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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Inflammation Pharmacology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1456058
This article is part of the Research Topic New Targets and Strategies for the Prevention and Treatment of Organ Fibrosis, Volume III View all 5 articles

Activation of AMPK/SIRT1/FOXO3a Signaling by BMS-477118 (Saxagliptin) Mitigates Chronic Colitis in Rats: Uncovering New Anti-Inflammatory and Antifibrotic Roles

Provisionally accepted
Elsayed A. Elmorsy Elsayed A. Elmorsy 1*Mahmoud Youssef Mahmoud Youssef 2Mohamed R. Abdel-Hamed Mohamed R. Abdel-Hamed 1Maha M. Amer Maha M. Amer 1Sahar R. Elghandour Sahar R. Elghandour 1Abdullah S. Alkhamiss Abdullah S. Alkhamiss 1Nahla B. Mohamed Nahla B. Mohamed 1Mostafa M. Khodeir Mostafa M. Khodeir 1Hossam A. Elsisi Hossam A. Elsisi 1Thamir S. Alsaeed Thamir S. Alsaeed 1Manal M. Kamal Manal M. Kamal 1Abousree Ellethy Abousree Ellethy 1Basem H. Elesawy Basem H. Elesawy 3Sameh Saber Sameh Saber 2*
  • 1 Qassim University, Buraidah, Al-Qassim, Saudi Arabia
  • 2 Delta University for Science and Technology, Al Mansurah, Egypt
  • 3 Taif University, Ta'if, Saudi Arabia

The final, formatted version of the article will be published soon.

    Ulcerative colitis (UC) is a debilitating chronic disease marked by persistent inflammation and intestinal fibrosis. Despite the availability of various treatments, many patients fail to achieve longterm remission, underscoring a significant unmet therapeutic need. BMS-477118, a reversible inhibitor of dipeptidyl peptidase 4 (DPP4), has demonstrated anti-inflammatory properties in preclinical and clinical studies with minimal adverse effects compared to other antidiabetic agents. However, the potential benefits of BMS-477118 in chronic UC have not yet been explored. In this study, we aimed to investigate the effects of BMS-477118 in rats subjected to chronic dextran sodium sulfate (DSS) administration. Our findings indicate that BMS-477118 activates the interconnected positive feedback loop involving AMPK, SIRT1, and FOXO3a, improving histological appearance in injured rat colons.BMS-477118 also reduced fibrotic changes associated with the chronic nature of the animal model, alleviated macroscopic damage and disease severity, and improved the colon weight-to-length ratio.Additionally, BMS-477118 prevented DSS-induced weight loss and enhanced tight junction proteins.These effects, in conjunction with reduced oxidative stress and its potential anti-inflammatory, antiapoptotic, and autophagy-inducing properties, fostered prolonged survival in rats with chronic UC.To conclude, BMS-477118 has the potential to activate the AMPK/SIRT1/FOXO3a signaling pathway in inflamed colons. These results suggest that the AMPK/SIRT1/FOXO3a pathway could be a new therapeutic target for UC. Further research is mandatory to explore the therapeutic possibilities of this pathway. Additionally, continued studies on the therapeutic potential of BMS-477118 and other DPP4 inhibitors are promising for creating new treatments for various conditions, including UC in diabetic patients.

    Keywords: BMS-477118 (saxagliptin), AMPK/SIRT1/FOXO3a, Chronic ulcerative colitis, intestinal inflammation/fibrosis, DPP4 inhibitors, Novel therapeutic target

    Received: 27 Jun 2024; Accepted: 09 Sep 2024.

    Copyright: © 2024 Elmorsy, Youssef, Abdel-Hamed, Amer, Elghandour, Alkhamiss, Mohamed, Khodeir, Elsisi, Alsaeed, Kamal, Ellethy, Elesawy and Saber. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Elsayed A. Elmorsy, Qassim University, Buraidah, 52571, Al-Qassim, Saudi Arabia
    Sameh Saber, Delta University for Science and Technology, Al Mansurah, Egypt

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.