resveratrol botanical origin, pharmacological

Chinese Journal of Natural Medicines 2013 11(1) 0001minus0015

ChineseJournal of Natural Medicines

Resveratrol botanical origin pharmacological activity and applications

WU Chun-Fu YANG Jing-Yu WANG Fang WANG Xiao-Xiao

Department of Pharmacology School of Life Science and Biopharmaceutics Shenyang Pharmaceutical University Shenyang 110016 China Engineering Technology and Research Center for Plant Polyphenols of Liaoning Province Shenyang 110016 China

Available online 20 Jan 2013

[ABSTRACT] In the past decade resveratrol one of the best well-known natural small molecules has been intensely studied and has shown various promising bioactivities A growing body of studies point out its potential application and suggest that resveratrol as a natural product has highly protective effects on several human diseases with mild side effects This review summarizes the botanical origin of resveratrol and highlights a series of valuable therapeutic potentials focusing on its pharmacological effects as well as its applied uses [KEY WORDS] Resveratrol Botanical origin Pharmacological effects Applications

[CLC Number] R93 R965 [Document code] A [Article ID] 1672-3651(2013)01-0001-15

1 Introduction

Plants produce thousands of low-molecular-weight natu-ral products The majority of these compounds (referred to as lsquosecondary metabolitesrsquo) play an important role in the de-fense of plants against infections or stress-inducing condi-tions Two classes of anti-microbial secondary molecules are known that is the phytoalexins and the phytoanticipins Phytoanticipins are pre-formed inhibitors of plant infections while phytoalexins are synthesized when plants are attacked by pathogenic organisms[1] Among the numerous identified phytoalexins resveratrol a stilbene compound catalogued as a polyphenol has attracted remarkable attention

Resveratrol (3 5 4rsquo-trihydroxystilbene or 3 5 4rsquo-stilbe- netriol MW 22825) is produced by several plant species such as grapes mulberries and peanuts It was first detected in the roots of white hellebore (Veratrum grandiflorum)[2] in 1940 and later in 1963 isolated from the roots of Polygonum cupsidatum a plant used in traditional Chinese amedicine[3]

[Received on] 03-Dec-2012 [Research funding] This project was supported by the National Key Scientific Project for New Drug Discovery and Development China (No 2010ZX09401-102) [Corresponding author] WU Chun-Fu Prof Tel 86-24-23986339 Fax 86-24-23986339 E-mail wucfsyphueducn These authors have no any conflict of interest to declare Copyright copy 2013 China Pharmaceutical University Published by Elsevier BV All rights reserved

The earliest finding on the beneficial effect of resveratrol to the human body comes from the epidemical investigation on the French paradox phenomenon that the incidence of coronary heart diseases in France was much lower than those in other countries even though the French had high-fat diets[4] Further studies indicate that resveratrol impacts on pleiotropic health benefits both in vitro and in vivo During the last 10 years the enormous amounts of studies on res-veratrol most notably focus on the mitigation of age-related diseases including neurodegenerative and cardiovascular diseases A majority of its cardioprotective properties are associated with its ability to exert vasorelaxation an-ti-inflammatory response and ROS scavenging Among other health benefits resveratrol possesses anti-tumor anti-diabetic and anti-obesity activities[5-8]

In spite of the vast progress made in the understanding of resveratrolrsquos pharmacological effects there is no article which comprehensively summarizes its resource pharma-cological activities and applications in detail In this paper we review most of the research on the valuable pharmacol-ogical activities of resveratrol published especially in the past five years Its botanical origins and its current and po-tential applications are also surveyed

2 Botanic Origin

21 Resveratrol production in natural plants Resveratrol has been identified in a significant number

of plant species (Table 1) and is found in a variety of vegeta-

WU Chun-Fu et al Chinese Journal of Natural Medicines 2013 11(1) 1minus15

ble foods including Japanese knotweed (Polygonum cuspi-datum)[9] peanut Vaccinium spp (including blueberry bil-berry and cranberry) Reynoutria japonica and Scots pine Currently resveratrol is usually extracted from red grapes

Table 1 Plant sources of resveratrol[11-14]

Family Genus Species Vitis Vitis spp

Vitaceae Tetrastigma Tetrastigma hypoglau-

cum Moraceae Morus Morus spp

Veratrum Veratrum spp Aloe Aloe spp Lilium Lilium spp Liliaceae

Ornithogalum Ornithogalum cauda-tum

Cassia Cassia spp Cercis Cercis chinensis Glycine Glycine max

Fabaceae

Bauhinia Bauhinia racemosa Rheum Rheum spp polygonum Polygonum spp Polygonaceae Fallopia Fallopia spp Picea

Pinaceae Pinus Pinus spp Festuca Festuca spp Hordeum Hordeum vulgare Poa Poa spp Stipa Stipa spp

Poaceae

Lolium Lolium spp Paeoniaceae Paeonia Paeonia lactiflora Myrtaceae Eucalyptus

Araliaceae Panax Panax pseudo-ginseng var notoginseng

Asteraceae Aster Aster tataricus Magnoliaceae Magnolia Magnolia officinalis

Arachis Arachis spp Fabaceae

Trifolium Trifolium spp Juglandaceae Juglans Juglans regia Moraceae Morus Morus alba Oleaceae Olea Olea europaea

Ericaceae Vaccinium Vaccinium myrtillus Vaccinium vitis-idaea Vaccinium oxycoccos

Rubus Rubus idaeus Rosaceae

Prunus Prunus mume Rhamnaceae Ziziphus Ziziphus jujuba Theaceae Camellia Bromeliaceae Ananas Ananas comosus Pandanaceae Pandanus Betulaceae Alnus Lauraceae Cinnamomum Gnetaceae Gnetum Gnetum montanum

and it has been estimated that fresh grape skin contains about 50minus100 microg of resveratrol per gram In red wine the concen-trations of resveratrol according to some authors are in the range of 15minus3 mgmiddotLminus1 while other reports suggest substan-tially higher amounts (4minus20 mgmiddotLminus1)[10] Significant quantities are also found in some white and rose wines In commercial grape juice the concentrations of resveratrol are approxi-mately 4 mgmiddotLminus1 (Table 2)

Table 2 Resveratrol content in wines or grape juice[10]

Beverage Total Resveratrol (mgmiddotLminus1)

Total Resveratrol in 150 mL winemg

Red Wines (Global) 198minus713 030minus107

Red Wines (Spanish) 192minus1259 029minus189

Red grape juice (Spanish) 114minus869 017minus130

Rose Wines (Spanish) 043minus352 006minus053

Pinot Noir 040minus200 006minus030

White Wines (Spanish) 005minus180 001minus027

Italian Red Wine 197minus567 03minus086

Chilean Merlot Wine 225 035

22 Structure of resveratrol

Resveratrol exists in the cis- and trans- stereoisomeric forms Usually this polyphenol is present in dietary products essentially in glycosylated forms known as piceid (resvera-trol-3-O-β-D-glucoside) Both cis- and trans-resveratrol exist naturally and appear to exert similar effects although yet the actions of the trans isoform are more widely investigated[1]

Fig 1 Chemical structures of trans- and cis-resveratrol Resveratrol (3 5 4rsquo-trihydroxystilbene) is a derivative of stilbene (stilbenoid) and exists as two diastereomers trans- (E) and cis- (Z) The trans- form is the preferred steric form in nature and is relatively stable It can undergo isomerisa-tion to the cis- form when exposed to ultraviolet irradiation

3 Pharmacological Activities

An increasing number of studies have examined the pharmacological properties of resveratrol related to many human diseases including cardiovascular disease diabetic mellitus neurodegenerative disease and cancer As inflam-mation can lead to further oxidative stress in a cycle that is associated with many diseases the anti-oxidative and


anti-inflammatory effects of resveratrol play a crucial role in the therapeutic processing even though the mechanisms of action need to be further evaluated 31 Anti-cardiovascular diseases 311 Anti-oxidant and anti-inflammatory effects of resveratrol in cardiovascular diseases

