Exploration of Potential Biomarkers and Mechanisms for COVID-19 and Asthma Based on Microarray Analysis

Aims: The aim of this study is to investigate the potential mechanisms of coronavirus disease (COVID-19) and asthma comor-bidities.Methods: GSE147507 and GSE143303 datasets were obtained from the Gene Expression Omnibus (GEO) database, the differ-ential expressed genes (DEGs) were identified, and the overlapping DEGs were obtained by determining the DEG intersection between the two datasets. A series of analyses of the shared DEGs were performed, including enrichment analysis, protein -protein interaction (PPI) network construction, construction of transcription factor (TF)/microRNA (miRNA)-gene interaction networks, drug-gene and disease-gene interactions, and receiver operating characteristic curve (ROC) analysis.Results: A total of 135 overlapping DEGs were obtained by determining the DEGs intersection between the GSE147507 and GSE143303 datasets. These overlapped DEGs were significantly enriched in the regulation of DNA-templated transcription, initi-ation, clathrin-sculpted gamma-aminobutyric acid transport vesicle, DNA binding, and eight KEGG (kyoto encyclopedia of genes and genomes) pathways. The PPI network revealed that HSPA8, SRSF1, NDUFAB1, PTEN, CCT8, HIST1H2BK, HIST2H2BE, DLAT, EIF3G, and WAC, with high scores, were the hub genes. In addition, 65 TFs (transcription factors) and 369 miRNAs tar-geted overlapping DEGs. Finally, these overlapped DEGs were also related to other diseases, such as hyperglycemia, metabolic acidosis, and lung neoplasm, and the top 10 drugs with the most significant potential included lanatoside C, digoxin, GW-8510, doxorubicin, daunorubicin, proscillaridin, anisomycin, helveticoside, ouabain, and bisacodyl. The ROC analysis results shown that these hub genes had good diagnostic performance.Conclusions: HSPA8, SRSF1, NDUFAB1, PTEN, CCT8, HIST1H2BK, HIST2H2BE, DLAT, EIF3G, WAC, FOXC1, GATA2, hsa-miR-93-5p, and hsa-miR-17-5p may play vital roles in COVID-19 (corona virus disease-2019)/asthma comorbidity. Lanatoside C, digoxin, GW-8510, doxorubicin, daunorubicin, proscillaridin, anisomycin, helveticoside, ouabain, and bisacodyl may serve as drug targets against COVID-19/asthma comorbidity.

Reverse tracking from drug-induced transcriptomes through multilayer molecular networks reveals hidden drug targets.

Identifying molecular targets of a drug is an essential process for drug discovery and development. The recent in-silico approaches are usually based on the structure information of chemicals and proteins. However, 3D structure information is hard to obtain and machine-learning methods using 2D structure suffer from data imbalance problem. Here, we present a reverse tracking method from genes to target proteins using drug-perturbed gene transcriptional profiles and multilayer molecular networks. We scored how well the protein explains gene expression changes perturbed by a drug. We validated the protein scores of our method in predicting known targets of drugs. Our method performs better than other methods using the gene transcriptional profiles and shows the ability to suggest the molecular mechanism of drugs. Furthermore, our method has the potential to predict targets for objects that do not have rigid structural information, such as coronavirus.

Identification of phytochemical compounds of Fagopyrum dibotrys and their targets by metabolomics, network pharmacology and molecular docking studies.

