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Medical Science Monitor: International Medical Journal of Experimental and Clinical Research logoLink to Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
. 2019 Aug 14;25:6051–6073. doi: 10.12659/MSM.915821

Network Pharmacology Identifies the Mechanisms of Action of Shaoyao Gancao Decoction in the Treatment of Osteoarthritis

Naiqiang Zhu 1,A,, Jingyi Hou 2,B,C, Guiyun Ma 1,B,D, Jinxin Liu 2,B,G
PMCID: PMC6705180  PMID: 31409761

Abstract

Background

Osteoarthritis (OA) affects the health and wellbeing of the elderly. Shaoyao Gancao decoction (SGD) is used in traditional Chinese medicine (TCM) for the treatment of OA and has two active components, shaoyao (SY) and gancao (GC). This study aimed to undertake a network pharmacology analysis of the mechanism of the effects of SGD in OA.

Material/Methods

The active compounds and candidates of SGD were obtained from the Traditional Chinese Medicine (TCM) Databases@Taiwan, the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, the STITCH database, the ChEMBL database, and PubChem. The network pharmacology approach involved network construction, target prediction, and module analysis. Significant signaling pathways of the cluster networks for SGD and OA were identified using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database.

Results

Twenty-three bioactive compounds were identified, corresponding to 226 targets for SGD. Also, 187 genes were closely associated with OA, of which 161 overlapped with the targets of SGD and were considered to be therapeutically relevant. Functional enrichment analysis suggested that SGD exerted its pharmacological effects in OA by modulating multiple pathways, including cell cycle, cell apoptosis, drug metabolism, inflammation, and immune modulation.

Conclusions

A novel approach was developed to systematically identify the mechanisms of the TCM, SGD in OA using network pharmacology analysis.

MeSH Keywords: Health Care Evaluation Mechanisms; Medicine, Chinese Traditional; Osteoarthritis, Knee

Background

Osteoarthritis (OA) is an age-related degenerative disease that is characterized by the degradation of joint cartilage and inflammation of the synovium [13]. The typical clinical signs and symptoms of OA are pain, swelling, and stiffness, usually associated with reduced activity and limitation of movement [4]. Chronic OA results in the formation of osteophytes, and deformation and narrowing of the joint space. OA significantly reduces the quality of life for patients and can result in physical disability, which has an increasing socioeconomic and healthcare burden [5,6]. Severe OA commonly results in joint replacement, particularly in elderly individuals [7]. Currently, pharmacological treatments for OA primarily include the use of oral pain medication, including opioid analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular injection of corticosteroids, and surgical treatment including osteotomy, arthroplasty, and arthrodesis [810]. However, pharmacological treatments for OA are aimed at alleviating the symptoms of the disease rather than treating the underlying causes, and have several side effects, including an increased risk of cardiovascular events and infection [11,12]. Therefore, more effective and safer therapeutic approaches are required for treating patients with OA.

Traditional Chinese medicine (TCM) has been used widely for several decades for the treatment of a range of diseases and has the advantage of being inexpensive and widely available, and because many medicines are derived from natural sources such as herbs, they have fewer side effects [13]. Several TCMs have been used to treat OA and are both effective and safe [14,15]. Therefore, for the treatment of OA, it would be helpful to identify the most effective TCM compounds. Previous studies have shown that Shaoyao Gancao decoction (SGD) is effective in reducing the clinical symptoms of OA by improving joint function and movement. SGD is an effective formula that has been described in the Treatise on Febrile and Miscellaneous Diseases (Shang Han Za Bing Lun) by the third-century Chinese physician Zhang Zhognjing. SGD contains two Chinese herbal medicines, shaoyao (SY) derived from Radix Paeoniae Alba, and gancao (GC) derived from Glycyrrhizae Radix et Rhizoma, in a 1: 1 ratio [16]. Pharmacological studies have shown that the two compounds in the SGD formulation have a synergistic effect in reducing inflammation, pain, and swelling and improving joint function in patients with OA [17]. However, the underlying pharmacological mechanisms of action of SGD and its components in the treatment of OA remain unclear, and the pharmacodynamic properties of its components and key targets remain to be identified.

Network pharmacology is a new and powerful method that integrates chemo-informatics, bio-informatics, network biology, network analysis and traditional pharmacology [18]. The method of network pharmacology conforms to the systemic or holistic view of TCM theory and is a novel strategy to elucidate the active compounds and potential mechanisms of TCM formulas. Therefore, this study aimed to use network pharmacology to identify the bioactive components and targets of SGD, to search for common targets for SGD in the treatment of OA, to understand the underlying mechanisms of action of the disease targets, and to mine for disease-related genes.

Material and Methods

Construction of a database of the components of Shaoyao Gancao decoction (SGD)

Figure 1 shows a schematic representation of the network pharmacology study of Shaoyao Gancao decoction (SGD) in the treatment of osteoarthritis (OA), including the two active components, shaoyao (SY) and gancao (GC). The data relating to the chemical compounds, SY and GC were derived from the Traditional Chinese Medicine (TCM) Databases@Taiwan (http://tcm.cmu.edu.tw/) [19], and the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database (http://lsp.nwu.edu.cn/tcmsp.php) [20]. In total, 365 compounds were identified in SGD after removing the duplicate data, including 280 compounds in GC and 85 compounds in SY.

Figure 1.

Figure 1

Schematic representation of network pharmacology study of Shaoyao Gancao decoction (SGD) in the treatment of osteoarthritis (OA). SGD – Shaoyao Gancao decoction; OA – osteoarthritis.

Screening of the active ingredients in SGD

The 365 potential compounds from SY and GC were filtered using two adsorption, distribution, metabolism, and excretion (ADME)-related models, integrating drug-likeness (DL) and oral bioavailability (OB). Drug-likeliness is a qualitative concept used in drug design to determine how drug-like a prospective compound is to describe and optimize pharmacokinetic and pharmaceutical properties [19,21]. Oral bioavailability indicates the drug-like nature of molecules as therapeutic agents and represents the relative amount of orally administered drug that reaches the blood circulation, shown by the convergence of the ADME process [22]. To identify the active components of SGD, the ingredients conforming to the requirements of both OB ≥30% and DL ≥0.18, based on the published literature and the information from the TCMSP database, were identified for further analysis [23]. Also, putative targets of potential compounds in SY and GC were identified from the STITCH, ChEMBL and PubChem databases, and those without target information were excluded.

Target genes related to the identified compounds

To identify the relevant targets of the potential compounds in SY and GC, the STITCH (http://stitch.embl.de/) [24], ChEMBL (http://www.ebi.ac.uk/chembl/) [25], and PubChem (http://pubchem.ncbi.nih.gov/) databases were used [26]. A final list of genes associated with compounds, with a confidence score of >0.7, was obtained that suggested a high confidence score according to STITCH. The ChEMBL is a manually curated database for storing standardized bioactivity, molecules, targets, and drug data, which are abstracted regularly from the primary medicinal chemistry literature [27]. The PubChem database is a resource for biological activities of small molecules, including substance information, compound structure, and bioactivity, and the data are experimentally validated. All the active ingredients identified in the present study were entered into the STITCH, ChEMBL and PubChem databases with the Homo sapiens species setting. The gene information, including the name, gene ID, and organism, was confirmed using the UniProt protein sequence resource (https://www.uniprot.org) [28]. After removing duplicates, the detailed information of targets obtained is described in Supplementary Table 1.

Related targets of osteoarthritis (OA)

Information on OA-associated target genes was collected from the following resources. DrugBank (https://www.drugbank.ca/) [29] is a comprehensive online database that provides extensive biochemical and pharmacological information on drugs and their mechanisms of action and targets, and 78 genes related to OA were identified from this database. GeneCards (http://www.genecards.org/) is a comprehensive database incorporating information on all annotated and predicted genes [30], which was searched using the keyword “osteoarthritis,” which identified 46 genes. The Online Mendelian Inheritance in Man® (OMIM) database (http://www.omim.org/) [31] is a comprehensive research resource of human genes and genetic phenotypes, from which 65 genes associated with OA were selected. There were 187 targets linked with OA after deleting redundant targets, and the information regarding these targets is provided in Supplementary Table 2.

Construction of the pharmacological networks

Network construction was established using four main steps. First, a compound-compound target network was established by linking compounds and predicted targets with a degree of >3. Second, a protein-protein interaction (PPI) network of compounds and targets was developed by linking the compound targets and predicted targets of other human proteins. Third, a PPI network of OA targets was constructed by linking the known OA-related targets and predicted targets of other human proteins. Fourth, a PPI network of targets for SGD and OA was developed by intersecting the PPI network of compounds and the PPI network of OA targets. The graphical and diagrammatic visualized networks were constructed using Cytoscape version 3.7.0 (http://www.cytoscape.org/) [32], which is a software package for visualizing network analysis.

Cluster analysis

Cluster analysis is a classification method that involves interconnected regions showing the inherent laws in the network [13]. The Molecular Complex Detection (MCODE) plug-in was used to detect densely connected regions and cluster analysis in the PPI network [33]. In this study, we selected significant cluster modules from the constructed PPI network using MCODE. The criteria settings were set as follows: node score cutoff=0.2; K-core=2; and degree of cutoff=2.

Gene Ontology (GO) and pathway enrichment analysis

The Gene Ontology (GO) database (http://geneontology.org/), including biological process, cell component, and molecular function terms, was used to identify the possible biological mechanisms using high-throughput genome or transcriptome data [34]. The Kyoto Encyclopedia of Genes and Genomes (KEGG) database (https://www.kegg.jp/) is a knowledge database for identifying the systematic functions and biological relevance of candidate targets [35]. In this study, GO functional annotation and KEGG pathway analysis were performed using Bioconductor clusterProfiler, an R package used for enrichment analysis of gene clusters [36].

Results

Screening for the active compounds of Shaoyao Gancao decoction (SGN) involved in osteoarthritis (OA)

From the two active components of Shaoyao Gancao decoction (SGD), shaoyao (SY) and gancao (GC), 365 compounds were obtained from the Traditional Chinese Medicine Systems Pharmacology(TCMSP) database and the traditional Chinese medicine (TCM) Databases@Taiwan, with 280 compounds from GC and 85 from SY. The values of oral bioavailability (OB) and drug-likeness (DL) (OB ≥30% and DL ≥0.18) were used to screen potential active compounds from GC and SY, and a total 23 active compounds met the screening standards. The properties of the compounds are shown in Table 1.

Table 1.

The active ingredients of the two components of Shaoyao Gancao decoction (SGD), shaoyao (SY) and gancao (GC).

