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1.
In Vivo ; 36(1): 371-374, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34972736

RESUMO

BACKGROUND: The epipharynx, with its high expression of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) entry factors angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2), is a primary target for SARS-CoV-2 replication in the early stage of Coronavirus Disease 19 (COVID-19). Epipharyngeal abrasive therapy (EAT) is a treatment for epipharyngitis in Japan which involves applying zinc chloride to the epipharyngeal mucosa. In this study, we evaluated the expression patterns of ACE2 and TMPRSS2 in tissue samples from patients before and after EAT. PATIENTS AND METHODS: The study subjects were seven patients that had not been treated with EAT and 11 patients that had. For immunohistochemical assessment of the epipharyngeal mucosa, the staining intensity of ACE2 and TMPRSS2 was described as an immunohistochemical score (IHC score). RESULTS: The IHC scores for ACE2 and TEMPRSS2 in the EAT-treated group were 3.40-fold and 1.81-fold lower, respectively, than those in the non-treated group (p=0.0208 and p=0.0244, respectively). CONCLUSION: EAT down-regulates the expression of SARS-CoV-2 entry factors ACE2 and TMPRSS2. Thus, EAT has potential as a novel COVID-19 preventative method.


Assuntos
COVID-19 , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2 , Humanos , Japão , Peptidil Dipeptidase A/genética , Serina Endopeptidases , Internalização do Vírus
2.
Endocrinology ; 163(1)2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34543404

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic continues to exert a significant impact on global health care systems, causing devastating mortality and morbidity. As time passes and our understanding of this novel respiratory virus deepens, it is increasingly clear that its effects extend beyond that of the respiratory system. The coronavirus responsible for COVID-19, severe acute respiratory syndrome coronavirus 2, obtains cellular access through the angiotensin-converting enzyme 2 (ACE2) receptor in a process requiring the transmembrane serine protease 2 (TMPRSS2) protein. Both ACE2 and TMPRSS2 are widely expressed in many endocrine glands. This, along with several case reports of thyroid and pituitary disruption in patients with COVID-19, has resulted in significant interest in its impact on the endocrine system. Indeed, as mortality is abated by the increasing availability of effective vaccines, there is increasing focus on the long-term effects on health in COVID-19 survivors. This review summarizes data investigating the effects of COVID-19 on each of the endocrine axes to guide appropriate investigations and optimal management.


Assuntos
COVID-19/metabolismo , Sistema Endócrino/metabolismo , SARS-CoV-2/fisiologia , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , COVID-19/virologia , Humanos , Pandemias , SARS-CoV-2/genética , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo
3.
Biochim Biophys Acta Mol Cell Res ; 1869(1): 119138, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34619164

RESUMO

The site-1 and site-2 proteases (S1P and S2P) were identified over 20 years ago, and the functions of both have been addressed in numerous studies ever since. Whereas S1P processes a set of substrates independently of S2P, the latter acts in concert with S1P in a mechanism, called regulated intramembrane proteolysis, that controls lipid metabolism and response to unfolded proteins. This review summarizes the molecular roles that S1P and S2P jointly play in these processes. As S1P and S2P deficiencies mainly affect connective tissues, yet with varying phenotypes, we discuss the segregated functions of S1P and S2P in terms of cell homeostasis and maintenance of the connective tissues. In addition, we provide experimental data that point at S2P, but not S1P, as a critical regulator of cell adaptation to proteotoxicity or lipid imbalance. Therefore, we hypothesize that S2P can also function independently of S1P activity.


Assuntos
Endopeptidases/metabolismo , Pró-Proteína Convertases/metabolismo , Proteólise , Serina Endopeptidases/metabolismo , Animais , Membrana Celular/metabolismo , Tecido Conjuntivo/enzimologia , Tecido Conjuntivo/metabolismo , Homeostase , Humanos
4.
J Cell Biol ; 221(2)2022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-34889941