As resveratrol is particularly abundant in red wine and shows the cardiovascular-beneficial properties in protecting isolated rat hearts from ischemiareperfusion injury[15] it has been assumed that the polyphenol is responsible for the puta-tive wine-positive cardiovascular properties A number of studies have reported that resveratrol exerts significant car-diovascular protective effects in various models of myocar-dial injury[16-18] and hypertension[16 18 19] Resveratrol has been found to promote endothelium-dependent vasodilation implying that resveratrol could lower blood pressure Direct evidence comes from experiments on hypertensive rats Mi-zutani et al showed that 3 weeks of resveratrol administra-tion lowers the systolic blood pressure of spontaneously hy-pertensive rats by 15 In another study resveratrol treat-ment for 2 weeks abolishes pressure over loadndashinduced car-diac hypertrophy and improves cardiac function and iso-volumetric relaxation[11]

The potential protection of resveratrol against cardio-vascular illnesses has been associated with a number of ef-fects As mentioned resveratrol can induce major anti-oxidant enzymes (eg glutathione peroxidase heme oxygenase superoxide dismutase) in cardiac and vascular cells[20-23] which results in a marked attenuation of oxidative stress Moreover resveratrol has been explored for a series of an-ti-inflammatory or anti-oxidative activities For instance resveratrol both down-regulates vascular and cardiac expres-sion of TNF-α and inhibits NADPH oxidases in the vascula-ture[24] It also inhibits mitochondrial production of ROS in the vasculature[25] In addition resveratrol is reported to in-hibit inflammatory processes inflammatory-related gene expression and attenuates monocyte adhesiveness to endothe-lial cells[26-34] all of which may contribute to its cardiopro-tective effects 312 Mechanism of action of resveratrol on cardiovascular diseases

Resveratrol is known to be a vasodilator through its abil-ity to enhance endothelial NO production to increase endo-thelial nitric oxide synthase (eNOS) expression in mouse arteries[35] and to decrease NADPH oxidase expression[36] Although the mechanisms of action of resveratrol are only partly understood some studies suggest that they result in the activation of membrane-bound structures such as estrogen receptors which leads to the intracellular cascade of signal-ing pathways that target AMP-activated protein kinase (AMPK) and could activate eNOS by phosphorylation of serine 1177 Recent studies also showed that the pathways mentioned above can activate sirtuin 1 (SIRT1) leading to decreased acetylation and activation of eNOS Lines of evi-

dence suggest the role for several sirtuins in the cardiovascu-lar system SIRT1 appears to play a regulatory role in endo-thelial function and promotes endothelium-dependent vaso-dilation and regenerative functions in endothelial and smooth muscle cells of the vascular wall[37] Arunachalam G et al also indicate that resveratrol enhances endothelia SIRT1 ex-pression under circumstances characterized by increased oxidative stress in vitro[38] Moreover resveratrol by way of an eNOS-dependent pathway induces mitochondrial bio-genesis both in cultured endothelial cells and in endothelia of mice with accelerated cardiovascular disease[39] Other re-search has focused on the endothelial vasoprotective effects of resveratrol and its decrease in the expression of angio-tensin 2 type 1 receptor in the vascular smooth muscle cells in vivo[40] A novel mechanism of action of resveratrol on cardioprotection is associated with autophagy Gurusamy et al have shown that resveratrol at lower doses (01 and 1 mmolL-1 in H9c2 cardiac myoblast cells and 25 mgkg-1middotd-1 in rats) induces cardiac autophagy shown by the enhanced formation of autophagosomes and its component LC3-II after hypoxiandashreoxygenation or ischemiandashreperfusion while this phenomena is attenuated by a higher dose of resveratrol Thus resveratrol-mediated cell survival is in part mediated through the induction of autophagy involving the mTOR- Rictor survival pathway[41] 32 Anti-diabeticobesity effect on metabolic diseases 321 The beneficial effects of resveratrol on diabetic dis-eases

Diabetes mellitus is a complex metabolic disease affect-ing about 5 of people all over the world In the last few years experiments in vitro and in vivo have provided evi-dence that resveratrol exerts protective effects in several metabolic diseases including hepatic lipid accumulation hyperlipidemia atherosclerosis and diabetes[42-44] The anti- hyperglycemic action of resveratrol has been investigated using obese rodents[45-46] or diabetic animal models (such as streptozotocin-induced and streptozotocin-nicotinamide-induced diabetic rats)[21 47-52] In addition administration of resveratrol to diabetic rats also lead to diminished glycosylated he-moglobin (HbA1C) levels which reflects the prolonged re-duction of glycemia[49] These data point out the valuable effects of resveratrol on diabetic diseases Type 2 diabetes develops slowly which would be undetected for years ac-companied by insulin resistance According to some animal studies resveratrol can reduce insulin secretion in freshly isolated rat pancreatic islets[53] Some studies focused on the protective action of resveratrol on the endocrine pancreas[54-56] For instance Lee et al[57] recently reported that resveratrol inhibits cytokine disturbance because exposure of isolated rat pancreatic islets to cytokines results in numerous unfa-vorable effects such as increased DNA binding of NF-κB increased production of NO and expression of iNOS Res-veratrol is considered to display its protective action against the cytokine-induced dysfunction of β cells because of acti-


vating NAD+-dependent protein deacetylase SIRT1[57] In streptozotocin-nicotinamide-induced diabetic rats oral ad-ministration of resveratrol significantly reduces blood levels of TNF-α IL-1β and IL-6[47]

On the other hand as oxidative stress is one of the most vital aspects leading to β cell failure in type 2 diabetes the strong anti-oxidant effect of resveratrol has been considered as high potential for diabetic treatment while the detailed relationship between resveratrol and animalshuman should be further investigated[58] Resveratrol administered to dia-betic rats substantially ameliorates the parameters of oxida-tive damage and increases the activities of the enzymes[22] NF-E2-related factor-2 (Nrf2) is a transcription factor that regulates coordinated key antioxidant responses in cells and its activation is therefore capable of protection in a wide va-riety of animal models of oxidative stress-related injury and inflammatory disease[25] Recent studies provide compelling evidence that resveratrol treatment can improve endothelial function in rodent models of type 2 diabetes by attenuating vascular inflammation and decreasing endothelial apoptosis Ungvari et al[22] have provided evidence that the activation of Nrf2 is an important mechanism by which resveratrol exerts its beneficial effects in the vascular endothelium Importantly the in vivo relevance of resveratrol-induced Nrf2 activation is supported by using Nrf2 knockout mice fed on a high-fat diet in which the endothelial protective effects of resveratrol are largely diminished compared with those of wild-type litter-mates fed on the same diet[59] 322 The benefit effects of resveratrol on lipid metabolism diseases

As already stated resveratrol was found to be beneficial for rat lipid metabolism almost thirty years ago[60-61] By us-ing the human hepatocarcinoma cell-line HepG2 which re-tains most of the functions of normal liver parenchymal cells[62 63] a significant decrease in the intracellular concen-tration of apo B was observed in response to increasing con-centrations of trans-resveratrol in the medium (up to 50 μmolmiddotLminus1) Moreover resveratrol also decreases the secretion rate of cholesterol esters and triglycerides The additional protection of resveratrol against diet-induced atherogenesis is due to alleviation of steatohepatitis Whole-genome expres-sion analysis reveals that resveratrol suppresses the athero-genic diet-induced alterations of the expression of genes re-lated to lipid metabolism In addition the mechanism of res-veratrol protection against metabolic diseases may be associ-ated with activating SIRT1 deacetylase Hou et al[64] indicate that resveratrol-activated SIRT1 acts upstream of AMPK signaling and hepatocellular lipid metabolism substantially preventing the impairment in phosphorylation of AMPK and its downstream target ACC (acetyl-CoA carboxylase) ele-vating expression of FAS (fatty acid synthase) and lipid ac-cumulation in human HepG2 hepatocytes exposed to high glucose

33 Anti-cancer activities 331 In vitro studies

For decades increasing studies have focused on the po-tential anti-cancer activity of resveratrol in various kinds of cancers as shown in Table 3 For example resveratrol in-duces cell death in human colorectal cancer cells (DLD1 and HT29)[65] Inhibition of breast cancer progression by resvera-trol has been reported in both estrogen-positive (MCF-7) and estrogen-negative (MDA-MB-231) breast cancer cells when treated with 1 mmolL-1 resveratrol in vitro[66]

