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1.
Int J Mol Sci ; 21(21)2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33158276

RESUMO

Binding to the host receptor is a critical initial step for the coronavirus SARS-CoV-2 spike protein to enter into target cells and trigger virus transmission. A detailed dynamic and energetic view of the binding mechanisms underlying virus entry is not fully understood and the consensus around the molecular origins behind binding preferences of SARS-CoV-2 for binding with the angiotensin-converting enzyme 2 (ACE2) host receptor is yet to be established. In this work, we performed a comprehensive computational investigation in which sequence analysis and modeling of coevolutionary networks are combined with atomistic molecular simulations and comparative binding free energy analysis of the SARS-CoV and SARS-CoV-2 spike protein receptor binding domains with the ACE2 host receptor. Different from other computational studies, we systematically examine the molecular and energetic determinants of the binding mechanisms between SARS-CoV-2 and ACE2 proteins through the lens of coevolution, conformational dynamics, and allosteric interactions that conspire to drive binding interactions and signal transmission. Conformational dynamics analysis revealed the important differences in mobility of the binding interfaces for the SARS-CoV-2 spike protein that are not confined to several binding hotspots, but instead are broadly distributed across many interface residues. Through coevolutionary network analysis and dynamics-based alanine scanning, we established linkages between the binding energy hotspots and potential regulators and carriers of signal communication in the virus-host receptor complexes. The results of this study detailed a binding mechanism in which the energetics of the SARS-CoV-2 association with ACE2 may be determined by cumulative changes of a number of residues distributed across the entire binding interface. The central findings of this study are consistent with structural and biochemical data and highlight drug discovery challenges of inhibiting large and adaptive protein-protein interfaces responsible for virus entry and infection transmission.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/virologia , Interações entre Hospedeiro e Microrganismos , Humanos , Pandemias , Pneumonia Viral/enzimologia , Pneumonia Viral/virologia , Ligação Proteica , Domínios Proteicos , Receptores Virais/metabolismo , Transdução de Sinais , Internalização do Vírus
2.
Comput Biol Med ; 126: 104051, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33131530

RESUMO

SARS-CoV-2 has ushered a global pandemic with no effective drug being available at present. Although several FDA-approved drugs are currently under clinical trials for drug repositioning, there is an on-going global effort for new drug identification. In this paper, using multi-omics (interactome, proteome, transcriptome, and bibliome) data and subsequent integrated analysis, we present the biological events associated with SARS-CoV-2 infection and identify several candidate drugs against this viral disease. We found that: (i) Interactome-based infection pathways differ from the other three omics-based profiles. (ii) Viral process, mRNA splicing, cytokine and interferon signaling, and ubiquitin mediated proteolysis are important pathways in SARS-CoV-2 infection. (iii) SARS-CoV-2 infection also shares pathways with Influenza A, Epstein-Barr virus, HTLV-I, Measles, and Hepatitis virus. (iv) Further, bacterial, parasitic, and protozoan infection pathways such as Tuberculosis, Malaria, and Leishmaniasis are also shared by this virus. (v) A total of 50 candidate drugs, including the prophylaxis agents and pathway specific inhibitors are identified against COVID-19. (vi) Betamethasone, Estrogen, Simvastatin, Hydrocortisone, Tositumomab, Cyclosporin A etc. are among the important drugs. (vii) Ozone, Nitric oxide, plasma components, and photosensitizer drugs are also identified as possible therapeutic candidates. (viii) Curcumin, Retinoic acids, Vitamin D, Arsenic, Copper, and Zinc may be the candidate prophylaxis agents. Nearly 70% of our identified agents are previously suggested to have anti-COVID-19 effects or under clinical trials. Among our identified drugs, the ones that are not yet tested, need validation with caution while an appropriate drug combination from these candidate drugs along with a SARS-CoV-2 specific antiviral agent is needed for effective COVID-19 management.


