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Cajaninstilbene Acid Ameliorates Acetaminophen-Induced Liver Injury Through Enhancing Sestrin2/AMPK-Mediated Mitochondrial Quality Control
Acetaminophen (APAP)-induced liver injury (AILI) is the main cause of acute liver failure in the developed countries. The present study aimed to evaluate the therapeutic efficacy of cajaninstilbene acid (CSA), a major stilbene compound derived from the leaves of pigeon pea [Cajanus cajan (L.) Millsp...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8957965/ https://www.ncbi.nlm.nih.gov/pubmed/35350766 http://dx.doi.org/10.3389/fphar.2022.824138 |
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author | Yan, Mingzhu Jin, Suwei Liu, Yongguang Wang, Lisha Wang, Zhi Xia, Tianji Chang, Qi |
author_facet | Yan, Mingzhu Jin, Suwei Liu, Yongguang Wang, Lisha Wang, Zhi Xia, Tianji Chang, Qi |
author_sort | Yan, Mingzhu |
collection | PubMed |
description | Acetaminophen (APAP)-induced liver injury (AILI) is the main cause of acute liver failure in the developed countries. The present study aimed to evaluate the therapeutic efficacy of cajaninstilbene acid (CSA), a major stilbene compound derived from the leaves of pigeon pea [Cajanus cajan (L.) Millsp.], against AILI. CSA (50, 75 mg/kg, p. o.) was administered to male C57BL/6 N mice 0.5 h after a toxic dose of APAP (300 mg/kg, i. p.). The direct effect of CSA on hepatocytes was tested on primary mouse hepatocytes. Serum transaminases, hematoxylin and eosin staining, TUNEL and propidium iodide staining were used to assess hepatic damage and cell death. The results demonstrated that APAP-induced liver injury was ameliorated by CSA, as evidenced by decreased alanine aminotransferase and aspartate aminotransferase levels in the serum, and fewer necrotic and apoptotic hepatocytes in vitro and in vivo. Consequently, the inflammation in response to APAP overdose was inhibited by CSA. Without affecting APAP metabolic activation, CSA interrupted the sustained JNK-Sab-ROS activation loop and alleviated oxidative stress. Additionally, CSA promoted mitochondrial quality control, including mitochondrial biogenesis and mitophagy, as revealed by increased PGC-1α, TFAM, LC3-Ⅱ, PINK1 and mitochondrial Parkin expression and decreased p62 expression. Further mechanistic investigations showed that independent of CAMKK2, LKB1-mediated AMPK activation, which was promoted by Sestrin2, might be responsible for the protective effect of CSA. Our study demonstrates that CSA alleviates APAP-induced oxidative stress and enhanced mitochondrial quality control through Sestrin2/AMPK activation, thereby protecting against AILI,. |
format | Online Article Text |
id | pubmed-8957965 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-89579652022-03-28 Cajaninstilbene Acid Ameliorates Acetaminophen-Induced Liver Injury Through Enhancing Sestrin2/AMPK-Mediated Mitochondrial Quality Control Yan, Mingzhu Jin, Suwei Liu, Yongguang Wang, Lisha Wang, Zhi Xia, Tianji Chang, Qi Front Pharmacol Pharmacology Acetaminophen (APAP)-induced liver injury (AILI) is the main cause of acute liver failure in the developed countries. The present study aimed to evaluate the therapeutic efficacy of cajaninstilbene acid (CSA), a major stilbene compound derived from the leaves of pigeon pea [Cajanus cajan (L.) Millsp.], against AILI. CSA (50, 75 mg/kg, p. o.) was administered to male C57BL/6 N mice 0.5 h after a toxic dose of APAP (300 mg/kg, i. p.). The direct effect of CSA on hepatocytes was tested on primary mouse hepatocytes. Serum transaminases, hematoxylin and eosin staining, TUNEL and propidium iodide staining were used to assess hepatic damage and cell death. The results demonstrated that APAP-induced liver injury was ameliorated by CSA, as evidenced by decreased alanine aminotransferase and aspartate aminotransferase levels in the serum, and fewer necrotic and apoptotic hepatocytes in vitro and in vivo. Consequently, the inflammation in response to APAP overdose was inhibited by CSA. Without affecting APAP metabolic activation, CSA interrupted the sustained JNK-Sab-ROS activation loop and alleviated oxidative stress. Additionally, CSA promoted mitochondrial quality control, including mitochondrial biogenesis and mitophagy, as revealed by increased PGC-1α, TFAM, LC3-Ⅱ, PINK1 and mitochondrial Parkin expression and decreased p62 expression. Further mechanistic investigations showed that independent of CAMKK2, LKB1-mediated AMPK activation, which was promoted by Sestrin2, might be responsible for the protective effect of CSA. Our study demonstrates that CSA alleviates APAP-induced oxidative stress and enhanced mitochondrial quality control through Sestrin2/AMPK activation, thereby protecting against AILI,. Frontiers Media S.A. 2022-03-08 /pmc/articles/PMC8957965/ /pubmed/35350766 http://dx.doi.org/10.3389/fphar.2022.824138 Text en Copyright © 2022 Yan, Jin, Liu, Wang, Wang, Xia and Chang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Yan, Mingzhu Jin, Suwei Liu, Yongguang Wang, Lisha Wang, Zhi Xia, Tianji Chang, Qi Cajaninstilbene Acid Ameliorates Acetaminophen-Induced Liver Injury Through Enhancing Sestrin2/AMPK-Mediated Mitochondrial Quality Control |
title | Cajaninstilbene Acid Ameliorates Acetaminophen-Induced Liver Injury Through Enhancing Sestrin2/AMPK-Mediated Mitochondrial Quality Control |
title_full | Cajaninstilbene Acid Ameliorates Acetaminophen-Induced Liver Injury Through Enhancing Sestrin2/AMPK-Mediated Mitochondrial Quality Control |
title_fullStr | Cajaninstilbene Acid Ameliorates Acetaminophen-Induced Liver Injury Through Enhancing Sestrin2/AMPK-Mediated Mitochondrial Quality Control |
title_full_unstemmed | Cajaninstilbene Acid Ameliorates Acetaminophen-Induced Liver Injury Through Enhancing Sestrin2/AMPK-Mediated Mitochondrial Quality Control |
title_short | Cajaninstilbene Acid Ameliorates Acetaminophen-Induced Liver Injury Through Enhancing Sestrin2/AMPK-Mediated Mitochondrial Quality Control |
title_sort | cajaninstilbene acid ameliorates acetaminophen-induced liver injury through enhancing sestrin2/ampk-mediated mitochondrial quality control |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8957965/ https://www.ncbi.nlm.nih.gov/pubmed/35350766 http://dx.doi.org/10.3389/fphar.2022.824138 |
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