Effects of resveratrol and methylprednisolone on biochemical, neurobehavioral and histopathological recovery after experimental spinal cord injury Placebo-controlled, randomised clinical trial: high-dose resveratrol treatment for non-alcoholic fatty liver disease Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. Effects of 6 months of resveratrol versus placebo on pentraxin 3 in patients with type 2 diabetes mellitus: a double-blind randomized controlled trial Effects of resveratrol alone or in combination with piperine on cerebral blood flow parameters and cognitive performance in human subjects: a randomised, double-blind, placebo-controlled, cross-over investigation. Alterations of antioxidant status in asymptomatic hypercholesterolemic individuals after resveratrol intake Trans-Resveratrol Alters Mammary Promoter Hypermethylation in Women at Increased Risk for Breast Cancer The effects of 30 days resveratrol supplementation on adipose tissue morphology and gene expression patterns in obese men Serum concentrations and gene expression of sirtuin 1 in healthy and slightly overweight subjects after caloric restriction or resveratrol supplementation: A randomized trial. Effects of resveratrol on cerebral blood flow variables and cognitive performance in humans: a double-blind, placebo-controlled, crossover investigation. Resveratrol Ameliorates Arterial Stiffness Assessed by Cardio-Ankle Vascular Index in Patients With Type 2 Diabetes Mellitus. Resveratrol improves ex vivo mitochondrial function but does not affect insulin sensitivity or brown adipose tissue in first degree relatives of patients with type 2 diabetes The effects of resveratrol on markers of oxidative stress in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled clinical trial Beneficial effects of acute trans-resveratrol supplementation in treated hypertensive patients with endothelial dysfunction Resveratrol levels and all-cause mortality in older community-dwelling adults. Six months of resveratrol supplementation has no measurable effect in type 2 diabetic patients. A randomized, double blind, placebo-controlled trial. Phase I Dose Escalation Pharmacokinetic Study in Healthy Volunteers of Resveratrol, a Potential Cancer Chemopreventive Agent The effects of polyphenol supplementation on adipose tissue morphology and gene expression in overweight and obese humans Anti-inflammatory and antioxidant effects of resveratrol in healthy smokers a randomized, double-blind, placebo-controlled, cross-over trial. Steady-State Pharmacokinetics and Tolerability of Trans-Resveratrol 2000mg Twice Daily with Food, Quercetin and Alcohol (Ethanol) in Healthy Human Subjects 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 One-year consumption of a grape nutraceutical containing resveratrol improves the inflammatory and fibrinolytic status of patients in primary prevention of cardiovascular disease. Resveratrol induces catalytic bioscavenger paraoxonase 1 expression and protects against chemical warfare nerve agent toxicity in human cell lines.
Abstract Aim : To investigate the neuroprotective effect of resveratrol in an experimental spinal cord injury ( SCI ) model in rats . Methods : Male Wistar albino rats weighing 200–250 g were r and omized into six groups . Weight-drop trauma was performed for SCI . Group 1 underwent laminectomy alone . Group 2 underwent laminectomy followed by SCI . Groups 3 , 4 , 5 , and 6 underwent laminectomy followed by SCI and received resveratrol ( 100 mg/kg ) , methylprednisolone ( MP ) ( 30 mg/kg ) , resveratrol ( 100 mg/kg ) plus MP ( 30 mg/kg ) , and ethanol ( 2 % ) , respectively . The rats were divided into two subgroups for biochemical analysis ( killed at 24 h after surgery ) and for neurobehavioral and histopathological evaluation ( killed at 6 weeks after surgery ) . Posttraumatic neurological recovery after surgery was recorded weekly . Results : Groups 3 and 5 revealed significantly lower malondialdehyde , nitric oxide , xanthine oxidase , and higher glutathione levels than group 4 ( P<0.05 ) . Neurological recovery rates were significantly better in groups 3 and 5 than group 4 ( P<0.05 ) . When spinal trauma size ratios were compared , there was no significant difference between treatment groups . Conclusion : Resveratrol treatment revealed better biochemical recovery in the acute stage of trauma than MP treatment . Although resveratrol and combined treatment revealed better neurobehavioral recovery than MP treatment ; resveratrol , MP , and combined treatment modalities improved histopathological recovery at the same level in the final stage of the experiment . Future studies involving different doses of resveratrol and different doses combinations with MP could promise better results as each drug has a different anti-oxidative mechanism of action ABSTRACT Objective “ The obesity epidemic ” has led to an increase in obesity-related conditions including non-alcoholic fatty liver disease ( NAFLD ) , for which effective treatments are in dem and . The polyphenol resveratrol prevents the development of experimental NAFLD through modulation of cellular pathways involved in calorie restriction . We aim ed to test the hypothesis that resveratrol alleviates NAFLD in a r and omised , clinical trial . Material s and methods A total of 28 overweight patients with transaminasemia and histological NAFLD were r and omised 1:1 to placebo or resveratrol 1.5 g daily for 6 months . Twenty-six participants completed the trial and underwent repeated clinical investigation , blood work , MR spectroscopy ; and 19 participants agreed to a repeat liver biopsy . Results Resveratrol treatment was generally not superior to placebo in improving plasma markers of liver injury ( primary outcome : alanine transaminase , p = 0.51 ) . Resveratrol-treated patients showed a 3.8 % decrease in liver lipid content ( p = 0.03 ) , with no difference between the two treatment arms ( p = 0.38 ) and no improvement of histological features .  