Assuntos
Antivirais , Betacoronavirus , Infecções por Coronavirus , Bases de Dados Genéticas , Descoberta de Drogas , Modelos Biológicos , Pandemias , Pneumonia Viral , Antivirais/química , Antivirais/farmacocinética , Antivirais/uso terapêutico , Betacoronavirus/genética , Betacoronavirus/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/genética , Infecções por Coronavirus/metabolismo , Humanos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/genética , Pneumonia Viral/metabolismo , Proteômica
4.
Int J Mol Sci ; 21(21)2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33114676

RESUMO

Interleukin-6 (IL-6) is a cytokine with multifaceted effects playing a remarkable role in the initiation of the immune response. The increased level of this cytokine in the elderly seems to be associated with the chronic inflammatory setting of the microenvironment in aged individuals. IL-6 also represents one of the main signals in communication between cancer cells and their non-malignant neighbours within the tumour niche. IL-6 also participates in the development of a premetastatic niche and in the adjustment of the metabolism in terminal-stage patients suffering from a malignant disease. IL-6 is a fundamental factor of the cytokine storm in patients with severe COVID-19, where it is responsible for the fatal outcome of the disease. A better understanding of the role of IL-6 under physiological as well as pathological conditions and the preparation of new strategies for the therapeutic control of the IL-6 axis may help to manage the problems associated with the elderly, cancer, and serious viral infections.


Assuntos
Envelhecimento/metabolismo , Infecções por Coronavirus/metabolismo , Interleucina-6/metabolismo , Neoplasias/metabolismo , Pneumonia Viral/metabolismo , Envelhecimento/patologia , Animais , Infecções por Coronavirus/patologia , Humanos , Interleucina-6/genética , Neoplasias/patologia , Pandemias , Pneumonia Viral/patologia , Transdução de Sinais
6.
Respir Res ; 21(1): 276, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087116

RESUMO

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) is frequently associated with hyperinflammation and hyperferritinemia. The latter is related to increased mortality in COVID-19. Still, it is not clear if iron dysmetabolism is mechanistically linked to COVID-19 pathobiology. METHODS: We herein present data from the ongoing prospective, multicentre, observational CovILD cohort study (ClinicalTrials.gov number, NCT04416100), which systematically follows up patients after COVID-19. 109 participants were evaluated 60 days after onset of first COVID-19 symptoms including clinical examination, chest computed tomography and laboratory testing. RESULTS: We investigated subjects with mild to critical COVID-19, of which the majority received hospital treatment. 60 days after disease onset, 30% of subjects still presented with iron deficiency and 9% had anemia, mostly categorized as anemia of inflammation. Anemic patients had increased levels of inflammation markers such as interleukin-6 and C-reactive protein and survived a more severe course of COVID-19. Hyperferritinemia was still present in 38% of all individuals and was more frequent in subjects with preceding severe or critical COVID-19. Analysis of the mRNA expression of peripheral blood mononuclear cells demonstrated a correlation of increased ferritin and cytokine mRNA expression in these patients. Finally, persisting hyperferritinemia was significantly associated with severe lung pathologies in computed tomography scans and a decreased performance status as compared to patients without hyperferritinemia. DISCUSSION: Alterations of iron homeostasis can persist for at least two months after the onset of COVID-19 and are closely associated with non-resolving lung pathologies and impaired physical performance. Determination of serum iron parameters may thus be a easy to access measure to monitor the resolution of COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT04416100.


Assuntos
Infecções por Coronavirus/complicações , Infecções por Coronavirus/metabolismo , Homeostase , Ferro/metabolismo , Pneumopatias/etiologia , Pneumopatias/metabolismo , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo , Adulto , Idoso , Anemia/etiologia , Proteína C-Reativa/análise , Estudos de Coortes , Infecções por Coronavirus/fisiopatologia , Feminino , Ferritinas/sangue , Seguimentos , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Interleucina-6/sangue , Pneumopatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Pandemias , Pneumonia Viral/fisiopatologia , Estudos Prospectivos , Tomografia Computadorizada por Raios X
7.
Phytomedicine ; 79: 153350, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33002827

