stilbenes and Body-Weight

The incidence of overweight and obesity has reached epidemic proportions, making the control of body weight and its complications a primary health problem. Diet has long played a first-line role in preventing and managing obesity. However, beyond the obvious strategy of restricting caloric intake, growing evidence supports the specific antiobesity effects of some food-derived components, particularly (poly)phenolic compounds. The relatively new rediscovery of active brown adipose tissue in adult humans has generated interest in this tissue as a novel and viable target for stimulating energy expenditure and controlling body weight by promoting energy dissipation. This review critically discusses the evidence supporting the concept that the antiobesity effects ascribed to (poly)phenols might be dependent on their capacity to promote energy dissipation by activating brown adipose tissue. Although discrepancies exist in the literature, most in vivo studies with rodents strongly support the role of some (poly)phenol classes, particularly flavan-3-ols and resveratrol, in promoting energy expenditure. Some human data currently are available and most are consistent with studies in rodents. Further investigation of effects in humans is warranted.

Topics: Adipose Tissue, Brown; Adrenergic Agonists; Animals; Anti-Obesity Agents; Body Weight; Diet; Disease Models, Animal; Energy Metabolism; Flavonoids; Humans; Obesity; Polyphenols; Resveratrol; Stilbenes; Tea; Thermogenesis; Uncoupling Protein 1

Science constantly seeks to identify new molecules that could be used as dietary functional ingredients in the fight against obesity and its co-morbidities. Among them, polyphenols represent a group of molecules of increasing interest. One of the most widely studied polyphenols is resveratrol (

Topics: Adipose Tissue; Animals; Body Weight; Clinical Trials as Topic; Diet; Drug Evaluation, Preclinical; Energy Metabolism; Humans; Obesity; Resveratrol; Stilbenes

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 randomized, placebo-controlled, double-blind clinical trial.. A total of 48 patients with T2D randomly 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 (O. Compared with the placebo group, resveratrol reduced plasma protein carbonyl content and PBMCs O. Our study demonstrated that 8 weeks of supplementation with 800 mg/day resveratrol has an antioxidant effect in the blood and PBMCs of patients with T2D. Clinical Trial Registry number and website IRCT registration number: IRCT2015072523336N1 and http://en.search.irct.ir/view/24752 .

Topics: Adult; Aged; Antioxidants; Biomarkers; Body Weight; C-Reactive Protein; Diabetes Mellitus, Type 2; Dietary Supplements; Double-Blind Method; Female; Humans; Hydrogen Peroxide; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Placebos; Protein Carbonylation; Resveratrol; Stilbenes

Resveratrol has been reported to lower glycemia in rodent models of type 2 diabetes associated with the stimulation of glucagon-like peptide 1 (GLP-1), which is known to slow gastric emptying, stimulate insulin secretion, and suppress glucagon secretion and energy intake.. We evaluated the effects of 5 wk of resveratrol treatment on GLP-1 secretion, gastric emptying, and glycemic control in type 2 diabetes.. Fourteen patients with diet-controlled type-2 diabetes [mean ± SEM glycated hemoglobin (HbA1c): 6.4 ± 0.2% (46.4 ± 2.2 mmol/mol)] received resveratrol (500 mg twice daily) or a placebo over two 5-wk intervention periods with a 5-wk washout period in between in a double-blind, randomized, crossover design. Before and after each intervention period (4 visits), body weight and HbA1c were measured, and patients were evaluated after an overnight fast with a standardized mashed-potato meal labeled with 100 μg (13)C-octanoic acid to measure blood glucose and plasma GLP-1 concentrations and gastric emptying (breath test) over 240 min. Daily energy intake was estimated from 3-d food diaries during the week before each visit.. Fasting and postprandial blood glucose and plasma total GLP-1 as well as gastric emptying were similar at each assessment, and the change in each variable from weeks 0 to 5 did not differ between resveratrol and placebo groups. Similarly, changes in HbA1c, daily energy intake, and body weight after 5 wk did not differ between the 2 treatments.. In patients with diet-controlled type 2 diabetes, 5 wk of twice-daily 500 mg-resveratrol supplementation had no effect on GLP-1 secretion, glycemic control, gastric emptying, body weight, or energy intake. Our observations do not support the use of resveratrol for improving glycemic control. This trial was registered at www.anzctr.org.au as ACTRN12613000717752.

Topics: Aged; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Double-Blind Method; Energy Intake; Female; Gastric Emptying; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Postprandial Period; Resveratrol; Stilbenes

Topics: Adrenal Glands; Adult; Appetite; Body Weight; Clinical Trials as Topic; Humans; Lipids; Male; Stilbenes; Thyroid Gland

Aflatoxin B1 (AFB1) is an extremely hazardous food/feed pollutant, posing a serious threat to health of human and animals. Particularly, exposure to AFB1 provokes enterocytes oxidative stress and inflammation, which lead to intestinal damage. Polydatin (PD), a stilbenoid glucoside, is known to possess antioxidant and anti-inflammatory properties and is being investigated for use in various disorders. The present study was intended at investigating the protective efficacy of polydatin against AFB1-induced ileum damage in mice. Kunming male mice received oral gavage of AFB1 (300 μg/kg body weight/day) and PD (100 mg/kg body weight/day) for 18 days. The results showed that mice exposed to AFB1 exhibited the impaired morphology, the suppressed disaccharidase activities, the down-regulated mRNA expressions of tight junction protein genes, oxidative stress, inflammation and the up-regulated mRNA expressions of genes related to mitophagy in the ileum, whereas PD treatment reversed the AFB1-induced disruption of ileal structure, digestion, barrier function, redox and immune status. The findings of the present study suggested that PD may have a potential benefit in preventing AFB1-induced ileum damage.

Topics: Aflatoxin B1; Animals; Body Weight; Glucosides; Humans; Ileum; Inflammation; Liver; Male; Mice; Oxidative Stress; RNA, Messenger; Stilbenes

Polydatin (PD) has many pharmacological activities; however, its bioavailability is still a critical cornerstone issue. The present investigation aimed to develop a novel oral formula of polydatin-loaded chitosan nanoparticles (PD-CSNPs) to improve PD therapeutic potential against type 2 diabetes. The interaction mechanism between PD and CSNPs was studied via Monte Carlo and molecular dynamics simulations. The formula was prepared and characterized by FTIR, XRD, TEM, and dynamic light scattering. The release profile of PD was studied in vitro, as well as the cytotoxicity effect versus Vero cell line and antidiabetic activity in type 2 diabetic rats were investigated. The practical results verified the formation of PD-CSNPs with entrapment efficiency of about 96.74 ± 0.39%, size average 144.25 ± 3.37 nm, and the prolonged release pattern was less than 20% after 12 hrs. The cytotoxicity study confirmed the safety of the formula at low and high doses. Moreover, the in vivo study revealed that PD-CSNPs exhibited highly significant antidiabetic efficacy in diabetic rats compared to free PD. To conclude, the current investigation proved that CSNPs are promising nanocarriers for nontoxic and effective PD delivery against type 2 diabetes.

Topics: Animals; Biomarkers; Body Weight; Chitosan; Chlorocebus aethiops; Diabetes Mellitus, Type 2; Drug Carriers; Drug Liberation; Glucosides; Hypoglycemic Agents; Male; Molecular Conformation; Molecular Dynamics Simulation; Nanoparticles; Particle Size; Rats; Rats, Wistar; Safety; Stilbenes; Vero Cells

The study investigates the effects of pterostilbene (PTE) on exercise endurance and circadian rhythm in sleep-restricted (SR) mice.. PTE ameliorates SR-induced exercise intolerance associated with circadian misalignment and mitochondrial dysfunction through AMPK/SIRT1/PGC-1α pathway.

Topics: AMP-Activated Protein Kinases; Animals; Body Weight; Circadian Rhythm; Eating; Fatigue; Male; Mice, Inbred C57BL; Mitochondria, Muscle; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphorylation; Physical Conditioning, Animal; Physical Endurance; Sirtuin 1; Sleep Deprivation; Stilbenes

Diabetes mellitus (DM) causes ototoxicity by inducing oxidative stress, microangiopathy, and apoptosis in the cochlear sensory hair cells. The natural anti-oxidant pterostilbene (PTS) (trans-3,5-dimethoxy-4-hydroxystylbene) has been reported to relieve oxidative stress and apoptosis in DM, but its role in diabetic-induced ototoxicity is unclear. This study aimed to investigate the effects of dose-dependent PTS on the cochlear cells of streptozotocin (STZ)-induced diabetic rats. The study included 30 albino male Wistar rats that were randomized into five groups: non-diabetic control (Control), diabetic control (DM), and diabetic rats treated with intraperitoneal PTS at 10, 20, or 40 mg/kg/day during the four-week experimental period (DM + PTS10, DM + PTS20, and DM + PTS40). Distortion product otoacoustic emission (DPOAE) tests were performed at the beginning and end of the study. At the end of the experimental period, apoptosis in the rat cochlea was investigated using caspase-8, cytochrome-c, and terminal deoxyribonucleotidyl transferase-mediated dUTP-biotin end labeling (TUNEL). Quantitative real-time polymerase chain reaction was used to assess the mRNA expression levels of the following genes: CASP-3, BCL-associated X protein (BAX), and BCL-2. Body weight, blood glucose, serum insulin, and malondialdehyde (MDA) levels in the rat groups were evaluated. The mean DPOAE amplitude in the DM group was significantly lower than the means of the other groups (0.9-8 kHz; P < 0.001 for all). A dose-dependent increase of the mean DPOAE amplitudes was observed with PTS treatment (P < 0.05 for all). The Caspase-8 and Cytochrome-c protein expressions and the number of TUNEL-positive cells in the hair cells of the Corti organs of the DM rat group were significantly higher than those of the PTS treatment and control groups (DM > DM + PTS10 > DM + PTS20 > DM + PTS40 > Control; P < 0.05 for all). PTS treatment also reduced cell apoptosis in a dose-dependent manner by increasing the mRNA expression of the anti-apoptosis BCL2 gene and by decreasing the mRNA expressions of both the pro-apoptosis BAX gene and its effector CASP-3 and the ratio of BAX/BCL-2 in a dose-dependent manner (P < 0.05 compared to DM for all). PTS treatment significantly improved the metabolic parameters of the diabetic rats, such as body weight, blood glucose, serum insulin, and MDA levels, consistent with our other findings (P < 0.05 compared to DM for all). PTS decreased the cochlear damage caused b

Topics: Acoustics; Animals; bcl-2-Associated X Protein; Body Weight; Caspase 3; Cochlea; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Gene Expression Regulation; Male; Ototoxicity; Protective Agents; Rats, Wistar; Stilbenes; Streptozocin

Visceral obesity and fatty liver are prevalent in postmenopausal women. The stilbene-rich extract of Cajanus cajan (L.) Millsp. has been reported to prevent ovariectomy-induced and diet-induced weight gain in animal models, and stilbenoids from C. cajan are thought to have the potential to prevent postmenopausal obesity and fatty liver.. Cajanolactone A (CLA) is the main stilbenoid from C. cajan with osteoblastogenic promoting activity. This study investigated the potential of CLA to prevent postmenopausal obesity and fatty liver. Underlying mechanisms were also investigated.. Ovariectomized C57BL/6 mice fed a regular diet were used as mimics of postmenopausal women and given 10, 20, or 40 mg/kg/d of CLA, 0.1 mg/kg/d of estradiol valerate (EV, positive control), or vehicle (OVX) orally for 16 weeks. Mice of the same age subjected to a sham operation were used as control (Sham). Body weights were recorded every 2 weeks for 16 weeks. Body compositions were analyzed via micro-CT. Serum levels of lipids, adipocytokines and aminotransferases were measured using the relevant kits. mRNA levels of genes of interest were detected by RT-qPCR. Proteomic study of perigonadal white adipose tissue (pWAT) was performed using tandem-mass-tags-based proteomic technology combined with Parallel-Reaction-Monitoring (PRM) validation.. CLA showed potential equivalent to that of EV to prevent ovariectomy-induced overweight, obesity, dyslipidemia, liver steatosis and liver dysfunction, but did not prevent uterine atrophy. In the liver, CLA significantly inhibited ovariectomy-induced upregulation in expression of lipogenic genes SREBP-1c and ChREBP, and stimulated the mRNA expression of apolipoprotein B gene ApoB. In pWAT, CLA reversed, or partially reversed ovariectomy-induced downregulation in the expression of a number of metabolism- and mitochondrial-function-related proteins, including Ndufa3, Pcx, Pdhb, Acly, Acaca, Aldh2, Aacs and Echs1. In addition, ovariectomy-inhibited mRNA expression of Pdhb, Aacs, Acsm5, Echs1, and Aldh2 genes in pWAT was also reversed.. CLA was demonstrated to be a potential non-estrogen-like drug candidate for prevention of postmenopausal obesity and fatty liver. The underlying mechanism might involve the inhibition of lipogenesis and promotion of triglycerides output in the liver, and the promotion of metabolism and mitochondrial functions of visceral white adipose tissue.

Topics: Adipose Tissue, White; Animals; Anti-Obesity Agents; Apolipoprotein B-100; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Body Weight; Cajanus; Diet; Female; Gene Expression Regulation; Lipogenesis; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Ovariectomy; Postmenopause; Stilbenes; Triglycerides

With more powerful penetrability and ionizing capability, high energetic neutron radiation (HENR) often poses greater threats than photon radiation, especially on such occasions as nuclear bomb exposure, nuclear accidents, aerospace conduction, and neutron-based radiotherapy. Therefore, there emerges an urgent unmet demand in exploring highly efficient radioprotectants against HENR. In the present study, high-throughput 14.1 MeV neutrons were generated by the high-intensity D-T fusion neutron generator (HINEG) and succeeded in establishing the acute radiation syndrome (ARS) mouse model induced by HENR. A series of preclinical studies, including morphopathological assessment, flow cytometry, peripheral complete blood, and bone marrow karyocyte counting, were applied showing much more serious detriments of HENR than the photon radiation. In specific, it was indicated that surviving fraction of polydatin- (PD-) treated mice could appreciably increase to up to 100% when they were exposed to HENR. Moreover, polydatin contributed much in alleviating the HENR-induced mouse body weight loss, spleen and testis indexes decrease, and the microstructure alterations of both the spleen and the bone marrow. Furthermore, we found that the HENR-damaged hematopoiesis was greatly prevented by PD treatment in such aspects as bone marrow hemocytogenesis, splenocytes balancing, or even the peripheral blood cellularity. The additional IHC investigations revealed that PD could exert potent hematopoiesis-promoting effects against HENR via suppressing apoptosis and promoting the antioxidative enzymes such as HO-1.

Topics: Animals; Antioxidants; Apoptosis; Body Weight; Bone Marrow Cells; Glucosides; Hematopoiesis; Heme Oxygenase-1; Kelch-Like ECH-Associated Protein 1; Lung; Male; Mice, Inbred BALB C; Neutrons; Radiation, Ionizing; Sirtuin 1; Spleen; Stilbenes; Survival Analysis

Obesity and related comorbidities are a major health concern. The drugs used to treat these conditions are largely inadequate or dangerous, and a well-researched approach based on nutraceuticals would be highly useful. Pterostilbene (Pt), i.e., 3,5-dimethylresveratrol, has been reported to be effective in animal models of obesity, acting on different metabolic pathways. We investigate here its ability to induce browning of white adipose tissue. Pt (5 µM) was first tested on 3T3-L1 mature adipocytes, and then it was administered (352 µmol/kg/day) to mice fed an obesogenic high-fat diet (HFD) for 30 weeks, starting at weaning. In the cultured adipocytes, the treatment elicited a significant increase of the levels of Uncoupling Protein 1 (UCP1) protein-a key component of thermogenic, energy-dissipating beige/brown adipocytes. In vivo administration antagonized weight increase, more so in males than in females. Analysis of inguinal White Adipose Tissue (WAT) revealed a trend towards browning, with significantly increased transcription of several marker genes (

Topics: 3T3-L1 Cells; Adipocytes, Brown; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Apoptosis Regulatory Proteins; Basic Helix-Loop-Helix Transcription Factors; Body Weight; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Female; Gene Expression Regulation; Male; Mice; Mice, Inbred C57BL; Obesity; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; PPAR gamma; Sirtuin 1; Stilbenes; T-Box Domain Proteins; Thermogenesis; Uncoupling Protein 1

Drug resistant bacteria are winning the fight over antibiotics with some bacteria not responding to any antibiotics, threatening modern medicine as we know it. The development of new, effective and safe antibiotics is critical for addressing this issue. Ramizol, a first-in-class styrylbenzene based antibiotic, is an investigational drug indicated for Clostridium difficile infections (CDI). The objective of this range-finding study was to evaluate the potential general toxicity (based on toxicological endpoints selected) and toxicokinetics of Ramizol in male and female rats that may arise from repeated exposure via oral gavage over a test period of at least 14 days at doses of 50 mg/kg, 500 mg/kg and 1500 mg/kg. There were no mortalities in this study and no Ramizol-related clinical observations. Additionally, there were no changes in mean body weight, body weight gain, food consumption or food efficiency for male and female rats attributable to Ramizol administration. The observed pharmacokinetic behavior showed the presence of Ramizol in plasma at 24 hours post-dosing combined with increasing AUC(0-24) values during the course of this study in groups administered 1500 mg/kg/day, which suggests that at least some dosing groups will show accumulation of compound during repeated dose studies. These toxicology results have shown Ramizol is well-tolerated at very high concentrations in rats and support the further drug development of Ramizol as a first-in-class antibiotic for the treatment of CDI.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Benzoates; Body Weight; Clostridium Infections; Dose-Response Relationship, Drug; Female; Male; Rats; Rats, Sprague-Dawley; Stilbenes

Resveratrol as well as caloric restriction were shown to extend lifespan in some model organisms and may possibly delay onset of ageing-related diseases in humans. Yet, resveratrol supplementation does not always extend lifespan of animal models or improve health status of humans. Because of interindividual differences in human microbiota, resveratrol metabolite production in the gut differs. While some individuals produce lunularin and dihydroresveratrol in their gut, others produce dihydroresveratrol only. Therefore, we addressed the question whether these metabolites differ in their biological impact on ageing and intraperitoneally injected 13-month-old C57BL/6JRj mice on an ad-libitum (AL) HFD with resveratrol, dihydroresveratrol or lunularin (24 mg/kg bodyweight; 3 times/week). Compared to mice injected with vehicle (AL-control), resveratrol and dihydroresveratrol did not change bodyweight and had no impact on insulin or glucose levels while lunularin slightly reduced feed intake and bodyweight gain. CR-mice showed lowered cholesterol, insulin and leptin levels, elevated adiponectin and phosphorylated AMPK levels in liver as well as increased transcription of Pck1 and Pgc1α when compared to the AL-control. In contrast, injections with the test substances did not change these parameters. We therefore conclude that in our model, resveratrol, lunularin and dihydroresveratrol did not act as CR mimetics.

Topics: Animals; Bibenzyls; Blood Glucose; Body Weight; Caloric Restriction; Diet, High-Fat; Eating; Gene Expression Regulation; Heme Oxygenase-1; Injections, Intraperitoneal; Insulin; Leptin; Liver; Membrane Proteins; Mice, Inbred C57BL; Phenols; Resveratrol; Sirtuin 1; Stilbenes

Pterostilbene (PTE) is a natural dimethylated analog of resveratrol, which exerts antioxidative, hypolipidemic and hypoglycemic effects; however, the underlying mechanism is not yet clear. In this study, we evaluated the effects of PTE on diabetic rats and clarified the underlying mechanism. Diabetes was induced in rats by streptozotocin (STZ) and a high-sugar and high-fat diet. Rats were then treated with PTE (20, 40 and 80 mg/kg/d) for 8 weeks. Oral glucose tolerance test (OGTT) was performed to measure the glycometabolism of the diabetic rats at the end of the treatment. Fasting blood glucose (FBG), fasting insulin (FINS) and lipid profile were determined using an automatic biochemistry analyzer and serum inflammatory factors were analyzed by enzyme-linked immunosorbent assay. Serum superoxide dismutase (SOD) and malondialdehyde (MDA) were also analyzed by spectrophotometry to evaluate the anti-oxidant effects. The expression of proteins of PPARγ and PI3K/Akt signaling pathway related proteins in adipose tissue of the diabetic rats was analyzed by Western blotting. PTE treatment significantly reduced weight loss, FBG, insulin resistance, serum lipid levels and inflammatory factors. PTE treatment also inhibited oxidative stress by decreasing MDA expression and increasing SOD expression. Simultaneously, PTE treatment significantly ameliorated morphological impairment of the pancreas in diabetic rats. Furthermore, PTE treatment significantly increased the protein expression of PPARγ, PI3K, p-Akt, GLUT4 and IRS-1 in adipose tissues of diabetic rats. This study suggests that PTE can exert antidiabetic effects via the PI3K/Akt signaling pathway.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diet, High-Fat; Fasting; Gene Expression Regulation; Hypoglycemic Agents; Insulin; Lipids; Male; Oxidative Stress; Pancreas; Phosphatidylinositol 3-Kinases; PPAR gamma; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Signal Transduction; Stilbenes

The decline of female reproductive function is an early phenotype of aging in humans, occurring only midway through the lifespan. Yet the number of women delaying pregnancy continues to rise in industrialized societies due to personal or socioeconomic circumstances, often resulting in subfertility or difficulty conceiving. There are few defined mechanisms associated with this etiology, and equally few effective therapies. To combat this problem, we used a novel emerging model, Nothobranchius guentheri, that recapitulates the age-associated spectrum of changes that adversely affect human fertility. We hypothesized that resveratrol (RSV), which activates SirT1 as an oxidative stress sensor and longevity assurance enzyme, would improve female fecundity in mid-life. RSV, a polyphenol found in grapes and red wine, has been touted as an anti-aging dietary supplement due to its ability to prolong both lifespan and health span. SirT1 is an NAD+ dependent histone deacetylase, whose activity is regulated by the nicotinamide to NAD+ salvage pathway, especially the rate-limiting enzyme NAMPT. We found that female N. guentheri fed 600μgRSV/g food into mid-life (~20weeks), beginning at sexual maturity, showed increased embryo production compared to those on Control diet. Furthermore, the RSV-fed fish had significantly increased NAMPT. This suggests that dietary RSV has a positive effect on female fertility, and that it may become an effective therapy to regulate sirtuin activity and combat reproductive senescence.

Topics: Age Factors; Animal Feed; Animals; Antioxidants; Body Weight; Diet; Female; Fertility; Fish Proteins; Fishes; Nicotinamide Phosphoribosyltransferase; Ovary; Resveratrol; Sexual Maturation; Sirtuin 1; Stilbenes

Topics: Adipocytes; Adipogenesis; Animals; Body Weight; Bone Marrow; Caffeic Acids; CCAAT-Enhancer-Binding Protein-alpha; Down-Regulation; Fatty Acid-Binding Proteins; Female; Forkhead Box Protein O3; Kruppel-Like Transcription Factors; Osteogenesis; Osteoporosis; PPAR gamma; Prednisone; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Up-Regulation; Wnt Signaling Pathway

The consumption of a high-fat diet (HFD) and obesity have been associated not only with metabolic diseases but also with neuropsychiatric diseases, such as depression and anxiety. However, results on the effects of an HFD on anxiety are controversial, since both anxiogenic and anxiolytic effects have been reported. In this study, we evaluated the effects of both short- and long-term intake of an HFD on anxiety-like behaviors. To explore the impact of time on the association between an HFD and anxiety, mice were fed with an HFD for 4 weeks or 12 weeks. Compared with control-diet mice, mice given an HFD for 4 weeks displayed anxiolytic-like behaviors. At the same time, we observed decreased SIRT1 expression in the mPFC and the amygdala of HFD-fed mice. Moreover, resveratrol, an activator of SIRT1, reversed the anxiolytic-like behaviors in HFD-fed mice. However, after 12 weeks of consuming a high-fat diet, mice did not exhibit any anti-anxiety behavior or further decreases in SIRT1 expression in the aforementioned brain regions compared with CD-fed mice. When EX-527, a SIRT1 inhibitor, was intraperitoneally injected, we observed anxiolytic effects in the CD-fed mice but not in the 12-week HFD-fed mice. Collectively, our data demonstrate that exposure to a short-term HFD can induce anxiolytic behaviors, which may be associated with decreased SIRT1 in the mPFC and the amygdala. However, this effect is abolished when the high-fat diet is extended to 12 weeks. Together, these results demonstrate that SIRT1 plays an essential role in regulating mood-related behaviors in HFD-fed mice.

Topics: Animals; Anxiety; Blood Glucose; Body Weight; Brain; Carbazoles; Diet, High-Fat; Gene Expression Regulation; Male; Mice, Inbred C57BL; Psychotropic Drugs; Resveratrol; Sirtuin 1; Stilbenes; Time Factors

Topics: Acetyl-CoA Carboxylase; Animals; Benzoxazoles; Body Weight; Diabetes Mellitus; Enzyme Activators; Fatty Acid Synthases; Fatty Liver; Gene Expression Regulation; Glucose Intolerance; Heterocyclic Compounds, 4 or More Rings; Hypoglycemic Agents; Male; Metabolic Syndrome; Mice, Inbred C57BL; Molecular Docking Simulation; Resveratrol; Sirtuin 1; Sterol Regulatory Element Binding Proteins; Stilbenes

The present study was aimed to investigate the effect of PVC on reproductive competence in adult male Wistar rats. Further, the study also encompasses the protective effect of trans-resveratrol on PVC-induced reproductive toxicity in rats. Adult male rats weighing 210-240 g were administered with either PVC at two different doses 100 and 500 mg/kg body weight, orally, daily for 60 days or resveratrol (20 mg/kg body weight/day) through gavage for 60 days on alternate days or both PVC (500 mg/kg body weight) and resveratrol. The results revealed significant reduction in the weights of reproductive organs, epididymal sperm count, viable-, motile-, and HOS-tail coiled sperm and testicular daily sperm production, steroidogenic enzyme activities, serum testosterone levels in PVC treated rats. Conversely the levels of lipid peroxidation increased significantly with a decrease in activity levels of antioxidant enzymes in the testis of PVC exposed rats. Exposure to PVC resulted in reduction in epithelial thickness and seminiferous tubule diameter. No significant changes in the selected reproductive variables were observed in the resveratrol alone treated control rats, whereas, co-administration of resveratrol and PVC resulted in a significant improvement in steroidogenesis and spermatogenesis and mitigated oxidative stress over PVC exposed rats.

Topics: Animals; Antioxidants; Body Weight; Dose-Response Relationship, Drug; Enzymes; Lipid Peroxidation; Male; Polyvinyl Chloride; Rats, Wistar; Reproduction; Resveratrol; Stilbenes

Because resveratrol (RSV) has been shown to improve learning and memory, so we investigated the potential benefit of RSV on learning and memory deficits in juvenile mice fed with a HC diet and explored the molecular mechanisms underlying this process.. Six-week-old C57BL/6J mice were divided into three different diet groups: control, HC diet, and HC + RSV diet. Serum insulin and insulin-like growth factor 1 (IGF-1) levels were measured using enzyme-linked immunosorbent assays. Protein expression was examined by immunohistochemistry and western blotting.. Administration of RSV daily (30 mg/kg) prevented the HC diet-induced increase in juvenile animal body weight but did not improve any other physiological conditions, including fasting blood glucose and serum cholesterol, triglyceride, insulin, and IGF-1 levels. However, RSV did prevent learning and memory deficits in the HC group. Peroxisome proliferator-activated receptor gamma (PPARγ) was downregulated in the CA1 region of the hippocampus in both the HC and HC + RSV groups, but the reduction was significantly greater in the HC + RSV group (P < .01 compared with the HC group). Moreover, although the HC diet reduced the number of p16-positive neurons, the HC + RSV diet significantly upregulated p16 expression in the CA1 region of the hippocampus (P < .01 compared with the HC group).. RSV protected against learning and memory impairments in juvenile animals fed with a HC diet, possibly via upregulation of p16 or downregulation of PPARγ in the hippocampal CA1 region.

Topics: Animals; Biomarkers; Body Weight; CA1 Region, Hippocampal; Diet, High-Fat; Female; Learning Disabilities; Male; Maze Learning; Memory; Memory Disorders; Mice, Inbred C57BL; Neuroprotection; Nootropic Agents; Random Allocation; Resveratrol; Sirtuin 1; Stilbenes

The aim of the present study was to investigate effects of resveratrol (RSV) over ovarian hyperstimulation syndrome (OHSS) in rat model.. 24 female Wistar rats (22 days old) were divided into four groups. Group 1 (control group; n = 6) received 0.1 ml intraperitoneal (IP) saline from days 22-26; group 2 (mild-stimulated group; n = 6) received 10 IU pregnant mare serum gonadotropin (PMSG) on day 24 and 10 IU of hCG 48 h later (day 26); group 3 (OHSS group; n = 6) was given 10 IU of PMSG for 4 consecutive days from day 22 and 30 IU hCG on the fifth day to induce OHSS; group 4 (OHSS + RSV group; n = 6) was treated the same as group 3, but received 60 mg/kg RSV 2 h before PMSG injection for 4 consecutive days and 2 h before the hCG injection on the fifth day.. Weight gain was highest in the OHSS group. Ovarian weights were lower in the treatment group than OHSS group. Peritoneal fluid VEGF levels were lower for RSV group compared to group 2 and 3. Total VEGF immunoreactivity was higher in OHSS group than group 1, 2 and 4.. These results indicate that RSV is beneficial for prevention of OHSS by reducing the increases in body and ovarian weight and VEGF activity. These effects may be mediated by anti-inflammatory, anti-oxidant and anti-angiogenic capacity of RSV.

Topics: Animals; Antioxidants; Body Weight; Disease Models, Animal; Female; Gonadotropins, Equine; Humans; Ovarian Hyperstimulation Syndrome; Ovary; Rats; Rats, Wistar; Resveratrol; Statistics, Nonparametric; Stilbenes; Vascular Endothelial Growth Factor A

Topics: Animals; Biomarkers; Body Weight; Bone and Bones; Disease Models, Animal; Glucosides; Humans; Mice; Organ Size; Osteoporosis; Ovariectomy; Plant Extracts; Protective Agents; Stilbenes; X-Ray Microtomography

Recent studies revealed that sirtuin 1 (SIRT1) is involved in the regulation of energy metabolism and its agonist resveratrol showed anti-obesity effect. This study aims to determine whether BTM-0512, a novel derivative of resveratrol, acts as an antagonist of obesity and to explore its possible mechanisms. High-fat diet (HFD)-induced obese mice were intragastrically administered with BTM-0512 (5, 10, and 20 mg/kg/day) or resveratrol (10 mg/kg/day). It was found that the body weight, Lee's index, ratio of visceral adipose tissue (VAT) to body weight, and blood glucose were significantly reduced in BTM-0512-treated mice when compared with those in mice treated with resveratrol. BTM-0512 up-regulated the expressions of SIRT1, full length PRDM16 (fPRDM16), total PRDM16 (tPRDM16, including fPPRDM16 and other PRDM16 isoforms), and uncoupling protein 1 (UCP1) in both brown and subcutaneous adipose tissues. Although BTM-0512 and resveratrol also up-regulated SIRT1 and tPRDM16 levels in VAT of HFD-induced obese mice, the expressions of fPRDM16, UCP1, and TMEM26 were down-regulated. In mouse primary subcutaneous preadipocytes cultured with or without adipogenic medium, BTM-0512 up-regulated fPRDM16, tPRDM16, and UCP1 expressions, which was reversed by SIRT1 antagonists. But in cultured brown and visceral adipocytes, the UCP1 protein level showed no significant change after treatment with 1 μM of BTM-0512. Moreover, transfection with human SIRT1 plasmid reduced lipid deposit, as well as the mRNA levels of fPRDM16, UCP1, and TMEM26, in cultured human visceral adipose-derived stem cells. In conclusion, BTM-0512 has stronger anti-obesity effect than resveratrol, which might be associated with activation of beige remodeling in subcutaneous adipose tissue.

Topics: Adipocytes; Adipose Tissue, Beige; Adipose Tissue, Brown; Animals; Blotting, Western; Body Weight; Cells, Cultured; Diet, High-Fat; DNA-Binding Proteins; Gene Expression; Humans; Male; Mice, Inbred C57BL; Molecular Structure; Obesity; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Sirtuin 1; Stilbenes; Subcutaneous Fat; Transcription Factors; Uncoupling Protein 1

SAMP8 mice exhibit multiple metabolic characteristics associated with age, and it is a suitable candidate for researching aging associated metabolic dysfunction.. We aimed to 1) explore how key metabolic markers will be altered in both liver and adipose tissue with aging in SAMP8 mice; and 2) how the combination of vitamin D (VD) with resveratrol (RSV) will affect aging associated metabolic impairment in liver and adipose tissue from SAMP8 mice.. SAMP8 mice and their control SAMR1 mice were divided into 5 groups, i.e. SAMR1, SAMP8, SAMP8 mice supplemented with VD, RSV and VD combined with RSV group, respectively. At the end of the intervention, glucose and insulin tolerance, p-AMP-activated protein kinase (AMPK) and amyloid precursor protein (APP), and endoplasmic reticulum (ER) stress markers in liver and adipose tissue, adiponectin secretion, p-NF-κBp65 and TNF-α protein expression in adipose tissue were determined.. Compared to SAMR1 control, SAMP8 mice demonstrate impaired glucose tolerance and reduction in circulating adiponectin level; in the liver, SAMP8 mice have reduction in p-Aktser473, elevation in PTP1B and APP, p-eIF2α, GRP78 and p-JNK protein expression. In epididymal (EPI) fat, SAMP8 mice also have elevated p-Aktser473 and PTP1B compared to SAMR1 mice. In both epididymal (EPI) and subcutaneous (SC) fat, there were elevated ER stress markers, reduced p-AMPK and elevated APP, as well as elevated p-NF-κBp65 and TNF-α protein expression from SAMP8 compared to SAMR1 mice. In liver, the combined intervention significantly restored p-Aktser473, p-eIF2α and p-JNK protein expression. In both EPI and SC fat, the combined intervention is effective for reducing p-NF-κB p65 and TNF-α in both fat depot, while only partially reduced ER stress markers in SC fat. As for adiponectin, their combination is unable to reverse reduction in adiponectin level. Adiponectin secretion in SC fat from VD, RSV and VDRSV group were also significantly reduced compared to SAMR1.. The combined intervention might exert greater beneficial effects for reversing aging associated metabolic dysfunction in liver and adipose tissue from SAMP8 mice.

Topics: Adipose Tissue; Aging; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Blood Glucose; Body Weight; Drug Combinations; Drug Evaluation, Preclinical; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Glucose Tolerance Test; Insulin Resistance; Liver; Male; Mice, Mutant Strains; Organ Size; Oxidative Stress; Resveratrol; Stilbenes; Vitamin D

Semen banking is often advised to male patients undergoing chemotherapy as the damage induced is profound and often irreversible. However, low success rates of assisted reproductive techniques (ART) using banked semen have led to the quest for alternative methods to treat chemotherapy-induced infertility. The present study therefore aimed to study the role of resveratrol against cisplatin induced testicular damage. Male albino mice were divided into five groups (n = 6 each), viz. normal control, resveratrol vehicle (4% ethanol), Cisplatin (7.5 mg/kg b.wt/week for 4 weeks), Resveratrol (1 mg/kg b.wt./orally for 28 days) and Resveratrol and Cisplatin combination group. Cisplatin treatment led to an increase in the activity of lactate dehydrogenase and an increase in the levels of lipid peroxidation. Glutathione levels were found to decrease with a concomitant increase in the levels of oxidized glutathione and altered status of antioxidant enzymes. Increased DNA fragmentation was also evident which was further confirmed by histopathological and FT-IR analysis. Resveratrol treatment in combination with cisplatin showed great promise in bringing down the damage statistics to near normal values in most of the parameters studied. Further studies in this direction are however needed to develop an alternative to current procedures adopted to treat chemotherapy-induced male infertility.

Topics: Animals; Antineoplastic Agents; Body Weight; Cisplatin; Injections, Intraperitoneal; Lipid Peroxidation; Male; Mice; Organ Size; Protective Agents; Resveratrol; Spermatozoa; Stilbenes; Structure-Activity Relationship; Testis

Lipogenesis is a process that involves the fatty acids synthesis. Resveratrol and enalapril have been studied for their beneficial physiological properties on the glucose and lipid metabolism.. The aim of the present study was to evaluate the oral administration of resveratrol and enalapril effects on glucose and lipid metabolism, evaluating the white pad lipogenesis genes expression in mice.. Swiss male mice were divided into four groups and treated for eight weeks as follows: Standard diet ad libitum (G1); Standard diet + Resveratrol (G2); Standard diet + Enalapril (G3); Standard diet + Resveratrol + Enalapril (G4), where resveratrol was administered with the food and enalapril with the water. Body weight, lipid profile, adiposity, glycemic parameters and epididymal adipocytes area were assessed. The expression levels of FAS, ACC, PPARγ and SREBP-1c were assessed by RT-PCR.. The main findings showed an improvement in the insulin sensitivity and glucose tolerance in the group G2 as compared to G1. Similar results were found for the fasting glucose levels. Decreased triglycerides were observed in the animals treated with resveratrol and enalapril, along with decreased weight of the epididymal adipose tissue in the animals of the G2 group. A mild reduction in the group G4 as compared to the group G1 was observed. Decreased mRNA expression of FAS, ACC and PPARγ in the G4 group when compared to the G1 group were observed.. In conclusion the resveratrol and enalapril association improved the glucose and lipid profiles by modulating the expression of some lipogenesis genes, which are critical regulators of metabolic homeostasis.

