Base de dados : MEDLINE
Pesquisa : D12.776.543.750.792 [Categoria DeCS]
Referências encontradas : 413 [refinar]
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[PMID]:28500171
[Au] Autor:Michael JV; Wurtzel JGT; Mao GF; Rao AK; Kolpakov MA; Sabri A; Hoffman NE; Rajan S; Tomar D; Madesh M; Nieman MT; Yu J; Edelstein LC; Rowley JW; Weyrich AS; Goldfinger LE
[Ad] Endereço:Department of Anatomy & Cell Biology.
[Ti] Título:Platelet microparticles infiltrating solid tumors transfer miRNAs that suppress tumor growth.
[So] Source:Blood;130(5):567-580, 2017 Aug 03.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Platelet-derived microparticles (PMPs) are associated with enhancement of metastasis and poor cancer outcomes. Circulating PMPs transfer platelet microRNAs (miRNAs) to vascular cells. Solid tumor vasculature is highly permeable, allowing the possibility of PMP-tumor cell interaction. Here, we show that PMPs infiltrate solid tumors in humans and mice and transfer platelet-derived RNA, including miRNAs, to tumor cells in vivo and in vitro, resulting in tumor cell apoptosis. MiR-24 was a major species in this transfer. PMP transfusion inhibited growth of both lung and colon carcinoma ectopic tumors, whereas blockade of miR-24 in tumor cells accelerated tumor growth in vivo, and prevented tumor growth inhibition by PMPs. Conversely, -deleted mice, which had reduced circulating microparticles (MPs), supported accelerated tumor growth which was halted by PMP transfusion. PMP targeting was associated with tumor cell apoptosis in vivo. We identified direct RNA targets of platelet-derived miR-24 in tumor cells, which included mitochondrial , and , a noncoding small nucleolar RNA. These RNAs were suppressed in PMP-treated tumor cells, resulting in mitochondrial dysfunction and growth inhibition, in an miR-24-dependent manner. Thus, platelet-derived miRNAs transfer in vivo to tumor cells in solid tumors via infiltrating MPs, regulate tumor cell gene expression, and modulate tumor progression. These findings provide novel insight into mechanisms of horizontal RNA transfer and add multiple layers to the regulatory roles of miRNAs and PMPs in tumor progression. Plasma MP-mediated transfer of regulatory RNAs and modulation of gene expression may be a common feature with important outcomes in contexts of enhanced vascular permeability.
[Mh] Termos MeSH primário: Plaquetas/metabolismo
Micropartículas Derivadas de Células/metabolismo
Neoplasias do Colo/metabolismo
Neoplasias Pulmonares/metabolismo
MicroRNAs/metabolismo
[Mh] Termos MeSH secundário: Animais
Micropartículas Derivadas de Células/transplante
Neoplasias do Colo/genética
Neoplasias do Colo/patologia
Neoplasias do Colo/terapia
Seres Humanos
Neoplasias Pulmonares/genética
Neoplasias Pulmonares/patologia
Neoplasias Pulmonares/terapia
Camundongos
NADH Desidrogenase/genética
NADH Desidrogenase/metabolismo
Metástase Neoplásica
Proteínas de Neoplasias/genética
Proteínas de Neoplasias/metabolismo
Receptores Ativados por Proteinase
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MicroRNAs); 0 (Mirn24 microRNA, mouse); 0 (NADH dehydrogenase subunit 2, mouse); 0 (Neoplasm Proteins); 0 (Receptors, Proteinase-Activated); 0 (protease-activated receptor 4, mouse); EC 1.6.99.3 (NADH Dehydrogenase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170824
[Lr] Data última revisão:
170824
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170514
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2016-11-751099


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[PMID]:28314697
[Au] Autor:Seki K; Mizuno Y; Sakashita T; Nakano S; Tanno J; Okazaki Y; Muramatsu T; Nishimura S; Senbonmatsu T
[Ad] Endereço:Department of Cardiology, Saitama Medical University, International Medical Center, Saitama, Japan.
