Resveratrol Metabolites Inhibit Human Metastatic Colon Cancer Cells
Progression and Synergize With Chemotherapeutic Drugs To Induce Cell Death
Mol Nutr Food Res. 2013 (Mar 14) [Epub ahead of print]
Altogether, our data provide significant new insight into the molecular mechanism of resveratrol (RSV_ and support the notion that despite low bioavailability in vivo, RSV biological effects could be mediated by its metabolites.
Diabetic Complications in Pregnancy:
Is Resveratrol a Solution?
Exp Biol Med (Maywood). 2013 (Feb 22) [Epub ahead of print]
Resveratrol, a polyphenol found largely in the skins of red grapes, is known to have antidiabetic action and is in clinical trials for the treatment of diabetes, insulin resistance, obesity and metabolic syndrome. Studies of resveratrol in a rodent model of diabetic embryopathy reveal that it significantly improves the embryonic outcome in terms of diminishing developmental abnormalities. Improvements in maternal and embryonic outcomes observed in rodent models may arise from resveratrol's antioxidative potential, antidiabetic action and antidyslipidemic nature. Whether resveratrol will have similar actions in human diabetic pregnancy is unknown. Here, we review the potential therapeutic use of resveratrol in diabetes and diabetic pregnancy.
Curcuminoids and Resveratrol As Anti-Alzheimer Agents
Taiwan J Obstet Gynecol. 2012 (Dec); 51 (4): 515–525
Alzheimer disease (AD) is by far the most common cause of dementia globally. This neurodegenerative disorder of the brain is chronic and progressive, characterized clinically by the deterioration in the key symptoms of behavioral and cognitive abilities. Treatment options for this disease currently are limited. Deposition of amyloid-ß and tau hyperphosphorylation are cardinal pathologic features of AD that lead to the formation of neuronal plaques and neurofibrillary tangles, respectively. In addition to mounting research on herbal compounds for the treatment of AD, curcuminoids and resveratrol appear to be beneficial as anti-AD agents.
Calorie Restriction-like Effects of 30 Days of Resveratrol Supplementation
on Energy Metabolism and Metabolic Profile in Obese Humans
Cell Metabolism 2011 (Nov 2); 14 (5): 612–622
The result of just 30 days on resveratrol were impressive: (1) The same gene regulators (AMPK, SIRT1 and PGC-1a) were activated in this study as are activated by caloric restriction and resveratrol in mice and endurance training in humans.
(2) Blood glucose levels and blood insulin levels were decreased and insulin sensitivity was improved.
(3) Triglyceride levels and levels of inflammation markers (eg IL-6 and TNFa) were decreased.
(4) Systolic and average blood pressure was decreased.
(5) Both gene expression and metabolic studies showed that mitochondrial efficiency was increased – especially the ability of mitochondria to generate energy from fat stores. In addition, fat stores in the muscle fibers responsible for endurance exercise were increased.
(6) Fat stores in the liver (a pathological condition associated with obesity that can lead to liver damage) were decreased and blood markers of liver health were improved.
(7) No adverse effects of resveratrol supplementation were observed. The authors concluded “[This study] shows that resveratrol supplementation exerts favorable metabolic adaptations that in many aspects mimic the effects of caloric restriction and/or endurance training.”
A Resveratrol and Polyphenol Preparation Suppresses Oxidative
and Inflammatory Stress Response to a High-Fat, High-Carbohydrate Meal
J Clin Endocrinol Metab. 2011 (May); 96 (5): 1409–1414
High-fat, high-carbohydrate (HFHC) meals are known to induce oxidative and inflammatory stress, an increase in plasma endotoxin concentrations, and an increase in the expression of suppressor of cytokine signaling-3 (SOCS-3). The intake of the supplement suppressed the meal-induced elevations of plasma endotoxin and LBP concentrations, the expression of p47(phox), TLR-4, CD14, SOCS-3, IL-1ß, and Keap-1, while enhancing Nrf-2 binding activity and the expression of NQO-1 and GST-P1 genes. A supplement containing resveratrol and muscadine polyphenols suppresses the increase in oxidative stress, lipopolysaccharide and LBP concentrations, and expression of TLR-4, CD14, IL-1ß and SOCS-3 in mononuclear cells after an HFHC meal. It also stimulates specific Nrf-2 activity and induces the expression of the related antioxidant genes, NQO-1 and GST-P1. These results demonstrate the acute antioxidant and antiinflammatory effects of resveratrol and polyphenolic compounds in humans in the postprandial state.
A Review of the Sirtuin System, Its Clinical Implications, and the
Potential Role of Dietary Activators Like Resveratrol: Part 1
Alternative Medicine Review 2010 (Sep); 15 (3): 245–263 ~ FULL TEXT
The silent information regulator (SIR) genes (sirtuins) comprise a highly conserved family of proteins, with one or more sirtuins present in virtually all species from bacteria to mammals. In mammals seven sirtuin genes - SIRT1 to SIRT7 - have been identified. Emerging from research on the sirtuins is a growing appreciation that the sirtuins are a very complicated biological response system that influences many other regulator molecules and pathways in complex manners. Responses of this system to environmental factors, as well as its role in health and disease, are currently incompletely characterized and at most partially understood. This article reviews the mammalian sirtuin system, discusses the dietary, lifestyle, and environmental factors that influence sirtuin activity, and summarizes research on the importance of vitamin B3 in supporting sirtuin enzyme activity, as well as the role specifically of the amide form of this vitamin - nicotinamide - to inhibit sirtuin enzyme activity. Polyphenols, especially resveratrol, influence sirtuins. Existing evidence on these nutritional compounds, as they relate to the sirtuin system, is reviewed. In Part 2 of this review, clinical situations where sirtuins might play a significant role, including longevity, obesity, fatty liver disease, cardiovascular health, neurological disease, and cancer, are discussed.