Topics: Adipocytes; Adipogenesis; Adipose Tissue, White; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Body Weight; Diet, High-Fat; Enalapril; Humans; Insulin Resistance; Lipid Metabolism; Lipogenesis; Male; Mice; Resveratrol; Stilbenes

Studies have demonstrated that resveratrol (a natural polyphenol) and caloric restriction activate Sirtuin-1 (SIRT1) and induce autophagy. Furthermore, autophagy is induced by the SIRT1-FoxO signaling pathway and was recently shown to be a critical protective mechanism against non-alcoholic fatty liver disease (NAFLD) development. We aimed to compare the effects of resveratrol and caloric restriction on hepatic lipid metabolism and elucidate the mechanism by which resveratrol supplementation and caloric restriction alleviate hepatosteatosis by examining the molecular interplay between SIRT1 and autophagy.. Eight-week-old male Wistar rats (40) were divided into four groups: the STD group, which was fed a standard chow diet; the HFD group, which was fed a high-fat diet; HFD-RES group, which was fed a high-fat diet plus resveratrol (200 mg/kg.bw); and the HFD-CR group, which was fed a high-fat diet in portions containing 70% of the mean intake of the HFD group rats. The groups were maintained for 18 weeks. Metabolic parameters, Oil Red O and hematoxylin-eosin staining of the liver, and the mRNA and protein expression of SIRT1, autophagy markers and endoplasmic reticulum(ER) stress-associated genes in the liver were assessed after the 18-week treatment. We found that resveratrol (200 mg/kg bw) and caloric restriction (30%) partially prevented hepatic steatosis and hepatocyte ballooning, increased the expression of SIRT1 and autophagy markers while decreasing ER stress markers in the liver and alleviated lipid metabolism disorder. Moreover, caloric restriction provided superior protection against HFD-induced hepatic fatty accumulation compared with resveratrol and the effects were associated with decreased total energy intake and body weight.. We conclude that the SIRT1-autophagy pathway and decreased ER stress are universally required for the protective effects of moderate caloric restriction (30%) and resveratrol (a pharmacological SIRT1 activator) supplementation against HFD-induced hepatic steatosis.

Topics: Animals; Autophagy; Blotting, Western; Body Weight; Caloric Restriction; Diet, High-Fat; Endoplasmic Reticulum Stress; Energy Intake; Lipid Metabolism; Liver; Male; Non-alcoholic Fatty Liver Disease; Organ Size; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Resveratrol; Sirtuin 1; Stilbenes

Obesity is clearly associated with an increased risk of breast cancer in postmenopausal women. The purpose was to determine if obesity alters the adipocyte adipokine secretion profile, thereby altering the adipose-dependent paracrine/endocrine growth microenvironment surrounding breast cancer cells (MCF7). Additionally, we determined whether resveratrol (RSV) supplementation can counteract any obesity-dependent effects on breast cancer tumor growth microenvironment. Obese ZDF rats received standard chow diet or diet supplemented with 200 mg/kg body weight RSV. Chow-fed Zucker rats served as lean controls. After 6 weeks, conditioned media (CM) prepared from inguinal subcutaneous adipose tissue (scAT) was added to MCF7 cells for 24 hrs. Experiments were also conducted using purified isolated adipocytes to determine whether any endocrine effects could be attributed specifically to the adipocyte component of adipose tissue. scAT from ZDF rats promoted cell cycle entry in MCF7 cells which was counteracted by RSV supplementation. RSV-CM had a higher ratio of ADIPO:LEP compared to ZDF-CM. This altered composition of the CM led to increased levels of pAMPKT172, p27, p27T198 and AdipoR1 while decreasing pAktT308 in MCF7 cells grown in RSV-CM compared to ZDF-CM. RSV-CM increased number of cells in G0/G1 and decreased cells in S-phase compared to ZDF-CM. Co-culture experiments revealed that these obesity-dependent effects were driven by the adipocyte component of the adipose tissue. Obesity decreased the ratio of adiponectin:leptin secreted by adipocytes, altering the adipose-dependent growth microenvironment resulting in increased breast cancer cell proliferation. Supplementation with RSV reversed these adipose-dependent effects suggesting a potential for RSV as a nutritional supplementation to improve breast cancer treatment in obese patients.

Topics: Adipocytes; Adipokines; Adipose Tissue; Animals; Body Weight; Breast Neoplasms; Cell Cycle; Cell Proliferation; Coculture Techniques; Culture Media, Conditioned; Endocrine System; Female; Humans; Male; MCF-7 Cells; Obesity; Rats; Rats, Zucker; Resveratrol; Stilbenes; Time Factors

Resveratrol (RSV), a natural polyphenol, has been reported to produce effect on genes transcription in lipid metabolism. In this study, we aim to explore the novel mechanisms of RSV on the regulation of caveolin-1 (Cav-1) transcription. Via body weight, blood glucose, serum lipid, and liver pathology detection, we found that RSV decreased body weight, blood glucose and lipid accumulation in rats fed high-fat diet. Based on co-immunoprecipitation (Co-IP) and western blotting assay, we found that RSV up-regulated klf5 phosphorylation and decreased the interaction of klf5 with c-Myc, which were accompanied by down-regulation of Cav-1 expression in livers of rats fed with high-fat diet. Moreover, in HEK293 cells, we observed RSV enhanced klf5 phosphorylation and separated the interaction of klf5 with c-Myc through inhibiting the activation of PI3K/PKD1/Akt pathway, which maybe promoted c-Myc binding to the promoter to inhibit Cav-1 expression. The results of the present study demonstrated that RSV activated klf5 phosphorylation by inhibiting PI3K/PKD1/Akt pathway, and then attenuated the interaction of klf5 with c-Myc, subsequently probably promoted the c-Myc binding to the promoter to repress Cav-1 expression.

Topics: Animals; Blood Glucose; Body Weight; Caveolin 1; Diet, High-Fat; Down-Regulation; HEK293 Cells; Humans; Kruppel-Like Transcription Factors; Lipids; Liver; Male; Phosphatidylinositol 3-Kinases; Phosphorylation; Promoter Regions, Genetic; Protein Kinase C; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Resveratrol; Stilbenes; Transcription, Genetic; Transforming Growth Factor beta

Nutritional interventions based on the use of natural bioactive compounds might offer new possibilities for reshaping obesity-associated bacterial dysregulation or dysbiosis and improving health. We evaluated whether pterostilbene supplementation could induce changes in gut microbiota composition and whether these modifications were associated with improvements in metabolic variables.. Zucker (fa/fa) rats were given a standard diet supplemented (n = 10) or not (n = 9) with pterostilbene (15 mg/kg body weight/day) by oral gavage for 6 weeks. Faucal samples at the beginning and at the end of the intervention period were analyzed by Illumina Mi-Seq sequencing approach. Pterostilbene exerted protective antiobesity effects, improved metabolic function (insulin sensitivity), and induced structural changes in gut microbiota composition. A decrease in the levels of Firmicutes and an increase in Verrucomicrobia phyla were detected in the pterostilbene-treated group. Bacterial species belonging to genera Akkermansia and Odoribacter were also increased. A strong inverse correlation between Akkermansia muciniphila and body weight was evidenced. Odoribacter splanchnicus showed a negative correlation with adiposity.. Pterostilbene modifies intestinal bacteria composition toward a healthier microbial profile and suggests that the antiobesity effects induced in Zucker rats could be associated with an enrichment of the mucin-degrading bacterial members, namely Akkermansia and Odoribacter genus.

Topics: Animals; Anti-Obesity Agents; Body Weight; Dietary Supplements; Dysbiosis; Gastrointestinal Microbiome; Obesity; Rats, Zucker; Stilbenes

To analyze whether a combination of quercetin (Q) and resveratrol (RSV) would induce a white adipose tissue (WAT) browning effect.. Thirty-six rats were fed an obesogenic diet and divided into four groups: control, treated with RSV (15 mg/kg body weight/day; RSV group), treated with Q (30 mg/kg body weight/day; Q group), or treated with both polyphenols (RSV + Q group).. After 6 weeks, body and WAT weights were significantly reduced in the RSV + Q group. In perirenal WAT of the control, RSV, and Q groups, white unilocular adipocytes appeared in the majority of cells, while in the RSV + Q group numerous multilocular adipocytes with positive immunostaining for UCP1 were observed. The presence of UCP1 was confirmed by Western blot. This group also revealed increased mRNA levels of Cidea, Hocx9, Bmp4, Slc27a1, Pat2, Atgl, and Atp5d. Interscapular brown adipose tissue weight showed no differences between groups, but the Cidea mRNA level was increased in the RSV group, the Cox-2 mRNA level in the RSV + Q group, and UCP1 protein expression in the RSV and the RSV + Q groups.. This study demonstrated that the RSV + Q combination produces a brown-like remodeling effect in perirenal WAT, as well as increased UCP1 protein expression in interscapular brown adipose tissue.

Topics: Adipocytes; Adipose Tissue, Brown; Adipose Tissue, White; Amino Acid Transport Systems, Neutral; Animals; Apoptosis Regulatory Proteins; Body Weight; Bone Morphogenetic Protein 4; Cyclooxygenase 2; Diet; Fatty Acid-Binding Proteins; Lipase; Quercetin; Rats; Resveratrol; RNA, Messenger; Stilbenes; Symporters; Uncoupling Protein 1

Inflammation and oxidative stress (OS) are key points in age progression. Both processes impact negatively in cognition and in brain functions. Resveratrol (RV) has been postulated as a potent antioxidant natural compound, with rejuvenating properties. Inducing a metabolic stress by high-fat (HF) diet in aged C56/BL6 (24 months) led to cognitive disturbances compared with control age mated and with young mice. These changes were prevented by RV. Molecular determinations demonstrated a significant increase in some inflammatory parameters (TNF-α, Cxcl10, IL-1, IL-6, and Ccl3) in old mice, but slight changes in OS machinery. RV mainly induced the recovery of the metabolically stressed animals. The study of key markers involved in senescence and rejuvenation (mitochondrial biogenesis and Sirt1-AMPK-PGC1-α) demonstrated that RV is also able to modulate the changes in these cellular metabolic pathways. Moreover, changes of epigenetic marks (methylation and acetylation) that are depending on OS were demonstrated. On the whole, results showed the importance of integrative role of different cellular mechanisms in the deleterious effects of age in cognition and the beneficial role of RV. The work presented in this study showed a wide range of processes modified in old age and by metabolic stress, weighting the importance of each one and the role of RV as a possible strategy for fighting against.

Topics: 5-Methylcytosine; Animals; Biomarkers; Body Weight; Cognitive Dysfunction; Energy Intake; Gene Expression Regulation; Glucose Tolerance Test; Inflammation; Male; Maze Learning; Memory; Mice, Inbred C57BL; Neuroprotective Agents; Oxidative Phosphorylation; Oxidative Stress; Resveratrol; Stilbenes; Stress, Physiological

Since the early 1990s human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) emerged as a global health pandemic, with sub-Saharan Africa the hardest hit. While the successful roll-out of antiretroviral (ARV) therapy provided significant relief to HIV-positive individuals, such treatment can also elicit damaging side-effects. Here especially HIV protease inhibitors (PIs) are implicated in the onset of cardio-metabolic complications such as type-2 diabetes and coronary heart disease. As there is a paucity of data regarding suitable co-treatments within this context, this preclinical study investigated whether resveratrol (RSV), aspirin (ASP) or vitamin C (VitC) co-treatment is able to blunt side-effects in a rat model of chronic PI exposure (Lopinavir/Ritonavir treatment for 4 months). Body weights and weight gain, blood metabolite levels (total cholesterol, HDL, LDL, triglycerides), echocardiography and cardiac mitochondrial respiration were assessed in PI-treated rats ± various co-treatments. Our data reveal that PI treatment significantly lowered body weight and cardiac respiratory function while no significant changes were found for heart function and blood metabolite levels. Moreover, all co-treatments ameliorated the PI-induced decrease in body weight after 4 months of PI treatment, while RSV co-treatment enhanced cardiac mitochondrial respiratory capacity in PI-treated rats. This pilot study therefore provides novel hypotheses regarding RSV co-treatment that should be further assessed in greater detail.

Topics: Animals; Body Weight; HIV Protease Inhibitors; Male; Mitochondria, Heart; Rats; Rats, Wistar; Resveratrol; Stilbenes

Topics: AMP-Activated Protein Kinases; Animals; Body Weight; Cardiovascular Diseases; Eating; Female; Fetal Growth Retardation; Heart; Male; Myocardium; Oxidative Stress; Phosphorylation; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes

3'-Hydroxypterostilbene (3'-HPT) is one of the active constituents of Sphaerophysa salsula and Pterocarpus marsupium. Despite many proposed therapeutic applications, the safety profile of 3'-HPT has not been established. The present work investigated 90 day repeated oral dose and reproductive (developmental) toxicity of 3'-HPT as a test substance in rats as per OECD guidelines. 90 day toxicity was conducted in sixty Sprague Dawley rats of each sex (120 rats), grouped into six dosage groups of 0 (control), 0 (control recovery), 20 (low dose), 80 (mid dose), 200 (high dose) and 200 (high dose recovery) mg/kg bwt/day (body weight/day) respectively. For the reproductive toxicity study forty Wistar rats of each sex (80 rats) divided into four dosage groups received 0 (vehicle control), 20 (low dose), 100 (mid dose) and 200 (high dose) mg/kg bwt/day of 3'-HPT respectively for a period of two weeks while pre-mating, mating, on the day before sacrifice, in females during pregnancy and four days of lactation period. Results showed no significant differences in body weight, food intake, absolute organ weight, haematology, with no adverse effects (toxicity) on biochemical values nor any abnormal clinical signs or behavioural changes were observed in any of the control/treatment groups, including reproductive and developmental parameters, gross and histopathological changes. In conclusion, the results suggested a No-Observed-Adverse-Effect-Level (NOAEL) of 200 mg/kg bwt/day in rats after oral administration, implying 3'-HPT did not exhibit any toxicity under the study conditions employed.

Topics: Administration, Oral; Animals; Body Weight; Dose-Response Relationship, Drug; Eating; Female; Humans; Lactation; Plant Extracts; Pregnancy; Pterocarpus; Rats; Reproduction; Stilbenes

The herbicide itself and the degradation products are highly toxic on biological systems. The aim of this study is to investigate the potential toxic effects of trifluralin (TRF) on the urinary system of male rats and to investigate the protective effects of resveratrol (RSV) in TRF-induced urinary system damage. A total of 35 male Wistar rats were randomly divided into: (1) control group, (2) sham group, (3) low dose TRF group (0.8 g/kg/day), (4) high dose TRF group (2 g/kg/day) and (5) high dose TRF + RSV group 10 mg/kg/day. RSV was administered for 21 days by intragastric gavage at a dose of 10 mg/kg/day after induction of TRF. Kidney, ureter and urinary bladder tissue was examined using light microscopy and ultrastructurally. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling was performed to detect apoptosis. Superoxide dismutase (SOD), glutathion peroxidase (GPx) and malondialdehyde (MDA) levels were also evaluated biochemically for oxidative stress parameters. Histological evaluation showed that TRF increases apoptosis and oxidative stress, causes histological tissue damages and biochemical changes in the kidneys but does not cause any damage to the ureter and bladder. Treatment with RSV significantly attenuated tissue damage in the urinary system of rats. Apopitotic cells were significantly decreased in the treatment group. Additionally, treatment with RSV decreased SOD and GPx levels and increased MDA levels in the kidney tissue of animals subjected to TRF. These results show that RSV can significantly minimize histological damage and biochemical differences in treating TRF-induced kidney injury in rats.

Topics: Animals; Antioxidants; Apoptosis; Body Weight; Dose-Response Relationship, Drug; Glutathione Peroxidase; In Situ Nick-End Labeling; Kidney Diseases; Male; Malondialdehyde; Oxidative Stress; Rats; Rats, Wistar; Resveratrol; Stilbenes; Superoxide Dismutase; Trifluralin; Urinary Tract

The aim of this study was to analyze whether the combination of resveratrol and quercetin showed additive or synergic effects on body fat accumulation and triacylglycerol metabolism in adipose tissue from rats fed an obesogenic diet.. Rats were divided into four dietary groups: a control group and three groups each treated with either resveratrol (15 mg/kg/day; RSV), quercetin (30 mg/kg/day; Q), or both (15 mg resveratrol/kg/day and 30 mg quercetin/kg/day; RSV + Q) for 6 weeks. White adipose tissues from several anatomical locations were dissected. Serum parameters were analyzed by using commercial kits. The activities of fatty acid synthase and heparin-releasable lipoprotein lipase (HR-LPL) were measured using spectrophotometric and fluorimetric methods, and protein expression of acetyl-CoA carboxylase (ACC), adipose tissue triglyceride lipase (ATGL), and hormone-sensitive lipase (HSL) by western blot.. The administration of either resveratrol or quercetin separately did not induce significant reductions in adipose tissue weights. By contrast, the combination of both molecules led to a significant reduction in all the fat depots analyzed. The percentage of reduction in each tissue was greater than the calculated additive effect. HR-LPL activity was reduced in RSV and RSV + Q groups. The activity of HSL was not modified. By contrast, ACC was inhibited and ATGL increased only by the combination of both polyphenols.. The results obtained demonstrate a synergistic effect between resveratrol and quercetin and suggest that when these molecules are combined, a great number of metabolic pathways involved in adipose tissue triacylglycerol accumulation are affected.

Topics: Acetyl-CoA Carboxylase; Adipose Tissue, White; Animals; Blood Glucose; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Drug Synergism; Fatty Acid Synthases; Fatty Acids, Nonesterified; Hydrogen-Ion Concentration; Lipid Metabolism; Lipoprotein Lipase; Male; Organ Size; Quercetin; Rats; Rats, Wistar; Resveratrol; Sterol Esterase; Stilbenes; Triglycerides

Maturation of the auditory pathway is dependent on the central nervous system myelination and it can be affected by pathologies such as neonatal hypoxic ischemic (HI) encephalopathy. Our aim was to evaluate the functional integrity of the auditory pathway and to visualize, by histological and cellular methods, the damage to the brainstem using a neonatal rat model of HI brain injury. To carry out this morphofunctional evaluation, we studied the effects of the administration of the antioxidants nicotine, melatonin, resveratrol and docosahexaenoic acid after hypoxia-ischemia on the inferior colliculus and the auditory pathway. We found that the integrity of the auditory pathway in the brainstem was altered as a consequence of the HI insult. Thus, the auditory brainstem response (ABR) showed increased I-V and III-V wave latencies. At a histological level, HI altered the morphology of the inferior colliculus neurons, astrocytes and oligodendricytes, and at a molecular level, the mitochondria membrane potential and integrity was altered during the first hours after the HI and reactive oxygen species (ROS) activity is increased 12 h after the injury in the brainstem. Following antioxidant treatment, ABR interpeak latency intervals were restored and the body and brain weight was recovered as well as the morphology of the inferior colliculus that was similar to the control group. Our results support the hypothesis that antioxidant treatments have a protective effect on the functional changes of the auditory pathway and on the morphological damage which occurs after HI insult.

Topics: Animals; Animals, Newborn; Antioxidants; Astrocytes; Body Weight; Disease Models, Animal; Docosahexaenoic Acids; Evoked Potentials, Auditory, Brain Stem; Gliosis; Hypoxia-Ischemia, Brain; Inferior Colliculi; Melatonin; Neurons; Neuroprotective Agents; Nicotine; Oligodendroglia; Organ Size; Random Allocation; Rats, Sprague-Dawley; Reactive Oxygen Species; Resveratrol; Stilbenes

Low-grade inflammation is seen with obesity and is suggested to be a mediator of insulin resistance. The eliciting factor of low-grade inflammation is unknown but increased permeability of gut bacteria-derived lipopolysaccharides (LPS) resulting in endotoxemia could be a candidate. Here we test the effect of LPS and the anti-inflammatory compound resveratrol on glucose homeostasis, insulin levels and inflammation. Mice were subcutaneously implanted with osmotic mini pumps infusing either low-dose LPS or saline for 28 days. Half of the mice were treated with resveratrol delivered through the diet. LPS caused increased inflammation of the liver and adipose tissue (epididymal and subcutaneous) together with enlarged spleens and increased number of leukocytes in the blood. Resveratrol specifically reduced the inflammatory status in epididymal fat (reduced expression of TNFa and Il1b, whereas the increased macrophage infiltration was unaltered) without affecting the other tissues investigated. By LC-MS, we were able to quantitate resveratrol metabolites in epididymal but not subcutaneous adipose tissue. LPS induced insulin resistance as the glucose-stimulated insulin secretion during an oral glucose tolerance test was increased despite similar plasma glucose level resulting in an increase in the insulinogenic index (IGI; delta0-15insulin/delta0-15glucose) from 13.73 to 22.40 pmol/mmol (P < 0.001). This aberration in insulin and glucose homeostasis was normalized by resveratrol.. Low-dose LPS enhanced the glucose-stimulated insulin secretion without affecting the blood glucose suggesting increased insulin resistance. Resveratrol restored LPS-induced alteration of the insulin secretion and demonstrated anti-inflammatory effects specifically in epididymal adipose tissue possibly due to preferential accumulation of resveratrol metabolites pointing towards a possible important involvement of this tissue for the effects on insulin resistance and insulin secretion.

Topics: Adipose Tissue; Animals; Antioxidants; Blood Glucose; Body Weight; Epididymis; Gene Expression Profiling; Glucose; Glucose Tolerance Test; Homeostasis; Inflammation; Insulin; Insulin Resistance; Insulin Secretion; Leukocytes; Lipopolysaccharides; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Osmosis; Resveratrol; Stilbenes

Heterotopic ossification (HO) consists of ectopic cartilage and bone formation following severe trauma or invasive surgeries, and a genetic form of it characterizes patients with Fibrodysplasia Ossificans Progressiva (FOP). Recent mouse studies showed that HO was significantly inhibited by systemic treatment with a corticosteroid or the retinoic acid receptor γ agonist Palovarotene. Because these drugs act differently, the data raised intriguing questions including whether the drugs affected HO via similar means, whether a combination therapy would be more effective or whether the drugs may hamper each other's action. To tackle these questions, we used an effective HO mouse model involving subcutaneous implantation of Matrigel plus rhBMP2, and compared the effectiveness of prednisone, dexamathaosone, Palovarotene or combination of. Each corticosteroid and Palovarotene reduced bone formation at max doses, and a combination therapy elicited similar outcomes without obvious interference. While Palovarotene had effectively prevented the initial cartilaginous phase of HO, the steroids appeared to act more on the bony phase. In reporter assays, dexamethasone and Palovarotene induced transcriptional activity of their respective GRE or RARE constructs and did not interfere with each other's pathway. Interestingly, both drugs inhibited the activity of a reporter construct for the inflammatory mediator NF-κB, particularly in combination. In good agreement, immunohistochemical analyses showed that both drugs markedly reduced the number of mast cells and macrophages near and within the ectopic Matrigel mass and reduced also the number of progenitor cells. In sum, corticosteroids and Palovarotene appear to block HO via common and distinct mechanisms. Most importantly, they directly or indirectly inhibit the recruitment of immune and inflammatory cells present at the affected site, thus alleviating the effects of key HO instigators.

Topics: Animals; Anti-Inflammatory Agents; Body Weight; Cartilage; Cell Movement; Dexamethasone; Disease Models, Animal; Drug Therapy, Combination; Genes, Reporter; Macrophages; Mast Cells; Mice, Inbred C57BL; NF-kappa B; Ossification, Heterotopic; Prednisone; Pyrazoles; Retinoids; Stilbenes; Transfection; Treatment Outcome

While resveratrol (RSV) is associated with the prevention of high-fat (HF) diet-induced insulin resistance, the effects on bone health combined with an HF-diet is unknown. Therefore, we determined the effect of RSV on bone microarchitecture in the presence of an HF-diet, while also elucidating molecular adaptations within bone that could contribute to bone health status.. Male C57BL6 mice were provided control (10% fat) or HF-diet (60% fat) in the presence or absence of RSV for 12 weeks. While RSV prevented HF diet-induced glucose intolerance, HF-RSV compromised tibial microarchitecture, mineral mass, and strength. The compromised outcomes following HF-RSV corresponded with higher markers of osteoclast-activation and bone-resorption (decreased OPG/RANKL ratio; increased cathepsin K), as well as higher markers of tibial mitochondrial content. A molecular model of elevated mitochondrial content (RIP140 knock out (KO) mice) was utilized to determine proof-of-principle that increasing mitochondrial content coincides with decrements in bone health. RIP140 KO mice displayed higher markers of mitochondrial content, and similar to HF-RSV, had compromised bone microarchitecture, lower BMD/strength, and higher markers of osteoclast-activation/bone-resorption.. These data show that in the presence of an HF-diet, RSV negatively alters bone health, a process associated with increased mitochondrial content and markers of bone resorption.

Topics: Adaptor Proteins, Signal Transducing; Animals; Body Weight; Bone Density; Bone Resorption; Diet, High-Fat; Male; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Nuclear Proteins; Nuclear Receptor Interacting Protein 1; Osteoclasts; RANK Ligand; Resveratrol; Stilbenes; Tibia

The main objective of current genetic modifications in crops is to boost agricultural production or to develop GM crops with an improved nutrient profile by introducing a new trait to the plants. A GM crop surpassing the ability of the introduced genetic characteristics has not been developed yet. Here, we show that the resveratrol-enriched rice DJ526, a GM crop, has unexpectedly high beneficial health effects surpassing the introduced genetic characteristic of resveratrol synthetic ability. The synergistic effect of its innate and transgenic properties not only ameliorates age-related deterioration but also boosts motor coordination and physical strength during the aging process. The gene expression profiling analyses by DNA chip showed that the gene expression pattern of mice fed resveratrol-enriched rice DJ526 was very different from mice fed either resveratrol or Dongjin rice alone, respectively, modifying expression of genes related to aging regulation, cell differentiation, extracellular matrix, neurogenesis, or secretion.

Topics: Adipose Tissue; Aging; Animals; Behavior, Animal; Body Weight; Collagen; Crops, Agricultural; Extracellular Matrix; Female; Food, Fortified; Gene Expression Profiling; Mice; Mice, Inbred C57BL; Motor Skills; Muscle Strength; Nutritive Value; Oligonucleotide Array Sequence Analysis; Oryza; Plants, Genetically Modified; Resveratrol; Stilbenes

Many studies have provided evidence to demonstrate the beneficial renal effects of resveratrol (RESV) due to its antioxidant character and its capacity for activation of surtuin 1. However, the molecular mechanisms underlying the protective role of RESV against kidney injury are still incompletely understood. The present study used Lepr db/db (db/db) and Lepr db/m (db/m) mice as models to evaluate the effect of RESV on diabetic nephropathy (DN). RESV reduced proteinuria and attenuated the progress of renal fibrosis in db/db mice. Treatment with RESV markedly attenuated the diabetes-induced changes in renal superoxide dismutase copper/zinc, superoxide dismutase manganese, catalase, and malonydialdehyde as well as the renal expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), α-smooth muscle actin (α-SMA), and E-cadherin in db/db mice. The kidney expression of the IGF-1 receptor (IGF-1R) was increased in db/db mice, but the expression of 3-hydroxy-3-methylglutaryl reductase degradation (HRD1), a ubiquitin E3 ligase, was significantly decreased in the DN model. RESV treatment dramatically decreased IGF-1R and increased HRD1 expressions, consistent with data obtained with HKC-8 cells. HRD1 physically interacted with IGF-1R in HKC-8 cells and liquid chromatography and tandem mass spectrometry (LC-MS/MS) data supported the concept that IGF-1R is one of the HRD1 substrates. HRD1 promoted the IGF-1R ubiquitination for degradation in HKC-8 cells, and the down-regulation of HRD1 reversed the protective effects of RESV in HKC-8 cells. In summary, we have demonstrated that RESV reduces proteinuria and attenuates the progression of renal fibrosis in db/db mice. These protective effects of RESV on DN were associated with the up-regulation of HRD1, induced by RESV, and the promotion of IGF-1R ubiquitination and degradation.

Topics: Animals; Biomarkers; Body Weight; Cell Line; Chromatography, Liquid; Diabetes Mellitus, Experimental; Down-Regulation; Epithelial-Mesenchymal Transition; Humans; Kidney; Male; Mice, Inbred C57BL; Organ Size; Oxidative Stress; Protective Agents; Protein Binding; Proteolysis; Receptor, IGF Type 1; Resveratrol; RNA, Messenger; Stilbenes; Tandem Mass Spectrometry; Transforming Growth Factor beta; Ubiquitin-Protein Ligases; Ubiquitination

The objective of the present work was to evaluate whether oral intake with resveratrol ameliorates overactive bladder in high-fat fed mice. Male C57BL6 mice fed with standard chow or high-fat diet to induce obesity received a two-week therapy with resveratrol (100mg/kg, given as a daily gavage). Weight and metabolic profile, together with cystometry and in vitro bladder contractions were evaluated. Measurements of gp91phox and SOD1 mRNA expressions and reactive-oxygen species (ROS) in bladder tissues, and serum TBARS were performed. Obese mice exhibited increases in body weight and epididymal fat mass, which were significantly reduced by oral treatment with resveratrol. Cystometric study in obese mice showed increases in non-voiding contractions, post-voiding pressure and voiding frequency that were reversed by resveratrol treatment. Likewise, the in vitro bladder overactivity in response to electrical-field stimulation (80V, 1-32Hz) or carbachol (1nM to 10mM) were normalized by resveratrol. The gp91phox and SOD1 mRNA expressions in bladder tissues were markedly higher in obese mice compared with lean group. In addition, ROS levels in bladder tissues and serum lipid peroxidation (TBARS assay) were markedly higher in obese compared with lean mice, all of which were reduced by resveratrol treatment. In lean group, resveratrol had no effect in any parameter evaluated. Our results show that two-week therapy of obese mice with resveratrol reduces the systemic and bladder oxidative stress, and greatly ameliorated the cystometry alterations and in vitro bladder overactivity. Resveratrol treatment could be an option to prevent obesity-associated overactive bladder.

Topics: Administration, Oral; Animals; Anti-Obesity Agents; Antioxidants; Body Weight; Diet, High-Fat; Gene Expression Regulation, Enzymologic; Male; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Muscle, Smooth; NADPH Oxidase 2; NADPH Oxidases; Obesity; Oxidative Stress; Resveratrol; RNA, Messenger; Stilbenes; Superoxide Dismutase-1; Time Factors; Urinary Bladder; Urinary Bladder, Overactive

This study was designed to investigate the anti‑osteoporotic activity of polydatin and its possible underlying mechanism. Osteoporosis was induced in mice by ovariectomy (OVX) and the mice were divided into 5 groups: An OVX only group, polydatin groups (10, 20 and 40 mg/kg) and a sham group (n=10/group). After 12 weeks of treatment, body weight, uterine index and the dry weight of thigh‑bones were recorded. In addition, the serum calcium, serum phosphorus, alkaline phosphatase (ALP) and osteoprotegerin (OPG) levels were also determined. Western blot analysis was then conducted to investigate the possible mechanism underlying the effect of polydatin via determining the expression of OPG, receptor activators of nuclear factor‑κB ligand (RANKL) and β‑catenin in the ST2 cell line. The results indicated that intraperitoneal injection of polydatin (10, 20 and 40 mg/kg/day) decreased body weight, and increased uterine index and dry weights of thigh‑bones of ovariectomized mice (P<0.05), and polydatin also significantly increased the serum calcium, phosphorus, ALP and OPG of ovariectomized mice (P<0.05). Results of western blot analysis showed that polydatin upregulated the ratio of OPG/RANKL (P<0.05) and β‑catenin protein in ST2 cells. In conclusion, the results demonstrated that polydatin exhibits anti‑osteoporotic activity via regulating osteoprotegerin, RANKL and β‑catenin.

Topics: Alkaline Phosphatase; Animals; beta Catenin; Biomarkers; Body Weight; Bone and Bones; Calcium; Cell Line; Disease Models, Animal; Female; Gene Expression Regulation; Glucosides; Mice; Osteoporosis; Osteoprotegerin; Ovariectomy; RANK Ligand; Stilbenes

The development of diabetic nephropathy (DN) relays mainly on control of blood glucose and restrains hyperglycemic-induced oxidative stress. Hence, the effect administration of resveratrol (RSV) (5mg/kg) alone or in combination with rosuvastatin (RSU) (10mg/kg) on development and progression of diabetic nephropathy (DN) was evaluated. Oral treatment of diabetic rats with RSV alone or co-administered with RSU improved renal dysfunction indicated by a significant decrease in serum creatinine, urinary protein and urinary TGF-β1 when compared with diabetic control rats. Also, a significant increase in body weight, relative kidney weight with a significant decrease in serum glucose and glycated hemoglobin in diabetic treated groups when compared with diabetic control group. Hyperglycemic-induced oxidative stress in diabetic control rats indicated by a significant decrease in renal activities of catalase, superoxide dismutase, glutathione peroxidase and reduced glutathione level with a significant increase in malondialdehyde levels. However, oral treatment of diabetic rats with RSV alone or co-administered with RSU improved the antioxidant status back to control values. Similarly, mRNA analysis of quantitative real time-PCR substantiated that RSV with RSU notably normalizes the renal expression of TGF-β1, fibronectin, NF-κB/p65, Nrf2, Sirt1 and FoxO1 in the diabetic group of rats. The histopathological observations of the combined treated diabetic rats effectively protect the kidneys from hyperglycemic-induced oxidative damage. These findings confirmed the renoprotective effects of RSV with RSU treatment through improving glycemic control and attenuating oxidative stress damage in renal tissues of diabetic rats.

Topics: Animals; Antioxidants; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Fibronectins; Gene Expression Regulation; Glycated Hemoglobin; Kidney; Male; Nerve Tissue Proteins; NF-kappa B; Oxidative Stress; Rats, Wistar; Real-Time Polymerase Chain Reaction; Resveratrol; Rosuvastatin Calcium; Sirtuin 1; Stilbenes; Transforming Growth Factor beta1

Chronic glucocorticoid exposure is known to cause depression and metabolic disorders. It is critical to improve abnormal metabolic status as well as depressive-like behaviors in patients with long-term glucocorticoid therapy. This study aimed to investigate the effects of resveratrol on the depressive-like behaviors and metabolic abnormalities induced by chronic corticosterone injection. Male ICR mice were administrated corticosterone (40 mg/kg) by subcutaneous injection for three weeks. Resveratrol (50 and 100 mg/kg), fluoxetine (20 mg/kg) and pioglitazone (10 mg/kg) were given by oral gavage 30 min prior to corticosterone administration. The behavioral tests showed that resveratrol significantly reversed the depressive-like behaviors induced by corticosterone, including the reduced sucrose preference and increased immobility time in the forced swimming test. Moreover, resveratrol also increased the secretion of insulin, reduced serum level of glucose and improved blood lipid profiles in corticosterone-treated mice without affecting normal mice. However, fluoxetine only reverse depressive-like behaviors, and pioglitazone only prevent the dyslipidemia induced by corticosterone. Furthermore, resveratrol and pioglitazone decreased serum level of glucagon and corticosterone. The present results indicated that resveratrol can ameliorate depressive-like behaviors and metabolic abnormalities induced by corticosterone, which suggested that the multiple effects of resveratrol could be beneficial for patients with depression and/or metabolic syndrome associated with long-term glucocorticoid therapy.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Blood Glucose; Body Weight; Corticosterone; Depression; Disease Models, Animal; Drug Administration Schedule; Fluoxetine; Lipids; Male; Mice; Mice, Inbred ICR; Pioglitazone; Resveratrol; Stilbenes; Swimming; Thiazolidinediones

Obesity is a global health concern. Piceatannol (Pic), an analog of resveratrol (Res), has many reported biological activities. In this study, we investigated the anti-obesity effect of Pic in a high-fat diet (HFD)-induced obese animal model. The results showed that Pic significantly reduced mouse body weight in a dose-dependent manner without affecting food intake. Serum total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL) levels, and blood glucose (GLU) were significantly lowered in Pic-treated groups. Pic significantly decreased the weight of liver, spleen, perigonadal and retroperitoneal fat compared with the HFD group. Pic significantly reduced the adipocyte cell size of perigonadal fat and decreased the weight of liver. Pic-treated mice showed higher phosphorylated adenosine 5'-monophosphate-activated protein kinase (pAMPK) and phosphorylated acetyl-CoA carboxylase (pACC) protein levels and decreased protein levels of CCAAT/enhancer-binding protein C/EBPα, peroxisome proliferator-activated receptor PPARγ and fatty acid synthase (FAS), resulting in decreased lipid accumulation in adipocytes and the liver. Pic altered the composition of the gut microbiota by increasing Firmicutes and

Topics: Adipogenesis; Animals; Anti-Obesity Agents; Body Weight; Cholesterol; Diet, High-Fat; Disease Models, Animal; Dose-Response Relationship, Drug; Eating; Gastrointestinal Microbiome; Gene Expression Regulation; Lipoproteins, HDL; Lipoproteins, LDL; Mice; Mice, Inbred C57BL; Obesity; Organ Size; Stilbenes

Myocardial fibrosis and inflammation are intricately linked in diabetic cardiomyopathy (DCM), and resveratrol has been shown to attenuate oxidative stress, inflammation, and fibrosis in several cell types or animal models. High mobility group box 1 (HMGB 1), a proinflammatory cytokine, has been reported to regulate fibrosis and inflammation in various organs. Then the present study aimed to reveal the expression of HMGB 1-mediated signaling pathway and oxidative stress in resveratrol-treated diabetic mice. The significant increase in serum HMGB 1 concentration in diabetic mice was attenuated by treatment with resveratrol. Similarly, western blot analysis revealed a significant increase of HMGB 1 protein in monocytes and heart tissues of diabetic mice, and resveratrol partly normalized the changes. In addition, resveratrol abrogated the increased expression of HMGB 1-mediated signaling pathway, oxidative stress, fibrosis, and inflammation in diabetic hearts. In conclusion, inhibition of HMGB 1-mediated signaling pathway and oxidative stress may contribute to resveratrol-induced anti-inflammatory and antifibrotic effects in DCM.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Fibrosis; Heart; HMGB1 Protein; Inflammation; Male; Membrane Glycoproteins; Mice; Monocytes; NADPH Oxidase 2; NADPH Oxidases; Oxidative Stress; Protective Agents; Resveratrol; Signal Transduction; Src Homology 2 Domain-Containing, Transforming Protein 1; Stilbenes

The aim of this study was to investigate the antitumor and antivascular effects of PD806, a new oral prodrug of AVE8063 in vitro and in vivo. The cytotoxicity of PD806 was determined against H22, Walker 256, A549, MCF-7, and BEL-7402 cells using MTT assays. Plasma pharmacokinetic analysis of AVE8063 generated in rats after a single oral administration of PD806 was carried out using the high-performance liquid chromatography method. H22 tumor-bearing mice models were used to show the antitumor activity. Antivascular responses were monitored by in vivo MRI and immunohistochemistry (CD31) in W256 tumor-bearing rats. A blood test and histopathology were performed to evaluate the toxicity of PD806. PD806 showed cytotoxicity against five types of tumor cell lines with the IC50 values in the micromolar concentration. A pharmacokinetic study indicated that PD806 converted into the active form, AVE8063, which showed a half-life of 5.24±0.70 h in rats. Daily oral administration of PD806 inhibited the growth of subcutaneously implanted H22 tumors in a dose-dependent manner. The tumor volume in the 300 mg/kg PD806 group was obviously smaller than that of the vehicle control group from day 6 onward (P<0.05), with inhibition rates of 62% on day 30. PD806 in the three-dose group significantly prolonged the survival of the H22 tumor-bearing mice (P<0.05). At 24 h after PD806 (150 and 200 mg/kg) was administered orally, tumor vascular shutdown was found on CE-T1WI with the presence of extended necrosis and tumor residue at the periphery. The enhancement ratio decreased significantly from 1.00±0.00 at baseline to 0.26±0.08 and 0.17±0.06, respectively (P<0.01). The necrosis ratio measured from CE-T1WI increased significantly from 34% in average at baseline to 52.96 and 60.30%, respectively (P<0.05). Immunohistochemical staining of tumor sections showed a marked reduction in CD31 staining vessels, with microvessel density reduced significantly to 8.71±1.76 and 3.33±1.04, respectively, compared with the vehicle control group (P<0.01). The results of hematology and histopathology showed that PD806 exerted no obvious toxicity during the treatment period. In conclusion, our results indicate that PD806 is an effective and safe vascular disrupting agent.