[Ti] Título:Demeanor of rivaroxaban in activated/inactivated FXa.
[So] Source:J Pharmacol Sci;133(3):156-161, 2017 Mar.
[Is] ISSN:1347-8648
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Activated factor X (FXa) plays an important role in thrombin generation and inflammation. Factor X is not converted constitutively to FXa, but only after intrinsic clotting factors are activated and/or cellular injury occurs. Although rivaroxaban is one of direct FXa inhibitors, its function in the inactivated coagulation cascade is unclear. In human umbilical vein endothelial cells that natively express protease-activated receptor-1 and -2, high dose rivaroxaban did not alter gene transcripts including pro-inflammatory genes in DNA microarray. Upon FXa stimulation, the expressions of pro-inflammatory genes such as monocyte chemoattractant protein-1 (MCP-1), intracellular adhesion molecule-1, and interleukin-8 were maximally increased at 4 h after stimulation, and were suppressed by rivaroxaban. To confirm these results, quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA) for MCP-1 were performed. FXa evoked the expression of MCP-1 maximally at 4 h after stimulation, whereas MCP-1 displayed a different temporal activation in ELISA. Interestingly, rivaroxaban inhibited both time courses of MCP-1 expression. These results suggest that rivaroxaban may not influence gene modulation in the inactivated coagulation state, but can attenuate the endothelial damage evoked by FXa and pro-inflammatory cytokine genes.
[Mh] Termos MeSH primário: Inibidores do Fator Xa/farmacologia
Fator Xa/farmacologia
Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos
Rivaroxabana/farmacologia
[Mh] Termos MeSH secundário: Células Cultivadas
Quimiocina CCL2/genética
Células Endoteliais da Veia Umbilical Humana/metabolismo
Seres Humanos
Molécula 1 de Adesão Intercelular/genética
Interleucina-8/genética
Análise de Sequência com Séries de Oligonucleotídeos
Receptores Ativados por Proteinase/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CCL2 protein, human); 0 (Chemokine CCL2); 0 (Factor Xa Inhibitors); 0 (IL8 protein, human); 0 (Interleukin-8); 0 (Receptors, Proteinase-Activated); 126547-89-5 (Intercellular Adhesion Molecule-1); 9NDF7JZ4M3 (Rivaroxaban); EC 3.4.21.6 (Factor Xa)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170801
[Lr] Data última revisão:
170801
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170319
[St] Status:MEDLINE


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[PMID]:28234145
[Au] Autor:Shimizu S; Tojima I; Takezawa K; Matsumoto K; Kouzaki H; Shimizu T
[Ad] Endereço:Department of Otorhinolaryngology, Shiga University of Medical Science, Otsu, Shiga, Japan.
[Ti] Título:Thrombin and activated coagulation factor X stimulate the release of cytokines and fibronectin from nasal polyp fibroblasts protease-activated receptors.
[So] Source:Am J Rhinol Allergy;31(1):13-18, 2017 Jan 01.
