Adipose-Derived Mesenchymal Stem Cells Inhibit JNK-Mediated Mitochondrial Retrograde Pathway to Alleviate Acetaminophen-Induced Liver Injury.
Adipose-Derived Mesenchymal Stem Cells Inhibit JNK-Mediated Mitochondrial Retrograde Pathway to Alleviate Acetaminophen-Induced Liver Injury.
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脂肪来源的间充质干细胞抑制 JNK 介导的线粒体逆行途径以减轻对乙酰氨基酚引起的肝损伤
DOI：
10.3390/antiox12010158
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发表时间：
2023-01-09
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影响因子：
--
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对乙酰氨基酚（APAP）是药物性肝损伤的主要原因，治疗选择有限。APAP过量引起过度的氧化应激，触发丘脑-核逆行途径，导致APAP诱导的肝损伤（AILI）。间充质干细胞治疗是治疗急性肝衰竭的一种有前途的工具。因此，本研究的目的是探讨脂肪间充质干细胞（AMSC）治疗AILI的有益作用，并揭示其潜在的治疗机制。以C57 BL/6小鼠为APAP过量的动物模型，以AML 12正常小鼠肝细胞为APAP过量的细胞模型。免疫组化染色、Western印迹、免疫荧光染色和RNA测序分析用于评估AMSC治疗的疗效和验证机制。我们发现AMSC治疗有效地改善了AILI，而延迟AMSC注射失去了与c-Jun N-末端激酶（JNK）介导的线粒体逆行通路相关的疗效。我们进一步发现AMSC治疗抑制JNK活化和线粒体易位，减少APAP诱导的线粒体损伤。AMSC处理的小鼠肝脏中活化的共济失调毛细血管扩张突变（ATM）和DNA损伤反应蛋白的下调表明AMSC阻断了JNK-ATM通路。总体而言，AMSC可能通过抑制JNK-ATM线粒体逆行途径而成为AILI的有效治疗方法，从而改善APAP诱导的线粒体功能障碍和肝损伤。
Acetaminophen (APAP) is the major cause of drug-induced liver injury, with limited treatment options. APAP overdose invokes excessive oxidative stress that triggers mitochondria-to-nucleus retrograde pathways, contributing to APAP-induced liver injury (AILI). Mesenchymal stem cell therapy is a promising tool for acute liver failure. Therefore, the purpose of this study was to investigate the beneficial effects of adipose-derived mesenchymal stem cell (AMSC) therapy on AILI and reveal the potential therapeutic mechanisms. C57BL/6 mice were used as the animal model and AML12 normal murine hepatocytes as the cellular model of APAP overdose. Immunohistochemical staining, Western blotting, immunofluorescence staining, and RNA sequencing assays were used for assessing the efficacy and validating mechanisms of AMSC therapy. We found AMSC therapy effectively ameliorated AILI, while delayed AMSC injection lost its efficacy related to the c-Jun N-terminal kinase (JNK)-mediated mitochondrial retrograde pathways. We further found that AMSC therapy inhibited JNK activation and mitochondrial translocation, reducing APAP-induced mitochondrial damage. The downregulation of activated ataxia telangiectasia-mutated (ATM) and DNA damage response proteins in AMSC-treated mouse liver indicated AMSCs blocked the JNK-ATM pathway. Overall, AMSCs may be an effective treatment for AILI by inhibiting the JNK-ATM mitochondrial retrograde pathway, which improves APAP-induced mitochondrial dysfunction and liver injury.
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影响因子：
5.9
作者：
Jaeschke H;McGill MR;Ramachandran A
通讯作者：
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DOI：
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发表时间：
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期刊：
Acta Cirúrgica Brasileira
影响因子：
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作者：
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