Topics: Administration, Oral; Angiogenesis Inhibitors; Aniline Compounds; Animals; Antineoplastic Agents; Body Weight; Cell Line, Tumor; Citrates; Half-Life; Humans; Male; Mice, Inbred Strains; Prodrugs; Rats, Sprague-Dawley; Stilbenes; Survival Rate; Xenograft Model Antitumor Assays

The increased consumption of high-fructose corn syrup (HFCS) may contribute to the worldwide epidemic of fatty liver. In this study, we have investigated whether HFCS intake (20% beverages) influences lipid synthesis and accumulation in conjunction with insulin receptor substrate-1/2 (IRS-1; IRS-2), endothelial nitric oxide synthase (eNOS), sirtuin 1 (SIRT1) and inducible NOS (iNOS) expressions in liver of rats. Resveratrol was tested for its potential efficacy on changes induced by HFCS.. Animals were randomly divided into four groups as control, resveratrol, HFCS and resveratrol plus HFCS (resveratrol + HFCS). HFCS was given as 20% solutions in drinking water. Feeding of all rats was maintained by a standard diet that enriched with or without resveratrol for 12 weeks.. Dietary HFCS increased triglyceride content and caused mild microvesicular steatosis in association with up-regulation of fatty acid synthase and sterol regulatory element binding protein (SREBP)-1c in liver of rats. Moreover, HFCS feeding impaired hepatic expression levels of IRS-1, eNOS and SIRT1 mRNA/proteins, but did not change iNOS level. Resveratrol promoted IRS, eNOS and SIRT1, whereas suppressed SREBP-1c expression in rats fed with HFCS.. Resveratrol supplementation considerably restored hepatic changes induced by HFCS. The improvement of hepatic insulin signaling and activation of SIRT1 by resveratrol may be associated with decreased triglyceride content and expression levels of the lipogenic genes of the liver.

Topics: Animals; Body Weight; Chemical and Drug Induced Liver Injury; Enzyme Activation; Fatty Acid Synthase, Type I; Gene Expression; High Fructose Corn Syrup; Insulin; Insulin Receptor Substrate Proteins; Liver; Male; Nitric Oxide Synthase Type III; Rats; Rats, Wistar; Resveratrol; RNA, Messenger; Signal Transduction; Sirtuin 1; Sterol Regulatory Element Binding Protein 1; Stilbenes; Triglycerides

The pathophysiology of non-alcoholic fatty liver disease remains to be elucidated, and the currently available treatments are not entirely effective. Polydatin, a stilbenoid compound derived from the rhizome of Polygonum cuspidatum, has previously been demonstrated to possess hepatoprotective effects. The present study aimed to determine the effects of polydatin supplementation on hepatic fat accumulation and injury in rats fed a high-fat diet. In addition, the mechanisms underlying the protective effects of polydatin were examined. Male Sprague Dawley rats were randomly divided into four groups and received one of four treatment regimes for 12 weeks: Control diet, control diet supplemented with polydatin, high-fat diet, or high-fat diet supplemented with polydatin. Polydatin was supplemented in the drinking water at a concentration of 0.3% (wt/vol). The results of the present study showed that long-term high-fat feeding resulted in fatty liver in rats, which was manifested by excessive hepatic neutral fat accumulation and elevated plasma alanine aminotransferase and aspartate aminotransferase levels. Polydatin supplementation alleviated the hepatic pathological changes, and attenuated the insulin resistance, as shown by an improved homeostasis model assessment of basal insulin resistance values and a glucose tolerance test. Polydatin supplementation also corrected abnormal leptin and adiponectin levels. Specifically, polydatin supplementation enhanced insulin sensitivity in the liver, as shown by improved insulin receptor substrate 2 expression levels and Akt phosphorylation in the rat liver, following high-fat diet feeding. The results of the present study suggest that polydatin protects rats against high-fat feeding-induced insulin resistance and hepatic steatosis. Polydatin may be an effective hepatoprotective agent and a potential candidate for the prevention of fatty liver disease and insulin resistance.

Topics: Adiponectin; Animals; Body Weight; Diet; Dietary Supplements; Disease Models, Animal; Fatty Liver; Gene Expression; Glucose Tolerance Test; Glucosides; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Leptin; Liver; Male; Rats; Stilbenes

1. To investigate the effects of tetrahydroxystilbene glucoside (TSG), the main active component of Polygonum multiflorum, on mouse liver cytochrome P450 (Cyp) enzyme protein expressions. Male mice were randomly divided into the control, TSG low (10 mg/kg) and high dose (40 mg/kg) groups. After TSG intragastrical administration for 3, 5 and 7 d, mice were sacrificed and the mouse body and liver weight were detected. The Cyp enzymes and various transcription factors such as AhR, PXR and PPARα protein expressions in mouse livers were measured by Western blotting assay. 2. No significant difference of mouse body and liver weight between the control and TSG treatment groups was detected. Additionally, TSG decreased Cyp1a2 and Cyp2e1 protein expressions after TSG treatment for 3, 5 and 7 d, respectively. Moreover, TSG suppressed Cyp3a11 protein expression after TSG treatment for 5 and 7 d. Furthermore, TSG high dose inhibited AhR and PXR protein expressions after TSG treatment for 5 and 7 d, while both TSG low dose and high dose obviously decreased PPARα protein level from TSG treatment for 3 d. 3. TSG has inhibitory effects on mouse liver Cyp1a2, Cyp2e1 and Cyp3a11 protein expressions through the suppression of AhR, PXR and PPARα activation.

Topics: Animals; Body Weight; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Glucosides; Liver; Male; Membrane Proteins; Mice; Organ Size; PPAR alpha; Pregnane X Receptor; Receptors, Aryl Hydrocarbon; Receptors, Steroid; Stilbenes

Obstructive sleep apnea can induce chronic intermittent hypoxia (CIH) during sleep and is associated with obesity and diabetes. Resveratrol (RSV), a polyphenolic phytoalexin, can regulate glucose metabolism, thereby reducing insulin resistance. The present study aimed to assess whether RSV attenuates CIH-induced insulin resistance in rats and the underlying mechanisms. A total of 40 rats were randomly assigned into five groups: i) Control; ii) subjected to CIH only; iii) subjected to CIH and treated with 3 mg/kg/day of RSV; iv) subjected to CIH and treated with 30 mg/kg/day of RSV; v) subjected to CIH and treated with 60 mg/kg/day of RSV. All animals were sacrificed following 28 days of treatment. Subsequently, the blood and livers were harvested and blood insulin and glucose levels were measured. Levels of sirtuin (Sirt) 1, insulin receptor (InsR) and glucose transporter 2 (Glut2) in the liver were measured. RSV treatment was demonstrated to suppress weight gain and improve hepatic morphology. RSV treatment also significantly reduced the homeostasis model assessment estimate of insulin resistance of the rats exposed to CIH. This effect occurred in a dose-dependent manner. RSV significantly upregulated liver Sirt1 levels and inhibited InsR and Glut2 expression in the liver. Additionally, RSV activated the phosphorylation of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and AKT. The present study demonstrates that RSV prevents CIH-induced insulin resistance in rats. Upregulation of Sirt1 and activation of PI3K/AKT signaling may be involved in this process.

Topics: Animals; Blood Glucose; Body Weight; Gene Expression Regulation; Glucose Transporter Type 2; Hypoxia; Insulin; Insulin Resistance; Liver; Male; Phosphatidylinositol 3-Kinases; Phosphorylation; Protective Agents; Proto-Oncogene Proteins c-akt; Rats; Receptor, Insulin; Resveratrol; RNA, Messenger; Signal Transduction; Sirtuin 1; Stilbenes

Our studies and others recently demonstrate that polydatin, a resveratrol glucoside, has antioxidative and cardioprotective effects. This study aims to investigate the direct effects of polydatin on Ang II-induced cardiac hypertrophy to explore the potential role of polydatin in cardioprotection. Our results showed that in primary cultured cardiomyocytes, polydatin blocked Ang II-induced cardiac hypertrophy in a dose-dependent manner, which were associated with reduction in the cell surface area and [(3)H]leucine incorporation, as well as attenuation of the mRNA expressions of atrial natriuretic factor and β-myosin heavy chain. Furthermore, polydatin prevented rat cardiac hypertrophy induced by Ang II infusion, as assessed by heart weight-to-body weight ratio, cross-sectional area of cardiomyocyte, and gene expression of hypertrophic markers. Further investigation demonstrated that polydatin attenuated the Ang II-induced increase in the reactive oxygen species levels and NADPH oxidase activity in vivo and in vitro. Polydatin also blocked the Ang II-stimulated increases of Nox4 and Nox2 expression in cultured cardiomyocytes and the hearts of Ang II-infused rats. Our results indicate that polydatin has the potential to protect against Ang II-mediated cardiac hypertrophy through suppression of NADPH oxidase activity and superoxide production. These observations may shed new light on the understanding of the cardioprotective effect of polydatin.

Topics: Angiotensin II; Animals; Atrial Natriuretic Factor; Body Weight; Cardiomegaly; Cells, Cultured; Glucosides; Male; Myocardium; Myocytes, Cardiac; NADPH Oxidases; Organ Size; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Resveratrol; RNA, Messenger; Signal Transduction; Stilbenes; Superoxides; Ventricular Myosins

Circadian rhythmic disorders induced by high-fat diet are associated with metabolic diseases. Resveratrol could improve metabolic disorder, but few reports focused on its effects on circadian rhythm disorders in a variety of studies. The aim of the present study was to analyze the potential effects of resveratrol on high-fat diet-induced disorders about the rhythmic expression of clock genes and clock-controlled lipid metabolism. Male C57BL/6 mice were divided into three groups: a standard diet control group (CON), a high-fat diet (HFD) group and HFD supplemented with 0.1% (w/w) resveratrol (RES). The body weight, fasting blood glucose and insulin, plasma lipids and leptin, whole body metabolic status and the expression of clock genes and clock-controlled lipogenic genes were analyzed at four different time points throughout a 24-h cycle (8:00, 14:00, 20:00, 2:00). Resveratrol, being associated with rhythmic restoration of fasting blood glucose and plasma insulin, significantly decreased the body weight in HFD mice after 11 weeks of feeding, as well as ameliorated the rhythmities of plasma leptin, lipid profiles and whole body metabolic status (respiratory exchange ratio, locomotor activity, and heat production). Meanwhile, resveratrol modified the rhythmic expression of clock genes (Clock, Bmal1 and Per2) and clock-controlled lipid metabolism related genes (Sirt1, Pparα, Srebp-1c, Acc1 and Fas). The response pattern of mRNA expression for Acc1 was similar to the plasma triglyceride. All these results indicated that resveratrol reduced lipogenesis and ultimately normalized rhythmic expression of plasma lipids, possibly via its action on clock machinery.

Topics: Animals; Body Weight; Chronobiology Disorders; Circadian Rhythm; Diet, High-Fat; Gene Expression Regulation; Lipid Metabolism; Lipids; Male; Mice, Inbred C57BL; Resveratrol; Stilbenes

Compelling evidence supports the role of oxidative stress and renal interstitial inflammation in the pathogenesis of hypertension. Resveratrol is a polyphenolic stilbene, which can lower oxidative stress by activating the transcription factor nuclear factor-E2-related factor-2 (Nrf2), the master regulator of numerous genes encoding antioxidant and phase II-detoxifying enzymes and molecules. Given the role of oxidative stress and inflammation in the pathogenesis of hypertension, we conducted this study to test the hypothesis that long-term administration of resveratrol will attenuate renal inflammation and oxidative stress and, hence, progression of hypertension in the young spontaneously hypertensive rats (SHR). SHR and control [Wistar-Kyoto (WKY)] rats were treated for 9 wk with resveratrol or vehicle in their drinking water. Vehicle-treated SHR exhibited renal inflammatory injury and oxidative stress, as evidenced by glomerulosclerosis, tubulointerstitial injury, infiltration of inflammatory cells, and increased levels of renal 8-isoprostane and protein carbonylation. This was associated with reduced antioxidant capacity and downregulations of Nrf2 and phase II antioxidant enzyme glutathione-S-transferase (GST). Resveratrol treatment mitigated renal inflammation and injury, reduced oxidative stress, normalized antioxidant capacity, restored Nrf2 and GST activity, and attenuated the progression of hypertension in SHR. However, resveratrol had no effect on these parameters in WKY rats. In conclusion, development and progression of hypertension in the SHR are associated with inflammation, oxidative stress, and impaired Nrf2-GST activity in the kidney. Long-term administration of resveratrol restores Nrf2 expression, ameliorates inflammation, and attenuates development of hypertension in SHR. Clinical studies are needed to explore efficacy of resveratrol in human hypertension.

Topics: Animals; Antioxidants; Blood Pressure; Body Weight; Drinking; Eating; Hypertension; Inflammation; Kidney; Male; NF-E2-Related Factor 2; Oxidative Stress; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Resveratrol; Stilbenes

The cardioprotective effects of resveratrol are well established in animal models of metabolic disease but are yet to be investigated in a combined model of hypertension and diabetes. This study investigated the ability of resveratrol's antioxidant and anti-inflammatory effects to prevent cardiovascular complications in the spontaneously hypertensive streptozotocin-induced diabetic rat. Diabetes was induced in eight-week-old male spontaneously hypertensive rats via a single intravenous injection of streptozotocin. Following this, resveratrol was administered orally for an eight-week period until the animals were sixteen weeks of age. Upon completion of the treatment regime assessments of oxidative stress, lipid peroxidation, inflammation, and cardiovascular function were made. Resveratrol administration to hypertensive-diabetic animals did not impact upon blood glucose or haemodynamics but significantly reduced oxidative stress, lipid peroxidation, and inflammatory cytokines. Reductions in systemic levels of oxidative stress and inflammation conferred improvements in vascular reactivity and left ventricular pump function and electrophysiology. This study demonstrates that resveratrol administration to hypertensive diabetic animals can elicit cardioprotective properties via antioxidant and anti-inflammatory effects. The observed preservation of cardiovascular function was independent of changes in blood glucose concentration and haemodynamics, suggesting that oxidative stress and inflammation are key components within the pathological cascade associated with hypertension and diabetes.

Topics: Acetylcholine; Animals; Blood Vessels; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Experimental; Drinking; In Vitro Techniques; Inflammation; Lipid Peroxidation; Male; Microelectrodes; Myocardial Contraction; Nitric Oxide; Nitroprusside; Norepinephrine; Oxidative Stress; Rats, Inbred SHR; Resveratrol; Stilbenes; Streptozocin; Ventricular Function

We previously found that passion fruit (Passiflora edulis) seeds contained a high amount of piceatannol (3,5,3',4'-trans-tetrahydroxystilbene), a natural analog of resveratrol (3,5,4'-trans-trihydroxystilbene). Resveratrol has been proposed as a potential anti-metabolic disorder compound, by its activation of sirtuin and AMP-activated protein kinase. Many reports show that resveratrol ameliorates diet-induced obesity and insulin resistance. However, it is not known whether piceatannol also affects diet-induced obesity. We explored the effect of piceatannol on high fat diet-fed mice. The results showed that piceatannol did not affect high fat diet-induced body weight gain or visceral fat gain in mice. However, piceatannol did reduce fasting blood glucose levels. Furthermore, to explore the potential of passion fruit seed extract containing piceatannol as a functional food, passion fruit seed extract was administered in a genetic diabetic mouse model (db/db mice). Single administration of passion fruit seed extract, as well as piceatannol reduced the blood glucose levels of these db/db mice. These results suggest that piceatannol and passion fruit seed extract may have potential application in the prevention of diabetes.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diet, High-Fat; Eating; Hypoglycemic Agents; Leptin; Male; Mice, Inbred C57BL; Passiflora; Plant Extracts; Seeds; Stilbenes

Osteoporosis is a disease characterized by loss of bone mass and degeneration of the microstructure of bone. Resveratrol (3,5,4-tri-hydroxystilbene; RESV) may delay the onset of a variety of age-related diseases. In the present study, an ovariectomized female rat model was used to detect the changes in microRNAs (miRNAs/miRs) following RESV treatment. Subsequently, the target genes of miRNA were predicted using TargetScan software and determined using a dual-luciferase reporter assay. Finally, the role of miR-338-3p in the proliferation and differentiation of human osteoblast (HOB) cells was confirmed. The predominant finding of the present study was the identification of an intact mechanism of the effect of RESV in osteoporosis treatment. The results suggested that RESV suppresses miR-338-3p, followed by an increase in the expression of runt-related transcription factor 2 in HOB cells.

Topics: Animals; Antioxidants; Base Sequence; Body Weight; Bone and Bones; Cell Differentiation; Cell Line; Cell Proliferation; Core Binding Factor Alpha 1 Subunit; Down-Regulation; Female; Gene Expression Regulation; Humans; MicroRNAs; Molecular Sequence Data; Osteoblasts; Osteoporosis; Ovariectomy; Phylogeny; Rats; Rats, Wistar; Resveratrol; Sequence Alignment; Stilbenes

Resveratrol has been shown to mimic the beneficial effects of dietary restriction (DR). We previously reported that DR delays stroke onset and extends the lifespan in Stroke-Prone Spontaneously Hypertensive rats (SHRSP). Therefore, we examined whether resveratrol mimics DR and delays stroke onset in SHRSP.. Cerebrovascular endothelial cells (CVECs) from SHRSP were treated with resveratrol, and the inflammatory gene expression levels and NFκB protein levels were measured. In order to address the effects of resveratrol in vivo, SHRSP (male, 10 weeks of age) were fed an experimental diet containing several doses of resveratrol (0 - 0.05% (w/w)), after which we measured the plasma cytokine levels and examined the stroke onset and lifespan.. Treatment with resveratrol (100 μM, 24 hours) in CVECs from SHRSP significantly decreased the interleukin (IL)-1β-induced monocyte chemoattractant protein-1 (MCP-1) mRNA expression levels and p50 and p65 protein levels in the nuclear fraction. When the SHRSP were fed a diet containing resveratrol for one week, the resveratrol treatment did not affect the plasma lipid and glucose levels, body weight or weight of each tissue. Resveratrol slightly, but not significantly, decreased the plasma levels of IL-1β and MCP-1 compared with that observed in the control group. In addition, resveratrol decreased the IL-1β and MCP-1 mRNA expression levels in the brain versus the control animals. However, no doses of resveratrol delayed stroke onset or extended the lifespan in SHRSP.. In this study, resveratrol did not delay stroke onset in SHRSP, although it partially suppressed systemic and cerebral inflammation. These results suggest that resveratrol does not mimic the beneficial effects of DR on stroke in vivo.

Topics: Adenylate Kinase; Animals; Antioxidants; Blood Glucose; Blood Pressure; Body Weight; Cerebrovascular Circulation; Chemokine CCL2; Endothelial Cells; Inflammation; Interleukin-1beta; Male; Rats; Rats, Inbred SHR; Resveratrol; Signal Transduction; Stilbenes; Stroke

Resveratrol is a polyphenol exhibiting antioxidant and neuroprotective effects in neurodegenerative diseases. However, neuroprotective properties during normal aging have not been clearly demonstrated. We analyzed the in vivo effects of chronic administration of resveratrol (20 mg/kg/day for 4 weeks) in old male rats (Wistar, 20 months), on tryptophan hydroxylase (TPH) and tyrosine hydroxylase (TH) activities which mediate central monoaminergic neurotransmitters synthesis, and besides, on hippocampal-dependent working memory test (radial maze). Our results show an age-related decline in neurochemical parameters that were reversed by resveratrol administration. The resveratrol treatment enhances serotonin (5-HT) levels in pineal gland, in hippocampus, and in striatum, and those of noradrenaline (NA) in hippocampus and also dopamine (DA) in striatum. These changes were largely due to an increased activity of TPH-1 (463 % in pineal gland), TPH-2 (70-51 % in hippocampus and striatum), and TH (150-36 % in hippocampus and striatum). Additionally, the observed hippocampal effects correlate with a resveratrol-induced restorative effect on working memory (radial maze). In conclusion, this study suggests resveratrol treatment as a restoring therapy for the impaired cognitive functions occurring along normal aging process, by preventing 5-HT, DA, and NA neurotransmission decline.

Topics: Aging; Animals; Body Temperature; Body Weight; Brain; Chromatography, High Pressure Liquid; Cognition; Male; Rats; Rats, Wistar; Resveratrol; Stilbenes; Tryptophan Hydroxylase; Tyrosine 3-Monooxygenase

This study was conducted to elucidate the genome-wide gene expression profile in streptozotocin induced diabetic rat liver tissues in response to resveratrol treatment and to establish differentially expressed transcription regulation networks with microarray technology. In addition to measure the expression levels of several antioxidant and detoxification genes, real-time quantitative polymerase chain reaction (qRT-PCR) was also used to verify the microarray results. Moreover, gene and protein expressions as well as enzymatic activities of main antioxidant enzymes; superoxide dismutase (SOD-1 and SOD-2) and glutathione S-transferase (GST-Mu) were analyzed. Diabetes altered 273 genes significantly and 90 of which were categorized functionally which suggested that genes in cellular catalytic activities, oxidation-reduction reactions, co-enzyme binding and terpenoid biosynthesis were dominated by up-regulated expression in diabetes. Whereas; genes responsible from cellular carbohydrate metabolism, regulation of transcription, cell signal transduction, calcium independent cell-to-cell adhesion and lipid catabolism were down-regulated. Resveratrol increased the expression of 186 and decreased the expression of 494 genes in control groups. While cellular and extracellular components, positive regulation of biological processes, biological response to stress and biotic stimulants, and immune response genes were up-regulated, genes responsible from proteins present in nucleus and nucleolus were mainly down-regulated. The enzyme assays showed a significant decrease in diabetic SOD-1 and GST-Mu activities. The qRT-PCR and Western-blot results demonstrated that decrease in activity is regulated at gene expression level as both mRNA and protein expressions were also suppressed. Resveratrol treatment normalized the GST activities towards the control values reflecting a post-translational effect. As a conclusion, global gene expression in the liver tissues is affected by streptozotocin induced diabetes in several specific pathways. The present data suggest the presence of several processes which contribute and possibly interact to impair liver functions in type 1 diabetes, several of which are potentially amenable to therapeutic interventions with resveratrol.

Topics: Animals; Body Weight; Diabetes Mellitus, Experimental; Gene Expression Profiling; Hyperglycemia; Liver; Male; Oxidative Stress; Rats; Rats, Wistar; Resveratrol; Stilbenes; Streptozocin

Metabolic homeostasis is maintained by the coordinated regulation of several physiological processes and organ crosstalk. Especially, the interaction between adipose tissue and liver is critical for the regulation of glucose and lipid metabolism. This study investigated the involvement of resveratrol (RSV) in the crosstalk between adipokine adiponectin and hepatokine fetuin-A. Adipocytes-hepatocytes co-culture system and a high-fat (HF) diet-induced obesity (DIO) mouse model were utilized. Protein levels of adiponectin and fetuin-A were analyzed in adipocytes and hepatocytes with the knockdown of adiponectin and fetuin-A, respectively. After six weeks of the HF diet treatment, RSV was delivered via an osmotic pump for four weeks. The experimental groups were lean control fed with a standard diet, HF diet-induced obese control and HF_RSV (8 mg/kg/day). After 4 weeks of each treatment, blood and tissues were collected, and the levels of adiponectin and fetuin-A were analyzed. RNA interference during co-culture of adipocytes and hepatocytes demonstrated the existence of crosstalk between adiponectin and fetuin-A. The four-week RSV treatment resulted in increased serum adiponectin and decreased serum fetuin-A in diet-induced obesity mice. The serum levels of adiponectin and fetuin-A were inversely related. In epididymal fat depots, RSV increased adiponectin, peroxisome proliferator-activated receptor (PPAR) alpha, PPAR gamma, sirtuin1 and AMP-activated protein kinase (AMPK). RSV lowered fetuin-A and NF-κB, and increased liver AMPK. These results demonstrate the crosstalk between adiponectin and fetuin-A, and suggest that RSV may be involved in adipose tissue and liver crosstalk through the interaction between adiponectin and fetuin-A.

Topics: Adipocytes; Adiponectin; alpha-2-HS-Glycoprotein; Animals; Body Weight; Coculture Techniques; Diet, High-Fat; Hepatocytes; Lipids; Liver; Male; Mice, Inbred C57BL; Obesity; Resveratrol; Stilbenes

In this study, effects of melatonin, quercetin and resveratrol on hepatocellular injury in streptozotocin (STZ)-induced experimental diabetes were aimed to be investigated by histological and biochemical methods. Thirty-five male Wistar albino rats were divided into five groups, namely, control, diabetes (STZ 45 mg/kg/single dose/intraperitoneally (ip)), diabetes + melatonin (10 mg/kg/30 days/ip), diabetes + quercetin (25 mg/kg/30 days/ip) and diabetes + resveratrol (10 mg/kg/30 days/ip). Initial and final blood glucose levels and body weights (BWs) were measured. At the end of the experimentation, following routine tissue processing procedure, sections were stained with haematoxylin-eosin (H-E), periodic acid Schiff and Masson's trichrome. Tissue malondialdehyde (MDA) and glutathione (GSH) levels and superoxide dismutase (SOD) and catalase (CAT) activities were examined. The diabetic rats had significantly higher blood glucose levels than those of control rats (p = 0.0001). Mean BWs of diabetic rats were significantly decreased when compared with the control rats (p = 0.0013). Histopathological alterations including cellular glycogen depletion, congestion, sinusoidal dilatation, inflammation and fibrosis were detected in diabetes group. On the other hand, histopathological changes markedly reduced in all of the treatment groups (p = 0.001). Mean tissue MDA level was increased but mean tissue CAT and SOD activities and GSH levels were decreased in the diabetes group. Melatonin, quercetin and resveratrol administered diabetic rats showed an increase in CAT activities and GSH levels and a decrease in MDA levels (p < 0.05, for all). Melatonin, quercetin and resveratrol administrations markedly reduced hepatocellular injury in STZ-induced experimental diabetes.

Topics: Animals; Antioxidants; Biomarkers; Blood Glucose; Body Weight; Catalase; Diabetes Complications; Diabetes Mellitus, Experimental; Hepatitis; Hepatocytes; Male; Melatonin; Oxidative Stress; Quercetin; Rats; Rats, Wistar; Resveratrol; Stilbenes; Superoxide Dismutase

Our objective was to investigate the effects of chronic unpredictable mild stress (CUMS) with or without selective serotonin reuptake inhibitor (fluoxetine) and anti-oxidant (resveratrol) on testicular functions and oxidative stress in rats. Fifty male rats were divided into 2 groups; control and CUMS. CUMS group was further subdivided into 4 subgroups administered water, fluoxetine, resveratrol and both. Sucrose intake, body weight gain, serum corticosterone, serotonin and testosterone levels, sperm count and motility, testicular malondialdehyde, superoxide dismutase (SOD), catalase, glutathione (GSH), and gene expression of steroidogenic acute-regulatory (StAR) protein and cytochrome P450 side chain cleavage (P450scc) enzyme were evaluated. CUMS decreased sucrose intake, weight gain, anti-oxidants (SOD, catalase, GSH), testosterone, serotonin, StAR and cytochrome P450scc gene expression, sperm count and motility and increased malondialdehyde and corticosterone. Fluoxetine increased malondialdehyde, sucrose intake, weight gain, serotonin and decreased anti-oxidants, StAR and cytochrome P450scc gene expression, sperm count and motility, testosterone, corticosterone in stressed rats. Administration of resveratrol increased anti-oxidants, sucrose intake, weight gain, serotonin, StAR and cytochrome P450scc gene expression, testosterone, sperm count and motility, and decreased malondialdehyde and corticosterone in stressed rats with or without fluoxetine. In conclusion, CUMS induces testicular dysfunctions and oxidative stress. While treatment of CUMS rats with fluoxetine decreases the depressive behavior, it causes further worsening of testicular dysfunctions and oxidative stress. Administration of resveratrol improves testicular dysfunctions and oxidative stress that are caused by CUMS and further worsened by fluoxetine treatment.

Topics: Animals; Antidepressive Agents, Second-Generation; Antioxidants; Body Weight; Depression; Fluoxetine; Gene Expression Regulation; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Resveratrol; Sperm Count; Sperm Motility; Stilbenes; Stress, Psychological; Swimming; Testis

There is limited knowledge on the gender differences in the effects of dietary fructose. In the current study, we investigated whether long-term fructose intake impacts metabolic parameters and vascular reactivity differently between male and female rats. Moreover, we tested whether resveratrol has a gender-specific effectiveness on the alterations.. Male and female rats were divided into four groups as control; resveratrol; fructose and resveratrol plus fructose. Fructose was given to the rats as 10% solution in drinking water for 24 weeks. All rats were fed with the standard diet with or without resveratrol.. High-fructose diet increased plasma insulin, triglyceride and VLDL levels as well as omental weights in both genders. Long-term dietary fructose causes marked increase in body weight of males, but not females. Dietary fructose impaired endothelial relaxation to acetylcholine and intensified contraction to phenylephrine in the aortas of male and female rats, but differently it also reduced insulin-induced vasodilation in aortas of female rats. These changes were associated with decreased expression levels of endothelial nitric oxide synthase (eNOS) mRNA and protein, but increased in inducible NOS (iNOS), in aortas of male and female rats. Dietary fructose suppressed expression levels of sirtuin 1 (SIRT1) and insulin receptor substrate-2 (IRS-2) mRNA in aortas from female rats. Resveratrol supplementation efficiently restored fructose-induced metabolic and vascular dysfunction in both genders probably by regulating eNOS and iNOS production. Moreover, the augmentations in SIRT1 and IRS-2 mRNA in females and IRS-1 mRNA in males may possibly contribute to the beneficial effects of resveratrol as well.. Long-term fructose intake may differently affect metabolic and vascular function between male and female rats, which are modified by resveratrol.

Topics: Acetylcholine; Animals; Antioxidants; Aorta; Body Weight; Diet; Female; Fructose; Insulin; Insulin Receptor Substrate Proteins; Lipoproteins, VLDL; Male; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Phenylephrine; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Resveratrol; Sex Factors; Sirtuin 1; Stilbenes; Triglycerides

This study aimed to investigate the differential protective effect of resveratrol (RSV) on oxidative stress and metabolic signaling pathways in fast- and slow-twitch skeletal muscles of rats with diabetes.. Diabetic rats were induced by streptozotocin (STZ) for 2 weeks and then administered with RSV (1, 10 and 100 μg/kg per day) for 1 week. We determined oxidative stress and protein expression by lucigenin-mediated chemiluminescence and Western immunoblot.. The superoxide anion production and copper-zinc superoxide dismutase (CuZnSOD) protein level were increased in fast-twitch muscle than in slow-twitch muscle of diabetes. The Akt and glycogen synthase kinase 3 (GSK-3) phosphorylations were reduced in both fast- and slow-twitch muscles of diabetes. Oxidative stress and GSK-3 dephosphorylation were corrected by RSV treatment in both fast- and slow-twitch muscles of diabetes. Furthermore, RSV treatment downregulated CuZnSOD protein level in diabetic fast-twitch muscle. In diabetic slow-twitch muscle, RSV treatment elevated manganese SOD (MnSOD) and phosphorylated Akt protein levels and reduced acetyl-CoA carboxylase (ACC) phosphorylation.. Our results suggested that fast-twitch muscle incurred more oxidative stress, whereas slow-twitch muscle altered metabolic signaling molecules activities under diabetic status. The antidiabetic effect of RSV on fast- and slow-twitch skeletal muscles was mediated by different antioxidative and metabolic signals.

Topics: Acetyl-CoA Carboxylase; Animals; Antioxidants; Blood Glucose; Blotting, Western; Body Weight; Cholesterol; Diabetes Mellitus, Experimental; Glycogen Synthase Kinase 3; Insulin; Male; Muscle Fibers, Fast-Twitch; Muscle Fibers, Slow-Twitch; Oxidative Stress; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Long-Evans; Resveratrol; Signal Transduction; Stilbenes; Superoxide Dismutase; Superoxides; Triglycerides

Mulberroside A (MUL) was purified from an ethanol extract of Morus alba root, and oxyresveratrol (OXY) was produced by enzymatic conversion of MUL. Normal rats, Triton WR-1339-induced hyperlipidemic rats, and high-cholesterol diet (HCD)-induced hyperlipidemic rats were orally treated with MUL or OXY (1-5mg/kg/day). MUL and OXY were administered 1h prior to concomitant treatment with Triton WR-1339 for a further 24h, whereas the drugs were administered concurrently with HCD for 4weeks. Oral MUL and OXY pre-treatment vs. water pre-treatment of Triton WR-1339-induced hyperlipidemic rats significantly (p<0.05) reduced the levels of serum lipids in a dose-dependent manner, while high-density lipoprotein cholesterol (HDL-C, or "good" cholesterol) levels were increased. Oral MUL and OXY treatment of HCD-fed rats also showed a significant (p<0.05) dose-dependent decrease in serum lipids, coronary artery risk index (CRI), and atherogenic index (AI), but not HDL-C. Furthermore, MUL and OXY treatment of HCD-induced hyperlipidemic rats demonstrated a significant dose-dependent improvement in the histological features of hepatic fatty degeneration. Aspartate aminotransferase and alanine aminotransferase values in OXY-treated normal rats were not significantly different from those in water-treated control rats. These results indicate that MUL and OXY might be developed as novel antihyperlipidemic agents.

Topics: Animals; Body Weight; Cholesterol, Dietary; Disaccharides; Hyperlipidemias; Hypolipidemic Agents; Lipids; Male; Morus; Plant Extracts; Polyethylene Glycols; Rats; Rats, Sprague-Dawley; Stilbenes

Adiponectin is an adipocyte derived protein that plays pivotal roles in anti-oxidation, anti-inflammatory and insulin-sensitizing properties by activating two receptors, AdipoR1 and AdipoR2. Recent studies have shown that the down-regulation of AdipoR1 is a known cause of diabetic nephropathy (DN). Resveratrol (Resv), a natural polyphenol, has been identified as a potent activator of forkhead transcription factor O1 (FoxO1) which can up-regulate the expression of AdipoR1. In the present study, we have investigated whether Resv can up-regulate the expression of AdipoR1 by activating FoxO1 that is in kidney of DN rats and mesangial cells (MCs) cultured in high glucose (HG, 30 mmol/L) medium. In vivo, we show that, in the renal cortex of diabetic rats, the expression of AdipoR1 was significantly reduced and correlated with an increase in the generation of malondialdehyde (MDA), Collagen IV and fibronectin proteins. However, administration with Resv significantly increased the expression of AdipoR1. This correlated with not only a decrease in generation of MDA, Collagen IV and fibronectin proteins levels but also more improved kidney pathological and biochemical indicators changes. In vitro, we show that HG-induced depression of FoxO1 activity was associated with the expression of Adipor1 in MCs. Treatment with Resv (20 μmol/L) caused an elevation in the activity of FoxO1 and a significantly increase in the expression of AdipoR1. Furthermore, inhibition of FoxO1 through short hairpin RNA markedly reduced the expression of Adipor1 in MCs cultured by Resv. In conclusion, Resv can significantly increase the expression of AdipoR1 by activating FoxO1 in diabetic kidney. These data also suggest that Resv may serve as a promising agent for preventing or treating DN.

