Int J Med Sci 2020; 17(16):2511-2530. doi:10.7150/ijms.46378

Research Paper

Investigating the mechanism of ShuFeng JieDu capsule for the treatment of novel Coronavirus pneumonia (COVID-19) based on network pharmacology

Xiao Chen1,3, Yun-Hong Yin2, Meng-Yu Zhang1, Jian-Yu Liu1, Rui Li1, Yi-Qing Qu2 Corresponding address

1. Department of Pulmonary and Critical Care Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
2. Department of Pulmonary and Critical Care Medicine, Qilu Hospital, Shandong University, Jinan, China.
3. Department of Respiratory Medicine, Tai'an City Central Hospital, Tai'an, China.

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Citation:
Chen X, Yin YH, Zhang MY, Liu JY, Li R, Qu YQ. Investigating the mechanism of ShuFeng JieDu capsule for the treatment of novel Coronavirus pneumonia (COVID-19) based on network pharmacology. Int J Med Sci 2020; 17(16):2511-2530. doi:10.7150/ijms.46378. Available from http://www.medsci.org/v17p2511.htm

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Abstract

ShuFeng JieDu capsule (SFJDC), a traditional Chinese medicine, has been recommended for the treatment of COVID-19 infections. However, the pharmacological mechanism of SFJDC still remains vague to date. The active ingredients and their target genes of SFJDC were collected from TCMSP. COVID-19 is a type of Novel Coronavirus Pneumonia (NCP). NCP-related target genes were collected from GeneCards database. The ingredients-targets network of SFJDC and PPI networks were constructed. The candidate genes were screened by Venn diagram package for enrichment analysis. The gene-pathway network was structured to obtain key target genes. In total, 124 active ingredients, 120 target genes of SFJDC and 251 NCP-related target genes were collected. The functional annotations cluster 1 of 23 candidate genes (CGs) were related to lung and Virus infection. RELA, MAPK1, MAPK14, CASP3, CASP8 and IL6 were the key target genes. The results suggested that SFJDC cloud be treated COVID-19 by multi-compounds and multi-pathways, and this study showed that the mechanism of traditional Chinese medicine (TCM) in the treatment of disease from the overall perspective.

Keywords: ShuFeng JieDu capsule, Novel Coronavirus Pneumonia, network pharmacology, mechanism, pathway, candidate genes

Introduction

Since December 2019, a novel coronavirus pneumonia (NCP) caused by new coronavirus (SARS-COV-2) has been prevalent in China and other countries, such as United States and Korea [1-3]. WHO named this novel coronavirus pneumonia COVID-19 on February 11, 2020 [4] and there was a total of 20 million reported cases of COVID-19 globally and 750,000 deaths as of August 10, 2020 [5].

Its transmission route is mainly through respiratory droplets, but also through contact transmission, which has the characteristics of rapid spread, strong infectivity and general susceptibility of various groups of people. COVID-19 mild patients present with fever, fatigue, dry cough and other symptoms, whereas severe patients can appear with dyspnea, acute respiratory distress syndrome (ARDS) or septic shock and other symptoms. There is no special drug at present [6,7].

The treatment of COVID-19 mainly consisted of bed rest; intensive supportive treatment; oxygen therapy; antiviral therapy; antimicrobial therapy and Chinese medicine treatment. Critical cases need respiratory support (high flow nasal oxygen therapy, non-invasive ventilator or invasive mechanical ventilator); circulatory support for critically ill patients; plasma treatment from recovered patients and immunotherapy [8,9]. Most of the infectious diseases caused by virus belong to the category of "plague" in ancient Chinese traditional medicine, which is caused by many evil spirits invading the body [10]. The traditional medicine, including traditional Chinese medicine (TCM), has a good therapeutic effect on it [11,12]. The Health and Health Commission of China and the State Administration of traditional Chinese Medicine in the "circular on the issuance of a new type of coronavirus infection pneumonia diagnosis and treatment program (version 5)" requested to strengthen the integration of Chinese and western medicine, and recommended a number of proprietary Chinese medicine in the process of diagnosis and treatment [13]. On the basis of the national plan and in accordance with the principle of "three conditions and conditions", local prevention and control projects have also been successively issued according to local conditions [14]. Recommended Chinese medicines include MaXing ShiGan Tang, QingFei PaiDu Tang, HuoXiang ZhengQi Capsules, JinHua QingGan Granules, LianHua QingWen Capsules or ShuFeng JieDu capsule [8]. One clinical study showed that LianHua QingWen could improve the symptoms of COVID-19 patients and shorten the course of disease [15]. A retrospective analysis study showed that the time of disappearance of clinical symptoms, recovery of body temperature, average length of stay in the integrated Chinese and western medicine treatment group (34) was significantly lower than that of the western medicine group (18) among the 52 COVID-19 patients [16].With QingFei PaiDu Tang combined with western medicine to treat the COVID-19 could significantly improve the patient's symptoms and achieved better results [17].

ShuFeng JieDu capsule (SFJDC) is a traditional Chinese medicine used to treat influenza in China [18]. SFJDC is composed of Polygoni Cuspidati Rhizoma Et Radix (PCRR), Forsythiae Fructus (FF), Isatidis Radix (IR), Herba Patriniae (HP), Phragmitis Rhizoma (PR), Verbenae Herb (VH), licorice (I), Radix Bupleuri (RB) (Table 1). SFJDC has antiviral, anti-inflammatory, antipyretic and immune regulatory effects [19]. SFJDC was commonly used for upper respiratory tract infection, pulmonary infection, AECOPD and other disease [20].This drug now is also recommended for the treatment of COVID-19 infections in the latest Diagnosis and Treatment of Pneumonia Caused by COVID-19 (version 5) [13,21]. Currently, SFJDC is recommended in the Diagnosis and Treatment of Pneumonia Caused by COVID-19 in 5 provinces and cities [22].

Network pharmacology is a new discipline based on the theory of system biology, which analyzes the biological systems and selects specific signal nodes for multi-target drug molecular design. Network pharmacology emphasizes the multi-pathway regulation of signaling pathways and the regulation of multi-component, multi-target, multi-pathway, linking active components in traditional chinese medicine with target genes from molecular and biological aspects [23]. Network pharmacology will help to understand the relationship among ingredients, genes and diseases and is suitable for the study of complex TCM or TCM compounds. The potential mechanism of preventing COVID-19 by HuoXiang ZhengQi oral solution was realized by network pharmacology and molecular docking [24]. The research group Jing Zhao elucidated the mechanism of QingFei PaiDu Tang in the treatment of COVID-19 using network pharmacology [25]. SFJDC could be efficacious for COVID-19, but active incredients, target genes and putative mechanism are not known.

 Table 1 

Herb composition of Shu Feng Jie Du Capsule (SFJDC)

English translationLatin nameChinese name
Hu-ZhangPolygoni Cuspidati Rhizoma Et Radix虎杖
Lian-QiaoForsythiae Fructus连翘
Ban-Lan-GenIsatidis Radix板蓝根
Chai-HuHerba Patriniae柴胡
Bai-Jiang-CaoPhragmitis Rhizoma败酱草
Ma-Bian-CaoVerbenae Herb马鞭草
Lu-Genlicorice芦根
Gan-CaoRadix Bupleuri甘草

In the present study, the network pharmacological was used to investigate the possible mechanism and target of SFJDC in the treatment of COVID-19. COVID-19 is a type of Novel Coronavirus Pneumonia (NCP). The active ingredients and their target genes of SFJDC were collected from TCMSP. NCP-related target genes were collected from GeneCards database. The putative mechanism of SFJDC against NCP were analyzed by GO and KEGG pathway. The flowchart of network pharmacology was shown in Figure 1. The study provided possible theoretical reference for SFJDC in the prevention and treatment of COVID-19.

Materials and Methods

Screening of active Ingredients in SFJDC

We identified the active ingredients of SFJDC from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP http://tcmspw.com/tcmsp.php) [26]. TCMSP is a unique herbal pharmacology platform that captures the relationship between drugs, target genes and diseases. The database includes the detection of natural compounds such as chemical, target and drug target networks. ADME is pharmacokinetics, which refers to the absorption, distribution, metabolism and excretion of exogenous chemicals by myosome. The four key parameters of ADME were blood-brain barrier (BBB), oral bioavailability (OB), Caco-2 permeability (Caco-2) and drug-likeness (DL) [27]. In this study select candidate compounds which has OB≥30%, DL≥ 0.18, Caco-2≥-0.4, BBB≥-0.3.Then we sorted out each active ingredient for identification of targets.

Identification of SFJDC putative target genes

This study used the TCMSP platform to obtain the putative target genes of active ingredients of SFJDC. The Uniprot (https://www.uniprot.org/) [28] database provides a comprehensive, high quality and freely available source of protein sequence and function information. The putative target information corresponding to the active ingredients were input into UniProt database to obtain the standard name of the action target genes.

Screening of NCP related targets

COVID-19 is a type of Novel Coronavirus Pneumonia (NCP). So We collected NCP related targets from GeneCards (https://www.genecards.org/), which is a searchable, integrative database that provides comprehensive, user-friendly information on all annotated and predicted human genes [29]. The key word “Novel Coronavirus Pneumonia” was used in the GeenCards database.

PPI (Protein-Protein Interaction) network construction of SFJDC putative and NCP related target genes

The PPI network of SFJDC putative and NCP related targets would be obtained from STRING (https://string-db.org/ ver11.0, update Jan 2019) [30]. Active interaction sources were set as follows: Textmining, Co-expression, Neighborhood, Experiments, Databases, Gene Fusion and Co-occurrence. The required minimum interaction score was set at 0.4 in PPI network of SFJDC related targets, PPI network of NCP was set at 0.9. The barplot were generated by the R software (https://www.r-project.org/ver 3.6.2) based on counts value.

Construction of SFJDC ingredient-target network

Perl (https://www.perl.org/get.html) is a programming language suitable for writing simple scripts as well as complex applications. We used Strawberry Perl 5.30.1.1 to prepare the ingredient-target network. Cytoscape is a universal open source software for large-scale integrated development of molecular interaction networks working data. Then the ingredients-targets network of SFJDC was constructed using Cytoscape 3.7.2 software [31].

PPI network construction of SFJDC against NCP

In order to reveal the mechanism of SFJDC against NCP, a PPI network was constructed by the BisoGenet client which is a Cytoscape plugin was used to visualize. In this plugin, Protein-protein interactions information is taken from the DIP, BIOGRID, HPRD, INTACT, MINT, BIND [32]. CytoNCA is a Cytoscape plugin integrating calculation, evaluation and visualization analysis for multiple centrality measure measures including Betweenness Centrality (BC), Degree Centrality (DC), Colseness Centrality (CC), Local average connectivity-based method (LAC), Eigenvector Centrality (EC) and Network Centrality (NC) [33].

