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1.  Chronic Resveratrol Treatment Protects Pancreatic Islets against Oxidative Stress in db/db Mice 
PLoS ONE  2012;7(11):e50412.
Resveratrol (RSV) has anti-inflammatory and anti-oxidant actions which may contribute to its cardiovascular protective effects. We examined whether RSV has any beneficial effects on pancreatic islets in db/db mice, an animal model of type 2 diabetes. The db/db and db/dm mice (non-diabetic control) were treated with (db-RSV) or without RSV (db-control) (20 mg/kg daily) for 12 weeks. After performing an intraperitoneal glucose tolerance test and insulin tolerance test, mice were sacrificed, the pancreas was weighed, pancreatic β-cell mass was quantified by point count method, and the amount of islet fibrosis was determined. 8-Hydroxydeoxyguanosine (8-OHdG), an oxidative stress marker, was determined in 24 h urine and pancreatic islets. RSV treatment significantly improved glucose tolerance at 2 hrs in db/db mice (P = 0.036), but not in db/dm mice (P = 0.623). This was associated with a significant increase in both pancreas weight (P = 0.011) and β-cell mass (P = 0.016). Islet fibrosis was much less in RSV-treated mice (P = 0.048). RSV treatment also decreased urinary 8-OHdG levels (P = 0.03) and the percentage of islet nuclei that were positive for 8-OHdG immunostaining (P = 0.019). We conclude that RSV treatment improves glucose tolerance, attenuates β-cell loss, and reduces oxidative stress in type 2 diabetes. These findings suggest that RSV may have a therapeutic implication in the prevention and management of diabetes.
doi:10.1371/journal.pone.0050412
PMCID: PMC3511555  PMID: 23226280
2.  Role of resveratrol-induced CD11b+ Gr-1+ myeloid derived suppressor cells (MDSCs) in the reduction of CXCR3+ T cells and amelioration of chronic colitis in IL-10−/− mice 
Brain, behavior, and immunity  2011;26(1):72-82.
Resveratrol, a naturally occurring polyphenol has received significant attention as a potent anti-inflammatory agent. Inflammatory bowel disease (IBD) is a chronic intestinal inflammation caused by hyperactivated effector immune cells that produce pro-inflammatory cytokines. Myeloid derived suppressor cells (MDSCs) are a heterogeneous population characterized by the co-expression of CD11b+ and Gr-1+ and have long been known for their immunosuppressive function. We report that resveratrol effectively attenuated overall clinical scores as well as various pathological markers of colitis in IL-10−/− mice by down regulating Th1 responses. Resveratrol lessened the colitis-associated decrease in body weight and increased levels of serum amyloid A (SAA), CXCL10 and colon TNF-α, IL-6, RANTES, IL-12 and IL-1β concentrations. After resveratrol treatment, the percentage of CXCR3 expressing T cells was decreased in the spleen, mesenteric lymph nodes (MLN), and intestinal lamina propria (LP). However, the percentage and absolute numbers of CD11b+ and Gr-1+cells in the lamina propria (LP) and spleen were increased after resveratrol treatment as compared with the vehicle treatment. Co-culture of resveratrol induced CD11b+ Gr-1+ cells with T cells, attenuated T cell proliferation, and most importantly reduced IFN-γ and GM-CSF production by LP derived T cells from vehicle treated IL-10−/− mice with chronic colitis. The current study suggests that administration of resveratrol into IL-10−/− mice induces immunosuppressive CD11b+ Gr-1+ MDSCs in the colon, which correlates with reversal of established chronic colitis, and down regulation of mucosal and systemic CXCR3+ expressing effector T cells as well as inflammatory cytokines in the colon. The induction of immunosuppressive CD11b+ Gr-1+ cells by resveratrol during colitis is unique, and suggests an as-yet-unidentified mode of anti-inflammatory action of this plant polyphenol.
doi:10.1016/j.bbi.2011.07.236
PMCID: PMC3506001  PMID: 21807089
Inflammation; Resveratrol; Colitis; CXCR3; CD11b+ and Gr-1+ and MDSCs
3.  Resveratrol Improves Oxidative Stress and Protects Against Diabetic Nephropathy Through Normalization of Mn-SOD Dysfunction in AMPK/SIRT1-Independent Pathway 
Diabetes  2011;60(2):634-643.
OBJECTIVE
Despite the beneficial effects of resveratrol (RSV) on cardiovascular disease and life span, its effects on type 2 diabetic nephropathy remain unknown. This study examined the renoprotective effects of RSV in db/db mice, a model of type 2 diabetes.
RESEARCH DESIGN AND METHODS
db/db mice were treated with RSV (0.3% mixed in chow) for 8 weeks. We measured urinary albumin excretion (UAE), histological changes (including mesangial expansion, fibronectin accumulation, and macrophage infiltration), oxidative stress markers (urinary excretion and mitochondrial content of 8-hydroxy-2'-deoxyguanosine [8-OHdG], nitrotyrosine expression), and manganese-superoxide dismutase (Mn-SOD) activity together with its tyrosine-nitrated modification and mitochondrial biogenesis in the kidney. Blood glucose, glycated hemoglobin, and plasma lipid profiles were also measured. The phosphorylation of 5′-AMP–activated kinase (AMPK) and expression of silent information regulator 1 (SIRT1) in the kidney were assessed by immunoblotting.