Topics: Animals; Body Weight; Collagen Type IV; Diabetic Nephropathies; Disease Models, Animal; Fibronectins; Forkhead Transcription Factors; Gene Expression Regulation; Glucose; Kidney; Lipid Peroxidation; Male; Mesangial Cells; Nerve Tissue Proteins; Oxidative Stress; Rats; Receptors, Adiponectin; Resveratrol; Stilbenes

Diabetes is associated with cognitive impairment and brain aging, with alterations in hippocampal neurogenesis and synaptic plasticity implicated in these changes. As the prevalence of diabetes continues to rise, readily implemented strategies are increasingly needed in order to protect the brain's cognitive functions. One possibility is resveratrol (RES) (3,5,4- trihydroxystilbene), a polyphenol of the phytoalexin family that has been shown to be protective in a number of neuropathology paradigms. In the present study, we sought to determine whether dietary supplementation with RES has potential for the protection of cognitive functions in diabetes. Diabetes was induced using streptozotocin, and once stable, animals received AIN93G rodent diet supplemented with RES for 6 weeks. Genome-wide expression analysis was conducted on the hippocampus and genes of interest were confirmed by quantitative, real-time polymerase chain reaction. Genome-wide gene expression analysis of the hippocampus revealed that RES supplementation of the diabetic group resulted in 481 differentially expressed genes compared to non-supplemented diabetic mice. Intriguingly, gene expression that was previously found significantly altered in the hippocampus of diabetic mice, and that is implicated in neurogenesis and synaptic plasticity (Hdac4, Hat1, Wnt7a, ApoE), was normalized following RES supplementation. In addition, pathway analysis revealed Jak-Stat signaling was the most significantly enriched pathway. The Jak-Stat pathway induces a pro-inflammatory signaling cascade, and we found most genes involved in this cascade (e.g. Il15, Il22, Socs2, Socs5) had significantly lower expression following RES supplementation. These data indicate RES could be neuroprotective and beneficial for the maintenance of cognitive function in diabetes.

Topics: Animals; Blood Glucose; Body Weight; Diet; Gene Expression; Hippocampus; Male; Mice; Mice, Inbred C57BL; Resveratrol; Stilbenes; Streptozocin

Trans-resveratrol (RSV) is a natural compound occurring in different foods and plants, which in vivo is rapidly conjugated with glucuronic acid and sulfate. Despite its demonstrated cardioprotective activity, the bioaccumulation of RSV or its metabolites in cardiac tissue is still unknown.. Diabetic rats were randomized to 1, 3 or 6 weeks of RSV treatment at two different doses (1 or 5 mg/kg/day). A dose and time-dependent accumulation was observed, with no detectable levels of RSV metabolites found in heart tissues after 1 week and significant concentrations of RSV-3-sulfate and RSV-3-glucuronide after 6 weeks of treatment (0.05 nmol/g of tissue and 0.01 nmol/g of tissue, respectively). Tissue accumulation of RSV metabolites was accompanied by an improvement of cardiac function in long-term diabetes, when myocardial morpho-functional damage is more evident, with an almost complete recovery of all hemodynamic parameters, at the highest RSV dose.. Even if a higher concentration of RSV in tissues cannot be ruled out after constant oral administration, an accumulation coherent with what is usually evaluated in cell based mechanistic studies is largely unattainable and the RSV unconjugated form would not be present in this paradigm. The current investigation provides data on myocardial tissue concentrations of RSV metabolites, after short/medium term RSV treatment. This knowledge constitutes a basic requirement for future studies aimed at reliably defining the molecular pathways underlying RSV-mediated cardioprotective effects and opens up new perspectives for research focused on testing phenolic compounds as adjuvants in degenerative heart diseases.

Topics: Animals; Biotransformation; Blood Glucose; Body Weight; Cardiotonic Agents; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Glucuronides; Heart Diseases; Hemodynamics; Male; Myocardium; Rats, Wistar; Resveratrol; Stilbenes; Sulfates; Time Factors

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.

Topics: Abdominal Fat; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Chromatography, High Pressure Liquid; Female; Lipids; Mice; Mice, Inbred C57BL; Obesity; Oryza; Plants, Genetically Modified; Resveratrol; Stilbenes

Depression is one of the most common neuropsychiatric disorders and has been associated with the neuroendocrine system and alterations in specific brain proteins. Resveratrol is a natural polyphenol enriched in polygonum cuspidatum and has diverse biological activities, including potent antidepressant-like effects. The present study attempts to explore the mechanisms underlying the antidepressant-like action of resveratrol by measuring serum corticosterone levels and the content of brain derived neurotrophic factor (BDNF) in the hippocampus and amygdala of rats exposed to the chronic unpredictable mild stress (CUMS). Male Wistar rats were subjected to the CUMS protocol for a period of 5 weeks to induce depressive-like behavior. Resveratrol treatment (20, 40 and 80mg/kg/i.p. 5 weeks) significantly reversed the CUMS-induced behavioral abnormalities (reduced sucrose preference, increased immobility time and decreased locomotor activity) and the elevated serum corticosterone levels observed in stressed rats. Additionally, 5-weeks of CUMS exposure significantly decreased BDNF levels in the hippocampus and amygdala, and was accompanied by decreased phosphorylation of extracellular signal-regulated kinase (pERK) and cAMP response element-binding protein (pCREB), while resveratrol treatment normalized these levels. All of these effects of resveratrol were essentially identical to that observed with the established antidepressant, desipramine. In conclusion, our study shows that resveratrol exerted antidepressant-like effects in CUMS rats, mediated in part by normalizing serum corticosterone levels while up-regulating pERK, pCREB and BDNF levels in the hippocampus and amygdala.

Topics: Animals; Antioxidants; Body Weight; Brain-Derived Neurotrophic Factor; Corticosterone; CREB-Binding Protein; Disease Models, Animal; Dose-Response Relationship, Drug; Exploratory Behavior; Food Deprivation; Food Preferences; Gene Expression Regulation; Male; Rats; Rats, Wistar; Resveratrol; Stilbenes; Stress, Psychological; Swimming; Time Factors

Resveratrol (RSV) regulates NAD bioavailability and sirtuin-related metabolism, which relates to aging, metabolic syndrome and non-alcoholic fatty liver disease. The purpose of this study was to investigate the effects of resveratrol on hepatic metaflammation in a rodent model of high-fat (HF) diet-induced obesity (DIO).. DIO was induced in a subset of mice given an HF diet (45% kcal fat). After 6weeks of HF diet feeding, RSV was delivered via an osmotic pump for 4weeks. The experimental groups were as follows: 1) lean control fed with a standard diet, 2) HF diet-induced obese control, and 3) HF_RSV (8mg/kg/day). After 4weeks of each treatment, blood and liver tissues were collected and the indices of glucose control, serum and liver triglyceride (TG), sirtuin pathway, inflammation, and NOD-like receptor family, pryin domain containing 3 (NLRP3) inflammasome were analyzed.. Body weight and food intake were not altered by administering resveratrol. Glucose control was impaired, and serum and liver TG levels were increased by the HF diet. Hepatic inflammation was aggravated in mice fed with the HF diet, as shown by the increased levels of the pro-inflammatory markers interleukin-1 (IL-1), IL-6 and tumor necrosis factor-alpha in the liver. However, resveratrol administration significantly improved glucose control, and serum and liver TG contents. Also, resveratrol treatment reduced the levels of the pro-inflammatory markers. These improvements were accompanied by alterations in sirtuin pathway and NLRP3 inflammasome activation.. These results demonstrate that resveratrol ameliorates hepatic metaflammation, accompanied by alterations in NLRP3 inflammasome.

Topics: Animals; Anti-Inflammatory Agents; Body Weight; Carrier Proteins; Diet, High-Fat; Drug Evaluation, Preclinical; Eating; Hepatitis; Inflammasomes; Liver; Male; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Organ Size; Resveratrol; Stilbenes

Recent studies have investigated the anti-obesity effect of resveratrol, but the pathways through which resveratrol resists obesity are not clear. In the present study, we hypothesize that resveratrol exerts anti-obesity effects that are likely mediated by mechanisms of regulating gut microbes, and in turn, improving fat storage and metabolism. Gut microbes, glucose and lipid metabolism in high-fat diet (HF) mice in vivo are investigated after resveratrol treatment. Several biochemical markers are measured. Fluorescence in situ hybridization and flow cytometry are used to monitor and quantify the changes in gut microbiota. The key genes related to fat storage and metabolism in the liver and visceral adipose tissues are measured by real-time PCR. The results show that resveratrol (200 mg per kg per day) significantly lowers both body and visceral adipose weights, and reduces blood glucose and lipid levels in HF mice. Resveratrol improves the gut microbiota dysbiosis induced by the HF diet, including increasing the Bacteroidetes-to-Firmicutes ratios, significantly inhibiting the growth of Enterococcus faecalis, and increasing the growth of Lactobacillus and Bifidobacterium. Furthermore, resveratrol significantly increases the fasting-induced adipose factor (Fiaf, a key gene negatively regulated by intestinal microbes) expression in the intestine. Resveratrol significantly decreases mRNA expression of Lpl, Scd1, Ppar-γ, Acc1, and Fas related to fatty acids synthesis, adipogenesis and lipogenesis, which may be driven by increased Fiaf expression. The Pearson's correlation coefficient shows that there is a negative correlation between the body weight and the ratios of Bacteroidetes-to-Firmicutes. Therefore, resveratrol mediates the composition of gut microbes, and in turn, through the Fiaf signaling pathway, accelerates the development of obesity.

Topics: Acetyl-CoA Carboxylase; Adipose Tissue; Angiopoietin-Like Protein 4; Angiopoietins; Animals; Bifidobacterium; Blood Glucose; Body Weight; Diet, High-Fat; Enterococcus faecalis; fas Receptor; Gastrointestinal Tract; Lactobacillus; Lipids; Lipogenesis; Liver; Male; Mice; Microbiota; Obesity; PPAR gamma; Resveratrol; Signal Transduction; Stearoyl-CoA Desaturase; Stilbenes

High-fat diet (HFD)-induced obesity is often associated with immune dysfunction. Resveratrol (trans-3,5,4'-trihydroxystilbene), which has well-founded immunity-related beneficial properties, was used to elucidate the regulatory effect on glucose metabolism and T-lymphocyte subsets in the development of HFD-induced obesity. Resveratrol, being associated with decreases of plasma leptin and plasma lipids and the release of oxidative stress, significantly decreased the body weight and fat masses in HF mice after 26 weeks of feeding. Furthermore, resveratrol decreased the fasting blood glucose and fasting plasma insulin and increased the CD3(+)CD4(+)/CD3(+)CD8(+) subsets percentages and the regulatory T cells (Tregs) production after 13 and 26 weeks of feeding. The results indicate that resveratrol, as an effective supplement for HFD, maintained glucose homeostasis by activating the PI3K and SIRT1 signaling pathways. Moreover, resveratrol activated the Nrf2 signaling pathway-mediated antioxidant enzyme expression to alleviate inflammation by protecting against oxidative damage and T-lymphocyte subset-related chronic inflammatory response in the development of HFD-induced obesity.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Blood Glucose; Body Weight; Diet, High-Fat; Fasting; Female; Inflammation; Insulin; Leptin; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Obesity; Oxidative Stress; Phosphatidylinositol 3-Kinases; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; T-Lymphocyte Subsets

Previous studies have indicated that resveratrol, a natural phytoestrogen, can act as an anti-aging therapy to resist age-related changes of several body tissues. However, the anti-aging effects of resveratrol on bone have been poorly investigated in this natural aging population. Accordingly, this study was design to evaluate the effects of resveratrol on bone mass and biomechanical properties in old rat femora.. Twenty 22-month-old male Wistar rats were divided into two randomly assigned groups (n=10). The first group was treated for 10 weeks with resveratrol (10 mg/kg per day) and the second group was left untreated (control). Rat femora were collected. Bone mass and bone microestructure were investigated by microcomputed tomography and histomorphometry. Biomechanical properties were determined by a three-point bending test. Plasma levels of CTX (carboxy-terminal telopeptide of type I collagen) and osteocalcin were also determined. Statistical analyses were performed by a Student two-tailed unpaired t-test. In all experiments, a value of p<0.05 was considered significant.. Microcomputed tomography analyses demonstrated that resveratrol-treated rats had significant higher bone volume, bone trabecular number, and cortical thickness and lower spacing between trabeculae in comparison to the control group. Histomorphometric analyses confirmed the increase of bone volume in resveratrol-treated rats compared to controls. Resveratrol-treated rats had significant higher bone flexural modulus, stiffness, and ultimate load compared to control group. Treatment was not associated with changes in plasma CTX or osteocalcin.. These findings demonstrate that resveratrol increases bone microstructure and bone mechanical properties in old male rats, suggesting that resveratrol might be used as anti-aging therapy to resist age-induced bone loss.

Topics: Aging; Animals; Biomarkers; Biomechanical Phenomena; Body Weight; Bone Resorption; Collagen Type I; Femur; Male; Organ Size; Osteocalcin; Peptides; Rats, Wistar; Rejuvenation; Resveratrol; Stilbenes; X-Ray Microtomography

Resveratrol is well known for its anti-inflammation and anti-oxidant properties, and has been shown to be effective in alleviating the development of obesity. The purpose of this investigation was to analyze the effect of resveratrol on renal damage in obese rats induced by a high-fat diet (HFD) and its possible mechanisms. Male Sprague-Dawley rats were divided into three groups: control, HFD, and HFD plus resveratrol (treated with 100 mg/kg/day resveratrol). Body weight, serum and urine metabolic parameters, and kidney histology were measured. Meanwhile, the activities of nuclear factor-κB (NF-κB) and superoxide dismutase (SOD), the content of malondialdehyde (MDA), and the protein levels of tumor necrosis factor (TNF-α), monocyte chemotactic protein-1 (MCP-1), nephrin and podocin in kidney were detected. Our work showed that resveratrol alleviated dyslipidemia and renal damage induced by HFD, decreased MDA level and increased SOD activity. Furthermore, the elevated NF-κB activity, increased TNF-α and MCP-1 levels, and reduced expressions of nephrin and podocin induced by HFD were significantly reversed by resveratrol. These results suggest resveratrol could ameliorate renal injury in rats fed a HFD, and the mechanisms are associated with suppressing oxidative stress and NF-κB signaling pathway that in turn up-regulate nephrin and podocin protein expression.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; Body Weight; Chemokine CCL2; Diet, High-Fat; Glucose Tolerance Test; Intracellular Signaling Peptides and Proteins; Kidney; Male; Malondialdehyde; Membrane Proteins; NF-kappa B; Oxidative Stress; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Fluoride, a well-established environmental carcinogen, has been found to cause various neurodegenerative diseases in human. Sub-acute exposure to fluoride at a dose of 20mg/kgb.w./day for 30 days caused significant alteration in pro-oxidant/anti-oxidant status of brain tissue as reflected by perturbation of reduced glutathione content, increased lipid peroxidation, protein carbonylation, nitric oxide and free hydroxyl radical production and decreased activities of antioxidant enzymes. Decreased proteolytic and transaminase enzymes' activities, protein and nucleic acid contents and associated DNA damage were observed in the brain of fluoride intoxicated rats. The neurotransmitters dopamine (DA), norepinephrine (NE) and serotonin level was also significantly altered after fluoride exposure. Protective effect of resveratrol on fluoride-induced metabolic and oxidative dysfunctions was evaluated. Resveratrol was found to inhibit changes in metabolic activities restoring antioxidant status, biogenic amine level and structural organization of the brain. Our findings indicated that resveratrol imparted antioxidative role in ameliorating fluoride-induced metabolic and oxidative stress in different regions of the brain.

Topics: Animals; Antioxidants; Biogenic Amines; Body Weight; Brain; DNA Damage; Fluorides; Gene Expression Regulation, Enzymologic; Male; Neuroprotective Agents; Nucleic Acids; Oxidative Stress; Rats; Rats, Wistar; Resveratrol; Stilbenes

The effect of the intake of antioxidant polyphenols such as resveratrol and others on survival and different parameters of life quality has been a matter of debate in the last years. We have studied here the effects of the polyphenols resveratrol and kaempferol added to the diet in a murine model undergoing long-term hypercaloric diet. Using 50 mice for each condition, we have monitored weight, survival, biochemical parameters such as blood glucose, insulin, cholesterol, triglycerides and aspartate aminotransferase, neuromuscular coordination measured with the rotarod test and morphological aspect of stained sections of liver and heart histological samples. Our data show that mice fed since they are 3-months-old with hypercaloric diet supplemented with any of these polyphenols reduced their weight by about 5-7% with respect to the controls fed only with hypercaloric diet. We also observed that mice fed with any of the polyphenols had reduced levels of glucose, insulin and cholesterol, and better marks in the rotarod test, but only after 1 year of treatment, that is, during senescence. No effect was observed in the rest of the parameters studied. Furthermore, although treatment with hypercaloric diets induced large changes in the pattern of gene expression in liver, we found no significant changes in gene expression induced by the presence of any of the polyphenols. Thus, our data indicate that addition of resveratrol or kaempferol to mice food produces an initial decrease in weight in mice subjected to hypercaloric diet, but beneficial effects in other parameters such as blood glucose, insulin and cholesterol, and neuromuscular coordination, only appear after prolonged treatments.

Topics: Alanine Transaminase; Animals; Blood Glucose; Body Weight; Cholesterol; Gene Expression Regulation; Insulin; Kaempferols; Liver; Male; Mice, Inbred C57BL; Obesity; Resveratrol; Rotarod Performance Test; Stilbenes; Survival Rate; Triglycerides

To investigate the effect of resveratrol (RES) on methotrexate (MTX)-induced testicular damage.. RES (10mg/kg/day) was given for 8 days orally and MTX (20mg/kg i.p.) was given at day 4 of the experiment, with or without RES in rat.. MTX decreased serum testosterone, induced histopathological testicular damage, and increased testicular tumor necrosis factor-α level and expression of nuclear factor-κB and cyclooxygenase-2. In MTX/RES group, significant reversal of these parameters was noticed, compared to MTX group. Testicular expression of multidrug resistance protein (Mrp) 3 was three- and five-folds higher in RES- and MTX/RES-treated groups, respectively. In vitro, using prostate cancer cells, each of MTX and RES alone induced cytotoxicity with IC50 0.18 ± 0.08 and 20.5 ± 3.6 μM, respectively. RES also significantly enhanced cytotoxicity of MTX.. Thus, RES has dual beneficial effects, as it promotes MTX tumor cytotoxicity, while protecting the testes, probably via up-regulation of testicular Mrp3 as a novel mechanism.

Topics: Animals; Antimetabolites, Antineoplastic; Antioxidants; Body Weight; Cell Line, Tumor; Drug Resistance, Multiple; Humans; Male; Methotrexate; Multidrug Resistance-Associated Proteins; Prostatic Neoplasms; Protective Agents; Rats; Rats, Wistar; Resveratrol; Stilbenes; Testis; Testosterone

Squamous cell carcinoma (SCC) is one of the commonest dermatological malignancies. Resveratrol (Res) is one type of polyphenolic compound which was first identified from the roots of Veratrum grandinorum in 1940. The previous studies found that Res can promote apoptosis of a variety of tumor cell, especially SCC cells. However it is rare to study the inhibition mechanism of Res in the animal model. In this study, through the establishment of human cutaneous SCC A431 xenografts in nude mice, we observed Res inhibition effect and investigated the inhibition mechanism by checking the expression of apoptosis-related factors, p53, ERK and survivin. The results showed that the xenograft volume and weight of Res groups were less than those of the control groups (P<0.05), but the net body mass of nude mice of Res groups was not significantly different from the control groups (P>0.05). The apoptotic index of Res groups were significantly higher than the control groups (P<0.05). The protein and mRNA expression of p53 and ERK were statistically positively correlated (P<0.05) and significantly increased in Res high- and medium-dose groups compared with the control groups (P<0.05). Moreover, the protein and mRNA expression of SVV were negatively correlated with p53 (P<0.05) and lower than the control groups (P<0.05). The results demonstrate Res inhibitory effect and indicate that the inhibition mechanism of Res is to upgrade the protein and mRNA expression of p53 and to downgrade the protein and mRNA expression of SVV, thus inducing the apoptosis of tumor cells.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Regulatory Proteins; Body Weight; Carcinoma, Squamous Cell; Cell Line, Tumor; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Humans; Inhibitor of Apoptosis Proteins; Mice; Mice, Inbred BALB C; Mice, Nude; Phytotherapy; Plant Extracts; Repressor Proteins; Resveratrol; RNA, Messenger; Skin Neoplasms; Stilbenes; Survivin; Transplantation, Heterologous; Tumor Suppressor Protein p53; Veratrum

Resveratrol has been clinically shown to possess a number of human health benefits. As a result, many attempts have been made to engineer resveratrol production in major cereal grains but have been largely unsuccessful. In this study, we report the creation of a transgenic rice plant that accumulates 1.9 µg resveratrol/g in its grain, surpassing the previously reported anti-metabolic syndrome activity of resveratrol through a synergistic interaction between the transgenic resveratrol and the endogenous properties of the rice. Consumption of our transgenic resveratrol-enriched rice significantly improved all aspects of metabolic syndrome and related diseases in animals fed a high-fat diet. Compared with the control animals, the resveratrol-enriched rice reduced body weight, blood glucose, triglycerides, total cholesterol, and LDL-cholesterol by 24.7%, 22%, 37.4%, 27%, and 59.6%, respectively. The resveratrol-enriched rice from our study may thus provide a safe and convenient means of preventing metabolic syndrome and related diseases without major lifestyle changes or the need for daily medications. These results also suggest that future transgenic plants could be improved if the synergistic interactions of the transgene with endogenous traits of the plant are considered in the experimental design.

Topics: Acyltransferases; Adipose Tissue; Animals; Blood Glucose; Body Weight; Chromatography, High Pressure Liquid; Female; Food, Fortified; Glucosides; Glucosyltransferases; Humans; Lipids; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Oryza; Plant Leaves; Plants, Genetically Modified; Resveratrol; Seeds; Sirtuin 1; Stilbenes

In mammals, the main component of the circadian system is the suprachiasmatic nucleus in the hypothalamus. However, circadian clocks are also present in most peripheral tissues, such as adipose tissue. The aim of the present study was to analyse the potential effects of resveratrol on changes induced by high-fat feeding in the expression of clock genes and clock-controlled genes in the white adipose tissue from rats. For this purpose, rats were divided into three groups: a control group, fed a standard diet, and two other groups, either fed a high-fat diet supplemented with resveratrol (RSV) or no resveratrol (HF). The expression of clock genes and clock-controlled genes was analysed by RT-PCR. Protein expression and fatty acid synthase (FAS) activity were also analysed. When comparing the controls, the RSV group showed similar patterns of response to the HF group, except for reverse erythroblastosis virus α (Rev-Erbα), which was down-regulated. The expression of this gene reached the same levels as in control rats. The response pattern of protein expression for Rev-Erbα was similar to that found for gene expression. High-fat feeding up-regulated all adipogenic genes and resveratrol did not modify them. In the HF group, the activity of FAS tended to increase, while resveratrol decreased. In conclusion, resveratrol reverses the change induced by high-fat feeding in the expression of Rev-Erbα in adipose tissue, which means that clock machinery is a target for this polyphenol. This change seems to be related to reduced lipogenesis, which might be involved in the body fat-lowering effect of this molecule.

Topics: Adipose Tissue; Animals; Antioxidants; Body Weight; Circadian Rhythm; CLOCK Proteins; Diet, High-Fat; Down-Regulation; Fatty Acid Synthases; Gene Expression Profiling; Gene Expression Regulation; Lipogenesis; Liver; Male; Nuclear Receptor Subfamily 1, Group D, Member 1; Rats; Rats, Wistar; Resveratrol; Stilbenes; Suprachiasmatic Nucleus

Obesity is associated with an increased risk of infectious diseases. It has been shown to have deleterious effects on cell-mediated immunity, including reducing thymocyte numbers and altering responses of thymocytes to pathogens. In the current study, we examined the efficacy of the antiobesity phytochemical resveratrol in preventing the deleterious effects of a high-fat diet on thymic anatomy and function. Compared to C57Bl/6 male mice fed a low-fat diet, mice on a high-fat diet had a significant increase in thymic weight and lipid content, and a disrupted anatomy, including a reduction of the medullary compartment and absence of a corticomedullary junction. There were a decrease in thymic cellularity and mature T-cell output, and a disrupted T-cell maturation, as evidenced by increased double-negative and decreased single- and double-positive thymocytes. Mice that had been fed resveratrol along with a high-fat diet had a dose-dependent reversal in all these parameters. Western blots from thymi showed that obese mice had lower levels of the key stimulators of lipid metabolism, phospho-5' adenosine monophosphate-activated protein kinase and its downstream target, carnitine palmitoyl transferase-1; this was restored to normal levels in resveratrol-fed mice. Resveratrol also reversed an increase in glycerol-3-phosphate acyltransferase-1, the enzyme that catalyzes the first step in triglycerol synthesis. Taken together, these results indicate that resveratrol is a potent inhibitor of the deleterious effects of diet-induced obesity on thymic anatomy and function, and this may hold promise in preventing obesity-related deficits in cell-mediated immunity.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Body Weight; Carnitine O-Palmitoyltransferase; Diet, High-Fat; Dose-Response Relationship, Drug; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Obesity; Organ Size; Resveratrol; Stilbenes; T-Lymphocytes; Thymus Gland

Resveratrol (RES) is a well-known phytocompound and food component which has antioxidative and multifunctional bioactivities. However, there is limited evidence for the effects of RES on physical fatigue and exercise performance. The purpose of this study was to evaluate the potential beneficial effects of trans-RES on fatigue and ergogenic functions following physiological challenge. Male ICR mice from four groups (n = 8 per group) were orally administered RES for 21 days at 0, 25, 50, and 125 mg/kg/day, which were respectively designated the vehicle, RES-25, RES-50, and RES-125 groups. The anti-fatigue activity and exercise performance were evaluated using forelimb grip strength, exhaustive swimming time, and levels of serum lactate, ammonia, glucose, and creatine kinase (CK) after a 15-min swimming exercise. The exhaustive swimming time of the RES-25 group (24.72 ± 7.35 min) was significantly (p = 0.0179) longer than that of vehicle group (10.83 ± 1.15 min). A trend analysis revealed that RES treatments increased the grip strength. RES supplementation also produced dose-dependent decreases in serum lactate and ammonia levels and CK activity and also an increase in glucose levels in dose-dependent manners after the 15-min swimming test. The mechanism was related to the increased energy utilization (as blood glucose), and decreased serum levels of lactate, ammonia, and CK. Therefore, RES could be a potential agent with an anti-fatigue pharmacological effect.

Topics: Ammonia; Animals; Antioxidants; Blood Glucose; Body Weight; Creatine Kinase; Dietary Supplements; Fatigue; Glycogen; Kidney; Lactic Acid; Liver; Male; Mice; Muscle, Skeletal; Physical Conditioning, Animal; Resveratrol; Stilbenes; Swimming

Oxidative stress is a key factor in the aging process and in the development of age-related diseases. Because nutritional interventions such as caloric restriction (CR) delay the onset of age-related diseases and increase the lifespan of many species, the impact of a moderate CR was tested on male grey mouse lemur (Microcebus murinus), which have a median survival time of 5.7 years in captivity. The effects of CR on these lemurs were compared with a potential mimetic, resveratrol (RSV), a polyphenol naturally found in grapes. We hypothesized that both CR and RSV impact oxidative DNA and RNA damage compared to standard-fed control (CTL) animals. Adult (3-4 years old) male mouse lemurs were assigned to three dietary groups: a CTL group, a CR group receiving 30% fewer calories than the CTL and a RSV group receiving the CTL diet supplemented with RSV (200 mg·day(-1)·kg(-1)). Oxidative stress was estimated after 3, 9, 15 and 21 months of treatment using the measurement of oxidized nucleosides in urine samples by mass spectrometry. The resting metabolic rate, adjusted for changes in body composition, was also measured to assess the potential relationship between oxygen consumption and oxidative damage markers. This study provides evidence for oxidative stress accumulation with age in grey mouse lemur. Dietary interventions resulted in a short-term increase in oxidative stress levels followed by reduced levels with increasing age. Moreover, in this photoperiod-dependent heterotherm primate, seasonal variations in oxidative stress were observed, which was likely due to a season-dependent, cost-benefit trade-off between torpor use and oxidative stress.

Topics: Aging; Animals; Antioxidants; Basal Metabolism; Body Composition; Body Weight; Caloric Restriction; Cheirogaleidae; DNA Damage; Male; Nucleosides; Oxidation-Reduction; Oxidative Stress; Resveratrol; RNA; Seasons; Stilbenes

Dietary intake of fructose and sucrose can cause development of metabolic and cardiovascular disorders. The consequences of high-fructose corn syrup (HFCS), a commonly consumed form of fructose and glucose, have poorly been examined. Therefore, in this study, we investigated whether HFCS intake (10% and 20% beverages for 12 weeks) impacts vascular reactivity to insulin and endothelin-1 in conjunction with insulin receptor substrate-1(IRS-1), endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) mRNA/proteins levels in aorta of rats. At challenge, we tested the effectiveness of resveratrol (28-30 mg/kg body weight/day) on outcomes of HFCS feeding. HFCS (20%) diet feeding increased plasma triglyceride, VLDL, cholesterol, insulin and glucose levels, but not body weights of rats. Impaired nitric oxide-mediated relaxation to insulin (10⁻⁹ to 3×10⁻⁶ M), and enhanced contraction to endothelin-1 (10⁻¹¹ to 10⁻⁸ M) were associated with decreased expression of IRS-1 and eNOS mRNA and protein, but increased expression of iNOS, in aortas of rats fed with HFCS. Resveratrol supplementation restored many features of HFCS-induced disturbances, probably by regulating eNOS and iNOS production. In conclusion, dietary HFCS causes vascular insulin resistance and endothelial dysfunction through attenuating IRS-1 and eNOS expressions as well as increasing iNOS in rats. Resveratrol has capability to recover HFCS-induced disturbances.

Topics: Animals; Body Weight; Cholesterol, VLDL; Endothelin-1; Fructose; Gene Expression; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Male; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Rats; Rats, Wistar; Resveratrol; RNA, Messenger; Stilbenes; Sweetening Agents; Triglycerides

Eating a "Westernized" diet high in fat and sugar leads to weight gain and numerous health problems, including the development of type 2 diabetes mellitus (T2DM). Rodent studies have shown that resveratrol supplementation reduces blood glucose levels, preserves β-cells in islets of Langerhans, and improves insulin action. Although rodent models are helpful for understanding β-cell biology and certain aspects of T2DM pathology, they fail to reproduce the complexity of the human disease as well as that of nonhuman primates. Rhesus monkeys were fed a standard diet (SD), or a high-fat/high-sugar diet in combination with either placebo (HFS) or resveratrol (HFS+Resv) for 24 months, and pancreata were examined before overt dysglycemia occurred. Increased glucose-stimulated insulin secretion and insulin resistance occurred in both HFS and HFS+Resv diets compared with SD. Although islet size was unaffected, there was a significant decrease in β-cells and an increase in α-cells containing glucagon and glucagon-like peptide 1 with HFS diets. Islets from HFS+Resv monkeys were morphologically similar to SD. HFS diets also resulted in decreased expression of essential β-cell transcription factors forkhead box O1 (FOXO1), NKX6-1, NKX2-2, and PDX1, which did not occur with resveratrol supplementation. Similar changes were observed in human islets where the effects of resveratrol were mediated through Sirtuin 1. These findings have implications for the management of humans with insulin resistance, prediabetes, and diabetes.

Topics: Animals; Blood Glucose; Body Weight; Cell Dedifferentiation; Densitometry; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Dietary Sucrose; Disease Models, Animal; Fluorescent Antibody Technique; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Glucose Tolerance Test; Glycated Hemoglobin; Homeobox Protein Nkx-2.2; Homeodomain Proteins; Insulin; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Macaca mulatta; Nuclear Proteins; Protective Agents; Resveratrol; Sirtuin 1; Stilbenes; Transcription Factors

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a polyphenolic phytoalexin that exerts cardioprotective, neuroprotective, and antioxidant effects. Recently it has been shown that obesity is associated with an increase in cerebral oxidative stress levels, which may enhance neurodegeneration. The present study evaluates the neuroprotective action of resveratrol in brain of obese (ob/ob) mice. Resveratrol was administered orally at the dose of 25 mg kg(-1) body weight daily for three weeks to lean and obese mice. Resveratrol had no effect on body weight or blood glucose levels in obese mice. Lipid peroxides were significantly increased in brain of obese mice. The enzymatic antioxidants superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase and nonenzymatic antioxidants tocopherol, ascorbic acid, and glutathione were decreased in obese mice brain. Administration of resveratrol decreased lipid peroxide levels and upregulated the antioxidant activities in obese mice brain. Our findings indicate a neuroprotective effect of resveratrol by preventing oxidative damage in brain tissue of obese mice.

Topics: Animals; Antioxidants; Blood Glucose; Body Weight; Brain; Hydrogen Peroxide; Lipid Peroxidation; Male; Malondialdehyde; Mice; Mice, Obese; Neuroprotective Agents; Obesity; Oxidative Stress; Resveratrol; Stilbenes; Thinness

Consumption of a high-fat diet (HFD) is correlated with increased oxidative stress and chronic inflammation in many organs. Regulatory T cells (Tregs) are essential negative regulators of inflammation. We hypothesized that resveratrol (trans-3,5,4'-trihydroxystilbene) could protect against HFD-induced oxidative stress and inflammation. Therefore, we examined the effect of resveratrol on oxidative stress and the relevant peripheral immune-regulating mechanisms in HFD-induced obese (DIO) and diet-resistant mice. C57BL/6 mice were fed a normal diet and an HFD for 13 weeks. Then the experimental group was subdivided into DIO and diet-resistant groups according to their body weights, which were further supplemented with 0.03% resveratrol and 0.06% resveratrol, respectively, for an additional 13 weeks. Resveratrol prevented the accumulation of chronic oxidative stress and suppression of Tregs production in HFD mice, modulated changes of cytokines in the plasma and spleen, and decreased expressions of inflammatory mediators compared with those of the DIO group. Our results indicate that resveratrol, as a feasible effective supplement for HFD, can relieve oxidative stress, inhibit inflammatory genes expression, and increase Tregs number via aryl hydrocarbon receptor activation inhibited by HFD, especially in DIO mice.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Body Weight; Cytokines; Diet, High-Fat; Dietary Fats; Dietary Supplements; Inflammation; Inflammation Mediators; Male; Mice; Mice, Inbred C57BL; Obesity; Oxidative Stress; Phytotherapy; Plant Extracts; Receptors, Aryl Hydrocarbon; Resveratrol; Spleen; Stilbenes; T-Lymphocytes, Regulatory

The National Institute on Aging Interventions Testing Program (ITP) was established to evaluate agents that are hypothesized to increase life span and/or health span in genetically heterogeneous mice. Each compound is tested in parallel at three test sites. It is the goal of the ITP to publish all results, negative or positive. We report here on the results of lifelong treatment of mice, beginning at 4 months of age, with each of five agents, that is, green tea extract (GTE), curcumin, oxaloacetic acid, medium-chain triglyceride oil, and resveratrol, on the life span of genetically heterogeneous mice. Each agent was administered beginning at 4 months of age. None of these five agents had a statistically significant effect on life span of male or female mice, by log-rank test, at the concentrations tested, although a secondary analysis suggested that GTE might diminish the risk of midlife deaths in females only.