 Figure 1 

The flowchart of the whole manuscript base on network pharmacology.

Int J Med Sci Image (Click on the image to enlarge.)
 Table 2 

The active ingredients of each herb contained in SFJDC

Mol IDMolecule NameOB (%)Caco-2BBBDLSource
MOL000173wogonin30.680.790.040.23FF
MOL000211Mairin55.380.730.220.78FF; RB
MOL000239Jaranol50.830.61-0.220.29RB
MOL000358beta-sitosterol36.911.320.990.75PR; PCRR; IR; FF; VH
MOL000359sitosterol36.911.320.870.75PR; IR; RB
MOL000392formononetin69.670.780.020.21RB
MOL000449Stigmasterol43.831.4410.76PR; IR; HP; I; VH
MOL000497licochalcone a40.790.82-0.210.29RB
MOL000791bicuculline69.670.720.020.88FF
MOL000953CLR37.871.431.130.68IR
MOL001484Inermine75.180.890.40.54RB
MOL001645Linoleyl acetate42.11.361.080.2HP
MOL001663(4aS,6aR,6aS,6bR,8aR,10R,12aR,14bS)-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-tetradecahydropicene-4a-carboxylic acid32.030.610.390.76VH
MOL001676Vilmorrianine C33.960.590.140.22PR
MOL001677asperglaucide58.020.28-0.220.52PR
MOL001689acacetin34.970.67-0.050.24PR; IR
MOL001697Sinoacutine63.390.720.360.53PR
MOL001749ZINC0386043443.591.040.60.35IR
MOL00175524-Ethylcholest-4-en-3-one36.081.461.220.76IR
MOL001756quindoline33.171.50.990.22IR
MOL001769beta-sitosterol dodecantate34.571.280.570.57IR
MOL001771poriferast-5-en-3beta-ol36.911.451.140.75IR
MOL001774Ineketone37.140.390.10.3IR
MOL001779Sinoacutine49.110.70.390.46IR
MOL001781Indigo38.20.830.020.26IR
MOL001782(2Z)-2-(2-oxoindolin-3-ylidene)indolin-3-one48.40.85-0.060.26IR
MOL0017832-(9-((3-methyl-2-oxopent-3-en-1-yl)oxy)-2-oxo-1,2,8,9-tetrahydrofuro[2,3-h]quinolin-8-yl)propan-2-yl acetate640.39-0.090.57IR
MOL001792DFV32.760.51-0.290.18IR; RB
MOL001793(E)-2-[(3-indole)cyanomethylene-]-3-indolinone54.591.060.220.32IR
MOL001800rosasterol35.871.280.890.75IR
MOL001803Sinensetin50.561.120.040.45IR
MOL001804Stigmasta-5,22-diene-3beta,7alpha-diol43.041.350.840.82IR
MOL001806Stigmasta-5,22-diene-3beta,7beta-diol42.561.370.810.83IR
MOL0018106-(3-oxoindolin-2-ylidene)indolo[2,1-b]quinazolin-12-one45.281.190.480.89IR
MOL001814(E)-3-(3,5-dimethoxy-4-hydroxy-benzylidene)-2-indolinone57.180.690.160.25IR
MOL001820(E)-3-(3,5-dimethoxy-4-hydroxyb-enzylidene)-2-indolinone65.170.28-0.170.25IR
MOL0018283-[(3,5-dimethoxy-4-oxo-1-cyclohexa-2,5-dienylidene)methyl]-2,4-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one51.840.810.030.56IR
MOL002311Glycyrol90.780.71-0.20.67RB
MOL002565Medicarpin49.2210.530.34RB
MOL002773beta-carotene37.182.251.520.58VH
MOL00328120(S)-dammar-24-ene-3β,20-diol-3-acetate40.230.930.280.82FF
MOL003290(3R,4R)-3,4-bis[(3,4-dimethoxyphenyl)methyl]oxolan-2-one52.30.780.170.48FF
MOL003295(+)-pinoresinol monomethyl ether53.080.6900.57FF
MOL003306ACon1_00169785.120.7600.57FF
MOL003308(+)-pinoresinol monomethyl ether-4-D-beta-glucoside_qt61.20.70.120.57FF
MOL0033153beta-Acetyl-20,25-epoxydammarane-24alpha-ol33.070.750.240.79FF
MOL003322FORSYTHINOL81.250.59-0.080.57FF
MOL003330(-)-Phillygenin95.040.750.070.57FF
MOL003344β-amyrin acetate42.061.361.10.74FF
MOL003347hyperforin44.030.870.40.6FF
MOL003348adhyperforin44.030.930.580.61FF
MOL003365Lactucasterol40.990.880.50.85FF
MOL003370Onjixanthone I79.160.840.040.3FF
MOL003656Lupiwighteone51.640.68-0.230.37RB
MOL0038967-Methoxy-2-methyl isoflavone42.561.160.560.2RB
MOL0045983,5,6,7-tetramethoxy-2-(3,4,5-trimethoxyphenyl)chromone31.970.750.080.59HP
MOL004609Areapillin48.960.6-0.290.41HP
MOL004624Longikaurin A47.720.080.090.53HP
MOL004628Octalupine47.820.480.30.28HP
MOL004644Sainfuran79.910.90.230.23HP
MOL004653(+)-Anomalin46.060.4600.66HP
MOL004718α-spinasterol42.981.280.790.76HP
MOL004805(2S)-2-[4-hydroxy-3-(3-methylbut-2-enyl)phenyl]-8,8-dimethyl-2,3-dihydropyrano[2,3-f]chromen-4-one31.7910.250.72RB
MOL004806euchrenone30.291.090.390.57RB
MOL004808glyasperin B65.220.47-0.090.44RB
MOL004810glyasperin F75.840.43-0.150.54RB
MOL004811Glyasperin C45.560.710.070.4RB
MOL004814Isotrifoliol31.940.53-0.250.42RB
MOL004815(E)-1-(2,4-dihydroxyphenyl)-3-(2,2-dimethylchromen-6-yl)prop-2-en-1-one39.620.66-0.120.35RB
MOL004820kanzonols W50.480.630.040.52RB
MOL004828Glepidotin A44.720.790.060.35RB
MOL004829Glepidotin B64.460.46-0.090.34RB
MOL004833Phaseolinisoflavan32.011.010.460.45RB
MOL004835Glypallichalcone61.60.760.230.19RB
MOL0048388-(6-hydroxy-2-benzofuranyl)-2,2-dimethyl-5-chromenol58.4410.340.38RB
MOL004848licochalcone G49.250.64-0.040.32RB
MOL0048493-(2,4-dihydroxyphenyl)-8-(1,1-dimethylprop-2-enyl)-7-hydroxy-5-methoxy-coumarin59.620.4-0.230.43RB
MOL004855Licoricone63.580.53-0.140.47RB
MOL004856RBnin A51.080.80.130.4RB
MOL004857RBnin B48.790.58-0.10.45RB
MOL0048633-(3,4-dihydroxyphenyl)-5,7-dihydroxy-8-(3-methylbut-2-enyl)chromone66.370.52-0.130.41RB
MOL0048662-(3,4-dihydroxyphenyl)-5,7-dihydroxy-6-(3-methylbut-2-enyl)chromone44.150.48-0.280.41RB
MOL004879Glycyrin52.610.59-0.130.47RB
MOL004882Licocoumarone33.210.840.060.36RB
MOL004883Licoisoflavone41.610.37-0.270.42RB
MOL004884Licoisoflavone B38.930.46-0.180.55RB
MOL004885licoisoflavanone52.470.39-0.220.54RB
MOL004891shinpterocarpin80.31.10.680.73RB
MOL004907Glyzaglabrin61.070.34-0.20.35RB
MOL004908Glabridin53.250.970.360.47RB
MOL004910Glabranin52.90.970.310.31RB
MOL004911Glabrene46.270.990.040.44RB
MOL004912Glabrone52.510.59-0.110.5RB
MOL0049131,3-dihydroxy-9-methoxy-6-benzofurano[3,2-c]chromenone48.140.48-0.190.43RB
MOL004915Eurycarpin A43.280.43-0.060.37RB
MOL004941(2R)-7-hydroxy-2-(4-hydroxyphenyl)chroman-4-one71.120.41-0.250.18RB
MOL004945(2S)-7-hydroxy-2-(4-hydroxyphenyl)-8-(3-methylbut-2-enyl)chroman-4-one36.570.72-0.040.32RB
MOL004948Isoglycyrol44.70.910.050.84RB
MOL004957HMO38.370.790.250.21RB
MOL0049591-Methoxyphaseollidin69.981.010.480.64RB
MOL0049663'-Hydroxy-4'-O-Methylglabridin43.7110.730.57RB
MOL0049743'-Methoxyglabridin46.160.940.470.57RB
MOL0049782-[(3R)-8,8-dimethyl-3,4-dihydro-2H-pyrano[6,5-f]chromen-3-yl]-5-methoxyphenol36.211.120.610.52RB
MOL004980Inflacoumarin A39.710.73-0.240.33RB
MOL004985icos-5-enoic acid30.71.221.090.2RB
MOL004988Kanzonol F32.471.180.560.89RB
MOL0049896-prenylated eriodictyol39.220.4-0.290.41RB
MOL0049917-Acetoxy-2-methylisoflavone38.920.740.160.26RB
MOL004996gadelaidic acid30.71.20.940.2RB
MOL005000RBnin G60.440.780.230.39RB
MOL005001RBnin H50.10.6-0.140.78RB
MOL005003Licoagrocarpin58.811.230.610.58RB
MOL005007Glyasperins M72.670.49-0.040.59RB
MOL005012Licoagroisoflavone57.280.710.090.49RB
MOL005016Odoratin49.950.42-0.240.3RB
MOL005017Phaseol78.770.76-0.060.58RB
MOL005018Xambioona54.851.090.520.87RB
MOL005020dehydroglyasperins C53.820.68-0.120.37RB
MOL005229Artemetin49.550.81-0.090.48VH
MOL005503Cornudentanone39.660.470.090.33VH
MOL008752Dihydroverticillatine42.690.560.110.84VH
MOL0132816,8-Dihydroxy-7-methoxyxanthone35.830.680.10.21PCRR
MOL013287Physovenine106.210.510.20.19PCRR
MOL013288Picralinal58.010.23-0.210.75PCRR

Identification of candidate genes (CGs) and enrichment analysis of CGs

The CGs were filtered with R software using the Venn Diagram package (https://cran.r-project.org/web/packages/VennDiagram/index.html). The CGs would be used for Gene Ontology (GO) analysis (including biological processes (BP), molecular functions (MF), and cellular components (CC)) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. GO and KEGG pathway analyses results were processed by the “enrichplot” (http://www.bioconductor.org/packages/release/bioc/html/enrichplot.html) “clusterProfiler” (http://www.bioconductor.org/packages/release/bioc/html/clusterProfiler.html) and “ggplot2” packages by R software. A P value of less than 0.05 was used regarded as statistically significant. At the same time, we input CGs into DAVID (https://david.ncifcrf.gov/) for functional enrichment analysis to obtain disease clustering.

