title: Activation of Akt and JNK/Nrf2/NQO1 pathway contributes to the protective effect of coptisine against AAPH-induced oxidative stress.
abstract: Coptisine (COP) is one of the main active constituents of Coptidis Rhizoma. Previous studies have clarified that COP possesses antioxidant activity, but its defensive effects against pathological characteristics accompanied by oxidative damage in animal models and antioxidant mechanism are still unclear. Therefore, our purpose was to confirm the antioxidant activity of COP and explore its mechanism of action. We first detected the effects of COP on intracellular reactive oxygen species (ROS), heart beating rate, lipid peroxidation and cell death in zebrafish model with AAPH-induced oxidative stress. The results showed that COP of 10μg/mL significantly reduced ROS production, the increase of heart beating rate, lipid peroxidation and cell death by 41.3%, 24.5%, 26.5% and 30.0%, respectively. In addition, COP of 0.8μg/mL also decreased ROS, increased glutathione (GSH) content and elevated activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) by 40.1%, 19.8%, 18.3% and 49.3%, respectively in HepG2 cells. Further assays were carried out to explore the mRNA expression in zebrafish and protein expression of key factors in HepG2 cells. We demonstrated that COP up-regulated phase II antioxidant enzymes NAD(P)H/quinone oxidoreductase 1 (NQO1) through activating the nuclear factor erythroid-2 related factor 2 (Nrf2). Moreover, as the upstream signalings of Nrf2, the protein kinase B (Akt) and c-Jun NH2-terminal kinase (JNK) signalings were also induced by COP. And up-regulating Nrf2-mediated NQO1 expression of COP was in Akt and JNK-dependent manner. Taken together, COP exerted its antioxidant activity against AAPH-induced toxicity involving in activating Akt and JNK/Nrf2/NQO1 pathway.
authors.affiliation: College of Pharmaceutical Sciences, Southwest University, Chongqing, 400716, China; Chongqing Productivity Promotion Centre for the Modernization of Chinese Medicine, Chongqing, 400716, China; Chongqing Engineering Research Center for Pharmaceutical Process and Quality Control, Chongqing, 400716, China.
authors.forename: Yin-Ran
authors.initials: YR
authors.lastname: Hu
authors.affiliation: College of Pharmaceutical Sciences, Southwest University, Chongqing, 400716, China; Chongqing Productivity Promotion Centre for the Modernization of Chinese Medicine, Chongqing, 400716, China; Chongqing Engineering Research Center for Pharmaceutical Process and Quality Control, Chongqing, 400716, China.
authors.forename: Hang
authors.initials: H
authors.lastname: Ma
authors.affiliation: College of Pharmaceutical Sciences, Southwest University, Chongqing, 400716, China; Chongqing Productivity Promotion Centre for the Modernization of Chinese Medicine, Chongqing, 400716, China; Chongqing Engineering Research Center for Pharmaceutical Process and Quality Control, Chongqing, 400716, China.
authors.forename: Zong-Yao
authors.initials: ZY
authors.lastname: Zou
authors.affiliation: College of Pharmaceutical Sciences, Southwest University, Chongqing, 400716, China; Chongqing Productivity Promotion Centre for the Modernization of Chinese Medicine, Chongqing, 400716, China; Chongqing Engineering Research Center for Pharmaceutical Process and Quality Control, Chongqing, 400716, China.
authors.forename: Kai
authors.initials: K
authors.lastname: He
authors.affiliation: College of Pharmaceutical Sciences, Southwest University, Chongqing, 400716, China; Chongqing Productivity Promotion Centre for the Modernization of Chinese Medicine, Chongqing, 400716, China; Chongqing Engineering Research Center for Pharmaceutical Process and Quality Control, Chongqing, 400716, China.
authors.forename: Yu-Bo
authors.initials: YB
authors.lastname: Xiao
authors.affiliation: School of Life Sciences, Southwest University, Chongqing, 400715, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: College of Pharmaceutical Sciences, Southwest University, Chongqing, 400716, China; Chongqing Productivity Promotion Centre for the Modernization of Chinese Medicine, Chongqing, 400716, China; Chongqing Engineering Research Center for Pharmaceutical Process and Quality Control, Chongqing, 400716, China.
authors.forename: Min
authors.initials: M
authors.lastname: Feng
authors.affiliation: School of Life Sciences, Southwest University, Chongqing, 400715, China.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Ye
authors.affiliation: College of Pharmaceutical Sciences, Southwest University, Chongqing, 400716, China; Chongqing Productivity Promotion Centre for the Modernization of Chinese Medicine, Chongqing, 400716, China; Chongqing Engineering Research Center for Pharmaceutical Process and Quality Control, Chongqing, 400716, China. Electronic address: xuegangli@swu.edu.cn.
authors.forename: Xue-Gang
authors.initials: XG
authors.lastname: Li
mesh_terms: D000578:Amidines / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001599:Berberine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D016877:Oxidants / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000578:Amidines; D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D016877:Oxidants; D029961:Zebrafish Proteins; C495638:nfe2l2a protein, zebrafish; C034384:coptisine; D001599:Berberine; C046728:2,2'-azobis(2-amidinopropane); D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C000614095:NQO1 protein, zebrafish; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D005978:Glutathione
keywords: Akt; Antioxidation; Coptisine; Coptisine (PubChem CID: 72322); JNK; L-ascorbic acid (PubChem CID: 54670067); NQO1; Nrf2