key: cord-0963007-anniuvxf
authors: Xiong, Haijun; Dong, Zhaowei; Lou, Guanhua; Gan, Qingxia; Wang, Jin; Huang, Qinwan
title: Analysis of the mechanism of Shufeng Jiedu capsule prevention and treatment for COVID-19 by network pharmacology tools
date: 2020-10-30
journal: Eur J Integr Med
DOI: 10.1016/j.eujim.2020.101241
sha: e810164a013df27a1a3bbc0f2e714455b8341677
doc_id: 963007
cord_uid: anniuvxf

INTRODUCTION: The novel coronavirus pneumonia that broke out in 2019 has become a global epidemic. According to the diagnosis and treatment plan issued in China and the existing clinical data, Shufeng Jiedu (SFJD) Capsule can be effectively used in the treatment of COVID-19 patients. This study aimed to explore its mechanism of action by network pharmacology and molecular docking technology. METHODS: The Chinese Medicine System Pharmacology Analysis Platform (TCMSP), a Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine (BATMAN-TCM), the Encyclopedia of Traditional Chinese Medicine (ETCM) and related literature records were used to search the composition and main active compounds of SFJD, and to screen out the targets of drug components. Disease-associated genes were obtained by the Human Gene Database (GeneCards), the Human Online Mendelian Inheritance Platform (OMIM) and the DisGeNET database, and the co-targeted genes/proteins as targets of both SFJD and COVID-19 were selected by the Comparative Toxicogenomics Database (CTD). Co-targeted genes/proteins were analyzed by STRING, the Database for Annotation, Visualization and Integrated Discovery (DAVID) and Reactome for proteins to protein interaction (PPI), pathway and GO (gene ontology) enrichment, and predicted by AutoDock for their high-precision docking simulation. In addition, the therapeutic effect for SFJD treatment on COVID-19 was validated by the Chinese medicine anti-novel coronavirus pneumonia drug effect prediction and analysis platform (TCMCOVID). RESULTS: Screening resulted in 163 compounds and 463 targeted genes. The PPI core network contains 76 co-targeted proteins. The Reactome pathways were enriched in signaling by interleukins, immune system, etc. Finally, 6 key proteins of TNF, IL-10, IL-2, IL-6, STAT1 and CCL2 were selected and successfully docked with 4 active ingredients of quercetin, luteolin, wogonin and kaempferol. CONCLUSION: SFJD may play a role in the prevention and treatment of COVID-19 through multiple active compounds acting on multiple targets and then multiple pathways.

Coronavirus disease 2019 (COVID-19) caused by a novel virus strain, 2019-nCoV/ SARS-CoV-2 spread rapidly around the world in the first half of 2020 causing a global pandemic [1] , and has posed a serious threat to global public health and economy [2] . COVID-19 is a respiratory illness. Traditional Chinese Medicine (TCM) plays a significant role in the treatment of respiratory diseases in China [3] . The research on antiviral TCM literature in the past 20 years suggests that the antiviral TCM is mainly based on clearing heat and detoxification [4] . SFJD capsule is a typical antibacterial and antiviral compound preparation used for this purpose.

understanding about the pathological evolution and a positive clinical efficacy on novel coronavirus pneumonia [8] . As an indispensable part of TCM, Chinese patent medicines are highly valued and critically acclaimed in their campaign to contain and tackle the epidemic, they can achieve considerable effects for both suspected cases under medical observation period, and confirmed individuals with serious underlying diseases or critical conditions [9] . At present, there is a report that ranks the frequencies of Chinese Patent Medicine recommendations by guidelines and expert consensus for treatment of COVID-19 in China. Among them, the top 10 Chinese Patent Medicines include Shufeng Jiedu (SFJD) Capsule [10] .