Construction of gene-pathway network

KEGG pathways that had significant changes of P<0.05 were further analyzed. The genes that significantly regulated pathways for gene-pathway network construction. The key target genes of SFJDC against NCP were screened by gene-pathway network.

Results

The active ingredients of each herb contained in SFJDC

One hundred and thirty-seven active ingredients were screened out of TCMSP based on ADME, 4 in PCRR, 17 in FF, 25 in IR, 9 in HP, 7 in PR, 7 in VH, 1 in I, 67 in RB and 13 of which were repeated. Finally, 124 candidate active components of each herb contained in SFJDC were screened for further analysis after removing duplation (Table 2).

Putative target genes of each herb in SFJDC and NCP related target genes

The 124 candidate active components were imported into TCMSP database and Uniport database to identify the Putative target genes of each herb in SFJDC. One hundred and ten components were finally selected after removing 14 ingredients which did not link to any target genes. The target genes of 110 compounds were collected. 1705 genes were identified, 103 in PR, 209 in IR, 65 in HP, 1052 in RB, 75 in PCRR, 173 in FF and 27 in I. There were 1585 genes of the eight herbs overlapped, which was suggestive of potential interaction between the compounds of SFJDCA in the course of treatment. A total of 120 genes were identified after removing duplation (Table 3). And 251 NCP related target genes were identified from Gene Cards database (Table 4).

PPI network of SFJDC putative and NCP related target genes

In this study, we constructed the PPI network of SFJDC putative and NCP related target genes separately. The network of SFJDC putative target genes which minimum interaction score was set at 0.4 contained 119 nodes and 1108 edges which indicated the target genes interactions after removing the discrete points (Figure 2A). According the PPI network, the top thirty genes were listed in Figure 2B. After hiding the discrete points, NCP-related target genes PPI network contained 248 nodes and 1235 edges (Figure 2C). Similarly, the first 30 related genes were shown in Figure 2D.

SFJDC ingredient-target network analysis

The ingredient-target network of SFJDC was constructed using the screened ingredients and their targets as shown in Figure 3. The network contained 117 nodes and 419 edges which indicated the compound-target genes interaction. A median of 110 candidate compouds was 5 degrees which indicating that most compounds of SFJDC were affected by multiple target genes. The top three effective ingredient according were Wogonin, licochalcone a and acacetin. Wogonin, licochalcone a and acacetin have 42, 30 and 23 target genes, respectively. And the OB of Wogonin, licochalcone a and acacetin were 30.68, 40.79 and 34.97%, respectively. Hence, they might be the crucial effective compounds of SFJDC according the network.

PPI network analysis of SFJDC against NCP

PPI network of SFJDC against NCP were visualized using Cytoscape software. The network contained 2407 nodes and 53639 edges was shown in Figure 4A. The average degree of all nodes was 44.5692 and we selected the nodes with more than 44.5692 degrees as significant genes. A subnetwork of significant genes for SFJDC against NCP was constructed which consisted of 766 nodes and 28872 edges (Figure 4B). The average value of BC was 711.9504. The significant genes were further screened and a new network was constructed with 169 nodes and 4238 edges (Figure 4C). 169 genes were eventually identified for SFJDC against NCP including 156 other human genes and 13 target genes.

Identification of candidate genes (CGs) and Enrichment analysis of CGs

Twenty-three candidate genes (CGs) were identified by using the VennDiagram package (Figure 5). Then R software was used to perform GO and KEGG pathway analysis of the CGs. GO of CGs was analyzed based on BP, CC, MF. 1215 GO terms were significantly enriched (P<0.05), 1148 in BP, 28 in CC, 39 in MF. Top 20 terms were shown in Figure 6. The data of top 20 GO analysis were listed in Table 5. Based on these GO terms data, we found that most significantly terms were response to lipopolysaccharide, response to molecule of bacterial origin, membrane raft, membrane microdomain, BH domain binding and death domain binding, suggested that SFJDC could treat NCP with multiple synergies.

The pathways that were significantly affected by SFJDC in the process of treating NCP were identified by KEGG pathway. 110 KEGG pathways were significantly enriched (P<0.05). Top twenty pathways were shown in Figure 7, color represented P value and size of the spot represented count of genes. Based on the analysis of KEGG pathway data (Table 6), the top five pathways such as Kaposi sarcoma-associated herpesvirus infection, AGE-RAGE signaling pathway in diabetic complications, Human cytomegalovirus infection, IL-17 signaling pathway and Hepatitis B, might be the core pharmacological mechanism of SFJDC for NCP.

In this study, we chose the functional annotation clustering and set the classification stringency as high in DAVID. A total of 20 functional annotation clusters were obtained (Table 7). Annotation Cluster 1 (enrichment score 6.04) contains three categories: Asthma, Bronchiolitis Viral, Respiratory Syncytial Virus Infections, respiratory syncytial virus bronchiolitis, and all of them were lung related diseases and Virus infection disease.

 Figure 2 

PPI network of SFJDC putative and NCP related target genes and the Barplot of PPI. (A) PPI network of SFJDC putative target genes. (B) PPI network of NCP related target genes. (C) Barplot showing the significant genes in PPI network of SFJDC. (D) Barplot showing the significant genes in PPI network of NCP. PPI, protein-protein interaction; SFJDC: ShuFeng JieDu capsule; NCP: Novel Coronavirus Pneumonia.

