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1.
J Virol ; 96(4): e0173921, 2022 02 23.
Статья в английский | MEDLINE | ID: covidwho-2193455

Реферат

Two strains of Middle East respiratory syndrome coronavirus (MERS-CoV), England 1 and Erasmus Medical Centre/2012 (EMC/2012), were used to challenge common marmosets (Callithrix jacchus) by three routes of infection: aerosol, oral, and intranasal. Animals challenged by the intranasal and aerosol routes presented with mild, transient disease, while those challenged by the oral route presented with a subclinical immunological response. Animals challenged with MERS-CoV strain EMC/2012 by the aerosol route responded with primary and/or secondary pyrexia. Marmosets had minimal to mild multifocal interstitial pneumonia, with the greatest relative severity being observed in animals challenged by the aerosol route. Viable virus was isolated from the host in throat swabs and lung tissue. The transient disease described is consistent with a successful host response and was characterized by the upregulation of macrophage and neutrophil function observed in all animals at the time of euthanasia. IMPORTANCE Middle East respiratory syndrome is caused by a human coronavirus, MERS-CoV, similar to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Humans typically exhibit fever, cough, shortness of breath, gastrointestinal issues, and breathing difficulties, which can lead to pneumonia and/or renal complications. This emerging disease resulted in the first human lethal cases in 2012 and has a case fatality rate of approximately 36%. Consequently, there is a need for medical countermeasures and appropriate animal models for their assessment. This work has demonstrated the requirement for higher concentrations of virus to cause overt disease. Challenge by the aerosol, intranasal, and oral routes resulted in no or mild disease, but all animals had an immunological response. This shows that an appropriate early immunological response is able to control the disease.


Тема - темы
COVID-19/metabolism , Disease Models, Animal , Middle East Respiratory Syndrome Coronavirus/metabolism , SARS-CoV-2/metabolism , Animals , Callithrix , Humans
2.
Metabolism ; 133: 155236, 2022 08.
Статья в английский | MEDLINE | ID: covidwho-2131881

Реферат

BACKGROUND: COVID-19 can cause multiple organ damages as well as metabolic abnormalities such as hyperglycemia, insulin resistance, and new onset of diabetes. The insulin/IGF signaling pathway plays an important role in regulating energy metabolism and cell survival, but little is known about the impact of SARS-CoV-2 infection. The aim of this work was to investigate whether SARS-CoV-2 infection impairs the insulin/IGF signaling pathway in the host cell/tissue, and if so, the potential mechanism and association with COVID-19 pathology. METHODS: To determine the impact of SARS-CoV-2 on insulin/IGF signaling pathway, we utilized transcriptome datasets of SARS-CoV-2 infected cells and tissues from public repositories for a wide range of high-throughput gene expression data: autopsy lungs from COVID-19 patients compared to the control from non-COVID-19 patients; lungs from a human ACE2 transgenic mouse infected with SARS-CoV-2 compared to the control infected with mock; human pluripotent stem cell (hPSC)-derived liver organoids infected with SARS-CoV-2; adipose tissues from a mouse model of COVID-19 overexpressing human ACE2 via adeno-associated virus serotype 9 (AAV9) compared to the control GFP after SARS-CoV-2 infection; iPS-derived human pancreatic cells infected with SARS-CoV-2 compared to the mock control. Gain and loss of IRF1 function models were established in HEK293T and/or Calu3 cells to evaluate the impact on insulin signaling. To understand the mechanistic regulation and relevance with COVID-19 risk factors, such as older age, male sex, obesity, and diabetes, several transcriptomes of human respiratory, metabolic, and endocrine cells and tissue were analyzed. To estimate the association with COVID-19 severity, whole blood transcriptomes of critical patients with COVID-19 compared to those of hospitalized noncritical patients with COVID-19. RESULTS: We found that SARS-CoV-2 infection impaired insulin/IGF signaling pathway genes, such as IRS, PI3K, AKT, mTOR, and MAPK, in the host lung, liver, adipose tissue, and pancreatic cells. The impairments were attributed to interferon regulatory factor 1 (IRF1), and its gene expression was highly relevant to risk factors for severe COVID-19; increased with aging in the lung, specifically in men; augmented by obese and diabetic conditions in liver, adipose tissue, and pancreatic islets. IRF1 activation was significantly associated with the impaired insulin signaling in human cells. IRF1 intron variant rs17622656-A, which was previously reported to be associated with COVID-19 prevalence, increased the IRF1 gene expression in human tissue and was frequently found in American and European population. Critical patients with COVID-19 exhibited higher IRF1 and lower insulin/IGF signaling pathway genes in the whole blood compared to hospitalized noncritical patients. Hormonal interventions, such as dihydrotestosterone and dexamethasone, ameliorated the pathological traits in SARS-CoV-2 infectable cells and tissues. CONCLUSIONS: The present study provides the first scientific evidence that SARS-CoV-2 infection impairs the insulin/IGF signaling pathway in respiratory, metabolic, and endocrine cells and tissues. This feature likely contributes to COVID-19 severity with cell/tissue damage and metabolic abnormalities, which may be exacerbated in older, male, obese, or diabetic patients.