Acute lung injury (ALI) is a clinically severe lung illness with high incidence rate and mortality. Especially, coronavirus disease 2019 (COVID-19) poses a serious threat to world wide governmental fitness. It has distributed to almost from corner to corner of the universe, and the situation in the prevention and control of COVID-19 remains grave. Traditional Chinese medicine plays a vital role in the precaution and therapy of sicknesses. At present, there is a lack of drugs for treating these diseases, so it is necessary to develop drugs for treating COVID-19 related ALI. Fagopyrum dibotrys (D. Don) Hara is an annual plant of the Polygonaceae family and one of the long-history used traditional medicine in China. In recent years, its rhizomes (medicinal parts) have attracted the attention of scholars at home and abroad due to their significant anti-inflammatory, antibacterial and anticancer activities. It can work on SARS-COV-2 with numerous components, targets, and pathways, and has a certain effect on coronavirus disease 2019 (COVID-19) related acute lung injury (ALI). However, there are few systematic studies on its aerial parts (including stems and leaves) and its potential therapeutic mechanism has not been studied. The phytochemical constituents of rhizome of F. dibotrys were collected using TCMSP database. And metabolites of F. dibotrys' s aerial parts were detected by metabonomics. The phytochemical targets of F. dibotrys were predicted by the PharmMapper website tool. COVID-19 and ALI-related genes were retrieved from GeneCards. Cross targets and active phytochemicals of COVID-19 and ALI related genes in F. dibotrys were enriched by gene ontology (GO) and KEGG by metscape bioinformatics tools. The interplay network entre active phytochemicals and anti COVID-19 and ALI targets was established and broke down using Cytoscape software. Discovery Studio (version 2019) was used to perform molecular docking of crux active plant chemicals with anti COVID-19 and ALI targets. We identified 1136 chemicals from the aerial parts of F. dibotrys, among which 47 were active flavonoids and phenolic chemicals. A total of 61 chemicals were searched from the rhizome of F. dibotrys, and 15 of them were active chemicals. So there are 6 commonly key active chemicals at the aerial parts and the rhizome of F. dibotrys, 89 these phytochemicals's potential targets, and 211 COVID-19 and ALI related genes. GO enrichment bespoken that F. dibotrys might be involved in influencing gene targets contained numerous biological processes, for instance, negative regulation of megakaryocyte differentiation, regulation of DNA metabolic process, which could be put down to its anti COVID-19 associated ALI effects. KEGG pathway indicated that viral carcinogenesis, spliceosome, salmonella infection, coronavirus disease - COVID-19, legionellosis and human immunodeficiency virus 1 infection pathway are the primary pathways obsessed in the anti COVID-19 associated ALI effects of F. dibotrys. Molecular docking confirmed that the 6 critical active phytochemicals of F. dibotrys, such as luteolin, (+) -epicatechin, quercetin, isorhamnetin, (+) -catechin, and (-) -catechin gallate, can combine with kernel therapeutic targets NEDD8, SRPK1, DCUN1D1, and PARP1. In vitro activity experiments showed that the total antioxidant capacity of the aerial parts and rhizomes of F. dibotrys increased with the increase of concentration in a certain range. In addition, as a whole, the antioxidant capacity of the aerial part of F. dibotrys was stronger than that of the rhizome. Our research afford cues for farther exploration of the anti COVID-19 associated ALI chemical compositions and mechanisms of F. dibotrys and afford scientific foundation for progressing modern anti COVID-19 associated ALI drugs based on phytochemicals in F. dibotrys. We also fully developed the medicinal value of F. dibotrys' s aerial parts, which can effectively avoid the waste of resources. Meanwhile, our work provides a new strategy for integrating metabonomics, network pharmacology, and molecular docking techniques which was an efficient way for recognizing effective constituents and mechanisms valid to the pharmacologic actions of traditional Chinese medicine.

Identifying diseases associated with Post-COVID syndrome through an integrated network biology approach.

A growing body of research shows that COVID-19 is now recognized as a multi-organ disease with a wide range of manifestations that can have long-lasting repercussions, referred to as post-COVID-19 syndrome. It is unknown why the vast majority of COVID-19 patients develop post-COVID-19 syndrome, or why patients with pre-existing disorders are more likely to experience severe COVID-19. This study used an integrated network biology approach to obtain a comprehensive understanding of the relationship between COVID-19 and other disorders. The approach involved building a PPI network with COVID-19 genes and identifying highly interconnected regions. The molecular information contained within these subnetworks, as well as the pathway annotations, were used to reveal the link between COVID-19 and other disorders. Using Fisher's exact test and disease-specific gene information, significant COVID-19-disease associations were discovered. The study discovered diseases that affect multiple organs and organ systems, thus proving the theory of multiple organ damage caused by COVID-19. Cancers, neurological disorders, hepatic diseases, cardiac disorders, pulmonary diseases, and hypertensive diseases are just a few of the conditions linked to COVID-19. Pathway enrichment analysis of shared proteins revealed the shared molecular mechanism of COVID-19 and these diseases. The findings of the study shed new light on the major COVID-19-associated disease conditions and how their molecular mechanisms interact with COVID-19. The novelty of studying disease associations in the context of COVID-19 provides new insights into the management of rapidly evolving long-COVID and post-COVID syndromes, which have significant global implications.Communicated by Ramaswamy H. Sarma.