Molecule ID Molecule name Structure OB DL Herb
MOL000359 Sitosterol graphic file with name medscimonit-25-6051-g007.jpg 36.91 0.75 SY
MOL000358 beta-Sitosterol graphic file with name medscimonit-25-6051-g007.jpg 36.91 0.75 SY
MOL000422 Kaempferol graphic file with name medscimonit-25-6051-g008.jpg 41.88 0.24 SY
MOL001924 Paeoniflorin graphic file with name medscimonit-25-6051-g009.jpg 53.87 0.79 SY
MOL000492 (+)-Catechin graphic file with name medscimonit-25-6051-g010.jpg 54.83 0.24 SY
MOL000211 Mairin graphic file with name medscimonit-25-6051-g011.jpg 55.38 0.78 BS
MOL001792 Liquiritigenin graphic file with name medscimonit-25-6051-g012.jpg 32.76 0.18 GC
MOL000500 Vestitol graphic file with name medscimonit-25-6051-g013.jpg 74.66 0.21 GC
MOL004328 Naringenin graphic file with name medscimonit-25-6051-g014.jpg 59.29 0.21 GC
MOL000392 Formononetin graphic file with name medscimonit-25-6051-g015.jpg 69.67 0.21 GC
MOL000417 Calycosin graphic file with name medscimonit-25-6051-g016.jpg 47.75 0.24 GC
MOL004991 7-Acetoxy-2-methylisoflavone graphic file with name medscimonit-25-6051-g017.jpg 83.71 0.27 GC
MOL000098 Quercetin graphic file with name medscimonit-25-6051-g018.jpg 46.43 0.28 GC
MOL000354 Isorhamnetin graphic file with name medscimonit-25-6051-g019.jpg 49.6 0.31 GC
MOL004910 Glabranin graphic file with name medscimonit-25-6051-g020.jpg 52.9 0.31 GC
MOL002565 Medicarpin graphic file with name medscimonit-25-6051-g021.jpg 49.22 0.34 GC
MOL004949 Isolicoflavonol graphic file with name medscimonit-25-6051-g022.jpg 45.17 0.42 GC
MOL004908 Glabridin graphic file with name medscimonit-25-6051-g023.jpg 53.25 0.47 GC
MOL001484 Inermine graphic file with name medscimonit-25-6051-g024.jpg 75.18 0.54 GC
MOL004827 Semilicoisoflavone B graphic file with name medscimonit-25-6051-g025.jpg 48.78 0.55 GC
MOL004959 1-Methoxyphaseollidin graphic file with name medscimonit-25-6051-g026.jpg 69.98 0.64 GC
MOL004903 Liquiritin graphic file with name medscimonit-25-6051-g027.jpg 65.69 0.74 GC
MOL004948 Isoglycyrol graphic file with name medscimonit-25-6051-g028.jpg 44.7 0.84 GC

Target screening of SGD in the treatment of osteoarthritis

In the present study, the STITCH, ChEMBL, and PubChem databases were used to screen 226 targets corresponding to the active ingredients in SGD, with 188 targets for SY, 146 targets for GC, and 108 for SY and GC. These gene targets included cellular tumor antigen p53 (TP53), chlorotoxin derivative (CA4), estrogen receptor beta (ESR2), and multidrug resistance protein 1 (ABCB1), which are involved in inflammation [37], cell proliferation [38], and angiogenesis [39]. DrugBank, GeneCards, and the Online Mendelian Inheritance in Man® (OMIM) databases were also used to screen 187 targets associated with OA, removing compounds with duplication targets (Supplementary Table 3). The obtained compounds and targets were used to construct the pharmacology network.

Compound-compound network targets

A compound-compound target network was developed to identify the relationship between the compounds of SGD and their candidate targets (Figure 2). The compound-compound target network consisted of 101 nodes (23 compounds and 78 compound targets) and 338 edges (degree >3). The average degree of 14.69 per compound in such a network was based on the network analysis, demonstrating the multitarget treatment characteristics of SGD. In this network, the values of the degree for quercetin (degree=63) and kaempferol (degree=54) were considerably higher than that of the other components, suggesting that two chemicals probably were served as significant therapeutic compounds in OA.

Figure 2.

Figure 2

The compound-compound target network of Shaoyao Gancao decoction (SGD) in the treatment of osteoarthritis (OA). Blue represents the compound targets, green represents the compounds of Shaoyao Gancao decoction (SGD), and red hexagons represent the central compounds of SGD.

Protein-protein interaction (PPI) network targets

The PPI networks of compound targets were developed to identify the interactions between SGD-related proteins and other relative proteins with 448 nodes (45 compound targets, 26 OA targets, 19 compound/OA targets, and other relevant proteins) and 1,869 edges (Figure 3) were constructed to determine the interactive effects of compounds modulated by SGD. About 19 intersection targets between compound targets and OA-related targets were identified in this network including, multidrug resistance protein 1 (ABCB1), multidrug resistance-associated protein 1(ABCC1), carbonic anhydrase 2, C-C motif chemokine 2, cytochrome P450 1A1 (CYP1A1), cytochrome P450 1A2 (CYP1A2), cytochrome P450 2C19, cytochrome P450 2C9 (CYP2C9), cytochrome P450 2D6 (CYP2D6), cytochrome P450 3A4 (CYP3A4), estrogen receptor (ER), estrogen receptor beta (ESR2), peroxisome proliferator-activated receptor alpha, peroxisome proliferator-activated receptor gamma, prostaglandin G/H synthase 2 (PTGS2), solute carrier organic anion transporter family member 1B1, TP53, UDP-glucuronosyltransferase 1–3 (UGT1A3), and UDP-glucuronosyltransferase 1–8.

Figure 3.

Figure 3

The protein-protein interaction (PPI) network of compound targets of Shaoyao Gancao decoction (SGD) in the treatment of osteoarthritis (OA). Incarnadine (crimson) represent other proteins, purple represent compound targets, yellow represent osteoarthritis (OA) targets, and green represent compound/OA targets).

PPI network of OA targets

The PPI network of OA targets was developed to identify the relationship between the OA-related targets and other proteins, with 394 nodes (123 OA targets and 271 other proteins that interacted with OA targets) and 2,184 edges (Figure 4). Considering the median values for degree (10), betweenness centrality (81.71), and closeness centrality (104.63), 27 highly connected nodes with degree >20, betweenness centrality >81.71, and closeness centrality >104.63 were identified as significant OA-related targets. These targets included collagen alpha-2(V) chain, collagen alpha-1(XII) chain, cytochrome P450 3A5 (CYP3A5), CYP2C9, collagen alpha-1(XI) chain, collagen alpha-1(VI) chain, collagen alpha-1 (III) chain, collagen alpha-1(I) chain, collagen alpha-1(IX) chain, CYP1A2, collagen alpha-1(II) chain, nuclear receptor coactivator 1 (NCOA1), collagen alpha-1(X) chain, nuclear factor NF-kappa-B p105 subunit, UDP-glucuronosyltransferase 1-1 (UGT1A1), vascular endothelial growth factor A, C-C motif chemokine 5, CYP3A4, collagen alpha-2 (I) chain, IL-8, thrombospondin-1, plasminogen activator inhibitor 1, parathyroid hormone, plasminogen, transforming growth factor beta-1 proprotein, IL-6, and transcription factor AP-1 (JUN).

Figure 4.

Figure 4

The protein-protein interaction (PPI) network of osteoarthritis (OA) targets. Green ovals represent osteoarthritis (OA) targets and purple ovals represent other human proteins that interacted with OA targets.

PPI network of targets for SGD in OA

To further identify the functional mechanisms of SGD in OA, the PPI network of targets for SGD in the treatment of OA was established by intersecting the two networks described above (Figure 5). The network was composed of 161 nodes (21 compound targets, 17 OA targets, 27 compound/OA targets, and 96 other proteins) and 546 edges (Figure 5). Based on the median values for degree, betweenness centrality, and closeness centrality, which were 6, 9.93, and 44.68, respectively, nodes with the degree, betweenness centrality, and closeness centrality values that were higher than the corresponding median values (degree >20, betweenness centrality >81.71, and closeness centrality >104.63) were considered as significant targets. The identified nodes included CYP3A4, nuclear receptor corepressor 1, TP53, JUN, CYP2C9, UGT1A1, CYP1A1, CYP1A2, NCOA1, nuclear receptor coactivator 2, UGT1A3, CYP3A5, CYP2D6, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, IL-6, and tyrosine-protein kinase JAK2.

Figure 5.

Figure 5

The protein-protein interaction (PPI) network of targets for Shaoyao Gancao decoction (SGD) in osteoarthritis (OA). Yellow ovals represent osteoarthritis (OA) targets, incarnadine (crimson) ovals represent compound targets, green ovals represent compound/OA targets, and blue ovals represent other human proteins that interacted with OA targets or compound targets.

Cluster analysis

The PPI network of targets for SGD in OA was analyzed by using Molecular Complex Detection (MCODE), and five modules were obtained (Figure 6A). The biological processes, molecular functions, and signaling pathways enriched by the targets in the cluster modules were used to clarify the integral regulation of SGD for the treatment of OA (Figure 6B, 6C). In Gene Ontology (GO) terms, we discovered that (i) fatty acid binding, hormone receptor binding, and microtubules; (ii) regulation of lipid metabolism, hormone receptor binding, and nuclear chromatin; (iii) protein phosphatase activator activity, adenylate cyclase binding, and negative regulation of ryanodine-sensitive calcium-release channel activity; (iv) chemokine receptor activity, C-C chemokine receptor activity, and caveola; and (v) X chromosome, cyclin-dependent protein kinase holoenzyme complex, and cyclin-dependent protein serine, were enriched in clusters, supporting the role of SGD in the treatment of OA. The KEGG enrichment analysis showed that the signaling pathways were enriched in different modules (Figure 6C) [40]. Module 1 was highly associated with drug metabolism, including cytochrome P450; Module 2 was highly associated with the 5′AMP-activated protein kinase (AMPK) signaling pathway; Module 3 was related to gastric acid secretion; Module 4 was associated with the tumor necrosis factor (TNF) signaling pathway and chemokine signaling pathway; Module 5 was associated with the p53 signaling pathway.

Figure 6.

Figure 6

Enrichment analysis of the targets for Shaoyao Gancao decoction (SGD) in osteoarthritis (OA). (A) Clusters of the merged protein-protein interaction (PPI) network. Yellow ovals represent osteoarthritis (OA) targets, incarnadine (crimson) ovals represent compound targets, green ovals represent compound/OA targets, and blue ovals represent other human proteins that interacted with OA targets or compound targets. (B) The Gene Ontology (GO) pathway enrichment analysis of each cluster. (C) The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of each cluster.

Discussion

Osteoarthritis (OA) is a common form of chronic arthritis that is associated with painful symptoms that affect the quality of life for patients [41,42]. Currently, the therapeutic strategies for OA are mainly symptomatic and do not treat the underlying causes. Herbal traditional Chinese medicines (TCMs) contain several compounds that will have multiple targets, pathways, and modes of action but have been shown to treat the in OA [43]. Although Shaoyao Gancao decoction (SGD) has been used for centuries as an effective TCM for OA, its pharmacological mechanisms of action have been unclear. In this study, a network pharmacology approach was applied to determine the underlying mechanisms of SGD in OA.