Int J Med Sci Image (Click on the image to enlarge.)
 Table 3 

Putative target genes of each herb in SFJDC

HerbMol IDMolnameTarget genes
FFMOL000173wogoninADRB2 AHSA1 AKT1 AR BAX BBC3 BCL2 CALM1 CASP3 CASP9 CCL2 CCND1 CDK2 CDKN1A CHEK1 DPP4 EIF6 ESR1 FSD1 GABRA1 GSK3B HSP90AA1 IL6 IL8RA JUN KDR MAPK14 MCL1 MMP1 NOS2 PPARG PRKCD PRSS1 PTGER3 PTGS1 PTGS2 RELA RXRA SCN5A TEP1 TNFSF15 TP63
RB FFMOL000211MairinPGR
RBMOL000239JaranolAR CALM1 CDK2 CHEK1 DPP4 ESR2 HSP90AA1 NCOA2 NOS2 PRSS1 PTGS1 PTGS2 SCN5A
PR IR; PCRR; FFMOL000358beta-sitosterolADRA1A ADRA1B ADRB2 BAX BCL2 CASP3 CASP8 CASP9 CHRM1 CHRM2 CHRM3 CHRM4 CHRNA2 DRD1 GABRA1 HSP90AA1 JUN KCNH2 MAP2 NCOA2 OPRM1 PGR PON1 PRKCA PTGS1 PTGS2 SCN5A SLC6A4
PR IR RBMOL000359sitosterolNCOA2 NR3C2 PGR
RBMOL000392formononetinACHE ADRA1A ADRB2 AR ATP5F1B CALM1 CCNA2 CDK2 CHEK1 CHRM1 DPP4 ESR1 ESR2 GSK3B HSD3B1 HSD3B2 HSP90AA1 HTR IL4 JUN MAOB MAPK14 ND6 NOS2 PKIA PPARG PPARG PRSS1 PTGS1 PTGS2 RXRA SLC6A3 SLC6A4
PR IR HP IMOL000449StigmasterolADH1C ADRA1A ADRA1B ADRA2A ADRB1 ADRB2 AKR1B1 CHRM1 CHRM2 CHRM3 CTRB1 GABRA1 IGHG1 LTA4H MAOA MAOB NCOA1 NCOA2 NR3C2 PGR PLAU PTGS1 PTGS2 RXRA SCN5A SLC6A2 SLC6A3
RBMOL000497licochalcone aADRA1B ADRB2 AR BCL2 CA2 CALM1 CCNA2 CCND1 CDK2 CDK4 CHEK1 CHRM1 EIF6 ESR1 ESR2 FOSL2 GSK3B HSP90AA1 MAPK1 MAPK14 NCOA2 NOS2 PPARG PTGS1 PTGS2 RB1 RELA SCN5A SLC6A3 STAT3
FFMOL000791bicucullineACHE ALDH3A1 AR BMPR2 CRH FOS GABBR1 GJA1 GJB1 GNRH1 GNRHR GRIN2D GRM1 GRM5 HSP90AA1 HTR KCNH2 KDR PTGS1 PTGS2 SCN5A SLC6A2 VCP
IRMOL000953CLRNCOA2 NR3C2 PGR
RBMOL001484InermineADRA1B ADRA1D ADRB2 CALM1 CHRM1 CHRM3 HSP90AA1 HTR3A IGHG1 OPRM1 PRSS1 PTGS1 PTGS2 RXRA SCN5A
HPMOL001645Linoleyl acetateNCOA2 PTGS1 PTGS2 RXRA
PRMOL001677asperglaucideHTR KCNH2 PRSS1 PTGS2
PR; IRMOL001689acacetinADRB2 AR BAX BCL2 CALM1 CASP3 CASP8 CDK2 CDKN1A CHEK1 CYP19A1 DPP4 FASLG FASN HSP90AA1 NCOA1 NCOA2 NOS2 PRSS1 PTGS1 PTGS2 RELA TP63
PRMOL001697SinoacutineACHE ADRA1A ADRA1B AR CHRM1 CHRM2 CHRM3 CHRM4 CHRM5 ESR1 ESR2 GABRA1 HTR OPRD1 OPRM1 PTGS1 PTGS2 SCN5A
IRMOL001749ZINC03860434ADRB2 CHRM1 CHRM3 SCN5A
IRMOL00175524-Ethylcholest-4-en-3-oneNR3C2 PGR
IRMOL001756quindolineMAOB NCOA2 PKIA PTGS1 PTGS2
IRMOL001771poriferast-5-en-3beta-olNCOA2 PGR
IRMOL001774IneketoneNR3C2
IRMOL001779SinoacutineACHE ADRA1B AR CALM1 CHRM1 CHRM3 CHRM5 DPP4 ESR1 ESR2 HSP90AA1 HTR NOS2 OPRD1 OPRM1 PTGS1 PTGS2 RXRA SCN5A
IRMOL001781IndigoCCNA2 CDK2 PTGS1 PTGS2 RXRA
IRMOL001782(2Z)-2-(2-oxoindolin-3-ylidene)indolin-3-oneAR CCNA2 CDK2 CHEK1 ESR1 GABRA1 GSK3B HSP90AA1 MAPK14 NOS2 PTGS1 PTGS2 RXRA
IRMOL0017832-(9-((3-methyl-2-oxopent-3-en-1-yl)oxy)-2-oxo-1,2,8,9-tetrahydrofuro[2,3-h]quinolin-8-yl)propan-2-yl acetateHSP90AA1 KCNH2 NCONA2 PRSS1 PTGS2
IR RBMOL001792DFVADRB2 ESR1 HSP90AA1 MAOB PKIA PTGS1 PTGS2 RXRA SLC6A4
IRMOL001793(E)-2-[(3-indole)cyanomethylene-]-3-indolinoneAR CCNA2 CDK2 CHEK1 ESR1 GSK3B HSP90AA1 MAPK14 NOS2 PTGS1 PTGS2 RXRA
IRMOL001800rosasterolPGR
IRMOL001803SinensetinACHE ADRA1B ADRB2 AR CALM1 CHEK1 DPP4 ESR2 F7 HSP90AA1 HTR KCNH2 NCOA1 NCOA2 NOS2 PRSS1 PTGS1 PTGS2 SCN5A
IRMOL001804Stigmasta-5,22-diene-3beta,7alpha-diolNCOA2 PGR
IRMOL0018106-(3-oxoindolin-2-ylidene)indolo[2,1-b]quinazolin-12-oneESR1 KDR PRSS1 PTGS1 PTGS2
IRMOL001814(E)-3-(3,5-dimethoxy-4-hydroxy-benzylidene)-2-indolinoneGABRA1 HSP90AA1 PTGS1 PTGS2 RXRA SCN5A
IRMOL001820(E)-3-(3,5-dimethoxy-4-hydroxyb-enzylidene)-2-indolinoneADRB2 CHRM1 GABRA1 HSP90AA1 PTGS1 PTGS2 RXRA SCN5A
IRMOL0018283-[(3,5-dimethoxy-4-oxo-1-cyclohexa-2,5-dienylidene)methyl]-2,4-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-oneF7 HSP90AA1 KCNH2 PRSS1 PTGS1 PTGS2 SCN5A
RBMOL002311GlycyrolCCNA2 CHEK1 ESR1 GSK3B HTR KDR MAPK14 NOS2 PPARG PTGS2
RBMOL002565MedicarpinADRA1A ADRA1B ADRA1D ADRB2 CALM1 CCNA2 CDK2 CHRM1 CHRM2 CHRM3 CHRM4 CHRM5 DPP4 DRD1 ESR1 ESR2 HSP90AA1 MAPK10 NOS2 OPRD1 OPRM1 PRSS1 PTGS1 PTGS2 RXRA SCN5A SLC6A3 SLC6A4
FFMOL003290(3R,4R)-3,4-bis[(3,4-dimethoxyphenyl)methyl]oxolan-2-oneADRA1B ADRA1D ADRB2 CALM1 CHRM3 ESR1 F7 HSP90AA1 KCNH2 NCOA2 PTGS2 SCN5A SLC6A3
FFMOL003295(+)-pinoresinol monomethyl etherADRA1B ADRB2 CALM1 HSP90AA1 KCNH2 NCOA1 NCOA2 PTGS1 PTGS2 RXRA RXRB SCN5A
FFMOL003306ACon1_001697ADRA1B ADRB2 CALM1 HSP90AA1 KCNH2 NCOA1 NCOA2 PTGS1 PTGS2 SCN5A
FFMOL003308(+)-pinoresinol monomethyl ether-4-D-beta-glucoside_qtADRB2 CALM1 HSP90AA1 KCNH2 NCOA1 NCOA2 PTGS2 SCN5A
FFMOL0033153beta-Acetyl-20,25-epoxydammarane-24alpha-olNR3C1
FFMOL003322FORSYTHINOLADRA1B ADRB2 CALM1 HSP90AA1 KCNH2 NCOA1 NCOA2 PTGS2 SCN5A
FFMOL003330(-)-PhillygeninADRA1B ADRB2 CALM1 CHRM1 CHRM3 CHRM5 HSP90AA1 IGHG1 KCNH2 NCOA2 PTGS2 SCN5A
FFMOL003347hyperforinCYP3A4 ICAM1 IL8RA NR1I2
FFMOL003370Onjixanthone ICALM1 CHEK1 DPP4 ESR2 HSP90AA1 NOS2 PTGS1 PTGS2 RXRA SCN5A
RBMOL003656LupiwighteoneAR CALM1 CCNA2 CDK2 CHEK1 DPP4 ESR1 ESR2 GSK3B HSP90AA1 HTR MAPK14 NCOA2 NOS2 PPARG PRSS1 PTGS2 SCN5A
RBMOL0038967-Methoxy-2-methyl isoflavoneACHE ADRA1B ADRA1D ADRB1 ADRB2 AR CALM1 CCNA2 CDK2 CHEK1 CHRM1 CHRM3 CHRM5 DPP4 DRD1 ESR1 ESR2 GABRA1 GSK3B HSP90AA1 HTR IGHG1 LTA4H MAOB MAPK14 NCOA1 NCOA2 NOS2 OPRM1 PKIA PPARG PRSS1 PTGS1 PTGS2 RXRA SCN5A SLC6A3 SLC6A4
HPMOL0045983,5,6,7-tetramethoxy-2-(3,4,5-trimethoxyphenyl)chromoneACHE AR CALM1 ESR1 ESR2 F7 HTR NCOA2 PRSS1 PTGS2
HPMOL004609AreapillinAR CALM1 DPP4 ESR2 F7 HSP90AA1 HTR IGHG1 NCOA1 NCOA2 NOS2 PRSS1 PTGS2 SCN5A
HPMOL004624Longikaurin ACHRM1 CHRM2 PRSS1
HPMOL004653(+)-AnomalinDPP4 HTR KCNH2 PTGS2
HPMOL004718α-spinasterolNCOA2 NR3C2 PGR
RBMOL004805(2S)-2-[4-hydroxy-3-(3-methylbut-2-enyl)phenyl]-8,8-dimethyl-2,3-dihydropyrano[2,3-f]chromen-4-oneAR CALM1 ESR1 ESR2 GSK3B KCNH2 MAPK14 NOS2 PPARG PTGS2
RBMOL004806euchrenoneBACE1 CALM1 ESR1 ESR2 KCNH2 NOS2 PTGS2 SCN5A
RBMOL004808glyasperin BACHE AR CALM1 CCNA2 CDK2 DPP4 ESR1 ESR2 F7 GSK3B HSP90AA1 HTR KDR NCOA2 NOS2 PPARG PRSS1 PTGS2
RBMOL004810glyasperin FAR CALM1 CCNA2 CDK2 ESR1 ESR2 GSK3B HSP90AA1 MAPK14 NOS2 PPARG PRSS1 PTGS1 PTGS2 SCN5A
RBMOL004811Glyasperin CACHE AR CALM1 CCNA2 CDK2 CHEK1 DPP4 ESR1 ESR2 GSK3B HSP90AA1 HTR KCNH2 MAPK14 NCOA2 NOS2 PPARG PRSS1 PTGS2 RXRA SCN5A
RBMOL004814IsotrifoliolAR CCNA2 CDK2 CHEK1 ESR1 ESR2 GSK3B HSP90AA1 MAPK14 NOS2 PTGS2
RBMOL004815(E)-1-(2,4-dihydroxyphenyl)-3-(2,2-dimethylchromen-6-yl)prop-2-en-1-oneADRA1B AR CA2 CALM1 CCNA2 CDK2 CHEK1 ESR1 ESR2 GSK3B MAPK14 NCOA2 NOS2 PPARG PTGS1 PTGS2 RXRA SCN5A