RESUMO

BACKGROUND: Vascular endothelial activation is pivotal for the pathological development of various infectious and inflammatory diseases. Therapeutic interventions to prevent endothelial activation are of great clinical significance to achieve anti-inflammatory strategy. Previous studies indicate that the total flavonoids from the endemic herbal medicine Nervilia fordii (Hance) Schltr exerts potent anti-inflammatory effect and protective effect against endotoxin lipopolysaccharide (LPS)-induced acute lung injury, and shows clinical benefit in severe acute respiratory syndromes (SARS). However, the exact effective component of Nervilia fordii and its potential mechanism remain unknown. PURPOSE: The aim of this study was to investigate the effect and mechanism of rhamnocitrin (RH), a flavonoid extracted from Nervilia fordii, on LPS-induced endothelial activation. METHODS: The in vitro endothelial cell activation model was induced by LPS in human umbilical vein endothelial cells (HUVECs). Cell viability was measured to determine the cytotoxicity of RH. RT-PCR, Western blot, fluorescent probe and immunofluorescence were conducted to evaluate the effect and mechanism of RH against endothelial activation. RESULTS: RH was extracted and isolated from Nervilia fordii. RH at the concentration from 10-7 M-10-5 M inhibited the expressions of interlukin-6 (IL-6) and -8 (IL-8), monocyte chemotactic protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell-adhesion molecule-1 (VCAM-1), and plasminogen activator inhibitor-1 (PAI-1) in response to LPS challenge. Mechanistically, RH repressed calcium store-operated Ca2+ entry (SOCE) induced by LPS, which is due to downregulation of stromal interaction molecule-1 (STIM-1) following upregulating microRNA-185 (miR-185). Ultimately, RH abrogated LPS-induced activation of SOCE-mediated calcineurin/NFATc3 (nuclear factor of activated T cells, cytoplasmic 3) signaling pathway. CONCLUSION: The present study identifies RH as a potent inhibitor of endothelial activation. Since vascular endothelial activation is a pivotal cause of excessive cytokine production, leading to cytokine storm and severe pathology in infectious diseases such as SARS and the ongoing COVID-19 pneumonia disease, RH might suggest promising therapeutic potential in the management of cytokine storm in these diseases.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Proteínas Sensoras de Cálcio Intracelular/metabolismo , Quempferóis/farmacologia , Proteínas de Membrana/metabolismo , Fatores de Transcrição NFATC/metabolismo , Proteínas de Neoplasias/metabolismo , Orchidaceae/química , Molécula 1 de Interação Estromal/metabolismo , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Endotélio Vascular/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Quempferóis/isolamento & purificação , Lipopolissacarídeos/farmacologia , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Molécula 1 de Adesão de Célula Vascular/metabolismo
8.
Artigo em Inglês | MEDLINE | ID: mdl-33031994

RESUMO

As the infected cases of COVID-19 reach more than 20 million with more than 778,000 deaths globally, an increase in psychiatric disorders including anxiety and depression has been reported. Scientists globally have been searching for novel therapies and vaccines to fight against COVID-19. Improving innate immunity has been suggested to block progression of COVID-19 at early stages, while omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been shown to have immunomodulation effects. Moreover, n-3 PUFAs have also been shown to improve mood disorders, thus, future research is warranted to test if n-3 PUFAs may have the potential to improve our immunity to counteract both physical and mental impact of COVID-19.


Assuntos
Ansiedade/prevenção & controle , Infecções por Coronavirus/prevenção & controle , Depressão/prevenção & controle , Suplementos Nutricionais , Ácidos Graxos Ômega-3/administração & dosagem , Fatores Imunológicos/administração & dosagem , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Ansiedade/imunologia , Ansiedade/metabolismo , Ansiedade/virologia , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Citocinas/biossíntese , Citocinas/imunologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/virologia , Depressão/imunologia , Depressão/metabolismo , Depressão/virologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/virologia , Ácidos Graxos Ômega-3/imunologia , Ácidos Graxos Ômega-3/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/imunologia , Fatores Imunológicos/metabolismo , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/virologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/virologia , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia
9.
BMJ Open ; 10(10): e043651, 2020 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-33040020