RESUMO

Prostate cancer aggressiveness and metastatic potential are influenced by gene expression and genomic aberrations, features that can be influenced by the 3D structure of chromosomes inside the nucleus. Using chromosome conformation capture (Hi-C), we conducted a systematic genome architecture comparison on a cohort of cell lines that model prostate cancer progression, from normal epithelium to bone metastasis. We describe spatial compartment identity (A-open versus B-closed) changes with progression in these cell lines and their relation to gene expression changes in both cell lines and patient samples. In particular, 48 gene clusters switch from the B to the A compartment, including androgen receptor, WNT5A, and CDK14. These switches are accompanied by changes in the structure, size, and boundaries of topologically associating domains (TADs). Further, compartment changes in chromosome 21 are exacerbated with progression and may explain, in part, the genesis of the TMPRSS2-ERG translocation. These results suggest that discrete 3D genome structure changes play a deleterious role in prostate cancer progression. .


Assuntos
Cromossomos Humanos/metabolismo , Progressão da Doença , Modelos Biológicos , Neoplasias da Próstata/patologia , Linhagem Celular Tumoral , Cromatina/metabolismo , Estudos de Coortes , Genes Neoplásicos , Genoma Humano , Humanos , Masculino , Metástase Neoplásica , Neoplasias da Próstata/genética , Serina Endopeptidases/metabolismo , Ativação Transcricional/genética
5.
Int J Mol Med ; 49(2)2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34935057

RESUMO

The pathophysiology of coronavirus disease 2019 (COVID­19) is mainly dependent on the underlying mechanisms that mediate the entry of severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) into the host cells of the various human tissues/organs. Recent studies have indicated a higher order of complexity of the mechanisms of infectivity, given that there is a wide­repertoire of possible cell entry mediators that appear to co­localise in a cell­ and tissue­specific manner. The present study provides an overview of the 'canonical' SARS­CoV­2 mediators, namely angiotensin converting enzyme 2, transmembrane protease serine 2 and 4, and neuropilin­1, expanding on the involvement of novel candidates, including glucose­regulated protein 78, basigin, kidney injury molecule­1, metabotropic glutamate receptor subtype 2, ADAM metallopeptidase domain 17 (also termed tumour necrosis factor­α convertase) and Toll­like receptor 4. Furthermore, emerging data indicate that changes in microRNA (miRNA/miR) expression levels in patients with COVID­19 are suggestive of further complexity in the regulation of these viral mediators. An in silico analysis revealed 160 candidate miRNAs with potential strong binding capacity in the aforementioned genes. Future studies should concentrate on elucidating the association between the cellular tropism of the SARS­CoV­2 cell entry mediators and the mechanisms through which they might affect the clinical outcome. Finally, the clinical utility as a biomarker or therapeutic target of miRNAs in the context of COVID­19 warrants further investigation.


Assuntos
COVID-19/metabolismo , MicroRNAs/metabolismo , Receptores Virais/metabolismo , SARS-CoV-2/metabolismo , Internalização do Vírus , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/genética , COVID-19/virologia , /metabolismo , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , MicroRNAs/genética , Neuropilina-1/genética , Neuropilina-1/metabolismo , Receptores Virais/genética , SARS-CoV-2/fisiologia , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Tropismo Viral
6.
Sci Rep ; 11(1): 23993, 2021 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-34907257

RESUMO

Previous work indicates that SARS-CoV-2 virus entry proteins angiotensin-converting enzyme 2 (ACE-2) and the cell surface transmembrane protease serine 2 (TMPRSS-2) are regulated by sex hormones. However, clinical studies addressing this association have yielded conflicting results. We sought to analyze the impact of sex hormones, age, and cardiovascular disease on ACE-2 and TMPRSS-2 expression in different mouse models. ACE-2 and TMPRSS-2 expression was analyzed by immunostaining in a variety of tissues obtained from FVB/N mice undergoing either gonadectomy or sham-surgery and being subjected to ischemia-reperfusion injury or transverse aortic constriction surgery. In lung tissues sex did not have a significant impact on the expression of ACE-2 and TMPRSS-2. On the contrary, following myocardial injury, female sex was associated to a lower expression of ACE-2 at the level of the kidney tubules. In addition, after myocardial injury, a significant correlation between younger age and higher expression of both ACE-2 and TMPRSS-2 was observed for lung alveoli and bronchioli, kidney tubules, and liver sinusoids. Our experimental data indicate that gonadal hormones and biological sex do not alter ACE-2 and TMPRSS-2 expression in the respiratory tract in mice, independent of disease state. Thus, sex differences in ACE-2 and TMPRSS-2 protein expression observed in mice may not explain the higher disease burden of COVID-19 among men.


