Identification and screening of Active Compounds and Targets for Tripterygium Wilfordii and Therapeutic Targets for IMN
A total of 42 active compounds of tripterygium wilfordii were obtained by searching the TCMSP database, and using ADME parameters such as OB, DL, Hdon and Hacc (Additional file 1). After finding the target data from TCMSP database, and deleting the repeated items, 153 targets were finally obtained. Then, we used UniprotKB database normalized the protein targets collected in TCMSP database. A total of 1485 therapeutic targets of IMN were acquired from GeneCards, DisGeNET and OMIMI databases after removing duplicates.
Drug-Disease Target PPI Network
The result of Venn diagram showed that 77 overlapping genes were identified between 153 genes related to tripterygium wilfordii and the 1485 genes related to IMN (Fig. 1, Table 1). To predicate the relationship between the overlapping genes, we uploaded the overlapping genes to the STRING database. A PPI network was built, with 77 nodes and 1009 edges (Fig. 2). The average node degree of was 26.20, and the average local clustering coefficient was 0.69. The result of PPI network indicated that there was a complex relationship between these genes. The results were used for further analysis through Cytoscape software, and the network was constructed as Fig. 3. The top ten targets AKT1, TNF, VEGFA, TP53, PTGS2, CXCL8, MAPK8, STAT3, JUN, and CASP3 have higher degree in this process, which explained their significance in the network.
Table 1: The overlapping genes between the IMN and tripterygium wilfordii.
Overlapping gnens name
|
HTR2A
|
CASP8
|
PON1
|
SLC6A4
|
AR
|
SLPI
|
BAX
|
BCL2
|
ALOX5
|
CASP3
|
CYP1A1
|
CYP1A2
|
CYP1B1
|
CYP3A4
|
DPP4
|
SELE
|
GSTM1
|
GSTP1
|
HMOX1
|
IKBKB
|
INSR
|
ICAM1
|
MMP1
|
MAPK8
|
NOS2
|
NOS3
|
PPARG
|
PIK3CG
|
AKT1
|
STAT1
|
SLC2A4
|
JUN
|
RELA
|
TNF
|
VCAM1
|
XDH
|
AKR1B1
|
ADRB1
|
XIAP
|
CCR7
|
C3
|
CXCR4
|
CDKN1A
|
IFNG
|
IL2
|
IL4
|
CXCL8
|
CD14
|
CD274
|
FOS
|
STAT3
|
CD80
|
CD86
|
TGFB1
|
CD40
|
PLAU
|
VEGFA
|
VTCN1
|
KCNMA1
|
KDR
|
NR3C2
|
ACHE
|
CA2
|
NR3C1
|
ESR1
|
ESR2
|
MAPK14
|
ADRB2
|
HSP90AA1
|
PTGS1
|
PTGS2
|
CASP9
|
TP53
|
CREB1
|
PLA2G4A
|
MMP9
|
TIMP1
|
GO Enrichment Analysis of Tripterygium Wilfordii for the Treatment of IMN.
A total of 1782 BP terms, 119 MF, and 25 CC terms were enriched for the 77 target genes. We selected the top 10 according to the P value as shown in Fig. 4. The results showed that tripterygium wilfordii treats IMN through various BPs, including response to lipopolysaccharide, response to molecule of bacterial origin, response to antibiotic, response to oxygen levels, positive regulation of cytokine production, regulation of reactive oxygen species metabolic process, positive regulation of reactive oxygen species metabolic process, response to hypoxia, response to metal ion. In the MF classification, the effect of tripterygium wilfordii for the treatment of IMN was mainly manifested in the following aspects: heme binding, tetrapyrrole binding, oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, cytokine receptor binding, nuclear receptor activity, steroid hormone receptor activity, virus receptor activity, exogenous protein binding, ubiquitin-like protein ligase binding. According to the enrichment results of CC, membrane was the main classification of the target proteins.
KEGG Pathway Enrichment Analysis of Tripterygium Wilfordii for the Treatment of IMN.
The result of of KEGG pathway enrichment analysis demonstrated that 75 genes were related to 144 signaling pathways. The details of 144 signaling pathways were shown in Additional file 2. We selected the top 10 according to the P value as shown in Fig. 5 and Additional file 3-6, which revealed that main processes of tripterygium wilfordii in treating IMN included AGE signaling pathway in diabetic complications, IL-17 signaling pathway, TNF signaling pathway, Toll-like receptor signaling pathway. In addition, there were some other pathways such as Kaposi sarcoma-associated herpesvirus infection, fluid shear stress and atherosclerosis, hepatitis B, toxoplasmosis, Epstein-Barr virus infection, Chagas disease, which revealed that tripterygium wilfordii has a potential application in other related diseases.
The Drug-Compound-Target-Signaling Pathway Network
In our research, a drug-compound-target-pathway network of of tripterygium wilfordii for IMN treatment was constructed (Fig. 6). The network consisted of 93nodes (1 for drug, 10 for components, 1 for disease, 77 for targets, and 4 for pathways). The integrative network showed that the therapeutic effect of tripterygium wilfordii on IMN might be attributed to the active components (triptolide, kaempferol, beta-sitosterol) acting on targets (AKT1, TNF, VEGFA, TP63, PTGS2, CXCL8, MAPK8, and STAT3 etc.) that regulate key pathways (AGE signaling pathway, IL-17 signaling pathway, TNF signaling pathway, and Toll-like receptor signaling pathway).