Resveratrol treatment was not associated with improvements in insulin sensitivity or markers of the metabolic syndrome , except for a transient decrease in systolic BP . Microarray analysis and qRT-PCR revealed no major changes in expression profile . Also , we report a serious adverse event in a patient who developed fever and bicytopenia . Conclusions In this placebo-controlled , high-dose and long-term study , resveratrol treatment had no consistent therapeutic effect in alleviating clinical or histological NAFLD , though there may be a small ameliorating effect on liver function tests and liver fat accumulation Although resveratrol has widely been studied for its potential health benefits , little is known about its metabolic effects in humans . Our aims were to determine whether the polyphenol resveratrol improves insulin sensitivity in type 2 diabetic patients and to gain some insight into the mechanism of its action . After an initial general examination ( including blood chemistry ) , nineteen patients enrolled in the 4-week-long double-blind study were r and omly assigned into two groups : a resveratrol group receiving oral 2 × 5 mg resveratrol and a control group receiving placebo . Before and after the second and fourth weeks of the trial , insulin resistance/sensitivity , creatinine-normalised ortho-tyrosine level in urine sample s ( as a measure of oxidative stress ) , incretin levels and phosphorylated protein kinase B (pAkt):protein kinase B ( Akt ) ratio in platelets were assessed and statistically analysed . After the fourth week , resveratrol  significantly decreased insulin resistance ( homeostasis model of assessment for insulin resistance ) and urinary ortho-tyrosine excretion , while it increased the pAkt : Akt ratio in platelets . On the other h and , it had no effect on parameters that relate to β-cell function ( i.e. homeostasis model of assessment of β-cell function ) . The present study shows for the first time that resveratrol  improves insulin sensitivity in humans , which might be due to a resveratrol-induced  decrease in oxidative stress that leads to a more efficient insulin signalling via the Akt pathway Abstract Aims The anti-inflammatory effects of the polyphenol resveratrol in patients with type 2 diabetes mellitus ( T2DM ) are controversial . Its role on pentraxin 3 ( PTX3 ) concentrations , a human acute phase protein , has never been evaluated . Our aim was to determine whether a two-dosage resveratrol supplementation ( 500 and 40 mg/day ) has an impact on PTX3 values in T2DM patients from a double-blind r and omized placebo-controlled trial .  Variations in total antioxidant status ( TAS ) were evaluated too . Methods A total of 192 T2DM patients were r and omized to receive resveratrol 500 mg/day ( Resv 500 arm ) , resveratrol 40 mg/day ( Resv 40 arm ) or placebo for 6 months . At baseline and at the trial end , PTX3 and TAS values were determined . Results A dose-dependent increase in PTX3 concentrations of 4.7 % ( Resv 40 arm ) and 26.3 % ( Resv 500 arm ) , and 8.0 % reduction after placebo were found . Adjusted mean differences of change versus placebo were 0.16 ( 95 % CI 0.01–0.32 ) and 0.25 ( 0.09–0.42 ) in the Resv 40 and Resv 500 arms , respectively . At subgroup analyses , lower diabetes duration , aspirin , alcohol use , younger age , female gender , smoking ( Resv 500 arm ) and female gender and aspirin use ( Resv 40 arm ) were associated with higher PTX3 increments . A dose-dependent increment in TAS values in the resveratrol arms ( 1.4 and 6.4 % for Resv 40 and Resv 500 , respectively ) , and a reduction in placebo arm ( −8.9 % ) were observed . Adjusted mean differences of change were 28.5 ( 95 % CI 10.1–46.8 ) and 44.8 ( 25.4–64.1 ) in the Resv 40 and Resv 500 arms , respectively . Conclusion Resveratrol supplementation  increased PTX3 and TAS levels in a dose-dependent manner in T2DM patients . At present , potential clinical implication s of these results remain unclear . Clinical Trials.gov IdentifierNCT02244879 Previous research has shown that resveratrol can increase cerebral blood flow ( CBF ) in the absence of improved cognitive performance in healthy , young human subjects during the performance of cognitively dem and ing tasks . This lack of cognitive effects may be due to low bioavailability and , in turn , reduced bioefficacy of resveratrol in vivo . Piperine can alter polyphenol pharmacokinetics , but previous studies have not investigated