1. Empagliflozin impact on experimentally induced acetaminophen toxicity: Imprint of mitochondrial dynamics, biogenesis, and cGAS/STING signal in amending liver insult.
- Author
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El-Gohary RM, Abdeen A, Ibrahim HA, Taher ES, Ghabrial MM, Younis RL, Khattab H, Seleem MA, Alwutayed KM, Mihaela O, Ioan BD, El-Nablaway M, Aldarmahi AA, Ibrahim AM, Al-Serwi RH, and Ghalwash AA
- Subjects
- Animals, Male, Mice, Liver metabolism, Liver drug effects, Liver pathology, Mice, Inbred BALB C, Mitochondrial Proteins metabolism, NF-kappa B metabolism, Organelle Biogenesis, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism, Signal Transduction drug effects, Acetaminophen toxicity, Acetaminophen adverse effects, Benzhydryl Compounds pharmacology, Benzhydryl Compounds toxicity, Chemical and Drug Induced Liver Injury metabolism, Chemical and Drug Induced Liver Injury drug therapy, Dynamins metabolism, Dynamins genetics, Glucosides pharmacology, GTP Phosphohydrolases metabolism, Membrane Proteins metabolism, Membrane Proteins genetics, Mitochondrial Dynamics drug effects, Nucleotidyltransferases metabolism
- Abstract
Acetaminophen (APAP) is one of the most clinically relevant medications associated with acute liver damage. A prolific deal of research validated the hepatoprotective effect of empagliflozin (EMPA); however, its effect on APAP-induced hepatotoxicity has still not been investigated. In this study, the prospective hepatoprotective impact of EMPA against APAP-induced hepatotoxicity was investigated. Twenty-eight Balb-C mice were assigned to four groups: control, APAP, EMPA10/APAP, and EMPA25/APAP. At the end of the experiment, serum hepatotoxicity biomarkers, MDA level, and GSH content were estimated. Hepatic mitofusin-2 (MFN2), optic atrophy 1 (OPA1), dynamin-related protein 1 (Drp1), and mitochondrial fission 1 protein (FIS1) were immunoassayed. PGC-1α, cGAS, and STING mRNA expression were assessed by real-time PCR. Histopathological changes and immunohistochemistry of INF-β, p-NF-κB, and iNOS were evaluated. APAP treatment caused significant hepatic functional impairment and increased hepatic MDA levels, as well as a concomitant decrease in GSH content. Marked elevation in Drp1 and FIS1 levels, INF-ß, p-NF-κB, and iNOS immunoreactivity, and reduction in MFN2 and OPA1 levels in the APAP-injected group, PGC-1α downregulation, and high expression of cGAS and STING were also documented. EMPA effectively ameliorated APAP-generated structural and functional changes in the liver, restored redox homeostasis and mitochondrial dynamics balance, and enhanced mitochondrial biogenesis, remarkably diminished hepatic expression of cGAS and STING, and elicited a reduction in hepatic inflammation. Moreover, the computational modeling data support the interaction of APAP with antioxidant system-related proteins as well as the interactions of EMPA against Drp1, cGAS, IKKA, and iNOS proteins. Our findings demonstrated for the first time that EMPA has an ameliorative impact against APAP-induced hepatotoxicity in mice via modulation of mitochondrial dynamics, biogenesis, and cGAS/STING-dependent inflammation. Thus, this study concluded that EMPA could be a promising therapeutic modality for acute liver toxicity., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
- Published
- 2024
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