After screening SGD for oral bioavailability (OB) (≥30%) and drug-likeness (DL) (≥0.18), 23 bioactive compounds were retrieved, including quercetin (OB=46.43; DL=0.28) and kaempferol (OB=41.88; DL=0.24) as potential bioactive compounds. Quercetin, one of the most abundant bioflavonoids, is known for its anti-oxidative [44], anti-inflammatory [45], antimicrobial [46], and antiviral activities [47] and its active role in promoting apoptosis in arthritic fibroblast-like synoviocytes and in protecting chondrocytes against oxidative stress [48]. Qiu et al. showed that quercetin reduced the symptoms of OA by reducing the level of reactive oxygen species (ROS), reversing mitochondrial dysfunction, and maintaining the integrity of the extracellular matrix (ECM) of the joint cartilage [49]. Kaempferol, a dietary element and an important bioflavonoid in vegetables and fruits [50], has a variety of pharmacological effects and acts as an anti-oxidant, anti-inflammatory, anti-apoptotic, anti-estrogenic, and neuroprotective agent [51]. Studies have shown that kaempferol significantly reduced in IL-1β-stimulated pro-inflammatory mediators in rat OA chondrocytes by inhibiting the NF-κB pathway [52]. Paeoniflorin (OB=53.87; DL=0.79) plays an important role in immune regulation [53], and hepatic protection [54]. Several studies have reported that liquirtin (OB=65.69; DL=0.74) has multiple pharmacological effects, as an immunomodulating agent, with anti-inflammatory, anti-allergic, anti-oxidant, and antiviral properties [55].

The PPI network of candidate targets for SGD in the treatment of OA was established based on the component and OA target networks with 161 overlapping genes. Using the median values for the degree of betweenness centrality and closeness of centrality (degree >20, betweenness centrality >81.71, and closeness centrality >104.63), 16 targets were regarded as significant. It was apparent that most of these targets, including CYP3A4, CYP2C9, CYP1A1, CYP1A2, CYP3A5, and CYP2D6 in the cytochrome P450 family, were strongly associated with drug metabolism. For instance, CYP2D6 is involved in the metabolism of the dual opioid agonist and norepinephrine-serotonin re-uptake during OA therapy [56]. CYP2C9 is involved in the metabolism of several nonsteroidal anti-inflammatory drugs (NSAIDs), contributing to the wide variability in pharmacokinetics in the metabolism of drugs [56,57]. Some targets, such as TP53 and JAK2, are associated with cell growth. TP53 is associated with OA, and the SIRT1/TP53 signaling pathway modulates the pathogenesis of OA [58]. JAK2 has a role not only in mediating angiotensin-2-induced ARHGEF1 phosphorylation [59], but also cell in the cycle by phosphorylating CNKN1B [60]. Previous studies have shown that the TCM, danshen, reduces cartilage damage in OA by regulating the JAK2/STAT3 and the AKT signaling pathways [61]. Also, JAK2 is a direct target of miR-216a-5p, and long non-coding RNA (lncRNA) DANCR regulates the proliferation, inflammation, and apoptosis of chondrocytes in OA via the miR-216a-5p-JAK2-STAT3 axis [62]. Xiong et al. found that leptin levels significantly increased in the synovial fluid of patients with OA of the temporomandibular joint (TMJ), stimulating IL-6 expression mainly via the JAK2/STAT3, p38 MAPK, and PI3K/Akt pathways [63]. Previous studies have shown that lncRNA gastric cancer-associated transcript 3 affects cell proliferation in OA by the IL-6/STAT3 signaling pathway [64].

Because clustering modules can demonstrate the biological mechanisms of key targets in disease, we classified the PPI network into five clusters (Figure 6A), and performed the Gene Ontology (GO) analysis (Figure 6B) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis (Figure 6C). Based on the GO terms, it may be proposed that the pharmacological effects of SGD in OA occurred by simultaneously activating these biological processes, cell components, and molecular functions. For example, Zhang et al. found that in a mouse model, pharmaceutical inhibition of the fatty acid binding pathway reduced the symptoms of OA induced by a high-fat diet [65]. Also, lipid metabolism is a chemical reaction involving lipids, which are compounds soluble in organic solvents [66]. Park et al. showed that the functional integrity of ABCD2 in modulating lipid metabolism was through the dysregulation of miR-141, and through ACSL4 in OA [67].

From the findings of the present study, based on the KEGG terms, the potential targets for SGD in the treatment of OA were associated with the 5′AMP-activated protein kinase (AMPK) signaling pathway, the tumor necrosis factor (TNF) signaling pathway, and the p53 signaling pathway. In the AMPK signaling pathway, AMPK serves as an intracellular sensor that not only regulates protein synthesis related to inflammation but also modulates the energy balance within chondrocytes [68]. Previous studies have shown that several bioactive compounds protect against cartilage degeneration in an OA model via the AMPK signaling pathway, including increased mitochondrial biogenesis and reduced mitochondrial dysfunction [69,70]. Zhou et al. showed that AMPK activity in chondrocytes was involved in joint homeostasis and that OA developed by promoting chondrocyte apoptosis and enhancing catabolic activity [71]. As for the TNF signaling pathway, it includes apoptosis, cell survival, inflammation, and immune function [72]. The TNF signaling pathway is important in protecting against the effects of OA, and the correlation between TNF-α levels and the degree of OA has previously been shown [73,74]. Also, the p53 signaling pathway is involved in coordinating cellular responses to different types of stress and in promoting tumor progression. Yan et al. showed that microRNA-34a had a role in chondrocyte apoptosis and proliferation by modulating the SIRT1/p53 signaling pathway in OA [58]. However, we found that pharmacological studies on the mechanisms and targets of the effects of SGD in the treatment of OA were previously limited. Based on the findings from the present study, future studies should be undertaken to assess the relationship between agents used in TCM, including SGD in OA, and their effects in terms of specific targets at the molecular level to validate the results based on data analysis.

Conclusions

This study aimed to undertake a network pharmacology analysis of the mechanism of the effects of the traditional Chinese medicine (TCM), Shaoyao Gancao decoction (SGD), in osteoarthritis (OA). The findings showed that SGD exerted its pharmacological effects in OA by modulating multiple pathways, including the cell cycle, cell apoptosis, drug metabolism, inflammation, and immune modulation. This study also provided a theoretical basis to determine the synergistic effects of TCM in treating diseases and the role of systematic network pharmacology in elucidating the potential mechanisms of action of TCMs. However, as this study was based on data mining and data analysis, further clinical validation studies should be undertaken on the role of SGD in OA.

Supplementary Materials

Supplementary Table 1.

GSD-associated target genes.

Gene symbol Herb
ABCC2 GC
APOB GC
ATAD5 GC
BAZ2B GC
BDNF GC
BRCA1 GC
CALM1 GC
CBR1 GC
CBR3 GC
CBX1 GC
CCL2 GC
GFER GC
GSK3A GC
HMOX1 GC
HSPA5 GC
LDLR GC
MAPK8 GC
MAPK9 GC
MAZF GC
MBNL1 GC
MLLT3 GC
MMP9 GC
NOS2 GC
PDE5A GC
PLA2G7 GC
PPME1 GC
RAPGEF1 GC
RAPGEF3 GC
SHBG GC
SLC5A1 GC
SLC5A2 GC
SLCO2B1 GC
SMAD3 GC
SMPD1 GC
TIM23 GC
UGT1A1 GC
UGT1A10 GC
UGT2B15 GC
ABCB11 SY
ABCG5 SY
ABCG8 SY
ADAM10 SY
ADAM17 SY
ALB SY
ALPI SY
ALPL SY
APOBEC3F SY
APOBEC3G SY
APOE SY
ARSA SY
BIRC5 SY
BLM SY
CAT SY
CDK1 SY
CFTR SY
CHRM1 SY
CISD1 SY
CTDSP1 SY
CTSD SY
CYCS SY
CYP2A7 SY
CYP7A1 SY
DHCR24 SY
DNMT1 SY
DRD2 SY
EHMT2 SY
GAA SY
GLI1 SY
GLI3 SY
GLS SY
GPBAR1 SY
GPT SY
HSD11B2 SY
HSF1 SY
HSP90AA1 SY
HSP90AB1 SY
ICAM1 SY
IL8 SY
KCNA5 SY
KCNH2 SY
KCNMA1 SY
LMNB1 SY
NOS3 SY
NPSR1 SY
NQO1 SY
NR1H2 SY
NR1H3 SY
NR1I2 SY
NR1I3 SY
PIM2 SY
PLCG1 SY
PLCG2 SY
PMP22 SY
PRKAA2 SY
PRKCB SY
PRKCE SY
PTPRS SY
PYGM SY
RACGAP1 SY
RARA SY
RECQL SY
RORC SY
RPS6KA3 SY
SAE1 SY
SOD1 SY
SP1 SY
SREBF1 SY
SREBF2 SY
STK16 SY
STK33 SY
SYK SY
TLR4 SY
UBA2 SY
UBE2I SY
UGT1A7 SY
UGT1A9 SY
UGT3A1 SY
XIAP SY
ABCB1 GC, SY
ABCC1 GC, SY
ABCG2 GC, SY
ACHE GC, SY
AHR GC, SY
AKR1B1 GC, SY
AKR1B10 GC, SY
AKT1 GC, SY
ALDH1A1 GC, SY
ALOX15 GC, SY
ALOX15B GC, SY
ALOX5 GC, SY
AMY1A GC, SY
APEX1 GC, SY
APP GC, SY
AR GC, SY
ATXN2 GC, SY
BACE1 GC, SY
BCHE GC, SY
CA1 GC, SY
CA12 GC, SY
CA2 GC, SY
CA4 GC, SY
CA7 GC, SY
CASP3 GC, SY
CDK6 GC, SY
CLK1 GC, SY
CYP19A1 GC, SY
CYP1A1 GC, SY
CYP1A2 GC, SY
CYP1B1 GC, SY
CYP2C19 GC, SY
CYP2C9 GC, SY
CYP2D6 GC, SY
CYP3A4 GC, SY
DAPK1 GC, SY
DPP4 GC, SY
DYRK1A GC, SY
EGFR GC, SY
ESR1 GC, SY
ESR2 GC, SY
ESRRA GC, SY
F2 GC, SY
FEN1 GC, SY
FLT3 GC, SY
GBA GC, SY
GLO1 GC, SY
GLP1R GC, SY
GMNN GC, SY
GSK3B GC, SY
HDAC9 GC, SY
HIF1A GC, SY
HPGD GC, SY
HSD17B1 GC, SY
HSD17B10 GC, SY
HSD17B2 GC, SY
IDH1 GC, SY
KDM4A GC, SY
KDM4E GC, SY
LMNA GC, SY
MAPT GC, SY
MDM2 GC, SY
MDM4 GC, SY
MPG GC, SY
NEU2 GC, SY
NFE2L2 GC, SY
NFKB1 GC, SY
NFKB2 GC, SY
NOX4 GC, SY
NR1H4 GC, SY
NR3C1 GC, SY
OPRD1 GC, SY
OPRK1 GC, SY
OPRM1 GC, SY
PAFAH1B3 GC, SY
PIM1 GC, SY
PIP4K2A GC, SY
PNLIP GC, SY
POLB GC, SY
POLH GC, SY
POLI GC, SY
POLK GC, SY
PON1 GC, SY
PPARA GC, SY
PPARD GC, SY
PPARG GC, SY
PREP GC, SY
PTGS1 GC, SY
PTGS2 GC, SY
PTH1R GC, SY
PTPN1 GC, SY
RAPGEF4 GC, SY
RELA GC, SY
RGS4 GC, SY
RXRA GC, SY
SIAE GC, SY
SLCO1B1 GC, SY
SLCO1B3 GC, SY
SMN1 GC, SY
TDP1 GC, SY
TOP2A GC, SY
TP53 GC, SY
TYR GC, SY
UGT1A3 GC, SY
UGT1A4 GC, SY
UGT1A8 GC, SY
USP1 GC, SY
XDH GC, SY

Supplementary Table 2.

