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1.
Cardiovasc Toxicol ; 21(6): 498-503, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33835386

RESUMO

In March 2019 began the global pandemic COVID-19 caused by the new Coronavirus SARS-CoV-2. The first cases of SARS-CoV-2 infection occurred in November-19 in Wuhan, China. The preventive measures taken did not prevent the rapid spread of the virus to all countries around the world. To date, there are about 2.54 million deaths, effective vaccines are in clinical trials. SARS-CoV-2 uses the ACE-2 protein as an intracellular gateway. ACE-2 is a key component of the Renin Angiotensin (RAS) system, a key regulator of cardiovascular function. Considering the key role of ACE-2 in COVID-19 infection, both as an entry receptor and as a protective role, especially for the respiratory tract, and considering the variations of ACE-2 and ACE during the stages of viral infection, it is clear the important role that the pharmacological regulation of RAS and ACE-2 can assume. This biological knowledge suggests different pharmacological approaches to treat COVID-19 by modulating RAS, ACE-2 and the ACE/ACE2 balance that we describe in this article.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Antivirais/uso terapêutico , Pulmão/efeitos dos fármacos , Receptores Virais/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , /efeitos dos fármacos , /metabolismo , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Antivirais/efeitos adversos , /virologia , Interações Hospedeiro-Patógeno , Humanos , Pulmão/enzimologia , Pulmão/virologia , Proteínas Recombinantes/uso terapêutico , /patogenicidade , Internalização do Vírus
2.
Biomolecules ; 11(3)2021 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800947

RESUMO

Many individuals infected with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) develop no or only mild symptoms, but some can go on onto develop a spectrum of pathologies including pneumonia, acute respiratory distress syndrome, respiratory failure, systemic inflammation, and multiorgan failure. Many pathogens, viral and non-viral, can elicit these pathologies, which justifies reconsidering whether the target of therapeutic approaches to fight pathogen infections should be (a) the pathogen itself, (b) the pathologies elicited by the pathogen interaction with the human host, or (c) a combination of both. While little is known about the immunopathology of SARS-CoV-2, it is well-established that the above-mentioned pathologies are associated with hyper-inflammation, tissue damage, and the perturbation of target organ metabolism. Mounting evidence has shown that these processes are regulated by endoproteinases (particularly, matrix metalloproteinases (MMPs)). Here, we review what is known about the roles played by MMPs in the development of COVID-19 and postulate a mechanism by which MMPs could influence energy metabolism in target organs, such as the lung. Finally, we discuss the suitability of MMPs as therapeutic targets to increase the metabolic tolerance of the host to damage inflicted by the pathogen infection, with a focus on SARS-CoV-2.


Assuntos
/metabolismo , Pulmão/fisiopatologia , Metaloproteinases da Matriz/metabolismo , Proteínas Quinases/metabolismo , /metabolismo , /enzimologia , /virologia , Comorbidade , Citocinas/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Inflamação/metabolismo , Inflamação/patologia , Pulmão/enzimologia , Pulmão/metabolismo , Pulmão/virologia , Inibidores de Metaloproteinases de Matriz/farmacologia , /fisiopatologia , /patogenicidade , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
3.
PLoS One ; 16(3): e0248730, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33725024

RESUMO

COVID-19 (coronavirus disease 2019) patients exhibiting gastrointestinal symptoms are reported to have worse prognosis. Ace2 (angiotensin-converting enzyme 2), the gene encoding the host protein to which SARS-CoV-2 spike proteins bind, is expressed in the gut and therefore may be a target for preventing or reducing severity of COVID-19. Here we test the hypothesis that Ace2 expression in the gastrointestinal and respiratory tracts is modulated by the microbiome. We used quantitative PCR to profile Ace2 expression in germ-free mice, conventional raised specific pathogen-free mice, and gnotobiotic mice colonized with different microbiota. Intestinal Ace2 expression levels were significantly higher in germ-free mice compared to conventional mice. A similar trend was observed in the respiratory tract. Intriguingly, microbiota depletion via antibiotics partially recapitulated the germ-free phenotype, suggesting potential for microbiome-mediated regulation of Ace2 expression. Variability in intestinal Ace2 expression was observed in gnotobiotic mice colonized with different microbiota, partially attributable to differences in microbiome-encoded proteases and peptidases. Together, these data suggest that the microbiome may be one modifiable factor determining COVID-19 infection risk and disease severity.


