Base de dados : MEDLINE
Pesquisa : D08.811.913.696.620.682.725.400.850.750 [Categoria DeCS]
Referências encontradas : 355 [refinar]
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[PMID]:28817624
[Au] Autor:Randolph ME; Cleary MM; Bajwa Z; Svalina MN; Young MC; Mansoor A; Kaur P; Bult CJ; Goros MW; Michalek JE; Xiang S; Keck J; Krasnoperov V; Gill P; Keller C
[Ad] Endereço:Children's Cancer Therapy Development Institute, Beaverton, Oregon, United States of America.
[Ti] Título:EphB4/EphrinB2 therapeutics in Rhabdomyosarcoma.
[So] Source:PLoS One;12(8):e0183161, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma affecting children and is often diagnosed with concurrent metastases. Unfortunately, few effective therapies have been discovered that improve the long-term survival rate for children with metastatic disease. Here we determined effectiveness of targeting the receptor tyrosine kinase, EphB4, in both alveolar and embryonal RMS either directly through the inhibitory antibody, VasG3, or indirectly by blocking both forward and reverse signaling of EphB4 binding to EphrinB2, cognate ligand of EphB4. Clinically, EphB4 expression in eRMS was correlated with longer survival. Experimentally, inhibition of EphB4 with VasG3 in both aRMS and eRMS orthotopic xenograft and allograft models failed to alter tumor progression. Inhibition of EphB4 forward signaling using soluble EphB4 protein fused with murine serum albumin failed to affect eRMS model tumor progression, but did moderately slow progression in murine aRMS. We conclude that inhibition of EphB4 signaling with these agents is not a viable monotherapy for rhabdomyosarcoma.
[Mh] Termos MeSH primário: Efrina-B2/metabolismo
Receptor EphB4/metabolismo
Rabdomiossarcoma/terapia
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Seres Humanos
Camundongos
Camundongos Transgênicos
Prognóstico
Rabdomiossarcoma/metabolismo
Rabdomiossarcoma/patologia
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ephrin-B2); EC 2.7.10.1 (Receptor, EphB4)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170818
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0183161


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[PMID]:28739744
[Au] Autor:Yin J; Cui Y; Li L; Ji J; Jiang WG
[Ad] Endereço:Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, U.K.
[Ti] Título:Overexpression of EPHB4 Is Associated with Poor Survival of Patients with Gastric Cancer.
[So] Source:Anticancer Res;37(8):4489-4497, 2017 08.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Increased expression of erythropoietin-producing human hepatoma (EPHB4) leads to enhanced cell migration, growth and adhesion in tumor cells. However, little is known regarding the effects of EPHB4 in gastric cancer. The present study aimed to examine the clinical relevance of EPHB4 and its association with the prognosis of gastric cancer. MATERIALS AND METHODS: EPHB4 transcript expression in 324 gastric cancer samples with paired adjacent normal gastric tissues was determined using quantitative polymerase chain reaction and the results were statistically analyzed against patient clinicopathological data. AGS and HGC27 cell lines were transfected with EPHB4 siRNA and the effects examined by functional analysis. RESULTS: EPHB4 mRNA levels in gastric cancer tissues were significantly elevated when compared to non-cancerous tissues (p=0.0110). Tissue samples from male patients exhibited lower expression than those from female patients (p=0.0110). Non-cardiac gastric tumors (fundus, corpus and pylorus) expressed a higher number of EPHB4 transcripts in comparison to cardiac gastric tumors (p<0.001). Increased expression of EPHB4 was significantly associated with poorer overall (p=0.0051) and progression-free (p=0.0262) survival. EPHB4 knockdown appeared to reduce post-wound migration of AGS cells (p=0.0057) and increase migration of HGC27 cells (p=0.0337). EPHB4 knockdown significantly increased adhesive ability in HGC27 (p<0.0001). CONCLUSION: The expression of EPHB4 was increased in gastric cancer and increased EPHB4 expression was correlated with poor survival. Knockdown of EPHB4 promoted adhesion and exerted diverse effects on migration of gastric cancer cells. Further investigations may highlight its predictive and therapeutic potential in gastric cancer.
