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1.
Cells ; 10(6)2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200500

RESUMO

The host nucleocytoplasmic trafficking system is often hijacked by viruses to accomplish their replication and to suppress the host immune response. Viruses encode many factors that interact with the host nuclear transport receptors (NTRs) and the nucleoporins of the nuclear pore complex (NPC) to access the host nucleus. In this review, we discuss the viral factors and the host factors involved in the nuclear import and export of viral components. As nucleocytoplasmic shuttling is vital for the replication of many viruses, we also review several drugs that target the host nuclear transport machinery and discuss their feasibility for use in antiviral treatment.


Assuntos
Núcleo Celular/metabolismo , Núcleo Celular/virologia , SARS-CoV-2/fisiologia , Fenômenos Fisiológicos Virais , Replicação Viral/fisiologia , Transporte Ativo do Núcleo Celular/fisiologia , COVID-19/metabolismo , COVID-19/virologia , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Internalização do Vírus , Vírus/patogenicidade
2.
Int J Mol Sci ; 22(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34205975

RESUMO

High-density lipoproteins (HDLs) are a class of blood particles, principally involved in mediating reverse cholesterol transport from peripheral tissue to liver. Omics approaches have identified crucial mediators in the HDL proteomic and lipidomic profile, which are involved in distinct pleiotropic functions. Besides their role as cholesterol transporter, HDLs display anti-inflammatory, anti-apoptotic, anti-thrombotic, and anti-infection properties. Experimental and clinical studies have unveiled significant changes in both HDL serum amount and composition that lead to dysregulated host immune response and endothelial dysfunction in the course of sepsis. Most SARS-Coronavirus-2-infected patients admitted to the intensive care unit showed common features of sepsis disease, such as the overwhelmed systemic inflammatory response and the alterations in serum lipid profile. Despite relevant advances, episodes of mild to moderate acute kidney injury (AKI), occurring during systemic inflammatory diseases, are associated with long-term complications, and high risk of mortality. The multi-faceted relationship of kidney dysfunction with dyslipidemia and inflammation encourages to deepen the clarification of the mechanisms connecting these elements. This review analyzes the multifaced roles of HDL in inflammatory diseases, the renal involvement in lipid metabolism, and the novel potential HDL-based therapies.


Assuntos
COVID-19/patologia , Lipoproteínas HDL/metabolismo , Sepse/patologia , Injúria Renal Aguda/etiologia , COVID-19/complicações , COVID-19/metabolismo , COVID-19/virologia , Colesterol/metabolismo , Proteínas do Sistema Complemento/metabolismo , Humanos , Metabolismo dos Lipídeos , Lipoproteínas HDL/química , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/fisiologia , Sepse/complicações , Sepse/metabolismo , Internalização do Vírus
3.
Crit Care ; 25(1): 234, 2021 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-34217339

RESUMO

BACKGROUND: The coronavirus disease 2019 (COVID-19) has induced a worldwide epidemiological event with a high infectivity and mortality. However, the predicting biomarkers and their potential mechanism in the progression of COVID-19 are not well known. OBJECTIVE: The aim of this study is to identify the candidate predictors of COVID-19 and investigate their underlying mechanism. METHODS: The retrospective study was conducted to identify the potential laboratory indicators with prognostic values of COVID-19 disease. Then, the prognostic nomogram was constructed to predict the overall survival of COVID-19 patients. Additionally, the scRNA-seq data of BALF and PBMCs from COVID-19 patients were downloaded to investigate the underlying mechanism of the most important prognostic indicators in lungs and peripherals, respectively. RESULTS: In total, 304 hospitalized adult COVID-19 patients in Wuhan Jinyintan Hospital were included in the retrospective study. CEA was the only laboratory indicator with significant difference in the univariate (P < 0.001) and multivariate analysis (P = 0.020). The scRNA-seq data of BALF and PBMCs from COVID-19 patients were downloaded to investigate the underlying mechanism of CEA in lungs and peripherals, respectively. The results revealed the potential roles of CEA were significantly distributed in type II pneumocytes of BALF and developing neutrophils of PBMCs, participating in the progression of COVID-19 by regulating the cell-cell communication. CONCLUSION: This study identifies the prognostic roles of CEA in COVID-19 patients and implies the potential roles of CEACAM8-CEACAM6 in the progression of COVID-19 by regulating the cell-cell communication of developing neutrophils and type II pneumocyte.


