Resveratrol: A Novel Target for Type 1 Diabetes
The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
This research proposal won the National Institute of Health (NIH's) Pathfinder Award in September 2008. This proposal aims to determine the molecular mechanisms underlying Sirt1 function as an anergic factor of T-cells, and to investigate how mis-regulated Sirt1 is involved in the development of T1D. We will also further examine the effects of resveratrol on preventing/treating T1D.
Reversal Effect of Resveratrol on
Multidrug Resistance in KBv200 Cell Line
Biomedicine & Pharmacotherapy 2008 (Aug 28);
A multidrug-resistant clone of human oral epidermoid carcinoma KB cells was isolated by stepwise selection on exposure to increasing doses of vincristine. The final clone, KBv200, obtained after ethylmethane sulfonate mutagenesis showed 156-fold higher resistance to vincristine than KB cells. The cells were also cross-resistant to paclitaxel and adriamycin. The aim of this study was to explore the reversal effect and potential mechanism of resveratrol on KBv200 cells. The results of gene detection showed that the expression levels of MDR1 and Bcl-2 were decreased upon resveratrol treatment. Resveratrol can efficiently reverse multidrug resistance in KBv200 cells. The potential mechanism may be via inhibiting the multidrug-resistant gene expressions and/or promoting cell apoptosis.
A Low Dose of Dietary Resveratrol Partially Mimics
Caloric Restriction and Retards Aging Parameters in Mice
PLoS ONE 2008 (Jun 4); 3 (6): e2264 ~ FULL TEXT
We fed mice from middle age (14-months) to old age (30-months) either a control diet, a low dose of resveratrol (4.9 mg kg(-1) day(-1)), or a calorie restricted (CR) diet and examined genome-wide transcriptional profiles. We report a striking transcriptional overlap of CR and resveratrol in heart, skeletal muscle and brain. Both dietary interventions inhibit gene expression profiles associated with cardiac and skeletal muscle aging, and prevent age-related cardiac dysfunction. Dietary resveratrol also mimics the effects of CR in insulin mediated glucose uptake in muscle.
Moderate Wine Consumption in the Prevention of Metabolic Syndrome and its Related Medical Complications
Endocr Metab Immune Disord Drug Targets 2008 (Jun); 8 (2): 89–98
In addition to the favorable effects of moderate ethanol intake on lipid profiles, polyphenols enriched in red wine possess multiple benefits on the MetS beyond alcohol through their anti-oxidant, anti-inflammatory, vascular-protective and insulin-sensitizing properties. Notable among these red wine polypheolic compounds is resveratrol, a phytoalexin that has recently attracted great attention due to its role in mimicking calorie restriction. This compound can act as a potent activator of the NAD(+)-dependent deacetylases sirtuins to expand the life span and to prevent the deleterious effects of excess intake on insulin resistance and metabolic derangement.
Resveratrol in Prevention and Treatment
of Common Clinical Conditions of Aging
Clinical Interventions in Aging 2008; 3 (2): 331–339 ~ FULL TEXT
Resveratrol is a potent member of the class of natural, plant-derived chemicals known as polyphenols. These help explain in part why a diet high in fruit and vegetables confers health benefits and are associated with reduced risk of common complex conditions such as cardiovascular disease, cancer, diabetes, and Alzheimer's disease. While a healthy diet and lifestyle is strongly recommended in prevention of such conditions, the future bodes well for the use of resveratrol and analogues of higher potency than the natural form for treatment of diseases that afflict humans, particularly as they age.
New Enlightenment of French Paradox: Resveratrol's Potential for Cancer Chemoprevention and Anti-cancer Therapy
Cancer Biol Ther 2007 (Dec); 6 (12): 1833–1836
Resveratrol is a phytoalexin produced by many plants, and the skin of red grapes is particularly rich in resveratrol which accounts for the "French Paradox". Besides its protection of the cardiovascular system, it can affect the processes underlying all three stages of carcinogenesis, involving tumor initiation, promotion and progression. It has also been shown to suppress angiogenesis and metastasis.
Resveratrol Alleviates Bleomycin-induced Lung Injury in Rats
Pulm Pharmacol Ther 2007 (Sep 3); 20 (6): 642–649
Bleomycin, a chemotherapeutic agent, can cause pulmonary fibrosis and impaired lung function. Bleomycin causes DNA strand to break and results in lipid peroxidation and oxidation of other cellular molecules. The objective of this study was to investigate the protective effects of resveratrol on pulmonary fibrosis induced by bleomycin. The study was carried out on rats received a placebo or resveratrol for 14 days. Bleomycin caused several biochemical changes: a significant decrease in lung glutathione levels, an increase in malondialdehyde levels, increased activity of myeloperoxidase and increased level of collagen contents of the lung tissue. These changes were reversed when the rats were treated with the antioxidant resveratrol. The study concluded that resveratrol can be used as a supplement to alleviate the side effects of bleomycin treatment.
