Potential mitigating impact of a dipeptidyl peptidase-IV inhibitor, vildagliptin, on oxazolone-induced ulcerative colitis: Targeting the role of PI3K/AKT/mTOR and AMPK/Nrf2 signaling pathways

• Published in: International immunopharmacology 2024-05, Vol.133, p.112110-112110, Article 112110
• Main Authors: Awad, Marwa Mahmoud, El-Gohary, Rehab M., Ibrahim, Sarah, Abdel Ghafar, Muhammad Tarek, Farghal, Eman E., Aboalsoud, Alshimaa, El-Shaer, Rehab Ahmed Ahmed
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases - metabolism; Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Autophagy; Colitis, Ulcerative - chemically induced; Colitis, Ulcerative - drug therapy; Colitis, Ulcerative - pathology; Colon - drug effects; Colon - pathology; Cytokines - metabolism; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Dipeptidyl-Peptidase IV Inhibitors - therapeutic use; Disease Models, Animal; Male; Mitochondrial dysfunction; NF-E2-Related Factor 2 - metabolism; Oxazolone; Oxidative Stress - drug effects; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Rats; Signal Transduction - drug effects; Signalling pathways; TOR Serine-Threonine Kinases - metabolism; Ulcerative colitis; Vildagliptin; Vildagliptin - pharmacology; Vildagliptin - therapeutic use
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2024.112110

[Display omitted] •Vilda merely mitigated colonic mitochondrial dysfunction and oxidative/ER stress.•Vilda alleviated OXZ-evoked UC via the induction of autophagy in colonic tissue.•The AMPK/Nrf2 axis exerted a master role in Vilda's coloprotective effect.•Vilda effectively suppressed PI3K/AKT/mTOR axis.•Vilda represents a glimmer of hope for UC patients. Growing evidence suggests that phosphoinositide 3-kinase (PI3K) and adenosine monophosphate-activated protein kinase (AMPK) signaling cascades are critical in ulcerative colitis (UC) pathophysiology by influencing gut mucosal inflammation. Recently, the coloprotective properties of dipeptidyl peptidase-IV (DPP-IV) inhibitors have emerged. Thus, this study assessed for the first time the potential mitigating impact of a DPP-IV inhibitor, vildagliptin (Vilda), on oxazolone (OXZ)-induced colitis in rats, targeting the role of PI3K/AKT/mTOR and AMPK/Nrf2 pathways. Thirty-two adult Albino rats were divided into four groups: control, Vilda (10 mg/kg/day orally), OXZ (300 µL of 5 % OXZ in 50 % aqueous ethanol solution introduced once into the colon via catheter), and Vilda+OXZ. Inflammatory cytokines (interleukin 13, tumor necrosis factor-α, interleukin 10), oxidative/endoplasmic reticulum stress markers (myeloperoxidase, reduced glutathione, catalase, CHOP), mitochondrial reactive oxygen species, adenosine triphosphate levels, and mitochondrial transmembrane potential were estimated. p-AMPK, p-AKT, beclin-1, and SQSTM1 levels were immunoassayed. Nrf2, PI3K, and mTOR expression levels were quantified using the real-time polymerase chain reaction. Furthermore, p-NF-ĸBp65 and LC3II immunoreactivity were evaluated. Vilda administration effectively ameliorated OXZ-induced colitis, as evidenced by the reduced Disease Activity Index, macroscopic colon damage score, colon weight/length ratio, ulcer index, and histopathological and electron microscopic changes in the colon tissues. Vilda treatment also counteracted OXZ-triggered inflammation, oxidative/endoplasmic reticulum stress, mitochondrial dysfunction, and enhanced autophagy in the colon. Vilda substantially suppressed PI3K/AKT/mTOR and activated the AMPK/Nrf2 pathway. Vilda has potent coloprotective and anti-ulcerogenic properties, primarily attributed to its antiinflammatory, antioxidant, and modulatory impact on mitochondrial dysfunction and autophagy activity. These effects were mostly mediated by suppressing PI3K/AKT/mTOR and activating AMPK/Nrf2 signaling ca