[Is] ISSN:1945-8932
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Nasal epithelial cells and infiltrating eosinophils express tissue factor, and high thrombin activity and excess fibrin deposition are found in nasal secretion and in nasal polyp from patients with chronic rhinosinusitis with nasal polyp (CRSwNP). Activated coagulation factors play important roles not only in thrombosis but also in inflammation through interaction with protease-activated receptors (PAR). However, little is known about the effects of activated coagulation factors on the release of cytokines and extracellular matrix from nasal polyp fibroblasts (NPF). PURPOSE: The purpose of this study was to analyze the expression of PARs, which are receptors for activated coagulation factors, on NPFs and to determine the roles of thrombin and activated coagulation factor X (FXa) in the release of cytokines and fibronectin from NPFs. METHODS: NPFs were obtained from patients with CRSwNP, and the messenger RNA (mRNA) and protein expression of PARs in these NPFs were examined. We then investigated whether thrombin or FXa stimulates the release of transforming growth factor (TGF) beta 1, fibronectin, eotaxin-1, interleukin (IL) 6, or IL-8 from cultured NPFs. The effects of PAR agonists on the release of cytokines and fibronectin were also examined. RESULTS: NPFs expressed the mRNA and proteins of all four PARs: PAR-1, PAR-2, PAR-3, and PAR-4. Both thrombin and FXa significantly stimulated the release of TGF beta 1, fibronectin, eotaxin-1, IL-6, and IL-8 from cultured NPFs. PAR-1 and PAR-2 agonists stimulated the secretion of TGF beta 1, fibronectin, eotaxin-1, IL-6, and IL-8. PAR-3 agonist stimulated the release of TGF beta 1, fibronectin, and eotaxin-1. PAR-4 agonist did not induce the release of these molecules. CONCLUSION: NPFs play important roles in the pathophysiology of CRSwNP such as in nasal polyp formation and inflammatory cell infiltration by releasing cytokines and extracellular matrix proteins. Activated coagulation factors, thrombin and FXa, stimulate the release of these cytokines and fibronectin from NPFs via PARs.
[Mh] Termos MeSH primário: Fator Xa/metabolismo
Fibroblastos/metabolismo
Pólipos Nasais/imunologia
Rinite/imunologia
Sinusite/imunologia
Trombina/metabolismo
[Mh] Termos MeSH secundário: Células Cultivadas
Doença Crônica
Citocinas/metabolismo
Fibroblastos/imunologia
Fibroblastos/patologia
Fibronectinas/metabolismo
Regulação da Expressão Gênica
Seres Humanos
Pólipos Nasais/patologia
Receptores Ativados por Proteinase/genética
Receptores Ativados por Proteinase/metabolismo
Rinite/patologia
Sinusite/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytokines); 0 (Fibronectins); 0 (Receptors, Proteinase-Activated); EC 3.4.21.5 (Thrombin); EC 3.4.21.6 (Factor Xa)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170421
[Lr] Data última revisão:
170421
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170225
[St] Status:MEDLINE
[do] DOI:10.2500/ajra.2017.31.4400


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[PMID]:28148395
[Au] Autor:Chanakira A; Westmark PR; Ong IM; Sheehan JP
[Ad] Endereço:Departments of Medicine/Hematology-Oncology and Pathology, University of Wisconsin-Madison, Madison, WI 53792, United States.
[Ti] Título:Tissue factor-factor VIIa complex triggers protease activated receptor 2-dependent growth factor release and migration in ovarian cancer.
[So] Source:Gynecol Oncol;145(1):167-175, 2017 04.
[Is] ISSN:1095-6859
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Enhanced tissue factor (TF) expression in epithelial ovarian cancer (EOC) is associated with aggressive disease. Our objective was to evaluate the role of the TF-factor VIIa-protease-activated receptor-2 (PAR-2) pathway in human EOC. METHODS: TCGA RNAseq data from EOC databases were analyzed for PAR expression. Cell and microparticle (MP) associated TF protein expression (Western blot) and MP-associated coagulant activity were determined in human EOC (SKOV-3, OVCAR-3 and CaOV-3) and control cell lines. PAR-1 and PAR-2 protein expressions were similarly examined. The PAR dependence of VEGF-A release (ELISA) and chemotactic migration in response to FVIIa and cellular proliferation in response to thrombin was evaluated with small molecule antagonists. RESULTS: Relative mRNA expression consistently demonstrated PAR-2>PAR-1≫PAR-3/4 in multiple EOC datasets. Human EOC cell line lysates confirmed expression of TF, PAR-1 and PAR-2 proteins. MPs isolated from EOC cell lines demonstrated markedly enhanced (4-10 fold) TF coagulant activity relative to control cell lines. FVIIa induced a dose-dependent increase in VEGF-A release (2.5-3 fold) from EOC cell lines that was abrogated by the PAR-2 antagonist ENMD-1068. FVIIa treatment of CaOV-3 and OVCAR-3 cells resulted in increased chemotactic migration that was abolished by ENMD-1068. Thrombin induced dose-dependent EOC cell line proliferation was completely reversed by the PAR-1 antagonist vorapaxar. Small molecule antagonists had no effect on these phenotypes without protease present. CONCLUSIONS: Enhanced activity of the TF-FVIIa-PAR-2 axis may contribute to the EOC progression via PAR-2 dependent signaling that supports an angiogenic and invasive phenotype and local thrombin generation supporting PAR-1 dependent proliferation.
