Resveratrol is a well known polyphenol largely produced in grapevine. It is a strong antioxidant and a free radical scavenger. It exhibits several beneficial effects for health including cancer. Resveratrol antioxidant activity is essential in the prevention of chemical-induced cancer by inhibiting initiation step of carcinogenesis process but it is also considered to inhibit cancer promotion and progression steps.While the effects of resveratrol on cancer cells are widely described, the data available on the antiproliferative potential of resveratrol derivatives remain weak. Nevertheless, resveratrol analogs could exhibit stronger potentials than the parent molecule. So, we compared the cellular effects of trans-resveratrol, trans-epsilon-viniferin and their respective acetate derivatives, as well as a polyphenol mixture extracted from grapevine shoots, called vineatrol. We studied their abilities to interfere with cell proliferation, their uptake and their effects on parameters of cellular state in human hepatoma cells (HepG2).Cell growth experiments show that resveratrol triacetate presents a slightly better antiproliferative potential than resveratrol. The dimer epsilon-viniferin,as well as its pentaacetate analog, is less powerful than resveratrol, although a similar uptake kinetics in cells. Interestingly, among the tested polyphenols, vineatrol is the most potent solution, indicating a possible synergistic effect of both resveratrol and epsilon-viniferin. We took advantage of the fluorescence properties of these compounds to evidence cellular uptake by using flow cytometry. In addition, by competition assay, we demonstrate that resveratrol triacetate enters in hepatic HepG2 cells by the same way as resveratrol. By autofluorescence in situ measurement we observed that resveratrol and related compounds induce deep changes in cells activity. These changes occur mainly by increasing NADPH cell content and the number of green fluorescent cytoplasmic granular structures which may be related to an induction of detoxifying enzyme mechanisms. (c) 2008 Elsevier Masson SAS. All rights reserved.

In order to provide a global analysis of the effects of endocrine disruptors on the hormone cellular bioavailability, we combined 17 beta-estradiol (E2) cellular flow studies with real-time PCR and Western blot expression measurements of genes involved in the hormone metabolism and excretion. Three endocrine disruptors commonly found in food were chosen for this study, which was conducted in the estrogen receptor (ER) negative hepatoblastoma HepG2 cell line: bisphenol A (BPA), genistein (GEN) and resveratrol (RES). We showed that 24h after a single dose treatment with genistein, resveratrol or bisphenol A, the expression of ATP-binding cassette transporters (the multidrug resistance or MDR, and the multidrug resistance associated proteins or MRP) uridine diphosphate-glucuronosyltransferases (UGT) and/or sulfotransferases (ST) involved in 17 beta-estradiol elimination process were significantly modulated and that 17 beta-estradiol cellular flow was modified. Resveratrol induced MDR1 and MRP3 expressions, bisphenol A induced MRP2 and MRP3 expressions, and both enhanced 17 beta-estradiol efflux. Genistein, on the other hand, inhibited ST1E1 and UGT1A1 expressions, and led to 17 beta-estradiol cellular retention. Thus, we demonstrate that bisphenol A, genistein and resveratrol modulate 17 beta-estradiol cellular bioavailability in HepG2 and that these modulations most probably involve legulations of 17 beta-estradiol phase II and III metabolism proteins. Up to now, the estrogenicity of environmental estrogenic pollutants has been based on the property of these compounds to bind to ERs. Our results obtained with ER negative cells provide strong evidence for the existence of ER-independent pathways leading to endocrine disruption. (C) 2008 Elsevier Inc. All rights reserved.

