Research Progression of Resveratrol on Its Physiology Function

Lei WANG Ying WANG Huihui CAO Yanhua YAN Ruihuan DU Zhijun LIU Jianhua WANG Zhe MENG

Abstract Resveratrol (Res) is a non-flavonoid polyphenol compound containing a stilbene structure, which mainly exists in grape, peanut, mulberry, Polygonum cuspidatum and other plants. It has a variety of biological activity such as anti-oxidation, anti-aging, anti-tumor and cardiovascular disease prevention. In this paper, we reviewed the current research on resveratrols biological activity and application, and prospected the application potential and development prospects of resveratrol in food, health products and biomedicine.

Key words Resveratrol; Physiological activity; application development

Received: April 9, 2020  Accepted: July 4, 2020

Supported by The Innovation Team Construction Project of Hebei Province Phase II Modern Agricultural Industry Technology System (HBCT2018120207); Tangshan Science and Technology Planning Project (19150204E); Hebei Province Innovation Ability Promotion Plan Project (20567673H).

Lei WANG (1982-), male, P. R. China, associate researcher, PhD, devoted to research of functional ingredients and food additives.

Ying WANG (1984-), female, P. R. China, associate researcher，devoted to functional ingredients and food additives.

#These authors contributed equally to this work.

*Corresponding author. E-mail: 416167083@qq.com.

Resveratrol (Res) is a non-flavonoid polyphenol compound containing a stilbene structure. It was first isolated from the roots of Veratrum grandiortua O. Loes in 1940. Later, in 1963, Res was found in the roots of the traditional Chinese medicine plant Polygonum cuspidatum. It is a kind of plant antitoxin that can resist infection secreted by Vitis plants under the influence of harsh environment such as foreign pathogens or ultraviolet radiation, and protects plants［1-2］. Resveratrol is a natural antioxidant that can scavenge free radicals in the body to delay aging, and has a wide range of biological and pharmacological activity, such as anti-tumor, anti-inflammatory, antioxidant, anti-radiation, immune regulation, cardiovascular protection, etc. Its role is deeply valued by the biology and medicine circles at home and abroad［3-4］.

Res extraction, Purification and Detection

Extraction

In recent years, with the maturity of the theory and the improvement of the system, the plant materials that can be widely used for the extraction of resveratrol have gradually increased, such as peanuts, grapes, mulberries, etc., and the extraction technology has also been more optimized.  In the past traditional extraction methods, the organic solvent extraction method requires a long time and a large solvent amount, and the extraction efficiency is not high［5］, while the high temperature required for refluxing during heating and refluxing extraction is likely to cause the decomposition or volatilization of active ingredients, which is unfavorable for the extraction of resveratrol［6］. Compared with these traditional extraction methods, the newly emerged methods of using microwave and ultrasonic technology to assist the extraction of resveratrol have many advantages. They can increase the extraction rate, shorten the extraction time, and shorten the production cycle［7］. Supercritical CO2 in the critical CO2 extraction method has the characteristics of stable properties, non-toxicity, and no pollution to the environment, and it is also one of the commonly used methods［8］. The emergence of these new extraction methods has greatly promoted the purification of resveratrol and the development of detection technology.

Purification

Resveratrol is a secondary metabolite in plants. The content in plant tissues is very low. In grape skins with higher resveratrol content, its content is only 10-100 μg/g. In order to obtain high-purity resveratrol products, the extract must be separated and purified［9］. At present, the purification of resveratrol often uses silica gel column chromatography, high-speed countercurrent chromatography and macroporous adsorption resin purification. Among them, silica gel column chromatography is cheap and can obtain a large amount of extraction, but the operation is relatively cumbersome, the yield is low, and the product has many impurities［10］; high-speed countercurrent chromatography has the characteristics of high separation efficiency, high product purity, no carrier adsorption and contamination of samples, large preparation volume and low solvent consumption; and macroporous adsorption resin separation and purification technology is widely used in the purification of flavonoids, alkaloids and other active ingredients［11］.

