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Pesquisa : D08.811.913.696.620.682.725.400.925.500 [Categoria DeCS]
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  1 / 1491 MEDLINE  
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[PMID]:29304157
[Au] Autor:Freytsis M; Baugh L; Liu Z; Georgakoudi I; Hinds PW; Black LD; Huggins GS
[Ad] Endereço:Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, United States of America.
[Ti] Título:Conditional deletion of RB1 in the Tie2 lineage leads to aortic valve regurgitation.
[So] Source:PLoS One;13(1):e0190623, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Aortic valve disease is a complex process characterized by valve interstitial cell activation, disruption of the extracellular matrix culminating in valve mineralization occurring over many years. We explored the function of the retinoblastoma protein (pRb) in aortic valve disease, given its critical role in mesenchymal cell differentiation including bone development and mineralization. APPROACH AND RESULTS: We generated a mouse model of conditional pRb knockout (cKO) in the aortic valve regulated by Tie2-Cre-mediated excision of floxed RB1 alleles. Aged pRb cKO animals showed significantly more aortic valve regurgitation by echocardiography compared to pRb het control animals. The pRb cKO aortic valves had increased leaflet thickness without increased cellular proliferation. Histologic studies demonstrated intense α-SMA expression in pRb cKO leaflets associated with disorganized extracellular matrix and increased leaflet stiffness. The pRb cKO mice also showed increased circulating cytokine levels. CONCLUSIONS: Our studies demonstrate that pRb loss in the Tie2-lineage that includes aortic valve interstitial cells is sufficient to cause age-dependent aortic valve dysfunction.
[Mh] Termos MeSH primário: Insuficiência da Valva Aórtica/genética
Valva Aórtica/patologia
Deleção de Genes
Genes do Retinoblastoma
Receptor TIE-2/genética
[Mh] Termos MeSH secundário: Animais
Linhagem da Célula
Cromatografia Líquida
Citocinas/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Microscopia de Força Atômica
Espectrometria de Massas em Tandem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Cytokines); EC 2.7.10.1 (Receptor, TIE-2); EC 2.7.10.1 (Tek protein, mouse)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180215
[Lr] Data última revisão:
180215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180106
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190623


  2 / 1491 MEDLINE  
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[PMID]:27778249
[Au] Autor:Campochiaro PA; Peters KG
[Ad] Endereço:Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. pcampo@jhmi.edu.
[Ti] Título:Targeting Tie2 for Treatment of Diabetic Retinopathy and Diabetic Macular Edema.
[So] Source:Curr Diab Rep;16(12):126, 2016 12.
[Is] ISSN:1539-0829
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Tie2 is a tyrosine kinase receptor located predominantly on vascular endothelial cells that plays a central role in vascular stability. Angiopoietin-1 (Angpt1), produced by perivascular cells, binds, clusters, and activates Tie2, leading to Tie2 autophosphorylation and downstream signaling. Activated Tie2 increases endothelial cell survival, adhesion, and cell junction integrity, thereby stabilizing the vasculature. Angiopoietin-2 (Angpt2) and vascular endothelial-protein tyrosine phosphatase (VE-PTP) are negative regulators increased by hypoxia; they inactivate Tie2, destabilizing the vasculature and increasing responsiveness to vascular endothelial growth factor (VEGF) and other inflammatory cytokines that stimulate vascular leakage and neovascularization. AKB-9778 is a small-molecule antagonist of VE-PTP which increases phosphorylation of Tie2 even in the presence of high Angpt2 levels. In preclinical studies, AKB-9778 reduced VEGF-induced leakage and ocular neovascularization (NV) and showed additive benefit when combined with VEGF suppression. In two clinical trials in diabetic macular edema (DME) patients, subcutaneous injections of AKB-9778 were safe and provided added benefit to VEGF suppression. Preliminary data suggest that AKB-9778 monotherapy improves diabetic retinopathy. These data suggest that Tie2 activation may be a valuable strategy to treat or prevent diabetic retinopathy.
