficacious concentrations of TQ. We hereby report an enhancement in the solubility, bioavailibility, and efficacy of TQ against blood stages of Plasmodium parasites without a corresponding increase in toxicity. PMID:25759576

  13. Exogenous Insulin Enhances Glucose-Stimulated Insulin Response in Healthy Humans Independent of Changes in Free Fatty Acids

    PubMed Central

    Lopez, Ximena; Cypess, Aaron; Manning, Raquel; O'Shea, Sheila; Kulkarni, Rohit N.

    2011-01-01

    Context: Islet β-cells express both insulin receptors and insulin signaling proteins. Recent studies suggest insulin signaling is physiologically important for glucose sensing. Objective: Preexposure to insulin enhances glucose-stimulated insulin secretion (GSIS) in healthy humans. We evaluated whether the effect of insulin to potentiate GSIS is modulated through regulation of free fatty acids (FFA). Design and Setting: Subjects were studied on three occasions in this single-site study at an academic institution clinical research center. Patients: Subjects included nine healthy volunteers. Interventions: Glucose-induced insulin response was assessed on three occasions after 4 h saline (low insulin/sham) or isoglycemic-hyperinsulinemic (high insulin) clamps with or without intralipid and heparin infusion, using B28 Asp-insulin that could be distinguished from endogenous insulin immunologically. During the last 80 min of all three clamps, additional glucose was administered to stimulate insulin secretion (GSIS) with glucose concentrations maintained at similar concentrations during all studies. Main Outcome Measure: β-Cell response to glucose stimulation was assessed. Results: Preexposure to exogenous insulin increased the endogenous insulin-secretory response to glucose by 32% compared with sham clamp (P = 0.001). This was accompanied by a drop in FFA during hyperinsulinemic clamp compared with the sham clamp (0.06 ± 0.02 vs. 0.60 ± 0.09 mEq/liter, respectively), which was prevented during the hyperinsulinemic clamp with intralipid/heparin infusion (1.27 ± 0.17 mEq/liter). After preexposure to insulin with intralipid/heparin infusion to maintain FFA concentration, GSIS was 21% higher compared with sham clamp (P < 0.04) and similar to preexposure to insulin without intralipid/heparin (P = 0.2). Conclusions: Insulin potentiates glucose-stimulated insulin response independent of FFA concentrations in healthy humans. PMID:21956413

  14. Lack of LCAT reduces the LPS-neutralizing capacity of HDL and enhances LPS-induced inflammation in mice.

    PubMed

    Petropoulou, Peristera-Ioanna; Berbée, Jimmy F P; Theodoropoulos, Vassilios; Hatziri, Aikaterini; Stamou, Panagiota; Karavia, Eleni A; Spyridonidis, Alexandros; Karagiannides, Iordanes; Kypreos, Kyriakos E

    2015-10-01

    HDL has important immunomodulatory properties, including the attenuation of lipopolysaccharide (LPS)-induced inflammatory response. As lecithin-cholesterol acyltransferase (LCAT) is a critical enzyme in the maturation of HDL we investigated whether LCAT-deficient (Lcat(-/-)) mice present an increased LPS-induced inflammatory response. LPS (100μg/kg body weight)-induced cytokine response in Lcat(-/-) mice was markedly enhanced and prolonged compared to wild-type mice. Importantly, reintroducing LCAT expression using adenovirus-mediated gene transfer reverted their phenotype to that of wild-type mice. Ex vivo stimulation of whole blood with LPS (1-100ng/mL) showed a similar enhanced pro-inflammatory phenotype. Further characterization in RAW 264.7 macrophages in vitro showed that serum and HDL, but not chylomicrons, VLDL or the lipid-free protein fraction of Lcat(-/-) mice, had a reduced capacity to attenuate the LPS-induced TNFα response. Analysis of apolipoprotein composition revealed that LCAT-deficient HDL lacks significant amounts of ApoA-I and ApoA-II and is primarily composed of ApoE, while HDL from Apoa1(-/-) mice is highly enriched in ApoE and ApoA-II. ApoA-I-deficiency did not affect the capacity of HDL to neutralize LPS, though Apoa1(-/-) mice showed a pronounced LPS-induced cytokine response. Additional immunophenotyping showed that Lcat(-/-) , but not Apoa1(-/-) mice, have markedly increased circulating monocyte numbers as a result of increased Cd11b(+)Ly6C(med) monocytes, whereas 'pro-inflammatory' Cd11b(+)Ly6C(hi) monocytes were reduced. In line with this observation, peritoneal macrophages of Lcat(-/-) mice showed a markedly dampened LPS-induced TNFα response. We conclude that LCAT-deficiency increases LPS-induced inflammation in mice due to reduced LPS-neutralizing capacity of immature discoidal HDL and increased monocyte number. PMID:26170061

  15. The use of betaine HCl to enhance dasatinib absorption in healthy volunteers with rabeprazole-induced hypochlorhydria.

    PubMed

    Yago, Marc R; Frymoyer, Adam; Benet, Leslie Z; Smelick, Gillian S; Frassetto, Lynda A; Ding, Xiao; Dean, Brian; Salphati, Laurent; Budha, Nageshwar; Jin, Jin Y; Dresser, Mark J; Ware, Joseph A

    2014-11-01

    Many orally administered, small-molecule, targeted anticancer drugs, such as dasatinib, exhibit pH-dependent solubility and reduced drug exposure when given with acid-reducing agents. We previously demonstrated that betaine hydrochloride (BHCl) can transiently re-acidify gastric pH in healthy volunteers with drug-induced hypochlorhydria. In this randomized, single-dose, three-way crossover study, healthy volunteers received dasatinib (100 mg) alone, after pretreatment with rabeprazole, and with 1500 mg BHCl after rabeprazole pretreatment, to determine if BHCl can enhance dasatinib absorption in hypochlorhydric conditions. Rabeprazole (20 mg b.i.d.) significantly reduced dasatinib Cmax and AUC0-∞ by 92 and 78%, respectively. However, coadministration of BHCl significantly increased dasatinib Cmax and AUC0-∞ by 15- and 6.7-fold, restoring them to 105 and 121%, respectively, of the control (dasatinib alone). Therefore, BHCl reversed the impact of hypochlorhydria on dasatinib drug exposure and may be an effective strategy to mitigate potential drug-drug interactions for drugs that exhibit pH-dependent solubility and are administered orally under hypochlorhydric conditions. PMID:25274610

  16. Alpha Linolenic Acid-enriched Diacylglycerol Enhances Postprandial Fat Oxidation in Healthy Subjects: A Randomized Double-blind Controlled Trail.

    PubMed

    Ando, Yasutoshi; Saito, Shinichiro; Oishi, Sachiko; Yamanaka, Nami; Hibi, Masanobu; Osaki, Noriko; Katsuragi, Yoshihisa

    2016-08-01

    Alpha linolenic acid-enriched diacylglycerol (ALA-DAG) reduces visceral fat area and body fat in rodents and humans compared to conventional triacylglycerol (TAG). Although ALA-DAG increases dietary fat utilization as energy in rodents, its effects in humans are not known. The present study was a randomized, placebo-controlled, double-blind, crossover intervention trial performed to clarify the effect of ALA-DAG on postprandial energy metabolism in humans. Nineteen healthy subjects participated in this study, and postprandial energy metabolism was evaluated using indirect calorimetry followed by 14-d repeated pre-consumption of TAG (rapeseed oil) as a control or ALA-DAG. As a primary outcome, ALA-DAG induced significantly higher postprandial fat oxidation than TAG. As a secondary outcome, carbohydrate oxidation tended to be decreased. In addition, postprandial energy expenditure was significantly increased by ALA-DAG compared to TAG. These findings suggest that daily ALA-DAG consumption stimulates dietary fat utilization as energy after a meal, as well as greater diet induced thermogenesis in healthy humans. In conclusion, repeated consumption of ALA-DAG enhanced postprandial fat metabolism after a meal, which may partially explain its visceral fat area-reducing effect. PMID:27430386

  17. Surface-enhanced Raman scattering from living cells: from differentiating healthy and cancerous cell to cytotoxicity assessment

