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[PMID]:27777004
[Au] Autor:Temple KJ; Duvernay MT; Maeng JG; Blobaum AL; Stauffer SR; Hamm HE; Lindsley CW
[Ad] Endereço:Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
[Ti] Título:Identification of the minimum PAR4 inhibitor pharmacophore and optimization of a series of 2-methoxy-6-arylimidazo[2,1-b][1,3,4]thiadiazoles.
[So] Source:Bioorg Med Chem Lett;26(22):5481-5486, 2016 11 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:This letter describes the further deconstruction of the known PAR4 inhibitor chemotypes (MWs 490-525 and with high plasma protein binding) to identify a minimum PAR4 pharmacophore devoid of metabolic liabilities and improved properties. This exercise identified a greatly simplified 2-methoxy-6-arylimidazo[2,1-b][1,3,4]thiadiazole scaffold that afforded nanomolar inhibition of both activating peptide and γ-thrombin mediated PAR4 stimulation, while reducing both molecular weight and the number of hydrogen bond donors/acceptors by ∼50%. This minimum PAR4 pharmacophore, with competitive inhibition, versus non-competitive of the larger chemotypes, allows an ideal starting point to incorporate desired functional groups to engender optimal DMPK properties towards a preclinical candidate.
[Mh] Termos MeSH primário: Agregação Plaquetária/efeitos dos fármacos
Receptores de Trombina/antagonistas & inibidores
Tiadiazóis/química
Tiadiazóis/farmacologia
[Mh] Termos MeSH secundário: Plaquetas/citologia
Plaquetas/efeitos dos fármacos
Plaquetas/metabolismo
Seres Humanos
Inibidores da Agregação de Plaquetas/química
Inibidores da Agregação de Plaquetas/farmacologia
Receptores de Trombina/metabolismo
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 (Platelet Aggregation Inhibitors); 0 (Receptors, Thrombin); 0 (Thiadiazoles); 0 (protease-activated receptor 4); EC 3.4.21.5 (Thrombin)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE
[do] DOI:10.1016/j.bmcl.2016.10.020


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[PMID]:28697175
[Au] Autor:Jiang L; Luan Y; Miao X; Sun C; Li K; Huang Z; Xu D; Zhang M; Kong F; Li N
[Ad] Endereço:Department of Medicine-Solna, Clinical Pharmacology Group, Karolinska University Hospital-Solna, Karolinska Institutet, Stockholm 171 76, Sweden.
[Ti] Título:Platelet releasate promotes breast cancer growth and angiogenesis via VEGF-integrin cooperative signalling.
[So] Source:Br J Cancer;117(5):695-703, 2017 Aug 22.
[Is] ISSN:1532-1827
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Selective platelet release of pro- or anti-angiogenic factors distinctly regulated angiogenesis. We hypothesised that selective release of platelet angiogenic factors could differently regulate tumour growth. METHODS: Breast cancer cell proliferation, cancer cell-induced endothelial tube formation in vitro, and tumour growth in vivo were studied in the presence of protease-activated receptor 1-stimulated platelet releasate (PAR1-PR; rich in pro-angiogenic factors) or PAR4-PR (rich in anti-angiogenic factors). RESULTS: The PAR1-PR and PAR4-PR supplementation (10%) similarly enhanced cell proliferation of MCF-7 and MDA-MB-231 breast cancer cells. The cancer cells triggered capillary-like tube formation of endothelial cells that was further enhanced by pro-angiogenic factor-rich PAR1-PR. The VEGF, but not SDF-1α, receptor blockade abolished PAR1-PR/PAR4-PR-enhanced cancer cell proliferation. Integrin blockade by RGDS had identical effects as VEGF inhibition. The Src and ERK inhibition diminished, whereas PI3K and PKC blockade abolished platelet releasate-enhanced cancer cell proliferation. Using a model of subcutaneous implantation of MDA-MB-231 cells in nude mice, PAR1-PR enhanced tumour growth more markedly than PAR4-PR, and seemed to achieve the exaggeration by promoting more profound tumour angiogenesis. CONCLUSIONS: Platelet releasate increases breast cancer cell proliferation through VEGF-integrin cooperative signalling. Pro-angiogenic factor-rich platelet releasate enhances cancer cell-induced angiogenesis more markedly, and thus exaggerates tumour growth in vivo.