Assuntos
/metabolismo , Colo/enzimologia , Microbioma Gastrointestinal , Intestino Delgado/enzimologia , Pulmão/enzimologia , Proteína da Polipose Adenomatosa do Colo/deficiência , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Feminino , Expressão Gênica , Interleucina-10/deficiência , Interleucina-10/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
5.
Anesthesiology ; 134(5): 792-808, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33721888

RESUMO

Acute respiratory distress syndrome is characterized by hypoxemia, altered alveolar-capillary permeability, and neutrophil-dominated inflammatory pulmonary edema. Despite decades of research, an effective drug therapy for acute respiratory distress syndrome remains elusive. The ideal pharmacotherapy for acute respiratory distress syndrome should demonstrate antiprotease activity and target injurious inflammatory pathways while maintaining host defense against infection. Furthermore, a drug with a reputable safety profile, low possibility of off-target effects, and well-known pharmacokinetics would be desirable. The endogenous 52-kd serine protease α1-antitrypsin has the potential to be a novel treatment option for acute respiratory distress syndrome. The main function of α1-antitrypsin is as an antiprotease, targeting neutrophil elastase in particular. However, studies have also highlighted the role of α1-antitrypsin in the modulation of inflammation and bacterial clearance. In light of the current SARS-CoV-2 pandemic, the identification of a treatment for acute respiratory distress syndrome is even more pertinent, and α1-antitrypsin has been implicated in the inflammatory response to SARS-CoV-2 infection.


Assuntos
Neutrófilos/efeitos dos fármacos , Proteínas Secretadas Inibidoras de Proteinases/administração & dosagem , alfa 1-Antitripsina/administração & dosagem , Animais , /enzimologia , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/imunologia , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Pulmão/imunologia , Neutrófilos/enzimologia , Neutrófilos/imunologia , Proteínas Secretadas Inibidoras de Proteinases/imunologia , /imunologia , alfa 1-Antitripsina/imunologia
6.
Science ; 371(6526): 265-270, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33446552

RESUMO

Removal of senescent cells (senolysis) has been proposed to be beneficial for improving age-associated pathologies, but the molecular pathways for such senolytic activity have not yet emerged. Here, we identified glutaminase 1 (GLS1) as an essential gene for the survival of human senescent cells. The intracellular pH in senescent cells was lowered by lysosomal membrane damage, and this lowered pH induced kidney-type glutaminase (KGA) expression. The resulting enhanced glutaminolysis induced ammonia production, which neutralized the lower pH and improved survival of the senescent cells. Inhibition of KGA-dependent glutaminolysis in aged mice eliminated senescent cells specifically and ameliorated age-associated organ dysfunction. Our results suggest that senescent cells rely on glutaminolysis, and its inhibition offers a promising strategy for inducing senolysis in vivo.


Assuntos
Envelhecimento/metabolismo , Senescência Celular/fisiologia , Glutaminase/metabolismo , Tecido Adiposo/enzimologia , Envelhecimento/genética , Amônia/metabolismo , Animais , Sobrevivência Celular , Senescência Celular/genética , Genes Essenciais , Glutaminase/genética , Humanos , Concentração de Íons de Hidrogênio , Pulmão/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pele/enzimologia
7.
Am J Physiol Heart Circ Physiol ; 319(3): H705-H721, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32762560