Osteoarthritis-associated target genes.

UniProt ID Gene symbol Description Organism Source
P43026 GDF5 Growth/differentiation factor 5 Homo sapiens OMIM
P02458 COL2A1 Collagen, type II, alpha-1 Homo sapiens OMIM
P16112 ACAN Aggrecan Homo sapiens OMIM
Q9BXN1 ASPN Asporin Homo sapiens OMIM
P84022 SMAD3 Mothers against decapentaplegic, drosophila, homolog OF, 3 Homo sapiens OMIM
P0DI81 TRAPPC2 Tracking protein particle complex, subunit 2 Homo sapiens OMIM
Q92765 FRZB Frizzled-related protein Homo sapiens OMIM
P20849 COL9A1 Collagen, type IX, alpha-1 Homo sapiens OMIM
Q99814 EPAS1 Endothelial pas domain protein 1 Homo sapiens OMIM
P49747 COMP Cartilage oligomeric matrix protein Homo sapiens OMIM
Q9UNA0 ADAMTS5 A disintegrin-like and metalloproteinase with thrombospondin type 1 Motif, 5 Homo sapiens OMIM
O15232 MATN3 Matrilin 3 Homo sapiens OMIM
Q14623 IHH Indian Hedgehog Homo sapiens OMIM
Q9NRR1 CYTL1 Cytokine-like protein 1 Homo sapiens OMIM
P49190 PTH2R Parathyroid hormone 2 receptor Homo sapiens OMIM
Q92731 ESR2 Estrogen receptor 2 Homo sapiens OMIM
P41159 LEP Leptin Homo sapiens OMIM
P0DP23 CALM1 Calmodulin 1 Homo sapiens OMIM
P41180 CASR Calcium-sensing receptor Homo sapiens OMIM
P98066 TNFAIP6 Tumor necrosis factor-apha-induced protein 6 Homo sapiens OMIM
Q92743 HTRA1 HTRA serine peptidase 1 Homo sapiens OMIM
P13942 COL11A2 Collagen, type XI, alpha-2 Homo sapiens OMIM
Q9UHF7 TRPS1 Trichorhinophalangeal syndrome, type I Homo sapiens OMIM
P11473 VDR Vitamin D receptor Homo sapiens OMIM
Q92633 LPAR1 Lysophosphatidic acid receptor 1 Homo sapiens OMIM
P30044 PRDX5 Peroxiredoxin 5 Homo sapiens OMIM
Q9HCJ1 ANKH ANK, mouse, Homolog OF Homo sapiens OMIM
Q9Y2L9 LRCH1 Leucine-rich repeats and calponin homology domain-containing 1 Homo sapiens OMIM
P98160 HSPG2 Heparan sulfate proteoglycan of basement membrane Homo sapiens OMIM
P56199 ITGA1 Integrin, alpha-1 Homo sapiens OMIM
P45452 MMP13 Matrix metalloproteinase 13 Homo sapiens OMIM
P02452 COL1A1 Collagen, type I, alpha-1 Homo sapiens OMIM
P03372 ESR1 Estrogen receptor 1 Homo sapiens OMIM
P13500 CCL2 Chemokine, CC Motif, ligand 2 Homo sapiens OMIM
Q16552 IL17A Interleukin 17A Homo sapiens OMIM
P78536 ADAM17 A disintegrin and metalloproteinase domain 17 Homo sapiens OMIM
P51884 LUM Lumican Homo sapiens OMIM
P48061 CXCL12 Chemokine, CXC Motif, ligand 12 Homo sapiens OMIM
P43235 CTSK Cathepsin K Homo sapiens OMIM
P11712 CYP2C9 Cytochrome P450, subfamily Iic, polypeptide 9 Homo sapiens OMIM
Q99969 RARRES2 Retinoic acid receptor responder 2 Homo sapiens OMIM
Q9NS15 LTBP3 Latent transforming growth factor-beta-binding protein 3 Homo sapiens OMIM
Q9HCN6 GP6 Glycoprotein VI, platelet Homo sapiens OMIM
P24001 IL32 Interleukin 32 Homo sapiens OMIM
Q92954 PRG4 Proteoglycan 4 Homo sapiens OMIM
O94907 DKK1 DICKKOPF, Xenopus, Homolog OF, 1 Homo sapiens OMIM
Q9H5V8 CDCP1 CUB domain-containing protein 1 Homo sapiens OMIM
Q9Y2U5 MAP3K2 Mitogen-activated protein kinase kinase kinase 2 Homo sapiens OMIM
Q8TCG1 CIP2A Cell proliferation-regulating inhibitor of protein phosphatase 2A Homo sapiens OMIM
P14784 IL2RB Interleukin 2 receptor, beta Homo sapiens OMIM
P17931 LGALS3 Lectin, galactoside-binding, soluble, 3 Homo sapiens OMIM
Q14050 COL9A3 Collagen, Type IX, alpha-3 Homo sapiens OMIM
P02751 FN1 Fibronectin 1 Homo sapiens OMIM
P30203 CD6 CD6 antigen Homo sapiens OMIM
Q96S44 TP53 Tumor protein P53 Homo sapiens OMIM
P31785 IL2RG Interleukin 2 receptor, gamma Homo sapiens OMIM
P55287 CDH11 Cadherin 11 Homo sapiens OMIM
Q8WVB3 HEXDC Hexosaminidase (glycosyl hydrolase family 20, catalytic domain)-containing protein Homo sapiens OMIM
O75711 SCRG1 Stimulator of chondrogenesis 1 Homo sapiens OMIM
P35354 PTGS2 Prostaglandin-endoperoxide synthase 2 Homo sapiens OMIM
Q12794 HYAL1 Hyaluronoglu-cosaminidase 1 Homo sapiens OMIM
Q8IUL8 CILP2 Cartilage intermediate layer protein 2 Homo sapiens OMIM
Q8WVQ1 CANT1 Calcium-activated nucleotidase 1 Homo sapiens OMIM
Q03692 COL10A1 Collagen, Type X, alpha-1 Homo sapiens OMIM
P10600 TGFB3 Transforming growth factor, beta-3 Homo sapiens OMIM
O15530 PDPK1 3-phosphoinositide-dependent protein kinase 1 Homo sapiens Drugbank
P52209 PGD 6-phosphogluconate dehydrogenase, decarboxylating Homo sapiens Drugbank
Q9Y215 COLQ Acetylcholinesterase Homo sapiens Drugbank
P78348 ASIC1 Acid-sensing ion channel 1 Homo sapiens Drugbank
O60218 AKR1B10 Aldo-keto reductase family 1 member B10 Homo sapiens Drugbank
P42330 AKR1C3 Aldo-keto reductase family 1 member C3 Homo sapiens Drugbank
P10275 AR Androgen receptor Homo sapiens Drugbank
Q07817 BCL2L1 Apoptosis regulator Bcl-2 Homo sapiens Drugbank
P09917 ALOX5 Arachidonate 5-lipoxygenase Homo sapiens Drugbank
Q2M3GO ABCB5 ATP-binding cassette sub-family B member 5 Homo sapiens Drugbank
Q96J66 ABCC11 ATP-binding cassette sub-family C member 11 Homo sapiens Drugbank
Q9UNQ0 ABCG2 ATP-binding cassette sub-family G member 2 Homo sapiens Drugbank
Q92887 ABCC2 Canalicular multispecific organic anion transporter 1 Homo sapiens Drugbank
O15438 ABCC3 Canalicular multispecific organic anion transporter 2 Homo sapiens Drugbank
P00918 CA2 Carbonic anhydrase 2 Homo sapiens Drugbank
P07451 CA3 Carbonic anhydrase 3 Homo sapiens Drugbank
P06276 BCHE Cholinesterase Homo sapiens Drugbank
P08185 SERPINA6 Corticosteroid-binding globulin Homo sapiens Drugbank
P25024 CXCR1 C-X-C chemokine receptor type 1 Homo sapiens Drugbank
P13569 CFTR Cystic fibrosis transmembrane conductance regulator Homo sapiens Drugbank
P04798 CYP1A1 Cytochrome P450 1A1 Homo sapiens Drugbank
P05177 CYP1A2 Cytochrome P450 1A2 Homo sapiens Drugbank
P11509 CYP2A6 Cytochrome P450 2A6 Homo sapiens Drugbank
P20813 CYP2B6 Cytochrome P450 2B6 Homo sapiens Drugbank
P33260 CYP2C18 Cytochrome P450 2C18 Homo sapiens Drugbank
P33261 CYP2C19 Cytochrome P450 2C19 Homo sapiens Drugbank
P10632 CYP2C8 Cytochrome P450 2C8 Homo sapiens Drugbank
P10635 CYP2D6 Cytochrome P450 2D6 Homo sapiens Drugbank
P05182 CYP2E1 Cytochrome P450 2E1 Homo sapiens Drugbank
P08684 CYP3A4 PCytochrome P450 3A4 Homo sapiens Drugbank
P20815 CYP3A5 Cytochrome P450 3A5 Homo sapiens Drugbank
P02693 FABP2 Fatty acid-binding protein, intestinal Homo sapiens Drugbank
P04150 NR3C1 Glucocorticoid receptor Homo sapiens Drugbank
P25021 HRH2 Histamine H2 receptor Homo sapiens Drugbank
Q04760 GLO1 Lactoylglutathione lyase Homo sapiens Drugbank
P23141 CES1 Liver carboxylesterase 1 Homo sapiens Drugbank
P27361 MAPK3 Mitogen-activated protein kinase 3 Homo sapiens Drugbank
P08183 ABCB1 Multidrug resistance protein 1 Homo sapiens Drugbank
P33527 ABCC1 Multidrug resistance-associated protein 1 Homo sapiens Drugbank
O15439 ABCC4 Multidrug resistance-associated protein 4 Homo sapiens Drugbank
O95255 ABCC6 Multidrug resistance-associated protein 6 Homo sapiens Drugbank
P05164 MPO Myeloperoxidase Homo sapiens Drugbank
Q07869 PPARA Peroxisome proliferator-activated receptor alpha Homo sapiens Drugbank
Q03181 PPARD Peroxisome proliferator-activated receptor delta Homo sapiens Drugbank
P37231 PPARG Peroxisome proliferator-activated receptor gamma Homo sapiens Drugbank
P14555 PLA2G2A Phospholipase A2, membrane associated Homo sapiens Drugbank
O43526 KCNQ2 Potassium voltage-gated channel subfamily KQT member 2 Homo sapiens Drugbank
O43525 KCNQ3 Potassium voltage-gated channel subfamily KQT member 3 Homo sapiens Drugbank
Q9Y5Y4 PTGDR2 Prostaglandin D2 receptor 2 Homo sapiens Drugbank
P34995 PTGER1 Prostaglandin E2 receptor EP1 subtype Homo sapiens Drugbank
Q8VDQ1 PTGR2 Prostaglandin reductase 2 Homo sapiens Drugbank
P19793 RXRA Retinoic acid receptor RXR-alpha Homo sapiens Drugbank
Q9Y5Y9 SCN10A Sodium channel protein type 10 subunit alpha Homo sapiens Drugbank
P35499 SCN4A Sodium channel protein type 4 subunit alpha Homo sapiens Drugbank
Q14973 SLC10A1 Sodium/bile acid cotransporter Homo sapiens Drugbank
P46059 SLC15A1 Solute carrier family 15 member 1 Homo sapiens Drugbank
Q9NSA0 SLC22A11 Solute carrier family 22 member 11 Homo sapiens Drugbank
O15244 SLC22A2 Solute carrier family 22 member 2 Homo sapiens Drugbank
Q8VC69 SLC22A6 Solute carrier family 22 member 6 Homo sapiens Drugbank
Q9Y694 SLC22A7 Solute carrier family 22 member 7 Homo sapiens Drugbank
Q8TCC7 SLC22A8 Solute carrier family 22 member 8 Homo sapiens Drugbank
P46721 SLCO1A2 Solute carrier organic anion transporter family member 1A2 Homo sapiens Drugbank
Q9Y6L6 SLCO1B1 Solute carrier organic anion transporter family member 1B1 Homo sapiens Drugbank
Q9NYB5 SLCO1C1 Solute carrier organic anion transporter family member 1C1 Homo sapiens Drugbank
O94956 SLCO2B1 Solute carrier organic anion transporter family member 2B1 Homo sapiens Drugbank
P07204 THBD Thrombomodulin Homo sapiens Drugbank
P00750 PLAT Tissue-type plasminogen activator Homo sapiens Drugbank
P02766 TTR Transthyretin Homo sapiens Drugbank
P48775 TDO2 Tryptophan 2,3-dioxygenase Homo sapiens Drugbank
P22309 UGT1A1 UDP-glucuronosyltransferase 1-1 Homo sapiens Drugbank
Q9HAW8 UGT1A10 UDP-glucuronosyltransferase 1-10 Homo sapiens Drugbank
P35503 UGT1A3 UDP-glucuronosyltransferase 1-3 Homo sapiens Drugbank
Q9HAW9 UGT1A8 UDP-glucuronosyltransferase 1-8 Homo sapiens Drugbank
O60656 UGT1A9 UDP-glucuronosyltransferase 1-9 Homo sapiens Drugbank
P06133 UGT2B4 UDP-glucuronosyltransferase 2B4 Homo sapiens Drugbank
P16662 UGT2B7 UDP-glucuronosyltransferase 2B7 Homo sapiens Drugbank
P02768 ALB Serum albumin Homo sapiens Drugbank, Genecards
P23219 PTGS1 Prostaglandin G/H synthase 1 Homo sapiens Drugbank, Genecards
P01584 IL1B Interleukin 1 Beta Homo sapiens Genecards
P08123 COL1A2 Collagen Type I Alpha 2 Chain Homo sapiens Genecards
P08254 MMP3 Matrix Metallopeptidase 3 Homo sapiens Genecards
P01375 TNF Tumor Necrosis Factor Homo sapiens Genecards
P08887 IL6 Interleukin 6 Homo sapiens Genecards
P03956 MMP1 Matrix Metallopeptidase 1 Homo sapiens Genecards
P01137 TGFB1 Transforming Growth Factor Beta 1 Homo sapiens Genecards
O75339 CILP Cartilage Intermediate Layer Protein Homo sapiens Genecards
Q9NUQ7 UFSP2 UFM1 Specific Peptidase 2 Homo sapiens Genecards
Q14055 COL9A2 Collagen Type IX Alpha 2 Chain Homo sapiens Genecards
O14788 TNFSF11 TNF Superfamily Member 11 Homo sapiens Genecards
P10145 CXCL8 C-X-C Motif Chemokine Ligand 8 Homo sapiens Genecards
O00300 TNFRSF11B TNF Receptor Superfamily Member 11b Homo sapiens Genecards
P01033 TIMP1 TIMP Metallopeptidase Inhibitor 1 Homo sapiens Genecards
O75173 ADAMTS4 ADAM Metallopeptidase With Thrombospondin Type 1 Motif 4 Homo sapiens Genecards
P50443 SLC26A2 Solute Carrier Family 26 Member 2 Homo sapiens Genecards
Q16832 DDR2 Discoidin Domain Receptor Tyrosine Kinase 2 Homo sapiens Genecards
Q9HBA0 TRPV4 Transient Receptor Potential Cation Channel Subfamily V Member 4 Homo sapiens Genecards
P02741 CRP C-Reactive Protein Homo sapiens Genecards
P22301 IL10 Interleukin 10 Homo sapiens Genecards
P36222 CHI3L1 Chitinase 3 Like 1 Homo sapiens Genecards
O15068 MCF2L MCF.2 Cell Line Derived Transforming Sequence Like Homo sapiens Genecards
P12107 COL11A1 Collagen Type XI Alpha 1 Chain Homo sapiens Genecards
Q14807 KIF22 Kinesin Family Member 22 Homo sapiens Genecards
P22003 BMP5 Bone Morphogenetic Protein 5 Homo sapiens Genecards
P48436 SOX9 SRY-Box 9 Homo sapiens Genecards
P18510 IL1RN Interleukin 1 Receptor Antagonist Homo sapiens Genecards
P02461 COL3A1 Collagen Type III Alpha 1 Chain Homo sapiens Genecards
P21941 MATN1 Matrilin 1, Cartilage Matrix Protein Homo sapiens Genecards
Q8WXS8 ADAMTS14 ADAM Metallopeptidase With Thrombospondin Type 1 Motif 14 Homo sapiens Genecards
P22607 FGFR3 Fibroblast Growth Factor Receptor 3 Homo sapiens Genecards
P51798 CLCN7 Chloride Voltage-Gated Channel 7 Homo sapiens Genecards
P35555 FBN1 Fibrillin 1 Homo sapiens Genecards
P10912 GHR Growth Hormone Receptor Homo sapiens Genecards
P02818 BGLAP Bone Gamma-Carboxyglutamate Protein Homo sapiens Genecards
P63092 GNAS GNAS Complex Locus Homo sapiens Genecards
Q16394 EXT1 Exostosin Glycosyltransferase 1 Homo sapiens Genecards
P01583 IL1A Interleukin 1 Alpha Homo sapiens Genecards
Q86Y38 XYLT1 Xylosyltransferase 1 Homo sapiens Genecards
P208908 COL5A1 Collagen Type V Alpha 1 Chain Homo sapiens Genecards
Q9GIY3 HLA-DRB1 Major Histocompatibility Complex, Class II, DR Beta 1 Homo sapiens Genecards
Q9Y2R2 PTPN22 Protein Tyrosine Phosphatase, Non-Receptor Type 22 Homo sapiens Genecards
O15266 SHOX Short Stature Homeobox Homo sapiens Genecards
Q93099 HGD Homogentisate 1,2-Dioxygenase Homo sapiens Genecards

