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Aim To explore the active compound of Maxingganshi decoction in treatment of novel coronavirus pneumonia(COVID-19). Methods With the help of TCMSP database, the chemical components and action targets of ephedra, almond, licorice, and gypsum in Maxingganshi decoction were searched, and then a C-T network, protein interaction analysis, GO functional enrichment analysis, and KEGG pathway enrichment were constructed. Analysis was performed to predict its mechanism of action. Results A total of 120 compounds in Maxingganshi decoction corresponded to 222 targets. PTGS2, ESR1, PPARG, AR, NOS2, NCOA2 acted on PI3K-Akt signaling pathway, TNF signaling pathway, IL-17 signaling pathway, T cell receptor signaling pathways, etc. The results of molecular docking showed that the affinity of quercetin, kaempferol, glabridin and other core compounds was similar to recommended drugs in treatment of COVID-19. Conclusions The active compounds of Maxingganshi decoction can target multiple pathways to achieve the therapeutic effect of COVID-19.Copyright © 2020 Publication Centre of Anhui Medical University. All rights reserved.
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Objective: Clinical associations between coronavirus disease (COVID-19) and ischemic stroke (IS) have been reported. This study aimed to investigate the shared genes between COVID-19 and IS and explore their regulatory mechanisms. Methods: Published datasets for COVID-19 and IS were downloaded. Common differentially expressed genes (DEGs) in the two diseases were identified, followed by protein-protein interaction (PPI) network analysis. Moreover, overlapping module genes associated with the two diseases were investigated using weighted correlation network analysis (WGCNA). Through intersection analysis of PPI cluster genes and overlapping module genes, hub-shared genes associated with the two diseases were obtained, followed by functional enrichment analysis and external dataset validation. Moreover, the upstream miRNAs and transcription factors (TFs) of the hub-shared genes were predicted. Results: A total of 91 common DEGs were identified from the clusters of the PPI network, and 129 overlapping module genes were screened using WGCNA. Based on further intersection analysis, four hub-shared genes in IS and COVID-19 were identified, including PDE5A, ITGB3, CEACAM8, and BPI. These hub-shared genes were remarkably enriched in pathways such as ECM-receptor interaction and focal adhesion pathways. Moreover, ITGB3, PDE5A, and CEACAM8 were targeted by 53, 32, and 3 miRNAs, respectively, and these miRNAs were also enriched in the aforementioned pathways. Furthermore, TFs, such as lactoferrin, demonstrated a stronger predicted correlation with the hub-shared genes. Conclusion: The four identified hub-shared genes may participate in crucial mechanisms underlying both COVID-19 and IS and may exhibit the potential to be biomarkers or therapeutic targets for the two diseases.
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Background: Primary Sjogren's syndrome (pSS) is a chronic, systemic, inflammatory autoimmune disease in which existing studies have found the presence of pSS-specific antibodies anti-SSA/ Ro in acute infection with COVID-19.1 The emergence of this phenomenon makes us aware that in the context of the long-term epidemic of COVID-19, it is necessary to further study the molecular mechanisms of the high susceptibility of pSS patients to COVID-19. Method(s): The gene expression profiles of 8 COVID-19 datasets and 5 pSS datasets were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between COVID-19 and PSS were identified using the limma software package and Weighted Gene Co-expression Network Analysis (WGCNA). A Venn diagram was used to discover common upregulated DEGs. To explore the possible pathogenesis of both diseases, common signaling pathways were explored by enriching DEGs using Gene Ontology (GO) and the Kyoto Gene and Genome Encyclopedia (KEGG) pathway. Protein-protein interactions (PPIs) were established to identify hub genes and key modules. The analysis of key gene expression characteristics by The Connectivity Map was used to predict potentially effective drugs. Finally, the CIBERSORT method was used to comprehensively evaluate the immune infiltrates of patients with COVID-19 and PSS to study the mechanisms that may have a common immune response or immune cell infiltration. Result(s): A total of 82 upregulated DEGs were identified in both COVID-19 and PSS (Figure 1 A-E). Functional enrichment analysis illustrated the important role of enhanced signaling pathways in response to virus defense and interferon-alpha in both diseases (Figure 1F).Three key modules including 25 hub genes were identified (Figure 1G). The correlation analysis of immune cell infiltration showed the expression of B cells memory resting decreased and NK cells resting increased significantly in the two diseases (Figure 1H, I). Finally, estradiol in drug prediction outcomes has been shown to reduce susceptibility to COVID-19 and its severity through its involvement in regulating immune cells, while the most common manifestation of dry eye in pSS patients is strongly associated with low estrogen. Conclusion(s): High defense response to virus and response to interferon-alpha in pSS patients might be a crucial susceptible factor for COVID-19 and predictive drugs such as estradiol, suggested by susceptibility genes common to COVID-19 and pSS, may help in the clinical treatment of both diseases.
