Deciphering the Potential Pharmaceutical Mechanism of GUI-ZHI-FU-LING-WAN on Systemic Sclerosis based on Systems Biology Approaches

Systemic sclerosis (SSc; scleroderma) is a complicated idiopathic connective tissue disease with seldom effective treatment. GUI-ZHI-FU-LING-WAN (GFW) is a classic Traditional Chinese Medicine (TCM) formula widely used for the treatment of SSc. However, the mechanism of how the GFW affects SSc remains unclear. In this study, the system biology approach was utilized to analyze herb compounds and related targets to get the general information of GFW. The KEGG enrichment analysis of 1645 related targets suggested that the formula is involved in the VEGF signaling pathway, the Toll-like receptor signaling pathway, etc. Quantitative and qualitative analysis of the relationship among the 3 subsets (formula targets, drug targets and disease genes) showed that the formula targets overlapped with 38.0% drug targets and 26.0% proteins encoded by disease genes. Through the analysis of SSc related microarray statistics from the GEO database, we also validated the consistent expression behavior among the 3 subsets before and after treatment. To further reveal the mechanism of prescription, we constructed a network among 3 subsets and decomposed it into 24 modules to decipher how GFW interfere in the progress of SSc. The modules indicated that the intervention may come into effect through following pathogenic processes: vasculopathy, immune dysregulation and tissue fibrosis. Vitro experiments confirmed that GFW could suppress the proliferation of fibroblasts and decrease the Th1 cytokine (TNF-α, MIP-2 and IL-6) expression for lipopolysaccharide (LPS) and bleomycin (BLM) stimulation in macrophages, which is consistent with previous conclusion that GFW is able to relieve SSc. The systems biology approach provides a new insight for deepening understanding about TCM.