RESULTS
RSV significantly reduced UAE and attenuated renal pathological changes in db/db mice. Mitochondrial oxidative stress and biogenesis were enhanced in db/db mice; however, Mn-SOD activity was reduced through increased tyrosine-nitrated modification. RSV ameliorated such alterations and partially improved blood glucose, glycated hemoglobin, and abnormal lipid profile in db/db mice. Activation of AMPK was decreased in the kidney of db/db mice compared with db/m mice. RSV neither modified AMPK activation nor SIRT1 expression in the kidney.
CONCLUSIONS
RSV ameliorates renal injury and enhanced mitochondrial biogenesis with Mn-SOD dysfunction in the kidney of db/db mice, through improvement of oxidative stress via normalization of Mn-SOD function and glucose-lipid metabolism. RSV has antioxidative activities via AMPK/SIRT1-independent pathway.
doi:10.2337/db10-0386
PMCID: PMC3028365  PMID: 21270273
4.  Resveratrol-Mediated Gamma Interferon Reduction Prevents Airway Inflammation and Airway Hyperresponsiveness in Respiratory Syncytial Virus-Infected Immunocompromised Mice ▿  
Journal of Virology  2011;85(24):13061-13068.
Respiratory syncytial virus (RSV) is the most important cause of severe, lower respiratory tract infections in infants, and RSV infections have been associated with chronic wheezing and asthma during childhood. However, the mechanism of RSV-induced airway inflammation and airway hyperresponsiveness (AHR) is poorly understood. Furthermore, there are presently neither effective vaccines nor drugs available for the prevention or treatment of RSV infections. In this study, we investigated the effect of the plant extract resveratrol as a means of preventing airway inflammation and attenuating RSV-induced AHR. Our data showed that resveratrol reduced RSV lung titers and the number of infiltrating lymphocytes present in bronchoalveolar lavage fluid (BALF) and reduced inflammation. Furthermore, resveratrol attenuated airway responses to methacholine following RSV infection and significantly decreased gamma interferon (IFN-γ) levels in BALF of RSV-infected mice. Data presented in this report demonstrated that resveratrol controlled Toll-like receptor 3 (TLR3) expression, inhibited the TRIF signaling pathway, and induced M2 receptor expression following RSV infection. These data support a role for the use of resveratrol as a means of reducing IFN-γ levels associated with RSV-mediated airway inflammation and AHR, which may be mediated via TLR3 signaling.
doi:10.1128/JVI.05869-11
PMCID: PMC3233156  PMID: 21937650
5.  Liver X receptor β: maintenance of epidermal expression in intrinsic and extrinsic skin aging 
Age  2009;31(4):365-372.
Aging in human skin is the composite of time-dependent intrinsic aging plus photoaging induced by chronic exposure to ultraviolet radiation. Nuclear hormone receptors coordinate diverse processes including metabolic homeostasis. Liver X receptor β (LXRβ) is a close human homologue of daf-12, a regulator of nematode longevity. LXRβ is positively regulated by sirtuin-1 and resveratrol, while LXRβ-null mice show transcriptional profiles similar to those seen in aged human skin. In these studies, we examined LXRβ expression in aged and photoaged human skin. Volunteers were recruited to assess intrinsic aging and photoaging. Epidermal LXRβ mRNA was examined by in situ hybridization while protein was identified by immunofluorescence. No significant changes were observed in either LXRβ mRNA or protein expression between young and aged volunteers (mRNA p = 0.90; protein p = 0.26). Similarly, LXRβ protein expression was unaltered in photoaged skin (p = 0.75). Our data therefore suggest that, while not playing a major role in skin aging, robust cutaneous expression implies a fundamental role for LXRβ in epidermal biology.
doi:10.1007/s11357-009-9111-6
PMCID: PMC2813049  PMID: 19697157
Nuclear hormone receptors; Skin; Aging; Liver X receptor
6.  Resveratrol suppresses colitis and colon cancer associated with colitis 
Resveratrol is a naturally occurring polyphenol that exhibits pleiotropic health beneficial effects including anti-inflammatory, cardio- and cancer-protective activities. It is recognized as one of the more promising natural molecules in the prevention and treatment of chronic inflammatory and autoimmune disorders. Ulcerative Colitis (UC) is an idiopathic, chronic inflammatory disease of the colon associated with a high colon cancer risk. Here, we used a Dextran Sulfate Sodium (DSS) mouse model of colitis, which resembles human UC pathology. Resveratrol mixed in food ameliorates DSS-induced colitis in mice in a dose-dependent manner. Resveratrol significantly improves inflammation score, down regulates the percentage of neutrophils in the mesenteric lymph nodes and lamina propiria, and modulates CD3+ T cells that express tumor necrosis factor-alpha and interferon gamma. Markers of inflammation and inflammatory stress (p53 and p53-Phospho-Serine 15), are also down regulated by resveratrol. Since chronic colitis drives colon cancer risk, we carried out experiments to determine the chemopreventive properties of resveratrol. Tumor incidence is reduced from 80% in mice treated with Azoxymethane (AOM) + DSS to 20% in AOM + DSS + Resveratrol (300 p.p.m.) treated mice. Tumor multiplicity also decreased with resveratrol treatment. AOM + DSS treated mice had 2.4 ± 0.7 tumors per animal compared with AOM + DSS + 300 p.p.m. resveratrol, which had 0.2 ± 0.13 tumors per animal. The current study indicates that resveratrol is a useful, non-toxic complementary and alternative strategy to abate colitis and potentially colon cancer associated with colitis.
doi:10.1158/1940-6207.CAPR-09-0117
PMCID: PMC2853724  PMID: 20332304
Inflammation; Resveratrol; Colitis; Colon Cancer
7.  Respiratory synctial virus infection in BALB/c mice previously immunized with formalin-inactivated virus induces enhanced pulmonary inflammatory response with a predominant Th2-like cytokine pattern. 