RESUMO

Myeloperoxidase (MPO)-derived hypochlorous (HOCl) reacts with membrane plasmalogens to yield α-chlorofatty aldehydes such as 2-chlorofatty aldehyde (2-ClFALD) and its metabolite 2-chlorofatty acid (2-ClFA). Recent studies showed that 2-ClFALD and 2-ClFA serve as mediators of the inflammatory responses to sepsis by as yet unknown mechanisms. Since no scavenger for chlorinated lipids is available and on the basis of the well-established role of the MPO/HOCl/chlorinated lipid axis in inflammatory responses, we hypothesized that treatment with MPO inhibitors (N-acetyl lysyltyrosylcysteine amide or 4-aminobenzoic acid hydrazide) would inhibit inflammation and proinflammatory mediator expression induced by cecal ligation and puncture (CLP). We used intravital microscopy to quantify in vivo inflammatory responses in Sham and CLP rats with or without MPO inhibition. Small intestines, mesenteries, and lungs were collected to assess changes in MPO-positive staining and lung injury, respectively, as well as free 2-ClFA and proinflammatory mediators levels. CLP caused neutrophil infiltration, 2-ClFA generation, acute lung injury, leukocyte-/platelet-endothelium interactions, mast cell activation (MCA), plasminogen activator inhibitor-1 (PAI-1) production, and the expression of several cytokines, chemokines, and vascular endothelial growth factor, changes that were reduced by MPO inhibition. Pretreatment with a PAI-1 inhibitor or MC stabilizer prevented CLP-induced leukocyte-endothelium interactions and MCA, and abrogated exogenous 2-ClFALD-induced inflammatory responses. Thus, we provide evidence that MPO instigates these inflammatory changes in CLP and that chlorinated lipids may serve as a mechanistic link between the enzymatic activity of MPO and PAI-1- and mast cell-dependent adhesive interactions, providing a rationale for new therapeutic interventions in sepsis.NEW & NOTEWORTHY Using two distinct myeloperoxidase (MPO) inhibitors, we show for the first time that MPO plays an important role in producing increases in free 2-chlorofatty aldehyde (2-ClFALD)-a powerful proinflammatory chlorinated lipid in plasma and intestine-a number of cytokines and other inflammatory mediators, leukocyte and platelet rolling and adhesion in postcapillary venules, and lung injury in a cecal ligation and puncture model of sepsis. In addition, the use of a plasminogen activator inhibitor-1 (PAI-1) inhibitor or a mast cell stabilizer prevented inflammatory responses in CLP-induced sepsis. PAI-1 inhibition also prevented the proinflammatory responses to exogenous 2-ClFALD superfusion. Thus, our study provides some of the first evidence that MPO-derived free 2-ClFA plays an important role in CLP-induced sepsis by a PAI-1- and mast cell-dependent mechanism.


Assuntos
Ceco/microbiologia , Ácidos Graxos/metabolismo , Ácido Hipocloroso/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/enzimologia , Peroxidase/metabolismo , Sepse/enzimologia , Aldeídos/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Ceco/cirurgia , Citocinas/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Inflamação/imunologia , Inflamação/microbiologia , Inflamação/prevenção & controle , Mediadores da Inflamação/antagonistas & inibidores , Intestino Delgado/enzimologia , Intestino Delgado/imunologia , Ligadura , Pulmão/enzimologia , Pulmão/imunologia , Mastócitos/enzimologia , Mastócitos/imunologia , Mesentério/enzimologia , Mesentério/imunologia , Peroxidase/antagonistas & inibidores , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Punções , Ratos Sprague-Dawley , Sepse/imunologia , Sepse/microbiologia , Sepse/prevenção & controle , Transdução de Sinais
8.
Life Sci ; 258: 118177, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738364

