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Review  |   September 2018
Resveratrol's Potential in the Adjunctive Management of Cardiovascular Disease, Obesity, Diabetes, Alzheimer Disease, and Cancer
Author Notes
  • From the Midwestern University/Chicago College of Osteopathic Medicine (Student Doctor Kulashekar and Dr Peuler) and the Department of Biomedical Sciences at Midwestern University (Ms Stom) in Downers Grove, Illinois. 
  • Financial Disclosures: None reported. 
  • Support: This work was supported by funds from the Biomedical Sciences Program and the Department of Pharmacology at Midwestern University. 
  •  *Address correspondence to Jacob D. Peuler, PhD, Midwestern University/Chicago College of Osteopathic Medicine, 555 31st St, Downers Grove, IL 60515-1235. Email: jpeule@midwestern.edu
     
Article Information
Cardiovascular Disorders / Endocrinology / Geriatric Medicine / Diabetes
Review   |   September 2018
Resveratrol's Potential in the Adjunctive Management of Cardiovascular Disease, Obesity, Diabetes, Alzheimer Disease, and Cancer
The Journal of the American Osteopathic Association, September 2018, Vol. 118, 596-605. doi:https://doi.org/10.7556/jaoa.2018.133
The Journal of the American Osteopathic Association, September 2018, Vol. 118, 596-605. doi:https://doi.org/10.7556/jaoa.2018.133
Web of Science® Times Cited: 2
Abstract

Resveratrol is a naturally occurring polyphenol that can be found in several human dietary sources, including red wine; many plants, especially grapes, berries, and nuts; and nutritional supplements. Findings from numerous preclinical experiments and clinical trials in humans suggest that resveratrol may play an important role in managing or preventing a variety of diseases. Some of the health benefits include cardioprotective effects; chemopreventive properties; metabolic changes, such as improved glycemic control; protection from diabetic consequences; and synergistic therapeutic effects when administered with other treatment modalities. Resveratrol has been found to be safe and reasonably well tolerated in humans, with mild to moderate gastrointestinal side effects. This review provides a summary of recent preclinical experiments and clinical trials pertaining to the effects of resveratrol on cardiovascular disease, obesity, diabetes, Alzheimer disease, and cancer. It also identifies suggested mechanisms by which resveratrol functions and presents issues surrounding resveratrol concentrations in vitro vs plasma levels reported in vivo.

Resveratrol is a naturally occurring polyphenol found in several human dietary sources, including red wine and nutritional supplements.1,2 Preclinical experiments and clinical trials in humans suggest that resveratrol may play an important role in preventing a variety of human diseases. Some of the health benefits attributed to resveratrol include cardioprotective effects,1,3-8 vasorelaxation,9-13 chemopreventive properties,1,14,15 metabolic changes,16-18 and protection from the serious consequences of diabetes.19-24 Resveratrol also shows therapeutic potential in patients with Alzheimer disease (AD)25-31 and cancer.32-36 
Much of the current research is aimed at resveratrol's potential for therapeutic use in humans.1,37 While studies have found resveratrol to be safe and reasonably well tolerated in humans, with only mild to moderate side effects, concerns remain regarding its bioavailability after in vivo administration.1,2,37-41 
The intention of this review is to provide a summary of preclinical experiments and clinical trials pertaining to the effects of resveratrol on cardiovascular disease, obesity, type 1 and type 2 diabetes mellitus, AD, and cancer; to present suggested mechanisms by which resveratrol functions; and to discuss issues surrounding its concentrations studied in vitro vs plasma levels studied in vivo. 
Resveratrol and Cardiovascular Disease
Interest in the effects of resveratrol on cardiovascular health spiked after the discovery that resveratrol was linked to cardiovascular benefits associated with the consumption of red wine.1 Several preclinical studies have shown that resveratrol improves cardiovascular function through a variety of mechanisms.1,4-7 In 2005, Liu et al7 studied the effects of resveratrol on cardiac hypertrophy in partially nephrectomized hypertensive rats. This 4-week study found that after daily oral dosing of resveratrol, the rats showed both decreased systolic blood pressure and heart weight. The investigators also measured levels of endothelin 1, angiotensin II, and nitric oxide as potential mechanistic targets. Endothelin 1 and angiotensin II both contribute to cardiac hypertrophy, whereas nitric oxide inhibits it. Because this study7 showed decreases in serum endothelin 1 and angiotensin II and an increase in serum nitric oxide after 4 weeks of resveratrol administration, the authors suggested that modulation of those factors may indicate a cardioprotective function of resveratrol. 
