key: cord-0843292-fgj6jtg3 authors: Zhu, Yi-Wei; Yan, Xiao-Feng; Ye, Ting-Jie; Hu, Jing; Wang, Xiao-Ling; Qiu, Feng-Jun; Liu, Cheng-Hai; Hu, Xu-Dong title: Analyzing the potential therapeutic mechanism of Huashi Baidu Decoction on severe COVID-19 through integrating network pharmacological methods date: 2021-01-18 journal: J Tradit Complement Med DOI: 10.1016/j.jtcme.2021.01.004 sha: eb223e79e0e35a70fd6380603967ab47025ef299 doc_id: 843292 cord_uid: fgj6jtg3 Background and Aim Huashi Baidu Decoction (HSBD) is a novel complex prescription which has positive effects on severe COVID-19. This study was aimed to discover key Chinese materia medica, main active compounds, hub therapeutic target proteins and core signal pathways in the potential therapeutic mechanism of HSBD on severe COVID-19 through integrating network pharmacological methods. Experimental procedure TCMSP, TCMID and STITCH databases were used to screen out active compounds and target proteins of HSBD. GeneCards database was used to screen out disease genes of severe COVID-19. The potential therapeutic targets of HSBD on severe COVID-19 were used to construct protein-protein interaction network through STRING database and the hub target proteins were discovered. Next, GO and KEGG enrichment analysis were carried out to discover core signal pathways. Finally, the network diagram of “Chinese materia medica-active compounds-therapeutic target proteins” was built, then key Chinese materia medica and main active compounds were selected. Results and Conclusion HSBD might treat severe COVID-19 through 45 potential target genes, among them, there were 13 hub target genes: RELA, TNF, IL6, IL1B, MAPK14, TP53, CXCL8, MAPK3, MAPK1, IL4, MAPK8, CASP8, STAT1. Meanswhile, GO_BiologicalProcess and KEGG signaling pathways analysis results showed that the core signal pathways were inflammation and immune regulation pathways. Finally, 4 key Chinese materia medica and 11 main active compounds were discovered in the HSBD. In conclusion, the therapeutic mechanism of HSBD on severe COVID-19 might involve its pharmacological effects of anti-inflammation and immune regulation via acting on 45 disease-related proteins of severe COVID-19. Taxonomy (classification by EVISE) Viral Pneumonia, COVID-19, Acute Respiratory Distress Syndrome, Septic Shock, Chinese Herbal Medicine showed that the core signal pathways were inflammation and immune regulation 24 pathways. Finally, 4 key Chinese materia medica and 11 main active compounds were 25 discovered in the HSBD. In conclusion, the therapeutic mechanism of HSBD on 26 severe COVID-19 might involve its pharmacological effects of anti-inflammation and 27 immune regulation via acting on 45 disease-related proteins of severe COVID-19. via retrieving TCMID database, 12 the target proteins of Gypsum Fibrosum were 98 obtained from STITCH (http://stitch.embl.de/). 13 The gene names corresponding to 99 the target proteins were searched through UniProt database. 14 All target proteins were 100 standardized as gene names and UniProt IDs utilizing the UniProtKB 101 (https://www.uniprot.org/) database with the "Homo sapiens" species. 14 102 corresponding gene sets were retrieved from the GeneCards database, then the 107 intersection of the three gene sets was collected to obtain the disease genes set of 108 In order to further clarify the interaction between potential target proteins, all 120 potential therapeutic target proteins of Huashi Baidu Decoction on severe COVID-19 121 were imported into Cyctoscape-3.8.0 and analyzed by STRING plug-in, 15 the protein 122 type was defined as "Homo sapiens", the relevant information on protein interactions 123 was obtained which was saved as TSV format file. Next, the network topology 124 parameters were analyzed by Cyctoscape-3.8.0 and the hub target proteins were 125 259, 3022 and 1009 disease genes of "novel coronavirus pneumonia", "acute 156 respiratory syndrome syndrom" and "septic shock" were collected respectively 157 through GeneCards databases, and 120 disease genes related to severe COVID-19 158 were screened out after intersection. 159 The structure, organization, biological process and function of the cell are mainly 171 achieved through the interaction between proteins in cells. Therefore, it is of great 172 significance to study the protein interactions and the network of protein-protein 173 interaction (PPI) for the understanding of cell structure and function. The PPI analysis 174 of 45 target proteins was carried out by using the STRING plug-in of Cytoscape-3.8.0. 175 The minimum score was set as the highest confidence 0.9 to ensure high cross 176 confidence information. There are 42 nodes and 174 edges in the PPI network 177 ( Fig.2A) , 3 disconnected proteins were excluded in the network. The larger the node, 178 the larger the Degree value. The thicker the edge, the higher the score, that is, the 179 J o u r n a l P r e -p r o o f closer the relationship between proteins. According to the further analysis of network 180 topology parameters, 13 hub target proteins with node Degree value > mean value 181 (7.73) and Betweenness Centrality value > mean value (0.028) were discovered. They 182 were RELA, TNF, IL6, IL1B, MAPK14, TP53, CXCL8, MAPK3, MAPK1, IL4, 183 MAPK8, CASP8 and STAT1. The target protein with higher Degree value and 184 Betweenness Centrality value plays more important role in the network, which is 185 likely to be the more core therapeutic target protein of Huashi Baidu Decoction on 186 severe COVID-19 (Supplementary Table 2) . GO_BiologicalProcess-EBI-UniProt-GOA_17.02.2020_00h00 database. 399 terms 208 were obtained with p value ≤ 0.05 as the threshold. The following showed 29 terms 209 Table 3 ). The main terms were related to cellular response to biotic stimulus, response 211 to lipopolysaccharide, cytokine activity, extrinsic apoptotic signaling pathway and so 212 on. 213 The top three terms in GO_BiologicalProcess enrichment results were "cell response 311 to biological stimulus", "response to lipolysaccharide", "cell response to 312 lipolysaccharide" (Fig.3, Supplementary Table 3 ). Septic shock is caused by infection 313 of extrinsic microorganism. Lipopolysaccharide is the most common endotoxin 314 secreted by gram-negative bacteria, and it is also the main inflammatory mediator that 315 leads to septic shock. 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