Evaluation of the key active ingredients of 'Radix Astragali and Rehmanniae Radix Mixture' and related signaling pathways involved in ameliorating diabetic foot ulcers from the perspective of TCM-related theories.

Background And Objective: Traditional Chinese Medicine is more inclined to holistic thinking than most modern pharmacological research. The multiple components and targets of traditional Chinese medicine have become a stumbling block in the study of drug action mechanisms in the life sciences. The current study aimed to reveal the active ingredients of "Radix Astragali and Rehmanniae Radix Mixture (RA-RRM)" involved in ameliorating diabetic foot ulcers and to analyze the related signaling pathways.

Method: The Traditional Chinese Medicine Systems Pharmacology Data base and Analysis Platform (TCMSP) was used to screen the active ingredients in RA-RRM based on the evaluation of the molecular weight (MW), bioavailability (OB), and transport of these active ingredients across intestinal epithelial cells (Caco-2) and the blood-brain barrier (BBB). The PubChem database was used to illustrate the structural formula and SMILES of these active ingredients in RA-RRM. The Swiss Target Prediction Database, DrugBank, Genecards, and CTD were used to predict the targets that were correlated with RA-RRM-based treatment of diabetic foot ulcers. Cytoscape 3.7.0 software was used to construct the protein/gene interaction network diagram, compound target interaction network diagram, and target pathway network diagram for these active ingredients in the amelioration of diabetic foot ulcers in RA-RRM. Topological parameter calculations of target information using Cytoscape 3.7.0 software yielded drug-disease targets were used to reveal the relationship between key active ingredients in RA-RMM and targets of interest for the treatment of diabetic foot. The disease targets of drug action were imported into the David database (GO and KEGG analysis) to analyze the enriched pathways and biological processes.

Results: The following results were obtained using the abovementioned screening and analysis. Fourteen key active ingredients in RA-RRM and 309 targets were found; among them, 85 targets were found to be related to diabetic foot ulcers using TCMSP. Twenty-three biological processes, 7 cell components and 14 molecular functions were found to ameliorate diabetic foot ulcers using GO analysis. In addition, 29 signaling pathways were found to be involved in RA-RRM-induced amelioration, including the NF-κB, TNF, TGF-β, VEGF, and HIF-1 signaling pathways, using KEGG analysis.

Conclusions: Based on current available evidence obtained from the abovementioned data/information databases and based on the perspective of TCM-related theories, the present study revealed the key active ingredients in RA-RRM and related signaling pathways in the treatment of diabetic foot ulcers, promoting further studies on and clinical applications of RA-RRM.