scholarly journals SARS-CoV-2 intervened by NSAIDs: A network pharmacology approach to decipher signaling pathway and interactive genes

Author(s):  
Ki Kwang Oh ◽  
Md. Adnan ◽  
Dong Ha Cho

Abstract Background: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) showed promising clinical efficacy toward COVID-19 patients as painkillers and anti-inflammatory agents. However, the prospective anti-COVID-19 mechanisms of NSAIDs are not evidently exposed. Therefore, we intended to decipher the most potent NSAIDs candidate(s) and its novel mechanism(s) against COVID-19 by network pharmacology.Method: FDA (U.S. Food & Drug Administration) approved twenty NSAIDs were used for this study. Genes related to selected NSAIDs and COVID-19 related genes were identified by the Similarity Ensemble Approach, Swiss Target Prediction, and PubChem databases. Venn diagram identified overlapping genes between NSAIDs and COVID-19 related genes. The interactive networking between NSAIDs and overlapping genes was analyzed by STRING. RStudio plotted the bubble chart of KEGG pathway enrichment analysis of overlapping genes. Finally, the binding affinity of NSAIDs against target genes was determined through molecular docking analysis.Results: Geneset enrichment analysis exhibited 26 signaling pathways against COVID-19. Inhibition of proinflammatory stimuli of tissues and/or cells by inactivating RAS signaling pathway was identified as the key anti-COVID-19 mechanism of NSAIDs. Besides, MAPK8, MAPK10, and BAD genes were explored as the associated genes of the RAS. Among twenty NSAIDs, 6MNA, rofecoxib, and indomethacin revealed promising binding affinity with the highest docking score against three identified genes, respectively.Conclusions: Overall, our proposed three NSAIDs (6MNA, rofecoxib, and indomethacin) might block the RAS by inactivating its associated genes, thus may alleviate excessive inflammation induced by SARS-CoV-2.

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Yinhe Deng ◽  
Quanjiang Li ◽  
Menglin Li ◽  
Tiantian Han ◽  
Guixian Li ◽  
...  

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 overlapping genes. Sixty-three core targets were obtained, including ALB, PPARγ, 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. This is the first identification of in-depth study of SXZKF against pharyngitis using network pharmacology. This new evidence could be informative in providing new support on the clinical effects of SXZKF on pharyngitis and for the development of personalized medicine for pharyngitis.


2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Mengshi Tang ◽  
Xi Xie ◽  
Pengji Yi ◽  
Jin Kang ◽  
Jiafen Liao ◽  
...  

Objective. To explore the main components and unravel the potential mechanism of simiao pill (SM) on rheumatoid arthritis (RA) based on network pharmacological analysis and molecular docking. Methods. Related compounds were obtained from TCMSP and BATMAN-TCM database. Oral bioavailability and drug-likeness were then screened by using absorption, distribution, metabolism, and excretion (ADME) criteria. Additionally, target genes related to RA were acquired from GeneCards and OMIM database. Correlations about SM-RA, compounds-targets, and pathways-targets-compounds were visualized through Cytoscape 3.7.1. The protein-protein interaction (PPI) network was constructed by STRING. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed via R packages. Molecular docking analysis was constructed by the Molecular Operating Environment (MOE). Results. A total of 72 potential compounds and 77 associated targets of SM were identified. The compounds-targets network analysis indicated that the 6 compounds, including quercetin, kaempferol, baicalein, wogonin, beta-sitosterol, and eugenol, were linked to ≥10 target genes, and the 10 target genes (PTGS1, ESR1, AR, PGR, CHRM3, PPARG, CHRM2, BCL2, CASP3, and RELA) were core target genes in the network. Enrichment analysis indicated that PI3K-Akt, TNF, and IL-17 signaling pathway may be a critical signaling pathway in the network pharmacology. Molecular docking showed that quercetin, kaempferol, baicalein, and wogonin have good binding activity with IL6, VEGFA, EGFR, and NFKBIA targets. Conclusion. The integrative investigation based on bioinformatics/network topology strategy may elaborate on the multicomponent synergy mechanisms of SM against RA and provide the way out to develop new combination medicines for RA.