Journal of Virology  1996;70(5):2852-2860.
Vaccination with formalin-inactivated respiratory syncytial virus (FI-RSV) caused excessive disease in infants upon subsequent natural infection with RSV. Recent studies with BALB/c mice have suggested that T cells are important contributors to lung immunopathology during RSV infection. In this study, we investigated vaccine-induced enhanced disease by immunizing BALB/c mice with live RSV intranasally or with FI-RSV intramuscularly. The mice were challenged with RSV 6 weeks later, and the pulmonary inflammatory response was studied by analyzing cells obtained by bronchoalveolar lavage 4 and 8 days after challenge. FI-RSV-immunized mice had an increased number of total cells, granulocytes, eosinophils, and CD4+ cells but a decreased number of CD8+ cells. The immunized mice also had a marked increase in the expression of mRNA for the Th2-type cytokines interleukin-5 (IL-5) and IL-13 as well as some increase in the expression of IL-10 (a Th2-type cytokine) mRNA and some decrease in the expression of IL-12 (a Th1-type cytokine) mRNA. The clear difference in the pulmonary inflammatory response to RSV between FI-RSV- and live-RSV-immunized mice suggests that this model can be used to evaluate the disease-enhancing potential of candidate RSV vaccines and better understand enhanced disease.
PMCID: PMC190142  PMID: 8627759
8.  Effect of resveratrol on alcohol-induced mortality and liver lesions in mice 
BMC Gastroenterology  2006;6:35.
Background
Resveratrol is a polyphenol with important antiinflammatory and antioxidant properties. We investigated the effect of resveratrol on alcohol-induced mortality and liver lesions in mice.
Methods
Mice were randomly distributed into four groups (control, resveratrol-treated control, alcohol and resveratrol-treated alcohol). Chronic alcohol intoxication was induced by progressively administering alcohol in drinking water up to 40% v/v. The mice administered resveratrol received 10 mg/ml in drinking water. The animals had free access to standard diet. Blood levels were determined for transaminases, IL-1 and TNF-α. A histological evaluation was made of liver damage, and survival among the animals was recorded.
Results
Transaminase concentration was significantly higher in the alcohol group than in the rest of the groups (p < 0.05). IL-1 levels were significantly reduced in the alcohol plus resveratrol group compared with the alcohol group (p < 0.05). TNF-α was not detected in any group. Histologically, the liver lesions were more severe in the alcohol group, though no significant differences between groups were observed. Mortality in the alcohol group was 78% in the seventh week, versus 22% in the alcohol plus resveratrol group (p < 0.001). All mice in the alcohol group died before the ninth week.
Conclusion
The results obtained suggest that resveratrol reduces mortality and liver damage in mice.
doi:10.1186/1471-230X-6-35
PMCID: PMC1657014  PMID: 17105669
9.  The Polyphenols Resveratrol and S17834 prevent the Structural and Functional Sequelae of Diet-Induced Metabolic Heart Disease in Mice 
Circulation  2012;125(14):1757-1764.
Background
Diet-induced obesity is associated with metabolic heart disease characterized by left ventricular (LV) hypertrophy and diastolic dysfunction. Polyphenols such as resveratrol (RSV) and the synthetic flavonoid derivative S17834 exert beneficial systemic and cardiovascular effects in a variety of settings including diabetes and chronic hemodynamic overload.
Methods and Results
We characterized the structural and functional features of a mouse model of diet-induced metabolic syndrome, and used the model to test the hypothesis that the polyphenols prevent myocardial hypertrophy and diastolic dysfunction. Male C57BL/6J mice were fed a normal diet or a diet high in fat and sugar (HFHS) with or without concomitant treatment with S17834 or RSV for up to 8 months. HFHS diet-fed mice developed progressive LV hypertrophy and diastolic dysfunction with preservation of systolic function in association with myocyte hypertrophy and interstitial fibrosis. In HFHS-fed mice there was increased myocardial oxidative stress with evidence of oxidant-mediated protein modification via tyrosine nitration and 4-OH-2-nonenol (HNE) adduction. HFHS-fed mice also exhibited increases in plasma fasting glucose, insulin and HOMA-IR indicative of insulin resistance. Treatment with S17834 or RSV prevented LV hypertrophy and diastolic dysfunction. For S17834, these beneficial effects were associated with decreases in oxidant-mediated protein modifications and hyper-insulinemia, and increased plasma adiponectin.