Resveratrol increases cellular cytotoxicity and inhibits the proliferation of B103 neuroblastoma cells by inducing mitochondria-mediated intrinsic caspase dependent pathway[67] Resveratrol and clofarabine cause synergistic anti-proliferative effect in MSTO-211H cells It is possible that the syner-gistic outcome is caused at least in part by inhibition of Akt phosphorylation suppression of Sp1 activation and down- regulation of c-Met cyclin D1 and p21[68] Resveratrol in-hibits lung cancer cell invasion and metastasis by suppressing TGF-β1-induced EMT and by down-regulating Snail and Slug expression[69] 332 In vivo studies

Resveratrol also possesses a strong anti-cancer property in various animal models in vivo as shown in Table 4 Inhibi-tion of cancer progression by resveratrol has been reported in nude mice inoculated with any of these cell lines Moreover in several mouse xenograft human neuroblastoma cells mod-els (SH-SY5Y NGP and SK-N-AS) resveratrol administra-tion (50 mmolL-1) results in significant shrinkage of tumors[81] Besides it also reduces the cancer progression when administered with 10 mgkgminus1 body weight (BW) for 2 days[70] Administration of 625 mgmiddotkgminus1 of resveratrol diet for 28 weeks suppresses prostate cancer progression in trans-genic adenocarcinoma mouse prostate (TRAMP) mice[81] The tumor growth is also inhibited in rats by oral administra-tion of 50 mgmiddotkg-1 BW per day for 5 weeks[82] In addition resveratrol also inhibits pancreatic and lung cancers by sup-pressing cell proliferation[71] and reducing metastatic growth of tumor in rat models[82] respectively 333 The anti-cancer mechanisms of resveratrol

The mechanisms of anti-cancer action of resveratrol de-pend on its ability to induce apoptosis in cancer cells through multiple related signaling pathways[65 72 74 83] For example in human neuroblastoma resveratrol induces loss of mito-chondrial membrane potentials triggering the release of cy-tochrome C and SmacDiablo and subsequently activates caspase-9 (CASP9) and caspase-3 (CASP3)[84] Trincheri et al[65] have reported that in human colorectal cancer resvera-trol induces apoptosis by down-regulating lysosomal cathep-sin D and its post-transcriptional factors Another report by Benitez et al[85] also shows that resveratrol additionally im-pacts on cell cycle arrest at the G0G1 phase and reduces the expression of cell growth factors in human cancer cell lines


Table 3 Anti-cancer properties of resveratrol in vitro

Reference Model Dose Outcomemechanism

van Ginkel et al (2007)[66]

Human neuroblastoma (SH-SY5Y NGP and SK-N-AS) cells

50minus200 μmolmiddotLminus1 resveratrol cells were treated for up to 10 days

Viability of cancer cells decreased by 85-90 after 5 days of treatment IC50 of 70-120 μmolmiddotLminus1 in the different cells after 48 h of treatment induced loss of mitochondrial potential leading to activation of proapoptotic caspases and subsequently programmed cell death

Trincheri et al (2007)[65]

Human colorectal cancer (DLD1 and HT29) cells

1minus100 μmolmiddotLminus1 resveratrol in the absence or presence of 1 μmolmiddotLminus1 fulvestrant

Induced cancer cell death anti-cancer activity not mediated through estrogen receptors proposed to be mediated by upregula-tion of lysosomal cathepsin D expression and caspase activation resulting in apoptosis

Su et al (2007)[70] Estrogen-positive (MCF-7) and estrogen-negative (MDA-MB-231) breast cancer cells

1 μM resveratrol Reduced proliferation in both estrogen-positive and estro-gen-negative human breast adenocarcinoma

Golka et al (2007)[71]

Human pancreatic cancer (S2-013 and CD18) cells

25minus100μmolmiddotLminus1 resveratrol treatment at 24 48 and 72 h

Inhibited cell proliferation in both cancer cells at 100 μmolmiddotLminus1 Induced time- and concentration-dependent transcriptional upregu-lation of macrophage inhibitory cytokine-1 (MIC-1) which pos-sesses anti-tumorigenic activity

Bhardwaj et al (2007)[72]

Human multiple myeloma (U266 and RPMI 8226) cells

50 μmolmiddotLminus1 resvera-trol

Inhibited proliferation in chemoresistant and chemosensitive cells by decreasing proliferative and anti-apoptotic factors mediated through suppression of NF-κB via IKK inhibition potentiated the apoptotic effects of bortezomib and thalidomide induced a G1 cell cycle arrest

Tang et al (2006)[73] Human breast cancer (MCF-7 and MDA-MB-231) cells


Induced nuclear accumulation of COX-2 in MCF-7 cells which associates with and facilitates the p53-dependent proapoptotic activity

Sun et al (2006)[74]

Human multiple myeloma (RPMI 8226 U266 and KM3) cells

50minus200μmolmiddotLminus1 resveratrol

Suppressed cell proliferation with IC50 of 131ndash187 μmolmiddotLminus1 after 24 h induced cell cycle arrest at G1 and S phases inhibited expres-sion of NF-κB and down-regulation of its anti-apoptotic gene products induced apoptosis

Hwang et al (2007)[75]

Etoposide-resistant HT-29 human colon cancer cells

50minus400 μmolmiddotLminus1

resveratrol

Induced cell growth inhibition with etoposide in etoposide-resistant cancer cells induced apoptosis with etoposide by modulation of AMP kinase signalling pathway and ROS production

Cecchinato et al (2007)[76]

MOLT-4 human T-cell acute lymphoblastic leukemia cells

16-128 μmolmiddotLminus1

resveratrol

Induced a decrease in cell viability through induction of apoptosis by increasing proapoptotic factors Bax p53 p21waf and modu-lated the p53 and PI3KAkt-mediated apoptosis pathway

Benitez et al(2007)[77]

Human prostrate-derived estrogen-sensitive LNCaP and estrogen-insensitive PC-3 cancer cell lines and PZ-HPV-7 normal cells

1minus150μmolmiddotLminus1 res-veratrol cells treated for 12minus72 h

Induced a dose- and time-dependent decrease in cancer cell prolif-eration and an increase in caspase-dependent apoptosis induced cell cycle arrest at G0G1 phase reduced the expression of cancer cell growth factors anti-cancer activity via diffrent mechanisms in the two cell types

Jin Sang Kil et al[78] RAW2647 cells 80 μmolmiddotLminus1 resveratrol reduced cell viability by apoptosis an evident toxic activity was observed at 80 μmolmiddotLminus1 At this cytotoxic dose a remarkable expression of HO-1 was also observed Both reduction of cell viability and expression of HO-1 correlated with reactive oxygen species (ROS) formation

Yu Bai et al[79] bladder cancer human bladder cancer cell line T24

50minus200 μmolmiddotLminus1 Resveratrol induced apoptosis through the modulation of Bcl-2 family proteins and activation of caspase 9 and caspase 3 followed by poly (ADP-ribose) polymerase degradation Treatment with resveratrol led to G1 phase cell cycle arrest in T24 cells by activa-tion of p21 and down-regulation of cyclin D1 cyclindependent kinase 4 and phosphorylated Rb

VM Adhami et al[80]

skin cancers

A431 cells 25minus100μmolmiddotLminus1 Resveratrol down-regulated pRb-E2FDP pathway members and

caused a G0G1 phase cell cycle arrest and then apoptosis

Abbreviations Akt protein kinase B AMP adenosine 5prime-monophosphate PI3K phosphatidylinositol 3prime-kinase ROS reactive oxygen species


Table 4 Anti-cancer properties of resveratrol in vivo

reference Model Dose Outcomemechanism

Su et al (2007)[70]

Female SCID mice with ortho-tropic inoculation of MCF-7 and MDA-MB-231 breast cancer cells into the mammary fat pad

10 mg resveratrolkg BW for 2 days orally

Reduced growth of 17β-estradiol-induced MCF-7 and MDA-MB-231 human breast adenocarcinoma in mice induced Akt inactiva-tion and modulation of Forkhead transcription factors resulting in tumor suppression in MDA-MB-231 cells

Busquets et al (2007)[82]