    NASA Astrophysics Data System (ADS)

    Kuku, Gamze; Sarıçam, Melike; Mert, Sevda; ćulha, Mustafa

    2015-05-01

    There is an ongoing effort to obtain molecular level information from living cells using surface-enhanced Raman scattering (SERS) not only to understand changes of cellular processes upon exposure to external stimuli but also to decide the status of cells; whether they are healthy or abnormal. In our research effort, we investigate how much information can be obtained from living cells to use for decision making about the cellular processes using SERS. The undertaken studies include cytotoxicity assessment of the nanomaterials and differentiation of the healthy and cancer cells. In the first case, A549 (lung cancer) and HDF (human dermal fibroblast) cells were incubated with 50 nm gold nanoparticles (AuNP) and exposed to three different nanoparticles (Zinc oxide nanoparticles (ZnO NPs), titanium dioxide nanoparticles (TiO2) and single walled carbon nanotubes (SWCNTs)) to perform SERS analysis and track the cellular response to these nanomaterials (NMs). After the principal component analysis on the spectral data, it was shown that the NPs exposed samples could be differentiated through SERS. In the second case, SERS spectra obtained from human kidney adenocarcinoma (ACHN), human kidney carcinoma (A-498) and non-cancerous human kidney embryonic cells (HEK 293) were used to diagnose metastatic, primary and non-cancerous cell lines. Linear discriminant analysis (LDA) based on principal component analysis (PCA) was applied to collected multidimensional SERS spectral data set to differentiate three different cell lines.

  18. The Impact of Lactobacillus plantarum WCFS1 Teichoic Acid D-Alanylation on the Generation of Effector and Regulatory T-cells in Healthy Mice

    PubMed Central

    Smelt, Maaike J.; de Haan, Bart J.; Bron, Peter A.; van Swam, Iris; Meijerink, Marjolein; Wells, Jerry M.; Kleerebezem, Michiel; Faas, Marijke M.; de Vos, Paul

    2013-01-01

    To date it remains unclear how probiotics affect the immune system. Bacterial envelope components may play an essential role, as these are the first to establish bacterial-host cell interactions. Teichoic acids (TAs), and especially lipoteichoic acids, are the most pro-inflammatory components of the gram-positive bacterial envelope. This effect is dependent on D-alanyl substitution of the TA backbone and interactions with TLR2 on host cells. Although the pro-inflammatory properties of TAs have been established in vitro, it remains unclear how TAs affect immunomodulation in vivo. In this study, we investigated the role of TA D-alanylation on L. plantarum–induced intestinal and systemic immunomodulation in vivo. For this, we compared the effect of L. plantarum WCFS1 and its TA D-Alanylation negative derivative (dltX-D) on the distribution of dendritic cell and T cell populations and responses in healthy mice. We demonstrated that the majority of the L. plantarum-induced in vivo immunomodulatory effects were dependent on D-alanylation (D-Ala), as some L. plantarum WCFS1-induced immune changes were not observed in the dltX-D-treated group and some were only observed after treatment with dltX-D. Strikingly, not only pro-inflammatory immune responses were abolished in the absence of D-Ala substitution, but also anti-inflammatory responses, such as the L. plantarum-induced generation of regulatory T cells in the spleen. With this study we provide insight in host-microbe interactions, by demonstrating the involvement of D-alanylation of TAs on the bacterial membrane in intestinal and systemic immunomodulation in healthy mice. PMID:23646181

  19. Gintonin enhances performance of mice in rotarod test: Involvement of lysophosphatidic acid receptors and catecholamine release.

    PubMed

    Lee, Byung-Hwan; Kim, Jisu; Lee, Ra Mi; Choi, Sun-Hye; Kim, Hyeon-Joong; Hwang, Sung-Hee; Lee, Myung Koo; Bae, Chun-Sik; Kim, Hyoung-Chun; Rhim, Hyewon; Lim, Kiwon; Nah, Seung-Yeol

    2016-01-26

    Ginseng has a long history of use as a tonic for restoration of vigor. One example of ginseng-derived tonic effect is that it can improve physical stamina under conditions of stress. However, the active ingredient and the underlying molecular mechanism responsible for the ergogenic effect are unknown. Recent studies show that ginseng contains a novel ingredient, gintonin, which consists of a unique class of herbal-medicine lysophosphatidic acids (LPAs). Gintonin activates G protein-coupled LPA receptors to produce a transient [Ca(2+)]i signal, which is coupled to diverse intra- and inter-cellular signal transduction pathways that stimulate hormone or neurotransmitter release. However, relatively little is known about how gintonin-mediated cellular modulation is linked to physical endurance. In the present study, systemic administration of gintonin, but not ginsenosides, in fasted mice increased blood glucose concentrations in a dose-dependent manner. Gintonin treatment elevated blood glucose to a maximum level after 30min. This elevation in blood glucose level could be abrogated by the LPA1/3 receptor antagonist, Ki16425, or the β-adrenergic receptor antagonist, propranolol. Furthermore, gintonin-dependent enhanced performance of fasted mice in rotarod test was likewise abrogated by Ki16425. Gintonin also elevated plasma epinephrine and norepinephrine concentrations. The present study shows that gintonin mediates catecholamine release through activation of the LPA receptor and that activation of the β-adrenergic receptor is coupled to liver glycogenolysis, thereby increasing the supply of glucose and enhancing performance in the rotarod test. Thus, gintonin acts via the LPA-catecholamine-glycogenolysis axis, representing a candidate mechanism that can explain how ginseng treatment enhances physical stamina. PMID:26706688

  20. Enhancing language performance with non-invasive brain stimulation--a transcranial direct current stimulation study in healthy humans.

    PubMed

    Sparing, Roland; Dafotakis, Manuel; Meister, Ingo G; Thirugnanasambandam, Nivethida; Fink, Gereon R

    2008-01-15

    In humans, transcranial direct current stimulation (tDCS) can be used to induce, depending on polarity, increases or decreases of cortical excitability by polarization of the underlying brain tissue. Cognitive enhancement as a result of tDCS has been reported. The purpose of this study was to test whether weak tDCS (current density, 57 microA/cm(2)) can be used to modify language processing. Fifteen healthy subjects performed a visual picture naming task before, during and after tDCS applied over the posterior perisylvian region (PPR), i.e. an area which includes Wernicke's area [BA 22]. Four different sessions were carried out: (1) anodal and (2) cathodal stimulation of left PPR and, for control, (3) anodal stimulation of the homologous region of the right hemisphere and (4) sham stimulation. We found that subjects responded significantly faster following anodal tDCS to the left PPR (p<0.01). No decreases in performance were detected. Our finding of a transient improvement in a language task following the application of tDCS together with previous studies which investigated the modulation of picture naming latency by transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS) suggest that tDCS applied to the left PPR (including Wernicke's area [BA 22]) can be used to enhance language processing in healthy subjects. Whether this safe, low cost, and easy to use brain stimulation technique can be used to ameliorate deficits of picture naming in aphasic patients needs further investigations. PMID:17804023

  1. Potentials and limits to enhance cognitive functions in healthy and pathological aging by tDCS.

    PubMed

    Prehn, Kristin; Flöel, Agnes

    2015-01-01

    Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that is increasingly used in research and clinical settings to enhance the effects of cognitive training. In our present review, we will first summarize studies using tDCS alone and in combination with cognitive training in older adults and patients with Alzheimer's dementia (AD). We will also review one study (Meinzer et al., 2014c) that showed an improvement in cognitive performance during anodal tDCS over the left inferior frontal cortex in patients with mild cognitive impairment (MCI) which is regarded as a prodromal stage of AD. Although promising short-term results have been reported, evidence from randomized controlled trials (RCTs) with sufficient sample sizes is scarce. In addition, stimulation protocols (in terms of intensity, duration, and repetition of stimulation) that lead to sustained improvements in outcome measures relevant for daily life still remain to be established. Following, we will discuss modulating factors such as technical parameters as well as the question whether there are specific cognitive functions (e.g., learning, memory consolidation, executive control) which are more amenable to tDCS enhancement than others. Finally, we will highlight future directions and limitations in this field and emphasize the need to conduct RCTs to establish efficacy of interventions for activities of daily life for a given patient population. PMID:26441526

