Network Pharmacology Analysis of Traditional Chinese Medicine Formula Xiao Ke Yin Shui Treating Type 2 Diabetes Mellitus

Abstract

Xiao Ke Yin Shui (XKYS) formula is a traditional Chinese medicine formula treating type 2 diabetes mellitus (T2DM). XKYS formula consists of four herbs, i.e., Coptidis rhizoma, Liriopes radix, bitter melon, and Cassiae semen. Herein, the chemical profiles of four herb extracts were investigated, and further analysis of the underlying mechanism of XKYS formula treating T2DM was performed using network pharmacology. The main components were selected for our network-based research. Targets of XKYS formula were mainly collected from two databases, SwissTargetPrediction and Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and the text-mining method was also implemented. T2DM relating genes and therapeutic targets were collected from five databases. Subsequently, STRING and Cytoscape were employed for the analysis of protein-protein interaction (PPI) networks. Functional annotation and pathway analysis were conducted to investigate the functions and relating pathways of target genes. The content of 12 compounds in the herb extracts was determined. With the analysis of PPI networks, a total of 76 genes were found to be important nodes and could be defined as the main target genes regulated by XKYS formula in the treatment of T2DM and its complications. Components in XKYS formula mainly regulate proteins including protein kinase B (Akt), phosphatidylinositol 3-kinase (PI3K), insulin receptor substrate (IRS), and tumor necrosis factor (TNF). XKYS formula exerts therapeutic effects in a synergetic manner and exhibits antidiabetic effect mainly via reducing insulin resistance. These findings could be guidelines in the further investigation of this formula.

Figure 1

HPLC spectra of four herb extracts. (a) TACR: M1, epiberberine; M2, coptisine; M3, palmatine; M4, berberine. (b) Monosaccharide composition of LRP. Fructose : glucose = 20.7 : 1. (c) BME: M7, momordicoside L; M8, 7β,25-dihydrocucurbita-5,23(E)-dien-19-al-3-O-β-D-allopyranoside; M10, momordicoside F₂. (d) CSE: M12, cassiaside; M14, rubrofusarin-6-O-β-D-gentiobioside, M16, glucoaurantio-obtusin; M17, aurantio-obtusin; M18, cassiaside C.

Figure 2

Protein-protein interaction networks. The mapping of PPI network was generated by the STRING server. (a) PPI network of genes regulated by XKYS formula (217 nodes, 2070 edges). (b) PPI network of genes relating to the pathophysiology of T2DM (602 nodes, 11595 edges). (c) 76 main target genes regulated by XKYS formula in the treatment of T2DM and its complications. This network contains 76 nodes and 333 edges. As shown in the color bar, nodes in red could be considered as important and nodes in green are less important in this network. The degree value of each node in Figure 2(c) is presented in Table 3.

Figure 3

GO functional annotation and KEGG analysis of 76 target genes. Biological process (a), molecular function (b), cellar components (c), and KEGG pathways (d) were sorted according to −log P values (P < 0.01). P value was calculated using a modified Fisher exact test, which ranges from 0 to 1. P value = 0 represents perfect enrichment. For each diagram, the x-axis presents GO or KEGG terms, whereas the y-axis is the −log P value of each term.

Figure 4

Component-target-pathway network of XKYS formula in the treatment of T2DM and its complications. Nodes in red are considered as important, and the green nodes are considered as less important. The degree of each node was presented in Supplementary Materials .