whether this affects the efficacy of the target compound . Therefore , the objective of the present study was to ascertain whether co-supplementation of piperine with resveratrol affects the bioavailability and efficacy of resveratrol  with regard to cognition and CBF . The present study utilised a r and omised , double-blind , placebo-controlled , within-subjects design , where twenty-three adults were given placebo , trans-resveratrol ( 250 mg ) and trans-resveratrol with 20 mg piperine on separate days at least a week apart . After a 40 min rest/absorption period , the participants performed a selection of cognitive tasks and CBF was assessed throughout the period , in the frontal cortex , using near-IR spectroscopy . The presence of resveratrol and its conjugates in the plasma was confirmed by liquid chromatography-MS analysis carried out following the administration of the same doses in a separate cohort ( n 6 ) . The results indicated that when co-supplemented , piperine and resveratrol significantly augmented CBF during task performance in comparison with placebo and resveratrol alone . Cognitive function , mood and blood pressure were not affected . The plasma concentrations of resveratrol and its metabolites were not significantly different between the treatments , which indicates that co-supplementation of piperine with resveratrol enhances the bioefficacy of resveratrol with regard to CBF effects , but not cognitive performance , and does this without altering bioavailability Abstract High cholesterol is one of the risk factors for atherogenesis , leading to oxidative stress and cardiovascular disease ( CVD ) . The focus of this study was to evaluate the role and the pathways of action of a natural antioxidant , resveratrol , in asymptomatic hypercholesterolemic ( AHC ) individuals . Forty healthy AHCs and normocholesterolemics ( NCs ) participated in the study . They received r and om-order resveratrol and placebo capsules for four weeks . Total antioxidant capacity ( TAC ) , vitamin E and total cholesterol ( TC ) were measured at baseline and at the end of each intervention . Resveratrol provided a direct antioxidant effect in healthy NC individuals , but in AHC individuals , with a higher dem and for antioxidant activity due to higher cholesterol levels , it acted by facilitating an increase in vitamin E. Our findings suggest that resveratrol acts synergistically with other antioxidants against oxidative stress and highlights the importance of hypercholesterolemic individuals consuming natural antioxidants instead of medications to reduce the risk of CVD , while the situation is still reversible Trans-resveratrol , present in high concentration in the skin of red grapes and red wine , has a dose-dependent antiproliferative effect in vitro , prevents the formation of mammary tumors , and has been touted as a chemopreventive agent . Based upon in vitro studies demonstrating that trans-resveratrol downregulates the expression of 1 ) DNA methyltransferases and 2 ) the cancer promoting prostagl and in (PG)E2 , we determined if trans-resveratrol had a dose-related effect on DNA methylation and prostagl and in expression in humans . Thirty-nine adult women at increased breast cancer risk were r and omized in double-blind fashion to placebo , 5 or 50 mg trans-resveratrol twice daily for 12 wk . Methylation assessment of 4 cancer-related genes ( p16 , RASSF-1α , APC , CCND2 ) was performed on mammary ductoscopy specimens . The predominant resveratrol species in serum was the glucuronide metabolite . Total trans-resveratrol and glucuronide metabolite serum levels increased after consuming both trans-resveratrol doses ( P < .001 for both ) . RASSF-1α methylation decreased with increasing levels of serum trans-resveratrol ( P = .047 ) . The change in RASSF-1α methylation was directly related to the change in PGE2 ( P = .045 ) . This work provides novel insights into the effects of trans-resveratrol on the breast of women at increased breast cancer risk , including a decrease in methylation of the tumor suppressor gene RASSF-1α . Because of the limited sample size , our findings should be vali date d in a larger study Polyphenolic compounds , such as resveratrol , have recently received widespread interest because of their ability to mimic effects of calorie restriction . The objective of the present study was to gain more insight into the effects of 30 days resveratrol supplementation on adipose tissue morphology and underlying processes . Eleven healthy obese men were supplemented with placebo and resveratrol for 30 days ( 150 mg per day ) , separated by a 4-week washout period in a double-blind r and omized crossover design . A postpr and ial abdominal subcutaneous adipose tissue biopsy was collected to assess adipose tissue morphology and gene expression using microarray analysis . Resveratrol significantly decreased adipocyte size , with a shift toward a reduction in the proportion of large and very-large adipocytes and an increase in small adipocytes . Microarray analysis revealed downregulation of Wnt and Notch signaling pathways and upregulation of pathways involved in cell cycle regulation after resveratrol supplementation , suggesting