A 2010 study6 on 2-kidney, 1-clip hypertensive rats showed that resveratrol could reverse multiple effects of hypertension, including increased blood pressure, aortic hypercontractility, reduced left ventricular function, and oxidative injury in cardiac, renal, and cerebral tissues. This experiment, which included 6 weeks of treatment with resveratrol, focused on its effects on oxidative damage induced by renovascular hypertension. Blood pressure was measured by tail cuff, and echocardiography was used to measure interventricular septal thickness, left ventricular diameter, and left ventricular posterior wall thickness. These values were used to calculate cardiac function in terms of ejection fraction, fractional shortening, left ventricular mass, and relative wall thickness. The study concluded that resveratrol significantly decreased blood pressure and improved cardiovascular function. It also found that resveratrol prevented reductions in biochemical parameters that implicate the presence of oxidative tissue damage, such as glutathione, sodium-potassium–activated adenosine triphosphatase, superoxide dismutase, and catalase activities. Overall, the study concluded that resveratrol not only helped to improve cardiovascular function but increased resistance to cardiovascular oxidative stress.6 
A similar study5 on cardiovascular function in DOCA (deoxycorticosterone acetate)-salt hypertensive rats found that 28 days of resveratrol exerted anti-inflammatory and antifibrotic effects, which the authors suggested played a role in its attenuation of adverse cardiovascular changes associated with hypertension. This study measured a number of cardiovascular parameters, including systolic blood pressure, left and right ventricular weights, thoracic aortic wall thickness, perivascular and interstitial collagen fractions from the left ventricle, diastolic stiffness, ejection fraction, and cardiac output. The overall conclusion was that resveratrol treatment attenuated numerous parameters of cardiac remodeling, such as systolic blood pressure, left ventricular wall thickness, diastolic thickness, and contractility. They also concluded that resveratrol decreased inflammatory cell infiltration and cardiac fibrosis, and, therefore, improvement in cardiac and vascular function.5 
In 2013, a study using mixed models of spontaneously hypertensive rats and angiotensin-infused hypertensive mice looked at mechanisms involved in resveratrol's apparent prevention of hypertension and cardiac hypertrophy after 5 and 2 weeks, respectively.4 The purpose was to confirm that the effects of resveratrol were not specific to the rat model. The study investigated a variety of mechanisms, including endothelial nitric oxide synthase (eNOS) phosphorylation, liver kinase B1 (LKB1)/adenosine monophosphate (AMP)-activated protein kinase (AMPK) signal transduction pathway, and the p70S6 kinase prohypertrophic signaling cascade. Increased levels of phosphorylated serine-1177 eNOS, a marker of eNOS activity, were observed following treatment with resveratrol. This finding suggests that nitric oxide bioavailability increased as a result of resveratrol. Correspondingly, phosphorylated AMPK levels and LKB1 activity were higher after resveratrol treatment. The authors also noted a reduction in 4-hydroxy-2-nonenal, a product of reactive lipid peroxidation, which further corresponds to the elevated LKB1-AMPK-eNOS signaling pathway. Furthermore, this study evaluated the p70S6 kinase pathway, which regulates protein synthesis and promotes hypertrophic growth of the myocardium. They found this pathway to be reduced after resveratrol treatment, suggesting a direct antihypertrophic effect of resveratrol. Overall, the study concluded that resveratrol acts to improve cardiovascular function, at least in part, by activation of eNOS through the LKB1-AMPK pathway, and to reduce hypertension-induced hypertrophy of the left ventricle through inhibition of prohypertrophic signaling pathways.4 
These in vivo studies identified various mechanisms by which long-term administration of resveratrol may improve cardiovascular function, such as modification of nitric oxide, angiotensin II, and endothelin 1. Other mechanisms, including anti-inflammatory or antifibrotic responses, cardiac remodeling, and activation or inactivation of specific signaling pathways, were also shown to have a role in the cardiovascular improvements. Although these articles focused on different aspects of cardiovascular function, one commonality was the ability of resveratrol to lower arterial blood pressure in different types of hypertensive animal models. Resveratrol has also been shown to lower blood pressure in humans, as shown in a meta-analysis of randomized controlled trials.8 A direct vasorelaxant effect appears to be one important action by which it does so—an action that has been demonstrated in vitro with various types of arteries isolated from humans9 and other animals.10-13 Mechanisms responsible for this action vary from vessel to vessel and are both endothelium-dependent and endothelium-independent, as discussed in those studies.9-13 
Resveratrol and Obesity
Many of resveratrol's benefits in obesity correlate with changes in cardiovascular function as already described. But other benefits of resveratrol in metabolic disease associated with obesity include improved dyslipidemia, hyperinsulinemia, and hyperleptinemia; anti-inflammatory effects; and calorie restriction mimicking.16,18 
A study16 of long-term oral administration of resveratrol was shown to reduce metabolic disturbances, as well as lower blood pressure in obese rats. This study investigated several functional alterations and related mechanisms that arise from metabolic syndrome. The dose of resveratrol administered to obese rats was noted to be comparable to doses in human dietary supplements. Several plasma parameters were measured, all of which were shown to have improved after 4 weeks of treatment with resveratrol. Insulin resistance and levels of glucose, insulin, blood leptin, triglycerides, free fatty acids, and cholesterol were all decreased. 