RESUMO

AIM: Omapatrilat is an antagonist of angiotensin-converting (ACE) and neprilysin-neuropeptidase (NEP) enzymes. The aim of our study is to show that omapatrilat may have beneficial effects as a treatment for polymicrobial sepsis. MAIN METHODS: A cecal ligation and puncture (CLP) sepsis model was used to evaluate 10 and 20 mg/kg doses of omapatrilat in mice (n = 30) fasted for 12 h. The lungs were removed 12 h after CLP, and lung levels of cytokines (tumor necrosis factor-alpha [TNF-α], interleukin-6 [IL-6], NF-κB), iNOS and eNOS mRNA expression, GSH and MDA levels, and ACE and NEP activities were determined. Histopathological examinations were also performed. KEY FINDINGS: Omapatrilat treatment provided a dose-dependent reduction in oxidative stress and inflammatory parameters in lung tissues. Omapatrilat administration decreased lung iNOS and eNOS mRNA levels at 20 mg/kg dose. Histopathological analysis revealed a decline in the thickening and edema areas in the alveolar septa in the Sepsis+OMA20 group. SIGNIFICANCE: Omapatrilat, a dual ACE and NEP inhibitor, protected lung tissue from sepsis damage by reducing ACE and NEP activities, by decreasing the mRNA expression levels of pro-inflammatory cytokines (TNF-α, IL-6, and NF-κB), by suppressing leukocyte infiltration and edema, by restoring iNOS and eNOS levels, and by restoring SOD activity and GSH and MDA levels, thereby reducing oxidative stress.


Assuntos
Neprilisina/metabolismo , Peptidil Dipeptidase A/metabolismo , Sepse/enzimologia , Transdução de Sinais , Animais , Biomarcadores/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Pulmão/enzimologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sepse/patologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
9.
Am J Respir Cell Mol Biol ; 63(5): 571-590, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32640172

RESUMO

PARP1, the major isoform of a family of ADP-ribosylating enzymes, has been implicated in the regulation of various biological processes including DNA repair, gene transcription, and cell death. The concept that PARP1 becomes activated in acute lung injury (ALI) and that pharmacological inhibition or genetic deletion of this enzyme can provide therapeutic benefits emerged over 20 years ago. The current article provides an overview of the cellular mechanisms involved in the pathogenetic roles of PARP1 in ALI and provides an overview of the preclinical data supporting the efficacy of PARP (poly[ADP-ribose] polymerase) inhibitors. In recent years, several ultrapotent PARP inhibitors have been approved for clinical use (for the therapy of various oncological diseases): these newly-approved PARP inhibitors were recently reported to show efficacy in animal models of ALI. These observations offer the possibility of therapeutic repurposing of these inhibitors for patients with ALI. The current article lays out a potential roadmap for such repurposing efforts. In addition, the article also overviews the scientific basis of potentially applying PARP inhibitors for the experimental therapy of viral ALI, such as coronavirus disease (COVID-19)-associated ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pulmão/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Lesão Pulmonar Aguda/enzimologia , Lesão Pulmonar Aguda/virologia , Animais , Antivirais/efeitos adversos , Betacoronavirus/patogenicidade , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/virologia , Interações Hospedeiro-Patógeno , Humanos , Pulmão/enzimologia , Pulmão/virologia , Pandemias , Pneumonia Viral/enzimologia , Pneumonia Viral/virologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Transdução de Sinais/efeitos dos fármacos
10.
Int J Mol Sci ; 21(13)2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32629995

RESUMO

Peptidylarginine deiminases (PADs) are a family of calcium-regulated enzymes that are phylogenetically conserved and cause post-translational deimination/citrullination, contributing to protein moonlighting in health and disease. PADs are implicated in a range of inflammatory and autoimmune conditions, in the regulation of extracellular vesicle (EV) release, and their roles in infection and immunomodulation are known to some extent, including in viral infections. In the current study we describe putative roles for PADs in COVID-19, based on in silico analysis of BioProject transcriptome data (PRJNA615032 BioProject), including lung biopsies from healthy volunteers and SARS-CoV-2-infected patients, as well as SARS-CoV-2-infected, and mock human bronchial epithelial NHBE and adenocarcinoma alveolar basal epithelial A549 cell lines. In addition, BioProject Data PRJNA631753, analysing patients tissue biopsy data (n = 5), was utilised. We report a high individual variation observed for all PADI isozymes in the patients' tissue biopsies, including lung, in response to SARS-CoV-2 infection, while PADI2 and PADI4 mRNA showed most variability in lung tissue specifically. The other tissues assessed were heart, kidney, marrow, bowel, jejunum, skin and fat, which all varied with respect to mRNA levels for the different PADI isozymes. In vitro lung epithelial and adenocarcinoma alveolar cell models revealed that PADI1, PADI2 and PADI4 mRNA levels were elevated, but PADI3 and PADI6 mRNA levels were reduced in SARS-CoV-2-infected NHBE cells. In A549 cells, PADI2 mRNA was elevated, PADI3 and PADI6 mRNA was downregulated, and no effect was observed on the PADI4 or PADI6 mRNA levels in infected cells, compared with control mock cells. Our findings indicate a link between PADI expression changes, including modulation of PADI2 and PADI4, particularly in lung tissue, in response to SARS-CoV-2 infection. PADI isozyme 1-6 expression in other organ biopsies also reveals putative links to COVID-19 symptoms, including vascular, cardiac and cutaneous responses, kidney injury and stroke. KEGG and GO pathway analysis furthermore identified links between PADs and inflammatory pathways, in particular between PAD4 and viral infections, as well as identifying links for PADs with a range of comorbidities. The analysis presented here highlights roles for PADs in-host responses to SARS-CoV-2, and their potential as therapeutic targets in COVID-19.


