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1.
Sci Rep ; 12(1): 4279, 2022 03 11.
Article in English | MEDLINE | ID: covidwho-1740476

ABSTRACT

The pandemic threat of COVID-19 has severely destroyed human life as well as the economy around the world. Although, the vaccination has reduced the outspread, but people are still suffering due to the unstable RNA sequence patterns of SARS-CoV-2 which demands supplementary drugs. To explore novel drug target proteins, in this study, a transcriptomics RNA-Seq data generated from SARS-CoV-2 infection and control samples were analyzed. We identified 109 differentially expressed genes (DEGs) that were utilized to identify 10 hub-genes/proteins (TLR2, USP53, GUCY1A2, SNRPD2, NEDD9, IGF2, CXCL2, KLF6, PAG1 and ZFP36) by the protein-protein interaction (PPI) network analysis. The GO functional and KEGG pathway enrichment analyses of hub-DEGs revealed some important functions and signaling pathways that are significantly associated with SARS-CoV-2 infections. The interaction network analysis identified 5 TFs proteins and 6 miRNAs as the key regulators of hub-DEGs. Considering 10 hub-proteins and 5 key TFs-proteins as drug target receptors, we performed their docking analysis with the SARS-CoV-2 3CL protease-guided top listed 90 FDA approved drugs. We found Torin-2, Rapamycin, Radotinib, Ivermectin, Thiostrepton, Tacrolimus and Daclatasvir as the top ranked seven candidate drugs. We investigated their resistance performance against the already published COVID-19 causing top-ranked 11 independent and 8 protonated receptor proteins by molecular docking analysis and found their strong binding affinities, which indicates that the proposed drugs are effective against the state-of-the-arts alternatives independent receptor proteins also. Finally, we investigated the stability of top three drugs (Torin-2, Rapamycin and Radotinib) by using 100 ns MD-based MM-PBSA simulations with the two top-ranked proposed receptors (TLR2, USP53) and independent receptors (IRF7, STAT1), and observed their stable performance. Therefore, the proposed drugs might play a vital role for the treatment against different variants of SARS-CoV-2 infections.


Subject(s)
COVID-19/drug therapy , COVID-19/genetics , Drug Repositioning , SARS-CoV-2/drug effects , Case-Control Studies , Gene Regulatory Networks/genetics , Genetic Markers/genetics , Humans , Molecular Docking Simulation , Protein Interaction Maps/genetics
2.
EBioMedicine ; 76: 103861, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1734342

ABSTRACT

BACKGROUND: Since late 2019, SARS-CoV-2 infection has resulted in COVID-19 accompanied by diverse clinical manifestations. However, the underlying mechanism of how SARS-CoV-2 interacts with host and develops multiple symptoms is largely unexplored. METHODS: Bioinformatics analysis determined the sequence similarity between SARS-CoV-2 and human genomes. Diverse fragments of SARS-CoV-2 genome containing Human Identical Sequences (HIS) were cloned into the lentiviral vector. HEK293T, MRC5 and HUVEC were infected with laboratory-packaged lentivirus or transfected with plasmids or antagomirs for HIS. Quantitative RT-PCR and chromatin immunoprecipitation assay detected gene expression and H3K27ac enrichment, respectively. UV-Vis spectroscopy assessed the interaction between HIS and their target locus. Enzyme-linked immunosorbent assay evaluated the hyaluronan (HA) levels of culture supernatant and plasma of COVID-19 patients. FINDINGS: Five short sequences (24-27 nt length) sharing identity between SARS-CoV-2 and human genome were identified. These RNA elements were highly conserved in primates. The genomic fragments containing HIS were predicted to form hairpin structures in silico similar to miRNA precursors. HIS may function through direct genomic interaction leading to activation of host enhancers, and upregulation of adjacent and distant genes, including cytokine genes and hyaluronan synthase 2 (HAS2). HIS antagomirs and Cas13d-mediated HIS degradation reduced HAS2 expression. Severe COVID-19 patients displayed decreased lymphocytes and elevated D-dimer, and C-reactive proteins, as well as increased plasma hyaluronan. Hymecromone inhibited hyaluronan production in vitro, and thus could be further investigated as a therapeutic option for preventing severe outcome in COVID-19 patients. INTERPRETATION: HIS of SARS-CoV-2 could promote COVID-19 progression by upregulating hyaluronan, providing novel targets for treatment. FUNDING: The National Key R&D Program of China (2018YFC1005004), Major Special Projects of Basic Research of Shanghai Science and Technology Commission (18JC1411101), and the National Natural Science Foundation of China (31872814, 32000505).


