Dunhuang Dabupi Decoction and its active components alleviate ulcerative colitis by activating glutathione metabolism and inhibiting JAK-STAT pathway in Drosophila and mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Dabupi Decoction (DBPD) originates from the ancient Dunhuang medical literature "Fu Xing Jue Visceral to Drug law legend" for more than 1000 years, which has been extensively employed to treat various diseases related to the spleen and stomach. However, limited studies focus on the mechanism of DBPD against ulcerative colitis (UC).

AIM OF THE STUDY: The beneficial effect and mechanism of DBPD against UC were detected by adopting both Drosophila melanogaster and C57BL/6J mouse models.

METHODS

The protective effect of DBPD against DSS-induced intestinal damage in flies was investigated by utilizing survival rate, locomotion, excretion, smurf, intestinal length, intestinal acid-base homeostasis, and Tepan blue assay. In mice, HE staining and ELISA kit were employed to assess serum histopathological damage and inflammatory factor levels. Subsequently, the molecular mechanism of DBPD was subsequently detected via DHE staining, immunofluorescence, transmission electron microscopy (TEM), real-time PCR, and transcriptomic sequencing. Additionally, liquid chromatography-mass spectrometry (LC-MS) and phenotype experiments in UC flies were utilized to identify the bioactive components of DBPD against UC.

RESULTS

Oral administration of DBPD remarkably alleviated DSS-induced body damage in flies by improving survival rate, locomotion, and excretion. It also remarkably rescued intestinal morphological damage, repaired acid-base homeostatic imbalance, inhibited intestinal epithelial cells (IECs) death and excessive proliferation of intestinal stem cells (ISCs), and improved ultrastructural damage of IECs in flies treated with DSS. Consistently, DBPD attenuated colitis symptoms, alleviated intestinal histopathological damage, and restored the expression of inflammatory factors in DSS-induced UC mice. As suggested by an integration of transcriptome data with molecular biology experiments, DBPD not only dramatically alleviated oxidative damage by activating the glutathione metabolic pathway, but also lowered inflammatory reaction by inhibiting the JAK-STAT pathway. Additionally, four compounds of DBPD, rhein acid, isoquercitrin, curcumin, and zeaxanthin were identified to alleviate the DSS-induced intestinal injury.

CONCLUSION

DBPD demonstrate immense potential for intestinal injury predominantly by activating the glutathione metabolic pathway to alleviate oxidative damage, and inhibiting the JAK-STAT pathway to mitigate inflammatory response. Rhein acid, isoquercitrin, curcumin, and zeaxanthin were the bioactive compounds of DBPD against UC.