Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Mol Genet Metab ; 123(3): 388-399, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29338979

RESUMO

Myofibrillary myopathies (MFM) are hereditary myopathies histologically characterized by degeneration of myofibrils and aggregation of proteins in striated muscle. Cardiomyopathy is common in MFM but the pathophysiological mechanisms are not well understood. The BAG3-Pro209Leu mutation is associated with early onset MFM and severe restrictive cardiomyopathy (RCM), often necessitating heart transplantation during childhood. We report on a young male patient with a BAG3-Pro209Leu mutation who underwent heart transplantation at eight years of age. Detailed morphological analyses of the explanted heart tissue showed intracytoplasmic inclusions, aggregation of BAG3 and desmin, disintegration of myofibers and Z-disk alterations. The presence of undegraded autophagosomes, seen by electron microscopy, as well as increased levels of p62, LC3-I and WIPI1, detected by immunohistochemistry and western blot analyses, indicated a dysregulation of autophagy. Parkin and PINK1, proteins involved in mitophagy, were slightly increased whereas mitochondrial OXPHOS activities were not altered. These findings indicate that altered autophagy plays a role in the pathogenesis and rapid progression of RCM in MFM caused by the BAG3-Pro209Leu mutation, which could have implications for future therapeutic strategies.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Autofagia/genética , Cardiomiopatia Restritiva/genética , Miocárdio/patologia , Cardiomiopatia Restritiva/diagnóstico por imagem , Cardiomiopatia Restritiva/cirurgia , Criança , Coração/diagnóstico por imagem , Transplante de Coração , Humanos , Leucina/genética , Imageamento por Ressonância Magnética , Masculino , Microscopia Eletrônica de Transmissão , Músculo Esquelético/patologia , Mutação , Miocárdio/ultraestrutura , Miofibrilas/patologia , Miofibrilas/ultraestrutura , Prolina/genética
2.
Nat Commun ; 7: 12329, 2016 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-27470974

RESUMO

Diffuse invasion of the surrounding brain parenchyma is a major obstacle in the treatment of gliomas with various therapeutics, including anti-angiogenic agents. Here we identify the epi-/genetic and microenvironmental downregulation of ephrinB2 as a crucial step that promotes tumour invasion by abrogation of repulsive signals. We demonstrate that ephrinB2 is downregulated in human gliomas as a consequence of promoter hypermethylation and gene deletion. Consistently, genetic deletion of ephrinB2 in a murine high-grade glioma model increases invasion. Importantly, ephrinB2 gene silencing is complemented by a hypoxia-induced transcriptional repression. Mechanistically, hypoxia-inducible factor (HIF)-1α induces the EMT repressor ZEB2, which directly downregulates ephrinB2 through promoter binding to enhance tumour invasiveness. This mechanism is activated following anti-angiogenic treatment of gliomas and is efficiently blocked by disrupting ZEB2 activity. Taken together, our results identify ZEB2 as an attractive therapeutic target to inhibit tumour invasion and counteract tumour resistance mechanisms induced by anti-angiogenic treatment strategies.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Efrina-B2/genética , Glioma/genética , Glioma/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Hipóxia Celular/genética , Regulação para Baixo/genética , Resistencia a Medicamentos Antineoplásicos/genética , Efrina-B2/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioma/irrigação sanguínea , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Invasividade Neoplásica , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Regulação para Cima/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...