Subject(s)
Gene Regulatory Networks/genetics , Genome, Human , Hyaluronic Acid/metabolism , RNA, Viral/genetics , SARS-CoV-2/genetics , Antagomirs/metabolism , Argonaute Proteins/genetics , Base Sequence , COVID-19/pathology , COVID-19/virology , Cell Line , Disease Progression , Enhancer Elements, Genetic/genetics , Humans , Hyaluronan Synthases/genetics , Hyaluronan Synthases/metabolism , Hyaluronic Acid/blood , MicroRNAs/genetics , RNA, Viral/chemistry , SARS-CoV-2/isolation & purification , SARS-CoV-2/pathogenicity , Up-Regulation
3.
Front Immunol ; 12: 700705, 2021.
Article in English | MEDLINE | ID: covidwho-1686468

ABSTRACT

A novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), arose late in 2019, with disease pathology ranging from asymptomatic to severe respiratory distress with multi-organ failure requiring mechanical ventilator support. It has been found that SARS-CoV-2 infection drives intracellular complement activation in lung cells that tracks with disease severity. However, the cellular and molecular mechanisms responsible remain unclear. To shed light on the potential mechanisms, we examined publicly available RNA-Sequencing data using CIBERSORTx and conducted a Ingenuity Pathway Analysis to address this knowledge gap. In complement to these findings, we used bioinformatics tools to analyze publicly available RNA sequencing data and found that upregulation of complement may be leading to a downregulation of T-cell activity in lungs of severe COVID-19 patients. Thus, targeting treatments aimed at the modulation of classical complement and T-cell activity may help alleviate the proinflammatory effects of COVID-19, reduce lung pathology, and increase the survival of COVID-19 patients.


Subject(s)
COVID-19/genetics , Complement Activation/genetics , Complement System Proteins/genetics , Gene Expression Profiling/methods , Lung/metabolism , T-Lymphocytes/metabolism , COVID-19/immunology , COVID-19/virology , Gene Regulatory Networks/genetics , Humans , Intracellular Space/genetics , Lung/immunology , Lung/microbiology , Lymphocyte Count , SARS-CoV-2/physiology , T-Lymphocyte Subsets/metabolism
4.
PLoS Comput Biol ; 17(10): e1008794, 2021 10.
Article in English | MEDLINE | ID: covidwho-1523394

ABSTRACT

There has been a spate of interest in association networks in biological and medical research, for example, genetic interaction networks. In this paper, we propose a novel method, the extended joint hub graphical lasso (EDOHA), to estimate multiple related interaction networks for high dimensional omics data across multiple distinct classes. To be specific, we construct a convex penalized log likelihood optimization problem and solve it with an alternating direction method of multipliers (ADMM) algorithm. The proposed method can also be adapted to estimate interaction networks for high dimensional compositional data such as microbial interaction networks. The performance of the proposed method in the simulated studies shows that EDOHA has remarkable advantages in recognizing class-specific hubs than the existing comparable methods. We also present three applications of real datasets. Biological interpretations of our results confirm those of previous studies and offer a more comprehensive understanding of the underlying mechanism in disease.