enhanced adipogenesis . Furthermore , lysosomal/phagosomal pathway and transcription factor EB were upregulated reflecting an alternative pathway of lipid breakdown by autophagy . Further research is necessary to investigate whether resveratrol improves adipose tissue function BACKGROUND Sirtuin 1 ( Sirt1 ) plays an important role in vascular biology , and influences aspects of age-dependent atherosclerosis . In animals , the sirtuin system is strongly influenced by resveratrol and caloric restriction , but its expression in humans is controversial . This study investigated the effects of resveratrol and caloric restriction on Sirt1 serum concentrations and vascular biomarkers in a healthy human population . METHODS AND RESULTS Forty-eight healthy participants ( 24 women ) aged 55 - 65years were r and omized to either 30days of resveratrol administration ( 500mg/day ) or caloric restriction ( 1000cal/day ) . Blood was collected at baseline and day 30 . Laboratory data analyzed were triglycerides , total cholesterol , HDL , VLDL , LDL , apolipoprotein A1 , apolipoprotein B , lipoprotein ( a ) , non-esterified fatty acids ( NEFA ) , glucose , insulin , oxidative stress , C-reactive protein , and Sirt1 . Expression of the Sirt1 gene was analyzed using real-time PCR . Caloric restriction diminished the abdominal circumference and improved the lipid profile , but not resveratrol intervention . Resveratrol and caloric restriction increased serum concentrations of Sirt1 , from 1.06±0.71 to 5.75±2.98ng/mL ; p<0.0001 , and from 1.65±1.81 to 5.80±2.23ng/mL ; p<0.0001 , respectively . Sirt1 increased in women and men in both interventions . On the other h and expression of Sirt1 mRNA was not different after caloric restriction and resveratrol treatment . CONCLUSIONS Caloric restriction and resveratrol significantly increased plasma concentrations of Sirt1 . The long-term impact of these interventions on atherosclerosis should be assessed BACKGROUND The many putative beneficial effects of the polyphenol resveratrol include an ability to bolster endogenous antioxidant defenses , modulate nitric oxide synthesis , and promote vasodilation , which thereby improves blood flow . Resveratrol may therefore modulate aspects of brain function in humans . OBJECTIVE The current study assessed the effects of oral resveratrol on cognitive performance and localized cerebral blood flow variables in healthy human adults . DESIGN In this r and omized , double-blind , placebo-controlled , crossover study , 22 healthy adults received placebo and 2 doses ( 250 and 500 mg ) of trans-resveratrol in counterbalanced order on separate days . After a 45-min resting absorption period , the participants performed a selection of cognitive tasks that activate the frontal cortex for an additional 36 min . Cerebral blood flow and hemodynamics , as indexed by concentration changes in oxygenated and deoxygenated hemoglobin , were assessed in the frontal cortex throughout the posttreatment period with the use of near-infrared spectroscopy . The presence of resveratrol and its conjugates in plasma was confirmed by HPLC after the same doses in a separate cohort ( n = 9 ) . RESULTS Resveratrol administration result ed in dose-dependent increases in cerebral blood flow during task performance , as indexed by total concentrations of hemoglobin . There was also an increase in deoxyhemoglobin after both doses of resveratrol , which suggested enhanced oxygen extraction , that became apparent toward the end of the 45-min absorption phase and was sustained throughout task performance . Cognitive function was not affected . Resveratrol metabolites were present in plasma throughout the cognitive task period . CONCLUSION These results showed that single doses of orally administered resveratrol can modulate cerebral blood flow variables Resveratrol has been reported to have potent anti-atherosclerotic effects in animal studies . However , there are few interventional studies in human patients with atherosclerogenic diseases . The cardio-ankle vascular index ( CAVI ) reflects arterial stiffness and is a clinical surrogate marker of atherosclerosis . The aim of the present study was to investigate the effect of resveratrol on arterial stiffness assessed by CAVI in patients with type 2 diabetes mellitus (T2DM).In this double-blind , r and omized , placebo-controlled study , 50 patients with T2DM received supplement of a 100 mg resveratrol tablet ( total resveratrol : oligo-stilbene 27.97 mg/100 mg/day ) or placebo daily for 12 weeks . CAVI was assessed at baseline and the end of study . Body weight ( BW ) , blood pressure ( BP ) , glucose and lipid metabolic parameters , and diacron-reactive oxygen metabolites ( d-ROMs ; an oxidative stress marker ) were also measured . Resveratrol supplementation decreased systolic BP ( -5.5 ± 13.0 mmHg ) , d-ROMs ( -25.6 ± 41.8 U.CARR ) , and CAVI ( -0.4 ± 0.7 ) significantly ( P < 0.05 ) and decreased BW ( -0.8 ± 2.1 kg , P = 0.083 ) and body mass index ( -0.5 ± 0.8 kg/m2 , P = 0.092 ) slightly compared to baseline , while there were no significant changes in the placebo group . Decreases in CAVI and d-ROMs were significantly greater in the resveratrol group than in the placebo