2021 ◽  
Author(s):  
Meng-Jin Hu ◽  
Gui-Hao Chen ◽  
Yue-Jin Yang

Abstract Purpose: The aim of this network pharmacology was to explore the potential active ingredients and mechanisms of Tongxinluo (TXL) against acute myocardial infarction (AMI).Methods: We selected active ingredients and targets of TXL according to TCMSP database and converted protein targets into gene symbol by UniProt database. Therapeutic gene targets on AMI were collected from DisGeNET and GeneCards databases. The overlapping genes between ingredients and AMI were identified using Venn diagram. Then, the interaction network between ingredients and overlapping genes was constructed, visualized, and analyzed by Cytoscape software. Protein-protein interaction (PPI) was analyzed by String database. Finally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of overlapping genes were carried out by metascape platform.Results: A total of 111 active ingredients, 184 ingredient-related genes, and 1020 AMI-related genes were retrieved using public databases. Eventually, 79 overlapping genes between TXL and AMI were identified. Cytoscape and PPI results suggested that the active ingredients and genes of TXL against AMI consisted of 66 active ingredients and 79 genes, among them beta-sitosterol and IL-6 were the uppermost active ingredient and hub gene, respectively. Metascape results exhibited that the key mechanism of TXL against AMI might be reducing oxidative stress in cell membrane by inactivating pathways in cancer.Conclusion: This network pharmacology study reveals potential mechanisms of multi-target and multi-component TXL in the treatment of AMI, providing scientific evidence for further expounding the active ingredients and mechanisms of TXL against AMI.


2020 ◽  
Author(s):  
Xue Fan ◽  
Xin Guo ◽  
Mingguo Xu

Abstract Background: Kawasaki disease (KD) isan acute self-limiting systemic vasculitis.In this study, a randomized controlled trial regarding berberine (main component of CoptidisRhizoma) function in treating KD was carried out and possible pharmacological mechanisms of CoptidisRhizoma (CR) on Kawasaki disease therapy were investigated using an integrated network pharmacology approach.Results: The BBR group was able to reduce the values of CRP, NLR and PLR significantly. Also, the effect of BBR improved the resistance rate of intravenous injection of gamma globulin significantly. In total, 9 compounds and 369 relative drug targets were collected from TCMSP, SWISS, SEA and STITCH database and 624 KD target genes were collected in DisGeNET, DrugBank and GeneCards database. The network analysis revealed that 41 targets might be the therapeutic targets of CR on KD, among which ATK1, RELA, SRC, CASP3 and MTOR ranked in top 5. Gene ontology enrichment analysis revealed that the reaction to bacteria-derived molecules and to lipopolysaccharide and the apoptosis process were the key biological procedures for CR treating KD. The KEGG pathway enrichment analysis pointed out that the four signaling pathways closely related to CR treating KD including age-rage signaling pathway, fluid shear stress and atherosclerosis, TNF signaling pathway and Toll-like receptor signaling pathway in diabetic complications.Conclusion: We concluded that the introduction of routine treatment combined with BBR in treating KD has advantages than routine treatment and can be considered as a preferred approach in KD. Network pharmacology showed that CR exerted the effect of prevention KD by regulating multi-targets and multi-components.


2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Yueying Tao ◽  
Kunming Tian ◽  
Ji Chen ◽  
Danfeng Tan ◽  
Yan Liu ◽  
...  

This study aims to predict the active ingredients, potential targets, signaling pathways and investigate the “ingredient-target-pathway” mechanisms involved in the pharmacological action of Danshiliuhao Granule (DSLHG) on liver fibrosis. Pharmacodynamics studies on rats with liver fibrosis showed that DSLHG generated an obvious anti-liver fibrosis action. On this basis, we explored the possible mechanisms underlying its antifibrosis effect using network pharmacology approach. Information about compounds of herbs in DSLHG was collected from TCMSP public database and literature. Furthermore, the oral bioavailability (OB) and drug-likeness (DL) were screened according to ADME features. Compounds with OB≥30% and DL≥0.18 were selected as active ingredients. Then, the potential targets of the active compounds were predicted by pharmacophore mapping approach and mapped with the target genes of the specific disease. The compound-target network and Protein-Protein Interaction (PPI) network were built by Cytoscape software. The core targets were selected by degree values. Furthermore, GO biological process analysis and KEGG pathway enrichment analysis were carried out to investigate the possible mechanisms involved in the anti-hepatic fibrosis effect of DSLHG. The predicted results showed that there were 108 main active components in the DSLHG formula. Moreover, there were 192 potential targets regulated by DSLHG, of which 86 were related to liver fibrosis, including AKT1, EGFR, and IGF1R. Mechanistically, the anti-liver fibrosis effect of DSLHG was exerted by interfering with 47 signaling pathways, such as PI3K-Akt, FoxO signaling pathway, and Ras signaling pathway. Network analysis showed that DSLHG could generate the antifibrosis action by affecting multiple targets and multiple pathways, which reflects the multicomponent, multitarget, and multichannel characteristics of traditional Chinese medicine and provides novel basis to clarify the mechanisms of anti-liver fibrosis of DSLHG.