C57B16 mice intramuscularly inoculated with Lewis lung carcinoma

Daily ip dose of 5 or 25 mg resvera-trolkg BW for 15 days

No observed inhibition of primary tumor growth in mice but reduction of number of metastases by up to 40 possibly via decreas-ing angiogenesis anti-tumor activity of res-veratrol may be dependent on the animal and cancer cell models used


Mouse xenograft models of hu-man neuroblastoma (NGP and SK-N-AS) cells

2minus50 mgmiddotkgminus1 resveratrolin Neobee M5 oil administered orally daily for 5 weeks

Dose-dependent inhibition (up to 70minus80) of tumor growth in the mouse models despite low bioavailability in serum and tumor tissue

Yu Bai et al[79] bladder cancer on bladder cancer xenograft model

ip injection of propylene glycol (vehi-cle group B) or a resveratrol concen-tration of 20 mgmiddotkgminus1 for 4 weeks (group C) Treatment with a resveratrol con-centration of 20 mgmiddotkgminus1 daily exerted anti-tumor effects on bladder cancer xenografts in vivo

Decrease the tumor growths tumor volumes

Abbreviations Akt protein kinase B BW body weight ip intraperitoneal Activation of other apoptotic pathways is also proposed as a possible mechanism of anti-cancer action of resveratrol and includes (1) increase in levels of proapoptotic Bax p53 and p21waf in T-cell acute lymphoblastic leukemia cells[75] (2) decrease in levels of anti-apoptotic Bcl-xL Bcl-2 cyclin D1 and TNF receptor-associated factor2[72 85] and (3) upstream inhibition of anti-apoptotic phosphatidylinositol 3prime-kinase (PI3K)Akt pathway[76] In addition resveratrol was previ-ously shown to down-regulate the expression of tumorigenic NF-κB and its regulated proapoptotic gene products and growth factors in multiple myeloma cells[74] 34 Anti-neurodegenerative diseases 341 The neuroprotective effects of resveratrol

The neuroprotective effects of resveratrol on various neurotoxicants have been investigated in vitro In hippocam-pal slice cultures derived from 6-8 days old rats resveratrol produces neuroprotection against oxygen-glucose depriva-tion-induced neuronal death[84] Other evidence comes from primary cortical neuron cultures derived from fetal rat brain Resveratrol (10minus50 micromolmiddotLminus1) is effective in protecting N-methyl-D-aspartate (NMDA)-induced neuronal death by inhibiting the elevation of intracellular calcium ([Ca2+]i) and production of ROS[86] Moreover neuroprotective effects of resveratrol can be seen in cultured neurons and also in mi-croglia[86-89] Our previous research suggests that resveratrol significantly avoids the lipopolysaccharide (LPS)-induced excessive microglial activation which is coupled with the release of several inflammatory factors (eg TNF-α and NO) in both primary cultured rat cortical microglia and the mouse microglial cell line N9[86]

To date resveratrol has been identified as an anti-aging compound which is implied in neurodegenerative disease therapy Resveratrol has shown its effects on animal models of Alzheimerrsquos disease (AD) Parkinsonrsquos disease (PD) Huntingtonrsquos disease amyotrophic lateral sclerosis and neu-ropathic pain[90-94] For instance for Alzheimerrsquos disease resveratrol treatment markedly inhibits polymerization of the β-amyloid peptide[95] Intriguingly resveratrol has no effect on the activity of β- and γ-secretases implicating it is not directly acting on β-amyloid production but stimulates the proteosomal degradation of β-amyloid peptides[96] Han et al[97] reported that the protective effects of resveratrol on β-amyloid protein-induced toxicity in cultured rat hippocam-pal cells are specifically related to activation of protein kinase C Recently it was reported that resveratrol promotes anti-aging pathways via the activation of several metabolic sensors including the AMP-activated protein kinase (AMPK) Since direct pharmacological and genetic activation of AMPK lowers extracellular Aβ accumulation orally admin-istered resveratrol leads to reduced cerebral Aβ levels and deposition in the cortex in mice[98] possibly by inhibiting the AMPK target mTOR (mammalian target of rapamycin) to trigger autophagy and lysosomal degradation of Aβ Resvera-trol mediates neuroprotective effects on several specific hallmarks of AD Long-term dietary resveratrol activates AMPK pathways and pro-survival routes such as SIRT1 in vivo It also reduces cognitive impairment and has a neuro-protective role decreasing the amyloid burden and reducing tau hyperphosphorylation[99]

For Parkinsonrsquos disease resveratrol (10minus40 mgkg-1middotd-1)


given orally for 10 weeks significantly protects dopaminer-gic neurotoxicity in substantia nigra in 6-hydroxydopamine- induced PD rats[100] Oral administration of resveratrol (50minus100 mgmiddotkgminus1) for 1minus2 weeks significantly prevents MPTP- induced loss of dopaminergic neurons and the deple-tion of striatal dopamine levels in mice[101] In a Huntingtonrsquos disease model 3-NP causes an obvious loss of body weight a decline in motor function and poor retention of memory By contrast pretreatment with resveratrol significantly improves the motor and cognitive impairment and ameliorates oxida-tive stress damage[102] In addition resveratrol reduces tactile allodynia produced by neuropathic pain in some animal mod-els such as the L5L6 spinal nerve ligation[103] and diabetic neuropathy[92] assays 342 Mechanism of action of resveratrol on neurodegen-erative diseases

Resveratrol has been found to afford neuroprotective ef-fects against neuro-inflammation in both in vivo and in vitro studies These activities of resveratrol against neuro-inflammation appear to target activated microglia resulting in the reduction of pro-inflammatory factors through the modula-tion of the signal transduction pathway[104] However wheth-er resveratrol exerts the inhibitory effect on microglial activation through inhibiting the modulation of signal trans-duction pathway which produces the pro-inflammatory fac-tors is not quite clear As an important transcription factor in the regulation of the expressions of pro-inflammatory media-tors and enzymes NF-κB can be activated by LPS or in-flammatory cytokines Our reports have demonstrated that resveratrol significantly suppresses the activation of NF-κB pathway in LPS-induced microglia through attenuating the IκBα phosphorylation and degradation[86-89] Moreover the mitogen-activated protein kinases (MAPKs) a group of sig-naling molecules that play important roles in inflammatory processes have been recognized as important upstream mod-ulators for the production of pro-inflammatory mediators and enzymes[105-106] We previously found that resveratrol sup-presses LPS-induced phosphorylation of p38 MAPKs in N9 microglial cells Besides a growing body of evidence suggests the involvement of oxidative stress in neurodegen-erative diseases[107] Previous studies have established that antioxidants inhibit NF-κB activation and block the expres-sion of inflammatory cytokines by inhibiting the generation of iROS[108] Therefore iROS may play important roles in microglial activation and suppressing the generation of iROS may be the main mechanism of resveratrol on inhibiting mi-croglial activation In accordance with this notion resveratrol provides neuroprotection via its scavenging properties on reactive oxygen species that are towards activated microglia[109-110] Taken together resveratrol may exert its anti-inflammatory effect by blocking NF-κB and MAPKs activation which may be partly due to its potent down-regul-

ation of iROS 35 Anti-genotoxicity induced by ethanol 351 The protective effects of resveratrol against etha-nol-induced DNA damage

Many in vivo or in vitro studies have shown the genotoxicity of ethanol which could induce DNA sin-gle-strand breaks in many cells[111-113] Resveratrol exerts significant activity against the genotoxicity induced by etha-nol both in laboratory animals and cultured cells For exam-ple oral administration of resveratrol (25 50 and 100 mgmiddotkgminus1) for 3 days before acute ethanol (50 gmiddotkgminus1 ip) or repeated administration of resveratrol together with ethanol (50 gmiddotkgminus1 po) for 30 consecutive days could significantly inhibit ethanol-induced DNA damage in mouse brain[111] Consistently pretreatment with resveratrol at 5 25 and 50 micromolL-1 significantly inhibited ethanol-induced oxidative DNA damage in human peripheral lymphocytes[114] Pre-treatment with trans-resveratrol (01minus100 μmolL-1) to the primary cultures of rat astrocytes slows down cell death and the DNA damage induced by ethanol exposure[115] 352 Mechanisms of resveratrol on ethanol-induced DNA damage

