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
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