group . Multivariate logistic regression analysis identified resveratrol supplementation as an independent predictor for a CAVI decrease of more than 0.5.In conclusion , 12-week resveratrol supplementation may improve arterial stiffness and reduce oxidative stress in patients with T2DM . Resveratrol may be beneficial in preventing the development of atherosclerosis induced by diabetes . However , a large-scale cohort study is required to vali date the present findings Objective Resveratrol supplementation improves metabolic health in healthy obese men , but not in patients with type 2 diabetes ( T2D ) when given as add-on therapy . Therefore , we examined whether resveratrol can enhance metabolic health in men at risk of developing T2D . Additionally , we examined if resveratrol can stimulate brown adipose tissue ( BAT ) . Methods Thirteen male first degree relatives ( FDR ) of patients with T2D received resveratrol ( 150 mg/day ) and placebo for 30 days in a r and omized , placebo controlled , cross-over trial . Results Resveratrol significantly improved ex vivo muscle mitochondrial function on a fatty acid-derived substrate . However , resveratrol did not improve insulin sensitivity , expressed as the rate of glucose disposal during a two-step hyperinsulinemic-euglycemic clamp . Also , intrahepatic and intramyocellular lipid content , substrate utilization , energy metabolism , and cold-stimulated 18F-FDG glucose uptake in BAT ( n = 8) remained unaffected by resveratrol . In vitro experiments in adipocytes derived from human BAT confirmed the lack of effect on BAT . Conclusions Resveratrol stimulates muscle mitochondrial function in FDR males , which is in concordance with previous results . However , no other metabolic benefits of resveratrol were found in this group . This could be attributed to subject characteristics causing alterations in metabolism of resveratrol and thereby affecting resveratrol 's effectiveness . Clinical Trials.gov ID NCT02129595 Abstract Aims Oxidative stress plays a pivotal role in the pathogenesis of type 2 diabetes ( T2D ) . In vitro and animal studies have shown that resveratrol exerts an antioxidant effect , but clinical trials addressing this effect in patients with T2D are limited . The aim of this study was to determine whether resveratrol supplementation affects oxidative stress markers in a r and omized , placebo-controlled , double-blind clinical trial . Methods A total of 48 patients with T2D r and omly were assigned to receive 800 mg/day resveratrol or placebo for 2 months . Plasma total antioxidant capacity , malondialdehyde concentration , protein carbonyl and total thiol contents , intracellular superoxide anion ( O2− · ) and hydrogen peroxide ( H2O2 ) in P BMC s , the expression of genes involved in oxidative stress responses ( Nrf2 , SOD , Cat , HO-1 , RAGE , NOS ) in P BMC s , and metabolic and anthropometric parameters were measured at the baseline and at the trial end . Results Compared with the placebo group , resveratrol reduced plasma protein carbonyl content and P BMC s O2− · level and significantly increased plasma total antioxidant capacity and total thiol content . Furthermore , the expression of Nrf2 and SOD was significantly increased after resveratrol consumption . Resveratrol had no significant effects on the metabolic and anthropometric parameters except for a significant reduction in weight , BMI , and blood pressure levels . Resveratrol was well tolerated , and no serious adverse event was occurred . Conclusions Our study demonstrated that 8 weeks of supplementation with 800 mg/day resveratrol has an antioxidant effect in the blood and P BMC s of patients with T2D . Clinical Trial Registry number and website I RCT registration number : I RCT 2015072523336N1 and http://en . search .i rct .ir/view/24752 ABSTRACT Endothelial dysfunction is a surrogate marker of cardiovascular risk . Resveratrol is known to improve endothelial function in animals , however , clinical trials are limited . We hypothesized that the acute trans-resveratrol supplementation improves endothelial function in treated hypertensive patients with endothelial dysfunction . Twenty-four hypertensive patients between 45 and 65 years-old with baseline endothelial dysfunction were enrolled in a r and omized , cross-over , double-blind , placebo-controlled trial . Individuals received either a single dose of trans-resveratrol ( 300 mg ) or placebo and were crossed-over after a one-week washout  period . Blood pressure ( BP ) measurements , aortic systolic blood pressure ( SBP ) and brachial flow-mediated dilation ( FMD ) were performed before and 1.5 hours after the intervention . FMD was significantly increased in women ( 4.2 ± 0.5 vs 7.1 ± 1.3 % , p = 0.026 ) but not in men ( 4.4 ± 0.9 vs 4.9 ± 0.8 % , p = 0.588 ) in the trans-resveratrol group . There was no statistical difference between baseline and final values of brachial BP and also no changes in aortic SBP . Patients with higher low-density lipoprotein  ( LDL ) cholesterol had better FMD response  to trans-resveratrol than patients with lower LDL cholesterol ( 7.4 ± 1.2 vs 4.3 ± 1.0 % , p = 0.004 ) . Our study demonstrated that the acute supplementation of trans-resveratrol