Dexmedetomidine alleviates hepatic ischaemia‐reperfusion injury via the PI3K/AKT/Nrf2‐NLRP3 pathway

Hepatic ischaemia‐reperfusion (I/R) injury constitutes a tough difficulty in liver surgery. Dexmedetomidine (Dex) plays a protective role in I/R injury. This study investigated protective mechanism of Dex in hepatic I/R injury. The human hepatocyte line L02 received hypoxia/reoxygenation (H/R) treat...

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Bibliographic Details
Published in:	Journal of cellular and molecular medicine Vol. 25; no. 21; pp. 9983 - 9994
Main Authors:	Wu, Yan, Qiu, Gaolin, Zhang, Hainie, Zhu, Leilei, Cheng, Gao, Wang, Yiqiao, Li, Yuanhai, Wu, Weiwei
Format:	Journal Article
Language:	English
Published:	England John Wiley & Sons, Inc 01-11-2021 John Wiley and Sons Inc
Subjects:	1-Phosphatidylinositol 3-kinase Abdomen AKT protein Animals Antibodies Antigens Apoptosis Biomarkers Biotechnology Dexmedetomidine Dexmedetomidine - pharmacology Disease Models, Animal Enzymes Gene Expression Regulation hepatic ischaemia‐reperfusion injury Hypoxia hypoxia/reoxygenation cell model Inflammasomes Inflammation Ischemia JUND Laboratory animals Liver Liver Diseases - drug therapy Liver Diseases - etiology Liver Diseases - metabolism Liver Diseases - pathology Medical prognosis MicroRNAs miR‐494 NF-E2-Related Factor 2 - metabolism NLR Family, Pyrin Domain-Containing 3 Protein - metabolism NLRP3 Original Oxidative stress Phosphatidylinositol 3-Kinases - metabolism PI3K/AKT/Nrf2 pathway Protective Agents - pharmacology Proteins Proto-Oncogene Proteins c-akt - metabolism Pyroptosis Rats Reperfusion Reperfusion Injury - drug therapy Reperfusion Injury - etiology Reperfusion Injury - metabolism Reperfusion Injury - pathology Signal Transduction - drug effects United States > US China pyroptosis JUND PI3K/AKT/Nrf2 pathway hepatic ischaemia-reperfusion injury miR-494 Dexmedetomidine NLRP3 hypoxia/reoxygenation cell model
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Summary:	Hepatic ischaemia‐reperfusion (I/R) injury constitutes a tough difficulty in liver surgery. Dexmedetomidine (Dex) plays a protective role in I/R injury. This study investigated protective mechanism of Dex in hepatic I/R injury. The human hepatocyte line L02 received hypoxia/reoxygenation (H/R) treatment to stimulate cell model of hepatic I/R. The levels of pyroptosis proteins and inflammatory factors were detected. Functional rescue experiments were performed to confirm the effects of miR‐494 and JUND on hepatic I/R injury. The levels of JUND, PI3K/p‐PI3K, AKT/p‐AKT, Nrf2, and NLRP3 activation were detected. The rat model of hepatic I/R injury was established to confirm the effect of Dex in vivo. Dex reduced pyroptosis and inflammation in H/R cells. Dex increased miR‐494 expression, and miR‐494 targeted JUND. miR‐494 inhibition or JUND upregulation reversed the protective effect of Dex. Dex repressed NLRP3 inflammasome by activating the PI3K/AKT/Nrf2 pathway. In vivo experiments confirmed the protective effect of Dex on hepatic I/R injury. Overall, Dex repressed NLRP3 inflammasome and alleviated hepatic I/R injury via the miR‐494/JUND/PI3K/AKT/Nrf2 axis.
Bibliography:	Funding information This study was supported by Possible mechanism of pncd in elderly patients based on sphingomics and proteomics; Natural Science Foundation of colleges and universities in Anhui Province (kj2019A1111); the grant from Anhui Medical University (No. 2018xkj062). The funding body did not participate in the design of the study and collection, analysis and interpretation of data and in writing the manuscript ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1582-1838 1582-4934
DOI:	10.1111/jcmm.16871