Resveratrol

Introduction:

Resveratrol is a beneficial nutrient found in the skin of red grapes, red wine, berries, peanuts, and other food products. It is a naturally occurring, powerful polyphenol (plant-derived) compound that has antioxidant properties, which fights against free radical damage. A number of laboratory human and animal-based studies suggest that resveratrol may provide health benefits against cancer, heart disease, and nervous system deterioration.

 

Mechanisms of resveratrol:

Rieko N. et al, expressed that the effects of resveratrol against cancer cells is attributed to the inhibition of prostaglandin (PG) synthesis by reducing both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) which may be involved in  formation of tumors. The author also stated that Resveratrol increases vascular nitric oxide (NO) levels which may have similar cardiovascular benefits associated with red wine consumption by relaxing vascular smooth muscle cells, increasing blood flow, and preventing thrombosis by decreasing platelet aggregation. The literature on resveratrol is contradictory and the wide range of concentrations and doses used both in vitro cell culture (artificial environment) and animal studies raises many questions about the concentrations achievable in vivo (within the study subject). Furthermore, resveratrol has a short initial half-life and is metabolized extensively in the body. (1)

Resveratrol and cancer:

Resveratrol and animal models of colon carcinogenesis: The relationship between resveratrol, a chemo-preventive compound and colon cancer was analyzed. Studies conducted in vitro (in an artificial environment outside the living organism) show that protective activity takes place by prevention of proliferation and the initiation of cell death (apoptosis). In animal models of colon carcinogenesis, the process by which normal cells are transformed into cancer cells, resveratrol not only reduces the number of lesions before the formation of a tumor but the risk of developing new tumors and the multiplicity of tumors. Current findings suggest that oral administration of resveratrol may contribute to the prevention of colon cancer. (2)

 

Resveratrol and multiple myeloma:

Bhardwaj, A et al looked to determine whether resveratrol can suppress cell growth in-vitro of multiple myeloma (cancer that starts in the plasma cells in bone marrow). Resveratrol inhibited the growth of multiple myeloma cells regardless of sensitivity or resistance to conventional chemotherapy agents. It also increased the apoptotic (cell death) effects of the targeted cancer drugs, bortezomib and thalidomide. Resveratrol decreased growth of cancer cells and genes that inhibit apoptosis (such as cyclin D1, cIAP-2, XIAP, survivin, Bcl-2, Bcl-xL, Bfl-1/A1, and TRAF2). These effects are able to occur through interruption of active NF-κB (plays pivotal roles in inflammatory responses and immunological reactions). Resveratrol also inhibited activation of STAT3 (plays a key role in many cellular processes such as cell growth and apoptosis pathways). The authors conclude that resveratrol may have a potential role in the treatment of multiple myeloma. (3)

 

Resveratrol and acute lymphoblastic leukemia cells:

Resveratrol was found by Cecchinato, V. et al to encourage apoptosis (cell death) in acute lymphoblastic leukemia cells by inhibiting the survival signaling pathways. Additionally, resveratrol increased production of pro-apoptotic proteins. As an anticancer agent, resveratrol alters many different signaling pathways, and may lead to suppression of tumor cell growth, reduced inflammation, and induce cancer cell death. Authors report that this data supports findings from other studies that suggest the use of resveratrol as a chemo-preventive agent. (4)

 

Resveratrol and breast cancer:

Lu R et al found that resveratrol was shown to inhibit growth of estrogen receptor-positive breast cancer cells in vitro. In the presence of estrogen, reveratrol was found in the study to acts as an ER resulting in the inhibition of human breast cancer cell growth. (5)

 

Resveratrol and esophageal cancer:

Resveratrol was found to suppress the growth of esophageal cancer cells by inducing apoptosis (cell death) in a dose and time dependent way (6).

