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N-Acetylcysteine Attenuates Ischemia-Reperfusion-Induced Apoptosis and Autophagy in Mouse Liver via Regulation of the ROS/JNK/Bcl-2 Pathway

BACKGROUND: Hepatic ischemia–reperfusion injury (HIRI) remains a pivotal clinical problem after hemorrhagic shock, transplantation, and some types of toxic hepatic injury. Apoptosis and autophagy play important roles in cell death during HIRI. It is also known that N-acetylcysteine (NAC) has signifi...

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Autores principales: Wang, Chengfen, Chen, Kan, Xia, Yujing, Dai, Weiqi, Wang, Fan, Shen, Miao, Cheng, Ping, Wang, Junshan, Lu, Jie, Zhang, Yan, Yang, Jing, Zhu, Rong, Zhang, Huawei, Li, Jingjing, Zheng, Yuanyuan, Zhou, Yingqun, Guo, Chuanyong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4181678/
https://www.ncbi.nlm.nih.gov/pubmed/25264893
http://dx.doi.org/10.1371/journal.pone.0108855
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author Wang, Chengfen
Chen, Kan
Xia, Yujing
Dai, Weiqi
Wang, Fan
Shen, Miao
Cheng, Ping
Wang, Junshan
Lu, Jie
Zhang, Yan
Yang, Jing
Zhu, Rong
Zhang, Huawei
Li, Jingjing
Zheng, Yuanyuan
Zhou, Yingqun
Guo, Chuanyong
author_facet Wang, Chengfen
Chen, Kan
Xia, Yujing
Dai, Weiqi
Wang, Fan
Shen, Miao
Cheng, Ping
Wang, Junshan
Lu, Jie
Zhang, Yan
Yang, Jing
Zhu, Rong
Zhang, Huawei
Li, Jingjing
Zheng, Yuanyuan
Zhou, Yingqun
Guo, Chuanyong
author_sort Wang, Chengfen
collection PubMed
description BACKGROUND: Hepatic ischemia–reperfusion injury (HIRI) remains a pivotal clinical problem after hemorrhagic shock, transplantation, and some types of toxic hepatic injury. Apoptosis and autophagy play important roles in cell death during HIRI. It is also known that N-acetylcysteine (NAC) has significant pharmacologic effects on HIRI including elimination of reactive oxygen species (ROS) and attenuation of hepatic apoptosis. However, the effects of NAC on HIRI-induced autophagy have not been reported. In this study, we evaluated the effects of NAC on autophagy and apoptosis in HIRI, and explored the possible mechanism involved. METHODS: A mouse model of segmental (70%) hepatic warm ischemia was adopted to determine hepatic injury. NAC (150 mg/kg), a hepatoprotection agent, was administered before surgery. We hypothesized that the mechanism of NAC may involve the ROS/JNK/Bcl-2 pathway. We evaluated the expression of JNK, P-JNK, Bcl-2, Beclin 1 and LC3 by western blotting and immunohistochemical staining. Autophagosomes were evaluated by transmission electron microscopy (TEM). RESULTS: We found that ALT, AST and pathological changes were significantly improved in the NAC group. Western blotting analysis showed that the expression levels of Beclin 1 and LC3 were significantly decreased in NAC-treated mice. In addition, JNK, p-JNK, Bax, TNF-α, NF-κB, IL2, IL6 and levels were also decreased in NAC-treated mice. CONCLUSION: NAC can prevent HIRI-induced autophagy and apoptosis by influencing the JNK signal pathway. The mechanism is likely to involve attenuation of JNK and p-JNK via scavenged ROS, an indirect increase in Bcl-2 level, and finally an alteration in the balance of Beclin 1 and Bcl-2.