Assuntos
Envelhecimento/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Cardiomiopatias/metabolismo , Castração/efeitos adversos , Serina Endopeptidases/metabolismo , Animais , Bronquíolos/metabolismo , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Túbulos Renais/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Alvéolos Pulmonares/metabolismo , Internalização do Vírus
7.
Physiol Res ; 70(S2): S125-S134, 2021 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-34913347

RESUMO

Genetic predispositions may influence geographical and interethnic differences in COVID-19 prevalence and mortality in affected populations. Of the many genes implicated in COVID-19 progression, a substantial number have no direct functional link on virus transfer/viability or on the host immune system. To address this knowledge deficit, a large number of in silico studies have recently been published. However, the results of these studies often contradict the findings of studies involving real patients. For example, the ACE2 has been shown to play an important role in regulating coronavirus entry into cells, but none of its variations have been directly associated with COVID-19 susceptibility or severity. Consistently was reported that increased risk of COVID-19 is associated with blood group A and with the APOE4 allele. Among other genes with potential impacts are the genes for CCR5, IL-10, CD14, TMPRSS2 and angiotensin-converting enzyme. Variants within the protein-coding genes OAS1 and LZTFL1 (transferred to the human genome from Neanderthals) are understood to be among the strongest predictors of disease severity. The intensive research efforts have helped to identify the genes and polymorphisms that contribute to SARS-CoV-2 infection and COVID-19 severity.


Assuntos
COVID-19/genética , Polimorfismo Genético , SARS-CoV-2/patogenicidade , Sistema ABO de Grupos Sanguíneos/genética , Enzima de Conversão de Angiotensina 2/genética , Animais , Apolipoproteínas E/genética , COVID-19/virologia , Progressão da Doença , Predisposição Genética para Doença , Hereditariedade , Interações Hospedeiro-Patógeno , Humanos , Fenótipo , Medição de Risco , Fatores de Risco , Serina Endopeptidases/genética
8.
Physiol Res ; 70(S2): S177-S194, 2021 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-34913351

RESUMO

Angiotensin-converting enzyme 2 (ACE2) was identified as a molecule that mediates the cellular entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several membrane molecules of the host cell must cooperate in this process. While ACE2 serves in a membrane receptor-mediating interaction with the surface spike (S) glycoprotein of SARS-CoV-2 located on the virus envelope, enzyme A disintegrin and metalloproteinase 17 (ADAM17) regulates ACE2 availability on the membrane and transmembrane protease serine 2 (TMPRSS2) facilitates virus-cell membrane fusion. Interestingly, ACE2, ADAM17 and TMPRSS2 show a daily rhythm of expression in at least some mammalian tissue. The circadian system can also modulate COVID-19 progression via circadian control of the immune system (direct, as well as melatonin-mediated) and blood coagulation. Virus/ACE2 interaction causes ACE2 internalization into the cell, which is associated with suppressed activity of ACE2. As a major role of ACE2 is to form vasodilatory angiotensin 1-7 from angiotensin II (Ang II), suppressed ACE2 levels in the lung can contribute to secondary COVID-19 complications caused by up-regulated, pro-inflammatory vasoconstrictor Ang II. This is supported by the positive association of hypertension and negative COVID-19 prognosis although this relationship is dependent on numerous comorbidities. Hypertension treatment with inhibitors of renin-angiotensin system does not negatively influence prognosis of COVID-19 patients. It seems that tissue susceptibility to SARS-CoV-2 shows negative correlation to ACE2 expression. However, in lungs of infected patient, a high ACE2 expression is associated with better outcome, compared to low ACE2 expression. Manipulation of soluble ACE2 levels is a promising COVID-19 therapeutic strategy.