The Chinese national guideline summarised the opinions and frontline experience of medical experts across the country to provide by far the best management for COVID-19 [11] . According to "Novel Coronavirus Pneumonia Diagnosis and Treatment Program (Trial Seventh Edition)" in China, it is recommended to use Chinese patent medicine Shufeng Jiedu Capsules (granules) during the medical observation period when there are clinical manifestations of fatigue and fever. [12] . According to the clinical trial results of 200 ordinary COVID-19 patients in Wuhan Third Hospital from January 27, 2020 to March 5, 2020, it was found that the combined application of SFJD capsules with Western medicine could significantly improve ordinary COVID-19 patients with clinical symptoms such as cough, expectoration, fatigue, chest tightness and wheezing, improve the effectiveness of the main symptoms, regulate the expression of related peripheral blood inflammation indicators, promote the absorption of lung inflammation, and increase the cure rate [13] . According to the clinical trial results of 200 patients with mild novel coronavirus pneumonia in outpatient clinics of Wuhan Central Hospital from January 24 to January 30, 2020, SFJD capsule combined with Abidol in the treatment of mild novel coronavirus pneumonia can significantly improve the blood composition of patients, the percentage level of white blood cells and lymphocytes, make the chest CT infected foci obvious absorption [14] . According to the clinical trial results of 70 COVID-19 patients diagnosed and treated at the COVID-19 designated hospital Bozhou People's Hospital from January 31, 2020 to February 11, 2020, it was shown that the addition of SFJD capsule can shorten the time for patients to improve their clinical symptoms and the time for SARS-CoV-2 to become negative [15] . SFJD capsule evolved from "Detox Powder" 9 , and it is commonly used for clinical treatment of acute upper respiratory tract infection caused by wind-heat syndrome [16] . Modern pharmacological studies have shown that SFJD capsules have a relatively broad inhibitory effect on common fungi, viruses, bacteria, etc. [9] , and have a broad-spectrum antiviral effect in vitro [17] . In addition, SFJD and antibiotic combination therapy can reduce the inflammatory response and improve prognosis for septic patients [18] . SFJD is an eight-herb prescription that Hu Zhang ( Polygoni cuspidati Rhizoma et Radix) is the monarchingredient; Ban Lan Gen ( Isatidis Radix) and Lian Qiao ( Forsythiae Fructus) are adjutant-ingredients; Lu Gen ( Phragmitis Rhizoma), Bai Jiang Cao ( Patrinia scabiosifolia Herba), Ma Bian Cao( Verbenae Herba) and Chai Hu( Bupleuri Radix) are assistant-ingredients; Gan Cao( Glycyrrhizae Radix et Rhizoma) is the envoy-ingredient [9] .

The TCM network pharmacology approach provides a new research paradigm for translating TCM from an experience-based medicine to an evidence-based medicine system. It was created to prioritize diseaseassociated genes, to predict the target profiles and pharmacological actions of herbal compounds, to reveal drug-gene-disease co-module associations, to screen synergistic multi-compounds from herbal formulae in a high-throughput manner, and to interpret the combinatorial rules and network regulation effects of herbal formulae [19] . Therefore, we used network pharmacology tools to study the molecular mechanism of SFJD against COVID-19, aiming to provide a theoretical basis for the clinical application of SFJD and more accurate and effective use in the treatment of clinical COVID-19 patients. As shown in Fig. 1 , to explore the molecular mechanism for SFJD against COVID-19, we tried to integrate the bioinformatics and network pharmacology tools [20] medicines and the compound components of each herbal medicine. It provides comprehensive evaluation data of human absorption, distribution, and metabolism (ADME) properties for each compound. It also provides targets of potentially active molecules and their disease information. BATMAN-TCM ( http://bionet.ncpsb.org/batman-tcm/ ) is the first online bioinformatics analysis tool specifically designed for studying the molecular mechanisms of traditional Chinese medicine, and it can predict the potential target of each query of Chinese medicine components. Choosing the 8 herbs of TCM composed of SFJD as keywords, the ETCM was used to query the meridian and the TCMSP and BATMAN-TCM were used to search the main active compounds of 8 herbs.

TCMSP was used to mine the targeted genes information of the main active compounds obtained in 2.1. Ingredients targeted genes of SFJD were made the official name through Uniport ( https://www.uniprot.org/ ). GeneCards ( https://www.genecards.org/ ) is a comprehensive database that can analyze human genetic data. Its main functions include analyzing gene expression, functional pathways, protein-protein interactions, and the relationship between genes and diseases. The DisGeNET ( http://www.disgenet.org/ ) database is one of the largest databases containing human diseases and related gene targets, including 17,549 genes and 24166 diseases. OMIM ( http://www.ncbi.nlm.nih.gov/omim ) is a database that records the genetic components of all known diseases and predicts their relationship with related genes in the human genome. As SFJD was used to treat symptoms such as fever and fatigue during the medical observation period of novel coronavirus pneumonia, "Novel coronavirus pneumonia", "COVID-19", "Fever" and "Fatigue" were used as keywords to mine disease-associated genes by GeneCards, DisGeNET and OMIM. Through the CTD ( http://ctdbase.org/ ) for Venn analysis, the co-targeted genes were obtained.

