A Novel Role of Dapagliflozin in Mitigation of Acetic Acid-Induced Ulcerative Colitis by Modulation of Monocyte Chemoattractant Protein 1 (MCP-1)/Nuclear Factor-Kappa B (NF-κB)/Interleukin-18 (IL-18)

Abstract

Colon illnesses, particularly ulcerative colitis, are considered a major cause of death in both men and women around the world. The present study investigated the underlying molecular mechanisms for the potential anti-inflammatory effect of Dapagliflozin (DAPA) against ulcerative colitis (UC) induced by intracolonic instillation of 3% v/v acetic acid (AA). DAPA was administered to rats (1 mg/kg, orally) for two weeks during the treatment regimen. Interestingly, compared to the normal group, a marked increase in the index of colon/body weight, colon weight/colon length ratio, serum lactate dehydrogenase (LDH), and C-reactive protein (CRP), besides decrease in the serum total antioxidant capacity (TAC), were reported in the AA control group (p ˂ 0.05). Elevation in colon monocyte chemoattractant protein (MCP1), Interleukin 18 (IL-18), and inflammasome contents were also reported in the AA control group in comparison with the normal group. In addition, colon-specimen immunohistochemical staining revealed increased expression of nuclear factor-kappa B (NF-κB) and Caspase-3 with histopathological changes. Moreover, DAPA significantly (p ˂ 0.05) reduced the colon/body weight index, colon weight/colon length ratio, clinical evaluation, and macroscopic scoring of UC, and preserved the histopathological architecture of tissues. The inflammatory biomarkers, including colon MCP1, IL-18, inflammasome, Caspase-3, and NF-κB, were suppressed following DAPA treatment and oxidants/antioxidants hemostasis was also restored. Collectively, the present data demonstrate that DAPA represents an attractive approach to ameliorating ulcerative colitis through inhibiting MCP1/NF-κB/IL-18 pathways, thus preserving colon function. Antioxidant, anti-inflammatory, and anti-apoptotic properties of DAPA are implicated in its observed therapeutic benefits.

Pylorus ligation-induced hyperacidity: synergistic prophylactic effects of linagliptin and L-arginine via up-regulation of EP4 receptor subtype and improvement of vascular endothelial damage

“…As a result of gastric mucosal damage, IL-1β induces the release of mucosal MCP-1 which will, in turn, stimulate the migration of lymphocytes and monocytes to the site of mucosal injury (ElMahdy et al 2021 ). Similar to Il-1β, MCP-1 acts in a dual mode where it can be considered an important defense mechanism against mucosal injury, while on the other hand, it can promote mucosal damage, epithelium disorder as intestinal metaplasia and can induce detrimental effects as a result of inducing proteases and ROS (Siriviriyakul et al 2020 ).…”

Fibrosis: Types, Effects, Markers, Mechanisms for Disease Progression, and Its Relation with Oxidative Stress, Immunity, and Inflammation

“…Fibrosis is marked by an increase in the inflammatory response, tissue destruction, and the release of numerous inflammatory cytokines, including TGF-β1, tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein (MCP-1), Interleukin-6 (IL-6), and IL-8. This results in a pro-inflammatory microenvironment that amplifies tissue injury [ 82 ]. EMT, which is becoming more and more well-documented as an essential component of tissue fibrogenesis following renal damage, is a process by which differentiated epithelial cells give rise to matrix-producing fibroblasts and myofibroblasts.…”

Editorial: Novel Therapeutic Approaches in Inflammatory Bowel Diseases

“…It also maintained the histopathological tissue architecture; suppressed inflammatory biomarkers including colon MCP1, IL-18, Caspase-3, and NF-κB; and successfully restored oxidant/antioxidant balance. These findings collectively suggest that DAPA could be a promising approach for ameliorating UC through its antioxidative, anti-inflammatory, and antiapoptotic properties [ 5 ]. Silva et al aimed to assess the effectiveness and safety of Hemin (a heme-oxygenase inducer) in a chronic 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis model in rodents.…”