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1.
Sci Rep ; 12(1): 1891, 2022 02 03.
Article in English | MEDLINE | ID: covidwho-1671627

ABSTRACT

The COVID-19 pandemic has produced broad clinical manifestations, from asymptomatic infection to hospitalization and death. Despite progress from genomic and clinical epidemiology research, risk factors for developing severe COVID-19 are incompletely understood and identification of modifiable risk factors is desperately needed. We conducted linkage disequilibrium score regression (LDSR) analysis to estimate cross-trait genetic correlation between COVID-19 severity and various polygenic phenotypes. To attenuate the genetic contribution of smoking and BMI, we further conducted sensitivity analyses by pruning genomic regions associated with smoking/BMI and repeating LDSR analyses. We identified robust positive associations between the genetic architecture of severe COVID-19 and both BMI and smoking. We observed strong positive genetic correlation (rg) with diabetes (rg = 0.25) and shortness of breath walking on level ground (rg = 0.28) and novel protective associations with vitamin E (rg = - 0.53), calcium (rg = - 0.33), retinol (rg = - 0.59), Apolipoprotein A (rg = - 0.13), and HDL (rg = - 0.17), but no association with vitamin D (rg = - 0.02). Removing genomic regions associated with smoking and BMI generally attenuated the associations, but the associations with nutrient biomarkers persisted. This study provides a comprehensive assessment of the shared genetic architecture of COVID-19 severity and numerous clinical/physiologic parameters. Associations with blood and plasma-derived traits identified biomarkers for Mendelian randomization studies to explore causality and nominates therapeutic targets for clinical evaluation.


Subject(s)
COVID-19/genetics , Genome-Wide Association Study , Linkage Disequilibrium/genetics , Body Mass Index , COVID-19/etiology , Diabetes Mellitus/genetics , Dyspnea/genetics , Female , Humans , Male , Mendelian Randomization Analysis , Multifactorial Inheritance , Nutrients , Patient Acuity , Phenotype , Regression Analysis , Risk Factors , Smoking/genetics
2.
J Endocrinol Invest ; 45(3): 537-550, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1474191

ABSTRACT

PURPOSE: Coronavirus Disease 2019 (COVID-19) severity and Diabetes mellitus affect each other bidirectionally. However, the cause of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection on the incidence of diabetes is unclear. In the SARS-CoV-2-infected cells, host microRNAs (miRNAs) may target the native gene transcripts as well as the viral genomic and subgenomic RNAs. Here, we investigated the role of miRNAs in linking Diabetes to SARS-CoV-2 infection in the human pancreas. METHODS: Differential gene expression and disease enrichment analyses were performed on an RNA-Seq dataset of human embryonic stem cell-derived (hESC) mock-infected and SARS-CoV-2-infected pancreatic organoids to obtain the dysregulated Diabetes-associated genes. The miRNA target prediction for the Diabetes-associated gene transcripts and the SARS-CoV-2 RNAs has been made to determine the common miRNAs targeting them. Minimum Free Energy (MFE) analysis was done to identify the miRNAs, preferably targeting SARS-CoV-2 RNAs over the Diabetes-associated gene transcripts. RESULTS: The gene expression and disease enrichment analyses of the RNA-Seq data have revealed five biomarker genes, i.e., CP, SOCS3, AGT, PSMB8 and CFB that are associated with Diabetes and get significantly upregulated in the pancreas following SARS-CoV-2-infection. Four miRNAs, i.e., hsa-miR-298, hsa-miR-3925-5p, hsa-miR-4691-3p and hsa-miR-5196-5p, showed preferential targeting of the SARS-CoV-2 genome over the cell's Diabetes-associated messenger RNAs (mRNAs) in the human pancreas. CONCLUSION: Our study proposes that the differential targeting of the Diabetes-associated host genes by the miRNAs may lead to diabetic complications or new-onset Diabetes that can worsen the condition of COVID-19 patients.