Detection

Currently commonly used detection methods include high performance liquid chromatography, capillary electrophoresis, thin layer chromatography and other technologies. High performance liquid chromatography has the characteristics of high sensitivity, high performance and high speed. It is widely used in the detection of resveratrol in wine, P. cuspidatum, peanut, Rumex gmelini Turcz, Polygonum multiflorum and other samples. Capillary electrophoresis is a separation and detection technology that has developed rapidly in recent years. Compared with HPLC (High-Performance Liquid Chromatographic, HPLC), capillary electrophoresis has the characteristics of higher column efficiency, faster separation speed, almost no consumption of solvent, and small sample amount, and can simultaneously separate and detect cis and trans isomers of resveratrol［12］. In addition, resveratrol is a stilbene compound, and compounds with similar structures are found in wine, P. cuspidatum, peanut and other samples. Therefore, in the analysis and identification, only a single determination method cannot achieve the precision and sensitivity of special requirements. Luan et al.［13］ applied solid phase microextraction and silicidation to process wine samples, and then used GC/MS (Gas Chromatograph/Mass Spectrometer, GC/MS) to qualitatively and quantitatively analyze the trans-resveratrol in the samples. Compared with solid-phase extraction, solid-phase micro-extraction has the characteristics of obvious chromatographic peak separation, small interference of miscellaneous peaks, and large peak area. It can be used for both gas chromatography and liquid chromatography［14］. The chromatographic techniques reported in the literature include thin-layer fluorescence scanning and capillary electrochemical detection.

The Biological Functions of Res

Antitumor activity

Among the various pharmacological effects of resveratrol, the most noticeable is its anti-tumor effect. Jang et al.［15］ first discovered that resveratrol has anti-cancer activity. Further studies have found that resveratrol can inhibit and even reverse the three stages of cancer (initiation, proliferation, and occurrence)［16］. Sabry et al.［17］ have shown that resveratrol can reduce the cytotoxicity and apoptosis induced by cisplatin in mice and germ cells. For cured cancer patients exposed to cisplatin, resveratrol can be used as a beneficial supplement to avoid secondary malignant tumors and abnormal reproduction. Studies in recent years have shown that resveratrol promotes the autolysis of cancer cells by inhibiting signal transduction regulated by MAPK (Mitogenactivated protein kinase) or NF-kB pathway［18-19］.

Effect on the cardiovascular system

Resveratrol can play a cardiovascular protective effect by reducing myocardial ischemia-reperfusion injury, vasodilation, and anti-atherosclerosis［20］. Physiological concentration (0.1 μmol/L) of resveratrol can relax blood vessels, thereby lowering blood pressure and reducing the risk of cardiovascular disease［21］. Research by Li et al.［22］ showed that resveratrol has a strong protective effect on reperfusion injury, and can reduce the incidence and duration of ventricular tachycardia and ventricular fibrillation and reduce mortality thereby. Resveratrol can increase the amount of nitric oxide in the blood of the carotid artery, reduce the level of lactate dehydrogenase, increase the developmental tension of blood vessels and increase arterial flow, and reduce the area of myocardial infarction. Wong et al.［23］ found in clinical studies that rapid cerebrovascular expansion can be caused in people with endothelial dysfunction and subclinical cognitive impairmen after eating resveratrol.

Antioxidant and anti-free radical effects

In recent years, it has been found that most polyphenols have significant anti-oxidation and anti-free radical effects. Kimura et al.［24］ reported that resveratrol at 1.3 μg/ml could significantly inhibit the auto-oxidative hemolysis of red blood cells in rats and the oxidative hemolysis caused by H2O2, and had a significant inhibitory effect on the production of lipid peroxides in the heart, liver, brain, and kidney of mice. Leonard et al.［25］ proved through experiments that resveratrol is an effective scavenger of hydroxyl, superoxide and metal inducing groups, and has a protective effect on lipid peroxidation and DNA damage caused by reactive oxygen species (ROS). Hung et al.［26］ confirmed that resveratrol can scavenge hydroxyl free radicals to protect DNA from damage. It can also inhibit the formation of glutathione disulfide and make glutathione in a reduced state, thereby inhibiting the formation of hydroxyl free radicals.