[Mh] Termos MeSH primário: Compostos de Anilina/uso terapêutico
Retinopatia Diabética/tratamento farmacológico
Edema Macular/tratamento farmacológico
Receptor TIE-2/antagonistas & inibidores
Ácidos Sulfônicos/uso terapêutico
[Mh] Termos MeSH secundário: Angiopoietina-1/fisiologia
Angiopoietina-2/fisiologia
Seres Humanos
Receptor TIE-2/fisiologia
Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/fisiologia
Transdução de Sinais
Fator A de Crescimento do Endotélio Vascular/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (AKB-9778); 0 (Angiopoietin-1); 0 (Angiopoietin-2); 0 (Aniline Compounds); 0 (Sulfonic Acids); 0 (Vascular Endothelial Growth Factor A); EC 2.7.10.1 (Receptor, TIE-2); EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 3)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171210
[Lr] Data última revisão:
171210
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE


  3 / 1491 MEDLINE  
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[PMID]:28902891
[Au] Autor:Mao L; Wang Y; Wang D; Han G; Fu S; Wang J
[Ad] Endereço:Department of Laboratory Medicine, Affiliated Nantong No. 3 Hospital of Nantong University, Nantong, Jiangsu, China.
[Ti] Título:TEMs but not DKK1 could serve as complementary biomarkers for AFP in diagnosing AFP-negative hepatocellular carcinoma.
[So] Source:PLoS One;12(9):e0183880, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND & AIMS: Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is prevalent worldwide. Despite its limitations, serum alpha-fetoprotein (AFP) remains the most widely-used biomarker for the diagnosis of HCC. This study aimed to assess whether measurement of peripheral plasma Dickkopf-1 (DKK1) and Tie2-expressing monocytes (TEMs) could overcome the limitations of AFP and improve the diagnostic accuracy of HCC. METHODS: Plasma DKK1 level and the percentage of TEMs in peripheral CD14+CD16+ monocytes from HCC patients (n = 82), HBV-related liver cirrhosis (LC) patients (n = 29), chronic hepatitis B (CHB) infected patients (n = 28) and healthy volunteers (n = 31) were analyzed by ELISA and flow cytometry. Receiver operating characteristic (ROC) curves were used to analyze a single biomarker, or a combination of two or three biomarkers. Univariate and multivariate analyses were performed to assess the significance of each marker in prediction of HCC and AFP-negative HCC from LC patients. RESULTS: The percentage of TEMs in peripheral CD14+CD16+ monocytes and plasma level of DKK1 in HCC group were significantly higher than those in LC, CHB and healthy control groups (all P-values <0.05). The percentage of TEMs alone was also significantly higher in AFP-negative HCC group than that in LC, CHB and healthy control groups (all P-values <0.05). Plasma DKK1 level alone could not distinguish between AFP-negative HCC and LC patients. ROC curves showed that the optimal diagnostic cutoff value was 550.93 ng/L for DKK1 and 4.95% for TEMs. There was no significant difference in AUC of DKK1, TEMs and AFP in HCC diagnosis between the four groups (all P>0.05). A combination of DKK1, TEMs and AFP measurements increased the AUC for HCC diagnosis as compared with either marker alone (0.833; 95%CI 0.768-0.886). The AUC for TEMs was 0.692 (95% CI 0.564-0.819) in differentiating AFP-negative HCC from LC, with a sensitivity of 80.0% and a specificity of 65.52%. Only TEMs prevailed as a significant predictor for AFP-negative HCC differentiating from LC patients in univariate and multivariate analyses (P = 0.016, P = 0.023). CONCLUSIONS: TEMs and DKK1 may prove to be potential complementary biomarkers for AFP in the diagnosis of HCC. TEMs rather than DKK1 could serve as a complementary biomarker for AFP in the differential diagnosis of AFP-negative HCC versus LC patients.