trans-Resveratrol is a polyphenol present in several plant species. Its chemopreventive properties against several diseases have been largely documented. To validate a model for the study of the factors influencing its biological fate at the hepatic level, the metabolism and the efflux of resveratrol were studied in the human hepatoblastoma cell line, HepG2. Comparative high-performance liquid chromatography analysis of cell culture media before and after deconjugation showed that resveratrol was rapidly conjugated; at the concentration of 10 μM, it was entirely metabolized at 8 h of incubation. Two main resveratrol metabolites, monosulfate and disulfate, were identified by atmospheric pressure chemical ionization-mass spectrometry, thanks to their quasi-molecular ion and their characteristic fragmentation. To correlate with the auto-induction of resveratrol metabolism evidenced in HepG2 cells after a pretreatment for 48 h with 10 μM resveratrol, the inducibility of phase II enzymes by resveratrol was studied by real-time quantitative reverse transcriptase-polymerase chain reaction and flow cytometry. Observed, in particular, were an increase in mRNA expression levels of three metabolizing enzymes, two isoforms of UDP-glucuronosyltransferases, UGT1A1 and UGT2B7 (5-fold increased), and a sulfotransferase, ST1E1, in cells pretreated for 24 h with 10 μM resveratrol. These results were correlated with an increase in protein expression, especially after 48 h of treatment. On the other hand, the intracellular resveratrol retention in cells treated with MK571 (3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid), a multidrug resistance-associated protein inhibitor, strongly suggests the involvement of this ABC transporter family in the efflux of resveratrol conjugates from human liver.

Resveratrol(3,4',5tri-hydroxystilbene) is a plant phoalexin produced in massive amount in grapevine skin in response to stress such as UV, phytosanitary treatment, and mostly following infection by Bothrytis cinerea. In this later case, the production of resveratrol inhibits the proliferation of the pathogen, thereby acting as a natural antifungal. Many experimental studies have reported interesting properties of trans-resveratrol as a preventive agent against important pathologies i.e. vascular diseases, cancers, viral infection or neurodegenerative processes. In addition, several epidemiological studies indicated that resveratrol would be the main micirocomponent of wine leading health benefits such as prevention of vaso-coronary diseases and cancer (so called the "French paradox"). Resveratrol prevents (or delays) carcinogenesis by inhibiting the three phases of cancer process: initiation, promotion, progression and invasion phases. It also exhibits pro-apoptic properties especially towards colorectal cancers. Importantly resveratrol is not toxic in animal models even at high dosage. Moreover plasmatic concentrations of resveratrol would to be sufficient for anti-invasive activity. The enterohepatic blood recirculation contributes to a delayed elimination of the molecule from the body which can also show a prolonged effect enhanced by its binding to plasmatic proteins. Interestingly resveratrol can sensitize to low doses of cytotoxic drugs and so provide new approaches to enhance the efficacy of anticancer therapy in human cancers.

Cardiovascular diseases are the leading cause of death in developed countries where the common pathological substrate underlying this process is atherosclerosis. Several new concepts have emerged in relation to mechanisms that contribute to the regulation of the vascular diseases and associated inflammatory effects. Recently, potential antioxidants (vitamin E, polyphenols) have received much attention as potential anti-atherosclerotic agents. Among the polyphenols with health benefic properties, resveratrol, a phytoalexin of grape, seem to be a good candidate protecting the vascular walls from oxidation, inflammation, platelet aggregation, and thrombus formation. In this review, we focus on the mechanism of resveratrol cardiovascular benefic effects. We analyze, in relation with the different steps of atherosclerotic process, the resveratrol properties at multiple levels, such as cellular signaling, enzymatic pathways, apoptosis, and gene expression. We show and discuss the relationship with reactive oxygen species, regulation of pro-inflammatory genes including cycloxygenases and cytokines in molecular inflammatory and aging processes, and how the regulation of these activites by resveratrol can lead to a prevention of vascular diseases.

Cardiovascular diseases are the leading cause of death in developed countries where the common pathological substrate underlying this process is atherosclerosis. Several new concepts have emerged in relation to mechanisms that contribute to the regulation of the vascular diseases and associated inflammatory effects. Recently, potential antioxidants (vitamin E, polyphenols) have received much attention as potential anti-atherosclerotic agents. Among the polyphenols with health benefic properties, resveratrol, a phytoalexin of grape, seem to be a good candidate protecting the vascular walls from oxidation, inflammation, platelet aggregation, and thrombus formation. In this review, we focus on the mechanism of resveratrol cardiovascular benefic effects. We analyze, in relation with the different steps of atherosclerotic process, the resveratrol properties at multiple levels, such as cellular signaling, enzymatic pathways, apoptosis, and gene expression. We show and discuss the relationship with reactive oxygen species, regulation of pro-inflammatory genes including cycloxygenases and cytokines in molecular inflammatory and aging processes, and how the regulation of these activites by resveratrol can lead to a prevention of vascular diseases.