One potential mechanism that was described in this study16 was AMPK phosphorylation because activation of AMPK leads to an increase in fatty acid oxidation and inhibits fatty acid synthesis. Western blot analysis of liver parameters showed an increase in phosphorylation of AMPK, which was doubled in comparison with that in the obese controls. A reduction of blood pressure by more than 79% was observed by the end of resveratrol administration. This study also found a notable reduction in inflammatory status. Interestingly, the authors reported that there was no significant reduction in overall body weight, although a moderate association was present. They also noted that resveratrol did not affect average daily food intake. The study concluded that resveratrol can be beneficial in the treatment of altered metabolic functions, as it was shown to reduce dyslipidemia, insulin resistance, hyperleptinemia, hypertension, and inflammatory status, as well as activate AMPK in target tissues of metabolic syndrome, such as liver and visceral adipose tissue.16 
Another study identified calorie restriction mimicking of resveratrol in obese men in a clinical trial.18 The men were given 150 mg of resveratrol per day orally for 30 days, and metabolic profile and energy metabolism were measured. Similar to the obese rat study,16 this study showed a reduction in levels of hepatic lipids, plasma glucose, triglycerides, and inflammatory markers, along with a decrease in systolic blood pressure. Assessment of whole-body energy expenditure, substrate utilization, ectopic lipid storage, mitochondrial function, and lipolysis revealed that resveratrol helped lower energy expenditure and improve metabolic and general health parameters.18 These results suggest that resveratrol mimics calorie restriction without reducing actual calorie intake, which would render it a more easily compliant method of treatment for patients with metabolic syndrome. 
Adverse metabolic changes are common consequences of obesity. The aforementioned preclinical and clinical studies show resveratrol to be an effective component in the management of such adverse metabolic changes, and they demonstrate overlapping effects with the cardiovascular benefits, thus improving multiple parameters associated with obesity and metabolic syndrome.16,18 
Resveratrol and Diabetes
Many articles have been published in the past several years that cover resveratrol's potential health benefits in diabetes mellitus in both human and animal studies.17,19-24 These articles also explore the protective effects resveratrol seems to exert against serious consequences associated with the disease, including loss of kidney function,19,20 poor cardiac health,21,24 and retinal degeneration.22,23 
A clinical study published in 201217 investigated the effects of resveratrol on glycemic control and other risk factors also associated with the disease. Patients with type 2 diabetes mellitus were given resveratrol (250 mg/d) in addition to their regular hypoglycemic agents and were compared with patients who took only those agents. The resveratrol group had a significant decrease in hemoglobin A1c, along with a reduction in systolic blood pressure, total cholesterol, and total protein compared with the control group. The cardiovascular benefits observed are not surprising, as diabetes mellitus is known to be associated with an increased risk of heart disease. Overall, the findings of this study suggest that resveratrol added to a regular hypoglycemic regimen can improve glycemic control in patients with type 2 diabetes mellitus and may be a potential adjunctive therapeutic agent in the management of this disease.17 
Additional research19 delved into the effects of resveratrol on specific pathologic conditions associated with diabetes. Kidney disease is a common complication of diabetes mellitus. To test the effects of resveratrol on its progression, researchers gave rats with streptozotocin-induced diabetes resveratrol for 15 days. Although the results did not show statistically significant reductions in blood glucose levels or sirtuin (SIRT) 2, the experimental group did show increased renal expression of leptin and overall decreased kidney damage on histopathologic analysis. 