RBMOL004820kanzonols WAR CALM1 CCNA2 CDK2 CHEK1 ESR1 ESR2 GSK3B MAPK14 NCOA1 NCOA2 NOS2 PPARG PRSS1 PTGS1 PTGS2 RXRA SCN5A
RBMOL004828Glepidotin AAR CALM1 CCNA2 CDK2 CHEK1 DPP4 ESR1 F7 GSK3B HSP90AA1 HTR IGHG1 KDR MAPK14 NOS2 PPARG PRSS1 PTGS1 PTGS2 RXRA SCN5A
RBMOL004829Glepidotin BADRA1B CALM1 ESR1 F7 HSP90AA1 IGHG1 NCOA1 PTGS1 PTGS2 RXRA SCN5A
RBMOL004833PhaseolinisoflavanACHE ADRA1B ADRB2 AR CALM1 CCNA2 CDK2 CHEK1 CHRM1 ESR1 ESR2 GSK3B MAPK14 NCOA1 NOS2 PPARG PRSS1 PTGS2 RXRA SCN5A
RBMOL004835GlypallichalconeADRA1B ADRB2 AR CA2 CALM1 CCNA2 CDK2 CHEK1 CHRM1 ESR1 ESR2 GSK3B HSP90AA1 LTA4H MAOB MAPK14 NCOA1 NOS2 PKIA PPARG PTGS1 PTGS2 SCN5A SLC6A3 SLC6A4
RBMOL0048388-(6-hydroxy-2-benzofuranyl)-2,2-dimethyl-5-chromenolESR1 HSP90AA1 NOS2 PTGS2 RXRA
RBMOL004848licochalcone GAR CALM1 CCNA2 CDK2 ESR1 ESR2 GSK3B HSP90AA1 IGHG1 KDR MAPK14 NCOA2 NOS2 PPARG PTGS2
RBMOL0048493-(2,4-dihydroxyphenyl)-8-(1,1-dimethylprop-2-enyl)-7-hydroxy-5-methoxy-coumarinAR CALM1 CDK2 CHEK1 DPP4 ESR1 ESR2 F7 GSK3B HSP90AA1 HTR KCNH2 KDR MAPK14 NCOA1 NCOA2 NOS2 PPARG PRSS1 PTGS2
RBMOL004855LicoriconeAR CALM1 CHEK1 ESR1 HTR KCNH2 KDR NCOA2 NOS2 PPARG PRSS1 PTGS2
RBMOL004856RBnin AACHE AR CALM1 CCNA2 CHEK1 DPP4 ESR1 ESR2 GSK3B HSP90AA1 HTR NCOA2 NOS2 PPARG PRSS1 PTGS2 SCN5A
RBMOL004857RBnin BADRA1B ADRB2 AR CALM1 CCNA2 CHEK1 DPP4 ESR1 ESR2 F7 GSK3B HSP90AA1 HTR KDR NCOA2 NOS2 PPARG PRSS1 PTGS2
RBMOL0048633-(3,4-dihydroxyphenyl)-5,7-dihydroxy-8-(3-methylbut-2-enyl)chromoneAR CALM1 CCNA2 CDK2 CHEK1 ESR1 GSK3B HSP90AA1 HTR MAPK14 NCOA2 NOS2 PPARG PRSS1 PTGS2
RBMOL0048662-(3,4-dihydroxyphenyl)-5,7-dihydroxy-6-(3-methylbut-2-enyl)chromoneADRB2 AR CALM1 CCNA2 CDK2 CHEK1 DPP4 F7 HSP90AA1 HTR PPARG PRSS1 PTGS2 SCN5A
RBMOL004879GlycyrinAR CALM1 CHEK1 DPP4 ESR1 ESR2 HTR KCNH2 KDR NCOA2 NOS2 PPARG PRSS1 PTGS2
RBMOL004882LicocoumaroneAR CCNA2 CDK2 ESR1 ESR2 GSK3B HSP90AA1
RBMOL004883LicoisoflavoneAR CALM1 CCNA2 CDK2 CHEK1 DPP4 ESR1 HSP90AA1 HTR KDR MAPK14 NCOA2 NOS2 PPARG PRSS1 PTGS2
RBMOL004884Licoisoflavone BACHE AR CALM1 CCNA2 CDK2 CHEK1 ESR1 ESR2 GSK3B HTR NOS2 PPARG PRSS1 PTGS2
RBMOL004885licoisoflavanoneACHE AR CALM1 CCNA2 CDK2 ESR1 ESR2 F7 GSK3B HSP90AA1 NCOA1 NOS2 PPARG PRSS1 PTGS1 PTGS2 SCN5A
RBMOL004891shinpterocarpinADRA1B ADRA1D ADRB2 AR CALM1 CCNA2 CDK2 CHRM1 CHRM3 ESR1 ESR2 GSK3B HTR3A KCNH2 MAPK14 NCOA1 NOS2 OPRD1 OPRM1 PPARG PRSS1 PTGS1 PTGS2 RXRA RXRB SCN5A
RBMOL004907GlyzaglabrinAR CCNA2 CDK2 CHEK1 DPP4 ESR1 ESR2 GSK3B HSP90AA1 MAPK14 NOS2 PPARG PRSS1 PTGS1 PTGS2
RBMOL004908GlabridinACHE ADRA1B ADRB2 AR CALM1 CCNA2 CDK2 CHEK1 CHRM1 ESR1 ESR2 GSK3B IGHG1 MAPK14 NCOA1 NCOA2 NOS2 PPARG PRSS1 PTGS2 RXRA RXRB SCN5A
RBMOL004910GlabraninCALM1 ESR1 HSP90AA1 NOS2 PTGS1 PTGS2 SCN5A
RBMOL004911GlabreneADRB2 AR CALM1 CDK2 ESR1 ESR2 GSK3B HSP90AA1 MAPK14 NCOA2 NOS2 PPARG PRSS1 PTGS1 PTGS2 RXRA SCN5A
RBMOL004912GlabroneACHE AR CALM1 CCNA2 CDK2 CHEK1 DPP4 ESR1 ESR2 GSK3B HTR MAPK14 NOS2 PPARG PRSS1 PTGS1 PTGS2 RXRA SCN5A
RBMOL0049131,3-dihydroxy-9-methoxy-6-benzofurano[3,2-c]chromenoneCCNA2 CDK2 CHEK1 ESR1 ESR2 GSK3B HSP90AA1 MAPK14 PPARG
RBMOL004915Eurycarpin AAR CALM1 CCNA2 CDK2 CHEK1 DPP4 ESR1 ESR2 GSK3B HSP90AA1 HTR MAPK14 NOS2 PPARG PRSS1 PTGS2 SCN5A
RBMOL004941(2R)-7-hydroxy-2-(4-hydroxyphenyl)chroman-4-onePTGS1 ESR1 PTGS2 RXRA ADRB2 HSP90AA1 MAOB PKIA CALM1 GABRA1 SLC6A4
RBMOL004945(2S)-7-hydroxy-2-(4-hydroxyphenyl)-8-(3-methylbut-2-enyl)chroman-4-oneNOS2
RBMOL004948IsoglycyrolAR DPP4 ESR1 GSK3B NOS2 PTGS2
RBMOL004957HMOADRB2 AR CALM1 CCNA2 CDK2 CHEK1 CHRM1 DPP4 ESR1 ESR2 GSK3B IGHG1 MAOB MAPK14 NOS2 PKIA PPARG PRSS1 PTGS1 PTGS2 RXRA SCN5A SLC6A3 SLC6A4
RBMOL0049591-MethoxyphaseollidinADRA1B ADRA1D ADRB2 AR CALM1 CCNA2 CDK2 ESR1 ESR2 GSK3B HSP90AA1 HTR KCNH2 KDR MAPK14 NCOA1 NCOA2 NOS2 PPARG PRSS1 PTGS1 PTGS2 RXRA SCN5A
RBMOL0049663'-Hydroxy-4'-O-MethylglabridinADRA1B ADRB2 AR CALM1 CCNA2 CDK2 CHEK1 ESR1 ESR2 F7 GSK3B HSP90AA1 KCNH2 KDR MAPK14 NCOA1 NCOA2 NOS2 PPARG PRSS1 PTGS1 PTGS2 SCN5A
RBMOL0049743'-MethoxyglabridinACHE ADRA1B ADRB2 AR CALM1 CCNA2 CDK2 CHEK1 ESR1 ESR2 F7 GSK3B HSP90AA1 KCNH2 MAPK14 NCOA1 NCOA2 NOS2 PPARG PRSS1 PTGS1 PTGS2 RXRA SCN5A
RBMOL0049782-[(3R)-8,8-dimethyl-3,4-dihydro-2H-pyrano[6,5-f]chromen-3-yl]-5-methoxyphenolACHE ADRA1B ADRB2 AR CALM1 CCNA2 CDK2 CHEK1 CHRM1 CHRM3 ESR1 ESR2 GSK3B KCNH2 MAPK14 NCOA1 NCOA2 NOS2 PPARG PRSS1 PTGS1 PTGS2 RXRA RXRB SCN5A SLC6A3
RBMOL004980Inflacoumarin AADRB2 AR CALM1 DPP4 ESR1 HSP90AA1 HTR NCOA2 PPARG PRSS1 PTGS1 PTGS2 SCN5A
RBMOL004985icos-5-enoic acidNCOA2
RBMOL004988Kanzonol FAR CALM1 ESR1 ESR2 NCOA2 PTGS2
RBMOL0049896-prenylated eriodictyolCALM1 ESR1 F7 HSP90AA1 NOS2 PTGS2 SCN5A
RBMOL0049917-Acetoxy-2-methylisoflavoneACHE ADRA1B ADRA1D ADRB2 AR CALM1 CDK2 CHEK1 DPP4 ESR1 GABRA1 GSK3B HSP90AA1 HTR MAPK14 NCOA2 NOS2 PPARG PRSS1 PTGS1 PTGS2 RXRA SCN5A
RBMOL004996gadelaidic acidNCOA2
RBMOL005000RBnin GAR CALM1 CCNA2 CHEK1 DPP4 ESR1 ESR2 GSK3B HSP90AA1 HTR MAPK14 NCOA2 NOS2 PPARG PRSS1 PTGS2
RBMOL005001RBnin HAR CALM1 CCNA2 ESR1 HSP90AA1 KDR NCOA2 PRSS1 PTGS2
RBMOL005003LicoagrocarpinACHE ADRA1B ADRB2 AR CALM1 CCNA2 CDK2 CHRM1 CHRM3 CHRM5 ESR1 ESR2 GSK3B HSP90AA1 HTR KCNH2 MAPK14 NCOA2 NOS2 PPARG PRSS1 PTGS1 PTGS2 RXRA RXRB SCN5A
RBMOL005007Glyasperins MACHE AR CALM1 CCNA2 CDK2 ESR1 ESR2 F7 GSK3B HSP90AA1 KCNH2 KDR NCOA1 NCOA2 NOS2 PPARD PPARG PRSS1 PTGS1 PTGS2 SCN5A
RBMOL005012LicoagroisoflavoneAR CALM1 CCNA2 CDK2 CHEK1 DPP4 ESR1 ESR2 GSK3B HTR MAPK14 NOS2 PPARG PRSS1 PTGS2 SCN5A
RBMOL005016OdoratinAR CALM1 CCNA2 CDK2 CHEK1 DPP4 ESR1 ESR2 GSK3B HSP90AA1 MAPK14 NCOA2 NOS2 PPARG PRSS1 PTGS1 PTGS2 RXRA SCN5A
RBMOL005017PhaseolAR CCNA2 CDK2 CHEK1 ESR1 GSK3B HSP90AA1 HTR KDR MAPK14 PPARG PTGS2
RBMOL005018XambioonaCALM1 ESR1 ESR2 NCOA2 NOS2 PTGS2
RBMOL005020dehydroglyasperins CADRB2 AR CALM1 CCNA2 CDK2 CHEK1 ESR1 ESR2 HSP90AA1 MAPK14 NCOA2 NOS2 PPARG PRSS1 PTGS2 SCN5A
PCRRMOL0132816,8-Dihydroxy-7-methoxyxanthoneADRB2 CA2 CDK2 CHEK1 DPP4 GSK3B HSP90AA1 MAPK14 PKIA PTGS1 PTGS2
PCRRMOL013287PhysovenineACHE ADRA1A ADRA1B ADRA2B ADRB2 AR CA2 CCNA2 CDK2 CHRM1 CHRM2 CHRM3 CHRNA2 DRD1 ESR1 ESR2 GABRA1 GRIA2 GSK3B HSP90AA1 HTR NOS2 OPRD1 OPRM1 PRSS1 PTGS1 PTGS2 RXRA SCN5A SLC6A2 SLC6A3 SLC6A4
PCRRMOL013288PicralinalAR OPRD1 OPRM1 SCN5A