The mechanism of resveratrol against ethanol-induced DNA damage is related to its potential anti-oxidative activity and its interference with the oxidative metabolism of ethanol in the cell For example in human peripheral lymphocytes resveratrol directly scavenges the hydroxyl radical produced during ethanol metabolism it significantly inhibits ethanol metabolism by regulating alcohol dehydrogenase 1B (ADH1B) and acetaldehyde dehydrogenase 2 (ALDH2) mRNA expressions at finally it reduces the level of hydroxyl radical produced from ethanol metabolism Moreover res-veratrol can also activate the base excision repair (BER) sys-tem in mRNA and protein levels in the DNA auto-repair process[114] 36 Other beneficial effects

Apart from the pharmacological properties mentioned above resveratrol exerts its benefits through some other therapeutic aspects For example Docherty et al have re-ported that resveratrol has anti-bacterial effects[116] Another study has reported its effects on longevity through preventing the Sirtuin-1-dependent induction of autophagy[117] Besides resveratrol can also be utilized to treat acute seizures prevent the acute seizure or status epilepticus induced development of chronic epilepsy and easy the chronic epilepsy typified by spontaneous recurrent seizures and cognitive dysfunction[118] Even its protective effects on skin disorders can be seen indicating its fascinating actions on a wide range of therapeu-tic proposals[80]

4 Other Studies

41 Pharmacokinetics bioavailability and metabolism After an oral dose of resveratrol (25 mg70 kg BW) to

healthy human subjects it is rapidly taken up with the plasma


resveratrol concentration (10minus40 nmolL-1) peaking about 30 min after consumption[119] Up to 70 of the ingested res-veratrol has been found to be bioavailable in humans based on the levels appearing in the plasma Resveratrol undergoes an enterohepatic cycle of metabolism After being taken up by enterocytes it appears in serum and urine predominantly as the glucuronide and sulfate conjugates[10] 42 Safety and tolerance

Tolerability to resveratrol appears with nausea and mild headaches occasionally reported and mild to moderate diar-rhea reported at larger doses These side effects occur with single daily dosing regimens In a study administering 2 000

mg twice daily over 1 week[120] there is statistical but not clinically significant raised serum bilirubin and potassium concentrations Daily dosage of 1 000 mg for 4 weeks would not change bilirubin concentrations[121-122] 43 Clinical trials of resveratrol

To date clinical trials that have examined the effect of resveratrol on cancer and insulin sensitivity are still limited but several trials are currently still ongoing (Table 5) The clinical trials highlight that resveratrol can be applied to ob-tain improved general health status and prevent chronic dis-ease in humans

Table 5 Summary of published clinical trials[125]

Aim of study Dose Participants (n) Results Reference

Bioavailability from resveratrol supplement (as capsules or in another matrix)

Safety and dose-finding 05 1 25 or 5 g capsules orallySingle dose

Healthy people (40)

Safe up to 5 g highest levels in blood were 15 h after intake Urinary excretion of resveratrol was rapid so a high dose of resveratrol may be insuffi-cient for chemopreventative properties

Boocock et al 2007[126]

Safety pharmacokinet-ics dosing with quercetin or alcohol

2000 mg capsules twice daily with food

Healthy people (8)

Resveratrol was well tolerated but 68 subjects reported diarrhea

La Porte et al 2010[120]

Effects of food on resveratrol absorption

400 mg Healthy people (24)

The extent of absorption was not affected by food but the rate of resveratrol absorption was delayed in the presence of food

Vaz-da-Silva M et al 2008[3]

Pharmacokinetics of multiple doses

2550100 or 150 mg capsules 6timesday

Healthy people (40)

Repeated dosing was well tolerated but still no high plasma concentrations of resveratrol Bioavai- lability was higher after morning administration

Almeida et al 2009[127]

Pharmacokinetics of repeated dosing versus age

200 mg capsules 3timesday Healthy people (24)

No difference in pharmacokinetics was seen in young versus old patients and resveratrol was well tolerated by all

Nunes et al 2009[128]

Bioavailability from red wine consumption

34 75 or 33 μgmiddotkgminus1 in three different wines

Healthy people (25)

The meal content did not affect resveratrol bioavailability Only trace amounts of resveratrol were found (in only some subjects) 30 min after ingestion

Vitaglione et al 2005[129]

Absorption and me-tabolism

036 mgmiddotkgminus1 Healthy people (12)

Urine excretion of glucuronide and sulfate conju-gates Peak concentrations of polyphenols does not appear high enough for chemopreventive activity

Goldberg et al 2003[119

130]

Pharmacokinetics and specific protein interac-tions

05 10 25 or 50 g caplets once daily for 29 days

Healthy people (40)

Resveratrol decreased levels of IGF-1 and IGFBP-3 which may contribute to chemopreven-tion Resveratrol was safe but at higher doses caused some gastrointestinal symptoms Plasma levels of metabolites exceeded those of resveratrol

Brown et al 2010[130]

Effects on pharma-cologic doses of drug and carcinogen-metabolizing enzymes

1 g Healthy people (42)

Resveratrol affects enzymes involved in cancer activation and detoxification and therefore may provide some chemopreventative properties How-ever resveratrol also altered drug efficacy

Chou HH et al 2010[121]

Bioavailability from resveratrol supplement

122 mgmiddotkgminus1 single dose Healthy people (9)

The metabolites were trans-resveratrol-3-sulfate trans-resveratrol-34-disulfate trans-resveratrol-3 5-disulfate trans-resveratrol-3-glucuronide and trans- resveratrol-4-glucuronide Up to 50 of the plasma trans-resveratrol-3-sulfate trans-resveratrol-disulfates and trans-resveratrol-glucuronides were bound to proteins

Burkon et al 2008[51]


003 05 or 1mgmiddotkgminus1 single dose

Healthy people (3)

Resveratrol levels were readily detected in the plasma and the urine The recovery of resveratrol in the plasma suggested a rapid absorption of resveratrol in the gastrointestinal tract

Meng et al 2004[131]


Continued

Aim of Study Dose Participants (n) Results Reference


032 064 096 or 192 mg delivered in grape juice (200 400 600 or 1 200 mL) single dose

Healthy people (3)

Resveratrol was only detected in the urine at when 600 and 1200 mL of grape juice were given In grape juice the level of free resveratrol is rather low Cis- and trans-Piceid are the major resveratrol derivatives in grape juice



05 or 1gmiddotkgminus1 single dose for 8 days

Colon cancer patients (20)

Trans-resveratrol (674 nmolmiddotg-1) and resveratrol-3- O-glucuronide (86 nmolmiddotg-1) were recovered from colonic tissue

Patel et al 2010[132]

Bioavailability of resveratrol

14 μgmiddotkgminus1 of resveratrol in different matrices single dose

Healthy people (11)

Despite similar doses of trans-resveratrol being administered the bioavailability of resveratrol from wine and grape juice is six fold higher than that from tablets

Ortuno et al 2010[133]

Bioavailability from 14C-resveratrol sup-plement

25mg taken orally and intrave-nously single dose

Healthy people (6)

Most of the oral dose was recovered in the urine Three main metabolic pathways were identified sulfate and glucuronic acid conjugation of the phenolic groups and hydrogenation of the aliphatic double bond

Walle et al 2004[134]

Bioavailability from moderate wine con-sumption

300 mLmiddotdminus1 intake of red or white wine

Healthy people (20)

Plasma resveratrol concentrations increased from 072 to 133 μmolmiddotL-1 for white wine and from 071 to 172 μmolmiddotL-1 for red wine

Gresele et al 2008[135]

Bioavailability from wine consumption

538 mg from 250 mL red wine single dose

Healthy people (11)

Resveratrol metabolites were incorporated into low density lipoproteins after a moderate intake of red wine The metabolites identified in low density lipoproteins were trans-resveratrol-3-O-glucuronide cis-resveratrol-3-O-glucuronide cis-resveratrol- 3-O-glucoside and free trans-resveratrol

Urpi-Sarda et al 2005[136]


0357 0398 or 256 mgmiddotdminus1 from 300 mL sparkling wine or 200 mL either white wine or red wine once daily for 28 days