SIRT1 Deacetylase Protects Against Neurodegeneration in Models for Alzheimer's Disease and Amyotrophic Lateral Sclerosis
EMBO J 2007 (Jul 11); 26 (13): 3169–3179
A progressive loss of neurons with age underlies a variety of debilitating neurological disorders, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), yet few effective treatments are currently available. HIn cell-based models for AD/tauopathies and ALS, SIRT1 and resveratrol, a SIRT1-activating molecule, both promote neuronal survival. Furthermore, injection of SIRT1 lentivirus in the hippocampus of p25 transgenic mice conferred significant protection against neurodegeneration. Thus, SIRT1 constitutes a unique molecular link between aging and human neurodegenerative disorders and provides a promising avenue for therapeutic intervention.
Resveratrol Improves Mitochondrial Function and Protects Against Metabolic Disease by Activating SIRT1 and PGC-1alpha
Cell 2006 (Dec 15); 127 (6): 1109–1122
Diminished mitochondrial oxidative phosphorylation and aerobic capacity are associated with reduced longevity. We tested whether resveratrol (RSV), which is known to extend lifespan, impacts mitochondrial function and metabolic homeostasis. Treatment of mice with RSV significantly increased their aerobic capacity, as evidenced by their increased running time and consumption of oxygen in muscle fibers. Importantly, RSV treatment protected mice against diet-induced-obesity and insulin resistance. These pharmacological effects of RSV combined with the association of three Sirt1 SNPs and energy homeostasis in Finnish subjects implicates SIRT1 as a key regulator of energy and metabolic homeostasis.
Resveratrol Improves Health and Survival of Mice on a High-calorie Diet
Nature 2006 (Nov 16); 444 (7117): 337–342 ~ FULL TEXT
Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.
Resveratrol Prolongs Lifespan and Retards the Onset
of Age-related Markers in a Short-lived Vertebrate
Curr Biol 2006 (Feb 7); 16 (3): 296–300
Here, the authors used the short-lived seasonal fish Nothobranchius furzeri with a maximum recorded lifespan of 13 weeks in captivity. Resveratrol was added to the food starting in early adulthood and caused a dose-dependent increase of median and maximum lifespan. In addition, resveratrol delays the age-dependent decay of locomotor activity and cognitive performances and reduces the expression of neurofibrillary degeneration in the brain. These results demonstrate that food supplementation with resveratrol prolongs lifespan and retards the expression of age-dependent traits in a short-lived vertebrate.
Prevention and Repair of DNA Damage by Selected Phytochemicals as Measured by Single Cell Gel Electrophoresis
J Environ Pathol Toxicol Oncol 2004; 23 (3): 215–226
The most remarkable aspect of the present study was that all four compounds (curcumin, resveratrol, indole-3-carbinol, and ellagic acid) helped in the recovery of DNA damage by accelerating DNA repair efficiency in the damaged cells. This was further substantiated by the observation on unscheduled DNA synthesis. Our results suggest that these agents are chemopreventive by virtue of their ability to protect DNA as well as to induce DNA repair.
Small Molecule Activators of Sirtuins
Extend Saccharomyces cerevisiae Lifespan
Nature 2003 (Sep 11); 425 (6954): 191–196
In diverse organisms, calorie restriction slows the pace of ageing and increases maximum lifespan. In the budding yeast Saccharomyces cerevisiae, calorie restriction extends lifespan by increasing the activity of Sir2 (ref. 1), a member of the conserved sirtuin family of NAD(+)-dependent protein deacetylases. Here we report the discovery of three classes of small molecules that activate sirtuins. We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIR1 for both the acetylated substrate and NAD(+), and increases cell survival by stimulating SIRT1-dependent deacetylation of p53. In yeast, resveratrol mimics calorie restriction by stimulating Sir2, increasing DNA stability and extending lifespan by 70%. We discuss possible evolutionary origins of this phenomenon and suggest new lines of research into the therapeutic use of sirtuin activators.
Cancer Chemopreventive Activity of Resveratrol,
A Natural Product Derived From Grapes
Science 1997 (Jan 10); 275 (5297): 218–220
Resveratrol was found to act as an antioxidant and antimutagen and to induce phase II drug-metabolizing enzymes (anti-initiation activity); it mediated anti-inflammatory effects and inhibited cyclooxygenase and hydroperoxidase functions (antipromotion activity); and it induced human promyelocytic leukemia cell differentiation (antiprogression activity). In addition, it inhibited the development of preneoplastic lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model. These data suggest that resveratrol, a common constituent of the human diet, merits investigation as a potential cancer chemopreventive agent in humans.
