title: Troxerutin inhibits 2,2',4,4'-tetrabromodiphenyl ether (BDE-47)-induced hepatocyte apoptosis by restoring proteasome function.
abstract: Proteasome dysfunction has been associated with the pathogeneses of a variety of diseases and with the neurotoxicities of environmental chemicals; however, whether proteasome dysfunction plays a role in the cellular toxicity of polybrominated diphenyl ethers (PBDEs) has not been investigated to date. Emerging evidence suggests that antioxidants exhibit evident beneficial effects on the cellular toxicity associated with PBDEs. In the present study, we investigated whether troxerutin attenuates BDE-47-induced hepatocyte apoptosis by restoring proteasome function and explored the mechanisms underlying this effect. Our results revealed that proteasome dysfunction was involved in the BDE-47-induced hepatocyte apoptosis in the mouse liver. Furthermore, our results revealed that troxerutin effectively inhibited hepatocyte apoptosis by restoring oxidative stress-mediated proteasome dysfunction in BDE-47-treated mice. Consequently, troxerutin markedly suppressed endoplasmic reticulum (ER) stress in the livers of the BDE-47-treated mice. The inhibitory effects of troxerutin on ER stress and apoptotic pathways were markedly blunted by treatment with epoxomicin (a selective inhibitor of proteasome). Ultimately, troxerutin dramatically blocked TRAF2-ASK1-JNK signaling and CHOP-mediated apoptosis signaling in the BDE-47-treated mouse livers. This study provides novel mechanistic insights into the toxicity of BDE-47 and indicates that troxerutin might be a candidate for the prevention of and therapy for BDE-47-induced hepatotoxicity.
authors: School of Environment Science and Spatial Informatics, China University of Mining and Technology, Xuzhou 221116, Jiangsu Province, PR China; Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu Province, PR China.
authors: Zi-Feng
authors: ZF
authors: Zhang
authors: School of Environment Science and Spatial Informatics, China University of Mining and Technology, Xuzhou 221116, Jiangsu Province, PR China; Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu Province, PR China.
authors: Qun
authors: Q
authors: Shan
authors: School of Environment Science and Spatial Informatics, China University of Mining and Technology, Xuzhou 221116, Jiangsu Province, PR China.
authors: Juan
authors: J
authors: Zhuang
authors: School of Environment Science and Spatial Informatics, China University of Mining and Technology, Xuzhou 221116, Jiangsu Province, PR China. Electronic address: zhangyq@163.com.
authors: Yan-Qiu
authors: YQ
authors: Zhang
authors: Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu Province, PR China; Jiangsu Xuzhou Sweetpotato Research Centre, Xuzhou 221131, Jiangsu Province, PR China.
authors: Xin
authors: X
authors: Wang
authors: Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu Province, PR China.
authors: Shao-Hua
authors: SH
authors: Fan
authors: Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu Province, PR China.
authors: Jun
authors: J
authors: Lu
authors: Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu Province, PR China.
authors: Dong-Mei
authors: DM
authors: Wu
authors: Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu Province, PR China.
authors: Bin
authors: B
authors: Hu
authors: Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu Province, PR China. Electronic address: ylzheng@jsnu.edu.cn.
authors: Yuan-Lin
authors: YL
authors: Zheng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D055768:Halogenated Diphenyl Ethers / Q000037:antagonists & inhibitors* / Q000633:toxicity; D022781:Hepatocytes / Q000187:drug effects* / Q000473:pathology; D006896:Hydroxyethylrutoside / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009842:Oligopeptides / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000502:physiology
chemical_list: D055768:Halogenated Diphenyl Ethers; D006896:Hydroxyethylrutoside; D009842:Oligopeptides; C511295:2,2',4,4'-tetrabromodiphenyl ether; C005865:troxerutin; D046988:Proteasome Endopeptidase Complex; C078846:epoxomicin
keywords: Endoplasmic reticulum stress; Hepatocyte apoptosis; Oxidative stress; Polybrominated diphenyl ethers; Proteasome dysfunction; Troxerutin