To analyze the effects of resveratrol at the cellular level, rats were subjected to shock and resuscitation with lactated Ringer solution or resveratrol and lactated Ringer solution. Blood samples were taken before the rats were euthanized for analysis of renal mitochondrial function and expression of antioxidant protein.20 Increased blood urea nitrogen, creatinine, and neutrophil gelatinase-associated lipocalin (NGAL) levels established the loss of kidney function and implied that decreased mitochondrial function was related to kidney impairment. The resveratrol-treated rats showed restoration of electron transport complex function, less reactive oxygen species production, and less lipid oxidation compared with the controls. The resveratrol-treated rats also had lower NGAL levels and increased SIRT1 mRNA levels. Thus, the study showed that resveratrol may mitigate the oxidative damage accompanying kidney failure by restoring renal cellular mitochondrial function and exerting an overall renal protective effect.20 
To assess cardioprotective effects of resveratrol in diabetes, hyperglycemic rats were treated with resveratrol and evaluated in live and euthanized states for cardiac function.21 Compared with controls, resveratrol-treated rats showed decreased reactive oxidative species and increased antioxidant levels in the heart. They also had increased cardiac mRNA and protein levels of SIRT1—a finding consistent with the findings of Wang et al.20 These results are supported by an in vitro study21 of cardiomyoblasts treated with resveratrol, which showed restoration of the NAD/NADH (nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide hydrogen) ratio and SIRT1 levels. In the resveratrol-treated hyperglycemic rats, the higher SIRT1 levels were accompanied by less binding of nuclear factor kB-p65 to DNA and deacetylated histone 3, a mechanism that decreases the expression of genes involved in inflammatory response and oxidative stress. The resveratrol-treated rats showed less cardiac muscle hypertrophy as a result and a subsequent improvement of their diabetic disease state.21 
To further investigate resveratrol's mode of action in the myocardium, mice with type 2 diabetes mellitus were treated with resveratrol for 3 weeks followed by myocardial ischemia induction. They were evaluated for injury, reperfusion, and adiponectin levels.24 Adiponectin is known to signal the fed state and is found in low levels in patients with diabetes, especially patients with a high body fat percentage. Before myocardial ischemia was induced, the mice treated with resveratrol showed significantly less cardiac hypertrophy, higher left ventricular ejection fraction, and decreased caspase 3 activity than mice not treated with resveratrol. After myocardial ischemia, the resveratrol-treated mice showed rescued levels of adiponectin and slightly increased adiponectin multimer levels. The researchers postulated that cardioprotection is offered via inhibition of adiponectin downregulators in the presence of resveratrol, allowing it to activate AMPK in target tissue.24 Thus, resveratrol might play a cardioprotective role in the context of diabetes. 
The effects of resveratrol on retinal protection were assessed in an experiment in which researchers administered resveratrol to rats with streptozotocin-induced diabetes for 7 months and observed changes on their retinas.22 In a separate experiment, they treated streptozotocin-treated Müller cells with resveratrol in vitro. The retinas of the resveratrol-treated diabetic rats showed significantly less apoptosis, as did the streptozotocin-treated Müller cells. They also saw increased expression of a potent inhibitor of specificity protein 1, a known mediator of cell death.22 
To determine the mechanism of resveratrol in human diabetic retinopathy, peripheral mononuclear cells isolated from patients with proliferative diabetic retinopathy were cultured and treated with resveratrol.23 SIRT1 is known to inhibit interleukin 17, a cytokine involved with inflammation and autoimmune diseases and implicated in the progression of proliferative diabetic retinopathy.23 The cells treated with resveratrol showed increased SIRT1 activation, followed by a significant decrease in interleukin 17 levels. These results suggest that resveratrol plays a role in reducing damage to the retina through a SIRT1-directed mechanism that reduces inflammation and spares retinal cells. 