Assuntos
Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Desiminases de Arginina em Proteínas/metabolismo , Betacoronavirus/isolamento & purificação , Estudos de Casos e Controles , Linhagem Celular , Infecções por Coronavirus/metabolismo , Citocinas/metabolismo , Bases de Dados Factuais , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Vesículas Extracelulares/metabolismo , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Pulmão/enzimologia , Pulmão/patologia , Pulmão/virologia , Pandemias , Pneumonia Viral/metabolismo , Mapas de Interação de Proteínas , Desiminases de Arginina em Proteínas/genética , RNA Mensageiro/metabolismo
12.
Artigo em Inglês | MEDLINE | ID: mdl-32673988

RESUMO

Pulmonary hypertension (PH) is a progressive and life-threating lung disorder characterized by elevated pulmonary artery pressure and vascular remodeling. PH is classified into five groups, and one of the most common and lethal forms, PH Group-III is defined as PH due to lung diseases and/or hypoxia. Due to the lack of studies in this group, PH-specific drug therapies including prostacyclin (PGI2) analogues have not been approved or recommended for use in these patients. PGI2 is synthesized by the PGI2 synthase (PGIS) enzyme, and its production is determined by measuring its stable metabolite, 6-keto-PGF1α. An impaired PGI2 pathway has been observed in PH animal models and in PH Group-I patients; however, there are contradictory results. The aim of this study is to determine whether PH Group-III is associated with altered expression of PGIS and production of PGI2 in humans. To explore this hypothesis, we measured PGIS expression (by western blot) and PGI2 production (by ELISA) in a large variety of preparations from the pulmonary circulation including human pulmonary artery, pulmonary vein, distal lung tissue, pulmonary artery smooth muscle cells (hPASMC), and bronchi in PH Group-III (n = 35) and control patients (n = 32). Our results showed decreased PGIS expression and/or 6-keto-PGF1α levels in human pulmonary artery, hPASMC, and distal lung tissue derived from PH Group-III patients. Moreover, the production of 6-keto-PGF1α from hPASMC positively correlated with PGIS expression and was inversely correlated with mean pulmonary artery pressure. On the other hand, PH Group-III pulmonary veins and bronchi did not show altered PGI2 production compared to controls. The deficit in PGIS expression and/or PGI2 production observed in pulmonary artery and distal lung tissue in PH Group-III patients may have important implications in the pathogenesis and treatment of PH Group-III.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Epoprostenol/metabolismo , Hipertensão Pulmonar/metabolismo , Oxirredutases Intramoleculares/metabolismo , Artéria Pulmonar/metabolismo , Brônquios/enzimologia , Brônquios/metabolismo , Hipóxia Celular/fisiologia , Células Cultivadas , Dinoprosta/metabolismo , Regulação para Baixo , Feminino , Humanos , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/fisiopatologia , Pulmão/enzimologia , Pulmão/metabolismo , Masculino , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/metabolismo , Artéria Pulmonar/enzimologia , Veias Pulmonares/enzimologia , Veias Pulmonares/metabolismo
14.
J Infect Dis ; 222(4): 556-563, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32526012

