title: N-acetylcysteine attenuates ischemia-reperfusion-induced apoptosis and autophagy in mouse liver via regulation of the ROS/JNK/Bcl-2 pathway.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Chengfen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Kan
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Weiqi
authors.initials: W
authors.lastname: Dai
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Shen
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Cheng
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Junshan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhu
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Huawei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Yingqun
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Chuanyong
authors.initials: C
authors.lastname: Guo
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D016207:Cytokines / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D008099:Liver / Q000098:blood supply* / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D008807:Mice, Inbred BALB C; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015427:Reperfusion Injury / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control
chemical_list: D016207:Cytokines; D020011:Protective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D000111:Acetylcysteine