[Mh] Termos MeSH primário: Plaquetas/metabolismo
Neoplasias da Mama/metabolismo
Integrinas/metabolismo
Neovascularização Patológica/metabolismo
Receptor PAR-1/metabolismo
Receptores de Trombina/metabolismo
Fator A de Crescimento do Endotélio Vascular/metabolismo
[Mh] Termos MeSH secundário: Adulto
Animais
Plaquetas/efeitos dos fármacos
Neoplasias da Mama/irrigação sanguínea
Neoplasias da Mama/patologia
Proliferação Celular
Células Endoteliais/efeitos dos fármacos
Células Endoteliais/fisiologia
Feminino
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Integrinas/antagonistas & inibidores
Células MCF-7
Masculino
Camundongos
Camundongos Nus
Meia-Idade
Oligopeptídeos/farmacologia
Compostos de Fenilureia/farmacologia
Fosfatidilinositol 3-Quinases/metabolismo
Proteína Quinase C/metabolismo
Quinolinas/farmacologia
Receptores CXCR4/antagonistas & inibidores
Transdução de Sinais
Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CXCR4 protein, human); 0 (Integrins); 0 (N-(2,4-difluorophenyl)-N'-(4-((6,7-dimethoxy-4-quinolyl)oxy)-2-fluorophenyl)urea); 0 (Oligopeptides); 0 (Phenylurea Compounds); 0 (Quinolines); 0 (Receptor, PAR-1); 0 (Receptors, CXCR4); 0 (Receptors, Thrombin); 0 (Vascular Endothelial Growth Factor A); 0 (protease-activated receptor 4); AC6UDA2MFC (arginyl-glycyl-aspartyl-serine); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2); EC 2.7.11.13 (Protein Kinase C)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170918
[Lr] Data última revisão:
170918
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170712
[St] Status:MEDLINE
[do] DOI:10.1038/bjc.2017.214


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[PMID]:28652403
[Au] Autor:Smith TH; Li JG; Dores MR; Trejo J
[Ad] Endereço:From the Biomedical Sciences Graduate Program and.
[Ti] Título:Protease-activated receptor-4 and purinergic receptor P2Y12 dimerize, co-internalize, and activate Akt signaling via endosomal recruitment of ß-arrestin.
[So] Source:J Biol Chem;292(33):13867-13878, 2017 Aug 18.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Vascular inflammation and thrombosis require the concerted actions of several different agonists, many of which act on G protein-coupled receptors (GPCRs). GPCR dimerization is a well-established phenomenon that can alter protomer function. In platelets and other cell types, protease-activated receptor-4 (PAR4) has been shown to dimerize with the purinergic receptor P2Y12 to coordinate ß-arrestin-mediated Akt signaling, an important mediator of integrin activation. However, the mechanism by which the PAR4-P2Y12 dimer controls ß-arrestin-dependent Akt signaling is not known. We now report that PAR4 and P2Y12 heterodimer internalization is required for ß-arrestin recruitment to endosomes and Akt signaling. Using bioluminescence resonance energy transfer, immunofluorescence microscopy, and co-immunoprecipitation in cells expressing receptors exogenously and endogenously, we demonstrate that PAR4 and P2Y12 specifically interact and form dimers expressed at the cell surface. We also found that activation of PAR4 but not of P2Y12 drives internalization of the PAR4-P2Y12 heterodimer. Remarkably, activated PAR4 internalization was required for recruitment of ß-arrestin to endocytic vesicles, which was dependent on co-expression of P2Y12. Interestingly, stimulation of the PAR4-P2Y12 heterodimer promotes ß-arrestin and Akt co-localization to intracellular vesicles. Moreover, activated PAR4-P2Y12 internalization is required for sustained Akt activation. Thus, internalization of the PAR4-P2Y12 heterodimer is necessary for ß-arrestin recruitment to endosomes and Akt signaling and lays the foundation for examining whether blockade of PAR4 internalization reduces integrin and platelet activation.