[Mh] Termos MeSH primário: Expressão Gênica
Receptor EphB4/genética
Neoplasias Gástricas/genética
Neoplasias Gástricas/mortalidade
[Mh] Termos MeSH secundário: Biomarcadores Tumorais
Adesão Celular/genética
Linhagem Celular Tumoral
Movimento Celular/genética
Proliferação Celular
Feminino
Técnicas de Silenciamento de Genes
Seres Humanos
Estimativa de Kaplan-Meier
Masculino
Gradação de Tumores
Estadiamento de Neoplasias
Prognóstico
RNA Interferente Pequeno/genética
Neoplasias Gástricas/tratamento farmacológico
Neoplasias Gástricas/patologia
Transcrição Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (RNA, Small Interfering); EC 2.7.10.1 (Receptor, EphB4)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE


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[PMID]:28687708
[Au] Autor:Amyere M; Revencu N; Helaers R; Pairet E; Baselga E; Cordisco M; Chung W; Dubois J; Lacour JP; Martorell L; Mazereeuw-Hautier J; Pyeritz RE; Amor DJ; Bisdorff A; Blei F; Bombei H; Dompmartin A; Brooks D; Dupont J; González-Enseñat MA; Frieden I; Gérard M; Kvarnung M; Hanson-Kahn AK; Hudgins L; Léauté-Labrèze C; McCuaig C; Metry D; Parent P; Paul C; Petit F; Phan A; Quere I; Salhi A; Turner A; Vabres P; Vicente A; Wargon O; Watanabe S; Weibel L; Wilson A; Willing M; Mulliken JB; Boon LM; Vikkula M
[Ad] Endereço:From Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium (M.A., R.H., M.V.); Center for Human Genetics, Cliniques Universitaires St Luc, Université catholique de Louvain, Brussels, Belgium (N.R.); Université catholique de Louvain, Brussels, Belgium (E.P.)
[Ti] Título:Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling.
[So] Source:Circulation;136(11):1037-1048, 2017 Sep 12.
[Is] ISSN:1524-4539
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Most arteriovenous malformations (AVMs) are localized and occur sporadically. However, they also can be multifocal in autosomal-dominant disorders, such as hereditary hemorrhagic telangiectasia and capillary malformation (CM)-AVM. Previously, we identified mutations in 50% of patients with CM-AVM. Herein we studied non-RASA1 patients to further elucidate the pathogenicity of CMs and AVMs. METHODS: We conducted a genome-wide linkage study on a CM-AVM family. Whole-exome sequencing was also performed on 9 unrelated CM-AVM families. We identified a candidate gene and screened it in a large series of patients. The influence of several missense variants on protein function was also studied in vitro. RESULTS: We found evidence for linkage in 2 loci. Whole-exome sequencing data unraveled 4 distinct damaging variants in in 5 families that cosegregated with CM-AVM. Overall, screening of detected 47 distinct mutations in 54 index patients: 27 led to a premature stop codon or splice-site alteration, suggesting loss of function. The other 20 are nonsynonymous variants that result in amino acid substitutions. In vitro expression of several mutations confirmed loss of function of EPHB4. The clinical features included multifocal CMs, telangiectasias, and AVMs. CONCLUSIONS: We found mutations in patients with multifocal CMs associated with AVMs. The phenotype, CM-AVM2, mimics -related CM-AVM1 and also hereditary hemorrhagic telangiectasia. -encoded p120RASGAP is a direct effector of EPHB4. Our data highlight the pathogenetic importance of this interaction and indicts EPHB4-RAS-ERK signaling pathway as a major cause for AVMs.
