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Network Pharmacology Identifies the Mechanisms of Sang-Xing-Zhi-Ke-Fang Against Pharyngitis

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Network Pharmacology Identifies the Mechanisms of Sang-Xing-Zhi-Ke-Fang Against Pharyngitis Hindawi Evidence-Based Complementary and Alternative Medicine Volume 2020, Article ID 2421916, 12 pages https://doi.org/10.1155/2020/2421916 Research Article Network Pharmacology Identifies the Mechanisms of Sang-Xing-Zhi-Ke-Fang against Pharyngitis Yinhe Deng,1 Quanjiang Li,1 Menglin Li,1 Tiantian Han,1 Guixian Li,1 and Qiong Liu 2 1College of First Clinical Medical, Guangzhou University of Chinese Medicine, Guangzhou 51000, China 2International Medical Department, #e First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 51000, China Correspondence should be addressed to Qiong Liu; [email protected] Received 1 April 2020; Revised 1 September 2020; Accepted 9 September 2020; Published 12 October 2020 Academic Editor: Roˆmulo Dias Novaes Copyright © 2020 Yinhe Deng et al. .is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Sang-Xing-Zhi-Ke-Fang (SXZKF) demonstrates good therapeutic effect against pharyngitis. Nevertheless, the pharmacological mechanism underlying its effectiveness is still unclear. Objective. To investigate the underlying mechanisms of SXZKF against pharyngitis using network pharmacology method. Methods. Bioactive ingredients of SXZKF were collected and screened using published literature and two public databases. Using four public databases, the overlapping genes between these bioactive compound-related and pharyngitis-related genes were identified by Venn diagram. Protein-protein interaction (PPI) was obtained using “Search Tool for the Retrieval of Interacting Genes (STRING)” database. “Database for Annotation, Visualization, and Integrated Discovery ver. 6.8 (DAVID 6.8)” was used to perform Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to explore the molecular mechanisms of SXZKF against pharyngitis. Finally, Cytoscape 3.7.2 software was used to construct and visualize the networks. Result. A total of 102 bioactive compounds were identified. Among them, 886 compounds-related and 6258 pharyngitis-related genes were identified, including 387 over- lapping genes. Sixty-three core targets were obtained, including ALB, PPARc, MAPK3, EGF, and PTGS2. Signaling pathways closely related to mechanisms of SXZKF for pharyngitis were identified, including serotonergic synapse, VEGF signaling pathway, Fc epsilon RI signaling pathway, Ras signaling pathway, MAPK signaling pathway, and influenza A. Conclusion. .is is the first identification of in-depth study of SXZKF against pharyngitis using network pharmacology. .is new evidence could be informative in providing new support on the clinical effects of SXZKF on pharyngitis and for the development of per- sonalized medicine for pharyngitis. 1. Introduction BiannBia that had been widely used for more than 200 years in China. SXZKF has been patented in China (patent Pharyngitis, a collective term for inflammation caused by number: 201910302604.4) in 2019 and the oral lozenge based various microorganisms in the pharynx, still has a high on it is being developed. SXZKF is composed of Mulberry incidence even with the rapid development of modern Leaf, Armeniacae Amarum Semen, Radix Glehniae, Radix medicine [1]. In China, acute pharyngitis is mainly treated Rehmanniae Praeparata, Loguat Leaf, Fritillary Bulb, Erio- with antiviral drugs, antibiotics or traditional Chinese botrya japonica .unb, Ligusticum chuanxiong hort, medicine (TCM) [2, 3]. TCM plays an increasingly im- Earthworm Lumbricus, Mentha haplocalyx Briq, and Exo- portant role in the treatment of chronic pharyngitis, for the carpium Citrus Grandis. Although we have previously etiology of chronic pharyngitis is complex, and many studies verified that SXZKF was effective against pharyngitis [6], the have shown that TCM shows significant effect on this disease active ingredients and molecular mechanisms of SXZKF in [4, 5]. the treatment of pharyngitis remains unknown. Sang-Xing-Zhi-Ke-Fang is a concoction based on Sang- Network pharmacology is a new discipline based on the Xing-Tang, which is originated form Wen Bing Tiao theory of systems biology, analyzing the network of 2 Evidence-Based Complementary and Alternative Medicine biological systems, and selecting specific signal nodes for centrality (CC) were analyzed for each node using the multitarget drug molecular design [7]. Based on the ideas plugin cytoNCA in Cytoscape 3.7.2 [16]. Preliminary and methodologies of network pharmacology, this study screening was carried out for nodes with a DC equal or aimed to obtain the main active ingredients of SXZKF, larger than the median of two. Finally, the nodes with BC screened out the core targets and main biological pathways, and CC, both larger than the median of two, were identified and explored the molecular mechanisms of SXZKF in the as the core targets [17]. treatment of pharyngitis. 