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Objective: To explore the potential components and mechanism of Yinlian jiedu decoction in the treatment of COVID-19. Method(s): The blood components in the formula of Yinlian jiedu decoction or compounds conforming to drug-like parameters were selected as the research objects.The components that meet the requirements in Lonicerae Japonicae Flos, Forsythiae Fructus, Bupleuri Radix, Scutellariae Radix, aboveground part of Agastache rugosa, Saposhnikoviae Radix, Menthae Haplocalycis Herba, Bombyx Batryticatus, Belamcandae Rhizoma, Platycodonis Radix, Aurantii Fructus, Fritillariae Thunbergii Bulbus, Phragmitis Rhizoma, fried Stemonae Radix, Eriobotryae Folium, Citri Reticulatae Pericarpium, Astragali Radix, Codonopsis Radix, fried Atrictylodis Macrocephalac Rhizoma, Coicis Semen, Salviae Miltiorrhizae Radix et Rhizoma, Chuanxiong Rhizama, Chebulae Fructus, Glycyrrhizae Radix et Rhizoma were searched and predicted through multiple network pharmacological data platforms.The Perl command was used to batch retrieve the upstream gene name of the prediction target in the UniProt database.The target genes were brought into the ClueGO software for GO function enrichment analysis, to explore the core metabolic pathways and signal pathways and clarify the mechanism of the treatment of COVID-19 with Yinlian jiedu decoction. Result(s): The compounds-targets network consisted of 309 compounds and 1 016 corresponding targets.The key targets involved MMP1, FASN, MPO, MMP3, NQO1, MMP12, ALOX5, PTGS2, GCLM, MMP2, EGFR, GSTP1, MET, ACEII, etc.There were 238 GO items in GO functional enrichment analysis(P<0.05), including 202 biological processes(BP), 9 cellular components(CC)and 27 molecular functions(MF).The results of molecular docking showed that puerarin had the best affinity with COVID-19. Conclusion(s): Puerarin in Yinlian jiedu decoction has a direct effect on ACEII.At the same time, multiple components of Yinlian jiedu decoction play a regulatory role in multiple pathways related to respiratory diseases by acting on multiple related targets. Copyright © 2021, Central Station of Chinese Medicinal Materials Information, National Medical Products Administration. All right reserved.
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Objective: To explore the potential action mechanism of Bupleuri Radix and Puerariae Lobatae Radix herb-pair in the treatment of Corona Virus Disease 2019(COVID-19)caused by 2019-nCoV virus through network pharmacology method, so as to provide theoretical guidance for further mechanism and clinical translational research. Method(s): The potential active ingredients and their respective related action targets of Bupleuri Radix and Puerariae Lobatae Radix were obtained through the TCMSP, and the COVID-19-related disease targets were searched by GeneCards database.The common targets from the both screenings were input into the STRING protein interaction online database to construct the interaction network of potential targets.The potential core targets were further screened by MCODE plug-ins.The "ingredients-targets-diseases" network and PPI network were constructed by Cytoscape 3.2.1 software, and GO function enrichment analysis and KEGG signal pathway enrichment analysis were carried out by DAVID v6.8 online software. Result(s): A total of 22 active ingredients and 226 drug targets were screened from Bupleuri Radix and Puerariae Lobatae Radix herb-pair, among which 47 were co-acting targets with COVID-19 and 21 were potential core targets.The results of GO functional enrichment analysis showed that it was mainly related to gene transcriptional expression, inflammatory response and immune system response, while KEGG signal pathway enrichment analysis showed that it was mainly associated with influenza A virus, TNF pathway, Toll-like receptor signal pathway and others. Conclusion(s): Bupleuri Radix and Puerariae Lobatae Radix herb-pair can exert an anti-2019-nCoV effect through its regulatory role in inflammatory reaction and immune system with a multi-ingredients, multi-targets and multi-pathways pharmacological characteristics. Copyright © 2021, Central Station of Chinese Medicinal Materials Information, National Medical Products Administration. All right reserved.