[Mh] Termos MeSH primário: Malformações Arteriovenosas/diagnóstico
Malformações Arteriovenosas/genética
Capilares/anormalidades
Mutação em Linhagem Germinativa/genética
Sistema de Sinalização das MAP Quinases/fisiologia
Mancha Vinho do Porto/diagnóstico
Mancha Vinho do Porto/genética
Receptor EphB4/genética
Proteína p120 Ativadora de GTPase/genética
[Mh] Termos MeSH secundário: Bases de Dados Genéticas
Feminino
Estudo de Associação Genômica Ampla/métodos
Seres Humanos
Masculino
Linhagem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RASA1 protein, human); 0 (p120 GTPase Activating Protein); EC 2.7.10.1 (Receptor, EphB4)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170709
[St] Status:MEDLINE
[do] DOI:10.1161/CIRCULATIONAHA.116.026886


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[PMID]:28254815
[Au] Autor:Ghori A; Freimann FB; Nieminen-Kelhä M; Kremenetskaia I; Gertz K; Endres M; Vajkoczy P
[Ad] Endereço:From the Department of Neurosurgery (A.G., F.B.F., M.N.-K., I.K., P.V.), Center for Stroke Research (K.G., M.E., P.V.), Department of Neurology (M.E.), and German Center for Neurodegenerative Diseases (M.E.), Charité, Universitätsmedizin Berlin, Germany; German Center for Cardiovascular Research (DZ
[Ti] Título:EphrinB2 Activation Enhances Vascular Repair Mechanisms and Reduces Brain Swelling After Mild Cerebral Ischemia.
[So] Source:Arterioscler Thromb Vasc Biol;37(5):867-878, 2017 May.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Cerebral edema caused by the disruption of the blood-brain barrier is a major complication after stroke. Therefore, strategies to accelerate and enhance neurovascular recovery after stroke are of prime interest. Our main aim was to study the role of ephrinB2/EphB4 signaling in mediating the vascular repair and in blood-brain barrier restoration after mild cerebral ischemia occlusion/reperfusion. APPROACH AND RESULTS: Here, we show that the guidance molecule ephrinB2 plays a key role in neurovascular protection and blood-brain barrier restoration after stroke. In a focal stroke model, we characterize the stroke-induced damage to cerebral blood vessels and their subsequent endogenous repair on a cellular, molecular, and functional level. EphrinB2 and its tyrosine kinase receptor EphB4 are upregulated early after stroke by endothelial cells and perivascular support cells, in parallel to their reassembly during neurovascular recovery. Using both retroviral and pharmacological approaches, we show that the inhibition of ephrinB2/EphB4 signaling suppresses post-middle cerebral artery occlusion neurovascular repair mechanisms resulting in an aggravation of brain swelling. In contrast, the activation of ephrinB2 after brain ischemia leads to an increased pericyte recruitment and increased endothelial-pericyte interaction, resulting in an accelerated neurovascular repair after ischemia. CONCLUSIONS: We show that reducing swelling could result in improved outcome because of reduction in damaged brain tissue. We also identify a novel role for ephrinB2/EphB4 signaling in the maintenance of the neurovascular homeostasis and provide a novel therapeutic approach in reducing brain swelling after stroke.
[Mh] Termos MeSH primário: Barreira Hematoencefálica/efeitos dos fármacos
Edema Encefálico/prevenção & controle
Efrina-B2/agonistas
Terapia Genética
Infarto da Artéria Cerebral Média/terapia
Neovascularização Fisiológica/efeitos dos fármacos
Fármacos Neuroprotetores/farmacologia
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Barreira Hematoencefálica/metabolismo
Barreira Hematoencefálica/patologia
Barreira Hematoencefálica/fisiopatologia
Edema Encefálico/genética
Edema Encefálico/metabolismo
Edema Encefálico/patologia
Linhagem Celular
Modelos Animais de Doenças
Células Endoteliais/metabolismo
Células Endoteliais/patologia
Efrina-B2/genética
Efrina-B2/metabolismo
Infarto da Artéria Cerebral Média/genética
Infarto da Artéria Cerebral Média/metabolismo
Infarto da Artéria Cerebral Média/fisiopatologia
Masculino
Camundongos Endogâmicos C57BL
Pericitos/metabolismo
Pericitos/patologia
Fosforilação
Interferência de RNA
Receptor EphB4/genética
Receptor EphB4/metabolismo
Índice de Gravidade de Doença
Transdução de Sinais/efeitos dos fármacos
Fatores de Tempo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (EFNB2 protein, mouse); 0 (Ephrin-B2); 0 (Neuroprotective Agents); EC 2.7.10.1 (Ephb4 protein, mouse); EC 2.7.10.1 (Receptor, EphB4)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170621
[Lr] Data última revisão:
170621
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170304
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.116.308620


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[PMID]:28234918
[Au] Autor:Lauridsen HM; Gonzalez AL
[Ad] Endereço:Department of Biomedical Engineering, Yale University, New Haven, CT, United States of America.