Antibacterial and antiviral effects

Resveratrol was first known as a plant antimicrobial agent produced by grape plants under adverse conditions such as fungal infection and ultraviolet radiation［27］. Evers et al.［28］ found that resveratrol could inhibit the replication of human cytomegalovirus DNA and block the cell signal induced by the virus. Wang et al.［29］ showed that resveratrol could weaken the ability of Proteus mirabilis to invade human bladder epithelial cells.

Effects on metabolism and life cycle

EL-Mowafy et al.［30］ have shown that resveratrol could be used as an estrogen antagonist and had intrinsic estrogen-like activity of inhibiting the growth of human breast cancer in the study of the effect of resveratrol on estrogen-dependent human breast cancer cell lines and human ovarian cancer. Rodgers et al.［31］ have shown that SIRT1 could regulate the aging of many species and control the liver gluconeogenesis/glycolysis pathway through the transcriptional coactivator PGC-1α. Heilbronn et al.［32］ reported that CR could regulate glucose utilization and insulin sensitivity, and increase the bodys metabolic rate. Resveratrol can perform the above related functions through the mediation of SIRT1.

Hepatoprotective effect

Lipid peroxides in higher animals will have a damaging effect on the liver. Studies have found that resveratrol has a strong inhibitory effect on lipid peroxidation and can effectively reduce lipids in serum and liver, thereby inhibiting the accumulation of lipid peroxides in the liver and reducing liver damage. Ouyang et al.［33］ reported that resveratrol had a significant protective effect on liver damage caused by two drugs: CCl4 and D-galactosamine (D-GaN). Liu et al.［34］ found that resveratrol also had anti-liver fibrosis effects. Lyu et al.［35］ observed the effect of resveratrol on CCl4 induced chronic liver fibrosis in rats, and found that resveratrol had a significant therapeutic effect on CCl4 induced liver fibrosis in rats.

Protection of the nervous system

The neuroprotective effect of resveratrol has been confirmed in in-vivo and in-vitro experiments. Resveratrol has a certain neuroprotective effect on primary neuronal cells and endothelial cells cultured in vitro, and has a protective effect on nerve damage caused by hypoxia and toxicants［36］. Lanzillotta et al.［37］ showed that 30 μmol/L resveratrol could reduce the cell damage in the mouse model of oxygen-glucose deprivation of primary neurons. Karlsson et al.［38］ have shown that resveratrol could protect mouse embryonic brain cells and prevent tert-butyl peroxide free radicals from damaging neurons containing cephalin cells. Resveratrol has a good protective effect on the nerves of stroke arterial models. Both resveratrol pretreatment and resveratrol treatment after modeling can significantly reduce cerebral infarction volume and brain water content［39］. The study of resveratrol (30 mg/kg) on bilateral middle cerebral artery occlusion model gerbils showed that it could reduce the brain damage of the model gerbils and improve the cognitive ability of the model gerbils［40］.

Anti-inflammatory effect

Resveratrol has strong anti-inflammatory effects both in vivo and in vitro. In-vitro experiments have shown that resveratrol can inhibit lipopolysaccharide from activating macrophage inducible nitric oxide synthase, thereby inhibiting the production of inflammatory factor nitric oxide and exerting anti-inflammatory effects. This pathway is produced by down-regulating the activity of nuclear factor-κB［41］. Takata et al.［42］ found that resveratrol could inhibit the activation of nuclear transcription factor NF-κB induced by TNF-α, down-regulate the expression of NF-κB downstream genes iNOS and COX-2, and selectively inhibit the catalytic activity of iNOS and COX-2, reducing the damage effect of inflammatory effect on joint damage. Rao et al.［43］ used different doses of resveratrol to gavage experimental osteoarthritis rabbits in their experiments, and the results showed that the IL6 concentration in the serum of the experimental osteoarthritis model animals decreased significantly and the effect was dose-dependent.