Subject(s)
COVID-19/epidemiology , Diabetes Mellitus/epidemiology , Diabetes Mellitus/genetics , MicroRNAs/genetics , Pancreas/virology , SARS-CoV-2/genetics , 3' Untranslated Regions/genetics , 5' Untranslated Regions/genetics , COVID-19/virology , Comorbidity , Gene Expression Regulation/genetics , Humans , Pancreas/chemistry , Pancreas/metabolism , RNA, Messenger/genetics , RNA, Viral/genetics
3.
Front Endocrinol (Lausanne) ; 12: 688071, 2021.
Article in English | MEDLINE | ID: covidwho-1399132

ABSTRACT

Coronavirus disease 19 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to scale and threaten human health and public safety. It is essential to identify those risk factors that lead to a poor prognosis of the disease. A predisposing host genetic background could be one of these factors that explain the interindividual variability to COVID-19 severity. Thus, we have studied whether the rs4341 and rs4343 polymorphisms of the angiotensin converting enzyme (ACE) gene, key regulator of the renin-aldosterone-angiotensin system (RAAS), could explain the different outcomes of 128 COVID-19 patients with diverse degree of severity (33 asymptomatic or mildly symptomatic, 66 hospitalized in the general ward, and 29 admitted to the ICU). We found that G allele of rs4341 and rs4343 was associated with severe COVID-19 in hypertensive patients, independently of gender (p<0.05). G-carrier genotypes of both polymorphisms were also associated with higher mortality (p< 0.05) and higher severity of COVID-19 in dyslipidemic (p<0.05) and type 2 diabetic patients (p< 0.01). The association of G alleles with disease severity was adjusted for age, sex, BMI and number of comorbidities, suggesting that both the metabolic comorbidities and the G allele act synergistically on COVID-19 outcome. Although we did not find a direct association between serum ACE levels and COVID-19 severity, we found higher levels of ACE in the serum of patients with the GG genotype of rs4341 and rs4343 (p<0.05), what could explain the higher susceptibility to develop severe forms of the disease in patients with the GG genotype, in addition to hypertension and dyslipidemia. In conclusion, our preliminary study suggests that the G-containing genotypes of rs4341 and rs4343 confer an additional risk of adverse COVID-19 prognosis. Thus, rs4341 and rs4343 polymorphisms of ACE could be predictive markers of severity of COVID-19 in those patients with hypertension, dyslipidemia or diabetes. The knowledge of these genetic data could contribute to precision management of SARS-CoV-2 infected patients when admitted to hospital.


Subject(s)
COVID-19/genetics , Diabetes Mellitus/genetics , Dyslipidemias/genetics , Genetic Variation/genetics , Hypertension/genetics , Peptidyl-Dipeptidase A/genetics , Adult , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/epidemiology , Diabetes Mellitus/diagnosis , Diabetes Mellitus/epidemiology , Dyslipidemias/diagnosis , Dyslipidemias/epidemiology , Female , Hospitalization/trends , Humans , Hypertension/diagnosis , Hypertension/epidemiology , Male , Middle Aged , Pilot Projects , Risk Factors , Severity of Illness Index , Spain/epidemiology
4.
Signal Transduct Target Ther ; 6(1): 300, 2021 08 11.
Article in English | MEDLINE | ID: covidwho-1351933

ABSTRACT

Elderly people and patients with comorbidities are at higher risk of COVID-19 infection, resulting in severe complications and high mortality. However, the underlying mechanisms are unclear. In this study, we investigate whether miRNAs in serum exosomes can exert antiviral functions and affect the response to COVID-19 in the elderly and people with diabetes. First, we identified four miRNAs (miR-7-5p, miR-24-3p, miR-145-5p and miR-223-3p) through high-throughput sequencing and quantitative real-time PCR analysis, that are remarkably decreased in the elderly and diabetic groups. We further demonstrated that these miRNAs, either in the exosome or in the free form, can directly inhibit S protein expression and SARS-CoV-2 replication. Serum exosomes from young people can inhibit SARS-CoV-2 replication and S protein expression, while the inhibitory effect is markedly decreased in the elderly and diabetic patients. Moreover, three out of the four circulating miRNAs are significantly increased in the serum of healthy volunteers after 8-weeks' continuous physical exercise. Serum exosomes isolated from these volunteers also showed stronger inhibitory effects on S protein expression and SARS-CoV-2 replication. Our study demonstrates for the first time that circulating exosomal miRNAs can directly inhibit SARS-CoV-2 replication and may provide a possible explanation for the difference in response to COVID-19 between young people and the elderly or people with comorbidities.


