PMID- 32705206
OWN - NLM
STAT- MEDLINE
DCOM- 20210426
LR  - 20210929
IS  - 1791-3004 (Electronic)
IS  - 1791-2997 (Print)
IS  - 1791-2997 (Linking)
VI  - 22
IP  - 3
DP  - 2020 Sep
TI  - Pretreatment with the ALDH2 activator Alda‑1 protects rat livers from 
      ischemia/reperfusion injury by inducing autophagy.
PG  - 2373-2385
LID - 10.3892/mmr.2020.11312 [doi]
AB  - Hepatic ischemia/reperfusion injury (HIRI) is a complex pathophysiological 
      process that often leads to poor clinical prognosis. Clinically, the effective 
      means to alleviate HIRI are limited. The aim of the present study was to 
      investigate whether Alda‑1, an activator of mitochondrial aldehyde dehydrogenase 
      2 (ALDH2), had a protective effect on HIRI and to investigate the mechanisms 
      underlying this protective effect. Sprague‑Dawley rats were treated with Alda‑1 
      or Daidzin, an ALDH2 inhibitor, 30 min before partial (70%) warm liver ischemia 
      to induce HIRI. The 48 rats were randomly divided into four groups: Sham, 
      ischemia injury (IR), IR‑Alda‑1, and IR‑Daidzin. After 6 and 24 h of reperfusion, 
      serum and liver tissue samples were collected and stored for further experiments. 
      Alanine aminotransferase, aspartate aminotransferase and hematoxylin & eosin 
      staining was used to evaluate the liver damage. Western blotting and reverse 
      transcription‑quantitative PCR were used to detect the expression of related 
      proteins and mRNA. TUNEL staining was used to observe the apoptosis of liver 
      cells. Transmission electron microscopy was used to detect the mitochondrial 
      injuries. Alda‑1 pretreatment ameliorated the HIRI‑induced damage to the liver 
      function and reduced histological lesions. Alda‑1 also increased ALDH2 activity 
      after HIRI. Moreover, the pretreatment with Alda‑1 reduced the accumulation of 
      toxic aldehyde 4‑hydroxy‑2‑nonenal, decreased the production of reactive oxygen 
      species and malondialdehyde, reversed the damage to the liver mitochondria, 
      attenuated hepatocyte apoptosis and inhibited the HIRI‑induced inflammatory 
      response, including high‑mobility group box 1/toll‑like receptor 4 signaling. 
      Alda‑1 also induced autophagy by upregulating autophagy‑related 7 and Rab7 
      increasing the microtubule associated protein 1 light chain 3 alphaII/I ratio and 
      inhibiting p62 expression. ALDH2‑induced autophagy was dependent on the 
      activation of the AKT/mammalian target of rapamycin (mTOR) and AMP‑activated 
      protein kinase (AMPK) signaling pathways. In conclusion, the findings of the 
      present study suggested that Alda‑1 may protect the liver against HIRI‑induced 
      damage, including hepatic enzyme injury, acetaldehyde accumulation, oxidative 
      stress, hepatocyte apoptosis and inflammation. Alda‑1 may confer this protection 
      by inducing autophagy through the AKT/mTOR and AMPK signaling pathways. 
      Therefore, ALDH2 could represent a potential pharmacological target in the 
      clinical treatment of HIRI.
FAU - Liu, Zhongzhong
AU  - Liu Z
AD  - Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of 
      Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of 
      Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China.
FAU - Ye, Shaojun
AU  - Ye S
AD  - Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of 
      Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of 
      Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China.
FAU - Zhong, Xiang
AU  - Zhong X
AD  - Department of General Surgery, The First Affiliated Hospital of Nanchang 
      University, Nangchang, Jiangxi 330006, P.R. China.
FAU - Wang, Wei
AU  - Wang W
AD  - Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of 
      Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of 
      Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China.
FAU - Lai, Chin-Hui
AU  - Lai CH
AD  - Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of 
      Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of 
      Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China.
FAU - Yang, Wang
AU  - Yang W
AD  - Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of 
      Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of 
      Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China.
FAU - Yue, Pengpeng
AU  - Yue P
AD  - Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of 
      Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of 
      Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China.
FAU - Luo, Jun
AU  - Luo J
AD  - Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of 
      Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of 
      Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China.
FAU - Huang, Xiaoying
AU  - Huang X
AD  - Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of 
      Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of 
      Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China.
FAU - Zhong, Zibiao
AU  - Zhong Z
AD  - Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of 
      Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of 
      Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China.
FAU - Xiong, Yan
AU  - Xiong Y
AD  - Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of 
      Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of 
      Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China.
FAU - Fan, Xiaoli
AU  - Fan X
AD  - Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of 
      Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of 
      Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China.
FAU - Li, Ling
AU  - Li L
AD  - Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of 
      Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of 
      Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China.
FAU - Wang, Yanfeng
AU  - Wang Y
AD  - Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of 
      Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of 
      Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China.
FAU - Ye, Qifa
AU  - Ye Q
AD  - Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of 
      Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of 
      Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China.
LA  - eng
PT  - Journal Article
DEP - 20200708
PL  - Greece
TA  - Mol Med Rep
JT  - Molecular medicine reports
JID - 101475259
RN  - 0 (Aldehydes)
RN  - 0 (Benzamides)
RN  - 0 (Benzodioxoles)
RN  - 0 (N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide)
RN  - 0 (Reactive Oxygen Species)
RN  - K1CVM13F96 (4-hydroxy-2-nonenal)
SB  - IM
MH  - Aldehydes/metabolism
MH  - Animals
MH  - Autophagy
MH  - Benzamides/*administration & dosage/pharmacology
MH  - Benzodioxoles/*administration & dosage/pharmacology
MH  - Disease Models, Animal
MH  - Gene Expression Regulation/drug effects
MH  - Liver Diseases/etiology/metabolism/*prevention & control
MH  - Liver Function Tests
MH  - Male
MH  - Oxidative Stress/drug effects
MH  - Random Allocation
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Reactive Oxygen Species/metabolism
MH  - Reperfusion Injury/metabolism/*prevention & control
PMC - PMC7411338
OTO - NOTNLM
OT  - aldH2
OT  - alda-1
OT  - hepatic ischemia/reperfusion injury
OT  - 4-Hne
OT  - autophagy
EDAT- 2020/07/25 06:00
MHDA- 2021/04/27 06:00
PMCR- 2020/07/08
CRDT- 2020/07/25 06:00
PHST- 2019/09/08 00:00 [received]
PHST- 2020/05/07 00:00 [accepted]
PHST- 2020/07/25 06:00 [entrez]
PHST- 2020/07/25 06:00 [pubmed]
PHST- 2021/04/27 06:00 [medline]
PHST- 2020/07/08 00:00 [pmc-release]
AID - mmr-22-03-2373 [pii]
AID - 10.3892/mmr.2020.11312 [doi]
PST - ppublish
SO  - Mol Med Rep. 2020 Sep;22(3):2373-2385. doi: 10.3892/mmr.2020.11312. Epub 2020 Jul 
      8.