Immunomodulatory effect

Studies have shown that resveratrols inhibitory effect on immune cells is selective. In vivo, resveratrol has only a slight inhibition of cell proliferation on normal lymphocytes, but has a significant pro-apoptotic effect on abnormal lymphocytes such as leukemia cells［43］. Feng et al.［44］ found that low-dose resveratrol could promote cell-mediated immune responses in mice, and low-dose ig administration could counteract the inhibitory effect of ethanol on delayed-type hypersensitivity in mice. Gao et al.［45］ showed that resveratrol (25 mmol/L) could significantly inhibit the proliferation of T cells and the production of lysed cells in vitro, but po resveratrol (2 mg/d) could not induce blood cytotoxicity, and only slightly weakened the immune response mediated by T cells. Tang et al.［46］ found that resveratrol had a better regulatory effect on the immune function of mice. Yu et al.［47］ confirmed in experiments that when the concentration of resveratrol was greater than 2.5 mg/L, resveratrol significantly inhibited lymphocyte transformation and human peripheral blood T cell proliferation. Sharma et al.［48］ also proved that resveratrol could inhibit the activity of T cells, B cells and macrophages.

Prospects

With the continuous in-depth research on resveratrol, the application of resveratrol in the food industry will become more and more extensive. In Japan, plant-derived resveratrol has been used as food; in China, plant extracts containing resveratrol are also made into lipid-lowering, beautifying, weight-reducing and anti-cancer capsules; and it can also be added to various wines to prepare a new type of low-alcohol, high-resveratrol health-care table wine that has a good preventive effect on cardiovascular diseases.

Due to the natural active health-care effect of resveratrol, the use of Chinas abundant raw material resources and the vigorous development of related products can not only increase the added value of products, but also regulate the health of the population. Therefore, it is of great significance to pay attention to the research and development of practical products while perfecting theoretical research.

Lei WANG et al. Research Progression of Resveratrol on Its Physiology Function

References

［1］ LI XK, LI HY, LI S, et al. Research progress of resveratrol［J］. Chinese Traditional and Herbal Drugs, 2016, 47(14): 2568-2578. (in Chinese)

［2］ ZHANG GL, GU GP, ZHANG WM, et al. Resveratrol plant resources and its production［J］. Chinese Wild Plant Resources, 2009, 28(5): 24-28. (in Chinese)

［3］ FENG R, CHEN JC, XUE LH, et al. Research progress on the preparation method and biological activity of resveratrol［J］. Chinese Journal of Tropical Crops, 2012, (6): 1148-1152. (in Chinese)

［4］ WHITLOCK NC, BAEK SJ. The anticancer effects of resveratrol: modulation of transcription factors［J］. Nutrition and cancer, 2012, 4(46): 493-502.

［5］ CAI YL. Study on the extraction, purification and performance of resveratrol—Research overview and development trend of resveratrol at home and abroad［D］. Beijing: Beijing University of Chemical Technology, 2010. (in Chinese)

［6］ WU JY. Studies on chemical constituents from seeds of Paeonia suffruticosa Andr［D］. Beijing: Beijing University of Chinese Medicine, 2014. (in Chinese)

［7］ LU Y, LI HL, LIN MD, et al. Simultaneous determination of contents of five major bioactive components contained in Polygoni cuspidati Rhizoma et Radix by microwave extraction-ultra performance liquid chromatography［J］. China Journal of Chinese Materia Medica, 2012, 37(13): 1994-1997. (in Chinese)

［8］ LIU T, WANG Y, LI Y, et al. Optimization of supercritical CO2 extraction of resveratrol from V.didii.Foex fruit wine residues by response surface methodology［J］. Science and Technology of Food Industry, 2015, 36(4): 193-198. (in Chinese)

［9］ JIANG RQ, LI JL. Research progress in separation, purification and detection technology of resveratrol［J］. Journal of Chinese Medicinal Materials, 2007, 30(3): 367-371. (in Chinese)

［10］ BAI Y, PAN JL, SU WW. Research progress of resveratrol and polydatin［J］. Journal of Chinese Medicinal Materials, 2004, 27(1): 55-59. (in Chinese)

［11］ LIU SX, CHENG LY, GENG W. Study on the purification of resveratrol by HSCCC［J］. The processing of agricultural products, 2005(9): 121-123. (in Chinese)

［12］ FAN EG, ZHANG K, YAO CY, et al. Determination of trans-resveratrol in China Great Wall “Fazenda” red wine by use of micellar electrokinetic chromatography［J］. Chromatographia, 2005, 62(5-6): 289-294.

