Parkinson's disease (PD) is a mysterious, chronic, multi-factorial and progressive disorder of the nervous system that is characterized by the selective loss of dopamine-producing cells of the substantia nigra leading to dopamine deficiency in the striatum. PD is exemplified by oxidative stress, α-synuclein accumulation, mitochondrial dysfunction, defective ubiquitin proteasome system, aberrant autophagy, inflammation, and atypical apoptosis, which eventually lead to slowness of movement, resting tremor, stiffness, and loss of balance. Despite incomprehensible etiology, timely diagnosis, and permanent cure, a handful of synthetic and natural agents rescue from the symptomatic features and delay disease progression. At low doses, a natural polyphenol, <em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em> (resveratrol), delays neurodegeneration in the cellular and animal models and lessens oxidative stress, mitochondrial dysfunction, aberrant apoptosis, and defective autophagy. The present article explains neuroprotective efficacy, advantages, and downsides of resveratrol in the conventional and preclinical models. This piece of writing also examines its probable neuroprotective mechanisms and constraints of realistic recital in clinical investigations and likely endeavors to minimize apprehensions.

Oxidative stress and inflammation are hypothesized to contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD). Resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>) is known for its antioxidant and anti-inflammatory properties. The study aimed to investigate the effects of resveratrol in a rat model with COPD on the regulation of oxidative stress and inflammation via the activation of Sirtuin1 (SIRTl) and proliferator-activated receptor-γ coactivator-1α (PGC-1α). Thirty Wistar rats were randomly divided into three groups: control group, COPD group and resveratrol intervention group. The COPD model was established by instilling with lipopolysaccharide (LPS) and challenging with cigarette smoke (CS). The levels of interleukin-6 (IL-6) and interleukin-8 (IL-8) in serum were measured. The levels of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) were measured. The expression levels of SIRT1 and PGC-1α in the lung tissues were examined by immunohistochemistry as well as real-time reverse <em>trans</em>criptase polymerase chain reaction (real-time RT-PCR) and western blotting analysis. After the treatment with resveratrol (50 mg/kg), compared with the COPD group, alleviation of inflammation and reconstruction in the small airways of the lungs were seen. Resveratrol might be correlated not only with the lower level of MDA and the higher activity of SOD, but also with the upregulation of SIRT1 and PGC-1α expression. Resveratrol treatment decreased serum levels of IL-6 and IL-8. Our findings indicate that resveratrol had a therapeutic effect in our rat COPD model, which is related to the inhibition of oxidative stress and inflammatory response. The mechanism may be related to the activation and upgrading of the SIRT1/PGC-1α signaling pathways. Thus resveratrol might be a therapeutic modality in COPD.

<em>trans</em>-Resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>), a phenolic compound present in grapes, wines, and peanuts, has been reported to have health benefits including anticarcinogenic effects and protection against cardiovascular diseases. Despite its importance, little is known about its bioavailability in both humans and animals. A fundamental step for this evaluation consisted in measuring this stilbene in blood. In the present work, a simple and rapid HPLC method with diode array-UV detection has been developed. Resveratrol contained in plasma was purified by solid-phase extraction using a C18 cartridge. The sample was rinsed with water and methanol-water (25:75 v/v), and <em>trans</em>-resveratrol was finally eluted with methanol. The collected fraction was evaporated under nitrogen and analyzed by HPLC. The method was validated by obtaining a linear correlation, a detection limit of 20 micrograms/L, and a good precision with a coefficient of variation of 2.85%. <em>trans</em>-Resveratrol administered orally to rats was detected in plasma. With this procedure, excellent separation of <em>trans</em>-resveratrol is achieved, thus allowing a rapid analysis of the sample for absorption, distribution, and metabolism studies.

