Dictamnine alleviates DSS-induced colitis mice by inhibiting ferroptosis of enterocytes via activating Nrf2-Gpx4 signaling pathway.

BACKGROUND

The treatment of ulcerative colitis (UC) remains a huge challenge worldwide. Dictamnine is a natural product derived from Dictamnus dasycarpus Turcz. root bark and possesses multi-pharmacological properties, including anti-inflammation effects. However, its protective effect on UC and its underlying mechanisms are unknown.

PURPOSE: Here we explored the protective effect and underlying mechanism of dictamnine against dextran sulfate sodium (DSS)-induced colitis in mice.

METHODS

The experimental colitis was established by adding 3% DSS on drinking water of mice and the effects of dictamnine (10, 20, 40 mg/kg, p.o, once a day by 10 days) in colon tissues was analyzed. NCM460 cell was induced by RSL3 to detect the effect of dictamnine on ferroptosis and the underlying mechanism. Pathological damage was determined by H&E. Indicators related to intestinal permeability were detected by FITC and immunofluorescence. Cytokines levels (TNF-α、IL-1β and IL-6), antioxidant enzymes activities (MDA and GSH), the level of Fe2+ Cytokines levels and Gpx4 activity were detected by ELISA. Finally, the activation of nuclear factor erythroid 2-like 2 (Nrf2) was detected to explore the mechanism.

RESULTS

The results indicated that dictamnine significantly attenuated DSS-induced colon pathological damage, intestinal barrier, cytokines levels, and increased the antioxidant enzymes activities. Moreover, dictamnine attenuated ferroptosis in DSS-induced colon injury and upregulated Gpx4 expression in DSS-induced mice. Mechanistic experiments revealed that dictamnine activated Nrf2 in mice.

CONCLUSION

Taken together, this study evaluates that dictamnine alleviates DSS-induced colitis mice by inhibiting ferroptosis of enterocytes and its protective effects are associated with activating the Nrf2-Gpx4 signaling pathway.