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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.
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
3.
Toxicon ; 206: 28-37, 2022 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-34929211

RESUMO

Trimeresurus gracilis (Tgc) is endemic to Taiwan and shown to be closely related with Ovophis okinavensis by previous phylogenetic analyses, but their taxonomic status remain controversial. Here, we cloned and sequenced ten of its venom serine-proteases (designated as Tgc-vSPs). All the Tgc-vSPs conserve the catalytic triads, six appear to be kallikrein-like (KNs) and four are plasminogen-activator homologs (PAHs and PAs). They are studied under four structural categories: (1) highly similar Tgc-KN1, Tgc-KN2 and Tgc-KN3, with four predicted N-glycosylation sites; (2) Tgc-KN4, with a single N -glycosylation site; (3) Tgc-KN5 and Tgc-KN6, with two distinct N-glycosylation sites; (4) Tgc-PAH1/PAH2, TgcPA3, and Tgc-PA4, with two conserved N-glycosylation sites. Additionally, Tgc-KN1, Tgc-KN4 and Tgc-PAH1 were purified by reversed-phase HPLC and identified by peptide-mass-fingerprinting. Results of BLAST and sequence alignments reveal that Tgc-KN1∼3 and Tgc-KN6 are most like the vSPs of rattlesnakes, while the sequences of Tgc-KN4, KN5 and Tgc-PAH1/PAH2 match closely to the partial sequences of three O. okinavensis vSPs. Thus, our results reveal non-overlapping similarities of Tgc-vSPs to the O. okinavensis vSPs and vSPs of the New World pitvipers. In addition, molecular phylogenetic analyses of the plasminogen-activator like vSPs reveal separate evolution of two clusters of the enzymes with distinct functions.


Assuntos
Venenos de Crotalídeos , Trimeresurus , Animais , Biologia Computacional , Filogenia , Análise de Sequência , Serina Proteases/genética , Trimeresurus/genética
4.
Islets ; 14(1): 1-13, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34636707

RESUMO

The aim of this study was to identify genes that are specifically expressed in pancreatic islet ß-cells (hereafter referred to as ß-cells). Large-scale complementary DNA-sequencing analysis was performed for 3,429 expressed sequence tags derived from murine MIN6 ß-cells, through homology comparisons using the GenBank database. Three individual ESTs were found to code for protease serine S1 family member 53 (Prss53). Prss53 mRNA is processed into both a short and long form, which encode 482 and 552 amino acids, respectively. Transient overexpression of myc-tagged Prss53 in COS-7 cells showed that Prss53 was strongly associated with the luminal surfaces of organellar membranes and that it underwent signal peptide cleavage and N-glycosylation. Immunoelectron microscopy and western blotting revealed that Prss53 localized to mitochondria in MIN6 cells. Short hairpin RNA-mediated Prss53 knockdown resulted in Ppargc1a downregulation and Ucp2 and Glut2 upregulation. JC-1 staining revealed that the mitochondria were depolarized in Prss53-knockdown MIN6 cells; however, no change was observed in glucose-stimulated insulin secretion. Our results suggest that mitochondrial Prss53 expression plays an important role in maintaining the health of ß-cells.


Assuntos
Células Secretoras de Insulina , Ilhotas Pancreáticas , Proteínas Mitocondriais , Serina Proteases/genética , Animais , Glucose , Insulina , Camundongos , Proteínas Mitocondriais/genética
5.
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
6.
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
7.
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
8.
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
9.
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
10.
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
11.
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
12.
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
13.
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
14.
PLoS One ; 16(12): e0261724, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34932608

RESUMO

Papillon-Lefèvre Syndrome (PLS) is an autosomal recessive monogenic disease caused by loss-of-function mutations in the CTSC gene, thus preventing the synthesis of the protease Cathepsin C (CTSC) in a proteolytically active form. CTSC is responsible for the activation of the pro-forms of the neutrophil serine proteases (NSPs; Elastase, Proteinase 3 and Cathepsin G), suggesting its involvement in a variety of neutrophil functions. In PLS neutrophils, the lack of CTSC protease activity leads to inactivity of the NSPs. Clinically, PLS is characterized by an early, typically pre-pubertal, onset of severe periodontal pathology and palmoplantar hyperkeratosis. However, PLS is not considered an immune deficiency as patients do not typically suffer from recurrent and severe (bacterial and fungal) infections. In this study we investigated an unusual CTSC mutation in two siblings with PLS, a 503A>G substitution in exon 4 of the CTSC gene, expected to result in an amino acid replacement from tyrosine to cysteine at position 168 of the CTSC protein. Both patients bearing this mutation presented with pronounced periodontal pathology. The characteristics and functions of neutrophils from patients homozygous for the 503A>G CTSC mutation were compared to another previously described PLS mutation (755A>T), and a small cohort of healthy volunteers. Neutrophil lysates from patients with the 503A>G substitution lacked CTSC protein and did not display any CTSC or NSP activity, yet neutrophil counts, morphology, priming, chemotaxis, radical production, and regulation of apoptosis were without any overt signs of alteration. However, NET formation upon PMA-stimulation was found to be severely depressed, but not abolished, in PLS neutrophils.