[Mh] Termos MeSH primário: Endocitose
Proteínas Proto-Oncogênicas c-akt/agonistas
Receptores Purinérgicos P2Y12/metabolismo
Receptores de Trombina/agonistas
Transdução de Sinais
beta-Arrestina 2/metabolismo
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Técnicas de Transferência de Energia por Ressonância de Bioluminescência
Células COS
Linhagem Celular Tumoral
Cercopithecus aethiops
Endossomos/metabolismo
Seres Humanos
Imunoprecipitação
Microscopia de Fluorescência
Multimerização Proteica
Transporte Proteico
Proteínas Proto-Oncogênicas c-akt/metabolismo
Receptor PAR-1/agonistas
Receptor PAR-1/química
Receptor PAR-1/genética
Receptor PAR-1/metabolismo
Receptores Purinérgicos P2Y12/química
Receptores Purinérgicos P2Y12/genética
Receptores de Trombina/química
Receptores de Trombina/genética
Receptores de Trombina/metabolismo
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
beta-Arrestina 2/química
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ARRB2 protein, human); 0 (P2RY12 protein, human); 0 (Receptor, PAR-1); 0 (Receptors, Purinergic P2Y12); 0 (Receptors, Thrombin); 0 (Recombinant Fusion Proteins); 0 (beta-Arrestin 2); 0 (protease-activated receptor 4); EC 2.7.11.1 (AKT1 protein, human); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170628
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.782359


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[PMID]:28424276
[Au] Autor:Sharma R; Waller AP; Agrawal S; Wolfgang KJ; Luu H; Shahzad K; Isermann B; Smoyer WE; Nieman MT; Kerlin BA
[Ad] Endereço:Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital.
[Ti] Título:Thrombin-Induced Podocyte Injury Is Protease-Activated Receptor Dependent.
[So] Source:J Am Soc Nephrol;28(9):2618-2630, 2017 Sep.
[Is] ISSN:1533-3450
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nephrotic syndrome is characterized by massive proteinuria and injury of specialized glomerular epithelial cells called podocytes. Studies have shown that, whereas low-concentration thrombin may be cytoprotective, higher thrombin concentrations may contribute to podocyte injury. We and others have demonstrated that plasma thrombin generation is enhanced during nephrosis, suggesting that thrombin may contribute to nephrotic progression. Moreover, nonspecific thrombin inhibition has been shown to decrease proteinuria in nephrotic animal models. We thus hypothesized that thrombin contributes to podocyte injury in a protease-activated receptor-specific manner during nephrosis. Here, we show that specific inhibition of thrombin with hirudin reduced proteinuria in two rat nephrosis models, and thrombin colocalized with a podocyte-specific marker in rat glomeruli. Furthermore, flow cytometry immunophenotyping revealed that rat podocytes express the protease-activated receptor family of coagulation receptors High-concentration thrombin directly injured conditionally immortalized human and rat podocytes. Using receptor-blocking antibodies and activation peptides, we determined that thrombin-mediated injury depended upon interactions between protease-activated receptor 3 and protease-activated receptor 4 in human podocytes, and between protease-activated receptor 1 and protease-activated receptor 4 in rat podocytes. Proximity ligation and coimmunoprecipitation assays confirmed thrombin-dependent interactions between human protease-activated receptor 3 and protease-activated receptor 4, and between rat protease-activated receptor 1 and protease-activated receptor 4 in cultured podocytes. Collectively, these data implicate thrombinuria as a contributor to podocyte injury during nephrosis, and suggest that thrombin and/or podocyte-expressed thrombin receptors may be novel therapeutic targets for nephrotic syndrome.
