KEAP1型
对乙酰氨基酚
氧化应激
粒体自噬
肝损伤
药理学
化学
活性氧
体内
解毒剂
生物化学
医学
生物
毒性
自噬
转录因子
细胞凋亡
基因
生物技术
有机化学
作者
Zhimin Gao,Wei Yi,Junyuan Tang,Yuling Sun,Jianrong Huang,Tian Lan,Xiaoyan Dai,Suowen Xu,Zhigang Jin,Xiaoqian Wu
摘要
Acetaminophen overdose is a leading cause of acute live failure worldwide. N-acetylcysteine (NAC), as the only antidote, is limited due to its narrow therapeutic time window. Here we demonstrated that Urolithin A (UA), a metabolite of ellagitannin natural products in the gastrointestinal flora, protected against acetaminophen-induced liver injury (AILI) and is superior to NAC in terms of dosage and therapeutical time window. Transcriptomics assay revealed that UA promotes mitophagy and activated Nrf2/ARE signaling in the liver. Consistent with that, mitophagy and Nrf2/ARE signaling were activated, with less oxidative stress in UA-treated liver. Subsequently, molecular docking and dynamics simulation study revealed a binding mode between UA and Nrf-2/Keap1 including the hydrogen-bonding network among oxygen atoms in UA with the Nrf-2/Keap1 residues Arg 415, Ser 508 and Ser 602, which in turn trigger Nrf2 nuclear translocation, subsequently leading to activation of Nrf-2 target genes (HO-1, NQO1). Of note, mitophagy inhibition failed to prevent the protection of UA against AILI, which instead was compromised with Nrf2 gene silencing both in vivo and in vitro. Collectively, our data indicate that UA alleviated acetaminophen-induced oxidative stress and hepatic necrosis via activating Nrf2/ARE signaling pathway, highlighting a therapeutical potential of UA for AILI.
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