 

Resveratrol and heart health:

Resveratrol and myocardial infarction:

Fukuda, S et al found evidence that resveratrol promotes angiogenesis (growth of new blood vessels) from pre-existing vessels in the ischemic heart (restriction in blood supply to tissues). Authors used a rat myocardial infarction (MI) or heart attack model and pretreated it with resveratrol. Following 3 weeks after MI occurred, a significant increase in angiogenesis mechanisms was observed. (7)

The effects of high dose resveratrol was tested on rats. A group of rats were given resveratrol at a dosage of 2.5 mg/kg, 5 mg/kg, 25 mg/kg or 50 mg/kg for 14 days. The results indicate that resveratrol administered at 2.5 or 5 mg/kg provided cardio-protection with the following positive results. Post-ischemic ventricular recovery improved, myocardial infarct size was reduced, and cardiomyocyte cell death was lower compared to the control group. On the other hand, resveratrol administration at 25 or 50 mg/kg reduced cardiac function and increased myocardial infarct size and increased cell death. (8)

Sato et al. demonstrated that an ethanol-free red wine extract as well as trans-resveratrol, one of the major antioxidants found in red wines, protected the hearts from the negative effects of ischemia (a restriction in blood supply to tissues). This was seen after an improvement in post-ischemic ventricular function and reduction of myocardial infarction occurred. Rats were treated with 10 μM trans-resveratrol (RVT), with 0.07% ethanol, or with 0.07% ethanol plus 10 mμM RVT. An hour after reperfusion or blood restoration, the findings suggested that the cardio-protective effects of the red wine were comparable to those provided by trans-resveratrol. (9)

 

Resveratrol and platelet aggregation:

Resveratrol has been found to exert a number of potentially beneficial cardioprotective effects, including inhibition of platelet aggregation in both men with normal blood pressure and in rabbits with high cholesterol. Platelets are the smallest blood cell produced in the bone marrow that react to injury and prevent bleeding by clot formation. Compared to normal animals, platelet aggregation increased by about 21.5% in the high-cholesterol fed group. Platelet aggregation in hypercholesterolemic rabbits was inhibited both by resveratrol at a dose of 4 mg per kilogram, and when Chinese red wine was given with or without alcohol at 4 ml/kg/day. (10)

 

Resveratrol and nerve protection:

A study focused on evaluating the protection of cells of the nervous system in mice. Resveratrol may help prevent neuronal loss in patients multiple sclerosis (MS) but more research is needed. Researches administered resveratrol or placebo once daily at a dose 500 mg/kg or 1000 mg/kg of resveratrol for 14 days to six week old female mice. Researchers found that extremely high dose resveratrol reduced damage to axons, the long slender part of a nerve cell in mice. The doses used in this study are unsafe but a lower dose may be a potential therapy for MS in the future and needs more investigation for efficacy and safety in humans. (11)

 

Resveratrol and lifespan:

A study conducted on middle-aged mice on high-calorie diets found that resveratrol produced changes associated with longer lifespan, including improved insulin function, increased mitochondrial number, and improved motor function. Resveratrol canceled out the ill effects of a high-calorie diet in 144 of 153 activated genes. The data implies that resveratrol may mimic in mice some of the effects of dietary or calorie restriction, offset the damaging effects of a high-fat diet, and extended lifespan. (12)

 

Resveratrol and COPD:

An ingredient found in red wine, resveratrol, may slow down the inflammatory process related to chronic obstructive pulmonary disease (COPD). In this study, researchers tested the effects of resveratrol on lung fluid samples taken from 15 cigarette smoking control subjects and 15 people with COPD. First, macrophages (cells involved in the inflammatory process) were artificially spurred into action by an interleukin ([IL]-1β) (a chemical released by the lung, which stimulates the growth and activity of cells that contribute to lung damage) or cigarette smoke to stimulate the release of interleukin IL-8 and granulocyte macrophage-colony stimulating factor (GM-CSF) before resveratrol was added by researchers. Resveratrol was added at a concentration of 100 micromoles per liter. The effect of resveratrol was examined on both basal and stimulated cytokine release. The introduction of resveratrol reduced basal release of interleukin in stimulated samples for both smokers and people with COPD by 94% and 88% respectively, and inhibited GM-CSF release by 79% and 76% respectively. It also nearly eliminated interleukin production all together in the non-stimulated samples, in essence reducing the number of cells that contribute to lung damage. Researchers believe that resveratrol may be an effective treatment option for COPD. (16)

