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[PMID]: 27628010 [Au] Autor: Shahidi M [Ad] Endereço: Hematology Department, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, 14155-6183, Iran. shahidi.m@iums.ac.ir. [Ti] Título: Thrombosis and von Willebrand Factor. [So] Source: Adv Exp Med Biol;906:285-306, 2017. [Is] ISSN: 0065-2598 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: One of the key players in both hemostasis and thrombosis is von Willebrand factor (vWF), which demonstrates a duality between these two processes. Thrombus is structured by numerous elements, including endothelial cells, platelets, plasma proteins and shear stress alteration. In circulation, once a vessel wall is injured, collagen is exposed and platelets attach to the site of injury. Accordingly, vWF mediates adherence of platelets to the damaged vessel wall by binding both to the collagen and platelet receptor. A growing body of data also indicates a role for neutrophil extracellular traps (NETs) in human thrombosis as scaffolds for vWF, promoting thrombosis. VWF also mediates the protection of factor VIII, a main cofactor of the intrinsic clotting pathway. Since vWF plays a critical role in both thrombotic and bleeding events, a decreased plasma level of this factor may point to a bleeding disorder, while an elevated plasma level may predict occurrence of thrombosis. Since thrombotic events are the foremost cause of death, inhibiting the vWF activity would be a novel prophylaxis to reduce these events. Though, accumulated data have made vWF a promising focus for research on cardiovascular diseases (CVD). This chapter, however, aims to clarify the role of vWF in thrombus formation and pathogenesis of thrombosis. [Mh] Termos MeSH primário: Proteína ADAMTS13/sangue Plaquetas/metabolismo Fator VIII/metabolismo Púrpura Trombocitopênica Trombótica/sangue Trombose/sangue Fator de von Willebrand/metabolismo [Mh] Termos MeSH secundário: Proteína ADAMTS13/genética Plaquetas/patologia Vasos Sanguíneos/lesões Vasos Sanguíneos/metabolismo Vasos Sanguíneos/patologia Armadilhas Extracelulares/metabolismo Fator VIII/genética Fator VIII/uso terapêutico Fibrinolíticos/uso terapêutico Regulação da Expressão Gênica Hemostasia/fisiologia Seres Humanos Troca Plasmática Adesividade Plaquetária Púrpura Trombocitopênica Trombótica/genética Púrpura Trombocitopênica Trombótica/patologia Púrpura Trombocitopênica Trombótica/terapia Receptores de Colágeno/sangue Receptores de Colágeno/genética Transdução de Sinais Tacrolimo/uso terapêutico Trombose/genética Trombose/patologia Trombose/terapia Fator de von Willebrand/genética [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Fibrinolytic Agents); 0 (Receptors, Collagen); 0 (von Willebrand Factor); 9001-27-8 (Factor VIII); EC 3.4.24.87 (ADAMTS13 Protein); EC 3.4.24.87 (ADAMTS13 protein, human); WM0HAQ4WNM (Tacrolimus) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170907 [Lr] Data última revisão: 170907 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160916 [St] Status: MEDLINE

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[PMID]: 27716777 [Au] Autor: Metcalfe C; Ramasubramoni A; Pula G; Harper MT; Mundell SJ; Coxon CH [Ad] Endereço: Oxford Molecular and Pathology Institute, South Parks Road, Oxford, OX1 3RE, United Kingdom. [Ti] Título: Thioredoxin Inhibitors Attenuate Platelet Function and Thrombus Formation. [So] Source: PLoS One;11(10):e0163006, 2016. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Thioredoxin (Trx) is an oxidoreductase with important physiological function. Imbalances in the NADPH/thioredoxin reductase/thioredoxin system are associated with a number of pathologies, particularly cancer, and a number of clinical trials for thioredoxin and thioredoxin reductase inhibitors have been carried out or are underway. Due to the emerging role and importance of oxidoreductases for haemostasis and the current interest in developing inhibitors for clinical use, we thought it pertinent to assess whether inhibition of the NADPH/thioredoxin reductase/thioredoxin system affects platelet function and thrombosis. We used small molecule inhibitors of Trx (PMX 464 and PX-12) to determine whether Trx activity influences platelet function, as well as an unbiased proteomics approach to identify potential Trx substrates on the surface of platelets that might contribute to platelet reactivity and function. Using LC-MS/MS we found that PMX 464 and PX-12 affected the oxidation state of thiols in a number of cell surface proteins. Key surface receptors for platelet adhesion and activation were affected, including the collagen receptor GPVI and the von Willebrand factor receptor, GPIb. To experimentally validate these findings we assessed platelet function in the presence of PMX 464, PX-12, and rutin (a selective inhibitor of the related protein disulphide isomerase). In agreement with the proteomics data, small molecule inhibitors of thioredoxin selectively inhibited GPVI-mediated platelet activation, and attenuated ristocetin-induced GPIb-vWF-mediated platelet agglutination, thus validating the findings of the proteomics study. These data reveal a novel role for thioredoxin in regulating platelet reactivity via proteins required for early platelet responses at sites of vessel injury (GPVI and GPIb). This work also highlights a potential opportunity for repurposing of PMX 464 and PX-12 as antiplatelet agents. [Mh] Termos MeSH primário: Plaquetas/efeitos dos fármacos Inibidores da Agregação de Plaquetas/farmacologia Tiorredoxinas/farmacologia Trombose/tratamento farmacológico [Mh] Termos MeSH secundário: Benzotiazóis/farmacologia Testes de Coagulação Sanguínea/métodos Plaquetas/metabolismo Dissulfetos/farmacologia Seres Humanos Hidroquinonas/farmacologia Imidazóis/farmacologia Ativação Plaquetária/efeitos dos fármacos Adesividade Plaquetária/efeitos dos fármacos Agregação Plaquetária/efeitos dos fármacos Testes de Função Plaquetária/métodos Glicoproteínas da Membrana de Plaquetas/metabolismo Receptores de Colágeno/metabolismo Ristocetina/farmacologia Trombose/metabolismo Fator de von Willebrand/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Benzothiazoles); 0 (Disulfides); 0 (Hydroquinones); 0 (IV 2 compound); 0 (Imidazoles); 0 (PMX 464); 0 (Platelet Aggregation Inhibitors); 0 (Platelet Membrane Glycoproteins); 0 (Receptors, Collagen); 0 (von Willebrand Factor); 0 (von Willebrand factor receptor); 1404-55-3 (Ristocetin); 52500-60-4 (Thioredoxins) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 170922 [Lr] Data última revisão: 170922 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161008 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0163006

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[PMID]: 27505889 [Au] Autor: Semeniak D; Kulawig R; Stegner D; Meyer I; Schwiebert S; Bösing H; Eckes B; Nieswandt B; Schulze H [Ad] Endereço: Institute of Experimental Biomedicine, University Hospital Würzburg, 97080 Würzburg, Germany. [Ti] Título: Proplatelet formation is selectively inhibited by collagen type I through Syk-independent GPVI signaling. [So] Source: J Cell Sci;129(18):3473-84, 2016 Sep 15. [Is] ISSN: 1477-9137 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Collagen receptors GPVI (also known as GP6) and integrin α2ß1 are highly expressed on blood platelets and megakaryocytes, their immediate precursors. After vessel injury, subendothelial collagen becomes exposed and induces platelet activation to prevent blood loss. Collagen types I and IV are thought to have opposite effects on platelet biogenesis, directing proplatelet formation (PPF) towards the blood vessels to prevent premature release within the marrow cavity. We used megakaryocytes lacking