Тема - темы
COVID-19 , Insulin , Interferon Regulatory Factor-1 , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/metabolism , HEK293 Cells , Humans , Insulin/metabolism , Interferon Regulatory Factor-1/metabolism , Male , Mice , Mice, Transgenic , Obesity/metabolism , Obesity/pathology , SARS-CoV-2 , Signal Transduction
3.
Nature ; 593(7857): 136-141, 2021 05.
Статья в английский | MEDLINE | ID: covidwho-2114170

Реферат

Transmission of SARS-CoV-2 is uncontrolled in many parts of the world; control is compounded in some areas by the higher transmission potential of the B.1.1.7 variant1, which has now been reported in 94 countries. It is unclear whether the response of the virus to vaccines against SARS-CoV-2 on the basis of the prototypic strain will be affected by the mutations found in B.1.1.7. Here we assess the immune responses of individuals after vaccination with the mRNA-based vaccine BNT162b22. We measured neutralizing antibody responses after the first and second immunizations using pseudoviruses that expressed the wild-type spike protein or a mutated spike protein that contained the eight amino acid changes found in the B.1.1.7 variant. The sera from individuals who received the vaccine exhibited a broad range of neutralizing titres against the wild-type pseudoviruses that were modestly reduced against the B.1.1.7 variant. This reduction was also evident in sera from some patients who had recovered from COVID-19. Decreased neutralization of the B.1.1.7 variant was also observed for monoclonal antibodies that target the N-terminal domain (9 out of 10) and the receptor-binding motif (5 out of 31), but not for monoclonal antibodies that recognize the receptor-binding domain that bind outside the receptor-binding motif. Introduction of the mutation that encodes the E484K substitution in the B.1.1.7 background to reflect a newly emerged variant of concern (VOC 202102/02) led to a more-substantial loss of neutralizing activity by vaccine-elicited antibodies and monoclonal antibodies (19 out of 31) compared with the loss of neutralizing activity conferred by the mutations in B.1.1.7 alone. The emergence of the E484K substitution in a B.1.1.7 background represents a threat to the efficacy of the BNT162b2 vaccine.


Тема - темы
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/therapy , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Synthetic/immunology , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/isolation & purification , Antibodies, Neutralizing/isolation & purification , Antibodies, Viral/isolation & purification , COVID-19/metabolism , COVID-19/virology , Female , HEK293 Cells , Humans , Immune Evasion/genetics , Immune Evasion/immunology , Immunization, Passive , Male , Middle Aged , Models, Molecular , Mutation , Neutralization Tests , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Vaccines, Synthetic/administration & dosage
4.
Cell Rep ; 39(13): 110989, 2022 06 28.
Статья в английский | MEDLINE | ID: covidwho-2121651

Реферат

The interleukin-12 (IL-12) family comprises the only heterodimeric cytokines mediating diverse functional effects. We previously reported a striking bimodal IL-12p70 response to lipopolysaccharide (LPS) stimulation in healthy donors. Herein, we demonstrate that interferon ß (IFNß) is a major upstream determinant of IL-12p70 production, which is also associated with numbers and activation of circulating monocytes. Integrative modeling of proteomic, genetic, epigenomic, and cellular data confirms IFNß as key for LPS-induced IL-12p70 and allowed us to compare the relative effects of each of these parameters on variable cytokine responses. Clinical relevance of our findings is supported by reduced IFNß-IL-12p70 responses in patients hospitalized with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or chronically infected with hepatitis C (HCV). Importantly, these responses are resolved after viral clearance. Our systems immunology approach defines a better understanding of IL-12p70 and IFNß in healthy and infected persons, providing insights into how common genetic and epigenetic variation may impact immune responses to bacterial infection.


Тема - темы
Interferon-beta , Interleukin-12 , Toll-Like Receptor 4 , COVID-19/immunology , COVID-19/metabolism , COVID-19/virology , Cytokines/immunology , Cytokines/metabolism , Humans , Interferon-beta/immunology , Interferon-beta/metabolism , Interleukin-12/immunology , Interleukin-12/metabolism , Lipopolysaccharides/pharmacology , Proteomics , SARS-CoV-2/immunology
5.
PLoS One ; 17(10): e0276460, 2022.
Статья в английский | MEDLINE | ID: covidwho-2089429