［13］ LUAN TG, LI GK, ZHANG ZX. Gas-phase postderivatization following solid-phase microextraction for rapid analysis of polyphenols in wine by gas chromatography-mass spectrometry［J］. Journal of Sun Yat-sen University: Medical Sciences, 2001, 40(1): 54-57. (in Chinese)

［14］ ANTOLOVICH M, PRENZLER P, ROBARDS K, et al. Sample preparation in the determination of phenolic compounds in fruits. Analyst, 2000(125): 989-1009.

［15］ JANG M, PEZZUTO J. Effect of resveratrol on 12-O-tetradecanoylphorbol-13-acetate induce oxidative evevts and gene expression in mousekin［J］. Cancer Lett, 1998, 134(1): 81-89.

［16］ AZIZ MH, KUMAR R, AHMAD N. Cancer chemoprevention by resveratrol: In vitro and in vivo studies and the underlying mechanisms［J］. Int J Oncol, 2003(23): 17-28.

［17］ SABRY MA. Influence of resveratrol on oxidative damage in genomic DNA and apoptosis induced by cisplatin［J］. Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 2012, 741(7): 22-31.

［18］ HOLME AL, PERVAIZ S. Resveratrol in cell fate decisions［J］. J Bioenerg Biomembr, 2007, 39(1): 59-63.

［19］ FULDA S, DEBATIN KM. Extrinsic versus intrinsic cell death induction pathways in anti-cancer chemotherapy［J］. Oncogene, 2006(25): 4798-4811.

［20］ NORATA GD, MARCHESI P, PASSAMONTI S, et al. Anti-inflammatory and anti-atherogenic effects of cathechin, caffeic acid and trans-resveratrol in apolipoprotein E deficient mice［J］. Atherosclerosis, 2007, 191(2): 265-271.

［21］ NICHOLSON SK, TUCKER GA, BRAMELD JM. Effects of dietary polyphenols on gene expression in human vascular endothelial cells［J］. Proc Nutr Soc, 2008, 67(1): 42-47.

［22］ LI MH, CHEN JK, HUANG SS, et al. Cardioprotective effect of resveratrol, a natural antioxidant derived from grapes［J］. Cardiovasc Res, 2000, 47(3): 549-555.

［23］ WONG RH, NEALON RS, SCHOLEY A, et al. Low dose resveratrol improves cerebrovascular function in type 2 diabetes mellitus［J］. Nutrition, metabolism, and cardiovascular diseases, 2016, 26(5): 393-399.

［24］ LUO L, HUANG YM. Effect of resveratrol on cognitive function in mice with Alzheimers disease［J］. Journal of Central South University: Medical Sciences, 2006, 31(4): 566-569. (in Chinese)

［25］ LEONARD SS, XIA C, JIANG BH, et al. Resveratrol scavenges reactive oxygen species and effects radical-induced cellular responses［J］. Biochem Biophys Res Commun, 2003, 309(4):1017-1026.

［26］ HUNG LM, CHEN JK, HUANG SS, et al. Cardiopmtective effect of resveralrol, a natural antioxidant derived from grapes［J］. Cardiovascular research, 2000(47): 549-555.

［27］ LANGCAKE P, PRYCE RJ. The production of resveratrol by Vistis vinifera and other members of the vitaceae as a response to infection or injury［J］. Physiol Plant Path, 1976(9): 77-86.

［28］ EVERS DL, WANG X, HUONG SM, et al. 3,4′,5-Trihydroxy-trans-stilbene (resveratrol) inhibits human cytomegalovirus replication and virus-induced cellular signaling［J］. Antiviral Res, 2004, 63(2): 85-95.

［29］ WANG WB, LAI HC, HSUEH PR, et al. Inhibition of swarming and virulence factor expression in Proteus mirabilis by resveratrol［J］. J Med Microbiol, 2006, 55(10): 1313-1321.

［30］ EL-MOWAFY AM, ABOU-ZEID LA, EDAFIOGHO I. Recognition of resveratrol by the human estrogen receptor-alpha: A molecular modeling approach to understand its biological actions［J］. Med Princ Pract, 2002, 11(2): 86-92.

［31］ RODGERS JT, LERIN C, HAAS W, et al. Nutrient control of glucose homeostasis through a complex PGC-1α and SIRT1［J］. Nature, 2005, 434 (7029): 113-118.

