Integrated network pharmacology and metabolomics to investigate the effects and possible mechanisms of Dehydroevodiamine against ethanol-induced gastric ulcers

Ethnopharmacological relevance: Tetradium ruticarpum (A.Juss.) T.G.Hartley, a traditional Chinese medicine with thousands of years of medicinal history, has been employed to address issues such as indigestion, abdominal pain, and vomiting. Dehydroevodiamine (DHE) is a quinazoline alkaloid extracted from traditional Chinese medicine Tetradium ruticarpum (A.Juss.) T.G.Hartley. Previous studies have shown that DHE has antiinflammatory, analgesic, and antioxidant activities. However, it is still unclear whether DHE has an effect on ethanol-induced gastric ulcers.Aim of the study: The objective of this study is to investigate the therapeutic efficacy and underlying mechanisms of action of DHE on ethanol-induced gastric ulcers using network pharmacology and metabolomics strategies. Methods: In this study, we used ethanol-induced rats as a model to assess the efficacy of DHE by biochemical indicator assays and pathological tissue detection. The integration of network pharmacology and metabolomics was used to explore possible mechanisms and was validated by western blot experiments. Finally, molecular docking was used to analyze the binding energy between DHE and the targets of PIK3CG and PLA2G2A. Results: DHE was able to reverse ethanol-induced abnormalities in biochemical indicators and improve pathological tissue. Network pharmacology results indicated that DHE may be involved in the regulation of gastric ulcers by modulating 79 targets, and metabolomics results showed that a total of 13 metabolites were changed before and after DHE administration. Integrating network pharmacology and metabolomics, PIK3CG and PLA2G2A were identified as possible targets to exert therapeutic effects. In addition, the MAPKs pathway may also be involved in the regulation of ethanol-induced gastric ulcers. Finally, molecular docking results showed that DHE had low binding energies with both PIK3CG and PLA2G2A.Conclusions: These findings suggest that DHE was able to exert a protective effect against ethanol-induced gastric ulcers by modulating multiple metabolites with multiple targets. This study provides a valuable reference for the development of antiulcer drugs.