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Sulfuretin protects hepatic cells through regulation of ROS levels and autophagic flux

Authors: Yu-ting Lu1,2,3, Yu-feng Xiao1,2, Yu-feng Li1,2, Jia Li1,2,3, Fa-jun Nan1,2, Jing-ya Li1,2
1 State Key Laboratory of Drug Research, The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China
2 University of Chinese Academy of Sciences, 100049 Beijing, China
3 School of Life Science and Technology, ShanghaiTech University, 201210 Shanghai, China
Correspondence to: Jia Li: jli@simm.ac.cn, Fa-jun Nan: fjnan@simm.ac.cn, Jing-ya Li: jyli@simm.ac.cn,
DOI: 10.1038/s41401-018-0193-5
Received: 13 July 2018
Accepted: 8 November 2018
Advance online: 18 December 2018

Abstract

Palmitate (PA) exposure induces stress conditions featuring ROS accumulation and upregulation of p62 expression, resulting in autophagic flux blockage and cell apoptosis. Sulfuretin (Sul) is a natural product isolated from Rhus verniciflua Stokes; the cytoprotective effect of Sul on human hepatic L02 cells and mouse primary hepatocytes under PA-induced stress conditions was investigated in this study. Sul induced mitophagy by activation of p-TBK1 and LC3 and produced a concomitant decline in p62 expression. Autophagosome formation and mitophagy were assessed by the sensitive dual fluorescence reporter mCherry-EGFP-LC3B, and mitochondrial fragmentation was analyzed using MitoTracker Deep Red FM. A preliminary structure–activity relationship (SAR) for Sul was also investigated, and the phenolic hydroxyl group was found to be pivotal for maintaining the cytoprotective bioactivity of Sul. Furthermore, experiments using flow cytometry and western blots revealed that Sul reversed the cytotoxic effect stimulated by the autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CQ), and its cytoprotective effect was almost eliminated when the autophagy-related 5 (Atg5) gene was knocked down. These studies suggest that, in addition to its antioxidative effects, Sul stimulates mitophagy and restores impaired autophagic flux, thus protecting hepatic cells from apoptosis, and that Sul has potential future medical applications for hepatoprotection.
Keywords: sulfuretin; palmitate; mitophagy; autophagic flux

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