Deciphering the Potential Pharmaceutical Mechanism of Chinese Traditional Medicine (Gui-Zhi-Shao-Yao-Zhi-Mu) on Rheumatoid Arthritis

Abstract

Gui-Zhi-Shao-Yao-Zhi-Mu (GSZ) decoction is a Traditional Chinese Medicine (TCM) formula commonly used for the treatment of Rheumatoid Arthritis (RA). The therapeutic effect of GSZ for RA treatment is supported by our clinical retrospective study. To uncover the potential mechanism underlying GSZ formula, we identified 1,327 targets of 673 compounds from 9 herbs that involve in Fc epsilon RI signaling pathway and regulation of immunoglobulin production. Comparison between formula targets with 79 RA drug targets and 675 RA disease genes showed that formula targets covered 31.6% RA drug targets and 19.9% RA disease genes. Formula specific targets presented expression patterns highly similar to the disease genes and drug targets based on the expression profiles of RA samples. Investigation of 10 inferred gene clusters from expression profiles with a target association network revealed that formula specific targets directly or indirectly interacted with disease genes that were essential for immune related biological processes (e.g. inflammatory responses, treatment response of rheumatoid arthritis, etc.). Our result indicated that GSZ disrupted the RA disease dysfunction modules and restored homeostasis in the human body. The systemic approach to infer therapeutic mechanisms of GSZ for RA treatment provides a new insight in the understanding of this TCM formula.

Figure 1. The relationships between herbs, compounds and targets.

(a) The number of compounds in each herbs. The numbers of compounds for herbs were 11 to 216. (b) The relationships between the 7 herbs sharing the same compounds. The links between herbs were constructed with the same compounds in Supplementary Table S1. The width of the edge is related to the similarity between herbs in compounds. (c) The relationship between compounds. The network shows the relationship between compounds sharing more than 5 targets. The links between compounds were constructed with the same targets. The width of the edge is related to the similarity between targets in compounds. (d) Distribution of targets in GSZ decoction, drug targets and disease genes.

Figure 2. Relationship between formula targets and disease genes.

(a) The number of targets in different compounds. The orange line stands for the number of unique targets of the compounds while the blue line represents the targets that overlap disease targets. (b) The ratio of formula targets and disease genes in immune system processes. The network was generated with ClueGO in Cytoscape.

Figure 3. Relationship between formula targets and drug targets.

(a) The number of targets in different drugs. The orange part represents unique targets of the every drug while the blue one represents the targets that overlap GSZ formula. (b) The ratio of formula targets and drug targets in immune system processes. The network was generated with ClueGO in Cytoscape.

Figure 4. Comparison of quantitative characters of GSZ targets, drug targets and RA disease genes.

(a) The changes in numbers of differentially expressed gene (DEG) during treatment on RA samples. (b) The distribution of GSZ targets, drug targtes and RA genes before treatment. (c) The distribution of GSZ targets, drug targtes and RA genes after treatment. (d) The correlated coefficients between gene pairs, drug-other genes, formula-other genes, disease-other genes, disease-drug genes, formula-drug genes and formula-disease genes.

Figure 5. Expression profiles of co-expressed DEGs.

The expression of genes in 4 different groups of RA sample, e.g. RA_ONLY, RA_OTHER, RA_TREAT, WT.

Figure 6. The PPI network of the GSZ formula targets, disease genes, drug targets and other connective targets.

The network was generated with ClueGO in Cytoscape. (red: formula targets; yellow: disease genes; blue: drug targets; green: disease genes and drug targets; orange: formula targets and disease genes; pastel pink: formula targets, disease genes and drug targets; gray: other genes).