Subject(s)
COVID-19/genetics , Diabetes Mellitus/genetics , MicroRNAs/genetics , Spike Glycoprotein, Coronavirus/genetics , Adult , Age Factors , Aged , COVID-19/blood , COVID-19/pathology , COVID-19/virology , China , Circulating MicroRNA/blood , Circulating MicroRNA/genetics , Cohort Studies , Diabetes Mellitus/blood , Diabetes Mellitus/pathology , Diabetes Mellitus/virology , Exercise , Exosomes/genetics , Exosomes/metabolism , Exosomes/virology , Female , Gene Expression Regulation , HEK293 Cells , Host-Pathogen Interactions/genetics , Humans , Male , MicroRNAs/blood , Middle Aged , SARS-CoV-2/genetics , SARS-CoV-2/growth & development , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/blood , Virus Replication
5.
Cell Metab ; 32(6): 1028-1040.e4, 2020 12 01.
Article in English | MEDLINE | ID: covidwho-1310646

ABSTRACT

Isolated reports of new-onset diabetes in individuals with COVID-19 have led to the hypothesis that SARS-CoV-2 is directly cytotoxic to pancreatic islet ß cells. This would require binding and entry of SARS-CoV-2 into ß cells via co-expression of its canonical cell entry factors, angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2); however, their expression in human pancreas has not been clearly defined. We analyzed six transcriptional datasets of primary human islet cells and found that ACE2 and TMPRSS2 were not co-expressed in single ß cells. In pancreatic sections, ACE2 and TMPRSS2 protein was not detected in ß cells from donors with and without diabetes. Instead, ACE2 protein was expressed in islet and exocrine tissue microvasculature and in a subset of pancreatic ducts, whereas TMPRSS2 protein was restricted to ductal cells. These findings reduce the likelihood that SARS-CoV-2 directly infects ß cells in vivo through ACE2 and TMPRSS2.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Diabetes Mellitus/metabolism , SARS-CoV-2/physiology , Serine Endopeptidases/metabolism , Virus Internalization , Angiotensin-Converting Enzyme 2/analysis , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/complications , COVID-19/genetics , Cells, Cultured , Diabetes Complications/genetics , Diabetes Complications/metabolism , Diabetes Mellitus/genetics , Gene Expression , Humans , Insulin-Secreting Cells/metabolism , Mice , Microvessels/metabolism , Pancreas/metabolism , RNA, Messenger/analysis , RNA, Messenger/genetics , Serine Endopeptidases/analysis , Serine Endopeptidases/genetics
6.
Brief Bioinform ; 22(6)2021 11 05.
Article in English | MEDLINE | ID: covidwho-1309589

ABSTRACT

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the newly discovered coronavirus, SARS-CoV-2. Increased severity of COVID-19 has been observed in patients with diabetes mellitus (DM). This study aimed to identify common transcriptional signatures, regulators and pathways between COVID-19 and DM. We have integrated human whole-genome transcriptomic datasets from COVID-19 and DM, followed by functional assessment with gene ontology (GO) and pathway analyses. In peripheral blood mononuclear cells (PBMCs), among the upregulated differentially expressed genes (DEGs), 32 were found to be commonly modulated in COVID-19 and type 2 diabetes (T2D), while 10 DEGs were commonly downregulated. As regards type 1 diabetes (T1D), 21 DEGs were commonly upregulated, and 29 DEGs were commonly downregulated in COVID-19 and T1D. Moreover, 35 DEGs were commonly upregulated in SARS-CoV-2 infected pancreas organoids and T2D islets, while 14 were commonly downregulated. Several GO terms were found in common between COVID-19 and DM. Prediction of the putative transcription factors involved in the upregulation of genes in COVID-19 and DM identified RELA to be implicated in both PBMCs and pancreas. Here, for the first time, we have characterized the biological processes and pathways commonly dysregulated in COVID-19 and DM, which could be in the next future used for the design of personalized treatment of COVID-19 patients suffering from DM as comorbidity.


Subject(s)
COVID-19/genetics , Diabetes Mellitus/genetics , SARS-CoV-2/genetics , Transcriptome/genetics , COVID-19/pathology , COVID-19/virology , Computational Biology , Diabetes Mellitus/pathology , Gene Expression Profiling , Gene Expression Regulation/genetics , Humans , Leukocytes, Mononuclear/pathology , Leukocytes, Mononuclear/virology , Protein Interaction Maps/genetics , SARS-CoV-2/pathogenicity
7.
Brief Bioinform ; 22(6)2021 11 05.
Article in English | MEDLINE | ID: covidwho-1254437

ABSTRACT

Despite the association of prevalent health conditions with coronavirus disease 2019 (COVID-19) severity, the disease-modifying biomolecules and their pathogenetic mechanisms remain unclear. This study aimed to understand the influences of COVID-19 on different comorbidities and vice versa through network-based gene expression analyses. Using the shared dysregulated genes, we identified key genetic determinants and signaling pathways that may involve in their shared pathogenesis. The COVID-19 showed significant upregulation of 93 genes and downregulation of 15 genes. Interestingly, it shares 28, 17, 6 and 7 genes with diabetes mellitus (DM), lung cancer (LC), myocardial infarction and hypertension, respectively. Importantly, COVID-19 shared three upregulated genes (i.e. MX2, IRF7 and ADAM8) with DM and LC. Conversely, downregulation of two genes (i.e. PPARGC1A and METTL7A) was found in COVID-19 and LC. Besides, most of the shared pathways were related to inflammatory responses. Furthermore, we identified six potential biomarkers and several important regulatory factors, e.g. transcription factors and microRNAs, while notable drug candidates included captopril, rilonacept and canakinumab. Moreover, prognostic analysis suggests concomitant COVID-19 may result in poor outcome of LC patients. This study provides the molecular basis and routes of the COVID-19 progression due to comorbidities. We believe these findings might be useful to further understand the intricate association of these diseases as well as for the therapeutic development.


Subject(s)
COVID-19/genetics , Diabetes Mellitus/genetics , Hypertension/genetics , Lung Neoplasms/genetics , Myocardial Infarction/genetics , Transcriptome/genetics , ADAM Proteins , COVID-19/virology , Computational Biology , Humans , Interferon Regulatory Factor-7 , Lung Neoplasms/pathology , Membrane Proteins , Myxovirus Resistance Proteins/genetics , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Transcription Factors/genetics
8.
Front Immunol ; 12: 597399, 2021.
Article in English | MEDLINE | ID: covidwho-1167337

ABSTRACT

There exists increasing evidence that people with preceding medical conditions, such as diabetes and cancer, have a higher risk of infection with SARS-CoV-2 and are more vulnerable to severe disease. To get insights into the possible role of the immune system upon COVID-19 infection, 2811 genes of the gene ontology term "immune system process GO: 0002376" were selected for coexpression analysis of the human targets of SARS-CoV-2 (HT-SARS-CoV-2) ACE2, TMPRSS2, and FURIN in tissue samples from patients with cancer and diabetes mellitus. The network between HT-SARS-CoV-2 and immune system process genes was analyzed based on functional protein associations using STRING. In addition, STITCH was employed to determine druggable targets. DPP4 was the only immune system process gene, which was coexpressed with the three HT-SARS-CoV-2 genes, while eight other immune genes were at least coexpressed with two HT-SARS-CoV-2 genes. STRING analysis between immune and HT-SARS-CoV-2 genes plotted 19 associations of which there were eight common networking genes in mixed healthy (323) and pan-cancer (11003) tissues in addition to normal (87), cancer (90), and diabetic (128) pancreatic tissues. Using this approach, three commonly applicable druggable connections between HT-SARS-CoV-2 and immune system process genes were identified. These include positive associations of ACE2-DPP4 and TMPRSS2-SRC as well as a negative association of FURIN with ADAM17. Furthermore, 16 drugs were extracted from STITCH (score <0.8) with 32 target genes. Thus, an immunological network associated with HT-SARS-CoV-2 using bioinformatics tools was identified leading to novel therapeutic opportunities for COVID-19.


Subject(s)
Diabetes Mellitus/metabolism , Neoplasms/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/genetics , COVID-19/immunology , COVID-19/metabolism , Databases, Genetic , Diabetes Mellitus/genetics , Diabetes Mellitus/immunology , Diabetes Mellitus/virology , Dipeptidyl Peptidase 4/genetics , Dipeptidyl Peptidase 4/metabolism , Furin/genetics , Furin/metabolism , Gene Expression Regulation/immunology , Gene Ontology , Genome-Wide Association Study , Genomics , Humans , Lymphocytes/immunology , Lymphocytes/metabolism , Neoplasms/genetics , Neoplasms/immunology , Neoplasms/virology , Pancreas/immunology , Pancreas/metabolism , Pancreas/virology , Protein Interaction Maps/genetics , Protein Interaction Maps/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism
9.
Epidemiol Prev ; 44(5-6 Suppl 2): 169-182, 2020.
Article in English | MEDLINE | ID: covidwho-1068137