S-adenosyl-L-methionine serves as a methyl donor in virtually all of the vast number of enzymatic <em>trans</em>methylation reactions including DNA methylation. On the basis of our former experiences we questioned the formation of a methyl cation or methyl radical in the enzymatic <em>trans</em>methylation reactions. The formation of formaldehyde from the methyl moiety of S-adenosyl-L-methionine has been demonstrated. It became increasingly evident that there is a formaldehyde cycle in biological systems in which the formation of the methyl group of L-methionine takes place through formaldehyde and the formation of formaldehyde from S-adenosyl-L-methionine is linked to different enzymatic <em>trans</em>methylation reactions. It is also known that during demethylation processes both formaldehyde and demethylated compound can be formed. The abnormalities of the originally controlled formaldehyde cycle and the uncontrolled enzymatic production of formaldehyde from endogenous and/or exogenous substrates may be potential risk factors in pathogenesis of different disorders. The formaldehyde generator and capturer molecules may potentially normalise these abnormal processes. <em>Trans</em>-resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>), which is as phytoalexin, occurs naturally in grapes and a variety of medicinal plants. According to our present observations it is a natural concentration-dependent formaldehyde capture molecule. It would seem that elimination of the uncontrolled formaldehyde with resveratrol may exert a double effect in biological systems. The elimination of formaldehyde with resveratrol (first step) may cause a cardioprotective effect and the reaction products between resveratrol and formaldehyde (second step) may act as a chemopreventive factor against cancer.

Lipopolysaccharide (LPS) is a glycolipid component of the cell wall of Gram-negative bacteria, which induces a deleterious effect on several organs, including the heart, eventually leading to septic shock and death. Endotoxemia-induced cardiotoxicity is characterized by disturbed intracellular redox balance, excessive reactive oxygen species (ROS) accumulation, inducing DNA, protein, and membrane lipid damage. Resveratrol (<em>trans</em>-<em>3,5,4</em>' <em>trihydroxystilbene</em>; RVT) is a phytoalexin polyphenol that exhibits antioxidant and -inflammatory properties. We investigated the putative effect of a subacute treatment with this natural compound on LPS-induced cardiotoxicity in the rat. We found that resveratrol counteracted LPS-induced lipoperoxidation and decreased superoxide dismutase (SOD) activity, but had no effect on the LPS-induced decrease in catalase (CAT) nor on the increase in peroxidase (POD) activity. Resveratrol also reversed LPS-induced myocardial nitric oxide (NO) elevation. More important, LPS-induced iron depletion from plasma to the myocardial compartment was abolished upon resveratrol treatment. All these data suggest that resveratrol is capable of alleviating LPS-induced cardiotoxicity, and that its mode of action may involve iron-shuttling proteins.

The presence of resveratrol (<em>3,5,4</em>'-<em>trihydroxystilbene</em>) and its beta-glucoside, piceid (resveratrol-3-beta-D-glucopyranoside), together with their isomers in wine appears to be one of the beneficial factors conferring a protective effect against cardiovascular disease through red wine ingestion. A total of 42 red and white wines was collected in areas from Hokkaido to Kyushu in Japan. The wines were fractionated with a C18 Sep-pak cartridge, and the active principles were eluted with ethyl acetate. Crude <em>trans</em>- and cis-piceid were extracted from a Chinese medicine, 'Kojohkon' (Polygonum cuspidatum), and their retention times and UV absorption were confirmed by HPLC. <em>trans</em>- and cis-Resveratrol, and <em>trans</em>- and cis-piceid were analyzed in a short C18 HPLC column, and cis-resveratrol was quantified from the amount of cis-isomer converted from authentic <em>trans</em>-resveratrol that had been treated by UV irradiation. The content of piceid is shown as the resveratrol equivalent. The average content of total stilbene compounds was 4.37 mg/liter in red wines, while only 0.68 mg/liter in white wines. Red wines made from Pinot noir, Merlot, and Zweigeltrebe grapes all had a high resveratrol content.

Resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>) is a natural phytochemical found in grapes and wine. Numerous biological effects of resveratrol have been reported in the last 10 years. In this paper, the competitive inhibition of intracellular uptake of glucose and dehydroascorbic acid in U937 and HL-60 cells by resveratrol is reported.

