The physiological effects of resveratrol and its potential application in high altitude medicine

Hui-li ZHU, Hong-jing NIE, Pei-bing LI, Bing-nan DENG, Rui-feng DUAN, Hong JIN, Zhao-li CHEN

Key Laboratory of Environmental Medicine, Environmental Medicine Research Center, Tianjin Institute of Health and Environmental Medicine, Tianjin 30050, China

The physiological effects of resveratrol and its potential application in high altitude medicine

Hui-li ZHU+, Hong-jing NIE+, Pei-bing LI, Bing-nan DENG, Rui-feng DUAN, Hong JIN, Zhao-li CHEN

Key Laboratory of Environmental Medicine, Environmental Medicine Research Center, Tianjin Institute of Health and Environmental Medicine, Tianjin 30050, China

doi 10.13459/j.cnki.cjap.2015.06.003

Resveratrol, as a natural polyphenolic compound, has a wide range of benef i cial ef f ects, which includes an-tumor, cardiovascular protecon, an-oxidant and estrogen-like ef f ects, and so on. Its various physiological properes are closely related to the therapeuc principle for prevenon and treatment of high altude hypoxia injury. Resveratrol may play an important role in relieving or curing high altude diseases, especially high altude polycythemia(HAPC). However, the literature about study and applicaon of resveratrol in plateau medicine fi eld is rarely reported up to now. In this review, we summarized the physiological ef f ects of resveratrol, discussed the possible main principle of resveratrol for HAPC therapy, and looked forward to resveratrol’s perspecve or potenal applicaon in high altude medicine.

resveratrol; an-oxidant; phytoestrogen; high altude medicine; high altude polycythemia

Introduction

Resveratrol (3,4’,5-trihydroxy-trans-stilbene), a natural non-flavonoid polyphenol compound, is present in a variety of plant species, including polygonum cuspidatum, grapes, peanuts and mulberries[1]. Resveratrol has attracted considerable attention because of its multiple pharmacological actions ranging from antibacterial and antiinflammation effect[2] to anticancer effect[3], antioxidative effect[4], estrogen-like effect [5], neuroprotective, immunoregulation, and cardiovascular protective activities[6]. It has been widely used in medicine, health care products, food, cosmetics and other fields. But the study and application of resveratrol in plateau medicine field is rarely reported. Its various physiological properties suggest that resveratrol has a potential effect in prevention and treatment of high altitudediseases especially high altitude polycythemia (HAPC). Therefore, in this review we summarized the physiological functions of resveratrol, discusses the relation between the physiological effects of resveratrol and medication principles of therapeutic measure of HAPC, looks forward to the application prospect of resveratrol in HAPC therapy and other areas of high altitude medicine. This review might provide theoretical basis for the further experimental study on the application ef f ect of resveratrol in high altitude medicine.

Anti-cancer activity

Resveratrol is a natural antitumor drugs with less side effect. Resveratrol’s potential chemopreventive and chemotherapeutic activities have been demonstrated in all three stages of carcinogenesis (initiation, promotion, and progression), in various murine models of human cancers[7]. Resveratrol has been shown to inhibit proliferation of many human tumor cells in vitro, which have led to a lot of pre-clinical animal studies to evaluate the cancer chemopreventive and chemotherapeutic potential of resveratrol[8]. One clinical trial sponsored by the National Cancer Institute and the other several clinical trials, are underway to investigate the use ofboth resveratrol and resveratrol-rich products, for prevention and treatment of colon cancer [9]. As a potential anti-cancer agent, resveratrol has been shown to exert anticancer ef f ects in dif f erent systems as follows: prevent the occurrence of cancer, suppress the proliferation of the cancer cells, induce apoptosis of the tumor cells, inhibit invasion and subsequent metastasis of various cancer cells. Moreover, as a radiosensitizer for antitumor therapy, resveratrol enhances the effectiveness of XRT in tumor cells, thus the radiation sensitization of tumor cells may allow for reduction of effective radiation dosage and potential side effects of radiotherapy. When combination with other anti-tumor substances and act on tumor cells, resveratrol can reduce the drugs dosage, and exert a synergistic effect[10-12]. Resveratrol has been demonstrated to affect a multitude of signal transduction pathways associated with tumorigenesis[13]. Epidermal growth factor receptor (EGFR) interacting with Stat3 is considered to be an attractive therapeutic target. Cichocki et al. compared the ef f ect of resveratrol and its methylthioderivatives on the expression and activation of EGFR and Stat3 in EGFR-overexpressing A431 cells, and then they found that there was a signif i cant reduction of EGFR with both phosphorylated residues in cells as a result of resveratrol at higher dose treatment [14]. Resveratrol is known to induce apoptosis through the induction of p53 phosphorylation and also suppresses AP1 and cyclooxygenase 2 activities, leading to cancer cell death[15]. These varied activities suggest that foods containing resveratrol could be benef i cial in helping to prevent cancer.