Реферат

Excessive neutrophil infiltration and dysfunction contribute to the progression and severity of hyper-inflammatory syndrome, such as in severe COVID19. In the current study, we re-analysed published scRNA-seq datasets of mouse and human neutrophils to classify and compare the transcriptional regulatory networks underlying neutrophil differentiation and inflammatory responses. Distinct sets of TF modules regulate neutrophil maturation, function, and inflammatory responses under the steady state and inflammatory conditions. In COVID19 patients, neutrophil activation was associated with the selective activation of inflammation-specific TF modules. SARS-CoV-2 RNA-positive neutrophils showed a higher expression of type I interferon response TF IRF7. Furthermore, IRF7 expression was abundant in neutrophils from severe patients in progression stage. Neutrophil-mediated inflammatory responses positively correlate with the expressional level of IRF7. Based on these results, we suggest that differential activation of activation-related TFs, such as IRF7 mediate neutrophil inflammatory responses during inflammation.


Тема - темы
COVID-19 , Neutrophils , Humans , COVID-19/genetics , COVID-19/metabolism , Inflammation/genetics , Interferon Type I/metabolism , Neutrophil Activation/genetics , Neutrophil Activation/physiology , Neutrophils/metabolism , RNA, Viral , RNA-Seq , SARS-CoV-2 , Single-Cell Analysis
7.
Biochemistry (Mosc) ; 86(4): 389-396, 2021 Apr.
Статья в английский | MEDLINE | ID: covidwho-2078751

Реферат

The novel coronavirus disease-2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a major public health emergency worldwide with over 118.27-million confirmed COVID-19 cases and 2.62-million deaths recorded, as of March 12, 2021. Although this disease primarily targets lungs, damages in other organs, such as heart, kidney, liver, and testis, may occur. Testis is the cornerstone of male reproduction, while reproductive health is the most valuable resource for continuity of the human race. Given the unique nature of SARS-CoV-2, the mechanisms of its impact on the testes have yet to be fully explored. Notably, coronaviruses have been found to invade target cells through the angiotensin-converting enzyme 2 receptor, which can be found in the respiratory, gastrointestinal, cardiovascular, urinary tract, and reproductive organs, such as testes. Coronavirus studies have suggested that testes might be a potential target for SARS-CoV-2 infection. The first etiopathogenic concept proposed by current hypotheses indicates that the virus can invade testes through the angiotensin-converting enzyme 2 receptor. Next, the activated inflammatory response in the testes, disease-associated fever, and COVID-19 medications might be implicated in testicular alterations. Although evidence regarding the presence of SARS-CoV-2 mRNA in semen remains controversial, this emphasizes the need for researchers to pay closer attention to sexually transmitted diseases and male fertility after recovering from COVID-19. In this review the latest updates regarding COVID-19-associated testicular dysfunction are summarized and possible pathogenic mechanisms are discussed.


Тема - темы
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Fertility , Pandemics , SARS-CoV-2/metabolism , Testis/metabolism , COVID-19/mortality , COVID-19/pathology , Humans , Male , Testis/pathology , Testis/virology
8.
Nature ; 610(7931): 381-388, 2022 10.
Статья в английский | MEDLINE | ID: covidwho-2050416

Реферат

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 and caused the devastating global pandemic of coronavirus disease 2019 (COVID-19), in part because of its ability to effectively suppress host cell responses1-3. In rare cases, viral proteins dampen antiviral responses by mimicking critical regions of human histone proteins4-8, particularly those containing post-translational modifications required for transcriptional regulation9-11. Recent work has demonstrated that SARS-CoV-2 markedly disrupts host cell epigenetic regulation12-14. However, how SARS-CoV-2 controls the host cell epigenome and whether it uses histone mimicry to do so remain unclear. Here we show that the SARS-CoV-2 protein encoded by ORF8 (ORF8) functions as a histone mimic of the ARKS motifs in histone H3 to disrupt host cell epigenetic regulation. ORF8 is associated with chromatin, disrupts regulation of critical histone post-translational modifications and promotes chromatin compaction. Deletion of either the ORF8 gene or the histone mimic site attenuates the ability of SARS-CoV-2 to disrupt host cell chromatin, affects the transcriptional response to infection and attenuates viral genome copy number. These findings demonstrate a new function of ORF8 and a mechanism through which SARS-CoV-2 disrupts host cell epigenetic regulation. Further, this work provides a molecular basis for the finding that SARS-CoV-2 lacking ORF8 is associated with decreased severity of COVID-19.