Assuntos
COVID-19/metabolismo , Antígeno Carcinoembrionário/metabolismo , Pneumonia Viral/metabolismo , Adulto , Idoso , Biomarcadores/metabolismo , Líquido da Lavagem Broncoalveolar/química , COVID-19/mortalidade , Comunicação Celular , China/epidemiologia , Progressão da Doença , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Nomogramas , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , SARS-CoV-2 , Análise de Sobrevida
4.
Front Endocrinol (Lausanne) ; 12: 644055, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220703

RESUMO

Objective: We aimed to measure insulin-like growth factor 1 (IGF1) and growth hormone (GH) in critically and non-critically ill patients with Covid-19 and assess them vis-a-vis clinical and laboratory parameters and prognostic tools. Subjects and Methods: We included patients who were admitted to the wards or the ICU of the largest Covid-19 referral hospital in Greece; patients with non-Covid-19 pneumonia served as controls. Apart from the routine laboratory work-up for Covid-19 we measured GH and IGF1 (and calculated normalized IGF-1 values as standard deviation scores; SDS), after blood sampling upon admission to the wards or the ICU. Results: We studied 209 critically and non-critically ill patients with Covid-19 and 39 control patients. Patients with Covid-19 who were ICU non-survivors were older and presented with a worse hematological/biochemical profile (including white blood cell count, troponin, glucose, aminotransferases and lactate dehydrogenase) compared to ICU survivors or Covid-19 survivors in the wards. Overall, IGF-1 SDS was higher in Covid-19 survivors compared to non-survivors (-0.96 ± 1.89 vs -2.05 ± 2.48, respectively, p=0.030). No significant differences were noted in GH between the groups. Nevertheless, in critically ill patients with Covid-19, the prognostic value of IGF-1 (raw data), IGF-1 (SDS) and GH for survival/non-survival was on a par with that of APACHE II and SOFA (with a marginal difference between GH and SOFA). Conclusion: In conclusion, our findings suggest that there might be an association between low IGF1 (and possibly GH) and poor outcome in patients with Covid-19.


Assuntos
COVID-19/metabolismo , COVID-19/patologia , Estado Terminal , Hormônio do Crescimento Humano/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/diagnóstico , COVID-19/mortalidade , Estudos de Casos e Controles , Estado Terminal/mortalidade , Feminino , Grécia/epidemiologia , Hospitalização/estatística & dados numéricos , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Prognóstico , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Sobreviventes/estatística & dados numéricos
5.
Arch Iran Med ; 24(5): 419-426, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-34196208

RESUMO

BACKGROUND: The pathogenesis of the COVID19 pandemic, that has killed one million nine hundred people and infected more the 90 million until end of 2020, has been studied by many researchers. Here, we try to explain its biological behavior based on our recent autopsy information and review of literature. METHODS: In this study, patients with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) result were considered eligible for enrollment. Histopathological examinations were done on 13 people who were hospitalized in Afzalipour hospital, Kerman, Iran. Clinical and laboratory data were reviewed. Tissue examination was done by light microscopy, immunohistochemistry and electron microscopy. RESULTS: The most frequent co-morbidity in the patients was cardiovascular disease. The common initial symptoms of COVID-19 infection were dyspnea and cough. In all cases, the number of white blood cells was higher than the normal range. Common histopathological findings were variable degrees of vasculitis as degenerative to necrotic changes of endothelium and trafficking of inflammatory cells in the vessel wall with fibrinoid necrosis. Tissue damage included interstitial acute inflammatory cells reaction with degenerative to necrotic changes of the parenchymal cells. CD34 and Factor VIII immunohistochemistry staining showed endothelial cell degeneration to necrosis at the vessel wall and infiltration by inflammatory cells. Electron microscopic features confirmed the degenerative damages in the endothelial cells. CONCLUSION: Our histopathological studies suggest that the main focus of the viral damage is the endothelial cells (endotheliopathica) in involved organs. Also, our findings suggest that degeneration of leukocytes occurs at the site of inflammation and release of cytokines (leukocytoclastica) resulting in a cytokine storm.