2019 ◽  
Vol 22 (6) ◽  
pp. 411-420 ◽  
Author(s):  
Xian-Jun Wu ◽  
Xin-Bin Zhou ◽  
Chen Chen ◽  
Wei Mao

Aim and Objective: Cardiovascular disease is a serious threat to human health because of its high mortality and morbidity rates. At present, there is no effective treatment. In Southeast Asia, traditional Chinese medicine is widely used in the treatment of cardiovascular diseases. Quercetin is a flavonoid extract of Ginkgo biloba leaves. Basic experiments and clinical studies have shown that quercetin has a significant effect on the treatment of cardiovascular diseases. However, its precise mechanism is still unclear. Therefore, it is necessary to exploit the network pharmacological potential effects of quercetin on cardiovascular disease. Materials and Methods: In the present study, a novel network pharmacology strategy based on pharmacokinetic filtering, target fishing, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, compound-target-pathway network structured was performed to explore the anti- cardiovascular disease mechanism of quercetin. Results:: The outcomes showed that quercetin possesses favorable pharmacokinetic profiles, which have interactions with 47 cardiovascular disease-related targets and 12 KEGG signaling pathways to provide potential synergistic therapeutic effects. Following the construction of Compound-Target-Pathway (C-T-P) network, and the network topological feature calculation, we obtained top 10 core genes in this network which were AKT1, IL1B, TNF, IL6, JUN, CCL2, FOS, VEGFA, CXCL8, and ICAM1. KEGG pathway enrichment analysis. These indicated that quercetin produced the therapeutic effects against cardiovascular disease by systemically and holistically regulating many signaling pathways, including Fluid shear stress and atherosclerosis, AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway, MAPK signaling pathway, IL-17 signaling pathway and PI3K-Akt signaling pathway.


2020 ◽  
Author(s):  
Lun Wu ◽  
Ying Wei ◽  
Wen-Bo Zhou ◽  
Jiao Zhou ◽  
Li-Hua Yang ◽  
...  

Abstract Background Borax, a boron compound, which is becoming widely recognized for its biological effects, including antioxidant activity, cytotoxicity, and potential therapeutic benefits. However, the specific molecular mechanisms underlying borax-induced anti-tumor effect still remain to be to further elucidated. MicroRNAs (miRNAs) may play key roles in cellular processes including tumor progression, cell apoptosis and cytotoxicity. Thus, this study aimed to investigate, whether miRNAs were involved in the borax-mediated anti-tumor effect using miRNA profiling of a human liver cancer cell line (HepG2) using gene-chip analysis.Methods Total RNA was extracted and purified from HepG2 cells that were treated with 4 mM borax for either 2 or 24 h. The samples underwent microarray analysis using an Agilent Human miRNA Array. Differentially expressed miRNAs were analysed by volcano plot and heatmap, and were validated using real-time fluorescent quantitative PCR (qPCR).ResultsAmong this, 2- or 24-h exposure to borax significantly altered the expression level of miRNAs in HepG2 cells, 4 or 14 were upregulated and 3 were downregulated compared with the control group, respectively (≥2-fold; P<0.05). GO enrichment analysis and KEGG pathway enrichment analysis revealed that target genes of differentially expressed miRNAs in HepG2 cells predominantly participated in MAPK signaling pathway, TGF-beta signaling pathway, NF-kappa B signaling pathway, etc; in 2-h borax treatment group, while Ras signaling pathway, FoxO signaling pathway, Cellular senescence, etc; involved in 24-h treatment group.Conclusions Result indicates that borax-induced anti-tumor effect may be associated with alterations in miRNAs.


2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Minglong Guan ◽  
Lan Guo ◽  
Hengli Ma ◽  
Huimei Wu ◽  
Xiaoyun Fan

Rosmarinic acid (RosA) is a natural phenolic acid compound, which is mainly extracted from Labiatae and Arnebia. At present, there is no systematic analysis of its mechanism. Therefore, we used the method of network pharmacology to analyze the mechanism of RosA. In our study, PubChem database was used to search for the chemical formula and the Chemical Abstracts Service (CAS) number of RosA. Then, the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) was used to evaluate the pharmacodynamics of RosA, and the Comparative Toxicogenomics Database (CTD) was used to identify the potential target genes of RosA. In addition, the Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of target genes were carried out by using the web-based gene set analysis toolkit (WebGestalt). At the same time, we uploaded the targets to the STRING database to obtain the protein interaction network. Then, we carried out a molecular docking about targets and RosA. Finally, we used Cytoscape to establish a visual protein-protein interaction network and drug-target-pathway network and analyze these networks. Our data showed that RosA has good biological activity and drug utilization. There are 55 target genes that have been identified. Then, the bioinformatics analysis and network analysis found that these target genes are closely related to inflammatory response, tumor occurrence and development, and other biological processes. These results demonstrated that RosA can act on a variety of proteins and pathways to form a systematic pharmacological network, which has good value in drug development and utilization.