[Mh] Termos MeSH primário: Glomérulos Renais/metabolismo
Nefrose/metabolismo
Podócitos/patologia
Receptor PAR-1/metabolismo
Receptores de Trombina/metabolismo
Trombina/metabolismo
[Mh] Termos MeSH secundário: Animais
Antitrombinas/farmacologia
Sobrevivência Celular
Células Cultivadas
Modelos Animais de Doenças
Expressão Gênica
Hirudinas/farmacologia
Seres Humanos
Imunofenotipagem
Nefrose/complicações
Nefrose/patologia
Nefrose/urina
Podócitos/metabolismo
Proteinúria/etiologia
Ratos
Receptor PAR-1/genética
Receptores de Trombina/genética
Transdução de Sinais
Trombina/antagonistas & inibidores
Trombina/farmacologia
Trombina/urina
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antithrombins); 0 (Hirudins); 0 (Receptor, PAR-1); 0 (Receptors, Thrombin); 0 (protease-activated receptor 3); 0 (protease-activated receptor 4); EC 3.4.21.5 (Thrombin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170421
[St] Status:MEDLINE
[do] DOI:10.1681/ASN.2016070789


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[PMID]:28179424
[Au] Autor:Lupu DS; Orozco LD; Wang Y; Cullen JM; Pellegrini M; Zeisel SH
[Ad] Endereço:Department of Nutrition, Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina, USA.
[Ti] Título:Altered methylation of specific DNA loci in the liver of -null mice results in repression of and and is associated with development of preneoplastic foci.
[So] Source:FASEB J;31(5):2090-2103, 2017 May.
[Is] ISSN:1530-6860
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Folate B -dependent remethylation of homocysteine is important, but less is understood about the importance of the alternative betaine-dependent methylation pathway-catalyzed by betaine-homocysteine methyltransferase (BHMT)-for establishing and maintaining adequate DNA methylation across the genome. We studied C57Bl/6J (betaine-homocysteine methyltransferase)-null mice at age 4, 12, 24, and 52 wk ( = 8) and observed elevation of -adenosylhomocysteine concentrations and development of preneoplastic foci in the liver (increased placental glutathione -transferase and cytokeratin 8-18 activity; starting at 12 wk). At 4 wk, we identified 63 differentially methylated CpGs (DMCs; false discovery rate < 5%) proximal to 81 genes (across 14 chromosomes), of which 18 were differentially expressed. Of these DMCs, 52% were located in one 15.5-Mb locus on chromosome 13, which encompassed the gene and defined a potentially sensitive region with mostly decreased methylation. Analyzing Hybrid Mouse Diversity Panel data, which consisted of 100 inbred strains of mice, we identified 97 DMCs that were affected by genetic variation in the same region, with 7 overlapping those found in -null mice ( < 0.001). At all time points, we found a hypomethylated region mapping to (IQ motif-containing GTPase activating protein 2) and (proteinase-activated receptor-3), 2 genes that were also silenced and underexpressed, respectively.-Lupu, D. S., Orozco, L. D., Wang, Y., Cullen, J. M., Pellegrini, M., Zeisel, S. H. Altered methylation of specific DNA loci in the liver of -null mice results in repression of and and is associated with development of preneoplastic foci.
[Mh] Termos MeSH primário: Metilação de DNA
DNA/metabolismo
Ácido Fólico/metabolismo
Fígado/metabolismo
Lesões Pré-Cancerosas/metabolismo
Receptores de Trombina/metabolismo
Proteínas Ativadoras de ras GTPase/metabolismo
[Mh] Termos MeSH secundário: Animais
Betaína-Homocisteína S-Metiltransferase/deficiência
Betaína-Homocisteína S-Metiltransferase/metabolismo
Metilação de DNA/fisiologia
Glutationa Transferase/metabolismo
Camundongos Endogâmicos C57BL
Camundongos Knockout
Receptores de Trombina/genética
Proteínas Ativadoras de ras GTPase/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Iqgap2 protein, mouse); 0 (Receptors, Thrombin); 0 (protease-activated receptor 3); 0 (ras GTPase-Activating Proteins); 9007-49-2 (DNA); 935E97BOY8 (Folic Acid); EC 2.1.1.5 (Betaine-Homocysteine S-Methyltransferase); EC 2.1.1.5 (Bhmt protein, mouse); EC 2.5.1.18 (Glutathione Transferase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170210
[St] Status:MEDLINE
[do] DOI:10.1096/fj.201601169R


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[PMID]:28126849
[Au] Autor:Ramachandran R; Mihara K; Thibeault P; Vanderboor CM; Petri B; Saifeddine M; Bouvier M; Hollenberg MD
[Ad] Endereço:Snyder Institute for Chronic Diseases and Department of Physiology and Pharmacology (R.R., K.M., M.S., M.D.H.), Mouse Phenomics Resource Laboratory, Snyder Institute for Chronic Diseases and Department of Microbiology, Immunology, and Infectious Diseases (B.P.), and Department of Medicine (M.D.H.),
[Ti] Título:Targeting a Proteinase-Activated Receptor 4 (PAR4) Carboxyl Terminal Motif to Regulate Platelet Function.