collagen receptors or treated megakaryocytes with blocking antibodies, and could demonstrate that collagen-I-mediated inhibition of PPF is specifically controlled by GPVI. Other collagen types competed for binding and diminished the inhibitory signal, which was entirely dependent on receptor-proximal Src family kinases, whereas Syk and LAT were dispensable. Adhesion assays indicate that megakaryocyte binding to collagens is mediated by α2ß1, and that collagen IV at the vascular niche might displace collagen I from megakaryocytes and thus contribute to prevention of premature platelet release into the marrow cavity and thereby directionally promote PPF at the vasculature. [Mh] Termos MeSH primário: Plaquetas/metabolismo Colágeno Tipo I/metabolismo Glicoproteínas da Membrana de Plaquetas/metabolismo Transdução de Sinais Quinase Syk/metabolismo [Mh] Termos MeSH secundário: Animais Medula Óssea/metabolismo Adesão Celular Diferenciação Celular Matriz Extracelular/metabolismo Feminino Fêmur/metabolismo Imuno-Histoquímica Masculino Megacariócitos/citologia Camundongos Endogâmicos C57BL Fenótipo Receptores de Colágeno/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Collagen Type I); 0 (Platelet Membrane Glycoproteins); 0 (Receptors, Collagen); 0 (platelet membrane glycoprotein VI); EC 2.7.10.2 (Syk Kinase); EC 2.7.10.2 (Syk protein, mouse) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 170731 [Lr] Data última revisão: 170731 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160810 [St] Status: MEDLINE [do] DOI: 10.1242/jcs.187971

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[PMID]: 27351420 [Au] Autor: Coelho NM; McCulloch CA [Ad] Endereço: Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Room 243, Fitzgerald Building, 150 College Street, Toronto, Ontario, M5S 3E2, Canada. n.miranda.coelho@gmail.com. [Ti] Título: Contribution of collagen adhesion receptors to tissue fibrosis. [So] Source: Cell Tissue Res;365(3):521-38, 2016 Sep. [Is] ISSN: 1432-0878 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: Fibrosis is the result of a wound-healing response that fails to restore normal tissue structure function. One of the critical hallmarks of fibrosis is disrupted collagen remodeling. In tissue homeostasis, the production, deposition and organization of collagen is balanced by the degradation and remodeling of collagen within the existing matrix. After injury or chronic infection, tissues initiate a wound-healing response that is intended to create a new ECM for restoring tissue structure and function. If the wound-healing response is dysregulated or if the tissue injury or infection is severe or long-lasting, collagen deposition exceeds collagen degradation and the tissue repair process leads to fibrosis. The fibrotic repair response is extraordinarily complex and involves a wide spectrum of cells, signaling pathways and regulatory systems, some of which can be readily disrupted and thereby contribute to fibrotic lesions. The dysregulated collagen remodeling is a common end-point of all fibrotic disorders, and one of the rate-limiting steps of collagen remodeling is the binding of cells to collagen fibrils by specific cell adhesion receptors. In this review, we describe how the expression and function of collagen adhesion receptors contribute to collagen processing events that contribute to tissue fibrosis. Graphical abstract Balance between collagen remodeling in health and disease. [Mh] Termos MeSH primário: Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo Receptores de Colágeno/metabolismo [Mh] Termos MeSH secundário: Animais Colágeno/metabolismo Fibrose Seres Humanos Integrinas/metabolismo Modelos Biológicos [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Integrins); 0 (Platelet Glycoprotein GPIb-IX Complex); 0 (Receptors, Collagen); 0 (adhesion receptor); 9007-34-5 (Collagen) [Em] Mês de entrada: 1705 [Cu] Atualização por classe: 170515 [Lr] Data última revisão: 170515 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160629 [St] Status: MEDLINE [do] DOI: 10.1007/s00441-016-2440-8