[Ti] Título:Biomimetic, ultrathin and elastic hydrogels regulate human neutrophil extravasation across endothelial-pericyte bilayers.
[So] Source:PLoS One;12(2):e0171386, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The vascular basement membrane-a thin, elastic layer of extracellular matrix separating and encasing vascular cells-provides biological and mechanical cues to endothelial cells, pericytes, and migrating leukocytes. In contrast, experimental scaffolds typically used to replicate basement membranes are stiff and bio-inert. Here, we present thin, porated polyethylene glycol hydrogels to replicate human vascular basement membranes. Like commercial transwells, our hydrogels are approximately 10µm thick, but like basement membranes, the hydrogels presented here are elastic (E: 50-80kPa) and contain a dense network of small pores. Moreover, the inclusion of bioactive domains introduces receptor-mediated biochemical signaling. We compare elastic hydrogels to common culture substrates (E: >2GPa) for human endothelial cell and pericyte monolayers and bilayers to replicate postcapillary venules in vitro. Our data demonstrate that substrate elasticity facilitates differences in vascular phenotype, supporting expression of vascular markers that are increasingly replicative of venules. Endothelial cells differentially express vascular markers, like EphB4, and leukocyte adhesion molecules, such as ICAM-1, with decreased mechanical stiffness. With porated PEG hydrogels we demonstrate the ability to evaluate and observe leukocyte recruitment across endothelial cell and pericyte monolayers and bilayers, reporting that basement membrane scaffolds can significantly alter the rate of vascular migration in experimental systems. Overall, this study demonstrates the creation and utility of a new and accessible method to recapture the mechanical and biological complexity of human basement membranes in vitro.
[Mh] Termos MeSH primário: Membrana Basal/química
Células Endoteliais/citologia
Neutrófilos/citologia
Pericitos/citologia
Engenharia Tecidual/métodos
[Mh] Termos MeSH secundário: Membrana Basal/metabolismo
Membrana Basal/ultraestrutura
Biomarcadores/metabolismo
Materiais Biomiméticos/química
Materiais Biomiméticos/metabolismo
Movimento Celular
Módulo de Elasticidade
Elasticidade
Células Endoteliais/metabolismo
Matriz Extracelular/química
Matriz Extracelular/metabolismo
Expressão Gênica
Seres Humanos
Hidrogéis/química
Hidrogéis/metabolismo
Molécula 1 de Adesão Intercelular/genética
Molécula 1 de Adesão Intercelular/metabolismo
Neutrófilos/metabolismo
Pericitos/metabolismo
Polietilenoglicóis/química
Porosidade
Cultura Primária de Células
Receptor EphB4/genética
Receptor EphB4/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Hydrogels); 0 (ICAM1 protein, human); 126547-89-5 (Intercellular Adhesion Molecule-1); 30IQX730WE (Polyethylene Glycols); EC 2.7.10.1 (Receptor, EphB4)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170225
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0171386


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[PMID]:28214829
[Au] Autor:Liu T; Zeng X; Sun F; Hou H; Guan Y; Guo D; Ai H; Wang W; Zhang G
[Ti] Título:EphB4 Regulates Self-Renewal, Proliferation and Neuronal Differentiation of Human Embryonic Neural Stem Cells in Vitro.