Subject(s)
Computational Biology/methods , Gene Regulatory Networks/genetics , Protein Interaction Maps/genetics , Algorithms , Databases, Genetic , Humans , Microbiota/genetics , Transcriptome/genetics
5.
Brain ; 144(12): 3727-3741, 2021 12 31.
Article in English | MEDLINE | ID: covidwho-1455243

ABSTRACT

Recently, we reported oligoadenylate synthetase 1 (OAS1) contributed to the risk of Alzheimer's disease, by its enrichment in transcriptional networks expressed by microglia. However, the function of OAS1 within microglia was not known. Using genotyping from 1313 individuals with sporadic Alzheimer's disease and 1234 control individuals, we confirm the OAS1 variant, rs1131454, is associated with increased risk for Alzheimer's disease. The same OAS1 locus has been recently associated with severe coronavirus disease 2019 (COVID-19) outcomes, linking risk for both diseases. The single nucleotide polymorphisms rs1131454(A) and rs4766676(T) are associated with Alzheimer's disease, and rs10735079(A) and rs6489867(T) are associated with severe COVID-19, where the risk alleles are linked with decreased OAS1 expression. Analysing single-cell RNA-sequencing data of myeloid cells from Alzheimer's disease and COVID-19 patients, we identify co-expression networks containing interferon (IFN)-responsive genes, including OAS1, which are significantly upregulated with age and both diseases. In human induced pluripotent stem cell-derived microglia with lowered OAS1 expression, we show exaggerated production of TNF-α with IFN-γ stimulation, indicating OAS1 is required to limit the pro-inflammatory response of myeloid cells. Collectively, our data support a link between genetic risk for Alzheimer's disease and susceptibility to critical illness with COVID-19 centred on OAS1, a finding with potential implications for future treatments of Alzheimer's disease and COVID-19, and development of biomarkers to track disease progression.


Subject(s)
2',5'-Oligoadenylate Synthetase/genetics , Alzheimer Disease/genetics , COVID-19/genetics , Genetic Linkage/genetics , Genetic Predisposition to Disease/genetics , Patient Acuity , Adolescent , Aged , Aged, 80 and over , Alzheimer Disease/diagnosis , Alzheimer Disease/epidemiology , COVID-19/diagnosis , COVID-19/epidemiology , Cells, Cultured , Female , Gene Regulatory Networks/genetics , Genetic Predisposition to Disease/epidemiology , Humans , Induced Pluripotent Stem Cells/physiology , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Young Adult
6.
Sci Rep ; 11(1): 18985, 2021 09 23.
Article in English | MEDLINE | ID: covidwho-1437690

ABSTRACT

The COVID-19 pandemic is raging. It revealed the importance of rapid scientific advancement towards understanding and treating new diseases. To address this challenge, we adapt an explainable artificial intelligence algorithm for data fusion and utilize it on new omics data on viral-host interactions, human protein interactions, and drugs to better understand SARS-CoV-2 infection mechanisms and predict new drug-target interactions for COVID-19. We discover that in the human interactome, the human proteins targeted by SARS-CoV-2 proteins and the genes that are differentially expressed after the infection have common neighbors central in the interactome that may be key to the disease mechanisms. We uncover 185 new drug-target interactions targeting 49 of these key genes and suggest re-purposing of 149 FDA-approved drugs, including drugs targeting VEGF and nitric oxide signaling, whose pathways coincide with the observed COVID-19 symptoms. Our integrative methodology is universal and can enable insight into this and other serious diseases.


Subject(s)
COVID-19/drug therapy , Drug Evaluation, Preclinical/methods , SARS-CoV-2/genetics , Antiviral Agents/therapeutic use , Artificial Intelligence , COVID-19/genetics , COVID-19/metabolism , Drug Repositioning/methods , Gene Regulatory Networks/genetics , Humans , Models, Theoretical , Pandemics , Pharmaceutical Preparations , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Signal Transduction/genetics
7.
Nat Commun ; 12(1): 652, 2021 01 28.
Article in English | MEDLINE | ID: covidwho-1397868