[Mh] Termos MeSH primário: Biomarcadores Tumorais/sangue
Carcinoma Hepatocelular/diagnóstico
Peptídeos e Proteínas de Sinalização Intercelular/sangue
Neoplasias Hepáticas/diagnóstico
Monócitos/patologia
Receptor TIE-2/metabolismo
alfa-Fetoproteínas/análise
[Mh] Termos MeSH secundário: Adulto
Idoso
Carcinoma Hepatocelular/sangue
Estudos de Casos e Controles
Diagnóstico Diferencial
Feminino
Seres Humanos
Neoplasias Hepáticas/sangue
Masculino
Meia-Idade
Monócitos/metabolismo
Sensibilidade e Especificidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (DKK1 protein, human); 0 (Intercellular Signaling Peptides and Proteins); 0 (alpha-Fetoproteins); EC 2.7.10.1 (Receptor, TIE-2)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170914
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0183880


  4 / 1491 MEDLINE  
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[PMID]:28898232
[Au] Autor:Wang X; Zhu Q; Lin Y; Wu L; Wu X; Wang K; He Q; Xu C; Wan X; Wang X
[Ad] Endereço:Department of Gynecology and Obstetrics, XinHua Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200092, China.
[Ti] Título:Crosstalk between TEMs and endothelial cells modulates angiogenesis and metastasis via IGF1-IGF1R signalling in epithelial ovarian cancer.
[So] Source:Br J Cancer;117(9):1371-1382, 2017 Oct 24.
[Is] ISSN:1532-1827
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Epithelial ovarian cancer (EOC) is the leading cause of death from gynaecologic malignancies and has a poor prognosis due to metastasis. Drugs targeting the angiogenesis pathway significantly improve patient outcome. However, the key factors linking angiogenesis and metastasis have not been elucidated. In this study, we found Tie2 expressing monocytes (CD14 Tie2 , TEMs) as key contributors to angiogenesis and metastasis of EOC. METHODS: Tissue slides were evaluated by immunofluorescence for the presence of total tissue macrophages and TEMs. The correlation between microvascular density (MVD) values and the TEMs number or ratio was calculated in both ovarian cancer tissues and peritoneum. The rate of TEMs in monocytes was evaluated in the peripheral blood of female healthy donors, benign cysts patients, and EOC patients using flow cytometry. The TEMs rate in ascites from EOC patients was also evaluated by flow cytometry. The concentration of Ang2, as the ligand of Tie2, was examined by ELISA in serum samples of EOC patients, benign cysts patients, and ascites samples of EOC patients. The effects of Ang2 on the migration and the cytokine expression of TEMs were further examined. The pro- angiogenesis activity of TEMs via IGF1 was performed in both in vivo and in vitro. And the IGF1 blocking test was performed using neutralising antibody. RESULTS: TEMs were significantly higher in tumour foci, peripheral blood and ascites in EOC patients. The proportion of TEMs among total tissue macrophages was positively correlated with tumour MVD. In vivo animal results showed that TEMs promoted EOC angiogenesis and metastasis. Further functional and mechanisms studies revealed that concentration of angiopoietin 2 (Ang2), a ligand of Tie2, was elevated in EOC ascites which further recruit TEMs in a dose-dependent manner as a powerful chemokine to TEMs. Recruited TEMs promoted endothelial cell function through IGF1-activated downstream signalling. Blocking secreted IGF1 using inhibiting antibody reduced TEMs mediated angiogenesis and metastasis. CONCLUSIONS: TEMs significantly increased in EOC patients and were recruited to tumour loci by the increased Ang2. The increased TEMs have diagnostic value in ovarian cancer and were positively correlated with the MVD in ovarian cancer tissue. Furthermore, TEMs promote angiogenesis via IGF1 in both in vivo and in vitro experimental systems after stimulation by Ang2. Altogether, this study paves the way to develop novel therapy targets as the axis of Ang2-TEMs-IGF1 in EOC.