Le resveratrol est un compose polyphenolique produit surtout par la vigne et, en consequence, trouve dans le vin. Des etudes epidemiologiques conduisent a penser que le resveratrol peut proteger contre des cancers chimiquement induits. La capacite du resveratrol a inhiber la proliferation cellulaire a ete etudiee dans des lignees cellulaires Fao d'hepatome de rat et HepG2 d'hepatoblastome humain. Les resultats montrent que le resveratrol entraine une forte inhibition de la proliferation cellulaire en fonction du temps et de la concentration de la molecule (gamme du micromolaire). Il est interessant de noter que la presence d'ethanol diminue le seuil de l'effet du resveratrol. Des concentrations de plus de 50μM sont toxiques, surtout dans les cellules Fao ou elles provoquent une augmentation de la liberation de lactate deshydrogenose dans le milieu de culture. L'effet du resveratrol dans les cellules HepG2 a ete etudie par cytometrie en flux qui a montre une perturbation importante du cycle cellulaire avec une accumulation de cellules dans les phases S et G2/M. En conclusion, le resveratrol entraine une forte inhibition de la proliferation de cellules derivees d'hepatocytes et l'alcool semble agir comme un agent potentialisateur.

The first peroxisome proliferator-activated receptor (PPAR) was cloned in 1990 by Issemann and Green. Many studies have reported the importance of this receptor in the control of gene expression of enzymes involved in lipid metabolic pathways including mitochondrial and peroxisomal fatty acid β-oxidation, lipoprotein structure [apolipoprotein (apo) A2, apo Clll], and fatty acid synthase. By using radiolabeled molecules, it was shown that peroxisome proliferators bind and activate PPAR. As an alternative method, we developed a fluorescent dansyl (1-dimethyl-aminonaphthalene-5-sulfonyl) derivative peroxisome proliferator from bezafibrate (DNS-X), a hypolipidemic agent that exhibits an in vitro peroxisome proliferative activity on rat Fao-hepatic derived cultured cells. However, until now, the effect of this new compound on the liver of animals and subcellular localization was unknown. In addition to in vivo rat studies, we present a more efficient large-scale technique of DNS-X purification. Treating rats (DNS-X in the diet at 0.3% w/w) for 6 d leads to a hepatomegaly and a marked increase in liver peroxisomal palmitoyl-CoA oxidase activity. We also developed a method to localize and quantify DNS-X in tissues or cell compartment organelles. The primarily cytosolic distribution of DNS-X was confirmed by direct visualization using fluorescence microscopy of cultured Fao cells. Finally, transfection assay demonstrated that DNS-X enhanced the PPARα activity as well as other peroxisome proliferators do.

The goal of this study was to characterize phosphorylated proteins and to evaluate the changes in their phosphorylation level under the influence of a peroxisome proliferator (PP) with hypolipidemic activity of the fibrate family. The incubation of rat hepatic derived Fao cells with ciprofibrate leads to an overphosphorylation of proteins, especially one of 85 kDa, indicating that kinase (or phosphatase) activities are modified. Moreover, immunoprecipitation of 32P-labeled cell lysates shows that the nuclear receptor, PP-activated receptor, α isoform, can exist in a phosphorylated form, and its phosphorylation is increased by ciprofibrate. This study shows that PP acts at different steps of cell signaling. These steps can modulate gene expression of enzymes involved in fatty acid metabolism and lipid homeostasis, as well as in detoxication processes.