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[PMID]: 26990302 [Au] Autor: Reigstad I; Smeland HY; Skogstrand T; Sortland K; Schmid MC; Reed RK; Stuhr L [Ad] Endereço: Department of Biomedicine, University of Bergen, Bergen, Norway. [Ti] Título: Stromal Integrin α11ß1 Affects RM11 Prostate and 4T1 Breast Xenograft Tumors Differently. [So] Source: PLoS One;11(3):e0151663, 2016. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: PURPOSE: It has been implied that the collagen binding integrin α11ß1 plays a role in carcinogenesis. As still relatively little is known about how the stromal integrin α11ß1 affects different aspects of tumor development, we wanted to examine the direct effects on primary tumor growth, fibrosis, tumor interstitial fluid pressure (PIF) and metastasis in murine 4T1 mammary and RM11 prostate tumors, using an in vivo SCID integrin α11-deficient mouse model. METHODS: Tumor growth was measured using a caliper, PIF by the wick-in-needle technique, activated fibroblasts by α-SMA immunofluorescence staining and fibrosis by transmission electron microscopy and picrosirius-red staining. Metastases were evaluated using hematoxylin and eosin stained sections. RESULTS: RM11 tumor growth was significantly reduced in the SCID integrin α11-deficient (α11-KO) compared to in SCID integrin α11 wild type (WT) mice, whereas there was no similar effect in the 4T1 tumor model. The 4T1 model demonstrated an alteration in collagen fibril diameter in the integrin α11-KO mice compared to WT, which was not found in the RM11 model. There were no significant differences in the amount of activated fibroblasts, total collagen content, collagen organization or PIF in the tumors in integrin α11-deficient mice compared to WT mice. There was also no difference in lung metastases between the two groups. CONCLUSION: Deficiency of stromal integrin α11ß1 showed different effects on tumor growth and collagen fibril diameter depending on tumor type, but no effect on tumor PIF or development of lung metastasis. [Mh] Termos MeSH primário: Proliferação Celular/genética Colágeno/metabolismo Integrinas/genética Neoplasias Mamárias Animais/patologia Neoplasias da Próstata/patologia Receptores de Colágeno/genética [Mh] Termos MeSH secundário: Actinas/biossíntese Animais Carcinogênese/genética Linhagem Celular Tumoral Feminino Xenoenxertos Integrinas/biossíntese Neoplasias Pulmonares/secundário Masculino Camundongos Camundongos Knockout Camundongos SCID Microscopia Eletrônica de Transmissão Receptores de Colágeno/biossíntese Carga Tumoral/genética [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Actins); 0 (Integrins); 0 (Receptors, Collagen); 0 (integrin alpha11beta1); 9007-34-5 (Collagen) [Em] Mês de entrada: 1608 [Cu] Atualização por classe: 170220 [Lr] Data última revisão: 170220 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160319 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0151663

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[PMID]: 26148229 [Au] Autor: Navab R; Strumpf D; To C; Pasko E; Kim KS; Park CJ; Hai J; Liu J; Jonkman J; Barczyk M; Bandarchi B; Wang YH; Venkat K; Ibrahimov E; Pham NA; Ng C; Radulovich N; Zhu CQ; Pintilie M; Wang D; Lu A; Jurisica I; Walker GC; Gullberg D; Tsao MS [Ad] Endereço: Princess Margaret Cancer Center and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada. [Ti] Título: Integrin α11ß1 regulates cancer stromal stiffness and promotes tumorigenicity and metastasis in non-small cell lung cancer. [So] Source: Oncogene;35(15):1899-908, 2016 Apr 14. [Is] ISSN: 1476-5594 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Integrin α11ß1 is a