[Mh] Termos MeSH primário: Endotélio Vascular/metabolismo
Fator de Crescimento Insulin-Like I/metabolismo
Monócitos/patologia
Neoplasias Epiteliais e Glandulares/irrigação sanguínea
Neoplasias Epiteliais e Glandulares/secundário
Neovascularização Patológica/patologia
Neoplasias Ovarianas/irrigação sanguínea
Neoplasias Ovarianas/secundário
Receptor TIE-2/metabolismo
Receptores de Somatomedina/metabolismo
[Mh] Termos MeSH secundário: Angiopoietina-2/metabolismo
Animais
Biomarcadores Tumorais/metabolismo
Movimento Celular
Células Cultivadas
Endotélio Vascular/citologia
Feminino
Seres Humanos
Camundongos
Camundongos Nus
Monócitos/metabolismo
Estadiamento de Neoplasias
Neoplasias Epiteliais e Glandulares/metabolismo
Neovascularização Patológica/metabolismo
Neoplasias Ovarianas/metabolismo
Prognóstico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiopoietin-2); 0 (Biomarkers, Tumor); 0 (IGF1R protein, human); 0 (Receptors, Somatomedin); 67763-96-6 (Insulin-Like Growth Factor I); EC 2.7.10.1 (Receptor, TIE-2)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171110
[Lr] Data última revisão:
171110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170913
[St] Status:MEDLINE
[do] DOI:10.1038/bjc.2017.297


  5 / 1491 MEDLINE  
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[PMID]:28760776
[Au] Autor:Hossain MB; Shifat R; Li J; Luo X; Hess KR; Rivera-Molina Y; Puerta Martinez F; Jiang H; Lang FF; Hung MC; Fueyo J; Gomez-Manzano C
[Ad] Endereço:Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA mbhossain@mdanderson.org cmanzano@mdanderson.org.
[Ti] Título:TIE2 Associates with Caveolae and Regulates Caveolin-1 To Promote Their Nuclear Translocation.
[So] Source:Mol Cell Biol;37(21), 2017 Nov 01.
[Is] ISSN:1098-5549
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:DNA repair pathways are aberrant in cancer, enabling tumor cells to survive standard therapies-chemotherapy and radiotherapy. Our group previously reported that, upon irradiation, the membrane-bound tyrosine kinase receptor TIE2 translocates into the nucleus and phosphorylates histone H4 at Tyr51, recruiting ABL1 to the DNA repair complexes that participate in the nonhomologous end-joining pathway. However, no specific molecular mechanisms of TIE2 endocytosis have been reported. Here, we show that irradiation or ligand-induced TIE2 trafficking is dependent on caveolin-1, the main component of caveolae. Subcellular fractionation and confocal microscopy demonstrated TIE2/caveolin-1 complexes in the nucleus, and using inhibitor or small interfering RNAs (siRNAs) against caveolin-1 or Tie2 inhibited their trafficking. TIE2 was found in caveolae and directly phosphorylated caveolin-1 at Tyr14 and This modification regulated the generation of TIE2/caveolin-1 complexes and was essential for TIE2/caveolin-1 nuclear translocation. Our data further demonstrate that the combination of TIE2 and caveolin-1 inhibitors resulted in significant radiosensitization of malignant glioma cells, which will guide the development of combinatorial treatment with radiotherapy for patients with glioblastoma.
[Mh] Termos MeSH primário: Cavéolas/metabolismo
Caveolina 1/metabolismo
Núcleo Celular/metabolismo
Glioma/metabolismo
Receptor TIE-2/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Regulação Neoplásica da Expressão Gênica/efeitos da radiação
Células HEK293
Células HeLa
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Fosforilação/efeitos da radiação
Transporte Proteico/efeitos da radiação
Regulação para Cima/efeitos da radiação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CAV1 protein, human); 0 (Caveolin 1); EC 2.7.10.1 (Receptor, TIE-2)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171111
[Lr] Data última revisão:
171111
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170802
[St] Status:MEDLINE


  6 / 1491 MEDLINE  
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[PMID]:28727816
[Au] Autor:Steiner N; Hajek R; Sevcikova S; Borjan B; Jöhrer K; Göbel G; Untergasser G; Gunsilius E
[Ad] Endereço:Department of Internal Medicine V (Hematology and Medical Oncology), Innsbruck Medical University, Anichstr. 35, Innsbruck, Austria.
[Ti] Título:High levels of FLT3-ligand in bone marrow and peripheral blood of patients with advanced multiple myeloma.
