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乌索酸 A 通过持续激活 Nrf2 保护小鼠免受对乙酰氨基酚诱导的肝损伤。

Urolithin A protects against acetaminophen-induced liver injury in mice via sustained activation of Nrf2.

机构信息

Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences& The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou511436, China.

Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China.

出版信息

Int J Biol Sci. 2022 Feb 28;18(5):2146-2162. doi: 10.7150/ijbs.69116. eCollection 2022.

DOI:10.7150/ijbs.69116
PMID:35342347
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8935220/
Abstract

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 and . 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.

摘要

对乙酰氨基酚过量是全球急性肝衰竭的主要原因。N-乙酰半胱氨酸（NAC）作为唯一的解毒剂，由于其治疗时间窗狭窄而受到限制。在这里，我们证明了尿石素 A（UA），一种肠道菌群中鞣花单宁天然产物的代谢物，可预防对乙酰氨基酚引起的肝损伤（AILI），并且在剂量和治疗时间窗方面优于 NAC。转录组学分析表明，UA 可促进肝脏中的线粒体自噬和 Nrf2/ARE 信号通路的激活。与这一结果一致，UA 处理的肝脏中出现了线粒体自噬和 Nrf2/ARE 信号通路的激活，氧化应激减少。随后，分子对接和动力学模拟研究揭示了 UA 与 Nrf-2/Keap1 之间的结合模式，包括 UA 中的氧原子与 Nrf-2/Keap1 残基 Arg 415、Ser 508 和 Ser 602 之间的氢键网络，从而触发 Nrf2 核转位，随后导致 Nrf-2 靶基因（HO-1、NQO1）的激活。值得注意的是，线粒体自噬抑制未能阻止 UA 对 AILI 的保护作用，反而与 Nrf2 基因沉默一起，均削弱了 UA 的保护作用。综上所述，我们的数据表明，UA 通过激活 Nrf2/ARE 信号通路缓解了对乙酰氨基酚引起的氧化应激和肝坏死，突出了 UA 在 AILI 中的治疗潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d03/8935220/7773143f465b/ijbsv18p2146g009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d03/8935220/7773143f465b/ijbsv18p2146g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d03/8935220/458d7584adb0/ijbsv18p2146g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d03/8935220/129f40d2fc4f/ijbsv18p2146g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d03/8935220/3a470ab3a8c8/ijbsv18p2146g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d03/8935220/342cce2c1a61/ijbsv18p2146g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d03/8935220/eb4eec30b1f5/ijbsv18p2146g008.jpg
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