Red wine is enriched in resveratrol, <em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>, a compound in grape skin that inhibits the development of pre-neoplastic lesions in mouse mammary tumor cells in culture and inhibits cancer cell proliferation in vitro. Grapes also contain other bioactive compounds including flavonoids, flavans, and anthocyanins. The estrogenic activities of extracts prepared from one white (Freie Weingärtner Wachau, Grüner Veltliner, Austria) and two red wines (Woodbridge, Cabernet Sauvignon, California; and Lenz Moser Prestige, Blaufränkisch Barrique, Austria) were examined and compared with those induced by estradiol (E(2)) and <em>trans</em>-resveratrol. First, the estrogenic activity of the wine extracts was evaluated in a yeast estrogen screen (YES) assay, in which yeast express copper-inducible estrogen receptor alpha (ERalpha) and an estrogen-response-element (ERE)-driven beta-galactosidase reporter. In YES, the white wine extract showed no estrogenic activity. In contrast, both of the red wine extracts showed estrogenic activity equivalent to that of 0.2 nM E(2). Similarly, the white wine extract showed no <em>trans</em>criptional activity with either ERalpha and ERbeta in <em>trans</em>iently <em>trans</em>fected CHO-K1 cells. In contrast, both red wine extracts stimulated ERE-reporter activity in a concentration-dependent manner that was inhibited by 4-hydroxytamoxifen (4-OHT), indicating that the observed <em>trans</em>criptional activity was ER-mediated. The red wine extracts showed significantly higher ERbeta versus ERalpha agonist activity. Resveratrol showed no agonist activity in YES but activated ERalpha and ERbeta in CHO-K1 cells in a concentration-dependent manner that was inhibited by 4-OHT. This indicates that resveratrol requires mammalian cell components that are absent in yeast for estrogen agonist activity, whereas the estrogenic activity of wine extracts is directly through ERalpha and does not require mammalian cell factors such as coactivators. The estrogenic activity in red wine found by using YES indicates that estrogenic compounds other than resveratrol are present. Chemical analysis clearly showed that the <em>trans</em>-resveratrol content of the red wine extracts was 1 order of magnitude below the detection limit for YES assay.

The interaction of resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>) and two of its derivatives (<em>3,5,4</em>'-tri-O-methylresveratrol and <em>3,5,4</em>'-tri-O-triacetylresveratrol) with biomembrane models, represented by dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles (MLV), has been studied by differential scanning calorimetry (DSC). The analysis of MLV prepared in the presence of increasing molar fraction of such compounds has been carried out to reveal their maximum interaction with biomembrane models. The results from these studies have been compared with kinetic experiments results, in order to detect the entity and rate of compound absorption by the biomembrane models. The findings indicate that the compounds affected the thermotropic properties of DMPC MLV by suppressing the pre<em>trans</em>ition peak and broadening the DMPC main phase <em>trans</em>ition calorimetric peak and shifting it to lower temperatures. The order of effectiveness found was resveratrol>> trimethylresveratrol>> triacetylresveratrol. The kinetic experiments reveal that in an aqueous medium the absorption of resveratrol by the biomembranes models is allowed, whereas the absorption of its derivatives is hindered; in contrast when a lipophilic medium is employed, all three compounds are easily absorbed.

Resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>; RSV), a natural polyphenol, exerts a beneficial effect on health and diseases. RSV targets and activates the NAD(+)-dependent protein deacetylase SIRT1; in turn, SIRT1 induces an intracellular antioxidative mechanism by inducing mitochondrial superoxide dismutase (SOD2). Most RSV found in plants is glycosylated, and the effect of these glycosylated forms on SIRT1 has not been studied. In this study, we compared the effects of RSV and two glycosyl RSVs, resveratrol-3-O-β-d-glucoside (3G-RSV; polydatin/piceid) and resveratrol-4'-O-β-d-glucoside (4'G-RSV), at the cellular level. In oxygen radical absorbance capacity and 2,2-diphenyl-1-picrylhydrazyl radical scavenging assays, the antioxidant activity of 3G-RSV was comparable to that of RSV, whereas the radical-scavenging efficiency of 4'G-RSV was less than 50% of that of RSV. However, 4'G-RSV, but not 3G-RSV, induced SIRT1-dependent histone H3 deacetylation and SOD2 expression in mouse C2C12 skeletal myoblasts; as with RSV, SIRT1 knockdown blunted these effects. RSV and 4'G-RSV, but not 3G-RSV, mitigated oxidative stress-induced cell death in C2C12 cells and primary neonatal rat cardiomyocytes. RSV and 4'G-RSV inhibited C2C12 cell proliferation, but 3G-RSV did not. RSV was found in both the intracellular and extracellular fractions of C2C12 cells that had been incubated with 4'G-RSV, indicating that 4'G-RSV was extracellularly deglycosylated to RSV, which was then taken up by the cells. C2C12 cells did not deglycosylate 3G-RSV. Our results point to 4'G-RSV as a useful RSV prodrug with high water solubility. These data also show that the in vitro antioxidative activity of these molecules did not correlate with their ability to protect cells from oxidative stress-induced apoptosis.

Resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>, Res) is a naturally occurring antioxidant found in grape berry skins and red wine. It has anti-inflammatory effects. In this study, we examined the effect of Res on the formation of phosphatidic acid (PA) and diglyceride (DG), in human neutrophils stimulated by formyl-methionyl-leucyl-phenylalanine (fMLP) or by phorbol 12-myristate 13-acetate (PMA). We measured the masses of PA and DG by using a nonradioactive method. Our results showed that Res inhibited the formation of PA in a concentration dependent manner with an IC(50) value of 42.4 and 60.9 microM in fMLP- and PMA-stimulated cells, respectively. Res also suppressed the formation of phosphatidylethanol (PEt), thereby implying inhibition of phospholipase D (PLD) activity. In addition, Res inhibited the formation of both diacylglycerol (DAG) and ether-linked acylglycerol (EAG) induced by fMLP and by PMA. Our results suggest that Res inhibition of PLD activity may contribute to its anti-inflammatory effects.

The Caco-2 cell monolayer permeability assay has become a standard model of human intestinal absorption and <em>trans</em>port. This paper reviews recent progress in increasing the throughput of Caco-2 cell monolayer assays and in expanding the scope of this assay to include modeling intestinal drug metabolism. The state-of-the-art in Caco-2 cell monolayer permeability assays combines multi-well plates fitted with semi-permeable inserts on which Caco-2 cells have been cultured with liquid chromatography-mass spectrometry (LC-MS) or LC-tandem mass spectrometry (LC-MS-MS) for the quantitative analysis of test compounds and the identification of their intestinal metabolites. After reviewing the progress in increasing the throughput of Caco-2 cell monolayer assays for both modeling human intestinal permeability or <em>trans</em>port and the metabolism of xenobiotic compounds, we demonstrate the application of LC-MS and LC-MS-MS to the measurement of resveratrol permeability and metabolism in the Caco-2 model. <em>trans</em>-Resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>) is a polyphenolic compound occurring in grapes, peanuts and other food sources, that is under investigation as a cancer chemoprevention agent. The apparent permeability coefficient for apical (AP) to basolateral (BL) movement of resveratrol was 2.0 x 10(-5)cm/sec. Resveratrol was not a substrate for P-glycoprotein or the multi-drug resistance associated proteins (MRP). No phase I metabolites were observed, but the phase II conjugates resveratrol-3-glucuronide and resveratrol-3-sulfate was identified based on LC-MS and LC-MS-MS analysis and comparison with synthetic standards. Although these data indicate that resveratrol diffuses rapidly across the intestinal epithelium, extensive phase II metabolism during absorption might reduce resveratrol bioavailability.

The potential cancer-preventive effects of resveratrol, evident from the data obtained by various studies, are summarized in this review. Resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>), a naturally occurring polyphenolic compound, was first isolated in 1940 as a constituent of the roots of white Hellebore (Veratrum grandiflorum O. Loes), and is now found to be present in various plants including grapes, berries, peanuts, and red wine. This review first briefly describes the current evidence on the link between resveratrol and cancer occurrence, based on epidemiological studies. Subsequently, investigations with resveratrol in animal models of colon carcinogenesis are presented, followed by a comprehensive compilation of resveratrol on cancer. In the second part, the article focuses on results from investigations on cancer-preventive mechanisms of resveratrol. Biological activities including antioxidant effects, modulation of carcinogen metabolism, anti-inflammatory potential, antioxidant properties, antiproliferative mechanisms by induction of apoptosis, and cell differentiation are discussed. Some novel information on its modulating effects on cell signaling pathway, metabolism studies, bioavailability, and cancer-preventive efficacy is also provided. Based on these findings, resveratrol may be used as a promising candidate for cancer chemoprevention.

