Regulation of IL-6/STAT-3/Wnt axis by nifuroxazide dampens colon ulcer in acetic acid-induced ulcerative colitis model: Novel mechanistic insight

• Published in: Life sciences (1973) 2021-07, Vol.276, p.119433, Article 119433
• Main Authors: Ali, Fares E.M., M. Elfiky, Mohamed, Fadda, Walaa A., Ali, Howaida S., Mahmoud, Amany Refaat, Mohammedsaleh, Zuhair M., Abd-Elhamid, Tarek Hamdy
• Format: Article
• Language: English
• Subjects: Acetic acid; Acetic Acid - toxicity; Acids; Animals; Anti-Bacterial Agents - toxicity; Anti-Infective Agents - pharmacology; Colitis, Ulcerative - chemically induced; Colitis, Ulcerative - metabolism; Colitis, Ulcerative - pathology; Colitis, Ulcerative - prevention & control; Colon; Disease Models, Animal; Dkk1 protein; Epithelial cell proliferation; Epithelial cells; Epithelium; Gene Expression Regulation - drug effects; Hematology; Hydroxybenzoates - pharmacology; IL-6/STAT-3/Wnt; Inflammation; Inflammatory bowel disease; Interleukin 6; Interleukin-6 - genetics; Interleukin-6 - metabolism; Intestine; Janus kinase; Male; NF-κB protein; Nifuroxazide; Nitrofurans - pharmacology; Rats; Rats, Wistar; Regeneration; Signal transduction; STAT-3 inhibitor; Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Sulfasalazine; Tumor necrosis factor-α; Ulcerative colitis; Ulcers; Wnt protein; Wnt1 Protein - genetics; Wnt1 Protein - metabolism
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2021.119433

Ulcerative colitis (UC) is a common intestinal problem characterized by the diffusion of colon inflammation and immunity dysregulation. Nifuroxazide, a potent STAT-3 inhibitor, exhibits diverse pharmacological properties. The present study aimed to elucidate a novel anti-colitis mechanism of nifuroxazide against the acetic acid-induced UC model. Rats were grouped into control (received vehicle), UC (2 ml of 5% acetic acid by intrarectal infusion), UC plus sulfasalazine (100 mg/kg/day, P.O.), UC plus nifuroxazide (25 mg/kg/day, P.O.), and UC plus nifuroxazide (50 mg/kg/day, P.O.) and lasted for 6 days. The present study revealed that nifuroxazide significantly reduced UC measures, hematological changes, and histological alteration. In addition, treatment with nifuroxazide significantly down-regulated serum CRP as well as the colonic expressions of MPO, IL-6, TNF-α, TLR-4, NF-κB-p65, JAK1, STAT-3, DKK1 in a dose-dependent manner. Besides, our results showed that the colonic Wnt expression was up-regulated with nifuroxazide treatment. In a dose-dependent manner, nifuroxazide markedly alleviated acetic acid-induced cellular infiltration and improved ulcer healing by increasing intestinal epithelial cell regeneration. Our results collectively indicate that nifuroxazide is an effective anti-colitis agent through regulation of colon inflammation and proliferation via modulation IL-6/STAT-3/Wnt signaling pathway. •Acetic acid successfully induced ulcerative colitis in rats.•Nifuroxazide significantly abrogated acetic acid-induced experimental colitis.•Nifuroxazide suppressed colon TLR-4/NF-κB-p65 and pro-inflammatory cytokines.•Nifuroxazide potentially regulated IL-6/STAT-3/Wnt signaling pathway in rat colon.