Empagliflozin impact on experimentally induced acetaminophen toxicity: Imprint of mitochondrial dynamics, biogenesis, and cGAS/STING signal in amending liver insult.

Autor: El-Gohary RM; Department of Medical Biochemistry, Faculty of Medicine, Tanta University, Tanta, Egypt., Abdeen A; Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Benha University, Toukh, Egypt., Ibrahim HA; Department of Medical Biochemistry, Faculty of Medicine, Tanta University, Tanta, Egypt., Taher ES; Department of Basic Medical and Dental Sciences, Faculty of Dentistry, Zarqa University, Zarqa, Jordan., Ghabrial MM; Department of Anatomy and Embryology, Faculty of Medicine, Tanta University, Tanta, Egypt., Younis RL; Department of Physiology, Faculty of Medicine, Tanta University, Tanta, Egypt., Khattab H; Department of Physiology, Faculty of Medicine, Tanta University, Tanta, Egypt., Seleem MA; Department of Medical Pharmacology, Faculty of Medicine, Tanta University, Tanta, Egypt., Alwutayed KM; Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia., Mihaela O; Department of Biology, Faculty of Agriculture, University of Life Sciences 'King Michael I' from Timisoara, Timisoara, Romania., Ioan BD; Department of Biology, Faculty of Agriculture, University of Life Sciences 'King Michael I' from Timisoara, Timisoara, Romania., El-Nablaway M; Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Riyadh, Saudi Arabia., Aldarmahi AA; Department of Basic Science, College of Science and Health Professions, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.; National Guard- Health Affairs, King Abdullah International Medical Research Centre, Jeddah, Saudi Arabia., Ibrahim AM; Department of Administration and Nursing Education, College of Nursing, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia.; Department of Family and Community Health Nursing, Faculty of Nursing, Port-Said University, Port Said, Egypt., Al-Serwi RH; Department of Basic Sciences, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia., Ghalwash AA; Department of Medical Biochemistry, Faculty of Medicine, Tanta University, Tanta, Egypt.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2024 Jul 31; Vol. 38 (14), pp. e23816.
DOI: 10.1096/fj.202400254RRR
Abstrakt: 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.)
Databáze: MEDLINE
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