Resveratrol and AD
Resveratrol is known to act on substrates that advance AD through various pathways. One of the most investigated pathways involves SIRT1, a deacetylase of several cell regulators. A study analyzing enzymes in mouse cortices and hippocampi found that decreased SIRT1 levels sped up neurodegeneration.25 Although increased SIRT1 expression accompanies more advanced AD, the authors proposed that elevated SIRT1 levels could exercise a neuroprotective effect on the brain during earlier stages of AD.25 In another study, in an attempt to connect SIRT1 to the pathologic biomarkers of AD, SAMP8 mice (a model of age-related AD) were treated with long-term resveratrol, then tested for object recognition.26 Mice treated with resveratrol scored higher than mice treated with placebo. Also, analysis of their harvested brains showed increased tissue levels of SIRT1 and AMPK and decreased tissue accumulation of amyloid β (Aβ) and other hallmarks of AD, such as Aβ40, Aβ42, and phosphorylated tau proteins, in specific brain regions. In another study, rats were treated with streptozotocin, a known inducer of AD and insulin resistance, and some rats were then treated with resveratrol.31 The resveratrol-treated rats had lower extracellular signal–regulated kinase levels, another protein implicated in the pathology of AD. They also performed better than controls on the Morris water maze, showing improvement in memory.31 These studies demonstrate that low SIRT1 levels are associated with AD, underlining the importance of finding ways to increase SIRT1 as a therapeutic measure. 
In an attempt to further explore resveratrol-SIRT1 mediated pathways, mice and cultured cells were treated with resveratrol and an SIRT1 inhibitor, DBC1 (deleted in breast cancer 1), and examined for SIRT1 activity.27 Resveratrol appeared to stall axonal degeneration in the presence of low concentrations of NAD+. It also caused disassociation of DBC1 from SIRT1 in dorsal root ganglia and significantly less Wallerian degeneration.27 In another study, cells exposed to smaller fragments of Aβ and resveratrol secreted less lactate dehydrogenase and had lower overall levels of intracellular calcium compared with controls, in addition to fewer instances of Aβ-induced apoptosis and higher expression of SIRT1.28 The increased expression of SIRT1 was accompanied by increased downstream expression of rho-associated kinase 1, an inhibitor of the pathologic Aβ processing pathway.28 This study's findings indicate that if resveratrol can increase rho-associated kinase 1 levels, it can reduce Aβ plaque formation in the brain. 
In an effort to establish the relationship between resveratrol and tau proteins associated with memory, rat hippocampal cells were treated with Aβ. The cells then displayed decreased levels of cellular antioxidants, as well as increased levels of tau protein.29 When treated with resveratrol, these cells showed a decrease in lipid peroxide levels accompanied by improved levels of antioxidants and memory-associated proteins.29 These findings support the aforementioned studies describing resveratrol as having an antioxidant-enhancing effect in peripheral tissues as well.20,21 
To investigate the safety and tolerability of resveratrol in patients with AD, a phase II trial analyzed AD biomarkers and other clinical endpoints in human participants with mild to moderate AD treated for 52 weeks with escalating doses of resveratrol starting at 500 mg per day.30 Compared with placebo, resveratrol appeared to stabilize the decline in cerebrospinal fluid (CSF) and plasma levels of Aβ40 expected with advancing dementia. Also, in patients with biomarker-confirmed AD (ie, CSF Aβ42 levels lower than 600 ng/mL at the start), resveratrol stabilized those levels. Resveratrol also blunted the decrease in Alzheimer's Disease Cooperative Study Activities of Daily Living scores during the 52-week period. Additionally, the resveratrol group showed a decrease in brain volume (excluding CSF, the brainstem, and the cerebellum) and an increase in ventricular volume, suggesting that resveratrol exerts powerful anti-inflammatory actions that result in decreased brain edema. These findings were more pronounced in a subgroup of patients who were apolipoprotein ε4 gene carriers than in a subgroup of patients who were not carriers of the gene. Although interpretation of these results remains unclear, all of the resveratrol doses were safe and well tolerated, with the most common adverse effects being nausea and diarrhea.30 These findings call for more research into how resveratrol's pharmacology and administration can be altered to improve its effects in humans with AD. 
Resveratrol and Cancer
Resveratrol has long been reported to have a number of chemopreventive properties, including blocking the initiation of carcinogenesis.1,14,15 Its use as an adjunct to conventional cancer treatment modalities has also been reported.33-36 In 2010, a clinical study in healthy volunteers reported resveratrol's role as a potential chemopreventive agent through its effect on circulating levels of insulinlike growth factor 1 (IGF-1) and IGF-binding protein 3 (IGFBP-3).14 The IGF signaling system is an important factor in cancer development. The study also assessed the safety of resveratrol. Healthy volunteers were given a daily dose of resveratrol at different levels (500-5000 mg) for 29 days.14 Resveratrol was found to be safe, owing to the lack of severe adverse reactions in the participants. Some mild adverse reactions were reported at the higher doses, including gastrointestinal symptoms such as abdominal pain, diarrhea, flatulence, and nausea. Although measurements of plasma concentrations of resveratrol and its 3 major metabolites revealed a rapid metabolism and low bioavailability, circulating levels of IGF-1 and IGFBP-3 were significantly reduced.14 These results suggest that IGF proteins may be relevant biomarkers of biological activity of resveratrol in humans, potentially constituting an anticarcinogenic mechanism. 
