Network Pharmacology-Based Approach to Comparatively Predict the Active Ingredients and Molecular Targets of Compound Xueshuantong Capsule and Hexuemingmu Tablet in the Treatment of Proliferative Diabetic Retinopathy

Abstract

Background. Compound Xueshuantong capsule (CXC) and Hexuemingmu tablet (HXMMT) are two important Chinese patent medicines (CPMs) frequently used to treat proliferative diabetic retinopathy (PDR), especially when complicated with vitreous hemorrhage (VH). However, a network pharmacology approach to understand the therapeutic mechanisms of these two CPMs in PDR has not been applied. Objective. To identify differences in the active ingredients between CXC and HXMMT and to comparatively predict and further analyze the molecular targets shared by these CPMs and PDR. Materials and methods. The differentially expressed messenger RNAs (mRNAs) between normal retinal tissues in healthy individuals and active fibrovascular membranes in PDR patients were retrieved from the Gene Expression Omnibus database. The active ingredients of CXC and HXMMT and the targets of these ingredients were retrieved from the Traditional Chinese Medicine Systems Pharmacology database. The intersections of the CPM (CXC and HXMMT) targets and PDR targets were determined. Then, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed, and the ingredient-target networks, protein-protein interaction networks, and KEGG-target (KEGG-T) networks were constructed. Results. CXC contains 4 herbs, and HXMMT contains 19. Radix salviae is the only herb common to both. CXC had 34 potential therapeutic targets in PDR, while HXMMT had these 34 and 10 additional targets. Both CPMs shared the following main processes: response to reactive oxygen species and oxidative stress, regulation of blood vessel diameter and size, vasoconstriction, smooth muscle contraction, hemostasis, and blood coagulation. The shared pathways included the AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway, relaxin signaling pathway, and IL-17 signaling pathway. Conclusions. Both CXC and HXMMT include components effective at treating PDR and affect the following main processes: response to reactive oxygen species and oxidative stress, regulation of blood vessels, and blood coagulation. Radix salviae, the only herb common to both CPMs, contains many useful active ingredients. The PDR-CXC and PDR-HXMMT networks shared 34 common genes (RELA, HSPA8, HSP90AA, HSP90AB1, BRCA, EWSR1, CUL7, HNRNPU, MYC, CTNNB1, MDM2, YWHAZ, CDK2, AR, FN1, HUWE1, TP53, TUBB, EP300, GRB2, VCP, MCM2, EEF1A1, NTRK1, TRAF6, EGFR, PRKDC, SRC, HDAC5, APP, ESR1, AKT1, UBC, and COPS5), and the PDR-HXMMT network has 10 additional genes (RNF2, VNL, RPS27, COPS5, XPO1, PARP1, RACK1, YWHAB, and ITGA4). The top 5 pathways with the highest gene ratio in both networks were the AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway, relaxin signaling pathway, IL-17 signaling pathway, and focal adhesion. Additional pathways such as neuroactive ligand-receptor interaction, chemokine signaling pathway, and AMPK signaling pathway were enriched with HXMMT targets. Thus, HXMMT has more therapeutic targets shared by different active ingredients and more abundant gene functions than CXC, which may be two major reasons why HXMMT is more strongly recommended than CXC as an auxiliary treatment for new-onset VH secondary to PDR. However, the underlying mechanisms still need to be further explored.