Supplementary Table 3.

SGD compound targets.

Gene symbol Herb
ABCC2 GC
APOB GC
ATAD5 GC
BAZ2B GC
BDNF GC
BRCA1 GC
CALM1 GC
CBR1 GC
CBR3 GC
CBX1 GC
CCL2 GC
GFER GC
GSK3A GC
HMOX1 GC
HSPA5 GC
LDLR GC
MAPK8 GC
MAPK9 GC
MAZF GC
MBNL1 GC
MLLT3 GC
MMP9 GC
NOS2 GC
PDE5A GC
PLA2G7 GC
PPME1 GC
RAPGEF1 GC
RAPGEF3 GC
SHBG GC
SLC5A1 GC
SLC5A2 GC
SLCO2B1 GC
SMAD3 GC
SMPD1 GC
TIM23 GC
UGT1A1 GC
UGT1A10 GC
UGT2B15 GC
ABCB11 SY
ABCG5 SY
ABCG8 SY
ADAM10 SY
ADAM17 SY
ALB SY
ALPI SY
ALPL SY
APOBEC3F SY
APOBEC3G SY
APOE SY
ARSA SY
BIRC5 SY
BLM SY
CAT SY
CDK1 SY
CFTR SY
CHRM1 SY
CISD1 SY
CTDSP1 SY
CTSD SY
CYCS SY
CYP2A7 SY
CYP7A1 SY
DHCR24 SY
DNMT1 SY
DRD2 SY
EHMT2 SY
GAA SY
GLI1 SY
GLI3 SY
GLS SY
GPBAR1 SY
GPT SY
HSD11B2 SY
HSF1 SY
HSP90AA1 SY
HSP90AB1 SY
ICAM1 SY
IL8 SY
KCNA5 SY
KCNH2 SY
KCNMA1 SY
LMNB1 SY
NOS3 SY
NPSR1 SY
NQO1 SY
NR1H2 SY
NR1H3 SY
NR1I2 SY
NR1I3 SY
PIM2 SY
PLCG1 SY
PLCG2 SY
PMP22 SY
PRKAA2 SY
PRKCB SY
PRKCE SY
PTPRS SY
PYGM SY
RACGAP1 SY
RARA SY
RECQL SY
RORC SY
RPS6KA3 SY
SAE1 SY
SOD1 SY
SP1 SY
SREBF1 SY
SREBF2 SY
STK16 SY
STK33 SY
SYK SY
TLR4 SY
UBA2 SY
UBE2I SY
UGT1A7 SY
UGT1A9 SY
UGT3A1 SY
XIAP SY
ABCB1 GC, SY
ABCC1 GC, SY
ABCG2 GC, SY
ACHE GC, SY
AHR GC, SY
AKR1B1 GC, SY
AKR1B10 GC, SY
AKT1 GC, SY
ALDH1A1 GC, SY
ALOX15 GC, SY
ALOX15B GC, SY
ALOX5 GC, SY
AMY1A GC, SY
APEX1 GC, SY
APP GC, SY
AR GC, SY
ATXN2 GC, SY
BACE1 GC, SY
BCHE GC, SY
CA1 GC, SY
CA12 GC, SY
CA2 GC, SY
CA4 GC, SY
CA7 GC, SY
CASP3 GC, SY
CDK6 GC, SY
CLK1 GC, SY
CYP19A1 GC, SY
CYP1A1 GC, SY
CYP1A2 GC, SY
CYP1B1 GC, SY
CYP2C19 GC, SY
CYP2C9 GC, SY
CYP2D6 GC, SY
CYP3A4 GC, SY
DAPK1 GC, SY
DPP4 GC, SY
DYRK1A GC, SY
EGFR GC, SY
ESR1 GC, SY
ESR2 GC, SY
ESRRA GC, SY
F2 GC, SY
FEN1 GC, SY
FLT3 GC, SY
GBA GC, SY
GLO1 GC, SY
GLP1R GC, SY
GMNN GC, SY
GSK3B GC, SY
HDAC9 GC, SY
HIF1A GC, SY
HPGD GC, SY
HSD17B1 GC, SY
HSD17B10 GC, SY
HSD17B2 GC, SY
IDH1 GC, SY
KDM4A GC, SY
KDM4E GC, SY
LMNA GC, SY
MAPT GC, SY
MDM2 GC, SY
MDM4 GC, SY
MPG GC, SY
NEU2 GC, SY
NFE2L2 GC, SY
NFKB1 GC, SY
NFKB2 GC, SY
NOX4 GC, SY
NR1H4 GC, SY
NR3C1 GC, SY
OPRD1 GC, SY
OPRK1 GC, SY
OPRM1 GC, SY
PAFAH1B3 GC, SY
PIM1 GC, SY
PIP4K2A GC, SY
PNLIP GC, SY
POLB GC, SY
POLH GC, SY
POLI GC, SY
POLK GC, SY
PON1 GC, SY
PPARA GC, SY
PPARD GC, SY
PPARG GC, SY
PREP GC, SY
PTGS1 GC, SY
PTGS2 GC, SY
PTH1R GC, SY
PTPN1 GC, SY
RAPGEF4 GC, SY
RELA GC, SY
RGS4 GC, SY
RXRA GC, SY
SIAE GC, SY
SLCO1B1 GC, SY
SLCO1B3 GC, SY
SMN1 GC, SY
TDP1 GC, SY
TOP2A GC, SY
TP53 GC, SY
TYR GC, SY
UGT1A3 GC, SY
UGT1A4 GC, SY
UGT1A8 GC, SY
USP1 GC, SY
XDH GC, SY