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Objective: To study the mechanism of Shufeng jiedu granules in treating Corona Virus Disease 2019(COVID-19)based on network pharmacology. Method(s): TCMSP database was used to search and screen the active components of Shufeng jiedu granules, GeneGards database was used to predict and screen disease targets, the common targets of the above two were input into the STRING database to obtain the target protein interaction network, the PPI network and the "traditional Chinese medicines-components-targets-diseases" network were constructed by using Cytoscape 3.7.2 software, and the GO function enrichment analysis and KEGG pathway enrichment analysis were carried out by using Cytoscape 3.7.2 software, R software and the corresponding program package. Result(s): A total of 207 active components and 1 006 traditional Chinese medicine component targets were screened, and 350 COVID-19-related targets were identified, so as to obtain 49 common drug-disease targets.GO functional enrichment analysis resulted in 1 575 items(P<0.05), KEGG enrichment analysis resulted in 120 related signaling pathways(P<0.05), mainly involving IL-17 signaling pathway, TNF signaling pathway, etc. Conclusion(s): Shufeng jiedu granules may achieve the therapeutic effect of COVID-19 through multi-targets, multi-pathways to regulate virus and inflammation-related pathways. Copyright © 2021, Central Station of Chinese Medicinal Materials Information, National Medical Products Administration. All right reserved.
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Background: Coronavirus disease 2019 (COVID-19) is often associated with enhanced platelet activation and thrombotic complications which may be reflected by altered microRNA (miRNA) levels in blood cells. Aim(s): We here investigated the expression of miRNAs in the background of platelet reactivity in severe COVID-19 and evaluated them for the prediction of disease mortality. Method(s): Platelet miRNAs were isolated from leukocyte-depleted platelets and profiled in COVID-19 survivors and non-survivors vs healthy controls using TaqMan Open Array. Candidate miRNAs showing at least 2-fold alteration between two groups were validated by RT-qPCR in 10 individuals from each group, and these data were correlated with clinical outcome in COVID-19. Differentially regulated miRNAs were bioinformatically analyzed to identify their mRNA targets and Cytoscape ClueGO was used for functional enrichment analysis. Platelet reactivity was evaluated via quantification of P-selectin expression, platelet-leukocyte aggregates and platelet-derived microparticles (PMPs) by flow cytometry. Result(s): Increased platelet activation was detected via elevated level of P-selectin positivity (6.5 vs 1.1%, P < 0.0001), platelet-monocyte aggregates (40 vs 17 %, P = 0.0315) and PMPs (22 vs 18 PMPs/10
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: Lung cancer is the most commonly occurring cancer in men worldwide. To search for new biological markers of this pathology, the transcriptome of the blood mononuclear cells from patients and healthy donors (residents of Kemerovo oblast, Russia) was studied using SurePrint G3 Human Gene Expression microarray technology. A total of 288 differentially expressed genes were identified, including 108 up-regulated genes and 180 down-regulated genes. Functional enrichment analysis using the WebGestalt resource and different databases (Gene Ontology, KEGG, and Reactome) indicated changes in the expression profiles of genes involved in the processes of immune response, protein synthesis, cell cycle control, and apoptosis. Analysis of protein–protein interactions using the STRING algorithm made it possible to identify functional clusters of gene products with different expression levels.