With STRING (search tool for the retrival of interacting genes/proteins) ( https://string-db.org ), we analyzed the co-targeted proteins that are encoded by disease-associated genes that interact with SFJD ingredient-targeted genes to explore their relationship within a PPI network. DAVID ( https://david.ncifcrf.gov/ ) is a biological information database that provides systematic and comprehensive biological function annotation information for large-scale gene or protein lists. Entered the above targets into DAVID, and selected the species as "homo sapiens", set the threshold value P ≤ 0.05 for GO enrichment analysis, and used Graphpad software to draw the results into histograms.

The Reactome Knowledgebase ( https://reactome.org ) provides molecular details of pathways and reactions in human biology. Reactome Knowledgebase is a new tool for studying biological pathways at a holistic level, and it can simplify data search and research related to biological pathways. We used it to draw two pathways that co-targeted genes set enriched.

The Chinese medicine anti-novel coronavirus pneumonia drug effect prediction and analysis platform (TCMAntiCOVID-19 V1.0, http://tcmatcov.bbtcml.com/ ) can realize the rapid prediction and analysis of the potential drug effect of traditional Chinese medicine or prescriptions and provide a reference for the evaluation of drug efficacy [21] . It compares the changes of network topological characteristics before and after drug intervention, and uses the disturbance rate to evaluate the effect of drugs on disease. Based on the TCMATCOV platform, SFJD was calculated and predicted to have a high disturbance score and to account for a high proportion of the classic anti-COVID-19 prescriptions used by clinicians. We built a component-drug target-disease protein interaction network on the TCMATCOV platform.

Combining the targets analyzed by the PPI and the TCMATCOV platform, the overlapping targets were selected as the core target genes, and then the compound with high frequency corresponding to the core target genes were used as the core compounds. Selected core compounds and download the sdf structure of the compound from the PubChem ( https://pubchem.ncbi.nlm.nih.gov/ ) database. The files were imported into AutoDock software to add charge and display rotatable keys and then saved in pdbqt format. The protein crystal structures corresponding to the core target genes were downloaded from the PDB database, imported into PyMOL software to remove water molecules and hetero molecules, imported into AutoDock software to add hydrogen atoms and charge operations, saved to pdbqt format. The above core compounds were used as ligands, and the proteins corresponding to the core target genes were used as receptors for molecular docking. From the 50 results, the one with the largest binding energy and the largest number of hydrogen bonds was selected as the final result. The results were analyzed and interpreted by PyMOL software.

The results of ETCM and literature search are shown in Table 1 . The seven other herbs except for Gan Cao are all categorized as bitter cold, mainly in the lung, stomach and liver meridians.

A total of 163 active ingredients of SFJD were retrieved through the TCMSP and BATMAN-TCM. In addition to Gan Cao, 43 compounds were excavated with oral bioavailability (OB) ≥ 50% and drug-likeness (DL) ≥ 0.18 as parameters. The remaining 7 herbs were excavated with OB ≥ 30% and DL ≥ 0.18 as parameters. There are 10 effective compounds in Hu Zhang, 26 in Lian Qiao, 42 in Ban Lan Gen, 17 in Chai Hu, 12 in Bai Jiang Cao, 12 in Ma Bian Cao, and 1 in Lu Gen. Sorted by DL value, Table 2 showed the top 20 active ingredients (more details showed in supplement material 1).

According to GeneCards, OMIM and DisGeNET search, 429 "Novel coronavirus pneumonia" target genes, 324 "COVID-19" target genes, 7385 "Fever" target genes, and 7384 "Fatigue" target genes were obtained. 383 disease-associated genes were obtained by Venn analysis, as shown in Fig. 2 (A) . Through TCMSP and BATMAN-TCM (score ≥ 20; P < 0.05) mining, 463 ingredients targeted genes of SFJD were obtained, which were subjected to Venn analysis with disease-associated genes to obtain 76 co-targeted genes of SFJD for preventing COVID-19, as shown in FIG. 2 (B) .

Using STRING, we analyzed the interactions of 76 proteins that are disease-associated genes interaction with SFJD ingredient-targeted genes on the condition of highest confidence of 0.900, and the multiple PPI enrichment were obvious ( P < 1.0e − 16). As shown in Fig. 3 , the circular nodes represent the genes, and the straight line between the nodes represents the connection between the two genes, The darker the line, the stronger the correlation. We abandoned the above proteins with no effect relationship, imported the results into the Cytoscape software as a TSV format file for target relationship mining, and arranged them in the order of Degree, Closeness, Betweenness and Topological Coefficient, and selected the targets with a Degree greater than or equal to 10 as the " important targets" ", the results were shown in Table 3 (more details showed in supplement material 3). We used DAVID to perform GO enrichment analysis on the above 76 proteins. Taking "Homo sapiens, p ≤ 0.05" as the screening condition, the top 20 were drawn as histograms, as shown in Fig. 4 (more details showed in supplement material 4). Among them, biological processes involve inflammatory response, positive regulation of transcription from RNA polymerase II promoter, immune response, etc.; molecular functions include ATP binding, cytokine activity and metal ion binding are the most significant; among the cellular components, extracellular space, extracellular exosome and nucleus are enriched more.