Abbreviations

ABCB1

multidrug resistance protein 1

ADME

adsorption, distribution, metabolism, and excretion

BP

biological processes

CC

cellular components

CM

Chinese Medicine

CYP1A1

cytochrome P450 1A1

CYP1A2

cytochrome P450 1A2

CYP2C9

cytochrome P450 2C9

CYP2D6

cytochrome P450 2D6

CYP3A4

cytochrome P450 3A4

CYP3A5

cytochrome P450 3A5

DL

drug-likeness

ESR2

estrogen receptor beta

GC

Gancao

GO

Gene Ontology

IL

interleukin

KEGG

Kyoto Encyclopedia of Genes and Genomes

lncRNA

long non-coding RNA

MCODE

Molecular Complex Detection

NCOA1

nuclear receptor coactivator 1

NSAID

nonsteroidal anti-inflammatory drug

OA

osteoarthritis

OB

oral bioavailability

PTGS2

prostaglandin G/H synthase 2

PPI

protein-protein interaction

SGD

Shaoyao-Gancao decoction

SY

shaoyao

TCM

Traditional Chinese medicine

TCMSP

Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform

TNF

tumor necrosis factor

TP53

cellular tumor antigen p53

UGT1A1

UDP-glucuronosyltransferase 1-1

UGT1A3

UDP-glucuronosyltranserase 1–3.

Footnotes

Source of support: The National Natural Science Foundation of China (Grant No. 81703659)

Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. The datasets generated and/or analyzed in this study included the Traditional Chinese Medicine Systems Pharmacology (TCMSP) repository, http://lsp.nwu.edu.cn/tcmsp.php; TCM@Taiwan, http://tcm.cmu.edu.tw/; STITCH, http://stitch.embl.de/; PubChem, http://pubchem.ncbi.nih.gov/; GeneCard, http://www.genecards.org/; ChEMBL, http://www.ebi.ac.uk/chembl/; the Kyoto Encyclopedia of Genes and Genomes (KEGG), https://www.kegg.jp/; OMIM, http://www.omim.org/; DrugBank, https://www.drugbank.ca/; Cytoscape, http://www.cytoscape.org/; and the Gene Ontology (GO) database, http://geneontology.org/.

Conflict of interest

None.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Table 1.

GSD-associated target genes.

Gene symbol Herb
ABCC2 GC
APOB GC
ATAD5 GC
BAZ2B GC
BDNF GC
BRCA1 GC
CALM1 GC
CBR1 GC
CBR3 GC
CBX1 GC
CCL2 GC
GFER GC
GSK3A GC
HMOX1 GC
HSPA5 GC
LDLR GC
MAPK8 GC
MAPK9 GC
MAZF GC
MBNL1 GC
MLLT3 GC
MMP9 GC
NOS2 GC
PDE5A GC
PLA2G7 GC
PPME1 GC
RAPGEF1 GC
RAPGEF3 GC
SHBG GC
SLC5A1 GC
SLC5A2 GC
SLCO2B1 GC
SMAD3 GC
SMPD1 GC
TIM23 GC
UGT1A1 GC
UGT1A10 GC
UGT2B15 GC
ABCB11 SY
ABCG5 SY
ABCG8 SY
ADAM10 SY
ADAM17 SY
ALB SY
ALPI SY
ALPL SY
APOBEC3F SY
APOBEC3G SY
APOE SY
ARSA SY
BIRC5 SY
BLM SY
CAT SY
CDK1 SY
CFTR SY
CHRM1 SY
CISD1 SY
CTDSP1 SY
CTSD SY
CYCS SY
CYP2A7 SY
CYP7A1 SY
DHCR24 SY
DNMT1 SY
DRD2 SY
EHMT2 SY
GAA SY
GLI1 SY
GLI3 SY
GLS SY
GPBAR1 SY
GPT SY
HSD11B2 SY
HSF1 SY
HSP90AA1 SY
HSP90AB1 SY
ICAM1 SY
IL8 SY
KCNA5 SY
KCNH2 SY
KCNMA1 SY
LMNB1 SY
NOS3 SY
NPSR1 SY
NQO1 SY
NR1H2 SY
NR1H3 SY
NR1I2 SY
NR1I3 SY
PIM2 SY
PLCG1 SY
PLCG2 SY
PMP22 SY
PRKAA2 SY
PRKCB SY
PRKCE SY
PTPRS SY
PYGM SY
RACGAP1 SY
RARA SY
RECQL SY
RORC SY
RPS6KA3 SY
SAE1 SY
SOD1 SY
SP1 SY
SREBF1 SY
SREBF2 SY
STK16 SY
STK33 SY
SYK SY
TLR4 SY
UBA2 SY
UBE2I SY
UGT1A7 SY
UGT1A9 SY
UGT3A1 SY
XIAP SY
ABCB1 GC, SY
ABCC1 GC, SY
ABCG2 GC, SY
ACHE GC, SY
AHR GC, SY
AKR1B1 GC, SY
AKR1B10 GC, SY
AKT1 GC, SY
ALDH1A1 GC, SY
ALOX15 GC, SY
ALOX15B GC, SY
ALOX5 GC, SY
AMY1A GC, SY
APEX1 GC, SY
APP GC, SY
AR GC, SY
ATXN2 GC, SY
BACE1 GC, SY
BCHE GC, SY
CA1 GC, SY
CA12 GC, SY
CA2 GC, SY
CA4 GC, SY
CA7 GC, SY
CASP3 GC, SY
CDK6 GC, SY
CLK1 GC, SY
CYP19A1 GC, SY
CYP1A1 GC, SY
CYP1A2 GC, SY
CYP1B1 GC, SY
CYP2C19 GC, SY
CYP2C9 GC, SY
CYP2D6 GC, SY
CYP3A4 GC, SY
DAPK1 GC, SY
DPP4 GC, SY
DYRK1A GC, SY
EGFR GC, SY
ESR1 GC, SY
ESR2 GC, SY
ESRRA GC, SY
F2 GC, SY
FEN1 GC, SY
FLT3 GC, SY
GBA GC, SY
GLO1 GC, SY
GLP1R GC, SY
GMNN GC, SY
GSK3B GC, SY
HDAC9 GC, SY
HIF1A GC, SY
HPGD GC, SY
HSD17B1 GC, SY
HSD17B10 GC, SY
HSD17B2 GC, SY
IDH1 GC, SY
KDM4A GC, SY
KDM4E GC, SY
LMNA GC, SY
MAPT GC, SY
MDM2 GC, SY
MDM4 GC, SY
MPG GC, SY
NEU2 GC, SY
NFE2L2 GC, SY
NFKB1 GC, SY
NFKB2 GC, SY
NOX4 GC, SY
NR1H4 GC, SY
NR3C1 GC, SY
OPRD1 GC, SY
OPRK1 GC, SY
OPRM1 GC, SY
PAFAH1B3 GC, SY
PIM1 GC, SY
PIP4K2A GC, SY
PNLIP GC, SY
POLB GC, SY
POLH GC, SY
POLI GC, SY
POLK GC, SY
PON1 GC, SY
PPARA GC, SY
PPARD GC, SY
PPARG GC, SY
PREP GC, SY
PTGS1 GC, SY
PTGS2 GC, SY
PTH1R GC, SY
PTPN1 GC, SY
RAPGEF4 GC, SY
RELA GC, SY
RGS4 GC, SY
RXRA GC, SY
SIAE GC, SY
SLCO1B1 GC, SY
SLCO1B3 GC, SY
SMN1 GC, SY
TDP1 GC, SY
TOP2A GC, SY
TP53 GC, SY
TYR GC, SY
UGT1A3 GC, SY
UGT1A4 GC, SY
UGT1A8 GC, SY
USP1 GC, SY
XDH GC, SY

Supplementary Table 2.

Osteoarthritis-associated target genes.

UniProt ID Gene symbol Description Organism Source
P43026 GDF5 Growth/differentiation factor 5 Homo sapiens OMIM
P02458 COL2A1 Collagen, type II, alpha-1 Homo sapiens OMIM
P16112 ACAN Aggrecan Homo sapiens OMIM
Q9BXN1 ASPN Asporin Homo sapiens OMIM
P84022 SMAD3 Mothers against decapentaplegic, drosophila, homolog OF, 3 Homo sapiens OMIM
P0DI81 TRAPPC2 Tracking protein particle complex, subunit 2 Homo sapiens OMIM
Q92765 FRZB Frizzled-related protein Homo sapiens OMIM
P20849 COL9A1 Collagen, type IX, alpha-1 Homo sapiens OMIM
Q99814 EPAS1 Endothelial pas domain protein 1 Homo sapiens OMIM
P49747 COMP Cartilage oligomeric matrix protein Homo sapiens OMIM
Q9UNA0 ADAMTS5 A disintegrin-like and metalloproteinase with thrombospondin type 1 Motif, 5 Homo sapiens OMIM
O15232 MATN3 Matrilin 3 Homo sapiens OMIM
Q14623 IHH Indian Hedgehog Homo sapiens OMIM
Q9NRR1 CYTL1 Cytokine-like protein 1 Homo sapiens OMIM
P49190 PTH2R Parathyroid hormone 2 receptor Homo sapiens OMIM
Q92731 ESR2 Estrogen receptor 2 Homo sapiens OMIM
P41159 LEP Leptin Homo sapiens OMIM
P0DP23 CALM1 Calmodulin 1 Homo sapiens OMIM
P41180 CASR Calcium-sensing receptor Homo sapiens OMIM
P98066 TNFAIP6 Tumor necrosis factor-apha-induced protein 6 Homo sapiens OMIM
Q92743 HTRA1 HTRA serine peptidase 1 Homo sapiens OMIM
P13942 COL11A2 Collagen, type XI, alpha-2 Homo sapiens OMIM
Q9UHF7 TRPS1 Trichorhinophalangeal syndrome, type I Homo sapiens OMIM
P11473 VDR Vitamin D receptor Homo sapiens OMIM
Q92633 LPAR1 Lysophosphatidic acid receptor 1 Homo sapiens OMIM
P30044 PRDX5 Peroxiredoxin 5 Homo sapiens OMIM
Q9HCJ1 ANKH ANK, mouse, Homolog OF Homo sapiens OMIM
Q9Y2L9 LRCH1 Leucine-rich repeats and calponin homology domain-containing 1 Homo sapiens OMIM
P98160 HSPG2 Heparan sulfate proteoglycan of basement membrane Homo sapiens OMIM
P56199 ITGA1 Integrin, alpha-1 Homo sapiens OMIM
P45452 MMP13 Matrix metalloproteinase 13 Homo sapiens OMIM
P02452 COL1A1 Collagen, type I, alpha-1 Homo sapiens OMIM
P03372 ESR1 Estrogen receptor 1 Homo sapiens OMIM
P13500 CCL2 Chemokine, CC Motif, ligand 2 Homo sapiens OMIM
Q16552 IL17A Interleukin 17A Homo sapiens OMIM
P78536 ADAM17 A disintegrin and metalloproteinase domain 17 Homo sapiens OMIM
P51884 LUM Lumican Homo sapiens OMIM
P48061 CXCL12 Chemokine, CXC Motif, ligand 12 Homo sapiens OMIM
P43235 CTSK Cathepsin K Homo sapiens OMIM
P11712 CYP2C9 Cytochrome P450, subfamily Iic, polypeptide 9 Homo sapiens OMIM
Q99969 RARRES2 Retinoic acid receptor responder 2 Homo sapiens OMIM
Q9NS15 LTBP3 Latent transforming growth factor-beta-binding protein 3 Homo sapiens OMIM
Q9HCN6 GP6 Glycoprotein VI, platelet Homo sapiens OMIM
P24001 IL32 Interleukin 32 Homo sapiens OMIM
Q92954 PRG4 Proteoglycan 4 Homo sapiens OMIM
O94907 DKK1 DICKKOPF, Xenopus, Homolog OF, 1 Homo sapiens OMIM
Q9H5V8 CDCP1 CUB domain-containing protein 1 Homo sapiens OMIM
Q9Y2U5 MAP3K2 Mitogen-activated protein kinase kinase kinase 2 Homo sapiens OMIM
Q8TCG1 CIP2A Cell proliferation-regulating inhibitor of protein phosphatase 2A Homo sapiens OMIM
P14784 IL2RB Interleukin 2 receptor, beta Homo sapiens OMIM
P17931 LGALS3 Lectin, galactoside-binding, soluble, 3 Homo sapiens OMIM
Q14050 COL9A3 Collagen, Type IX, alpha-3 Homo sapiens OMIM
P02751 FN1 Fibronectin 1 Homo sapiens OMIM
P30203 CD6 CD6 antigen Homo sapiens OMIM
Q96S44 TP53 Tumor protein P53 Homo sapiens OMIM
P31785 IL2RG Interleukin 2 receptor, gamma Homo sapiens OMIM
P55287 CDH11 Cadherin 11 Homo sapiens OMIM
Q8WVB3 HEXDC Hexosaminidase (glycosyl hydrolase family 20, catalytic domain)-containing protein Homo sapiens OMIM
O75711 SCRG1 Stimulator of chondrogenesis 1 Homo sapiens OMIM
P35354 PTGS2 Prostaglandin-endoperoxide synthase 2 Homo sapiens OMIM
Q12794 HYAL1 Hyaluronoglu-cosaminidase 1 Homo sapiens OMIM
Q8IUL8 CILP2 Cartilage intermediate layer protein 2 Homo sapiens OMIM
Q8WVQ1 CANT1 Calcium-activated nucleotidase 1 Homo sapiens OMIM
Q03692 COL10A1 Collagen, Type X, alpha-1 Homo sapiens OMIM
P10600 TGFB3 Transforming growth factor, beta-3 Homo sapiens OMIM
O15530 PDPK1 3-phosphoinositide-dependent protein kinase 1 Homo sapiens Drugbank
P52209 PGD 6-phosphogluconate dehydrogenase, decarboxylating Homo sapiens Drugbank
Q9Y215 COLQ Acetylcholinesterase Homo sapiens Drugbank
P78348 ASIC1 Acid-sensing ion channel 1 Homo sapiens Drugbank
O60218 AKR1B10 Aldo-keto reductase family 1 member B10 Homo sapiens Drugbank
P42330 AKR1C3 Aldo-keto reductase family 1 member C3 Homo sapiens Drugbank
P10275 AR Androgen receptor Homo sapiens Drugbank
Q07817 BCL2L1 Apoptosis regulator Bcl-2 Homo sapiens Drugbank
P09917 ALOX5 Arachidonate 5-lipoxygenase Homo sapiens Drugbank
Q2M3GO ABCB5 ATP-binding cassette sub-family B member 5 Homo sapiens Drugbank
Q96J66 ABCC11 ATP-binding cassette sub-family C member 11 Homo sapiens Drugbank
Q9UNQ0 ABCG2 ATP-binding cassette sub-family G member 2 Homo sapiens Drugbank
Q92887 ABCC2 Canalicular multispecific organic anion transporter 1 Homo sapiens Drugbank
O15438 ABCC3 Canalicular multispecific organic anion transporter 2 Homo sapiens Drugbank
P00918 CA2 Carbonic anhydrase 2 Homo sapiens Drugbank
P07451 CA3 Carbonic anhydrase 3 Homo sapiens Drugbank
P06276 BCHE Cholinesterase Homo sapiens Drugbank
P08185 SERPINA6 Corticosteroid-binding globulin Homo sapiens Drugbank
P25024 CXCR1 C-X-C chemokine receptor type 1 Homo sapiens Drugbank
P13569 CFTR Cystic fibrosis transmembrane conductance regulator Homo sapiens Drugbank
P04798 CYP1A1 Cytochrome P450 1A1 Homo sapiens Drugbank
P05177 CYP1A2 Cytochrome P450 1A2 Homo sapiens Drugbank
P11509 CYP2A6 Cytochrome P450 2A6 Homo sapiens Drugbank
P20813 CYP2B6 Cytochrome P450 2B6 Homo sapiens Drugbank
P33260 CYP2C18 Cytochrome P450 2C18 Homo sapiens Drugbank
P33261 CYP2C19 Cytochrome P450 2C19 Homo sapiens Drugbank
P10632 CYP2C8 Cytochrome P450 2C8 Homo sapiens Drugbank
P10635 CYP2D6 Cytochrome P450 2D6 Homo sapiens Drugbank
P05182 CYP2E1 Cytochrome P450 2E1 Homo sapiens Drugbank
P08684 CYP3A4 PCytochrome P450 3A4 Homo sapiens Drugbank
P20815 CYP3A5 Cytochrome P450 3A5 Homo sapiens Drugbank
P02693 FABP2 Fatty acid-binding protein, intestinal Homo sapiens Drugbank
P04150 NR3C1 Glucocorticoid receptor Homo sapiens Drugbank
P25021 HRH2 Histamine H2 receptor Homo sapiens Drugbank
Q04760 GLO1 Lactoylglutathione lyase Homo sapiens Drugbank
P23141 CES1 Liver carboxylesterase 1 Homo sapiens Drugbank
P27361 MAPK3 Mitogen-activated protein kinase 3 Homo sapiens Drugbank
P08183 ABCB1 Multidrug resistance protein 1 Homo sapiens Drugbank
P33527 ABCC1 Multidrug resistance-associated protein 1 Homo sapiens Drugbank
O15439 ABCC4 Multidrug resistance-associated protein 4 Homo sapiens Drugbank
O95255 ABCC6 Multidrug resistance-associated protein 6 Homo sapiens Drugbank
P05164 MPO Myeloperoxidase Homo sapiens Drugbank
Q07869 PPARA Peroxisome proliferator-activated receptor alpha Homo sapiens Drugbank
Q03181 PPARD Peroxisome proliferator-activated receptor delta Homo sapiens Drugbank
P37231 PPARG Peroxisome proliferator-activated receptor gamma Homo sapiens Drugbank
P14555 PLA2G2A Phospholipase A2, membrane associated Homo sapiens Drugbank
O43526 KCNQ2 Potassium voltage-gated channel subfamily KQT member 2 Homo sapiens Drugbank
O43525 KCNQ3 Potassium voltage-gated channel subfamily KQT member 3 Homo sapiens Drugbank
Q9Y5Y4 PTGDR2 Prostaglandin D2 receptor 2 Homo sapiens Drugbank
P34995 PTGER1 Prostaglandin E2 receptor EP1 subtype Homo sapiens Drugbank
Q8VDQ1 PTGR2 Prostaglandin reductase 2 Homo sapiens Drugbank
P19793 RXRA Retinoic acid receptor RXR-alpha Homo sapiens Drugbank
Q9Y5Y9 SCN10A Sodium channel protein type 10 subunit alpha Homo sapiens Drugbank
P35499 SCN4A Sodium channel protein type 4 subunit alpha Homo sapiens Drugbank
Q14973 SLC10A1 Sodium/bile acid cotransporter Homo sapiens Drugbank
P46059 SLC15A1 Solute carrier family 15 member 1 Homo sapiens Drugbank
Q9NSA0 SLC22A11 Solute carrier family 22 member 11 Homo sapiens Drugbank
O15244 SLC22A2 Solute carrier family 22 member 2 Homo sapiens Drugbank
Q8VC69 SLC22A6 Solute carrier family 22 member 6 Homo sapiens Drugbank
Q9Y694 SLC22A7 Solute carrier family 22 member 7 Homo sapiens Drugbank
Q8TCC7 SLC22A8 Solute carrier family 22 member 8 Homo sapiens Drugbank
P46721 SLCO1A2 Solute carrier organic anion transporter family member 1A2 Homo sapiens Drugbank
Q9Y6L6 SLCO1B1 Solute carrier organic anion transporter family member 1B1 Homo sapiens Drugbank
Q9NYB5 SLCO1C1 Solute carrier organic anion transporter family member 1C1 Homo sapiens Drugbank
O94956 SLCO2B1 Solute carrier organic anion transporter family member 2B1 Homo sapiens Drugbank
P07204 THBD Thrombomodulin Homo sapiens Drugbank
P00750 PLAT Tissue-type plasminogen activator Homo sapiens Drugbank
P02766 TTR Transthyretin Homo sapiens Drugbank
P48775 TDO2 Tryptophan 2,3-dioxygenase Homo sapiens Drugbank
P22309 UGT1A1 UDP-glucuronosyltransferase 1-1 Homo sapiens Drugbank
Q9HAW8 UGT1A10 UDP-glucuronosyltransferase 1-10 Homo sapiens Drugbank
P35503 UGT1A3 UDP-glucuronosyltransferase 1-3 Homo sapiens Drugbank
Q9HAW9 UGT1A8 UDP-glucuronosyltransferase 1-8 Homo sapiens Drugbank
O60656 UGT1A9 UDP-glucuronosyltransferase 1-9 Homo sapiens Drugbank
P06133 UGT2B4 UDP-glucuronosyltransferase 2B4 Homo sapiens Drugbank
P16662 UGT2B7 UDP-glucuronosyltransferase 2B7 Homo sapiens Drugbank
P02768 ALB Serum albumin Homo sapiens Drugbank, Genecards
P23219 PTGS1 Prostaglandin G/H synthase 1 Homo sapiens Drugbank, Genecards
P01584 IL1B Interleukin 1 Beta Homo sapiens Genecards
P08123 COL1A2 Collagen Type I Alpha 2 Chain Homo sapiens Genecards
P08254 MMP3 Matrix Metallopeptidase 3 Homo sapiens Genecards
P01375 TNF Tumor Necrosis Factor Homo sapiens Genecards
P08887 IL6 Interleukin 6 Homo sapiens Genecards
P03956 MMP1 Matrix Metallopeptidase 1 Homo sapiens Genecards
P01137 TGFB1 Transforming Growth Factor Beta 1 Homo sapiens Genecards
O75339 CILP Cartilage Intermediate Layer Protein Homo sapiens Genecards
Q9NUQ7 UFSP2 UFM1 Specific Peptidase 2 Homo sapiens Genecards
Q14055 COL9A2 Collagen Type IX Alpha 2 Chain Homo sapiens Genecards
O14788 TNFSF11 TNF Superfamily Member 11 Homo sapiens Genecards
P10145 CXCL8 C-X-C Motif Chemokine Ligand 8 Homo sapiens Genecards
O00300 TNFRSF11B TNF Receptor Superfamily Member 11b Homo sapiens Genecards
P01033 TIMP1 TIMP Metallopeptidase Inhibitor 1 Homo sapiens Genecards
O75173 ADAMTS4 ADAM Metallopeptidase With Thrombospondin Type 1 Motif 4 Homo sapiens Genecards
P50443 SLC26A2 Solute Carrier Family 26 Member 2 Homo sapiens Genecards
Q16832 DDR2 Discoidin Domain Receptor Tyrosine Kinase 2 Homo sapiens Genecards
Q9HBA0 TRPV4 Transient Receptor Potential Cation Channel Subfamily V Member 4 Homo sapiens Genecards
P02741 CRP C-Reactive Protein Homo sapiens Genecards
P22301 IL10 Interleukin 10 Homo sapiens Genecards
P36222 CHI3L1 Chitinase 3 Like 1 Homo sapiens Genecards
O15068 MCF2L MCF.2 Cell Line Derived Transforming Sequence Like Homo sapiens Genecards
P12107 COL11A1 Collagen Type XI Alpha 1 Chain Homo sapiens Genecards
Q14807 KIF22 Kinesin Family Member 22 Homo sapiens Genecards
P22003 BMP5 Bone Morphogenetic Protein 5 Homo sapiens Genecards
P48436 SOX9 SRY-Box 9 Homo sapiens Genecards
P18510 IL1RN Interleukin 1 Receptor Antagonist Homo sapiens Genecards
P02461 COL3A1 Collagen Type III Alpha 1 Chain Homo sapiens Genecards
P21941 MATN1 Matrilin 1, Cartilage Matrix Protein Homo sapiens Genecards
Q8WXS8 ADAMTS14 ADAM Metallopeptidase With Thrombospondin Type 1 Motif 14 Homo sapiens Genecards
P22607 FGFR3 Fibroblast Growth Factor Receptor 3 Homo sapiens Genecards
P51798 CLCN7 Chloride Voltage-Gated Channel 7 Homo sapiens Genecards
P35555 FBN1 Fibrillin 1 Homo sapiens Genecards
P10912 GHR Growth Hormone Receptor Homo sapiens Genecards
P02818 BGLAP Bone Gamma-Carboxyglutamate Protein Homo sapiens Genecards
P63092 GNAS GNAS Complex Locus Homo sapiens Genecards
Q16394 EXT1 Exostosin Glycosyltransferase 1 Homo sapiens Genecards
P01583 IL1A Interleukin 1 Alpha Homo sapiens Genecards
Q86Y38 XYLT1 Xylosyltransferase 1 Homo sapiens Genecards
P208908 COL5A1 Collagen Type V Alpha 1 Chain Homo sapiens Genecards
Q9GIY3 HLA-DRB1 Major Histocompatibility Complex, Class II, DR Beta 1 Homo sapiens Genecards
Q9Y2R2 PTPN22 Protein Tyrosine Phosphatase, Non-Receptor Type 22 Homo sapiens Genecards
O15266 SHOX Short Stature Homeobox Homo sapiens Genecards
Q93099 HGD Homogentisate 1,2-Dioxygenase Homo sapiens Genecards

Supplementary Table 3.

SGD compound targets.

Gene symbol Herb
ABCC2 GC
APOB GC
ATAD5 GC
BAZ2B GC
BDNF GC
BRCA1 GC
CALM1 GC
CBR1 GC
CBR3 GC
CBX1 GC
CCL2 GC
GFER GC
GSK3A GC
HMOX1 GC
HSPA5 GC
LDLR GC
MAPK8 GC
MAPK9 GC
MAZF GC
MBNL1 GC
MLLT3 GC
MMP9 GC
NOS2 GC
PDE5A GC
PLA2G7 GC
PPME1 GC
RAPGEF1 GC
RAPGEF3 GC
SHBG GC
SLC5A1 GC
SLC5A2 GC
SLCO2B1 GC
SMAD3 GC
SMPD1 GC
TIM23 GC
UGT1A1 GC
UGT1A10 GC
UGT2B15 GC
ABCB11 SY
ABCG5 SY
ABCG8 SY
ADAM10 SY
ADAM17 SY
ALB SY
ALPI SY
ALPL SY
APOBEC3F SY
APOBEC3G SY
APOE SY
ARSA SY
BIRC5 SY
BLM SY
CAT SY
CDK1 SY
CFTR SY
CHRM1 SY
CISD1 SY
CTDSP1 SY
CTSD SY
CYCS SY
CYP2A7 SY
CYP7A1 SY
DHCR24 SY
DNMT1 SY
DRD2 SY
EHMT2 SY
GAA SY
GLI1 SY
GLI3 SY
GLS SY
GPBAR1 SY
GPT SY
HSD11B2 SY
HSF1 SY
HSP90AA1 SY
HSP90AB1 SY
ICAM1 SY
IL8 SY
KCNA5 SY
KCNH2 SY
KCNMA1 SY
LMNB1 SY
NOS3 SY
NPSR1 SY
NQO1 SY
NR1H2 SY
NR1H3 SY
NR1I2 SY
NR1I3 SY
PIM2 SY
PLCG1 SY
PLCG2 SY
PMP22 SY
PRKAA2 SY
PRKCB SY
PRKCE SY
PTPRS SY
PYGM SY
RACGAP1 SY
RARA SY
RECQL SY
RORC SY
RPS6KA3 SY
SAE1 SY
SOD1 SY
SP1 SY
SREBF1 SY
SREBF2 SY
STK16 SY
STK33 SY
SYK SY
TLR4 SY
UBA2 SY
UBE2I SY
UGT1A7 SY
UGT1A9 SY
UGT3A1 SY
XIAP SY
ABCB1 GC, SY
ABCC1 GC, SY
ABCG2 GC, SY
ACHE GC, SY
AHR GC, SY
AKR1B1 GC, SY
AKR1B10 GC, SY
AKT1 GC, SY
ALDH1A1 GC, SY
ALOX15 GC, SY
ALOX15B GC, SY
ALOX5 GC, SY
AMY1A GC, SY
APEX1 GC, SY
APP GC, SY
AR GC, SY
ATXN2 GC, SY
BACE1 GC, SY
BCHE GC, SY
CA1 GC, SY
CA12 GC, SY
CA2 GC, SY
CA4 GC, SY
CA7 GC, SY
CASP3 GC, SY
CDK6 GC, SY
CLK1 GC, SY
CYP19A1 GC, SY
CYP1A1 GC, SY
CYP1A2 GC, SY
CYP1B1 GC, SY
CYP2C19 GC, SY
CYP2C9 GC, SY
CYP2D6 GC, SY
CYP3A4 GC, SY
DAPK1 GC, SY
DPP4 GC, SY
DYRK1A GC, SY
EGFR GC, SY
ESR1 GC, SY
ESR2 GC, SY
ESRRA GC, SY
F2 GC, SY
FEN1 GC, SY
FLT3 GC, SY
GBA GC, SY
GLO1 GC, SY
GLP1R GC, SY
GMNN GC, SY
GSK3B GC, SY
HDAC9 GC, SY
HIF1A GC, SY
HPGD GC, SY
HSD17B1 GC, SY
HSD17B10 GC, SY
HSD17B2 GC, SY
IDH1 GC, SY
KDM4A GC, SY
KDM4E GC, SY
LMNA GC, SY
MAPT GC, SY
MDM2 GC, SY
MDM4 GC, SY
MPG GC, SY
NEU2 GC, SY
NFE2L2 GC, SY
NFKB1 GC, SY
NFKB2 GC, SY
NOX4 GC, SY
NR1H4 GC, SY
NR3C1 GC, SY
OPRD1 GC, SY
OPRK1 GC, SY
OPRM1 GC, SY
PAFAH1B3 GC, SY
PIM1 GC, SY
PIP4K2A GC, SY
PNLIP GC, SY
POLB GC, SY
POLH GC, SY
POLI GC, SY
POLK GC, SY
PON1 GC, SY
PPARA GC, SY
PPARD GC, SY
PPARG GC, SY
PREP GC, SY
PTGS1 GC, SY
PTGS2 GC, SY
PTH1R GC, SY
PTPN1 GC, SY
RAPGEF4 GC, SY
RELA GC, SY
RGS4 GC, SY
RXRA GC, SY
SIAE GC, SY
SLCO1B1 GC, SY
SLCO1B3 GC, SY
SMN1 GC, SY
TDP1 GC, SY
TOP2A GC, SY
TP53 GC, SY
TYR GC, SY
UGT1A3 GC, SY
UGT1A4 GC, SY
UGT1A8 GC, SY
USP1 GC, SY
XDH GC, SY

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