  2. Potentials and limits to enhance cognitive functions in healthy and pathological aging by tDCS

    PubMed Central

    Prehn, Kristin; Flöel, Agnes

    2015-01-01

    Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that is increasingly used in research and clinical settings to enhance the effects of cognitive training. In our present review, we will first summarize studies using tDCS alone and in combination with cognitive training in older adults and patients with Alzheimer’s dementia (AD). We will also review one study (Meinzer et al., 2014c) that showed an improvement in cognitive performance during anodal tDCS over the left inferior frontal cortex in patients with mild cognitive impairment (MCI) which is regarded as a prodromal stage of AD. Although promising short-term results have been reported, evidence from randomized controlled trials (RCTs) with sufficient sample sizes is scarce. In addition, stimulation protocols (in terms of intensity, duration, and repetition of stimulation) that lead to sustained improvements in outcome measures relevant for daily life still remain to be established. Following, we will discuss modulating factors such as technical parameters as well as the question whether there are specific cognitive functions (e.g., learning, memory consolidation, executive control) which are more amenable to tDCS enhancement than others. Finally, we will highlight future directions and limitations in this field and emphasize the need to conduct RCTs to establish efficacy of interventions for activities of daily life for a given patient population. PMID:26441526

  3. Trehalose dimycolate enhances survival of fission neutron-irradiated mice and Klebsiella pneumoniae-challenged irradiated mice

    SciTech Connect

    McChesney, D.G.; Ledney, G.D.; Madonna, G.S. )

    1990-01-01

    The survival of B6D2F1 female mice exposed to lethal doses of fission neutron radiation is increased when trehalose dimycolate (TDM) preparations are given either 1 h after exposure or 1 day before exposure to radiation. TDM in an emulsion of squalene, Tween 80, and saline was the most effective formulation for increasing the 30-day survival of mice when given 1 day before (90%) or 1 h after (88%) exposure to radiation. An aqueous suspension of a synthetic analog of TDM was less effective at increasing 30-day survival (60%) when given 1 day prior to radiation exposure and not effective when given 1 h after radiation. Mice receiving a sublethal dose (3.5 Gy) of fission neutron radiation and either the TDM emulsion or synthetic TDM 1 h after irradiation were substantially more resistant to challenge with 10, 100, 1000, or 5000 times the LD50/30 dose of Klebsiella pneumoniae than untreated mice.

  4. Enhanced expression of Nrf2 in mice attenuates the fatty liver produced by a methionine- and choline-deficient diet

    SciTech Connect

    Zhang, Yu-Kun Jennifer; Yeager, Ronnie L.; Tanaka, Yuji; Klaassen, Curtis D.

    2010-06-15

    Oxidative stress has been proposed as an important promoter of the progression of fatty liver diseases. The current study investigates the potential functions of the Nrf2-Keap1 signaling pathway, an important hepatic oxidative stress sensor, in a rodent fatty liver model. Mice with no (Nrf2-null), normal (wild type, WT), and enhanced (Keap1 knockdown, K1-kd) expression of Nrf2 were fed a methionine- and choline-deficient (MCD) diet or a control diet for 5 days. Compared to WT mice, the MCD diet-caused hepatosteatosis was more severe in the Nrf2-null mice and less in the K1-kd mice. The Nrf2-null mice had lower hepatic glutathione and exhibited more lipid peroxidation, whereas the K1-kd mice had the highest amount of glutathione in the liver and developed the least lipid peroxidation among the three genotypes fed the MCD diet. The Nrf2 signaling pathway was activated by the MCD diet, and the Nrf2-targeted cytoprotective genes Nqo1 and Gst{alpha}1/2 were induced in WT and even more in K1-kd mice. In addition, Nrf2-null mice on both control and MCD diets exhibited altered expression profiles of fatty acid metabolism genes, indicating Nrf2 may influence lipid metabolism in liver. For example, mRNA levels of long chain fatty acid translocase CD36 and the endocrine hormone Fgf21 were higher in livers of Nrf2-null mice and lower in the K1-kd mice than WT mice fed the MCD diet. Taken together, these observations indicate that Nrf2 could decelerate the onset of fatty livers caused by the MCD diet by increasing hepatic antioxidant and detoxification capabilities.

  5. Enhanced expression of Nrf2 in mice attenuates the fatty liver produced by a methionine- and choline-deficient diet☆

    PubMed Central

    Zhang, Yu-Kun Jennifer; Yeager, Ronnie L.; Tanaka, Yuji; Klaassen, Curtis D.

    2011-01-01

    Oxidative stress has been proposed as an important promoter of the progression of fatty liver diseases. The current study investigates the potential functions of the Nrf2–Keap1 signaling pathway, an important hepatic oxidative stress sensor, in a rodent fatty liver model. Mice with no (Nrf2-null), normal (wild type, WT), and enhanced (Keap1 knockdown, K1-kd) expression of Nrf2 were fed a methionine- and choline-deficient (MCD) diet or a control diet for 5 days. Compared to WT mice, the MCD diet-caused hepatosteatosis was more severe in the Nrf2-null mice and less in the K1-kd mice. The Nrf2-null mice had lower hepatic glutathione and exhibited more lipid peroxidation, whereas the K1-kd mice had the highest amount of glutathione in the liver and developed the least lipid peroxidation among the three genotypes fed the MCD diet. The Nrf2 signaling pathway was activated by the MCD diet, and the Nrf2-targeted cytoprotective genes Nqo1 and Gstα1/2 were induced in WT and even more in K1-kd mice. In addition, Nrf2-null mice on both control and MCD diets exhibited altered expression profiles of fatty acid metabolism genes, indicating Nrf2 may influence lipid metabolism in liver. For example, mRNA levels of long chain fatty acid translocase CD36 and the endocrine hormone Fgf21 were higher in livers of Nrf2-null mice and lower in the K1-kd mice than WT mice fed the MCD diet. Taken together, these observations indicate that Nrf2 could decelerate the onset of fatty livers caused by the MCD diet by increasing hepatic antioxidant and detoxification capabilities. PMID:20350562

  6. Conditional deletion of cardiomyocyte peroxisome proliferator-activated receptor γ enhances myocardial ischemia-reperfusion injury in mice.

    PubMed

    Hobson, Michael J; Hake, Paul W; O'Connor, Michael; Schulte, Christine; Moore, Victoria; James, Jeanne M; Piraino, Giovanna; Zingarelli, Basilia

    2014-01-01

    The nuclear transcription factor peroxisome proliferator-activated receptor γ (PPARγ) is a key regulator of the inflammatory response to an array of biologic insults. We have previously demonstrated that PPARγ ligands reduce myocardial ischemia-reperfusion injury in rodents. In the current study, we directly determined the role of cardiomyocyte PPARγ in ischemia-reperfusion injury, using a model of conditional cardiomyocyte-specific deletion of PPARγ in vivo. In mice, α-myosin heavy chain-restricted Cre-mediated PPARγ deficiency was induced by tamoxifen treatment (30 mg/kg intraperitoneally) for 4 days (PPARγ mice), whereas controls included mice treated with the oil diluent vehicle (PPARγ mice). Western blot and histochemical analyses confirmed that expression of PPARγ protein was abolished in cardiomyocytes of mice treated with tamoxifen, but not with vehicle. After tamoxifen or vehicle treatment, animals were subjected to 30-min ligation of the left anterior descending coronary artery followed by 2-h reperfusion. In PPARγ mice, myocardial ischemia and reperfusion induced extensive myocardial damage, which was associated with elevated tissue activity of myeloperoxidase, indicating infiltration of neutrophils, and elevated plasma levels of troponin I when compared with PPARγ mice. Upon echocardiographic analysis, PPARγ mice also demonstrated ventricular dilatation and systolic dysfunction. Plasma levels of the proinflammatory cytokines interleukin 1β and interleukin 6 were higher in PPARγ mice when compared with PPARγ mice. These pathological events in PPARγ mice were associated with enhanced nuclear factor κB DNA binding in the infarcted hearts. Thus, our data suggest that cardiomyocyte PPARγ is a crucial protective receptor and may prevent reperfusion injury by modulating mechanisms of inflammation. PMID:24089001

