title: Differential cell-protective function of two resveratrol (trans-3,5,4'-trihydroxystilbene) glucosides against oxidative stress.
abstract: Resveratrol (trans-3,5,4'-trihydroxystilbene; 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.
authors.affiliation: Department of Pharmacology, School of Medicine, Sapporo Medical University, S1, W17, Chu-ouku, Sapporo 060-8556, Japan.
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Hosoda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kuno
authors.forename: Yusuke S
authors.initials: YS
authors.lastname: Hori
authors.forename: Katsuki
authors.initials: K
authors.lastname: Ohtani
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Wakamiya
authors.forename: Azusa
authors.initials: A
authors.lastname: Oohiro
authors.forename: Hiroki
authors.initials: H
authors.lastname: Hamada
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Horio
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000737:chemistry; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D019610:Cytoprotection / Q000187:drug effects*; D016166:Free Radical Scavengers / Q000494:pharmacology; D005609:Free Radicals / Q000737:chemistry; D005960:Glucosides / Q000494:pharmacology; D007150:Immunohistochemistry; D051379:Mice; D032446:Myoblasts / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D029604:Phytolacca americana / Q000737:chemistry; D010851:Picrates / Q000737:chemistry; D016133:Polymerase Chain Reaction; D051381:Rats; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000235:genetics; D013267:Stilbenes / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D001713:Biphenyl Compounds; D002839:Chromans; D016166:Free Radical Scavengers; D005609:Free Radicals; D005960:Glucosides; D010851:Picrates; D013267:Stilbenes; C004931:1,1-diphenyl-2-picrylhydrazyl; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000077185:Resveratrol; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid