title: Antioxidant mechanism of isoflavone metabolites in hydrogen peroxide-stimulated rat primary astrocytes: critical role of hemeoxygenase-1 and NQO1 expression.
abstract: The brain is highly vulnerable to oxidative stress, thus controlling oxidative stress is considered to be an important therapeutic target for neurodegenerative diseases. In this study, we found that two isoflavone metabolites (tectorigenin and glycitein) inhibited hydrogen peroxide-induced reactive oxygen species (ROS) generation and subsequent cell death in rat primary astrocytes. The isoflavone metabolites increased the expression of phase II antioxidant enzymes, such as hemeoxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1), and pre-treatment of cells with their specific inhibitors or small interfering RNA (siRNA) reversed the antioxidant and cytoprotective effects of isoflavones. The results suggest that the antioxidant/cytoprotective effects of isoflavone metabolites are at least because of increased HO-1 and NQO1 expression. Further mechanistic studies revealed that isoflavones increase the binding of transcription factors [nuclear factor-E2-related factor 2 (Nrf2) and c-Jun] to the antioxidant response element (ARE) on HO-1 and NQO1 promoters. Down-regulation of Nrf2 and/or c-Jun using dominant-negative mutants (DNMs) or siRNA diminished the expression of HO-1 and NQO1, suggesting that Nrf2 and c-Jun are key transcription factors modulating HO-1/NQO1 expression. Moreover, PI3 kinase and mitogen-activated protein kinase (MAPK) signaling pathways were shown to be involved in HO-1 and/or NQO1 expression by isoflavones. Our data collectively suggest that HO-1 and NQO1 play a critical role in antioxidant effects of isoflavone metabolites in rat brain astrocytes.
authors.affiliation: Department of Molecular Medicine and Tissue Injury Defense Research Center, Ewha Womans University Medical School, Seoul, Korea.
authors.forename: Jin-Sun
authors.initials: JS
authors.lastname: Park
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Jung
authors.forename: Yeon-Hui
authors.initials: YH
authors.lastname: Jeong
authors.forename: Jin-Won
authors.initials: JW
authors.lastname: Hyun
authors.forename: Thi Kim Van
authors.initials: TK
authors.lastname: Le
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
authors.forename: Eung-Chil
authors.initials: EC
authors.lastname: Choi
authors.forename: Hee-Sun
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000493:pharmacokinetics*; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D045744:Cell Line, Tumor; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007529:Isoflavones / Q000737:chemistry / Q000493:pharmacokinetics*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis / Q000235:genetics*; D016877:Oxidants / Q000494:pharmacology; D051381:Rats
chemical_list: D000975:Antioxidants; D007529:Isoflavones; D016877:Oxidants; C120039:tectorigenin; C086566:glycitein; D006861:Hydrogen Peroxide; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat