Hindawi

Evidence-Based Complementary and Alternative Medicine

Volume 2021, Article ID 5570968, 15 pages
https://doi.org/10.1155/2021/5570968

Research Article
Integrated Molecular Docking with Network Pharmacology to
Reveal the Molecular Mechanism of Simiao Powder in the
Treatment of Acute Gouty Arthritis

Yihua Fan ,1,2 Wei Liu ,1,2 Yue Jin ,1,2 Xu Hou,3 Xuewu Zhang,4 Hudan Pan,5 Hang Lu,1,2
and Xiaojing Guo1,2
1
First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
2
National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
3
Department of Endocrinology and Metabolic Diseases, Shandong Provincial Hospital
Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
4
Department of Rheumatology, People Hospital of Beijing University, Bejing 100044, China
5
Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery,
State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology,
Macao 999078, China

Correspondence should be addressed to Wei Liu; [email protected]

Received 14 January 2021; Revised 12 March 2021; Accepted 16 April 2021; Published 28 April 2021

Academic Editor: Jun Jiang

Copyright © 2021 Yihua Fan et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background. The incidence of gout has been rapidly increasing in recent years with the changing of diet. At present, modern
medications used in the clinical treatment of gout showed several side effects, such as gastrointestinal damage and the increased
risk of cardiovascular disease. The traditional Chinese prescription Simiao Powder (SMP) has a long history in the treatment of
acute gouty arthritis (AGA) and has a good curative effect. However, the mechanism and target of its therapeutic effects are still
not completely understood. Methods. Potential active compounds (PACs) and targets of SMP were found in the TCMSP database,
and the disease target genes related to AGA were obtained by searching CTD, DisGeNET, DrugBank, GeneCards, TTD, OMIM,
and PharmGKB disease databases with “acute gouty arthritis” and “Arthritis, Gouty” as keywords, respectively. The network of
“Traditional Chinese medicine (TCM)-PACs-potential targets of acute gouty arthritis” was constructed with the Cytoscape 3.7.2
software, and the target genes of acute gouty arthritis were intersected with genes regulated by active compounds of SMP. The
resultant common gene targets were input into Cytoscape 3.7.2 software, and the BisoGenet plug-in was used to construct a PPI
network. The GO functional enrichment analysis and KEGG pathway enrichment analysis of the intersecting target proteins were
performed using R software and corresponding program packages. The molecular docking verification was carried out between
the potentially active compounds of SMP and the core target at the same time. Results. 40 active components and 203 targets were
identified, of which 95 targets were common targets for the drugs and diseases. GO function enrichment analysis revealed that
SMP regulated several biological processes, such as response to lipopolysaccharide and oxidative stress, RNA polymerase II
transcription regulator complex, protein kinase complex, and other cellular and molecular processes, including DNA-binding
transcription factor binding. Results of KEGG pathway analysis showed that SMP was associated with AGA-related pathways such
as interleukin-17 (IL-17), tumor necrosis factor (TNF), p53, and hypoxia-inducible factor 1 (HIF-1) signaling pathways. The
results of molecular docking showed that active compounds in SMP exhibited strong binding to five core protein receptors (TP53,
FN1, ESR1, CDK2, and HSPA5). Conclusions. Active components of SMP, such as quercetin, kaempferol, wogonin, baicalein,
beta-sitosterol, and rutaecarpine, showed therapeutic effects on AGA. These compounds were strongly associated with core target
proteins (such as TP53, FN1, ESR1, CDK2, and HSPA5). This study reveals that IL-17, TNF, p53, and HIF-1 signaling pathways
mediate the therapeutic effects of SMP on AGA. These findings expand our understanding of the mechanism of SMP in the
treatment of AGA.
2 Evidence-Based Complementary and Alternative Medicine

1. Introduction “multiway” and “multitarget” approach to drug analysis. It is

similar to the thoughts of TCM compound prescription, as
Gouty arthritis (GA) is characterized by acute onset of single well as the characteristics of the overall TCM compatibility
joint redness, swelling, heat, and pain at night or in the and comprehensive and multipathway treatment of diseases.
morning. The pain progressively worsens, and in severe The present study employed network pharmacology and
cases, patients often suffer from cutting pain, which often molecular docking techniques to establish the active com-
reaches a peak within 24 hours [1]. The number of gout ponents of SMP in AGA treatment and predicted the po-
patients has increased drastically due to dietary changes and tential target and drug action pathways of SMP. Collectively,
high intake of high-purine foods and beer [2]. According to we aimed to explore the potential mechanism of action of
the gout epidemic survey in Hong Kong, the prevalence of SMP and provide a reference for pharmacological research
gout increased from 1.56% in 2006 to −2.92% in 2016 [3]. In and clinical application of this prescription. The specific flow
the United States, the prevalence of gout was about 3.9% in chart is shown in Figure 1.
2016, with an estimated 9.2 million gout patients [4]. Acute
gouty arthritis (AGA) is the first symptom of gout. Severe 2. Methods
pain can reduce the quality of life of patients. Recurrent
acute arthritis can destroy joints and damage internal organs 2.1. Screening of Drug Components and SMP Targets.
[5]. Gout treatment guidelines issued in 2012 by the Rhizoma Atractylodis (Cang Zhu), Cortex Phellodendri
American College of Rheumatology (ACR) recommend (Huang Bo), Radix Vladimiriae (Niu Xi), and Semen Coicis
nonsteroidal anti-inflammatory drugs (NSAIDs) or oral (Yi Yi Ren), SMP components, were acquired from the
colchicine for acute attacks of gout [6]. It has been reported traditional Chinese medicine systems pharmacology data-
that NSAIDs are harmful to the gastrointestinal tract, liver, base and analysis platform (TCMSP, http://tcmspw.com/
and kidney, central nervous system, etc. [7]. Colchicine is an tcmsp.php), capturing all the potential active components of
anti-inflammatory drug commonly used in the treatment of drugs in SMP. We screened the active compounds in SMP
acute gout. However, when taken in large doses, it easily following the standards of oral bioavailability (OB) ≥30%
causes gastrointestinal tract discomfort, liver and kidney and drug-likeness (DL) ≥0.18. Then, a search was under-
damage, or heart disease. Meanwhile, it may lead to poi- taken for corresponding targets of active compounds on the
soning in elderly patients [8]. Therefore, safer and more TCMSP platform. The identified drug targets were input into
effective drugs for the treatment of AGA are urgently the UniProt database (https://www.uniprot.org/). To obtain
needed. the abbreviation of the human gene for each target, we set
Simiao Powder (SMP) is a well-known prescription used the protein type as “Homo sapiens.”
in ancient China for the treatment of joint pain [9]. This
prescription originated from Chengfang Biandu in the Qing
Dynasty (1904 A.D.). SMP is composed of Rhizoma Atrac- 2.2. Search and Screening of AGA-Related Genes. The search
tylodis (Cang Zhu), Cortex Phellodendri (Huang Bo), Radix for target genes related to AGA was achieved using the terms
Vladimiriae (Niu Xi), and Semen Coicis (Yi Yi Ren), and it “acute gouty arthritis” and “Arthritis, Gouty” in the Human
could clear heat, dry dampness, and promote blood circu- Gene Database (GeneCards, https://www.genecards.org/),
lation to invigorate the tendons. In the gouty arthritis model, Online Mendelian Inheritance in Man (OMIM, https://
Lin et al. revealed that SMP treatment could effectively relieve www.omim.org/), the Pharmacogenomics Knowledge Base
joint symptoms and improve laboratory indexes (e.g., serum database (PharmGKB, https://www.pharmgkb.org/), Drug-
uric acid content or inflammatory cytokines IL-1b, IL-9, IFN- Bank database (https://www.drugbank.ca/), DisGeNET da-
g, and so on). Moreover, the anti-inflammatory effect of SMP tabase (https://www.disgenet.org/), the Therapeutic Target
was stronger than febuxostat [10]. A systematic review and Database (TTD, http://db.idrblab.net/ttd/), and Compara-
meta-analysis demonstrated that SMP possesses anti-in- tive Toxicogenomics Database (CTD, http://ctdbase.org/).
flammatory, analgesic, and uric acid-lowering effects and The results of the above databases were integrated to obtain
hence can treat AGA. Jiawei reported that SMP is superior to the target genes of AGA after deleting the repeated genes.
other anti-inflammatory drugs or combined uric acid-low-
ering drugs. Compared to modern medications, SMP is as- 2.3. Potential SMP Targets in the Treatment of AGA. We
sociated with fewer adverse events [11]. However, the intersected the targets regulated by active compounds in
mechanism and the therapeutic target of SMP in the man- SMP with the disease target genes of AGA. After that,
agement of AGA are vague and are the main limiting factors common targets were obtained. The R 4.0.2 software and its
for its widespread clinical application [11]. Venn diagram package were employed to generate a Venn
The entire human body is a complex network, and the diagram of the SMP-AGA-related target.
occurrence and progression of a disease are the results of the
comprehensive action of multiple factors. Single-targeted
therapy cannot meet the needs of multitarget and multi- 2.4. Network Construction of Potential Active Compound-
pathway treatment of diseases. The network pharmacology Potential Target. The potential targets and active com-
concept put forward by Hopkins in 2007 [12] provides a pounds corresponding to the potential targets of SMP in
Evidence-Based Complementary and Alternative Medicine 3

Simiao powder obtained using R4.2.0 software and its “org.Hs.eg.db”

package. Then, the “clusterProfiler” and other program
packages were adopted for GO functional enrichment
analysis of the target. A histogram was constructed after
Acute gouty screening out the first 10 functional categories of biological
arthritis process (BP), cellular component (CC), and molecular
TCMSP CTD, function (MF). The target proteins were subjected to the
DisGeNET, KEGG enrichment analysis, whereby the first 30 KEGG
DrugBank, pathways were selected to construct the histogram. Infor-
GeneCards,
TTD, OMIM, mation of the first 20 KEGG pathways was introduced into
PharmGKB Cytoscape 3.7.2 to draw the KEGG pathway-gene network
Active compounds and map. After that, we selected a signal pathway closely related
Targets related to AGA
compound-related targets to GA for visual display.

2.7. SMP Potential Active Compounds and Protein Molecular

Docking. The 2D structure of the potential compound was
Network of drug-PAC-potential target of AGA retrieved from PubChem (https://pubchem.ncbi.nlm.nih.
gov/). For small molecules, their energy was minimized
using ChemBio3D 2014 software. The 2D structure was
converted into a 3D structure. We downloaded the 3D
structure of the core target protein from the Protein Data
Protein-protein interaction networks of the Simiao Powder
Bank (PDB) database (http://www.rcsb.org). Using the
Pymol software, the target protein receptor molecules
were processed, including dehydration and removal of
ligand small molecules. The target protein receptor
GO and KEGG enrichment analysis molecule was hydrogenated using Autodock Tools 4.2.6
network of KEGG signaling pathway-gene
software. The center coordinate and size of the box were
set based on the position of the active site of the protein
molecule and the area where it potentially acted on the
ligand small molecule. Molecular docking was achieved
Molecular docking simulation
using AutoDock Vina, whereby lower binding energy
Figure 1: Flow diagram of the study. depicted a better affinity between the receptor and the
ligand. The binding energy ≤0 kcal/mol indicated that the
compound could bind and interact with the target,
AGA treatment were introduced into Cytoscape 3.7.2
whereas the binding energy <−5 kcal/mol demonstrated a
software. Then, we constructed the network of “TCM-active
very strong binding force. The docking results with the
compound-potential targets” and conducted the visualiza-
best binding force between each core target protein and
tion display.
active compound were simultaneously presented in 2D
images and 3D structures.
2.5. Construction of the Protein-Protein Interaction (PPI)
Network and Screening of Core Targets. The intersection 3. Results
target was imported into Cytoscape 3.7.2 software. The PPI
network was constructed via its plug-in BisoGenet with the 3.1. Target Screening of SMP and AGA. In total, 403 com-
following data sources: DIP, BIOGRID, HPRD, BIND, pounds of SMP were obtained from the TCMSP database,
MINT, and INTACT. The plug-in CytoNCA was employed including 49 from Rhizoma Atractylodis (Cang Zhu), 140
for topology analysis. Then, the degree centrality (DC) from Cortex Phellodendri (Huang Bo), 176 from Radix
betweenness centrality (BC) of each node was calculated. A Vladimiriae (Niu Xi), and 38 from Semen Coicis (Yi Yi Ren).
larger DC and BC of the node at the protein location implied Besides, 52 active compounds were screened according to
that the protein was more important in the constructed PPI OB ≥ 30% and DL ≥ 0.18, including 4 from Rhizoma
network [13]. Because we screened out various important Atractylodis (Cang Zhu), 25 from Cortex Phellodendri
target proteins, other protein interaction parameters, such as (Huang Bo), 17 from Radix Vladimiriae (Niu Xi), and 6 from
closeness centrality (CC) and eigenvector centrality (EC), Semen Coicis (Yi Yi Ren). After eliminating repeated active
were further applied to screen core target proteins. compounds, 40 active compounds were obtained. From the
TCMSP platform, 916 targets of the 40 active compounds
were obtained, including 60 from Rhizoma Atractylodis
2.6. Gene Ontology (GO) Functional Enrichment and the Kyoto (Cang Zhu), 430 from Cortex Phellodendri (Huang Bo), 384
Encyclopedia of Genes and Genomes (KEGG) Pathway En- from Radix Vladimiriae (Niu Xi), and 42 from Semen Coicis
richment Analyses. The ID of the intersection target was (Yi Yi Ren). After eliminating repeated targets, 203 targets
4 Evidence-Based Complementary and Alternative Medicine

and their abbreviations were obtained. Information of active transcription regulator complex, protein kinase complex,
compounds and the number of action targets of TCM in and membrane raft); 145 items via MF enrichment analysis
SMP are outlined in Table 1. Through a search in GeneCards, (including DNA-binding transcription factor binding, heme
OMIM, PharmGKB, DrugBank, DisGeNET, TTD, and CTD binding, and RNA polymerase II-specific DNA-binding
databases, 1,204 target genes associated with AGA were transcription factor binding). To draw the GO function
obtained (Figure 2). histogram of SMP in AGA treatment, we selected the top 10
BP, CC, and MF results at P < 0.05 (Figure 6).
To further elucidate the pathways regulated by the
3.2. Potential Targets and Corresponding Active Compounds of
therapeutic target genes, we did a KEGG pathway analysis.
SMP in the Treatment of AGA. The drug-disease intersection
Results revealed that these target genes were distributed in
target (the potential target of SMP in AGA treatment) was
155 pathways. To construct a histogram, the pathways with
obtained by intersecting the 203 drug targets with 1204
the top 30 enriched genes were selected (Figure 7). GA-
disease targets using R software, with 95 potential targets
related pathways were mainly associated with IL-17, TNF,
(Figure 3). Notably, 33 active compounds corresponded to
p53, and HIF-1 signaling pathways. We also analyzed the
the 95 potential targets. They were the active compounds of
association of the top 20 pathways with their corresponding
SMP in AGA treatment.
target genes by constructing a KEGG pathway-gene network
diagram (Figure 8). There were 83 nodes (including 20
3.3. Construction of TCM-PACs-Potential Target of AGA pathways and 63 target genes) and 403 lines. Based on the
Network. We drew and analyzed the potential targets of number of regulatory pathways, the top five genes were
SMP in the treatment of AGA using Cytoscape 3.7.2 network RELA, TP53, MAPK1, IKBKB, and CHUK with 16, 15, 15,
drawing software. Then, a PAC-potential target network 15, and 15 regulatory pathways, respectively. A strong re-
diagram of SMP for AGA treatment was constructed lationship existed between GA and inflammation (the IL-17
(Figure 4). The network diagram comprised 133 nodes pathway is closely related to inflammation). Therefore, we
(including 95 target genes, 33 drug active components, 4 constructed a diagram to demonstrate the association of the
TCM, and 1 disease name) and 250 edges. We further regulatory target of SMP with the IL-17 pathway (Figure 9).
calculated the degree of the compound in the figure. No-
tably, a higher degree implied that the compound played a
more critical role in the network. The top six active com- 3.6. Molecular Docking. Using the AutoDock Vina software,
pounds included MOL000098-quercetin, MOL000422- PACs in the network map of “TCM-PAC-potential targets of
kaempferol, MOL000173-wogonin, MOL002714-baicalein, AGA” were docked with five core target proteins (TP53, FN1,
MOL000358beta-sitosterol, and MOL002662-rutaecarpine, ESR1, CDK2, and HSPA5) in PPI. A higher binding activity
with 79, 30, 21, 18, 12, and 7 as the corresponding target between the compound and the target protein receptor implied
numbers, respectively. lower binding energy. Results demonstrated that the docking of
33 active compounds with the 5 core target protein receptors
was less than 0 kcal/mol (a majority was less than −5 kcal/mol)
3.4. Construction of PPI Network, Topological Analysis, and (Table 2). The molecular docking results of the compounds with
Determination of Core Targets. After obtaining the potential the highest binding energy corresponding to the five targets are
target genes, they were imported into Cytoscape 3.7.2 displayed in 2D images and 3D structures (Figure 10).
software. We then drew the PPI network diagram using the
Bisogent plug-in and obtained 5,264 nodes and 133,011
connections (Figure 5(a)). For the first topology analysis, 4. Discussion
DC ≥ 74 and 982 nodes and 43,726 connections were ob-
The repeated attacks and protracted course of acute gouty
tained (Figure 5(b)). The second topology analysis was
arthritis can lead to joint swelling, deformity, and de-
conducted with BC ≥ 925.611 (average), CC ≥ 0.581 (aver-
struction of bone and joint cartilage. Tophi can be formed in
age), and EC ≥ 0.096 (average) to identify the crucial target
many parts of the body, and it could seriously invade joints,
genes; eventually, 54 nodes and 829 lines were obtained.
kidneys, and even aorta and heart valves in severe cases
Target proteins with the top five degree values were selected
[14–16]. For the treatment of gout, anti-inflammatory an-
as the core target proteins in the protein network
algesics are mainly used in the acute stage. After the pain of
(Figure 5(c)), where TP53 protein, FN1 protein, ESR1
patients is completely relieved, the use of uric acid-lowering
protein, CDK2 protein, and HSPA5 protein corresponded to
drugs to correct the serum uric acid level is adopted
946 edges, 781 edges, 1,762 edges, 687 edges, and 445 edges,
[7, 17, 18]. Studies have found that although febuxostat and
respectively.
allopurinol can effectively reduce blood uric acid levels, they
can also increase the risk of cardiovascular disease [19].
3.5. GO Functional Enrichment and KEGG Pathway En- Traditional Chinese medicine compounds could function in
richment Analyses. For GO analysis, BP, CC, and MF were anti-inflammatory analgesics and lowering uric acid at the
included, and 1,938 items were obtained via BP enrichment same time, which has certain advantages compared with
analysis (including response to lipopolysaccharide, oxidative anti-inflammatory analgesics alone [20–22]. Besides, its
stress, reactive oxygen species (ROS), etc.); 36 items via CC relatively fewer adverse reactions and lower price have
enrichment analysis (including RNA polymerase II attracted more and more scholars’ attention.
Evidence-Based Complementary and Alternative Medicine 5

Table 1: Active compounds and their number of targets of SMP.

No. Source ID Compound OB DL Number
1 Huangbo, Niuxi MOL000098 quercetin 46.43 0.28 138
2 Niuxi MOL000422 kaempferol 41.88 0.24 55
3 Cangzhu, Niuxi MOL000173 wogonin 30.68 0.23 41
4 Niuxi MOL002714 baicalein 33.52 0.21 33
5 Huangbo MOL000790 Isocorypalmine 35.77 0.59 31
6 Huangbo, Niuxi MOL000358 beta-sitosterol 36.91 0.75 28
7 Huangbo MOL001455 (S) -Canadine 53.83 0.77 28
8 Huangbo, Niuxi, Yiyiren MOL000449 Stigmasterol 43.83 0.76 27
9 Huangbo MOL002670 Cavidine 35.64 0.81 24
10 Huangbo MOL000787 Fumarine 59.26 0.83 22
11 Huangbo MOL002651 Dehydrotanshinone II A 43.76 0.4 18
12 Cangzhu MOL000188 3β-acetoxyatractylone 40.57 0.22 17
13 Huangbo, Niuxi MOL000785 palmatine 64.6 0.65 16
14 Huangbo MOL002662 rutaecarpine 40.3 0.6 14
15 Huangbo, Niuxi MOL001454 berberine 36.86 0.78 14
16 Huangbo MOL006422 thalifendine 44.41 0.73 12
17 Huangbo MOL002894 berberrubine 35.74 0.73 11
18 Huangbo MOL002644 Phellopterin 40.19 0.28 9
19 Niuxi MOL002897 piberberine 43.09 0.78 9
20 Huangbo, Niuxi MOL001458 coptisine 30.67 0.86 8
21 Huangbo MOL001131 phellamurin_qt 56.6 0.39 7
22 Niuxi MOL003847 Inophyllum E 38.81 0.85 6
23 Huangbo MOL002668 Worenine 45.83 0.87 6
24 Yiyiren MOL001323 Sitosterol alpha1 43.28 0.78 5
25 Huangbo MOL002666 Chelerythrine 34.18 0.78 5
26 Yiyiren MOL000953 CLR 37.87 0.68 3
27 Niuxi MOL004355 Spinasterol 42.98 0.76 3
28 Huangbo MOL002663 Skimmianin 40.14 0.2 3
29 Yiyiren MOL000359 sitosterol 36.91 0.75 3
30 Niuxi MOL001006 poriferasta-7 42.98 0.76 3
31 Huangbo MOL002641 Phellavin_qt 35.86 0.44 3
32 Yiyiren MOL001494 Mandenol 42 0.19 3
33 Huangbo MOL001771 poriferast-5-en-3beta-ol 36.91 0.75 2
34 Huangbo MOL000622 Magnograndiolide 63.71 0.19 2
35 Cangzhu MOL000184 NSC63551 39.25 0.76 1
36 Huangbo, Niuxi MOL002643 delta 7-stigmastenol 37.42 0.75 1
37 Huangbo MOL005438 campesterol 37.58 0.71 1
38 Cangzhu, Niuxi MOL000085 beta-daucosterol_qt 36.91 0.75 1
39 Yiyiren MOL008121 2-Monoolein 34.23 0.29 1
40 Niuxi MOL012461 28-norolean-17-en-3-ol 35.93 0.78 1

According to Figure 4, the key active components of degree value in Figure 4, was established as one of the
SMP in the treatment of GA were quercetin, kaempferol, crucial active compounds.
wogonin, baicalein, beta-sitosterol, and rutaecarpine. These PACs in SMP have a certain curative effect on
Quercetin is the active compound of Cortex Phellodendri inhibiting inflammation and lowering blood uric acid level
(Huang Bo) and Radix Vladimiriae (Niu Xi), kaempferol is [23]. Among them, quercetin, baicalein, wogonin, and
the active compound of Radix Vladimiriae (Niu Xi), rutaecarpine showed strong anti-inflammatory effects
wogonin is the active compound of Rhizoma Atractylodis [19–21]. Baicalein could inhibit the activity of NF-κB and
(Cang Zhu) and Radix Vladimiriae (Niu Xi), baicalein is some inflammatory factors, such as monocyte chemotactic
the active compound of Radix Vladimiriae (Niu Xi), protein-1 (MCP-1), interleukins, tumor necrosis factor,
beta-sitosterol is the active compound of Cortex Phello- and cellular adhesion molecules. In addition, it also clears
dendri (Huang Bo) and Radix Vladimiriae (Niu Xi), and the reactive oxygen species (ROS) to show anti-inflam-
rutaecarpine is the active compound of Cortex Phellodendri matory and antioxidant effects [24]. Moreover, wogonin, a
(Huang Bo). Among them, quercetin and wogonin are the flavonoid from medicinal plants, has shown various bio-
common active components of two traditional Chinese logical activities. It potentially inhibits the production of
medicines, which is similar to the compatibility and syn- inflammatory mediators by macrophages and lymphocytes
ergism of TCM compounds. Considering Semen Coicis (Yi [25]. Inhibition of NF-κB and mitogen-activated protein
Yi Ren) as an indispensable TCM in this prescription, the kinase (MAPK) pathways in rutaecarpine-derivative R3
active ingredient stigmasterol, characterized by a great inhibits the NLRP3 inflammasome activation, which
6 Evidence-Based Complementary and Alternative Medicine

DisGeNET
CTD
135
828 7 11
DrugBank

TTD 3
1 5 31
1
1

1 1
1 2
4

1 31 31

6 3
2 GeneCards

PharmGkb 64
OMIM
Figure 2: Venn diagram of disease targets.

Disease Drug

1109 95 108

Figure 3: Venn diagram of drug targets and disease targets.

MOL000173
MOL000358
MOL001454 MOL000098
MOL001458 MOL001455 AGA
MOL000449 MOL002666
MOL000785 MOL001131 NFKBIA FN1 IFNG VCAM1 GSTP1 CYCS BCL2 ADRB2 FOS

MOL002897 MOL002662 CYP1B1 SPP1 RASSF1 GSTM2 NR3C1 SELE MMP2 PON1 PPARA
MMP3 STAT1 PTGS2 CASP9 CASP3 RUNX2 CYP2B6 CCND1 HSF1
MOL003847 MOL000790
Huangbo Cangzhu PPARD CXCL2 PPARG RELA CYP3A4 MAPK8 BAX CCNB1 FOSL1

MOL001006 MOL002670 GSTM1 NOS3 FABP5 PARP1 COL1A1 HSPB1 EGF NR1I2 NR1I3
CYP1A2 INSR VEGFA RASA1 IL1A CASP8 BCL2L1 TP53 CDKN1A
MOL002714 MOL006422
NOS2 IRF1 E2F1 NFE2L2 IL1B PTGS1 HMOX1 MAPK14 EGFR

MOL000422 MOL002651 FOSL2 CXCL8 NCOA2 CHUK JUN IGFBP3 CA2 IKBKB GSK3B
Yiyiren Niuxi
AHR MMP9 PRKCA HK2 ESR1 ABCG2 CDK2 MPO COL3A1
MOL004355 MOL000787
ALOX5 THBD RB1 AKR1C3 MAPK1 SOD1 MAOB ACACA CCL2
MOL001323 MOL002668 CYP1A1 HSPA5 ICAM1 MYC SERPINE1

MOL001494 MOL002644
MOL000359 MOL002894
MOL008121 MOL002641
MOL000953 MOL001771
MOL000188

Figure 4: A network of the drug-PAC-potential target of AGA. The left circle represents the active ingredients. Different colors distinguish
drug sources of each ingredient; blue represents the active ingredient from Cortex Phellodendri (Huang Bo), yellow represents the active
ingredient from Rhizoma Atracylodis (Cang Zhu), orange represents the active ingredient from Semen Coicis (Yi Yi Ren), green represents
the active ingredient from Radix Vladimiriae (Niu Xi), and purple represents the common ingredient of various drugs. The square node on
the right denotes the target.
Evidence-Based Complementary and Alternative Medicine 7

SNX13

PKNOX2

ADIRF NPIPA1
BEND4BNC2 TMEM44
NPIPA2
LOC100996717

RGS22
FCAMR
RFX4
CHL1 TMEM216
NDUFA4
DLX3
NPAS3 PTP4A3
GCHFR PPP1R26 MPO
SLC4A4

POU4F2
MAOB
FKBP11
SERPINA7
ZFAT
KCNQ2 EN1
NUDT10
IFI27 TCTN3 PSMB4 EIF3A
TUBB
PSMD13 MORF4L1
KEAP1
DUSP26 TUBGCP3
DDC
RBAK ZNF467 SNRPB
AMFR PRDX2 EIF3I
PSMB3 HNRNPABLOC101929876 NOP58
GPR39 DOPEY2 ALKBH8 ACSBG1 USP31 ND4L PSMD3 NME2 RPL38
XYLT1 SCN8A
JAZF1STOML1 ANKRD6AK4 IQCG GSTK1PIK3R3 ARF6 U2AF1L5
KIAA0368 ALDOA
MS4A3
HOXD9
EBF3 LPIN1
SIX4
ZMYM6
FABP1
CR2
CYTH4 DUSP22 NLRP10
ITPKC
NME1-NME2
KIF11 SF3A3
CACYBP NCBP1
PSMA4 PSMC4 ESRRBTNFRSF1B
HNRNPH2
UTP14A RPL30
EBNA1BP2
RPS23
CNBP
HSP90AA1
GJB5 NEK10 AGBL2 LDHB SNRPD1 MYO18A RPS26RPS12 RPL35A
POTEJ
MAN1A2 RBBP9 SLC4A8 ATXN7L3B ALOX15B DNM2RBM4 ALYREF RC3H1 RPS15
RPL32
CD86
CACUL1 IFITM2
OPN1LW MTERF4
SNAPC5
ZIC3 ROBO4TNP1
CABLES2
CEACAM5
CNTN2 IL27RA
MUC12
NUP153 PSMB1 SART1
PLCG1 SNRPD2 NAP1L1
PDIA3
HNRNPUL1 SERBP1
TUBB3
RPLP1 CD4
RPS21
PSMD8
GAPDH
ENTPD6 HOXD8NKTR HLF
FANCE GUCY1A3 TRIM40 HAX1 STK11CSNK2A1 GRK5 RPS25
WNK3 SRMS PSMA7 CALR
AHRR NPRL3 CDKN3 IFI35 KLF2
DMTF1 ENTPD5TFAP2B
REG3A SCTR MTNR1B LGALS3 ERBB3
PSMD7
IARS DSP
ICAM1
MEPCE RBMX TTN
RPS13
RPL26 VCP
IRAK1BP1 SP2 DBP NPRL2 FAM50A HNRNPL CEP57 RIPK3 RPS10
TAGLN2 LGALS3BP
RPL31 RPS15A
YY2 NPIPB13 ITPKBSNRK SOX8 NFAT5 FN3KRP
EIF1AD CSNK1G2 ZNF227 PTPRCAP HOXB2
EYA1 PRPF8 PTBP1 DYNC1H1 RPL7
RPS18 AHSA1
EEF2KMT NFE2L3 SNAPC3 CREG1 FOSB
IFNGR2 KRT81 TRMT11 CYTH3 NBEAL2
NAA25 GUCY1B3 DENND5B FOXK2 TP63MYO1C PUF60 MTOR RPL22RPL21
DMKN CUX1 CENPS
MECR
TRIM59
TEP1 NR5A2 C3orf62 HMGN1 INSM1 PROX1
IRF9 ATP9A
CBLL1
DEDD2 TPPP
REV3L CER1CNKSR1
AMMECR1L
ZNF398
ANKRD2
NLRC5
MINPP1
DUSP2
ASRGL1 SCGB2A2
SUSD1
AES DCTN1
KIF5B
HNRNPH3
RELB
RAC1
SKI
CFTR TUBA1B RPN1
RPS4X CAPZA1 RPL7A
PCMT1
RPS11 SNU13
RPL13A
RPL36
CUL1
HHEX POLR3H KCNE3 HOXC8 CDC14A
PARP9CCNF
CITED1 ZNF518A
ATG16L2 PPFIA4
KRBA1 PRSS2 APOBEC3D TRRAP SF3B2
PTGES3
PDCD6 HNRNPC
NFKB2 RBM14 SRPK1 RPL13 RPS14 RPS9
RNASEL SELENOP IL2RA SNX27 JMY BATF ZMIZ2 PCYT1A MFAP4 PSMA5 CCT5 BTKRPL35
MTIF3 PGC POLG2 TWIST2KLF11 MSX1 BEX1 RWDD3 ARID5AGREB1 PPIB PSMC2
FBN3SNAPC1
PFKFB1 BACH2
NKX2-5
KAT6B
CELA2B
MNT EPC2
C18orf21 MAFB FAAP100NRF1
ACP5 SPIB DNAJC13
DPF3 NFATC3
S100A13 LMO3 TP53INP1
HOXA10
CP ELK4NKIRAS2
MKLN1
MAFA
ZNF212
TRIB1DUSP4 LURAP1L
TRAPPC13
IL18PRTN3 IFNG ADAMTS4
UBXN7 SMARCAD1 PDLIM7FBXW7
ENO1
C1QBP
MATR3
SRPK2
SF3B3 SYNCRIP EEF2
RPSA RPL23A EIF4G1RPS19
RPL8
NCSTN
CUL3
PKIACENPO
ZFPM1 ERCC5FBXO32 SMG5
PFKFB2TNFSF10 SRA1 GMEB1 CLIP3MSH3 PER2 TH CHD9TMEM54 PTPN7
STYK1 MMP26 ZNF652 TXN PSMD11CCT2 MAP3K14ATP5B
RPL6 HNRNPDLERG RPL12
CCDC158 DTD1CSN3 CACNG4
TSPYL4
FBXO45 GABRB3
MYOCD
POU1F1
KLF6 CUEDC2
HOXD13 SMYD3
BATF2
MYO9B
ARID3B
NR4A2 ITPK1 MSTO1
LOC100653061 HOXA5
RHOBTB3 SPTB
TBC1D2
PIK3R5 CTR9 ATR RANBP9 DYNLL1 CRY1 PSMA6 SF3A1
COPS6 RPL4
BDP1TFDP2
MTHFSD PARP3
POU2F2 WDR73 MRM3
GMFB HSPB6 NEUROD1 SYCE1
MAGEB18 JMJD7-PLA2G4B
CD53 KCNA3 BCLAF1 ITCH UBA1 ABCE1 UCHL5 FBL RPL3
NR0B1
LIN54 MED25
CENPX NELL1 CEBPG TNNI3 TRAPPC11
GAS2L1ARHGAP9 KLK2 SLC4A2FGF5 SENP3 DDX3X EEF1G PSMB5
CCNJ DLX5 FNDC11 TADA1 CSNK1G1 FOXR2
SPSB1 ZMIZ1
MRFAP1 CEBPD
ZNHIT3 RXRGACTL6B ISL1 IL24 AGER
AGTPBP1
THAP11 RAD23A NEDD8 FBXO25 RPL27
TMEM97
DUSP6
GTF2A2 KDM4D FBXO42
RFPL2
APITD1-CORTNFIXNUTM1
CCNT2
HOXC9
SUPT7L
GADD45B
MOK
TRIM65
CCDC50
CENPC
MED19
ICE2 DDIT4 NFIC
TCEAL1
LOC101060399
E2F2
ZNF668
MYBL2
JDP2
UPF3A
NMNAT1
EPSTI1
MLKL
TTC3
E4F1
USP12
NFATC4
CREB5
STK40
FBXO21
LRRC1RNF38
NOXA1 MICALL2
SLIT2
OSMR INPP5B ITPKA
HIVEP3
IP6K2 ROBO1 IL13RA2
SLC4A3
MTA1
CHEK2
PAK2
HIST1H1A TOP2A
USP9X YBX1 LIMA1 PKM CD81 SF3B1
RPL10
ADRB2
HRAS
HSD17B10
RPS8 NOP56
SPP1 ESR1
RNF39 CCL18 BUD13
YY1AP1THAP8 DUSP7
SMA4
ELOF1
HOXB6BATF3
MSX2
ELK3 ZBTB3
TXNRD2
MKL1
PDX1
KDM3A
CALCOCO1
AKR7A2 CDR2
DET1ATF7
TEAD1
METTL21C
E2F3
RNF40 KDM5A
XPO6
NR2F1
IRF8
FOXJ2
NTMT1
SETD1A
PPP2R3A
GSG2
RNF166 NR1I3
GLI3
BCL3
PRDM14
ETS2 OAZ1
PLAGL1 KLF10 ERF
SASH1
CDX2
BTG2
RAD54L2
IKZF4
HBP1
CSAD
TNNT2
PPIL2
TCL1A
PTK6
RASGRF1
MOAP1NSMCE4A
IL15RA
DEDD ZNHIT1
ADH5
ST14
ETV3
FGFR4
CDC14B
GNG11
DPYSL5
SELE
NPPA PTPRR C4B
EDA2R
XAF1
DUSP16
PLA2G4B DHX34
ATXN1
SMARCB1PRKCD
ZBTB16 HNRNPD SRRM2 PSMD2 KPNB1
HNRNPRSFPQ CUL4A
PAXIP1 ACTG1 ISG15ILF2
ATP5A1 TGM2
CCT6A CCT8 RPS16 PSMC6 RPL37ARPL27A NCK2 SNW1

BC ≥ 925.611
CREBZF
HMGN2 DUSP9 ZNF423
CCNE2 TAF5
SRCAP MAGOHB
NFE2L1
MZT2B ERCC1
MYB UQCC2
KLF5 NRBF2PPP2R5E ZNF148
NFE2 RNF34 ZBTB25 DUSP3 SMARCD1
GOLGA2 MAX HSPD1 ILF3 IRS4
DDX21 RPL5 RPS27 RPL10L
PLIN4 SENP5 CCNO PATZ1
FAR1 FAAP20FOXA1 CRTC3 LIFR
ATF6
HAND1
MED27KMT5C ING5 MAF POLR2D ANAPC10
NUB1 TRO
PRDM1
CDKN1C
METAP2GLMN MNDA
PAX2 GFI1 WSB1 ATPIF1 ITGAM TIMP1 ZNRF3 DEFA1 CRKL PPP2R1A
PCBP1 RPS3
RPS2 SNRPA1
ALKBH7 ACY1
ZNF420 ARL6IP4 RPA4
STAC3
TRIM6-TRIM34
MAFF
AFF1
KPNA5
GTF2H4
FBXO31 SAP130
MAGEA10
MECOM KDM2B LIN9
WDHD1 HINFP
GATA4
NHP2
SHOC2
PHF21AKLF4
CCNC
FAM175A MED7
JUNBMAFK
REPS2
FRAT2
MED15
CASC3
PPP1R13L NFYA
NCOA4
MED17
DNTTIP2
LRBA
IGF2R
CAMK1
XPA
ZBTB7A
MASP1
TXN2 TLR2
FIBPGMNN
NFYC
SLKSTX17
MAPKAPK2
CPNE7
EHHADH
ZSWIM8
DGKZ
REV1
LANCL2
PACSIN1
ANKHD1 IFNGR1
STK39
ATF1
THRSP
NTRK3
PLK3
PPARGC1B
IL6ST
IER5
USP24
DFNA5HMGXB3
NOTCH4
GRM5
NEFH
MYH3 MYL3 C6orf120
ABHD16A
KRT7APBB3 SLC1A1
SEMG2
MOB3B MST1
HIST2H3D
MAP1LC3B SEC23A GTF2I AP2M1
PTPN1
CDKN2A
PPP1CB KPNA2 RAD21 PTEN
EPS15
PTK2
PSMA2 MAP1LC3A
SNRPD3 DDX18
RPL17 SRPRB
RPS17
CDK2
SH3D21 GCKR
DLX2
DISP3
NFU1 ZNF366
CCDC106
TSTD2 TRIP11
ANKZF1
TAF5L
SULT1E1
FBXO4
YEATS2
TMEM161A
SREBF2
MXD1 LIN37
SERPINB4
KDM6A
MED9
MPP1
HOXB9
TAF11
HSPB8
AFF4GTF2F2
MED16
RAD9A
TWIST1CEBPE
CASP8AP2
TLN2
TRIM8
SRF
RADIL
THRB
ERCC2MED1
NR0B2
QKI
VRK1TXNIP HERC5
BICD2
RASSF9
PRC1
ATF4
BCAS3
KANK2
IRF1FANCD2
BHLHE41
VPS33B
MYCBP2
HNRNPA1L2
MRPS25 ARNT
BCL6
SENP1
FBXO18
HNF1A ETV1
CRNKL1
GPR37
EGR1
EHMT1
ENC1
RLIM
RAC3
NR1H3
TULP3
ZBTB33
CCND2
AXIN2 NAV1
TFDP1
JUND
COL4A5
OTUD5 SCAMP1 SH3BGRL3
STAP2
PPP3R2BMPR1A SOX4CAMK4
PPP3CC CCDC180
APOA2
CSF3R PPP1R14A
INCA1
ZNF133TSPAN2 MEP1B
RPL41
CST6
IL13
CFAP57
DOK6
SPOCK1 HIST2H3ASDCBP TNIK
PCM1
KRT18 RBX1 NONODDX17
AURKA
HDGFPSMD4 HNRNPA2B1
RBM39 RPL23 RPS6
RPL15 RPL34 HSP90AB1 HNRNPA1 EEF1A1
FAM133B ELAVL2 CCNJL
MTMR1 CHD5 FOSL1
E2F6TRIP4
TRMT1L
TRAFD1
FOXN1
BLID BRF1PADI4 ELP3
DNMT3L
NR5A1 MITF ID3 FOSL2
BACH1
BHLHE40 VDR KIDINS220
NCF1C
SERTAD1
RANBP3C7orf25
RFFL
MTF2 PDK3AREG
TICAM1 MAP3K2ITGB6 COL3A1 COMMD6 IL6R NLRP4 PTGIS HIST1H1C HGSPDCD6IP ERBB2 CADPSMA3 NCL
HNRNPA1 TSG101PABPC1
RPS3A RPL18 RPL18A
ZCCHC11 RNF25
CETN1
UBE2Q1 PAGR1 RORA
ETV4
CCNB1IP1 TPP2
TEX11
EP400 POLR2I
ARHGEF1
NKX2-1 MX1
DUSP1
RBBP5 USP10
NMI
RNF20 CRIP2
PPARA
GATA1
BOLA2
MED14
NCOA3
E2F4 MED24 DACH1
MGEA5
WASL
LEF1 PHF1APBA3 FAM175B
SERPINA4
GJA1 MLH3 SH2B1
CAV2
KCNIP3CDH5
GABRR1LINGO1
CHEK1 SUPT16H PSMC5 TUBA4A SMURF2 TUBB
RAF1
CUL5 TARDBP ACTA1 RPL11
RPLP0
AURKAIP1 KRT72
ZBTB37
MAGEA2B
ELF1 MAP9
TAF4B
PRTFDC1 ZBTB2
BTAF1
THAP12
PNRC2
ELL3
CDYL
FOXR1
FLYWCH2 CIZ1
PPP3CBTONSL
UBASH3A
DBF4
ARID4A
CXXC1
CDCA7L
INO80 RTF1
EPC1 DMAP1
GLYR1
MED21
SATB2
SIN3B
CEBPB
HCFC1
HIST2H2AA3
HNF4A
TCF12 AKT3
DDIT3
L3MBTL1
RECQL
DTX3L
CEBPA
PSPC1
DNAJC9
ADNP
AGO1
CDK8
TUBB1
NRIP1
FOXP3
TCEAL4
FOXO3
HIST2H3C
AKAP8L
MCM10 TBP
NOL3
TOPORS
RBFOX2
KMT2A
SMARCD3
TSPYL2
TAF12
NEFM
NKD2
AKAP8
HIF1AN
SIRT2
RXRB
S100B
NAF1
ATF3
TTI2 CC2D1A
MUL1
EIF4EBP1
SPI1
GATA2 AKAP13
NCOA6PPARGC1AMYL6B
ESRRA
CCNB2
WT1
CDC25C KLK9
HEMGN
ERAL1
MAPKAPK3
ARG1
OTUD7B
PDGFA
RRAS2
GRM7
MEF2C
DEC1
CLEC3B
USP28
SHARPIN
TMEM62
LACRT
JMJD1C
NEB
SDC4
PPM1D
METTL3
PATJ ARNTL
C3IL16SERPINA1
ZBTB24
EGLN3 TNFRSF10A STAT4
KLF8
CD82
GALNT12
CITED2
PDGFB A1BG GRIA3
CLDN1 SERPINA5
HFE
FGF7MEP1A
PTPRH
CHAT LRG1
ITIH1 DEFA1B COL9A3 STAT5A CLU TAB2 JUP
ANXA2 SMN1 RUVBL1 HNRNPU PRPF19 RPS20 RPL19
PSMD6
RPL10A
RPS28 HSPA8
HELZ2 SLX4IP DNAJC2 SNRPN
MSL2CETN2
LRWD1
NR2E3 PARP10 VAT1
LSM12
JMJD6 YY1
SERPINB5
APLP2 NCOA1
POU2F1
SNAI1 FANCC
CPSF1
BAG4 BAP1
CENPB PLD1
HDAC7 CA2 ERCC3 FRK
ARHGDIB
C6COG7 C9orf3PROC PZP CCR2 MMP8 FOXQ1 NR4A1 PTPN11 UBL4A GRB2

CC ≥ 0.581
PADI1 FOXO6 KMT5BANAPC11 PRCC LZTR1
KDM4BBRD3
COPS8 SRP9 NKRF
BRPF1MARK2
DES
HMGA1 COPRS STAT6ANAPC2
EIF4E2
VTA1
CSTA EPAS1
PIAS1 PRNP IRF2 SH2D2A FERUBXN11 VWFELANE APBA2 MAP3K21 MMP10 BCL6 RAN
CRABP1
SLC30A9 ROR1
DNAJC4 PNISR AZGP1
USF2 TAF9B
PTP4A1
ZBTB48
ZFP91-CNTF
KMT2D TAF6
RBM5
ARPC5
VAMP8
FOXC1
NSD1PRRC2C
MED10
CIITA
ZNF219
TOPBP1
TAF4
PRPF4B
LGALS7B
SPIN1
PCGF2
YTHDF2
POLR2H
RPP30
MLLT1
MAGEA11
POLD1
CHD7FAM193B
GTF2F1
ORC2
NSD2
SATB1
MSL1
SMARCA1 DHFR
RING1
KAT2A
EID1
ANAPC7
GYS1
AHR
FBXW8
TCEA1P2
CTCF
THRA
NFYB
SMC3
ZFP36
CREB1
ATRCCNT1
CCND3
CEP350
DDB2
PGR
PSMF1
ANP32E
GPS2
EHMT2 WDR5
SMAD7
HIST1H2BA
KMT2B
CBX2
FOXK2
FTH1
RYBPGTF3C3
DCUN1D5
POLR2G
HIST2H2AC
ID1
MORF4L2
MEF2A
DEUP1
MYL12A
CEP70
KAT7
SPOP ERC1 FOXM1
ZNF131
RUNX1
RXRA
HEY2
BANP
APPBP2
RARA
SETD7
DHX36
CHFR RASSF1
CDK3
MRPL28
NSD3
POLA2
PPFIA1
NR1H2
SHMT1
CDC25AHRNR
DRG1
GPS1
PIAS4
NEXN
IRF7
FIP1L1
CCNG1
FZR1
PPIL1
CHD8
KMT5A
WDR83
PRKD1
MTA3
SAFB2
MAP3K5
NFATC2IP
HMMR
NUP35
CCND1
CDC34
SMAD6
PRKAA2
CTBP2
NEK9
TRMT2A
ANKRD17 TFAP2A
ELK1
RPS6KA2
MYOC
ARNT2
ELP2
CREM
CARHSP1
CISH
SPTLC1
DHFRP1 CTSG
PRKAR2A
RNH1
RRM2B
STAT2LIPH
GRB10
ZNF510
ARID3A
RGS7
SDC2
MXI1 DZIP1
COMT
BAAT
CTSV
PSMC3IP IL2RG
CNKSR2
GLCE
CAPN7
PTPRE
ITGA3
RGS11 PPP2R5B IL1B
IFNAR2
GABRR2
PTGS1
PSENEN
TMPRSS6
THBD
CNTRLMAPK9
RBPJ
ANP32B
SMARCA2YY1 SMARCC1 PLK1
SPTAN1
CFL1
IRAK1
UQCRC2
SHC1 ARRB1
RACK1
DDX5
EED
ARRB2
FBXO6
CUL2CAND1 WWOX
CCT3 RPL14
DHX15PRDX1
RPS5 INSR
PRPF4
RPLP2 LYAR NTRK1
PARG ZNF281 PDLIM1 CEBPZ
TUBA4B
VAC14HNRNPAB CALD1 SREBF1
UBTF KAT2B PCBP2 DACT1RNF126
ETF1 WAC IFNAR1
SOCS2
C11orf84 CPNE6 ANKRD13D
ZBTB9 IL12RB1 DOK5 DHX9
NTN4
CT55
NT5DC2 EDRF1 PLA2G12A
SPDYA
PCDHA4
SUPT3H
NGLY1
PDAP1
METTL22
WIPI1
CCNK
MBD2
HELLS
HSF4
POLR2K
U2SURP
HMGB2
RFX5
CHAF1B
WDR18
HIST2H2AB
ING1
LSM3
POLR2F
FARSBMAFG
MLLT3
SLC25A4
RBM17
ATAD2
TOX4
STK38 LMO7
RNF146
KANSL1
PAF1ING4HERC4
EDF1
PIAS2
BRD7
TFAP4
ATRX
MAX
FOXO1RPS6KA5
CCDC6
MEN1 POLR2C
PNKP
FHL3
EIF5B
MAP1S
IVNS1ABP
SNIP1 RBM4
NCOA2
OGT
POLR2J
CTBP1
CHD4
DPF2
POLR2A
POLA1
ANP32A
RUNX2
E2F1
ERCC6
NR2C2
OLA1
BLM
SMARCA2CNOT9
KAT8
HIVEP1 JUN
AMOTL2 CCNE1
SPEN
TRIM24
TFIP11
SMARCD2
CDC45
CREBBPEIF2A
HIST1H2AA
MRGBP
PPID
ZBTB16
MTA2
CTR9
PPARG
WDR26
KEAP1
CDC73
PIAS3
SKP2 TRIM54
FBXW7
PKN1
MINK1
USP4
TNFAIP3AKT2CHAF1A
TRIB3
PRMT2
GSK3A
PCBD1
TCERG1
LOC100996724 BRCC3
POLL
CDKN2C
LDOC1
ITGB5
ARHGEF5
DST
ZBTB8A
FHL2
EPN1
PTPRS
ARIH2
MAPK12
FADD
TSC2
PPP2R5A
KDM2A
DDX6
RAP1GDS1
ARPC3
KRAS
BAIAP2
ARAP1RCHY1
KRTAP10-7
ASB15
DDX58
LOC400927-CSNK1E ETS1
MAP2K6TIAM1
RNF14
NUMB
ITK
MAP2K3
ADAM15
PTPN12
SNTB2
TLR4
SUV39H2
PPP4R3A
CRADD
TLDC1GRIN2A
HBEGF
RCAN1
ANK1
LAMA1
DNAJB12
CCL2
C4A
NKIRAS1KRT86
C1QB
SEMG1
IL1A
KLK3EDNRB
NEK11 MMP1
TNFRSF11B CCR1
BCAN
FSTL3
CCR3
COMPSPOCK3 MED20EHMT2ANP32A
PPM1GRBBP7
LYN
SMAD4 PPP2CA
MCM5
SMN2 CDC5L IKBKE VCAM1 COPS5CUL1
EEF1A1 HNRNPM
SKP1RPL24
HNRNPH1
HIST1H2BE
TUBB2A
RPS24 RPL9 HSPD1
XDH NABP1 RRN3
BPHL SOX10
ZNF496 HAND2
FCHSD2
MYCN
FAM98A TAF10MRPL53
LOC107984053 MED6
LMNB2
UBE2O
LMO2
COPS7A
TDG
TRRAP
GLI1 ZNF24 NRDC
MYOD1
PELP1
CBX4
TOLLIPSETDB1
AKAP5
KLC2
POM121
HIST2H3A
PPP2R5D
LOX RNF114
FKBP3
PPARD
ARIH1
NCOR2
MARK3 ARPC2HIPK3
CDK11B
IKZF3PPM1A
STK24
STAT5A
UBE2E2
MYEF2
RGS3
RB1CC1
STRAP MRPS34 OPA1
PTPA NFKBIECARD11
KSR1FES ALPP DOK1 SOS1 BNIP3L UCK2
FGG HOXC10 TFPI
PCOLCE
ACANCMA1
ITGAD NME5
ATRNL1 CASP7 MCM4 TP53BP1 HTT
LOC400927-CSNK1E EWSR1 ITGA4 HSPB1
PAN2
RPS27A CUL4B NOS2 LDHA
RPS7 HNRNPA0
TAF1C MYLK2
RBM28 RPRD1A
CARD8 CCAR1
TFDP3 SLC9A1MEF2D
SMARCAD1
RBL2 SUPT5H
CENPERBBP7 RBM3SSX2IP
MORF4L1
TLE1
PPP2R2A
RNF41
DCAF1 HDAC4
CDC27
RB1 NFATC1 MED12
FOS
NOTCH1
BIRC2 ELOC
RRM2
CASP9 DVL1
TRIM39
IRS2
FEN1 MAP2K2 MAP2K4
SPAG9 PTPN6
GZMB
BAD FGRRASL10B
RGS20 PAK6
SRGN
ROBO2 SH2B2
HLA-DRB5 COL4A6 VHL TRAF6
MYH9 STAU1 TUFMGAN HNRNPU

DC ≥ 74
ZNF142 CDK7
ANAPC4 SYMPK
USP39
TAF7
WDR82 MAP4 NUP62
ANP32B SMARCA4
CDK9
HIST1H4J
SRSF6
HIST1H4C
CENPA RCOR3
UNG
DNMT3A
PIM1UCHL1
HNRNPH3 RIPK2
MNAT1 PRKAR1A
HIST1H1B
AXIN1
BRAP
NEK2 HES1
SNAP29
PFDN2
TPX2
CD19 ALDH3B1
ASXL1
DPYSL2 VRK2 HCLS1
ATP2B2
RABGEF1
FBP2
PRKCQ NCAPG2 KSR2ADCY5 RNASE1 CBX4 HIST1H3F SMARCE1 U2AF2
SMTN YBX2 GIPC2 SBF2
NAT9
BTBD10 NEIL3LYL1 ING3
TOE1
ZSCAN1
CAMSAP3 MBD3
HIST1H2BL
TRAF3IP2
RFC1 TADA3
ALYREF
GTF2BPPP1R12A
KAT6A
C2CD5
H3F3A RBPJ CPSF6
SMARCC1
PDE4D
FRS3
CHMP4B
SART1
FOXA3 KDM5B UBE2E1
MAD1L1
HIST1H4B STXBP1
SIN3A CDK6
EP300
HIST1H1C
TP53BP1
KRT17
SIRT1
ZNF512B
MAPK8IP2
CARM1
AR
CBX5
SMAD4
CEP55
CCT5
CDKN1B
CPSF7
COPS4 MAPK14 GABARAPL1
ZBTB17 CASK
APPL1
STAT3 SOCS3
PALLD
MAPK11
TNIP1
PKMYT1
KCTD13 AK2
SIAH2MYO5A
ARFGAP3
LIMK1
PIK3CA
PECAM1
EXOC7
DNAJB4 TMEM185A
PPP3R1 PRKCH
MDK MCAM
PLAT
COL4A2 NPDC1ARRDC3
CCL5
FRAT1 SPARC ADRB3 CPB2 CBX5 PIK3R1
HIST1H3D MCM2VIM EIF6
LINC00312 OGG1
UTP3TPP1PSG1 PAX5 RNGTTARID1A GEMIN2
PHLDB2
PPP2R5CPRMT8
HIST2H3D
LLGL2 MFAP1
WIZ MCM4
SRSF5
HIST1H2BE
CSTF3 TP63 TERT
USP1
LRRFIP2
PRRC2A RRM1 SRPK1
HDAC3
IST1
WNK1CDC20
GTF2IDYNLT1
SMAD9
RFWD2
AGO2 NR1H4
ATN1
MBP PARK7
EIF4A2
LMO4LAMTOR5
PDGFRA PTGS2
FBP1 BRAF
YES1SOCS6
CDK5RAP3
PPP1R13B IGFBP3MAPK8IP1 ATP2B4 SH2D1A ELMO1 ITGAL
ADAMTS1 HAPLN1 MMP17ACKR1 RPS6KA5 CUL3 NPM1 PSMD12
RAB41 KDM4C
PHLPP1
RPF2
ANXA6 WDR33
TAF2PHF20 PPP1R8 FMNL1USF1
XPCLIG3
RBM15
TRIM25
BCOR
RBM7
HIST3H3
BAG1
YEATS4 PAWRRALY
SHMT2
PDHB
MACF1
SPICE1
HIST1H2BI
SNRPC
HIST1H2BC
ATP6V1C1
RCC1
ACTL6A
NCOR1
BRMS1
PARP1EEF2
KRT5
ATM SP1
HIST1H4K
SAFB
CEP63
SMN2
CCDC85B
BUB1B
SLC25A1
DDB1
SMAD1
C11orf54
CTNNA1
UBR5
RPS6KA1
SMAD3
IRAK1
MED13 ESR2
DVL2
CRY1
NR4A1
CDC25B
ATXN7
PSMC5 TAX1BP1
GRIP1 AP3M1
PPP4C
RASA1 KRT10
TFAP2C
SORBS3
CHEK2
TYK2
BCR
CRTC2
ELF3BUB1
WWP1
SOS2 PTPRJ
JAK2 HIPK2
TGFB1
IL2RB
PLG
CORO7 LNX2
EPOR
COL1A2
TNPO2
EFNB1
GNG12MAPKAPK5
ILKAP
LAT
TNFRSF25
PTPRO
CHST10
AAK1PRRG4
COMMD10
MAGI3
NID1 COL7A1
CXCL2 ACKR2
DNMT1
HIST1H2BG
SMC1A
IKBKB SMAD2FLNA
GRB2 RPA1
CUL7 FN1
ATP1A1 DDX1 U2AF1 CEP76
FN1 HIST1H3F

EC ≥ 0.096
TAF13 SGSM2 TCOF1
NCAPG
RPRD1B
GNL2 TUBGCP4
LUC7L2HIST1H4A
DSG2 PCNA
EEF1B2
HIST1H4H FOXB1
KAT5
DHX15HDAC1
RBBP8FHOD1 SUMO1 MAPK8
MAP1B
H1F0
ITGB3BP SNCATMX2-CTNND1
ELOB
GABARAP
CHEK1 MALT1 F2R MMP9 GNA14 THBS2 STAT1 CTNNA1OTUB1 HSPA8 G3BP1
CCT4
CABYR
MUT TRIM6
KNDC1
FBXO8
PARP4
CENPK DCTN3
SLC25A20
ZNF503 DPF1 STAB2UHRF1BP1L
PIWIL4
SCML2
LDB1
CDC7
KIF26B
MAGEA2
ESPL1CPSF3
DDX52
L3MBTL2
CSTF1
ZNF302
CHD1
MRPL43
KMT2E
TARBP2
RNF4
GTF3C2
TAF1A ATXN2
S100A7
G3BP2
POLR2E
GTF2H1
DTL
CBX1
KCND3
CIAPIN1
PFKL KPNA6
RSL1D1
KMT2C
DYRK1A
SCO2
FOXQ1
H3F3AP4
TBC1D4
HIST2H2AA4
ANGPTL4 TOB1
MDN1
LBR
USP37
LUZP1
SUMO3
HIST1H1A
SRSF9
LRIF1
HIST4H4
CDT1
RBBP4
SMC1A
NUDT21
FANCA
BIRC6
TADA2A
HIST1H4D
HIST1H4L
CNOT7
UIMC1
HIST2H2BE
HIST1H2BD
POLR2L
SMARCE1
SKP1
HIST1H3I
HIST1H3B
HIST1H3D
YBX3 CNOT1
HIST2H4B
HIST1H2BG
PSME3
HIST1H4I
SERBP1
COPS2
GADD45A
HDAC9
FLAD1
HAUS1
NFATC2
TRIM27
CIRBPSUMO2
HIST1H3C
SGTB
USP15
HIST1H3J
FOXS1 SIRT6
EIF4B
AURKB
TP53
TRIM28
EEF2K
FLNB
MED23
NR3C1
PIK3C3
DAXX
HMGB1
TJP1
STK4
HDAC2
XRCC1
KIAA1549
CDK4
TSSC1
HIST2H4A
HNRNPK
HIST1H3H UBE2I
H2AFX
PHC2
BARD1
RELA
CDK1
CCNA2NPEPPS
YAP1
PCKPNA3
CAPZA1
CLINT1
UBE2D2
RUVBL1
SORBS1
ATXN1
BTRC
PRKDC
APCUSP2
TMOD1
DSP
RBX1
NIN GLUL
SLC2A1
BRD4
RFC4
S100A8
TERF2IP
PPP1CCGSK3B
MAPK9
EIF3D AP1B1
IRS4
RNF43
OTUD4
HIF1A
TRAF2
MOB4 KHDRBS1
SF3B2
WWOX
UBE2S
STAT1
GRB7
NEDD4
SET
RANBP9
MAP3K7
WAS
MAP1LC3B
PRKCD
CTTN
CDH1
SMURF2
FHL1MLH1
RAP1B
TFCP2
NAA10
SUPT6H
VPS28
SMAD5
CASP8
ERRFI1
DYRK1B
GSTP1
PFKPPLAUR
VAV1
CAST
FBXO11
HDAC8
ADRM1
TNNT1
LCK
NCKAP1
OXSR1
MAP2K1
CASP6
ACTN2
PRKCZ
PGD
FBXL12
CBFB
HCK
CXCR4
ABL2
MAP3K11
GAB2
DEAF1
ECDTIMP2
RASSF5
ADAP1
SMPD1
TGFBRAP1
PLD2 GABPB1
FABP3
IDSTHBS1
EFEMP1
MAP3K12
RHOC
BMP2K
LTBP1
TNS3
AP3S1
RALGDS
ICA1
C8orf44-SGK3
PODXL
DDR2 HRG
NAIP F8
IL1RN
CXCL12
TNXB CCL8
JAK2
CDC27 MTA2 HMGA1 SET
SPTBN1
KAT5
SOX2
PIN1
MCM7 HIST1H3B
HIST1H3A
HIST1H3E IKBKG
YWHAZ NTRK1
EGFR CENPJOBSL1RNF2 HUWE1
SMURF1 RPS6KB2
SFN
NUMA1 SLC25A5
ACTN4MYBBP1A ZBTB1 CAND1
BTBD2
METTL13 MKNK2
MIF4GD
SUPT20H RAD50
GIGYF2
LAMP2 RBM45
KPNA4SRRM1
SF3A3RPS7
HIST1H2BF DR1
SMC2
ATP5B
MCM6
XRCC5CCNB1RAD51
DNAJA3
CSNK2A1 AURKA
WDR77WDR48 MAPK1
DAPK1
CDKN2A
RET
UCHL5
DNAJC7
SH3KBP1 UBASH3B
JAK1 CREB3L3
CD2AP
LATS1
USP42 ITCH ZFYVE9
CAMK2D SOX9
TNFRSF10B MAPK15 NCOA7 ZFYVE28 XIAP TUBG1 SRSF5 LUZP4
ZNF182 ACTL8SEPT8 EXOSC7
ANKMY2
HIST1H2BB
LGALS7
ING2 HIST1H2AB
HIST1H2BKMOV10
HIRIP3
RRP12
H2AFYDKC1
MARCKS
RAPGEF2
C14orf166
HIST1H4EKIF1A
CD81
EEF1AKMT3 PSMA7
H3F3B GART
SAMHD1 TAF1
HNRNPC
TBL1X
HIST1H3G
RAD21
JUP
FBXW11
MCM3 ST13 PSMD5
ORC4
PGAM5
XRCC6
HIST1H3F
HTT
VPS26A
PML
APLP1
HERC2
PTRF
CCT8AES
ATXN3
MTA1
ACLY
CHUK
MDC1
ACACA
NFKB1 RAB11B
TGM2
MAPRE1
CDC42
TMSB4X
ACTR2
ANXA2
YWHAB
FOXK1
PSMA4
TMEM63B IMPDH2
PAK1
STAT5B
DNM1L
MAPK3OPTN
MEOX2NR2C1
MAP2K7
CREB3
RPS6KA4
PFN1
CSNK1E
CLTCL1
PPP3CA
SEC61B
SEC24C
CTNND1
MAVS FGFR3
TNK2
PRKCSH
TMED9
RAB14 AGR2
ITGB3
NCF1
CAMK2A
CEACAM1
CCP110
EXOC8
LPL TDRD7SLFN11
REPS1 CD93LRP1B SSTR3
KIAA1191
ANKRD11 BGN COMMD7
HBG1CXCL5
IL1R1 SLA2 SELL
VCAN OFD1 IQCB1 KHDRBS1
STAT3 HIST1H3G PRPF40A
PRKCAESR1
C12orf65
SIRT5RAI1
FOXD4
TMED1 RUSC2
FERMT3 PIM2
SERPINB9
NVL
FOXP1
RIOK1
PTCD3
RPS27L
TRMT6
GLOD4
SMC4
GRWD1
GSR
ELL
DAP3 AICDA
DDX20
ARHGEF2
CDC6 HIRA
POLE
NR2F6
UTP14A
SUPT16H
VARS
SMARCC2
GADD45GIP1
MYBBP1A
ACTA2
C14orf1
NOC2L
LYZ RPS25
TAF9 UPF1
SIPA1
SUGP2
PRMT1
TOP1
GAR1 TARS
KIF11
SSB
APEX1
PASK
DYRK2
LCOR
SRRM2
SARNP PUF60
BMI1
ID2
EIF2AK2
HIST1H4F
CAMKK2
COPS6HIST1H3A
HIST1H3E
DDX21
MAGED1
RPL13
KIF5A
HNRNPR
HNRNPA0DDX17
TPM4
BRCA1
GADD45G
HECW2
MEPCE
RPS23
EZH2
ESR1
EED
SMURF1
FOXG1
TOP2A TBL1XR1
SMARCB1
DDX5
MDM2
NUP153
HDAC5
EEF1D DNAJB1
AARS
CEP135
USP7
GAPDH
TOMM70
TRIM32
TMEM135
PSMD7
BCLAF1
MYO1C
PRMT5
EWSR1
KDM1A
TP73
HSPA4
YWHAE
BANF1
SKI
PFDN5
KPNA2
CTNNB1
RACK1
HSP90AA1
NARS
HSPA1B
MSH2
NFE2L2
RPS27A ANXA7
PSMA3
BAG6
APP
HSP90AB1
KRT31
SKIL
MTOR
MYO19
BRCA2
RBMX
ZNF638
IKBKB
CRK
PNO1
TRAF4
NDRG1
IRF5
PPP1CA CLU
CASP7
GTF3C4
AMOT
PPP2CB
ERBIN
ABL1
SRC
GRN
MYH10
MAPK7
STRN
RELB
SCRIB
BCAR1
TTN
STK3
PTPN2
ATP2B1
PLCG1
ANXA5
UXT BID
RBCK1
EIF1AX
BCAP31
KRTAP10-3
TOM1L1
PTK2B
TPT1
BTK
ENAH
EPS8
GNB4
ARRDC1
EFEMP2
CSK
USP33
MAP2K5
PRKCE
NOTCH2
TARSL2 ITGB4
MAP3K10
ASB4
KRTAP10-11
LRP1NRASAFAP1
FGFR1
TGIF1
NOS1 FGB
GRIN2B
PDK1
MAPK8IP3
PLA2G4A
ANGPT2
PIK3CB
SDC1
COL1A1
IFT57
FGA
TRMO
HPCAL1
CSF2RB
ASCC1 BCL2A1
SERPING1
COG5
TRPV1
MMP2
SELPLG
COL2A1 MMP3
GPC1
SH2B3
TAS2R7 PTTG1IP
CCL7
CCL13
LYVE1 KISS1 NCOA6
DAB2 PPP2CB
PELP1
DDB1
SSRP1 EMDEPRS HIST1H3J MYC
HIST1H3C VCP SIRT7
APP CDK2 RPA3FUS
LRRK2
EIF4A3 TRAF1
HSPA1L PSMD14
PSMC1 SRSF3
LRPPRC JAK1 PHLDA3
YWHAZ
C1orf123 REXO4TTC37 BOLA2-SMG1P6
HIST1H2BJ
RIOX2 NAP1L4SURF2
CSTF2PSME4 SAT1CSNK1A1
DNAJC8 BCAS2 MED4
CUL4B CEP76
SYNCRIP
CCT4
CSNK2A3 CUL1 SNU13
MATR3 SRPK2 YWHAQ
NASPUBE2D3
LUC7L3
CEP128 PLK1
RBL1DGCR8
ACTG1
PPP2CA CASP3
TUBGCP2
ENO1 MAD2L1
PRKCA CBL
P4HA1 PIK3R1 TEPSIN
ERBB2
STAM2 MAP4K1 DCPSTCAP EXOC3 PRR12 MMP7
LGALS8 ZFP36L1 SDK1 SERPINA6
CCKBR MMP25 CEP135 TK1 CCNB1 HNRNPKTP53 CCDC8HSP90AB1 PSMD1 HNRNPA3
MRPL27
AKAP12
CCDC97
DDAH2 PNP SLIRP
HIST1H2AD
ANKHD1-EIF4EBP3
APLF NELFB NCBP1
TRA2A
EIF3H SND1
ZMYND11
SRPRA KRT14
RPAP3
HSPA6
SF3B1
THRAP3 SF3A1
HADHA
SNRPD1SRP14 MCM5RPA2
G3BP1
PAICS HNRNPD
PTBP1
PSMD11 PSMC4
CUL4A
MED20
RPL38 DDX39B
TAB2
MYC
UNC45A
RPSA SNW1 TBK1
TRAF1
STK11
YWHAG
HSF1
MAP3K1 VIM EPRS
PDLIM7
SMAD2
STUB1
RBM26 SDCBP
ACTA1
CAPN1
PHB
PDCD6IP RICTOR
DDX54
ARPC1B
PKN2 EIF3M
NCK2
PIK3R2 GSN
DAB2
IKBKAP
PRKCI PRKCBOS9
PTK2
MUC1 GNB5LAMA4
CABLES1MLST8 GAB1
IER3 ITGB2
PTPRK EPB42
RIN3 COL4A1
RRAS IGF1CSF2RA INSRR
SERPINF2 CAPN3TAC1 SUV39H1 FBF1
MDM2 PARK2 TUBA1C YBX3
RSPH3 NCCRP1 GSTM4
AKIP1 SHISA5SERPINB2
ZFP91
CHTF18
NCAPH2
DIS3L2
PWP1
TBC1D1
MRPS5
EIF4G3
ABR
NPAT
DIS3
ATAD5
MACROD1 HOXB7
ERCC6L
PDXK
LAS1L
WDR6
FTSJ3
ORC5
PRPF4
DCAF8
U2AF1L5
RBM48
MRPS2
ZBTB7B
GRPEL1
MYOF
FANCI
POLB
PSMD14
CCNH
ZNF622MYO1B
MRTO4
TAF1B
NCBP2
CBLC
MRPS23
EXOSC8
SSRP1
RPS21
MRPL39 UBA2
RPS18
PAX6
BRD8
RPL14HDAC11
SMARCA5
RPS2
GBAS
RAE1
EIF2S1
SNRPA1
PAFAH1B3
NAP1L1
DCTN2
CEP57
PARP2 S USP16
SRSF2
MAST3
ILF3
UHRF2
FBL
PAXIP1
TNFRSF14
CCHCR1
COMMD3-BMI1
TCF3
SF3B3
LC9A3R1
HNRNPF
FAS
PTN
CEP250
SUZ12
FKBP5
RPA3
LMNA
SF1
PRPF40A
CHD3
HSPA1L
IFI16 CNBP
RCN1
SYNPO
SFPQ
HNRNPUL1
CDK2
PHB2
CDC5L
TCEA1
GARS
NCL
SOX2
KIF5B
GRK5
MCM7
RPA1
LOC101929876
SIRT7
TAL1OBSL1
TUBB PSMC1
NPM1DDX3X
COPS5
TCF4
CDKN1A
XPO1
PAN2
CCT7
ARRB2
I
VCAM1
VHL
NUAK1
LAMTOR3RAN
YWHAZ
EEF1A1
FUBP3
HNRNPH1
TNFRSF1A TAB1
ATF2
SG15
HDAC6
PPP1CB
FLNA
SUV39H1
PPM1G
CASP4
HIPK1
UBC
ZYX
IKBKG
SPTAN1
ELAVL1
HUWE1
FUS
SQSTM1
CLTC
PCM1
KPNB1
ACTB
PQBP1
HNRNPA3
XPO5
SPTBN1
PIN1
PUM1
DYNC1H1
GRB2
XPNPEP1
AP2M1
TP53BP2
CSNK2B
TMEM33
AKT1
HIST1H1E
TCP1
HSPA1A HGS
FLNC
PAK2
IGF2BP1
NUMA1
PTEN IRF3
AP1M1
WWP2
DYNLL1
SHC1
PRKACA
BAX
TK1
CSNK1D
CCNA1
PSMA6
CEP290
MAST2
PGK1
DIAPH1
RAF1
SYK
A2M
HRAS
CD40
SEC16A
ERBB3
NCK1
FKBP1A
TRAF3
CD4
TPM1
GNB2 BIRC3
NOS3
KRTAP10-9
PPP2R1B
TANK
LOC100996717
TNPO1
PPM1B
FYN
FASLG
BIRC7
SORBS2
INPPL1
LOC653513
TSN CASP10
ATG12
MAPK10 MET
PSEN2
CLASP2
WASF1
P3H1RNF130
COMMD4
KIT PTPN3TF ARHGEF11
KNSTRN
RCAN2
NBR1 SNX17
GNG5
MYLK MCL1
NAT2
AXL
LRIG1 HTRA1
COL18A1
SHANK1
GJB1VPS51
EPHA3
RHO
NAXD
CCR10
BTC
TGFBIMTHFR
GMPR2
ARSB
COG6 SCUBE3
PF4 TBC1D24
IL12A
IL1R2
CCL17
ZYXH3F3A WDR5
NR3C1 AURKB
LMNA AKT1
SLC25A6 SRSF7HIST1H3HXPO1 SUZ12
UBC FBXW11
CEP250
SNRNP70
PRKAB1 UBASH3B
WDR1
TUBB4A NOP2 UPF1 HDAC5
AGAP3 TCF20 RBM41 CDK15
ARGLU1TOP2B
ABCF1 CPNE2
RBM10
NOP58 RPL8
AIPMAT2A
DNAJC10 RPS24ICAM1
SNX9 ANXA1
HNRNPU
SENP3
PSMB9 SMN1
CAND1 ERG
TRIM21
CCT2
POLR2B IPO8
TUBG1
TNFRSF1B GOLGA2
IQGAP1
FLOT1
VCP DNM2
TSC22D1
CDC37
HSPA8 CDK5
TUBB4B
DPM1 ESYT1 DCC
RPS6KB1
GOPC
DNAAF5
USO1
TUBB3
TLN1 USP13
SYNE2 KDR
CRKL
PSEN1
DCAF7
GAPVD1 ADD1
SH3GL3KRT16
ITGB1 INSR NUCB1
PLCG2
BMX
SLC9A3R2 GRIA2
AKAP6 WNT3A ITGB7
MAG PTPN22 COL8A2 BCR
SUMO1 MCC SNRNP200 HDAC5 EPB41PABPC4 NDRG1
DDX24
BPIFB3
UST SLC7A9 NME2P1
HIST1H2BH
ZNF197
CRPRIOX1
MRPL10
STXBP3
HIST1H2BN
GEMIN6
POLRMT
PPFIBP1
LYPLA1
RBM23
DNMT3B
DOT1L
SSU72
MAD2L1BP
USP47
ARMC8
SS18 CFL2
XBP1
GTF2E2
PKP1
HAUS8
POLR1B
DNAJA4
PRPF8
PPHLN1
NLRP2
H1FX
RFC3
FAU
NAT10
TRIM33
RRP1B
TPI1
TRIP12CHD1LRPL7A
POP1PES1
MVP
RPS4X
EIF3C
ORC1
RPL32
SNRPE
BUB3
MRPS22
SSBP1 EFTUD2
RPS11
RPS20
KLC3
RPS8
VPS35
SART3 MGMT
PRPF6
USP20
EIF3E
RPL12
RC3H1
RUVBL2
UBE2E3
EIF4A1
SEPT11
SNX2
CTNNBL1
DNAJA2
MAGEA6
PABPC1
RPS14
SNRNP200
RNF2
HNRNPM
RPL10
CAPZB
DNMT1 CCT3
RPS13
STAU1
PSMC2
MAP3K4
NONO
OFD1
SRSF1
HNRNPA1
HSPB1
RBM14-RBM4
CUL3
CUL5
CUL2
NCAPHSUB1
UBE2K
HSPB2 CCDC8
FBXO25
MAP3K3
DCUN1D1
YBX1
BIRC5
ABCE1 NINL
MCM2 NTRK1
TERF1
SRP9P1
GAN
CSNK2A2 CCAR2
MPG
ARRB1
PSMC3
ZWINT
KPNA1
TOMM22
PKD1
DCTN1
UBE2H
SFN
HNRNPH2
UBE3A
PIK3R3
NUFIP1
SLC25A6
PTGES3
DBNL
OTUB1
GANAB
CENPJ
CDK11A
KRT18
PDCD6
SMARCD1
TRAF6
RIF1PSMD9
DGCR14
CACYBP
NFKBIA
FN1
TUBB2A
PTPN1
PKM
PSMB1
HABP4
GORASP2
TGFBR1
ADSS
UBE2D1
RPTOR
TPM2
PTPN11
PLEC
EPS15
TMEM189-UBE2V1
SGK1 RIPK3
ACTC1BCL10
ACTN4
FSCN1
BCL2L11
AP3D1
GNAI3
LYN
ALB
AP1G1
AP2B1
PLSCR1
IRS1
ATG5
GRM1
CAV1
MDM4
TSC1
FRS2
PIGS
AP2A1
CFLAR AAMP
EXOC4TNF
LARP4
LOC100996763
FLOT2
CAMK2G NME4
IGF1R
SARS
ATP13A2
DNAJB9 NOD1
NRG1
NUCB2
PLCB2
GRK6
CD79ABCL2L2
GNAI1
TCF7L2
HSPG2
CCR5 TNP2
PMAIP1
ZNF16
SOCS7
AGT
STON2
DOCK4
CTGF
WASF3 DDR1 BBC3
ITLN1
BIK
RECKOGDHL
CXCL1 ADAM12
LPA
BMP1
C1S DUSP5 HIST2H3C
BRD4 RCN1
DVL2
HIST3H3
CDKN1A
GSK3B SSB
TNFRSF1A
HDAC1
HIST1H3I SNW1 HSPA5
HSP90AA1
RUVBL2
HSPA1B MAP3K1
ACTL6A
HSP90B1 HNRNPF STIP1 EEF1A2
EFTUD2 GOLT1B TP53
PLCH1 USP38EIF4EBP3
FOXJ3 MYL9 FXR1 KDM6B
PPP1R15A
NCAPD3
APTX CKAP2
ATP2A3 GNL3
RNF115
TSC22D3
STOM
PRDM2
RCC2
KCMF1
PABPN1
CDK14
ERCC8
MRPS27
ZHX1
BASP1
SNRPD3
SSR1
SNRPF
CEP152
SEC22B
CEP162
ILF2
RPL18
RPL5
THOC1 CBX3
NOP56
RPL11
GLO1
POLR1C
SMCHD1 EIF3F
STRN4
MBD1
DEK
GEMIN4
NDUFA2
SCNN1G
CYP1A1
LARS DUTASH2L
RPS6KB2
HDGF MSH6
IPO4
DHX9
C8orf33
SRSF7
LDHBTSG101
BPTF
IKBKE
NEDD8
U2AF2
CUL7
TUBGCP3
RAD23APPP2R1A
CDKN2AIP
RBBP6
CIAO1
REL
KIAA0368
ITGA4
RAB5C BYSL
LRRK2
PARK2 UBB
NFKBIB
EGFR
MYO18A
STK26
PSMD10
FKBPL
PYCARD
ARHGDIA
BAG3 MSN
TUBA1A
ATG7QARS
CLTB
GABARAPL2
DDX19B
RANGAP1
EPB41
ARAF
ECT2
COPB1
SERPINH1
COPS3ALK
UBA1
PSMA1
GDI1
PTMA
SAV1
ERLEC1
ACTN1
EZR
PPP2R2D STAG2
UBE2M
NEDD9
PINK1
DAB2IP
SH3GLB1
SGTA
BLK
TMEM25
PRKACB
RALA
ZAP70 NGFR
PDGFRB
NOTCH2NL
TNKS2
PPP1R9B
RNF138
TNIP2
CBLB PICK1
SHROOM3
ABCA1
WASHC3
GET4
PTCH1
GNA13 EGF
EPHA2
MCAT
ELAVL3
GRIN1
GNG2
NCAM1 SHC2
AATK
CAV3 NAA50
FBN1
IL1RAP BICD1
VAV3
F2 HPD
IGFBP7
SGCANID2 COL4A3 AMY2B
COL4A4
SCGB1A1
TIMP4 MMS19SIN3A TUBA1A PSMC3
EZH2 YWHAQ H2AFX
RPA2 HLA-B
YWHAG SAP18
DKC1
FUS HIST1H3I HIST1H3H
CCNB3 FASTKD2
DHX29ZSCAN20
CDK2AP1
ARHGAP25 EMG1
ABCF3PDS5B
GDF9
MYCBP CAMSAP2
GNL3L PYGB
CDK16
EIF3G
APEH
TRPC4AP
RPL31
ZW10LYAR
SNRPB
TPR
DDX24
CEP120
MYO1D
RPL29
MAPRE2 EIF5AL1
EIF3I
USP11
RPS28
FBF1
HIST1H1D
RPL19 BRF2
RPL18A
HSPH1
PSMA2
UHRF1
GCN1
RPS3
COIL
EIF4A3
RPLP0RPS6
RPL17
TUBB4A
EIF4E
SNRNP70
HNRNPA2B1
NCSTN
TARDBP HSPA4L
APBB1
ZBTB1
PIWIL1
BAG2
COPG1
CEP170
NUP50
UBL4A RPS3A
HSPA9
IGF2BP3
CLIC1
RBM14
CCT6A
TRAP1
ILK
SF3B6
NF2
CFTR
MCC
DBN1
TXLNA
NME2
HLA-B
USP8
EEF1G
HSPA5
FBXO6
NFKB2
VTNSVIL
SNRPA
STIP1
MYH9
TIMM50
PSMA5
P4HB
FAF1
UBQLN1
YWHAH
RPGRIP1L SNX6
UBE2G2
CAB39
PRKAA1
IMMT
PRDX1
LIMA1
PDIA6
KCTD17
KRT1
DNM1
IGHG1
MYO6 DECR1
LNX1
RAC1 AFDN
PEX19
MAPT
NTRK2
CAP1
AIMP1
BECN1PDE4DIP
IGBP1
DIABLO
ITSN2
CKS1B
CAPNS1
UTP4
CALR
SAP30BP
ITGAV
TGFB1I1 TTC5
ERLIN2
RYK
GLRX3
RAI14
CDK5R1
LRP2
CTSB TAZ
GRAP2
ERBB4
SERPINE1
MPDZ
SNCG
ITGA5
EPB41L5
TRAM1
EPHB2
RIN1 PPP1R9A
NLRC4
SLACHST15
COMMD5
PLAU CD9 SLC6A9
CCL4 MID1IP1 YAP1
CBX3 BCL2 COPS2 HIST2H4B NFKBIA EP300 PSMA1 VCL LUC7L2
PCBP2 ACIN1 TARDBP COPS5 HSPA5 SRRM2
ASTE1RBMS2
SLC39A10 RNF187
DPH1
PCSK7
ARHGEF17
SWAP70
CRIPAKPRAM1
PTP4A2 HN1L
SCFD1
PURA
UBXN8
SPDL1
PDCD5GRIPAP1
MARCKSL1SBDS
KIF2C
PSIP1
PNN DSG1
DFFA
UBR4
KHSRP
SEPT2
ERH EIF3L
NDE1
USP22
RPL22
RHOU
ENO2
NME1
EIF4G2
WDR76RPS26
ASF1A
SCAMP3
H2AFV
XRN2 EDC4
CNTROB
CDC16
AIRE
HNRNPUL2
FABP5
RPS6KA3
MRPS9
IGF2BP2
RPL24
LUZP4 SDF4
HIST1H2AE
RPL15
ESRRB
DICER1 LIG4
RPL27
RPL30
RPL6
HADHB
GMPS
AHNAKTMOD3
HYOU1
RBM39
RFC5
HECTD1 CTPS1
TTC1
WRAP73 RPL3
RPL37A
PPP5C
IDH3A CKB
FLIIPOT1
SNRPD2
UBE2V1
RPL23A
LRSAM1
MAP3K14
CNTRL
NUP205
UBE2C
PSMD4MKS1
AHSA1
UBE2E4P
HSP90B1
EMD
PSMD13
TRMT10C
UBXN7
LGALS3BP
PSMD12
RPL23
PIR
RANBP2
HNRNPDL
PXN
ARF6
PRPF19
MAP1LC3A
ALDOA
EIF3A
RPS27
C1QBP
FASN
SAE1
TOR1AIP1
HNRNPL
TIA1
MTNR1B
CAD RIPK1
UBE2N
MED31
IPO5
PFKM
MTNR1A
DROSHA
SUMO4
PARD3
UBE3C
PSMB4
DERL1
PSMD2
SRPRB
MAP1LC3C
NDUFS1
XIAP
USP9X PCBP1
CFL1
ARHGAP32
KRT2
CASP2
EIF4G1
TUBA4A ASNS
CORO1B
LYPD3
RHOA
ACTR3PTPN14
CRYAB
PDIA3
ATAD3A
GNB1
ZPR1
RALBP1
MKRN1
PDLIM5
MYO5C
CANX
UFM1
CASP1
BCL2L1 COPB2
NUBP2
TFRC
PAFAH1B2
CHCHD3
SHANK3
SURF4 PTTG1
PRKCG
APOA1
SNAPINERN1
KLK5
HTRA2 BIN1
BCL2
PDE3A CHMP3
PNPT1
TEAD4
DLG4
CCDC155
PTPRC
FAT1
CD5
BCL2L10
RAPGEF1
PTPN5
HBZ
SH3BGRL
TRAPPC3
SH2D3C LSR
HGF
FAHDCN
ADAM17
NDFIP1
EXT2
LPCAT1
ALPI PAM
GLG1
FBLN2HRK CXCL8
XK COL13A1
MATN2 LCN2
MFSD13A
SPICE1 H2AFY
NCOR1 DAXXCHD4SIRT1 PPP1CC PHB2 XRCC5
PARP1 BRCA1 ACTB GAPDH
DCUN1D1 THRAP3
ILK
PXN
PSME3
PA2G4
SLC25A3
EIF3E
VAPA
MCM2
C2orf73
GZMM RNF220 NSUN5
SARS2 IFIT1
METTL18
MRPL24RHOB EIF3CL
MOGS NLK
RPS5
UBE2A
GFAP
U2AF1 CCDC88A
PRKRA
RPL21 TRIM29
SREK1
DARS RPLP1
CALU
UBE2L3
RPL35 SLC25A5
DOK4
MMS19EIF6 PHF10
VCLPDS5A
PTP4A3
ATP5A1
CORO1C
RAB7A
PDCD4
TFG AHCYL1
LRPPRC
GTF3C1
IQCB1 PSMD1
G6PD TJP2
ALAS1 SOCS1
TGFBR2 SELENOS
VASP
SCYL2 MST1R
SP3
PICALM
UBXN6
TBCD DYX1C1
CD44RGS2
ARL3
DNAJC11 RNF5 LRPAP1
TMSB10 LRP6
NCDN ZFYVE21
PTPRB
HOXA9 DAD1 CXCR1 AIDA PPP4R4 EREG USP29 KMT2A HIST1H4D SRSF1
DHX40 PRPSAP1 SIK2 RAVER1 TTK
MAGED2 RPL34
ATAD3B
ACIN1 RPS17
LAMP1 RPL4
RPS16WWC1 LDHA
PRKAB1 RDX
PSME1 PKP2 STMN1 TPRKB
FKBP8
FAF2 NOSIP OCLN
IGHM TNS4 ARHGAP5 HSPA4 HSPA1A SRRM1
SPACA7 ANO5 TBC1D3B ADAMTS10 POTEE
TUBA8
WBSCR22
SEPT10 NAMPT
LBPMRPL9RPL36AL
GIPC1 NR1I2
SEPT7
UTP15 EIF5
HMGA2DAPK3
PHGDH
NUP133 CSE1L
RPL7 RPS19
RPS15A
VAPA
PA2G4
SORT1
RPL9
TXN GSTK1
XRN1 PPP6R1
IARS SAMM50
OCIAD1
LATS2
PSMD6
DNAJB11
SEC23A
PPIA ABLIM1
PCMT1 ATG9A
HAX1
TNIK
NSFGDI2
TMEM17 RARS
SYN1
PRDX3 AP2A2
NDC80 NOV
PPP2R2B
PDHA1
GNAI2
SLC25A41
MDH2
MAZ
TNFSF11HSBP1 SLC12A2
GPRASP1
ANKS1A
PDIA2BDKRB2
NCKIPSD
NOTCH3 F13A1
FAM173A
LDLR
MEX3D MMP14 RGS16 KRT27 AP1ARCCL4L1 HDAC4 SP1HIST1H4L SQSTM1 XRCC6 BTRC SRSF2 SNCA TRA2A
POU4F1 DUSP10
DCLK1 RIOK2
BCCIP
HERC1
PACS1 PHKG2 RPL35A
THOC5
IGSF21
SULT1A1 RNF32
HSPA2
BOLA2B MRPL38
GTPBP4 LARP1
DNAJB6
DDX18
HK1EIF2S2 ATP6V1A
MTCH2
RFC2
DHX30
RPL10A PPIB RPS10
GOLT1B
KRT19
PSMB2 KDM4A OSGEP
S100A9
RPN1
NUP155CLK3
TUBA1C
CPVL
DDX1 TUBA1B
PSMC6 HSPD1 TPM3SPP1
DNAJA1
TCTN1
TUBB2B MYL6 NSFL1C
CEP57L1
DIMT1 TBXA2R
KBTBD7
ATIC
PTGES3L-AARSD1
USP14 RAB4A
FKBP4
PANK4
TRIM3
DSTN
SPG20
ACTBL2
ADRB2
USP36
COMMD1
ARPC5L KCTD9
CAP2
MAPRE3 TXNDC11
RPE
FNIP1
EXOC6
CD40LG
GLB1
BNIP3
TRPV6 SLC5A1
SLC4A10
SHC4 RGS5 MEGF6 CHAF1A
CTBP1 HIST1H2BC
NCOA1 TSC22D1 RAB7A PRKDC
CTNNB1IQGAP1 HSPA9CLTC
TUBB4B UBE2D2 INPPL1
UBE3DSERAC1 ZSWIM7 S100A2 NTPCR
MRPL12 RPL26L1
PLCB1
UBXN2B RBM25
HECTD3 RCN2 EIF4ENIF1
HAUS2
RPL27A
PEPD
ADAR
PTPN13 NECAP2 NUDC
SAP18
UNC119
TUFMMEX3C
UBXN1
CKAP4
CEP72
PRMT3
SNURF
CD59 SSR4
BAG5
RAB1A
UFD1L TMEM216 ATP1A1
KIF22
CDIPT
PACSIN3
PSMD3GRK2PSMB7 HDLBP
ALDOC
VDAC1
NDN LGALS3
RAB10 NOMO1
CYTH2 RER1
EXOC2 AP1S2 DPP4 CXCR2 PON1 HDAC3 HIST1H4J TRIM28 UBE2I BAG2 ARHGDIA
ACBD6 FILIP1 HIST1H2BO SETD2 SQRDL
PRIM1 ARL1BRIX1
DCXMRPS28 GLUD1P5
RPS12
NOP2DOK2TELO2SLC25A3
AATF
PUS1
UBAP2L MARS
SNX3
THOP1 CPNE1
NOS2
DHPS
MTHFD1
PHLDA3
AMBRA1
CHD6 ATP5C1
PSMD8 ARPC4
S100A4
VPS29 LGALS1
PRDX2
ATP2A2
AIMP2 MAP4K4
VAV2 ETFA
REST MME
SYVN1
RNF31
RNF128 FLT1
VPS13A
HOOK2 CNN2
PIP5K1A IGFBP5
HECW1 MAPKAP1 BDNFITGA2 SLC4A1
ANKS1B EXOC6B
TGFA BTD
COCH MYLK3 CFB ACKR4 GARS TCF3 SRC BARD1
HDAC6 CCAR2 GNAI2
KCTD3 PHLDA1 NABP2
LUZP6 MAP3K20
PLIN3 RPLP2
ASS1
EPPK1 HNRNPLL
FUBP1
EBNA1BP2
THOC2 BRERAB11A
RPS9 SOD1 HK2
EPB41L3
NME1-NME2
SEC31A
PSMB5
WRN TXNL1
CLNS1A ATP5F1IBTK COPA TECR NUDCD3
GCLM TTLL12 NT5E
CAPN2 C1QA FBN2 H3F3B NOTCH1 CDK1 UBB QARS IGBP1
TUBE1 SPATA7
ZNF121
RBM6ZBTB5
RPS4Y1 SPEG CMSS1
PRKYANK2CS POP7
PMF1
UAP1
NCOA5 SH3BP4
MRPS14
PABPC3
EXOSC10
MSI2
DMWD
SEPT9
GBP2
RPL10L
GFPT1
TIAL1
EIF3JHEXIM1
MKNK1
SRP72
TSNAX
RPL13A
PPIL3
ZCCHC10
CEP164
RPS15
RSU1
ATP6V1H
AIFM1
FNBP1
RPL36
EEF1A2
EIF3BEIF4H
ELMSAN1
PRDX6
RPL28
EIF2S3
EIF3K
VDAC2
IPO9
SDHA
HSPE1
KRT8
TOMM40
AKR1B1
HSD17B4
LASP1 ATP6V1B2
CKAP5
HSD17B10
MRPL40
TKT
UQCRC2
NUP93
ECSIT POLD2
STOML2
KLC1
UBQLN4
EXOC5
RNF11 CHGB
FARSA
PTPRF
FDPS
MKI67
TCTN3 PRKG1
PTPN23
PON2
LONRF1 GBF1 CCNL2
UGP2
MPRIP
PIK3C2A
ALPL
NANS PDIA4
UBE2V2
PRKAR1B
TIMM13
ATG16L1
PCSK9
CTSD
VPS45
PBK
PEA15
UGDH
GRB14
ARHGEF7ASB6
ACP1
MCCC2
CYLC2
CCDC47
RABEP1
TP53RK
TIMM23
LGALS9 PTPRA
NRP1
PTPRG
S100A6
CD36
GALEADRA1B KLK11
SCN5A LIPE CD7
GAD1 BLCAP CMTM3
TNC CXCL6 MED23 USP15
KAT2B PIK3R2 WDR77
ATF2 P4HB
FAF2
HIST1H4B SMAD3
BMI1
COMMD3-BMI1 YWHAE
BAG3
DNAJA1 PCNA CDC37 PLEC TPM3
CALU CDC5L
FAM71D GALR3
HIST1H2AH
TOP1MT
MBNL1
MPHOSPH6
ACOT7 MTDHMRPS18B
GPATCH8
MRPL23 TXNL4A TUBB6PRKCDBP TRADD
PABPC4 EPB41L2
CKS2
UBR1
BTF3KARS
NUMBL
CPS1
PRDX5UBE4B
NPLOC4
ENO3 LPP
ARF1
SOD2
UFL1
IPO7
DYNC1I1
LOC101930123
NSUN2 XPO7
ATXN2L
DDX39A
RANBP1
STX5
SNX1 LOC107984923
FKBP14 UBL7
AHCY
SIVA1SHC3
BBS7 HBB
SNCAIP SAR1A IGF2
FCGR2BSOCS4 SGK3 BMF
BCL2L12
TIMP3
TMTC4 MUC3A CEBPA HIST1H2BF DCAF1 HIST1H4E RELA HIST1H4I HDAC2 YWHAB
ABL1 NEDD4 TCP1 PHGDH
C10orf90
MYL12B
POF1B PPA1
IQGAP2 PDCD11
PGAM1
CDK20 ZFAND2B
TOMM34
MAGEC2
EIF2B5
HSF2
DDX27
DLD INSIG2
RPN2
TOMM20
NUP85 HELZ
OSBP
RINT1
RPL26
RTCB
DAZAP1
TAGLN2
PPP1R2
AGO4 SPECC1L
FMR1CCDC14
IARS2
DOCK7 AMFR
EIF2B1 PEBP1 LRRK1
PI4KA
ZBTB20
SLC3A2
YARS
SLC25A11
FH EHD1
LONP1
HLA-C
GNA12
ATP5O
DCAF6 PGM1
ADD3
HBA1
EXOC1
TEX264
RAC2
APOEIPO11
WWC2
LCP2
TSHR COQ8A
COL17A1COG4
CUL9 PRELP
RBSN
C22orf29
ACPP
NOSTRIN ITGA8RRAD POMGNT1 THRA ESR2 RAB1A HIST1H4F CRK
NF2 KPNA1 TKT POT1
ATP5C1 PTPN6
RNF144BMON2 DHX37 ESF1TTI1
NDUFS2
CAPRIN1 MYH14 ATXN10
PPIF STK25 RAB35NAA15MAP3K8
LMNB1 PSMB3
TRIM41
CA9 SH3GL2
GATA3
OXCT1 CCNDBP1 RTN4
NDUFV1 COQ9
ITPACOX2
EEA1UFC1
SEL1L
PLAASEC13
ABCD3 CTSL LCMT1
PTPRD
AGTR1 LSM12P1 SNAI2 LAPTM4B DHRS1 CXCL13 H3F3AP4 IMMT HIST2H4A USP7 TERF1 MAP3K3TRAF2 EEF1D CCT7
C11orf98 DSG3 GUSBP3
HEATR1
DNAJC17
MRPL13
TBL3
LOC102724985
ARMT1
SEC31B PCDH7
MTHFD1L
GLUD1MDH1
ATP6AP1PITPNA
CTNNA2
PFKFB3
SYT1
EIF2B3
NMD3GPI
ARMC6
CNP
DDX47
TXNRD1
MARCH5
ROCK1
WDR36
OSBPL10
APOD
PYCR2 PLS3
ARF4
PRSS23
WDR1
ALDH3A2
AARSD1
PPP6C
KIF2A
ARFGAP1
LIMCH1
DYNC1LI1
NMT1
CLIC4
OR10B1P
TMUB1
PDHX
NDUFA4
SUCLA2
PPT1
UBE2B
SNX4
APBB2
UBR2
ALKBH3
RAB11FIP5
MIF
ABCF2
ZC3HC1
DDOST
HIP1R
SEC61A1
TTC9C
NCAPD2
LIMK2
ARHGAP1
PAFAH1B1
ATP1B3
SNAP23
TNPO3
SLC25A10
UMPS
GPX4
FBLN1
DIAPH3
PIN4
NDUFA9
METTL23 S100A1
PGRMC1
NUP188
USP18
FAM83D
POR
ISG20L2
AFG3L2
CRELD2
CPT1ATES
LTN1
SRMFIS1
PRSS50
ITPR1
PPP2R3C
TEC
PSMG2
DNAJC3
AP1M2
G
CELF2VEGFA
SLC25A12
ADCY9
RIA1 PLD3
COMMD8
HIGD1A
AMBP
TGM1
APOH
FZD5DBI
GNA15 CLEC18A
INS PCED1A
GIMAP5
PTHLH
HSD3B7
NRP2 CNMD ELOC
CREBBP
UBR5
SH3KBP1
HIST1H4A
NFKB1
HIST1H4H PPP1CA
TOP1 PRMT5
CDK9
CASP3 ACTR2
EIF4BCSE1L MTNR1A
PGK1 MYO19 HNRNPH1 U2AF2 NPM1 YWHAG HIST1H3C
MAP1A
APOO
LBHD1
APOBEC3C
FDFT1
DDX3Y
ARL13B
BUB1B-PAK6
LGMN
NOMO2
CDH13
VPS39
MRPL41
MPV17
IQGAP3
PHOSPHO2-KLHL23
PMF1-BGLAP
EXOSC1
ALDH18A1 FOXO4
ISLR
SP110
SEC23B
MTPN
PHKA2
NOL9
EIF5A2
ARFGEF1
ATP1A3
HACD3
GOT1
UBD PPIH
ADSL
SEPHS1
CASP14
PPIG
DDX50
ACOT13
PSMB6
SEPT6
OAT XPOT
ATP5I
RAB27A
DSC1 CAT
SPR
PSAT1
AKTIP
NDUFS3
PELO TAB3 BIRC8
EHD4
SRSF3
ACAT1
MCTS1
C15orf48 AKR1A1
TALDO1
RPL37
CDK13
LRRC59
HIP1 IDE
DNM3
TCTN2
RFWD3
NDUFA8
COPG2
NACA2
VPS4B
AP1S1
TMED10
PRKAG1
SMYD2
CYC1
ARCN1
CSRP1
TMEM67 SDHAF2
CAMKMT
CHMP4A
EIF5A
HERC3
APOBNUP210
CLTACBR1
NMT2
ALOX5
TMX1
TOR1AIP2
ASB17
PTGDS
PAX8
SACM1L UVRAG
BAK1
PI4K2A
COMMD2
CASR RAP2B SPSB4 F11R
PTPN18
GNA11 FAM187B
BAIAP2L1 RIMS2
ITM2B
GRIA4
COG1FABP4
ALCAM
NCBP2-AS2
DCBLD2 SPARCL1 DNMT3L CEBPB FLOT1 TADA2ASYK
MED4
UBE2L3
MAPK1 HIST1H4K AR
HIST1H4C
RBBP4
HIST4H4 FYN POLR2A
CANX
SF1 CBL MDC1 ECT2
TIMM50
CSNK2A3
SSBP1 RAE1 HNRNPR
WDR66
GALNT6MYO9A
PEX1 SCAF1
ETFBKMT
LIG1CENPF
SDPRCDC123
HADH
PDXDC1
ATP5L
BRINP1
MEOX1
GOLGA3
COX17
SFTPC EMC3
EIF2AK3
PSMG1
ACADVL
SPACA1
ETFB ESD
TTC27AHSG
HSD17B12
MAP7D1
ASB10
CYCS
HSPBP1
EIF2B2
UBFD1
NOL11
C12orf10
BZW1
GSTO1
TYMS
ATP6V1D
RHOD
PEX5
RNF213
TMEM132A
IDH3B
COPE ATP1B1
MPPED1
WEE1
BTF3L4
PLOD3 KRT9
HBA2
CYB5R3
DEGS1
NRBP1
LETM1
PHKB
UBE2G1
SORD
ESYT2
GOT2
TAP1
SIM2
MYH13 INPP5K
ACSL4
NDFIP2
CHMP1A
POLDIP2 ASPH
HMOX1
DHRS7B
RNF103-CHMP3
NLRP1 AGR3 AGAP2
GORASP1
KLK7GON7WNT4 AAMDC
KIAA0319L
JSRP1DDX60 PGF
TBP
KAT2A PML
MCM3 TLN1
SMARCA4 STUB1
CHUK SUMO2
PHB
CSNK2B SMARCC2
TBK1
SMC3 SIRT6 FLNB
MSN IGF1R
PRKAA1
EIF2AK2
HNRNPK
RPL36A
UROD KLHL5
UBE2F DNAJC19 KIAA1524BZW2 IDH3G
HIST2H2BF LDHC RNF125
IGLL5 DCD
CMTM5 EPB41L1
CLN5
IFIT5 CLGNNCLN AQP1 CORO2A LOC102724652
METTL21A BFAR CD68 COL6A2 NRGN NCOR2 RARA KDM1A ELAVL1
CAV1RBM14-RBM4 RHOA
DNAJC1 UQCRB COLEC11 APAF1 GSTZ1 BCL2L14RIN2 VDAC1
AGAP5
ZNF385A
ANO3DNAH2
UNC5CL
GPX2HPCAL4 CC2D1B
DNAJC21 KPRP
AKR1C2
ETHE1
LANCL1
NFS1
TSFM
SERPINB12
HEATR3 KIF5C
CTPS2
RMDN3 SRI
CTSA
SFXN3
SKIV2L
HIBCH
NDUFA5
CEPT1
CLPX
FERMT2
SIRT3
PBXIP1
FKBP1B
NDUFV2
SEC63
ARFGAP2
HEXB
ANKRD13ADLAT
IDH1
COTL1
LSM14A
SNAP25AGFG1
SLC25A13
ASPM
SYNE4
GSTM3NAPA
GSPT2
TCEA2
MAST1
SLC1A5
TMEM189
CRIP1
ILVBL
AKAP11
AAAS SPCS2
FNBP1LSPSB2 RAB3A
KCNE4
KLHL23
MYL1QPCTL
S100A14 RGS10
SOCS5
NMRK2 NLRX1
CHRNA9APCSHBD
ADIPOR1 RAPH1
CYR61CRYAA VEGFB
GRK3
CHN2 RNF183INHA NAPSA
MARCH6
CCL22 INTS6L SETD6
SEMA3FUBIAD1
CHAC2 CD200R1 RPGRIP1L CDC73TGFBR1 NUDC
UBQLN4PRKCB
UBE2N
MAPK3 SEC16A
MAPK14 JUN
RB1 DBN1
PRMT1
PRKACA CDC20
IPO5
KHSRP
CTTN
UBQLN1 ALB HIST1H3D
TANGO2
EIF2B4 TRAK2 GNPAT
AP2S1 RABL6 ANTXR1
CLNK
OPRD1
B4GALT7
RBM12 ARL2
ERP29 NOTCH2NL SETDB1 NUDT21MAPRE1 IFI16 HIST1H2BI
DGKD OSBPL9
NDRG2
XPO4RECQL4
OARD1
FLG2 TFAM
ARFGEF3 TBL2 PELI2 LDHAL6A
THEM6 SDF2L1ICK PDCD10
CAPG YTHDF1
MICAL1
SEPT4 QDPR
RNF19A BACE1NSDHLPNPLA2
CPM RUBCNTRPC3 EPHB4 TMEM30AITPRIP C1QC CHD3BAG6 RANBP2 NOC2L
ARRDC5LCE3A DYNC2LI1 PGM2 ASGR1 PRPS2 NUTF2 NQO1
HIST1H2BM
GK COQ6 HSDL2GLRX APRT
CNNM3
HBG2 GCDH
TG
CD6CNN1
M6PR WWC3 ARRDC4 GABRG2 BAX HIST2H2BEUBE2D3 HIF1A PAK1 ACTN1
MAPK8 DNAJB1
CAPN1 VDAC2 ARAF RPA1
CCDC70
NBAS
ADPRHL2
RIC8BCETN3
STT3A
PCLAF
JKAMPZMPSTE24
ARR3 IPO13
HN1
MFN1
SBF1
ANXA3ORM1
ATP5J2 PITPNB
CLIC5
SGPL1 SLC27A2
ALDH1B1
PTGES2
AP1G2 PIK3C2B
ACO2
FAM162A
ZNF135
SYNJ2BP FKBP7TRIO MCURNASEH2C
RGS17
BNIP2 TRIAP1 COLEC10 CALB1
TMEM168
BECN2
TCF4 SGTA PPARGFUBP1 FOS SMARCA5
UBE3A
YWHAH PPIA UBE2D1 EZR
CAPZB
PDGFRB ILF3
BVES VPS13D SNX15 GNPDA2
BROX
DHRS4L2
BRI3BP
LY6G5B ABCG2 ZNF746LCP1
CERS2
BLOC1S1 ATP5D
IDH2
CISD2BLVRA
SH2D3A CABP1 SMAP2
ANG SP7 SAAL1 UGT8 GSKIP CDK8 CSNK2A2 NFATC2 CASP8 CDH1 AIRE
PRKCZ HSPE1 RIF1SYNPO
AASS WNT9B AKR1B10 CCS GRHPR TTLL5 LYPLA2
SPRED1
RDH13
MIPEP ASL
PANX1 GNAT2 TRAPPC5
CLCN3 OLFM1TMEM259 COL6A3
ZNF804A TCTN2 MEN1 TP73 UHRF1 MSH2
MCM6TRIM27 IRS1
TRIM29 MAP2K1
MAGED1 ITGA4
RAB15 MTMR2
ANKRD27 TSNAXIP1
AVL9PI4K2B
SUCLG1
PHKA1 DHRS4
TBCE
CUEDC1
NDUFAF3
RAB18ACOT9
ARHGEF15
GLUD2
PHOX2A
SCD MINOS1
STX4
CDC20B
NAPG LDHAL6B GFM1SLC7A5
BNIPL
PTGDR
MARCH2 FST SPTBN4
SV2A GAMT
C9 PDE5A
ZDHHC7 HSF1
CEP128
E2F1
CARM1 RANGAP1
CDK4 RCC1 SMAD1
MAPT
MGMT
CEP170
AP2B1
AHCYL1 HIST1H3A
PALM3 KIAA0087 ACAP2 CEP78 ZNF431 NAT1 SPATA31A3
SLC2A12 HMGB1 TP53BP2
ERICH6
AIFM2ALDH1A1 PRUNE1 DBR1
FADS2 CELF3 ITGA9 SDF2 CYB5A
REXO2
LACTB2
SPNCRABP2
ENPP1
TBRG4
THADA MYH8
ATOX1CTU2 RGS19
AVEN
FXYD6 DHCR24 ABCA2
SLC39A6
GNPTAB
PDZD2
FZD1 SPRR1A
TARS2
AKR1C1 GSTT2
NCOA2
MET
MED1 HECW2 NCOA3
CENPAHIST1H2BD
RASA1
NFATC1 ATM SKP2
APC ITGB1 RAD50 CSNK1A1TAB1
FAF1
TRIM21
UBXN1
MPG HDAC11
RAD51
GABARAPL2 KRT31
DHX9
GPX7 LRRC40 ADCY3 CYP3A4 FBLN7 TM9SF3 ZDHHC21 HSPH1 SVIL REL LRIF1 TOMM40
AKR1B15 C4BPA GNB2
HIST1H3J
FABP7
MGST1
RAP2C SIL1
KCNE1RGS4
DENR ADKACOT8 DPYSL3
ARHGAP39
NAT14
CASP12
PFKFB4GPM6B
CRYGC CLPP
BNIP1
ITIH2 LCT CREB1
RXRA HCFC1 CCND1
USP11 CDKN1B FKBP5 CDC42 MAP3K7 AXIN1 RIPK1 ANXA7
CDK5
YES1 PRKDC
TMCO3 PGM5 RAB43HIBADH IGHG3 ARHGAP26 RGS9 PTGER1 PTMA DYRK1A
MLH1 PIAS4
GUCA1A AVPR1B
RGN RMDN1 SPAG1 ANKRD7
TOR3A TKTL2 ACADSB
MPC2 YBEY
PGAP1 HIST1H1T
MPI PMP2
RTN1
CAMLG
ITIH4
ATAD1
MYL4
HPCA
PTGIR MZB1
ST7
C12orf57 SLC39A14
RHBDF1 GSTT2B TAF1
CEP162 MYOD1
CDK6
GADD45A
LCK
CSNK1E HERC2
TAF9 RNF11
RAB5C
LNX1
COQ9
UBC
BICDL1
AGAP4 RIMS4 HBE1 GDF15 GHITM VDR SSX2IP HIST2H2AC EPAS1NCK1 SOD1 PIAS1 SUPT5H LATS2
PSEN1
BIRC2
MAP3K5
HMGN5TNFAIP2 PHYHIPL SPNS1 ANKRD13B CCNA2
CBX1 FHL2HAUS1 BCL2L1
AGAP7P ATG4D ZFYVE1 CRYBB2
C15orf57 PNPLA6 GPM6A
SCRN2 NYX NINL ETS1
GTSF1 TTC39C
GLT8D2
TOR4A MIA
SGCZASTL
GSTT1
MT1A
TMBIM6 CD163
AMD1 AMH SLC39A11
CARS2
CYP2S1
UNC119 TERF2IP
RBL1 CUL7
CYP1B1 ARHGAP28 SPRR3 SERPINB11UPK3B FOXB1
TLE1 FAS FZR1
ENPP2CLIC2 TBC1D8 HNF4A TRAF3
SPACA4 BLVRB HTR4 KIT
NCL XRCC6
MTIF2 PDE10A
AVPR1A ODF3L2
GOLGA8A
RGS8
IDI1
MRAP2
ADGRG1 C1RL MGARP PEMT HIST1H3GHIST1H3E
UGT2B10 KCNIP1 RNF121 TMEM17
SLC5A3 ALOX5AP KCNJ6
HTR3A
LOXL3 KCNJ3 CEND1 TP53AIP1
C2orf50 LOC100996763
CMTM8 KCNJ5
APOLD1
HIST1H3B
CYP1A2 GLB1L3
TMEM263
LTC4S HKDC1
N6AMT1 MT1E PLA2G2D
LRRC4
SLC52A2
IGKV3-20
GPRC5B
HHIPL2 DSEL

KCNJ9

UGT2B7

(a) (b) (c)

Figure 5: Protein-protein interaction network of the Simiao Powder.

Response to lipopolysaccharide
Response to molecule of bacterial origin
Response to oxidative stress
Response to reactive oxygen species
Cellular response to chemical stress

BP
Response to metal ion
Response to nutrient levels
Response to steroid hormone
Cellular response to oxidative stress
Response to antibiotic
Transcription regulator complex
RNA polymerase II transcription regulator complex q value
Protein kinase complex
Serine/threonine protein kinase complex
Membrane raft 1e − 05

CC
Membrane microdomain
Vesicle lumen 2e − 05
Membrane region
3e − 05
Cyclin−dependent protein kinase holoenzyme complex
Nuclear chromatin
DNA−binding transcription factor binding
Heme binding
Tetrapyrrole binding
RNA polymerase II−specific DNA−binding transcription factor binding
Nuclear receptor activity
MF

Ligand−activated transcription factor activity

DNA−binding transcription activator activity, RNA polymerase II−specific
DNA−binding transcription activator activity
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen
Ubiquitin−like protein ligase binding
0 10 20 30
Figure 6: GO functional enrichment analysis.GO analysis of putative targets. The y-axis demonstrates the top 10 significantly enriched BP,
CC, and MF categories, whereas the x-axis displays the number of enrichment genes of these terms (P < 0.05). The color denotes the different
P value range, and the redder it is, the more significant enrichment.

consequently lowers the expression of proinflammatory uric acid level and the formation of ROS, consequently
cytokine IL-1β [26, 27]. The pathogenesis of GA is highly reducing the deposition of gout urate crystals [29]. Ad-
associated with the inflammatory cascade induced by the ditional studies found that quercetin could reduce serum
activation of the inflammatory bodies of NLRP3 [2]. Thus, uric acid levels in hyperuricemia mice and impede renal
the inhibitory effect of rutaecarpine on the inflammatory insufficiency. This was achieved via the regulation of renal
body activation of NLRP3 may influence GA treatment. organic ion transport protein and uromodulin, and dem-
Besides, quercetin and kaempferol may significantly elevate onstrated fewer side effects than allopurinol [30, 31]. Beta-
the total antioxidant capacity and inhibit the xanthine sitosterol (SIT), the main compound among various
oxidase (XOD) effect in hyperuricemia rats [28]. In another phytosterols, can reduce the expression of chemokines and
study, inhibition of XOD activity could reduce the serum inflammatory cytokines. It then regulates various biological
8 Evidence-Based Complementary and Alternative Medicine

AGE-RAGE signaling pathway in diabetic complications

Fluid shear stress and atherosclerosis
Kaposi sarcoma−associated herpesvirus infection
IL-17 signaling pathway
Hepatitis B
Small cell lung cancer
TNF signaling pathway
Hepatitis C
Prostate cancer
Human cytomegalovirus infection
Measles
Pancreatic cancer
q value
Bladder cancer
Epstein-Barr virus infection
5.0e − 12
Colorectal cancer
Toxoplasmosis 1.0e − 11
Endocrine resistance 1.5e − 11
Chagas disease
p53 signaling pathway 2.0e − 11
Apoptosis
Influenza A
Osteoclast differentiation
Relaxin signaling pathway
HIF-1 signaling pathway
Platinum drug resistance
Human papillomavirus infection
Chronic myeloid leukemia
Human T-cell leukemia virus 1 infection
Hepatocellular carcinoma
Toll-like receptor signaling pathway
0 10 20
Figure 7: KEGG pathway enrichment analysis. Note. KEGG enrichment analysis of putative targets. The y-axis outlines the top 30
significantly enriched KEGG pathways, whereas the x-axis displays the number of enrichment genes of these terms (P < 0.05). The color
denotes the different P value range; the redder it is, the more significant enrichment.

functions, including anti-inflammatory, analgesic, immu- CDK2. In consequence, a reduction in chemotaxis of

nomodulatory, and antimicrobial functions [32, 33]. Also, primary neutrophils outlines the role of CDK2 in regu-
stigmasterol can inhibit the inflammation induced by so- lating inflammation [39]. Estrogen receptor 1 (ESR1) is a
dium urate crystals and XOD activity in mice, a phe- subtype of human ESR, expressed in chondrocytes, stromal
nomenon that validates its antigout effect [34]. cells, and osteoblasts [41]. In particular, ESR can induce the
Herein, to obtain the core target proteins of SMP in the transcription of related target genes to promote the pro-
treatment of GA disease, the PPI network of intersecting liferation and differentiation of tissue cells as they bind to
target proteins was constructed. Also, we performed two estrogen [42]. Heat shock protein family A member 5
topological screens on the SMP target for GA treatment (HSPA5) gene can also participate in the inflammatory
based on DC, BC, CC, and EC. TP53, FN1, ESR1, CDK2, process of various types of osteoarthritis as it encodes the
and HSPA5 were the five core target proteins. Based on the binding immunoglobulin protein (BiP) of the endoplasmic
existing reports, TP53, also known as p53, contributes to reticulum Hsp70 family [43].
transcriptional regulation of the cell cycle, DNA repair, cell Following the KEGG signal pathway analysis, the
survival, and cell metabolism [35]. Inhibition of p53 exerts mechanisms of SMP in the treatment of AGA were mainly
a substantial effect on promoting the senescence of anti-inflammation and protection of the cartilage. The
IL-1β-induced chondrocytes [36]. The potential role of critical inflammatory signaling pathways included TNF and
TP53 in the regulation of inflammation has been described, IL-17, whereas the apoptosis signaling pathways included
whereby it significantly inhibits the production of proin- p53 and HIF.
flammatory factor IL-6 [37]. The overexpression of FN1 can Current pieces of research on the mechanism of gout
activate TGF-Akt/PI3K/Akt signal pathway to promote cell have reported that the phagocytosis of MSU crystal triggers
viability and differentiation capacity [38]. Cyclin-depen- the change of inflammatory cell state of synovial cells in GA
dent kinase (CDK) is the main regulator of cell division. It pathogenesis [14]. For instance, the deposition of MSU
can be potentially triggered by different cyclins at different crystals promotes the local release of TNF-α and IL-1β,
cell cycle stages [39], and it can regulate the secretion of which causes persistent gout episodes [44]. IL-17 also
inflammatory cytokines in macrophages [40] and inhibit stimulates macrophages and monocytes to produce
Evidence-Based Complementary and Alternative Medicine 9

hsa05169
hsa04668 hsa05160

hsa05162 hsa04115

hsa05145 hsa05212

CASP3 E2F1 IGFBP3 CXCL8 GSTP1 PTGS2 HMOX1

hsa05142 BCL2 FOSL1 EGF CASP8 PRKCA RB1 ALOX5 hsa04657
NFKBIA IRF1 BCL2L1 EGFR CDKN1A ESR1 IL1B
JUN RASSF1 CCNB1 STAT1 ICAM1 BAX CYCS
hsa05163 MAPK1 IL1A RELA SERPINE1 MYC PARP1 MMP2 hsa04933
TP53 GSK3B FOS GSTM2 CDK2 MMP9 NFE2L2
MAPK8 THBD MMP3 NOS2 VEGFA FN1 MAPK14
hsa04210 SELE PPARA GSTM1 IFNG COL3A1 COL1A1 NOS3 hsa01522

VCAM1 CHUK CASP9 CXCL2 CCL2 CCND1 IKBKB

hsa05219 hsa05215

hsa05418 hsa05210

hsa05222 hsa05167
hsa05161

Figure 8: A network of KEGG signaling pathway-gene. Red triangles denote pathways, whereas yellow square nodes denote genes. The
larger the shape of the node is, the more genes or pathways are connected to it.

IL-17 SIGNALLING PATHWAY

IL-17E targeting cells

IL-17E T cells, Macrophage,
Producing cells Nuocyte, Ih2 cell, MMP-type2 cell,
CD4+ T cell, Mast cell, Epithelial cell
Eosinophil, Casp Apoptosis Apoptosis
TRADD FADD
Basophil, IL-17RA Th2 cytokines
IL-17RE
Epithelial cell IL-17RB Induces Th2 cell
NF-kB DNA IL-4 IL-5 IL-13
Act1 TRAF6 responses and
AP-1 Chemokines suppresses Th17 cell
responses
IL-17A and IL-17F IL-17A and IL-17F TARC Eotaxin
Producing cells targeting cells
CD4+ T cell, CD8+ T cell, Epithelial cell, Keratinocyte,
NF-kB signaling
y T, NKT cell, Endothelial cell, Macrophage, IKK pathway
T cell, B cell, Fibroblast IKKγ
LTi-like cell, Epithelial cell TAB2 Chemokines
TRAF3 NF-kB
TAB-3 IKKα CXCL5 CXCL8
ANAPC5 +P CXCL1 CXCL2
+P
A20 TAK1 IKKβ IkBα
CXCL10 CCL2 CCL7 CCL20
TBK1 MAPK signaling Cytokines
pathway
IL-17RA Hsp90 +P +U DNA IL-6 TNFα COX2 Autoimmune pathology
IL-17RA
Act1 TRAF6 MAPKs AP-1 Neutrophil recruitment
IL-17RF IL-17RC G-CSF GM-CSF Immunity to extracellular
Th17 cell +P Anti-microbial pathogens
differentiation TRAF5 C/EBPβ defensin MUC5AC MUC5B
IKKi
Cytokine-cytokine TRAF2 SF2 mRNA
TRAF4 +P S100A7 S100A8 S100A9 LCN2
receptor interaction stability
HuR Tissue remodeling

USP25 MMP1 MMP3 MMP9 MMP13

ERK
IL-17C
Producing cells GSK3β
CD4+ T cell, DC,
Macrophage, Keratinocyte IL-17C targeting cells
Monocyte Inflammatory gene
Inflammation
IL-17RA NF-kB DNA IL-1β TNFα IL-6 IFN-γ
IL-17C Host defence
IL-17RE Act1 TRAF6 Autoimmune
AP-1 Antibacterial peptides
IL-17B Th17 cytokines
Producing cells
Condricytes, Neuron IL-17B targeting cells
Monocyte, Endothelial cell
Inflammatory gene
IL-17RB DNA Proinflammatory
IL-17B NF-kB
IL-17RB Act1 TRAF6 IL-1β TNFα activities
AP-1
IL-17D
Producing cells
CD4+ T cell, B cell IL-17D targeting cells
Endothelial cell, Myeloid progenitor Proinflammatory
activities
IL-17D ?

Figure 9: The IL-17 signaling pathway. The green nodes in the road map denote the genes existing in our SMP network.
10 Evidence-Based Complementary and Alternative Medicine

Table 2: The affinity of the putative compounds with core targets.

Affinity -TP53 Affinity-FN1 (kcal/ Affinity-ESR1 Affinity-CDK2 Affinity -HSPA5 (kcal/
Compound
(kcal/mol) mol) (kcal/mol) (kcal/mol) mol)
Dehydrotanshinone II A −7.6 −4.0 −8.7 −11.5 −8.3
3β-acetoxyatractylone −6.8 −3.3 −8.7 −8.6 −6.9
baicalein −6.6 −4.0 −8.4 −8.7 −9.7
kaempferol −6.4 −3.9 −8.3 −8.4 −8.8
wogonin −6.9 −3.9 −8.3 −8.7 −7.9
quercetin −6.5 −3.9 −8.1 −8.8 −8.2
Phellopterin −6.6 −3.4 −7.9 −8.5 −7.0
phellamurin_qt −7.4 −3.8 −7.2 −9.4 −7.8
Mandenol −4.3 −1.6 −7.1 −6.4 −4.2
rutaecarpine −8.3 −4.2 −7.0 −10.5 −9.6
2-Monoolein −4.9 −2.1 −6.6 −6.5 −4.7
Spinasterol −7.9 −3.8 −6.5 −9.1 −8.3
beta-sitosterol −7.3 −3.4 −6.5 −10.6 −7.6
Phellavin_qt −7.1 −3.7 −6.2 −9.5 −7.7
CLR −7.0 −3.2 −6.1 −9.9 −8.1
poriferast-5-en-3beta-ol −7.6 −3.1 −6.1 −9.9 −7.0
sitosterol −6.8 −3.1 −6.0 −10.2 −7.7
Stigmasterol −7.8 −3.9 −5.9 −9.8 −8.1
Sitosterol alpha1 −7.2 −3.6 −5.6 −9.8 −8.4
Fumarine −7.4 −3.9 −5.5 −9.5 −8.9
Chelerythrine −7.6 −3.6 −5.5 −10.4 −8.2
Worenine −7.7 −4.3 −5.4 −10.9 −9.0
poriferasta-7 −7.1 −3.5 −5.3 −10.4 −7.6
epiberberine −6.8 −3.8 −5.1 −9.4 −8.6
Cavidine −6.9 −3.9 −4.9 −8.7 −8.1
berberine −7.3 −3.8 −4.8 −9.6 −8.0
thalifendine −6.8 −4.0 −4.7 −9.6 −8.3
(S)-Canadine −6.7 −3.8 −4.7 −9.1 −8.1
berberrubine −6.9 −3.8 −4.7 −9.5 −7.6
Inophyllum E −8.6 −4.4 −4.2 −11.7 −9.7
coptisine −7.4 −4.0 −4.2 −10.1 −8.9
Isocorypalmine −6.5 −3.9 −4 −8.7 −7.5
palmatine −6.5 −3.6 −3.6 −8.8 −7.2

proinflammatory factors, including IL-1β, TNF-α, and IFN- chondrocyte apoptosis [53]. p53 can regulate cell differ-
c (Figure 9). As a powerful proinflammatory cytokine, IL-17 entiation and senescence. The inhibition of p53 expression
can increase serum IL-17 levels 8 hours following the acute potentially improves senescence and affects the destruction
attack of gout [45]. Moreover, in several arthritic animal of IL-1β-induced chondrocytes [36]. Compared to the
models, the inhibition of IL-17 expression was found to limit inflammatory signaling pathway, the HIF-1 signaling
inflammation and reduce joint erosion [46]. The TNF sig- pathway is slightly less in gout studies. As a transcription
naling pathway has also proved to be a crucial inflammatory factor, activation of HIF-1α expression in synovial cells
signal pathway. Signal transduction is mediated by TNF may be induced during hypoxia. Synovial hyperplasia
receptor 1 (TNFR1) and receptor-2 (TNFR2). TNFR2 is, in follows the repeated infiltration of inflammatory cells in the
most cases, expressed in immune cells. It binds to TNF-α joint. On the other hand, hypoxia is associated with im-
and TNF-β to regulate immune response [47]. TNF-α is a mune cell infiltration and synovial hyperplasia. Therefore,
proinflammatory cytokine produced by different cell types, the upregulation of synovium-derived HIF-1α occurs in the
such as macrophages, lymphocytes, and fibroblasts, and pathogenesis of rheumatoid arthritis (RA) and osteoar-
reflects inflammation, infection, and other environmental thritis (OA), which are hypoxia-associated diseases
stresses [48]. Previous reports showed that inhibition of [54, 55]. HIF-1α exerts a regulatory role in the function of
TNF-α expression in synovial cells during AGA could ef- immune cells. Activated LPS-induced macrophages can
fectively inhibit local inflammation [49, 50]. also express HIF-1α, which is crucial in glycolysis and the
The physiological dose of soluble uric acid exerts a induction of proinflammation [56]. The therapeutic effect
specific protective effect on cartilage [51]. However, fol- of SMP on AGA may be derived through the regulation of
lowing repeated attacks by GA, the articular cartilage edge the inflammatory signal pathway, p53 apoptosis signal, and
is damaged, the articular surface becomes irregular, the HIF-1signaling pathway. And other top-ranked signaling
joint space becomes narrow, and MSU deposition occurs pathways, such as the AGE-RAGE signaling pathway in
[52]. A study found that reduced articular cartilage matrix diabetic complications, fluid shear stress, and atheroscle-
secretion in patients with GA was associated with rosis, etc., still lack their gout-related studies, which are
Evidence-Based Complementary and Alternative Medicine 11

C23
C22

C24
Arg342 (A)
C21

C25 C16
C20

Phe328 (A) O3 C13

C17
C1
C5 Phe338 (A)
C14
C2 C6
O4C4
C7 C15
O1 C3

C9 C8

O2
Asn345 (A) O5C12 Phe341 (A)
C10

C11 C18

C19
Inophyllum E-TP53

Inophyllum E-TP53
(a) (b)
C11

C14

C1

O4
C7 C2
O1
Ser34 (B) Arg32 (B)
C3 C4

O3
C10
C5 C12
O5C19
C9 C6
C13

C18
C15
O2
C8 C17

C20
C21
Inophyllum E-FN1
C16

C25
C22

C24
C23
Asn35 (B)

Inophyllum E-FN1

(c) (d)
Leu525 (A)

Gly521 (A) Met421 (A)

His524 (A)
C18

C9
C10 Met343 (A)
C8
C19
Ile424 (A) C2 C7
C3

C1
C4 Dehydrotanshinone II A-ESR1
C6
O3 Ala350 (A)
C5
C14
Met388 (A) C11
C13
O1
O2
C12 Leu346 (A)
C15C16

Leu391 (A) C17

Leu387 (A)

Glu353 (A)

Arg394 (A)

Dehydrotanshinone II A-ESR1

(e) (f )
Figure 10: Continued.
12 Evidence-Based Complementary and Alternative Medicine

Asp145 (A)

Phe80 (A)

Leu134 (A)
Phe82 (A)
C23 C22
Val18 (A) C24
C21
C16 C25C20 Ala144 (A)
C17 C13
O3
Lys33 (A) C1 C5 Glu81 (A)
C14 C6 C2
C4 O4
C15 C7
C3O1 O

C8C9 3.11 C
Gly11 (A) O2 N CA
Ala31 (A)
C12 O5
C10
Ile10 (A) CB
C18 C11 CD2
C19
Inophyllum E-CDK2
CG
CD1

Asp86 (A) Gly13 (A)

His84 (A)
Gln85 (A)

Inophyllum E-CDK2
(g) (h)
O C

CA
N
Gly36 (A) Lys96 (A) CG2
CG
CB
Thr37 (A)
O
CE
CD CB
O OG1
C C
NZ

3.17 O5 CA
CA OD1 2.89
N
N
O4
CB CG 2.86
O3
C8 Baicalein-HSPA5
Asp34 (A)
OD2 3.11 O
C9
C4 C7
C1
O2
C Gly227 (A)
CA
C2
C5 O1
C6
Thr38 (A) 3.04 N Gly226 (A)
C3
C10
C15
C11

C14
C12
Tyr39 (A)
C13
Asp391 (A)

Ile61 (A)
Baicalein-HSPA5

(i) (j)

Figure 10: A diagram for the five core targets molecular docking of SMP gouty arthritis treatment.

likely to be the future direction of gout mechanism with Inophyllum E. The target protein CDK2 residue Leu83 (A)
research. forms a hydrogen bond with Inophyllum E, whereas the
According to the space matching and energy matching residues Asp34 (A), Lys96 (A), Thr37 (A), and Gly227 (A) of
relationship between molecules, the core target protein of SMP the target protein HSPA5 form five hydrogen bonds with
in AGA treatment was docked with active compounds. This baicalein. The main forces between ligand and protein are
provides a reference for the subsequent research and devel- hydrophobic force and hydrogen bond, which both are
opment of targeted drugs. The 2D image of molecular docking chemical bonds with strong binding force. According to Ta-
depicts the binding mode between the core target protein and ble 2, key components of SMP have strong binding activity with
the compound as well as the interaction with the surrounding core target proteins, such as TP53, FN1, ESR1, CDK2, and
amino acid residues. Hydrophobic interaction best describes HSPA5, suggesting that SMP may play its pharmacological role
the main association of target protein TP53, FN1, and ESR1 by regulating these key targets. However, there are still some
Evidence-Based Complementary and Alternative Medicine 13

shortcomings in this study, and the conclusions need to be ESR1: Estrogen receptor 1
further verified by in vivo, in vitro, and clinical trials. HSPA5: Heat shock protein family A (Hsp70) member
5
5. Conclusion BiP: Binding immunoglobulin protein
TNFR1: TNF receptor 1
The present study systematically expounds the core com- TNFR2: TNF receptor-2
pounds and molecular action mechanism of SMP in the RA: Rheumatoid arthritis
treatment of AGA. The core compounds of SMP, including OA: Osteoarthritis.
quercetin, kaempferol, wogonin, baicalein, and beta-sitos-
terol, were screened via network pharmacology, whereas the
core targets of AGA including TP53, FN1, ESR1, CDK2, and Data Availability
HSPA5 were screened out via PPI. These core compounds
The data for this study can be provided by the corresponding
are characterized by stable binding activity to the core
author (Wei Liu: [email protected]).
targets. Also, SMP could regulate signal pathways related to
AGA disease, for example, TNF, IL-17, p53, and HIF sig-
naling pathways. These findings suggest the potential syn- Conflicts of Interest
ergistic role of SMP in treating AGA via multiple
There are no conflicts of interest between these authors.
components, multitargets, multiple biological functions, and
multiple signal pathways.
Authors’ Contributions
Abbreviations Yihua Fan, Wei Liu, and Yue Jin have contributed equally to
this work and are co-first authors.
SMP: Simiao Powder
AGA: Acute gouty arthritis
TCM: Traditional Chinese medicine Acknowledgments
IL-17: Interleukin-17
TNF: Tumor necrosis factor The authors would like to thank Freescience (http://www.
HIF-1: Hypoxia-inducible factor 1 home-for-researchers.com) for the help with the English
GA: Gouty arthritis language. This research was financially supported by the
ACR: American College of Rheumatology National Natural Science Foundation of China (Nos.
NSAIDs: Nonsteroidal anti-inflammatory drugs 81673927 and 82074377), the National Key Research and
TCMSP: Traditional Chinese medicine systems Development Project (No. 2018YFC1705201), the Tianjin
pharmacology database and analysis platform Science and Technology Commission Program (No.
OB: Oral bioavailability 2019ZD12), Tianjin Key Specialty Program (20200602-1),
DL: Drug-likeness the Special Scientific Research for Traditional Chinese
OMIM: Online Mendelian Inheritance in Man Medicine (No. 201507001-07), and Qihuang Scholar of the
PharmGKB: Pharmacogenomics Knowledge Base database “Hundred and Thousand” Talent Project of the Inheritance
TTD: Therapeutic Target Database and Innovation of Traditional Chinese Medicine (Qihuang
CTD: Comparative Toxicogenomics Database Project) (No. 201901011w).
PACs: Potential active compounds
PPI: Protein-protein interaction References
DC: Degree centrality
[1] R. Terkeltaub, “What makes gouty inflammation so variable?”
BC: Betweenness centrality
BMC Medicine, vol. 15, no. 1, p. 158, 2017.
CC: Closeness centrality [2] T. Pascart and F. Lioté, “Gout: state of the art after a decade of
EC: Eigenvector centrality developments,” Rheumatology (Oxford, England), vol. 58,
GO: Gene ontology no. 1, pp. 27–44, 2019.
KEGG: Kyoto Encyclopedia of Genes and Genomes [3] M. Tsoi, “Epidemiology of gout in Hong Kong: a population-
BP: Biological process based study from 2006 to 2016,” Arthritis Research & Therapy,
CC: Cellular component vol. 22, no. 1, p. 204, 2020.
MF: Molecular function [4] M. Chen-Xu, “Contemporary prevalence of gout and hy-
PDB: Protein Data Bank peruricemia in the United States and decadal trends: the
ROS: Reactive oxygen species national health and nutrition examination survey,
MSU: Monosodium urate 2007–2016,” Arthritis & Rheumatology (Hoboken, N.J.),
vol. 71, no. 6, pp. 991–999, 2019.
NF-κB: Nuclear factor-kappa B
[5] L. Staurengo-Ferrari, “Trans-chalcone attenuates pain and
MAPK: Mitogen-activated protein kinase inflammation in experimental acute gout arthritis in mice,”
XOD: Xanthine oxidase Frontiers in Pharmacology, vol. 9, p. 1123, 2018.
SIT: Beta-sitosterol [6] D. Khanna, P. P. Khanna, J. D. Fitzgerald et al., “2012
XO: Xanthine oxidase American College of Rheumatology guidelines for manage-
CDK: Cyclin-dependent kinase ment of gout. Part 2: therapy and antiinflammatory
14 Evidence-Based Complementary and Alternative Medicine

prophylaxis of acute gouty arthritis,” Arthritis Care & Re- advancements,” Traditional Medicine Research, vol. 4, no. 5,
search, vol. 64, no. 10, pp. 1447–1461, 2012. p. 257, 2019.
[7] S. Bindu, S. Mazumder, and U. Bandyopadhyay, “Non-steroidal [23] H. Wang, H. Duan, S. Chen et al., “Chinese herbal medicine
anti-inflammatory drugs (NSAIDs) and organ damage: a current si-miao-san decoction for acute gouty arthritis: a protocol for
perspective,” Biochemical Pharmacology, vol. 180, Article ID systematic review and meta-analysis of randomized con-
114147, 2020. trolled trials,” Medicine, vol. 99, no. 32, Article ID e21510,
[8] Y. Jiang, “Colchicine: risk of severe toxicity and death from 2020.
drug overdose,” Chinese Journal of Pharmacoepidemiology, [24] L. Baandrup, S. Dinda, S. DasSharma, R. Banik,
vol. 20, no. 2, p. 102, 2011. A. Chakraborty, and M. Dinda, “Therapeutic potentials of
[9] M. A.-O. Tang, “Integrating network pharmacology with baicalin and its aglycone, baicalein against inflammatory
molecular docking to unravel the active compounds and disorders,” European Journal of Medicinal Chemistry, vol. 131,
potential mechanism of simiao pill treating rheumatoid ar- pp. 68–80, 2017.
thritis,” Evidence-Based Complementary and Alternative [25] D. L. Huynh, T. H. Ngau, N. H. Nguyen, G.-B. Tran, and
Medicine, vol. 2020, Article ID 5786053, 16 pages, 2020. C. T. Nguyen, “Potential therapeutic and pharmacological
[10] X. Lin, “Simiao decoction alleviates gouty arthritis by mod- effects of Wogonin: an updated review,” Molecular Biology
ulating proinflammatory cytokines and the gut ecosystem,” Reports, vol. 47, no. 12, pp. 9779–9789, 2020.
Frontiers in Pharmacology, vol. 11, 2020. [26] Q. Qin, H. Liu, J. Shou, Y. Jiang, H. Yu, and X. Wang, “The
[11] Y.-F. Liu, Y. Huang, C.-Y.-Z. Wen et al., “The effects of inhibitor effect of RKIP on inflammasome activation and
modified simiao decoction in the treatment of gouty arthritis: inflammasome-dependent diseases,” Cellular & Molecular
a systematic review and meta-analysis,” Evidence-Based Immunology, vol. 18p. 992, 1004.
Complementary and Alternative Medicine, vol. 2017, p. 12, [27] J. Luo, X. Wang, X. Jiang et al., “Rutaecarpine derivative R3
2017. attenuates atherosclerosis via inhibiting NLRP3 inflamma-
[12] A. L. Hopkins, “Network pharmacology,” Nature Biotech- some-related inflammation and modulating cholesterol
nology, vol. 25, no. 10, pp. 1110-1111, 2007. transport,” The FASEB Journal, vol. 34, no. 1, pp. 1398–1411,
[13] Y. Wang, “Drug target prediction based on the herbs com- 2020.
ponents: the study on the multitargets pharmacological [28] F. Haidari, “Effects of parsley (Petroselinum crispum) and its
mechanism of qishenkeli acting on the coronary heart dis- flavonol constituents, kaempferol and quercetin, on serum
ease,” Evidence-Based Complementary and Alternative Med- uric acid levels, biomarkers of oxidative stress and liver
icine, vol. 2012, Article ID 698531, 10 pages, 2012. xanthine oxidoreductase aactivity in Oxonate-induced
[14] B. N. Cronstein and P. Sunkureddi, “Mechanistic aspects of hyperuricemic rats,” Iranian Journal of Pharmaceutical Re-
inflammation and clinical management of inflammation in search: IJPR, vol. 10, no. 4, pp. 811–819, 2011.
acute gouty arthritis,” JCR: Journal of Clinical Rheumatology, [29] S. Ahmad, “Therapeutic efficacy of urinile against gouty ar-
vol. 19, no. 1, pp. 19–29, 2013. thritis,” Dose-Response, vol. 18, no. 4, 2020.
[15] M. H. Pillinger and B. F. Mandell, “Therapeutic approaches in [30] Q.-H. Hu, X. Zhang, X. Wang, R.-Q. Jiao, and L.-D. Kong,
the treatment of gout,” Seminars in Arthritis and Rheumatism, “Quercetin regulates organic ion transporter and uromodulin
vol. 50, no. 3, pp. S24–S30, 2020. expression and improves renal function in hyperuricemic
[16] C. Yokose, N. Lu, H. Xie et al., “Heart disease and the risk of mice,” European Journal of Nutrition, vol. 51, no. 5,
allopurinol-associated severe cutaneous adverse reactions: a pp. 593–606, 2012.
general population-based cohort study,” Canadian Medical [31] J. X. Zhu, Y. Wang, L. D. Kong, C. Yang, and X. Zhang,
Association Journal, vol. 191, no. 39, pp. E1070–E1077, 2019. “Effects of Biota orientalis extract and its flavonoid constit-
[17] Y.-F. Huang, C. Bai, F. He, Y. Xie, and H. Zhou, “Review on uents, quercetin and rutin on serum uric acid levels in
the potential action mechanisms of Chinese medicines in oxonate-induced mice and xanthine dehydrogenase and
treating coronavirus disease 2019 (COVID-19),” Pharmaco- xanthine oxidase activities in mouse liver,” Journal of Eth-
logical Research, vol. 158, Article ID 104939, 2020. nopharmacology, vol. 93, no. 1, pp. 133–140, 2004.
[18] X. Zheng, F. Wu, X. Lin, L. Shen, and Y. Feng, “Developments [32] Q. Yang, D. Yu, and Y. Zhang, “β-sitosterol attenuates the
in drug delivery of bioactive alkaloids derived from traditional intracranial aneurysm growth by suppressing TNF-α-mediated
Chinese medicine,” Drug Delivery, vol. 25, no. 1, pp. 398–416, mechanism,” Pharmacology, vol. 104, pp. 303–311, 2019.
2018. [33] S. Babu and S. Jayaraman, “An update on β-sitosterol: a
[19] L. Li, “Insights into the action mechanisms of traditional potential herbal nutraceutical for diabetic management,”
Chinese medicine in osteoarthritis,” Evidence-based Com- Biomedicine & Pharmacotherapy, vol. 131, Article ID 110702,
plementary and Alternative Medicine, vol. 2017, Article ID 2020.
5190986, 13 pages, 2017. [34] C. Martins de Sá Müller, G. B. Coelho, M. Carolina de Paula
[20] X. He, X. Wang, J. Fang et al., “The genus Achyranthes: a Michel Araújo, and D. A. Saúde-Guimarães, “Lychnophora
review on traditional uses, phytochemistry, and pharmaco- pinaster ethanolic extract and its chemical constituents
logical activities,” Journal of Ethnopharmacology, vol. 203, ameliorate hyperuricemia and related inflammation,” Journal
pp. 260–278, 2017. of Ethnopharmacology, vol. 242, Article ID 112040, 2019.
[21] H.-C. Ko, Y.-H. Wang, K.-T. Liou et al., “Anti-inflammatory [35] E. M. Pinto and G. P. Zambetti, “What 20 years of research has
effects and mechanisms of the ethanol extract of Evodia taught us about the TP53 p.R337H mutation,” Cancer,
rutaecarpa and its bioactive components on neutrophils and vol. 126, no. 21, pp. 4678–4686, 2020.
microglial cells,” European Journal of Pharmacology, vol. 555, [36] H. Lu, D. Wang, H. Li et al., “GPR39 agonist TC-G 1008
no. 2-3, pp. 211–217, 2007. ameliorates IL-1β-induced chondrocyte senescence,” Artifi-
[22] W. Yan-Hang and K.-W. Zeng, “Natural products as a crucial cial Cells, Nanomedicine, and Biotechnology, vol. 47, no. 1,
source of anti-inflammatory drugs: recent trends and pp. 2612–2617, 2019.
Evidence-Based Complementary and Alternative Medicine 15

[37] T. Zhang, “p53 predominantly regulates IL-6 production and [53] F. Zhu, L. Yin, and L. Ji, “Suppressive effect of sanmiao
suppresses synovial inflammation in fibroblast-like synovio- formula on experimental gouty arthritis by inhibiting cartilage
cytes and adjuvant-induced arthritis,” Arthritis Research & matrix degradation: an in vivo and in vitro study,” pp. 36–42,
Therapy, vol. 18, no. 1, p. 271, 2016. 2016.
[38] H. Zhang, X. Chen, P. Xue, X. Ma, and J. Li, “FN1 promotes [54] G. George, G. L. Shyni, and K. G. Raghu, “Current and novel
chondrocyte differentiation and collagen production via TGF- therapeutic targets in the treatment of rheumatoid arthritis,”
β/PI3K/Akt pathway in mice with femoral fracture,” Gene, Inflammopharmacology, vol. 28, no. 6, pp. 1457–1476, 2020.
Article ID 145253, 2020. [55] Y. Yu, W. Cai, J. Zhou et al., “Anti-arthritis effect of berberine
[39] A. Y. Hsu, D. Wang, S. Liu et al., “Phenotypical microRNA associated with regulating energy metabolism of macrophages
screen reveals a noncanonical role of CDK2 in regulating through AMPK/HIF-1α pathway,” International Immuno-
neutrophil migration,” Proceedings of the National Academy pharmacology, vol. 87, Article ID 106830, 2020.
of Sciences, vol. 116, no. 37, pp. 18561–18570, 2019. [56] M. Wu, “Chaetocin attenuates gout in mice through inhib-
[40] P. Laphanuwat and S. Jirawatnotai, “Immunomodulatory iting HIF-1α and NLRP3 inflammasome-dependent IL-1β
roles of cell cycle regulators,” Frontiers in Cell and Devel- secretion in macrophages,” Archives of Biochemistry and
opmental Biology, vol. 7, p. 23, 2019. Biophysics, vol. 670, pp. 94–103, 2019.
[41] Y. Oshima, K.-i. Matsuda, A. Yoshida, N. Watanabe,
M. Kawata, and T. Kubo, “Localization of estrogen receptors
alpha and beta. In the articular surface of the rat femur,” Acta
Histochemica et Cytochemica, vol. 40, no. 1, pp. 27–34, 2007.
[42] W. Liu, F. M. Shao, L. Yan, H. X. Cao, and D. Qiu, “Poly-
morphisms in the gene encoding estrogen receptor alpha are
associated with osteoarthritis in Han Chinese women,” In-
ternational Journal of Clinical and Experimental Medicine,
vol. 7, no. 12, pp. 5772–5777, 2014.
[43] J. Wang, J. Lee, D. Liem, and P. Ping, “HSPA5 Gene encoding
Hsp70 chaperone BiP in the endoplasmic reticulum,” Gene,
vol. 618, pp. 14–23, 2017.
[44] Y. Zamudio-Cuevas, J. Fernández-Torres, G. A. Martı́nez-
Nava et al., “Phagocytosis of monosodium urate crystals by
human synoviocytes induces inflammation,” Experimental
Biology and Medicine, vol. 244, no. 5, pp. 344–351, 2019.
[45] Y. Liu, Q. Zhao, Y. Yin, M. A. McNutt, T. Zhang, and Y. Cao,
“Serum levels of IL-17 are elevated in patients with acute
gouty arthritis,” Biochemical and Biophysical Research Com-
munications, vol. 497, no. 3, pp. 897–902, 2018.
[46] M. I. Koenders, E. Lubberts, B. Oppers-Walgreen et al.,
“Blocking of interleukin-17 during reactivation of experi-
mental arthritis prevents joint inflammation and bone erosion
by decreasing RANKL and interleukin-1,” The American
Journal of Pathology, vol. 167, no. 1, pp. 141–149, 2005.
[47] M. K. McCoy and M. G. Tansey, “TNF signaling inhibition in
the CNS: implications for normal brain function and neu-
rodegenerative disease,” Journal of Neuroinflammation, vol. 5,
no. 1, p. 45, 2008.
[48] S. Abramson and Y. Yazici, “Biologics in development for
rheumatoid arthritis: relevance to osteoarthritis,” Advanced
Drug Delivery Reviews, vol. 58, no. 2, pp. 212–225, 2006.
[49] Z. Wang, X. Fan, Y. Xu, K. Chen, X. Yu, and G. Sun, “Efficacy
of Xixiancao (Herba Siegesbeckiae Orientalis) on interactions
between nuclear factor kappa-B and inflammatory cytokines
in inflammatory reactions of rat synovial cells induced by
sodium urate,” Journal of Traditional Chinese Medi-
cine � Chung I Tsa Chih Ying Wen pan, vol. 40, no. 5,
pp. 774–781, 2020.
[50] A. Liu, “The effects of carvacrol on inflammatory cytokines
and the apoptosis of cartilage in rats with gouty arthritis,”
Journal of Clinical and Experimental Medicine, vol. 16, no. 6,
pp. 531–534, 2017.
[51] J. Lai, “Physiological concentrations of soluble uric acid are
chondroprotective and anti-inflammatory,” Scientific Reports,
vol. 7, no. 1, p. 2359, 2017.
[52] F. Oliviero, A. Scanu, and L. Punzi, “Metabolism of crystals
within the joint,” Reumatismo, vol. 63, no. 4, pp. 221–229,
2012.