Cardiovascular protective activity

Recent discoveries showed that resveratrol also contributes multi-dimensional benefits on the cardiovascular system. The “French paradox” is a phenomenon that associates a diet rich in saturated fatty acids and a moderate consumption of red wine to a low prevalence of cardiovascular diseases. Several studies have demonstrated that resveratrol is the major red wine polyphenol, and that it has been advanced as a reason for the relatively lower cardiovascular mortality and morbidity in French populations with considerable cardiovascular risk factors[16-17]. The resveratrol protection against cardiovascular illnesses has been associated to a number of effects, which include: (i) modulation of lipid and lipoprotein metabolism; (ii) prevention of platelet aggregation, induction of fibrinolysis, inhibition of thrombus formation; (iii) protection of endothelial cells against apoptosis and induction of neovascularisation of the infarcted myocardium; (iv) antioxidant, scavenging free-radical and inhibition of lipid peroxidation; (v) promotion of vasodilatation; (vi) inhibition of proinflammatory cytokines; (vii) reduction of ischemia/reperfusion injury[18-22]. Resveratrol can also increase pulse pressure, promote blood capillary open, improve microcirculation, enhance heart function, and ameliorate shock [23]. In addition, the cardiovascular pharmacological ef f ects of resveratrol is linked to the angiotensin converting enzyme inhibitor effect which resveratrol has[24]. Moreover, resveratrol can protect myocardiocytes from injury induced by long range hypothermic preservation.is protective ef f ect may be mediated by up-regulation of Sirt-1 expression[25].

Antioxidant activity

Oxidative stress constitutes a unifying mechanism of injury of many types of disease processes. Oxidative injury occurs when there is a serious imbalance between the generation of reactive oxygen species (ROS) and the antioxidant defense systems in the body so that the latter become overwhelmed[26]. Resveratrol, as a natural antioxidant, can protect the human body from free radicals and ROS ef f ects. Resveratrol exerts its antioxidant activity mainly including scavenging of free radicals, inhibition of lipid oxidation, modulation of antioxidant enzyme activities and so on[27]. Resveratrol has been emphasized as an effective scavenger of hydroxyl, superoxide, and metal-induced radicals as well as showing antioxidant abilities in cells producing ROS[28]. Resveratrol exerts a protective ef f ect against lipid peroxidation in the cell membranes and DNA damage caused by ROS[29]. Resveratrol scavenges ROS, improves oxidative stress, retards the progress of many chronic diseases as well as lipid peroxidation, perhaps through mechanism of increasing the activity of antioxidant enzymes that metabolize ROS, such as SOD, or decreasing the activity of enzymes that play a role in ROS production [6,30]. In addition, Studies have demonstrated that antioxidant potency of resveratrol is higher than that of the most commonly used antioxidant compounds such as butylated hydroxyanisole(BHA), butylated hydroxytoluene(BHT), vitamin C and E[30,31].