Тема - темы
COVID-19 , Epigenesis, Genetic , Histones , Host Microbial Interactions , Molecular Mimicry , SARS-CoV-2 , Viral Proteins , COVID-19/genetics , COVID-19/metabolism , COVID-19/virology , Chromatin/genetics , Chromatin/metabolism , Chromatin Assembly and Disassembly , Epigenome/genetics , Histones/chemistry , Histones/metabolism , Humans , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Viral Proteins/chemistry , Viral Proteins/genetics , Viral Proteins/metabolism
9.
Curr Opin Immunol ; 78: 102252, 2022 Oct.
Статья в английский | MEDLINE | ID: covidwho-2031214

Реферат

The outbreak of the COVID-19 pandemic one year after the centennial of the 1918 influenza pandemic reaffirms the catastrophic impact respiratory viruses can have on global health and economy. A key feature of SARS-CoV-2 and influenza A viruses (IAV) is their remarkable ability to suppress or dysregulate human immune responses. Here, we summarize the growing knowledge about the interplay of SARS-CoV-2 and antiviral innate immunity, with an emphasis on the regulation of type-I or -III interferon responses that are critically implicated in COVID-19 pathogenesis. Furthermore, we draw parallels to IAV infection and discuss shared innate immune sensing mechanisms and the respective viral countermeasures.


Тема - темы
COVID-19 , Influenza, Human , Interferons , SARS-CoV-2 , Humans , COVID-19/immunology , COVID-19/metabolism , COVID-19/virology , Immunity, Innate , Influenza A virus/immunology , Influenza, Human/immunology , Influenza, Human/metabolism , Influenza, Human/virology , Interferons/immunology , Pandemics , SARS-CoV-2/immunology
10.
J Virol ; 96(17): e0096722, 2022 09 14.
Статья в английский | MEDLINE | ID: covidwho-1986331

Реферат

Host factors play critical roles in SARS-CoV-2 infection-associated pathology and the severity of COVID-19. In this study, we systematically analyzed the roles of SARS-CoV-2-induced host factors, doublecortin-like kinase 1 (DCLK1), and S100A9 in viral pathogenesis. In autopsied subjects with COVID-19 and pre-existing chronic liver disease, we observed high levels of DCLK1 and S100A9 expression and immunosuppressive (DCLK1+S100A9+CD206+) M2-like macrophages and N2-like neutrophils in lungs and livers. DCLK1 and S100A9 expression were rarely observed in normal controls, COVID-19-negative subjects with chronic lung disease, or COVID-19 subjects without chronic liver disease. In hospitalized patients with COVID-19, we detected 2 to 3-fold increased levels of circulating DCLK1+S100A9+ mononuclear cells that correlated with disease severity. We validated the SARS-CoV-2-dependent generation of these double-positive immune cells in coculture. SARS-CoV-2-induced DCLK1 expression correlated with the activation of ß-catenin, a known regulator of the DCLK1 promoter. Gain and loss of function studies showed that DCLK1 kinase amplified live virus production and promoted cytokine, chemokine, and growth factor secretion by peripheral blood mononuclear cells. Inhibition of DCLK1 kinase blocked pro-inflammatory caspase-1/interleukin-1ß signaling in infected cells. Treatment of SARS-CoV-2-infected cells with inhibitors of DCLK1 kinase and S100A9 normalized cytokine/chemokine profiles and attenuated DCLK1 expression and ß-catenin activation. In conclusion, we report previously unidentified roles of DCLK1 in augmenting SARS-CoV-2 viremia, inflammatory cytokine expression, and dysregulation of immune cells involved in innate immunity. DCLK1 could be a potential therapeutic target for COVID-19, especially in patients with underlying comorbid diseases associated with DCLK1 expression. IMPORTANCE High mortality in COVID-19 is associated with underlying comorbidities such as chronic liver diseases. Successful treatment of severe/critical COVID-19 remains challenging. Herein, we report a targetable host factor, DCLK1, that amplifies SARS-CoV-2 production, cytokine secretion, and inflammatory pathways via activation of ß-catenin(p65)/DCLK1/S100A9/NF-κB signaling. Furthermore, we observed in the lung, liver, and blood an increased prevalence of immune cells coexpressing DCLK1 and S100A9, a myeloid-derived proinflammatory protein. These cells were associated with increased disease severity in COVID-19 patients. Finally, we used a novel small-molecule inhibitor of DCLK1 kinase (DCLK1-IN-1) and S100A9 inhibitor (tasquinimod) to decrease virus production in vitro and normalize hyperinflammatory responses known to contribute to disease severity in COVID-19.


Тема - темы
COVID-19 , Doublecortin-Like Kinases , COVID-19/metabolism , COVID-19/pathology , Calgranulin B/metabolism , Chemokines/metabolism , Cytokines/metabolism , Doublecortin-Like Kinases/antagonists & inhibitors , Doublecortin-Like Kinases/metabolism , Humans , Intracellular Signaling Peptides and Proteins/genetics , Leukocytes, Mononuclear/metabolism , Quinolones/pharmacology , SARS-CoV-2 , beta Catenin/metabolism
11.
Curr Opin Hematol ; 28(5): 339-344, 2021 09 01.
Статья в английский | MEDLINE | ID: covidwho-1956624