stromal cell-specific receptor for fibrillar collagens and is overexpressed in carcinoma-associated fibroblasts (CAFs). We have investigated its direct role in cancer progression by generating severe combined immune deficient (SCID) mice deficient in integrin α11 (α11) expression. The growth of A549 lung adenocarcinoma cells and two patient-derived non-small cell lung carcinoma (NSCLC) xenografts in these α11 knockout (α11(-/-)) mice was significantly impeded, as compared with wild-type (α11(+/+)) SCID mice. Orthotopic implantation of a spontaneously metastatic NCI-H460SM cell line into the lungs of α11(-/-) and α11(+/+) mice showed significant reduction in the metastatic potential of these cells in the α11(-/-) mice. We identified that collagen cross-linking is associated with stromal α11 expression, and the loss of tumor stromal α11 expression was correlated with decreased collagen reorganization and stiffness. This study shows the role of integrin α11ß1, a receptor for fibrillar collagen in differentiation of fibroblasts into CAFs. Furthermore, our data support an important role for α11 signaling pathway in CAFs, promoting tumor growth and metastatic potential of NSCLC cells and being closely associated with collagen cross-linking and the organization and stiffness of fibrillar collagen matrices. [Mh] Termos MeSH primário: Adenocarcinoma/patologia Carcinoma Pulmonar de Células não Pequenas/patologia Fibroblastos/fisiologia Integrina beta1/fisiologia Integrinas/fisiologia Neoplasias Pulmonares/patologia Receptores de Colágeno/fisiologia Células Estromais/fisiologia [Mh] Termos MeSH secundário: Animais Linhagem Celular Tumoral Colágeno/metabolismo Cruzamentos Genéticos Elasticidade Proteínas da Matriz Extracelular/metabolismo Perfilação da Expressão Gênica Regulação Neoplásica da Expressão Gênica Xenoenxertos Seres Humanos Cadeias alfa de Integrinas Camundongos Camundongos Endogâmicos Camundongos Knockout Camundongos SCID Invasividade Neoplásica Proteínas de Neoplasias/metabolismo Proteínas Quinases/metabolismo Transdução de Sinais [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Extracellular Matrix Proteins); 0 (Integrin alpha Chains); 0 (Integrin beta1); 0 (Integrins); 0 (Neoplasm Proteins); 0 (Receptors, Collagen); 0 (integrin alpha11, mouse); 0 (integrin alpha11beta1); 9007-34-5 (Collagen); EC 2.7.- (Protein Kinases) [Em] Mês de entrada: 1609 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 150707 [St] Status: MEDLINE [do] DOI: 10.1038/onc.2015.254

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[PMID]: 26527274 [Au] Autor: Yuan C; Huang JH; Liu M; Huang M [Ad] Endereço: State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, People's Republic of China. [Ti] Título: Expression and crystallographic studies of the ligand-binding region of the human endocytic collagen receptor uPARAP. [So] Source: Acta Crystallogr F Struct Biol Commun;71(Pt 11):1442-7, 2015 Nov. [Is] ISSN: 2053-230X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Urokinase plasminogen activator receptor-associated protein (uPARAP) is an endocytic receptor that internalizes collagen for lysosomal degradation and plays an important role in matrix remodelling. Previous recombinant protein production of uPARAP in Pichia pastoris generated protein with highly heterogeneous glycans that was prone to proteolytic degradation, resulting in highly twinned crystals. In this study, the uPARAP ligand-binding region was expressed in stably transfected Drosophila S2 insect cells. The recombinant protein was homogeneous after purification by metal-affinity and anion-exchange chromatography. Crystals were obtained at two different pH values (5.3 and 7.4) and diffracted to 2.44 and 3.13 Å resolution, respectively. A model of the ligand-binding region of uPARAP was obtained by molecular replacement combined with autobuilding. As the first