 

Resveratrol adverse reactions and interactions:

Resveratrol may worsen atherosclerosis. Atherosclerosis results in arterial wall thickening as a result of the accumulation of fatty materials such as cholesterol. Resveratrol inhibits platelet activation and has anti-inflammatory properties, but paradoxically, it promotes atherosclerosis in rabbits with hypercholesterolemia. The effects of resveratrol were examined on the development of atherosclerotic in rabbits fed 0.5% cholesterol. At the end of the 60-day study period, all rabbits (fed or not fed cholesterol) had similar liver function and had hypercholesterolemia or high levels of cholesterol in the blood. However, compared to the control group, resveratrol-treated rabbits had an increase in atherosclerotic lesions (p<0.002). This suggests that resveratrol results in atherosclerotic development, rather than protecting against it. (13)

Resveratrol has multiple toxicities at high doses. Researchers administered rats dosage of 0, 300, 1000, and 3000 mg/kg of body weight per day of trans-resveratrol for 4 weeks. Administration of 3000 mg/kg/daily resulted in the most reported adverse events: 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. Renal (kidney) lesions were also observed as well as increased liver weights among females. Administration of 1000 mg/kg/daily resulted in reduced body weight gain (females only) and elevated white blood cell count (males only). No adverse or side effects were observed at 300 mg resveratrol per kilogram body weight per day in rats. (14)

Trans-resveratrol dose limits were evaluated in an animal study. Juan, et al evaluated the toxicity of high doses of trans-resveratrol on Sprague-Dawley male rats. Trans-resveratrol was administered at 20 mg orally per kilogram body weight to rats daily for 28 days, and no treatment-related adverse effects were reported. This dose would be equivalent to a 70-kg person taking 1.4 g of trans-resveratrol per day. Bodyweight, food intake, water intake, blood chemistry and hematology lab work was not affected which suggests that a dose of 20 mg per kilogram per day does not result in toxic adverse events in rats. (15)

Inhibition of platelet aggregation occurred in rabbits treated with resveratrol. Platelet aggregation in hypercholesterolemic rabbits was inhibited both by resveratrol at a dose of 4 mg per kilogram, and when Chinese red wine was given with or without alcohol at 4 ml/kg/day (9). Therefore resveratrol may result in an increased risk of bleeding in patients taking warfarin, Coumadin, heparin, aspirin, and non-steroidal anti-inflammatory drugs.

 

Assessment and Plan: Resveratrol

• Resveratrol has promising potential health benefits against cancer, heart disease, and nervous system deterioration but there is not enough research-based evidence to ensure either the benefits or safety in humans. Resveratrol supplements may be a dangerous due to the lack of regulation, unknown effective dose, and lack of standardization.

 

• There have been several promising potential benefits of resveratrol on various cancers in in-vitro and in animal studies requiring research for confirmation in humans.

 

• Oral administration of resveratrol to animals was found to reduce tumor formation in animal models of colon cancer (2).

 

• An in-vitro study showed that resveratrol inhibited the growth of multiple myeloma cells regardless of sensitivity or resistance to conventional chemotherapy agents (3).

 

• Cecchinato, V. et al found that resveratrol encouraged apoptosis (cell death) in acute lymphoblastic leukemia cells by inhibiting the survival signaling pathways, and increased production of pro-apoptotic proteins (4).

 

• Lu R et al found that resveratrol inhibited growth of estrogen receptor-positive breast cancer cells in vitro resulting in the inhibition of human breast cancer cell growth (5).

 

• Zhou HB, et al found that resveratrol suppressed the growth of esophageal cancer cells by inducing apoptosis (cell death) in a dose and time dependent way (6).

 

• Resveratrol was found to possess several potential benefits for heart health in in-vitro and in animal studies requiring more research for confirmation in humans.

 

• Fukuda, S et al found that resveratrol promoted angiogenesis (growth of new blood vessels) from pre-existing vessels of an ischemic heart (restriction in blood supply to tissues) in a rat model of myocardial infarction (MI) (7).

