基于代谢组学与网络药理学探讨石斛复方治疗大鼠乙酸型胃溃疡机制OA

Objective:To investigate the mechanisms of Dendrobii Caulis compound formula(DAC)containing Dendrobii Caulis,Citri Reticulatae Pericarpium,and Amomi Fructus in the treatment of gastric ulcer(GU).Methods:The active components of DAC and their targets were screened using databases such as the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),while GU-related targets were retrieved from databases including GeneCards.The STRING platform combined with Cytoscape 3.9.1 software was used to construct network diagrams and identify core components and key targets.Gene Ontology(GO)functional annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses were performed,and molecular docking was conducted to verify binding activity.A GU rat model was established by injection of 70%glacial acetic acid.Rats were randomly divided into a control group,a model group,an omeprazole group(4 mg·kg-1),and DAC low-,medium-,and high-dose groups(0.4,0.8,and 1.6 g·kg-1),followed by continuous intragastric administration for 14 days.Pathological changes were observed by hematoxylin-eosin(HE)staining and periodic acid-Schiff(PAS)staining.Oxidative stress indicators were measured.The expression of epidermal growth factor(EGF)and its receptor(EGFR)was detected by immunohistochemistry.The expression of phosphatidylinositol 3-kinase/protein kinase B(PI3K/Akt)pathway-related proteins was detected by Western blot.Gastric tissue metabolomic profiles were analyzed using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UHPLC-Q-TOF-MS).Principal component analysis(PCA)was used to analyze intergroup differences,screen differential metabolites,and perform metabolic pathway enrichment.Results:Forty-two active components of DAC were identified,including erianin,dendrobine,and hesperetin,and 379 potential targets were obtained,mainly including phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha(PIK3CA),EGFR,and SRC proto-oncogene(SRC).KEGG analysis indicated that DAC mainly affected the PI3K/Akt signaling pathway and the EGFR tyrosine kinase inhibitor resistance pathway.Molecular docking results showed that the binding energies between the main active components of DAC and the core targets PIK3CA,EGFR,and SRC were all<-8 kcal·mol-1.Animal experiments demonstrated that the high-dose DAC group significantly improved gastric tissue lesions in GU rats,promoted gastric mucosal mucus secretion,decreased serum malondialdehyde(MDA)levels,and increased the activities of superoxide dismutase(SOD)and glutathione peroxidase(GSH-Px).Meanwhile,it significantly upregulated the protein expression levels of EGF,EGFR,phosphorylated PI3K(p-PI3K),and phosphorylated Akt(p-Akt)in gastric tissues.Metabolomic analysis identified 79 differential metabolites,mainly enriched in linoleic acid metabolism,taurine and hypotaurine metabolism,and arachidonic acid metabolism pathways.Conclusion:DAC can promote mucosal regeneration,enhance antioxidant capacity,and regulate the metabolism of linoleic acid,arachidonic acid,and taurine.Its mechanism may be related to the PI3K/Akt signaling pathway and targets such as PIK3CA,EGFR,and SRC.