Assuntos
COVID-19/complicações , COVID-19/patologia , Células Endoteliais/patologia , Leucócitos/patologia , Adulto , Idoso , COVID-19/metabolismo , Estudos de Coortes , Citocinas/metabolismo , Feminino , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Pericardite/patologia , Pericardite/virologia , Dermatopatias/patologia , Dermatopatias/virologia
7.
Front Endocrinol (Lausanne) ; 12: 644055, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1295630

RESUMO

Objective: We aimed to measure insulin-like growth factor 1 (IGF1) and growth hormone (GH) in critically and non-critically ill patients with Covid-19 and assess them vis-a-vis clinical and laboratory parameters and prognostic tools. Subjects and Methods: We included patients who were admitted to the wards or the ICU of the largest Covid-19 referral hospital in Greece; patients with non-Covid-19 pneumonia served as controls. Apart from the routine laboratory work-up for Covid-19 we measured GH and IGF1 (and calculated normalized IGF-1 values as standard deviation scores; SDS), after blood sampling upon admission to the wards or the ICU. Results: We studied 209 critically and non-critically ill patients with Covid-19 and 39 control patients. Patients with Covid-19 who were ICU non-survivors were older and presented with a worse hematological/biochemical profile (including white blood cell count, troponin, glucose, aminotransferases and lactate dehydrogenase) compared to ICU survivors or Covid-19 survivors in the wards. Overall, IGF-1 SDS was higher in Covid-19 survivors compared to non-survivors (-0.96 ± 1.89 vs -2.05 ± 2.48, respectively, p=0.030). No significant differences were noted in GH between the groups. Nevertheless, in critically ill patients with Covid-19, the prognostic value of IGF-1 (raw data), IGF-1 (SDS) and GH for survival/non-survival was on a par with that of APACHE II and SOFA (with a marginal difference between GH and SOFA). Conclusion: In conclusion, our findings suggest that there might be an association between low IGF1 (and possibly GH) and poor outcome in patients with Covid-19.


Assuntos
COVID-19/metabolismo , COVID-19/patologia , Estado Terminal , Hormônio do Crescimento Humano/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/diagnóstico , COVID-19/mortalidade , Estudos de Casos e Controles , Estado Terminal/mortalidade , Feminino , Grécia/epidemiologia , Hospitalização/estatística & dados numéricos , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Prognóstico , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Sobreviventes/estatística & dados numéricos
8.
Cells ; 10(6)2021 06 07.
Artigo em Inglês | MEDLINE | ID: covidwho-1259432

RESUMO

The host nucleocytoplasmic trafficking system is often hijacked by viruses to accomplish their replication and to suppress the host immune response. Viruses encode many factors that interact with the host nuclear transport receptors (NTRs) and the nucleoporins of the nuclear pore complex (NPC) to access the host nucleus. In this review, we discuss the viral factors and the host factors involved in the nuclear import and export of viral components. As nucleocytoplasmic shuttling is vital for the replication of many viruses, we also review several drugs that target the host nuclear transport machinery and discuss their feasibility for use in antiviral treatment.


Assuntos
Núcleo Celular/metabolismo , Núcleo Celular/virologia , SARS-CoV-2/fisiologia , Fenômenos Fisiológicos Virais , Replicação Viral/fisiologia , Transporte Ativo do Núcleo Celular/fisiologia , COVID-19/metabolismo , COVID-19/virologia , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Internalização do Vírus , Vírus/patogenicidade
9.
Int J Mol Sci ; 22(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: covidwho-1256567

RESUMO

High-density lipoproteins (HDLs) are a class of blood particles, principally involved in mediating reverse cholesterol transport from peripheral tissue to liver. Omics approaches have identified crucial mediators in the HDL proteomic and lipidomic profile, which are involved in distinct pleiotropic functions. Besides their role as cholesterol transporter, HDLs display anti-inflammatory, anti-apoptotic, anti-thrombotic, and anti-infection properties. Experimental and clinical studies have unveiled significant changes in both HDL serum amount and composition that lead to dysregulated host immune response and endothelial dysfunction in the course of sepsis. Most SARS-Coronavirus-2-infected patients admitted to the intensive care unit showed common features of sepsis disease, such as the overwhelmed systemic inflammatory response and the alterations in serum lipid profile. Despite relevant advances, episodes of mild to moderate acute kidney injury (AKI), occurring during systemic inflammatory diseases, are associated with long-term complications, and high risk of mortality. The multi-faceted relationship of kidney dysfunction with dyslipidemia and inflammation encourages to deepen the clarification of the mechanisms connecting these elements. This review analyzes the multifaced roles of HDL in inflammatory diseases, the renal involvement in lipid metabolism, and the novel potential HDL-based therapies.