Assuntos
Proteína ADAM17/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , Ritmo Circadiano , Sistema Renina-Angiotensina , SARS-CoV-2/patogenicidade , Serina Endopeptidases/metabolismo , Animais , COVID-19/fisiopatologia , COVID-19/terapia , COVID-19/virologia , Interações Hospedeiro-Patógeno , Humanos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Periodicidade , Prognóstico , SARS-CoV-2/metabolismo , Transdução de Sinais , Fatores de Tempo
9.
Physiol Res ; 70(S2): S195-S208, 2021 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-34913352

RESUMO

In this review, we discuss the role of pulmonary surfactant in the host defense against respiratory pathogens, including novel coronavirus SARS-CoV-2. In the lower respiratory system, the virus uses angiotensin-converting enzyme 2 (ACE2) receptor in conjunction with serine protease TMPRSS2, expressed by alveolar type II (ATII) cells as one of the SARS-CoV-2 target cells, to enter. ATII cells are the main source of surfactant. After their infection and the resulting damage, the consequences may be severe and may include injury to the alveolar-capillary barrier, lung edema, inflammation, ineffective gas exchange, impaired lung mechanics and reduced oxygenation, which resembles acute respiratory distress syndrome (ARDS) of other etiology. The aim of this review is to highlight the key role of ATII cells and reduced surfactant in the pathogenesis of the respiratory form of COVID-19 and to emphasize the rational basis for exogenous surfactant therapy in COVID-19 ARDS patients.


Assuntos
Células Epiteliais Alveolares/metabolismo , COVID-19/metabolismo , Pulmão/metabolismo , Proteínas Associadas a Surfactantes Pulmonares/metabolismo , SARS-CoV-2/patogenicidade , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/imunologia , Células Epiteliais Alveolares/virologia , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , COVID-19/tratamento farmacológico , COVID-19/imunologia , COVID-19/virologia , Interações Hospedeiro-Patógeno , Humanos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/virologia , Surfactantes Pulmonares/uso terapêutico , Receptores Virais/metabolismo , SARS-CoV-2/imunologia , Serina Endopeptidases/metabolismo , Internalização do Vírus
10.
Front Immunol ; 12: 714027, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34950129

RESUMO

In the coronavirus disease 2019 (COVID-19) health crisis, one major challenge is to identify the susceptibility factors of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) in order to adapt the recommendations for populations, as well as to reduce the risk of COVID-19 development in the most vulnerable people, especially patients with chronic respiratory diseases such as cystic fibrosis (CF). Airway epithelial cells (AECs) play a critical role in the modulation of both immune responses and COVID-19 severity. SARS-CoV-2 infects the airway through the receptor angiotensin-converting enzyme 2, and a host protease, transmembrane serine protease 2 (TMPRSS2), plays a major role in SARS-CoV-2 infectivity. Here, we show that Pseudomonas aeruginosa increases TMPRSS2 expression, notably in primary AECs with deficiency of the ion channel CF transmembrane conductance regulator (CFTR). Further, we show that the main component of P. aeruginosa flagella, the protein flagellin, increases TMPRSS2 expression in primary AECs and Calu-3 cells, through activation of Toll-like receptor-5 and p38 MAPK. This increase is particularly seen in Calu-3 cells deficient for CFTR and is associated with an intracellular increased level of SARS-CoV-2 infection, however, with no effect on the amount of virus particles released. Considering the urgency of the COVID-19 health crisis, this result may be of clinical significance for CF patients, who are frequently infected with and colonized by P. aeruginosa during the course of CF and might develop COVID-19.


Assuntos
Fibrose Cística , Flagelina/metabolismo , Infecções por Pseudomonas/complicações , Mucosa Respiratória/virologia , SARS-CoV-2/patogenicidade , Serina Endopeptidases/metabolismo , Proteínas de Bactérias/metabolismo , COVID-19/complicações , Células Cultivadas , Humanos , Pseudomonas aeruginosa , Mucosa Respiratória/metabolismo
11.
Front Immunol ; 12: 781352, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34950146

RESUMO

After the outburst of the SARS-CoV-2 pandemic, a worldwide research effort has led to the uncovering of many aspects of the COVID-19, among which we can count the outstanding role played by inflammatory cytokine milieu in the disease progression. Despite that, molecular mechanisms that regulate SARS-CoV-2 pathogenesis are still almost unidentified. In this study, we investigated whether the pro-inflammatory milieu of the host affects the susceptibility of SARS-CoV-2 infection by modulating ACE2 and TMPRSS2 expression. Our results indicated that the host inflammatory milieu favors SARS-CoV-2 infection by directly increasing TMPRSS2 expression. We unveiled the molecular mechanism that regulates this process and that can be therapeutically advantageously targeted.