2021 ◽  
Author(s):  
Xi Cen ◽  
Yan Wang ◽  
LeiLei Zhang ◽  
XiaoXiao Xue ◽  
Yan Wang ◽  
...  

Abstract BackgroundType 2 diabetes mellitus (T2DM) is regarded as Pi Dan disease in traditional Chinese medicine (TCM). Dahuang Huanglian Xiexin Decoction (DHXD), a classical TCM formula, has been used for treating Pi Dan disease in clinic, its pharmacological mechanism has not been elucidated. MethodsThis study used network pharmacological analysis and molecular docking approach to explore the mechanism of DHXD on T2DM. Firstly, the compounds in DHXD were obtained from TCMSP and TCMID databases, the potential targets were determined based on TCMSP and UniProt databases. Next, Genecards, Digenet and UniProt databases were used to identify the targets of T2DM. Then, the protein-protein interaction (PPI) network was established with overlapping genes of T2DM and compounds, and the core targets in the network were identified and analyzed. Then, the David database was used for GO and KEGG enrichment analysis. Finally, the target genes were selected and the molecular docking was completed by Autodock software to observe the binding level of active components with target genes.ResultsA total of 397 related components and 128 overlapping genes were identified. After enrichment analysis, it was found that HIF-1, TNF, IL-17 and other signaling pathways, as well as DNA transcription, gene expression, apoptosis and other cellular biological processes had the strongest correlation with the treatment of T2DM by DHXD, and most of them occurred in the extracellular space, plasma membrane and other places, which were related to enzyme binding and protein binding. In addition, 42 core genes of DHXD, such as VEGFA, TP53 and MAPK1, were considered as potential therapeutic targets, indicating the potential mechanism of DHXD on T2DM. Finally, the results of molecular docking showed that HIF-1 pathway had strong correlation with the target genes INSR and GLUT4, quercetin and berberine had the strongest binding power with them respectively.ConclusionThis study summarized the main components of DHXD in the treatment of T2DM, identified the core genes and pathways, and systematically analyzed the interaction of related targets, trying to lay the foundation for clarifying the potential mechanism of DHXD on T2DM, so as to carry out further research in the future.


2020 ◽  
Vol 11 ◽  
Author(s):  
Yanni Lai ◽  
Qiong Zhang ◽  
Haishan Long ◽  
Tiantian Han ◽  
Geng Li ◽  
...  

Background: Ganghuo Kanggan decoction (GHKGD) is a clinical experience prescription used for the treatment of viral pneumonia in the Lingnan area of China, and its clinical effect is remarkable. However, the mechanism of GHKGD in influenza is still unclear.Objective: To predict the active components and signaling pathway of GHKGD and to explore its therapeutic mechanism in influenza and to verified it in vivo using network pharmacology.Methods: The potential active components and therapeutic targets of GHKGD in the treatment of influenza were hypothesized through a series of network pharmacological strategies, including compound screening, target prediction and pathway enrichment analysis. Based on the target network and enrichment results, a mouse model of influenza A virus (IAV) infection was established to evaluate the therapeutic effect of GHKGD on influenza and to verify the possible molecular mechanism predicted by network pharmacology.Results: A total of 116 candidate active compounds and 17 potential targets were identified. The results of the potential target enrichment analysis suggested GHKGD may involve the RLR signaling pathway to reduce inflammation in the lungs. In vivo experiments showed that GHKGD had a protective effect on pneumonia caused by IAV-infected mice. Compared with the untreated group, the weight loss in the GHKGD group in the BALB/c mice decreased, and the inflammatory pathological changes in lung tissue were reduced (p &lt; 0.05). The expression of NP protein and the virus titers in lung were significantly decreased (p &lt; 0.05). The protein expression of RIG-I, NF-kB, and STAT1 and the level of MAVS and IRF3/7 mRNA were remarkably inhibited in GHKGD group (p &lt; 0.05). After the treatment with GHKGD, the level of Th1 cytokines (IFN-γ, TNF-α, IL-2) was increased, while the expression of Th2 (IL-5, IL4) cytokines was reduced (p &lt; 0.05).Conclusion: Through a network pharmacology strategy and in vivo experiments, the multi-target and multi-component pharmacological characteristics of GHKGD in the treatment of influenza were revealed, and regulation of the RLR signaling pathway during the anti-influenza process was confirmed. This study provides a theoretical basis for the research and development of new drugs from GHKGD.


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