Реферат

PURPOSE OF REVIEW: Protein S (PS) is an essential natural anticoagulant. PS deficiency is a major contributor to acquired hypercoagulability. Acquired hypercoagulability causes myocardial infarction, stroke, and deep vein thrombosis in millions of individuals. Yet, despite its importance in hemostasis, PS is the least understood anticoagulant. Even after 40 years since PS was first described, we are still uncovering information about how PS functions. The purpose of this review is to highlight recent findings that advance our understanding of the functions of PS and explain hypercoagulability caused by severe PS deficiency. RECENT FINDINGS: PS has long been described as a cofactor for Activated Protein C (APC) and Tissue Factor Pathway Inhibitor (TFPI). However, a recent report describes direct inhibition of Factor IXa (FIXa) by PS, an activity of PS that had been completely overlooked. Thrombophilia is becoming a more frequently reported disorder. Hereditary PS deficiency is an anticoagulant deficiency that results eventually in thrombophilia. In addition, PS deficiency is a predisposing factor for venous thromboembolism (VTE), but an effect of PS deficiency in arterial thrombosis, such as arterial ischemic stroke, is uncertain. Plasma PS concentration decreases in pregnant women. Inherited thrombophilias are important etiologies for recurrent pregnancy loss, and anticoagulation therapy is of benefit to women with recurrent pregnancy loss who had documented only PS deficiency.Hypoxia is a risk factor for VTE, and hypoxia downregulates plasma PS level. Importantly, COVID-19 can lead to hypoxemia because of lung damage from IL6-driven inflammatory responses to the viral infection. Because hypoxia decreases the abundance of the key anticoagulant PS, we surmise that the IL6-induced cytokine explosion combined with hypoxemia causes a drop in PS level that exacerbates the thrombotic risk in COVID-19 patients. SUMMARY: This review is intended to advance understanding of the anticoagulant function of an important plasma protein, PS. Despite 40+ years of research, we have not had a complete description of PS biology as it pertains to control of blood coagulation. However, the picture of PS function has become sharper with the recent discovery of FIXa inhibition by PS. Hemostasis mediated by PS now includes regulation of FIXa activity alongside the cofactor activities of PS in the TFPI/APC pathways. In addition, the direct inhibition of FIXa by PS suggests that PS, particularly a small derivative of PS, could be used to treat individuals with PS deficiencies or abnormalities that cause thrombotic complications.


Тема - темы
COVID-19/complications , Hemostasis , Protein S/metabolism , SARS-CoV-2/isolation & purification , Thrombophilia/pathology , COVID-19/metabolism , COVID-19/virology , Humans , Thrombophilia/etiology , Thrombophilia/metabolism
12.
Proc Natl Acad Sci U S A ; 119(30): e2123065119, 2022 07 26.
Статья в английский | MEDLINE | ID: covidwho-1947760

Реферат

SARS-CoV-2, the causative agent of the COVID-19 pandemic, undergoes continuous evolution, highlighting an urgent need for development of novel antiviral therapies. Here we show a quantitative mass spectrometry-based succinylproteomics analysis of SARS-CoV-2 infection in Caco-2 cells, revealing dramatic reshape of succinylation on host and viral proteins. SARS-CoV-2 infection promotes succinylation of several key enzymes in the TCA, leading to inhibition of cellular metabolic pathways. We demonstrated that host protein succinylation is regulated by viral nonstructural protein (NSP14) through interaction with sirtuin 5 (SIRT5); overexpressed SIRT5 can effectively inhibit virus replication. We found succinylation inhibitors possess significant antiviral effects. We also found that SARS-CoV-2 nucleocapsid and membrane proteins underwent succinylation modification, which was conserved in SARS-CoV-2 and its variants. Collectively, our results uncover a regulatory mechanism of host protein posttranslational modification and cellular pathways mediated by SARS-CoV-2, which may become antiviral drug targets against COVID-19.


Тема - темы
Antiviral Agents , COVID-19 , Host-Pathogen Interactions , Molecular Targeted Therapy , Protein Processing, Post-Translational , SARS-CoV-2 , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/metabolism , COVID-19/virology , Caco-2 Cells , Exoribonucleases/metabolism , Host-Pathogen Interactions/drug effects , Humans , Protein Processing, Post-Translational/drug effects , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Sirtuins/metabolism , Succinates/metabolism , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effects
13.
Biophys Chem ; 288: 106824, 2022 09.
Статья в английский | MEDLINE | ID: covidwho-1944352

