Targeting autophagy to modulate hepatic ischemia/reperfusion injury: A comparative study between octreotide and melatonin as autophagy modulators through AMPK/PI3K/AKT/mTOR/ULK1 and Keap1/Nrf2 signaling pathways in rats.

Autor: Mohamed DZ; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt. Electronic address: PG_55472@pharm.tanta.edu.eg., El-Sisi AEE; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt. Electronic address: sisialadin@yahoo.com., Sokar SS; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt. Electronic address: dr_samia_sokar@yahoo.com., Shebl AM; Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt; Sultan Qaboos University Hospital, Muscat, Sultanate of Oman. Electronic address: Abdelhadi.shebl@yahoo.com., Abu-Risha SE; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt. Electronic address: sally.abouresha@pharm.tanta.edu.eg.
Jazyk: angličtina
Zdroj: European journal of pharmacology [Eur J Pharmacol] 2021 Apr 15; Vol. 897, pp. 173920. Date of Electronic Publication: 2021 Feb 09.
DOI: 10.1016/j.ejphar.2021.173920
Abstrakt: Hepatic ischemia-reperfusion (HIR) injury is a common pathophysiological process in many clinical settings. This study was designed to compare the protective role of octreotide (somatostatin analogue, OCT) and melatonin (N-acetyl-5-methoxytryptamine, MLT) through the modulation of autophagy against HIR injury in rats. Male albino rats were divided into sham, HIR, OCT at three doses (50, 75, and 100 μg/kg), MLT, MLT + OCT75, compound C (AMPK inhibitor, CC), and CC + OCT75 groups. Ischemia was induced for 30 min followed by 24 h reperfusion. Biochemical, histopathological, immunohistochemical, lipid peroxidation, ELISA, qPCR, and western blot techniques were performed in our study. Liver autophagy was restored by OCT at doses (50 or 75 μg/kg) as indicated by elevating the expressions of Beclin-1, ATG7, and LC3 accompanied by the reduction of p62 expression through induction of AMPK/S317-ULK1 and inhibition of PI3K/AKT/mTOR/S757-ULK1 signaling pathways. As well, OCT maintained the integrity of the Keap1-Nrf2 system for the normal hepatic functions via controlling the Keap1 turnover through autophagy in a p62-dependent manner, resulting in upholding a series of anti-oxidant and anti-inflammatory cascades. These effects were abolished by compound C. On the other hand, MLT showed a decrease in the autophagy markers via inhibiting AMPK/pS317-ULK1 and activating PI3K/AKT/mTOR/pS757-ULK1 pathways. Autophagy inhibition with MLT markedly reversed the hepatoprotective effects of OCT75 after HIR injury. Finally, our results proved for the first time that OCT75 was more effective than MLT as it was sufficient to induce protective autophagy in our HIR model, which led to the induction of Nrf2-dependent AMPK/autophagy pathways.
(Copyright © 2021 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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