Resveratrol was shown to suppress colon cancer by a p53-dependent mechanism in an experiment that compared human colorectal cells with the p53 gene vs p53 knockout cells.32 The p53 group treated with resveratrol showed increased apoptosis, poly–adenosine diphosphate–ribose polymerase cleavage, and evidence of DNA damage compared with the knockout group treated with resveratrol. In a subsequent experiment, resveratrol-treated cells had depleted soluble topoisomerase II, which is highly expressed in malignant cells and correlates with higher rates of double-stranded breaks in DNA. The researchers demonstrated a sparing effect on topoisomerase I and the absence of DNA intercalation, suggesting that nonmalignant cells were relatively spared.32 These findings further strengthen resveratrol's therapeutic potential as a chemotherapeutic agent in the management of various cancers. 
Several studies have explored the possibility of resveratrol acting through synergistic mechanisms with current cancer treatment modalities. One study34 investigated the chemical efficacy of 5-fluorouracil in concert with resveratrol in colorectal cancer cells. 5-fluorouracil is used frequently in cancer treatment but is also notorious for its correlation with increased metastasis in many subgroups of patients.34 When treated with resveratrol and 5-fluorouracil together, the tumor cells showed decreased proliferation and viability and more apoptosis in vitro. A molecular analysis of the cells showed increased cadherin and claudin levels in the experimental resveratrol and 5-fluorouracil group compared with the controls. The mechanism for this finding was established: resveratrol inhibited the NF-kB signaling pathway, which is known to promote epithelial-mesenchymal transition and metastasis.34 Thus, by facilitating improved cell-to-cell adhesion, resveratrol shows the potential to counter a toxic adverse effect of 5-fluorouracil while allowing it to exercise its chemotherapeutic potential on malignant cells. 
Another investigation looked at resveratrol's potential in the management of non–small cell lung cancer with gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor that recipients can rapidly develop resistance against.33 Cells that showed resistance to gefitinib accumulation were able to accumulate it when treated with resveratrol. Compared with cells treated with gefitinib alone, the cells treated with both resveratrol and gefitinib showed decreased levels of enzymes that metabolize gefitinib, increased epidermal growth factor receptor phosphorylation inhibition, increased apoptosis and autophagic cell death, and a higher proportion of cells in G2/M phase cell cycle arrest.33 These results imply that gefitinib was able to act more efficiently in the presence of resveratrol. 
To investigate ways to increase the sensitivity of radiation-resistant glioma cells to treatment, SU-2 stem cells were treated with resveratrol and radiation and compared with controls.35 Fewer cells survived, and a significantly larger fraction showed the presence of autophagosomes and abnormal nuclei associated with apoptosis. These cells also showed reduced ability to repair themselves. Resveratrol and radiation were thus shown to be effective together in vitro. To further investigate the combined efficacy in an in vivo model, mice with xenograft tumors were treated with resveratrol and radiation.35 They displayed increased levels of apoptosis markers and reduced levels of antiapoptotic markers associated with cancer. 