Assessment of GO-Based Protein Interaction Affinities in the Large-Scale Human-Coronavirus Family Interactome.

SARS-CoV-2 is a novel coronavirus that replicates itself via interacting with the host proteins. As a result, identifying virus and host protein-protein interactions could help researchers better understand the virus disease transmission behavior and identify possible COVID-19 drugs. The International Committee on Virus Taxonomy has determined that nCoV is genetically 89% compared to the SARS-CoV epidemic in 2003. This paper focuses on assessing the host-pathogen protein interaction affinity of the coronavirus family, having 44 different variants. In light of these considerations, a GO-semantic scoring function is provided based on Gene Ontology (GO) graphs for determining the binding affinity of any two proteins at the organism level. Based on the availability of the GO annotation of the proteins, 11 viral variants, viz., SARS-CoV-2, SARS, MERS, Bat coronavirus HKU3, Bat coronavirus Rp3/2004, Bat coronavirus HKU5, Murine coronavirus, Bovine coronavirus, Rat coronavirus, Bat coronavirus HKU4, Bat coronavirus 133/2005, are considered from 44 viral variants. The fuzzy scoring function of the entire host-pathogen network has been processed with ~180 million potential interactions generated from 19,281 host proteins and around 242 viral proteins. ~4.5 million potential level one host-pathogen interactions are computed based on the estimated interaction affinity threshold. The resulting host-pathogen interactome is also validated with state-of-the-art experimental networks. The study has also been extended further toward the drug-repurposing study by analyzing the FDA-listed COVID drugs.

Preventing Respiratory Viral Diseases with Antimicrobial Peptide Master Regulators in the Lung Airway Habitat.

The vast surface area of the respiratory system acts as an initial site of contact for microbes and foreign particles. The whole respiratory epithelium is covered with a thin layer of the airway and alveolar secretions. Respiratory secretions contain host defense peptides (HDPs), such as defensins and cathelicidins, which are the best-studied antimicrobial components expressed in the respiratory tract. HDPs have an important role in the human body's initial line of defense against pathogenic microbes. Epithelial and immunological cells produce HDPs in the surface fluids of the lungs, which act as endogenous antibiotics in the respiratory tract. The production and action of these antimicrobial peptides (AMPs) are critical in the host's defense against respiratory infections. In this study, we have described all the HDPs secreted in the respiratory tract as well as how their expression is regulated during respiratory disorders. We focused on the transcriptional expression and regulation mechanisms of respiratory tract HDPs. Understanding how HDPs are controlled throughout infections might provide an alternative to relying on the host's innate immunity to combat respiratory viral infections.

Recognition of Differentially Expressed Molecular Signatures and Pathways Associated with COVID-19 Poor Prognosis in Glioblastoma Patients.

Glioblastoma (GBM) is a type of brain cancer that is typically very aggressive and difficult to treat. Glioblastoma cases have been reported to have increased during COVID-19. The mechanisms underlying this comorbidity, including genomic interactions, tumor differentiation, immune responses, and host defense, are not completely explained. Therefore, we intended to investigate the differentially expressed shared genes and therapeutic agents which are significant for these conditions by using in silico approaches. Gene expression datasets of GSE68848, GSE169158, and GSE4290 studies were collected and analyzed to identify the DEGs between the diseased and the control samples. Then, the ontology of the genes and the metabolic pathway enrichment analysis were carried out for the classified samples based on expression values. Protein-protein interactions (PPI) map were performed by STRING and fine-tuned by Cytoscape to screen the enriched gene module. In addition, the connectivity map was used for the prediction of potential drugs. As a result, 154 overexpressed and 234 under-expressed genes were identified as common DEGs. These genes were found to be significantly enriched in the pathways involved in viral diseases, NOD-like receptor signaling pathway, the cGMP-PKG signaling pathway, growth hormone synthesis, secretion, and action, the immune system, interferon signaling, and the neuronal system. STAT1, CXCL10, and SAMDL were screened out as the top 03 out of the top 10 most critical genes among the DEGs from the PPI network. AZD-8055, methotrexate, and ruxolitinib were predicted to be the possible agents for the treatment. The current study identified significant key genes, common metabolic signaling networks, and therapeutic agents to improve our perception of the common mechanisms of GBM-COVID-19.