Assuntos
COVID-19/patologia , Lipoproteínas HDL/metabolismo , Sepse/patologia , Injúria Renal Aguda/etiologia , COVID-19/complicações , COVID-19/metabolismo , COVID-19/virologia , Colesterol/metabolismo , Proteínas do Sistema Complemento/metabolismo , Humanos , Metabolismo dos Lipídeos , Lipoproteínas HDL/química , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/fisiologia , Sepse/complicações , Sepse/metabolismo , Internalização do Vírus
10.
Crit Care ; 25(1): 234, 2021 07 03.
Artigo em Inglês | MEDLINE | ID: covidwho-1295477

RESUMO

BACKGROUND: The coronavirus disease 2019 (COVID-19) has induced a worldwide epidemiological event with a high infectivity and mortality. However, the predicting biomarkers and their potential mechanism in the progression of COVID-19 are not well known. OBJECTIVE: The aim of this study is to identify the candidate predictors of COVID-19 and investigate their underlying mechanism. METHODS: The retrospective study was conducted to identify the potential laboratory indicators with prognostic values of COVID-19 disease. Then, the prognostic nomogram was constructed to predict the overall survival of COVID-19 patients. Additionally, the scRNA-seq data of BALF and PBMCs from COVID-19 patients were downloaded to investigate the underlying mechanism of the most important prognostic indicators in lungs and peripherals, respectively. RESULTS: In total, 304 hospitalized adult COVID-19 patients in Wuhan Jinyintan Hospital were included in the retrospective study. CEA was the only laboratory indicator with significant difference in the univariate (P < 0.001) and multivariate analysis (P = 0.020). The scRNA-seq data of BALF and PBMCs from COVID-19 patients were downloaded to investigate the underlying mechanism of CEA in lungs and peripherals, respectively. The results revealed the potential roles of CEA were significantly distributed in type II pneumocytes of BALF and developing neutrophils of PBMCs, participating in the progression of COVID-19 by regulating the cell-cell communication. CONCLUSION: This study identifies the prognostic roles of CEA in COVID-19 patients and implies the potential roles of CEACAM8-CEACAM6 in the progression of COVID-19 by regulating the cell-cell communication of developing neutrophils and type II pneumocyte.


Assuntos
COVID-19/metabolismo , Antígeno Carcinoembrionário/metabolismo , Pneumonia Viral/metabolismo , Adulto , Idoso , Biomarcadores/metabolismo , Líquido da Lavagem Broncoalveolar/química , COVID-19/mortalidade , Comunicação Celular , China/epidemiologia , Progressão da Doença , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Nomogramas , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , SARS-CoV-2 , Análise de Sobrevida
11.
Biomolecules ; 11(6)2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201172

RESUMO

The phytotherapeutic properties of Glycyrrhiza glabra (licorice) extract are mainly attributed to glycyrrhizin (GR) and glycyrrhetinic acid (GA). Among their possible pharmacological actions, the ability to act against viruses belonging to different families, including SARS coronavirus, is particularly important. With the COVID-19 emergency and the urgent need for compounds to counteract the pandemic, the antiviral properties of GR and GA, as pure substances or as components of licorice extract, attracted attention in the last year and supported the launch of two clinical trials. In silico docking studies reported that GR and GA may directly interact with the key players in viral internalization and replication such as angiotensin-converting enzyme 2 (ACE2), spike protein, the host transmembrane serine protease 2, and 3-chymotrypsin-like cysteine protease. In vitro data indicated that GR can interfere with virus entry by directly interacting with ACE2 and spike, with a nonspecific effect on cell and viral membranes. Additional anti-inflammatory and antioxidant effects of GR cannot be excluded. These multiple activities of GR and licorice extract are critically re-assessed in this review, and their possible role against the spread of the SARS-CoV-2 and the features of COVID-19 disease is discussed.


Assuntos
Anti-Inflamatórios/farmacologia , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Ácido Glicirretínico/farmacologia , Ácido Glicirrízico/farmacologia , SARS-CoV-2/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , COVID-19/metabolismo , Ácido Glicirretínico/uso terapêutico , Glycyrrhiza/química , Ácido Glicirrízico/uso terapêutico , Humanos , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Internalização do Vírus/efeitos dos fármacos
12.
Biomolecules ; 11(6)2021 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204735

RESUMO

The receptor for advanced glycation-end products (RAGE) is a multiligand receptor with a role in inflammatory and pulmonary pathologies. Hyperactivation of RAGE by its ligands has been reported to sustain inflammation and oxidative stress in common comorbidities of severe COVID-19. RAGE is essential to the deleterious effects of the renin-angiotensin system (RAS), which participates in infection and multiorgan injury in COVID-19 patients. Thus, RAGE might be a major player in severe COVID-19, and appears to be a useful therapeutic molecular target in infections by SARS-CoV-2. The role of RAGE gene polymorphisms in predisposing patients to severe COVID-19 is discussed. .