multidomain crystal structure of the mannose receptor family, structural characterization of the uPARAP ligand-binding region will provide insight into the pH-induced conformational rearrangements of the mannose receptor family. [Mh] Termos MeSH primário: Endocitose/fisiologia Lectinas de Ligação a Manose/química Lectinas de Ligação a Manose/genética Glicoproteínas de Membrana/química Glicoproteínas de Membrana/genética Receptores de Superfície Celular/química Receptores de Superfície Celular/genética Receptores de Colágeno/química Receptores de Colágeno/genética [Mh] Termos MeSH secundário: Sequência de Aminoácidos Cristalografia por Raios X Regulação da Expressão Gênica Seres Humanos Ligantes Lectinas de Ligação a Manose/biossíntese Glicoproteínas de Membrana/biossíntese Dados de Sequência Molecular Ligação Proteica/fisiologia Receptores de Superfície Celular/biossíntese Receptores de Colágeno/biossíntese [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Ligands); 0 (MRC2 protein, human); 0 (Mannose-Binding Lectins); 0 (Membrane Glycoproteins); 0 (Receptors, Cell Surface); 0 (Receptors, Collagen) [Em] Mês de entrada: 1609 [Cu] Atualização por classe: 171101 [Lr] Data última revisão: 171101 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 151104 [St] Status: MEDLINE [do] DOI: 10.1107/S2053230X15018944

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[PMID]: 26471267 [Au] Autor: Gupta N; Li W; McIntyre TM [Ad] Endereço: From the Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland, OH; and Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH. [Ti] Título: Deubiquitinases Modulate Platelet Proteome Ubiquitination, Aggregation, and Thrombosis. [So] Source: Arterioscler Thromb Vasc Biol;35(12):2657-66, 2015 Dec. [Is] ISSN: 1524-4636 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: OBJECTIVE: Platelets express a functional ubiquitin-proteasome system. Mass spectrometry shows that platelets contain several deubiquitinases, but whether these are functional, modulate the proteome, or affect platelet reactivity are unknown. APPROACH AND RESULTS: Platelet lysates contained ubiquitin-protein deubiquitinase activity hydrolyzing both Lys48 and Lys63 polyubiquitin conjugates that was suppressed by the chemically unrelated deubiquitinase inhibitors PYR41 and PR619. These inhibitors acutely and markedly increased monoubiquitination and polyubiquitination of the proteome of resting platelets. PYR41 (intravenous, 15 minutes) significantly impaired occlusive thrombosis in FeCl3-damaged carotid arteries, and deubiquitinase inhibition reduced platelet adhesion and retention during high shear flow of whole blood through microfluidic chambers coated with collagen. Total internal reflection microscopy showed that adhesion and spreading in the absence of flow were strongly curtailed by these inhibitors with failure of stable process extension and reduced the retraction of formed clots. Deubiquitinase inhibition also sharply reduced homotypic platelet aggregation in response to not only the incomplete agonists ADP and collagen acting through glycoprotein VI but also to the complete agonist thrombin. Suppressed aggregation was accompanied by curtailed procaspase activating compound-1 binding to activated IIb/IIIa and inhibition of P-selectin translocation to the platelet surface. Deubiquitinase inhibition abolished the agonist-induced spike in intracellular calcium, suppressed Akt phosphorylation, and reduced agonist-stimulated phosphatase and tensin homolog phosphatase phosphorylation. Platelets express the proteasome-associated deubiquitinases USP14 and UCHL5, and selective inhibition of these enzymes by b-AP15 reproduced the inhibitory effect of the general deubiquitinase inhibitors on ex vivo platelet function. CONCLUSIONS: Remodeling of the ubiquitinated platelet proteome by deubiquitinases promotes