ABSTRACT

Injury and loss of oligodendrocytes can cause demyelinating diseases such as multiple sclerosis. To improve our understanding of human oligodendrocyte development, which could facilitate development of remyelination-based treatment strategies, here we describe time-course single-cell-transcriptomic analysis of developing human stem cell-derived oligodendrocyte-lineage-cells (hOLLCs). The study includes hOLLCs derived from both genome engineered embryonic stem cell (ESC) reporter cells containing an Identification-and-Purification tag driven by the endogenous PDGFRα promoter and from unmodified induced pluripotent (iPS) cells. Our analysis uncovers substantial transcriptional heterogeneity of PDGFRα-lineage hOLLCs. We discover sub-populations of human oligodendrocyte progenitor cells (hOPCs) including a potential cytokine-responsive hOPC subset, and identify candidate regulatory genes/networks that define the identity of these sub-populations. Pseudotime trajectory analysis defines developmental pathways of oligodendrocytes vs astrocytes from PDGFRα-expressing hOPCs and predicts differentially expressed genes between the two lineages. In addition, pathway enrichment analysis followed by pharmacological intervention of these pathways confirm that mTOR and cholesterol biosynthesis signaling pathways are involved in maturation of oligodendrocytes from hOPCs.


Subject(s)
Genetic Heterogeneity , Genetic Variation , Induced Pluripotent Stem Cells/metabolism , Oligodendrocyte Precursor Cells/metabolism , Single-Cell Analysis/methods , Transcriptome/genetics , Astrocytes/cytology , Astrocytes/metabolism , Cell Differentiation/genetics , Cell Line , Cell Lineage/genetics , Cholesterol/biosynthesis , Embryonic Stem Cells/cytology , Embryonic Stem Cells/metabolism , Gene Regulatory Networks/genetics , Humans , Induced Pluripotent Stem Cells/cytology , Oligodendrocyte Precursor Cells/cytology , Receptor, Platelet-Derived Growth Factor alpha/genetics , Receptor, Platelet-Derived Growth Factor alpha/metabolism , Signal Transduction/genetics , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism
8.
Nat Commun ; 12(1): 724, 2021 02 01.
Article in English | MEDLINE | ID: covidwho-1387326

ABSTRACT

Recent advances in cell-free synthetic biology have given rise to gene circuit-based sensors with the potential to provide decentralized and low-cost molecular diagnostics. However, it remains a challenge to deliver this sensing capacity into the hands of users in a practical manner. Here, we leverage the glucose meter, one of the most widely available point-of-care sensing devices, to serve as a universal reader for these decentralized diagnostics. We describe a molecular translator that can convert the activation of conventional gene circuit-based sensors into a glucose output that can be read by off-the-shelf glucose meters. We show the development of new glucogenic reporter systems, multiplexed reporter outputs and detection of nucleic acid targets down to the low attomolar range. Using this glucose-meter interface, we demonstrate the detection of a small-molecule analyte; sample-to-result diagnostics for typhoid, paratyphoid A/B; and show the potential for pandemic response with nucleic acid sensors for SARS-CoV-2.


Subject(s)
Biosensing Techniques/methods , Gene Regulatory Networks/genetics , Glucose/analysis , Nucleic Acids/analysis , Point-of-Care Systems , Point-of-Care Testing , Biosensing Techniques/instrumentation , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/virology , Glucose/metabolism , Humans , Nucleic Acids/genetics , Pandemics , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Typhoid Fever/blood , Typhoid Fever/diagnosis , Typhoid Fever/microbiology
9.
Arch Virol ; 166(1): 271-274, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1384460

ABSTRACT

Viral RNAs can perturb the miRNA regulatory network, competing with host RNAs as part of their infective process. An in silico competing endogenous RNA (ceRNA) analysis has been carried on SARS-CoV-2. The results suggest that, in humans, the decrease of microRNA activity caused by viral RNAs can lead to a perturbation of vesicle trafficking and the inflammatory response, in particular by enhancing KLF10 activity. The results suggest also that, during the study of the mechanics of viral infections, it could be of general interest to investigate the competition of viral RNA with cellular transcripts for shared microRNAs.