Network pharmacology reveals multitarget mechanism of action of drugs to be repurposed for COVID-19.

The coronavirus disease 2019 pandemic accelerated drug/vaccine development processes, integrating scientists all over the globe to create therapeutic alternatives against this virus. In this work, we have collected information regarding proteins from SARS-CoV-2 and humans and how these proteins interact. We have also collected information from public databases on protein-drug interactions. We represent this data as networks that allow us to gain insights into protein-protein interactions between both organisms. With the collected data, we have obtained statistical metrics of the networks. This data analysis has allowed us to find relevant information on which proteins and drugs are the most relevant from the network pharmacology perspective. This method not only allows us to focus on viral proteins as the main targets for COVID-19 but also reveals that some human proteins could be also important in drug repurposing campaigns. As a result of the analysis of the SARS-CoV-2-human interactome, we have identified some old drugs, such as disulfiram, auranofin, gefitinib, suloctidil, and bromhexine as potential therapies for the treatment of COVID-19 deciphering their potential complex mechanism of action.

Systems biology models to identify the influence of SARS-CoV-2 infections to the progression of human autoimmune diseases.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been circulating since 2019, and its global dominance is rising. Evidences suggest the respiratory illness SARS-CoV-2 has a sensitive affect on causing organ damage and other complications to the patients with autoimmune diseases (AD), posing a significant risk factor. The genetic interrelationships and molecular appearances between SARS-CoV-2 and AD are yet unknown. We carried out the transcriptomic analytical framework to delve into the SARS-CoV-2 impacts on AD progression. We analyzed both gene expression microarray and RNA-Seq datasets from SARS-CoV-2 and AD affected tissues. With neighborhood-based benchmarks and multilevel network topology, we obtained dysfunctional signaling and ontological pathways, gene disease (diseasesome) association network and protein-protein interaction network (PPIN), uncovered essential shared infection recurrence connectivities with biological insights underlying between SARS-CoV-2 and AD. We found a total of 77, 21, 9, 54 common DEGs for SARS-CoV-2 and inflammatory bowel disorder (IBD), SARS-CoV-2 and rheumatoid arthritis (RA), SARS-CoV-2 and systemic lupus erythematosus (SLE) and SARS-CoV-2 and type 1 diabetes (T1D). The enclosure of these common DEGs with bimolecular networks revealed 10 hub proteins (FYN, VEGFA, CTNNB1, KDR, STAT1, B2M, CD3G, ITGAV, TGFB3). Drugs such as amlodipine besylate, vorinostat, methylprednisolone, and disulfiram have been identified as a common ground between SARS-CoV-2 and AD from drug repurposing investigation which will stimulate the optimal selection of medications in the battle against this ongoing pandemic triggered by COVID-19.

Immune-Related Protein Interaction Network in Severe COVID-19 Patients toward the Identification of Key Proteins and Drug Repurposing.

Coronavirus disease 2019 (COVID-19) is still an active global public health issue. Although vaccines and therapeutic options are available, some patients experience severe conditions and need critical care support. Hence, identifying key genes or proteins involved in immune-related severe COVID-19 is necessary to find or develop the targeted therapies. This study proposed a novel construction of an immune-related protein interaction network (IPIN) in severe cases with the use of a network diffusion technique on a human interactome network and transcriptomic data. Enrichment analysis revealed that the IPIN was mainly associated with antiviral, innate immune, apoptosis, cell division, and cell cycle regulation signaling pathways. Twenty-three proteins were identified as key proteins to find associated drugs. Finally, poly (I:C), mitomycin C, decitabine, gemcitabine, hydroxyurea, tamoxifen, and curcumin were the potential drugs interacting with the key proteins to heal severe COVID-19. In conclusion, IPIN can be a good representative network for the immune system that integrates the protein interaction network and transcriptomic data. Thus, the key proteins and target drugs in IPIN help to find a new treatment with the use of existing drugs to treat the disease apart from vaccination and conventional antiviral therapy.