agonist-stimulated intracellular signal transduction and platelet responsiveness. [Mh] Termos MeSH primário: Plaquetas/enzimologia Agregação Plaquetária Complexo de Endopeptidases do Proteassoma/sangue Trombose/enzimologia Proteases Específicas de Ubiquitina/sangue [Mh] Termos MeSH secundário: Aminopiridinas/farmacologia Animais Benzoatos/farmacologia Plaquetas/efeitos dos fármacos Cloretos Modelos Animais de Doenças Inibidores Enzimáticos/farmacologia Compostos Férricos Seres Humanos Camundongos Endogâmicos C57BL Técnicas Analíticas Microfluídicas Microscopia de Interferência Piperidonas/farmacologia Agregação Plaquetária/efeitos dos fármacos Testes de Função Plaquetária Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo Pirazóis/farmacologia Receptores de Colágeno/sangue Receptores de Trombina/sangue Transdução de Sinais Tiocianatos/farmacologia Trombose/sangue Trombose/induzido quimicamente Trombose/prevenção & controle Ubiquitina Tiolesterase/antagonistas & inibidores Ubiquitina Tiolesterase/sangue Proteases Específicas de Ubiquitina/antagonistas & inibidores Ubiquitinação [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; VIDEO-AUDIO MEDIA [Nm] Nome de substância: 0 (2,6-diaminopyridine-3,5-bis(thiocyanate)); 0 (3,5-bis((4-nitrophenyl)methylidene)-1-prop-2-enoylpiperidin-4-one); 0 (4-(4-(5-nitrofuran-2-ylmethylene)-3, 5-dioxopyrazolidin-1-yl)benzoic acid ethyl ester); 0 (Aminopyridines); 0 (Benzoates); 0 (Chlorides); 0 (Enzyme Inhibitors); 0 (Ferric Compounds); 0 (Piperidones); 0 (Platelet Glycoprotein GPIIb-IIIa Complex); 0 (Pyrazoles); 0 (Receptors, Collagen); 0 (Receptors, Thrombin); 0 (Thiocyanates); EC 3.1.2.15 (USP14 protein, human); EC 3.4.19.12 (UCHL5 protein, human); EC 3.4.19.12 (Ubiquitin Thiolesterase); EC 3.4.19.12 (Ubiquitin-Specific Proteases); EC 3.4.25.1 (Proteasome Endopeptidase Complex); U38V3ZVV3V (ferric chloride) [Em] Mês de entrada: 1603 [Cu] Atualização por classe: 170220 [Lr] Data última revisão: 170220 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 151017 [St] Status: MEDLINE [do] DOI: 10.1161/ATVBAHA.115.306054

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[PMID]: 25634355 [Au] Autor: Schulz JN; Zeltz C; Sørensen IW; Barczyk M; Carracedo S; Hallinger R; Niehoff A; Eckes B; Gullberg D [Ad] Endereço: Department of Dermatology, University of Cologne, Cologne, Germany. [Ti] Título: Reduced granulation tissue and wound strength in the absence of α11ß1 integrin. [So] Source: J Invest Dermatol;135(5):1435-1444, 2015 May. [Is] ISSN: 1523-1747 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Previous wound healing studies have failed to define a role for either α1ß1 or α2ß1 integrin in fibroblast-mediated wound contraction, suggesting the involvement of another collagen receptor in this process. Our previous work demonstrated that the integrin subunit α11 is highly induced during wound healing both at the mRNA and protein level, prompting us to investigate and dissect the role of the integrin α11ß1 during this process. Therefore, we used mice with a global ablation of either α2 or α11 or both integrin subunits and investigated the repair of excisional wounds. Analyses of wounds demonstrated that α11ß1 deficiency results in reduced granulation tissue formation and impaired wound contraction, independently of the presence of α2ß1. Our combined in vivo and in vitro data further demonstrate that dermal fibroblasts lacking α11ß1 are unable to efficiently convert to myofibroblasts, resulting in scar tissue with compromised tensile strength. Moreover, we suggest that the reduced stability of the scar is a consequence of poor collagen remodeling in α11(-/-) wounds associated with defective transforming growth factor-ß-dependent JNK signaling. [Mh] Termos MeSH primário: Cicatriz/patologia Cicatriz/fisiopatologia Tecido de Granulação/fisiologia Integrinas/deficiência