Assuntos
Fator de Transcrição GATA2/metabolismo , Interleucina-1beta/metabolismo , SARS-CoV-2/patogenicidade , Serina Endopeptidases/metabolismo , Internalização do Vírus , Células A549 , COVID-19 , Humanos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
12.
Arch Microbiol ; 204(1): 77, 2021 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-34953136

RESUMO

The aim of this scoping review was to identify knowledge gaps and to describe the current state of the research on the association between TMPRSS2 and the essential beta coronaviruses (Beta-CoVs) infection and the molecular mechanisms for this association. We searched MEDLINE (OVID), EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL). We included 13 studies. Evidence shows an essential role of TMPRSS2 in Spike protein activation, entry, and spread into host cells. Co-expression of TMPRSS2 with cell surface receptors (ACE2 or DPP4) increased virus entry. This serine protease is involved in the formation of large syncytia between infected cells. TMPRSS2 cleaved the Spike protein of SARS-CoV, SARS-CoV-2, and MERS-CoV, and increased virus propagation. Accumulating evidence suggests that TMPRSS2 is an essential protease for virus replication. We highlighted its critical molecular role in membrane fusion and the impact in viral mRNA replication, then promoting/driving pathogenesis and resistance.


Assuntos
COVID-19 , Infecções por Coronavirus/genética , Serina Endopeptidases , COVID-19/genética , Linhagem Celular , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio , Vírus da SARS , SARS-CoV-2 , Serina Endopeptidases/genética , Glicoproteína da Espícula de Coronavírus , Internalização do Vírus
13.
J Biosci ; 462021.
Artigo em Inglês | MEDLINE | ID: mdl-34785628

RESUMO

Since the start of the pandemic, SARS-CoV-2 has infected almost 200 million human hosts and is set to encounter and gain entry in many more in the coming months. As the coronavirus flourish, the evolutionary pressure selects those variants that can complete the infection cycle faster and reproduce in large numbers compared to others. This increase in infectivity and transmissibility coupled with the immune response from high viral load may cause moderate to severe disease. Whether this leads to enhanced virulence in the prevalent Alpha and Delta variants is still not clear. This review describes the different types of SARS-CoV-2 variants that are now prevalent, their emergence, the mutations responsible for their growth advantages, and how they affect vaccine efficacy and increase chances of reinfection. Finally, we have also summarized the efforts made to recognize and predict the mutations, which can cause immune escape and track their emergence through impactful genomic surveillance.


Assuntos
Anticorpos Neutralizantes/química , COVID-19/epidemiologia , Genoma Viral , Evasão da Resposta Imune/genética , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/química , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/imunologia , Anticorpos Neutralizantes/genética , Anticorpos Neutralizantes/imunologia , Sítios de Ligação , COVID-19/patologia , COVID-19/transmissão , COVID-19/virologia , Vacinas contra COVID-19 , Humanos , Modelos Moleculares , Mutação , Filogenia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Receptores Virais/química , Receptores Virais/genética , Receptores Virais/imunologia , SARS-CoV-2/classificação , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Serina Endopeptidases/química , Serina Endopeptidases/genética , Serina Endopeptidases/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Virulência
14.
Nanoscale ; 13(45): 19218-19237, 2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34787160