Conclusions
RSV and S17834 administered concurrently with a HFHS diet prevent the development of LV hypertrophy, interstitial fibrosis and diastolic dysfunction. Multiple mechanisms may contribute to the beneficial effects of the polyphenols including a reduction in myocardial oxidative stress and related protein modifications, amelioration of insulin resistance and increased plasma adiponectin. The polyphenols RSV and S17834 may be of value in the prevention of diet-induced metabolic heart disease.
doi:10.1161/CIRCULATIONAHA.111.067801
PMCID: PMC3354628  PMID: 22388319
left ventricular hypertrophy; diastolic dysfunction; 4-OH-2-nonenol; metabolic syndrome; oxidative stress
10.  Cognitive Performances Are Selectively Enhanced during Chronic Caloric Restriction or Resveratrol Supplementation in a Primate 
PLoS ONE  2011;6(1):e16581.
Effects of an 18-month treatment with a moderate, chronic caloric restriction (CR) or an oral supplementation with resveratrol (RSV), a potential CR mimetic, on cognitive and motor performances were studied in non-human primates, grey mouse lemurs (Microcebus murinus).
Thirty-three adult male mouse lemurs were assigned to three different groups: a control (CTL) group fed ad libitum, a CR group fed 70% of the CTL caloric intake, and an RSV group (RSV supplementation of 200 mg.kg−1.day−1) fed ad libitum. Three different cognitive tests, two motor tests, one emotional test and an analysis of cortisol level were performed in each group.
Compared to CTL animals, CR or RSV animals did not show any change in motor performances evaluated by rotarod and jump tests, but an increase in spontaneous locomotor activity was observed in both groups. Working memory was improved by both treatments in the spontaneous alternation task. Despite a trend for CR group, only RSV supplementation increased spatial memory performances in the circular platform task. Finally, none of these treatments induced additional stress to the animals as reflected by similar results in the open field test and cortisol analyses compared to CTL animals.
The present data provided the earliest evidence for a beneficial effect of CR or RSV supplementation on specific cognitive functions in a primate. Taken together, these results suggest that RSV could be a good candidate to mimic long-term CR effects and support the growing evidences that nutritional interventions can have beneficial effects on brain functions even in adults.
doi:10.1371/journal.pone.0016581
PMCID: PMC3031601  PMID: 21304942
11.  Priming with live respiratory syncytial virus (RSV) prevents the enhanced pulmonary inflammatory response seen after RSV challenge in BALB/c mice immunized with formalin-inactivated RSV. 
Journal of Virology  1997;71(9):6935-6939.
To investigate enhanced disease associated with a formalin-inactivated (FI) respiratory syncytial virus (RSV) vaccine, we studied the pulmonary inflammatory response to RSV in BALB/c mice immunized with live RSV, FI-RSV, or combinations of the two. After RSV challenge, the number of granular cells, the ratio of CD4+/CD8+ lymphocytes, and the level of Th2-like cytokine mRNAs in the bronchoalveolar lavage specimens in mice immunized first with live RSV and then with FI-RSV were lower than that in FI-RSV-immunized mice and close to that in live RSV-immunized mice. These data suggest that prior live RSV infection prevents most of the enhanced inflammatory response seen in FI-RSV-immunized mice and might explain lack of enhanced disease in older FI-RSV-immunized children. A live RSV vaccine might similarly decrease the risk of enhanced disease with non-live RSV vaccines.
PMCID: PMC191977  PMID: 9261421
12.  Distinct Effects of Calorie Restriction and Resveratrol on Diet-Induced Obesity and Fatty Liver Formation 
The potential of resveratrol to mimic beneficial effects of calorie restriction (CR) was investigated. We compared the effects of both CR (70% of ad libitum energy intake) or resveratrol (2 g/kg or 4 g/kg food) on high-fat diet-induced obesity and fatty liver formation in C57Bl/6J mice, and we examined their effects on calorimetry, metabolic performance, and the expressions of inflammatory genes and SIRT proteins. We found that resveratrol with 4 g/kg dose partially prevented hepatic steatosis and hepatocyte ballooning and induced skeletal muscle SIRT1 and SIRT4 expression while other examined parameter were unaffected by resveratrol. In contrast, CR provided superior protection against diet-induced obesity and fatty liver formation as compared to resveratrol, and the effects were associated with increased physical activity and ameliorated adipose tissue inflammation. CR increased expressions of SIRT3 in metabolically important tissues, suggesting that the beneficial effects of CR are mediated, at least in part, via SIRT3-dependent pathways.
doi:10.1155/2011/525094
PMCID: PMC3184417  PMID: 21977315
13.  The effects of resveratrol and selected metabolites on the radiation and antioxidant response 
Cancer Biology & Therapy  2011;12(10):915-923.