[So] Source:Cell Physiol Biochem;41(2):819-834, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: EphB4 belongs to the largest family of Eph receptor tyrosine kinases. It contributes to a variety of pathological progresses of cancer malignancy. However, little is known about its role in neural stem cells (NSCs). This study examined whether EphB4 is required for proliferation and differentiation of human embryonic neural stem cells (hNSCs) in vitro. METHODS: We up- and down-regulated EphB4 expression in hNSCs using lentiviral over-expression and shRNA knockdown constructs and then investigated the influence of EphB4 on the properties of hNSCs. RESULTS: Our results show that shRNA-mediated EphB4 reduction profoundly impaired hNSCs self-renewal and proliferation. Furthermore, detection of differentiation revealed that knockdown of EphB4 inhibited hNSCs differentiation towards a neuronal lineage and promoted hNSCs differentiation to glial cells. In contrast, EphB4 overexpression promoted hNSCs self-renewal and proliferation, further induced hNSCs differentiation towards a neuronal lineage and inhibited hNSCs differentiation to glial cells. Moreover, we found that EphB4 regulates cell proliferation mediated by the Abl-CyclinD1 pathway. CONCLUSION: These studies provide strong evidence that fine tuning of EphB4 expression is crucial for the proliferation and neuronal differentiation of hNSCs, suggesting that EphB4 might be an interesting target for overcoming some of the therapeutic limitations of neuronal loss in brain diseases.
[Mh] Termos MeSH primário: Células-Tronco Neurais/metabolismo
Receptor EphB4/metabolismo
[Mh] Termos MeSH secundário: Pontos de Checagem do Ciclo Celular
Diferenciação Celular
Linhagem da Célula
Proliferação Celular
Células Cultivadas
Ciclina D1/metabolismo
Quinase 4 Dependente de Ciclina/metabolismo
Seres Humanos
Células-Tronco Neurais/citologia
Neurônios/citologia
Proteínas Proto-Oncogênicas c-abl/metabolismo
Interferência de RNA
RNA Interferente Pequeno/metabolismo
Receptor EphB4/antagonistas & inibidores
Receptor EphB4/genética
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Small Interfering); 136601-57-5 (Cyclin D1); EC 2.7.10.1 (Receptor, EphB4); EC 2.7.10.2 (Proto-Oncogene Proteins c-abl); EC 2.7.11.22 (Cyclin-Dependent Kinase 4)
[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:170220
[St] Status:MEDLINE
[do] DOI:10.1159/000459693


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[PMID]:27726217
[Au] Autor:Wang L; Zhang J; Wang C; Qi Y; Du M; Liu W; Yang C; Yang P
[Ad] Endereço:Department of Periodontology, School of Stomatology, Shandong University, Jinan, Shandong, China.
[Ti] Título:Low concentrations of TNF-α promote osteogenic differentiation via activation of the ephrinB2-EphB4 signalling pathway.
[So] Source:Cell Prolif;50(1), 2017 Feb.
[Is] ISSN:1365-2184
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: Low concentrations of tumour necrosis factor-alpha (TNF-α) have been reported to promote osteogenic differentiation. In this study, a series of in vitro experiments was performed to investigate underlying molecular mechanisms involved. MATERIALS AND METHODS: MC3T3-E1 murine preosteoblasts were treated with TNF-α at doses of 0, 0.1 or 1 ng/mL. The ephrinB2-EphB4 signalling pathway was activated using ephrinB2-fc, or inhibited using lentiviruses encoding siRNAs specifically targeting EphB4. Cell proliferation/survival was evaluated using the Cell Counting Kit-8 (CCK-8) assay, and expression levels of Runx2, BSP, ephrinB2 and EphB4 were determined using RT-PCR and Western blotting. ALP activity in these cells was also determined, and mineral nodule formation was evaluated with alizarin red S staining. RESULTS: Low concentrations of TNF-α had no influence on cell proliferation/survival. However, expression levels of Runx2, BSP, ephrinB2 and EphB4, as well as ALP activity and mineral nodule formation, were significantly enhanced in MC3T3-E1 cells treated with low concentrations of TNF-α. Moreover, activation of the ephrinB2-EphB4 signalling pathway by ephrinB2-fc enhanced TNF-α-induced osteogenic differentiation, while down-regulation of EphB4 level reversed the positive effect of TNF-α. CONCLUSIONS: Low concentrations of TNF-α promoted osteogenic differentiation via activation of the ephrinB2-EphB4 signalling pathway.