Assuntos
COVID-19/metabolismo , Inflamação/metabolismo , Estresse Oxidativo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Sistema Renina-Angiotensina , Animais , COVID-19/genética , COVID-19/patologia , Humanos , Inflamação/genética , Inflamação/patologia , Polimorfismo Genético , Receptor para Produtos Finais de Glicação Avançada/genética , Fatores de Risco , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença
13.
Sci Signal ; 14(690)2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230209

RESUMO

Inorganic polyphosphates (polyPs) are linear polymers composed of repeated phosphate (PO4 3-) units linked together by multiple high-energy phosphoanhydride bonds. In addition to being a source of energy, polyPs have cytoprotective and antiviral activities. Here, we investigated the antiviral activities of long-chain polyPs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In molecular docking analyses, polyPs interacted with several conserved amino acid residues in angiotensin-converting enzyme 2 (ACE2), the host receptor that facilitates virus entry, and in viral RNA-dependent RNA polymerase (RdRp). ELISA and limited proteolysis assays using nano- LC-MS/MS mapped polyP120 binding to ACE2, and site-directed mutagenesis confirmed interactions between ACE2 and SARS-CoV-2 RdRp and identified the specific amino acid residues involved. PolyP120 enhanced the proteasomal degradation of both ACE2 and RdRp, thus impairing replication of the British B.1.1.7 SARS-CoV-2 variant. We thus tested polyPs for functional interactions with the virus in SARS-CoV-2-infected Vero E6 and Caco2 cells and in primary human nasal epithelial cells. Delivery of a nebulized form of polyP120 reduced the amounts of viral positive-sense genomic and subgenomic RNAs, of RNA transcripts encoding proinflammatory cytokines, and of viral structural proteins, thereby presenting SARS-CoV-2 infection in cells in vitro.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Polifosfatos/farmacologia , SARS-CoV-2/efeitos dos fármacos , Administração por Inalação , Sequência de Aminoácidos , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Antivirais/administração & dosagem , Antivirais/química , COVID-19/metabolismo , COVID-19/virologia , Células CACO-2 , Chlorocebus aethiops , RNA-Polimerase RNA-Dependente de Coronavírus/química , RNA-Polimerase RNA-Dependente de Coronavírus/genética , RNA-Polimerase RNA-Dependente de Coronavírus/metabolismo , Citocinas/metabolismo , Células HEK293 , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Técnicas In Vitro , Modelos Biológicos , Simulação de Acoplamento Molecular , Nebulizadores e Vaporizadores , Polifosfatos/administração & dosagem , Polifosfatos/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Domínios e Motivos de Interação entre Proteínas , Proteólise/efeitos dos fármacos , RNA Viral/genética , RNA Viral/metabolismo , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Homologia de Sequência de Aminoácidos , Transdução de Sinais/efeitos dos fármacos , Células Vero , Replicação Viral/efeitos dos fármacos
14.
Nutrients ; 13(6)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207745

RESUMO

It has recently been hypothesized that vitamin K could play a role in COVID-19. We aimed to test the hypotheses that low vitamin K status is a common characteristic of patients hospitalized with COVID-19 compared to population controls and that low vitamin K status predicts mortality in COVID-19 patients. In a cohort of 138 COVID-19 patients and 138 population controls, we measured plasma dephosphorylated-uncarboxylated Matrix Gla Protein (dp-ucMGP), which reflects the functional vitamin K status in peripheral tissue. Forty-three patients died within 90 days from admission. In patients, levels of dp-ucMGP differed significantly between survivors (mean 877; 95% CI: 778; 995) and non-survivors (mean 1445; 95% CI: 1148; 1820). Furthermore, levels of dp-ucMGP (pmol/L) were considerably higher in patients (mean 1022; 95% CI: 912; 1151) compared to controls (mean 509; 95% CI: 485; 540). Cox regression survival analysis showed that increasing levels of dp-ucMGP (reflecting low vitamin K status) were associated with higher mortality risk (sex- and age-adjusted hazard ratio per doubling of dp-ucMGP was 1.49, 95% CI: 1.03; 2.24). The association attenuated and became statistically insignificant after adjustment for co-morbidities (sex, age, CVD, diabetes, BMI, and eGFR adjusted hazard ratio per doubling of dp-ucMGP was 1.22, 95% CI: 0.82; 1.80). In conclusion, we found that low vitamin K status was associated with mortality in patients with COVID-19 in sex- and age-adjusted analyses, but not in analyses additionally adjusted for co-morbidities. Randomized clinical trials would be needed to clarify a potential role, if any, of vitamin K in the course of COVID-19.