Реферат

The novel coronavirus that caused COVID-19 pandemic is SARS-CoV-2. Although various vaccines are currently being used to prevent the disease's severe consequences, there is still a need for medications for those who become infected. The SARS-CoV-2 has a variety of proteins that have been studied extensively since the virus's advent. In this review article, we looked at chemical to molecular aspects of the various structures studied that have pharmaceutical activity and attempted to find a link between drug activity and compound structure. For example, designing of the compounds which bind to the allosteric site and modify hydrogen bonds or the salt bridges can disrupt SARS-CoV2 RBD-ACE2 complex. It seems that quaternary ammonium moiety and quinolin-1-ium structure could act as a negative allosteric modulator to reduce the tendency between spike-ACE2. Pharmaceutical structures with amino heads and hydrophobic tails can block envelope protein to prevent making mature SARS-CoV-2. Also, structures based on naphthalene pharmacophores or isosteres can form a strong bond with the PLpro and form a π-π and the Mpro's active site can be occupied by octapeptide compounds or linear compounds with a similar fitting ability to octapeptide compounds. And for protein RdRp, it is critical to consider pH and pKa so that pKa regulation of compounds to comply with patients is very effective, thus, the presence of tetrazole, phenylpyrazole groups, and analogs of pyrophosphate in the designed drugs increase the likelihood of the RdRp active site inhibition. Finally, it can be deduced that designing hybrid drug molecules along with considering the aforementioned characteristics would be a suitable approach for developing medicines in order to accurate targeting and complete inhibition this virus.


Тема - темы
COVID-19/drug therapy , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Humans , Pandemics , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Protein Binding , RNA, Viral/metabolism , RNA-Dependent RNA Polymerase , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry
14.
J Immunotoxicol ; 18(1): 93-104, 2021 07 24.
Статья в английский | MEDLINE | ID: covidwho-1947806

Реферат

The aging immune system is characterized by a low-grade chronic systemic inflammatory state ("inflammaging") marked by elevated serum levels of inflammatory molecules such as interleukin (IL)-6 and C-reactive protein (CRP). These inflammatory markers were also reported to be strong predictors for the development/severity of Type 2 diabetes, obesity, and COVID-19. The levels of these markers have been positively associated with those of advanced glycation end-products (AGEs) generated via non-enzymatic glycation and oxidation of proteins and lipids during normal aging and metabolism. Based on the above observations, it is clinically important to elucidate how dietary AGEs modulate inflammation and might thus increase the risk for aging-exacerbated diseases. The present narrative review discusses the potential pro-inflammatory properties of dietary AGEs with a focus on the inflammatory mediators CRP, IL-6 and ferritin, and their relations to aging in general and Type 2 diabetes in particular. In addition, underlying mechanisms - including those related to gut microbiota and the receptors for AGEs, and the roles AGEs might play in affecting physiologies of the healthy elderly, obese individuals, and diabetics are discussed in regard to any greater susceptibility to COVID-19.


Тема - темы
COVID-19/metabolism , Diabetes Mellitus, Type 2/metabolism , Glycation End Products, Advanced/metabolism , Inflammation Mediators/metabolism , SARS-CoV-2/physiology , Aging , Animals , Diet , Dysbiosis , Gastrointestinal Microbiome , Glycation End Products, Advanced/immunology , Homeostasis , Humans , Immunity , Lipid Metabolism
15.
Cell Mol Life Sci ; 79(6): 316, 2022 May 27.
Статья в английский | MEDLINE | ID: covidwho-1941440

Реферат

AXL, a TAM receptor tyrosine kinase (RTK), and its ligand growth arrest-specific 6 (GAS6) are implicated in cancer metastasis and drug resistance, and cellular entry of viruses. Given this, AXL is an attractive therapeutic target, and its inhibitors are being tested in cancer and COVID-19 clinical trials. Still, astonishingly little is known about intracellular mechanisms that control its function. Here, we characterized endocytosis of AXL, a process known to regulate intracellular functions of RTKs. Consistent with the notion that AXL is a primary receptor for GAS6, its depletion was sufficient to block GAS6 internalization. We discovered that upon receptor ligation, GAS6-AXL complexes were rapidly internalized via several endocytic pathways including both clathrin-mediated and clathrin-independent routes, among the latter the CLIC/GEEC pathway and macropinocytosis. The internalization of AXL was strictly dependent on its kinase activity. In comparison to other RTKs, AXL was endocytosed faster and the majority of the internalized receptor was not degraded but rather recycled via SNX1-positive endosomes. This trafficking pattern coincided with sustained AKT activation upon GAS6 stimulation. Specifically, reduced internalization of GAS6-AXL upon the CLIC/GEEC downregulation intensified, whereas impaired recycling due to depletion of SNX1 and SNX2 attenuated AKT signaling. Altogether, our data uncover the coupling between AXL endocytic trafficking and AKT signaling upon GAS6 stimulation. Moreover, our study provides a rationale for pharmacological inhibition of AXL in antiviral therapy as viruses utilize GAS6-AXL-triggered endocytosis to enter cells.