[So] Source:PLoS One;12(7):e0181487, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Multiple myeloma (MM) is still incurable due to resistance against various therapies. Thus, the identification of biomarkers predicting progression is urgently needed. Here, we evaluated four biomarkers in bone marrow and peripheral blood of MM patients for their prognostic significance. MATERIALS & METHODS: Bone marrow- and peripheral blood plasma levels of FLT3-L, soluble TIE2, endostatin, and osteoactivin were determined in patients with monoclonal gammopathy of undetermined significance (MGUS, n = 14/n = 4), patients with newly diagnosed MM (NDMM, n = 42/n = 31) and patients with relapsed/refractory MM (RRMM, n = 27/n = 16) by sandwich ELISA. RESULTS: Median FLT3-L expression increased from MGUS (58.77 pg/ml in bone marrow; 80.40 pg/ml in peripheral blood) to NDMM (63.15 pg/ml in bone marrow; 85.05 pg/ml in peripheral blood) and was maximal in RRMM (122 pg/ml in bone marrow; 160.47 pg/ml in peripheral blood; NDMM vs. RRMM p<0.001). A cut-off value of FLT3-L >92 pg/ml in bone marrow and >121 pg/ml in peripheral blood was associated with relapse or refractoriness in MM patients. FLT3-L was found to be a high predictive marker for discrimination between NDMM and RRMM as well in bone marrow as in peripheral blood (AUC 0.75 in bone marrow; vs 0.84 in peripheral blood). CONCLUSION: High levels of FLT3-L in bone marrow and peripheral blood of MM patients identify patients with progressive disease and are associated with relapse or refractoriness in MM patients. FLT3-L could be useful as a marker to identify RRMM patients and should be evaluated as target for future therapies.
[Mh] Termos MeSH primário: Medula Óssea/metabolismo
Proteínas de Membrana/metabolismo
Mieloma Múltiplo/metabolismo
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Biomarcadores Tumorais/metabolismo
Diagnóstico Diferencial
Endostatinas/metabolismo
Ensaio de Imunoadsorção Enzimática
Feminino
Seres Humanos
Masculino
Glicoproteínas de Membrana/metabolismo
Meia-Idade
Prognóstico
Curva ROC
Receptor TIE-2/metabolismo
Recidiva
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (Endostatins); 0 (GPNMB protein, human); 0 (Membrane Glycoproteins); 0 (Membrane Proteins); 0 (flt3 ligand protein); EC 2.7.10.1 (Receptor, TIE-2)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170721
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0181487


  7 / 1491 MEDLINE  
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[PMID]:28720059
[Au] Autor:Yang P; Chen N; Yang D; Crane J; Huang B; Dong R; Yi X; Guo J; Cai J; Wang Z
[Ad] Endereço:1 Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
[Ti] Título:Cervical cancer cell-derived angiopoietins promote tumor progression.
[So] Source:Tumour Biol;39(7):1010428317711658, 2017 Jul.
[Is] ISSN:1423-0380
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Metastatic or recurrent cervical cancer has limited treatment options and a high rate of mortality. Although anti-vascular endothelial growth factor drugs have shown great promise as a therapeutic target for treatment of advanced cervical cancer, drug resistance and class-specific side effects negate long-term benefits. The identification of alternative anti-angiogenic factors will be critical for future drug development for advanced or recurrent cervical cancer. In this study, we found that angiopoietins and Tie receptors were highly expressed in cervical cancer cells. Tie-2 expression in tumor cells predicted poorer prognosis. Wound closure assay and Transwell assay showed that upregulated or downregulated Ang-1 and Ang-2 expression promoted or reduced cervical cancer cell lines migration and invasion, respectively. In subcutaneous xenograft models of cervical cancer, downregulation of Ang-1 and Ang-2 attenuated tumor growth. The expression of vimentin and endomucin and microvessel density were all significantly decreased in the siAng-1 group and siAng-2 group relative to the infection control group. Our data support that dual inhibition of Ang-1 and Ang-2 may be an alternative target for anti-angiogenic adjuvant therapy in advanced or recurrent cervical squamous cell cancer.
