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Toxicol Lett. 2014 Nov 4;230(3):454-66. doi: 10.1016/j.toxlet.2014.08.017. Epub 2014 Aug 26.

Triptolide-induced oxidative stress involved with Nrf2 contribute to cardiomyocyte apoptosis through mitochondrial dependent pathways.

Author information

1
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
2
Center of Laboratory Animals, Sun Yat-sen University, Guangzhou 510006, PR China.
3
Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
4
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.

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.

KEYWORDS:

Apoptosis; Cardiotoxicity; Mitochondrion; Nrf2; Oxidative stress; Triptolide

PMID:
25169008
DOI:
10.1016/j.toxlet.2014.08.017
[Indexed for MEDLINE]

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