Protective effect of dimethyl fumarate against ethanol-provoked gastric ulcers in rats via regulation of HMGB1/TLR4/NF-κB, and PPARγ/SIRT1/Nrf2 pathways: Involvement of miR-34a-5p

• Published in: Archives of biochemistry and biophysics 2024-09, Vol.759, p.110103, Article 110103
• Main Authors: Elbaz, Eman M., Abdel Rahman, Amina A.S., El-Gazar, Amira A., Ali, Bassam Mohamed
• Format: Article
• Language: English
• Subjects: Dimethyl fumarate; Gastric ulcer; HMGB1; miR-34a-5p; Nrf2
• ISSN: 0003-9861; 1096-0384; 1096-0384
• DOI: 10.1016/j.abb.2024.110103

Aberration of the gastric mucosal barrier homeostasis circuit is one of the key features linked to the onset of gastric ulcers (GU). This work aimed to inspect the gastroprotective influence of dimethyl fumarate (DMF) on ethanol-induced GU in rats and to decipher the possible mechanisms entailed. Rats were pretreated with either DMF (80 mg/kg) or omeprazole (OMP) (20 mg/kg) by oral gavage for 2 weeks. After 24 h of starvation, ethanol (5 ml/kg, oral) was employed to trigger GU in rats, while carboxymethyl cellulose (CMC) was used as a control. Ethanol notably elevated both macroscopic and microscopic gastric damage. DMF and OMP exhibited similar effects on gastric ulcer healing. DMF intervention led to a substantial improvement in gastric insults. DMF significantly reduced ethanol-triggered gastric lesions, as manifested by decreased gastric secretion, acidity, ulcer surface area percent, reduced leukocyte incursion, and increased mucus percent. DMF upregulated miR-34a-5p expression concomitant with the suppression of high mobility group box1 (HMGB1) and inflammatory responses in gastric mucosal homogenate. DMF improved GU by restoring reduced antioxidant defense mechanisms through the coactivation of nuclear factor erythroid 2-related factor-2 (Nrf2), peroxisome proliferator-activated receptor gamma (PPARγ), and sirtuin1 (SIRT1), indicating the protective role of the PPARγ/SIRT1/Nrf2 pathway. Intriguingly, DMF mitigated apoptosis in ethanol-elicited GU. Taken together, this research implies the potential for the repurposing of DMF as an innovative gastroprotective medication to reestablish the balance of the gastric mucosal barrier via the attenuation of gastric inflammation, oxidative stress, and apoptosis. [Display omitted] •Dimethyl fumarate ameliorates ethanol-induced gastric ulcers in a rat model.•Dimethyl fumarate curbs inflammation, oxidative stress, and apoptosis.•The positive effect of dimethyl fumarate is linked to the regulation of HMGB1/TLR4/NF-κB and PPARγ/SIRT1/Nrf2 pathways.•Dimethyl fumarate could serve as a feasible gastroprotective remedy, potentially delaying the onset of gastric ulcers.