ABSTRACT

As the Coronavirus situation (COVID-19) continues to evolve, many questions concerning the factors relating to the diffusion and severity of the disease remain unanswered.Whilst opinions regarding the weight of evidence for these risk factors, and the studies published so far are often inconclusive or offer contrasting results, the role of comorbidities in the risk of serious adverse outcomes in patients affected with COVID-19 appears to be evident since the outset. Hypertension, diabetes, and obesity are under discussion as important factors affecting the severity of disease. Air pollution has been considered to play a role in the diffusion of the virus, in the propagation of the contagion, in the severity of symptoms, and in the poor prognosis. Accumulating evidence supports the hypothesis that environmental particulate matter (PM) can trigger inflammatory responses at molecular, cellular, and organ levels, sustaining respiratory, cardiovascular, and dysmetabolic diseases.To better understand the intricate relationships among pre-existing conditions, PM, and viral infection, we examined the response at the molecular level of T47D human breast adenocarcinoma cells exposed to different fractions of PM. T47D cells express several receptors, including the aryl hydrocarbon receptor (AhR), and ACE2, the main - but not the only - receptor for SARS-CoV-2 entry.PM samples were collected in an urban background site located in the Northern area of the City of Bologna (Emilia-Romagna Region, Northern Italy) during winter 2013. T47D cells were exposed to organic or aqueous (inorganic) extracts at the final concentration of 8 m3 for a 4-hour duration. Both the concentration and the exposure time were chosen to resemble an average outdoor exposure. RNA was extracted from cells, purified and hybridised on 66k microarray slides from Agilent.The lists of differentially expressed genes in PM organic extracts were evaluated by using Metacore, and an enrichment analysis was performed to identify pathways maps, process networks, and disease by biomarkers altered after T47D treatment.The analysis of the modulated genes gave evidence for the involvement of PM in dysmetabolic diseases, including diabetes and obesity, and hypertension through the activation of the aryl hydrocarbon receptor (AhR) canonical pathway.On the basis of current knowledge, existing data, and exploratory experimental evidence, we tease out the likely molecular interplay that can ultimately tip the disease outcome into severity. Looking beyond ACE2, several additional key markers are identified. Disruption of these targets worsens pre-existing conditions and/or exacerbates the adverse effects induced by SARS-CoV-2 infection. Whilst appropriately designed, epidemiological studies are very much needed to investigate these associations based on our hypothesis of investigation, by reviewing recent experimental and epidemiological evidence, here we speculate and provide new insights on the possible role of environmental pollution in the exacerbation of effects by SARS-CoV-2 and other respiratory viruses. This work is intended to assist in the development of appropriate investigative approaches to protect public health.


Subject(s)
Air Pollution/adverse effects , COVID-19/epidemiology , Particulate Matter/adverse effects , SARS-CoV-2/physiology , Angiotensin-Converting Enzyme 2/physiology , COVID-19/etiology , Cell Line, Tumor , Comorbidity , Coronaviridae/physiology , Cytochrome P-450 CYP1A1/physiology , Diabetes Mellitus/epidemiology , Diabetes Mellitus/genetics , Diabetes Mellitus/metabolism , Disease Susceptibility , Gene Expression Profiling , Gene Expression Regulation/drug effects , Humans , Hypertension/epidemiology , Hypertension/genetics , Hypertension/metabolism , Inflammation/epidemiology , Inflammation/genetics , Inflammation/metabolism , Italy , Obesity/epidemiology , Obesity/genetics , Obesity/metabolism , Particulate Matter/pharmacology , Receptors, Aryl Hydrocarbon/physiology , Receptors, Virus/physiology , Risk , SARS-CoV-2/ultrastructure , Signal Transduction
10.
Med Hypotheses ; 146: 110448, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-969015

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is able to produce an excessive host immune reaction and may leads to severe disease- a life-threatening condition occurring more often in patients suffering from comorbidities such as hypertension, diabetes and obesity. Infection by human corona viruses highly depends on host microRNA (miR) involved in regulation of host innate immune response and inflammation-modulatory miR-146a is among the first miRs induced by immune reaction to a virus. Moreover, recent analysis showed that miR-146 is predicted to target at the SARS-CoV-2 genome. As the dominant regulator of Toll-like receptors (TLRs) downstream signaling, miR-146a may limit excessive inflammatory response to virus. Downregulation of circulating miR-146a was found in diabetes, obesity and hypertension and it is reflected by enhanced inflammation and fibrosis, systemic effects accompanying severe COVID-19. Thus it could be hypothesized that miR-146a deficiency may contribute to severe COVID-19 state observed in diabetes, obesity and hypertension but further investigations are needed.