[So] Source:Mol Pharmacol;91(4):287-295, 2017 Apr.
[Is] ISSN:1521-0111
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Thrombin initiates human platelet aggregation by coordinately activating proteinase-activated receptors (PARs) 1 and 4. However, targeting PAR1 with an orthosteric-tethered ligand binding-site antagonist results in bleeding, possibly owing to the important role of PAR1 activation on cells other than platelets. Because of its more restricted tissue expression profile, we have therefore turned to PAR4 as an antiplatelet target. We have identified an intracellular PAR4 C-terminal motif that regulates calcium signaling and -arrestin interactions. By disrupting this PAR4 calcium/ -arrestin signaling process with a novel cell-penetrating peptide, we were able to inhibit both thrombin-triggered platelet aggregation in vitro and clot consolidation in vivo. We suggest that targeting PAR4 represents an attractive alternative to blocking PAR1 for antiplatelet therapy in humans.
[Mh] Termos MeSH primário: Plaquetas/metabolismo
Receptores de Trombina/química
Receptores de Trombina/metabolismo
[Mh] Termos MeSH secundário: Motivos de Aminoácidos
Sequência de Aminoácidos
Animais
Plaquetas/efeitos dos fármacos
Sinalização do Cálcio/efeitos dos fármacos
Peptídeos Penetradores de Células/farmacologia
Células HEK293
Seres Humanos
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Camundongos
Proteínas Mutantes/química
Proteínas Mutantes/metabolismo
Transporte Proteico/efeitos dos fármacos
Relação Estrutura-Atividade
Trombose/patologia
beta-Arrestinas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cell-Penetrating Peptides); 0 (Mutant Proteins); 0 (Receptors, Thrombin); 0 (beta-Arrestins); 0 (protease-activated receptor 4)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170509
[Lr] Data última revisão:
170509
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170128
[St] Status:MEDLINE
[do] DOI:10.1124/mol.116.106526


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[PMID]:28086031
[Au] Autor:Maeno M; Lee C; Kim DM; Da Silva J; Nagai S; Sugawara S; Nara Y; Kihara H; Nagai M
[Ad] Endereço:1 Department of Restorative Dentistry and Biomaterials Sciences, Harvard School of Dental Medicine, Boston, MA, USA.
[Ti] Título:Function of Platelet-Induced Epithelial Attachment at Titanium Surfaces Inhibits Microbial Colonization.
[So] Source:J Dent Res;96(6):633-639, 2017 Jun.
[Is] ISSN:1544-0591
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The aim of this study was to evaluate the barrier function of platelet-induced epithelial sheets on titanium surfaces. The lack of functional peri-implant epithelial sealing with basal lamina (BL) attachment at the interface of the implant and the adjacent epithelium allows for bacterial invasion, which may lead to peri-implantitis. Although various approaches have been reported to combat bacterial infection by surface modifications to titanium, none of these have been successful in a clinical application. In our previous study, surface modification with protease-activated receptor 4-activating peptide (PAR4-AP), which induced platelet activation and aggregation, was successful in demonstrating epithelial attachment via BL and epithelial sheet formation on the titanium surface. We hypothesized that the platelet-induced epithelial sheet on PAR4-AP-modified titanium surfaces would reduce bacterial attachment, penetration, and invasion. Titanium surface was modified with PAR4-AP and incubated with platelet-rich plasma (PRP). The aggregated platelets released collagen IV, a critical BL component, onto the PAR4-AP-modified titanium surface. Then, human gingival epithelial cells were seeded on the modified titanium surface and formed epithelial sheets. Green fluorescent protein (GFP)-expressing Escherichia coli was cultured onto PAR4-AP-modified titanium with and without epithelial sheet formation. While Escherichia coli accumulated densely onto the PAR4-AP titanium lacking epithelial sheet, few Escherichia coli were observed on the epithelial sheet on the PAR4-AP surface. No bacterial invasion into the interface of the epithelial sheet and the titanium surface was observed. These in vitro results indicate the efficacy of a platelet-induced epithelial barrier that functions to prevent bacterial attachment, penetration, and invasion on PAR4-AP-modified titanium.