RESUMO

Patients who died from COVID-19 often had comorbidities, such as hypertension, diabetes, and chronic obstructive lung disease. Although angiotensin-converting enzyme 2 (ACE2) is crucial for SARS-CoV-2 to bind and enter host cells, no study has systematically assessed the ACE2 expression in the lungs of patients with these diseases. Here, we analyzed over 700 lung transcriptome samples from patients with comorbidities associated with severe COVID-19 and found that ACE2 was highly expressed in these patients compared to control individuals. This finding suggests that patients with such comorbidities may have higher chances of developing severe COVID-19. Correlation and network analyses revealed many potential regulators of ACE2 in the human lung, including genes related to histone modifications, such as HAT1, HDAC2, and KDM5B. Our systems biology approach offers a possible explanation for increased COVID-19 severity in patients with certain comorbidities.


Assuntos
Infecções por Coronavirus/epidemiologia , Pulmão/enzimologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/epidemiologia , Estudos de Casos e Controles , Transtornos Cerebrovasculares/epidemiologia , Transtornos Cerebrovasculares/genética , Comorbidade , Doença das Coronárias/epidemiologia , Doença das Coronárias/genética , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/genética , Complicações do Diabetes/epidemiologia , Complicações do Diabetes/genética , Epigenômica , Feminino , Humanos , Hipertensão/epidemiologia , Hipertensão/genética , Masculino , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/enzimologia , Pneumonia Viral/genética , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/genética , Índice de Gravidade de Doença , Biologia de Sistemas , Transcriptoma
15.
Toxicol Lett ; 331: 112-121, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32534005

RESUMO

Roxadustat is the first orally administered, small-molecule hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that has been submitted for FDA regulatory approval to treat anemia secondary to chronic kidney diseases. Its usage has also been suggested for pulmonary fibrosis; however, the corresponding therapeutic effects remain to be investigated. The in vitro effects of roxadustat on cobalt chloride (CoCl2)-stimulated pulmonary fibrosis with L929 mouse fibroblasts as well as on an in vivo pulmonary fibrosismice model induced with bleomycin (BLM; intraperitoneal injection, 50 mg/kg twice a week for 4 continuous weeks) were investigated. It found that the proliferation of L929 cells was inhibited and the production of collagen I, collagen III, prolyl hydroxylase domain protein 2 (PHD2), HIF-1α, α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), transforming growth factor-ß1 (TGF-ß1) and p-Smad3 were reduced relative to that in the CoCl2 or BLM group after roxadustat treatment. Roxadustat ameliorated pulmonary fibrosis by reducing the pathology score and collagen deposition as well as decreasing the expression of collagen I, collagen III, PHD2, HIF-1α, α-SMA, CTGF, TGF-ß1 and p-Smad3/Smad3. Our cumulative results demonstrate that roxadustat administration can attenuate experimental pulmonary fibrosis via the inhibition of TGF-ß1/Smad activation.


Assuntos
Fibroblastos/efeitos dos fármacos , Glicina/análogos & derivados , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Isoquinolinas/uso terapêutico , Pulmão/efeitos dos fármacos , Fibrose Pulmonar/prevenção & controle , Animais , Bleomicina/farmacologia , Técnicas de Cultura de Células , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Fibroblastos/enzimologia , Glicina/farmacologia , Glicina/uso terapêutico , Hidroxiprolina/metabolismo , Isoquinolinas/farmacologia , Pulmão/enzimologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/enzimologia
17.
Artigo em Inglês | MEDLINE | ID: mdl-32423095