Receptores de Colágeno/deficiência Resistência à Tração/fisiologia Cicatrização/fisiologia [Mh] Termos MeSH secundário: Animais Diferenciação Celular/fisiologia Células Cultivadas Colágeno/fisiologia Feminino Tecido de Granulação/patologia Técnicas In Vitro Integrinas/genética Integrinas/fisiologia MAP Quinase Quinase 4/fisiologia Masculino Camundongos Camundongos Endogâmicos C57BL Camundongos Knockout Modelos Animais Miofibroblastos/patologia Miofibroblastos/fisiologia Receptores de Colágeno/genética Receptores de Colágeno/fisiologia Transdução de Sinais/fisiologia Fator de Crescimento Transformador beta/fisiologia [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Integrins); 0 (Receptors, Collagen); 0 (Transforming Growth Factor beta); 0 (integrin alpha11beta1); 9007-34-5 (Collagen); EC 2.7.12.2 (MAP Kinase Kinase 4) [Em] Mês de entrada: 1507 [Cu] Atualização por classe: 170903 [Lr] Data última revisão: 170903 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 150131 [St] Status: MEDLINE

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MEDLINE

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[PMID]: 24962729 [Au] Autor: Talior-Volodarsky I; Arora PD; Wang Y; Zeltz C; Connelly KA; Gullberg D; McCulloch CA [Ad] Endereço: Matrix Dynamics Group, University of Toronto, Toronto, Ontario, Canada. [Ti] Título: Glycated Collagen Induces α11 Integrin Expression Through TGF-ß2 and Smad3. [So] Source: J Cell Physiol;230(2):327-36, 2015 Feb. [Is] ISSN: 1097-4652 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The adhesion of cardiac fibroblasts to the glycated collagen interstitium in diabetics is associated with de novo expression of the α11 integrin, myofibroblast formation and cardiac fibrosis. We examined how methylglyoxal-glycated collagen regulates α11 integrin expression. In cardiac fibroblasts plated on glycated collagen but not glycated fibronectin, there was markedly increased α11 integrin and α-smooth muscle actin expression. Compared with native collagen, binding of purified α11ß1 integrin to glycated collagen was reduced by >fourfold, which was consistent with reduced fibroblast attachment to glycated collagen. Glycated collagen strongly enhanced the expression of TGF-ß2 but not TGF-ß1 or TGF-ß3. The increased expression of TGF-ß2 was inhibited by triple helical collagen peptides that mimic the α11ß1 integrin binding site on type I collagen. In cardiac fibroblasts transfected with α11 integrin luciferase promoter constructs, glycated collagen activated the α11 integrin promoter. Analysis of α11 integrin promoter truncation mutants showed a novel Smad2/3 binding site located between -809 and -1300 nt that was required for promoter activation. We conclude that glycated collagen in the cardiac interstitium triggers an autocrine TGF-ß2 signaling pathway that stimulates α11 integrin expression through Smad2/3 binding elements in the α11 integrin promoter, which is important for myofibroblast formation and fibrosis. [Mh] Termos MeSH primário: Colágeno/metabolismo Fibronectinas/metabolismo Integrinas/metabolismo Miofibroblastos/metabolismo Receptores de Colágeno/metabolismo Proteína Smad3/metabolismo Fator de Crescimento Transformador beta2/metabolismo [Mh] Termos MeSH secundário: Células Cultivadas Seres Humanos Proteína Smad2/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Fibronectins); 0 (Integrins); 0 (Receptors, Collagen); 0 (SMAD2 protein, human); 0 (SMAD3 protein, human); 0 (Smad2 Protein); 0 (Smad3 Protein); 0 (Transforming Growth Factor beta2); 0 (fibronectin, glycosylated); 0 (integrin alpha11beta1); 9007-34-5 (Collagen) [Em] Mês de entrada: 1510 [Cu] Atualização por classe: 150807 [Lr] Data última revisão: 150807 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 140626 [St] Status: MEDLINE [do] DOI: 10.1002/jcp.24708

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