Resveratrol Abstracts 4

© 2012

Neuroprotective properties of resveratrol in different neurodegenerative disorders

         (Albani, Polito et al. 2010) Download

The natural phytocompound resveratrol has been considered for many years a potential anticancer drug, but recently it has come to the attention of neuroscientist too, as it displays neuroprotective actions and activates the sirtuins' family member SIRT. Sirtuins are enzymes with preferential deacetylase activity. Human sirtuins are coded by seven genes (SIRT). The most investigated sirtuin is SIRT, which is involved in several physiologic and pathologic processes including apoptosis, autophagy, diabetes, cancer, cardiovascular disorders, and neurodegeneration. Resveratrol has neuroprotective features both in vitro and in vivo in models of Alzheimer's disease (AD), but it has proved to be beneficial also in ischemic stroke, Parkinson's disease, Huntington's disease, and epilepsy. Here, we summarize the in vitro and in vivo experimental results highlighting the possible role of resveratrol as neuroprotective biofactor with a particular focus on AD.

Unbalanced metabolism of endogenous estrogens in the etiology and prevention of human cancer

         (Cavalieri and Rogan 2011) Download

Among the numerous small molecules in the body, the very few aromatic ones include the estrogens and dopamine. In relation to cancer initiation, the estrogens should be considered as chemicals, not as hormones. Metabolism of estrogens is characterized by two major pathways. One is hydroxylation to form the 2- and 4-catechol estrogens, and the second is hydroxylation at the 16alpha position. In the catechol pathway, the metabolism involves further oxidation to semiquinones and quinones, including formation of the catechol estrogen-3,4-quinones, the major carcinogenic metabolites of estrogens. These electrophilic compounds react with DNA to form the depurinating adducts 4-OHE(1)(E(2))-1-N3Ade and 4-OHE(1)(E(2))-1-N7Gua. The apurinic sites obtained by this reaction generate the mutations that may lead to the initiation of cancer. Oxidation of catechol estrogens to their quinones is normally in homeostasis, which minimizes formation of the quinones and their reaction with DNA. When the homeostasis is disrupted, excessive amounts of catechol estrogen quinones are formed and the resulting increase in depurinating DNA adducts can lead to initiation of cancer. Substantial evidence demonstrates the mutagenicity of the estrogen metabolites and their ability to induce transformation of mouse and human breast epithelial cells, and tumors in laboratory animals. Furthermore, women at high risk for breast cancer or diagnosed with the disease, men with prostate cancer, and men with non-Hodgkin lymphoma all have relatively high levels of estrogen-DNA adducts, compared to matched control subjects. Specific antioxidants, such as N-acetylcysteine and resveratrol, can block the oxidation of catechol estrogens to their quinones and their reaction with DNA. As a result, the initiation of cancer can be prevented.

Reversing atherosclerosis?

            (Curtiss 2009) Download

Beneficial effects of resveratrol on atherosclerosis

         (Fan, Zhang et al. 2008) Download

Atherosclerosis, a progressive disease characterized by the accumulation of lipids and fibrous elements in the arteries, is a most important contributor to cardiovascular diseases. Resveratrol is a naturally occurring phytopolyphenol compound and shows the ability to reduce the risk of cardiovascular diseases. In this review, beneficial effects of resveratrol on the initiation and progression of atherosclerosis, including regulation of vasodilator and vasoconstrictor production, inhibition of oxidative stress/reactive oxygen species generation, anti-inflammation, inhibition of modification of low-density lipoproteins, anti-platelet aggregation, and its abilities to impede progression and modulate complications of atherosclerosis, are discussed.

CD36 modulates migration of mouse and human macrophages in response to oxidized LDL and may contribute to macrophage trapping in the arterial intima

            (Park, Febbraio et al. 2009) Download

The trapping of lipid-laden macrophages in the arterial intima is a critical but reversible step in atherogenesis. However, the mechanism by which this occurs is not clearly defined. Here, we tested in mice the hypothesis that CD36, a class B scavenger receptor expressed on macrophages, has a role in this process. Using both in vivo and in vitro migration assays, we found that oxidized LDL (oxLDL), but not native LDL, inhibited migration of WT mouse macrophages but not CD36-deficient cells. We further observed a crucial role for CD36 in modulating the in vitro migratory response of human peripheral blood monocyte-derived macrophages to oxLDL. oxLDL also induced rapid spreading and actin polymerization in CD36-sufficient but not CD36-deficient mouse macrophages in vitro. The underlying mechanism was dependent on oxLDL-mediated CD36 signaling, which resulted in sustained activation of focal adhesion kinase (FAK) and inactivation of Src homology 2-containing phosphotyrosine phosphatase (SHP-2). The latter was due to NADPH oxidase-mediated ROS generation, resulting in oxidative inactivation of critical cysteine residues in the SHP-2-active site. Macrophage migration in the presence of oxLDL was restored by both antioxidants and NADPH oxidase inhibitors, which restored the dynamic activation of FAK. We conclude therefore that CD36 signaling in response to oxLDL alters cytoskeletal dynamics to enhance macrophage spreading, inhibiting migration. This may induce trapping of macrophages in the arterial intima and promote atherosclerosis.

Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases

            (Park, Ahmad et al. 2012) Download

Resveratrol, a polyphenol in red wine, has been reported as a calorie restriction mimetic with potential antiaging and antidiabetogenic properties. It is widely consumed as a nutritional supplement, but its mechanism of action remains a mystery. Here, we report that the metabolic effects of resveratrol result from competitive inhibition of cAMP-degrading phosphodiesterases, leading to elevated cAMP levels. The resulting activation of Epac1, a cAMP effector protein, increases intracellular Ca(2+) levels and activates the CamKKbeta-AMPK pathway via phospholipase C and the ryanodine receptor Ca(2+)-release channel. As a consequence, resveratrol increases NAD(+) and the activity of Sirt1. Inhibiting PDE4 with rolipram reproduces all of the metabolic benefits of resveratrol, including prevention of diet-induced obesity and an increase in mitochondrial function, physical stamina, and glucose tolerance in mice. Therefore, administration of PDE4 inhibitors may also protect against and ameliorate the symptoms of metabolic diseases associated with aging.

Resveratrol toxicity: effects on risk factors for atherosclerosis and hepatic oxidative stress in standard and high-fat diets

            (Rocha, Souza et al. 2009) Download

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.

What is new for an old molecule? Systematic review and recommendations on the use of resveratrol

            (Vang, Ahmad et al. 2011) Download

BACKGROUND: Resveratrol is a natural compound suggested to have beneficial health effects. However, people are consuming resveratrol for this reason without having the adequate scientific evidence for its effects in humans. Therefore, scientific valid recommendations concerning the human intake of resveratrol based on available published scientific data are necessary. Such recommendations were formulated after the Resveratrol 2010 conference, held in September 2010 in Helsingor, Denmark. METHODOLOGY: Literature search in databases as PUBMED and ISI Web of Science in combination with manual search was used to answer the following five questions: (1)Can resveratrol be recommended in the prevention or treatment of human diseases?; (2)Are there observed "side effects" caused by the intake of resveratrol in humans?; (3)What is the relevant dose of resveratrol?; (4)What valid data are available regarding an effect in various species of experimental animals?; (5)Which relevant (overall) mechanisms of action of resveratrol have been documented? CONCLUSIONS/SIGNIFICANCE: The overall conclusion is that the published evidence is not sufficiently strong to justify a recommendation for the administration of resveratrol to humans, beyond the dose which can be obtained from dietary sources. On the other hand, animal data are promising in prevention of various cancer types, coronary heart diseases and diabetes which strongly indicate the need for human clinical trials. Finally, we suggest directions for future research in resveratrol regarding its mechanism of action and its safety and toxicology in human subjects.


References

Albani, D., L. Polito, et al. (2010). "Neuroprotective properties of resveratrol in different neurodegenerative disorders." Biofactors 36(5): 370-6.

Cavalieri, E. L. and E. G. Rogan (2011). "Unbalanced metabolism of endogenous estrogens in the etiology and prevention of human cancer." J Steroid Biochem Mol Biol 125(3-5): 169-80.

Curtiss, L. K. (2009). "Reversing atherosclerosis?" N Engl J Med 360(11): 1144-6.

Fan, E., L. Zhang, et al. (2008). "Beneficial effects of resveratrol on atherosclerosis." J Med Food 11(4): 610-4.

Park, S. J., F. Ahmad, et al. (2012). "Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases." Cell 148(3): 421-33.

Park, Y. M., M. Febbraio, et al. (2009). "CD36 modulates migration of mouse and human macrophages in response to oxidized LDL and may contribute to macrophage trapping in the arterial intima." J Clin Invest 119(1): 136-45.

Rocha, K. K., G. A. Souza, et al. (2009). "Resveratrol toxicity: effects on risk factors for atherosclerosis and hepatic oxidative stress in standard and high-fat diets." Food Chem Toxicol 47(6): 1362-7.

Vang, O., N. Ahmad, et al. (2011). "What is new for an old molecule? Systematic review and recommendations on the use of resveratrol." PLoS One 6(6): e19881.