Network pharmacology evaluation of the active ingredients and potential targets of XiaoLuoWan for application to uterine fibroids.

Yonghui Yu,Fang Yang,Hong Liu

doi:10.1042/bsr20202342

Abstract

XiaoLuoWan (XLW) is a classical formula in traditional Chinese medicine (TCM) that has satisfactory therapeutic effects for uterine fibroids (UFs). However, its underlying mechanisms remain unclear. To elucidate the pharmacological actions of XLW in treating UFs, an ingredient–target–disease framework was proposed based on network pharmacology strategies. The active ingredients in XLW and their putative targets were obtained from the TCM systems pharmacology database and analysis platform (TCMSP) and Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine (BATMAN-TCM) platforms. The known therapeutic targets of UFs were acquired from the DigSee and DrugBank databases. Then, the links between putative XLW targets and therapeutic UF targets were identified to establish interaction networks by Cytoscape. Finally, Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of overlapping gene targets were performed in the STRING database and visualized in R software. In total, 9 active compounds were obtained from 74 ingredients, with 71 curative targets predicted in XLW. Moreover, 321 known therapeutic targets were closely related to UFs, with 29 targets overlapping with XLW and considered interacting genes. Pathway enrichment revealed that the calcium signaling pathway was significantly enriched and the mitogen-activated protein kinase (MAPK) signaling pathway, cAMP signaling pathway, cancer and vascular smooth muscle contraction pathways, cGMP-PKG signaling pathway, and AGE-RAGE signaling pathway were closely associated with XLW intervention for UFs. In conclusion, the network pharmacology detection identified 9 available chemicals as the active ingredients in XLW that may relieve UFs by regulating 29 target genes involved in the calcium signaling pathway, MAPK pathway and cAMP pathway. Network pharmacology analyses may provide more convincing evidence for the investigation of classical TCM prescriptions, such as XLW.

Highlights

Uterine fibroids (UFs), which are known as leiomyomas or myomas, are the most common benign pelvic tumors and affect 50–60% of women of child-bearing age [1] and 70% of women up to 50 years of age [2]
After elimination of overlapping targets, 71 targets were obtained (Figure 2) and the protein and gene names were identified in UniProtKB, in which the organism was limited to H. sapiens
The Cinnamon Twig and Poria Pill (GuiZhi FuLing Wan) formula was the most frequently prescribed for UFs in traditional Chinese medicine (TCM) clinics, and it has beneficial effects on both fibroid characteristics and sex hormones in vivo [42] and can efficiently inhibit the survival of leiomyoma cells in vitro [43]

Summary

Introduction

Uterine fibroids (UFs), which are known as leiomyomas or myomas, are the most common benign pelvic tumors and affect 50–60% of women of child-bearing age [1] and 70% of women up to 50 years of age [2]. Current mainstream treatments include surgical procedures and medical therapies [6]. Associated surgeries, such as hysterectomy or myomectomy, may not increase pregnancy rates [7] or reverse pregnancy loss [8] and may increase the risk of mortality [9,10]. Nonextirpative procedures for UFs including uterine artery embolization, focused ultrasound, laparoscopic radiofrequency ablation were reported to show similar outcomes to myomectomy. Drug-based therapy, such as gonadotropin-releasing hormone (GnRH) agonists, which is the only agent for short-term management of UFs approved by Food and Drug Administration (FDA) [12], may cause symptoms associated with false menopause and dormant fertility after long-term intervention [13]. Novel effective alternatives with fewer side effects must be developed

Methods

Results

Conclusion