[Mh] Termos MeSH primário: Angiopoietina-1/genética
Receptor TIE-2/genética
Neoplasias do Colo do Útero/genética
Proteínas de Transporte Vesicular/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Angiopoietina-1/biossíntese
Animais
Carcinogênese/genética
Proliferação Celular/genética
Feminino
Regulação Neoplásica da Expressão Gênica
Células HeLa
Seres Humanos
Camundongos
Meia-Idade
Invasividade Neoplásica/genética
Invasividade Neoplásica/patologia
Recidiva Local de Neoplasia/genética
Recidiva Local de Neoplasia/patologia
Neovascularização Patológica/genética
Neovascularização Patológica/patologia
Prognóstico
Receptor TIE-2/biossíntese
Neoplasias do Colo do Útero/patologia
Proteínas de Transporte Vesicular/biossíntese
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ANGPT1 protein, human); 0 (Angiopoietin-1); 0 (C11orf2 protein, human); 0 (Vesicular Transport Proteins); EC 2.7.10.1 (Receptor, TIE-2)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170726
[Lr] Data última revisão:
170726
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170720
[St] Status:MEDLINE
[do] DOI:10.1177/1010428317711658


  8 / 1491 MEDLINE  
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[PMID]:28705795
[Au] Autor:Hubert A; Bochenek ML; Schütz E; Gogiraju R; Münzel T; Schäfer K
[Ad] Endereço:From the Center for Cardiology, Cardiology I (A.H., M.L.B., E.S., R.G., T.M., K.S.) and Center for Thrombosis and Hemostasis (M.L.B.), University Medical Center Mainz, Germany.
[Ti] Título:Selective Deletion of Leptin Signaling in Endothelial Cells Enhances Neointima Formation and Phenocopies the Vascular Effects of Diet-Induced Obesity in Mice.
[So] Source:Arterioscler Thromb Vasc Biol;37(9):1683-1697, 2017 Sep.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Obesity is associated with elevated circulating leptin levels and hypothalamic leptin resistance. Leptin receptors (LepRs) are expressed on endothelial cells, and leptin promotes neointima formation in a receptor-dependent manner. Our aim was to examine the importance of endothelial LepR (End.LepR) signaling during vascular remodeling and to determine whether the cardiovascular consequences of obesity are because of hyperleptinemia or endothelial leptin resistance. APPROACH AND RESULTS: Mice with loxP-flanked LepR alleles were mated with mice expressing Cre recombinase controlled by the inducible endothelial receptor tyrosine kinase promoter. Obesity was induced with high-fat diet. Neointima formation was examined after chemical carotid artery injury. Morphometric quantification revealed significantly greater intimal hyperplasia, neointimal cellularity, and proliferation in End.LepR knockout mice, and similar findings were obtained in obese, hyperleptinemic End.LepR wild-type animals. Analysis of primary endothelial cells confirmed abrogated signal transducer and activator of transcription-3 phosphorylation in response to leptin in LepR knockout and obese LepR wild-type mice. Quantitative PCR, ELISA, and immunofluorescence analyses revealed increased expression and release of endothelin-1 in End.LepR-deficient and LepR-resistant cells, and ET receptor A/B antagonists abrogated their paracrine effects on murine aortic smooth muscle cell proliferation. Reduced expression of peroxisome proliferator-activated receptor-γ and increased nuclear activator protein-1 staining was observed in End.LepR-deficient and LepR-resistant cells, and peroxisome proliferator-activated receptor-γ antagonization increased endothelial endothelin-1 expression. CONCLUSIONS: Our findings suggest that intact endothelial leptin signaling limits neointima formation and that obesity represents a state of endothelial leptin resistance. These observations and the identification of endothelin-1 as soluble mediator of the cardiovascular risk factor obesity may have relevant therapeutic implications.