RESUMO

(1) Background: Combating viral disease outbreaks has doubtlessly been one of the major public health challenges for the 21st century. (2) Methods: The host entry machinery required for COVID-19 (SARS-CoV-2) infection was examined for the gene expression profiles and polymorphism. (3) Results: Lung, kidney, small intestine, and salivary glands were among the tissues which expressed the entry machinery coding genes Ace2, Tmprss2, CtsB, and CtsL. The genes had no significant expression changes between males and females. The four human population groups of Europeans, Africans, Asians, and Americans had specific and also a common pool of rare variants for the X-linked locus of ACE2 receptor. Several specific and common ACE2 variants including S19P, I21T/V, E23K, A25T, K26R, T27A, E35D/K, E37K, Y50F, N51D/S, M62V, N64K, K68E, F72V, E75G, M82I, T92I, Q102P, G220S, H239Q, G326E, E329G, G352V, D355N, H378R, Q388L, P389H, E467K, H505R, R514G/*, and Y515C were of the utmost importance to the viral entry and infection. The variants of S19P, I21T, K26R, T27A, E37K, N51D, N64K, K68E, F72V, M82I, G326E, H378R, Q388L, and P389H also had significant differences in frequencies among the population groups. Most interestingly, the analyses revealed that more than half of the variants can exist in males, i.e., as hemizygous. (4) Conclusions: The rare variants of human ACE2 seem to be one of the determinant factors associated with fitness in the battle against SARS viruses. The hemizygous viral-entry booster variants of ACE2 describe the higher SARS-CoV-2 mortality rate in males. This is also supported by the lack of gender bias for the gene expression profiles of entry machinery. A personalized medicine strategy is conceived for isolating high-risk individuals in epidemic circumstances.


Assuntos
Infecções por Coronavirus/mortalidade , Coronavirus , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/mortalidade , Polimorfismo Genético , Grupos Populacionais , Receptores Virais , Sexismo , Internalização do Vírus , Betacoronavirus , Coronavirus/isolamento & purificação , Coronavirus/patogenicidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/genética , Feminino , Humanos , Pulmão/enzimologia , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Peptidil Dipeptidase A/genética , Pneumonia Viral/diagnóstico , Pneumonia Viral/genética , Serina Endopeptidases , Síndrome Respiratória Aguda Grave/genética , Síndrome Respiratória Aguda Grave/metabolismo , Síndrome Respiratória Aguda Grave/virologia , Fatores Sexuais
18.
J Autoimmun ; 112: 102463, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32303424

RESUMO

It has been reported that SARS-CoV-2 may use ACE2 as a receptor to gain entry into human cells, in a way similar to that of SARS-CoV. Analyzing the distribution and expression level of ACE2 may therefore help reveal underlying mechanisms of viral susceptibility and post-infection modulation. In this study, we utilized previously uploaded information on ACE2 expression in various conditions including SARS-CoA to evaluate the role of ACE2 in SARS-CoV and extrapolate that to COVID-19. We found that the expression of ACE2 in healthy populations and patients with underlying diseases was not significantly different. However, based on the elevated expression of ACE2 in cigarette smokers, we speculate that long-term smoking may be a risk factor for COVID-19. Analysis of ACE2 in SARS-CoV infected cells suggests that ACE2 is not only a receptor but is also involved in post-infection regulation, including immune response, cytokine secretion, and viral genome replication. Moreover, we constructed Protein-protein interaction (PPI) networks and identified hub genes in viral activity and cytokine secretion. Our findings may help clinicians and researchers gain more insight into the pathogenesis of SARS-CoV-2 and design therapeutic strategies for COVID-19.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/enzimologia , Regulação Enzimológica da Expressão Gênica , Pulmão/enzimologia , Peptidil Dipeptidase A/biossíntese , Pneumonia Viral/enzimologia , Fumar/efeitos adversos , Infecções por Coronavirus/patologia , Humanos , Pandemias , Pneumonia Viral/patologia , Mapas de Interação de Proteínas
19.
Infect Dis Poverty ; 9(1): 45, 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32345362