  7. Conditional deletion of cardiomyocyte peroxisome proliferator-activated receptor-γ enhances myocardial ischemia-reperfusion injury in mice

    PubMed Central

    Hobson, Michael J.; Hake, Paul W.; O’Connor, Michael; Schulte, Christine; Moore, Victoria; James, Jeanne M.; Piraino, Giovanna; Zingarelli, Basilia

    2013-01-01

    The nuclear transcription factor peroxisome proliferator-activated receptor-γ (PPARγ) is a key regulator of the inflammatory response to an array of biologic insults. We have previously demonstrated that PPARγ ligands reduce myocardial ischemia-reperfusion injury in rodents. In the current study, we directly determined the role of cardiomyocyte PPARγ in ischemia-reperfusion injury, employing a model of conditional cardiomyocyte-specific deletion of PPARγ in vivo. In mice, α-myosin heavy chain-restricted Cre-mediated PPARγ deficiency was induced by tamoxifen treatment (30 mg/kg intraperitoneally) for 4 days (PPARγ−/− mice); whereas controls included mice treated with the oil diluent vehicle (PPARγ+/+ mice). Western blot and histochemical analyses confirmed that expression of PPARγ protein was abolished in cardiomyocytes of mice treated with tamoxifen, but not with vehicle. After tamoxifen or vehicle treatment, animals were subjected to 30 min ligation of the left anterior descending coronary artery followed by 2 hrs reperfusion. In PPARγ−/− mice, myocardial ischemia and reperfusion induced extensive myocardial damage, which was associated with elevated tissue activity of myeloperoxidase, indicating infiltration of neutrophils, and elevated plasma levels of troponin-I when compared to PPARγ+/+ mice. PPARγ−/− mice also demonstrated ventricular dilatation and systolic dysfunction upon echocardiographic analysis. Plasma levels of the pro-inflammatory cytokines interleukin-1β and interleukin-6 were higher in PPARγ−/− mice when compared to PPARγ+/+ mice. These pathological events in PPARγ−/− mice were associated with enhanced nuclear factor-κB DNA binding in the infarcted hearts. Thus, our data suggests that cardiomyocyte PPARγ is a crucial protective receptor and may prevent reperfusion injury by modulating mechanisms of inflammation. PMID:24089001

  8. Monocyte/macrophage androgen receptor suppresses cutaneous wound healing in mice by enhancing local TNF-alpha expression.

    PubMed

    Lai, Jiann-Jyh; Lai, Kuo-Pao; Chuang, Kuang-Hsiang; Chang, Philip; Yu, I-Chen; Lin, Wen-Jye; Chang, Chawnshang

    2009-12-01

    Cutaneous wounds heal more slowly in elderly males than in elderly females, suggesting a role for sex hormones in the healing process. Indeed, androgen/androgen receptor (AR) signaling has been shown to inhibit cutaneous wound healing. AR is expressed in several cell types in healing skin, including keratinocytes, dermal fibroblasts, and infiltrating macrophages, but the exact role of androgen/AR signaling in these different cell types remains unclear. To address this question, we generated and studied cutaneous wound healing in cell-specific AR knockout (ARKO) mice. General and myeloid-specific ARKO mice exhibited accelerated wound healing compared with WT mice, whereas keratinocyte- and fibroblast-specific ARKO mice did not. Importantly, the rate of wound healing in the general ARKO mice was dependent on AR and not serum androgen levels. Interestingly, although dispensable for wound closure, keratinocyte AR promoted re-epithelialization, while fibroblast AR suppressed it. Further analysis indicated that AR suppressed wound healing by enhancing the inflammatory response through a localized increase in TNF-alpha expression. Furthermore, AR enhanced local TNF-alpha expression via multiple mechanisms, including increasing the inflammatory monocyte population, enhancing monocyte chemotaxis by upregulating CCR2 expression, and enhancing TNF-alpha expression in macrophages. Finally, targeting AR by topical application of a compound (ASC-J9) that degrades AR protein resulted in accelerated healing, suggesting a potential new therapeutic approach that may lead to better treatment of wound healing. PMID:19907077

  9. Cell and tissue distribution of synthetic oligonucleotides in healthy and tumor-bearing nude mice. An autoradiographic, immunohistological, and direct fluorescence microscopy study.

    PubMed Central

    Plenat, F.; Klein-Monhoven, N.; Marie, B.; Vignaud, J. M.; Duprez, A.

    1995-01-01

    Antisense oligonucleotides have the ability to inhibit individual gene expression in the potential treatment of cancer and viral diseases. However, the way parenterally administered oligonucleotides distribute themselves into healthy tissues or tumors is poorly understood. In this study, the cell and tissue distribution of two modified or unmodified phosphodiester pentadeca-beta-oligonucleotides intravenously administered to healthy or tumor-bearing nude mice was assessed by autoradiography as well as by direct fluorescence and immunoenzymatic histological methods. Resistance of oligonucleotides to degradation by nuclease activity was previously studied in vitro. Using these methods we were able to show the following: 1) within minutes, oligonucleotides permeate all cells and tissues with the exceptions of erythrocytes and intervertebral discs; 2) cell and tissue distribution does not depend on the sequence of the given oligonucleotide; 3) concentration of oligonucleotides is higher within the connective tissue cells than in the interstitial matrix; 4) after uptake, oligomers partition throughout all of the cellular compartments, including at the highest intracellular concentrations in the nuclei; 5) oligonucleotides penetrate easily the tumor cell compartments, oligonucleotide diffusion being unimpeded by the extracellular matrix. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 PMID:7604874

  10. A2B Adenosine Receptor Blockade Enhances Macrophage-Mediated Bacterial Phagocytosis and Improves Polymicrobial Sepsis Survival in Mice

    PubMed Central

    Belikoff, Bryan G.; Hatfield, Stephen; Georgiev, Peter; Ohta, Akio; Lukashev, Dmitriy; Buras, Jon A.; Remick, Daniel G.; Sitkovsky, Michail

    2013-01-01

    Antimicrobial treatment strategies must improve to reduce the high mortality rates in septic patients. In noninfectious models of acute inflammation, activation of A2B adenosine receptors (A2BR) in extracellular adenosine-rich microenvironments causes immunosuppression. We examined A2BR in antibacterial responses in the cecal ligation and puncture (CLP) model of sepsis. Antagonism of A2BR significantly increased survival, enhanced bacterial phagocytosis, and decreased IL-6 and MIP-2 (a CXC chemokine) levels after CLP in outbred (ICR/CD-1) mice. During the CLP-induced septic response in A2BR knockout mice, hemodynamic parameters were improved compared with wild-type mice in addition to better survival and decreased plasma IL-6 levels. A2BR deficiency resulted in a dramatic 4-log reduction in peritoneal bacteria. The mechanism of these improvements was due to enhanced macrophage phagocytic activity without augmenting neutrophil phagocytosis of bacteria. Following ex vivo LPS stimulation, septic macrophages from A2BR knockout mice had increased IL-6 and TNF-α secretion compared with wild-type mice. A therapeutic intervention with A2BR blockade was studied by using a plasma biomarker to direct therapy to those mice predicted to die. Pharmacological blockade of A2BR even 32 h after the onset of sepsis increased survival by 65% in those mice predicted to die. Thus, even the late treatment with an A2BR antagonist significantly improved survival of mice (ICR/CD-1) that were otherwise determined to die according to plasma IL-6 levels. Our findings of enhanced bacterial clearance and host survival suggest that antagonism of A2BRs offers a therapeutic target to improve macrophage function in a late treatment protocol that improves sepsis survival. PMID:21242513

  11. n-3 polyunsaturated fatty acids supplementation enhances hippocampal functionality in aged mice