[Mh] Termos MeSH primário: Movimento Celular
Fator VIIa/metabolismo
Neoplasias Epiteliais e Glandulares/genética
Neoplasias Ovarianas/genética
RNA Mensageiro/metabolismo
Receptor PAR-1/genética
Receptor PAR-2/genética
Tromboplastina/metabolismo
Fator A de Crescimento do Endotélio Vascular/metabolismo
[Mh] Termos MeSH secundário: Western Blotting
Linhagem Celular Tumoral
Proliferação Celular
Quimiotaxia
Feminino
Seres Humanos
Invasividade Neoplásica
Neoplasias Epiteliais e Glandulares/metabolismo
Neoplasias Epiteliais e Glandulares/patologia
Neoplasias Ovarianas/metabolismo
Neoplasias Ovarianas/patologia
Receptor PAR-1/metabolismo
Receptor PAR-2/metabolismo
Receptores Ativados por Proteinase/genética
Receptores Ativados por Proteinase/metabolismo
Transdução de Sinais
Trombina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (RNA, Messenger); 0 (Receptor, PAR-1); 0 (Receptor, PAR-2); 0 (Receptors, Proteinase-Activated); 0 (VEGFA protein, human); 0 (Vascular Endothelial Growth Factor A); 9035-58-9 (Thromboplastin); EC 3.4.21.21 (Factor VIIa); EC 3.4.21.5 (Thrombin)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170203
[St] Status:MEDLINE


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[PMID]:28120492
[Au] Autor:Palm E; Demirel I; Bengtsson T; Khalaf H
[Ad] Endereço:School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
[Ti] Título:The role of toll-like and protease-activated receptors and associated intracellular signaling in Porphyromonas gingivalis-infected gingival fibroblasts.
[So] Source:APMIS;125(2):157-169, 2017 Feb.
[Is] ISSN:1600-0463
[Cp] País de publicação:Denmark
[La] Idioma:eng
[Ab] Resumo:Porphyromonas gingivalis, which is considered a keystone agent in periodontitis, has evolved elaborate mechanisms to grow and survive in a hostile milieu. The gingival fibroblast is the major cell type in the gingiva and is considered to be important in the periodontitis-associated inflammation. As a part of the innate immune response, they produce cytokines such as CXCL8 and interleukin (IL)-6 which are believed to contribute to the destruction of the tooth-supporting tissues. This study investigates how the expression of protease-activated receptors (PAR1, PAR2) and toll-like receptors (TLR2, TLR4) changes with P. gingivalis exposure and how silencing of one receptor affects the expression of the other receptors. The importance of protein kinase C (PKC) and p38 in the regulation of CXCL8 and IL-6 was also examined. Receptors were knockdown with small-interfering RNA. PKC or p38 was blocked prior to stimulation with P. gingivalis. Fibroblasts were able to compensate for PAR1 knockdown with increased expression of PAR2. PKC and p38 were involved in the regulation of P. gingivalis-induced CXCL8 and IL-6. Our results indicate that PAR1 and PAR2 could be implicated in periodontitis and that PKC and P38 play a role in the inflammatory response in P. gingivalis-infected gingival fibroblasts.