[Mh] Termos MeSH primário: Plaquetas/fisiologia
Implantes Dentários
Materiais Dentários/química
Inserção Epitelial
Peri-Implantite/prevenção & controle
Receptores de Trombina/química
Titânio/química
[Mh] Termos MeSH secundário: Aderência Bacteriana/efeitos dos fármacos
Dente Suporte
Escherichia coli
Seres Humanos
Técnicas In Vitro
Peri-Implantite/etiologia
Plasma Rico em Plaquetas
Propriedades de Superfície
Cicatrização
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Dental Implants); 0 (Dental Materials); 0 (Receptors, Thrombin); 0 (protease-activated receptor 4); D1JT611TNE (Titanium)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170808
[Lr] Data última revisão:
170808
[Sb] Subgrupo de revista:D; IM
[Da] Data de entrada para processamento:170114
[St] Status:MEDLINE
[do] DOI:10.1177/0022034516688888


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[PMID]:27784794
[Au] Autor:Duvernay MT; Temple KJ; Maeng JG; Blobaum AL; Stauffer SR; Lindsley CW; Hamm HE
[Ad] Endereço:Department of Pharmacology (M.T.D., K.J.T., J.G.M., A.L.B., S.R.S., C.W.L., H.E.H.) and Vanderbilt Center for Neuroscience Drug Discovery (K.J.T., A.L.B., S.R.S., C.W.L.), Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Chemistry, Vanderbilt University, Nashville, Tenne
[Ti] Título:Contributions of Protease-Activated Receptors PAR1 and PAR4 to Thrombin-Induced GPIIbIIIa Activation in Human Platelets.
[So] Source:Mol Pharmacol;91(1):39-47, 2017 Jan.
[Is] ISSN:1521-0111
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human platelets display a unique dual receptor system for responding to its primary endogenous activator, α-thrombin. Because of the lack of efficacious antagonists, the field has relied on synthetic peptides and pepducins to describe protease-activated receptor PAR1 and PAR4 signaling. The precise contributions of each receptor have not been established in the context of thrombin. We took advantage of newly discovered PAR antagonists to contrast the contribution of PAR1 and PAR4 to thrombin-mediated activation of the platelet fibrin receptor (GPIIbIIIa). PAR1 is required for platelet activation at low but not high concentrations of thrombin, and maximal platelet activation at high concentrations of thrombin requires PAR4. As the concentration of thrombin is increased, PAR1 signaling is quickly overcome by PAR4 signaling, leaving a narrow window of low thrombin concentrations that exclusively engage PAR1. PAR4 antagonism reduces the maximum thrombin response by over 50%. Thus, although the PAR1 response still active at higher concentrations of thrombin, this response is superseded by PAR4. Truncation of a known PAR4 antagonist and identification of the minimum pharmacophore converted the mechanism of inhibition from noncompetitive to competitive, such that the antagonist could be outcompeted by increasing doses of the ligand. Fragments retained efficacy against both soluble and tethered ligands with lower cLogP values and an increased free fraction in plasma. These reversible, competitive compounds represent a route toward potentially safer PAR4 antagonists for clinical utility and the development of tools such as radioligands and positron emission tomography tracers that are not currently available to the field for this target.