2.5. Pathway Analyses and Construction of Compounds- 2. Material and Methods Targets-Pathways (C-T-P) Network. Pathway enrichment 2.1. Screening of Bioactive Compounds of SXZKF. analysis for overlapping genes was performed using DAVID Information of the bioactive compounds in SXZKF was ver. 6.8 (https://david.ncifcrf.gov/) with the “Homo sapiens” obtained from Traditional Chinese Medicine Systems setting. Generally, the results of KEGG pathway enrichment Pharmacology Database and Analysis Platform (TCMSP, were considered to have statistically significant and neces- http://lsp.nwu.edu.cn/tcmsp.php) and Bioinformatics sary functional mechanisms of pharyngitis when P < 0:05. To Analysis Tool for Molecular mechanism of Traditional ensure the accuracy of this study, we set the screening Chinese Medicine (BATMAN-TCM, http://bionet.ncpsb. criteria as P < 0:01. Bubble chart of the concerned KEGG org/batman-tcm/) [8]. .e active ingredients of SXZKF pathways was plotted using the OmicShare tools (https:// were filtered using the following criteria: (i) oral bioavail- www.omicshare.com/tools). Finally, Cytoscape 3.7.2 was ability (OB) ≥ 30% and (ii) drug-likeness (DL) ≥ 0.18 [9, 10]. used to establish and visualize the network of interactions Other ingredients were obtained through literature analysis between compounds, targets, and signaling pathways that [11, 12]. are closely related to pharyngitis. .e complete workflow of the analysis is given in Figure 1. 2.2. Screening of Target Genes of Bioactive Compounds and 3. Results Pharyngitis. Target genes of bioactive compounds of SXZKF were obtained from TCMSP, and the Universal Protein 3.1. Bioactive Compounds of SXZKF. Ninety-three bioactive Database (UniProt, https://www.uniprot.org/) was then compounds were identified from TCMSP and BATMAN- used to remove nonhuman target gene names. To ensure the TCM, while another nine bioactive compounds were reliability of prediction, only target genes with “Reviewed/ identified through literature survey. Among these, 29 Swiss-Prot” rots “Human” in UniProt would be selected compounds were identified from Mulberry Leaf, 19 com- [13, 14]. .e targets related to pharyngitis were obtained pounds from Semen Armeniacae Amarum Semen, 8 com- from Comparative Toxicogenomics Database (CTD, http:// pounds from Radix Glehniae, 2 compounds from Radix ctdbase.org/) [15] and .e Human Gene Database (Gene- Rehmanniae Praeparata, 18 compounds from Loguat Leaf, Cards, http://www.genecards.org/). By searching the key- 10 compounds from Mentha haplocalyx Briq, 7 compounds word “pharyngitis,” target genes of pharyngitis were from Fritillary Bulb, 7 compounds from Ligusticum identified. chuanxiong hort, 10 compounds from Exocarpium Citrus Grandis, and 9 compounds from Earthworm Lumbricus (Table S1). 2.3. Establishment of Herbs-Compounds-Targets (H-C-T) Network. .e overlapping target genes relating to both the bioactive compounds and pharyngitis were identified and 3.2. Target Genes of SXZKF and Pharyngitis. A total of 886 visualized by Venn diagrams (http://bioinformatics.psb. targets genes (Table S2) of 63 bioactive compounds were ugent.be/webtools/Venn/). .en, Cytoscape 3.7.2 software retrieved from TCMSP and screened by UniProt, and no was used to visualize and analyze the network of interactions genes were related to another 39 compounds. On the other between overlapping genes, bioactive compounds, and hand, 6258 targets related to pharyngitis were obtained herbs; we named it the H-C-T network. (5150 targets from CTD, 1803 targets from GeneCards; among them 695 duplicate targets), and the information is listed in Table S3. As shown in Figure 2, the Venn diagram 2.4. Analysis of Network Topological Features. STRING da- showed that 387 overlapping target genes were identified by tabase (https://string-db.org/) was used to obtain the matching the SXZKF compounds-related target genes with protein-protein interactions (PPI) by uploading 387 CTD and GeneCards pharyngitis-related target genes. overlapping targets between active compounds and phar- yngitis. Species was limited to “Homo sapiens” with a confidence score >0.4. Cytoscape 3.7.2 was used to con- 3.3. Analysis of H-C-T Network. Based on the Venn diagram struct the network of PPI, and then the topological features and the results of TCMSP retrieval, we can obtain that the of the network were analyzed to screen out the core targets 387 potential targets were linked to 19 compounds of SXZKF that play a crucial part in the PPI network. .e degree against pharyngitis, as shown in Table S4. To get a better centrality (DC), betweenness
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