Excess reactive oxygen species (ROS) generated from ionizing radiation (IR) or endogenous sources like cellular respiration and inflammation produce cytotoxic effects that can lead to carcinogenesis. Resveratrol (RSV), a polyphenol with antioxidant and anticarcinogenic capabilities, has shown promise as a potential radiation modifier. The present study focuses on examining the effects of RSV or RSV metabolites as a radiation modifier in normal tissue. RSV or a RSV metabolite, piceatannol (PIC) did not protect human lung fibroblasts (1522) from the radiation-induced cell killing. Likewise, neither RSV nor PIC afforded protection against lethal total body IR in C3H mice. Additional research has shown protection in cells against hydrogen peroxide when treated with RSV. Therefore, clonogenic survival was measured in 1522 cells with RSV and RSV metabolites. Only the RSV derivative, piceatannol (PIC), showed protection against hydrogen peroxide mediated cytotoxicity; whereas, RSV enhanced hydrogen peroxide sensitivity at a 50 µM concentration; the remaining metabolites evaluated had little to no effect on survival. PIC also showed enhancement to peroxide exposure at a higher concentration (150 µM). A potential mechanism for RSV-induced sensitivity to peroxides could be its ability to block 1522 cells in the S-phase, which is most sensitive to hydrogen peroxide treatment. In addition, both RSV and PIC can be oxidized to phenoxyl radicals and quinones, which may exert cytotoxic effects. These cytotoxic effects were abolished when HBED, a metal chelator, was added. Taken together RSV and many of its metabolic derivatives are not effective as chemical radioprotectors and should not be considered for clinical use.
doi:10.4161/cbt.12.10.17714
PMCID: PMC3280907  PMID: 22024758
resveratrol; piceatannol; antioxidants; oxidative stress; peroxide; ionizing radiation; quinones
14.  Treatment of obesity with the resveratrol-enriched rice DJ-526 
Scientific Reports  2014;4:3879.
Obesity is the most prevalent disease in the world which poses a serious risk for various chronic diseases. However, currently there are not any therapeutic agents that reduce body weight without causing serious side effects. In order to prevent and/or treat obesity and related diseases through a nutraceutical approach, we created a resveratrol-enriched transgenic rice accumulating 1.4 μg/g of resveratrol in its grain, DJ-526. Feeding of mice with the resveratrol-enriched rice DJ-526 showed excellent anti-obesity effect with reduction of body weights and abdominal fat volumes compared to the control by 20.0% and 31.3%, respectively. Also, the consumption of the resveratrol-enriched rice DJ526 significantly improved the blood lipid profiles and glucose levels in the animal experiments. Our resveratrol-enriched rice DJ-526 rice could provide both safe and convenient way for people with obesity and related diseases without major change of lifestyle or unwanted side effects from medication.
doi:10.1038/srep03879
PMCID: PMC3902431  PMID: 24464364
15.  Grape Resveratrol Increases Serum Adiponectin and Downregulates Inflammatory Genes in Peripheral Blood Mononuclear Cells: A Triple-Blind, Placebo-Controlled, One-Year Clinical Trial in Patients with Stable Coronary Artery Disease 
Purpose
The grape and wine polyphenol resveratrol exerts cardiovascular benefits but evidence from randomized human clinical trials is very limited. We investigated dose-depending effects of a resveratrol-containing grape supplement on stable patients with coronary artery disease (CAD) treated according to currently accepted guidelines for secondary prevention of cardiovascular disease.
Methods
In a triple-blind, randomized, placebo-controlled, one-year follow-up, 3-arm pilot clinical trial, 75 stable-CAD patients received 350 mg/day of placebo, resveratrol-containing grape extract (grape phenolics plus 8 mg resveratrol) or conventional grape extract lacking resveratrol during 6 months, and a double dose for the following 6 months. Changes in circulating inflammatory and fibrinolytic biomarkers were analyzed. Moreover, the transcriptional profiling of inflammatory genes in peripheral blood mononuclear cells (PBMCs) was explored using microarrays and functional gene expression analysis.
Results
After 1 year, in contrast to the placebo and conventional grape extract groups, the resveratrol-containing grape extract group showed an increase of the anti-inflammatory serum adiponectin (9.6 %, p = 0.01) and a decrease of the thrombogenic plasminogen activator inhibitor type 1 (PAI-1) (−18.6 %, p = 0.05). In addition, 6 key inflammation-related transcription factors were predicted to be significantly activated or inhibited, with 27 extracellular-space acting genes involved in inflammation, cell migration and T-cell interaction signals presenting downregulation (p < 0.05) in PBMCs. No adverse effects were detected in relation to the study products.
Conclusions
Chronic daily consumption of a resveratrol-containing grape nutraceutical could exert cardiovascular benefits in stable-CAD patients treated according to current evidence-based standards, by increasing serum adiponectin, preventing PAI-1 increase and inhibiting atherothrombotic signals in PBMCs.
Electronic supplementary material
The online version of this article (doi:10.1007/s10557-012-6427-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s10557-012-6427-8
PMCID: PMC3555235  PMID: 23224687
Resveratrol; Coronary artery disease; Adiponectin; Plasminogen activator inhibitor type 1 (PAI-1); Cardiovascular; Clinical trial
16.  Respiratory Syncytial Virus (RSV) Infection in Elderly Mice Results in Altered Antiviral Gene Expression and Enhanced Pathology 
PLoS ONE  2014;9(2):e88764.