RESUMO

OBJECTIVES: COVID-19 causes lung parenchymal and endothelial damage that lead to hypoxic acute respiratory failure (hARF). The influence of hARF severity on patients' outcomes is still poorly understood. DESIGN: Observational, prospective, multicentre study. SETTING: Three academic hospitals in Milan (Italy) involving three respiratory high dependency units and three general wards. PARTICIPANTS: Consecutive adult hospitalised patients with a virologically confirmed diagnosis of COVID-19. Patients aged <18 years or unable to provide informed consent were excluded. INTERVENTIONS: Anthropometrical, clinical characteristics and blood biomarkers were assessed within the first 24 hours from admission. hARF was graded as follows: severe (partial pressure of oxygen to fraction of inspired oxygen ratio (PaO2/FiO2) <100 mm Hg); moderate (PaO2/FiO2 101-200 mm Hg); mild (PaO2/FiO2 201-300 mm Hg) and normal (PaO2/FiO2 >300 mm Hg). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the assessment of clinical characteristics and in-hospital mortality based on the severity of respiratory failure. Secondary outcomes were intubation rate and application of continuous positive airway pressure during hospital stay. RESULTS: 412 patients were enrolled (280 males, 68%). Median (IQR) age was 66 (55-76) years with a PaO2/FiO2 at admission of 262 (140-343) mm Hg. 50.2% had a cardiovascular disease. Prevalence of mild, moderate and severe hARF was 24.4%, 21.9% and 15.5%, respectively. In-hospital mortality proportionally increased with increasing impairment of gas exchange (p<0.001). The only independent risk factors for mortality were age ≥65 years (HR 3.41; 95% CI 2.00 to 5.78, p<0.0001), PaO2/FiO2 ratio ≤200 mm Hg (HR 3.57; 95% CI 2.20 to 5.77, p<0.0001) and respiratory failure at admission (HR 3.58; 95% CI 1.05 to 12.18, p=0.04). CONCLUSIONS: A moderate-to-severe impairment in PaO2/FiO2 was independently associated with a threefold increase in risk of in-hospital mortality. Severity of respiratory failure is useful to identify patients at higher risk of mortality. TRIAL REGISTRATION NUMBER: NCT04307459.


Assuntos
Infecções por Coronavirus/patologia , Mortalidade Hospitalar , Hospitalização , Oxigênio/sangue , Pneumonia Viral/patologia , Síndrome do Desconforto Respiratório do Adulto/etiologia , Síndrome Respiratória Aguda Grave/etiologia , Índice de Gravidade de Doença , Idoso , Betacoronavirus , Gasometria , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Feminino , Hospitais , Humanos , Hipóxia , Unidades de Terapia Intensiva , Itália/epidemiologia , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pressão Parcial , Pneumonia Viral/metabolismo , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Estudos Prospectivos , Síndrome do Desconforto Respiratório do Adulto/mortalidade , Síndrome do Desconforto Respiratório do Adulto/terapia , Síndrome do Desconforto Respiratório do Adulto/virologia , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/mortalidade , Insuficiência Respiratória/terapia , Insuficiência Respiratória/virologia , Fatores de Risco , Síndrome Respiratória Aguda Grave/mortalidade , Síndrome Respiratória Aguda Grave/terapia , Síndrome Respiratória Aguda Grave/virologia
10.
Front Endocrinol (Lausanne) ; 11: 583006, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33101215

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its clinical manifestation (COVID-19; coronavirus disease 2019) have caused a worldwide health crisis. Disruption of epithelial and endothelial barriers is a key clinical turning point that differentiates patients who are likely to develop severe COVID-19 outcomes: it marks a significant escalation in respiratory symptoms, loss of viral containment and a progression toward multi-organ dysfunction. These barrier mechanisms are independently compromised by known COVID-19 risk factors, including diabetes, obesity and aging: thus, a synergism between these underlying conditions and SARS-CoV-2 mechanisms may explain why these risk factors correlate with more severe outcomes. This review examines the key cellular mechanisms that SARS-CoV-2 and its underlying risk factors utilize to disrupt barrier function. As an outlook, we propose that glucagon-like peptide 1 (GLP-1) may be a therapeutic intervention that can slow COVID-19 progression and improve clinical outcome following SARS-CoV-2 infection. GLP-1 signaling activates barrier-promoting processes that directly oppose the pro-inflammatory mechanisms commandeered by SARS-CoV-2 and its underlying risk factors.


Assuntos
Envelhecimento/patologia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/epidemiologia , Diabetes Mellitus/fisiopatologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Inflamação/fisiopatologia , Obesidade/fisiopatologia , Pneumonia Viral/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Humanos , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia
11.
FASEB J ; 34(9): 11347-11354, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-33078484

RESUMO

A relationship between COVID-19 infection and an increasing incidence of atrial fibrillation has been observed. However, the underlying pathophysiology as a precipitant to AF has not been reviewed. This paper will consider the possible pathological and immunological AF mechanisms as a result, of COVID-19 infection. We discuss the role myocardial microvascular pericytes expressing the ACE-2 receptor and their potential for an organ-specific cardiac involvement with COVID-19. Dysfunctional microvascular support by pericytes or endothelial cells may increase the propensity for AF via increased myocardial inflammation, fibrosis, increased tissue edema, and interstitial hydrostatic pressure. All of these factors can lead to electrical perturbances at the tissue and cellular level. We also consider the contribution of Angiotensin, pulmonary hypertension, and regulatory T cells as additional contributors to AF during COVID-19 infection. Finally, reference is given to two common drugs, corticosteroids and metformin, in COVID-19 and how they might influence AF incidence.