[Mh] Termos MeSH primário: Plaquetas/metabolismo
Integrina beta3/metabolismo
Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo
Receptor PAR-1/metabolismo
Receptores de Trombina/metabolismo
Trombina/farmacologia
[Mh] Termos MeSH secundário: Plaquetas/efeitos dos fármacos
Seres Humanos
Ligantes
Receptor PAR-1/antagonistas & inibidores
Receptores de Trombina/antagonistas & inibidores
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Integrin beta3); 0 (Ligands); 0 (Platelet Glycoprotein GPIb-IX Complex); 0 (Receptor, PAR-1); 0 (Receptors, Thrombin); 0 (glycoprotein receptor GPIb-IX); 0 (protease-activated receptor 4); EC 3.4.21.5 (Thrombin)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170509
[Lr] Data última revisão:
170509
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161028
[St] Status:MEDLINE


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[PMID]:27935972
[Au] Autor:Su D; Wang X; Campbell MR; Porter DK; Pittman GS; Bennett BD; Wan M; Englert NA; Crowl CL; Gimple RN; Adamski KN; Huang Z; Murphy SK; Bell DA
[Ad] Endereço:Environmental Genomics Group, Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, United States of America.
[Ti] Título:Distinct Epigenetic Effects of Tobacco Smoking in Whole Blood and among Leukocyte Subtypes.
[So] Source:PLoS One;11(12):e0166486, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Tobacco smoke exposure dramatically alters DNA methylation in blood cells and may mediate smoking-associated complex diseases through effects on immune cell function. However, knowledge of smoking effects in specific leukocyte subtypes is limited. To better characterize smoking-associated methylation changes in whole blood and leukocyte subtypes, we used Illumina 450K arrays and Reduced Representation Bisulfite Sequencing (RRBS) to assess genome-wide DNA methylation. Differential methylation analysis in whole blood DNA from 172 smokers and 81 nonsmokers revealed 738 CpGs, including 616 previously unreported CpGs, genome-wide significantly associated with current smoking (p <1.2x10-7, Bonferroni correction). Several CpGs (MTSS1, NKX6-2, BTG2) were associated with smoking duration among heavy smokers (>22 cigarettes/day, n = 86) which might relate to long-term heavy-smoking pathology. In purified leukocyte subtypes from an independent group of 20 smokers and 14 nonsmokers we further examined methylation and gene expression for selected genes among CD14+ monocytes, CD15+ granulocytes, CD19+ B cells, and CD2+ T cells. In 10 smokers and 10 nonsmokers we used RRBS to fine map differential methylation in CD4+ T cells, CD8+ T cells, CD14+, CD15+, CD19+, and CD56+ natural killer cells. Distinct cell-type differences in smoking-associated methylation and gene expression were identified. AHRR (cg05575921), ALPPL2 (cg21566642), GFI1 (cg09935388), IER3 (cg06126421) and F2RL3 (cg03636183) showed a distinct pattern of significant smoking-associated methylation differences across cell types: granulocytes> monocytes>> B cells. In contrast GPR15 (cg19859270) was highly significant in T and B cells and ITGAL (cg09099830) significant only in T cells. Numerous other CpGs displayed distinctive cell-type responses to tobacco smoke exposure that were not apparent in whole blood DNA. Assessing the overlap between these CpG sites and differential methylated regions (DMRs) with RRBS in 6 cell types, we confirmed cell-type specificity in the context of DMRs. We identified new CpGs associated with current smoking, pack-years, duration, and revealed unique profiles of smoking-associated DNA methylation and gene expression among immune cell types, providing potential clues to hematopoietic lineage-specific effects in disease etiology.