Resveratrol's potential has also been evaluated with cisplatin, an alkylating antineoplastic agent in the context of epithelial ovarian carcinoma in mice.36 The cells were treated with vehicle control alone, cisplatin, or resveratrol. The resveratrol and cisplatin groups both showed similar smaller tumor sizes compared with controls, suggesting that on its own, resveratrol might exert cancer inhibitory mechanisms as powerful as cisplatin, though far less toxic. The resveratrol-treated mice also displayed decreased glucose uptake on positron emission tomography in the tumor region. In a subsequent experiment, another group of mice was treated with cisplatin followed by maintenance doses of resveratrol. Compared with the group that was treated with cisplatin alone, the cisplatin-resveratrol group had less tumor growth. An analysis of the harvested tumors showed a large number of autophagosomes and fewer signs of actively proliferating cells. In a related experiment carried out on ovarian carcinoma cells, samples treated with resveratrol had less oxygen consumption to extracellular acidification rate ratio and less glycolysis when oxidative phosphorylation was completely blocked. The authors proposed that resveratrol might exercise a caloric restrictive mechanism and suggested that it might have therapeutic potential in certain types of ovarian cancers.36 
Conclusion
Numerous preclinical experiments and clinical trials in humans have shown resveratrol to have the potential for therapeutic use in disease states such as cardiovascular disease, obesity, diabetes, AD, and cancer. Resveratrol has been found to be safe and reasonably well tolerated in humans, with only mild to moderate gastrointestinal adverse effects being reported, even at relatively high doses.14,30 Resveratrol is easily obtained through dietary substances such as supplements (see the Table for recommended doses), but its systemic (plasma) bioavailability in vivo following metabolism has been reported as notably low when compared with concentrations that typically produce statistically significant effects in vitro.14,38 Conceivably, as observed in vivo in the liver and kidney,39 resveratrol may accumulate over time up to concentrations several times higher than seen in plasma in the various target tissues discussed in this review, ie, up to levels often observed in vitro. Further investigation is important to facilitate the translation of experimental findings in vitro into human benefits in vivo.37,41 
Table.
Suggested Adult Daily Doses of Resveratrol Supplement Based on Studies Demonstrating Beneficial Effects in Humans by Disease
Disease States Benefits Recommended Dose, mg
Cardiovascular disease8,17,18 Decreases systolic blood pressure ≥150
Obesity18 Decreases glucose and triglyceride levels 150
Diabetes17 Decreases HbA1c and cholesterol levels 250
Alzheimer disease30 Attenuates decline in ADCS-ADL scores 500-2000
Cancer14 Decreases IGF-1 and IGFBP-3 500-5000

Abbreviations: ADCS-ADL, Alzheimer's Disease Cooperative Study Activities of Daily Living; HbA1c, hemoglobin A1c; IGF-1, insulinlike growth factor 1; IGFBP-3, IGF-binding protein 3.

Table.
Suggested Adult Daily Doses of Resveratrol Supplement Based on Studies Demonstrating Beneficial Effects in Humans by Disease
Disease States Benefits Recommended Dose, mg
Cardiovascular disease8,17,18 Decreases systolic blood pressure ≥150
Obesity18 Decreases glucose and triglyceride levels 150
Diabetes17 Decreases HbA1c and cholesterol levels 250
Alzheimer disease30 Attenuates decline in ADCS-ADL scores 500-2000
Cancer14 Decreases IGF-1 and IGFBP-3 500-5000

Abbreviations: ADCS-ADL, Alzheimer's Disease Cooperative Study Activities of Daily Living; HbA1c, hemoglobin A1c; IGF-1, insulinlike growth factor 1; IGFBP-3, IGF-binding protein 3.

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Table.
Suggested Adult Daily Doses of Resveratrol Supplement Based on Studies Demonstrating Beneficial Effects in Humans by Disease
Disease States Benefits Recommended Dose, mg
Cardiovascular disease8,17,18 Decreases systolic blood pressure ≥150
Obesity18 Decreases glucose and triglyceride levels 150
Diabetes17 Decreases HbA1c and cholesterol levels 250
Alzheimer disease30 Attenuates decline in ADCS-ADL scores 500-2000
Cancer14 Decreases IGF-1 and IGFBP-3 500-5000

Abbreviations: ADCS-ADL, Alzheimer's Disease Cooperative Study Activities of Daily Living; HbA1c, hemoglobin A1c; IGF-1, insulinlike growth factor 1; IGFBP-3, IGF-binding protein 3.

Table.
Suggested Adult Daily Doses of Resveratrol Supplement Based on Studies Demonstrating Beneficial Effects in Humans by Disease
Disease States Benefits Recommended Dose, mg
Cardiovascular disease8,17,18 Decreases systolic blood pressure ≥150
Obesity18 Decreases glucose and triglyceride levels 150
Diabetes17 Decreases HbA1c and cholesterol levels 250
Alzheimer disease30 Attenuates decline in ADCS-ADL scores 500-2000
Cancer14 Decreases IGF-1 and IGFBP-3 500-5000

Abbreviations: ADCS-ADL, Alzheimer's Disease Cooperative Study Activities of Daily Living; HbA1c, hemoglobin A1c; IGF-1, insulinlike growth factor 1; IGFBP-3, IGF-binding protein 3.

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