Тема - темы
Endocytosis , Intercellular Signaling Peptides and Proteins , Proto-Oncogene Proteins , Receptor Protein-Tyrosine Kinases , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/metabolism , COVID-19/therapy , Clathrin/metabolism , Clathrin/physiology , Endocytosis/drug effects , Endocytosis/genetics , Endocytosis/physiology , Humans , Intercellular Signaling Peptides and Proteins/genetics , Intercellular Signaling Peptides and Proteins/physiology , Neoplasms/metabolism , Neoplasms/therapy , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins/physiology , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/physiology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/genetics , Receptor Protein-Tyrosine Kinases/physiology
16.
PLoS One ; 17(7): e0271112, 2022.
Статья в английский | MEDLINE | ID: covidwho-1933379

Реферат

The outbreak of the coronavirus disease 2019 caused by the severe acute respiratory syndrome coronavirus 2 triggered a global pandemic where control is needed through therapeutic and preventive interventions. This study aims to identify natural compounds that could affect the fusion between the viral membrane (receptor-binding domain of the severe acute respiratory syndrome coronavirus 2 spike protein) and the human cell receptor angiotensin-converting enzyme 2. Accordingly, we performed the enzyme-linked immunosorbent assay-based screening of 10 phytochemicals that already showed numerous positive effects on human health in several epidemiological studies and clinical trials. Among these phytochemicals, epigallocatechin gallate, a polyphenol and a major component of green tea, could effectively inhibit the interaction between the receptor-binding domain of the severe acute respiratory syndrome coronavirus 2 spike protein and the human cell receptor angiotensin-converting enzyme 2. Alternately, in silico molecular docking studies of epigallocatechin gallate and angiotensin-converting enzyme 2 indicated a binding score of -7.8 kcal/mol and identified a hydrogen bond between R393 and angiotensin-converting enzyme 2, which is considered as a key interacting residue involved in binding with the severe acute respiratory syndrome coronavirus 2 spike protein receptor-binding domain, suggesting the possible blocking of interaction between receptor-binding domain and angiotensin-converting enzyme 2. Furthermore, epigallocatechin gallate could attenuate severe acute respiratory syndrome coronavirus 2 infection and replication in Caco-2 cells. These results shed insight into identification and validation of severe acute respiratory syndrome coronavirus 2 entry inhibitors.


Тема - темы
Angiotensin-Converting Enzyme 2 , COVID-19 , Catechin , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/drug therapy , COVID-19/metabolism , COVID-19/virology , Caco-2 Cells , Catechin/analogs & derivatives , Catechin/pharmacology , Humans , Molecular Docking Simulation , Peptidyl-Dipeptidase A/metabolism , Protein Binding , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism
17.
World J Microbiol Biotechnol ; 38(9): 161, 2022 Jul 14.
Статья в английский | MEDLINE | ID: covidwho-1930506

Реферат

A violacein-producing bacterium was isolated from a mud sample collected near a hot spring on Kümbet Plateau in Giresun Province and named the GK strain. According to the phylogenetic tree constructed using 16S rRNA gene sequence analysis, the GK strain was identified and named Janthinobacterium sp. GK. The crude violacein pigments were separated into three different bands on a TLC sheet. Then violacein and deoxyviolacein were purified by vacuum liquid column chromatography and identified by NMR spectroscopy. According to the inhibition studies, the HIV-1 RT inhibition rate of 1 mM violacein from the GK strain was 94.28% and the CoV-2 spike RBD:ACE2 inhibition rate of 2 mM violacein was 53%. In silico studies were conducted to investigate the possible interactions between violacein and deoxyviolacein and three reference molecules with the target proteins: angiotensin-converting enzyme 2 (ACE2), HIV-1 reverse transcriptase, and SARS-CoV-2 spike receptor binding domain. Ligand violacein binds strongly to the receptor ACE2, HIV-1 reverse transcriptase, and SARS-CoV-2 spike receptor binding domain with a binding energy of -9.94 kcal/mol, -9.32 kcal/mol, and -8.27 kcal/mol, respectively. Deoxyviolacein strongly binds to the ACE2, HIV-1 reverse transcriptase, and SARS-CoV-2 spike receptor binding domain with a binding energy of -10.38 kcal/mol, -9.50 kcal/mol, and -8.06 kcal/mol, respectively. According to these data, violacein and deoxyviolacein bind to all the receptors quite effectively. SARS-CoV-2 spike protein and HIV-1-RT inhibition studies with violacein and deoxyviolacein were performed for the first time in the literature.