RESUMO

BACKGROUND: Since its discovery in December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 2 180 000 people worldwide and has caused more than 150 000 deaths as of April 16, 2020. SARS-CoV-2, which is the virus causing coronavirus disease 2019 (COVID-19), uses the angiotensin-converting enzyme 2 (ACE2) as a cell receptor to invade human cells. Thus, ACE2 is the key to understanding the mechanism of SARS-CoV-2 infection. This study is to investigate the ACE2 expression in various human tissues in order to provide insights into the mechanism of SARS-CoV-2 infection. METHODS: We compared ACE2 expression levels across 31 normal human tissues between males and females and between younger (ages ≤ 49 years) and older (ages > 49 years) persons using two-sided Student's t test. We also investigated the correlations between ACE2 expression and immune signatures in various tissues using Pearson's correlation test. RESULTS: ACE2 expression levels were the highest in the small intestine, testis, kidneys, heart, thyroid, and adipose tissue, and were the lowest in the blood, spleen, bone marrow, brain, blood vessels, and muscle. ACE2 showed medium expression levels in the lungs, colon, liver, bladder, and adrenal gland. ACE2 was not differentially expressed between males and females or between younger and older persons in any tissue. In the skin, digestive system, brain, and blood vessels, ACE2 expression levels were positively associated with immune signatures in both males and females. In the thyroid and lungs, ACE2 expression levels were positively and negatively associated with immune signatures in males and females, respectively, and in the lungs they had a positive and a negative correlation in the older and younger groups, respectively. CONCLUSIONS: Our data indicate that SARS-CoV-2 may infect other tissues aside from the lungs and infect persons with different sexes, ages, and races equally. The different host immune responses to SARS-CoV-2 infection may partially explain why males and females, young and old persons infected with this virus have markedly distinct disease severity. This study provides new insights into the role of ACE2 in the SARS-CoV-2 pandemic.


Assuntos
Betacoronavirus , Peptidil Dipeptidase A/genética , Receptores Virais/genética , Adulto , Fatores Etários , Idoso , Encéfalo/enzimologia , Sistema Cardiovascular/enzimologia , Sistema Cardiovascular/imunologia , Sistema Digestório/enzimologia , Sistema Digestório/imunologia , Glândulas Endócrinas/enzimologia , Glândulas Endócrinas/imunologia , Feminino , Perfilação da Expressão Gênica , Humanos , Sistema Imunitário/enzimologia , Interferons/imunologia , Pulmão/enzimologia , Pulmão/imunologia , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos , Peptidil Dipeptidase A/sangue , RNA-Seq , Receptores Virais/sangue , Fatores Sexuais , Sistema Urogenital/enzimologia
20.
Viruses ; 12(4)2020 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-32268515

RESUMO

Previous studies reported that Angiotensin converting enzyme 2 (ACE2) is the main cell receptor of SARS-CoV and SARS-CoV-2. It plays a key role in the access of the virus into the cell to produce the final infection. In the present study we investigated in silico the basic mechanism of ACE2 in the lung and provided evidences for new potentially effective drugs for Covid-19. Specifically, we used the gene expression profiles from public datasets including The Cancer Genome Atlas, Gene Expression Omnibus and Genotype-Tissue Expression, Gene Ontology and pathway enrichment analysis to investigate the main functions of ACE2-correlated genes. We constructed a protein-protein interaction network containing the genes co-expressed with ACE2. Finally, we focused on the genes in the network that are already associated with known drugs and evaluated their role for a potential treatment of Covid-19. Our results demonstrate that the genes correlated with ACE2 are mainly enriched in the sterol biosynthetic process, Aryldialkylphosphatase activity, adenosylhomocysteinase activity, trialkylsulfonium hydrolase activity, acetate-CoA and CoA ligase activity. We identified a network of 193 genes, 222 interactions and 36 potential drugs that could have a crucial role. Among possible interesting drugs for Covid-19 treatment, we found Nimesulide, Fluticasone Propionate, Thiabendazole, Photofrin, Didanosine and Flutamide.


Assuntos
Antivirais , Infecções por Coronavirus/tratamento farmacológico , Descoberta de Drogas , Pulmão/enzimologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Receptores Virais/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Biologia Computacional , Simulação por Computador , Infecções por Coronavirus/virologia , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/virologia , Mapeamento de Interação de Proteínas , Receptores Virais/genética
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