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Oleanolic acid alleviating ischemia-reperfusion injury in rat severe steatotic liver via KEAP1/NRF2/ARE.
- Source :
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International immunopharmacology [Int Immunopharmacol] 2024 Sep 10; Vol. 138, pp. 112617. Date of Electronic Publication: 2024 Jul 06. - Publication Year :
- 2024
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Abstract
- Severe steatosis in donor livers is contraindicated for transplantation due to the high risk of ischemia-reperfusion injury (IRI). Although Ho-1 gene-modified bone marrow mesenchymal stem cells (HO-1/BMMSCs) can mitigate IRI, the role of gut microbiota and metabolites in this protection remains unclear. This study aimed to explore how gut microbiota and metabolites contribute to HO-1/BMMSCs-mediated protection against IRI in severe steatotic livers. Using rat models and cellular models (IAR20 and THLE-2 cells) of steatotic liver IRI, this study revealed that ischemia-reperfusion led to significant liver and intestinal damage, heightened immune responses, impaired liver function, and altered gut microbiota and metabolite profiles in rats with severe steatosis, which were partially reversed by HO-1/BMMSCs transplantation. Integrated microbiome and metabolome analyses identified gut microbial metabolite oleanolic acid as a potential protective agent against IRI. Experimental validation showed that oleanolic acid administration alone alleviated IRI and inhibited ferroptosis in both rat and cellular models. Network pharmacology and molecular docking implicated KEAP1/NRF2 pathway as a potential target of oleanolic acid. Indeed, OA experimentally upregulated NRF2 activity, which underlies its inhibition of ferroptosis and protection against IRI. The gut microbial metabolite OA protects against IRI in severe steatotic liver by promoting NRF2 expression and activity, thereby inhibiting ferroptosis.<br />Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024. Published by Elsevier B.V.)
- Subjects :
- Animals
Humans
Male
Rats
Antioxidant Response Elements
Cell Line
Disease Models, Animal
Ferroptosis drug effects
Liver pathology
Liver drug effects
Liver metabolism
Mesenchymal Stem Cell Transplantation
Rats, Sprague-Dawley
Signal Transduction drug effects
Fatty Liver drug therapy
Gastrointestinal Microbiome drug effects
Kelch-Like ECH-Associated Protein 1 metabolism
NF-E2-Related Factor 2 metabolism
Oleanolic Acid pharmacology
Reperfusion Injury drug therapy
Reperfusion Injury metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1878-1705
- Volume :
- 138
- Database :
- MEDLINE
- Journal :
- International immunopharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 38972213
- Full Text :
- https://doi.org/10.1016/j.intimp.2024.112617