Тема - темы
Angiotensin-Converting Enzyme 2 , COVID-19 , HIV-1 , Indoles , Spike Glycoprotein, Coronavirus , COVID-19/metabolism , COVID-19/virology , HIV-1/metabolism , Indoles/metabolism , Indoles/pharmacology , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Phylogeny , Protein Binding , RNA, Ribosomal, 16S , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism
18.
Front Immunol ; 13: 916512, 2022.
Статья в английский | MEDLINE | ID: covidwho-1911050

Реферат

Coronavirus disease 2019 (COVID-19) is a systemic disease associated with injury (thinning) of the endothelial glycocalyx (eGC), a protective layer on the vascular endothelium. The aim of this translational study was to investigate the role of the eGC-degrading enzyme heparanase (HPSE), which is known to play a central role in the destruction of the eGC in bacterial sepsis. Excess activity of HPSE in plasma from COVID-19 patients correlated with several markers of eGC damage and perfused boundary region (PBR, an inverse estimate of glycocalyx dimensions of vessels with a diameter 4-25 µm). In a series of translational experiments, we demonstrate that the changes in eGC thickness of cultured cells exposed to COVID-19 serum correlated closely with HPSE activity in concordant plasma samples (R = 0.82, P = 0.003). Inhibition of HPSE by a nonanticoagulant heparin fragment prevented eGC injury in response to COVID-19 serum, as shown by atomic force microscopy and immunofluorescence imaging. Our results suggest that the protective effect of heparin in COVID-19 may be due to an eGC-protective off-target effect.


Тема - темы
COVID-19 , Glucuronidase , Glycocalyx , COVID-19/metabolism , COVID-19/pathology , Glucuronidase/metabolism , Glycocalyx/metabolism , Glycocalyx/pathology , Heparin/pharmacology , Humans
19.
PLoS One ; 17(6): e0270418, 2022.
Статья в английский | MEDLINE | ID: covidwho-1910682

Реферат

Thymidine kinase 2 (TK2) deficiency in humans leads to a myopathic form of mitochondrial DNA (mtDNA) deficiency. Here we present a skeletal and cardiac muscle specific TK2 knockout mouse (mTk2 KO). The mice showed dilated hearts and markedly reduced adipose tissue during week 12 to 16. A severe decrease of mtDNA was found only in skeletal muscle and heart tissue in mTk2 KO mice. Expression analysis of key metabolic genes of 16 weeks knockout mice showed significant changes of genes involved in lipid metabolism, with different patterns in heart and skeletal muscle. Our study further suggests that lipoprotein lipase (LPL) from liver supports the metabolism when heart and skeletal muscle were impaired due to mitochondrial dysfunction. The angiotensin-converting enzyme 2 (ACE2), which is involved in glucose homeostasis, was also affected by mtDNA deficiency in our study. Interestingly, both the gene and protein expression of ACE2 were increased in cardiac tissue of mTk2 KO mice. Since ACE2 is a receptor for the SARS-CoV-2 virus, its regulation in relation to mitochondrial function may have important clinical implications.


Тема - темы
Angiotensin-Converting Enzyme 2 , COVID-19 , Lipid Metabolism Disorders , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/genetics , COVID-19/metabolism , DNA, Mitochondrial/genetics , DNA, Mitochondrial/metabolism , Lipid Metabolism , Lipid Metabolism Disorders/genetics , Lipid Metabolism Disorders/metabolism , Lipid Metabolism Disorders/virology , Mice , Mice, Knockout , Mitochondria/genetics , Mitochondria/metabolism , Muscle, Skeletal/metabolism , SARS-CoV-2 , Up-Regulation
20.
Sci Rep ; 12(1): 3446, 2022 03 02.
Статья в английский | MEDLINE | ID: covidwho-1908225

Реферат

The COVID19 pandemic has led to multipronged approaches for treatment of the disease. Since de novo discovery of drugs is time consuming, repurposing of molecules is now considered as one of the alternative strategies to treat COVID19. Antibacterial peptides are being recognized as attractive candidates for repurposing to treat viral infections. In this study, we describe the anti-SARS-CoV-2 activity of the well-studied antibacterial peptides gramicidin S and melittin obtained from Bacillus brevis and bee venom respectively. The EC50 values for gramicidin S and melittin were 1.571 µg and 0.656 µg respectively based on in vitro antiviral assay. Significant decrease in the viral load as compared to the untreated group with no/very less cytotoxicity was observed. Both the peptides treated to the SARS-CoV-2 infected Vero cells showed viral clearance from 12 h onwards with a maximal viral clearance after 24 h post infection. Proteomics analysis indicated that more than 250 proteins were differentially regulated in the gramicidin S and melittin treated SARS-CoV-2 infected Vero cells against control SARS-CoV-2 infected Vero cells after 24 and 48 h post infection. The identified proteins were found to be associated in the metabolic and mRNA processing of the Vero cells post-treatment and infection. Both these peptides could be attractive candidates for repurposing to treat SARS-CoV-2 infection.


Тема - темы
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Gramicidin/therapeutic use , Melitten/therapeutic use , SARS-CoV-2/isolation & purification , Animals , COVID-19/metabolism , COVID-19/virology , Chlorocebus aethiops , Humans , Proteomics , Vero Cells
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