Assuntos
Catepsina C/genética , Armadilhas Extracelulares/metabolismo , Neutrófilos/patologia , Doença de Papillon-Lefevre/genética , Serina Proteases/metabolismo , Adulto , Apoptose , Catepsina C/metabolismo , Citometria de Fluxo , Humanos , Mutação com Perda de Função/genética , Pessoa de Meia-Idade , Doença de Papillon-Lefevre/enzimologia , Doença de Papillon-Lefevre/patologia , Espécies Reativas de Oxigênio/metabolismo , Análise de Sequência de DNA
15.
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
16.
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
17.
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
18.
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
19.
Sheng Wu Gong Cheng Xue Bao ; 37(11): 3988-4000, 2021 Nov 25.
Artigo em Chinês | MEDLINE | ID: mdl-34841799

RESUMO

Kunitz-type serine protease inhibitors are a class of ubiquitous protease inhibitors, which play important roles in various life activities. The structures of such inhibitors are generally stable, and are usually characterized by the presence of one or several Kunitz domains in tandem, which are able to bind to serine proteases in a manner similar to substrate binding, thereby inhibiting enzyme activity. In terms of function, Kunitz-type serine protease inhibitors are involved in processes such as blood coagulation and fibrinolysis, tumor immunity, inflammation regulation, and resistance to bacterial and fungal infections. This article summarizes the advances of Kunitz-type serine protease inhibitors and provides new ideas for the development of novel Kunitz-type serine protease inhibitors.


Assuntos
Serina Proteases , Inibidores de Serino Proteinase , Inibidores de Proteases
20.
Int J Mol Sci ; 22(21)2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34768820

RESUMO

Disseminated intravascular coagulation (DIC) is a severe condition characterized by the systemic formation of microthrombi complicated with bleeding tendency and organ dysfunction. In the last years, it represents one of the most frequent consequences of coronavirus disease 2019 (COVID-19). The pathogenesis of DIC is complex, with cross-talk between the coagulant and inflammatory pathways. The objective of this study is to investigate the anti-inflammatory action of ultramicronized palmitoylethanolamide (um-PEA) in a lipopolysaccharide (LPS)-induced DIC model in rats. Experimental DIC was induced by continual infusion of LPS (30 mg/kg) for 4 h through the tail vein. Um-PEA (30 mg/kg) was given orally 30 min before and 1 h after the start of intravenous infusion of LPS. Results showed that um-PEA reduced alteration of coagulation markers, as well as proinflammatory cytokine release in plasma and lung samples, induced by LPS infusion. Furthermore, um-PEA also has the effect of preventing the formation of fibrin deposition and lung damage. Moreover, um-PEA was able to reduce the number of mast cells (MCs) and the release of its serine proteases, which are also necessary for SARS-CoV-2 infection. These results suggest that um-PEA could be considered as a potential therapeutic approach in the management of DIC and in clinical implications associated to coagulopathy and lung dysfunction, such as COVID-19.


Assuntos
Amidas/uso terapêutico , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Coagulação Intravascular Disseminada/tratamento farmacológico , Etanolaminas/uso terapêutico , Ácidos Palmíticos/uso terapêutico , Sepse/complicações , Amidas/química , Amidas/farmacologia , Animais , Transtornos da Coagulação Sanguínea/etiologia , COVID-19/patologia , COVID-19/virologia , Citocinas/sangue , Citocinas/metabolismo , Modelos Animais de Doenças , Coagulação Intravascular Disseminada/etiologia , Etanolaminas/química , Etanolaminas/farmacologia , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Lipopolissacarídeos/toxicidade , Pulmão/metabolismo , Pulmão/patologia , Masculino , Mastócitos/citologia , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Ácidos Palmíticos/química , Ácidos Palmíticos/farmacologia , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Ratos , Ratos Sprague-Dawley , SARS-CoV-2/isolamento & purificação , Sepse/patologia , Serina Proteases/metabolismo
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