[Mh] Termos MeSH primário: Diferenciação Celular/efeitos dos fármacos
Efrina-B2/metabolismo
Osteogênese/efeitos dos fármacos
Receptor EphB4/metabolismo
Transdução de Sinais/efeitos dos fármacos
Fator de Necrose Tumoral alfa/farmacologia
[Mh] Termos MeSH secundário: Fosfatase Alcalina/metabolismo
Animais
Western Blotting
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Subunidade alfa 1 de Fator de Ligação ao Core/genética
Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo
Efrina-B2/genética
Sialoproteína de Ligação à Integrina/genética
Sialoproteína de Ligação à Integrina/metabolismo
Camundongos
Interferência de RNA
RNA Mensageiro/metabolismo
RNA Interferente Pequeno/metabolismo
Reação em Cadeia da Polimerase em Tempo Real
Receptor EphB4/antagonistas & inibidores
Receptor EphB4/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Core Binding Factor Alpha 1 Subunit); 0 (Ephrin-B2); 0 (Ibsp protein, mouse); 0 (Integrin-Binding Sialoprotein); 0 (RNA, Messenger); 0 (RNA, Small Interfering); 0 (Tumor Necrosis Factor-alpha); EC 2.7.10.1 (Ephb4 protein, mouse); EC 2.7.10.1 (Receptor, EphB4); EC 3.1.3.1 (Alkaline Phosphatase)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170206
[Lr] Data última revisão:
170206
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161012
[St] Status:MEDLINE
[do] DOI:10.1111/cpr.12311


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[PMID]:27388534
[Au] Autor:Pierscianek D; Wolf S; Keyvani K; El Hindy N; Stein KP; Sandalcioglu IE; Sure U; Mueller O; Zhu Y
[Ad] Endereço:Department of Neurosurgery, Universitatsklinikum Essen, Germany.
[Ti] Título:Study of angiogenic signaling pathways in hemangioblastoma.
[So] Source:Neuropathology;37(1):3-11, 2017 Feb.
[Is] ISSN:1440-1789
[Cp] País de publicação:Australia
[La] Idioma:eng
[Ab] Resumo:Hemangioblastoma (HB) is mainly located in the brain and the spinal cord. The tumor is composed of two major components, namely neoplastic stromal cells and abundant microvessels. Thus, hyper-vascularization is the hallmark of this tumor. Despite the identification of germline and/or epigenetic mutations of Von Hippel Lindau (VHL) gene as an important pathogenic mechanism of HB, little is known about the molecular signaling involved in this highly vascularized tumor. The present study investigated the key players of multiple angiogenic signaling pathways including VEGF/VEGFR2, EphB4/EphrinB2, SDF1α/CXCR4 and Notch/Dll4 pathways in surgical specimens of 22 HB. The expression of key angiogenic factors was detected by RT -PCR and Western blot. Immunofluorescent staining revealed the cellular localization of these proteins. We demonstrated a massive upregulation of mRNA levels of VEGF and VEGFR2, CXCR4 and SDF1α, EphB4 and EphrinB2, as well as the main components of Dll4-Notch signaling in HB. An increase in the protein expression of VEGF, CXCR4 and the core-components of Dll4-Notch signaling was associated with an activation of Akt and Erk1/2 and accompanied by an elevated expression of PCNA. Immuofluorescent staining revealed the expression of VEGF and CXCR4 in endothelial cells as well as in tumor cells. Dll4 protein was predominantly found in tumor cells, whereas EphB4 immunoreactivity was exclusively detected in endothelial cells. We conclude that multiple key angiogenic pathways were activated in HB, which may synergistically contribute to the abundant vascularization in this tumor. Identification of these aberrant pathways provides potential targets for a possible future application of anti-angiogenic therapy for this tumor, particularly when a total surgical resection becomes difficult due to the localization or multiplicity of the tumor.
