Systems Pharmacology Dissection of Multi-Scale Mechanisms of Action of Huo-Xiang-Zheng-Qi Formula for the Treatment of Gastrointestinal Diseases

Abstract

Multi-components Traditional Chinese Medicine (TCM) treats various complex diseases (multi-etiologies and multi-symptoms) via herbs interactions to exert curative efficacy with less adverse effects. However, the ancient Chinese compatibility theory of herbs formula still remains ambiguous. Presently, this combination principle is dissected through a systems pharmacology study on the mechanism of action of a representative TCM formula, Huo-xiang-zheng-qi (HXZQ) prescription, on the treatment of functional dyspepsia (FD), a chronic or recurrent clinical disorder of digestive system, as typical gastrointestinal (GI) diseases which burden human physical and mental health heavily and widely. In approach, a systems pharmacology platform which incorporates the pharmacokinetic and pharmaco-dynamics evaluation, target fishing and network pharmacological analyses is employed. As a result, 132 chemicals and 48 proteins are identified as active compounds and FD-related targets, and the mechanism of HXZQ formula for the treatment of GI diseases is based on its three function modules of anti-inflammation, immune protection and gastrointestinal motility regulation mainly through four, i.e., PIK-AKT, JAK-STAT, Toll-like as well as Calcium signaling pathways. In addition, HXZQ formula conforms to the ancient compatibility rule of "Jun-Chen-Zuo-Shi" due to the different, while cooperative roles that herbs possess, specifically, the direct FD curative effects of GHX (serving as Jun drug), the anti-bacterial efficacy and major accompanying symptoms-reliving bioactivities of ZS and BZ (as Chen), the detoxication and ADME regulation capacities of GC (as Shi), as well as the minor symptoms-treating efficacy of the rest 7 herbs (as Zuo). This work not only provides an insight of the therapeutic mechanism of TCMs on treating GI diseases from a multi-scale perspective, but also may offer an efficient way for drug discovery and development from herbal medicine as complementary drugs.

Keywords: Huo-xiang-zheng-qi; TCM; compatibility theory; functional dyspepsia; gastrointestinal diseases; systems pharmacology.

FIGURE 1

Workflow of the systems pharmacology approach.

FIGURE 2

The species distribution of the bioactive chemical pool of HZXQ.

FIGURE 3

The profile distributions of eight important molecular properties of DrugBank drugs and herbal compounds.

FIGURE 4

The combination rules of HXZQ herbs based on the TCM “Jun-Chen-Zuo-Shi” theory.

FIGURE 5

C-T network of the HXZQ formula, where circles and hexagons represent bioactive compounds and corresponding FD targets, respectively. Among the targets, purple, green and blue hexagons represent the inflammatory, immunological and gastrointestinal targets, respectively. The blue violet hexagons are immune and inflammation overlapped targets, whereas the olivaceous hexagons are the immune, inflammation and gastrointestine superimposed targets, respectively. Node size is proportional to its degree.

FIGURE 6

The degree and betweenness of active compounds (A) and targets (B) of HXZQ formula.

FIGURE 7

Gene Ontology (GO) analysis of the target genes, where y-axis is the significantly enriched ‘Biological Process’ categories in GO relative to the target genes, and x-axis is the enrichment scores of these terms (p-value ≤ 0.05 and FDR ≤ 0.05).

FIGURE 8

The Inf-C-T network of HXZQ formula, where hexagons and circles represent all inflammation-related targets and corresponding candidate compounds, respectively. The gray edges represent the mutual relation among the targets and chemicals. Node size is proportional to its degree.

FIGURE 9

The Imm-C-T network of HXZQ formula, where hexagons and circles represent the immunization-related targets and corresponding active compounds, respectively. The gray edges represent the interaction among the targets and chemicals. Node size is proportional to its degree.

FIGURE 10

The Gas-C-T network of HXZQ formula, where hexagons and circles represent the GI motility-related targets and corresponding interacting compounds, respectively. The edges represent the mutual relations among the targets and chemicals. Node size is proportional to its degree.

FIGURE 11

The distribution of target proteins on FD-related essential pathways. The line color corresponds to the pathway’s color.

FIGURE 12

Binding explorations of selected C-T interactions. (A) CHRM3-HP02; (B) CHRM3-GC08; (C) GSK3B-BX02; (D) GSK3B-GHX06; (E) PTGS2-CP03; (F) PTGS2-GHX06. The molecules are displayed as ball and stick models, H-bonds are shown as dotted red lines with distance unit of Å. Atoms O and N are colored as red and blue, respectively.