Gene-pathway network analysis

The construction of gene-pathway network is based on significant enrichment pathway and regulated these ways, which was shown in Figure 8. The V shapes represented pathway and the squares represent target genes in the network. The network showed that RELA was the core target gene which had largest degree. Other five genes also had larger degree such as MAPK1, MAPK14, CASP3, CASP8 and IL6. They might be the key target genes using SFJDC in the process of treating NCP. All of the above analysis could reveal a new strategy for drug development on NCP.

Discussion

The theory of TCM has been formed and developed for thousands of years in China. In China, TCM has a good therapeutic effect on COVID-19, which has been written into the diagnosis and treatment guidelines. The guideline points out that the combination of traditional Chinese and western medicine should be strengthened in the treatment process [34]. SFJDC is a traditional Chinese medicine, mainly used to treat upper respiratory tract infections, such as influenza, sore throat, mumps, streptococcus, etc. [21]. Now, SFJDC has become an effective drug for the treatment of COVID-19 [35]. In recent years, the research on Chinese medicine prescriptions has developed to the level of effective parts, components, components. Network pharmacology can better understand and demonstrate the interaction between multi-component multi-target and disease [36]. This study aims to analyze the active components and potential mechanism of SFJDC in the treatment of COVID-19 through network pharmacology.

In the present study, the ingredients-targets network of SFJDC was constructed using 110 ingredients and 120 targets. The network contained 117 nodes and 419 edges which indicated the compound-target genes interaction. The results showed that most compounds of SFJDC were affected by multiple target genes, such as Wogonin, licochalcone a and acacetin acted on 42, 30 and 23 target genes, respectively. Various compounds of SFJDC may have the same targets to achieve synergy. Wogonin, a naturally occurring flavonoid, has been shown to multi-activity, such as anti-inflammatory, anti-fibrosis, anti-cancer and chondroprotective properties [37]. Study showed that wogonin had an anti-infulenza activity by modulation of AMPK pathway [38]. Licochalcone a, a flavonoid extracted from licorice toot, was known for its anti-inflammatory, anti-cancer, anti-oxidative and anti-bacterial bioactivity [39]. Acacetin, a flavone compound, played an important role in anti-inflammatory and anti-peroxidative [40].

 Table 4 

Known therapeutic target genes for COVID-19

GeneGC IdScoreGeneGC IdScore
TNFGC06P03339733.08ITGALGC16P0304724.07
IL6GC07P02276531.28STAT6GC12M0570954.04
CXCL8GC04P07374031.05BAK1GC06M0335724.03
CD40LGGC0XP13664930.56PIK3CGGC07P1068654.02
IL10GC01M20676730.33FOSGC14P0752784.01
IFNGGC12M06806427.48HELLSGC10P0945014
CRPGC01M15971525.76CPGC03M1491623.96
STAT1GC02M19096422.73APOA1GC11M1168353.95
MBL2GC10M05276022.1RPS27AGC02P0552313.91
TP53GC17M00766119CREBBPGC16M0037263.87
CCL2GC17P03425518.13TFRCGC03M1960273.83
IL2GC04M12245117.68LMAN1GC18M0593273.82
CCL5GC17M03587116.71PLA2G4AGC01P1867983.81
IFNA1GC09P02147816.65CEACAM5GC19P0417093.65
EGFRGC07P05501916.29PRKCAGC17P0663023.65
CXCL10GC04M07602115.3EIF2S1GC14P0673593.65
TGFB1GC19M04130114.98CLEC12AGC12P0099513.61
IL1BGC02M11282913.78SUMO1GC02M2022063.59
ACE2GC0XM01549412.32CCR3GC03P0462273.56
CSF2GC05P13207311.95UBBGC17P0163803.53
PPARGGC03P01228711.93MAPKAPK2GC01P2066843.48
CCR5GC03P04638411.37CD3DGC11M1183383.47
CXCL9GC04M07600111.3CHKBGC22M0505783.43
GPTGC08P14450211.12PPIAGC07P0448083.43
MAPK1GC22M02175411.09RUNX1GC21M0347873.42
CASP3GC04M18462710.88BCL2L1GC20M0316643.4
IFNB1GC09M02107710.77GZMAGC05P0551023.38
ALBGC04P07339710.68IRF1GC05M1324813.35
FGF2GC04P12282610.53CD81GC11P0023773.35
SFTPDGC10M07993710.47CST3GC20M0236083.29
CXCR3GC0XM07161510.18PTGS1GC09P1223703.24
IL4GC05P13267310.12F10GC13P1131223.22
HLA-BGC06M0312899.84CBLGC11P1192063.18
CD79AGC19P0418779.73CXCL11GC04M0760333.13
CXCL2GC04M0740979.61MAVSGC20P0038273.12
ACEGC17P0634779.6KPNB1GC17P0476493.1
TMPRSS2GC21M0414649.59SLC17A5GC06M0735933.07
IRF3GC19M0496599.51ITGA5GC12M0543963
MAPK3GC16M0301179.37ARF1GC01P2280822.99
IL17AGC06P0521869.29IFNL1GC19P0392962.97
IL5GC05M1325419.27GRB2GC17M0753182.86
ICAM1GC19P0102709.22CD3EGC11P1183042.84
CCL3GC17M0360889.2ATF2GC02M1750722.78
IL13GC05P1326569.19CEACAM3GC19P0417962.72
MAPK8GC10P0483069.08HAVCR2GC05M1570632.7
TTRGC18P0315579.04JAK1GC01M0648332.69
IL18GC11M1121438.58NPM1GC05P1713872.67
ANPEPGC15M0897848.58TBK1GC12P0644512.64
PIK3R1GC05P0682158.57F11GC04P1862652.63
CTSLGC09P0877258.52VHLGC03P0102052.63
CD209GC19M0077398.45IL16GC15P0811592.59
DDX58GC09M0324558.2KPNA2GC17P0680352.57
FURINGC15P0908688.08RELBGC19P0450022.57
ADAGC20M0446207.97FCER2GC19M0076892.56
APOEGC19P0449067.97PIK3CBGC03M1386522.55
MAPK14GC06P0460477.77PRSS2GC07P1447312.54
DPP4GC02M1619927.64RAPGEF3GC12M0477362.52
NFKB1GC04P1025017.61BECN1GC17M0428102.51
HLA-AGC06P0332117.44HAVCR1GC05M1570072.48
SERPINE1GC07P1011277.43ISG15GC01P0010012.41
PIK3CAGC03P1791487.27PMLGC15P0739942.41
PTGS2GC01M1866407.24PRKCEGC02P0456512.39
CD14GC05M1406317.16CEACAM1GC19M0425072.38
MX1GC21P0414207.07PIK3CDGC01P0096292.37
IFIH1GC02M1622676.99ERN1GC17M0640392.37
BCL2GC18M0631236.96IFITM1GC11P0003132.36
FCGR2AGC01P1615056.67IRAK3GC12P0661882.35
CDK4GC12M0577436.64NPTX1GC17M0804662.35
HSPA5GC09M1252346.59HFEGC06P0260872.34
BAXGC19P0489546.53TLR10GC04M0387732.33
CCL11GC17P0342856.47SLC40A1GC02M1895602.3
CATGC11P0344606.43LCKGC01P0322512.29
HMOX1GC22P0353806.28EIF2AK3GC02M0886372.27
SOD1GC21P0316596.25POU5F1GC06M0311772.25
G6PDGC0XM1545316.06VAPAGC18P0099042.15
CD4GC12P0067866.01CARD9GC09M1363612.15
TFGC03P1336665.96TRIM25GC17M0568362.13
CTRLGC16M0679275.95HNRNPA1GC12P0542802.05
IL1AGC02M1127735.93CCND3GC06M0419341.99
PIK3C2AGC11M0171655.92MYOM2GC08P0020451.97
PARP1GC01M2263605.91PRKRAGC02M1784311.96
RELAGC11M0656535.89SOCS3GC17M0783561.95
NOS2GC17M0277565.85LCN1GC09P1355211.91
EIF2AK2GC02M0370995.83EIF4EGC04M0988711.91
GAPDHGC12P0066305.81ICAM2GC17M0640021.89
NOS3GC07P1509905.77BST2GC19M0174031.88
CTSBGC08M0118425.72IFITM2GC11P0003001.87
CCL4GC17P0361035.69KPNA4GC03M1604941.83
CASP8GC02P2012335.65DROSHAGC05M0314011.78
ANXA5GC04M1216675.59USP7GC16M0088921.78
F8GC0XM1548355.58CD46GC01P2077521.74
CREB1GC02P2075295.55AHSGGC03P1866121.73
SH2D3AGC19M0067525.54BAG3GC10P1196511.72
HLA-DRB1GC06M0325785.48TMPRSS11AGC04M0679091.69
TMPRSS11DGC04M0678205.38APODGC03M1955681.66
BMP6GC06P0077265.32PRKCBGC16P0238721.64
SMAD3GC15P0670635.2RHOBGC02P0204471.64
MASP2GC01M0110265.13ITGA6GC02P1724271.63
IFITM3GC11M0003195.11STAT2GC12M0563411.62
HLA-CGC06M0312725.11CALM1GC14P0903961.61
BADGC11M0642735.04OAS1GC12P1129061.6
CANXGC05P1796784.97BCL2L2GC14P0250331.6
MCL1GC01M1506734.77IFI27GC14P0941041.6
CCL7GC17P0342704.71PSMC6GC14P0527071.55
CASP6GC04M1096884.7TFR2GC07M1006201.5
EGR1GC05P1384654.66SPI1GC11M0596941.45
ITGB1GC10M0329004.64IGKCGC02M0890811.44
RNASE3GC14P0208914.63PHB2GC12M0069651.44
STING1GC05M1394764.5CD151GC11P0008831.42
CD34GC01M2078804.48ITGA1GC05P0527881.42
DUSP1GC05M1727684.42FAHGC15P0801521.4
RB1GC13P0483034.41NUDT2GC09P0343291.36
ADAM17GC02M0094884.4AQP1GC07P0309111.35
HSPB1GC07P0763024.33TMPRSS13GC11M1179001.32
EEF1A1GC06M0735154.33CD3GGC11P1183441.28
TOLLIPGC11M0012744.31PCSK5GC09P0758901.23
CCR1GC03M0462184.3CBLBGC03M1056551.21
EZRGC06M1587654.27TMEM233GC12P1195941.18
LCN2GC09P1281494.26ANXA11GC10M0801501.13
TRAF3GC14P1043124.23CLEC4DGC12P0085091.1
SMAD7GC18M0489194.18NMRAL1GC16M0044611.07
TXNGC09M1102434.17HPGDSGC04M0942980.84
ICAM3GC19M0103354.15SLC39A14GC08P0223670.83
VCPGC09M0350564.15OR8U9GC11Pi001930.35
NLRP12GC19M0537934.14C8GGC09P1369440.31
ANXA2GC15M0603474.12
 Figure 3 

Ingredient-target network of SFJDC. The blue ovals represent target genes; the green, light blue, yellow, pink, purple and light yellow rectangulars represent the ingredients from PR, IR, HP, RB, PCRR, FF; the red rectangulars represent the ingredients from mlti-herb. PR: Phragmitis Rhizoma; IR: Isatidis Radix; HP: Herba Patriniae; RB:Radix Bupleuri; PCRR: Polygoni Cuspidati Rhizoma Et Radix; FF: Forsythiae Fructus.