Resveratrol, <em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>, is a polyphenolic compound which has been reported to mimic the gene expression patterns seen in whole animals undergoing dietary restriction. The mechanism of action of resveratrol remains poorly understood, but modulation of both cellular proliferation and apoptosis has been proposed as important routes by which the molecule may exert its effects. This study reports the effects of both resveratrol and dihydroresveratrol (a primary in vivo metabolite) on the proliferative capacity of human primary fibroblasts. No generalised reduction in the growth fraction was observed when fibroblasts derived from three different tissues were treated with resveratrol at concentrations of 10 μm or less. However, concentrations above 25 μm produced a dose-dependent reduction in proliferation. This loss of the growth fraction was paralleled by an increase in the senescent fraction as determined by staining for senescence associated beta galactosidase and dose recovery studies conducted over a 7-day period. Entry into senescence in response to treatment with resveratrol could be blocked by a 30-min preincubation with the p38 MAP kinase inhibitor SB203580. No effects on proliferation were observed when cells were treated with dihydroresveratrol at concentrations of up to 100 μm.

<AbstractText>Resveratrol (RESV; <em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>) has emerged as a potential new therapeutic for age-related atherosclerotic diseases. However, the effect of RESV on cellular aging and its underlying mechanisms remain unknown. Therefore, the aim of this study was to examine whether RESV can delay cellular aging through upregulation of autophagy.</AbstractText><p><div><b>Materials and methods</b></div>Human umbilical endothelial vein cells (HUVECs) were divided into four groups: the control group, and the hydrogen peroxide (H₂O₂) alone, H₂O₂ + RESV pretreatment, and H₂O₂ + 3-methyladenine (3-MA) + RESV pretreatment intervention groups. The cell viability was evaluated by a cell counting kit-8 assay. Superoxide dismutase (SOD) activity and intracellular reactive oxygen species (ROS) levels were tested using commercial kits. Senescence-related β-galactosidase activities were detected by immunohistochemical staining. The expression levels of aging-related and autophagy-related markers, including phosphorylated Rb (p-Rb), LC3, and p62, with or without RESV were measured by Western blotting.</p><p><div><b>Results</b></div>Pretreatment with 10 µM RESV increased the cell viability and SOD levels. The remarkably higher positive rate of senescence-associated β-galactosidase and increased intracellular ROS levels in the H₂O₂ treatment group were reversed by treatment with 10 µM RESV. As compared to the H₂O₂ treatment group, 10 µM RESV could upregulate autophagy through the regulation of p-Rb, LC3, and p62 levels. The anti-aging effect of RESV via an autophagy regulation mechanism was further confirmed by the suppression of these effects with 3-MA treatment.</p><AbstractText>RESV may reverse and delay the aging process of HUVECs via upregulation of autophagy and could be a candidate therapeutic for age-related atherosclerotic diseases.</AbstractText>

Resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>) is a nutritional supplement with anti-inflammatory properties. The present study investigated the long-term anti-inflammatory property of resveratrol in the retinas of type 2 diabetic rats. Male Wistar rats were divided into four groups: normal control, diabetic control, resveratrol-treated normal rats and resveratrol-treated diabetic rats. Type 2 diabetes was induced by a single dose injection of streptozotocin (50 mg/kg; i.p.) 15 min after the administration of nicotinamide (110 mg/kg; i.p.) in 12-h fasted rats (the streptozotocin-nicotinamide type 2 diabetic model). Oral resveratrol administration (5 mg/kg per day for 4 months) significantly improved glucose tolerance, and alleviated hyperglycemia and weight loss in diabetic rats. Furthermore, resveratrol administration significantly decreased the elevated levels of nuclear factor-κB activity, and mRNA expression, tumour necrosis factor alpha level and apoptotic cells in the retinas of the diabetic rats. Furthermore, resveratrol did not significantly affect plasma insulin levels. Long-term resveratrol administration has beneficial anti-inflammatory properties in a rat model of diabetes. However, whether resveratrol exerts its effects directly or through reducing blood glucose levels requires further investigation.

Resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>), a polyphenolic compound found largely in the skins of red grapes, has been used as a nutritional supplement or an investigational new drug for prevention of cardiovascular diseases. Previous reports showed that resveratrol had a protective effect against oxidative agent-induced cell injury. Our studies indicate that resveratrol plays a role in the differentiation of cardiomyoblasts. The cardiomyoblast cell line, H9c2, was exposed to 30-120 microM resveratrol for up to 5 days. Resveratrol inhibits cardiomyoblast proliferation without causing cells injury. Moreover, resveratrol treatment modulated the differentiation of morphological characteristics including elongation and cell fusion in cardiomyoblasts. Proliferation and differentiation of H9c2 cells were further revealed by measurement of the mRNA expression of a cell cycle marker (CDK2), a differentiation marker (myogenin), and a contractile apparatus protein (MLC-2). Gene expression analysis revealed that resveratrol promoted entry into cell cycle arrest but extended the myogenic differentiation progress. These results have implications for the role of resveratrol in modulating cell cycle control and differentiation in cardiomyoblasts.

We previously found that passion fruit (Passiflora edulis) seeds contained a high amount of piceatannol (3,5,3',4'-<em>trans</em>-tetrahydroxystilbene), a natural analog of resveratrol (<em>3,5,4</em>'-<em>trans</em>-<em>trihydroxystilbene</em>). Resveratrol has been proposed as a potential anti-metabolic disorder compound, by its activation of sirtuin and AMP-activated protein kinase. Many reports show that resveratrol ameliorates diet-induced obesity and insulin resistance. However, it is not known whether piceatannol also affects diet-induced obesity. We explored the effect of piceatannol on high fat diet-fed mice. The results showed that piceatannol did not affect high fat diet-induced body weight gain or visceral fat gain in mice. However, piceatannol did reduce fasting blood glucose levels. Furthermore, to explore the potential of passion fruit seed extract containing piceatannol as a functional food, passion fruit seed extract was administered in a genetic diabetic mouse model (db/db mice). Single administration of passion fruit seed extract, as well as piceatannol reduced the blood glucose levels of these db/db mice. These results suggest that piceatannol and passion fruit seed extract may have potential application in the prevention of diabetes.

The inhalation anesthetic, isoflurane, induces learning and memory impairment. Mitochondrial dysfunction and oxidative stress are thought to play important roles in isoflurane-induced neuroapoptosis. In this study, we treated neuronal cells with isoflurane for 6 h. We found that isoflurane induced the opening of mitochondrial permeability <em>trans</em>ition pores, increased the levels of reactive oxygen species and the activation of caspase‑3, and decreased the mitochondrial membrane potential and the intracellular calcium ion concentration. Resveratrol (RESV; <em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>), a naturally occurring phytoalexin, is found at high concentrations in the skin of red grapes and red wine and has been demonstrated to have anti-infective, antioxidant and cardioprotective functions. Our findings demonstrated that the neuroprotective effects of RESV were independent on its direct radical scavenging properties. Following treatment of the cells with various concentrations of RESV, we found that RESV induced the expression of mitochondrial superoxide dismutase and catalase activity, and reduced mitochondrial oxidative stress and damage. The data from the present study demonstrate that RESV effectively protects neuronal cells from isoflurane-induced cytotoxicity by activating the Akt signaling pathway.

It has been reported that resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>) from Vitis plants has various cardioprotective effects. Vitis plants also include various resveratrol tetramers. The aim of our study is to clarify the pharmacological properties of resveratrol tetramers. We isolated two resveratrol tetramers as major products of Vitis plants. One is vitisin A, a complex of two resveratrol dimers, (+)-epsilon-viniferin and ampelopsin B, and the other is hopeaphenol, composed of 2 mol ampelopsin B. Vitisin A (30-300 nM) unexpectedly dose-dependently facilitated swelling and depolarization of mitochondria and cytochrome c release from mitochondria, which are indices of cardiomyocyte apoptosis. Furthermore, vitisin A induced apoptosis in the primary culture of adult rat ventricular myocytes. On the other hand, hopeaphenol (1-10 microM) dose-dependently inhibited Ca(2+) (30 microM)-induced mitochondrial depolarization and cytochrome c release from mitochondria but had not affected mitochondrial swelling. Moreover, hopeaphenol inhibited vitisin A-induced apoptosis. In structural and functional studies, we further confirmed that vitisin B, one of the resveratrol tetramers having (+)-epsilon-viniferin unit, induces mitochondrial swelling and cytochrome c release from mitochondria like vitisin A and that vitisifuran A, one of the resveratrol tetramers having the ampelopsin B unit, inhibits Ca(2+)-induced cytochrome c release from mitochondria like hopeaphenol. These results show that resveratrol tetramers have at least two opposite effects on cardiomyocytes; the one having the (+)-epsilon-viniferin unit induces cardiomyocyte apoptosis, and the other having ampelopsin B but not (+)-epsilon-viniferin unit inhibits it.