promoted an improvement in endothelial function , especially in women and those with higher LDL-cholesterol , despite no changes in BP . List of Abbreviation : Aix : augmentation index ; AP : augmentation pressure ; BP : blood pressure ; BMI : body Mass Index ; CVD : cardiovascular disease ; FMD : flow-mediated dilation ; FRS : Framingham Risk Score ; HDL : high-density lipoprotein ; LDL : low-density lipoprotein ; NO : nitric oxide ; SPSS : Statistical Package for Social Sciences ; ROS : reactive oxygen species ; SBP : systolic blood pressure ; TG : triglycerides IMPORTANCE Resveratrol , a polyphenol found in grapes , red wine , chocolate , and certain berries and roots , is considered to have antioxidant , anti-inflammatory , and anticancer effects in humans and is related to longevity in some lower organisms . OBJECTIVE To determine whether resveratrol levels achieved with diet are associated with inflammation , cancer , cardiovascular disease , and mortality in humans . DESIGN Prospect i ve cohort study , the Invecchiare in Chianti ( InCHIANTI ) Study ( " Aging in the Chianti Region " ) , 1998 to 2009 conducted in 2 villages in the Chianti area in a population -based sample of 783 community-dwelling men and women 65 years or older . EXPOSURES Twenty-four-hour urinary resveratrol metabolites . MAIN OUTCOMES AND MEASURES Primary outcome measure was all-cause mortality . Secondary outcomes were markers of inflammation ( serum C-reactive protein [ CRP ] , interleukin [IL]-6 , IL-1β , and tumor necrosis factor [ TNF ] ) and prevalent and incident cancer and cardiovascular disease . RESULTS Mean ( 95 % CI ) log total urinary resveratrol metabolite concentrations were 7.08 ( 6.69 - 7.48 ) nmol/g of creatinine . During 9 years of follow-up , 268 ( 34.3 % ) of the participants died . From the lowest to the highest quartile of baseline total urinary resveratrol metabolites , the proportion of participants who died from all causes was 34.4 % , 31.6 % , 33.5 % , and 37.4 % , respectively ( P = .67 ) . Participants in the lowest quartile had a hazards ratio for mortality of 0.80 ( 95 % CI , 0.54 - 1.17 ) compared with those in the highest quartile of total urinary resveratrol in a multivariable Cox proportional hazards model that adjusted for potential confounders . Resveratrol levels were not significantly associated with serum CRP , IL-6 , IL-1β , TNF , prevalent or incident cardiovascular disease , or cancer . CONCLUSIONS AND RELEVANCE In older community-dwelling adults , total urinary resveratrol metabolite concentration was not associated with inflammatory markers , cardiovascular disease , or cancer or predictive of all-cause mortality . Resveratrol levels achieved with a Western diet did not have a substantial influence on health status and mortality risk of the population in this study The polyphenol resveratrol is considered to exert many beneficial actions , such as antioxidant , anti-inflammatory , insulin-sensitizer and anticancer effects . Its benefits in patients with type 2 diabetes mellitus ( T2DM ) are controversial . Our aims were to determine whether resveratrol supplementation at two different dosages ( 500 and 40mg/day ) for 6 months i ) reduced the concentrations of C-reactive-protein ( CRP ) and ii ) ameliorated the metabolic pattern of T2DM patients .  In the present double-blind , r and omized , placebo-controlled trial , 192 T2DM patients were r and omized to receive resveratrol 500mg/day ( Resv500arm ) , resveratrol 40mg/day ( Resv40arm ) or placebo for 6-months . At baseline and at the trial end , CRP values , anthropometric , metabolic and liver parameters were determined . No serious adverse event occurred . A dose-dependent , though not significant , CRP decrease of 5.6 % ( Resv40arm ) and 15.9 % ( Resv500arm ) was observed vs placebo . We failed to detect significant differences in weight , BMI , waist circumference , and values of arterial blood pressure , fasting glucose , glycated hemoglobin , insulin , C-peptide , free fatty acids , liver transaminases , uric acid , adiponectin , interleukin-6 , in both the Resv500 and Resv40 arms vs placebo . Total cholesterol and triglycerides slightly increased in the Resv500arm . Subgroup analyses revealed that lower diabetes duration ( in both Resv500 and Resv40arms ) , and , in the Resv500arm , younger age , aspirin use and being a smoker were associated with a significantly higher CRP reduction vs placebo . The supplementations with 40mg/day or 500mg/day resveratrol did neither reduce CRP concentrations , nor improve the metabolic pattern of T2DM patients The red grape constituent resveratrol possesses cancer chemopreventive properties in rodents . The hypothesis was tested that , in healthy humans , p.o . administration of resveratrol is safe and results in measurable plasma levels of resveratrol . A phase I study of oral resveratrol ( single doses of 0.5 , 1 , 2.5 , or 5 g ) was conducted in 10 healthy volunteers per dose level .  