Ethyl pyruvate ameliorates hepatic ischemia-reperfusion injury by inhibiting intrinsic pathway of apoptosis and autophagy.
BACKGROUND
Hepatic ischemia-reperfusion (I/R) injury is a pivotal clinical problem occurring in many clinical conditions such as transplantation, trauma, and hepatic failure after hemorrhagic shock. Apoptosis and autophagy have been shown to contribute to cell death in hepatic I/R injury. Ethyl pyruvate, a stable and simple lipophilic ester, has been shown to have anti-inflammatory properties. In this study, the purpose is to explore both the effect of ethyl pyruvate on hepatic I/R injury and regulation of intrinsic pathway of apoptosis and autophagy.


METHODS
Three doses of ethyl pyruvate (20 mg/kg, 40 mg/kg, and 80 mg/kg) were administered 1 h before a model of segmental (70%) hepatic warm ischemia was established in Balb/c mice. All serum and liver tissues were obtained at three different time points (4 h, 8 h, and 16 h).


RESULTS
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and pathological features were significantly ameliorated by ethyl pyruvate (80 mg/kg). The expression of Bcl-2, Bax, Beclin-1, and LC3, which play an important role in the regulation of intrinsic pathway of apoptosis and autophagy, was also obviously decreased by ethyl pyruvate (80 mg/kg). Furthermore, ethyl pyruvate inhibited the HMGB1/TLR4/ NF-κb axis and the release of cytokines (TNF-α and IL-6).


CONCLUSIONS
Our results showed that ethyl pyruvate might attenuate to hepatic I/R injury by inhibiting intrinsic pathway of apoptosis and autophagy, mediated partly through downregulation of HMGB1/TLR4/ NF-κb axis and the competitive interaction with Beclin-1 of HMGB1.
Department of Gastroenterology, The Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Miao
M
Shen
Department of Gastroenterology, The Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Jie
J
Lu
Department of Gastroenterology, The Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Weiqi
W
Dai
Department of Gastroenterology, The Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Fan
F
Wang
Department of Gastroenterology, The Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Ling
L
Xu
Department of Gastroenterology, The Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Kan
K
Chen
Department of Gastroenterology, The Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Lei
L
He
Department of Gastroenterology, The Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Ping
P
Cheng
Department of Gastroenterology, The Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Yan
Y
Zhang
Department of Gastroenterology, The Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Chengfen
C
Wang
Department of Gastroenterology, The Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Dong
D
Wu
Department of Gastroenterology, The Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Jing
J
Yang
Department of Gastroenterology, The Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Rong
R
Zhu
Department of Gastroenterology, The Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Huawei
H
Zhang
Department of Gastroenterology, The Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Yinqun
Y
Zhou
Department of Gastroenterology, The Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Chuanyong
C
Guo
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000032:analysis; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D024243:HMGB1 Protein / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008869:Microtubule-Associated Proteins / Q000032:analysis; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D011773:Pyruvates / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D051028:bcl-2-Associated X Protein / Q000032:analysis; D000093242:Interleukin-6 Inhibitors
D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D024243:HMGB1 Protein; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D011773:Pyruvates; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D000093242:Interleukin-6 Inhibitors; C494827:Bax protein, mouse; C115010:Becn1 protein, mouse; C582808:HMGB1 protein, mouse; C480860:Map1lc3b protein, mouse; C046522:ethyl pyruvate