RESUMO

The global dissemination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has seriously endangered human health. The number of confirmed cases is still increasing; however, treatment options are limited. Transmembrane protease serine 2 (TMPRSS2), as a key protease that primes the binding of SARS-CoV-2 spike protein and angiotensin-converting enzyme 2 (ACE2), has become an attractive target and received widespread attention. Thus, four potential drugs (bromhexine, camostat, gabexate, and nafamostat) were used to explore the mechanism of binding with TMPRSS2 in this work. A 65 ns molecular dynamics simulation was performed three times for each drug-TMPRSS2 system for reliable energy calculation and conformational analysis, of which the simulations of nafamostat-TMPRSS2 systems were further extended to 150 ns three times due to the discovery of two binding modes. Through the results of calculating binding free energy by nine methods, the binding affinity of camostat, gabexate, and nafamostat to TMPRSS2 showed great advantages compared with bromhexine, where the nafamostat was surprisingly found to present two reasonable binding conformations (forward and reverse directions). Two negatively charged amino acids (Asp435 and Glu299) can clamp the two positively charged groups (guanidinium group and amidinium group) in either forward or reverse fashion, and the forward one is more stable than the reverse. In addition, compared with gabexate, the dimethylamino group in camostat forms more van der Waals interactions with surrounding hot-spots His296 and Val280, resulting in a stronger affinity to TMPRSS2. For bromhexine, multiple binding sites are displayed in the binding pocket due to its small molecular structure, and van der Waals interactions play the dominant role in the binding process. In particular, six typical hot-spots were identified in the last three serine protease inhibitor systems, i.e., Asp435, Ser436, Gln438, Trp461, Ser463, and Gly464. The guanidinium groups of the drugs have powerful interactions with adjacent residues due to the formation of more hydrogen bonds, suggesting that this may be the critical site for drug design against TMPRSS2. This work provides valuable molecular insight into these four drug-TMPRSS2 binding mechanisms and is helpful for designing and screening drugs targeting TMPRSS2.


Assuntos
COVID-19 , Preparações Farmacêuticas , Humanos , Simulação de Dinâmica Molecular , SARS-CoV-2 , Serina Endopeptidases/genética , Glicoproteína da Espícula de Coronavírus
15.
Front Cell Infect Microbiol ; 11: 763152, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34790590

RESUMO

The pathobiont Streptococcus pneumoniae causes life-threatening diseases, including pneumonia, sepsis, meningitis, or non-invasive infections such as otitis media. Serine proteases are enzymes that have been emerged during evolution as one of the most abundant and functionally diverse group of proteins in eukaryotic and prokaryotic organisms. S. pneumoniae expresses up to four extracellular serine proteases belonging to the category of trypsin-like or subtilisin-like family proteins: HtrA, SFP, PrtA, and CbpG. These serine proteases have recently received increasing attention because of their immunogenicity and pivotal role in the interaction with host proteins. This review is summarizing and focusing on the molecular and functional analysis of pneumococcal serine proteases, thereby discussing their contribution to pathogenesis.


Assuntos
Otite Média , Infecções Pneumocócicas , Humanos , Serina Endopeptidases/genética , Streptococcus pneumoniae/genética , Subtilisina , Tripsina
16.
Sovrem Tekhnologii Med ; 12(6): 98-108, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34796023

RESUMO

The rapidly accumulating information about the new coronavirus infection and the ambiguous results obtained by various authors necessitate further research aiming at prevention and treatment of this disease. At the moment, there is convincing evidence that the pathogen affects not only the respiratory but also the central nervous system (CNS). The aim of the study is to provide an insight into the molecular mechanisms underlying the damage to the CNS caused by the new coronavirus SARS-CoV-2. Results: By analyzing the literature, we provide evidence that the brain is targeted by this virus. SARS-CoV-2 enters the body with the help of the target proteins: angiotensin-converting enzyme 2 (ACE2) and associated serine protease TMPRSS2 of the nasal epithelium. Brain damage develops before the onset of pulmonary symptoms. The virus spreads through the brain tissue into the piriform cortex, basal ganglia, midbrain, and hypothalamus. Later, the substantia nigra of the midbrain, amygdala, hippocampus, and cerebellum become affected. Massive death of neurons, astrogliosis and activation of microglia develop at the next stage of the disease. By day 4, an excessive production of proinflammatory cytokines in the brain, local neuroinflammation, breakdown of the blood-brain barrier, and impaired neuroplasticity are detected. These changes imply the involvement of a vascular component driven by excessive activity of matrix metalloproteinases, mediated by CD147. The main players in the pathogenesis of COVID-19 in the brain are products of angiotensin II (AT II) metabolism, largely angiotensin 1-7 (AT 1-7) and angiotensin IV (AT IV). There are conflicting data regarding their role in damage to the CNS in various diseases, including the coronavirus infection.The second participant in the pathogenesis of brain damage in COVID-19 is CD147 - the inducer of extracellular matrix metalloproteinases. This molecule is expressed on the endothelial cells of cerebral microvessels, as well as on leukocytes present in the brain during neuroinflammation. The CD147 molecule plays a significant role in maintaining the structural and functional integrity of the blood-brain barrier by controlling the basal membrane permeability and by mediating the astrocyte-endothelial interactions. Via the above mechanisms, an exposure to SARS-CoV-2 leads to direct damage to the neurovascular unit of the brain.