Resveratrol and its metabolites were identified in plasma and urine by high-performance liquid chromatography-t and em mass spectrometry and quantitated by high-performance liquid chromatography-UV . Consumption of resveratrol did not cause serious adverse events . Resveratrol and six metabolites were recovered from plasma and urine . Peak plasma levels of resveratrol at the highest dose were 539 ± 384 ng/mL ( 2.4 μmol/L , mean ± SD ; n = 10 ) , which occurred 1.5 h post-dose . Peak levels of two monoglucuronides and resveratrol-3-sulfate were 3- to 8-fold higher . The area under the plasma concentration curve ( AUC ) values for resveratrol-3-sulfate and resveratrol monoglucuronides were up to 23 times greater than those of resveratrol . Urinary excretion of resveratrol and its metabolites was rapid , with 77 % of all urinary agent-derived species excreted within 4 h after the lowest dose . Cancer chemopreventive effects of resveratrol in cells in vitro require levels of at least 5 μmol/L. The results presented here intimate that consumption of high-dose resveratrol might be insufficient to elicit systemic levels commensurate with cancer chemopreventive efficacy . However , the high systemic levels of resveratrol conjugate metabolites suggest that their cancer chemopreventive properties warrant investigation . ( Cancer Epidemiol Biomarkers Prev 2007;16(6):1246–52 ABSTRACT Dietary polyphenols have beneficial effects on adipose tissue mass and function in rodents , but human studies are scarce . In a r and omized , placebo-controlled study , 25 ( 10 women ) overweight and obese humans received a combination of the polyphenols epigallocatechin-gallate and resveratrol ( 282 mg/d , 80 mg/d , respectively , EGCG+RES , n = 11 ) or placebo ( PLA , n = 14 ) supplementation for 12 weeks . Abdominal subcutaneous adipose tissue ( SAT ) biopsies were collected for assessment of adipocyte morphology and micro-array analysis . EGCG+RES had no effects on adipocyte size and distribution compared with PLA . However , we identified pathways contributing to adipogenesis , cell cycle and apoptosis were significantly downregulated by EGCG+RES versus PLA . Furthermore , EGCG+RES significantly decreased expression of pathways related to energy metabolism , oxidative stress , inflammation , and immune defense as compared with PLA . In conclusion , the SAT gene expression profile indicates a reduced cell turnover after 12-week EGCG+RES in overweight-obese subjects . It remains to be eluci date d whether these alterations translate into long-term metabolic effects OBJECTIVE Smokers are characterized by a low- grade systemic inflammatory state and an oxidant-antioxidant imbalance . Few human studies were conducted on the effects of resveratrol , a natural compound with anti-inflammatory and antioxidant properties , and no trial on smokers has been performed to date . We evaluated whether resveratrol has beneficial effects on markers of inflammation and oxidative stress in smokers . METHODS AND RESULTS A r and omized , double- blind , cross-over trial was performed in 50 healthy adult smokers : 25 were r and omly allocated to " resveratrol-first " ( 30-days : 500 mg resveratrol/day , 30-days wash-out , 30-days placebo ) and 25 to " placebo-first " ( 30-days placebo , 30-days wash-out , 30-days 500 mg resveratrol/day ) . Resveratrol significantly reduced C-reactive protein ( CRP ) and triglyceride concentrations , and increased Total Antioxidant Status ( TAS ) values . After analyzing data with general linear models to assess period and carry-over effects , the ratios of the values after resveratrol to those after placebo were respectively : 0.47 ( 95%CI 0.38 - 0.59 ) -CRP- and 0.71 ( 95%CI 0.65 - 0.78 ) -triglycerides- , while TAS increased by 74.2 μmol/L ( 95%CI 60.8 - 87.6 ) . Uric acid , glucose , insulin , cholesterol , liver enzyme concentrations , and weight , waist circumference , and blood pressure values did not significantly change after resveratrol supplementation . CONCLUSIONS Because resveratrol has anti-inflammatory , anti-oxidant , and hypotriglyceridemic effects , its supplementation may beneficially affect the increased cardiovascular risk of healthy smokers Background and Objective Trans-resveratrol is a polyphenol , which is found in red wine and has cancer chemo-preventive properties and disease-preventive properties . The pharmacokinetics of trans-resveratrol have been investigated in single-dose studies and in studies with relatively low dosages . The present study aim ed to investigate the steady-state pharmacokinetics and tolerability of trans-resveratrol 2000 mg twice daily with food , quercetin and alcohol ( ethanol ) . Methods This was a two-period , open-label , single-arm , within-subject control study in eight healthy subjects . The steady-state 12-hour pharmacokinetics of trans-resveratrol 2000 mg twice daily were studied with a st and ard breakfast , a high-fat breakfast , quercetin 500 mg twice daily and 5 % alcohol 100 mL. Trans-resveratrol plasma concentrations were determined using liquid chromatography with t and em mass spectrometry . Results The mean ( SD ) area under the plasma concentration-time curve from 0 to 12 hours ( AUC12 ) and maximum plasma concentration ( Cmax ) of trans-resveratrol  were 3558 ( 2195 ) ng •h/mL and 1274 ( 790 ) ng/mL , respectively , after the st and ard breakfast . The high-fat breakfast significantly decreased the AUC12 and Cmax by 45 % and 46 % , respectively , when compared with the st and ard breakfast . Quercetin 500 mg twice daily or 5 % alcohol 100mL did not influence trans-resveratrol pharmacokinetics . Diarrhoea was reported in six of the eight subjects . Significant but not clinical ly relevant changes from baseline were observed in serum potassium and total bilirubin levels . Conclusion Trans-resveratrol 2000 mg twice daily result ed in adequate exposure and was well tolerated by healthy subjects , although diarrhoea was frequently observed . In order to maximize trans-resveratrol exposure , it should be taken with a st and ard breakfast and not with a high-fat meal . Furthermore , combined intake with quercetin or alcohol did not influence trans-resveratrol exposure Purpose The grape and wine polyphenol resveratrol exerts cardiovascular benefits but evidence from r and omized 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 , r and omized , 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 ( P BMC s ) 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 P BMC s. 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 st and ards , by increasing serum adiponectin , preventing PAI-1 increase and inhibiting atherothrombotic signals in P BMC The search for complementary treatments in primary prevention of cardiovascular disease ( CVD ) is a high-priority challenge . Grape and wine polyphenol resveratrol confers CV benefits , in part by exerting anti-inflammatory effects . However , the evidence in human long-term clinical trials has yet to be established . We aim ed to investigate the effects of a dietary resveratrol-rich grape supplement on the inflammatory and fibrinolytic status of subjects at high risk of CVD and treated according to current guidelines for primary prevention of CVD . Seventy-five patients undergoing primary prevention of CVD participated in this triple-blinded , r and omized , parallel , dose-response , placebo-controlled , 1-year follow-up trial . Patients , allocated in 3 groups , consumed placebo ( maltodextrin ) , a resveratrol-rich grape supplement ( resveratrol 8 mg ) , or a conventional grape supplement lacking resveratrol , for the first 6 months and a double dose for the next 6 months . In contrast to placebo and conventional grape supplement , the resveratrol-rich grape supplement  significantly decreased high-sensitivity C-reactive protein ( -26 % , p = 0.03 ) , tumor necrosis factor-α ( -19.8 % , p = 0.01 ) , plasminogen activator inhibitor type 1 ( -16.8 % , p = 0.03 ) , and interleukin-6/interleukin-10 ratio ( -24 % , p = 0.04 ) and increased anti-inflammatory interleukin-10 ( 19.8 % , p = 0.00 ) . Adiponectin ( 6.5 % , p = 0.07 ) and soluble intercellular adhesion molecule-1 ( -5.7 % , p = 0.06 ) tended to increase and decrease , respectively . No adverse effects were observed in any patient . In conclusion , 1-year consumption of a resveratrol-rich grape supplement  improved the inflammatory and fibrinolytic status in patients who were on statins for primary prevention of CVD and at high CVD risk ( i.e. , with diabetes or hypercholesterolemia plus ≥1 other CV risk factor ) . Our results show for the first time that a dietary intervention with grape resveratrol could complement the gold st and ard therapy in the primary prevention of CVD Current advances in enzyme bioscavenger prophylactic therapy against chemical warfare nerve agent ( CWNA ) exposure are moving towards the identification of catalytic bioscavengers that can de grade large doses of organophosphate ( OP ) nerve agents without self destruction . This is a preferred method compared to therapy with the purified stoichiometric bioscavenger , butyrylcholinesterase , which binds OPs 1:1 and would thus require larger doses for treatment . Paraoxonase-1 ( PON-1 ) is one such catalytic bioscavenger that has been shown to hydrolyze OP insecticides and contribute to detoxification in animals and humans . Here we investigated the effects of a common red wine ingredient , Resveratrol ( RSV ) , to induce the expression of PON-1 in the human hepatic cell line HC04 and evaluated the protection against CWNA simulants . Dose-response curves showed that a concentration of 20 microM RSV was optimal in inducing PON-1 expression in HC04 cells . RSV at 20 microM increased the extracellular PON-1 activity approximately 150 % without significantly affecting the cells . Higher doses of RSV were cytotoxic to the cells . Resveratrol also induced PON-1 in the human lung cell line A549 . RSV pre-treatment significantly ( P = 0.05 ) protected the hepatic cells against exposure to 2x LD(50 ) of soman and sarin simulants . However , lung cells were protected against soman simulant exposure but not against sarin simulant exposure following RSV treatment . In conclusion , these studies indicate that dietary inducers , such as RSV , can up-regulate PON-1 , a catalytic bioscavenger , which can then hydrolyze and protect against CWNA-induced toxicity , providing a prospect i ve new method to protect against CWNA exposure
Resveratrol  significantly improves adiponectin but does not affect leptin concentrations .
Abstract The results of human clinical trials have revealed that the effects of resveratrol on adipokines are inconsistent .