Olmesartan attenuates type 2 diabetes-associated liver injury: Cross-talk of AGE/RAGE/JNK, STAT3/SCOS3 and RAS signaling pathways.

Autor: Abo El-Nasr NME; Department of Pharmacology, Medical Division, National Research Centre, Giza, Egypt. Electronic address: nm.el-nasr@nrc.sci.eg., Saleh DO; Department of Pharmacology, Medical Division, National Research Centre, Giza, Egypt., Mahmoud SS; Department of Pharmacology, Medical Division, National Research Centre, Giza, Egypt., Nofal SM; Department of Pharmacology, Medical Division, National Research Centre, Giza, Egypt., Abdelsalam RM; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt., Safar MM; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt; Department of Pharmacology and Biochemistry, Faculty of Pharmacy, The British University in Egypt, Egypt., El-Abhar HS; Department of Pharmacology, Toxicology and Biochemistry, Faculty of Pharmaceutical Sciences & Pharmaceutical Industry, Future University, Cairo, Egypt.
Jazyk: angličtina
Zdroj: European journal of pharmacology [Eur J Pharmacol] 2020 May 05; Vol. 874, pp. 173010. Date of Electronic Publication: 2020 Feb 14.
DOI: 10.1016/j.ejphar.2020.173010
Abstrakt: Olmesartan (OLM), an angiotensin receptor blocker, was tested against diabetes/insulin resistance (IR) models associated with renal/cardiovascular complications. Methods: we tested its potential role against diabetes-induced hepatic hitches using an IR/type2 diabetic (IR/D) model induced by high fat/high fructose diet for 7 weeks ​+ ​a single sub-diabetogenic dose of streptozotocin (35mg/kg; i.p). IR/D rats were orally treated with OLM (10 ​mg/kg), pioglitazone (PIO; 5 or 10 ​mg/kg) or their combinations for 4 consecutive weeks. OLM alone opposed the detrimental effects of IR/D; it significantly improved metabolic parameters, liver function, and abated hepatic oxidative stress, and inflammatory cytokine interleukin-6 (IL-6) and its upstream mediator nuclear factor kappa B. Consequently, OLM turned off the downstream cue p-Jak2/STAT3/SOCS3. Moreover, it suppressed the elevated AGE/RAGE/p-JNK pathway and increased the PPARγ/adiponectin cue to signify its anti-inflammatory and anti-oxidant capacity (GSH, MDA). Nevertheless, co-administration of OLM to PIO showed a synergistic improvement in all the aforementioned parameters in a dose dependent manner. Additionally, OLM with PIO 10 provoked a surge in hepatic PPARγ and adiponectin (5 and 6 folds) with a sharp decrease of about 85% in the NF-κB/IL-6/p-STAT3/SCOS3 pathway. These effects were confirmed by the histopathological study. In conclusion, OLM and its combination with PIO enhanced insulin sensitivity and guarded against hepatic complications associated with type 2 diabetes probably via modulating various inter-related pathways; namely, metabolic alteration, renin-angiotensin system, inflammatory trajectories, as well as oxidative stress. This study manifests the potential synergistic effects of OLM as an adjuvant therapy to the conventional antidiabetic therapies.
(Copyright © 2020. Published by Elsevier B.V.)
Databáze: MEDLINE
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