Healthy people (20)

Significant increases in total resveratrol metabolites were observed in the urine after consumption of sparkling white or red wine

Zamora-Ros et al 2006[58]

Oxidative stress and inflammation

Oxidative stress and

Inflammation

Polygonum cupsidatum extract containing 40 mg of resveratrol daily for 6 weeks

Healthy people (20)

The extract induced a significant reduction in reactive oxygen species generation as shown by a decrease in the expression of P47 (phox) NFκB JNK-1 PTP-1B SOCS-3 in mononuclear cells when compared to placebo and baseline The extract also suppressed plasma concentrations of TNF-α IL-6 and CRP

Ghanim et al 2010[137]

Markers of oxidative stress inflammation Nrf-2 binding activity the concentrations of endotoxin

High-fat high carbohydrate meal with 100 mg resveratrol and 75 mg grape skin polyphenols 2 visits 1 week apart

Healthy people (10)

The supplement containing resveratrol and mus-cadine polyphenols suppresses the increase in oxidative stress lipopolysaccharide and lipoprotein binding protein concentrations and expression of TLR-4 CD14 IL-1β and SOCS-3 in mononuclear cells after a high-fat high carbohydrate meal


Cardiovascular effects

Cognitive performance and localized cerebral blood flow

250 or 500mg capsules once daily on 3 separate days

Healthy people (24)

Resveratrol dose-dependently increased flow during task performance concentrations of haemo-globin and enhanced cognitive function

Kennedy et al 2010[138]

Endothelial function and cardiovascular health

30 90 or 270 mg in a random-ized double-blind crossover design each dose for 6 days

Overweight obese men (14) and postmeno-pausal women (5) with border-line hyperten-sion

Flow-mediated dilation of the brachial artery increased 45 min following 30 90 and 270 mg doses of resveratrol

Wong et al 2010[139]


Continued Aim of Study Dose Participants (n) Results Reference

Cancer

A Phase-I pilot study in which the effects of resveratrol are exam-ined on Wnt signalling in the normal colonic mucosa and colon cancer tissue

4 groups N = 3 80 g of grape powder dissolved in water N = 2 120 g of grape powder dissolved in water N = 2 20 mg of res-veratrol (capsule containing also quercetin) N = 1 80 mg of resveratrol (capsule containing also quercetin daily for two weeks

Colorectal cancer patients (8)

Grape powder (80 g) which contains low doses of resveratrol in combination with other bioactive components can inhibit the Wnt pathway in colo-nic cancer patients but this effect is confined to the normal colonic mucosa

Nguyen et al 2009[140]

Chemopreventive activity

05 or 1 gmiddotdminus1 Single dose for 8 days


Resveratrol reduced tumor cell proliferation by 5 Patel et al 2010[141]

Effect on drug and carcinogen metaboliz-ing enzymes

1 g caplets Once daily for 28 days

Healthy men (11) and women (31)

Resveratrol intervention inhibited the phenotypic indices of CYP3A4CYP2D6 and CYP2C9 and induced the phenotypic index of 1A2 Overall GST and UGT1A1 activities were minimally affected by the intervention although an induction of GST-π level and UGT1A1 activity was observed in individuals with low baseline enzyme levelactivity

Chow et al 2010[121]

Chemo preventive properties



Resveratrol decreased circulating IGF-1 and IGFBP-3 in circulating plasma The decrease was most marked at 25 g The observed decrease might contribute to cancer chemo preventive activity


Diabetes obesity and metabolism

Insulin sensitivity 25 or 5 g Daily for 28 days Type 2 diabet-ics

Decreased fasting and postprandial glucose and insulin at 5 g

Elliot et al 2009[142]

Insulin sensitivity 5 mg capsules Twice daily for 4 weeks

Diabetic men (19)

Resveratrol significantly decreased insulin resis-tance (as measured by HOMA index) while it increased the pAktAkt ratio in platelets Urinary ortho-tyrosine excretion (a measure of oxidative stress) decreased by resveratrol

Brasnyo et al 2011[143]

Metabolic effects 75 mg of resveratrol in a ran-domized double-blind placebo controlled crossover design Twice daily for 30 days

Healthy obese men (11)

Resveratrol improved the metabolic profile res-veratrol reduced sleeping and resting metabolic rate In muscle resveratrol activated the AMPK-SIRT1-PGC1α axis Resveratrol reduced blood glucose and insulin levels reduced liver fat storage improved muscle mitochondrial function and reduced inflammation markers in the blood

Timmers et al 2011[144]

Glucose tolerance and vascular function

1 15 or 2 g Daily for 4 weeks Older men (3) and women (7) with impaired glucose toler-ance

Decreased peak glucose and 3 h glucose AUC following a meal at 15 and 2 g Matsuda index for insulin sensitivity improved at 15 and 2 g Trend towards improved hyperemia index

Crandall et al 2012[145]

5 Applications

51 General food Resveratrol has been found in some foods and drinks In

healthy individuals under a high-fat diet intake of 240 mL of red wine daily effectively counteracted the diet-induced en-dothelial dysfunction Moreover the administration of a red grape polyphenol extract which contained a high-content of resveratrol can acutely improve endothelial function in pa-tients with coronary heart disease Oral supplementation with purple grape juice decreases platelet aggregation increases platelet-derived NO release and decreases superoxide pro-

duction in healthy subjects[123] In healthy human volunteers a moderate wine consumption (300 mLmiddotdminus1 for 2 weeks) is able to evaluate the release of nitrite plus nitrate NO metabo-lites by modulated platelets[124] These reports suggest that resveratrol is an excellent choice for humansrsquo diet even is a continuous supply is needed 52 Health food

Though limited data are available on the efficacy of res-veratrol as healthy food the clinical trials that are available have shown much promise that resveratrol might be applied to improve general health status and prevent chronic disease in humans Notably the Food and Drug Administration of


China has already give license to the ldquoResveratrol capsulerdquo (062g resveratrol100g capsule) as a health food (SFDA Approval Number G20050342)

6 Further Perspectives

From the studies reviewed in this article it can be seen that resveratrol indicates highly potential effects for several human diseases Despite the increasing amount of in vitro and in vivo studies trying to elucidate the mechanisms of action of the resveratrol many questions remain to be subse-quently examined and elucidated Moreover clinical investi-gations are urgently needed to be carried out These studies will provide a basis for the prospective applications of res-veratrol in the treatment and prevention of human diseases

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the expression of the antioxidantcytoprotective heme oxygenase-1 in RAW2647 cells [J] Biomed Pharmacother 2011 1(2) 146-152

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[81] Harper CE Patel BB Wang J et al Resveratrol suppresses prostate cancer progression in transgenic mice [J] Carcinogenesis 2007 28(9) 1946-1953

[82] Busquets S Ametller E Fuster G et al Resveratrol a natural diphenol reduces metastatic growth in an experimental cancer model [J] Cancer Lett 2007 245(1) 144-148

[83] El-mohsen MA Bayele H Kuhnle G et al Distribution of [3H] trans-resveratrol in rat tissues following oral administration [J] Brit J Nutr 2006 96(01) 62-70

[84] Zamin LL Dillenburg-Pilla P Argenta Comiran R et al Protective effect of resveratrol against oxygenndashglucose deprivation in organotypic hippocampal slice cultures involvement of PI3-K pathway [J] Neurobiol Dis 2006 24(1) 170-182

[85] Benitez DA Pozo Guisado E Alvarez Barrientos A et al Mechanisms involved in resveratrol-induced apoptosis and cell cycle arrest in prostate cancer-derived cell lines [J] J Androl 2007 28(2) 282-293

[86] Bi XL Yang JY Dong YX et al Resveratrol inhibits nitric oxide and TNF-α production by lipopolysaccharide-activated microglia [J] Int Immunopharmacol 2005 5(1) 185-193

[87] Meng X Chen G Yang J et al Inhibitory effect of a novel resveratrol derivative on nitric oxide production in lipopolysaccharide-activated microglia [J] Pharmazie 2008 63(9) 671-675

[88] Meng XL Yang JY Chen GL et al Effects of resveratrol and its derivatives on lipopolysaccharide-induced microglial activation and their structurendashactivity relationships [J] Chem-Biol Interact 2008 174(1) 51-59

[89] Meng XL Yang JY Chen GL et al RV09 a novel resveratrol analogue inhibits NO and TNF-α production by LPS-activated microglia [J] Int Immunopharmacol 2008 8(8) 1074-1082

[90] Gao ZB Hu GY Trans-resveratrol a red wine ingredient inhibits voltage-activated potassium currents in rat hippocampal neurons [J] Brain Res 2005 1056(1) 68-75

[91] Rosen DR Siddique T Patterson D et al Mutations in CuZn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis [J] Nature 1993 362(6415) 59-62

[92] Sharma S Kulkarni SK Chopra K Effect of resveratrol a polyphenolic phytoalexin on thermal hyperalgesia in a mouse model of diabetic neuropathic pain [J] Fund Clin Pharmacol 2007 21(1) 89-94

[93] Singh N Pillay V Choonara YE Advances in the treatment of Parkinsons disease [J] Prog Neurobiol 2007 81(1) 29-44

[94] Solans A Zambrano A Rodriacuteguez M et al Cytotoxicity of a mutant huntingtin fragment in yeast involves early alterations in mitochondrial OXPHOS complexes II and III [J] Hum Mol Genet 2006 15(20) 3063-3081

[95] Riviere C Richard T Quentin L et al Inhibitory activity of


stilbenes on Alzheimerrsquos β-amyloid fibrils in vitro [J] Bioorg Med Chem 2007 15(2) 1160-1167

[96] Marambaud P Zhao H Davies P Resveratrol promotes clearance of Alzheimers disease amyloid-β peptides [J] J Biol Chem 2005 280(45) 37377-37382

[97] Han YS Zheng WH Bastianetto S et al Neuroprotective effects of resveratrol against β-amyloid-induced neurotoxicity in rat hippocampal neurons involvement of protein kinase C [J] Brit J Pharmacol 2004 141(6) 997-1005

[98] Vingtdeux V Giliberto L Zhao H et al AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-β peptide metabolism [J] J Biol Chem 2010 285(12) 9100-9113

[99] Porquet D Casadesus G Bayod S et al Dietary resveratrol prevents Alzheimerrsquos markers and increases life span in SAMP8 [J] Age 2012

[100] Jin F Wu Q Lu YF et al Neuroprotective effect of resveratrol on 6-OHDA-induced Parkinsons disease in rats [J] Eur J Pharmacol 2008 600(1-3) 78-82

[101] Blanchet J Longpre F Bureau G et al Resveratrol a red wine polyphenol protects dopaminergic neurons in MPTP-treated mice [J] Prog Neuro-Psychoph 2008 32(5) 1243-1250

[102] Kumar P Padi S SV Naidu PS et al Effect of resveratrol on 3-nitropropionic acid-induced biochemical and behavioural changes possible neuroprotective mechanisms [J] Behav Pharmacol 2006 17(5-6) 485-492

[103] Bermudez Ocana DY Ambriz Tututi M Perez Severiano F et al Pharmacological evidence for the participation of NOndashcyclic GMPndashPKGndashK+ channel pathway in the antiallodynic action of resveratrol [J] Pharmacol Biochem Be 2006 84(3) 535-542

[104] Zhang F Liu J Shi JS Anti-inflammatory activities of resveratrol in the brain role of resveratrol in microglial activation [J] Eur J Pharmacol 2010 636(1) 1-7

[105] Hou RCW Chen YS Chen CH et al Protective effect of 1 2 4-benzenetriol on LPS-induced NO production by BV2 microglial cells [J] J Biomed Sci 2006 13(1) 89-99

[106] Jung WK Ahn YW Lee SH et al Ecklonia cava ethanolic extracts inhibit lipopolysaccharide-induced cyclooxygenase-2 and inducible nitric oxide synthase expression in BV2 microglia via the MAP kinase and NF-[kappa] B pathways [J] Food Chem Toxicol 2009 47(2) 410-417

[107] Barnham KJ Masters CL Bush AI Neurodegenerative diseases and oxidative stress [J] Nat Rev Drug Discov 2004 3(3) 205-214

[108] Wang JY Wen LL Huang YN et al Dual effects of antioxidants in neurodegeneration direct neuroprotection against oxidative stress and indirect protection via suppression of gliamediated inflammation [J] Curr Pharm Design 2006 12(27) 3521-3533

[109] Candelario-Jalil E de Oliveira AC Graf S et al Resveratrol potently reduces prostaglandin E2 production and free radical formation in lipopolysaccharide-activated primary rat microglia [J] J Neuroinflamm 2007 4(25) 1-12

[110] Lorenz P Roychowdhury S Engelmann M et al Oxyresveratrol and resveratrol are potent antioxidants and free radical scavengers effect on nitrosative and oxidative stress derived from microglial cells [J] Nitric Oxide 2003 9(2) 64-76

[111] Guo L Wang LH Sun B et al Direct in vivo evidence of protective effects of grape seed procyanidin fractions and other antioxidants against ethanol-induced oxidative DNA damage in mouse brain cells [J] J Agric Food Chem 2007 55(14) 5881-5891

[112] Yan Y Yang JY Mou YH et al Possible metabolic pathways of ethanol responsible for oxidative DNA damage in human peripheral lymphocytes [J] Alcohol Clin Exp Res 2011 35(1) 1-9

[113] Guo L Yang JY Wu CF Oxidative DNA damage induced by ethanol in mouse peripheral leucocytes [J] Basic Clin Pharmacol Toxicol 2008 103(3) 222-227

[114] Yan Y Yang JY Mou YH et al Differences in the activities of resveratrol and ascorbic acid in protection of ethanol-induced oxidative DNA damage in human peripheral lymphocytes [J] Food Chem Toxicol 2012 50(2) 168-174

[115] Gonthier B Allibe N Cottet-Rousselle C et al Specific Conditions for Resveratrol Neuroprotection against Ethanol-Induced Toxicity [J] J Toxicol 2012 2012 973134

[116] Docherty JJ Mc Ewen HA Sweet TJ et al Resveratrol inhibition of Propionibacterium acnes [J] J Antimicrob Chemother 2007 59(6) 1182-1184

[117] Morselli E Maiuri M Markaki M et al Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy [J] Cell Death Dis 2010 1(1) e10

[118] Shetty A K Promise of resveratrol for easing status epilepticus and epilepsy [J] Pharmacol Therapeut 2011 131(3) 269-286

[119] Goldberg D Yan J Soleas G Absorption of three wine-related polyphenols in three different matrices by healthy subjects [J] Clin Biochem 2003 36(1) 79-87

[120] La PC Voduc N Zhang G et al Steady-state pharmacokinetics and tolerability of trans-resveratrol 2000mg twice daily with food quercetin and alcohol (ethanol) in healthy human subjects [J] Clin Pharmacokinet 2010 49(7) 449-454

[121] Chow H Garland L Hsu C et al Resveratrol modulates drug and carcinogen-metabolizing enzymes in a healthy volunteer study [J] Cancer Prev Res 2010 3(9) 1168-1175

[122] Chachay VS Kirkpatrick CMJ Hickman IJ et al Resveratrol-pills to replace a healthy diet[J] Brit J Clin Pharmacol 2010 72(1) 27-38

[123] Gresele P Cerletti C Guglielmini G et al Effects of resveratrol and other wine polyphenols on vascular function an update [J] J Nutr Biochem 2011 22(3) 201-211

[124] Miceli M Alberti L Bennardini F et al Effect of low doses of ethanol on platelet function in long-life abstainers and moderate wine drinkers [J] Life Sci 2003 73(12) 1557-1566

[125] Timmers S Auwerx J Schrauwen P The journey of resveratrol from yeast to human [J] Aging 2012 4(3) 1-13

[126] Boocock D Patel K Faust G et al Quantitation of trans resveratrol and detection of its metabolites in human ‐

plasma and urine by high performance liquid chromatography [J] J Chromatogr B Analyt Technol Biomed Life Sci 2007 848(2) 182-187

[127] Almeida L Vazda S M Falcao A et al Pharmacokinetic and safety profile of trans-resveratrol in a rising multiple-dose study in healthy volunteers [J] Mol Nutr Food Res 2009 53(1) 7-15