Subject(s)
COVID-19/complications , Diabetes Mellitus/genetics , Hypertension/complications , MicroRNAs/genetics , Obesity/complications , Pandemics , SARS-CoV-2 , COVID-19/genetics , COVID-19/immunology , Diabetes Complications/genetics , Diabetes Complications/immunology , Diabetes Mellitus/immunology , Down-Regulation , Humans , Hypertension/genetics , Hypertension/immunology , Immunity, Innate/genetics , Inflammation/complications , Inflammation/genetics , Inflammation/immunology , MicroRNAs/metabolism , Models, Biological , Obesity/genetics , Obesity/immunology , Risk Factors , Severity of Illness Index
11.
Sci Rep ; 10(1): 20848, 2020 11 30.
Article in English | MEDLINE | ID: covidwho-951959

ABSTRACT

The emergence of the SARS-CoV-2 virus and subsequent COVID-19 pandemic initiated intense research into the mechanisms of action for this virus. It was quickly noted that COVID-19 presents more seriously in conjunction with other human disease conditions such as hypertension, diabetes, and lung diseases. We conducted a bioinformatics analysis of COVID-19 comorbidity-associated gene sets, identifying genes and pathways shared among the comorbidities, and evaluated current knowledge about these genes and pathways as related to current information about SARS-CoV-2 infection. We performed our analysis using GeneWeaver (GW), Reactome, and several biomedical ontologies to represent and compare common COVID-19 comorbidities. Phenotypic analysis of shared genes revealed significant enrichment for immune system phenotypes and for cardiovascular-related phenotypes, which might point to alleles and phenotypes in mouse models that could be evaluated for clues to COVID-19 severity. Through pathway analysis, we identified enriched pathways shared by comorbidity datasets and datasets associated with SARS-CoV-2 infection.


Subject(s)
COVID-19/mortality , COVID-19/pathology , Computational Biology/methods , Animals , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/genetics , Comorbidity , Cytokine Release Syndrome/mortality , Databases, Genetic , Diabetes Mellitus/epidemiology , Diabetes Mellitus/genetics , Disease Models, Animal , Hepatitis/epidemiology , Hepatitis/genetics , Humans , Kidney Diseases/epidemiology , Kidney Diseases/genetics , Lung Diseases/epidemiology , Lung Diseases/genetics , Mice , Respiratory Distress Syndrome/mortality , SARS-CoV-2 , Severity of Illness Index
12.
Stem Cell Rev Rep ; 17(1): 94-112, 2021 02.
Article in English | MEDLINE | ID: covidwho-841111

ABSTRACT

Coronavirus disease 2019 (COVID-19) is caused by novel coronavirus Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was first time reported in December 2019 in Wuhan, China and thereafter quickly spread across the globe. Till September 19, 2020, COVID-19 has spread to 216 countries and territories. Severe infection of SARS-CoV-2 cause extreme increase in inflammatory chemokines and cytokines that may lead to multi-organ damage and respiratory failure. Currently, no specific treatment and authorized vaccines are available for its treatment. Renin angiotensin system holds a promising role in human physiological system specifically in regulation of blood pressure and electrolyte and fluid balance. SARS-CoV-2 interacts with Renin angiotensin system by utilizing angiotensin-converting enzyme 2 (ACE2) as a receptor for its cellular entry. This interaction hampers the protective action of ACE2 in the cells and causes injuries to organs due to persistent angiotensin II (Ang-II) level. Patients with certain comorbidities like hypertension, diabetes, and cardiovascular disease are under the high risk of COVID-19 infection and mortality. Moreover, evidence obtained from several reports also suggests higher susceptibility of male patients for COVID-19 mortality and other acute viral infections compared to females. Analysis of severe acute respiratory syndrome coronavirus (SARS) and Middle East respiratory syndrome coronavirus (MERS) epidemiological data also indicate a gender-based preference in disease consequences. The current review addresses the possible mechanisms responsible for higher COVID-19 mortality among male patients. The major underlying aspects that was looked into includes smoking, genetic factors, and the impact of reproductive hormones on immune systems and inflammatory responses. Detailed investigations of this gender disparity could provide insight into the development of patient tailored therapeutic approach which would be helpful in improving the poor outcomes of COVID-19. Graphical abstract.