Topics: Age Factors; Aging; Animals; Body Weight; Curcumin; Drug Evaluation, Preclinical; Female; Longevity; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred DBA; Models, Animal; Motor Activity; Oxaloacetic Acid; Pregnancy; Resveratrol; Sex Characteristics; Stilbenes; Tea; Triglycerides

Duchenne muscular dystrophy (DMD) is a lethal genetic disease with no cure. Reducing inflammation or increasing utrophin expression can alleviate DMD pathology. Resveratrol can reduce inflammation and activate the utrophin promoter. The aims of this study were to identify an active dose of resveratrol in mdx mice and examine if this dose decreased inflammation and increased utrophin expression.. 5-week old mdx mice were given 0, 10, 100, or 500 mg/kg of resveratrol everyday for 10 days. Sirt1 was measured by qRT-PCR and used to determine the most active dose. Muscle inflammation was measured by H&E staining, CD45 and F4/80 immunohistochemistry. IL-6, TNFα, PGC-1α, and utrophin gene expression were measured by qRT-PCR. Utrophin, Sirt1, and PGC-1α protein were quantified by western blot.. The 100 mg/kg dose of resveratrol, the most active dose, increased Sirt1 mRNA 60 ± 10% (p < 0.01), reduced immune cell infiltration 21 ± 6% (H&E) and 42 ± 8% (CD45 immunohistochemistry (p < 0.05)), reduced macrophage infiltration 48 ± 10% (F4/80 immunohistochemistry (p < 0.05)), and increased IL-6, PGC-1α, and utrophin mRNA 247 ± 77%, 27 ± 17%, and 43 ± 23% respectively (p ≤ 0.05). Utrophin, Sirt1, and PGC-1α protein expression did not change.. Resveratrol may be a therapy for DMD by reducing inflammation.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Dietary Supplements; Disease Models, Animal; Inflammation Mediators; Leukocytes; Macrophages; Male; Mice; Mice, Inbred mdx; Muscle Development; Muscle, Skeletal; Muscular Dystrophy, Duchenne; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Resveratrol; RNA, Messenger; Sirtuin 1; Stilbenes; Trans-Activators; Transcription Factors; Up-Regulation; Utrophin

The synergic effect of regular exercise and resveratrol, a polyphenolic compound with potent antioxidant activity, was investigated against kainate-induced seizures and oxidative stress in mice. After 6 weeks of swimming training, the total body weight decreased and the blood concentration of lactate stabilized statistically in comparison with the sedentary mice, indicate that the training program increased the aerobic resistance of mice. Kainate (30 mg/kg) evoked seizure activity 5 min after injection, and seizure activity was measured seizure rating scores every 5 min up to 2 h. As previously well known experiments, regular exercise and resveratrol (40 mg/kg, daily supplementation for 6 weeks) have an inhibitory effect on kainate-induced seizure activity and oxidative stress. In particularly, a synergistic cooperation of regular exercise and resveratrol was observed in seizure activity, mortality and oxidative stress especially in SOD activity. These results suggest that regular exercise along with an anti-convulsant agent such as resveratrol could be a more efficient method for the prevention of seizure development than exercise alone.

Topics: Anaerobic Threshold; Animals; Antioxidants; Body Weight; Catalase; Kainic Acid; Lactic Acid; Male; Mice; Mice, Inbred ICR; Oxidative Stress; Physical Conditioning, Animal; Resveratrol; Seizures; Stilbenes; Superoxide Dismutase; Swimming

A series of studies have recently demonstrated that the oxidative stress, nuclear factor-kappa B (NF-κB) activation and the subsequent coordinated inflammatory responses played an important role in the pathogenesis of urate nephropathy (UN). Polydatin has been suggested to have the properties of anti-oxidative, anti-inflammatory and nephroprotective effects. However, the possible protective and beneficial effects of polydatin on UN are not fully elucidated. Therefore, we investigated the potential beneficial effects and possible mechanisms of polydatin on UN. In this study, polydatin showed inhibitory activities on xanthine oxidase to repress the level of serum uric acid in vivo and in vitro. Further investigations revealed that polydatin displayed little toxic effects and significantly ameliorated the renal function in fructose-induced UN mice. The nephroprotective activities of polydatin was not only due to the effects on remarkably attenuating the oxidative stress induced by uric acid, but also on markedly suppressing the oxidative stress-related inflammatory cascade, including decreasing the expressions of NF-κB p65, COX-2 and iNOS proteins and inhibiting the productions of TNF-α, PGE(2) and IL-1β. These findings elucidated that polydatin exhibited prominent nephroprotective activities and low toxic effects.

Topics: Animals; Blood Chemical Analysis; Body Weight; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Drugs, Chinese Herbal; Fructose; Glucosides; Inflammation; Interleukin-1beta; Kidney; Kidney Diseases; Male; Mice; Mice, Inbred Strains; NF-kappa B; Nitric Oxide Synthase Type II; Oxidative Stress; Protective Agents; Stilbenes; Tumor Necrosis Factor-alpha; Uric Acid; Xanthine Oxidase

In adult rats, trans-resveratrol attenuates kainic acid (KA)-induced convulsions and the associated hippocampal neurotoxicity. Increased neuronal survival was correlated with reduced lipid peroxidation. Since free radical generation after KA is age dependent and does not correlate with the onset of seizure-induced injury, the present study investigated whether daily trans-resveratrol treatment in development could protect the juvenile hippocampus from seizures and onset of damage at postnatal (P) day 21. Rat pups were treated with daily injections of trans-resveratrol under three dosage regimens (1-15 mg/kg and 20-50mg/kg). Weight, electroencephalography (EEG), histology, and N-methyl-d-aspartate (NMDA) receptor expression were determined. Malondialdehyde (MDA) concentration was assessed from separate animals. trans-Resveratrol did not interfere with growth or attenuate KA-induced EEG seizures. However, modest protection was afforded in the CA1, the subregion most sensitive to injury at this age. The CA3 and entorhinal amygdala cortex (AMG/EC) were not spared. Changes in NR1 subunit or NR1 C2 splice variant expression were also not prevented. Baseline MDA concentrations of hippocampal subfields were low at P14, P21, and P60 and high in aged adults. Glutamate (100 μM) to stimulate peroxidation products was significant at young ages but was much greater at older ages. After KA, elevated MDA levels were observed at 24h but only in adult preparations. Thus, while antioxidant therapy with trans-resveratrol may be considered as an adjunctive therapy to hinder epileptic activity and neurodegeneration at adult ages, it had only modest effects at young ages when production of free radicals within limbic structures is limited in this experimental model of seizures.

Topics: Age Factors; Analysis of Variance; Animals; Animals, Newborn; Body Weight; Brain Waves; Cell Count; Disease Models, Animal; Electroencephalography; Excitatory Amino Acid Agonists; Female; Gene Expression Regulation, Developmental; Hippocampus; Kainic Acid; Lipid Peroxidation; Male; Malondialdehyde; Neuroprotective Agents; Phosphopyruvate Hydratase; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Resveratrol; Status Epilepticus; Stilbenes

Trans-resveratrol is a phenolic compound enriched in polygonum cuspidatum and has diverse biological activities. There is only limited information about the antidepressant-like effect of trans-resveratrol. The present study investigated whether trans-resveratrol has antidepressant-like activity in rats exposed to chronic stress by using two behavioral tasks, shuttle box and sucrose preference tests. The monoamines (5-HT, noradrenaline and dopamine) and their metabolites as well as monoamine oxidase (MAO) enzyme activities in different brain regions were also measured. Compared to unstressed rats, those exposed to chronic stress paradigm showed performance deficits in the shuttle box, reduced sucrose preference, less weight gain and the increase in the ratio of adrenal gland to body weight, which were reversed by chronic treatment with trans-resveratrol (40 and 80 mg/kg, i.g.). The neurochemical assay showed that higher dose of trans-resveratrol (80 mg/kg) produced a marked increase of 5-HT levels in three brain regions, the frontal cortex, hippocampus and hypothalamus. Noradrenaline and dopamine levels were also increased both in the frontal cortex and striatum. Furthermore, chronic treatment with trans-resveratrol was found to inhibit monoamine oxidase-A (MAO-A) activity in all the four brain regions, particularly in the frontal cortex and hippocampus; while MAO-B activity was not affected. These findings indicate that the antidepressant-like effect of trans-resveratrol involves the regulation of the central serotonin and noradrenaline levels and the related MAO-A activities.

Topics: Adrenal Glands; Animals; Antidepressive Agents; Body Weight; Brain; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Escape Reaction; Fluoxetine; Food Preferences; Gene Expression Regulation; Imipramine; Male; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Stress, Psychological; Sucrose; Sweetening Agents; Time Factors; Water Deprivation

Resveratrol (trans-3,4',5-trihydroxystilbene) is a naturally occurring phytoalexin produced by plants in response to various stresses. Several studies have shown that resveratrol is present in significant amounts in a variety of human diets, including wines, grapes, berries, and peanuts, and it possesses several beneficial health properties, such as atheroprotective, anti-obesity, anti-cancer, anti-inflammatory and antioxidant activities. In this study, we evaluated the effect of resveratrol on the pathogenesis of obesity and the metabolic profile of nutrients in non-high fat-fed obese OLETF rats.. Although lipid parameters in the serum and liver were not changed, the accumulation of abdominal white adipose tissues was markedly prevented in resveratrol diet-fed OLETF rats after 4 weeks of feeding. The results of the respiratory gas analysis indicated that dietary resveratrol induced the partial enhancement of fat metabolism and sparing actions for carbohydrate and protein at 1 week and 3 weeks of feeding in OLETF rats. Additionally, the adipose mRNA level of carnitine palmitoyltransferase in the resveratrol diet-fed OLETF rats was higher than the control rats after 4 weeks of feeding.. Our study demonstrated that dietary resveratrol can prevent obesity through a change in the metabolic profile of nutrients in obese OLETF rats.

Topics: Adipose Tissue, White; Animals; Body Weight; Carnitine O-Palmitoyltransferase; Cholesterol; Food, Formulated; Gene Expression; Glycogen; Lipid Metabolism; Liver; Male; Metabolome; Obesity; Rats; Rats, Inbred OLETF; Resveratrol; RNA, Messenger; Stilbenes; Triglycerides; Up-Regulation

This study was designed to investigate the possible effectiveness of resveratrol (trans-3,5,4'-trihydroxystilbene) administration on oxidative stress, nuclear factor κB (NF-κB) activity and apoptosis rate in streptozotocin-nicotinamide-induced diabetic retinopathy.. Male Wistar rats were divided into four groups: normal control, diabetic control, normal rats treated with resveratrol, and diabetic rats treated with resveratrol. Diabetes was induced by injection of streptozotocin (50 mg/kg; ip), 15 min after the prescription of nicotinamide (110 mg/kg; ip) in 12 h fasted rats.. Four-month oral resveratrol administration (5 mg/kg/day) significantly alleviated hyperglycemia, weight loss, enhancement of oxidative markers (lipid peroxidation index and oxidized to reduced glutathione ratio) and superoxide dismutase activity in both blood and retinas of the diabetic rats. Moreover, resveratrol administration to diabetic rats improved the elevated levels of retinas NF-κB activity and apoptosis rate. On the other hand, four months resveratrol administration prevented from disarrangement and reduction in thickness of retinal layers.. These beneficial antidiabetic observations suggest that resveratrol may be considered as a therapeutic supplement to prevent from diabetic retinopathy.

Topics: Administration, Oral; Animals; Antioxidants; Apoptosis; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Glutathione; Glycated Hemoglobin; Insulin; Lipid Peroxidation; Male; NF-kappa B; Niacinamide; Oxidation-Reduction; Oxidative Stress; Rats; Rats, Wistar; Resveratrol; Retina; Signal Transduction; Stilbenes; Streptozocin; Superoxide Dismutase; Time Factors

Vessel leakage and loss of pericytes are early signs of diabetic retinopathy (DR), which leads to vision loss. Upregulation of the vascular endothelial growth factor (VEGF) during diabetes plays a key role in mediating these vascular lesions. The aim of this study is to investigate the effects of resveratrol, a natural plant-derived phytoalexin, on vascular damage and VEGF induction in mouse retinas of early diabetes.. Diabetes was induced in C57BL/6 mice by five consecutive-intraperitoneal injections of 55 mg/kg of streptozotocin (STZ). Animals injected with buffer only were used as controls. Beginning 1 month after the fifth injection of STZ or buffer, 20 mg/kg of resveratrol was administered by oral gavage daily for 4 weeks to diabetic and control mice, and all mice were killed 2 months after the injections. We assessed vessel leakage, pericyte loss and VEGF protein expression in mouse retinas of 2-month diabetes compared with controls with or without resveratrol treatment.. Diabetes led to increase vessel leakage, pericyte loss and VEGF protein level in the mouse retinas compared with controls; however, these changes were effectively blocked by resveratrol treatment.. Our data suggest that resveratrol is effective to decrease vascular lesions and VEGF induction in mouse retinas of early diabetes.

Topics: Animals; Antineoplastic Agents, Phytogenic; Blood Glucose; Blood-Retinal Barrier; Blotting, Western; Body Weight; Capillary Permeability; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Enzyme-Linked Immunosorbent Assay; Male; Mice; Mice, Inbred C57BL; Pericytes; Resveratrol; Retina; Retinal Vessels; Stilbenes; Vascular Endothelial Growth Factor A

An analytical approach for the determination of trans-resveratrol (3,5,4'-trihydroxy-trans-stilbene) and its glucuronide and sulfate conjugates in dog plasma by LC-MS/MS (without enzymatic hydrolysis of the conjugates) was validated to support pre-clinical toxicological and pharmacological studies. The approach required two independent sample extractions and consequent instrument runs. Samples for resveratrol determination were prepared by protein precipitation with acetonitrile; acetonitrile-methanol was used instead for resveratrol metabolites. Chromatographic separation was performed using a C18 column (30 mm × 2.0 mm) at a flow rate of 0.25 mL/min. For resveratrol the mobile phase consisted of A: 5mM ammonium acetate in water-isopropanol (98:2, v/v) and B: methanol-isopropanol (98:2, v/v) and for metabolites the mobile phase was modified as follows: A: 0.1% (v/v) formic acid in water and B: 0.1% (v/v) formic acid in acetonitrile. Total run time was 12 min for each run with retention times of about 4-5 min for all analytes. A turbo ion spray source was used operating in negative mode for resveratrol and resveratrol sulfate and in positive mode for resveratrol glucuronide. Calibration curves were linear from 5 to 1000 ng/mL for resveratrol and its glucuronide, and 10-2000 ng/mL for resveratrol sulfate. Linearity was assessed using the internal standard method for resveratrol and the external standard method for the metabolites. Method accuracy was 90-112% of the true value for all analytes with precision of 9% RSD or less for all validation experiments. The validated method was applied to a preclinical toxicology study in dogs after oral administration (200-1200 mg/kg) of the agent. Peak plasma resveratrol concentration (C(max)) for most animals was observed within 1-5 h of dosing, with group mean values in the 1.7-9.9 μg/mL (7.5-43 μM) range. Area under the plasma concentration-time curve (AUC) mean values for resveratrol ranged from 3.6 to 44 h μg/mL for all study groups and were generally proportional to the dose, with no consistent statistically significant changes observed for gender or number of doses. Mean molecular-weight adjusted ratios of resveratrol metabolites to resveratrol for AUC ranged from 1 to 9 for resveratrol glucuronide and from 2 to 11 for resveratrol sulfate.

Topics: Animals; Body Weight; Calibration; Chromatography, Liquid; Dogs; Dose-Response Relationship, Drug; Drug Stability; Female; Glucuronides; Humans; Limit of Detection; Male; Molecular Structure; Rats; Reference Standards; Reproducibility of Results; Resveratrol; Species Specificity; Stilbenes; Sulfuric Acid Esters; Tandem Mass Spectrometry; Time Factors

Resveratrol, a naturally occurring polyphenol, has been shown to protect the heart and brain against ischemic injury. The current study investigated the effects of administration with either a 1 or 10-mg/kg dose of resveratrol on CA1 neuronal injury and behavioral/cognitive impairments after 10-min global ischemia in rats. The open-field, eight-arm radial maze and object recognition tests served to evaluate effects of resveratrol treatment on ischemia-induced locomotor activity, and spatial and recognition memory impairments, respectively. CA1 and CA3 neuronal injury was assessed upon completion of behavioral testing, 85 days postischemia. A separate series of groups served to assess neuronal injury at 7 days postischemia. Global ischemia (10 min) led to approximately 50% CA1 cell injury, which was prevented at both short (7 days) and long (85 days) postischemic intervals by resveratrol treatment. Importantly, despite comparable neuronal protection, the two resveratrol doses showed distinct behavioral effects. Thus, the 10-mg/kg resveratrol dose led to an enhanced locomotor activity in the open-field 4-days postischemia and an impaired spatial memory in the delayed nonmatching to sample and delayed matching to sample radial-maze tasks initiated on day 13 postischemia. These findings suggest independent actions of resveratrol on distinct physiological systems mediating cellular survival and functional recovery and dose-related actions of the polyphenol on behavioral and memory processes.

Topics: Animals; Behavior, Animal; Blood Glucose; Body Weight; Brain Ischemia; Dose-Response Relationship, Drug; Exploratory Behavior; Hippocampus; Male; Maze Learning; Motor Activity; Neuroprotective Agents; Oxidative Stress; Rats; Rats, Wistar; Resveratrol; Stilbenes

Increased utrophin expression is known to reduce pathology in dystrophin-deficient skeletal muscles. Transgenic over-expression of PGC-1α has been shown to increase levels of utrophin mRNA and improve the histology of mdx muscles. Other reports have shown that PGC-1α signaling can lead to increased oxidative capacity and a fast to slow fiber type shift. Given that it has been shown that slow fibers produce and maintain more utrophin than fast skeletal muscle fibers, we hypothesized that over-expression of PGC-1α in post-natal mdx mice would increase utrophin levels via a fiber type shift, resulting in more slow, oxidative fibers that are also more resistant to contraction-induced damage. To test this hypothesis, neonatal mdx mice were injected with recombinant adeno-associated virus (AAV) driving expression of PGC-1α. PGC-1α over-expression resulted in increased utrophin and type I myosin heavy chain expression as well as elevated mitochondrial protein expression. Muscles were shown to be more resistant to contraction-induced damage and more fatigue resistant. Sirt-1 was increased while p38 activation and NRF-1 were reduced in PGC-1α over-expressing muscle when compared to control. We also evaluated if the use a pharmacological PGC-1α pathway activator, resveratrol, could drive the same physiological changes. Resveratrol administration (100 mg/kg/day) resulted in improved fatigue resistance, but did not achieve significant increases in utrophin expression. These data suggest that the PGC-1α pathway is a potential target for therapeutic intervention in dystrophic skeletal muscle.

Topics: Animals; Biomechanical Phenomena; Body Weight; Dependovirus; Dietary Supplements; Gene Transfer Techniques; Mice; Mice, Inbred mdx; Muscle Contraction; Muscle Fatigue; Muscle Fibers, Fast-Twitch; Muscle Fibers, Slow-Twitch; Muscular Dystrophy, Animal; Myosins; Organ Size; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Recovery of Function; Resveratrol; Stilbenes; Trans-Activators; Transcription Factors

Senescence of vascular cells contributes to the development of cardiovascular diseases and the overall aging. This study was undertaken to investigate the effects of resveratrol (Res) on amelioration of vascular cell aging and the role of SIRT1/nicotinamide adenine dinucleotide phosphate (NADPH) oxidase pathway.. Adult male Wistar rats were treated with a high-fat/sucrose diet (HFS) in the presence or absence of Res for 3 months. HFS and in vitro treatment with high glucose increased the senescence cells and reactive oxygen species production in rat aorta and cultured bovine aortic endothelial cells (BAECs), respectively, which was attenuated by Res treatment. Res protected against HFS- or high-glucose-induced increase in NADPH oxidase p47phox expression and decrease in SIRT1 level. Apocynin, a NADPH oxidase inhibitor, down-regulated p47phox protein expression, but had no influence on SIRT1 protein; sirtinol, a SIRT1 inhibitor, aggravated the decrease in SIRT1 protein level and the increase in p47phox protein expression induced by high glucose.. Our studies suggested that Res was able to reverse the senescence process in aorta induced by HFS in rats or induced by the exposure to high glucose in cultured BAECs. The underlying mechanism is at least SIRT1/NADPH oxidase pathway dependent.

Topics: Animals; Aorta; Body Weight; Cattle; Cells, Cultured; Cellular Senescence; Diet, High-Fat; Endothelium, Vascular; Glucose; Lipids; Male; NADPH Oxidases; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species; Resveratrol; Sirtuin 1; Stilbenes

Catch-up growth (CUG) after food restriction can increase the risks for insulin resistance-related diseases, and to our knowledge, no previous studies have addressed how bone is influenced by CUG when refeeding diet content differs. The objective of this study was to investigate the bone status resulting from CUG induced by varying refeeding dietary patterns, and to assess the potential influencing factors and the effect of resveratrol on bone status during CUG. Experimental rats were randomly divided into five groups: normal chow (NC) group; CUG group (CUG, containing two subgroups, respectively, refeeding with normal chow or high-fat diet); high-fat diet (HF) group; and resveratrol intervention groups (CUGE and HFE). Bone parameters were detected by dual-energy X-ray absorptiometry. Serum concentrations of tumor necrosis factor (TNF)-α, body weight and food intake were also recorded. Our results showed that food restriction induced a significant decrease in bone parameters. Eight-week CUG by normal chow had a greater degree of improvement in bone mineral density than high-fat diet, and even returned to normal level similar to NC. Bone parameters were elevated in varying degrees in the HF group compared with the NC group. In the resveratrol intervention groups, bone parameters significantly increased. Furthermore, bone parameters were inversely related with serum TNF-α concentrations, but showed positive correlation with body weight. In conclusion, the study shows that CUG can partially reverse the deleterious effects of caloric restriction on bone health, especially in the refeeding with normal chow group. Moreover, resveratrol has a protective effect on bone status during the period of CUG. Serum TNF-α levels and body weight also seem to play an important role in regulating bone parameters.

Topics: Absorptiometry, Photon; Animals; Antioxidants; Body Weight; Bone and Bones; Bone Density; Caloric Restriction; Male; Malnutrition; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes

High-fructose corn syrup (HFCS) is used in many prepared foods and soft drinks. However, limited data is available on the consequences of HFCS consumption on metabolic and cardiovascular functions. This study was, therefore, designed to assess whether HFCS drinking influences the endothelial and vascular function in association with metabolic disturbances in rats. Additionally, resveratrol was tested at challenge with HFCS. We investigated the effects of HFCS (10% and 20%) and resveratrol (50mg/l) beverages on several metabolic parameters as well as endothelial relaxation, vascular contractions, expressions of endothelial nitric oxide synthase (eNOS), sirtuin 1 (SIRT1), gp91(phox) and p22(phox) proteins and superoxide generation in the aortas. Consumption of HFCS (20%) increased serum triglyceride, VLDL and insulin levels as well as blood pressure. Impaired relaxation to acetylcholine and intensified contractions to phenylephrine and angiotensin II were associated with decreased eNOS and SIRT1 whereas increased gp91(phox) and p22(phox) proteins, along with provoked superoxide production in the aortas from HFCS-treated rats. Resveratrol supplementation efficiently restored HFCS-induced deteriorations. Thus, intake of HFCS leads to vascular dysfunction by decreasing vasoprotective factors and provoking oxidative stress in association with metabolic disturbances. Resveratrol has a protective potential against the harmful consequences of HFCS consumption.

Topics: Animals; Antioxidants; Aorta, Thoracic; Blood Glucose; Blood Pressure; Blotting, Western; Body Weight; Fructose; Insulin; Lipids; Male; NADPH Oxidases; Nitric Oxide; Phenylephrine; Rats; Rats, Wistar; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; Superoxides; Vascular Diseases; Vasoconstrictor Agents

Mitochondrial dysfunction occurs in sensory neurons and may contribute to distal axonopathy in animal models of diabetic neuropathy. The adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) signalling axis senses the metabolic demands of cells and regulates mitochondrial function. Studies in muscle, liver and cardiac tissues have shown that the activity of adenosine monophosphate-activated protein kinase and PGC-1α is decreased under hyperglycaemia. In this study, we tested the hypothesis that deficits in adenosine monophosphate-activated protein kinase/PGC-1α signalling in sensory neurons underlie impaired axonal plasticity, suboptimal mitochondrial function and development of neuropathy in rodent models of type 1 and type 2 diabetes. Phosphorylation and expression of adenosine monophosphate-activated protein kinase/PGC-1α and mitochondrial respiratory chain complex proteins were downregulated in dorsal root ganglia of both streptozotocin-diabetic rats and db/db mice. Adenoviral-mediated manipulation of endogenous adenosine monophosphate-activated protein kinase activity using mutant proteins modulated neurotrophin-directed neurite outgrowth in cultures of sensory neurons derived from adult rats. Addition of resveratrol to cultures of sensory neurons derived from rats after 3-5 months of streptozotocin-induced diabetes, significantly elevated adenosine monophosphate-activated protein kinase levels, enhanced neurite outgrowth and normalized mitochondrial inner membrane polarization in axons. The bioenergetics profile (maximal oxygen consumption rate, coupling efficiency, respiratory control ratio and spare respiratory capacity) was aberrant in cultured sensory neurons from streptozotocin-diabetic rats and was corrected by resveratrol treatment. Finally, resveratrol treatment for the last 2 months of a 5-month period of diabetes reversed thermal hypoalgesia and attenuated foot skin intraepidermal nerve fibre loss and reduced myelinated fibre mean axonal calibre in streptozotocin-diabetic rats. These data suggest that the development of distal axonopathy in diabetic neuropathy is linked to nutrient excess and mitochondrial dysfunction via defective signalling of the adenosine monophosphate-activated protein kinase/PGC-1α pathway.

Topics: Adenosine Triphosphate; AMP-Activated Protein Kinases; Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; Body Weight; Cells, Cultured; Diabetes Mellitus, Experimental; Disease Models, Animal; Dose-Response Relationship, Drug; Ganglia, Spinal; Gene Expression Regulation; Green Fluorescent Proteins; Hyperalgesia; Male; Membrane Potentials; Mice; Mitochondrial Diseases; Mitochondrial Membranes; Mutation; Nerve Fibers, Myelinated; Neurites; Oxygen Consumption; Patch-Clamp Techniques; Peripheral Nervous System Diseases; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Physical Stimulation; Rats; Rats, Sprague-Dawley; Reaction Time; Resveratrol; RNA-Binding Proteins; Sensory Receptor Cells; Signal Transduction; Stilbenes; Transcription Factors; Transduction, Genetic

Metabolic syndrome and oxidative stress are common complications of type 2 diabetes mellitus. The present study was designed to determine whether resveratrol, a widely used nutritional supplement, can improve insulin sensitivity, metabolic complication as well as hepatic oxidative stress in fructose-fed rats. Male Sprague Dawley rats (180-200 g) were divided into four groups with 8 animals each. Fructose-fed insulin resistant group (Dia) animals were fed 65% fructose (Research diet, USA) for a period of 8 weeks, whereas control group (Con) animals were fed 65% cornstarch (Research Diet, USA). Resveratrol, 10 mg/kg/day (Dia+Resv) or metformin 300 mg/kg/day (Dia+Met) were administered orally to the 65% fructose-fed rats for 8 weeks. At the end of the feeding schedule, Dia group had insulin resistance along with increased blood glucose, triglyceride, uric acid and nitric oxide (NO) levels. Significant (p<0.05) increase in hepatic TBARS and conjugated dienes, and significant (p<0.05) decrease in hepatic SOD and vitamin C was observed in Dia group compared to Con group. Administration of metformin or resveratrol significantly (p<0.05) normalized all the altered metabolic parameters. However, a marked insulin sensitizing action was only observed in the Dia+Resv group. Similarly, while metformin administration failed to normalize the increased TBARS levels and decreased SOD activity, resveratrol showed a more promising effect of all oxidative stress parameters measured in the present study. Attenuation of hepatic oxidative stress in fructose-fed rat liver after resveratrol administration was associated with significant (p<0.05) increase in nuclear level of NRF2 compared with other groups. The present study demonstrates that resveratrol is more effective than metformin in improving insulin sensitivity, and attenuating metabolic syndrome and hepatic oxidative stress in fructose-fed rats.

Topics: Animals; Ascorbic Acid; Blood Glucose; Body Weight; Catalase; Eating; Fructose; Glucose Tolerance Test; Glutathione; Insulin; Insulin Resistance; Liver; Male; Metabolic Syndrome; Metformin; NF-E2-Related Factor 2; Nitric Oxide; Oxidative Stress; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Triglycerides; Uric Acid

Resveratrol (Res) displays potent anti-oxidant activity and is a selective estrogen receptor modulator. The aim of the present study is to investigate whether Res consumption protects ovariectomized (OVX) rats chronically treated with D-galactose (D-gal) from developing memory decline and whether Res administration decreases pathological changes in the endometrium and lumen of the uterus compared with estradiol replacement therapy. Rats were divided into 6 groups: 1) Sham control group; 2) OVX+D-gal 100mg/kg group (OVX+D-gal); 3-5) OVX, D-gal and Res 20, 40, 80 mg/kg treated groups; and 6) OVX, D-gal and estradiol valerate 0.8 mg/kg treated group (ET). Twelve weeks later, in a Morris water maze test, the OVX+D-gal rats exhibited a significant memory impairment compared with the Sham control rats, which was accompanied by decreased total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-Px) activities and an increased thiobarbituric acid reactive substances (TBARS) level in the serum. In addition, the TBARS and protein carbonylation levels increased in the hippocampus. The beneficial roles of the 40 and 80 mg/kg Res treatments were manifested in the prevention of memory decline and markedly decreased oxidant stress indices. The disruption of the cristae in the mitochondria and the irregular nuclei and condensed chromatin in the pyramidal cells of the hippocampal CA1 region were also reduced after Res treatment. Furthermore, edema in the endometrium and lymphocyte infiltration was avoided in all three of the Res-treated groups compared with the ET group. These results suggest that Res is useful not only in protecting OVX+D-gal rats from developing memory decline by increasing the anti-oxidation but also in avoiding the effects on the uterus.

Topics: Animals; Antioxidants; Body Weight; Eating; Emotions; Estradiol; Female; Galactose; Glutathione Peroxidase; Hippocampus; Maze Learning; Memory; Memory Disorders; Motor Activity; Neurons; Ovariectomy; Oxidation-Reduction; Protein Carbonylation; Rats; Rats, Wistar; Resveratrol; Stilbenes; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Uterus

This study investigated the effects of resveratrol (RV) on diabetes-related metabolic changes in a spontaneous model of type 2 diabetes, as well as activation of AMP-activated protein kinase (AMPK) and downstream targets.. C57BL/KsJ-db/db mice were fed a normal diet with RV (0.005% and 0.02%, w/w) or rosiglitazone (RG, 0.001%, w/w) for 6 weeks. Both doses of RV significantly decreased blood glucose, plasma free fatty acid, triglyceride, apo B/apo AІ levels and increased plasma adiponectin levels. RV activated AMPK and downstream targets leading to decreased blood HbA1c levels, hepatic gluconeogenic enzyme activity, and hepatic glycogen, while plasma insulin levels, pancreatic insulin protein, and skeletal muscle GLUT4 protein were higher after RV supplementation. The high RV dose also significantly increased hepatic glycolytic gene expression and enzyme activity, along with skeletal muscle glycogen synthase protein expression, similar to RG. Furthermore, RV dose dependently decreased hepatic triglyceride content and phosphorylated I kappa B kinase (p-IKK) protein expression, while hepatic uncoupling protein (UCP) and skeletal muscle UCP expression were increased.. RV potentiates improving glycemic control, glucose uptake, and dyslipidemia, as well as protecting against pancreatic β-cell failure in a spontaneous type 2 diabetes model. Dietary RV has potential as an antidiabetic agent via activation of AMPK and its downstream targets.

Topics: Adiponectin; AMP-Activated Protein Kinases; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dietary Supplements; Dyslipidemias; Glucose Transporter Type 4; Glycated Hemoglobin; Glycogen; Insulin; Insulin Secretion; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Muscle, Skeletal; Resveratrol; Rosiglitazone; Stilbenes; Thiazolidinediones; Triglycerides

Reactive oxygen species production has recently been established as an essential contributor in the development of diabetic nephropathy (DN). Resveratrol, a natural anti-oxidants with biological activity, is known to be an activator of sirtuin1 (Sirt1). Forkhead transcription factor O1 (FoxO1) plays a role not only in regulating metabolism but also in oxidant stress. The present study was carried out to examine whether resveratrol had protective effect on diabetic kidney by modulation of the Sirt1/FoxO1 pathway. To investigate the effect of FoxO1 on oxidant stress, male Sprague-Dawley rats were injected with a single dose of 60 mg/kg streptozotocin (STZ) to induce diabetes. Here we show that the FoxO1 activity was significantly reduced and with a concomitant decrease in the expression of FoxO1 target gene, catalase in diabetic kidney. The FoxO1 downregulation correlated with an increase in the generation of malondialdehyde (MDA), a decrease in the activity of SOD and an increase in the expression of collagen IV and fibronectin proteins in renal cortex of diabetic rats. Treatment with the sirtuin agonist resveratrol, with an increase in the expression of Sirt1, significantly increased FoxO1 activity in diabetic kidney. This correlated with a decrease in the generation of MDA, an increase in the activity of SOD, a partial reversal of collagen IV and fibronectin proteins levels and more improved kidney pathological and biochemical indicators changes. Together these results indicate that it is characterized by decreased activity of FoxO1 in diabetic kidney. These data also suggest that modulation of the Sirt1/FoxO1 pathway may be a potentially useful therapeutic target for DN.

Topics: Animals; Antioxidants; Body Weight; Catalase; Collagen Type IV; Diabetic Nephropathies; Fibronectins; Forkhead Transcription Factors; Gene Expression Regulation; Kidney; Male; Nerve Tissue Proteins; Organ Size; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Resveratrol; Sirtuin 1; Stilbenes

We have previously shown that adult offspring exposed to a prenatal hypoxic insult leading to intrauterine growth restriction (IUGR) are more susceptible to cardiovascular pathologies. Our objectives were to evaluate the interaction between hypoxia-induced IUGR and postnatal diet in the early development of cardiovascular pathologies. Furthermore, we sought to determine whether the postnatal administration of resveratrol could prevent the development of cardiovascular disorders associated with hypoxia-induced IUGR. On day 15 of pregnancy, Sprague-Dawley rats were randomly assigned to hypoxia (11.5% oxygen), to induce IUGR, or normal oxygen (control) groups. For study A, male offspring (3 wk of age) were randomly assigned a low-fat (LF, <10% fat) or a high-fat (HF, 45% fat) diet. For study B, offspring were randomized to either HF or HF+resveratrol diets. After 9 wk, cardiac and vascular functions were evaluated. Prenatal hypoxia and HF diet were associated with an increased myocardial susceptibility to ischemia. Blood pressure, in vivo cardiac function, and ex vivo vascular function were not different among experimental groups; however, hypoxia-induced IUGR offspring had lower resting heart rates. Our results suggest that prenatal insults can enhance the susceptibility to a second hit such as myocardial ischemia, and that this phenomenon is exacerbated, in the early stages of life by nutritional stressors such as a HF diet. Supplementing HF diets with resveratrol improved cardiac tolerance to ischemia in offspring born IUGR but not in controls. Thus we conclude that the additive effect of prenatal (hypoxia-induced IUGR) and postnatal (HF diet) factors can lead to the earlier development of cardiovascular pathology in rats, and postnatal resveratrol supplementation prevented the deleterious cardiovascular effects of HF diet in offspring exposed to prenatal hypoxia.

Topics: Animals; Blood Pressure; Body Weight; Diet, High-Fat; Female; Fetal Growth Retardation; Heart; Heart Rate; Hypoxia; Male; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes

Emerging evidence suggests that both adult cardiac cell and the cardiac stem/progenitor cell (CSPC) compartments are involved in the patho-physiology of diabetic cardiomyopathy (DCM). We evaluated whether early administration of Resveratrol, a natural antioxidant polyphenolic compound, in addition to improving cardiomyocyte function, exerts a protective role on (i) the progenitor cell pool, and (ii) the myocardial environment and its impact on CSPCs, positively interfering with the onset of DCM phenotype. Adult Wistar rats (n = 128) with streptozotocin-induced type-1 diabetes were either untreated (D group; n = 54) or subjected to administration of trans-Resveratrol (i.p. injection: 2.5 mg/Kg/day; DR group; n = 64). Twenty-five rats constituted the control group (C). After 1, 3 or 8 weeks of hyperglycemia, we evaluated cardiac hemodynamic performance, and cardiomyocyte contractile properties and intracellular calcium dynamics. Myocardial remodeling and tissue inflammation were also assessed by morphometry, immunohistochemistry and immunoblotting. Eventually, the impact of the diabetic "milieu" on CSPC turnover was analyzed in co-cultures of healthy CSPCs and cardiomyocytes isolated from D and DR diabetic hearts. In untreated animals, cardiac function was maintained during the first 3 weeks of hyperglycemia, although a definite ventricular remodeling was already present, mainly characterized by a marked loss of CSPCs and adult cardiac cells. Relevant signs of ventricular dysfunction appeared after 8 weeks of diabetes, and included: 1) a significant reduction in ±dP/dt in comparison with C group, 2) a prolongation of isovolumic contraction/relaxation times, 3) an impaired contraction of isolated cardiomyocytes associated with altered intracellular calcium dynamics. Resveratrol administration reduced atrial CSPC loss, succeeded in preserving the functional abilities of CSPCs and mature cardiac cells, improved cardiac environment by reducing inflammatory state and decreased unfavorable ventricular remodeling of the diabetic heart, leading to a marked recovery of ventricular function. These findings indicate that RSV can constitute an adjuvant therapeutic option in DCM prevention.

Topics: Actins; Animals; Apoptosis; Blood Glucose; Body Weight; Calcium Signaling; Cell Count; Coculture Techniques; Diabetes Mellitus, Type 1; Endothelial Cells; Hemodynamics; HMGB1 Protein; Intracellular Space; Male; Myocardium; Myocytes, Cardiac; Rats; Rats, Wistar; Resveratrol; Stem Cells; Stilbenes; Ventricular Remodeling

Acute lymphoblastic leukemia (ALL) with translocation t(4;11) is a high-risk leukemia found in 60-85% of infants with ALL and is often refractory to conventional chemotherapeutics after relapse. To evaluate the efficacy of dietary resveratrol in vivo, 5-week-old NOD.CB17-Prkdcscid/J mice were fed a control diet or a diet containing 0.2% w/w resveratrol. After 3 weeks of dietary treatment, mice were engrafted with the human t(4;11) ALL line SEM by tail vein injection. Engraftment was monitored by evaluating the presence of human CD19+ cells in peripheral blood using flow cytometry. Relative to control diet, dietary resveratrol did not delay the engraftment of the leukemia cells. To determine if dietary resveratrol could increase efficacy of a chemotherapeutic agent, vincristine was injected intraperitoneally into leukemic mice fed the control or supplemented diet. Survival curves and monitoring the percentage of human leukemia cells in peripheral blood showed that resveratrol did not inhibit leukemia cell growth or influence the activity of vincristine. Mass spectrometric analysis of mouse serum revealed that the majority of resveratrol was present as glucuronidated and sulfated metabolites. These data do not support the concept that dietary resveratrol has potential as a preventative agent against the growth of high-risk t(4;11) ALL.