    PubMed Central

    Cutuli, Debora; De Bartolo, Paola; Caporali, Paola; Laricchiuta, Daniela; Foti, Francesca; Ronci, Maurizio; Rossi, Claudia; Neri, Cristina; Spalletta, Gianfranco; Caltagirone, Carlo; Farioli-Vecchioli, Stefano; Petrosini, Laura

    2014-01-01

    As major components of neuronal membranes, omega-3 polyunsaturated acids (n-3 PUFA) exhibit a wide range of regulatory functions, modulating from synaptic plasticity to neuroinflammation, from oxidative stress to neuroprotection. Recent human and animal studies indicated the n-3 PUFA neuroprotective properties in aging, with a clear negative correlation between n-3 PUFA levels and hippocampal deficits. The present multidimensional study was aimed at associating cognition, hippocampal neurogenesis, volume, neurodegeneration and metabolic correlates to verify n-3 PUFA neuroprotective effects in aging. To this aim 19 month-old mice were given n-3 PUFA mixture, or olive oil or no dietary supplement for 8 weeks during which hippocampal-dependent mnesic functions were tested. At the end of behavioral testing morphological and metabolic correlates were analyzed. n-3 PUFA supplemented aged mice exhibited better object recognition memory, spatial and localizatory memory, and aversive response retention, without modifications in anxiety levels in comparison to controls. These improved hippocampal cognitive functions occurred in the context of an enhanced cellular plasticity and a reduced neurodegeneration. In fact, n-3 PUFA supplementation increased hippocampal neurogenesis and dendritic arborization of newborn neurons, volume, neuronal density and microglial cell number, while it decreased apoptosis, astrocytosis and lipofuscin accumulation in the hippocampus. The increased levels of some metabolic correlates (blood Acetyl-L-Carnitine and brain n-3 PUFA concentrations) found in n-3 PUFA supplemented mice also pointed toward an effective neuroprotection. On the basis of the present results n-3 PUFA supplementation appears to be a useful tool in health promotion and cognitive decline prevention during aging. PMID:25202271

  12. Nitration of β-Lactoglobulin but Not of Ovomucoid Enhances Anaphylactic Responses in Food Allergic Mice

    PubMed Central

    Diesner, Susanne C.; Schultz, Cornelia; Ackaert, Chloé; Oostingh, Gertie J.; Ondracek, Anna; Stremnitzer, Caroline; Singer, Josef; Heiden, Denise; Roth-Walter, Franziska; Fazekas, Judit; Assmann, Vera E.; Jensen-Jarolim, Erika; Stutz, Hanno; Duschl, Albert; Untersmayr, Eva

    2015-01-01

    Background We revealed in previous studies that nitration of food proteins reduces the risk of de novo sensitization in a murine food allergy model. In contrast, in situations with preformed specific IgE antibodies, in vitro experiments suggested an increased capacity of effector cell activation by nitrated food proteins. Objective The aim of this study was to investigate the influence of protein nitration on the effector phase of food allergy. Design BALB/c mice were immunized intraperitoneally (i.p.) with the milk allergen β-lactoglobulin (BLG) or the egg allergen ovomucoid (OVM), followed by intragastric (i.g.) gavages to induce a strong local inflammatory response and allergen-specific antibodies. Subsequently, naïve and allergic mice were intravenously (i.v.) challenged with untreated, sham-nitrated or nitrated BLG or OVM. Anaphylaxis was monitored by measuring core body temperature and determination of mouse mast cell protease-1 (mMCP-1) levels in blood. Results A significant drop of body temperature accompanied with significantly elevated concentrations of the anaphylaxis marker mMCP-1 were only observed in BLG allergic animals challenged with nitrated BLG and not in OVM allergic mice challenged with nitrated OVM. SDS-PAGE and circular dichroism analysis of the differentially modified allergens revealed an effect of nitration on the secondary protein structure exclusively for BLG together with enhanced protein aggregation. Conclusion Our data suggest that nitration affects differently the food allergens BLG and OVM. In the case of BLG, structural changes favored dimerization possibly explaining the increased anaphylactic reactivity in BLG allergic animals. PMID:25955653

  13. Dual Inhibition of Endocannabinoid Catabolic Enzymes Produces Enhanced Antiwithdrawal Effects in Morphine-Dependent Mice

    PubMed Central

    Ramesh, Divya; Gamage, Thomas F; Vanuytsel, Tim; Owens, Robert A; Abdullah, Rehab A; Niphakis, Micah J; Shea-Donohue, Terez; Cravatt, Benjamin F; Lichtman, Aron H

    2013-01-01

    Inhibition of the endocannabinoid catabolic enzymes, monoacylglycerol lipase (MAGL) or fatty acid amide hydrolase (FAAH) attenuates naloxone-precipitated opioid withdrawal signs in mice via activation of CB1 receptors. Complete FAAH inhibition blocks only a subset of withdrawal signs, whereas complete MAGL inhibition elicits enhanced antiwithdrawal efficacy, but is accompanied with some cannabimimetic side effects. Thus, the primary objective of the present study was to determine whether combined, full FAAH inhibition and partial MAGL represents an optimal strategy to reduce opioid withdrawal. To test this hypothesis, we examined whether combined administration of high-dose of the FAAH inhibitor PF-3845 and low-dose of the MAGL inhibitor JZL184, as well as the novel dual FAAH-MAGL inhibitor SA-57, which is 100-fold more potent in inhibiting FAAH than MAGL, would prevent spontaneous withdrawal in morphine-dependent mice, a model with greater face validity than precipitating withdrawal with μ-opioid receptor antagonists. Strikingly, a combination of low-dose JZL184 and high-dose PF-3845 as well as the dual inhibitor SA-57 reduced all abrupt withdrawal signs (ie, platform jumping, paw flutters, head shakes, diarrhea, and total body weight loss), but did not elicit any cannabimimetic side effects. In addition, JZL184 or PF-3845 blocked naloxone-precipitated hypersecretion in morphine-dependent small intestinal tissue. Collectively, these results are the first to show that endocannabinoid catabolic enzyme inhibitors reduce abrupt withdrawal in morpine-dependent mice and are effective in a novel in vitro model of opioid withdrawal. More generally, these findings support the idea that joint MAGL and FAAH inhibition represents a promising approach for the treatment of opioid dependence. PMID:23303065

  14. Healthy Water, Healthy People.

    ERIC Educational Resources Information Center

    Etgen, John

    2002-01-01

    Describes a hands-on activity, Hitting the Mark, which is found in the "Healthy Water, Healthy People Water Quality Educators Guide" in terms of its objectives, materials, background, procedures, activities, and assessment. (KHR)

  15. Attenuating GABAA Receptor Signaling in Dopamine Neurons Selectively Enhances Reward Learning and Alters Risk Preference in Mice

    PubMed Central

    Parker, Jones G.; Wanat, Matthew J.; Soden, Marta E.; Ahmad, Kinza; Zweifel, Larry S.; Bamford, Nigel S.; Palmiter, Richard D.

