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

Overview

Journal Front Pharmacol

Date 2024 Oct 3

PMID 39359253

Authors

Elsayed A Elmorsy

Mahmoud E Youssef

Mohamed R Abdel-Hamed

Maha M Amer

Sahar R Elghandour

Abdullah S Alkhamiss

Nahla B Mohamed

Mostafa M Khodeir

Hossam A Elsisi

Thamir Saad Alsaeed

Manal M Kamal

Abousree T Ellethy

Basem H Elesawy

Sameh Saber

Affiliations

Soon will be listed here.

Abstract

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.

References

Canto C, Gerhart-Hines Z, Feige J, Lagouge M, Noriega L, Milne J . AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature. 2009; 458(7241):1056-60. PMC: 3616311. DOI: 10.1038/nature07813. View

Chen Z, Yu J, Fu M, Dong R, Yang Y, Luo J . Dipeptidyl peptidase-4 inhibition improves endothelial senescence by activating AMPK/SIRT1/Nrf2 signaling pathway. Biochem Pharmacol. 2020; 177:113951. DOI: 10.1016/j.bcp.2020.113951. View

Saber S, Yahya G, Gobba N, Sharaf H, Alshaman R, Alattar A . The Supportive Role of NSC328382, a P2X7R Antagonist, in Enhancing the Inhibitory Effect of CRID3 on NLRP3 Inflammasome Activation in Rats with Dextran Sodium Sulfate-Induced Colitis. J Inflamm Res. 2021; 14:3443-3463. PMC: 8313402. DOI: 10.2147/JIR.S315938. View

Kania D, Gonzalvo J, Weber Z . Saxagliptin: a clinical review in the treatment of type 2 diabetes mellitus. Clin Ther. 2011; 33(8):1005-22. DOI: 10.1016/j.clinthera.2011.06.016. View

Youssef M, El-Azab M, Abdel-Dayem M, Yahya G, Alanazi I, Saber S . Electrocardiographic and histopathological characterizations of diabetic cardiomyopathy in rats. Environ Sci Pollut Res Int. 2021; 29(17):25723-25732. DOI: 10.1007/s11356-021-17831-6. View

Alvarez S, Blanco A, Fresno M, Munoz-Fernandez M . TNF-α contributes to caspase-3 independent apoptosis in neuroblastoma cells: role of NFAT. PLoS One. 2011; 6(1):e16100. PMC: 3029262. DOI: 10.1371/journal.pone.0016100. View

Othman A, Ashour Ibrahim I, Saleh S, Abo-Elmatty D, Mesbah N, Abdel-Hamed A . The Safety and Efficacy of Combining Saxagliptin and Pioglitazone Therapy in Streptozocin-Induced Diabetic Rats. Biomedicines. 2023; 11(12). PMC: 10741989. DOI: 10.3390/biomedicines11123300. View

Daza-Arnedo R, Rico-Fontalvo J, Pajaro-Galvis N, Leal-Martinez V, Abuabara-Franco E, Raad-Sarabia M . Dipeptidyl Peptidase-4 Inhibitors and Diabetic Kidney Disease: A Narrative Review. Kidney Med. 2021; 3(6):1065-1073. PMC: 8664739. DOI: 10.1016/j.xkme.2021.07.007. View

Abdelhady R, Saber S, Abdel-Reheim M, Alamri M, Alfaifi J, Adam M . Unveiling the therapeutic potential of exogenous β-hydroxybutyrate for chronic colitis in rats: novel insights on autophagy, apoptosis, and pyroptosis. Front Pharmacol. 2023; 14:1239025. PMC: 10570820. DOI: 10.3389/fphar.2023.1239025. View

10.

Foerster E, Mukherjee T, Cabral-Fernandes L, Rocha J, Girardin S, Philpott D . How autophagy controls the intestinal epithelial barrier. Autophagy. 2021; 18(1):86-103. PMC: 8865220. DOI: 10.1080/15548627.2021.1909406. View

11.

Mankan A, Lawless M, Gray S, Kelleher D, McManus R . NF-kappaB regulation: the nuclear response. J Cell Mol Med. 2009; 13(4):631-43. PMC: 3822870. DOI: 10.1111/j.1582-4934.2009.00632.x. View

12.

Nazio F, Strappazzon F, Antonioli M, Bielli P, Cianfanelli V, Bordi M . mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6. Nat Cell Biol. 2013; 15(4):406-16. DOI: 10.1038/ncb2708. View

13.

Chassaing B, Aitken J, Malleshappa M, Vijay-Kumar M . Dextran sulfate sodium (DSS)-induced colitis in mice. Curr Protoc Immunol. 2014; 104:15.25.1-15.25.14. PMC: 3980572. DOI: 10.1002/0471142735.im1525s104. View

14.

Kanasaki K, Shi S, Kanasaki M, He J, Nagai T, Nakamura Y . Linagliptin-mediated DPP-4 inhibition ameliorates kidney fibrosis in streptozotocin-induced diabetic mice by inhibiting endothelial-to-mesenchymal transition in a therapeutic regimen. Diabetes. 2014; 63(6):2120-31. DOI: 10.2337/db13-1029. View

15.

Le Berre C, Honap S, Peyrin-Biroulet L . Ulcerative colitis. Lancet. 2023; 402(10401):571-584. DOI: 10.1016/S0140-6736(23)00966-2. View

16.

Abdelhamid A, Youssef M, Cavalu S, Mostafa-Hedeab G, Youssef A, Elazab S . Carbocisteine as a Modulator of Nrf2/HO-1 and NFκB Interplay in Rats: New Inspiration for the Revival of an Old Drug for Treating Ulcerative Colitis. Front Pharmacol. 2022; 13:887233. PMC: 9214041. DOI: 10.3389/fphar.2022.887233. View

17.

Brunet A, Sweeney L, Sturgill J, Chua K, Greer P, Lin Y . Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 2004; 303(5666):2011-5. DOI: 10.1126/science.1094637. View

18.

Yuan J, Zhao X, Hu Y, Sun H, Gong G, Huang X . Autophagy regulates the degeneration of the auditory cortex through the AMPK-mTOR-ULK1 signaling pathway. Int J Mol Med. 2018; 41(4):2086-2098. PMC: 5810242. DOI: 10.3892/ijmm.2018.3393. View

19.

Helal M, Megahed N, Abd Elhameed A . Saxagliptin mitigates airway inflammation in a mouse model of acute asthma via modulation of NF-kB and TLR4. Life Sci. 2019; 239:117017. DOI: 10.1016/j.lfs.2019.117017. View

20.

Zohny M, Alrouji M, Alhajlah S, AlOmeir O, El-Din Ewees M, Abdel Ghaffar D . Diacetylrhein, an anthraquinone antiarthritic agent, suppresses dextran sodium sulfate-induced inflammation in rats: A possible mechanism for a protective effect against ulcerative colitis. Biomed Pharmacother. 2022; 154:113651. DOI: 10.1016/j.biopha.2022.113651. View