[Mh] Termos MeSH primário: Fossa Craniana Posterior/metabolismo
Regulação Neoplásica da Expressão Gênica
Hemangioblastoma/metabolismo
Neovascularização Patológica/metabolismo
Transdução de Sinais/fisiologia
Neoplasias da Base do Crânio/metabolismo
Neoplasias da Coluna Vertebral/metabolismo
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Quimiocina CXCL12/genética
Quimiocina CXCL12/metabolismo
Fossa Craniana Posterior/patologia
Células Endoteliais/metabolismo
Células Endoteliais/patologia
Efrina-B2/genética
Efrina-B2/metabolismo
Feminino
Hemangioblastoma/genética
Hemangioblastoma/patologia
Seres Humanos
Masculino
Meia-Idade
Neovascularização Patológica/genética
Neovascularização Patológica/patologia
Receptor EphB4/genética
Receptor EphB4/metabolismo
Receptores CXCR4/genética
Receptores CXCR4/metabolismo
Receptores Notch/genética
Receptores Notch/metabolismo
Neoplasias da Base do Crânio/genética
Neoplasias da Base do Crânio/patologia
Neoplasias da Coluna Vertebral/genética
Neoplasias da Coluna Vertebral/patologia
Regulação para Cima
Fator A de Crescimento do Endotélio Vascular/genética
Fator A de Crescimento do Endotélio Vascular/metabolismo
Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CXCR4 protein, human); 0 (Chemokine CXCL12); 0 (Ephrin-B2); 0 (Receptors, CXCR4); 0 (Receptors, Notch); 0 (Vascular Endothelial Growth Factor A); EC 2.7.10.1 (KDR protein, human); EC 2.7.10.1 (Receptor, EphB4); EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170214
[Lr] Data última revisão:
170214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160709
[St] Status:MEDLINE
[do] DOI:10.1111/neup.12316


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[PMID]:26817610
[Au] Autor:Wang M; Collins MJ; Foster TR; Bai H; Hashimoto T; Santana JM; Shu C; Dardik A
[Ad] Endereço:Department of Vascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, China; Vascular Biology and Therapeutics Program and Department of Surgery, Yale University School of Medicine, New Haven, Conn.
[Ti] Título:Eph-B4 mediates vein graft adaptation by regulation of endothelial nitric oxide synthase.
[So] Source:J Vasc Surg;65(1):179-189, 2017 Jan.
[Is] ISSN:1097-6809
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Vein graft adaptation is characterized by loss of expression of the tyrosine kinase receptor Eph-B4, the embryonic determinant of venous identity, without increased expression of its ligand ephrin-B2, the embryonic determinant of arterial identity. Endothelial nitric oxide synthase (eNOS) is an important mediator of vessel remodeling. We hypothesized that the mechanism of action of Eph-B4 during vein graft adaptation might be through regulation of downstream eNOS activity. METHODS: Mouse lung endothelial cells were stimulated with ephrin-B2/Fc, without and with preclustering, without and with the eNOS inhibitor N -nitro-l-arginine methyl ester hydrochloride or the Eph-B4 inhibitor NVP-BHG712, and assessed by Western blot and immunofluorescence for eNOS and Eph-B4 phosphorylation. Nitric oxide (NO) production was assessed using an NO-specific chemiluminescence analyzer. Cell migration was assessed using a Transwell assay. Human and mouse vein graft specimens were examined for eNOS activity by Western blot, and vessel remodeling was assessed in vein grafts in wild-type or eNOS knockout mice. RESULTS: Ephrin-B2/Fc stimulated both Eph-B4 and eNOS phosphorylation in a bimodal temporal distribution (n = 4; P < .05), with preclustered ephrin-B2/Fc causing prolonged peak Eph-B4 and eNOS phosphorylation as well as altered subcellular localization (n = 4; P < .05). Ephrin-B2/Fc increased NO release (n = 3; P < .01) as well as increased endothelial cell migration (n = 6; P < .05) in an eNOS-dependent fashion. Both human and mouse vein grafts showed increased eNOS phosphorylation compared with normal veins (n = 3; P < .05). Vein grafts from eNOS knockout mice showed less dilation and less wall thickening compared with wild-type vein grafts (n = 7; P < .05). CONCLUSIONS: eNOS is a mediator of vein graft adaptation to the arterial environment. Eph-B4 stimulates eNOS phosphorylation in vitro and may mediate vein graft adaptation by regulation of eNOS activity in vivo.