Novel Immune-Related Genetic Expression for Primary Sjögren's Syndrome.

Objective: To identify novel immune-related genes expressed in primary Sjögren's syndrome (pSS). Methods: Gene expression profiles were obtained from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) were screened. The differences in immune cell proportion between normal and diseased tissues were compared, weighted gene co-expression network analysis was conducted to identify key modules, followed by a protein-protein interaction (PPI) network generation and enrichment analysis. The feature genes were screened and verified using the GEO datasets and quantitative real-time PCR (RT-qPCR). Results: A total of 345 DEGs were identified, and the proportions of gamma delta T cells, memory B cells, regulatory T cells (Tregs), and activated dendritic cells differed significantly between the control and pSS groups. The turquoise module indicated the highest correlation with pSS, and 252 key genes were identified. The PPI network of key genes showed that RPL9, RBX1, and RPL31 had a relatively higher degree. In addition, the key genes were mainly enriched in coronavirus disease-COVID-2019, hepatitis C, and influenza A. Fourteen feature genes were obtained using the support vector machine model, and two subtypes were identified. The genes in the two subtypes were mainly enriched in the JAK-STAT, p53, and toll-like receptor signaling pathways. The majority of the feature genes were upregulated in the pSS group, verified using the GEO datasets and RT-qPCR analysis. Conclusions: Memory B cells, gamma delta T cells, Tregs, activated dendritic cells, RPL9, RBX1, RPL31, and the feature genes possible play vital roles in the development of pSS.

Identifying potential novel insights for COVID-19 pathogenesis and therapeutics using an integrated bioinformatics analysis of host transcriptome.

The molecular mechanisms underlying the pathogenesis of COVID-19 have not been fully discovered. This study aims to decipher potentially hidden parts of the pathogenesis of COVID-19, potential novel drug targets, and identify potential drug candidates. Two gene expression profiles were analyzed, and overlapping differentially expressed genes (DEGs) were selected for which top enriched transcription factors and kinases were identified, and pathway analysis was performed. Protein-protein interaction (PPI) of DEGs was constructed, hub genes were identified, and module analysis was also performed. DGIdb database was used to identify drugs for the potential targets (hub genes and the most enriched transcription factors and kinases for DEGs). A drug-potential target network was constructed, and drugs were ranked according to the degree. L1000FDW was used to identify drugs that can reverse transcriptional profiles of COVID-19. We identified drugs currently in clinical trials, others predicted by different methods, and novel potential drug candidates Entrectinib, Omeprazole, and Exemestane for combating COVID-19. Besides the well-known pathogenic pathways, it was found that axon guidance is a potential pathogenic pathway. Sema7A, which may exacerbate hypercytokinemia, is considered a potential novel drug target. Another potential novel pathway is related to TINF2 overexpression, which may induce potential telomere dysfunction and damage DNA that may exacerbate lung fibrosis. This study identified new potential insights regarding COVID-19 pathogenesis and treatment, which might help us improve our understanding of the mechanisms of COVID-19.

Detection of spreader nodes in human-SARS-CoV protein-protein interaction network.