Assuntos
Fibrilação Atrial/etiologia , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Fibrilação Atrial/metabolismo , Infecções por Coronavirus/metabolismo , Células Endoteliais/metabolismo , Humanos , Pandemias , Peptidil Dipeptidase A/metabolismo , Pericitos/metabolismo , Pneumonia Viral/metabolismo , Sistema Renina-Angiotensina
12.
Sci Rep ; 10(1): 18689, 2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-33122784

RESUMO

The COVID-19 fatality rate is high when compared to the H1N1pdm09 (pandemic Influenza A virus H1N1 subtype) rate, and although both cause an aggravated inflammatory response, the differences in the mechanisms of both pandemic pneumonias need clarification. Thus, our goal was to analyze tissue expression of interleukins 4, 13, (IL-4, IL-13), transforming growth factor-beta (TGF-ß), and the number of M2 macrophages (Sphingosine-1) in patients who died by COVID-19, comparing with cases of severe pneumopathy caused by H1N1pdm09, and a control group without lung injury. Six lung biopsy samples of patients who died of SARS-CoV-2 (COVID-19 group) were used and compared with ten lung samples of adults who died from a severe infection of H1N1pdm09 (H1N1 group) and eleven samples of patients who died from different causes without lung injury (CONTROL group). The expression of IL-4, IL-13, TGF-ß, and M2 macrophages score (Sphingosine-1) were identified through immunohistochemistry (IHC). Significantly higher IL-4 tissue expression and Sphingosine-1 in M2 macrophages were observed in the COVID-19 group compared to both the H1N1 and the CONTROL groups. A different mechanism of diffuse alveolar damage (DAD) in SARS-CoV-2 compared to H1N1pdm09 infections were observed. IL-4 expression and lung remodeling are phenomena observed in both SARS-CoV-2 and H1N1pdm09. However, SARS-CoV-2 seems to promote lung damage through different mechanisms, such as the scarce participation Th1/Th17 response and the higher participation of the Th2. Understanding and managing the aggravated and ineffective immune response elicited by SARS-CoV-2 merits further clarification to improve treatments propose.


Assuntos
Infecções por Coronavirus/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Pulmão/metabolismo , Pneumonia Viral/metabolismo , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Infecções por Coronavirus/patologia , Feminino , Humanos , Interleucina-13/genética , Interleucina-4/genética , Pulmão/patologia , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/patologia , Esfingosina/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
13.
Channels (Austin) ; 14(1): 403-412, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33092458

RESUMO

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has prompted an urgent need to identify effective medicines for the prevention and treatment of the disease. A comparative analysis between SARS-CoV-2 and Hepatitis C Virus (HCV) can expand the available knowledge regarding the virology and potential drug targets against these viruses. Interestingly, comparing HCV with SARS-CoV-2 reveals major similarities between them, ranging from the ion channels that are utilized, to the symptoms that are exhibited by patients. Via this comparative analysis, and from what is known about HCV, the most promising treatments for COVID-19 can focus on the reduction of viral load, treatment of pulmonary system damages, and reduction of inflammation. In particular, the drugs that show most potential in this regard include ritonavir, a combination of peg-IFN, and lumacaftor-ivacaftor. This review anaylses SARS-CoV-2 from the perspective of the role of ion homeostasis and channels in viral pathomechanism. We also highlight other novel treatment approaches that can be used for both treatment and prevention of COVID-19. The relevance of this review is to offer high-quality evidence that can be used as the basis for the identification of potential solutions to the COVID-19 pandemic.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Hepacivirus/metabolismo , Canais Iônicos/metabolismo , Pneumonia Viral/metabolismo , Animais , Betacoronavirus/patogenicidade , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Hepacivirus/patogenicidade , Hepatite C/metabolismo , Hepatite C/virologia , Humanos , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia
14.
BMC Pulm Med ; 20(1): 269, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33066765