Subject(s)
COVID-19/epidemiology , Cardiovascular Diseases/epidemiology , Hypertension/epidemiology , SARS-CoV-2/pathogenicity , Angiotensin-Converting Enzyme 2/genetics , COVID-19/complications , COVID-19/genetics , COVID-19/virology , Cardiovascular Diseases/complications , Cardiovascular Diseases/genetics , Cardiovascular Diseases/virology , Diabetes Mellitus/epidemiology , Diabetes Mellitus/genetics , Diabetes Mellitus/virology , Female , Humans , Hypertension/complications , Hypertension/genetics , Hypertension/virology , Male , Renin-Angiotensin System/genetics , Sex Characteristics
13.
Hum Genomics ; 14(1): 35, 2020 10 02.
Article in English | MEDLINE | ID: covidwho-810348

ABSTRACT

Precision medicine aims to empower clinicians to predict the most appropriate course of action for patients with complex diseases like cancer, diabetes, cardiomyopathy, and COVID-19. With a progressive interpretation of the clinical, molecular, and genomic factors at play in diseases, more effective and personalized medical treatments are anticipated for many disorders. Understanding patient's metabolomics and genetic make-up in conjunction with clinical data will significantly lead to determining predisposition, diagnostic, prognostic, and predictive biomarkers and paths ultimately providing optimal and personalized care for diverse, and targeted chronic and acute diseases. In clinical settings, we need to timely model clinical and multi-omics data to find statistical patterns across millions of features to identify underlying biologic pathways, modifiable risk factors, and actionable information that support early detection and prevention of complex disorders, and development of new therapies for better patient care. It is important to calculate quantitative phenotype measurements, evaluate variants in unique genes and interpret using ACMG guidelines, find frequency of pathogenic and likely pathogenic variants without disease indicators, and observe autosomal recessive carriers with a phenotype manifestation in metabolome. Next, ensuring security to reconcile noise, we need to build and train machine-learning prognostic models to meaningfully process multisource heterogeneous data to identify high-risk rare variants and make medically relevant predictions. The goal, today, is to facilitate implementation of mainstream precision medicine to improve the traditional symptom-driven practice of medicine, and allow earlier interventions using predictive diagnostics and tailoring better-personalized treatments. We strongly recommend automated implementation of cutting-edge technologies, utilizing machine learning (ML) and artificial intelligence (AI) approaches for the multimodal data aggregation, multifactor examination, development of knowledgebase of clinical predictors for decision support, and best strategies for dealing with relevant ethical issues.


Subject(s)
Coronavirus Infections/genetics , Diabetes Mellitus/genetics , Neoplasms/genetics , Pneumonia, Viral/genetics , Precision Medicine/trends , COVID-19 , Cardiomyopathies , Coronavirus Infections/epidemiology , Data Analysis , Diabetes Mellitus/epidemiology , Genomics/trends , Humans , Metabolomics/trends , Neoplasms/epidemiology , Pandemics , Pneumonia, Viral/epidemiology , Proteomics/trends
14.
In Vivo ; 34(5): 3029-3032, 2020.
Article in English | MEDLINE | ID: covidwho-740633

ABSTRACT

BACKGROUND/AIM: Reports indicate that coronaviridae may inhibit insulin secretion. In this report we aimed to describe the course of glycemia in critically ill patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. PATIENTS AND METHODS: We studied 36 SARS-CoV-2 patients (with no history of diabetes) in one intensive care unit (ICU). All the patients were admitted for hypoxemic respiratory failure; all but four required mechanical ventilation. The mean (±SD) age of the patients was 64.7 (9.7) years; 27 were men; the mean (±SD) duration of ICU stay was 12.9 (8.3 days). RESULTS: Twenty of 36 patients presented with hyperglycemia; brief intravenous infusions of short-acting insulin were administered in six patients. As of May 29 2020, 11 patients had died (seven with hyperglycemia). In 17 patients the Hyperglycemia Index [HGI; defined as the area under the curve of (hyper)glycemia level*time (h) divided by the total time in the ICU] was <16.21 mg/dl (0.90 mmol/l), whereas in three patients the HGI was ≥16.21 mg/dl (0.90 mol/l) and <32.25 mg/dl (1.79 mmol/l). CONCLUSION: In our series of ICU patients with SARS-CoV-2 infection, and no history of diabetes, a substantial number of patients had hyperglycemia, to a higher degree than would be expected by the stress of critical illness, lending credence to reports that speculated a tentative association between SARS-CoV-2 and hyperglycemia. This finding is important, since hyperglycemia can lead to further infectious complications.