Assuntos
COVID-19/mortalidade , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Hospitalização , Deficiência de Vitamina K/mortalidade , Vitamina K/sangue , Adulto , Idoso , Biomarcadores/sangue , Coagulação Sanguínea , COVID-19/complicações , COVID-19/metabolismo , Proteínas de Ligação ao Cálcio/sangue , Estudos de Coortes , Proteínas da Matriz Extracelular/sangue , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Análise de Regressão , SARS-CoV-2 , Trombose/metabolismo , Deficiência de Vitamina K/sangue , Deficiência de Vitamina K/complicações , Adulto Jovem
15.
Nat Commun ; 12(1): 4068, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210968

RESUMO

SARS-CoV-2 attacks various organs, most destructively the lung, and cellular entry requires two host cell surface proteins: ACE2 and TMPRSS2. Downregulation of one or both of these is thus a potential therapeutic approach for COVID-19. TMPRSS2 is a known target of the androgen receptor, a ligand-activated transcription factor; androgen receptor activation increases TMPRSS2 levels in various tissues, most notably prostate. We show here that treatment with the antiandrogen enzalutamide-a well-tolerated drug widely used in advanced prostate cancer-reduces TMPRSS2 levels in human lung cells and in mouse lung. Importantly, antiandrogens significantly reduced SARS-CoV-2 entry and infection in lung cells. In support of this experimental data, analysis of existing datasets shows striking co-expression of AR and TMPRSS2, including in specific lung cell types targeted by SARS-CoV-2. Together, the data presented provides strong evidence to support clinical trials to assess the efficacy of antiandrogens as a treatment option for COVID-19.


Assuntos
Antagonistas de Androgênios/farmacologia , Benzamidas/farmacologia , COVID-19/tratamento farmacológico , Nitrilas/farmacologia , Feniltioidantoína/farmacologia , Serina Endopeptidases/metabolismo , Internalização do Vírus/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/síntese química , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , COVID-19/metabolismo , COVID-19/virologia , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Pulmão/metabolismo , Pulmão/virologia , Masculino , Camundongos , SARS-CoV-2/efeitos dos fármacos , Serina Endopeptidases/genética
16.
Curr Rheumatol Rep ; 23(8): 63, 2021 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-34216297

RESUMO

PURPOSE: Myositis as a rare manifestation of COVID-19 is only recently being reported. This review examines the current literature on COVID-19-induced myositis focusing on etiopathogenesis, clinical presentations, diagnostic practices, and therapeutic challenges with immunosuppression, and the difficulties experienced by rheumatologists in established myositis in the COVID-19 era. RECENT FINDINGS: COVID-19 is associated with a viral myositis attributable to direct myocyte invasion or induction of autoimmunity. COVID-19-induced myositis may be varied in presentation, from typical dermatomyositis to rhabdomyolysis, and a paraspinal affliction with back pain. It may or may not present with acute exponential elevations of enzyme markers such as creatine kinase (CK). Virus-mediated muscle inflammation is attributed to ACE2 (angiotensin-converting enzyme) receptor-mediated direct entry and affliction of muscle fibers, leading on to innate and adaptive immune activation. A greater recognition of the stark similarity between anti-MDA5-positive myositis with COVID-19 has thrown researchers into the alley of exploration - finding common etiopathogenic basis as well as therapeutic strategies. For patients with established myositis, chronic care was disrupted during the pandemic with several logistic challenges and treatment dilemmas leading to high flare rates. Teleconsultation bridged the gap while ushering in an era of patient-led care with the digital transition to tools of remote disease assessment. COVID-19 has brought along greater insight into unique manifestations of COVID-19-related myositis, ranging from direct virus-induced muscle disease to triggered autoimmunity and other etiopathogenic links to explore. A remarkable shift in the means of delivering chronic care has led patients and caregivers worldwide to embrace a virtual shift with teleconsultation and opened doorways to a new era of patient-led care.