Topics: Animals; Antineoplastic Agents, Phytogenic; Body Weight; Cell Line, Tumor; Diet; Female; Glucuronides; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Transplantation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Resveratrol; Stilbenes; Sulfates; Tumor Burden; Vincristine; Xenograft Model Antitumor Assays

In the present study, resveratrol, a polyphenolic SIRT1 activator was evaluated for its SIRT1 activation in an in vitro fluorescent based assay (EC(50) : 7 μM). The efficacy of resveratrol was also evaluated in ob/ob mice for its antidiabetic and associated metabolic effects. Mice aged 5-8 weeks were included in four groups; control and resveratrol at 5, 15, 50 mg/kg, b.i.d. and were dosed orally. After 4 weeks of drug treatment, body weights were noted and random blood glucose and insulin was estimated for the antidiabetic effect. Animals were also subjected to the oral glucose tolerance test to observe any improvement in the glucose excursion. Triglycerides, total cholesterol, adiponectin and free fatty acid levels were also estimated. The results showed that resveratrol exhibited significant antihyperglycemic activity with an improvement in the insulin levels compared with the control mice. There was also a significant improvement observed in the glucose excursion in the oral glucose tolerance test performed for 120 min; although an insignificant improvement in the triglycerides, total cholesterol, adiponectin and free fatty acid levels was observed at different doses of resveratrol tested. The present findings suggest that resveratrol is an antihyperglycemic agent and drugs similar to resveratrol can be considered as an effective therapeutic adjuvant for the current treatment of diabetes mellitus.

Topics: Adiponectin; Animals; Body Weight; Chemotherapy, Adjuvant; Cholesterol; Diabetes Mellitus, Type 2; Enzyme Activation; Fatty Acids, Nonesterified; Glucose; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Mice; Resveratrol; Sirtuin 1; Stilbenes; Triglycerides

Resveratrol has been shown to have vasoprotective effects by upregulating oxidative defense mechanisms in a variety of pathophysiological conditions. However, the effect of resveratrol on diabetic oxidative stress and vascular and metabolic abnormalities is not completely understood. Therefore, this study was designed to evaluate whether long-term resveratrol supplementation has a protective effect on vascular function and integrity in association with metabolic parameters and oxidative stress in insulin-dependent diabetes.. Diabetes was induced in rabbits with alloxan and maintained for 8 weeks. We used a resveratrol dose of 5 mg/L (10 weeks, starting 14 days before alloxan injection) and 50 mg/L (8 or 10 weeks, starting concomitantly or 14 days before alloxan injection) in the drinking water of rabbits.. Relaxation to acetylcholine was impaired (control 75.6 ± 3.59%, versus diabetic 42.23 ± 2.53%) and contractions to phenylephrine increased (control 136.89 ± 2.27%, versus diabetic 159.37 ± 6.27%) in aortas from diabetic animals. These changes were associated with increased basal or NAD(P)H-induced superoxide production, as well as lipid peroxide and superoxide dismutase (SOD) levels in the aortic samples. The maximal relaxation to acetylcholine improved by 75.74 ± 9.04% in diabetic rabbits treated with resveratrol. The increased contractions to phenylephrine were not restored to control values after resveratrol treatments, but sensitivity to the contractions tended to decrease. Resveratrol increased nitrite/nitrate levels and suppressed basal or NAD(P)H-induced superoxide production and lipid peroxide levels in the aortas. Importantly, resveratrol increased serum insulin levels without affecting blood glucose and the lipid profile in diabetic rabbits. Using electron microscopic examinations, resveratrol was found to markedly protect the endothelial integrity from diabetes.. Overall, there was no noticeable difference between resveratrol treatment groups on the recovery from diabetes. Our results indicate that resveratrol alleviates type 1 diabetes-induced vasculopathy by decreasing vascular oxidative stress and thereby increasing the bioavailability of nitric oxide without changing metabolic abnormalities.

Topics: Acetylcholine; Animals; Antioxidants; Blood Glucose; Body Weight; Catalase; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Estrogens; Insulin; Lipid Peroxides; Lipids; Male; NADP; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Rabbits; Resveratrol; Stilbenes; Superoxide Dismutase; Testosterone; Time Factors; Vascular Diseases

Doxorubicin (DOX) is an anthracycline drug with a wide spectrum of clinical antineoplastic activity, but increased apoptosis has been implicated in its cardiotoxicity. Resveratrol (RES) was shown to harbour major health benefits in diseases associated with oxidative stress. In this study, we aimed to determine the effect of RES on DOX-induced myocardial apoptosis in mice.. Male Balb/c mice were randomized to one of the following four treatments: saline, RES, DOX, or RES plus DOX (10 mice in each group). DOX treatment markedly depressed cardiac function, decreased the heart weight, the body weight, and the ratio of heart weight to body weight, but inversely increased the level of protein carbonyl, malondialdehyde, and serum lactate dehydrogenase, and induced mitochondrial cytochrome c release and cardiomyocyte apoptosis. However, these effects of DOX were ameliorated by its combination with RES. Further studies with a co-immunoprecipitation assay revealed an interaction between p53 and Sirtuin 1 (SIRT1). It was found by western blot and electrophoretic mobility shift assay that DOX treatment increased p53 protein acetylation and cytochrome c release from mitochondria, activated p53 binding at the Bax promoter, and up-regulated Bax expression, but supplementation with RES could weaken all these effects.. The protective effect of RES against DOX-induced cardiomyocyte apoptosis is associated with the up-regulation of SIRT1-mediated p53 deacetylation.

Topics: Acetylation; Animals; Antineoplastic Agents; Antioxidants; Apoptosis; bcl-2-Associated X Protein; Body Weight; Cytochromes c; Doxorubicin; Gene Expression; Male; Mice; Mice, Inbred BALB C; Myocardium; Myocytes, Cardiac; Organ Size; Oxidative Stress; Resveratrol; Sirtuin 1; Stilbenes; Tumor Suppressor Protein p53; Ventricular Dysfunction, Left

Women are exposed to estrogen in several forms, such as oral contraceptive pills and hormone replacement therapy. Although estrogen was believed to be cardioprotective, lately, its beneficial effects are being questioned. Recent studies indicate that oxidative stress in the rostral ventrolateral medulla (RVLM) may play a role in the development of hypertension. Therefore, we hypothesized that chronic exposure to low levels of estradiol-17β (E(2)) leads to hypertension in adult-cycling female Sprague Dawley (SD) rats potentially through generation of superoxide in the RVLM. To test this hypothesis, young adult (3 or 4 mo old) female SD rats were either sham-implanted or implanted (subcutaneously) with slow-release E(2) pellets (20 ng/day) for 90 days. A group of control and E(2)-treated animals were fed lab chow or chow containing resveratrol (0.84 g/kg of chow), an antioxidant. Rats were implanted with telemeters to continuously monitor blood pressure (BP) and heart rate (HR). At the end of treatment, the RVLM was isolated for measurements of superoxide. E(2) treatment significantly increased mean arterial pressure (mmHg) and HR (beats/min) compared with sham rats (119.6 ± 0.8 vs. 105.1 ± 0.7 mmHg and 371.7 ± 1.5 vs. 354.4 ± 1.3 beats/min, respectively; P < 0.0001). Diastolic and systolic BP were significantly increased in E(2)-treated rats compared with control animals. Superoxide levels in the RVLM increased significantly in the E(2)-treated group (0.833 ± 0.11 nmol/min·mg) compared with control (0.532 ± 0.04 nmol/min·mg; P < 0.05). Treatment with resveratrol reversed the E(2)-induced increases in BP and superoxide levels in the RVLM. In conclusion, these findings support the hypothesis that chronic exposure to low levels of E(2) induces hypertension and increases superoxide levels in the RVLM and that this effect can be reversed by resveratrol treatment.

Topics: Animals; Antioxidants; Blood Pressure; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Eating; Estradiol; Estrogens; Heart Rate; Hypertension; Male; Medulla Oblongata; Oxidative Stress; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Superoxides

Scientific research is constantly looking for new molecules to be used as functional ingredients to combat obesity. The aim of the present study was to analyse whether resveratrol and conjugated linoleic acid (CLA) together could reduce body fat more efficiently than their separate administration. Thirty-six male Wistar rats were randomly divided into four groups: controls rats (C), rats treated with resveratrol (RSV), rats treated with CLA (CLA) and rats treated with a combination of resveratrol and CLA (RSV+CLA). All rats were fed on an obesogenic diet. In RSV and RSV+CLA groups, the rats received 30 mg resveratrol/kg body weight/day. In CLA and RSV+CLA groups, an equimolecular mixture of trans-10,cis-12 and cis-9,trans-11 was added to the diet to reach 0.5% of the active isomer trans-10,cis-12. After 6 weeks of treatment, white adipose tissue from different anatomical locations was dissected and weighed. Serum triacylglycerols, total and HDL cholesterols, glucose, insulin, fructosamine and TNF-α were measured. A glucose tolerance test was also performed. Separately, resveratrol and CLA significantly reduced body fat but did not do so when combined: 20% in the RSV group and 18% in CLA group but 7% in the RSV+CLA group. Resveratrol reduced serum triacylglycerols. No differences were found among groups in serum cholesterol. Resveratrol, as well as the combination RSV+CLA, improved glycaemic control. These results demonstrate that the combination RSV+CLA reduces the effectiveness of each compound on body fat-lowering action, but it maintains the positive effect of resveratrol on glycaemic control. Consequently, this combination has no usefulness in obesity prevention.

Topics: Adipose Tissue, White; Animals; Area Under Curve; Blood Glucose; Body Weight; Drug Evaluation, Preclinical; Drug Therapy, Combination; Energy Intake; Glucose Tolerance Test; Linoleic Acids, Conjugated; Lipids; Male; Obesity; Organ Size; Rats; Rats, Wistar; Resveratrol; Stilbenes; Treatment Failure

Our aim was to investigate whether trans-resveratrol (t-resveratrol), a red wine constituent known for its cardioprotective effects, was able to influence CD40 ligand (CD40L) and its receptor CD40 in platelets of hypercholesterolemic rats. Sixty Wistar rats were divided into 5 groups: control (C), ethanol (E), t-resveratrol (R), hypercholesterolemia (HC), and hypercholesterolemia plus t-resveratrol (HCR). Rats in the C, E, and R groups were fed a normal diet for 80 days. For 20 days before sacrifice, we intraperitoneally (i.p.) administered 0.1 mL ethanol (50% v/v) to the E group, and 0.1 mL t-resveratrol (20 mg·kg(-1)·day(-1)) to the R group. Rats in the HC and HCR groups were fed a 5% cholesterol diet for 80 days. Rats in the HCR group were administered i.p. 0.1 mL t-resveratrol (20 mg·kg(-1)·day(-1)) for 20 days before sacrifice. Serum levels of total cholesterol (TC), low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C), very low-density lipoprotein (VLDL-C), and total triglycerides (TG) were assayed with a commercial colorimetric kit. Platelet P-selectin, CD40, and CD40L expression was determined by flow cytometry. sCD40L and IL6 levels were measured by ELISA. In the HC group, we observed a significant increase in serum TC, LDL-C, VLDL-C, TG, sCD40, and IL-6 levels and platelet activation markers compared with levels in the control group. However, t-resveratrol administration to the HC group (HCR group) attenuated the increase in lipids, sCD40, and IL-6 and down-regulated platelet P-selectin, CD40, and CD40L expressions. A positive correlation was found for serum lipids and all the platelet activation markers. Our study showed that the CD40-CD40L dyad is up-regulated in the presence of hypercholesterolemia and that t-resveratrol administration down-regulated the increase.

Topics: Animals; Body Weight; CD40 Antigens; CD40 Ligand; Cholesterol; Hypercholesterolemia; Male; P-Selectin; Platelet Activation; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Resveratrol; Stilbenes

This study explored the efficacy of curcumin and resveratrol in maintaining adequate zinc levels to regulate p21 and cyclooxygenase-2 (cox-2) during benzo[a]pyrene (BP)-induced lung carcinogenesis. The mice were segregated into five groups, which included normal control, BP treated, BP plus curcumin treated, BP plus resveratrol treated, and BP plus curcumin plus resveratrol-treated groups. BP treatment resulted in a significant decrease in the zinc levels and protein expression of p21. On the contrary, the enzyme activity of cox-2 showed a significant increase in the BP-treated mice. Interestingly, combined supplementation of curcumin and resveratrol to BP-treated mice resulted in an appreciable improvement in the zinc levels and protein expression of p21. In contrast, synergistic supplementation with phytochemicals resulted in a significant decrease in the enzyme activities of cox-2 in BP-treated mice. This study, therefore, concludes that combined treatment with curcumin and resveratrol maintains adequate zinc levels and regulates inflammation by cox-2 and cell cycle arrest by p21 during lung carcinogenesis in mice.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzo(a)pyrene; Blotting, Western; Body Weight; Carcinogens; Curcumin; Cyclin-Dependent Kinase Inhibitor p21; Cyclooxygenase 2; Disease Progression; Drug Synergism; Immunoenzyme Techniques; Lung Neoplasms; Male; Mice; Organ Size; Resveratrol; Stilbenes; Zinc

Endothelial dysfunction is a hallmark of hypertension and vascular oxidative stress can contribute to endothelial dysfunction and hypertension development. Resveratrol is an antioxidant polyphenol which improves endothelium dependent relaxation, the mechanisms of which are unknown. Also, the role of resveratrol in hypertension remains to be established. The purpose of this study was to investigate the mechanisms of resveratrol induced improvement of endothelial function and establish its role in hypertension. SHR and WKY rats, 3-4 weeks old, were treated with resveratrol in drinking water for 10 weeks, untreated SHR and WKY rats served as controls. At the end of the treatment, control SHR exhibited increased blood pressure, oxidative stress and attenuated endothelium dependent relaxation in comparison to WKY rats. The impaired endothelium function in SHR was associated with lower nitrite/nitrate levels, elevated nitrotyrosine content and eNOS uncoupling. Resveratrol treatment attenuated hypertension development in SHR as indicated by lower blood pressure in resveratrol treated SHR (SHR-R) compared to control SHR. SHR-R also exhibited reduced H(2)O(2) content and elevated superoxide dismutase activity. Resveratrol treatment normalized endothelium dependent vasorelaxation in SHR. In parallel, resveratrol restored nitrite/nitrate levels and normalized nitrotyrosine content in SHR. SHR exhibited increased l-arginine dependent superoxide production which was blocked by NOS inhibitor l-NNA, suggesting eNOS uncoupling. eNOS uncoupling was prevented by resveratrol treatment. In conclusion, early treatment with resveratrol lowers oxidative stress, preserves endothelial function and attenuates development of hypertension in SHR. More importantly, prevention of eNOS uncoupling and NO scavenging could represent novel mechanisms for resveratrol-mediated antihypertensive effects.

Topics: Animals; Antioxidants; Blood Pressure; Body Weight; Drinking; Eating; Endothelium, Vascular; Heart; Hypertension; Male; Nitric Oxide; Nitric Oxide Synthase Type III; Organ Size; Oxidative Stress; Rats; Rats, Inbred SHR; Resveratrol; Stilbenes; Tyrosine

Longevity extension in Drosophila melanogaster by feeding diet supplemented with chemicals throughout adulthood can cause harmful side effects. We tested the effect of larval diet supplementation with five different concentrations of resveratrol and one concentration of Aloe vera extract on the adult longevity of short-lived D melanogaster populations. Resveratrol and A vera extract supplementation of larval diet extended adult longevity in both the male and female flies without reducing fecundity but by efficient reactive oxygen species scavenging through increased antioxidant enzymes activity and better neuroprotection as indicated by increased locomotor activity in adult males.

Topics: Aging; Aloe; Animals; Body Weight; Catalase; Drosophila melanogaster; Female; Fertility; Larva; Lipids; Longevity; Motor Activity; Resveratrol; Stilbenes; Superoxide Dismutase

A prenatal hypoxic insult leading to intrauterine growth restriction (IUGR) increases the susceptibility to develop metabolic syndrome (MetS) later in life. Since resveratrol (Resv), the polyphenol produced by plants, exerts insulin-sensitizing effects, we tested whether Resv could prevent deleterious metabolic effects of being born IUGR.. Pregnant rats were exposed to either a normoxic (control; 21% O(2)) or a hypoxic (IUGR; 11.5% O(2)) environment during the last third of gestation. After weaning, male offspring were randomly assigned to receive either a high-fat (HF; 45% fat) diet or an HF diet with Resv (4 g/kg diet) for 9 weeks when various parameters of the MetS were measured.. Relative to normoxic controls, hypoxia-induced IUGR offspring developed a more severe MetS, including glucose intolerance and insulin resistance, increased intra-abdominal fat deposition and intra-abdominal adipocyte size, and increased plasma triacylglycerol (TG) and free fatty acids, as well as peripheral accumulation of TG, diacylglycerol, and ceramides. In only IUGR offspring, the administration of Resv reduced intra-abdominal fat deposition to levels comparable with controls, improved the plasma lipid profile, and reduced accumulation of TG and ceramides in the tissues. Moreover, Resv ameliorated insulin resistance and glucose intolerance as well as impaired Akt signaling in the liver and skeletal muscle of IUGR offspring and activated AMP-activated protein kinase, which likely contributed to improved metabolic parameters in Resv-treated IUGR rats.. Our results suggest that early, postnatal administration of Resv can improve the metabolic profile of HF-fed offspring born from pregnancies complicated by IUGR.

Topics: Animals; Antioxidants; Body Weight; Calorimetry, Indirect; Dietary Fats; Energy Intake; Female; Fetal Growth Retardation; Hypoxia; Insulin Resistance; Male; Metabolic Syndrome; Motor Activity; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Resveratrol; Stilbenes

To characterize the subchronic oral toxicity of resveratrol, CD rats received daily gavage doses of 0, 200, 400, or 1000 mg resveratrol/kg/day, and beagle dogs received daily capsule doses of 0, 200, 600, or 1200 mg resveratrol/kg/day for 90 days. Resveratrol induced only minimal toxicity, consisting of dose-related reductions in body weight gain in female rats and both sexes of dogs, and a statistically significant increase in bilirubin levels in rats at the 1000 mg/kg/day dose. Clinical observations, hematology, ophthalmology, neurotoxicity evaluations (functional observational batteries), organ weights, and gross pathology provided no biologically significant evidence of resveratrol toxicity in either species. In rats, the high dose of resveratrol reduced the incidence of cardiomyopathy; no other microscopic changes were seen. Histopathologic changes in dogs were limited to minimal inflammatory infiltrates in the kidney and urinary bladder, which were not considered toxicologically significant. A cardiovascular safety pharmacology (telemetry) study in dogs revealed no evidence of resveratrol toxicity. Based on body weight effects, the No Observed Adverse Effect Level (NOAEL) for resveratrol was 200mg/kg/day in rats and 600 mg/kg/day in dogs. The apparent cardioprotective activity of resveratrol in rats demonstrates that its potentially beneficial activities may extend beyond efficacy in cancer prevention.

Topics: Administration, Oral; Animals; Antineoplastic Agents, Phytogenic; Body Weight; Cardiotonic Agents; Dogs; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Kidney; Male; No-Observed-Adverse-Effect Level; Organ Size; Polyphenols; Rats; Resveratrol; Stilbenes; Toxicity Tests, Subchronic; Urinary Bladder

Heart failure (HF) is characterized by contractile dysfunction associated with altered energy metabolism. This study was aimed at determining whether resveratrol, a polyphenol known to activate energy metabolism, could be beneficial as a metabolic therapy of HF. Survival, ventricular and vascular function as well as cardiac and skeletal muscle energy metabolism were assessed in a hypertensive model of HF, the Dahl salt-sensitive rat fed with a high-salt diet (HS-NT). Resveratrol (18 mg/kg/day; HS-RSV) was given for 8 weeks after hypertension and cardiac hypertrophy were established (which occurred 3 weeks after salt addition). Resveratrol treatment improved survival (64% in HS-RSV versus 15% in HS-NT, p<0.001), and prevented the 25% reduction in body weight in HS-NT (P<0.001). Moreover, RSV counteracted the development of cardiac dysfunction (fractional shortening -34% in HS-NT) as evaluated by echocardiography, which occurred without regression of hypertension or hypertrophy. Moreover, aortic endothelial dysfunction present in HS-NT was prevented in resveratrol-treated rats. Resveratrol treatment tended to preserve mitochondrial mass and biogenesis and completely protected mitochondrial fatty acid oxidation and PPARα (peroxisome proliferator-activated receptor α) expression. We conclude that resveratrol treatment exerts beneficial protective effects on survival, endothelium-dependent smooth muscle relaxation and cardiac contractile and mitochondrial function, suggesting that resveratrol or metabolic activators could be a relevant therapy in hypertension-induced HF.

Topics: Animals; Body Weight; Disease Models, Animal; Endothelium, Vascular; Energy Metabolism; Heart; Heart Failure; Hemodynamics; Hypertension; Male; Mitochondria; Rats; Rats, Inbred Dahl; Resveratrol; Signal Transduction; Stilbenes; Survival Analysis

Resveratrol, a polyphenol compound with anti-inflammatory properties, has been previously evaluated for its beneficial effects in several ulcerative colitis models. However, the current study elucidates the effect of resveratrol on adhesion molecules, as well as its antioxidant efficacy in a trinitrobenzene sulfonic acid (TNBS)-induced ulcerative-colitis model. Colitis was induced by rectal instillation of TNBS, followed by daily per os administration of either sulphasalazine (300 mg/kg) or resveratrol (2 and 10 mg/kg) for 7 days. Administration of resveratrol decreased the ulcerative area and colon mass index; these effects were further supported by the reduction in colon inflammation grades, as well as histolopathological changes, and reflected by the stalling of body mass loss. The anti-inflammatory effects of resveratrol were indicated by lowered myeloperoxidase activity, and by suppressing ICAM-1 and VCAM-1 levels in the colon and serum. In addition, it restored a reduced colonic nitric oxide level and reinstated its redox balance, as evidenced by the suppression of lipid peroxides and prevention of glutathione depletion. The anti-ulcerative effect of the higher dose of resveratrol was comparable with those of sulphasalazine. The study confirms the anti-ulcerative effect of resveratrol in TNBS-induced experimental colitis via reduction of neutrophil infiltration, inhibition of adhesive molecules, and restoration of the nitric oxide level, as well as the redox status.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Cell Adhesion Molecules; Colitis, Ulcerative; Colon; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Glutathione; Inflammation; Intercellular Adhesion Molecule-1; Lipid Peroxidation; Male; Peroxidase; Rats; Rats, Wistar; Resveratrol; Stilbenes; Sulfasalazine; Trinitrobenzenesulfonic Acid; Vascular Cell Adhesion Molecule-1

Cyclooxygenase (COX), which have the isoforms of COX-1 and COX-2, is the key enzyme of prostaglandins biosynthesis. Especially, COX-2 is induced in inflammatory disease such as Diabetes Mellitus (DM). Resveratrol (RSV), a natural antioxidant, has a beneficial role in prevention of inflammatory disease. We investigated the changes of COX-1 and COX-2 mRNA expression and protein level in diabetic rat kidney after RSV treatment. Three months-old, 44 Wistar albino male rats, which were divided into six groups such as control group, sodium citrate buffer (sham control) group, diabetic group (DM), Dimethyl Sulfoxide induced control group, RSV treated sham control group (RSV) and RSV treated diabetic group (DM + RSV) were used for the study. Experimental diabetes was induced by intraperitoneal injection of 55 mg/kg Streptozotocin. After the induction of chronic diabetes 10 mg/kg per day RSV was administered intraperitoneally for 4 weeks. In this study. RSV has no significant effect on COX-1 mRNA expression in diabetic rat kidney (P > 0.05). Immunohistochemical study showed that COX-1 expression was slightly inhibited in RSV group and was not significantly supressed in DM + RSV group. When comparing control and treated groups, there were no significant differences in COX-2 mRNA or protein levels (P > 0.05). In conclusion, our results indicate that resveratrol do not significantly affect COX gene and protein expression. Therefore, different therapy strategies such as combination with other antidiabetic drugs may tried in STZ induced animal model for reducing diabetic symptoms and altering COX-1 and COX-2 mRNA or protein levels.

Topics: Animals; Body Weight; Cyclooxygenase 1; Cyclooxygenase 2; Diabetes Mellitus, Experimental; Gene Expression Regulation, Enzymologic; Immunohistochemistry; Kidney; Male; Rats; Rats, Wistar; Resveratrol; RNA, Messenger; Software; Stilbenes

Transgenic alfalfa (Medicago sativa L.), which accumulated resveratrol-glucoside (RG), was incorporated into diets and fed to female, 6-wk-old CF-1 mice for 5 wk. Mice fed diets containing transgenic alfalfa with supplemented alpha -galactosidase had significantly fewer azoxymethane (AOM)-induced aberrant crypt foci (ACF) in their colon relative to mice fed the transgenic alfalfa diets without added alpha -galactosidase (P = 0.02). Resveratrol-aglycone (Rag) was detected in the colon of 100% of mice fed transgenic alfalfa diets with supplemented alpha -galactosidase and in 60% of mice fed transgenic alfalfa without alpha -galactosidase (P < 0.05). Colonic concentrations of Rag (< 0.5 nmol/g tissue) in mice fed transgenic alfalfa with alpha -galactosidase (0.22 +/- 0.18 nmol/g tissue) tended to be higher than in animals fed diets without alpha -galactosidase (0.1 +/- 0.08 nmol/g tissue; P = 0.09). The use of N-(Bn-butyl)-deoxygalactonojirimycin, an inhibitor of lactase-phlorizin hydrolase (LPH), in transport studies with everted jejunal sacs from CF-1 mice (N = 8) suggested that LPH is involved in the intestinal deglycosylation of RG. Our collective findings suggest that RG from transgenic alfalfa is metabolized and absorbed in the upper intestine and does not reach the colon in sufficient amounts to inhibit ACF.

Topics: Animals; Azoxymethane; Body Weight; Chromatography, High Pressure Liquid; Colonic Neoplasms; Eating; Female; Glucosides; Lactase-Phlorizin Hydrolase; Medicago sativa; Mice; Plants, Genetically Modified; Precancerous Conditions; Resveratrol; Stilbenes

Oxidative stress in liver injury is a major pathogenetic factor in progress of liver fibrosis. Resveratrol, a representative antioxidant derived from grapes, has been reported to show widespread pharmacological properties. In this study, we investigated the protective effects of resveratrol on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. Rats were treated with resveratrol daily by oral gavage for seven days after a single intraperitoneal injection of DMN (40 mg/kg). Resveratrol remarkably recovered body and liver weight loss due to DMN-induced liver fibrosis. Liver histology showed that resveratrol alleviated the infiltration of inflammatory cells and fibrosis of liver tissue. Resveratrol decreased the level of malondialdehyde and increased the levels of glutathione peroxidase and superoxide dismutase. Also, resveratrol significantly inhibited the mRNA expression of inflammatory mediators including inducible nitric oxide, tumor necrosis factor-alpha and interleukin-1beta. In addition, resveratrol showed not only reduced mRNA expression of fibrosis-related genes such as transforming growth factor beta 1, collagen type I, and alpha-smooth muscle actin, but also a significant decrease of hydroxyproline in rats with DMN-induced liver fibrosis. Our results suggest that resveratrol could be used to treat liver injury and fibrosis and be useful in preventing the development of liver fibrosis and cirrhosis.

Topics: Animals; Antioxidants; Biomarkers; Body Weight; Dimethylnitrosamine; Lipid Peroxidation; Liver; Liver Cirrhosis, Experimental; Male; Organ Size; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes

This study investigated the effects of resveratrol, a natural polyphenol with neuroprotective properties, on retinal neuronal cell death mediated by diabetes-induced activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII).. Diabetes was induced in C57BL/6 mice by five consecutive intraperitoneal injections of 55 mg/kg streptozotocin (STZ). Control mice received buffer. All mice were killed 2 months after the injections, and the extent of neuronal cell death, CaMKII, and phospho-CaMKII protein expression levels and CaMKII kinase activity were examined in the retinas. To assess the role of CaMKII in the death of retinal neurons, a small-interfering RNA (siRNA) or specific inhibitor of CaMKII was injected into the right vitreous humor, and vehicle only was injected into the left vitreous humor, 2 days before death. Resveratrol (20 mg/kg) was administered by oral gavage daily for 4 weeks, beginning 1 month after the fifth injection of either STZ or buffer.. The death of retinal ganglion cells (RGCs), CaMKII, phospho-CaMKII protein levels, and CaMKII activity were all greatly increased in the retinas of diabetic mice compared with controls, 2 months after induction of diabetes. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL)-positive signals co-localized with CaMKII- and phospho-CaMKII immunoreactive RGCs. However, in addition to CaMKII knockdown and inhibition by siRNA or a specific inhibitor, respectively, resveratrol provided complete protection from diabetes-induced retinal cell death.. In the present study, resveratrol prevented diabetes-induced RGC death via CaMKII downregulation, implying that resveratrol may have potential therapeutic applications for prevention of diabetes-induced visual dysfunction.

Topics: Animals; Antioxidants; Apoptosis; Blood Glucose; Blotting, Western; Body Weight; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cell Count; Diabetes Mellitus, Experimental; Down-Regulation; Enzyme Inhibitors; In Situ Nick-End Labeling; Male; Mice; Phosphorylation; Resveratrol; Retina; Retinal Ganglion Cells; Signal Transduction; Statistics, Nonparametric; Stilbenes

This study tested the hypothesis that resveratrol supplementation would lower oxidative stress in exercised muscles of aged mice. Young (3 months) and aged (27 months) C57BL/6 mice received a control or a 0.05% trans-resveratrol-supplemented diet for 10 days. After 7 days of dietary intervention, 20 maximal electrically evoked isometric contractions were obtained from the plantar flexors of one limb in anesthetized mice. Exercise was conducted for three consecutive days. Resveratrol supplementation blunted the exercise-induced increase in xanthine oxidase activity in muscles from young (25%) and aged (53%) mice. Resveratrol lowered H(2)O(2) levels in control (13%) and exercised (38%) muscles from aged animals, reduced Nox4 protein in both control and exercised muscles of young (30%) and aged mice (40%), and increased the ratio of reduced glutathione to oxidized glutathione in exercised muscles from young (38%) and aged (135%) mice. Resveratrol prevented the increase in lipid oxidation, increased catalase activity, and increased MnSOD activity in exercised muscles from aged mice. These data show that dietary resveratrol suppresses muscle indicators of oxidative stress in response to isometric contractions in aged mice.

Topics: Aging; Animals; Body Weight; Citrate (si)-Synthase; Eating; Glutathione; Hydrogen Peroxide; Lipid Peroxidation; Mice; Mice, Inbred C57BL; Muscle Contraction; Muscle Fatigue; Muscle, Skeletal; NADPH Oxidases; Oxidative Stress; Resveratrol; Stilbenes; Superoxide Dismutase; Xanthine Oxidase

The underlying causes of denervation of the neuromuscular junction and eventual motor neuron death in amyotrophic lateral sclerosis (ALS) have not been resolved. The superoxide dismutase 1 (SOD1)(G93A) mutant mouse is a frequently used animal model of ALS. We hypothesized that resveratrol (RSV), a polyphenolic molecule that enhances mammalian NAD(+)-dependent SIRT1 deacetylases and may increase life span, would improve motor function and survival in the SOD1 mouse model via modulation of p53 acetylation. Data were collected for mean survival times, neuromuscular performance on the ROTOR-ROD™ (San Diego Instruments, San Diego, CA, USA), body weight, and p53 acetylation. Mean survival times were not statistically different (P=.23) between control and experimental (RSV-fed) groups (mean +/- SD, control [n=11] 138 +/- 6 days vs. experimental [n=10] 135 +/- 8 days). Performance was not significantly different between groups at time points corresponding to 50%, 80%, and 90% mean life span (P=.46), nor did RSV treatment attenuate body weight loss. Thus although manipulation of SIRT1 deacetylase activity has effects at the protein level in healthy aging organisms, we conclude that RSV treatment does not lead to functional improvement or increased longevity in a mouse model of ALS. We speculate that RSV-mediated modulation of p53 acetylation is either incapable of increasing or insufficient to increase motor performance and longevity in this model of ALS.

Topics: Acetylation; Amyotrophic Lateral Sclerosis; Animals; Body Weight; Diet; Disease Models, Animal; Longevity; Mice; Mice, Mutant Strains; Mutation; Psychomotor Performance; Resveratrol; Sirtuin 1; Stilbenes; Superoxide Dismutase; Superoxide Dismutase-1; Tumor Suppressor Protein p53

The pool of ovarian primordial follicles is established during embryonic development or at birth. During the development from primordial to primary, secondary, and antral follicles, only a small portion of follicles can mature and successfully ovulate; the others are destined to degenerate through apoptotic or atretic loss. As aging advances, females ultimately enter the cessation phase of the estrous cycle and are no longer capable of fertilization. The presumption is that if we can slow down the process of folliculogenesis or decrease follicle loss, females may have a larger ovarian follicular reserve and a longer reproductive lifespan. In our study, rats underwent intragastric administration with tea polyphenols, quercetin (meletin), genistein, or resveratrol, once a day for 4 months (from age 12 to 15 months), to test whether they have positive effects on follicular reserve or ovarian functions. The results showed that rats treated with tea polyphenols (27.8 +/- 3.2) and quercetin (36.5 +/- 4.1) had a comparable number of healthy follicles to those of controls (26.9 +/- 3.8), although significantly fewer atretic follicles were observed in the tea polyphenol group (43.4 +/- 5.9 vs 79.7 +/- 7.5; p < 0.001). Remarkably, both genistein- and resveratrol-treated rats had more healthy follicles (respectively, 42.8 +/- 3.9, p < 0.05; and 51.9 +/- 6.4, p < 0.001) and fewer atretic follicles (respectively, 58.4 +/- 8.0, p < 0.05; and 51.0 +/- 6.2, p < 0.01) than controls. These results indicate that genistein and resveratrol can increase the ovarian follicular reserve and prolong the ovarian lifespan in rats, and their positive effects may be not only due to their intervention in the transition from primordial to primary follicle, but also due to the inhibiting effect on follicular atresia.

Topics: Aging; Animals; Body Weight; Cell Count; Drug Evaluation, Preclinical; Estrous Cycle; Female; Flavonoids; Genistein; Ovarian Follicle; Phenols; Plant Extracts; Polyphenols; Quercetin; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Tea

Hyperlipidemia is one of the vital coronary risk factors and is positively related to morbidity and mortality of coronary heart disease. There are numerous herbal medicines which are reported to exert good hypolipidemic actions with few side effects. In the present study, the hypolipidemic effects of polydatin, a compound from Polygonum cuspidatum Sieb. et Zucc, on hyperlipidemic rabbits were evaluated. Thirty-two male rabbits were fed a high fat/cholesterol diet for 6 weeks and another eight male rabbits fed a basic diet served as normal control. Three weeks after a high fat/cholesterol diet, the animals were orally administrated polydatin (25, 50, and 100 mg kg(-1) per day) by intubation for 3 weeks. The results showed that polydatin markedly decreased the serum levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) in hyperlipidemic rabbits. The ratio of TC to high-density lipoprotein cholesterol (HDL-C) and the liver coefficient were also reduced. But both polydatin and high fat/cholesterol diet did not evidently affect body weight in hyperlipidemic rabbits. All these results suggest that polydatin from Polygonum cuspidatum has favorable potency to develop a hypolipemic and/or hepatoprotective agent in clinic. However the mechanism of hypolipemic action of polydatin is in need of further clarity.

Topics: Animals; Body Weight; Cholesterol, Dietary; Cholesterol, HDL; Cholesterol, LDL; Fallopia japonica; Glucosides; Hyperlipidemias; Hypolipidemic Agents; Male; Phytotherapy; Plant Extracts; Plant Roots; Rabbits; Stilbenes; Triglycerides

Hepatocellular carcinoma (HCC) is one of the most common cancers and lethal diseases. In view of the limited treatment and a grave prognosis of liver cancer, preventive control has been emphasized. Resveratrol, a polyphenol found in grape skins, peanuts, berries and red wine, has been shown to possess potent growth inhibitory effects against various human cancer cells. Although resveratrol has been found to exhibit chemopreventive actions in experimentally induced skin, breast, colon and esophagus rodent tumors, chemopreventive potential of this dietary constituent has not been explored well against experimental liver cancer. We evaluated the inhibitory effect of resveratrol using a two-stage model of rat hepatocarcinogenesis in Sprague-Dawley rats. Initiation was performed by a single intraperitoneal injection of diethylnitrosamine (DENA, 200 mg/kg), followed by promotion with phenobarbital (0.05%) in drinking water. The rats had free access to food supplemented with resveratrol equivalent to 50, 100 or 300 mg/kg body weight/day. Resveratrol treatment was started 4 weeks prior to the initiation and continued for 20 weeks. Resveratrol dose-dependently reduced the incidence, total number and multiplicity of visible hepatocyte nodules. Mean nodular volume and nodular volume as percentage of liver volume were also inhibited upon resveratrol treatment. Histopathological examination of liver tissue confirmed the protective effect of resveratrol. Immunohistochemical detection of cell proliferation and assay of apoptosis indicated a decrease in cell proliferation and increase of apoptotic cells in the livers of resveratrol-supplemented rats. Resveratrol also induced the expression of pro-apoptotic protein Bax, reduced anti-apoptotic Bcl-2 expression, with a concurrent increase in Bax/Bcl-2 ratio with respect to DENA control. The present study provides evidence, for the first time, that resveratrol exerts a significant chemopreventive effect on DENA-initiated hepatocarcinogenesis through inhibition of cell proliferation and induction of apoptosis. Resveratrol-induced apoptogenic signal during rat liver carcinogenesis may be mediated through the downregulation of Bcl-2 and upregulation of Bax expression. Due to a favorable toxicity profile, resveratrol can potentially be developed as a chemopreventive drug against human HCC.

