title: A novel semisynthetic flavonoid 7-O-galloyltaxifolin upregulates heme oxygenase-1 in RAW264.7 cells via MAPK/Nrf2 pathway.
abstract: Quercetin and gallic acid are natural activators of the transcription factor Nrf2, which regulates the expression of many cytoprotective enzymes including heme oxygenase-1 (HO-1). We developed procedures for the synthesis of monogalloyl esters of quercetin and taxifolin (dihydroquercetin), namely, 3-O-galloylquercetin and 7-O-galloyltaxifolin, and examined their effect on the Nrf2 pathway in RAW264.7 cells. Unlike quercetin and free gallic acid, 3-O-galloylquercetin and natural quercetin derivatives isoquercitrin (quercetin-3-O-β-d-glucoside) and taxifolin had no effect on the expression of HO-1. In contrast, 7-O-galloyltaxifolin increased both mRNA and protein levels of HO-1 at concentrations of 25 μM and above. The induction of HO-1 by 7-O-galloyltaxifolin was primarily associated with the production of reactive oxygen species and phosphorylation of mitogen-activated protein kinases (MAPKs), including p38 MAPKs and ERKs, followed by nuclear accumulation of Nrf2 and downregulation of Keap1, a negative regulator of Nrf2. We conclude that 7-O-galloyltaxifolin upregulates HO-1 via activation of the MAPK/Nrf2 signaling pathway.
authors.affiliation: Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, Olomouc 77515, Czech Republic. vrbambv@seznam.cz
authors.forename: Jiří
authors.initials: J
authors.lastname: Vrba
authors.forename: Radek
authors.initials: R
authors.lastname: Gažák
authors.forename: Marek
authors.initials: M
authors.lastname: Kuzma
authors.forename: Barbora
authors.initials: B
authors.lastname: Papoušková
authors.forename: Jan
authors.initials: J
authors.lastname: Vacek
authors.forename: Martin
authors.initials: M
authors.lastname: Weiszenstein
authors.forename: Vladimír
authors.initials: V
authors.lastname: Křen
authors.forename: Jitka
authors.initials: J
authors.lastname: Ulrichová
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010766:Phosphorylation; D011794:Quercetin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: C579811:7-O-galloyltaxifolin; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D011794:Quercetin; D051547:Heme Oxygenase-1; D000111:Acetylcysteine