[128] Nunes T Almeida L Rocha J et al Pharmacokinetics of trans-resveratrol following repeated administration in healthy


elderly and young subjects [J] J Clin Pharmacol 2009 49(12) 1477-1482

[129] Vitaglione P Sforza S Galaverna G et al Bioavailability of trans-resveratrol from red wine in humans [J] Mol Nutr Food Res 2005 49(5) 495-504

[130] Brown V Patel K Viskaduraki M et al Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers safety pharmacokinetics and effect on the insulin-like growth factor axis [J] Cancer Res 2010 70(22) 9003-9011

[131] Meng X Maliakal P Lu H et al Urinary and plasma levels of resveratrol and quercetin in humans mice and rats after ingestion of pure compounds and grape juice [J] J Agric Food Chem 2004 52(4) 935-942

[132] Patel K Brown V Jones D et al Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients [J] Cancer Res 2010 70(19) 7392-7399

[133] J Ortuntildeo MI Covas M Farre et al Matrix effects on the bioavailability of resveratrol in humans [J] Food Chem 2010 120(4) 1123-1130

[134] Walle T Hsieh F DeLegge M et al High absorption but very low bioavailability of oral resveratrol in humans [J] Drug Metab Dispos 2004 32(12) 1377-1382

[135] Gresele P Pignatelli P Guglielmini G et al Resveratrol at concentrations attainable with moderate wine consumption stimulates human platelet nitric oxide production [J] J Nutr 2008 138(9) 1602-1608

[136] Urpi SM Jauregui O Lamuela RR et al Uptake of diet resveratrol into the human low-density lipoprotein Identification and quantification of resveratrol metabolites by liquid chromatography coupled with tandem mass spectrometry [J] Anal Chem 2005 77(10) 3149-3155

[137] Ghanim H Sia C Korzeniewski K et al A resveratrol and

polyphenol preparation suppresses oxidative and inflammatory stress response to a high-fat high-carbohydrate meal [J] J Clin Endocrinol Metab 2011 96(5) 1409-1414

[138] Kennedy D Wightman E Reay J et al Effects of resveratrol on cerebral blood flow variables and cognitive performance in humans a double-blind placebo-controlled crossover investigation [J] Am J Clin Nutr 2010 91(6) 1590-1597

[139] Wong RH PR H JD B Acute resveratrol supplementation improves flow-mediated dilatation in overweightobese individuals with mildly elevated blood pressure [J] Nutr Metab Cardiovasc Dis 2011 21(11) 851-856

[140] Nguyen A Martinez M Stamos M et al Results of a phase I pilot clinical trial examining the effect of plant-derived resveratrol and grape powder on Wnt pathway target gene expression in colonic mucosa and colon cancer [J] Cancer Manag Res 2009 1 25-37

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[143] Brasnyo P Molnar G Mohas M et al Resveratrol improves insulin sensitivity reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients [J] Br J Nutr 2011 106(3) 383-389

[144] Timmers S Konings E Bilet L et al Calorie Restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans [J] Cell Metab 2011 14(5) 612-622

[145] Crandall J Oram V Trandafirescu G et al Pilot study of resveratrol in older adults with impaired glucose tolerance [J] J Gerontol A-Biol 2012 67(12) 1307-1312

白藜芦醇的植物来源药理活性及应用

吴春福杨静玉王芳王笑笑

沈阳药科大学生命科学与生物制药学院药理系沈阳110016

辽宁省植物多酚研究与开发工程技术研究中心沈阳110016

【摘要】在过去的数十年中白藜芦醇作为一种广为人知的化合物表现出多种生物活性大量的研究表明白藜芦醇

作为一种天然产物不仅具有潜在的应用价值而且对多种人类疾病有治疗作用且副作用较小本文综述了白藜芦醇的生物来

源药理作用及临床应用现状【关键词】白藜芦醇植物来源药理学作用应用

【基金项目】 ldquo重大新药创制rdquo科技重大专项ldquo十一五rdquo课题ldquo辽宁省国家创新药物孵化(本溪)基地建设项目 (No 2010ZX09401-102) 资助


ble foods including Japanese knotweed (Polygonum cuspi-datum)[9] peanut Vaccinium spp (including blueberry bil-berry and cranberry) Reynoutria japonica and Scots pine Currently resveratrol is usually extracted from red grapes

Table 1 Plant sources of resveratrol[11-14]

Family Genus Species Vitis Vitis spp

Vitaceae Tetrastigma Tetrastigma hypoglau-

cum Moraceae Morus Morus spp

Veratrum Veratrum spp Aloe Aloe spp Lilium Lilium spp Liliaceae

Ornithogalum Ornithogalum cauda-tum

Cassia Cassia spp Cercis Cercis chinensis Glycine Glycine max

Fabaceae

Bauhinia Bauhinia racemosa Rheum Rheum spp polygonum Polygonum spp Polygonaceae Fallopia Fallopia spp Picea

Pinaceae Pinus Pinus spp Festuca Festuca spp Hordeum Hordeum vulgare Poa Poa spp Stipa Stipa spp

Poaceae

Lolium Lolium spp Paeoniaceae Paeonia Paeonia lactiflora Myrtaceae Eucalyptus

Araliaceae Panax Panax pseudo-ginseng var notoginseng

Asteraceae Aster Aster tataricus Magnoliaceae Magnolia Magnolia officinalis

Arachis Arachis spp Fabaceae

Trifolium Trifolium spp Juglandaceae Juglans Juglans regia Moraceae Morus Morus alba Oleaceae Olea Olea europaea

Ericaceae Vaccinium Vaccinium myrtillus Vaccinium vitis-idaea Vaccinium oxycoccos

Rubus Rubus idaeus Rosaceae

Prunus Prunus mume Rhamnaceae Ziziphus Ziziphus jujuba Theaceae Camellia Bromeliaceae Ananas Ananas comosus Pandanaceae Pandanus Betulaceae Alnus Lauraceae Cinnamomum Gnetaceae Gnetum Gnetum montanum

and it has been estimated that fresh grape skin contains about 50minus100 microg of resveratrol per gram In red wine the concen-trations of resveratrol according to some authors are in the range of 15minus3 mgmiddotLminus1 while other reports suggest substan-tially higher amounts (4minus20 mgmiddotLminus1)[10] Significant quantities are also found in some white and rose wines In commercial grape juice the concentrations of resveratrol are approxi-mately 4 mgmiddotLminus1 (Table 2)

Table 2 Resveratrol content in wines or grape juice[10]

Beverage Total Resveratrol (mgmiddotLminus1)

Total Resveratrol in 150 mL winemg

Red Wines (Global) 198minus713 030minus107

Red Wines (Spanish) 192minus1259 029minus189

Red grape juice (Spanish) 114minus869 017minus130

Rose Wines (Spanish) 043minus352 006minus053

Pinot Noir 040minus200 006minus030

White Wines (Spanish) 005minus180 001minus027

Italian Red Wine 197minus567 03minus086

Chilean Merlot Wine 225 035

22 Structure of resveratrol

Resveratrol exists in the cis- and trans- stereoisomeric forms Usually this polyphenol is present in dietary products essentially in glycosylated forms known as piceid (resvera-trol-3-O-β-D-glucoside) Both cis- and trans-resveratrol exist naturally and appear to exert similar effects although yet the actions of the trans isoform are more widely investigated[1]

Fig 1 Chemical structures of trans- and cis-resveratrol Resveratrol (3 5 4rsquo-trihydroxystilbene) is a derivative of stilbene (stilbenoid) and exists as two diastereomers trans- (E) and cis- (Z) The trans- form is the preferred steric form in nature and is relatively stable It can undergo isomerisa-tion to the cis- form when exposed to ultraviolet irradiation

3 Pharmacological Activities

An increasing number of studies have examined the pharmacological properties of resveratrol related to many human diseases including cardiovascular disease diabetic mellitus neurodegenerative disease and cancer As inflam-mation can lead to further oxidative stress in a cycle that is associated with many diseases the anti-oxidative and









































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130]



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Cancer

























Diabetic men (19)











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Cancer

























Diabetic men (19)











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130]



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resveratrol botanical origin, pharmacological

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