Elderly persons are more susceptible to RSV-induced pneumonia than young people, but the molecular mechanism underlying this susceptibility is not well understood. In this study, we used an aged mouse model of RSV-induced pneumonia to examine how aging alters the lung pathology, modulates antiviral gene expressions, and the production of inflammatory cytokines in response to RSV infection. Young (2–3 months) and aged (19–21 months) mice were intranasally infected with mucogenic or non-mucogenic RSV strains, lung histology was examined, and gene expression was analyzed. Upon infection with mucogenic strains of RSV, leukocyte infiltration in the airways was elevated and prolonged in aged mice compared to young mice. Minitab factorial analysis identified several antiviral genes that are influenced by age, infection, and a combination of both factors. The expression of five antiviral genes, including pro-inflammatory cytokines IL-1β and osteopontin (OPN), was altered by both age and infection, while age was associated with the expression of 15 antiviral genes. Both kinetics and magnitude of antiviral gene expression were diminished as a result of older age. In addition to delays in cytokine signaling and pattern recognition receptor induction, we found TLR7/8 signaling to be impaired in alveolar macrophages in aged mice. In vivo, induction of IL-1β and OPN were delayed but prolonged in aged mice upon RSV infection compared to young. In conclusion, this study demonstrates inherent differences in response to RSV infection in young vs. aged mice, accompanied by delayed antiviral gene induction and cytokine signaling.
doi:10.1371/journal.pone.0088764
PMCID: PMC3928298  PMID: 24558422
17.  Effects of resveratrol on proliferation and apoptosis in rat ovarian theca-interstitial cells 
Molecular Human Reproduction  2010;16(4):251-259.
Polycystic ovary syndrome (PCOS) is characterized by ovarian dysfunction and associated with ovarian theca-interstitial (T-I) cell hyperplasia, hyperinsulinemia, systemic inflammation and oxidative stress. This in vitro study tested whether rat T-I cell growth with or without insulin can be altered by resveratrol, a natural polyphenol with anti-carcinogenic, anti-inflammatory, anti-proliferative and antioxidant properties. Rat T-I cells were cultured with and without resveratrol and/or insulin, and the effects on DNA synthesis, number of viable cells and markers of apoptosis were evaluated. Resveratrol alone induced a potent concentration-dependent inhibition of cell growth by inhibiting DNA synthesis, decreasing the number of viable cells and increasing the activity of executioner caspases 3 and 7; these effects of resveratrol counteracted the pro-proliferative and anti-apoptotic effects of insulin. Immunofluorescence analysis of cells incubated with resveratrol showed concentration- and time-dependent morphological changes consistent with apoptosis. The present findings indicate that resveratrol promotes apoptosis to reduce rat T-I cell growth in vitro as well as inhibiting insulin-induced rat T-I cell growth. This suggests a possibility that resveratrol and/or mechanisms mediating its effect may be relevant to the development of novel treatments for PCOS, which is characterized by both excessive ovarian mesenchyma growth and hyperinsulinemia.
doi:10.1093/molehr/gaq002
PMCID: PMC2834407  PMID: 20067985
apoptosis; insulin; ovarian theca-interstitial cells; proliferation; resveratrol
18.  Prevention of age-related T cell apoptosis defect in CD2-fas-transgenic mice  
T cell dysfunction and thymic involution are major immunologic abnormalities associated with aging. Fas (CD95) is a bifunctional molecule that is critical for apoptosis and stimulation during T cell development, but the role of Fas during aging has not been determined. Fas expression and function on T cells from old (22-26-mo-old) mice was compared with young (2-mo-old) mice and old CD2-fas-transgenic mice. Fas expression and ligand-induced apoptosis were decreased on T cells from old mice compared with young mice. This correlated with an age- related increase in CD44+Fas- T cells. There was a marked decrease in the proliferation of T cells from old mice after anti-CD3 stimulation compared with young mice. Anti-CD3-stimulated T cells from young mice exhibited increased production of interleukin (IL)-2 and decreased production of interferon-gamma and IL-10 compared with old mice. There was an age-related decrease in the total thymocyte count from 127 +/- 10 cells in young mice compared with 26 +/- 8 x 10(6) in old mice. In 26-mo-old CD2-fas-transgenic mice, Fas and CD44 expression, Fas-induced apoptosis, T cell proliferation, and cytokine production were comparable to that of the young mice. These results suggest that T cell senescence with age is associated with defective apoptosis, and that the CD2-fas transgene allows maintenance of Fas apoptosis function and T cell function in aged mice comparable to that of young mice.
PMCID: PMC2192099  PMID: 7540646
19.  Control of RSV-induced Lung Injury by Alternatively Activated Macrophages Is IL-4Rα-, TLR4-, and IFN-β-dependent 
Mucosal immunology  2010;3(3):291-300.
Severe RSV-induced bronchiolitis has been associated with a mixed “Th1” and “Th2” cytokine storm. We hypothesized that differentiation of “alternatively activated” macrophages (AA-Mϕ) would mediate resolution of RSV-induced lung injury. RSV induced IL-4 and IL-13 by murine lung and peritoneal macrophages, IL-4Rα/STAT6-dependent AA-Mϕ differentiation, and significantly enhanced inflammation in lungs of IL-4Rα−/− mice. Adoptive transfer of wild type (WT) macrophages to IL-4Rα−/− mice restored RSV-inducible AA-Mϕ phenotype and diminished lung pathology. RSV-infected TLR4−/− and IFN-β−/− macrophages and mice also failed to express AA-Mϕ markers, but exhibited sustained proinflammatory cytokine production (e.g., IL-12) in vitro and in vivo and epithelial damage in vivo. TLR4 signaling is required for PPARγ expression, a DNA-binding protein that induces AA-Mϕ genes, while IFN-β regulates IL-4, IL-13, IL-4Rα, and IL-10 expression in response to RSV. RSV-infected cotton rats treated with a COX-2 inhibitor increased expression of lung AA-Mϕ. These data suggest new treatment strategies for RSV that promote AA-Mϕ differentiation.