[Mh] Termos MeSH primário: Fibroblastos/imunologia
Fibroblastos/microbiologia
Porphyromonas gingivalis/imunologia
Receptores Ativados por Proteinase/metabolismo
Transdução de Sinais
Receptores Toll-Like/metabolismo
[Mh] Termos MeSH secundário: Western Blotting
Células Cultivadas
Perfilação da Expressão Gênica
Seres Humanos
Interleucina-6/metabolismo
Interleucina-8/metabolismo
Proteína Quinase C/metabolismo
Reação em Cadeia da Polimerase em Tempo Real
Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (IL6 protein, human); 0 (IL8 protein, human); 0 (Interleukin-6); 0 (Interleukin-8); 0 (Receptors, Proteinase-Activated); 0 (Toll-Like Receptors); EC 2.7.11.13 (Protein Kinase C); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170207
[Lr] Data última revisão:
170207
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170126
[St] Status:MEDLINE
[do] DOI:10.1111/apm.12645


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[PMID]:28063023
[Au] Autor:Gryka RJ; Buckley LF; Anderson SM
[Ad] Endereço:Pharmaceutical Sciences Department, School of Pharmacy, Cedarville University, 251 North Main Street, Cedarville, OH, 45314, USA. rgryka@cedarville.edu.
[Ti] Título:Vorapaxar: The Current Role and Future Directions of a Novel Protease-Activated Receptor Antagonist for Risk Reduction in Atherosclerotic Disease.
[So] Source:Drugs R D;17(1):65-72, 2017 Mar.
[Is] ISSN:1179-6901
[Cp] País de publicação:New Zealand
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Despite the current standard of care, patients with cardiovascular disease remain at a high risk for recurrent events. Inhibition of thrombin-mediated platelet activation through protease-activated receptor-1 antagonism may provide reductions in atherosclerotic disease beyond those achievable with the current standard of care. OBJECTIVE: Our primary objective is to evaluate the clinical literature regarding the role of vorapaxar (Zontivity™) in the reduction of cardiovascular events in patients with a history of myocardial infarction and peripheral artery disease. In particular, we focus on the potential future directions for protease-activating receptor antagonists in the treatment of a broad range of atherosclerotic diseases. DATA SOURCES: A literature search of PubMed and EBSCO was conducted to identify randomized clinical trials from August 2005 to June 2016 using the search terms: 'vorapaxar', 'SCH 530348', 'protease-activated receptor-1 antagonist', and 'Zontivity™'. Bibliographies were searched and additional resources were obtained. RESULTS: Vorapaxar is a first-in-class, protease-activated receptor-1 antagonist. The Thrombin Receptor Antagonist for Clinical Event Reduction (TRACER) trial did not demonstrate a significant reduction in a broad primary composite endpoint. However, the Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P-TIMI 50) trial examined a more traditional composite endpoint and found a significant benefit with vorapaxar. Vorapaxar significantly increased bleeding compared with standard care. Ongoing trials will help define the role of vorapaxar in patients with peripheral arterial disease, patients with diabetes mellitus, and other important subgroups. The use of multivariate modeling may enable the identification of subgroups with maximal benefit and minimal harm from vorapaxar. CONCLUSION: Vorapaxar provides clinicians with a novel mechanism of action to further reduce the burden of ischemic heart disease. Identification of patients with a high ischemic risk and low bleeding risk would enable clinicians to maximize the utility of this unique agent.