Assuntos
Astrócitos/metabolismo , Encéfalo/metabolismo , COVID-19/metabolismo , SARS-CoV-2/metabolismo , Angiotensina I/metabolismo , Angiotensina II/análogos & derivados , Angiotensina II/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Basigina , Humanos , Fragmentos de Peptídeos/metabolismo , Serina Endopeptidases/metabolismo
17.
Front Biosci (Landmark Ed) ; 26(10): 740-751, 2021 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-34719202

RESUMO

Objectives: To quantify the integrated levels of ACE2 and TMPRSS2, the two well-recognized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry-related genes, and to further identify key factors contributing to SARS-CoV-2 susceptibility in head and neck squamous cell carcinoma (HNSC). Methods: We developed a metric of the potential for tissue infected with SARS-CoV-2 ("TPSI") based on ACE2 and TMPRSS2 transcript levels and compared TPSI levels between tumor and matched normal tissues across 11 tumor types. For further analysis of HNSC, weighted gene co-expression network analysis (WGCNA), functional analysis, and single sample gene set enrichment analysis (ssGSEA) were conducted to investigate TPSI-relevant biological processes and their relationship with the immune landscape. TPSI-related factors were identified from clinical and mutational domains, followed by lasso regression to determine their relative effects on TPSI levels. Results: TPSI levels in tumors were generally lower than in the normal tissues. In HNSC, the genes highly associated with TPSI were enriched in viral entry-related processes, and TPSI levels were positively correlated with both eosinophils and T helper 17 (Th17) cell infiltration. Furthermore, the site of onset, human papillomaviruses (HPV) status, and nuclear receptor binding SET domain protein 1 (NSD1) mutations were identified as the most important factors shaping TPSI levels. Conclusions: This study identified the infection risk of SARS-CoV-2 between tumor and normal tissues, and provided evidence for the risk stratification of HNSC.


Assuntos
Enzima de Conversão de Angiotensina 2/genética , COVID-19/genética , Carcinoma de Células Escamosas/genética , Neoplasias de Cabeça e Pescoço/genética , Serina Endopeptidases/genética , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , COVID-19/virologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/virologia , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiologia , Serina Endopeptidases/metabolismo , Internalização do Vírus
20.
Front Immunol ; 12: 743022, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34603330

RESUMO

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. The virus primarily affects the lungs where it induces respiratory distress syndrome ranging from mild to acute, however, there is a growing body of evidence supporting its negative effects on other system organs that also carry the ACE2 receptor, such as the placenta. The majority of newborns delivered from SARS-CoV-2 positive mothers test negative following delivery, suggesting that there are protective mechanisms within the placenta. There appears to be a higher incidence of pregnancy-related complications in SARS-CoV-2 positive mothers, such as miscarriage, restricted fetal growth, or still-birth. In this review, we discuss the pathobiology of COVID-19 maternal infection and the potential adverse effects associated with viral infection, and the possibility of transplacental transmission.


Assuntos
COVID-19/patologia , Placenta/patologia , Placenta/virologia , Complicações Infecciosas na Gravidez/virologia , Aborto Espontâneo/virologia , Enzima de Conversão de Angiotensina 2/metabolismo , Feminino , Retardo do Crescimento Fetal/virologia , Humanos , Troca Materno-Fetal/fisiologia , Gravidez , SARS-CoV-2/patogenicidade , Serina Endopeptidases/metabolismo , Natimorto
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