doi:10.1038/mi.2010.6
PMCID: PMC2875872  PMID: 20404812
20.  Plasmacytoid Dendritic Cells Promote Host Defense Against Acute Pneumovirus Infection via the TLR7-MyD88-Dependent Signaling Pathway 
Human respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in infants. In human infants, plasmacytoid dendritic cells (pDC) are recruited to the nasal compartment during infection and initiate host defense through the secretion of type I IFN, IL-12 and IL-6. However, RSV-infected pDCs are refractory to TLR7-mediated activation. Here, we used the rodent-specific pathogen, pneumonia virus of mice (PVM), to determine the contribution of pDC and TLR7-signaling to the development of the innate inflammatory and early adaptive immune response. In wild-type (WT) but not TLR7- or myeloid differentiation protein 88 (MyD88)-deficient mice, PVM inoculation led to a marked infiltration of pDCs and increased expression of type I, II and III IFNs. The delayed induction of IFNs in the absence of TLR7 or MyD88 was associated with a diminished innate inflammatory response and augmented virus recovery from lung tissue. In the absence of TLR7, PVM-specific CD8+ T cell cytokine production was abrogated. The adoptive transfer of TLR7-sufficient but not TLR7-deficient pDC to TLR7-gene-deleted mice recapitulated the antiviral responses observed in WT mice and promoted virus clearance. In summary, TLR7-mediated signaling by pDC is required for appropriate innate responses to acute pneumovirus infection. It is conceivable that as-yet-unidentified defects in the TLR7 signaling pathway may be associated with elevated levels of RSV-associated morbidity and mortality among otherwise healthy human infants.
doi:10.4049/jimmunol.1002635
PMCID: PMC3404606  PMID: 21482736
21.  Are zinc-bound metallothionein isoforms (I+II and III) involved in impaired thymulin production and thymic involution during ageing? 
Background
With advancing age, thymic efficiency shows progressive decline due to thymic involution allowing impaired cell-mediated immunity and the appearance of age-related diseases. The intrinsic cause of thymic involution is still undefined. Chronic inflammation and high glucocorticoids (GCs) may be involved. However, transgenic mice, with increased GC sensitivity and over expression of GC receptors, display delayed age-associated thymic involution. This fact suggests that other substances may affect thymic involution. Among them, both isoforms of metallothioneins (MTs) I+II and III are the major candidates because their increments leads to organ atrophy in constant stress and are induced by IL-6, which increases in ageing. Enhanced MTs in ageing allows constant sequester of zinc ions and no subsequent zinc release leading to low zinc ion bioavailability for thymic efficiency. This sequester is very limited in very old age. Thus, we have investigated the MTmRNA (I+II and III) in the thymus from young, old and very old mice.
Methods
MTmRNA and IL-6mRNA (RT-PCR) in the thymus from different donors were tested. Concomitantly, TECs proliferation, zinc ion bioavailability (ratio total thymulin/active thymulin), thymulin activity and corticosterone were tested from different donors.
Results
Both isoforms of MTmRNA and IL-6mRNA increase in old thymus coupled with low zinc ion bioavailability, reduced TECs proliferation, impaired thymulin activity and enhanced plasma corticosterone in comparison with young. Conversely, although the thymus is involuted in very old mice because of no changes in thymus weight in comparison to old mice, reduced MTmRNA, especially MT-I+II isoforms, and low IL6mRNA occur. Concomitantly, good zinc ion bioavailability, maintained TECs proliferation, satisfactory thymulin activity and reduced corticosterone are observed in very old mice.
Conclusions
The concomitant increments by high IL-6 of both MT isoforms in the thymus from old mice may be involved in thymic involution because provoking low zinc ion bioavailability, which is relevant for thymic efficiency. By contrast, the limited increments of MTs by low IL-6 induce good zinc ion bioavailability and satisfactory thymic efficiency in very old mice. Therefore, abnormal increased MTs may provoke complete thymic involution during ageing and the possible appearance of age-related diseases. If their increments are instead limited by low inflammation, healthy ageing and longevity may be reached.
doi:10.1186/1742-4933-1-5
PMCID: PMC544958  PMID: 15679929
Thymic involution; Metallothioneins; IL-6; glucocorticoids; zinc; TECs; inflammation; ageing; longevity
22.  Dietary Resveratrol Prevents the Development of Food Allergy in Mice 
PLoS ONE  2012;7(9):e44338.
Background
Resveratrol is a bioactive polyphenol enriched in red wine that exhibits many beneficial health effects via multiple mechanisms. However, it is unclear whether resveratrol is beneficial for the prevention of food allergy. This study investigated whether resveratrol inhibited the development of food allergy by using a mouse model of the disease.