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spelling pubmed-41816782014-10-07 N-Acetylcysteine Attenuates Ischemia-Reperfusion-Induced Apoptosis and Autophagy in Mouse Liver via Regulation of the ROS/JNK/Bcl-2 Pathway Wang, Chengfen Chen, Kan Xia, Yujing Dai, Weiqi Wang, Fan Shen, Miao Cheng, Ping Wang, Junshan Lu, Jie Zhang, Yan Yang, Jing Zhu, Rong Zhang, Huawei Li, Jingjing Zheng, Yuanyuan Zhou, Yingqun Guo, Chuanyong PLoS One Research Article BACKGROUND: Hepatic ischemia–reperfusion injury (HIRI) remains a pivotal clinical problem after hemorrhagic shock, transplantation, and some types of toxic hepatic injury. Apoptosis and autophagy play important roles in cell death during HIRI. It is also known that N-acetylcysteine (NAC) has significant pharmacologic effects on HIRI including elimination of reactive oxygen species (ROS) and attenuation of hepatic apoptosis. However, the effects of NAC on HIRI-induced autophagy have not been reported. In this study, we evaluated the effects of NAC on autophagy and apoptosis in HIRI, and explored the possible mechanism involved. METHODS: A mouse model of segmental (70%) hepatic warm ischemia was adopted to determine hepatic injury. NAC (150 mg/kg), a hepatoprotection agent, was administered before surgery. We hypothesized that the mechanism of NAC may involve the ROS/JNK/Bcl-2 pathway. We evaluated the expression of JNK, P-JNK, Bcl-2, Beclin 1 and LC3 by western blotting and immunohistochemical staining. Autophagosomes were evaluated by transmission electron microscopy (TEM). RESULTS: We found that ALT, AST and pathological changes were significantly improved in the NAC group. Western blotting analysis showed that the expression levels of Beclin 1 and LC3 were significantly decreased in NAC-treated mice. In addition, JNK, p-JNK, Bax, TNF-α, NF-κB, IL2, IL6 and levels were also decreased in NAC-treated mice. CONCLUSION: NAC can prevent HIRI-induced autophagy and apoptosis by influencing the JNK signal pathway. The mechanism is likely to involve attenuation of JNK and p-JNK via scavenged ROS, an indirect increase in Bcl-2 level, and finally an alteration in the balance of Beclin 1 and Bcl-2. Public Library of Science 2014-09-29 /pmc/articles/PMC4181678/ /pubmed/25264893 http://dx.doi.org/10.1371/journal.pone.0108855 Text en © 2014 Wang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Wang, Chengfen
Chen, Kan
Xia, Yujing
Dai, Weiqi
Wang, Fan
Shen, Miao
Cheng, Ping
Wang, Junshan
Lu, Jie
Zhang, Yan
Yang, Jing
Zhu, Rong
Zhang, Huawei
Li, Jingjing
Zheng, Yuanyuan
Zhou, Yingqun
Guo, Chuanyong
N-Acetylcysteine Attenuates Ischemia-Reperfusion-Induced Apoptosis and Autophagy in Mouse Liver via Regulation of the ROS/JNK/Bcl-2 Pathway
title N-Acetylcysteine Attenuates Ischemia-Reperfusion-Induced Apoptosis and Autophagy in Mouse Liver via Regulation of the ROS/JNK/Bcl-2 Pathway
title_full N-Acetylcysteine Attenuates Ischemia-Reperfusion-Induced Apoptosis and Autophagy in Mouse Liver via Regulation of the ROS/JNK/Bcl-2 Pathway
title_fullStr N-Acetylcysteine Attenuates Ischemia-Reperfusion-Induced Apoptosis and Autophagy in Mouse Liver via Regulation of the ROS/JNK/Bcl-2 Pathway
title_full_unstemmed N-Acetylcysteine Attenuates Ischemia-Reperfusion-Induced Apoptosis and Autophagy in Mouse Liver via Regulation of the ROS/JNK/Bcl-2 Pathway
title_short N-Acetylcysteine Attenuates Ischemia-Reperfusion-Induced Apoptosis and Autophagy in Mouse Liver via Regulation of the ROS/JNK/Bcl-2 Pathway
title_sort n-acetylcysteine attenuates ischemia-reperfusion-induced apoptosis and autophagy in mouse liver via regulation of the ros/jnk/bcl-2 pathway
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4181678/
https://www.ncbi.nlm.nih.gov/pubmed/25264893
http://dx.doi.org/10.1371/journal.pone.0108855
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