Subject(s)
Coronavirus Infections/therapy , Diabetes Mellitus/therapy , Hyperglycemia/therapy , Insulin/metabolism , Pneumonia, Viral/therapy , Betacoronavirus/pathogenicity , Blood Glucose/metabolism , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/virology , Diabetes Mellitus/genetics , Diabetes Mellitus/virology , Female , Hospitalization , Humans , Hyperglycemia/complications , Hyperglycemia/virology , Intensive Care Units , Male , Middle Aged , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/virology , Respiration, Artificial , Respiratory Insufficiency/physiopathology , Respiratory Insufficiency/therapy , SARS-CoV-2 , Severe Acute Respiratory Syndrome/complications , Severe Acute Respiratory Syndrome/therapy , Severe Acute Respiratory Syndrome/virology
15.
Life Sci ; 258: 118202, 2020 Oct 01.
Article in English | MEDLINE | ID: covidwho-691888

ABSTRACT

Pandemic coronavirus disease-2019, commonly known as COVID-19 caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a highly contagious disease with a high mortality rate. Various comorbidities and their associated symptoms accompany SARS-CoV-2 infection. Among the various comorbidities like hypertension, cardiovascular disease and chronic obstructive pulmonary disease, diabetes considered as one of the critical comorbidity, which could affect the survival of infected patients. The severity of COVID-19 disease intensifies in patients with elevated glucose level probably via amplified pro-inflammatory cytokine response, poor innate immunity and downregulated angiotensin-converting enzyme 2. Thus, the use of ACE inhibitors or angiotensin receptor blockers could worsen the glucose level in patients suffering from novel coronavirus infection. It also observed that the direct ß-cell damage caused by virus, hypokalemia and cytokine and fetuin-A mediated increase in insulin resistance could also deteriorate the diabetic condition in COVID-19 patients. This review highlights the current scenario of coronavirus disease in pre-existing diabetic patients, epidemiology, molecular perception, investigations, treatment and management of COVID-19 disease in patients with pre-existing diabetes. Along with this, we have also discussed unexplored therapies and future perspectives for coronavirus infection.


Subject(s)
Coronavirus Infections/epidemiology , Diabetes Mellitus/epidemiology , Pneumonia, Viral/epidemiology , Angiotensin-Converting Enzyme 2 , Antiviral Agents/therapeutic use , Betacoronavirus/isolation & purification , COVID-19 , Comorbidity , Coronavirus Infections/drug therapy , Coronavirus Infections/genetics , Diabetes Mellitus/drug therapy , Diabetes Mellitus/genetics , Disease Management , Humans , Hypoglycemic Agents/therapeutic use , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/genetics , Polymorphism, Genetic , SARS-CoV-2
16.
Biochem Biophys Res Commun ; 528(3): 413-419, 2020 07 30.
Article in English | MEDLINE | ID: covidwho-436643

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a worldwide pandemic. It has a high transmission rate among humans, and is a threat to global public health. However, there are no effective prophylactics or therapeutics available. It is necessary to identify vulnerable and susceptible groups for adequate protection and care against this disease. Recent studies have reported that COVID-19 has angiotensin-converting enzyme 2 (ACE2) as a functional receptor, which may lead to the development of severe cerebrovascular diseases (CVD), including strokes, in patients with risk factors for CVD such as diabetes and smoking. Thus, the World Health Organization (WHO) advised caution against COVID-19 for smokers and patients with underlying clinical symptoms, including cardiovascular diseases. Here, we observed ACE2 expression in the brain of rat middle cerebral artery occlusion (MCAO) model and evaluated the effects of cigarette smoke extract (CSE) and diabetes on ACE2 expression in vessels. We showed that the levels of ACE2 expression was increased in the cortex penumbra after ischemic injuries. CSE treatment significantly elevated ACE2 expression in human brain vessels. We found that ACE2 expression was upregulated in primary cultured human blood vessels with diabetes compared to healthy controls. This study demonstrates that ACE2 expression is increased in ischemic brains and vessels exposed to diabetes or smoking, makes them vulnerable to COVID-19 infection.


Subject(s)
Betacoronavirus/metabolism , Brain Ischemia/virology , Brain/blood supply , Diabetes Mellitus , Peptidyl-Dipeptidase A/biosynthesis , Receptors, Virus/biosynthesis , Smokers , Stroke/virology , Up-Regulation , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/pathogenicity , Brain/drug effects , Brain Ischemia/genetics , Brain Ischemia/metabolism , COVID-19 , Coronavirus Infections/genetics , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Diabetes Mellitus/genetics , Diabetes Mellitus/metabolism , Disease Models, Animal , Disease Susceptibility , Infarction, Middle Cerebral Artery/complications , Male , Mice , Mice, Inbred C57BL , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/genetics , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Rats , Rats, Sprague-Dawley , Receptors, Virus/genetics , SARS-CoV-2 , Smoke/adverse effects , Stroke/genetics , Stroke/metabolism , Up-Regulation/drug effects
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