Biology of the CellVolume 91, Issue 7 p. 565-565 Inhibition of hepatic derived cells proliferation by resveratrol Dominique Delmas, Dominique Delmas Université de Bourgogne, LBMC, 6, Bd Gabriel 21000 DIJON, FranceSearch for more papers by this authorBrigitte Jannin, Brigitte Jannin Université de Bourgogne, LBMC, 6, Bd Gabriel 21000 DIJON, FranceSearch for more papers by this authorMalki Mustapha Cherkaoui, Malki Mustapha Cherkaoui Université de Bourgogne, LBMC, 6, Bd Gabriel 21000 DIJON, FranceSearch for more papers by this authorJean-Pierre Berlot, Jean-Pierre Berlot Université de Bourgogne, LBMC, 6, Bd Gabriel 21000 DIJON, FranceSearch for more papers by this authorNorbert Latruffe, Norbert Latruffe Université de Bourgogne, LBMC, 6, Bd Gabriel 21000 DIJON, FranceSearch for more papers by this author Dominique Delmas, Dominique Delmas Université de Bourgogne, LBMC, 6, Bd Gabriel 21000 DIJON, FranceSearch for more papers by this authorBrigitte Jannin, Brigitte Jannin Université de Bourgogne, LBMC, 6, Bd Gabriel 21000 DIJON, FranceSearch for more papers by this authorMalki Mustapha Cherkaoui, Malki Mustapha Cherkaoui Université de Bourgogne, LBMC, 6, Bd Gabriel 21000 DIJON, FranceSearch for more papers by this authorJean-Pierre Berlot, Jean-Pierre Berlot Université de Bourgogne, LBMC, 6, Bd Gabriel 21000 DIJON, FranceSearch for more papers by this authorNorbert Latruffe, Norbert Latruffe Université de Bourgogne, LBMC, 6, Bd Gabriel 21000 DIJON, FranceSearch for more papers by this author First published: 01 February 2012 https://doi.org/10.1016/S0248-4900(99)90302-7AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume91, Issue7September 1999Pages 565-565 RelatedInformation

Biology of the CellVolume 84, Issue 1-2 p. 95-95 Peroxisome proliferation in rodents and human: A model of cell organelle biogenesis Corinne Pacot, Corinne Pacot Université de Bourgogne, LBMC, BP 138, 21004 DIJON CEDEX.Search for more papers by this authorPatricia Passilly, Patricia Passilly Université de Bourgogne, LBMC, BP 138, 21004 DIJON CEDEX.Search for more papers by this authorMarie-Claude Clemencet, Marie-Claude Clemencet Université de Bourgogne, LBMC, BP 138, 21004 DIJON CEDEX.Search for more papers by this authorOlivier Bardot, Olivier Bardot Université de Bourgogne, LBMC, BP 138, 21004 DIJON CEDEX.Search for more papers by this authorFrançoise Caira, Françoise Caira Université de Bourgogne, LBMC, BP 138, 21004 DIJON CEDEX.Search for more papers by this authorCherkaoui Mustapha Malki, Cherkaoui Mustapha Malki Université de Bourgogne, LBMC, BP 138, 21004 DIJON CEDEX.Search for more papers by this authorBrigitte Jannin, Brigitte Jannin Université de Bourgogne, LBMC, BP 138, 21004 DIJON CEDEX.Search for more papers by this authorNorbert Latruffe, Norbert Latruffe Université de Bourgogne, LBMC, BP 138, 21004 DIJON CEDEX.Search for more papers by this author Corinne Pacot, Corinne Pacot Université de Bourgogne, LBMC, BP 138, 21004 DIJON CEDEX.Search for more papers by this authorPatricia Passilly, Patricia Passilly Université de Bourgogne, LBMC, BP 138, 21004 DIJON CEDEX.Search for more papers by this authorMarie-Claude Clemencet, Marie-Claude Clemencet Université de Bourgogne, LBMC, BP 138, 21004 DIJON CEDEX.Search for more papers by this authorOlivier Bardot, Olivier Bardot Université de Bourgogne, LBMC, BP 138, 21004 DIJON CEDEX.Search for more papers by this authorFrançoise Caira, Françoise Caira Université de Bourgogne, LBMC, BP 138, 21004 DIJON CEDEX.Search for more papers by this authorCherkaoui Mustapha Malki, Cherkaoui Mustapha Malki Université de Bourgogne, LBMC, BP 138, 21004 DIJON CEDEX.Search for more papers by this authorBrigitte Jannin, Brigitte Jannin Université de Bourgogne, LBMC, BP 138, 21004 DIJON CEDEX.Search for more papers by this authorNorbert Latruffe, Norbert Latruffe Université de Bourgogne, LBMC, BP 138, 21004 DIJON CEDEX.Search for more papers by this author First published: 1995 https://doi.org/10.1016/0248-4900(96)81367-0AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume84, Issue1-21995Pages 95-95 RelatedInformation