We used the Reactome knowledgebase as the enrichment tool with co-targeted genes for Reactome pathways enrichment. As shown in Table 4 (more details showed in supplement material 5), the results indicated that the pathways were enriched in interleukin-10 signaling, interleukin-4 and interleukin-13 signaling, signaling by interleukins, cytokine signaling in the immune system, the immune system and other pathways. These pathways are important in storms caused by COVID-19. With the Reactome knowledgebase, we draw the simulation diagrams for SFJD treatment during SARS-CoV-2 infection in the immune system ( Fig. 5 A ) , cytokine signaling in immune system (HSA-1280215, Fig. 5 B ) , signaling by interleukins (R-HSA-449147, Fig. 5 C ) which showed the possible targets for SFJD and SARS-CoV-2 with hit gene numbers and false discovery rate (FDR) scores. These simulation diagrams have vividly illustrated the mechanism of SFJD treatment for COVID-19.

As shown in Fig. 6 , we built a component-drug target-disease protein interaction network on the TCMATCOV platform, which included the component-drug target relationship (from BATMAN-TCM, with a confidence score of 20) , and protein interactions between drug targets and disease proteins relationship (from STRING with a confidence score of 0.5). The data showed that the SFJD therapeutic effect on COVID-19 was very close to the positive control (HSZF), which had been reported to be useful in clinical. We also validated the herbs in SFJD prescription, and the data showed in Table 5 . TCMATCOV is a COVID-19 severe disease network based on SARS simulation. We used it to predict 126 Table 4 The co-targeted genes Reactome pathways enrichment analysis (top10). Table 6 Information of core target genes. anti-COVID-19 target genes. However, we used GeneGards, DisGeNET, OMIM and other databases to select 76 co-targeted genes based on the clinical symptoms of fever and fatigue during the medical observation period. As shown in Table 6 , the targets predicted by these two methods were subjected to Venn analysis, and the eight genes obtained were used as core target genes for the prevention and treatment of COVID-19, and the corresponding high-frequency compounds were used as core compounds.

According to the binding energy and the number of hydrogen bonds, especially the greater the absolute value of the binding energy, the better the molecular docking result. The two proteins most related to the four core compounds were selected, as shown in Fig. 7 and Table 7 (original data showed in supplement material 7). Quercetin has the largest relationship with TNF and STAT1 . Luteolin has the largest relationship with IL-2 and STAT1 . Wogonin has the largest relationship with TNF and CCL2 . Kaempferol has the largest relationship with IL-10 and IL-6 . These results can prove that SFJD ingredients work with COVID-19 targeted proteins in molecular docking simulation.

Interleukin-6 ( IL-6 ) plays an important role in cytokine release syndrome [22] . Some research has found that cytokines play an important role in the pathogenesis of COVID-19. Also, IL-6 seems more relevant in the evaluation of the condition of COVID-19 patients [23] . In addition to the core proteins such as IL-6 , which are involved in molecular docking simulation, the T-helper 1 cytokines ( IL1B, IFN-, IP10 , and MCP1 ) increase in patients infected by SARS-COV-2 [24] and other co-targeted genes such as IFNG and MAPK are also involved. IFNG is generally considered to be an inflammatory cytokine that plays a key role in antitumor immunity. Studies have found that high levels of IFNG activate the JAK1-STAT1-caspase pathway and induce apoptosis in non-small cell lung cancer [25] . MAPK can regulate many important cell physiological/pathological processes such as cell growth, differentiation, stress adaptation to the environment, and inflammatory response [26] . Thus, combined with the enrichment analysis results of GO and Reactome pathway, cytokines and other molecules involved in immune response and inflammation are conceivable therapeutic targets for SFJD. COVID-19 can spread quickly through respiratory tract droplets, close contact, and aerosols. In addition, there are reports that direct evidence of the active SARS-CoV-2 replication in the patient's rectum during the incubation period, which might explain SARS-CoV-2 fecaloral transmission [27] . Clinical studies of patients with COVID-19 have shown that coronavirus can cause a variety of human diseases, including respiratory symptoms, gastrointestinal diseases [28] , varying degrees of liver injury or liver dysfunction [29] , thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, ocular symptoms, dermatologic complications [30] and so on.