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has spread to almost 100 countries, infected over 31 M patients and resulted in 961 K deaths worldwide as of 21st September 2020. The major clinical feature of severe COVID-19 requiring ventilation is acute respiratory distress syndrome (ARDS) with multi-functional failure as a result of a cytokine storm with increased serum levels of cytokines. The pathogenesis of the respiratory failure in COVID-19 is yet unknown, but diffuse alveolar damage with interstitial thickening leading to compromised gas exchange is a plausible mechanism. Hypoxia is seen in the COVID-19 patients, however, patients present with a distinct phenotype. Intracellular levels of nitric oxide (NO) play an important role in the vasodilation of small vessels. To elucidate the intracellular levels of NO inside of RBCs in COVID-19 patients compared with that of healthy control subjects. METHODS: We recruited 14 COVID-19 infected cases who had pulmonary involvement of their disease, 4 non-COVID-19 healthy controls (without pulmonary involvement and were not hypoxic) and 2 hypoxic non-COVID-19 patients subjects who presented at the Masih Daneshvari Hospital of Tehran, Iran between March-May 2020. Whole blood samples were harvested from patients and intracellular NO levels in 1 × 106 red blood cells (RBC) was measured by DAF staining using flow cytometry (FACS Calibour, BD, CA, USA). RESULTS: The Mean florescent of intensity for NO was significantly enhanced in COVID-19 patients compared with healthy control subjects (P ≤ 0.05). As a further control for whether hypoxia induced this higher intracellular NO, we evaluated the levels of NO inside RBC of hypoxic patients. No significant differences in NO levels were seen between the hypoxic and non-hypoxic control group. CONCLUSIONS: This pilot study demonstrates increased levels of intracellular NO in RBCs from COVID-19 patients. Future multi-centre studies should examine whether this is seen in a larger number of COVID-19 patients and whether NO therapy may be of use in these severe COVID-19 patients.


Assuntos
Dióxido de Carbono/metabolismo , Infecções por Coronavirus/metabolismo , Eritrócitos/metabolismo , Hipóxia/metabolismo , Óxido Nítrico/metabolismo , Oxigênio/metabolismo , Pneumonia Viral/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Assintomáticas , Betacoronavirus , Gasometria , Estudos de Casos e Controles , Infecções por Coronavirus/sangue , Infecções por Coronavirus/complicações , Feminino , Citometria de Fluxo , Humanos , Hipóxia/sangue , Hipóxia/etiologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pressão Parcial , Projetos Piloto , Pneumonia Viral/sangue , Pneumonia Viral/complicações , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/metabolismo , Vasodilatação , Adulto Jovem
15.
Drugs Aging ; 37(11): 779-785, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33084001

RESUMO

This paper presents a brief overview of the complex interaction between age, hypertension, the renin-angiotensin-aldosterone system (RAAS), inflammation, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. Coronavirus disease 2019 (COVID-19) is more frequent and more severe in comorbid elderly patients, especially those with hypertension, diabetes, obesity, or cardiovascular diseases. There are concerns regarding the use of RAAS inhibitors in patients with COVID-19. Some physicians have considered the need for interrupting RAAS inhibition in order to reduce the possibility of SARS-CoV2 entering lung cells after binding to angiotensin-converting enzyme 2 (ACE2) receptors. We offer a different point of view in relation to the need for continuing to use RAAS inhibitors in patients with COVID-19. We focused our article on elderly patients because of the distinctive imbalance between the immune response, which is depressed, and the exacerbated inflammatory response, 'inflammaging', which makes the geriatric patient an appropriate candidate for therapeutic strategies aimed at modulating the inflammatory response. Indeed, COVID-19 is an inflammatory storm that starts and worsens during the course of the disease. During the COVID-19 pandemic, various therapeutic approaches have been tested, including antiviral drugs, interferon, anti-interleukins, hydroxychloroquine, anti-inflammatories, immunoglobulins from recovered patients, and heparins. Some of these therapeutic approaches did not prove to be beneficial, or even induced serious complications. Based on current evidence, in the early stages of the disease modulation of the inflammatory response through the inhibition of neprilysin and modulation of the RAAS could affect the course and outcome of COVID-19.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Betacoronavirus , Infecções por Coronavirus , Hipertensão/tratamento farmacológico , Inflamação , Pandemias , Pneumonia Viral , Idoso , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/imunologia , Humanos , Fatores Imunológicos/farmacologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Neprilisina/antagonistas & inibidores , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Sistema Renina-Angiotensina/efeitos dos fármacos
16.
Int J Mol Sci ; 21(21)2020 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-33114359

