A network pharmacology approach to investigate the pharmacological effects of Guizhi Fuling Wan on uterine fibroids

Abstract

To investigate the pharmacological mechanism of Guizhi Fuling Wan (GFW) in the treatment of uterine fibroids, a network pharmacology approach was used. Information on GFW compounds was collected from traditional Chinese medicine (TCM) databases, and input into PharmMapper to identify the compound targets. Genes associated with uterine fibroids genes were then obtained from the GeneCards and Online Mendelian Inheritance in Man databases. The interaction data of the targets and other human proteins was also collected from the STRING and IntAct databases. The target data were input into the Database for Annotation, Visualization and Integrated Discovery for gene ontology (GO) and pathway enrichment analyses. Networks of the above information were constructed and analyzed using Cytoscape. The following networks were compiled: A compound-compound target network of GFW; a herb-compound target-uterine fibroids target network of GWF; and a compound target-uterine fibroids target-other human proteins protein-protein interaction network, which were subjected to GO and pathway enrichment analyses. According to this approach, a number of novel signaling pathways and biological processes underlying the effects of GFW on uterine fibroids were identified, including the negative regulation of smooth muscle cell proliferation, apoptosis, and the Ras, wingless-type, epidermal growth factor and insulin-like growth factor-1 signaling pathways. This network pharmacology approach may aid the systematical study of herbal formulae and make TCM drug discovery more predictable.

Keywords: Guizhi Fuling Wan; formula; mechanism; network pharmacology; uterine fibroids.

Figure 1.

Compound-compound target network of Guizhi Fuling Wan. This network comprised of 362 compound targets and 27 compounds. Pink hexagons represent the compound targets; pink, red, green, orange and purple circles indicate compounds of Cinnamomi Ramulus, Poria Cocos (Schw.) Wolf., Cortex Moutan, Radix Paeoniae Rubra and Persicae Semen, respectively; and blue triangles indicate the common compounds of Cortex Moutan and Radix Paeoniae Rubra.

Figure 2.

Herb-compound target-uterine fibroids target network of Guizhi Fuling Wan. Green diamonds, pink circles, blue hexagons and green hexagon represent the herbs, compound targets, uterine fibroids targets and compound-uterine fibroids targets, respectively; light lines indicate associations between herbs and other nodes; and dark lines indicate associations between fibroids targets, compound-uterine fibroids targets and compound targets. C.R., Cinnamomi Ramulus; C.M., Cortex Moutan; P.S., Persicae Semen; P.C.W., Poria Cocos (Schw.) Wolf.; R.P.R., Radix Paeoniae Rubra.

Figure 3.

GO enrichment analysis of compound targets, uterine fibroids targets and compound target/uterine fibroids targets. According to the associated biological processes, compound targets of Guizhi Fuling Wan and uterine fibroids targets were related to various molecular mechanisms of uterine fibroids. Green diamonds, pink circles, green circles and blue circles represent the herbs, compound targets, uterine fibroids targets and compound-uterine fibroids targets, respectively; light lines indicate associations between herbs and other nodes; and dark lines indicate associations between compound-uterine fibroids targets and compound targets. EGF, epidermal growth factor; FGF, fibroblast growth factor; IGF, insulin-like growth factor; VEGF, vascular endothelial growth factor; TGF-β, transforming growth factor-β.

Figure 4.

Pathway enrichment analysis of compound targets, uterine fibroids targets and compound targets/uterine fibroids targets. According to pathway enrichment analysis, compound targets of GFW and uterine fibroids targets were related to various pathways. Green diamonds and pink, orange and blue circles represent the herbs, compound targets, uterine fibroids targets and compound-uterine fibroids targets, respectively; Red squares indicate the pathway; red lines indicate the associations between pathways and targets; green lines indicate the associations between herbs and targets; orange lines indicate the associations between uterine fibroids targets and other nodes; and blue lines indicate the associations between compound-uterine fibroids targets and other nodes. PI3K, phosphoinositide 3-kinase; Akt, protein kinase B; Erk, extracellular signal-regulated kinase; NF-κB, nuclear factor-κB; TGF-β, transforming growth factor-β; IGF, insulin-like growth factor; EGF, epidermal growth factor; Wnt, wingless-type; VEGF, vascular endothelial growth factor; mTOR, mechanistic target of rapamycin; MAPK, mitogen-activated protein kinase; PDGF, platelet-derived growth factor; C.R., Cinnamomi Ramulus; C.M., Cortex Moutan; P.S., Persicae Semen; P.C.W., Poria Cocos(Schw.) Wolf.; R.P.R., Radix Paeoniae Rubra.

Figure 5.

Compound target-uterine fibroids target-other human proteins protein-protein interaction network. Blue, pink, green and red circles indicate the other human proteins, compound targets, compound-uterine fibroids targets and uterine fibroids targets, respectively. The lines represent the nodes associated through protein-protein interactions.

Figure 6.

GO enrichment analysis of compound targets, uterine fibroids targets, compound targets/uterine fibroids targets and other human proteins. According to the associated biological processes, the nodes were categorized into four modules. Green diamonds and pink, green, blue and purple circles indicate the herbs, compound targets, other human proteins, uterine fibroids targets and compound-uterine fibroids targets, respectively; light lines represent associations between herbs and other nodes; and dark lines represent associations between compound targets, other human proteins, uterine fibroids targets and compound-uterine fibroids targets. EGF, epidermal growth factor; FGF, fibroblast growth factor; IGF, insulin-like growth factor; VEGF, vascular endothelial growth factor.

Figure 7.

Pathway enrichment analysis of compound targets, uterine fibroids targets, compound targets/uterine fibroids targets and other human proteins. Pathway enrichment indicated that the major nodes were primarily linked to the indicated pathways. Green diamonds and light pink, dark pink, orange and blue circles indicate the herbs, compound targets, other human proteins, uterine fibroids targets and compound-uterine fibroids targets, respectively; red squares indicate the pathways; red lines indicate the associations between pathways and targets; green lines indicate the associations between herbs and targets; orange lines indicate the associations between uterine fibroids targets and other nodes; and blue lines indicate the associations between compound-uterine fibroids targets and other nodes. PI3K, phosphoinositide 3-kinase; Akt, protein kinase B; mTOR, mechanistic target of rapamycin; TGF-β, transforming growth factor-β; NF-κB, nuclear factor-κB; IGF, insulin-like growth factor; EGF, epidermal growth factor; Wnt, wingless-type; VEGF, vascular endothelial growth factor; MAPK, mitogen-activated protein kinase.