Most of SFJD components are bitter cold herbs with the effect of clearing heat and detoxification, and mainly belong to the lung meridian, which plays an obvious therapeutic role on the syndrome of windheat syndrome of upper scorched lung. Amazingly, the therapeutic effect of each component of SFJD is not only limited to the lung, but also has a certain protective effect on the damage of other tissues and organs. The effective core compounds of SFJD such as quercetin, luteolin, wogonin, Kaempferol, etc. were screened through network pharmacology. They are mainly natural flavonoids, which exist in many nat-ural medicinal materials and have various pharmacological activities. Quercetin can improve immune function via NF-B signaling pathway triggered by TNF- [31] . It has a protective effect against the liver tissues of rats [32] and colitis of mice [33] . Both in vivo and in vitro experiments have demonstrated that quercetin can alter cell cycle [34] . Highlights Quercetin ameliorates hypoxia-evoked apoptosis [35] . Luteolin has anti-inflammatory [36] , anti-oxidation [ 37 , 38 ] , protecting the kidneys [39] and other pharmacological effects. It can potently inhibit influenza virus replication in vitro [40] . Kaempferol has the effect of inhibiting cell proliferation and inducing apoptosis [41] . It can protect the liver against propacetamol-induced injury [42] and protect mice from liver failure [43] . Kaempferol showed attenuation in sepsisinduced acute lung injury in mice [44] . In addition, it has the effect of antitumor and cardioprotective [45] . Wogonin attenuated tubular damage, suppressed kidney inflammation and inhibited NF-B activation in the injured kidney, thereby exhibiting the renoprotective effect [46] and it is a promising nephroprotective agent [47] . Pro-apoptosis effect of wogonin in vivo was verified in situ [48] . Wogonin exhibits a cytotoxic effect on lung cancer cells [49] and exerts potent anticancer effects on colorectal cancer cells [50] . Wogonin has documented a wide Fig. 7 . Continued spectrum of anti-inflammatory and antitumor activities, including inhibiting regulatory T cells, regulating effector T cell functions, and mediating macrophage immunity [51] . In addition, wogonin possesses a potent anti-influenza activity mediated by regulation of AMPK activation [52] . The multiple protective effects of these active ingredients on other tissues and organs may be one of the reasons for SFJD to reduce the symptoms of COVID-19 patients. TCM is a combination of multiple components to play a therapeutic effect, in addition to these four core compounds, the remaining components also play a pivotal role.

Recently, there are many clinical applications of TCM in the treatment of COVID-19 and many scholars have also studied its mechanism through network pharmacology, as shown in Table 8 . Through comparison, it is found that whether it is a single medicine or a prescription, TCM treats COVID-19 mostly by regulating inflammatory factors. Our research found that SFJD not only regulates inflammation, but also mainly participates in regulating the immune system to treat COVID-19.

However, the data in TCMCOVID is based on SARS and is not completely consistent with SARS COV2, and the original data used in this database is the result of analysis of mice. Thus, using this tool to verify analysis results has certain limitations. In addition, TCM prescription is a complex system, not simply the accumulation of ingredients, and network pharmacology has limitations. In order to be safe and effective for clinical use, further in vivo and in vitro activity evaluation and pharmacological verification are needed.

The preventive and therapeutic effect of SFJD on COVID-19 may contribute in participating in the moderate immune system, antiinflammatory, anti-virus and other methods through the action of quercetin, luteolin, kaempferol, baicalein and other active ingredients on core targets such as IL-6, IL-10, TNF , etc. Combined with clinical research and network pharmacological analysis, in the early onset of COVID-19, non-infant patients with acute upper respiratory tract infection with heat toxin attacking the lung syndrome, fever, fatigue and other symptoms, timely oral SFJD capsule for a certain course of treatment can reduce or eliminate the patient's clinical symptoms.

Q-WH is the corresponding authors on the study. H-JX and Z-WD are first authors and responsible for collecting materials and writing the paper. G-HL, Q-XG and JW helped in organizing the information and edited the article pictures. All authors read and approved the final manuscript.

This work is financially supported by the Xinglin Scholars Talent Promotion Plan of Chengdu University of Traditional Chinese Medicine (Code: QNXZ2018023 and Core: XSGG2019008).

The authors declare that they have no competing interests. 

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

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We are indebted to our alma mater, Chengdu University of Traditional Chinese Medicine for providing convenience in the collection of documents. Thanks for all the help from everyone in our lab.

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.eujim.2020.101241 .