    2011-01-01

    Phasic dopamine transmission encodes the value of reward-predictive stimuli and influences both learning and decision-making. Altered dopamine signaling is associated with psychiatric conditions characterized by risky choices such as pathological gambling. These observations highlight the importance of understanding how dopamine neuron activity is modulated. While excitatory drive onto dopamine neurons is critical for generating phasic dopamine responses, emerging evidence suggests that inhibitory signaling also modulates these responses. To address the functional importance of inhibitory signaling in dopamine neurons, we generated mice lacking the β3 subunit of the GABAA receptor specifically in dopamine neurons (β3-KO mice) and examined their behavior in tasks that assessed appetitive learning, aversive learning, and risk preference. Dopamine neurons in midbrain slices from β3-KO mice exhibited attenuated GABA-evoked inhibitory post-synaptic currents. Furthermore, electrical stimulation of excitatory afferents to dopamine neurons elicited more dopamine release in the nucleus accumbens of β3-KO mice as measured by fast-scan cyclic voltammetry. β3-KO mice were more active than controls when given morphine, which correlated with potential compensatory upregulation of GABAergic tone onto dopamine neurons. β3-KO mice learned faster in two food-reinforced learning paradigms, but extinguished their learned behavior normally. Enhanced learning was specific for appetitive tasks, as aversive learning was unaffected in β3-KO mice. Finally, we found that β3-KO mice had enhanced risk preference in a probabilistic selection task that required mice to choose between a small certain reward and a larger uncertain reward. Collectively, these findings identify a selective role for GABAA signaling in dopamine neurons in appetitive learning and decision-making. PMID:22114279

  16. FOXN1 recombinant protein enhances T-cell regeneration after hematopoietic stem cell transplantation in mice.

    PubMed

    Song, Yinhong; Su, Min; Zhu, Jing; Di, Wen; Liu, Yalan; Hu, Rong; Rood, Debra; Lai, Laijun

    2016-06-01

    A prolonged period of T-cell recovery is the major challenge in hematopoietic stem cell transplantation (HSCT). Thymic epithelial cells (TECs) are the major component of the thymic microenvironment for T-cell generation. However, TECs undergo degeneration over time. FOXN1 plays a critical role in TEC development and is required to maintain adult TECs for thymopoiesis. To investigate the potential application of FOXN1, we have cloned and expressed recombinant FOXN1 protein (rFOXN1) that was fused with cell-penetrating peptides. We show here that the rFOXN1 protein can translocate from the cell surface into the cytoplasm and nucleus. Administration of rFOXN1 into both congenic and allogeneic HSCT recipient mice increased the number of TECs, resulting in enhanced thymopoiesis that led to an increased number of functional T cells in the periphery. The increased number of TECs is due to the enhanced survival and proliferation of TECs. Our results suggest that rFOXN1 has the potential to be used in enhancing T-cell regeneration in patients following HSCT. PMID:27125859

  17. High-resolution contrast-enhanced optical coherence tomography in mice retinae

    NASA Astrophysics Data System (ADS)

    Sen, Debasish; SoRelle, Elliott D.; Liba, Orly; Dalal, Roopa; Paulus, Yannis M.; Kim, Tae-Wan; Moshfeghi, Darius M.; de la Zerda, Adam

    2016-06-01

    Optical coherence tomography (OCT) is a noninvasive interferometric imaging modality providing anatomical information at depths of millimeters and a resolution of micrometers. Conventional OCT images limit our knowledge to anatomical structures alone, without any contrast enhancement. Therefore, here we have, for the first time, optimized an OCT-based contrast-enhanced imaging system for imaging single cells and blood vessels in vivo inside the living mouse retina at subnanomolar sensitivity. We used bioconjugated gold nanorods (GNRs) as exogenous OCT contrast agents. Specifically, we used anti-mouse CD45 coated GNRs to label mouse leukocytes and mPEG-coated GNRs to determine sensitivity of GNR detection in vivo inside mice retinae. We corroborated OCT observations with hyperspectral dark-field microscopy of formalin-fixed histological sections. Our results show that mouse leukocytes that otherwise do not produce OCT contrast can be labeled with GNRs leading to significant OCT intensity equivalent to a 0.5 nM GNR solution. Furthermore, GNRs injected intravenously can be detected inside retinal blood vessels at a sensitivity of ˜0.5 nM, and GNR-labeled cells injected intravenously can be detected inside retinal capillaries by enhanced OCT contrast. We envision the unprecedented resolution and sensitivity of functionalized GNRs coupled with OCT to be adopted for longitudinal studies of retinal disorders.

  18. Humanized θ-Defensins (Retrocyclins) Enhance Macrophage Performance and Protect Mice from Experimental Anthrax Infections▿

    PubMed Central

    Welkos, S.; Cote, C. K.; Hahn, U.; Shastak, O.; Jedermann, J.; Bozue, J.; Jung, G.; Ruchala, P.; Pratikhya, P.; Tang, T.; Lehrer, R. I.; Beyer, W.

    2011-01-01

    Retrocyclins are humanized versions of the θ-defensin peptides expressed by the leukocytes of several nonhuman primates. Previous studies, performed in serum-free media, determined that retrocyclins 1 (RC1) and RC2 could prevent successful germination of Bacillus anthracis spores, kill vegetative B. anthracis cells, and inactivate anthrax lethal factor. We now report that retrocyclins are extensively bound by components of native mouse, human, and fetal calf sera, that heat-inactivated sera show greatly enhanced retrocyclin binding, and that native and (especially) heat-inactivated sera greatly reduce the direct activities of retrocyclins against spores and vegetative cells of B. anthracis. Nevertheless, we also found that retrocyclins protected mice challenged in vivo by subcutaneous, intraperitoneal, or intranasal instillation of B. anthracis spores. Retrocyclin 1 bound extensively to B. anthracis spores and enhanced their phagocytosis and killing by murine RAW264.7 cells. Based on the assumption that spore-bound RC1 enters phagosomes by “piggyback phagocytosis,” model calculations showed that the intraphagosomal concentration of RC1 would greatly exceed its extracellular concentration. Murine alveolar macrophages took up fluorescently labeled retrocyclin, suggesting that macrophages may also acquire extracellular RC1 directly. Overall, these data demonstrate that retrocyclins are effective in vivo against experimental murine anthrax infections and suggest that enhanced macrophage function contributes to this property. PMID:21768520

  19. Humanized theta-defensins (retrocyclins) enhance macrophage performance and protect mice from experimental anthrax infections.

    PubMed

    Welkos, S; Cote, C K; Hahn, U; Shastak, O; Jedermann, J; Bozue, J; Jung, G; Ruchala, P; Pratikhya, P; Tang, T; Lehrer, R I; Beyer, W

    2011-09-01

    Retrocyclins are humanized versions of the -defensin peptides expressed by the leukocytes of several nonhuman primates. Previous studies, performed in serum-free media, determined that retrocyclins 1 (RC1) and RC2 could prevent successful germination of Bacillus anthracis spores, kill vegetative B. anthracis cells, and inactivate anthrax lethal factor. We now report that retrocyclins are extensively bound by components of native mouse, human, and fetal calf sera, that heat-inactivated sera show greatly enhanced retrocyclin binding, and that native and (especially) heat-inactivated sera greatly reduce the direct activities of retrocyclins against spores and vegetative cells of B. anthracis. Nevertheless, we also found that retrocyclins protected mice challenged in vivo by subcutaneous, intraperitoneal, or intranasal instillation of B. anthracis spores. Retrocyclin 1 bound extensively to B. anthracis spores and enhanced their phagocytosis and killing by murine RAW264.7 cells. Based on the assumption that spore-bound RC1 enters phagosomes by "piggyback phagocytosis," model calculations showed that the intraphagosomal concentration of RC1 would greatly exceed its extracellular concentration. Murine alveolar macrophages took up fluorescently labeled retrocyclin, suggesting that macrophages may also acquire extracellular RC1 directly. Overall, these data demonstrate that retrocyclins are effective in vivo against experimental murine anthrax infections and suggest that enhanced macrophage function contributes to this property. PMID:21768520

  20. Smaller Dendritic Spines, Weaker Synaptic Transmission, but Enhanced Spatial Learning in Mice Lacking Shank1

    PubMed Central

    Hung, Albert Y.; Futai, Kensuke; Sala, Carlo; Valtschanoff, Juli G.; Ryu, Jubin; Woodworth, Mollie A.; Kidd, Fleur L.; Sung, Clifford C.; Miyakawa, Tsuyoshi; Bear, Mark F.; Weinberg, Richard J.; Sheng, Morgan

    2009-01-01

    Experience-dependent changes in the structure of dendritic spines may contribute to learning and memory. Encoded by three genes, the Shank family of postsynaptic scaffold proteins are abundant and enriched in the postsynaptic density (PSD) of central excitatory synapses. When expressed in cultured hippocampal neurons, Shank promotes the maturation and enlargement of dendritic spines. Recently, Shank3 has been genetically implicated in human autism, suggesting an important role for Shank proteins in normal cognitive development. Here, we report the phenotype of Shank1 knock-out mice. Shank1 mutants showed altered PSD protein composition; reduced size of dendritic spines; smaller, thinner PSDs; and weaker basal synaptic transmission. Standard measures of synaptic plasticity were normal. Behaviorally, they had increased anxiety-related behavior and impaired contextual fear memory. Remarkably, Shank1-deficient mice displayed enhanced performance in a spatial learning task; however, their long-term memory retention in this task was impaired. These results affirm the importance of Shank1 for synapse structure and function in vivo, and they highlight a differential role for Shank1 in specific cognitive processes, a feature that may be relevant to human autism spectrum disorders. PMID:18272690

  1. Berberine enhances antidiabetic effects and attenuates untoward effects of canagliflozin in streptozotocin-induced diabetic mice.