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Rationale: The SARS-CoV-2 pandemic has underscored the need for novel anti-infectious strategies, including host-directed therapeutics, against existing and emerging respiratory pathogens. We have reported that an aerosolized therapeutic comprised of a Toll-like receptor (TLR)-2/6 agonist, Pam2CSK4, and a TLR-9 agonist, ODN M362, stimulate pathogen-agnostic innate immune responses in lung epithelial cells. This therapeutic (“Pam2-ODN”) promotes synergistic microbicidal activity and host survival benefit against pneumonia caused by a wide range of pathogens. Here, we study the immunomodulatory signaling mechanisms required to effect this inducible epithelial resistance. Methods: Bioinformatic analysis of transcriptional responses from human and mouse lung epithelium al cells to influenza A H1N1 or SARS-CoV-2 (GSE147507) or Pam2-ODN (GSE289984, GSE26864) were analyzed using R and IPA software to identify essential transcription factors (TFs). Lung cell population dynamics were studied for TFs related to Pam2-ODN immunomodulatory signaling using high-throughput imaging flow cytometry (IFC). Human or mouse lung epithelial cells were stimulated with PBS or Pam2-ODN and single or dual inhibitors of TFs before challeng with influenza A H3N2 (IAV) or coronavirus OC43 (CoV) to compare the epithelium-specific transcriptional control of relevant TFs using in-cell western blotting, IFC and hemagglutination for viral burdens. Results: Functional enrichment analysis revealed RelA and cJUN to be major immunomodulatory TFs of Pam2-ODN and activators of leukocyte- and epithelial-derived antiviral immune mechanisms targeting replication of influenza A and SARS-CoV-2. Cell population dynamics studied from mouse lungs confirmed activation of RelA and cJUN in CD45+, EpCAM- leukocytes and in CD45-, EpCAM+ epithelial cells, with predominant activation of the lung epithelium and none or minimal activation of structural cell populations such as fibroblasts or endothelial cells. Studies of epithelium-specific signaling in vitro revealed co-activation of RelA-(pS536) and cJun- (pS73) TFs with Pam2-ODN, and earlier onset of cJUN phosphorylation and nuclear translocation with Pam2-ODN after IAV or CoV infection. Individual or dual inhibition of RelA and/or cJUN activity in vitro disrupted the antiviral activity of Pam2-ODN of IAV infected cells. Conclusion: Pam2-ODN induces unique, pathogen-agnostic protective signaling in lung epithelial cells that involves cooperative activation of RelA and cJUN. This combined TF signaling mechanism is not observed in other structural lung cell populations after Pam2-ODN exposure. Further, the phospho-regulation dynamics of RelA and cJUN are not replicated by IAV or CoV infection alone, suggesting a novel therapeutic process that can be leveraged to protect individuals against pneumonia. (Figure Presented).
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Aims: The aim of this study was to extract the signaling mediators or biological pathways that link covid-19 to other diseases such as type 1 diabetes mellitus (T1DM). Methods: Microarray data of covid-19 (GSE164805) was extracted from Gene Expression Omnibus (GEO) and analyses were performed by R package and GEO2R. Functional enrichment analysis was done to extract enriched molecular pathways (MP), biological process (BP) and molecular function (MF). Then commonly up- and down-regulated genes in covid-19 and T1DM were extracted by comparing deferentially expressed genes (DEGs) of GSE164805 and GSE9006. Results: Down-regulated DEGs in the severely progressing covid-19 patients (SPCP) had a link to T1DM. Major histocompatibility system (MHC) class II, gamma interferon (IFNγ), and IL-1B were enriched in extracted pathway that leads to T1DM. In addition, comparing extracted DEGs from GSE164805 and GSE9006 indicated that MTUS1, EGR1 and EGR3 are the genes that are up-regulated in both SPCP and T1DM. Conclusion: The findings of this study indicate that coincidence of SARS-COV-2 infection and T1DM may increase the severity of both diseases. Although covid-19 reduced the T cell mediated immune response, but increased mediators of T-cell signaling pathway such as IL-1 in both diseases. This could potentiate the inflammation response and worsens the severity of covid-19 cytokine storm or increase the resistance to insulin.
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Viroporins, integral viral membrane ion channel proteins, interact with host-cell proteins deregulating physiological processes and activating inflammasomes. Severity of COVID-19 might be associated with hyperinflammation, thus we aimed at the complete immunoinformatic analysis of the SARS-CoV-2 viroporin E, P0DTC4. We also identified the human proteins interacting with P0DTC4 and the enriched molecular functions of the corresponding genes. The complete sequence of P0DTC4 in FASTA format was processed in 10 databases relative to secondary and tertiary protein structure analyses and prediction of optimal vaccine epitopes. Three more databases were accessed for the retrieval and the molecular functional characterization of the P0DTC4 human interactors. The immunoinformatics analysis resulted in the identification of 4 discontinuous B-cell epitopes along with 1 linear B-cell epitope and 11 T-cell epitopes which were found to be antigenic, immunogenic, nonallergen, nontoxin, and unable to induce autoimmunity thus fulfilling prerequisites for vaccine design. The functional enrichment analysis showed that the predicted host interactors of P0DTC4 target the cellular acetylation network. Two of the identified host-cell proteins - BRD2 and BRD4 - have been shown to be promising targets for antiviral therapy. Thus, our findings have implications for COVID-19 therapy and indicate that viroporin E could serve as a promising vaccine target against SARS-CoV-2. Validation experiments are required to complement these in silico results.