Consumption of high-fat diet (HFD) is related with increased oxidative stress and dysfunctional mitochondria in many organs. The effects of resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>) that can protect T lymphocytes in various disease conditions on the HFD-induced apoptosis of CD4(+) CD25(+) CD127(low/-) regulatory T cells (Tregs) were studied, and the possible mechanism was postulated. Resveratrol significantly decreased Tregs death induced by 20-wk HFD, being associated with the reduction of reactive oxygen species production and the alleviation of HFD-induced loss of mitochondrial membrane potential (Δψm) in Tregs. Furthermore, resveratrol increased the expression of factors that regulated mitochondrial biogenesis in Tregs. Finally, resveratrol recovered the HFD-induced activation of apoptotic markers in Tregs. Resveratrol protected Tregs against HFD-induced apoptosis by reducing oxidative stress, restoring mitochondrial functional activities, and stimulating mitochondrial biogenesis.

<em>Trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em> (<em>trans</em>-resveratrol, RES) exhibits very low bioavailability due to extensive conjugative metabolism. Whether RES metabolites exhibit pharmacologic activity is of great interest. The present study aimed at synthesis of monoconjugates of RES - the 3- and 4' monosulfates (R3S and R4'S), and the 3- and 4' monoglucuronides (R3G and R4'G). Synthesis, purification, and yield are described. Synthesized metabolites were utilized to develop a sensitive LC-MS(n) assay for direct quantitation of all analytes. The assay was validated for intra- and inter-day precision and accuracy. Synthesis of RES conjugates and development and validation of a sensitive bioanalytical assay were applied to pharmacokinetic evaluation of RES and its circulating monoconjugates in C57BL mice. The study is a first report of direct quantitation of RES monosulfates and monoglucuronides. These results will aid in characterizing the disposition of RES and its major or active metabolites in vivo.

The phytochemical resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>) has drawn great interest as health-promoting food ingredient and potential therapeutic agent. However, resveratrol shows vanishingly low water solubility; this limits its uptake and complicates the development of effective therapeutic forms. Glycosylation should be useful to enhance resveratrol solubility, with the caveat that unselective attachment of sugars could destroy the molecule's antioxidant activity. UGT71A15 (a uridine 5'-diphosphate α-D-glucose-dependent glucosyl<em>trans</em>ferase from apple) was used to synthesize resveratrol 3,5-β-D-diglucoside; this was about 1700-fold more water-soluble than the unglucosylated molecule (∼0.18 mM), yet retained most of the antioxidant activity. Resveratrol 3-β-D-glucoside, which is the naturally abundant form of resveratrol, was a practical substrate for perfect site-selective conversion into the target diglucoside in quantitative yield (g L-1 concentration).

Bile acids are a special group of biological surfactants which can express different physiological and pharmacological effects. Micellar solutions of bile acids can solubilizate poorly soluble organic substances and improve their resorbtion. Above their critical micellar concentration (CMC) values, bile acids can cause interruption of membrane's integrity. Resveratrol (<em>trans</em>-<em>3,5,4</em>'-<em>trihydroxystilbene</em>) is a stilbene phytoalexine and studies reported that it can prevent or reduce diseases such as cancer and coronary heart disease. In this study, we examined affinity of different bile acids (CA, 12-MDCA, 12-MCA, 7-MCA, 7,12-DCA, 3,7,12-TCA) micellar solutions for resveratrol solubilization. CMC values for bile acids were determined by conductivity measurements. Concentration of micellar solutions were 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0 CMC value, for each acid respectively. At the same time, we investigated membranolytical potential of each acid. Solubilizated resveratrol was quantified using HPLC system with UV detection. Membranolytical potential was determined from citrate rabbit blood. Structures of mixed micelles of each bile acid and resveratrol were explained, and multiple linear regression equations for solubilization of resveratrol on different concentrations of bile acids were obtained. Micellar solution of 3,7,12-TCA had the biggest affinity for resveratrol solubilization and then, in decreasing order 7-MCA>7, 12-DCA>12-MCA>12-MDCA>CA. Also, 3,7,12-TCA had the lowest membranolytical potential.