Activation of AMPK/SIRT1/FOXO3a signaling by BMS-477118 (saxagliptin) mitigates chronic colitis in rats: uncovering new anti-inflammatory and antifibrotic roles.

Autor:	Elmorsy EA; Department of Pharmacology and Therapeutics, College of Medicine, Qassim University, Buraidah, Saudi Arabia., Youssef ME; Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt., Abdel-Hamed MR; Department of Anatomy, College of Medicine, Qassim University, Buraidah, Saudi Arabia.; Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt., Amer MM; Department of Anatomy, College of Medicine, Qassim University, Buraidah, Saudi Arabia.; Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt., Elghandour SR; Department of Anatomy and Histology, College of Medicine, Qassim University, Buraidah, Saudi Arabia., Alkhamiss AS; Department of Pathology, College of Medicine, Qassim University, Buraidah, Saudi Arabia., Mohamed NB; Department of Pathology, College of Medicine, Qassim University, Buraidah, Saudi Arabia., Khodeir MM; Department of Pathology, College of Medicine, Qassim University, Buraidah, Saudi Arabia.; Department of Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt., Elsisi HA; Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraidah, Saudi Arabia.; Department of Clinical Pharmacology, Faculty of Medicine, Zagazig University, Zagazig, Egypt., Alsaeed TS; Department of Biology and Immunology, College of Medicine, Qassim University, Buraidah, Saudi Arabia., Kamal MM; Department of Medical Physiology, Faculty of Medicine, Assiut University, Assiut, Egypt.; Department of Physiology, College of Medicine, Qassim University, Buraidah, Saudi Arabia., Ellethy AT; Department of Oral and Medical Basic Sciences, Biochemistry Division, College of Dentistry, Qassim University, Buraidah, Saudi Arabia., Elesawy BH; Department of Pathology, College of Medicine, Taif University, Taif, Saudi Arabia.; Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt., Saber S; Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt.
Jazyk:	angličtina
Zdroj:	Frontiers in pharmacology [Front Pharmacol] 2024 Sep 18; Vol. 15, pp. 1456058. Date of Electronic Publication: 2024 Sep 18 (Print Publication: 2024).
DOI:	10.3389/fphar.2024.1456058
Abstrakt:	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 long-term 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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Elmorsy, Youssef, Abdel-Hamed, Amer, Elghandour, Alkhamiss, Mohamed, Khodeir, Elsisi, Alsaeed, Kamal, Ellethy, Elesawy and Saber.)
Databáze:	MEDLINE
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