RESUMO

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) has produced significant health emergencies worldwide, resulting in the declaration by the World Health Organization of the coronavirus disease 2019 (COVID-19) pandemic. Acute respiratory syndrome seems to be the most common manifestation of COVID-19. A high proportion of patients require intensive care unit admission and mechanical ventilation (MV) to survive. It has been well established that angiotensin-converting enzyme type 2 (ACE2) is the primary cellular receptor for SARS-CoV-2. ACE2 belongs to the renin-angiotensin system (RAS), composed of several peptides, such as angiotensin II (Ang II) and angiotensin (1-7) (Ang-(1-7)). Both peptides regulate muscle mass and function. It has been described that SARS-CoV-2 infection, by direct and indirect mechanisms, affects a broad range of organ systems. In the skeletal muscle, through unbalanced RAS activity, SARS-CoV-2 could induce severe consequences such as loss of muscle mass, strength, and physical function, which will delay and interfere with the recovery process of patients with COVID-19. This article discusses the relationship between RAS, SARS-CoV-2, skeletal muscle, and the potentially harmful consequences for skeletal muscle in patients currently infected with and recovering from COVID-19.


Assuntos
Infecções por Coronavirus/metabolismo , Músculo Esquelético/fisiopatologia , Atrofia Muscular/etiologia , Pneumonia Viral/metabolismo , Sistema Renina-Angiotensina , Animais , Infecções por Coronavirus/complicações , Infecções por Coronavirus/fisiopatologia , Humanos , Músculo Esquelético/metabolismo , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/fisiopatologia
17.
Sci Rep ; 10(1): 16824, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033346

RESUMO

The biological mechanisms involved in SARS-CoV-2 infection are only partially understood. Thus we explored the plasma metabolome of patients infected with SARS-CoV-2 to search for diagnostic and/or prognostic biomarkers and to improve the knowledge of metabolic disturbance in this infection. We analyzed the plasma metabolome of 55 patients infected with SARS-CoV-2 and 45 controls by LC-HRMS at the time of viral diagnosis (D0). We first evaluated the ability to predict the diagnosis from the metabotype at D0 in an independent population. Next, we assessed the feasibility of predicting the disease evolution at the 7th and 15th day. Plasma metabolome allowed us to generate a discriminant multivariate model to predict the diagnosis of SARS-CoV-2 in an independent population (accuracy > 74%, sensitivity, specificity > 75%). We identified the role of the cytosine and tryptophan-nicotinamide pathways in this discrimination. However, metabolomic exploration modestly explained the disease evolution. Here, we present the first metabolomic study in SARS-CoV-2 patients which showed a high reliable prediction of early diagnosis. We have highlighted the role of the tryptophan-nicotinamide pathway clearly linked to inflammatory signals and microbiota, and the involvement of cytosine, previously described as a coordinator of cell metabolism in SARS-CoV-2. These findings could open new therapeutic perspectives as indirect targets.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Citosina/sangue , Metaboloma , Metabolômica/métodos , Niacinamida/sangue , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Triptofano/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Diagnóstico Precoce , Feminino , França/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Prognóstico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Índice de Gravidade de Doença
18.
Invest Ophthalmol Vis Sci ; 61(12): 13, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33049061

RESUMO

Purpose: The coronavirus disease 2019 (COVID-19) pandemic severely challenges public health and necessitates the need for increasing our understanding of COVID-19 pathogenesis, especially host factors facilitating virus infection and propagation. The aim of this study was to investigate key factors for cellular susceptibility to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection in the ocular surface cells. Methods: We combined co-expression and SARS-CoV-2 interactome network to predict key genes at COVID-19 in ocular infection based on the premise that genes underlying a disease are often functionally related and functionally related genes are often co-expressed. Results: The co-expression network was constructed by mapping the well-known angiotensin converting enzyme (ACE2), TMPRSS2, and host susceptibility genes implicated in COVID-19 genomewide association study (GWAS) onto a cornea, retinal pigment epithelium, and lung. We found a significant co-expression module of these genes in the cornea, revealing that cornea is potential extra-respiratory entry portal of SARS-CoV-2. Strikingly, both co-expression and interaction networks show a significant enrichment in mitochondrial function, which are the hub of cellular oxidative homeostasis, inflammation, and innate immune response. We identified a corneal mitochondrial susceptibility module (CMSM) of 14 mitochondrial genes by integrating ACE2 co-expression cluster and SARS-CoV-2 interactome. The gene ECSIT, as a cytosolic adaptor protein involved in inflammatory responses, exhibits the strongest correlation with ACE2 in CMSM, which has shown to be an important risk factor for SARS-CoV-2 infection and prognosis. Conclusions: Our co-expression and protein interaction network analysis uncover that the mitochondrial function related genes in cornea contribute to the dissection of COVID-19 susceptibility and potential therapeutic interventions.