 

• Resveratrol at a dose of 2.5 or 5 mg/kg improved post-ischemic ventricular recovery, reduced myocardial infarct size, and reduced cardiomyocyte cell compared to the control group, but doses at 25 or 50 mg/kg had multiple harmful heart effects (8).

 

• Sato et al. demonstrated that an ethanol-free red wine extract and trans-resveratrol are cardio-protective against ischemia (restriction in blood supply to tissues) by functioning as a strong antioxidant (9). These findings support the benefits of red wine on heart health which may be a much safer way of obtaining the benefit of resveratrol rather than resveratrol supplements due to safety concerns of lack of regulation, unknown effective dose, and lack of standardization.

 

• Resveratrol (and red wine) also provides cardio-protection by mechanism of the inhibition of platelet aggregation (10). This may result in lower risk of thrombosis in atherosclerotic coronary arteries.

 

• Resveratrol enhanced longevity in mice but there is no reliable research yet available on lifespan enhancement by resveratrol in humans. A study conducted on middle-aged mice on high-calorie diets found that resveratrol improved insulin function, increased mitochondria, improved motor function, minimized ill effects of a high-calorie diet, produced the effects of calorie restriction, and extended the lifespan of middle-aged mice (12).

 

• Resveratrol may help prevent neuronal loss in patients multiple sclerosis (MS), but more research is needed. Researchers used extremely high doses of resveratrol in mice which reduced damage to axons of nerve cells (11). The doses used in the study are extremely unsafe in humans but a lower dose may be a potential therapy for MS in the future. As noted above, high doses were associated with detrimental cardiac effects (8).

 

• Resveratrol and COPD: Researchers believe that resveratrol may be an effective future treatment option for COPD by reducing the release of interleukins significantly (16), but more research is needed.

 

• Resveratrol adverse reactions, interactions:

 

• Resveratrol-treated rabbits had an increase in atherosclerotic lesions compared to a control group (13). This suggests that resveratrol results in atherosclerotic development, rather than protecting against it.

 

• Resveratrol had no adverse effects at a dose of 300 mg per kilogram but had multiple toxicities at doses of 3000 mg per kilogram including elevated BUN, creatinine, alkaline phosphatase, alanine aminotransferase, total bilirubin, and albumin; reduced hemoglobin, hematocrit, and red cell counts; and increased white cell counts, renal (kidney) lesions, increased liver weights among females, reduced body weight gain with 1000 mg per kilogram (females only), and elevated white blood cell count with 1000 mg per kilogram (males only) (14).

 

• Juan, et al found that trans-resveratrol given to rats at a dose of 20 mg orally per kilogram did not result in toxic adverse events (15).

 

• Platelet aggregation in hypercholesterolemic rabbits was inhibited both by resveratrol at a dose of 4 mg per kilogram, and with Chinese red wine was given with or without alcohol at 4 ml/kg/day (9). Therefore resveratrol may result in an increased risk of bleeding in patients with bleeding disorders or in patients taking warfarin, Coumadin, heparin, aspirin, and non-steroidal anti-inflammatory medications.

 

 

References:

1.Rieko Nakata, Satoru Takahashi, and Hiroyasu Inoue. Recent Advances in the Study on Resveratrol. Biol. Pharm. Bull. 2012 March; 35(3): 273—279. https://www.jstage.jst.go.jp/article/bpb/35/3/35_3_273/_pdf

 

2.Juan ME, Alfaras I, Planas JM. Colorectal cancer chemoprevention by trans-resveratrol. Pharmacol Res. 2012 Jun; 65(6):584-91. http://www.ncbi.nlm.nih.gov/pubmed/22465196

 

3.Bhardwaj A, Sethi G, Vadhan-Raj S, Bueso-Ramos C, Takada Y, Gaur U, Nair AS, Shishodia S, Aggarwal BB. Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-kappaB-regulated antiapoptotic and cell survival gene products in human multiple myeloma cells. Blood. 2007 Mar 15;109(6):2293-302. http://www.ncbi.nlm.nih.gov/pubmed/17164350

 

