Analysis of Network Pharmacological Efficacy and Therapeutic Effectiveness in Animal Models for Functional Dyspepsia of Foeniculi fructus

Abstract

For centuries, Foeniculi fructus (F. fructus) has been used as a traditional herbal medicine in China and Europe and is widely used as a natural therapy for digestive disorders, including indigestion, flatulence, and bloating. The mechanism of F. fructus that alleviates functional dyspepsia was analyzed through network pharmacology, and its therapeutic effect on an animal model of functional dyspepsia were investigated. The traditional Chinese medicine systems pharmacology (TCMSP) database was used to investigate the compounds, targets, and associated diseases of F. fructus. Information on the target genes was classified using the UniProtdatabase. Using the Cytoscape 3.9.1 software, a network was constructed, and the Cytoscape string application was employed to examine genes associated with functional dyspepsia. The efficacy of F. fructus on functional dyspepsia was confirmed by treatment with its extract in a mouse model of loperamide-induced functional dyspepsia. Seven compounds targeted twelve functional dyspepsia-associated genes. When compared to the control group, F. fructus exhibited significant suppression of symptoms in a mouse model of functional dyspepsia. The results of our animal studies indicated a close association between the mechanism of action of F. fructus and gastrointestinal motility. Based on animal experimental results, the results showed that F. fructus provided a potential means to treat functional dyspepsia, suggesting that its medical mechanism for functional dyspepsia could be described by the relationship between seven key compounds of F. fructus, including oleic acid, β-sitosterol, and 12 functional dyspepsia-related genes.

Keywords: Foeniculi fructus; TCMSP; functional dyspepsia; network pharmacology; traditional medicine.

Figure 1

The study protocol schematic.

Figure 2

UPLC profiles of three major compounds identified in F. fructus. (A) UPLC profile of the commercial standard compounds. (B) UPLC profile of three major compounds in F. fructus. 4-Methoxybenzoic acid and R-(a)-phellandrene were analyzed at 330 nm, and the anethole was analyzed at 306 nm. Black line: 4-Methoxybenzoic acid. Green line: R-(a)-phellandrene. Red line: Anethole.

Figure 3

Compound-target network of F. fructus. The node size depends on the number of connected edges. The compound is represented as a red square-shaped node, and the targets are represented as a blue round-shaped node.

Figure 4

The Venn diagram of bioactive compounds of F. fructus related to GI disease.

Figure 5

Network of functional dyspepsia related genes and F. fructus target genes. There were 12 genes in common in two places.

Figure 6

Network of compounds of F. fructus and functional dyspepsia-related genes.

Figure 7

Results of F. fructus (FF) on gastric emptying. The experimental schedule is summarized in (A). For 3 days, mice (n = 6/group) were treated by po with 25, 50, and 100 mg/kg of FF or 3 mg/kg of mosapride and then treated by IP injection with 10 mg/kg of loperamide. After the treatment of phenol red, results of visualization (B), weight of stomach (C), and results of gastric emptying (D) are presented. The data are organized as the mean ± SEM. * p < 0.05, ** p < 0.01 for the Control group; # p < 0.05 for the loperamide group.

Figure 8

Results of F. fructus (FF) on GI motility-associated molecules in stomach tissue. The analyses of Western blot for nNOS, TMEM16A, and TRPM7 (A) and semi-quantifications (B) were conducted (n = 3). The analyses of mRNA expression of GI motility-associated genes were performed (C) (n = 3) in the stomach tissue. The data are organized as the mean ± SEM. * p < 0.05, *** p < 0.001 for the Control group; # p < 0.05, ## p < 0.01, ### p < 0.001 for the loperamide group.

Figure 9

Results of F. fructus (FF) on small intestinal motility. For 3 days, mice (n = 6/group) were treated by po with 25, 50, and 100 mg/kg of FF or 3 mg/kg of mosapride and then treated by IP injection with 10 mg/kg of loperamide. After 30 min of treatment with Evans blue, the distances stained were checked and quantified. The data are organized as the mean ± SEM. *** p < 0.001 for the Control group; ### p < 0.001 for the loperamide group.