Int J Med Sci Image (Click on the image to enlarge.)
 Figure 4 

PPI network of SFJDC against NCP. (A)The whole network of SFJDC against NCP contained 2,407 nodes and 53,639 edges. (B) A subnetwork of significant genes from A consisted of 766 nodes and 28872 edges. (C) PPI network of more significant genes from B with 169 nodes and 4238 edges. BC: Betweenness Centrality; DC: Degree Centrality.

Int J Med Sci Image (Click on the image to enlarge.)
 Table 5 

The data of top twenty GO terms including BP, CC, MF

GO categoryIDDescriptionP-valueP.adjustCount
BPGO:0032496response to lipopolysaccharide1.27E-172.31E-1413
BPGO:0002237response to molecule of bacterial origin2.10E-172.31E-1413
BPGO:0071222cellular response to lipopolysaccharide1.39E-121.02E-099
BPGO:0071219cellular response to molecule of bacterial origin1.89E-121.04E-099
BPGO:0071216cellular response to biotic stimulus4.96E-122.18E-099
BPGO:2001234negative regulation of apoptotic signaling pathway1.96E-107.20E-088
BPGO:0010038response to metal ion2.37E-107.45E-089
BPGO:0048545response to steroid hormone3.89E-101.07E-079
BPGO:0022407regulation of cell-cell adhesion5.82E-101.42E-079
BPGO:0048608reproductive structure development1.05E-092.23E-079
BPGO:0061458reproductive system development1.12E-092.23E-079
BPGO:0009314response to radiation1.48E-092.65E-079
BPGO:0006979response to oxidative stress1.57E-092.65E-079
BPGO:0042110T cell activation2.01E-093.16E-079
BPGO:0034612response to tumor necrosis factor2.19E-093.22E-078
BPGO:0034349glial cell apoptotic process2.37E-093.25E-074
BPGO:0002573myeloid leukocyte differentiation3.55E-094.59E-077
BPGO:0070997neuron death5.17E-096.31E-078
BPGO:0097191extrinsic apoptotic signaling pathway6.78E-097.86E-077
BPGO:0070482response to oxygen levels1.36E-081.50E-068
CCGO:0045121membrane raft1.27E-066.17E-056
CCGO:0098857membrane microdomain1.30E-066.17E-056
CCGO:0098589membrane region1.61E-066.17E-056
CCGO:0005741mitochondrial outer membrane4.97E-050.0012438344
CCGO:0005667transcription factor complex5.41E-050.0012438345
CCGO:0031968organelle outer membrane7.97E-050.0013611414
CCGO:0019867outer membrane8.29E-050.0013611414
CCGO:0046930pore complex0.0003244410.0046638422
CCGO:1904813ficolin-1-rich granule lumen0.0003921710.0050110743
CCGO:0005819spindle0.0006407040.0073680924
CCGO:0090575RNA polymerase II transcription factor complex0.0008698520.0090939093
CCGO:0000307cyclin-dependent protein kinase holoenzyme complex0.0010893460.0104395682
CCGO:0101002ficolin-1-rich granule0.0012534280.0110880153
CCGO:0044798nuclear transcription factor complex0.0015902310.0130626163
CCGO:0005901caveola0.0038919010.0298379112
CCGO:1902554serine/threonine protein kinase complex0.0046880150.033695112
CCGO:0035578azurophil granule lumen0.0050043730.033853112
CCGO:0034774secretory granule lumen0.0059468040.0355108453
CCGO:1904949ATPase complex0.0061279750.0355108452
CCGO:0060205cytoplasmic vesicle lumen0.0068568950.0355108453
MFGO:0051400BH domain binding2.29E-071.91E-053
MFGO:0070513death domain binding2.29E-071.91E-053
MFGO:0019902phosphatase binding3.42E-060.0001708985
MFGO:0033613activating transcription factor binding4.09E-060.0001708984
MFGO:0002020protease binding2.08E-050.0006294254
MFGO:0005126cytokine receptor binding2.82E-050.0006294255
MFGO:0019903protein phosphatase binding2.96E-050.0006294254
MFGO:0031625ubiquitin protein ligase binding3.02E-050.0006294255
MFGO:0044389ubiquitin-like protein ligase binding4.02E-050.0007460425
MFGO:0004707MAP kinase activity0.0001456440.002432262
MFGO:0097153cysteine-type endopeptidase activity involved in apoptotic process0.0001679180.0025493042
MFGO:0004708MAP kinase kinase activity0.0001917550.0026685882
MFGO:0005123death receptor binding0.000217150.0027895472
MFGO:0020037heme binding0.0006875480.0082014683
MFGO:0097718disordered domain specific binding0.0008324590.008830782
MFGO:0046906tetrapyrrole binding0.0008460630.008830783
MFGO:0001085RNA polymerase II transcription factor binding0.0010261330.0097074693
MFGO:0016248channel inhibitor activity0.0011039990.0097074692
MFGO:0016705oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen0.0011044430.0097074693
MFGO:0004712protein serine/threonine/tyrosine kinase activity0.0014124920.0117273162
 Figure 5 

Twenty-three overlapping genes between SFJDC and NCP.

Int J Med Sci Image (Click on the image to enlarge.)

In addition, they have high OB and acacetin from 2 herbs (PR, IR) of SFJDC. The three main ingredients were anti-inflammatory and COVID-19 caused by a series of inflammatory storms. Hence, they might be the crucial effective compounds of SFJDC according the network.

PPI network of SFJDC against NCP were visualized using Cytoscape software to obtain the candidate target genes. In order to obtain the more accurate genes, two parameters including DC and BC were used to screen nodes and structure a new network. 169 genes were eventually identified for SFJDC against NCP including 156 other human genes and 13 target genes.

Twenty-three candidate genes (CGs) were identified by using the VennDiagram package. CGs were enriched in BP, CC, MF by GO enrichment analysis. Based on GO terms data, we found that some terms were response to lipopolysaccharide or bacterial origin, membrane raft, membrane microdomain, BH domain binding and cytokine receptor binding. COVID-19 infections leaded to a strong immune response and inflammatory storm in which a large number of cytokines were activated, so SFJDC might regulate COVID-19 through the above biological processes.

SFJDC, as a TCM formula, has multi-component, multi-target-gene, multi-pathway. In the present study, 110 KEGG pathways were significantly enriched. Seven of the top 20 pathways were associated with viral infection including Kaposi sarcoma-associated herpesvirus infection, Human cytomegalovirus infection, Hepatitis B, Influenza A, Epstein-Barr virus infection, Human immunodeficiency virus 1 infection and Measles, and three were associated with lung disease contained tuberculosis, pertussis and small cell lung cancer. Multiple targets of SFJDC may also inhibit the activation of cytokines and reduce inflammation by regulating cytokine pathways, such as IL-17 signaling pathway and TNF signaling pathway. In this study, we obtained 20 functional annotation clusters through DAVID. Annotation Cluster1 including Asthma, Bronchiolitis Viral, Respiratory Syncytial Virus Infections, respiratory syncytial virus bronchiolitis were lung related diseases and Virus infection disease.

Gene-pathway network was constructed to the core and key target genes. The network showed that RELA had largest degree, was the core target gene. Other top five genes such as MAPK1, MAPK14, CASP3, CASP8 and IL6 might be the key target genes. The pathophysiological process of Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-COV-2) infection is similar to that of SARS-CoV infection, with a strong inflammatory response. The SARS-COV-2 virus mainly targets respiratory epithelial cells, alveolar epithelial cells, vascular endothelial cells and pulmonary macrophages, all of which express Angiotensin converting enzyme 2 (ACE2) receptor, triggering the generation of pro- inflammatory cytokines and chemokines (including IL-6, TNF, IL-10 and MCP1) [41]. The NF-kB family member RELA is a widely expressed and effective transcriptional activator that activates the expression of many inflammatory through exposure to pathogens and inflammatory cytokines [42]. RELA may play an important role in the infection of COVID-19. MAPK1 and MAPK14 are members of the MAPK family, which can regulate multiple cellular processes, such as response to oxidative stress, anti-inflammatory, immune response, apoptosis and cell proliferation [43]. Joseph et al showed SASR-CoV-2 could induce severe inflammation by directly activating p38 MAPK pathway and many p38 MAPK inhibitors are in the clinical stage and should be considered for clinical trial for severe COVID-19 infection [44]. CASP3 and CASP8, a family of cysteine-dependent proteases, play an important role in these events through activation of other apoptotic proteins mediated by proteolysis and cleavage of nuclear proteins [45]. In Krahling's study, infection of 293/ACE2 cells with SARS-CoV activated apoptosis-associated events, such as caspase3, caspase 8[46]. Therefore, we conclude that CASP3 and CASP8 may be activated and play an important role in the pathophysiological process of COVID-19. Higher plasma level of IL-6 was found in ICU patients with COVID-19[47]. Tocilizumab, a recombinant humanized anti-human IL-6 receptor monoclonal antibody, improved the clinical outcome in 20 severe and critical COVID-19 patients and is an effective treatment to reduce mortality [48].

 Figure 6 

Gene ontology terms of CGs. The top 20 GO functional terms were selected (P<0.05). BP: biological processes; CC: cellular components; MF: molecular functions.

Int J Med Sci Image (Click on the image to enlarge.)
 Figure 7 

KEGG pathway enrichment of CGs. The top 20 pathways were identified. Color represented P value and size of the spot represented count of genes.

