https://scholars.lib.ntu.edu.tw/handle/123456789/641432
標題: | Roles of oxidative stress/JNK/ERK signals in paraquat-triggered hepatic apoptosis | 作者: | Lee, Kuan-I Fang, Kai-Min Kuo, Chun-Ying Huang, Chun-Fa SHING-HWA LIU Liu, Jui-Ming Lai, Wei-Cheng Chang, Kai-Chih Su, Chin-Chuan Chen, Ya-Wen |
關鍵字: | Apoptosis; ERK1/2; Hepatotoxicity; JNK; Oxidative stress; Paraquat | 公開日期: | 2024 | 出版社: | Elsevier B.V. | 卷: | 6 | 來源出版物: | Current Research in Toxicology | 摘要: | Paraquat (PQ), a toxic and nonselective bipyridyl herbicide, is one of the most extensively used pesticides in agricultural countries. In addition to pneumotoxicity, the liver is an important target organ for PQ poisoning in humans. However, the mechanism of PQ in hepatotoxicity remains unclear. In this study, we found that exposure of rat hepatic H4IIE cells to PQ (0.1-2 mM) induced significant cytotoxicity and apoptosis, which was accompanied by mitochondria-dependent apoptotic signals, including loss of mitochondrial membrane potential (MMP), cytosolic cytochrome c release, and changes in the Bcl-2/Bax mRNA ratio. Moreover, PQ (0.5 mM) exposure markedly induced JNK and ERK1/2 activation, but not p38-MAPK. Blockade of JNK and ERK1/2 signaling by pretreatment with the specific pharmacological inhibitors SP600125 and PD98059, respectively, effectively prevented PQ-induced cytotoxicity, mitochondrial dysfunction, and apoptotic events. Additionally, PQ exposure stimulated significant oxidative stress-related signals, including reactive oxygen species (ROS) generation and intracellular glutathione (GSH) depletion, which could be reversed by the antioxidant N-Acetylcysteine (NAC). Buffering the oxidative stress response with NAC also effectively abrogated PQ-induced hepatotoxicity, MMP loss, apoptosis, and phosphorylation of JNK and ERK1/2 protein, however, the JNK or ERK inhibitors did not suppress ROS generation in PQ-treated cells. Collectively, these results demonstrate that PQ exposure induces hepatic cell toxicity and death via an oxidative stress-dependent JNK/ERK activation-mediated downstream mitochondria-regulated apoptotic pathway. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/641432 | ISSN: | 2666027X | DOI: | 10.1016/j.crtox.2024.100155 |
顯示於: | 毒理學研究所 |
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