［32］ HEILBRONN LK, DE JONGE L, FRISARD MI, et al. Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial［J］. JAMA, 2006, 295(13): 1539-1548.

［33］ OUYANG CH, FAN Q, WU JL. Protective effect of resveratrol on chemical-induced liver injury in female mice［J］. Lishizhen Medicine and Materia Medica Research, 2006, 17(5): 760-762. (in Chinese)

［34］ LIU YG, LIU YZ, XIE SL. Experimental study of resveratrol against liver fibrosis in vitro［J］. China Pharmacy, 2007, 18(4): 265-266. (in Chinese)

［35］ LYU QJ, XIE JQ, WEN LQ. Effects of resveratrol on chronic liver fibrosis in rats［J］. Chinese Journal of New Drugs, 2005, 14(7): 855-858. (in Chinese)

［36］ ZAMIN LL, PATRíCIA DP, RICARDO AC, et al. Protective effect of resveratrol against oxygen-glucose deprivation in organotypic hippocampal slice cultures: Involvement of PI3-K pathway［J］. Neurobiol Dis, 2006, 24(1): 170-182.

［37］ LANZILLOTTA A, PIGNATARO G, BRANCA C, et al. Targeted acetylation of NF-kappaB/ReIA and histones by epigenetic drugs reduces post-ischemic brain injury in mice with an extended therapeutic window［J］. Neurobiol Dis, 2012, 49(1):177-189.

［38］ KARLSSON J, EMGARD M, BRUNDIN P, et al. Trans-resveratrol protects embryonic mesencephalic cells from tert-butyl hydroperoxide: Electron paramagnetic resonance spin trapping evidence for a radical scavenging mechanism［J］. J Neurochem, 2000, 75(1):141-150.

［39］ REN J, FAN C, CHEN N, et al. Resveratrol pretreatment attenuates cerebral ischemic injury by upregulating expression of transcription factor Nrf2 and HO-1 in rats［J］. Neurochem Res, 2011, 36(12): 2352-2362.

［40］ WANG Q, XU J, ROTTINGHAUS GE, et al. Resveratrol protects against global cerebral ischemic injury in gerbils［J］. Brain Res, 2002, 958(2):439-447.

［41］ SHEN F, CHEN SJ, DONG XJ, et al. Suppression of IL-8 gene transcription by resveratrol in phorbol ester treated human monocytic cells［J］. J Asian Nat Prod Res, 2003, 5(2): 151-157.

［42］ TAKADA Y, BHARDWAJ A, POTDAR P, et al. Nonsteroidal antinflammaatory agents differ in their ability to suppress NF-KB activation, inhition of expression of cyclooxygenase-2 and cyclin D1, and abrogation of tumor cell proliferation［J］. Oncogene, 2004, 23(57): 9247-258.

［43］ WANG C, HUA ZC. Research advances of the immunomodulatory effect of resveratrol［J］. Chinese Journal of Biochemical Pharmaceutics, 2012, 33(1): 84-87.(in Chinese)

［44］ FENG YH, ZHOU WL, WU QL, et al. Low dose of resveratrol enhanced immune response of mice［J］. Acta Pharmacol Sin, 2002, 23(10): 893-897.

［45］ GAO X, DEEB D, MEDIA J, et al. Immunomodulatory activity of resveratrol: discrepant in vitro and in vivo immunological effects［J］. Biochem Pharmacol, 2003, 66(12): 2427-2435.

［46］ TANG MZ, HONG ZZ, LI XY. Immunomodulatory function study of resveratrol on immune system in rates［J］. Modern Journal of Integrated Traditional Chinese and Western Medicine, 2005, 14(18): 2381-2382. (in Chinese)

［47］ YU L, WU SL, ZHANG M, et al. Effects of resveratrol and its combination with cyclosporine A on the immune function of human peripheral blood T cells［J］. Chinese Journal of Cellular and Molecular Immunology, 2003, 19(6): 549-551.(in Chinese)

［48］ SHARMA S, CHOPRA K, KULKARNI SK, et al. Resveratrol and curcumin suppress immune response through CD28/CTLA-4 and CD80 co-stimulatory pathway［J］. Clin Exp Immunol, 2007, 147(1): 155-163.