[Isovanillic acid alleviates dextran sulfate sodium-induced ulcerative colitis in mice by improving mitochondrial function via activating the PPARγ pathway].

OBJECTIVES

To investigate the protective effect of isovanillic acid (IVA) against dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and its underlying mechanism.

METHODS

Forty-eight male C57BL/6 mice were randomly divided into 6 groups (n=8), including a control group and 5 DSS model groups with daily gavage of saline containing 0.1% DMSO, low-, medium- or high-dose IVA (50, 100, and 150 mg/kg, respectively), or 5-ASA (100 mg/kg) for 10 days. Body weight and disease activity index (DAI) of the mice were monitored, and colon length and pathologies were assessed after the treatments. Immunofluorescence staining, Western blotting, TUNEL staining, and JC-1 staining were used to evaluate the effects of IVA on barrier function, apoptosis, and mitochondrial function in the mouse models and DSS-induced NCM460 cells. Network pharmacology was employed to predict potential signaling pathways.

RESULTS

The DSS-treated mice showed significantly decreased body weight, increased DAI score, shortened colon length, elevated colonic IL-6 and IL-1β expressions, and severe mucosal damage. IVA, especially at the medium and high doses, obviously improved these changes. Treatment with medium-dose IVA-M significantly increased colonic expressions of ZO-1 and claudin-1, decreased intestinal epithelial cell apoptosis rate and expressions of Bax and cleaved caspase-3, and increased Bcl-2 expression, TOMM20-positive cell counts, and activities of mitochondrial respiratory chain complexes I and IV. In NCM460 cells, IVA treatment obviously reversed DSS-induced mitochondrial impairment, reduced epithelial cell apoptosis, and enhanced expressions of ZO-1 and claudin-1. Network pharmacology analysis suggested that IVA potentially targeted the PPARγ pathway, which was confirmed by increased PPARγ protein expression in IVA-treated mice and NCM460 cells. Treatment with the PPARγ antagonist GW9662 significantly attenuated the protective effect of IVA in DSS-induced NCM460 cells.

CONCLUSIONS

IVA alleviates DSS-induced colitis in mice by protecting mitochondrial function via activating the PPARγ pathway and suppressing inflammation and apoptosis.