A Review of the Sirtuin System, Its Clinical Implications, and the
Potential Role of Dietary Activators Like Resveratrol: Part 2
Alternative Medicine Review 2010 (Dec); 15 (4): 313–328 ~ FULL TEXT
The silent information regulator (SIR) genes (sirtuins) comprise a highly conserved family of proteins, with one or more sirtuins present in virtually all species from bacteria to mammals. In mammals seven sirtuin genes - SIRT1 to SIRT7 - have been identified. Emerging from research on the sirtuins is a growing appreciation that they are a very complicated biological response system that influences many other regulator molecules and pathways in complex manners. Part 1 of this article provided an overview of the mammalian sirtuin system, discussed the dietary, lifestyle, and environmental factors that influence sirtuin activity, and summarized research on the importance of vitamin B3 in supporting sirtuin enzyme activity, as well as the role specifically of the amide form of this vitamin - nicotinamide - to inhibit sirtuin enzyme activity. In Part 2 of this review, clinical situations where sirtuins might play a significant role, including longevity, obesity, fatty liver disease, cardiovascular health, neurological disease, and cancer are discussed. Research on the ability of nutritional substances, especially resveratrol, to influence sirtuin expression and function, and hence alter the courses of some clinical situations, is also reviewed.
Alternative Medicine Review 2010 (Jul); 15 (2): 152–158 ~ FULL TEXT
Resveratrol is a polyphenol compound found in many plant species including grapes, peanuts, cranberries, Japanese giant knotweed, and others. Polyphenols, including flavonoids, flavonols, catechins, and stilbenes are present in the human diet in plant materials, where they act as antioxidants and protect the plant from damage from bacteria, fungi, and ultraviolet radiation. Resveratrol exerts anti-aging effects in animals. Numerous invitro and animal studies have shown that resveratrol has potent antioxidant and anti-inflammatory effects, promotes vascular endothelial function, enhances lipid metabolism, and has anticancer activity.
Resveratrol Impaired the Morphological Transition of Candida Albicans
Under Various Hyphae-inducing Conditions
J Microbiol Biotechnol. 2010 (May); 20 (5): 942–945
The ability of the human fungal pathogen Candida albicans to undergo the morphological transition from a single yeast form to pseudohyphal and hyphal forms in response to various conditions is known to be an important for its virulence. Many studies have shown the pharmacological effects of resveratrol, a phytoalexin polyphenolic compound. In this study, we investigated the antifungal activity of resveratrol against C. albicans. Both yeast-form and mycelial growth of C. albicans were inhibited by resveratrol.
Antiviral Activity of Resveratrol
Biochem Soc Trans 2010 (Feb); 38 (Pt 1): 50–53
Resveratrol is a natural compound produced by certain plants on various stimuli. In recent years, extensive research on resveratrol has been carried out, demonstrating its capacity to prevent a wide variety of conditions, including cardiovascular diseases and cancer, and to control fungal, bacterial and viral infections. In the present review, we summarize the current knowledge of the activity of resveratrol against viral infection and describe the possible molecular pathways through which resveratrol exerts its antiviral activity.
AMPK Signaling Activation by Resveratrol Modulates
Amyloid-beta Peptide Metabolism
Journal of Biological Chemistry 2010 (Jan 14) [Epub ahead of print]
Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by Abeta peptide deposition into cerebral amyloid plaques. (IN this study)... orally administered resveratrol in mice was detected in the brain where it activated AMPK and reduced cerebral Abeta levels and deposition in the cortex. These data suggest that resveratrol and pharmacological activation of AMPK have therapeutic potential against Alzheimer's disease.
Consuming a Diet Supplemented With Resveratrol Reduced Infection-related
Neuroinflammation and Deficits in Working Memory in Aged Mice
Rejuvenation Res 2009 (Dec); 12 (6): 445–453
Aged mice treated peripherally with lipopolysaccharide (LPS) show an exaggerated neuroinflammatory response and cognitive deficits compared to adults. Considerable evidence suggests resveratrol, a polyphenol found in red grapes, has potent anti-inflammatory effects in the periphery, but its effects on the central inflammatory response and cognitive behavior are unknown. (This study found that)... resveratrol may be useful for attenuating acute cognitive disorders in elderly individuals with an infection.
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.
Inhibition of Protein Glycation by Skins and Seeds
of the Muscadine Grape
Biofactors 2007; 30 (3): 193–200
The formation of advanced glycation end products (AGEs) leading to protein glycation and cross-linking is associated with the pathogenesis of diabetic complications. The inhibition of protein glycation by phenolic and flavonoid antioxidants demonstrates that the process is mediated, in part, by oxidative processes. In this study, the effects of seed and skin extracts of the muscadine grape on AGEs formation were examined. Gallic acid, catechin and epicatechin, the three major polyphenols in the seeds, all significantly decreased the AGE product related fluorescence at a concentration of 50 microM. These results suggest that consumption of the muscadine grape may have some benefit in altering the progression of diabetic complications.
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 (only organically grown) 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.
Effect of Wine Phenolics on Cytokine-induced C-reactive Protein Expression
Journal of Thrombosis and Hemostasis 2007 (Jun); 5 (6): 1309–1317 ~ FULL TEXT
In the present study, we evaluated the effect of various wine polyphenolic compounds and several active synthetic derivatives of resveratrol on the inflammatory cytokines (IL-1beta + IL-6)-induced CRP expression in Hep3B cells. Among the wine phenolics tested, quercetin and resveratrol, in a dose-dependent manner, suppressed cytokine-induced CRP expression.
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
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.