[Mh] Termos MeSH primário: Aterosclerose/tratamento farmacológico
Lactonas/farmacologia
Lactonas/uso terapêutico
Inibidores da Agregação de Plaquetas/farmacologia
Inibidores da Agregação de Plaquetas/uso terapêutico
Piridinas/farmacologia
Piridinas/uso terapêutico
Receptores Ativados por Proteinase/antagonistas & inibidores
[Mh] Termos MeSH secundário: Aterosclerose/metabolismo
Seres Humanos
Comportamento de Redução do Risco
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Lactones); 0 (Platelet Aggregation Inhibitors); 0 (Pyridines); 0 (Receptors, Proteinase-Activated); ZCE93644N2 (vorapaxar)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170503
[Lr] Data última revisão:
170503
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170108
[St] Status:MEDLINE
[do] DOI:10.1007/s40268-016-0158-4


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[PMID]:28004386
[Au] Autor:Ebrahimi S; Rahmani F; Behnam-Rassouli R; Hoseinkhani F; Parizadeh MR; Keramati MR; Khazaie M; Avan A; Hassanian SM
[Ad] Endereço:Department of Medical Biochemistry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
[Ti] Título:Proinflammatory signaling functions of thrombin in cancer.
[So] Source:J Cell Physiol;232(9):2323-2329, 2017 Sep.
[Is] ISSN:1097-4652
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Thrombin-induced activation of protease-activated receptors (PARs) represents a link between inflammation and cancer. Proinflammatory signaling functions of thrombin are associated with several inflammatory diseases including neurodegenerative, cardiovascular, and of special interest in this review cancer. Thrombin-induced inflammatory responses up-regulates expression of cytokines, adhesion molecules, angiogenic factors, and matrix-degrading proteases that facilitate tumor cells proliferation, angiogenesis, invasion, and metastasis. This review summarizes the current knowledge about the mechanisms of thrombin-mediated proinflammatory responses in cancer pathology for a better understanding and hence a better management of this disease.
[Mh] Termos MeSH primário: Mediadores da Inflamação/metabolismo
Inflamação/metabolismo
Neoplasias/metabolismo
Transdução de Sinais
Trombina/metabolismo
[Mh] Termos MeSH secundário: Proteínas Angiogênicas/metabolismo
Animais
Moléculas de Adesão Celular
Movimento Celular
Proliferação Celular
Citocinas/metabolismo
Seres Humanos
Inflamação/patologia
Metástase Neoplásica
Neoplasias/patologia
Neovascularização Patológica
Peptídeo Hidrolases
Receptores Ativados por Proteinase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Angiogenic Proteins); 0 (Cell Adhesion Molecules); 0 (Cytokines); 0 (Inflammation Mediators); 0 (Receptors, Proteinase-Activated); EC 3.4.- (Peptide Hydrolases); EC 3.4.21.5 (Thrombin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170808
[Lr] Data última revisão:
170808
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161223
[St] Status:MEDLINE
[do] DOI:10.1002/jcp.25753


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[PMID]:27995367
[Au] Autor:de Oliveira P; Juliano MA; Tanaka AS; Carmona AK; Dos Santos SM; de Barros BC; Maza PK; Puccia R; Suzuki E
[Ad] Endereço:Department of Microbiology, Immunology, and Parasitology, Escola Paulista de Medicina - Universidade Federal de São Paulo, Rua Botucatu, 862 - Ed. Antônio C. M. Paiva - 6 andar, São Paulo, SP, 04023-062, Brazil.
[Ti] Título:Paracoccidioides brasiliensis induces cytokine secretion in epithelial cells in a protease-activated receptor-dependent (PAR) manner.
[So] Source:Med Microbiol Immunol;206(2):149-156, 2017 Apr.
[Is] ISSN:1432-1831
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Paracoccidioides brasiliensis is one of the etiological agents of the human systemic mycosis paracoccidioidomycosis. Protease-activated receptors (PARs) are expressed in many cell types and comprise a family of G protein-coupled receptors (PAR-1, PAR-2, and PAR-4), which may be activated by proteases secreted by several pathogens. In the present study, we showed that the pathogenic fungus P. brasiliensis secretes components that promote interleukin (IL)-6 and IL-8 secretion by the lung epithelial cell line A549. Cytokine secretion was reduced by antagonistic peptides for PAR-1 and PAR-2, but not for PAR-4. P. brasiliensis proteases were isolated from fungal culture supernatants in a p-aminomethylbenzamidine-Sepharose column. The obtained fractions were tested for enzymatic activity against fluorescence resonance energy transfer (FRET) peptides derived from sequences that spanned the activation sites of human PARs. The eluted fraction, termed PbP, contained protease activities that were able to hydrolyze the FRET peptides. PbP also induced IL-6 and IL-8 secretion in A549 epithelial cells, which was reduced upon heat inactivation of PbP, incubation with antagonistic peptides for PAR-1 and PAR-2, and the protease inhibitors aprotinin, leupeptin, and E-64. Together, these results show for the first time that P. brasiliensis yeasts secrete proteases that activate PARs in lung epithelial cells, leading to cytokine secretion.
