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.

Autor: Awad MM; Physiology Department, Faculty of Medicine, Tanta University, Tanta, Egypt. Electronic address: Marwa.saleh@med.tanta.edu.eg., El-Gohary RM; Medical Biochemistry Department, Faculty of Medicine,Tanta University,Tanta, Egypt. Electronic address: Rehab.elgohary@med.tanta.edu.eg., Ibrahim S; Human Anatomy and Embryology Department, Faculty of Medicine, Tanta University, Tanta, Egypt. Electronic address: Sara.ibrahim@med.tanta.edu.eg., Abdel Ghafar MT; Clinical Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt. Electronic address: mohamed.abdelghafar@med.tanta.edu.eg., Farghal EE; Clinical Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt. Electronic address: eman.farghal@med.tanta.edu.eg., Aboalsoud A; Pharmacology Depatrtment, Faculty of Medicine, Tanta University, Tanta, Egypt. Electronic address: alshimaa.taha@med.tanta.edu.eg., El-Shaer RAA; Physiology Department, Faculty of Medicine, Tanta University, Tanta, Egypt. Electronic address: rehab.elshaer@med.tanta.edu.eg.
Jazyk: angličtina
Zdroj: International immunopharmacology [Int Immunopharmacol] 2024 May 30; Vol. 133, pp. 112110. Date of Electronic Publication: 2024 Apr 22.
DOI: 10.1016/j.intimp.2024.112110
Abstrakt: 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 cascades, suggesting a potential role of Vilda in UC therapy.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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