Topics: Animals; Anticarcinogenic Agents; Apoptosis; Body Weight; Cell Proliferation; Diethylnitrosamine; Disease Models, Animal; Dose-Response Relationship, Drug; Drinking; Drug Screening Assays, Antitumor; Eating; Female; Immunohistochemistry; Liver Neoplasms, Experimental; Organ Size; Phenobarbital; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes

Hyperlipidaemias are common in obese people, and they increase the risk of cardiovascular diseases such as coronary heart disease (CHD) and atherosclerosis (AS). Previous studies have shown that several drugs can depress serum cholesterol. However, they could cause serious side effects in various clinical settings. The objective of the present study was to evaluate the lipid-lowering effects of polydatin in high-fat/cholesterol (HFC)-fed hamsters. The levels of lipids in hamsters were measured enzymatically before and after the administration of polydatin. Significant differences between HFC and HFC+polydatin were detected for those concentrations. Decreased levels of serum TC, TG and LDL-C and the concentrations of hepatic TG were found. Experimental results also showed that polydatin elevated LDL-C/HDL-C and TC/HDL-C ratios. In concert with other effects, serum cholesterol-lowering effect in hamsters may contribute to the regulation properties attributed to polydatin.

Topics: Animals; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Cricetinae; Fallopia japonica; Glucosides; Hyperlipidemias; Hypolipidemic Agents; Male; Mesocricetus; Stilbenes; Triglycerides

The beneficial action of moderate wine consumption is increasingly being attributed to resveratrol (trans-3,4',5-trihydroxystilbene). To test the safety of resveratrol use as a dietary supplement, 24 male Wistar rats were initially divided into three groups: (C, n=6) was given standard chow and water; (R, n=6) received standard chow and 6 mg/l resveratrol in its drinking water (1mg/kg/day), and (HFD, n=12) received high-fat diet and water. In order to more appropriately study the effects of resveratrol on high-fat diet, after 30 days of treatments, HFD-rats were divided into two subgroups (n=6/group):(HFD) remained receiving high-fat diet and water; (HFD-R) given high-fat diet and 6 mg/l resveratrol in its drinking water (1mg/kg/day). The total experimental period was 45 days. The resveratrol dose took into account its average concentration in wine, the time variability of wine ingestion, and so of resveratrol consumption in humans. HFD-rats had hyperglycaemia, dyslipidemia, increased serum oxidized-LDL (ox-LDL) and hepatic oxidative stress. Comparing HFD-R and HFD-rats, resveratrol improved lipid profile and glucose level, enhanced superoxide dismutase, thus reducing ox-LDL and hepatic oxidative stress. Resveratrol, in standard-fed-rats reduced glutathione-antioxidant defense system and enhanced hepatic lipid hydroperoxide. In conclusion, based on the results of this single dose preliminary study with resveratrol in the drinking water of male Wistar rats for 30 days, it may be concluded that resveratrol may have beneficial effects in high-fat diets (e.g. ox-LDL, decreased serum and hepatic oxidativestress), but not in standard-fed diets (effects produced include enhanced hepatic oxidative stress). Further studies are indicated.

Topics: Animals; Antioxidants; Atherosclerosis; Blood Glucose; Body Weight; Diet; Dietary Fats; Dietary Supplements; Glutathione; Lipid Peroxides; Lipids; Lipoproteins, LDL; Liver; Male; Organ Size; Oxidative Stress; Rats; Rats, Wistar; Resveratrol; Risk Factors; Stilbenes; Triglycerides; Wine

Recent studies have shown that resveratrol (3,5,4'-trihydroxystilbene), a polyphenolic compound found in grapes and red wine, has various beneficial effects on cardiovascular diseases and prolongs the life span of mice fed a high-fat diet. We hypothesized that resveratrol may attenuate vascular inflammatory response induced by angiotensin (Ang) II. We examined the effect of resveratrol on Ang II-induced interleukin (IL)-6 expression in vascular smooth muscle cells (VSMCs). Resveratrol significantly attenuated Ang II-induced IL-6 mRNA expression and IL-6 protein in the supernatant of VSMC in a dose-dependent manner. Resveratrol suppressed the IL-6 gene promoter activity. Resveratrol inhibited the Ang II-induced cAMP-response element-binding protein and nuclear factor-kappa B activity, which are critical for Ang II-induced IL-6 gene activation. An increase in the serum concentration of IL-6 induced by Ang II infusion was attenuated by an oral administration of resveratrol. Resveratrol also inhibited Ang II-induced hypertension and perivascular fibrosis of the heart. Although hydralazine reduced blood pressure level equal to resveratrol, it did not reduce the Ang II-induced IL-6 production and perivascular fibrosis. These data suggest that the inhibition of Ang II-induced vascular inflammation and high blood pressure by resveratrol may contribute, at least in part, to the anti-atherogenic effects of resveratrol.

Topics: Angiotensin II; Animals; Antioxidants; Blood Pressure; Blotting, Northern; Blotting, Western; Body Weight; Cells, Cultured; DNA; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; Fibrosis; Heart Rate; Interleukin-6; Luciferases; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Promoter Regions, Genetic; Rats; Resveratrol; Stilbenes; Vascular Diseases

Implantation of bone marrow-derived mononuclear cells (BMMCs) is known to accelerate blood flow recovery in a hindlimb ischemia model in mice. However, the neovascularization capacity of BMMCs from diabetic mice is impaired. Resveratrol, a natural polyphenolic compound abundant in red wine, is known to extend the lifespan of high cholesterol-fed mice. We tested whether resveratrol improves the neovascularization capacity of BMMCs from diabetic mice. Diabetes was induced by the injection of streptozotocin into C57B/6 mice. BMMCs from normal mice and diabetic mice were implanted into the ischemic limb induced by ligation of the unilateral femoral artery. Blood flow recovery measured by the laser Doppler method was significantly decreased in mice that received BMMCs from diabetic mice compared with BMMCs from normal mice. However, ex vivo treatment of BMMCs from diabetic mice, but not from normal mice, with resveratrol for 30 min significantly improved blood flow recovery. Capillary density measured by PECAM-1 positive cells was significantly increased in mice that received either normal BMMCs or diabetic BMMCs treated with resveratrol. Treatment of BMMCs from diabetic mice with resveratrol increased mRNA expression of vascular endothelial growth factor and endothelial nitric oxide synthase and decreased production of reactive oxygen species. Resveratrol improved the impaired neovascularization capacity of BMMCs derived from diabetic mice. The effects of resveratrol may be due to a reduction of oxidative stress and an induction of angiogenic factors. Resveratrol may be beneficial by improving the neovascularization capacity of BMMCs in patients with diabetes mellitus.

Topics: Animals; Antioxidants; Blood Pressure; Body Weight; Bone Marrow Cells; Capillaries; Diabetes Mellitus, Experimental; Heart Rate; Hindlimb; Ischemia; Laser-Doppler Flowmetry; Malondialdehyde; Mice; Mice, Inbred C57BL; Monocytes; Neovascularization, Physiologic; Nitric Oxide Synthase Type III; Oxidative Stress; Reactive Oxygen Species; Receptors, Vascular Endothelial Growth Factor; Regional Blood Flow; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Stilbenes; Superoxide Dismutase; Vascular Endothelial Growth Factor A

The aim of the present study was to investigate the effects of resveratrol (RV), an important neuroprotective compound on NTPDase, 5'-nucleotidase and acetylcholinesterase (AChE) activities in cerebral cortex synaptosomes of streptozotocin (STZ)-induced diabetic rats. The animals were divided into six groups (n=8): control/saline; control/RV 10mg/kg; control/RV 20mg/kg; diabetic/saline; diabetic/RV 10mg/kg; diabetic/RV 20mg/kg. After 30 days of treatment with resveratrol the animals were sacrificed and the cerebral cortex was removed for synaptosomes preparation and enzymatic assays. The results demonstrated that NTPDase and 5'-nucleotidase activities were significantly increased in the diabetic/saline group (p<0.05) compared to control/saline group. Treatment with resveratrol significantly increased NTPDase, 5'-nucleotidase activities in the diabetic/RV10 and diabetic/RV20 groups (p<0.05) compared to diabetic/saline group. When resveratrol was administered per se there was also an increase in the activities of these enzymes in the control/RV10 and control/RV20 groups (p<0.05) compared to control/saline group. AChE activity was significantly increased in the diabetic/saline group (p<0.05) compared to control/saline group. The treatment with resveratrol prevented this increase in the diabetic/RV10 and diabetic/RV20 groups. In conclusion, this study demonstrated that the resveratrol interfere with the purinergic and cholinergic neurotransmission by altering NTPDase, 5'-nucleotidase and AChE activities in cerebral cortex synaptosomes of diabetic rats. In this context, we can suggest that resveratrol should be considered potential therapeutics and scientific tools to be investigated in brain disorders associated with the diabetes.

Topics: 5'-Nucleotidase; Acetylcholinesterase; Adenosine Triphosphatases; Animals; Blood Glucose; Body Weight; Cerebral Cortex; Diabetes Mellitus, Experimental; Enzyme Inhibitors; Male; Random Allocation; Rats; Rats, Wistar; Resveratrol; Stilbenes; Synaptosomes

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

Topics: Animals; Antioxidants; Blotting, Western; Body Weight; Brain; Diabetes Mellitus, Type 2; Dietary Fats; Eating; Glucose; Homeostasis; Hyperglycemia; Liver; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Protein Serine-Threonine Kinases; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Sirtuin 1; Stilbenes

Development and progression of many malignancies, including colorectal cancer, are associated with activation of multiple signaling pathways. Therefore, inhibition of these signaling pathways with noncytotoxic natural products represents a logical preventive and/or therapeutic approach for colon cancer. Curcumin and resveratrol, both of which inhibit the growth of transformed cells and colon carcinogenesis, were selected to examine whether combining them would be an effective preventive and/or therapeutic strategy for colon cancer. Indeed, the combination of curcumin and resveratrol was found to be more effective in inhibiting growth of p53-positive (wt) and p53-negative colon cancer HCT-116 cells in vitro and in vivo in SCID xenografts of colon cancer HCT-116 (wt) cells than either agent alone. Analysis by Calcusyn software showed synergism between curcumin and resveratrol. The inhibition of tumors in response to curcumin and/or resveratrol was associated with the reduction in proliferation and stimulation of apoptosis accompanied by attenuation of NF-kappaB activity. In vitro studies have further demonstrated that the combinatorial treatment caused a greater inhibition of constitutive activation of EGFR and its family members as well as IGF-1R. Our current data suggest that the combination of curcumin and resveratrol could be an effective preventive/therapeutic strategy for colon cancer.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Body Weight; Cell Cycle; Cell Nucleus; Cell Proliferation; Cell Survival; Colonic Neoplasms; Curcumin; Dose-Response Relationship, Drug; Drug Synergism; Female; HCT116 Cells; Humans; Mice; Mice, SCID; NF-kappa B; Nuclear Proteins; Phosphorylation; Receptors, Growth Factor; Resveratrol; Software; Stilbenes; Tumor Burden; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Recently resveratrol, a compound naturally occurring in various plants, has been proposed as a potential anti-obesity compound. The aim of the present work was to analyse the effects of different doses of resveratrol on body fat and serum parameters in rats. Thirty-two male Sprague-Dawley rats were randomly divided into four groups and fed on a hypercaloric diet for 6 weeks. The doses oftrans-resveratrol used were 6, 30 and 60 mg/kg body weight/d in RSV1, RSV2 and RSV3 groups respectively. The stability of resveratrol when added to the diet was evaluated. Blood samples were collected, and white adipose tissue from different anatomical locations, interscapular brown adipose tissue, gastrocnemious muscles and liver were weighed. Commercial kits were used to measure serum cholesterol, glucose, triacylglycerols and non-esterified fatty acids. While the lowest dose did not have a body fat reducing effect, the intermediate dose reduced all the white adipose depots. The highest dose significantly reduced mesenteric and subcutaneous depots but not epididymal and perirenal tissues. Although the reduction in all the anatomical locations analysed was 19% in the RSV3 group, in the RSV2 group it was 24%. No significant differences among the experimental groups were found in brown adipose tissue, gastrocnemious muscle or liver weights. Serum parameters were not affected by resveratrol intake because no differences among the experimental groups were observed. These results suggest that resveratrol is a molecule with potential anti-obesity effect. The most effective of the three experimental doses was 30 mg/kg body weight/d.

Topics: Adipose Tissue; Adiposity; Animal Feed; Animals; Anti-Obesity Agents; Body Weight; Dietary Fats; Dose-Response Relationship, Drug; Male; Models, Biological; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Time Factors

Cajanus cajan L. is a natural plant, which contains a lot of potential active components. In the present study, we identified the effects of the stilbene extract from Cajanus cajan L. (sECC) on hepatic cholesterol metabolism in diet-induced (for 4 weeks) hyperlipidemic Kunming mice. All experimental mice were divided into 5 groups: control group, high lipid model group, sECC-treated with 200 or 100 mg kg(-1), and simvastatin (Sim, 12 mg kg(-1)) treated group. The mice were fed with fat and cholesterol-enriched chow except control mice that were fed with standard diet. The effects of sECC were investigated by monitoring serum and liver lipid profile (i. e. cholesterol homeostasis) in mice. To further explore the mechanism of sECC, hepatic cholesterol 7alpha-hydroxylase (CYP7A1) and low density lipoprotein (LDL) receptor expressions in cholesterol homeostasis were analyzed by reverse transcription PCR. After 4 weeks pretreatment, the mice in the high lipid model group showed markedly higher serum and hepatic lipid contents than control group (P< 0.01). Compared with high lipid model group, the increased serum and hepatic lipid contents were markedly attenuated by sECC (200 mg kg(-1)), the serum and hepatic total cholesterol were reduced by 31.5% and 22.7% (P<0.05), respectively. The triglyceride contents of serum and liver were also lowered by 23.0% and 14.4%, respectively. At the same times, serum LDL cholesterol decreased by 53.0% (P<0.01). The mRNA expressions of hepatic CYP7A1 and LDL-receptor were significantly enhanced in the mice administered with sECC (200 mg kg(-1)), whereas those expressions were suppressed by the fat and cholesterol-enriched diet. These data indicate that sECC reduces the atherogenic properties of dietary cholesterol in mice. It is indicated that expression enhancement of hepatic LDL-receptor and cholesterol 7alpha-hydroxylase may be responsible for the hypercholesterolemic effect.

Topics: Animals; Anticholesteremic Agents; Body Weight; Cajanus; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Cholesterol, LDL; Drugs, Chinese Herbal; Gene Expression Regulation; Hypercholesterolemia; Liver; Male; Mice; Organ Size; Plant Leaves; Plants, Medicinal; Receptors, LDL; RNA, Messenger; Stilbenes; Triglycerides

An active area of aging research is focused on identifying compounds having the ability to mimic the effects of caloric restriction (CR). From 2 to 5 months of age, we fed male B6C3F(1) mice either a 40% CR diet, a control diet supplemented with a commercially available nutraceutical mixture (NCM) containing resveratrol, quercetin and inositol hexaphosphate, or a diet supplemented with an equivalent dose of chemical-grade resveratrol (RES; 1.25 mg resveratrol kg(-1) day(-1)) from 2 to 5 months of age. Cardiac gene expression profiles were generated for the three groups of treated mice and compared to age-matched control (CO) mice. All three treatments were associated with changes in several cytoskeletal maintenance pathways, suggesting that RES and NCM are able to mimic short-term CR. CR uniquely affected several immune function pathways while RES uniquely affected multiple stress response pathways. Pathway analysis revealed that NCM (but not CR or RES) regulated multiple metabolic pathways that were also changed by long-term CR, including glucose and lipid metabolism, oxidative phosphorylation and chromatin assembly. Examination of key genes and pathways affected by NCM suggests that Foxo1 is a critical upstream mediator of its actions.

Topics: Aging; Animals; Blood Glucose; Body Weight; Caloric Restriction; Dietary Supplements; Drug Evaluation, Preclinical; Gene Expression Profiling; Gene Expression Regulation; Insulin; Male; Mice; Mice, Inbred Strains; Myocardium; Oligonucleotide Array Sequence Analysis; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Stilbenes

Environmental toxins can destroy the physiological process of spermatogenesis and even lead to male infertility. Resveratrol (RES) is a natural phytoalexin with a wide range of biological activities. Some recent researches have demonstrated that RES can increase sperm output and protect sperm from apoptosis caused by physical damage. However, there is no evidence indicating that it can also exhibit a similar activity in testis injury caused by environmental toxins. This study was designed to evaluate the protective effect of resveratrol on testis damaged by environmental toxins and to elucidate the possible mechanism of its protective effect.. In this study 2, 5-hexanedione (2, 5-HD) was used as the injury agent. Forty male SD rats were randomly divided into 5 groups. During the first 5 weeks, group A was raised normally, groups B, C, D and E were exposed to 1% 2, 5-HD; during the following 9 weeks, group C, D, E received intragastric administration of different concentrations of resveratrol (20 mg x kg(-1) x d(-1), 40 mg x kg(-1) x d(-1) and 80 mg x kg(-1) x d(-1)), while groups A and B were treated by carboxymethylcellulose. Physical signs, body weight gain and testis weight were comparatively observed. Numbers and diameters of seminiferous tubules were analyzed following HE staining. In addition, expression of the c-kit protein and gene in spermatogenic cells in every group was detected with immunohistochemistry, Western blot or RT-PCR.. The 2, 5-HD treatment resulted in physical signs that became worse and in emarciated testis. HE staining and immunohistochemistry showed that seminiferous tubules became emarcid, obsolete spermatogonia being stagnant and expression of c-kit protein being depressed. After oral administration of resveratrol, the 2, 5-HD-induced physical signs were improved and close to the normal rats. The gain of body weight increased (P < 0.01). The recovery of testis weight was significant (P < 0.01). At the histological level, the seminiferous epithelia began to differentiate (P < 0.01); and even the physiological process of spermatogenesis restarted. Moreover, expression of c-kit protein and gene function resumed, although its expression remained different from the normal group. The diameter of and number of seminiferous tubules and the expression level of c-kit protein and gene activity were much closer to the normal group with increased doses of the resveratrol through oral administration.. Resveratrol could ameliorate markedly the dyszoospermia induced by 2, 5-HD and induce spermatogenesis. The expression of c-kit, which is a specific marker protein of spermatogenic cell membranes, could be regulated by resveratrol.

Topics: Animals; Body Weight; Hexanones; Immunohistochemistry; Male; Organ Size; Proto-Oncogene Proteins c-kit; Rats; Rats, Sprague-Dawley; Resveratrol; RNA, Messenger; Seminiferous Tubules; Spermatogenesis; Stilbenes; Testis

Resveratrol, a polyphenolic activator of the silent information regulation 2 homolog 1 (SIRT1), is known to extend lifespan and improve metabolic disease. The aim of the present study is to test whether resveratrol protects against metabolic steatohepatitis through the modulation of lipid metabolism-related genes.. We used a mouse model in which steatohepatitis can be induced by an atherogenic diet (Ath diet) to evaluate the effects of resveratrol on steatotic hepatitis and hepatic gene expression.. The Ath diet induced excessive weight gain, hepatomegaly, dyslipidemia, and steatohepatitis after 8 weeks. The addition of resveratrol protected against Ath diet-induced changes and also alleviated steatohepatitis. Whole-genome expression analysis revealed that an Ath diet altered the hepatic expression of genes involved in lipid metabolism, and the addition of resveratrol to the diet reversed that effect. Real-time PCR and Western blot analysis confirmed the Ath diet up-regulated the levels of genes related to lipogenesis and down-regulated genes involved in lipolysis. Resveratrol clearly suppressed the Ath diet-induced alterations of the expression of genes related to lipid metabolism.. Resveratrol ameliorated dyslipidemia and steatohepatitis induced by the Ath diet, and its beneficial effects were associated with the altered expression of hepatic genes involved in lipid metabolism.

Topics: Animals; Antioxidants; Body Weight; Diet, Atherogenic; Eating; Fatty Liver; Gene Expression; Lipid Metabolism; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Oligonucleotide Array Sequence Analysis; Organ Size; Resveratrol; Stilbenes

Resveratrol, a polyphenolic phytoalexin, has free-radical scavenging activity and we found that it induces chromosomal aberrations, micronuclei, and sister chromatid exchanges in vitro. We synthesized its analogue 4-hydroxy-trans-stilbene (4-OH) and found that it has the same in vitro clastogenic activities as resveratrol, suggesting that the 4' hydroxy group of resveratrol is responsible for the effect. We fed resveratrol and 4-OH to young adult ICR mice at 0, 0.2, 2, or 20 ppm in their standard powder diet for 6 months and investigated the antioxidative effects. Half of each group was given 3000 ppm potassium bromate (KBrO(3)) in water for the last week to cause oxidative damage. Body weight gain tended to increase in males at 0.2 ppm resveratrol or 4-OH, and in females at 2 ppm 4-OH. Micronucleus (MN) analysis in bone marrow erythrocytes showed that the KBrO(3) tendency to induce MN was not prevented by the dietary resveratrol or 4-OH, which themselves did not induce MN under the present conditions. In this pilot study, resveratrol and 4-OH showed no obvious effect, either beneficial or adverse, at doses that are feasible in daily life for humans.

Topics: Animals; Antioxidants; Body Weight; Diet; Feeding Behavior; Female; Male; Malondialdehyde; Mice; Mice, Inbred ICR; Micronucleus Tests; Pilot Projects; Resveratrol; Stilbenes

We examined the effects of trans-resveratrol on male reproductive functions; ex-vivo penile erection and in-vivo sperm counts and quality. For the ex-vivo study, the relaxation effects of resveratrol on isolated New Zealand white rabbit corpus cavernosum, precontracted by phenylephrine (5x10(-5) M) were measured. The in-vivo study measured reproductive organ weights, blood testosterone levels, testicular histopathology, sperm counts, as well as the epididymal sperm motility and deformity of male ICR mice given an oral dose of resveratrol (50 mg/ kg) for 28 days. Resveratrol elicited a concentration-dependent relaxing effect on corpus cavernosum, leading to a median effective concentration (EC50) of 0.29 mg/mL. Repeated treatment with resveratrol (50 mg/kg) did not cause an increase in body weight, reproductive organ weight or testicular microscopic findings; however, resveratrol did elicit an increase in blood testosterone concentration, testicular sperm counts and epididymal sperm motility by 51.6%, 15.8% and 23.3%, respectively, without influence on sperm deformity. In conclusion, we propose that resveratrol has a positive effect on male reproductive function by triggering a penile erection, as well as enhancing blood testosterone levels, testicular sperm counts, and epididymal sperm motility.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Genitalia, Male; In Vitro Techniques; Male; Mice; Mice, Inbred ICR; Muscle Relaxation; Muscle, Smooth; No-Observed-Adverse-Effect Level; Organ Size; Penile Erection; Rabbits; Resveratrol; Sperm Count; Sperm Motility; Spermatozoa; Stilbenes; Testis; Testosterone

Cajanus cajan (L) is a natural plant which contains a lot of potential active components. In the present study, we identified the effects of the stilbenes containing extract-fraction from Cajanus cajan L (sECC) on diet-induced (for 4 weeks) hypercholesterolemia in Kunming mice. All experimental mice were divided into 5 groups: control group, model group, sECC-treated with 200 or 100 mg/kg/day, and simvastatin group. The effects of sECC were investigated by monitoring serum and liver lipid profile (cholesterol homeostasis and triglyceride) as well as serum superoxide dismutase activity in those mice. To further explore the mechanism of sECC, hepatic 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase), cholesterol 7α-hydroxylase (CYP7A1), and low density lipoprotein receptor (LDL receptor) expressions in cholesterol homeostasis were analyzed by reverse transcription PCR. After 4 weeks pretreatment, compared with model group, the increased serum and hepatic total cholesterol were markedly attenuated by sECC (200 mg/kg) by 31.4% and 22.7% (p<0.01), respectively, the triglyceride levels of serum and liver were also lowered by 22.98% and 14.39%, respectively. At the same time, serum LDL cholesterol decreased by 52.8% (p<0.01) accompanied with the activities of serum superoxide dismutase increased by 20.98%. Atherogenic index and body weight were also reduced markedly. The mRNA expressions of HMG-CoA reductase, CYP7A1, and LDL-receptor were significantly enhanced in the mice administered with sECC (200 mg/kg/day), whereas those expressions were suppressed by the hypercholesterolemic diet. These data indicate that sECC reduces the atherogenic properties of dietary cholesterol in mice. Its hypocholesterolemic effect may involve enhancement of the hepatic LDL-receptor and cholesterol 7alpha-hydroxylase expression levels and bile acid synthesis.

Topics: Animals; Anticholesteremic Agents; Body Weight; Cajanus; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Cholesterol, LDL; Hydroxymethylglutaryl CoA Reductases; Hypercholesterolemia; Lipids; Liver; Male; Mice; Plant Extracts; Receptors, LDL; Stilbenes; Superoxide Dismutase

Deficiency in the vasorelaxant capacity is a result of an oxidative stress in diabetic animals and seems to be an etiological factor of vascular complications of diabetes. The present study was designed to examine whether resveratrol (RSV), a polyphenolic compound which is naturally present in grape and red wine, has a protective effect on diabetic aorta. Resveratrol (5 mg/kg/d, i.p.) was administered for 42 d to streptozotocin (STZ) (60 mg/kg) induced diabetic rats. Loss of weight, hyperglycemia, and elevated levels of plasma malondialdehyde (MDA) were observed in diabetic rats. Resveratrol treatment was significantly effective for these metabolic and biochemical abnormalities. The contractile responses of the aorta were recorded. Compared with control subjects, the aorta showed significantly enhanced contractile responses to noradrenaline (NA), but not to potassium chloride (KCl), in diabetic rats. Treatment of diabetic rats with resveratrol significantly reversed the increases in responsiveness and sensitivity of aorta to noradrenaline. In diabetic aorta, the relaxation response to acetylcholine (Ach) was found to be significantly decreased compared with control subjects, and resveratrol treatment reversed this; no such change was observed in the relaxation response to sodium nitroprusside (SNP). These results indicated that resveratrol significantly improved not only glucose metabolism and oxidative injury but also impaired vascular responses in streptozotocin induced diabetic rats.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Blood Glucose; Blood Vessels; Body Weight; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Endothelium, Vascular; Male; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Nitroprusside; Oxidative Stress; Rats; Rats, Wistar; Resveratrol; Stilbenes; Thoracic Arteries; Vasoconstrictor Agents; Vasodilator Agents

Administration of different doses of the diphenol resveratrol had no effect on the growth of an intramuscularly implanted experimental tumour, the Lewis lung carcinoma. These results do not agree with previous reports where a clear effect of resveratrol was shown on tumour burden in both mice and rats. However, administration of the diphenol had a clear anti-metastatic effect, decreasing both the number and the weight of the lung metastases. Similar effects were observed both at 5 and 25mg/kg body weight per day, resulting in an approximately 40% reduction in the number of metastases. These results suggest that resveratrol could be tentatively given as a preventive agent in cancer patients undergoing radiotherapy or chemotherapy.

Topics: Animals; Antineoplastic Agents, Phytogenic; Body Weight; Carcinoma, Lewis Lung; Cell Line, Tumor; Dose-Response Relationship, Drug; Eating; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Resveratrol; Stilbenes

Epidemiologic studies have linked the consumption of fruits and vegetables to reduced risk of several types of cancer. Laboratory animal model studies have provided evidence that stilbenes, phenolic compounds present in grapes and blueberries, play a role in inhibiting the risk of certain cancers. Pterostilbene, a naturally occurring stilbene from blueberries, was tested for its preventive activity against colon carcinogenesis.. Experiments were designed to study the inhibitory effect of pterostilbene against the formation of azoxymethane-induced colonic aberrant crypt foci (ACF) preneoplastic lesions in male F344 rats. Beginning at 7 weeks of age, rats were treated with azoxymethane (15 mg/kg body weight s.c., once weekly for 2 weeks). One day after the second azoxymethane treatment, rats were fed experimental diets containing 0 or 40 ppm of pterostilbene. At 8 weeks after the second azoxymethane treatment, all rats were sacrificed, and colons were evaluated for ACF formation and for inhibition of inducible nitric oxide synthase (iNOS) and proliferating cell nuclear antigen. Effects on mucin MUC2 were also determined.. Administration of pterostilbene for 8 weeks significantly suppressed azoxymethane-induced formation of ACF (57% inhibition, P < 0.001) and multiple clusters of aberrant crypts (29% inhibition, P < 0.01). Importantly, dietary pterostilbene also suppressed azoxymethane-induced colonic cell proliferation and iNOS expression. Inhibition of iNOS expression by pterostilbene was confirmed in cultured human colon cancer cells.. The results of the present study suggest that pterostilbene, a compound present in blueberries, is of great interest for the prevention of colon cancer.

Topics: Animals; Azoxymethane; Blueberry Plants; Body Weight; Colonic Neoplasms; Male; Models, Chemical; Mucin-2; Mucins; Nitric Oxide Synthase Type II; Plant Extracts; Proliferating Cell Nuclear Antigen; Rats; Rats, Inbred F344; Stilbenes; Time Factors

The effects of vaticanol C (Vat-C), a novel resveratrol tetramer, were studied in a mouse metastatic mammary cancer model carrying mutations in p53 that produce a metastatic spectrum similar to that seen in human breast cancers.. Mammary tumors, induced by inoculation of syngeneic BALB/c mice with BJMC3879 cells, were subsequently treated with Vat-C at 0, 100 and 200 ppm in their diet.. The in vitro study demonstrated that Vat-C induced apoptosis, as inferred by morphological changes, nucleosomal DNA fragmentation and elevated activities of caspases. Although tumor volumes were not apparently suppressed in mice treated with Vat-C, the multiplicity of lymph node metastasis was significantly decreased in the 200-ppm group. Furthermore, the multiplicity of lung metastasis was also significantly lower in the 200-ppm group. In any category of organ metastasis, the number of organs with metastasis tended to be lower in the 200-ppm group, but these findings were not statistically significant. The levels of apoptosis were significantly higher in the 200-ppm group, but DNA synthesis only a tended to be lower in this group. Microvessel density in tumors also tended to be lower in the Vat-C-treated groups. Moreover, the numbers of lymphatic vessels having intraluminal tumor cells was significantly lower in mammary tumors of mice given 100 and 200-ppm Vat-C, indicating a reduction in migrating tumor cells into the lymphatic vessels of tumor tissue.. These results suggest that the observed antimetastatic activity of Vat-C may be of clinical significance as an adjuvant therapy in metastatic human breast cancer having p53 mutations, and may also be useful as a chemopreventative of breast cancer development.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Body Weight; Female; Genes, p53; Lung Neoplasms; Lymphatic Metastasis; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Mutation; Stilbenes; Tumor Cells, Cultured

Resveratrol has been reported to have antitumoural effects and recently it has been demonstrated that resveratrol partially blocks skeletal muscle wasting by interfering with NF-kappaB activation. We decided to investigate the potential anti-wasting properties of resveratrol on different models of cancer cachexia in experimental animals.. Incubations of isolated extensor digitorum longus muscles in the presence of 30 microM of resveratrol caused a significant decrease in the rate of protein degradation. However, administration of resveratrol in vivo to both rats bearing the Yoshida AH-130 ascites hepatoma (at the dose of 1 mg/kg body weight) and mice bearing the Lewis lung carcinoma (at two different doses, 5 and 25 mg/kg body weight) had no effect on skeletal muscle mass or body weight in tumour-bearing rodents. In addition, a combination of resveratrol (3 mg/kg body weight) and fish oil was also unable to induce any changes in skeletal muscle weights.. It is therefore concluded from this study that resveratrol is unable to influence muscle mass in vivo and has no potential role as anticachectic agent for the treatment of muscle wasting associated with tumour growth.

Topics: Animals; Body Weight; Cachexia; Carcinoma, Lewis Lung; Disease Models, Animal; Energy Intake; Fish Oils; Male; Mice; Mice, Inbred C57BL; Muscle Proteins; Muscle, Skeletal; Neoplasms, Experimental; NF-kappa B; Organ Size; Random Allocation; Rats; Rats, Wistar; Resveratrol; Sarcoma, Yoshida; Stilbenes

Extracts from Rhei Rhizoma extracts (RR) have been reported to attenuate metabolic disorders such as diabetic nephropathy, hypercholesterolemia and platelet aggregation. With this study we investigated the anti-diabetic action of 70% ethanol RR extract in streptozotocin-induced diabetic mice, and determined the action mechanism of active compounds of RR in vitro. In the diabetic mice, serum glucose levels at fasting and post-prandial states and glucose area under the curve at modified oral glucose tolerance tests were lowered without altering serum insulin levels, indicating that RR contained potential anti-diabetic agents. The fractions fractionated from RR extracts by XAD-4 column revealed that 60%, 80% and 100% methanol fractions enhanced insulin sensitivity and inhibited alpha-glucoamylase activity. The major compounds of these fractions were sennosides, rhein and rhaponticin. Rhaponticin and rhein enhanced insulin-stimulated glucose uptake in 3T3-L1 adipocytes. Rhaponticin increased adipocytes with a differentiating effect similar to pioglitazone, but rhein and sennoside B decreased triglyceride accumulation. Sennoside A and B inhibited alpha-glucoamylase activity as much as acarbose. In conclusion, a crude extract of RR improves glucose intolerance by enhancing insulin-stimulated glucose uptake and decreasing carbohydrate digestion via inhibiting alpha-glucoamylase activity. Rhein and rhaponticin are potential candidates for hypoglycemic agents.

Topics: Adipocytes; Animals; Anthraquinones; Blood Pressure; Body Weight; Cell Differentiation; Cell Line; Diabetes Mellitus, Experimental; Enzyme Inhibitors; Ethanol; Fibroblasts; Glucan 1,4-alpha-Glucosidase; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Plant Extracts; Senna Extract; Sennosides; Solvents; Stilbenes; Triglycerides

Nitric oxide (NO) plays an important role in the modulation of glomerular disease. The renal protective effect of resveratrol (RVT), a polyphenolic phytoalexin, was investigated in the 5/6th nephrectomized rats.. Resveratrol (5 mg/kg, PO) was administered for 12 weeks to 5/6th nephrectomized (NX) rats together with and without nitro L-arginine methyl ester (L-NAME) (10 mg/kg, IP). We evaluated the effect of these agents on proteinuria, hypertension, renal function, glomerulosclerosis, and urinary excretion of nitric oxide metabolites.. 5/6th NX resulted in elevation in systolic blood pressure (SBP), reduced the urinary excretion of NO metabolites, increased urinary protein excretion, and deranged renal function and glomerulosclerosis. Treatment of animals with resveratrol significantly attenuated the increase in SBP, preserved the normal renal function, reduced the urinary protein excretion, increased the urinary excretion of NO metabolites, and prevented the glomerulosclerosis. Co-administration of animals with L-NAME along with resveratrol prevented the protection observed with resveratrol.. These findings indicate that resveratrol exerts its protective effect in 5/6 NX rats through a nitric oxide pathway.

Topics: Animals; Antineoplastic Agents, Phytogenic; Blood Pressure; Body Weight; Disease Models, Animal; Eating; Enzyme Inhibitors; Kidney Function Tests; Male; Nephrectomy; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Proteinuria; Rats; Rats, Wistar; Renal Insufficiency, Chronic; Resveratrol; Stilbenes; Survival Rate

Resveratrol is a phytoalexin with strong antioxidant and anti-inflammatory effects reaching high concentrations in red wine. The aim of our study was to test the effects of resveratrol pretreatment on cholecystokinin-octapeptide (CCK-8)-induced acute pancreatitis in rats. Animals were divided into a control group, a group treated with CCK-8 and a group receiving 10 mg/kg resveratrol prior to CCK-8 administration. Resveratrol ameliorated the CCK-8-induced changes in the laboratory parameters, and reduced the histological damage in the pancreas. The drug failed to improve the pancreatic antioxidant state, but increased the amount of hepatic reduced glutathione and prevented the reduction of hepatic catalase activity. Resveratrol-induced inhibition of nuclear factor kappa B (NF-kappaB) activation or reduction of the pancreatic tumor necrosis factor-alpha (TNF-alpha) concentration could not be demonstrated. In conclusion, the beneficial effects of resveratrol on acute pancreatitis seem to be mediated by the antioxidant effect of resveratrol or by an NF-kappaB-independent anti-inflammatory mechanism.