[Mh] Termos MeSH primário: Metilação de DNA
Epigenômica/métodos
Leucócitos/metabolismo
Fumar
[Mh] Termos MeSH secundário: Adulto
Fosfatase Alcalina/genética
Proteínas Reguladoras de Apoptose/genética
Linfócitos B/metabolismo
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética
Ilhas de CpG/genética
Proteínas de Ligação a DNA/genética
Epigênese Genética
Feminino
Proteínas Ligadas por GPI/genética
Expressão Gênica
Estudo de Associação Genômica Ampla/métodos
Granulócitos/metabolismo
Seres Humanos
Leucócitos/classificação
Masculino
Proteínas de Membrana/genética
Meia-Idade
Monócitos/metabolismo
Receptores de Trombina/genética
Proteínas Repressoras/genética
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Análise de Sequência de DNA/métodos
Linfócitos T/metabolismo
Fatores de Transcrição/genética
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AHRR protein, human); 0 (Apoptosis Regulatory Proteins); 0 (Basic Helix-Loop-Helix Transcription Factors); 0 (DNA-Binding Proteins); 0 (GFI1 protein, human); 0 (GPI-Linked Proteins); 0 (IER3 protein, human); 0 (Membrane Proteins); 0 (Receptors, Thrombin); 0 (Repressor Proteins); 0 (Transcription Factors); 0 (protease-activated receptor 4); EC 3.1.3.1 (ALPPL2 protein, human); EC 3.1.3.1 (Alkaline Phosphatase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170714
[Lr] Data última revisão:
170714
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161210
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0166486


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[PMID]:27924164
[Au] Autor:Zhang Y; Elgizouli M; Schöttker B; Holleczek B; Nieters A; Brenner H
[Ad] Endereço:Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
[Ti] Título:Smoking-associated DNA methylation markers predict lung cancer incidence.
[So] Source:Clin Epigenetics;8:127, 2016.
[Is] ISSN:1868-7083
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Newly established blood DNA methylation markers that are strongly associated with smoking might open new avenues for lung cancer (LC) screening. We aimed to assess the performance of the top hits from previous epigenome-wide association studies in prediction of LC incidence. In a prospective nested case-control study, DNA methylation at (cg05575921), (cg06126421), and (cg03636183) were measured by pyrosequencing in baseline whole blood samples of 143 incident LC cases identified during 11 years of follow-up and 457 age- and sex-matched controls without diagnosis of LC until the end of follow-up. The individual and joint associations of the 3 markers with LC risk were estimated by logistic regression, adjusted for potential confounders including smoking status and cigarette pack-years. The predictive performance was evaluated for both the individual markers and their combinations derived from multiple algorithms. RESULTS: Pronounced demethylation of all 3 markers was observed at baseline among cases compared to controls. Risk of developing LC increased with decreasing DNA methylation levels, with adjusted ORs (95% CI) of 15.86 (4.18-60.17), 8.12 (2.69-4.48), and 10.55 (3.44-32.31), respectively, for participants in the lowest quartile of , , and compared to participants in the highest 2 quartiles of each site among controls. The individual 3 markers exhibited similar accuracy in predicting LC incidence, with AUCs ranging from 0.79 to 0.81. Combination of the 3 markers did not improve the predictive performance (AUC = 0.80). The individual markers or their combination outperformed self-reported smoking exposure particularly in light smokers. No variation in risk prediction was identified with respect to age, follow-up time, and histological subtypes. CONCLUSIONS: , , and methylation in blood DNA are predictive for LC development, which might be useful for identification of risk groups for further specific screening, such as CT examination.
[Mh] Termos MeSH primário: Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética
Cromossomos Humanos Par 16/genética
Metilação de DNA
Neoplasias Pulmonares/epidemiologia
Receptores de Trombina/genética
Proteínas Repressoras/genética
Fumar/genética
[Mh] Termos MeSH secundário: Idoso
Estudos de Casos e Controles
Epigênese Genética
Feminino
Marcadores Genéticos/genética
Predisposição Genética para Doença
Seres Humanos
Incidência
Modelos Logísticos
Neoplasias Pulmonares/genética
Masculino
Meia-Idade
Estudos Prospectivos
Análise de Sequência de DNA/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (AHRR protein, human); 0 (Basic Helix-Loop-Helix Transcription Factors); 0 (Genetic Markers); 0 (Receptors, Thrombin); 0 (Repressor Proteins); 0 (protease-activated receptor 4)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170718
[Lr] Data última revisão:
170718
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161208
[St] Status:MEDLINE
[do] DOI:10.1186/s13148-016-0292-4



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