Assuntos
Betacoronavirus , Córnea/metabolismo , Infecções por Coronavirus/genética , Regulação da Expressão Gênica , Genes Mitocondriais/genética , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , RNA/genética , Linhagem Celular , Córnea/patologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Humanos , Pandemias , Peptidil Dipeptidase A/biossíntese , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo
19.
Rev Cardiovasc Med ; 21(3): 365-384, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-33070542

RESUMO

Angiotensin-converting enzyme 2 (ACE2), the host cell-binding site for SAR-CoV-2, poses two-fold drug development problems. First, the role of ACE2 itself is still a matter of investigation, and no specific drugs are available targeting ACE2. Second, as a consequence of SARS-CoV-2 interaction with ACE2, there is an impairment of the renin-angiotensin system (RAS) involved in the functioning of vital organs like the heart, kidney, brain, and lungs. In developing antiviral drugs for COVID-19, ACE2, RNA-dependent RNA polymerase (RdRp), and the specific enzymes involved in the viral and cellular gene expression have been the primary targets. SARS-CoV-2 being a new virus with unusually high mortality, there has been a need to get medicines in an emergency, and the drug repurposing has been a primary strategy. Considering extensive mortality and morbidity throughout the world, we have made a maiden attempt to discover the drugs interacting with RAS and identify the lead compounds from herbal plants using molecular docking. Both host ACE2 and viral RNA-dependent RNA polymerase (RdRp) and ORF8 appear to be the primary targets for the treatment of COVID-19. While the drug repurposing of currently approved drugs seems to be one strategy for the treatment of COVID-19, purposing phytochemicals may be another essential strategy for discovering lead compounds. Using in silico molecular docking, we have identified a few phytochemicals that may provide insights into designing herbal and synthetic therapeutics to treat COVID-19.


Assuntos
Betacoronavirus , Infecções por Coronavirus/terapia , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/terapia , Antivirais , Infecções por Coronavirus/metabolismo , Humanos , Peptidil Dipeptidase A/efeitos dos fármacos , Pneumonia Viral/metabolismo
20.
Clin Lab ; 66(10)2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33073969

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an emerging global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 mainly affects the tissues expressing angiotensinconverting enzyme 2 (ACE2). ACE2 is used as a receptor for the virus to enter the cells. Once SARS-CoV-2 enters the cells, it leads to further events through signaling pathways. This pathophysiological condition can appear as changes in laboratory tests. METHOD: However, the lack of studies in this area is strongly felt. The present study was conducted to review the most common abnormalities in laboratory tests caused by COVID-19 and their related molecular pathways and outcomes. RESULTS: It showed that the levels of IL-6, CRP, PCT, AST/ALT, bilirubin, ALP, GGT, LDH, ferritin, D-dimer, and neutrophils increased. Conversely, the levels of albumin and lymphocytes decreased. Since most of these parameters were related to hepatic function, their alterations indicated liver injury. CONCLUSIONS: Overall, the parameters CRP, D-dimer, and CBC are more important in diagnosis. Moreover, it seems that MAPK and NF-κB are the most frequent signaling pathways in which alterations may contribute to the pathogenesis of the virus. Altogether, our review encourages researchers to study signaling pathways as potential molecular targets to achieve effective treatment.


Assuntos
Betacoronavirus , Técnicas de Laboratório Clínico/métodos , Infecções por Coronavirus , Pandemias , Pneumonia Viral , Transdução de Sinais , Betacoronavirus/isolamento & purificação , Betacoronavirus/fisiologia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Erros de Diagnóstico/prevenção & controle , Descoberta de Drogas/métodos , Humanos , Pneumonia Viral/diagnóstico , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
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