    PubMed

    Tian, Cai-Ming; Jiang, Xin; Ouyang, Xiao-Xi; Zhang, Ya-Ou; Xie, Wei-Dong

    2016-07-01

    The present study aimed at determining whether berberine can enhance the antidiabetic effects and alleviate the adverse effects of canagliflozin in diabetes mellitus. Streptozotocin-induced diabetic mice were introduced, and the combined effects of berberine and canagliflozin on glucose metabolism and kidney functions were investigated. Our results showed that berberine combined with canagliflozin (BC) increased reduction of fasting and postprandial blood glucose, diet, and water intake compared with berberine or canagliflozin alone. Interestingly, BC showed greater decrease in blood urea nitrogen and creatinine levels and lower total urine glucose excretion than canagliflozin alone. In addition, BC showed increased phosphorylated 5' AMP-activated protein kinase (pAMPK) expression and decreased tumor necrosis factor alpha (TNFα) levels in kidneys, compared with berberine or canagliflozin alone. These results indicated that BC was a stronger antidiabetic than berberine or canagliflozin alone with less negative side effects on the kidneys in the diabetic mice. The antidiabetic effect was likely to be mediated by synergically promoting the expression of pAMPK and reducing the expression of TNFα in kidneys. The present study represented the first report that canagliflozin combined with berberine was a promising treatment for diabetes mellitus. The exact underlying mechanisms of action should be investigated in future studies. PMID:27507202

  2. Quantitative assessment of microvasculopathy in arcAβ mice with USPIO-enhanced gradient echo MRI

    PubMed Central

    Deistung, Andreas; Ielacqua, Giovanna D; Seuwen, Aline; Kindler, Diana; Schweser, Ferdinand; Vaas, Markus; Kipar, Anja; Reichenbach, Jürgen R; Rudin, Markus

    2015-01-01

    Magnetic resonance imaging employing administration of iron oxide-based contrast agents is widely used to visualize cellular and molecular processes in vivo. In this study, we investigated the ability of R2* and quantitative susceptibility mapping to quantitatively assess the accumulation of ultrasmall superparamagnetic iron oxide (USPIO) particles in the arcAβ mouse model of cerebral amyloidosis. Gradient-echo data of mouse brains were acquired at 9.4 T after injection of USPIO. Focal areas with increased magnetic susceptibility and R2* values were discernible across several brain regions in 12-month-old arcAβ compared to 6-month-old arcAβ mice and to non-transgenic littermates, indicating accumulation of particles after USPIO injection. This was concomitant with higher R2* and increased magnetic susceptibility differences relative to cerebrospinal fluid measured in USPIO-injected compared to non-USPIO-injected 12-month-old arcAβ mice. No differences in R2* and magnetic susceptibility were detected in USPIO-injected compared to non-injected 12-month-old non-transgenic littermates. Histological analysis confirmed focal uptake of USPIO particles in perivascular macrophages adjacent to small caliber cerebral vessels with radii of 2–8 µm that showed no cerebral amyloid angiopathy. USPIO-enhanced R2* and quantitative susceptibility mapping constitute quantitative tools to monitor such functional microvasculopathies. PMID:26661253

  3. Standardized Prunella vulgaris var. lilacina Extract Enhances Cognitive Performance in Normal Naive Mice.

    PubMed

    Park, Se Jin; Ahn, Young Je; Lee, Hyung Eun; Hong, Eunyoung; Ryu, Jong Hoon

    2015-11-01

    Adult hippocampal neurogenesis is closely associated with neuronal plasticity, cognitive function and the etiology of neurological diseases. We previously reported that the standardized ethanolic extract of Prunella vulgaris var. lilacina (EEPV) can be used for the prevention and treatment of cognitive impairments associated with Alzheimer's disease or schizophrenia. In the present study, we investigated the effects of EEPV on cognitive ability in normal naive mice and the underlying mechanism(s) governing these effects, including adult hippocampal neurogenesis. In the passive avoidance task, sub-chronic administration of EEPV (25 or 50 mg/kg, p.o.) for 14 days markedly induced the improvement of cognitive function in mice. In addition, sub-chronic administration of EEPV (25 or 50 mg/kg) for 14 days significantly increased neural cell proliferation and the number of immature neurons, but not newly generated cell survival, in the hippocampal dentate gyrus. Increased ERK, Akt and GSK-3β phosphorylation levels in the hippocampus were also observed after such administration. Our results indicate that EEPV may enhance cognitive function via the activation of various intracellular signaling molecules and the up-regulation of adult hippocampal neurogenesis. PMID:26376910

  4. Targeting β1-integrin signaling enhances regeneration in aged and dystrophic muscle in mice.

    PubMed

    Rozo, Michelle; Li, Liangji; Fan, Chen-Ming

    2016-08-01

    Interactions between stem cells and their microenvironment, or niche, are essential for stem cell maintenance and function. Our knowledge of the niche for the skeletal muscle stem cell, i.e., the satellite cell (SC), is incomplete. Here we show that β1-integrin is an essential niche molecule that maintains SC homeostasis, and sustains the expansion and self-renewal of this stem cell pool during regeneration. We further show that β1-integrin cooperates with fibroblast growth factor 2 (Fgf2), a potent growth factor for SCs, to synergistically activate their common downstream effectors, the mitogen-activated protein (MAP) kinase Erk and protein kinase B (Akt). Notably, SCs in aged mice show altered β1-integrin activity and insensitivity to Fgf2. Augmenting β1-integrin activity with a monoclonal antibody restores Fgf2 sensitivity and improves regeneration after experimentally induced muscle injury. The same treatment also enhances regeneration and function of dystrophic muscles in mdx mice, a model for Duchenne muscular dystrophy. Therefore, β1-integrin senses the SC niche to maintain responsiveness to Fgf2, and this integrin represents a potential therapeutic target for pathological conditions of the muscle in which the stem cell niche is compromised. PMID:27376575

  5. RNA Interference of Myocyte Enhancer Factor 2A Accelerates Atherosclerosis in Apolipoprotein E-Deficient Mice

    PubMed Central

    Zhao, Yu-xia; Liu, Gang-qiong; Zhang, Jin-ying

    2015-01-01

    Objective Myocyte enhancer factor-2A (MEF 2A) has been shown to be involved in atherosclerotic lesion development, but its role in preexisting lesions is still unclear. In the present study we aim to assess the role of MEF 2A in the progression of pre-existing atherosclerosis. Methods Eighty apolipoprotein E-deficient mice (APOE KO) were randomly allocated to control, scramble and MEF 2A RNA interference (RNAi) groups, and constrictive collars were used to induce plaque formation. Six weeks after surgery, lentiviral shRNA construct was used to silence the expression of MEF 2A. Carotid plaques were harvested for analysis 4 weeks after viral vector transduction. Inflammatory gene expression in the plasma and carotid plaques was determined by using ELISAs and real-time RT-PCR. Results The expression level of MEF 2A was significantly reduced in plasma and plaque in the RNAi group, compared to the control and NC groups, whereas the expression level of pro-inflammatory cytokines was markedly increased. Silencing MEF 2A using lentiviral shRNA significantly reduced the plaque collagen content and fibrous cap thickness, as well as increased plaque area. However, silencing MEF 2A had no obvious effect on plaque lipid content. Conclusions Lentivirus-mediated MEF 2A shRNA accelerates inflammation and atherosclerosis in APOE KO mice, but has no effect on lipoprotein levels in plasma. PMID:25793529

