Exploration of the Medication Rules and Mechanism of Patents for External Chinese Medicine Compound Formulas Against Diabetic Foot Ulcers Based on Data Mining,Network Pharmacology,Molecular Simulation and Experimental Validation
Objective The medication rules and mechanism of patents for external Chinese medicine compound formulas against diabetic foot ulcers(DFU)in National Intellectual Property Administration were analyzed and the results were validated by experiments.Methods The database of patents for external Chinese medicine compound formulas on the treatment of DFU were retrieved according to the inclusion and exclusion criteria.Patent set of external Chinese medicine compound formulas on the treatment of DFU were constructed after deduplication.The frequency,properties,flavors,meridian tropism,association rules and cluster analysis were further performed to screen the core external Chinese medicine datasets in the treatment of DFU.Then network model of disease-core Chinese medicinals-active ingredients-common targets was constructed.Protein-protein interaction(PPI)networks were built via common targets.Gene oncology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis were performed by Metascape platform.Molecular docking and dynamics simulations were employed to evaluate the binding affinity and stability between key targets and active ingredients.The effect of active ingredients on cell proliferation were analyzed by CCK-8,and qPCR was used to evaluate the effect of active ingredients on PI3K and Akt signaling pathway.Results A total of 98 patents for external Chinese medicine compound formulas on the treatment of DFU were screened,including 281 Chinese medicinals.Among them,Chinese herbal medicines in cold property are the most used drugs.Heat-clearing Chinese herbs and Chinese herbs for liver meridians are widely used.Data mining revealed that Angelica Sinensis Radix,Phellodendri Chinese Cortex,and Carthami Flos were top 3 core drugs in terms of frequency.A total of 85 active ingredients and 889 targets of the core drugs were obtained.Then,166 shared targets were screened after intersecting with DFU targets and targets of the core drugs.Eight core targets,including TNF-α and PPARγ were identified through PPI network topology analysis.GO and KEGG pathway enrichment analysis proved that active compounds of core drugs mainly acted on inflammation and cell apoptosis via multiple-signaling pathways,such as PI3K/Akt to treat DFU.Molecular docking and dynamics simulations demonstrated that there were good binding affinities and stabilities between core targets and their corresponding active ingredients.Meanwhile,stigmasterol shown high biosafety and enhanced the transcriptional level of PI3K and Akt in experimental validation.Conclusion In summary,this study confirmed that the essential characteristic of external compound in treating DFU were clearing away heat and removing toxins,invigorating blood and dissolving stasis.The key active ingredients,stigmasterol and dihydroniloticin,mainly targeted PPARγ and TNF-α.Stigmasterol could obviously upregulate PI3K and Akt signaling pathway to display the therapeutic effect on DFU.
diabetic foot ulcerpatents for external Chinese medicine compound formulasdata miningnetwork pharmacologymolecular dockingdynamics simulationexperimental validationclearing heat and removing toxinsinvigorating blood and dissolving stasis
NETL
NSTL
万方数据