4.Cecchinato V, Chiaramonte R, Nizzardo M, Cristofaro B, Basile A, Sherbet GV, Comi P. Resveratrol-induced apoptosis in human T-cell acute lymphoblastic leukaemia MOLT-4 cells. Biochem Pharmacol. 2007 Dec 3;74(11):1568-74. http://www.ncbi.nlm.nih.gov/pubmed/17868649

 

5.Lu R., Serrero G. Resveratrol, a natural product derived from grape, exhibits antiestrogenic activity and inhibits the growth of human breast cancer cells. J. Cell. Physiol., 1999; 179: 297-304. http://www.ncbi.nlm.nih.gov/pubmed/10228948

 

6.Zhou HB, Yan Y, Sun YN, Zhu JR. Resveratrol induces apoptosis in human esophageal carcinoma cells. World J Gastroenterol 2003;9:408–411. http://www.ncbi.nlm.nih.gov/pubmed/12632486

 

7.Fukuda S, Kaga S, Zhan L, Bagchi D, Das DK, Bertelli A and Maulik N. Resveratrol ameliorates myocardial damage by inducing vascular endothelial growth factor-angiogenesis and tyrosine kinase receptor Flk-1. Cell Biochem Biophys 2006; 44(1):43-9. http://www.ncbi.nlm.nih.gov/pubmed?term=Resveratrol%20Ameliorates%20myocardial%20damage%20by%20inducing%20vascular

 

8.Dudley J, Das S, Mukherjee S, Das DK. Resveratrol, a unique phytoalexin present in red wine, delivers either survival signal or death signal to the ischemic myocardium depending on dose. J Nutr Biochem. 2009 Jun;20(6):443-52. http://www.ncbi.nlm.nih.gov/pubmed/18789672

 

9.Sato M, Ray PS, Maulik G, Maulik N, Engelman RM, Bertelli AA, Bertelli A, Das DK. Myocardial protection with red wine extract. J Cardiovasc Pharmacol. 2000 Feb; 35(2): 263–268. http://www.ncbi.nlm.nih.gov/pubmed/10672859

 

10.Wang Z, Huang Y, Zou J, Cao K, Xu Y, Wu JM. Effects of red wine and wine polyphenol resveratrol on platelet aggregation in vivo and in vitro. Int J Mol Med. 2002;9(1):77-79. http://www.ncbi.nlm.nih.gov/pubmed/11745001

 

11.Shindler KS, Ventura E, Dutt M, Elliott P, Fitzgerald DC, Rostami A. Oral resveratrol reduces neuronal damage in a model of multiple sclerosis. J Neuroopththalmol. 2010 Dec;30(4):328-39. http://www.ncbi.nlm.nih.gov/pubmed/21107122?dopt=Abstract&holding=npg

 

12.Baur JA, Pearson KJ, Price NL, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006;444:337-342. http://www.ncbi.nlm.nih.gov/pubmed/17086191?dopt=Abstract

 

13.Wilson T, Knight TJ, Beitz DC, Lewis DS, Engen RL. Resveratrol promotes atherosclerosis in hypercholesterolemic rabbits. Life Sci. 1996;59(1):PL15–21. http://www.ncbi.nlm.nih.gov/pubmed/8684261

 

14.Crowell JA, Korytko PJ, Morrissey RL, Booth TD, Levine BS. Resveratrol-associated renal toxicity. Toxicol Sci 2004; 82: 614-619. http://www.ncbi.nlm.nih.gov/pubmed/15329443

 

15.Juan, M. E., Vinardell, M. P., and Planas, J. M. The daily oral administration of high doses of trans-resveratrol to rats for 28 days is not harmful. J. Nutr. 2002 Feb; 132(2): 257–260. http://www.ncbi.nlm.nih.gov/pubmed/11823587

 

16.Culpitt SV, Rogers DF, Fenwick PS, Shah P, De Matos C, Russell RE, Barnes PJ, Donnelly LE. Inhibition by red wine extract, resveratrol, of cytokine release by alveolar macrophages in COPD. Thorax 2003. 58:942–946. http://www.ncbi.nlm.nih.gov/pubmed/14586044