Methodology/Principal Findings
Mice fed standard diet or standard diet plus resveratrol were sensitized by intragastric administration of ovalbumin (OVA) and mucosal adjuvant cholera toxin (CT). Several manifestations of food allergy were then compared between the mice. The effects of resveratrol on T cells or dendritic cells were also examined by using splenocytes from OVA-specific T cell-receptor (TCR) transgenic DO11.10 mice or mouse bone marrow-derived dendritic cells (BMDCs) in vitro. We found that mice fed resveratrol showed reduced OVA-specific serum IgE production, anaphylactic reaction, and OVA-induced IL-13 and IFN-ã production from the mesenteric lymph nodes (MLNs) and spleens in comparison to the control mice, following oral sensitization with OVA plus CT. In addition, resveratrol inhibited OVA plus CT-induced IL-4, IL-13, and IFN-ã production in splenocytes from DO11.10 mice associated with inhibition of GATA-3 and T-bet expression. Furthermore, resveratrol suppressed the OVA plus CT-induced CD25 expression and IL-2 production in DO11.10 mice-splenocytes in association with decreases in CD80 and CD86 expression levels. Finally, resveratrol suppressed CT-induced cAMP elevation in association with decreases in CD80 and CD86 expression levels in BMDCs.
Conclusions/Significance
Ingestion of resveratrol prevented the development of a food allergy model in mice. Given the in vitro findings, resveratrol might do so by inhibiting DC maturation and subsequent early T cell activation and differentiation via downregulation of CT-induced cAMP activation in mice. These results suggest that resveratrol may have potential for prophylaxis against food allergy.
doi:10.1371/journal.pone.0044338
PMCID: PMC3433457  PMID: 22962611
23.  Cell surface immunoglobulin. XI. The appearance of an IgD-like molecule on murine lymphoid cells during ontogeny 
An Ig molecule containing L chains and H chains similar to human delta- chains has been detected on the surface of radioiodinated murine lymphoid cells. Newborn mice have only IgM on their splenocytes. Between 10 and 15 days, the IgD-like molecule appears and increases in amount until 3 mo of age, when it is the predominant cell surface Ig in terms of radioactivity. IgD is found only in peripheral lymphoid tissues and is present in larger amounts on peripheral lymph node cells (approximately 85% of surface Ig) than on splenocytes (approximately 50%). IgD is also present in comparable amounts on cells from both nu/nu and germfree mice, indicating that its expression may be independent of both thymic influence and antigenic stimulation. These studies suggest that there is a switch from cell surface IgM to IgD that occurs during differentiation of virgin B lymphocytes in the spleen.
PMCID: PMC2190500  PMID: 1090697
24.  Influenza Virus Lung Infection Protects from Respiratory Syncytial Virus–Induced Immunopathology 
The Journal of Experimental Medicine  2000;192(9):1317-1326.
The effect of infection history is ignored in most animal models of infectious disease. The attachment protein of respiratory syncytial virus (RSV) induces T helper cell type 2–driven pulmonary eosinophilia in mice similar to that seen in the failed infant vaccinations in the 1960s. We show that previous influenza virus infection of mice: (a) protects against weight loss, illness, and lung eosinophilia; (b) attenuates recruitment of inflammatory cells; and (c) reduces cytokine secretion caused by RSV attachment protein without affecting RSV clearance. This protective effect can be transferred via influenza-immune splenocytes to naive mice and is long lived. Previous immunity to lung infection clearly plays an important and underestimated role in subsequent vaccination and infection. The data have important implications for the timing of vaccinations in certain patient groups, and may contribute to variability in disease susceptibility observed in humans.
PMCID: PMC2193356  PMID: 11067880
viral immunology; murine model; eosinophils; major histocompatibility complex tetramers; mucosal immunology
25.  Caloric restriction or resveratrol supplementation and ageing in a non-human primate: first-year outcome of the RESTRIKAL study in Microcebus murinus 
Age  2010;33(1):15-31.
A life-long follow-up of physiological and behavioural functions was initiated in 38-month-old mouse lemurs (Microcebus murinus) to test whether caloric restriction (CR) or a potential mimetic compound, resveratrol (RSV), can delay the ageing process and the onset of age-related diseases. Based on their potential survival of 12 years, mouse lemurs were assigned to three different groups: a control (CTL) group fed ad libitum, a CR group fed 70% of the CTL caloric intake and a RSV group (200 mg/kg.day–1) fed ad libitum. Since this prosimian primate exhibits a marked annual rhythm in body mass gain during winter, animals were tested throughout the year to assess body composition, daily energy expenditure (DEE), resting metabolic rate (RMR), physical activity and hormonal levels. After 1 year, all mouse lemurs seemed in good health. CR animals showed a significantly decreased body mass compared with the other groups during long day period only. CR or RSV treatments did not affect body composition. CR induced a decrease in DEE without changes in RMR, whereas RSV induced a concomitant increase in DEE and RMR without any obvious modification of locomotor activity in both groups. Hormonal levels remained similar in each group. In summary, after 1 year of treatment CR and RSV induced differential metabolic responses but animals successfully acclimated to their imposed diets. The RESTRIKAL study can now be safely undertaken on a long-term basis to determine whether age-associated alterations in mouse lemurs are delayed with CR and if RSV can mimic these effects.
doi:10.1007/s11357-010-9156-6
PMCID: PMC3063642  PMID: 20532988
Ageing; Food restriction; Resveratrol; Energy balance; Biomarkers; Doubly labelled water method

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