Subject(s)
Gene Regulatory Networks/genetics , RNA, Messenger/genetics , RNA, Viral/genetics , SARS-CoV-2/genetics , A549 Cells , COVID-19/pathology , Cell Line, Tumor , Early Growth Response Transcription Factors/genetics , Early Growth Response Transcription Factors/metabolism , Humans , Kruppel-Like Transcription Factors/genetics , Kruppel-Like Transcription Factors/metabolism , MicroRNAs/genetics
10.
Brief Bioinform ; 22(6)2021 11 05.
Article in English | MEDLINE | ID: covidwho-1369062

ABSTRACT

Single-cell RNA sequencing has enabled to capture the gene activities at single-cell resolution, thus allowing reconstruction of cell-type-specific gene regulatory networks (GRNs). The available algorithms for reconstructing GRNs are commonly designed for bulk RNA-seq data, and few of them are applicable to analyze scRNA-seq data by dealing with the dropout events and cellular heterogeneity. In this paper, we represent the joint gene expression distribution of a gene pair as an image and propose a novel supervised deep neural network called DeepDRIM which utilizes the image of the target TF-gene pair and the ones of the potential neighbors to reconstruct GRN from scRNA-seq data. Due to the consideration of TF-gene pair's neighborhood context, DeepDRIM can effectively eliminate the false positives caused by transitive gene-gene interactions. We compared DeepDRIM with nine GRN reconstruction algorithms designed for either bulk or single-cell RNA-seq data. It achieves evidently better performance for the scRNA-seq data collected from eight cell lines. The simulated data show that DeepDRIM is robust to the dropout rate, the cell number and the size of the training data. We further applied DeepDRIM to the scRNA-seq gene expression of B cells from the bronchoalveolar lavage fluid of the patients with mild and severe coronavirus disease 2019. We focused on the cell-type-specific GRN alteration and observed targets of TFs that were differentially expressed between the two statuses to be enriched in lysosome, apoptosis, response to decreased oxygen level and microtubule, which had been proved to be associated with coronavirus infection.


Subject(s)
COVID-19/genetics , RNA-Seq , SARS-CoV-2/genetics , Software , Algorithms , COVID-19/epidemiology , COVID-19/virology , Cluster Analysis , Gene Regulatory Networks/genetics , Humans , Neural Networks, Computer , SARS-CoV-2/pathogenicity , Single-Cell Analysis
11.
Sci Rep ; 11(1): 10793, 2021 05 24.
Article in English | MEDLINE | ID: covidwho-1242045

ABSTRACT

Finding novel biomarkers for human pathologies and predicting clinical outcomes for patients is challenging. This stems from the heterogeneous response of individuals to disease and is reflected in the inter-individual variability of gene expression responses that obscures differential gene expression analysis. Here, we developed an alternative approach that could be applied to dissect the disease-associated molecular changes. We define gene ensemble noise as a measure that represents a variance for a collection of genes encoding for either members of known biological pathways or subunits of annotated protein complexes and calculated within an individual. The gene ensemble noise allows for the holistic identification and interpretation of gene expression disbalance on the level of gene networks and systems. By comparing gene expression data from COVID-19, H1N1, and sepsis patients we identified common disturbances in a number of pathways and protein complexes relevant to the sepsis pathology. Among others, these include the mitochondrial respiratory chain complex I and peroxisomes. This suggests a Warburg effect and oxidative stress as common hallmarks of the immune host-pathogen response. Finally, we showed that gene ensemble noise could successfully be applied for the prediction of clinical outcome namely, the mortality of patients. Thus, we conclude that gene ensemble noise represents a promising approach for the investigation of molecular mechanisms of pathology through a prism of alterations in the coherent expression of gene circuits.