The entire world is witnessing the coronavirus pandemic (COVID-19), caused by a novel coronavirus (n-CoV) generally distinguished as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). SARS-CoV-2 promotes fatal chronic respiratory disease followed by multiple organ failure, ultimately putting an end to human life. International Committee on Taxonomy of Viruses (ICTV) has reached a consensus that SARS-CoV-2 is highly genetically similar (up to 89%) to the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), which had an outbreak in 2003. With this hypothesis, current work focuses on identifying the spreader nodes in the SARS-CoV-human protein-protein interaction network (PPIN) to find possible lineage with the disease propagation pattern of the current pandemic. Various PPIN characteristics like edge ratio, neighborhood density, and node weight have been explored for defining a new feature spreadability index by which spreader proteins and protein-protein interaction (in the form of network edges) are identified. Top spreader nodes with a high spreadability index have been validated by Susceptible-Infected-Susceptible (SIS) disease model, first using a synthetic PPIN followed by a SARS-CoV-human PPIN. The ranked edges highlight the path of entire disease propagation from SARS-CoV to human PPIN (up to level-2 neighborhood). The developed network attribute, spreadability index, and the generated SIS model, compared with the other network centrality-based methodologies, perform better than the existing state-of-art.

Unraveling the molecular crosstalk between Atherosclerosis and COVID-19 comorbidity.

BACKGROUND: Corona virus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) has created ruckus throughout the world. Growing epidemiological studies have depicted atherosclerosis as a comorbid factor of COVID-19. Though both these diseases are triggered via inflammatory rage that leads to injury of healthy tissues, the molecular linkage between them and their co-influence in causing fatality is not yet understood. METHODS: We have retrieved the data of differentially expressed genes (DEGs) for both atherosclerosis and COVID-19 from publicly available microarray and RNA-Seq datasets. We then reconstructed the protein-protein interaction networks (PPIN) for these diseases from protein-protein interaction data of corresponding DEGs. Using RegNetwork and TRRUST, we mapped the transcription factors (TFs) in atherosclerosis and their targets (TGs) in COVID-19 PPIN. RESULTS: From the atherosclerotic PPIN, we have identified 6 hubs (TLR2, TLR4, EGFR, SPI1, MYD88 and IRF8) as differentially expressed TFs that might control the expression of their 17 targets in COVID-19 PPIN. The important target proteins include IL1B, CCL5, ITGAM, IFIT3, CXCL1, CXCL2, CXCL3 and CXCL8. Consequent functional enrichment analysis of these TGs have depicted inflammatory responses to be overrepresented among the gene sets. CONCLUSION: Finally, analyzing the DEGs in cardiomyocytes infected with SARS-CoV-2, we have concluded that MYD88 is a crucial linker of atherosclerosis and COVID-19, the co-existence of which lead to fatal outcomes. Anti-inflammatory therapy targeting MYD88 could be a potent strategy for combating this comorbidity.

HiDeF: identifying persistent structures in multiscale 'omics data.

In any 'omics study, the scale of analysis can dramatically affect the outcome. For instance, when clustering single-cell transcriptomes, is the analysis tuned to discover broad or specific cell types? Likewise, protein communities revealed from protein networks can vary widely in sizes depending on the method. Here, we use the concept of persistent homology, drawn from mathematical topology, to identify robust structures in data at all scales simultaneously. Application to mouse single-cell transcriptomes significantly expands the catalog of identified cell types, while analysis of SARS-COV-2 protein interactions suggests hijacking of WNT. The method, HiDeF, is available via Python and Cytoscape.

Potential compound from herbal food of Rhizoma Polygonati for treatment of COVID-19 analyzed by network pharmacology: Viral and cancer signaling mechanisms.

Rhizoma Polygonati (huangjing in Chinese, ) is a medicine food homology herb used as a component of traditional Chinese medicine treating COVID-19 in the current pandemic emergency in China but the mechanisms remain elusive. Here using TCMSP and Swiss Target Prediction databases to sort out the potential targets of the main chemical components and GenCLiP3, NCBI, and GeneCard databases to search for COVID-19 related targets, the chemical compound-target-pathway network was analyzed. Each component was molecularly docked with host cell target angiotensin converting enzyme II, SARS-CoV-2 targets Spike protein, RNA-dependent RNA polymerase, or 3CL hydrolase. Our results showed a higher affinity of the compound diosgenin and (+)-Syringaresinol-O-beta-D-glucoside binding to the three SARS-CoV-2 proteins compared to the other compounds tested. Thus, our data suggest that potential compounds in Rhizoma Polygonati may act on different targets with viral and cancer related signaling and have a great potential in treatment of COVID-19.