title: Isotetrandrine ameliorates tert-butyl hydroperoxide-induced oxidative stress through upregulation of heme oxygenase-1 expression.
abstract: 1R, 1'S-isotetrandrine, a naturally occurring plant alkaloid found in Mahonia of Berberidaceae, possesses anti-inflammatory, antibacterial, and antiviral properties, but the antioxidative activity and mechanism action remain unclear. In this study, we demonstrated the antioxidative effect and mechanism of 1R, 1'S-isotetrandrine against tert-butyl hydroperoxide-induced oxidative damage in HepG2 cells. We found that 1R, 1'S-isotetrandrine suppressed cytotoxicity, reactive oxygen species generation, and glutathione depletion. Additionally, our study confirmed that 1R, 1'S-isotetrandrine significantly increased the antioxidant enzyme heme oxygenase-1 expression and nuclear translocation of factor-erythroid 2 p45-related factor 2 (Nrf2). Specifically, the nuclear translocation of Nrf2 induced by 1R, 1'S-isotetrandrine was associated with Nrf2 negative regulatory protein Keap1 inactivation and phosphorylation of both extracellular signal-regulated protein kinase and c-Jun NH2-terminal kinase. Preincubation with thiol-reducing agents reduced 1R, 1'S-isotetrandrine-induced heme oxygenase-1 expression, and treatment with either extracellular signal-regulated protein kinase or c-Jun NH2-terminal kinase inhibitors attenuated the levels of 1R, 1'S-isotetrandrine-induced Nrf2 activation and heme oxygenase-1 expression. Furthermore, the cytoprotective effect of 1R, 1'S-isotetrandrine was abolished by heme oxygenase-1, extracellular signal-regulated protein kinase, and c-Jun NH2-terminal kinase inhibitors. These results indicated that the 1R, 1'S-isotetrandrine ameliorated tert-butyl hydroperoxide-induced oxidative damage through upregulation of heme oxygenase-1 expression by the dissociation of Nrf2 from Nrf2-Keap1 complex via extracellular signal-regulated protein kinase and c-Jun NH2-terminal kinase activation and Keap1 inactivation.
authors.affiliation: Institute of Translational Medicine, The First Hospital, Jilin University, Changchun 130001, China.
authors.forename: Lidong
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Translational Medicine, The First Hospital, Jilin University, Changchun 130001, China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Ci
authors.affiliation: Institute of Translational Medicine, The First Hospital, Jilin University, Changchun 130001, China.
authors.forename: Hongming
authors.initials: H
authors.lastname: Lv
authors.affiliation: Institute of Translational Medicine, The First Hospital, Jilin University, Changchun 130001, China.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institute of Translational Medicine, The First Hospital, Jilin University, Changchun 130001, China Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China Suzhou Institute of Systems Medicine, Suzhou 215123, China Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA fxfqin1@gmail.com.
authors.forename: F Xiaofeng
authors.initials: FX
authors.lastname: Qin
authors.affiliation: Institute of Translational Medicine, The First Hospital, Jilin University, Changchun 130001, China Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China Suzhou Institute of Systems Medicine, Suzhou 215123, China Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA 18604430993@sina.cn.
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000975:Antioxidants / Q000494:pharmacology*; D044182:Benzylisoquinolines / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D044182:Benzylisoquinolines; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; C009438:tetrandrine; D020122:tert-Butylhydroperoxide; D051547:Heme Oxygenase-1; D005978:Glutathione
keywords: HO-1; ITD; Nrf2; oxidative stress