Topics: Acute Disease; Amylases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspartate Aminotransferases; Blood Glucose; Blood Urea Nitrogen; Body Weight; Calcium; Catalase; Creatinine; Glutathione; Glutathione Peroxidase; Immunohistochemistry; Injections, Intraperitoneal; Injections, Subcutaneous; Lipase; Liver; Male; NF-kappa B; Nitric Oxide Synthase Type III; Organ Size; Pancreas; Pancreatitis; Rats; Rats, Wistar; Resveratrol; Sincalide; Stilbenes; Superoxide Dismutase; Time Factors; Triglycerides; Tumor Necrosis Factor-alpha

Resveratrol (RES) is a phytoestrogen that has the ability to bind to estrogen receptors (ERs) and evoke biological effects that parallel those exerted by endogenous and synthetic estrogens. We have shown in previous studies that adult female rats acutely exposed to RES exhibit estrous cycle irregularity, ovarian hypertrophy, and alterations in sociosexual behavior. The present experiment characterizes the prolonged effects of maternal RES exposure throughout the lactational period on subsequent behavior, reproductive tissues, and brain morphology of the adult offspring. During adulthood, female offspring exposed to RES throughout nursing exhibited reduced body weight and increased ovarian weight, but exhibited normal estrous cyclicity and sociosexual behavior, without changes in the volume of the sexually dimorphic nucleus of the preoptic area or the anteroventral periventricular nucleus of the hypothalamus. During adulthood, males exposed to RES throughout nursing exhibited decreased body weight and plasma testosterone concentration, increased testicular weight, and reduced sociosexual behavior. These males also had significantly smaller sexually dimorphic nucleus of the preoptic area volumes and larger anteroventral periventricular nucleus volumes compared to male controls. These data suggest that postnatal exposure to RES may affect estrogenic activity in specific peripheral tissues (e.g., the gonads), while inducing antiestrogenic effects in the brain. Thus, the present study supports recent in vitro and in vivo findings that RES differs from most other phytoestrogens by acting as a possible mixed ER agonist/antagonist, depending on the tissue-specific availability of ER subtypes that are preferentially localized in specific brain regions and throughout the reproductive tract. More importantly these data indicate that maternal consumption of phytoestrogens during lactation can have lasting effects on the offspring that may not become apparent until they reach adulthood.

Topics: Animals; Animals, Newborn; Body Weight; Brain; Female; Male; Ovary; Phytoestrogens; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Reproduction; Resveratrol; Seminal Vesicles; Sexual Behavior, Animal; Stilbenes; Testis; Uterus

The effects of resveratrol, a polyphenolic phytoalexin present in red wine have been investigated on hyperalgesia and cold allodynia in streptozotocin (STZ) induced diabetic rats. Diabetes was induced by a single intraperitoneal injection of streptozotocin (65mg/kg). After 4-weeks of STZ injection, diabetic rats exhibited a significant thermal hyperalgesia and cold allodynia along with increased plasma glucose and decreased body weights as compared with controls rats. Chronic treatment with resveratrol (10mg/kg orally) from week 4 to week 6 significantly attenuated the cold allodynia and thermal hyperalgesia. The results emphasize the role of oxidative stress in development of hyperalgesia and cold allodynia in diabetic animals and point towards the potential of resveratrol as an adjuvant therapy for the prevention and treatment of diabetic neuropathy.

Topics: Animals; Antioxidants; Blood Glucose; Body Weight; Cold Temperature; Diabetes Mellitus, Experimental; Hot Temperature; Hyperalgesia; Immersion; Male; Phytoalexins; Plant Extracts; Rats; Rats, Sprague-Dawley; Resveratrol; Sesquiterpenes; Stilbenes; Terpenes

Moderate consumption of red wine is associated with a reduced risk of coronary heart disease (CHD). This phenomenon is based on data from epidemiological observations known as the French paradox, and has been attributed to CHD-protective phytochemicals, e.g. resveratrol in red wine. Since red wine also contains alcohol, it is conceivable that alcohol interacts with resveratrol to elicit the observed cardioprotective effects. To determine whether resveratrol has alcohol-independent affects, we compared cardioprotective properties of dealcoholized Chinese red wine with alcohol-containing Chinese red wine having comparable amounts of resveratrol, using a hypercholesterolemic rabbit model and resveratrol as a reference. Animals fed a high cholesterol (1.5%) diet were simultaneously given water containing resveratrol (3 mg/kg/day) or red wine (4 ml/kg/day) containing 3.98 mg/l and 3.23 mg/l resveratrol for regular and dealcoholized red wine, respectively, for a 12-week duration. Total, HDL- and LDL-cholesterol and triglyceride levels in the plasma were measured before and after the cholesterol challenge. Atherosclerotic plaques in the thoracic aorta were evaluated using histochemical methods. Vascular and endothelial functions in the femoral artery were also assessed by ultrasonographic image analysis. High cholesterol-fed animals showed a significant increase in plasma levels of total, HDL- and LDL-cholesterol, but not triglycerides, compared to those fed a regular diet. Dietary cholesterol-elicited lipid changes were similarly observed in animals concurrently fed dealcoholized red wine, red wine or resveratrol. In contrast, whereas atherosclerotic lesions were clearly evident in specimens prepared from the thoracic aorta of high cholesterol-fed animals, the size, density, and mean area of atherosclerotic plaques, and thickness of the intima layer were significantly reduced in rabbits given dealcoholized red wine, red wine, or resveratrol. These results were in agreement with data obtained by an ultrasound analysis of endothelial function, which showed a 25% reduction in flow-mediated dilation (FMD) in rabbits fed a high cholesterol diet compared to animals on control diet. This decrease was effectively prevented by the simultaneous exposure to dealcoholized red wine, red wine, or resveratrol. Our study shows that animals given dealcoholized red wine exhibited cardio-active effects comparable to those of animals orally administered resveratrol, and suggests t

Topics: Analysis of Variance; Animals; Aorta, Thoracic; Atherosclerosis; Body Weight; Cholesterol, Dietary; Dose-Response Relationship, Drug; Ethanol; Femoral Artery; Hypercholesterolemia; Lipids; Male; Rabbits; Resveratrol; Stilbenes; Vasodilation; Vasodilator Agents; Wine

Resveratrol, (3,5,4'-trihydoxystilbene) a compound found in grapes, mulberries, and peanuts, has antimycotic, antiviral, and beneficial cardiovascular and cancer preventive activities. It is being developed for several clinical indications. To evaluate the potential toxicity of resveratrol, rats were administered by gavage 0, 300, 1000, and 3000 mg trans-resveratrol per kilogram body weight per day for 4 weeks. Most of the adverse events occurred in the rats administered 3000 mg per kilogram body weight per day. These included increased clinical signs of toxicity; reduced final body weights and food consumption; elevated BUN, creatinine, alkaline phosphatase, alanine aminotransferase, total bilirubin, and albumin; reduced hemoglobin, hematocrit, and red cell counts; and increased white cell counts. Increases in kidney weights and clinically significant renal lesions, including an increased incidence and severity of nephropathy, were observed. Diffuse epithelial hyperplasia in the bladder was considered, equivocal and of limited biological significance. No histological effects on the liver were observed, despite the clinical chemistry changes and increased liver weights in the females. Effects seen in the group administered 1000 mg resveratrol per kilogram body weight per day included reduced body weight gain (females only) and elevated white blood cell count (males only). Plasma resveratrol concentrations in blood collected 1 h after dose administration during week 4 were dose related but were relatively low given the high dosage levels; conjugates were not measured. Under the conditions of this study, the no observed adverse effect level was 300 mg resveratrol per kilogram body weight per day in rats.

Topics: Animals; Anticarcinogenic Agents; Body Weight; Dose-Response Relationship, Drug; Female; Intubation, Gastrointestinal; Kidney; Kidney Diseases; Leukocyte Count; Male; No-Observed-Adverse-Effect Level; Organ Size; Rats; Resveratrol; Sex Characteristics; Stilbenes

The aim of this study was to analyse the multigenerational effects of para-nonylphenol (NP) and resveratrol (RES) on the body weight, organ weight and reproductive fitness of outbred CD-1 mice. The data indicate that in male mice, NP had an effect on the weight of selected reproductive organs and the kidneys in the parental (P) generation males. Effects on selected reproductive organs, the liver and kidneys in the F1-generation males were also seen. In females, effects of NP on body weight and kidney weight were seen in the P generation, but no effects on any measured parameter were seen in the F1 generation. RES had no effect on body weight but did have some effect on selected male and female reproductive organs in the P generation. RES altered the spleen and liver weights of P-generation males and the kidney weight of F1-generation males. Acrosomal integrity (using a monoclonal antibody against intra-acrosomal sperm proteins) was assessed for both generations of NP- and RES-treated mice. A significant reduction in acrosomal integrity was seen in both generations of NP-treated, but not in RES-treated, mice. Fewer offspring were observed in the second litter of the F2 generation of mice treated with NP; no similar effect was seen in RES-treated mice. The litter sex ratio was not different from controls. Unlike RES, NP had a negative effect on spermatogenesis and sperm quality with a resultant impact on in vivo fertility.

Topics: Acrosome; Animals; Animals, Outbred Strains; Body Weight; Environmental Pollutants; Female; Fertility; Genitalia, Female; Genitalia, Male; Infertility, Male; Isoflavones; Kidney; Litter Size; Liver; Male; Mice; Organ Size; Ovarian Follicle; Phenols; Phytoestrogens; Plant Preparations; Pregnancy; Resveratrol; Sex Ratio; Spermatogenesis; Stilbenes

The major object of this study was to characterize the effect of prepubertal trans-3,4',5-trihydroxystilbene (resveratrol) exposure on N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis in female Sprague-Dawley rats. Prepubertal rats (15 to 19 days of age) were treated daily with either 10 or 100 mg/kg resveratrol for 5 days, and were compared with resveratrol-untreated animals (30 rats in each group). Six rats in each group were autopsied at 49 days of age, and their growth was evaluated. All remaining rats were given 50 mg/kg MNU, followed by monitoring for occurrence of mammary carcinoma. A dose of 100 mg/kg (but not 10 mg/kg) resveratrol significantly increased incidence of rat with mammary carcinomas > or =1 cm and multiplicity (all histologically detected mammary carcinomas per rat), but did not affect latency, compared with untreated controls. Resveratrol did not affect body weight increase, but 100 mg/kg resveratrol caused slightly earlier vaginal opening. Although all rats cycled, resveratrol-treated animals exhibited significantly increased irregularity of estrous cycle, spending more time in the estrus phase. Thus, short resveratrol treatment of prepubertal female rats affected endocrine function, and accelerated development of MNU-induced mammary carcinomas.

Topics: Age Factors; Alkylating Agents; Animals; Body Weight; Dose-Response Relationship, Drug; Estrous Cycle; Female; Isoflavones; Mammary Neoplasms, Experimental; Methylnitrosourea; Phytoestrogens; Plant Preparations; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes

trans-3,5,4'-Trihydroxystilbene (trans-resveratrol) is a phytochemical present in peanuts, grapes and wine with beneficial effects such as protection against cardiovascular disease and cancer prevention. The purpose of this study was to evaluate whether high doses of trans-resveratrol have harmful effects on Sprague-Dawley rats. trans-Resveratrol was administered orally to male rats for 28 d at a dose of 20 mg/(kg x d), 1000 times the amount consumed by a 70-kg person taking 1.4 g of trans-resveratrol/d. Body weight, and food and water consumption did not differ between rats treated with trans-resveratrol and the control group. Hematologic and biochemical variables were not affected by the treatment. Histopathologic examination of the organs obtained at autopsy did not reveal any alterations. These results support the view that repeated consumption of trans-resveratrol at 20 mg/(kg x d) does not adversely affect the variables tested in rats.

Topics: Administration, Oral; Animals; Antineoplastic Agents, Phytogenic; Antioxidants; Arachis; Body Weight; Drinking; Eating; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Time Factors; Viscera; Vitis; Wine

Resveratrol is a phytoestrogen naturally found in grapes and is a major constituent of wine thought to exert both cardioprotective and chemopreventive activities. Recent studies show that this bioflavonoid binds to and activates gene transcription via the estrogen receptor (ER) subtypes ERalpha and ERbeta. Previous studies have focused primarily on the in vitro effects of resveratrol (RES) in estrogen-sensitive tissues or in carcinogenic cell lines, while frequently neglecting to document its potential effects in animal models with intact neuroendocrine systems. However, the present studies were designed to systematically characterize the in vivo effects of RES on reproductive physiology and behavior in adult female rats. In gonadally intact females, RES consumption reduced body weight, disrupted estrous cyclicity, and induced ovarian hypertrophy. However, in ovariectomized females RES (10-1000 microg) injections did not appear to mimic 17 beta-estradiol benzoate (EB)-induced behavioral responses and had no lasting effects on subsequent estrogen sensitivity or sociosexual behavior. The present studies support recent in vitro findings that RES differs from other phytoestrogens by acting as a possible mixed agonist/antagonist, depending on the availability of specific ER isoforms localized in the reproductive tract and brain of the female rat.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Estradiol; Estrogens; Estrogens, Non-Steroidal; Estrous Cycle; Female; Isoflavones; Organ Size; Ovariectomy; Ovary; Phytoestrogens; Plant Preparations; Rats; Rats, Sprague-Dawley; Reproduction; Resveratrol; Sexual Behavior, Animal; Stilbenes; Uterus; Vagina

Resveratrol has been shown to induce vasorelaxation. In this study, we investigated the mechanism(s) of resveratrol-induced vasorelaxation in resistance mesenteric arteries from male lean and dietary-induced obese rats. Compared with lean rats, arteries from dietary-obese rats showed significant (P<0.001) endothelial dysfunction, as indicated by a decrease (>20%) in maximal acetylcholine-induced vasorelaxation. Resveratrol (5-35 micromol/l) induced concentration-dependent relaxation of mesenteric arteries preconstricted with noradrenaline (8 micromol/l) or KCl (125 mmol/l) from both lean and dietary-obese rats. There were no significant differences between the two groups, achieving a maximum relaxation of >95% at a concentration of 35 micromol/l. In noradrenaline-preconstricted arteries from lean rats, N(G)-nitro-L-arginine methyl ester (L-NAME; 100 and 300 micromol/l) caused a significant (P<0.01) concentration-dependent rightward shift in reseveratrol activity, with no effect on maximal responses. However, L-NAME (100 and 300 micromol/l) did not alter the effects of reseveratrol on arteries from dietary-obese rats, giving superimposed concentration-responses curves. Indomethacin was also ineffective in altering resveratrol activity in arteries from both lean and dietary-obese rats. In noradrenaline-precontracted arteries from dietary-obese rats, responses to resveratrol were not attenuated by endothelial denudation, indicating an action independent of the endothelium. This study indicates that: (a) the maximal effects of resveratrol on resistance arteries from lean and dietary-obese rats are not effected by endothelial dysfunction, and (b) the effects of resveratrol in lean animals (where endothelial function is not impaired), but not in dietary-obese rats, are mediated via NO.

Topics: Acetylcholine; Animals; Body Weight; Dose-Response Relationship, Drug; Drug Interactions; Endothelium, Vascular; Indomethacin; Male; Mesenteric Arteries; NG-Nitroarginine Methyl Ester; Norepinephrine; Obesity; Rats; Rats, Wistar; Resveratrol; Stilbenes; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

The stilbene derivative resveratrol (RES) is a phytoalexin of grapes, peanuts and other fruits. It is structurally related to stilbene estrogens and an estrogenic potential of RES has recently been demonstrated in a number of in vitro studies. In this investigation, the uterotrophic responses of immature Wistar rats to subcutaneous administration of RES (18, 58, and 575 mg/ kg) and the reference estrogen ethinylestradiol (EE2; 0.3, 1, 3, 30 microg/kg) on three consecutive days were determined. Uterine weight, histopathological changes, immunohistochemical expression of nuclear estrogen receptor-alpha (ERalpha) and progesterone receptor (PR) protein, gene expression of ERalpha and PR at the messenger ribonucleic acid (mRNA) level and peroxidase induction were examined. EE2 dose dependently increased uterine weight, enlarged the uterine lumen and induced hypertrophy of epithelial, stromal and myometrial cells. Expression of ERalpha protein in epithelial, stromal and myometrial nuclei and of PR protein in epithelial nuclei was reduced in EE2-treated rats, while PR protein in stromal and myometrial nuclei was increased in a dose-dependent manner. EE2 increased messenger ribonucleic acid (mRNA) levels of uterine PR and induced peroxidase activity. In contrast, RES rather mildly decreased uterine weight, while histology did not reveal differences between controls and RES-treated rats. Expression of nuclear ERalpha protein was dose dependently decreased in epithelial, stromal and myometrial cells of RES-treated rats, while nuclear PR protein content was similar in controls and RES-treated rats. Following administration of RES, a trend toward reduced levels of ERalpha and PR mRNA was found, while no peroxidase induction occurred. Plasma levels of RES, 45 min after the administration of a single subcutaneous dose of 500 mg/kg, were in the range 1-2 microM. In summary, an estrogenic potential of RES could not be substantiated in this in vivo study, although the most effective route of administration and extremely high doses were used and plasma levels were in the range reported to be effective in vitro. Whether other pharmacological properties of RES could mediate the observed changes in RES-treated animals is discussed.

Topics: Animals; Body Weight; Estradiol Congeners; Estrogen Receptor alpha; Estrogens, Non-Steroidal; Ethinyl Estradiol; Female; Gene Expression; Immunohistochemistry; Organ Size; Peroxidase; Rats; Rats, Wistar; Receptors, Estrogen; Receptors, Progesterone; Resveratrol; RNA, Messenger; Sexual Maturation; Stilbenes; Uterus

Resveratrol is a naturally occurring phytoalexine found in medicinal plants. We found that resveratrol, at doses of 2.5 and 10 mg/kg, significantly reduced the tumor volume (42%), tumor weight (44%) and metastasis to the lung (56%) in mice bearing highly metastatic Lewis lung carcinoma (LLC) tumors, but not at a dose of 0.6 mg/kg. Resveratrol did not affect the number of CD4(+), CD8(+) and natural killer (NK)1.1.(+) T cells in the spleen. Therefore, the inhibitory effects of resveratrol on tumor growth and lung metastasis could not be explained by natural killer or cytotoxic T-lymphocyte activation. In addition, resveratrol inhibited DNA synthesis most strongly in LLC cells; its 50% inhibitory concentration (IC(50)) was 6.8 micromol/L. Resveratrol at 100 micromol/L increased apoptosis to 20.6 +/- 1.35% from 12.1 +/- 0.36% (P < 0.05) in LLC cells, and decreased the S phase population to 22.1 +/- 1.03% and 29.2 +/- 0.27% from 35.2 +/- 1.72% (P < 0.05) at concentrations of 50 and 100 micromol/L, respectively. Resveratrol inhibited tumor-induced neovascularization at doses of 2.5 and 10 mg/kg in an in vivo model. Moreover, resveratrol significantly inhibited the formation of capillary-like tube formation from human umbilical vein endothelial cells (HUVEC) at concentrations of 10-100 micromol/L; the degree of the inhibition of capillary-like tube formation by resveratrol was 45.5% at 10 micromol/L, 50.2% at 50 micromol/L and 52.6% at 100 micromol/L. Resveratrol inhibited the binding of vascular endothelial growth factor (VEGF) to HUVEC at concentrations of 10-100 micromol/L, but not at concentrations of 1 and 5 micromol/L. The degree of inhibition of VEGF binding to HUVEC by resveratrol was 16.9% at 10 micromol/L, 53.2% at 50 micromol/L and 47.8% at 100 micromol/L. We suggest that the antitumor and antimetastatic activities of resveratrol might be due to the inhibition of DNA synthesis in LLC cells and the inhibition of LLC-induced neovascularization and tube formation (angiogensis) of HUVEC by resveratrol

Topics: Angiogenesis Inhibitors; Animals; Anticarcinogenic Agents; Apoptosis; Body Weight; Carcinoma, Lewis Lung; CD4-CD8 Ratio; Cell Cycle; Disease Models, Animal; DNA; Female; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neovascularization, Pathologic; Organ Size; Polygonaceae; Resveratrol; Spleen; Stilbenes; Thymus Gland; Tumor Cells, Cultured

The effect of resveratrol, a polyphenolic compound present in grapes and other plants, on proteinuria, hypoalbuminemia and hyperlipidemia was studied in rats with glomerulonephritis. The nephritis was induced by an intravenous injection of anti-rat kidney glomerular basement membrane rabbit antiserum. Nephritic rats were given oral intubation of resveratrol (5 mg/day/100 g body weight) for 14 days, while control nephritic rats as well as normal ones were similarly given vehicle alone. By resveratrol treatment, enlargement in liver and kidney due to nephritis induction was significantly reduced, together with partial restoration of nephritis-induced reduction in body weight gain. Both proteinuria and hypoalbuminemia, characteristic symptoms to nephrotic syndrome, were significantly remedied, that is, urinary protein excretion was suppressed and serum albumin concentration was increased by resveratrol treatment. Resveratrol also suppressed significantly hyperlipidemia incident to nephritis, the hypotriglyceridemic action being more prominent than the hypocholesterolemic one. From these results, resveratrol is suggested to be a potent anti-glomerulonephritic food factor capable of suppressing proteinuria, hypoalbuminemia and hyperlipidemia at the same time.

Topics: Administration, Oral; Albumins; Animals; Anti-Inflammatory Agents, Non-Steroidal; Basement Membrane; Blood Urea Nitrogen; Body Weight; Cholesterol; Disease Models, Animal; Eating; Glomerulonephritis; Hyperlipidemias; Hypoproteinemia; Kidney; Kidney Glomerulus; Liver; Male; Organ Size; Proteinuria; Rabbits; Rats; Rats, Wistar; Resveratrol; Stilbenes; Triglycerides

Resveratrol is a potent anti-inflammatory and anti-oxidant flavinoid found in red wine. Resveratrol has been shown to improve ventricular function and decrease lactic dehydrogenase release after ischemia in rats. The aim of this study was to test whether resveratrol could provide direct cardioprotection to myocytes during acute myocardial infarction.. Anesthetized, open-chest rabbits (N= 24) were subjected to 30 minute coronary artery occlusion followed by 3 hr reperfusion. Before the onset of ischemia (15 minutes), the rabbits were randomly assigned (n = 8 in each group) to either high-dose (1.5 mg/kg) resveratrol, low-dose (0.15 mg/kg) resveratrol or ethanol vehicle, and the effects on infarct size and regional myocardial blood flow (RMBF) were tested.. Hemodynamic parameters and size of ischemic risk region (29% to 35% of the left ventricle) were similar in all groups. Infarct size, expressed as a mean (SEM) percentage of the risk region, was 46% (5%) of the risk region in controls, 46% (7%) in the low-dose group and 54% (3%) in the high-dose group (p = .53). Thus, treatment with resveratrol had no effect on infarct size at either dose. There were no differences in RMBF in the risk zone or in nonischemic tissue, during either occlusion or reperfusion.. In this intact model of ischemia and reperfusion, resveratrol fails to provide cardioprotection. The mechanism of other beneficial effects (e.g., improvement of function) that are observed with resveratrol probably do not result from increased RMBF or a reduction in myocardial necrosis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Blood Pressure; Body Weight; Flavonoids; Heart Rate; Heart Ventricles; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Rabbits; Regional Blood Flow; Resveratrol; Risk Factors; Stilbenes; Wine

Trans-3,4,5-trihydroxystilbene (resveratrol), a polyphenolic compound found in juice and wine from dark-skinned grape cultivars, was recently shown to bind to estrogen receptors in vitro, where it activated transcription of estrogen-responsive reporter genes. The purpose of this 6-day study in weanling rats was to determine the dose response (1, 4, 10, 40, and 100 microg/day) effects of orally administered resveratrol on estrogen target tissues. The solvent (10% ethanol) had no significant effect on any measurement or derived value. 17Beta-estradiol treatment (100 microg/day) decreased the growth rate, final body weight, serum cholesterol, and radial bone growth (periosteal bone formation and mineral apposition rates) at the tibia-fibula synostosis. In the uterus, 17beta-estradiol treatment increased wet weight, epithelial cell height, and steady state messenger RNA levels for insulin-like growth factor I. In contrast, resveratrol treatment had no significant effect on body weight, serum cholesterol, radial bone growth, epithelial cell height, or messenger RNA levels for insulin-like growth factor I. Resveratrol treatment resulted in slight increases in uterine wet weight, but significance was achieved at the 10-microg dose only. A second experiment was performed to determine whether a high dose of resveratrol (1000 microg/day) antagonizes the ability of estrogen to lower serum cholesterol. As was shown for the lower doses, resveratrol had no effect on body weight, uterine wet weight, uterine epithelial cell height, cortical bone histomorphometry, or serum cholesterol. 17Beta-estradiol significantly lowered serum cholesterol, and this response was antagonized by cotreatment with resveratrol. These in vivo results suggest, in contrast to prior in vitro studies, that resveratrol has little or no estrogen agonism on reproductive and nonreproductive estrogen target tissues and may be an estrogen antagonist.

Topics: Administration, Oral; Animals; Body Weight; Cholesterol; Dose-Response Relationship, Drug; Estradiol; Estrogens; Female; Growth; Organ Size; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Uterus; Weaning

Free radical scavengers can protect against the genotoxicity induced by chemical carcinogens by decreasing oxidative damage. The protective effect of the antioxidants melatonin, resveratrol, vitamin E, butylated hydroxytoluene and 2-mercaptoethylamine, and the spin-trapping compound alpha-phenyl-N-tert-butyl nitrone (PBN) against oxidative DNA damage was studied in the kidney of rats treated with the kidney-specific carcinogen potassium bromate (KBrO3). KBrO3 was given to rats previously treated with melatonin, resveratrol, PBN, vitamin E, butylated hydroxytoluene, or 2-mercaptoethylamine. Oxidative damage to kidney DNA was estimated 6 hours afterwards by measuring 8-oxo-7,8-dihydro-2'-deoxyguanosine (oxo8dG) referred to deoxyguanosine (dG) by means of high performance liquid chromatography with electrochemical-coulometric and ultraviolet detection. Levels of oxo8dG in the renal genomic DNA significantly increased by more than 100% after the KBrO3 treatment. This increase was completely abolished by the treatment with resveratrol and was partially prevented by melatonin, PBN and vitamin E. Resveratrol and PBN also prevented the increase in relative kidney weight induced by KBrO3. These results show that various different antioxidants and a free radical trap, working in either the water-soluble or the lipid-soluble compartments, can prevent the oxidative DNA damage induced in the kidney by the carcinogen KBrO3.

Topics: Animals; Anticarcinogenic Agents; Antioxidants; Body Weight; Bromates; Carcinogens; Cyclic N-Oxides; DNA Damage; Kidney; Male; Melatonin; Nitrogen Oxides; Organ Size; Rats; Rats, Wistar; Resveratrol; Spin Labels; Stilbenes; Vitamin E

The relation between tumor tissue blood flow (tBF) reduction and antitumor effects was investigated. Changes in tBF of normal tissues (liver, kidney cortex, bone marrow and brain cortex) and tumors (Yoshida sarcoma subline, LY80 and Sato lung carcinoma, SLC) due to i.v. administration of AC7700 (1, 3, 10 mg/kg), one of the combretastatin A-4 derivatives, were measured with the hydrogen clearance method. The change in blood flow in tumor microfoci was also observed directly using a rat transparent chamber. Chemotherapy against the solid tumors (LY80, SLC) was performed by administering AC7700 7 times at intervals of 3 days and the effect on the tumor growth, the histological effect, the effect on lymph node metastasis and the survival rate were investigated. Tumor tBF showed a dose-dependent response to AC7700. Although tumor tBF decreased markedly at a dose of 1 mg/kg, it tended to recover partly within several hours. At 10 mg/kg, however, tumor tBF completely stopped within approximately 30 min and never recovered in many regions. The irreversible stoppage of tumor tBF was observed in large s.c. tumors and in microfoci as well. On the other hand, in normal tissues, tBF changes due to AC7700 were not uniform. In the liver, although tBF decreased by approximately 50% at 10 mg/kg AC7700, it recovered within 8 h. In the brain, although the mean maximum reduction was 35%, the blood flow recovered to the original level within 24 h. The blood flow in the kidney cortex did not change at all. In the bone marrow, tBF decreased by approximately 80%. Generally, the blood flow reduction in normal tissues tended to be reversible. The effect on tumor growth and the histological effect were also dependent on the dose of AC7700. The tumor growth was markedly inhibited by 10 mg/ kg AC7700 and extensive necrosis was induced. Lymph node metastases were significantly inhibited and survival was prolonged significantly. In the control group, all 8 SLC tumor-bearing rats died of cancer, the presence of which was verified by gross and microscopic evaluation, within 45 days after tumor implantation. On the other hand, in the treated group, 2 of 8 rats recovered completely and survived. No obvious side effects such as body weight loss, anemia or diarrhea were observed at the dose used in this experiment. From these results, we conclude that strong antitumor effects are obtained by stopping tumor tBF irreversibly and by shutting off the nutritional supply into tumor tissue. AC7700

Topics: Animals; Antineoplastic Agents; Blood Pressure; Body Weight; Disease Models, Animal; Drug Screening Assays, Antitumor; Lymphatic Metastasis; Male; Neoplasm Transplantation; Neoplasms, Experimental; Rats; Regional Blood Flow; Serine; Stilbenes; Survival Rate

Glucose levels in rats with hyperglycemia induced by streptozotocin were determined after i.p. administration of marsupsin (1), pterosupin (2), and pterostilbene (3), three important phenolic constituents of the heartwood of Pterocarpus marsupium. Marsupsin and pterostilbene significantly lowered the blood glucose level of hyperglycemic rats, and the effect was comparable to that of 1,1-dimethylbiguanide (metformin).

Topics: Animals; Benzofurans; Blood Glucose; Body Weight; Cresols; Diabetes Mellitus, Experimental; Female; Glucosides; Hypoglycemic Agents; Male; Metformin; Phenols; Plants, Medicinal; Rats; Stilbenes; Wood

Carcinogenicities of the N-formyl (N-OH-FAS), N-acetyl (N-OH-AAS) and N-propionyl (N-OH-PAS) derivatives of N-hydroxy-trans-4-aminostilbene (N-OH-AS) were investigated in male and female CD rats. They were injected, i.p. 10 mumol/kg body weight (bwt) twice a week for 6 weeks, and they were killed at the end of 62 weeks. The N-formyl, N-acetyl and N-propionyl derivatives of N-hydroxy-4-aminobiphenyl (N-OH-ABP) were similarly injected at a dose of 100 mumol/kg bwt for comparison in female CD rats. Tumors of the liver, mammary gland and ear duct were produced in the female rats by these N-OH-AS derivatives. N-OH-AAS and N-OH-PAS were more active in the induction of mammary and ear duct tumors than N-OH-FAS. These N-OH-AS derivatives produced more tumors than did the N-OH-ABP derivatives, even at 1/10 dose of the N-OH-ABP derivatives. In male CD rats, these N-OH-AS derivatives produced peritesticular mesothelioma and tumors of the pancreas and ear duct. N-OH-PAS also produced tumors of the small intestine and lung. The acetyl and propionyl derivatives were more carcinogenic than the formyl derivative of N-OH-AS for both male and female CD rats, suggesting that cytosolic acetyltransferases may be more important than the microsomal ones in activating these carcinogens.

Topics: Acetyltransferases; Amides; Animals; Biotransformation; Body Weight; Carcinogenicity Tests; Carcinogens; Female; Male; Neoplasms, Experimental; Rats; Stilbenes

The acute toxicity of the carcinogen trans-4-dimethylaminostilbene was studied in Wistar rats. The animals die after oral administration of 50 mg/kg (LD50) with a latency period of 11 days. Specific lesions of the stomach epithelium together with acute bone marrow incapacity and toxic effects on peripheral blood cells lead to acute anemia, which is considered to be the cause of death. Histological observations indicate that the stomach lesions develop in three phases. Firstly, necroses appear in the proliferative area predominantly in the antrum. This leads, secondly, to cystic transformation of the antrum, cardia, and Brunner's glands and further to peptic erosions and ulcerations. Thirdly, mitotic activity increases. With lethal doses, cell replacement remains incomplete. There ist a correlation between the proliferation rate of different cell types and their susceptibility; but this cannot entirely account for the tissue-specific, systemic effects of trans-4-dimethylaminostilbene. Metabolic activation is also involved, since enzyme induction with methylcholanthrene inhibits toxicity. The study disclosed a new target tissue which may now be used to investigate the mechanism of action of reactive metabolites of an aromatic amine in acute experiments. The same stomach lesions were also observed with adriamycin. With this compound, however, the intestine is also involved.

Topics: Acute Disease; Alanine Transaminase; Animals; Aspartate Aminotransferases; Body Weight; Carcinogens; Chronic Disease; Doxorubicin; Eating; Female; Gastric Mucosa; Lethal Dose 50; Male; Mice; Necrosis; Rats; Rats, Inbred Strains; Species Specificity; Stilbenes; Stomach Diseases

After repeated administration of trans-4-acetylaminostilbene to rats, DNA-bound metabolites accumulate to the greatest extent in liver and kidney, which are considered to be nontarget tissues for this carcinogen. To test whether the persistent DNA adducts represent procarcinogenic lesions, an initiation-promotion experiment was carried out using trans-4-acetylaminostilbene as an initiator and phenobarbital, DDT and diethylstilbestrol as promoters. In addition, partial hepatectomy was performed in some groups. Partial hepatectomy alone or in combination with promoters led to the formation of preneoplastic enzyme deficient foci, hyperplastic nodules and hepatoma in great yields. In addition, mammary tumors were observed with diethylstilbestrol promotion. The results support our proposal that aminostilbene derivatives produce procarcinogenic DNA-lesions in many, if not all, tissues and that secondary factors determine when and where tumors arise.

Topics: Adenoma, Bile Duct; Animals; Bile Duct Neoplasms; Body Weight; Carcinogens; DNA; Female; Hyperplasia; Liver; Liver Neoplasms, Experimental; Liver Regeneration; Neoplasms, Experimental; Precancerous Conditions; Rats; Rats, Inbred Strains; Stilbenes

Compounds (1), (2), (3), and (4) caused no adverse toxic effects and yielded no evidence of carcinogenic activity in a 2-year feeding study in albino rats at dietary levels up to 1000 ppm. Compounds (2), (3) and (4) were without effect in a 2-year study in beagle dogs at levels up to 2000 ppm. Compound (1) at levels of 400 and 1000 ppm led to decreased weight gains in some dogs and caused doserelated pathology consisting of inflammatory changes on the serosal surfaces of abdominal viscera and increased hematopoietic acitivty of the spleen and liver cords. These effect could have been due to the feeding of material, without adjustment of pH, for the first 30 weeks of the study.

Topics: Aging; Animals; Biphenyl Compounds; Body Weight; Carcinogens; Coloring Agents; Diet; Dogs; Female; Male; Organ Size; Rats; Species Specificity; Stilbenes; Triazoles

Four fluorescent whitening agents (FWAs), compounds (1), (2), (3) and (4) (see table 1) were investigated for their effects on the reproductive performance of albino rats through 3 successive 2-litter generations at dietary levels of 40, 200, and 1000 ppm. Except for slight and random effects of compound (4) on pup survival, no adverse effects were observed. The random effects with compound (4) were not consistently related to either dose level or cumulative duration of exposure through the 3 generations.

Topics: Animals; Behavior, Animal; Biphenyl Compounds; Body Weight; Coloring Agents; Female; Male; Mice; Organ Size; Reproduction; Sexual Behavior, Animal; Stilbenes; Triazoles

Topics: Animals; Body Weight; Cell Division; Cell Movement; Contraceptives, Postcoital; Dimethylamines; Embryo Implantation; Environment, Controlled; Female; Organ Size; Ovary; Ovum; Phenyl Ethers; Pituitary Gland; Pregnancy; Rats; Stilbenes; Uterus; Water

Topics: Adrenal Glands; Androstenedione; Animals; Body Weight; Diet; Diethylstilbestrol; Injections, Intramuscular; Luteinizing Hormone; Male; Organ Size; Prolactin; Prostate; Rats; Seminal Vesicles; Stilbenes; Testis; Testosterone

Topics: Animals; Body Weight; Carcinogens; Carcinoma, Squamous Cell; Chromatography, Thin Layer; Diet; Ear Neoplasms; Ear, External; Female; Leukemia, Experimental; Male; Mammary Neoplasms, Experimental; Rats; Sex Factors; Spectrum Analysis; Stilbenes; Ultraviolet Rays

Topics: Adrenal Glands; Animals; Ascorbic Acid; Body Weight; Cold Temperature; Formaldehyde; Liver; Male; Organ Size; Rats; Shock; Stilbenes; Stress, Physiological; Testis

Topics: Animals; Body Weight; Carcinoma, Squamous Cell; Ear Neoplasms; Female; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Rats; Sebaceous Gland Neoplasms; Stilbenes

Topics: Adrenal Glands; Animals; Body Weight; Female; Heparin Antagonists; Infarction; Kidney; Kidney Cortex Necrosis; Liver; Necrosis; Organ Size; Ovary; Pituitary Gland; Pituitary Hormones, Posterior; Quaternary Ammonium Compounds; Rats; Spleen; Stilbenes; Thyroid Gland; Tissue Extracts; Uterus

Topics: Alopecia; Animals; Appetite; Body Weight; Cholesterol; Clomiphene; Dogs; Eye; Female; Genitalia, Female; Genitalia, Male; Growth; Lens, Crystalline; Male; Organ Size; Ovulation; Pituitary Gland; Rats; Spermatozoa; Stilbenes; Testis

Topics: Adrenocorticotropic Hormone; Aldosterone; Animals; Arginine Vasopressin; Blood Pressure; Body Weight; Cortisone; Desoxycorticosterone; Hormones; Hypertension; Norepinephrine; Progesterone; Rats; Rats, Inbred SHR; Research; Sodium Chloride; Spironolactone; Stilbenes; Testosterone; Thyroid Hormones; Vasopressins