[Mh] Termos MeSH primário: Lesões das Artérias Carótidas/complicações
Dieta Hiperlipídica
Células Endoteliais/metabolismo
Leptina/metabolismo
Músculo Liso Vascular/metabolismo
Miócitos de Músculo Liso/metabolismo
Neointima
Obesidade/complicações
Receptores para Leptina/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Animais
Artérias Carótidas/metabolismo
Artérias Carótidas/patologia
Lesões das Artérias Carótidas/genética
Lesões das Artérias Carótidas/metabolismo
Lesões das Artérias Carótidas/patologia
Movimento Celular
Proliferação Celular
Células Cultivadas
Modelos Animais de Doenças
Células Endoteliais/patologia
Endotelina-1/metabolismo
Feminino
Genótipo
Integrases
Masculino
Camundongos Endogâmicos C57BL
Camundongos Knockout
Músculo Liso Vascular/patologia
Miócitos de Músculo Liso/patologia
Obesidade/genética
Obesidade/metabolismo
Obesidade/patologia
PPAR gama/metabolismo
Comunicação Parácrina
Fenótipo
Fosforilação
Regiões Promotoras Genéticas
Receptor TIE-2/genética
Receptores de Endotelina/metabolismo
Receptores para Leptina/deficiência
Receptores para Leptina/genética
Fator de Transcrição STAT3/metabolismo
Remodelação Vascular
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Endothelin-1); 0 (Leptin); 0 (PPAR gamma); 0 (Receptors, Endothelin); 0 (Receptors, Leptin); 0 (STAT3 Transcription Factor); 0 (Stat3 protein, mouse); 0 (leptin receptor, mouse); EC 2.7.10.1 (Receptor, TIE-2); EC 2.7.10.1 (Tek protein, mouse); EC 2.7.7.- (Cre recombinase); EC 2.7.7.- (Integrases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170715
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.117.309798


  9 / 1491 MEDLINE  
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[PMID]:28705792
[Au] Autor:Prakash S; Borreguero LJJ; Sylva M; Flores Ruiz L; Rezai F; Gunst QD; de la Pompa JL; Ruijter JM; van den Hoff MJB
[Ad] Endereço:From the Department of Medical Biology, Academic Medical Center, Amsterdam, The Netherlands (S.P., M.S., F.R., Q.D.G., J.M.R., M.J.B.v.d.H.); Cardiovascular Imaging Laboratory, Centro Nacional de Investigación Cardiovascular, Madrid, Spain (L.J.J.B., L.F.R.); and Intercellular Signaling in Cardiovas
[Ti] Título:Deletion of Fstl1 (Follistatin-Like 1) From the Endocardial/Endothelial Lineage Causes Mitral Valve Disease.
[So] Source:Arterioscler Thromb Vasc Biol;37(9):e116-e130, 2017 Sep.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Fstl1 (Follistatin-like 1) is a secreted protein that is expressed in the atrioventricular valves throughout embryonic development, postnatal maturation, and adulthood. In this study, we investigated the loss of Fstl1 in the endocardium/endothelium and their derived cells. APPROACH AND RESULTS: We conditionally ablated Fstl1 from the endocardial lineage using a transgenic Tie2-Cre mouse model. These mice showed a sustained Bmp and Tgfß signaling after birth. This resulted in ongoing proliferation and endocardial-to-mesenchymal transition and ultimately in deformed nonfunctional mitral valves and a hypertrophic dilated heart. Echocardiographic and electrocardiographic analyses revealed that loss of Fstl1 leads to mitral regurgitation and left ventricular diastolic dysfunction. Cardiac function gradually deteriorated resulting in heart failure with preserved ejection fraction and death of the mice between 2 and 4 weeks after birth. CONCLUSIONS: We report on a mouse model in which deletion of Fstl1 from the endocardial/endothelial lineage results in deformed mitral valves, which cause regurgitation, heart failure, and early cardiac death. The findings provide a potential molecular target for the clinical research into myxomatous mitral valve disease.