[Mh] Termos MeSH primário: Citocinas/secreção
Células Epiteliais/metabolismo
Células Epiteliais/microbiologia
Paracoccidioides
Receptores Ativados por Proteinase/metabolismo
[Mh] Termos MeSH secundário: Células A549
Linhagem Celular
Sobrevivência Celular/imunologia
Endopeptidases/metabolismo
Células Epiteliais/efeitos dos fármacos
Seres Humanos
Interleucina-6/secreção
Interleucina-8/secreção
Paracoccidioides/enzimologia
Paracoccidioides/imunologia
Paracoccidioidomicose/imunologia
Paracoccidioidomicose/metabolismo
Paracoccidioidomicose/microbiologia
Peptídeos/metabolismo
Inibidores de Proteases/farmacologia
Proteólise/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytokines); 0 (Interleukin-6); 0 (Interleukin-8); 0 (Peptides); 0 (Protease Inhibitors); 0 (Receptors, Proteinase-Activated); EC 3.4.- (Endopeptidases)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161221
[St] Status:MEDLINE
[do] DOI:10.1007/s00430-016-0490-x


  9 / 413 MEDLINE  
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[PMID]:28058009
[Au] Autor:Ceuleers H; Van Spaendonk H; Hanning N; Heirbaut J; Lambeir AM; Joossens J; Augustyns K; De Man JG; De Meester I; De Winter BY
[Ad] Endereço:Hannah Ceuleers, Hanne Van Spaendonk, Nikita Hanning, Jelena Heirbaut, Joris G De Man, Benedicte Y De Winter, Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, 2610 Antwerp, Belgium.
[Ti] Título:Visceral hypersensitivity in inflammatory bowel diseases and irritable bowel syndrome: The role of proteases.
[So] Source:World J Gastroenterol;22(47):10275-10286, 2016 Dec 21.
[Is] ISSN:2219-2840
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Proteases, enzymes catalyzing the hydrolysis of peptide bonds, are present at high concentrations in the gastrointestinal tract. Besides their well-known role in the digestive process, they also function as signaling molecules through the activation of protease-activated receptors (PARs). Based on their chemical mechanism for catalysis, proteases can be classified into several classes: serine, cysteine, aspartic, metallo- and threonine proteases represent the mammalian protease families. In particular, the class of serine proteases will play a significant role in this review. In the last decades, proteases have been suggested to play a key role in the pathogenesis of visceral hypersensitivity, which is a major factor contributing to abdominal pain in patients with inflammatory bowel diseases and/or irritable bowel syndrome. So far, only a few preclinical animal studies have investigated the effect of protease inhibitors specifically on visceral sensitivity while their effect on inflammation is described in more detail. In our accompanying review we describe their effect on gastrointestinal permeability. On account of their promising results in the field of visceral hypersensitivity, further research is warranted. The aim of this review is to give an overview on the concept of visceral hypersensitivity as well as on the physiological and pathophysiological functions of proteases herein.
[Mh] Termos MeSH primário: Dor Abdominal/etiologia
Hiperalgesia/etiologia
Doenças Inflamatórias Intestinais/complicações
Intestinos/enzimologia
Síndrome do Intestino Irritável/complicações
Peptídeo Hidrolases/metabolismo
[Mh] Termos MeSH secundário: Dor Abdominal/tratamento farmacológico
Dor Abdominal/enzimologia
Dor Abdominal/fisiopatologia
Animais
Seres Humanos
Hiperalgesia/tratamento farmacológico
Hiperalgesia/enzimologia
Hiperalgesia/fisiopatologia
Doenças Inflamatórias Intestinais/tratamento farmacológico
Doenças Inflamatórias Intestinais/enzimologia
Doenças Inflamatórias Intestinais/fisiopatologia
Absorção Intestinal
Intestinos/inervação
Síndrome do Intestino Irritável/tratamento farmacológico
Síndrome do Intestino Irritável/enzimologia
Síndrome do Intestino Irritável/fisiopatologia
Permeabilidade
Inibidores de Proteases/uso terapêutico
Receptores Ativados por Proteinase/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Protease Inhibitors); 0 (Receptors, Proteinase-Activated); EC 3.4.- (Peptide Hydrolases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170608
[Lr] Data última revisão:
170608
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170107
[St] Status:MEDLINE
[do] DOI:10.3748/wjg.v22.i47.10275


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[PMID]:27788223
[Au] Autor:French SL; Paramitha AC; Moon MJ; Dickins RA; Hamilton JR
[Ad] Endereço:Australian Centre for Blood Diseases, Monash University, Melbourne, Australia.
[Ti] Título:Humanizing the Protease-Activated Receptor (PAR) Expression Profile in Mouse Platelets by Knocking PAR1 into the Par3 Locus Reveals PAR1 Expression Is Not Tolerated in Mouse Platelets.
[So] Source:PLoS One;11(10):e0165565, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Anti-platelet drugs are the mainstay of pharmacotherapy for heart attack and stroke prevention, yet improvements are continually sought. Thrombin is the most potent activator of platelets and targeting platelet thrombin receptors (protease-activated receptors; PARs) is an emerging anti-thrombotic approach. Humans express two PARs on their platelets-PAR1 and PAR4. The first PAR1 antagonist was recently approved for clinical use and PAR4 antagonists are in early clinical development. However, pre-clinical studies examining platelet PAR function are challenging because the platelets of non-primates do not accurately reflect the PAR expression profile of human platelets. Mice, for example, express Par3 and Par4. To address this limitation, we aimed to develop a genetically modified mouse that would express the same repertoire of platelet PARs as humans. Here, human PAR1 preceded by a lox-stop-lox was knocked into the mouse Par3 locus, and then expressed in a platelet-specific manner (hPAR1-KI mice). Despite correct targeting and the predicted loss of Par3 expression and function in platelets from hPAR1-KI mice, no PAR1 expression or function was detected. Specifically, PAR1 was not detected on the platelet surface nor internally by flow cytometry nor in whole cell lysates by Western blot, while a PAR1-activating peptide failed to induce platelet activation assessed by either aggregation or surface P-selectin expression. Platelets from hPAR1-KI mice did display significantly diminished responsiveness to thrombin stimulation in both assays, consistent with a Par3-/- phenotype. In contrast to the observations in hPAR1-KI mouse platelets, the PAR1 construct used here was successfully expressed in HEK293T cells. Together, these data suggest ectopic PAR1 expression is not tolerated in mouse platelets and indicate a different approach is required to develop a small animal model for the purpose of any future preclinical testing of PAR antagonists as anti-platelet drugs.
[Mh] Termos MeSH primário: Plaquetas/metabolismo
Moléculas de Adesão Celular/metabolismo
Perfilação da Expressão Gênica
Receptores Ativados por Proteinase/metabolismo
[Mh] Termos MeSH secundário: Animais
Camundongos
Receptores Ativados por Proteinase/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cell Adhesion Molecules); 0 (Pard3 protein, mouse); 0 (Receptors, Proteinase-Activated)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170606
[Lr] Data última revisão:
170606
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161028
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0165565



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