Network Pharmacology and Animal Experiment of Paliurus ramosissimus Intervention in Experimental Colitis-Associated Colorectal Precancerous Lesions
Objective:To investigate the interventional effects of Paliurus ramosissimus(PR)on colitis-associated colorectal precancerous lesions and explore the underlying mechanism.Methods:Gene Ontology(GO)annotation,Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis,and molecular docking were employed to predict the potential targets and pathways of betulinic acid(the main pharma-cological constituent of PR extract)on colitis-associated colorectal precancerous lesions.The mouse model of experimental colitis-associated colorectal precancerous lesions was established by intraperitoneal injection of azoxymethane(AOM)and intake of dextran sulfate sodium(DSS)via drinking water in a circulating manner.After administration of PR extract at 820 mg/kg and 205 mg/kg by gavage for 42 consecu-tive days,the disease activity index(DAI)and colorectal histopathology of the modeled mice were observed.ELISA was performed to meas-ure the levels of carcinoembryonic antigen(CEA),interleukin(IL)-1β,and tumor necrosis factor(TNF)-α in blood.Quantitative real-time polymerase chain reaction(qRT-PCR)was employed to determine the mRNA level of signal transducer and activator of transcription 3(Stat3)in the colorectal tissue.Results:A total of 157 potential targets of betulinic acid for intervention in colitis-associated colorectal pre-cancerous lesions were predicted.The targets were annotated to 874 biological processes(e.g.,responses to hormones,protein tyrosine ki-nase signaling pathway,and positive regulation of cell migration),75 molecular functions(e.g.,binding to kinase and protein kinase activi-ty),and 37 cell components(e.g.,membrane raft and glutamatergic synapse).The targets were mainly enriched in the cancer pathway,proteoglycan in cancer,lipid and atherosclerosis,prostate cancer,JAK-STAT signaling pathway,etc.Betulinic acid showed the binding en-ergy less than-5 kcal/mol with IL-1β,STAT3,and other targets.Compared with the normal control group,the model control group showed increased mortality(P＜0.05),elevated spleen index and histopathological scores(P＜0.01),atypical hyperplasia suggesting precancerous lesions,elevated serum levels of CEA,IL-1β,and TNF-α(P＜0.01),and up-regulated mRNA level of Stat3(P＜0.01).Compared with the model control group,the administration of PR extract at 820 mg/kg decreased the histopathological scores(P＜0.05),lowered the serum levels of CEA,IL-1β,and TNF-α(P＜0.01),and down-regulated the mRNA level of Stat3(P＜0.01).Conclusion:The gavage with PR extract can inhibit AOM/DSS-induced experimental colitis-associated colorectal precancerous lesions by reducing inflammation and down-reg-ulating the expression of Stat3.
Paliurus ramosissimusBetulinic acidColitis-associated colorectal cancerNetwork pharmacologyMolecular dockingCarci-noembryonic antigen(CEA)Signal transducer and activator of transcription 3(STAT3)
NETL
NSTL
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