Estrogenic activity

The chemical structure of resveratrol is similar to that of the synthetic estrogen diethylstilbestrol. Resveratrol could bind to estrogen receptors (ERs), ac-tivate transcription of estrogen regulated genes and thus could be considered as phytoestrogen[32]. It has been shown that resveratrol binds ERs in the low micromolar range with comparable af finity albeit with lower affinity than estradiol with which resveratrol competes at the ERs [33]. Resveratrol may act as a superagonist in activating hormone receptor-mediated gene transcription in spite of the lower binding affinity [32,34]. Dissimilar from other estrogen analogs which have the affinity towards ER-β higher than that with ER-α, resveratrol has equal af fi nity for both ER-α and ER-β[35]. Although resveratrol binds to both ERα and ERβ with similar affinity, it seems to exert strong transcriptional ef f ects via ERβ[34]. In order to identify the role of ERs in the resveratrolinduced mitochondrial superoxide dismutase(Mn-SOD) upregulation, using inhibitors and agonists of ERα and ERβ, Robb et al. use RNAi to knockdown MnSOD to demonstrate that both the increase in cellular stress resistance and the delayed replicative growth elicited in mammalian cells by micromolar resveratrol are mediated by MnSOD induction.eir results indicate that resveratrol interacts with ERβ to increase MnSOD expression in various cell lines, rendering these cells slow growing and resistant to a variety of exogenous stressors [36]. Resveratrol binding to ERβ suppressed the expression of the α form of ER[37]. However, resveratrol seems to have antagonist activity with ERα but not with ERβ[33]. It is now generally agreed that resveratrol acts as a mixed agonist/antagonist at low concentrations or in absence of 17β-estradiol, but as a pure anti-estrogen at higher concentrations and in the presence of 17β-estradiol [38-39]. That is, resveratrol acts as an estrogen-agonist or antagonist that depends upon the level of endogenous estrogen, gender and menopausal status [40].

Other ef f ects

Several other properties of resveratrol have been reported, includes: antibacterial effect[41], antiinflammation[2], immunomodulatory effect[42], neuroprotection[43], anti-aging[44], radioprotective ef f ect [45], Antiviral ef f ect[46], and so on.

The principle of prevention and treatment of HAPC

In China, the area of highland over sea level 3 000 meters occupies more than one fourth in the total area of the land. In the highland, the cold and dry climate, hypobaric, hypoxia, strong ultraviolet radiation, and other factors would have a widespread impact on human psychology and physiology. People may subject to different degrees of acute, chronic high altitude disease. One of the most representatives of the chronic mountain sickness is HAPC. HAPC is a kind of disease featuring in excessive erythropoiesis caused by the lacking of adaptability when people enter plateau circumstance with long-term exposure to hypoxia. Excessive erythrocytosis may cause blood viscosity increase, blood flow decrease, microcirculation disturbance, oxygen free radical metabolism imbalance and other adverse results, and subsequent clinical symptoms [47].is disease occurs much more common in immigrant Han Chinese than in native people residence at high altitude.

At present, no treatment has been shown to be effective for curing HAPC.e principle of treatment includes general therapy, oxygen therapy, reducing the number of red blood cells and the blood viscosity, improving blood circulation [48]. For these reasons we can use estrogen, angiotensin converting enzyme inhibitors, and respiratory stimulant to inhibit the production of red blood cells[49]. The other therapeutic measures such as anticoagulants, improvement of microcirculation, antiplatelet aggregation, expansion of blood volume and dilation of coronary artery may be ef f ective to HAPC.

The potential application of resveratrol in HAPC

Several studies indicate that oxidative stress increased under hypobaric hypoxia conditions. Hypoxia is also associated with an increase in ROS generation which leads to oxidative damage to lipids, proteins, and DNAs [50-51]. Liu et al.[52] found that the patients with HAPC have obvious oxygen free radical metabolism imbalance. Tharakn et al.[53] reported that some native highlander tribes in India oen eat the seeds of Trichopus zeylanicus, which have been shown to scavenge free radicals and reduce the levels of lipid peroxidation and DNA damage by their antioxidant capacity, depending upon the polyphenol and sulfhydyl content. In additional, antioxidant supplementation has been shown to have beneficial ef f ects and can attenuate and/or prevent the oxidative damage associated with high altitude[50]. Resveratrol shows strong antioxidant activity, which supports the potential use of resveratrol in high altitude medicine, especially in HAPC.