Assuntos
COVID-19/fisiopatologia , Miosite/fisiopatologia , Rabdomiólise/fisiopatologia , Imunidade Adaptativa/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Autoanticorpos/imunologia , Dor nas Costas/etiologia , COVID-19/complicações , COVID-19/imunologia , COVID-19/metabolismo , Creatina Quinase/metabolismo , Dermatomiosite/etiologia , Dermatomiosite/imunologia , Dermatomiosite/metabolismo , Dermatomiosite/fisiopatologia , Humanos , Imunidade Inata/imunologia , Helicase IFIH1 Induzida por Interferon/imunologia , Miastenia Gravis/etiologia , Miastenia Gravis/imunologia , Miastenia Gravis/metabolismo , Miastenia Gravis/fisiopatologia , Miosite/etiologia , Miosite/imunologia , Miosite/metabolismo , Músculos Paraespinais/fisiopatologia , Receptores de Coronavírus/metabolismo , Rabdomiólise/etiologia , Rabdomiólise/imunologia , Rabdomiólise/metabolismo , SARS-CoV-2
17.
Bioengineered ; 12(1): 2274-2287, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34077310

RESUMO

Xuebijing Injection have been found to improve the clinical symptoms of COVID-19 and alleviate disease severity, but the mechanisms are currently unclear. This study aimed to investigate the potential molecular targets and mechanisms of the Xuebijing injection in treating COVID-19 via network pharmacology and molecular docking analysis. The main active ingredients and therapeutic targets of the Xuebijing injection, and the pathogenic targets of COVID-19 were screened using the TCMSP, UniProt, and GeneCard databases. According to the 'Drug-Ingredients-Targets-Disease' network built by STRING and Cytoscape, AKT1 was identified as the core target, and baicalein, luteolin, and quercetin were identified as the active ingredients of the Xuebijing injection in connection with AKT1. R language was used for enrichment analysis that predict the mechanisms by which the Xuebijing injection may inhibit lipopolysaccharide-mediated inflammatory response, modulate NOS activity, and regulate the TNF signal pathway by affecting the role of AKT1. Based on the results of network pharmacology, a molecular docking was performed with AKT1 and the three active ingredients, the results indicated that all three active ingredients could stably bind with AKT1. These findings identify potential molecular mechanisms by which Xuebijing Injection inhibit COVID-19 by acting on AKT1.


Assuntos
Antivirais/administração & dosagem , COVID-19/tratamento farmacológico , COVID-19/metabolismo , Medicamentos de Ervas Chinesas/administração & dosagem , SARS-CoV-2 , Antivirais/farmacocinética , Antivirais/farmacologia , Engenharia Biomédica , Medicamentos de Ervas Chinesas/farmacocinética , Medicamentos de Ervas Chinesas/farmacologia , Flavanonas/administração & dosagem , Humanos , Injeções , Luteolina/administração & dosagem , Simulação de Acoplamento Molecular , Pandemias , Ligação Proteica , Mapas de Interação de Proteínas , Proteínas Proto-Oncogênicas c-akt/química , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quercetina/administração & dosagem , Transdução de Sinais/efeitos dos fármacos
18.
Molecules ; 26(10)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064568

RESUMO

Resveratrol is a phytoalexin produced by many plants as a defense mechanism against stress-inducing conditions. The richest dietary sources of resveratrol are berries and grapes, their juices and wines. Good bioavailability of resveratrol is not reflected in its high biological activity in vivo because of resveratrol isomerization and its poor solubility in aqueous solutions. Proteins, cyclodextrins and nanomaterials have been explored as innovative delivery vehicles for resveratrol to overcome this limitation. Numerous in vitro and in vivo studies demonstrated beneficial effects of resveratrol in cardiovascular diseases (CVD). Main beneficial effects of resveratrol intake are cardioprotective, anti-hypertensive, vasodilatory, anti-diabetic, and improvement of lipid status. As resveratrol can alleviate the numerous factors associated with CVD, it has potential as a functional supplement to reduce COVID-19 illness severity in patients displaying poor prognosis due to cardio-vascular complications. Resveratrol was shown to mitigate the major pathways involved in the pathogenesis of SARS-CoV-2 including regulation of the renin-angiotensin system and expression of angiotensin-converting enzyme 2, stimulation of immune system and downregulation of pro-inflammatory cytokine release. Therefore, several studies already have anticipated potential implementation of resveratrol in COVID-19 treatment. Regular intake of a resveratrol rich diet, or resveratrol-based complementary medicaments, may contribute to a healthier cardio-vascular system, prevention and control of CVD, including COVID-19 disease related complications of CVD.


