Investigation on Intervention Mechanism of Ellagic Acid on Gastrointestinal Bleeding Based on in Vivo Exposure and Network Pharmacology

OBJECTIVE To analyze and identify the exposed components in rats after oral administration of ellagic acid by ultra performance liquid chromatography-quadrupole-time of flight mass spectrometry(UPLC-Q-TOF-MS) technology, and to explore the mechanism of ellagic acid and its exposed components in the treatment of gastrointestinal bleeding(GIB) in combination with network pharmacology. METHODS The UPLC-Q-TOF-MS was applied to detect metabolites in rats after oral administration of ellagic acid. The PharmMapper and SwissTargetPrediction database were used to predict the potential targets of the ingredients. And GIB disease-related targets were obtained from GeneCards, OMIM, and DRUGBANK database. The drug-disease common target genes were uploaded to STRING 11.0 for the construction of the protein-protein interaction(PPI) network. To obtain the core targets, CytoScape 3.8.2 was used to visualize and analyze the PPI network. The gene ontology(GO) analysis and Kyoto encyclopedia of genes and genomes(KEGG) pathway enrichment analysis were performed on the common targets by Metascape. The component-target-pathway network was constructed by CytoScape 3.8.2. Finally, AutoDockVina 1.1.2 software was used for molecular docking to verify the affinity of key components and core targets. RESULTS Based on UPLC-Q-TOF-MS analysis, the in vivo exposure components of ellagic acid were identified, including the prototype components of ellagic acid and 10 urolithins metabolites. Through network pharmacological prediction, 500 potential action targets were found, as well as 1 117 GIB related targets. SRC, PIK3R1, HRAS and others were the core targets from the PPI network. It was found that these components were mainly involved in signaling pathways such as PI3K-Akt signaling pathway, EGFR tyrosine kinase inhibitor resistance pathway, focal adhesion signaling pathway and others. The GO analysis mainly involved in the regulation of kinase activity, protein serine/threonine/tyrosine kinase activity, protein phosphorylation and so on. Molecular docking results showed that 11 components could target to 6 core proteins. CONCLUSION This study suggests that ellagic acid and urolithins might exert hemostatic effects by reducing oxidative stress and inhibiting inflammatory responses, as well as provides a scientific basis for the material basis and mechanism of ellagic acid-related traditional Chinese medicine in the treatment of GIB.