Subject(s)
COVID-19/pathology , Gene Expression , Influenza, Human/pathology , Sepsis/pathology , Area Under Curve , COVID-19/complications , COVID-19/virology , Electron Transport Complex I/genetics , Electron Transport Complex I/metabolism , Gene Regulatory Networks/genetics , Humans , Influenza A Virus, H1N1 Subtype/genetics , Influenza A Virus, H1N1 Subtype/isolation & purification , Influenza, Human/complications , Influenza, Human/virology , Oxidative Stress/genetics , Peroxisomes/genetics , Peroxisomes/metabolism , Proportional Hazards Models , ROC Curve , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Sepsis/complications , Sepsis/genetics , Sepsis/mortality , Severity of Illness Index , Survival Rate , User-Computer Interface
12.
Brief Bioinform ; 22(6)2021 11 05.
Article in English | MEDLINE | ID: covidwho-1228438

ABSTRACT

Coronavirus Disease 2019 (COVID-19), although most commonly demonstrates respiratory symptoms, but there is a growing set of evidence reporting its correlation with the digestive tract and faeces. Interestingly, recent studies have shown the association of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection with gastrointestinal symptoms in infected patients but any sign of respiratory issues. Moreover, some studies have also shown that the presence of live SARS-CoV-2 virus in the faeces of patients with COVID-19. Therefore, the pathophysiology of digestive symptoms associated with COVID-19 has raised a critical need for comprehensive investigative efforts. To address this issue we have developed a bioinformatics pipeline involving a system biological framework to identify the effects of SARS-CoV-2 messenger RNA expression on deciphering its association with digestive symptoms in COVID-19 positive patients. Using two RNA-seq datasets derived from COVID-19 positive patients with celiac (CEL), Crohn's (CRO) and ulcerative colitis (ULC) as digestive disorders, we have found a significant overlap between the sets of differentially expressed genes from SARS-CoV-2 exposed tissue and digestive tract disordered tissues, reporting 7, 22 and 13 such overlapping genes, respectively. Moreover, gene set enrichment analysis, comprehensive analyses of protein-protein interaction network, gene regulatory network, protein-chemical agent interaction network revealed some critical association between SARS-CoV-2 infection and the presence of digestive disorders. The infectome, diseasome and comorbidity analyses also discover the influences of the identified signature genes in other risk factors of SARS-CoV-2 infection to human health. We hope the findings from this pathogenetic analysis may reveal important insights in deciphering the complex interplay between COVID-19 and digestive disorders and underpins its significance in therapeutic development strategy to combat against COVID-19 pandemic.


Subject(s)
COVID-19/drug therapy , Gastrointestinal Tract/virology , SARS-CoV-2/drug effects , COVID-19/virology , Comorbidity , Computational Biology , Gastrointestinal Tract/pathology , Gene Regulatory Networks/genetics , Humans , Pandemics , Protein Interaction Maps/genetics , SARS-CoV-2/pathogenicity , Systems Biology
13.
Sci Rep ; 10(1): 17628, 2020 10 19.
Article in English | MEDLINE | ID: covidwho-933709

ABSTRACT

Genes are organized in functional modules (or pathways), thus their action and their dysregulation in diseases may be better understood by the identification of the modules most affected by the disease (aka disease modules, or active subnetworks). We describe how an algorithm based on the Core&Peel method is used to detect disease modules in co-expression networks of genes. We first validate Core&Peel for the general task of functional module detection by comparison with 42 methods participating in the Disease Module Identification DREAM challenge. Next, we use four specific disease test cases (colorectal cancer, prostate cancer, asthma, and rheumatoid arthritis), four state-of-the-art algorithms (ModuleDiscoverer, Degas, KeyPathwayMiner, and ClustEx), and several pathway databases to validate the proposed algorithm. Core&Peel is the only method able to find significant associations of the predicted disease module with known validated relevant pathways for all four diseases. Moreover, for the two cancer datasets, Core&Peel detects further eight relevant pathways not discovered by the other methods used in the comparative analysis. Finally, we apply Core&Peel and other methods to explore the transcriptional response of human cells to SARS-CoV-2 infection, finding supporting evidence for drug repositioning efforts at a pre-clinical level.


