Targeting SIRT1/FoxO3a/Nrf2 and PI3K/AKT Pathways with Rebamipide Attenuates Acetic Acid-Induced Colitis in Rats

Abstract

Rebamipide is a quinolone derivative that has been commonly used for the treatment of gastric and duodenal ulcers. However, the molecular mechanisms of rebamipide against acetic acid-evoked colitis have not been adequately examined. Hence, the current study aimed to investigate the ameliorative effect of rebamipide in a rat model of acetic acid-evoked ulcerative colitis and the linked mechanisms pertaining to SIRT1/FoxO3a/Nrf2 and PI3K/AKT pathways. Herein, colitis was induced by the intrarectal administration of 3% acetic acid solution in saline (v/v) while rebamipide was administered by oral gavage (100 mg/kg/day) for seven days before the colonic insult. The colonic injury was examined by macroscopical and microscopical examination. The current findings demonstrated that rebamipide significantly improved the colonic injury by lowering the colonic disease activity index and macroscopic mucosal injury score. Moreover, it mitigated the histopathological aberrations and microscopical damage score. The favorable outcomes of rebamipide were driven by combating inflammation evidenced by dampening the colonic expression of NF-κBp65 and the pro-inflammatory markers CRP, TNF-α, and IL-6. In the same context, rebamipide curtailed the colonic pro-inflammatory PI3K/AKT pathway as seen by downregulating the immunostaining of PI3K and p-AKT(Ser473) signals. In tandem, rebamipide combated the colonic pro-oxidant events and augmented the antioxidant milieu by significantly diminishing the colonic TBARS and replenishing GSH, SOD, GST, GPx, and CAT. In the same regard, rebamipide stimulated the colonic upstream SIRT1/FoxO3a/Nrf2 axis by upregulating the expression of SIRT1, FoxO3a, and Nrf2, alongside downregulating Keap-1 gene expression. These antioxidant actions were accompanied by upregulation of the protein expression of the cytoprotective signal PPAR-γ in the colons of rats. In conclusion, the present findings suggest that the promising ameliorative features of rebamipide against experimental colitis were driven by combating the colonic inflammatory and oxidative responses. In perspective, augmentation of colonic SIRT1/FoxO3a/Nrf2 and inhibition of PI3K/AKT pathways were engaged in the observed favorable outcomes.

Activation of AMPK/mTOR-Driven Autophagy and Suppression of the HMGB1/TLR4 Pathway with Pentoxifylline Attenuates Doxorubicin-Induced Hepatic Injury in Rats

“…To minimize bias, an expert pathologist blinded to the identity of treatment groups conducted the processing of specimens in immunohistochemistry. Beclin 1 and SQSTM-1/p62 protein levels were detected by immunohistochemical staining in paraffin-embedded hepatic sections according to a routine immunohistochemistry protocol [ 50 ]. In brief, the 5-µm sections were deparaffinized, cleared, and processed for antigen retrieval using citrate buffer (50 mM, pH = 6.8).…”

Buspirone attenuated methotrexate‐induced hippocampal toxicity in rats by regulating Nrf2/HO‐1, PPAR‐γ, NF‐κB/nNOS, and ROS/NLRP3/caspase‐1 signaling pathways

“…[12] Strong evidence reported that PPAR-γ/Nrf2 signals co-activation had shown promise in counteracting oxidative stress and inflammation in different models. [13][14][15] Pyroptosis is a type of programmed lytic cell death marked by proinflammatory intracellular contents release, and it differs from apoptosis and necrosis in terms of signaling mechanism. [16] Pyroptosis is a caspase-1-dependent inflammatory form of cell death.…”