[Mh] Termos MeSH primário: Linhagem da Célula
Endocárdio/metabolismo
Células Endoteliais/metabolismo
Proteínas Relacionadas à Folistatina/deficiência
Insuficiência Cardíaca/metabolismo
Insuficiência da Valva Mitral/metabolismo
Prolapso da Valva Mitral/metabolismo
Valva Mitral/metabolismo
Disfunção Ventricular Esquerda/metabolismo
[Mh] Termos MeSH secundário: Animais
Proteínas Morfogenéticas Ósseas/metabolismo
Proliferação Celular
Modelos Animais de Doenças
Progressão da Doença
Endocárdio/patologia
Células Endoteliais/patologia
Transição Epitelial-Mesenquimal
Proteínas Relacionadas à Folistatina/genética
Predisposição Genética para Doença
Sistema de Condução Cardíaco/metabolismo
Sistema de Condução Cardíaco/fisiopatologia
Insuficiência Cardíaca/genética
Insuficiência Cardíaca/patologia
Insuficiência Cardíaca/fisiopatologia
Integrases/genética
Camundongos Knockout
Valva Mitral/patologia
Valva Mitral/fisiopatologia
Insuficiência da Valva Mitral/genética
Insuficiência da Valva Mitral/patologia
Insuficiência da Valva Mitral/fisiopatologia
Prolapso da Valva Mitral/genética
Prolapso da Valva Mitral/patologia
Prolapso da Valva Mitral/fisiopatologia
Fenótipo
Receptor TIE-2/genética
Transdução de Sinais
Fatores de Tempo
Fatores de Transcrição/metabolismo
Fator de Crescimento Transformador beta/metabolismo
Disfunção Ventricular Esquerda/genética
Disfunção Ventricular Esquerda/patologia
Disfunção Ventricular Esquerda/fisiopatologia
Função Ventricular Esquerda
Remodelação Ventricular
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bone Morphogenetic Proteins); 0 (Follistatin-Related Proteins); 0 (Fstl1 protein, mouse); 0 (Transcription Factors); 0 (Transforming Growth Factor beta); EC 2.7.10.1 (Receptor, TIE-2); EC 2.7.10.1 (Tek protein, mouse); EC 2.7.7.- (Cre recombinase); EC 2.7.7.- (Integrases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170715
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.117.309089


  10 / 1491 MEDLINE  
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[PMID]:28620713
[Au] Autor:Kabra M; Zhang W; Rathi S; Mandal AK; Senthil S; Pyatla G; Ramappa M; Banerjee S; Shekhar K; Marmamula S; Mettla AL; Kaur I; Khanna RC; Khanna H; Chakrabarti S
[Ad] Endereço:Kallam Anji Reddy Molecular Genetics Laboratory, Brien Holden Eye Research Centre, L.V. Prasad Eye Institute, Hyderabad, India.
[Ti] Título:Angiopoietin receptor TEK interacts with CYP1B1 in primary congenital glaucoma.
[So] Source:Hum Genet;136(8):941-949, 2017 Aug.
[Is] ISSN:1432-1203
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Primary congenital glaucoma (PCG) is a severe autosomal recessive ocular disorder associated with considerable clinical and genetic heterogeneity. Recently, rare heterozygous alleles in the angiopoietin receptor-encoding gene TEK were implicated in PCG. We undertook this study to ascertain the second mutant allele in a large cohort (n = 337) of autosomal recessive PCG cases that carried heterozygous TEK mutations. Our investigations revealed 12 rare heterozygous missense mutations in TEK by targeted sequencing. Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of TEK and CYP1B1 by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::CYP1B1 (p.A115P), TEK (p.Q214P)::CYP1B1 (p.E229K), and TEK (p.I148T)::CYP1B1 (p.R368H) exhibit perturbed interaction. The mutations also diminished the ability of TEK to respond to ligand stimulation, indicating perturbed TEK signaling. Overall, our data suggest that interaction of TEK and CYP1B1 contributes to PCG pathogenesis and argue that TEK-CYP1B1 may perform overlapping as well as distinct functions in manifesting the disease etiology.
[Mh] Termos MeSH primário: Citocromo P-450 CYP1B1/genética
Glaucoma/congênito
Glaucoma/genética
Receptor TIE-2/genética
[Mh] Termos MeSH secundário: Alelos
Estudos de Coortes
Citocromo P-450 CYP1B1/metabolismo
Feminino
Frequência do Gene
Genoma Humano
Genômica
Células HEK293
Haplótipos
Heterozigoto
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Desequilíbrio de Ligação
Masculino
Mutação de Sentido Incorreto
Linhagem
Receptor TIE-2/metabolismo
Reprodutibilidade dos Testes
Alinhamento de Sequência
Análise de Sequência de DNA
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 1.14.14.1 (CYP1B1 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP1B1); EC 2.7.10.1 (Receptor, TIE-2)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170808
[Lr] Data última revisão:
170808
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170617
[St] Status:MEDLINE
[do] DOI:10.1007/s00439-017-1823-6



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