Assuntos
COVID-19/tratamento farmacológico , Doenças Cardiovasculares , Resveratrol , SARS-CoV-2/metabolismo , Disponibilidade Biológica , COVID-19/complicações , COVID-19/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Humanos , Resveratrol/farmacocinética , Resveratrol/uso terapêutico
19.
Molecules ; 26(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34068970

RESUMO

Due to the complicated pathogenic pathways of coronavirus disease 2019 (COVID-19), related medicinal therapies have remained a clinical challenge. COVID-19 highlights the urgent need to develop mechanistic pathogenic pathways and effective agents for preventing/treating future epidemics. As a result, the destructive pathways of COVID-19 are in the line with clinical symptoms induced by severe acute coronary syndrome (SARS), including lung failure and pneumonia. Accordingly, revealing the exact signaling pathways, including inflammation, oxidative stress, apoptosis, and autophagy, as well as relative representative mediators such as tumor necrosis factor-α (TNF-α), nuclear factor erythroid 2-related factor 2 (Nrf2), Bax/caspases, and Beclin/LC3, respectively, will pave the road for combating COVID-19. Prevailing host factors and multiple steps of SARS-CoV-2 attachment/entry, replication, and assembly/release would be hopeful strategies against COVID-19. This is a comprehensive review of the destructive signaling pathways and host-pathogen interaction of SARS-CoV-2, as well as related therapeutic targets and treatment strategies, including potential natural products-based candidates.


Assuntos
Antivirais/uso terapêutico , Produtos Biológicos/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , SARS-CoV-2/fisiologia , Transdução de Sinais/efeitos dos fármacos , Humanos
20.
Crit Care ; 25(1): 186, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34074313

RESUMO

BACKGROUND: In acute respiratory distress syndrome (ARDS), extravascular lung water index (EVLWi) and pulmonary vascular permeability index (PVPI) measured by transpulmonary thermodilution reflect the degree of lung injury. Whether EVLWi and PVPI are different between non-COVID-19 ARDS and the ARDS due to COVID-19 has never been reported. We aimed at comparing EVLWi, PVPI, respiratory mechanics and hemodynamics in patients with COVID-19 ARDS vs. ARDS of other origin. METHODS: Between March and October 2020, in an observational study conducted in intensive care units from three university hospitals, 60 patients with COVID-19-related ARDS monitored by transpulmonary thermodilution were compared to the 60 consecutive non-COVID-19 ARDS admitted immediately before the COVID-19 outbreak between December 2018 and February 2020. RESULTS: Driving pressure was similar between patients with COVID-19 and non-COVID-19 ARDS, at baseline as well as during the study period. Compared to patients without COVID-19, those with COVID-19 exhibited higher EVLWi, both at the baseline (17 (14-21) vs. 15 (11-19) mL/kg, respectively, p = 0.03) and at the time of its maximal value (24 (18-27) vs. 21 (15-24) mL/kg, respectively, p = 0.01). Similar results were observed for PVPI. In COVID-19 patients, the worst ratio between arterial oxygen partial pressure over oxygen inspired fraction was lower (81 (70-109) vs. 100 (80-124) mmHg, respectively, p = 0.02) and prone positioning and extracorporeal membrane oxygenation (ECMO) were more frequently used than in patients without COVID-19. COVID-19 patients had lower maximal lactate level and maximal norepinephrine dose than patients without COVID-19. Day-60 mortality was similar between groups (57% vs. 65%, respectively, p = 0.45). The maximal value of EVLWi and PVPI remained independently associated with outcome in the whole cohort. CONCLUSION: Compared to ARDS patients without COVID-19, patients with COVID-19 had similar lung mechanics, but higher EVLWi and PVPI values from the beginning of the disease. This was associated with worse oxygenation and with more requirement of prone positioning and ECMO. This is compatible with the specific lung inflammation and severe diffuse alveolar damage related to COVID-19. By contrast, patients with COVID-19 had fewer hemodynamic derangement. Eventually, mortality was similar between groups. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: ClinicalTrials.gov (NCT04337983). Registered 30 March 2020-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04337983 .


Assuntos
COVID-19/metabolismo , Permeabilidade Capilar , Água Extravascular Pulmonar/metabolismo , Síndrome do Desconforto Respiratório/metabolismo , Índice de Gravidade de Doença , COVID-19/complicações , Hemodinâmica , Humanos , Pulmão/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica/métodos , Prognóstico , Edema Pulmonar/metabolismo , Termodiluição
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