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COVID-19) Based on Network Pharmacology Xiao Chen1,3, Yun-Hong Yin2, Meng-Yu Zhang1, Jian-Yu Liu1, Rui Li1, Yi-Qing Qu2

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COVID-19) Based on Network Pharmacology Xiao Chen1,3, Yun-Hong Yin2, Meng-Yu Zhang1, Jian-Yu Liu1, Rui Li1, Yi-Qing Qu2 Int. J. Med. Sci. 2020, Vol. 17 2511 Ivyspring International Publisher International Journal of Medical Sciences 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 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. 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: [email protected]. © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2020.03.26; Accepted: 2020.08.25; Published: 2020.09.12 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. Key words: ShuFeng JieDu capsule; Novel Coronavirus Pneumonia; network pharmacology, mechanism, pathway; candidate genes Introduction Since December 2019, a novel coronavirus dyspnea, acute respiratory distress syndrome (ARDS) pneumonia (NCP) caused by new coronavirus (SARS- or septic shock and other symptoms. There is no COV-2) has been prevalent in China and other special drug at present [6,7]. countries, such as United States and Korea [1-3]. The treatment of COVID-19 mainly consisted of WHO named this novel coronavirus pneumonia bed rest; intensive supportive treatment; oxygen COVID-19 on February 11, 2020 [4] and there was a therapy; antiviral therapy; antimicrobial therapy and total of 20 million reported cases of COVID-19 Chinese medicine treatment. Critical cases need globally and 750,000 deaths as of August 10, 2020 [5]. respiratory support (high flow nasal oxygen therapy, Its transmission route is mainly through non-invasive ventilator or invasive mechanical respiratory droplets, but also through contact ventilator); circulatory support for critically ill transmission, which has the characteristics of rapid patients; plasma treatment from recovered patients spread, strong infectivity and general susceptibility of and immunotherapy [8,9]. Most of the infectious various groups of people. COVID-19 mild patients diseases caused by virus belong to the category of present with fever, fatigue, dry cough and other "plague" in ancient Chinese traditional medicine, symptoms, whereas severe patients can appear with which is caused by many evil spirits invading the http://www.medsci.org Int. J. Med. Sci. 2020, Vol. 17 2512 body [10]. The traditional medicine, including regulation of multi-component, multi-target, multi- traditional Chinese medicine (TCM), has a good pathway, linking active components in traditional therapeutic effect on it [11,12]. The Health and Health chinese medicine with target genes from molecular Commission of China and the State Administration of and biological aspects [23]. Network pharmacology traditional Chinese Medicine in the "circular on the will help to understand the relationship among issuance of a new type of coronavirus infection ingredients, genes and diseases and is suitable for the pneumonia diagnosis and treatment program (version study of complex TCM or TCM compounds. The 5)" requested to strengthen the integration of Chinese potential mechanism of preventing COVID-19 by and western medicine, and recommended a number HuoXiang ZhengQi oral solution was realized by of proprietary Chinese medicine in the process of network pharmacology and molecular docking [24]. diagnosis and treatment [13]. On the basis of the The research group Jing Zhao elucidated the national plan and in accordance with the principle of mechanism of QingFei PaiDu Tang in the treatment of "three conditions and conditions", local prevention COVID-19 using network pharmacology [25]. SFJDC and control projects have also been successively could be efficacious for COVID-19, but active issued according to local conditions [14]. incredients, target genes and putative mechanism are Recommended Chinese medicines include MaXing not known. ShiGan Tang, QingFei PaiDu Tang, HuoXiang ZhengQi Capsules, JinHua QingGan Granules, Table 1. Herb composition of Shu Feng Jie Du Capsule (SFJDC) LianHua QingWen Capsules or ShuFeng JieDu capsule [8]. One clinical study showed that LianHua English translation Latin name Chinese name Hu-Zhang Polygoni Cuspidati Rhizoma Et Radix 虎杖 QingWen could improve the symptoms of COVID-19 Lian-Qiao Forsythiae Fructus 连翘 patients and shorten the course of disease [15]. A Ban-Lan-Gen Isatidis Radix 板蓝根 retrospective analysis study showed that the time of Chai-Hu Herba Patriniae 柴胡 Bai-Jiang-Cao Phragmitis Rhizoma 败酱草 disappearance of clinical symptoms, recovery of body Ma-Bian-Cao Verbenae Herb 马鞭草 temperature, average length of stay in the integrated Lu-Gen licorice 芦根 Chinese and western medicine treatment group (34) Gan-Cao Radix Bupleuri 甘草 was significantly lower than that of the western medicine group (18) among the 52 COVID-19 patients In the present study, the network [16].With QingFei PaiDu Tang combined with pharmacological was used to investigate the possible western medicine to treat the COVID-19 could mechanism and target of SFJDC in the treatment of significantly improve the patient’s symptoms and COVID-19. COVID-19 is a type of Novel Coronavirus achieved better results [17]. Pneumonia (NCP). The active ingredients and their ShuFeng JieDu capsule (SFJDC) is a traditional target genes of SFJDC were collected from TCMSP. Chinese medicine used to treat influenza in China NCP-related target genes were collected from [18]. SFJDC is composed of Polygoni Cuspidati GeneCards database. The putative mechanism of Rhizoma Et Radix (PCRR), Forsythiae Fructus (FF), SFJDC against NCP were analyzed by GO and KEGG Isatidis Radix (IR), Herba Patriniae (HP), Phragmitis pathway. The flowchart of network pharmacology Rhizoma (PR), Verbenae Herb (VH), licorice (I), Radix was shown in Figure 1. The study provided possible Bupleuri (RB) (Table 1). SFJDC has antiviral, anti- theoretical reference for SFJDC in the prevention and inflammatory, antipyretic and immune regulatory treatment of COVID-19. effects [19]. SFJDC was commonly used for upper respiratory tract infection, pulmonary infection, Materials and Methods AECOPD and other disease [20].This drug now is also recommended for the treatment of COVID-19 Screening of active Ingredients in SFJDC infections in the latest Diagnosis and Treatment of We identified the active ingredients of SFJDC Pneumonia Caused by COVID-19 (version 5) [13,21]. from Traditional Chinese Medicine Systems Currently, SFJDC is recommended in the Diagnosis Pharmacology Database and Analysis Platform and Treatment of Pneumonia Caused by COVID-19 in (TCMSP http://tcmspw.com/tcmsp.php) [26]. 5 provinces and cities [22]. TCMSP is a unique herbal pharmacology platform Network pharmacology is a new discipline that captures the relationship between drugs, target based on the theory of system biology, which analyzes genes and diseases. The database includes the the biological systems and selects specific signal detection of natural compounds such as chemical, nodes for multi-target drug molecular design. target and drug target networks. ADME is Network pharmacology emphasizes the multi- pharmacokinetics, which refers to the absorption, pathway regulation of signaling pathways and the distribution, metabolism and excretion of exogenous http://www.medsci.org Int. J. Med. Sci. 2020, Vol. 17 2513 chemicals by myosome. The four key parameters of mining, Co-expression, Neighborhood, Experiments, ADME were blood-brain barrier (BBB), oral Databases, Gene Fusion and Co-occurrence. The bioavailability (OB), Caco-2 permeability (Caco-2) and required minimum interaction score was set at 0.4 in drug-likeness (DL) [27]. In this study select candidate PPI network of SFJDC related targets, PPI network of compounds which has OB≥30%, DL≥ 0.18, NCP was set at 0.9. The barplot were generated by the Caco-2≥-0.4, BBB≥-0.3.Then we sorted out each active R software
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