Subject(s)
Algorithms , Coronavirus Infections/pathology , Gene Regulatory Networks/genetics , Neoplasms/pathology , Pneumonia, Viral/pathology , COVID-19 , Coronavirus Infections/genetics , Databases, Genetic , Drug Repositioning , Gene Expression Profiling , Gene Ontology , Genome-Wide Association Study , Humans , Neoplasms/genetics , Pandemics , Pneumonia, Viral/genetics , User-Computer Interface
14.
Arch Virol ; 166(1): 271-274, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-928484

ABSTRACT

Viral RNAs can perturb the miRNA regulatory network, competing with host RNAs as part of their infective process. An in silico competing endogenous RNA (ceRNA) analysis has been carried on SARS-CoV-2. The results suggest that, in humans, the decrease of microRNA activity caused by viral RNAs can lead to a perturbation of vesicle trafficking and the inflammatory response, in particular by enhancing KLF10 activity. The results suggest also that, during the study of the mechanics of viral infections, it could be of general interest to investigate the competition of viral RNA with cellular transcripts for shared microRNAs.


Subject(s)
Gene Regulatory Networks/genetics , RNA, Messenger/genetics , RNA, Viral/genetics , SARS-CoV-2/genetics , A549 Cells , COVID-19/pathology , Cell Line, Tumor , Early Growth Response Transcription Factors/genetics , Early Growth Response Transcription Factors/metabolism , Humans , Kruppel-Like Transcription Factors/genetics , Kruppel-Like Transcription Factors/metabolism , MicroRNAs/genetics
15.
Toxicol Appl Pharmacol ; 406: 115237, 2020 11 01.
Article in English | MEDLINE | ID: covidwho-752826

ABSTRACT

Improvement of COVID-19 clinical condition was seen in studies where combination of antiretroviral drugs, lopinavir and ritonavir, as well as immunomodulant antimalaric, chloroquine/hydroxychloroquine together with the macrolide-type antibiotic, azithromycin, was used for patient's treatment. Although these drugs are "old", their pharmacological and toxicological profile in SARS-CoV-2 - infected patients are still unknown. Thus, by using in silico toxicogenomic data-mining approach, we aimed to assess both risks and benefits of the COVID-19 treatment with the most promising candidate drugs combinations: lopinavir/ritonavir and chloroquine/hydroxychloroquine + azithromycin. The Comparative Toxicogenomics Database (CTD; http://CTD.mdibl.org), Cytoscape software (https://cytoscape.org) and ToppGene Suite portal (https://toppgene.cchmc.org) served as a foundation in our research. Our results have demonstrated that lopinavir/ritonavir increased the expression of the genes involved in immune response and lipid metabolism (IL6, ICAM1, CCL2, TNF, APOA1, etc.). Chloroquine/hydroxychloroquine + azithromycin interacted with 6 genes (CCL2, CTSB, CXCL8, IL1B, IL6 and TNF), whereas chloroquine and azithromycin affected two additional genes (BCL2L1 and CYP3A4), which might be a reason behind a greater number of consequential diseases. In contrast to lopinavir/ritonavir, chloroquine/hydroxychloroquine + azithromycin downregulated the expression of TNF and IL6. As expected, inflammation, cardiotoxicity, and dyslipidaemias were revealed as the main risks of lopinavir/ritonavir treatment, while chloroquine/hydroxychloroquine + azithromycin therapy was additionally linked to gastrointestinal and skin diseases. According to our results, these drug combinations should be administrated with caution to patients suffering from cardiovascular problems, autoimmune diseases, or acquired and hereditary lipid disorders.


Subject(s)
Betacoronavirus , Computer Simulation , Data Mining/methods , Toxicogenetics/methods , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Azithromycin/administration & dosage , Azithromycin/adverse effects , COVID-19 , Chloroquine/administration & dosage , Chloroquine/adverse effects , Coronavirus Infections/drug therapy , Coronavirus Infections/genetics , Databases, Genetic , Drug Therapy, Combination , Gene Regulatory Networks/drug effects , Gene Regulatory Networks/genetics , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/adverse effects , Lopinavir/administration & dosage , Lopinavir/adverse effects , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/genetics , Ritonavir/administration & dosage , Ritonavir/adverse effects , SARS-CoV-2
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