Arsenic trioxide preconditioning attenuates hepatic ischemia- reperfusion injury in mice: Role of ERK/AKT and autophagy.
10.1097/CM9.0000000000003411
- Author:
Chaoqun WANG
1
;
Hongjun YU
1
;
Shounan LU
1
;
Shanjia KE
1
;
Yanan XU
1
;
Zhigang FENG
2
;
Baolin QIAN
1
;
Miaoyu BAI
1
;
Bing YIN
1
;
Xinglong LI
1
;
Yongliang HUA
3
;
Zhongyu LI
1
;
Dong CHEN
1
;
Bangliang CHEN
1
;
Yongzhi ZHOU
1
;
Shangha PAN
1
;
Yao FU
4
;
Hongchi JIANG
5
;
Dawei WANG
6
;
Yong MA
1
Author Information
1. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Minimal Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China.
2. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Department of General Surgery, The Affiliated Hospital of Inner Mongolia Minzu University, Tongliao, Inner Mongolia 028000, China.
3. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Pediatric Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China.
4. Department of Ultrasound, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China.
5. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China.
6. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Anorectal Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China.
- Publication Type:Journal Article
- Keywords:
Arsenic trioxide;
Autophagy;
ERK;
Ischemia/reperfusion;
Liver;
PI3K-AKT;
Phosphoinositide 3-kinase-serine/threonine kinase;
Regeneration
- MeSH:
Animals;
Arsenic Trioxide;
Autophagy/physiology*;
Reperfusion Injury/prevention & control*;
Mice;
Male;
Proto-Oncogene Proteins c-akt/physiology*;
Arsenicals/therapeutic use*;
Oxides/therapeutic use*;
Liver/metabolism*;
Extracellular Signal-Regulated MAP Kinases/metabolism*;
Mice, Inbred C57BL
- From:
Chinese Medical Journal
2025;138(22):2993-3003
- CountryChina
- Language:English
-
Abstract:
BACKGROUND:Arsenic trioxide (ATO) is indicated as a broad-spectrum medicine for a variety of diseases, including cancer and cardiac disease. While the role of ATO in hepatic ischemia/reperfusion injury (HIRI) has not been reported. Thus, the purpose of this study was to identify the effects of ATO on HIRI.
METHODS:In the present study, we established a 70% hepatic warm I/R injury and partial hepatectomy (30% resection) animal models in vivo and hepatocytes anoxia/reoxygenation (A/R) models in vitro with ATO pretreatment and further assessed liver function by histopathologic changes, enzyme-linked immunosorbent assay, cell counting kit-8, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Small interfering RNA (siRNA) for extracellular signal-regulated kinase (ERK) 1/2 was transfected to evaluate the role of ERK1/2 pathway during HIRI, followed by ATO pretreatment. The dynamic process of autophagic flux and numbers of autophagosomes were detected by green fluorescent protein-monomeric red fluorescent protein-LC3 (GFP-mRFP-LC3) staining and transmission electron microscopy.
RESULTS:A low dose of ATO (0.75 μmol/L in vitro and 1 mg/kg in vivo ) significantly reduced tissue necrosis, inflammatory infiltration, and hepatocyte apoptosis during the process of hepatic I/R. Meanwhile, ATO obviously promoted the ability of cell proliferation and liver regeneration. Mechanistically, in vitro studies have shown that nontoxic concentrations of ATO can activate both ERK and phosphoinositide 3-kinase-serine/threonine kinase (PI3K-AKT) pathways and further induce autophagy. The hepatoprotective mechanism of ATO, at least in part, relies on the effects of ATO on the activation of autophagy, which is ERK-dependent.
CONCLUSION:Low, non-toxic doses of ATO can activate ERK/PI3K-AKT pathways and induce ERK-dependent autophagy in hepatocytes, protecting liver against I/R injury and accelerating hepatocyte regeneration after partial hepatectomy.
