Genistein and/or sulfasalazine ameliorate acetic acid-induced ulcerative colitis in rats via modulating INF-γ/JAK1/STAT1/IRF-1, TLR-4/NF-κB/IL-6, and JAK2/STAT3/COX-2 crosstalk

Ulcerative Colitis (UC) is a chronic idiopathic inflammatory bowel disease in which the colon's lining becomes inflamed. Exploring herbal remedies that can recover mucosal damage is becoming popular in UC. The study aims to investigate the probable colo-protective effect of a natural isoflavone, genistein (GEN), and/or a drug, sulfasalazine (SZ), against acetic acid (AA)-induced UC in rats, in addition to exploring the possible underlying mechanisms. UC was induced by the intrarectal installation of 1-2 ml of 5% diluted AA for 24 h. Ulcerated rats were allocated into the disease group and three treated groups, with SZ (100 mg/kg), GEN (100 mg/kg), and their combination for 14 days, besides the control groups. The anti-colitic efficacy of GEN and/or SZ was evidenced by hindering the AA-induced weight loss, colon edema, and macroscopic scores, besides reduced disease activity index and colon weight/length ratio. Furthermore, treatments attenuated the colon histopathological injury scores, increased the number of goblet cells, and lessened fibrosis. Both treatments reduced the up-regulation of INF-γ/JAK1/STAT1 and INF-γ /TLR-4/ NF-κB signaling pathways and modulated the IRF-1/iNOS/NO and IL-6/JAK2/STAT3/COX-2 pathways and consequently, reduced the levels of TNF-α and IL-1β. Moreover, both treatments diminished oxidative stress, which appeared by reducing the MPO level and elevating the SOD activity, and hindered apoptosis; proved by the decreased immunohistochemical expression of caspase-3. The current findings offer novel insights into the protective effects of GEN and suggest a superior benefit of combining GEN with SZ, over either drug alone, in the UC management.