Int J Med Sci Image (Click on the image to enlarge.)
 Table 6 

The data of top twenty KEGG pathway

IDDescriptionP-valueP.adjustCount
hsa05167Kaposi sarcoma-associated herpesvirus infection5.39E-168.46E-1413
hsa04933AGE-RAGE signaling pathway in diabetic complications1.13E-158.85E-1411
hsa05163Human cytomegalovirus infection6.58E-153.45E-1313
hsa04657IL-17 signaling pathway4.27E-141.68E-1210
hsa05161Hepatitis B2.60E-136.81E-1211
hsa04668TNF signaling pathway2.60E-136.81E-1210
hsa05164Influenza A1.78E-114.00E-1010
hsa05133Pertussis2.57E-115.04E-108
hsa05152Tuberculosis3.16E-115.50E-1010
hsa05169Epstein-Barr virus infection9.46E-111.48E-0910
hsa05170Human immunodeficiency virus 1 infection1.60E-102.29E-0910
hsa05142Chagas disease (American trypanosomiasis)2.86E-103.74E-098
hsa05140Leishmaniasis1.57E-091.90E-087
hsa04210Apoptosis2.89E-093.24E-088
hsa05162Measles3.24E-093.40E-088
hsa05132Salmonella infection4.64E-094.55E-089
hsa01522Endocrine resistance8.69E-098.03E-087
hsa04625C-type lectin receptor signaling pathway1.32E-081.15E-077
hsa05145Toxoplasmosis2.22E-081.83E-077
hsa05130Pathogenic Escherichia coli infection6.53E-085.13E-078

It has been clinically confirmed that SFJDC is effective in the treatment of COVID-19. Wang et al shown that conventional treatment combined with SFJDC treatment for 4 cases of COVID-19 patients could significantly improve symptoms and promote viral negative conversion [49]. Another study including 70 COVID-19 patients found that SFJDC combined with Arbidol for COVID-19 compared with single using Arbidol could significantly shorten the time of clinical symptoms improvement and COVID-19 negative conversion [50].

To summarise, the compound and targets of SFJDC were systematically studied by applying network pharmacology. Wogonin, licochalcone a and acacetin regulated the most targets associated with NCP. RELA, MAPK1, MAPK14, CASP3, CASP8 and IL6 were the core and key genes in the gene-network of SFJDC for the treatment of NCP. SFJDC regulated novel coronavirus pneumonia by multi-compound and multi-target, which provided theoretical support for SFJDC against COVID-19. More mechanism and roles require further clinical validation.

Abbreviations

ACE2: Angiotensin converting enzyme 2; ARDS: acute respiratory distress syndrome; BBB: blood-brain barrier; BC: Betweenness Centrality; BP: biological processes; Caco-2: Caco-2 permeability; CC: cellular components; CC: Colseness Centrality; CG: candidate genes; DC: Degree Centrality; DL: drug-likeness (DL); EC: Eigenvector Centrality; FF: Forsythiae Fructus; GO: Gene Ontology; HP: Herba Patriniae; I: licorice; IR: Isatidis Radix; KEGG: Kyoto Encyclopedia of Genes and Genomes; LAC: Local average connectivity-based method; LHQWG: LianHua QingWen granules; MF: molecular functions; NC: Network Centrality; NCP: Novel Coronavirus Pneumonia; OB: oral bioavailability; PCRR: Polygoni Cuspidati Rhizoma Et Radix; PPI: protein-protein interaction; PR: Phragmitis Rhizoma; RB: Radix Bupleuri; SFJDC: ShuFeng JieDu capsule; SARS-COV-2: Severe Acute Respiratory Syndrome-Coronavirus-2; TCM: Traditional Chinese Medicine; TCMSP: Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform; VH: Verbenae Herb.

 Table 7 

The functional annotation clustering of CGs

Annotation ClusterTermCountP-value
Annotation Cluster 1 (Score:6.04)Asthma|Bronchiolitis, Viral|Respiratory Syncytial Virus Infections78.50E-07
respiratory syncytial virus bronchiolitis78.50E-07
Bronchiolitis, Viral|Respiratory Syncytial Virus Infections71.04E-06
Annotation Cluster 2 (Score:4.91)Coronary Artery Disease|Inflammation55.45E-07
non-Hodgkin lymphoma41.90E-06
Recurrence|Venous Thromboembolism52.48E-06
Arthritis52.66E-06
Brain Ischemia|Hypertension|Osteoporosis|Stroke53.69E-06
diabetes, type 161.38E-05
melanoma52.10E-05
Inflammation|Venous Thromboembolism42.24E-05
Chlamydia Infections|Inflammation|Trachoma42.24E-05
Brain Ischemia|Inflammation|Stroke42.24E-05
Pre-Eclampsia43.32E-04
Migraine Disorders44.52E-04
Annotation Cluster 3 (Score:4.89)Chorioamnionitis|Fetal Membranes, Premature Rupture|Infection of amniotic sac and membranes74.94E-07
Chorioamnionitis|Fetal Membranes, Premature Rupture|Infection of amniotic sac and membranes|Obstetric Labor, Premature|Pre-Eclampsia|Premature Birth75.10E-07
Coronary Artery Disease71.56E-04
Alzheimer's disease87.10E-04
Annotation Cluster 4 (Score:4.44)Hodgkin Disease|Inflammation43.40E-06
Sarcoidosis54.99E-06
Adenocarcinoma|Stomach Neoplasms45.74E-05
kidney failure, chronic52.02E-04
esophageal cancer43.20E-04
Annotation Cluster 5
(Score:4.26)
Lymphoma, Non-Hodgkin|Lymphoma, Non-Hodgkin's53.30E-05
Leukemia, Myelogenous, Chronic, BCR-ABL Positive|Neovascularization, Pathologic44.02E-05
Leukemia, Myelogenous, Chronic, BCR-ABL Positive41.29E-04
Annotation Cluster 6 (Score:4.09)Tuberculosis, Pulmonary52.31E-06
systemic lupus erythematosus58.88E-05
hepatitis C, chronic43.56E-04
Tuberculosis46.16E-04
Annotation Cluster 7 (Score:4.04)Helicobacter Infections|Inflammation|Precancerous Conditions|Stomach Neoplasms49.23E-07
Stomach Neoplasms53.54E-05
patent ductus arteriosus56.13E-05
Cystic Fibrosis41.29E-04
stomach cancer45.46E-04
rheumatoid arthritis40.003880586
Annotation Cluster 8 (Score:3.94)Infection|Inflammation|Premature Birth55.26E-05
Inflammation|Premature Birth55.77E-05
Connective Tissue Diseases|Fetal Diseases|Inflammation|Musculoskeletal Diseases|Pregnancy Complications, Hematologic|Premature Birth|Skin Diseases55.77E-05
Asthma49.96E-04
Annotation Cluster 9 (Score:3.84)Atherosclerosis72.07E-05
Myocardial Infarction72.05E-04
Alzheimer's disease87.10E-04
Annotation Cluster 10 (Score:3.78)Brain Ischemia|Stroke51.86E-05
Peripheral Vascular Diseases44.02E-05
Cardiovascular Diseases52.60E-04
Hypercholesterolemia|LDLC levels40.004054968
Annotation Cluster 11 (Score:3.55)Restenosis41.81E-04
Arthritis, Rheumatoid|Rheumatoid Arthritis51.98E-04
Endometriosis46.16E-04
Annotation Cluster 12 (Score:3.28)Alcoholism|Liver Cirrhosis, Alcoholic32.12E-04
Esophageal Neoplasms|Hyperglycemia|Oesophageal neoplasm32.12E-04
Biliary Tract Neoplasms|Inflammation35.66E-04
Arthritis, Psoriatic|Psoriatic arthropathy36.21E-04
cardiovascular30.002488197
Annotation Cluster 13 (Score:3.18)Otitis Media|Recurrence32.47E-04
Brucellosis35.12E-04
Graft vs Host Disease|Hematologic Neoplasms|Neoplasm Recurrence, Local35.12E-04
Kawasaki disease36.21E-04
Atopy30.003077333
Annotation Cluster 14 (Score:2.82)Atherosclerosis|Inflammation|Retinal Vein Occlusion31.23E-04
Dermatitis, Atopic|Eczema allergic37.41E-04
juvenile arthritis30.001084437
graft-versus-host disease30.002834545
Graft vs Host Disease30.005354403
hepatitis C30.008600238
Annotation Cluster 15 (Score:2.80)Uveitis, Anterior31.23E-04
Pancreatitis, Chronic38.05E-04
stroke, ischemic30.004142278
Glomerulonephritis, IGA30.016033469
Annotation Cluster 16 (Score:2.76)giant cell arteritis35.12E-04
Malaria, Falciparum30.002163435
Malaria30.004882851
Annotation Cluster 17 (Score:2.72)Cardiovascular Diseases|Inflammation31.50E-04
skin cancer, non-melanoma30.001084437
Adenoma|Colorectal Neoplasms30.002954755
Depression30.028362664
Annotation Cluster 18 (Score:2.68)Endometriosis|Uterine Diseases31.50E-04
Hepatitis B, Chronic30.006357795
Pulmonary Disease, Chronic Obstructive30.009415863
Annotation Cluster 19 (Score:2.63)respiratory syncytial virus33.68E-04
Q fever34.61E-04
Graves' disease|Graves' disease30.001490775
Graves' disease30.001579503
Diabetes Mellitus, Insulin-Dependent|Diabetes Mellitus, Type 130.006532757
Premature Birth30.01182929
Kidney Diseases30.012294446
Annotation Cluster 20 (Score:2.47)Carcinoma, Squamous Cell|Mouth Neoplasms30.001084437
Helicobacter Infections|Stomach Neoplasms30.002377534
Precursor Cell Lymphoblastic Leukemia-Lymphoma30.015509841
 Figure 8 

Gene-pathway network of SFJDC against NCP. The V shapes represented pathway and the squares represent target genes in the network.

Int J Med Sci Image (Click on the image to enlarge.)

Acknowledgements

Author contributions

YQQ, XC designed the study; YHY and MYZ performed the data collection; JYL and RL analyzed the data; XC drafted the manuscript; YQQ revised the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported by the fund from New Coronavirus Pneumonia emergency research project of Shandong University (2020XGA02).

Data Accessibility

Publicly available databases were analyzed in our study. The active ingredients and putative target genes of SFJDC from TCMSP can be found in http://tcmspw.com/tcmsp.php. NCP-related target genes were from GeneCards (https://www.genecards.org/).

Competing Interests

The authors have declared that no competing interest exists.

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Author contact

Corresponding address Corresponding author: Yi-Qing Qu, MD, PhD, Department of Pulmonary and Critical Care Medicine, Qilu Hospital, Shandong University, Jinan, China. Tel: +86 531 82169335; Fax: +86 531 82967544; E-mail: quyiqingedu.cn.


Received 2020-3-26
Accepted 2020-8-25
Published 2020-9-12