Resveratrol’s structure is similar to diethylstilbestrol. Resveratrol possesses estrogen-like ef f ect whichcan inhibit the production of erythropoietin(EPO). Resveratrol also has angiotensin converting enzyme inhibitor effect which may decrease red blood cell production. We can infer that resveratrol has high therapeutic potential for the treatment of HAPC by reducing the number of red blood cells. On the other hand, resveratrol has extensive vasodilatory effect, which can effectively improve microcirculation[54-55]. With its anti-platelet aggregation activity, resveratrol has a therapeutic potential in improving the blood stasis of the patients with HAPC.

Previous studies showed when collaborating with other substances to inhibit tumor cells, resveratrol can not only reduce the dosage of the drugs but also improve the effect. Combination of resveratrol and curcumin showed an improved in vitro antioxidant effects[56]. Mixed resveratrol with Auricularia auricular polysaccharides could produce a synergistic antioxidant effect[57]. There was a study to investigate whether resveratrol combined with artemisinin (ART) possess synergistic effect on different cancer cells, the results suggested that combination of ART and resveratrol exhibited the strong anticancer ef f ect, markedly reduced the ability of cell migration, and significantly increased the apoptosis and necrosis rather than use singly[58].ese data all indicate that resveratrol is likely to enhance the treatment effect, can reduce the dosage and side ef f ects of other drugs when combined with resveratrol.

Application prospect of resveratrol in other areas of the high altitude medicine

Wang et al. showed that hypoxia increased lactate dehydrogenase (LDH) release, decreased cell viability. Resveratrol pretreatment decreased LDH release and increased cell viability, suppressed the mRNA expression of inducible nitric oxide synthase (iNOS) and HIF-1a as well as NO production in hypoxia-induced cardiomyocytes. These results suggested that resveratrol attenuates acute hypoxic injury in cardiomyocytes, and the mechanism might be associated with inhibition of iNOS-NO signaling pathway via HIF-1a[59]. Another study showed that mutated EPO reporter did not respond to hypoxia or to SIRT1 expression, which supports the contention that SIRT1 regulates the reporter activities through HIF-1. Moreover, HIF-1 was inactivated by a SIRT1 activator (resveratrol), and activated by SIRT1 inhibitors (NAM and splitomicin). Given that the inhibitory ef f ects of resveratrol on HIF-1a acetylation and activation were reversed by SIRT1 knock down, it is suggested that resveratrol inhibits HIF-1a through its activation of SIRT1[60]. It is demonstrated that resveratrol has shown protective effects against ultraviolet radiation-mediated oxidative stress and cutaneous damages including skin cancer[61]. So resveratrol can be used to treat skin disorders caused by the strong ultraviolet ray in plateau area. Physical exercise or an enhanced level of physical activity at high altitude exacerbates the extent of the oxidative challenge. Due to good capability of scavenging free radicals, resveratrol becomes a good antioxidant supplements for high intensity endurance training, alleviation of oxidative stress injury, elimination of movement muscle fatigue, retention of endurance sports ability, increase of muscle strength, and so on[62], Hence, resveratrol may be helpful to recover physical fi tness aer daily training in the plateau.e other physiological ef f ects of resveratrol, such as antiinf f ammatory, immunomodulatory, antibacterial and antiviral, may also be helpful for people to improve organism immunity, disease-resistant and antiinfection in plateau area.

In a word, resveratrol, as a natural polyphenolic compound, has a wide range of beneficial effects, such as anti-tumor, cardiovascular protection, anti-oxidant, estrogen-like effects, anti-aggregation of platelet, vasodilatory effect, and so on. Taken fully into account of physiological functions and applications of resveratrol, resveratrol perhaps has a potential to become an ef f ective drug candidate for the prevention and treatment of plateau hypoxia injury or diseases. Some studies should be done to verify it in the future.

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Zhao-li CHEN, MD, Associate Professor, Key Laboratory of Environmental Medicine, Environmental Medicine Research Center, Tianjin Institute of Health and Environmental Medicine, 1 Dali Road, Heping District, Tianjin 30050, China. Tel: 86-22-84655288; E-mail: zhaolichen@126.com

+ese two authors contributed equally to this work

Received 2015-10-12; accepted 2015-11-20