  6. Quantitative assessment of microvasculopathy in arcAβ mice with USPIO-enhanced gradient echo MRI.

    PubMed

    Klohs, Jan; Deistung, Andreas; Ielacqua, Giovanna D; Seuwen, Aline; Kindler, Diana; Schweser, Ferdinand; Vaas, Markus; Kipar, Anja; Reichenbach, Jürgen R; Rudin, Markus

    2016-09-01

    Magnetic resonance imaging employing administration of iron oxide-based contrast agents is widely used to visualize cellular and molecular processes in vivo. In this study, we investigated the ability of [Formula: see text] and quantitative susceptibility mapping to quantitatively assess the accumulation of ultrasmall superparamagnetic iron oxide (USPIO) particles in the arcAβ mouse model of cerebral amyloidosis. Gradient-echo data of mouse brains were acquired at 9.4 T after injection of USPIO. Focal areas with increased magnetic susceptibility and [Formula: see text] values were discernible across several brain regions in 12-month-old arcAβ compared to 6-month-old arcAβ mice and to non-transgenic littermates, indicating accumulation of particles after USPIO injection. This was concomitant with higher [Formula: see text] and increased magnetic susceptibility differences relative to cerebrospinal fluid measured in USPIO-injected compared to non-USPIO-injected 12-month-old arcAβ mice. No differences in [Formula: see text] and magnetic susceptibility were detected in USPIO-injected compared to non-injected 12-month-old non-transgenic littermates. Histological analysis confirmed focal uptake of USPIO particles in perivascular macrophages adjacent to small caliber cerebral vessels with radii of 2-8 µm that showed no cerebral amyloid angiopathy. USPIO-enhanced [Formula: see text] and quantitative susceptibility mapping constitute quantitative tools to monitor such functional microvasculopathies. PMID:26661253

  7. Perinatal exposure to methoxychlor enhances adult cognitive responses and hippocampal neurogenesis in mice

    PubMed Central

    Martini, Mariangela; Calandreau, Ludovic; Jouhanneau, Mélanie; Mhaouty-Kodja, Sakina; Keller, Matthieu

    2014-01-01

    During perinatal life, sex steroids, such as estradiol, have marked effects on the development and function of the nervous system. Environmental estrogens or xenoestrogens are man-made chemicals, which animal and human population encounter in the environment and which are able to disrupt the functioning of the endocrine system. Scientific interest in the effects of exposure to xenoestrogens has focused more on fertility and reproductive behaviors, while the effects on cognitive behaviors have received less attention. Therefore, the present study explored whether the organochlorine insecticide Methoxychlor (MXC), with known xenoestrogens properties, administered during the perinatal period (from gestational day 11 to postnatal day 8) to pregnant-lactating females, at an environmentally relevant dose (20 µg/kg (body weight)/day), would also affect learning and memory functions depending on the hippocampus of male and female offspring mice in adulthood. When tested in adulthood, MXC perinatal exposure led to an increase in anxiety-like behavior and in short-term spatial working memory in both sexes. Emotional learning was also assessed using a contextual fear paradigm and MXC treated male and female mice showed an enhanced freezing behavior compared to controls. These results were correlated with an increased survival of adult generated cells in the adult hippocampus. In conclusion, our results show that perinatal exposure to an environmentally relevant dose of MXC has an organizational effect on hippocampus-dependent memory and emotional behaviors. PMID:24982620

  8. Towards understanding sex differences in visceral pain: enhanced reactivation of classically-conditioned fear in healthy women.

    PubMed

    Benson, Sven; Kattoor, Joswin; Kullmann, Jennifer S; Hofmann, Sarah; Engler, Harald; Forsting, Michael; Gizewski, Elke R; Elsenbruch, Sigrid

    2014-03-01

    Sex differences in learned fear regarding aversive gastrointestinal stimuli could play a role in the female preponderance of chronic abdominal pain. In a fear conditioning model with rectal pain as unconditioned stimulus (US), we compared healthy males and females with respect to neural responses during aversive visceral learning, extinction and re-activation of fear memory (i.e., reinstatement). To do so, conditioned visual stimuli (CS(+)) were consistently paired with painful rectal distensions as US, while different visual stimuli (CS(-)) were presented without US. During extinction, both CSs were presented without US, whereas during reinstatement, a single, unpaired US was presented. In region-of-interest analyses, sexes were compared with respect to conditioned anticipatory neural activation (CS(+)>CS(-)). The results revealed that in late acquisition, CS+ presentation induced significantly greater anticipatory activation of the insula in women. During extinction, women demonstrated reduced activation of the posterior cingulate cortex. During reinstatement, the CS(+) led to greater activation of the hippocampus, thalamus and cerebellum in women. These group effects in neural activation during learning and memory processes were not accounted for by sex differences in pain thresholds, pain ratings, or stress parameters. In conclusion, this is the first study to support sex differences in neural processes mediating aversive visceral learning. Our finding of enhanced neural responses during reinstatement in key brain areas relevant for memory suggests enhanced reactivation of old fear memory trace in women. Sex differences in "gut memories" could play a role in the female preponderance of chronic abdominal pain. PMID:24398396

  9. Taurine-Induced Long-Lasting Enhancement of Synaptic Transmission in Mice: Role of Transporters

    PubMed Central

    Sergeeva, O A; Chepkova, A N; Doreulee, N; Eriksson, K S; Poelchen, W; Mönnighoff, I; Heller-Stilb, B; Warskulat, U; Häussinger, D; Haas, H L

    2003-01-01

    Taurine, a major osmolyte in the brain evokes a long-lasting enhancement (LLETAU) of synaptic transmission in hippocampal and cortico-striatal slices. Hippocampal LLETAU was abolished by the GABA uptake blocker nipecotic acid (NPA) but not by the taurine-uptake inhibitor guanidinoethyl sulphonate (GES). Striatal LLETAU was sensitive to GES but not to NPA. Semiquantitative PCR analysis and immunohistochemistry revealed that taurine transporter expression is significantly higher in the striatum than in the hippocampus. Taurine transporter-deficient mice displayed very low taurine levels in both structures and a low ability to develop LLETAU in the striatum, but not in the hippocampus. The different mechanisms of taurine-induced synaptic plasticity may reflect the different vulnerabilities of these brain regions under pathological conditions that are accompanied by osmotic changes such as hepatic encephalopathy. PMID:12824447

  10. The enhancement of immune function and activation of NF-κB by resveratrol-treatment in immunosuppressive mice.

    PubMed

    Lai, Xin; Pei, Qingsheng; Song, Xu; Zhou, Xun; Yin, Zhongqiong; Jia, Renyong; Zou, Yuanfeng; Li, Lixia; Yue, Guizhou; Liang, Xiaoxia; Yin, Lizi; Lv, Cheng; Jing, Bo

    2016-04-01

    Resveratrol, a kind of natural product found in over 70 plants, possesses both immunomodulatory and anticancer effects. Many reports have shown that resveratrol has the bidirectional regulation effects on antigen presenting and cellular immunity. However, few reports have evaluated the effects of resveratrol on reinforcing immunity recovery via activating nuclear factor -κappa B (NF-κB). In the present study, we investigated the effects of resveratrol on recovery and reconstruction of immune function by detecting nonspecific and specific immunity in immunosuppressive mice. We found that, compared to the immunosuppressive mice, the spleen index and spleen lymphocyte proliferation of resveratrol-treated mice (30mg/kg body weight) were enhanced. After resveratrol-treatment (15mg/kg body weight), the function of peritoneal macrophages was enhanced and the CD4+ cells were increased in peripheral blood. The expressions of serum cytokines related to immune function, including interleukin (IL)-1α/β, IL-2, tumor necrosis factor-α and NF-κB were up-regulated in a dose-dependent manner. The expression of the transcription factor NF-κB in spleen was enhanced after resveratrol-treatment. The immuno-enhancement effects of resveratrol were similar to that of levamisole (served as positive control). These results demonstrated that resveratrol had potent immune enhancement activity in immunosuppressive mice, and one possible mechanism of action was to activate the NF-κB. PMID:26854575