[Mh] Termos MeSH primário: Óxido Nítrico Sintase Tipo III/metabolismo
Receptor EphB4/metabolismo
Veia Safena/transplante
Remodelação Vascular
Veia Cava Inferior/transplante
[Mh] Termos MeSH secundário: Adaptação Fisiológica
Animais
Movimento Celular
Células Cultivadas
Inibidores Enzimáticos/farmacologia
Efrina-B2/farmacologia
Genótipo
Seres Humanos
Camundongos Endogâmicos C57BL
Camundongos Knockout
NG-Nitroarginina Metil Éster/farmacologia
Óxido Nítrico/metabolismo
Óxido Nítrico Sintase Tipo III/antagonistas & inibidores
Óxido Nítrico Sintase Tipo III/deficiência
Óxido Nítrico Sintase Tipo III/genética
Fenótipo
Fosforilação
Veia Safena/enzimologia
Veia Safena/patologia
Transdução de Sinais
Fatores de Tempo
Veia Cava Inferior/efeitos dos fármacos
Veia Cava Inferior/enzimologia
Veia Cava Inferior/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Ephrin-B2); 31C4KY9ESH (Nitric Oxide); EC 1.14.13.39 (NOS3 protein, human); EC 1.14.13.39 (Nitric Oxide Synthase Type III); EC 1.14.13.39 (Nos3 protein, mouse); EC 2.7.10.1 (Ephb4 protein, mouse); EC 2.7.10.1 (Receptor, EphB4); V55S2QJN2X (NG-Nitroarginine Methyl Ester)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170516
[Lr] Data última revisão:
170516
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160129
[St] Status:MEDLINE


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[PMID]:28077917
[Au] Autor:Shen LL; Zhang LX; Wang LM; Zhou RJ; Yang CZ; Zhang J; Yang PS
[Ad] Endereço:Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong University, Jinan, Shandong, China; Liaocheng People's Hospital, Liaocheng, Shandong, China.
[Ti] Título:Disturbed Expression of EphB4, but Not EphrinB2, Inhibited Bone Regeneration in an In Vivo Inflammatory Microenvironment.
[So] Source:Mediators Inflamm;2016:6430407, 2016.
[Is] ISSN:1466-1861
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The important role of ephrinB2-EphB4 signaling pathway in bone remodeling has been well established. However, it is still unclear whether this bidirectional signaling also has effects on the regenerative processes of bone defects created in an inflammatory microenvironment. In this study, an experimental animal model of bone defects treated with lentiviruses was prepared and an inflammatory microenvironment was established. Expression levels of bone marker genes were monitored in the newly formed bone tissue using quantitative reverse transcriptase polymerase chain reaction and western blot. Immunohistochemical (IHC) staining and histomorphometric analysis were also performed to evaluate bone healing processes. Compared with the pLenti6.3-ctrl group, the pLenti6.3-ephb4siRNA group exhibited lower expression levels of bone formation marker genes and a higher level of NFATc1 in the new bone tissue. In addition, the newly formed bone was thinner and the number of giant osteoclasts was higher in the pLenti6.3-ephb4siRNA group than that in the pLenti6.3-ctrl group. In contrast, there was no significant difference between the pLenti6.3-efnb2siRNA group and the pLenti6.3-ctrl group. In conclusion, EphB4 plays an irreplaceable role in bone regeneration in an inflammatory microenvironment, whereas the functional loss of ephrinB2 can be effectively compensated, most possibly by other ephrins with similar chemical structures.
[Mh] Termos MeSH primário: Regeneração Óssea
Inflamação
Fatores de Transcrição NFATC/metabolismo
Receptor EphB2/metabolismo
Receptor EphB4/metabolismo
[Mh] Termos MeSH secundário: Animais
Remodelação Óssea
Osso e Ossos/metabolismo
Diferenciação Celular
Modelos Animais de Doenças
Regulação da Expressão Gênica
Células HEK293
Seres Humanos
Imuno-Histoquímica
Lentivirus/genética
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Osteoblastos/metabolismo
Osteoclastos/metabolismo
Osteogênese
RNA Interferente Pequeno/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NFATC Transcription Factors); 0 (Nfatc1 protein, mouse); 0 (RNA, Small Interfering); EC 2.7.10.1 (Ephb2 protein, mouse); EC 2.7.10.1 (Ephb4 protein, mouse); EC 2.7.10.1 (Receptor, EphB2); EC 2.7.10.1 (Receptor, EphB4)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170804
[Lr] Data última revisão:
170804
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170113
[St] Status:MEDLINE
[do] DOI:10.1155/2016/6430407



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