title: Triptolide-induced oxidative stress involved with Nrf2 contribute to cardiomyocyte apoptosis through mitochondrial dependent pathways.
abstract: Triptolide (TP), a major active ingredient extracted from the widely used Chinese herb Tripterygium wilfordii Hook f. (TWHF), has been demonstrated to possess various biological activities. However, the clinical applications of TP are limited by its narrow therapeutic window and severe toxicity. The current study aimed to investigate the roles of reactive oxygen species (ROS) and mitochondria in TP-induced cardiac injury. Male BALB/C mice were intravenously (i.v.) treated with a single dose of TP (1.2 mg/kg). After 24h, TP induced the oxidative stress, mitochondrial dysfunction, apoptotic damage, and pathological changes of heart tissue. In vitro studies also indicated that the cytotoxic effects of TP involved the ROS-mediated mitochondria-dependent pathway in H9c2 cells. TP treatment increased the accumulation of ROS and subsequently triggered cell apoptosis by depolarizing the mitochondrial membrane potential (ΔΨm), reduced the ratio of Bax/Bcl-2, released cytochrome c and, ultimately, activated caspase-3. Nrf2, as well as its downstream antioxidants, were also suppressed by TP. Taken together, these results suggest that TP induces cardiotoxicity in vivo and in vitro via oxidative stress, which was associated with down regulated Nrf2 activation, and the mitochondria-mediated apoptotic signaling pathway.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Chen
authors.initials: C
authors.lastname: Xi
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Wang
authors.affiliation: Center of Laboratory Animals, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Xinglu
authors.initials: X
authors.lastname: Fu
authors.affiliation: Center of Laboratory Animals, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Liang
authors.initials: L
authors.lastname: Jinqiang
authors.affiliation: Center of Laboratory Animals, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Jin
authors.initials: J
authors.lastname: Jin
authors.affiliation: Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
authors.forename: Jingfen
authors.initials: J
authors.lastname: Xu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China; Center of Laboratory Animals, Sun Yat-sen University, Guangzhou 510006, PR China. Electronic address: hzhiying@mail.sysu.edu.cn.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D004224:Diterpenes / Q000633:toxicity*; D004852:Epoxy Compounds / Q000633:toxicity; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D010616:Phenanthrenes / Q000633:toxicity*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494827:Bax protein, mouse; D004224:Diterpenes; D004852:Epoxy Compounds; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D010616:Phenanthrenes; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; C001899:triptolide; D045304:Cytochromes c; C505409:Casp3 protein, mouse; D053148:Caspase 3
keywords: Apoptosis; Cardiotoxicity; Mitochondrion; Nrf2; Oxidative stress; Triptolide