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1.
Eur J Prev Cardiol ; 25(1_suppl): 42-50, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29708032

RESUMO

Background Sporadic non-syndromic thoracic aortic aneurysms (SNSTAAs) are less well understood than familial non-syndromic or syndromic ones. The study aimed at defining the peculiar morphologic and molecular changes occurring in the media layer of SNSTAAs. Design This study was based on a single centre design. Methods Media layer samples taken from seven carefully selected SNSTAAs and seven reference patients (controls) were investigated via quantitative polymerase chain reaction, proteomics-bioinformatics, immunoblotting, quantitative histology, and immunohistochemistry/immunofluorescence. Results In SNSTAAs media, aortic smooth muscle cells numbers were halved due to an apoptotic process coupled with a negligible cell proliferation. Cystathionine γ-lyase was diffusely up-regulated. Surviving aortic smooth muscle cells exhibited diverging phenotypes: in inner- and outer-media contractile cells prevailed, having higher contents of smooth-muscle-α-actin holoprotein (45-kDa) and of caspase-3-cleaved smooth-muscle-α-actin 25-kDa fragments; in mid-media, aortic smooth muscle cells exhibited a synthetic/secretor phenotype, down-regulating vimentin, but up-regulating glial fibrillary acidic protein, trans-Golgi network 46 protein, Jagged1 (172-kDa) holoprotein, and Jagged1's receptor Notch1. Extracellular soluble Jagged1 (42-kDa) fragments accumulated. Conclusions In SNSTAAs, there is a relentless aortic smooth muscle cells attrition caused by the up-regulated cystathionine γ-lyase. In mid-media, synthetic/secretor aortic smooth muscle cells intensify Jagged1/NOTCH1 signalling in the attempt to counterbalance the weakened aortic wall, due to aortic smooth muscle cells net loss and mechanical stress. Synthetic/secretor aortic smooth muscle cells are apoptosis-prone, and the accruing thrombin-cleaved Jagged1 fragments counteract the otherwise useful effects of Jagged1/NOTCH1 signalling, thus hampering tissue homeostasis/remodelling, and aortic smooth muscle cells adhesion, differentiation, and migration.


Assuntos
Aneurisma da Aorta Torácica/genética , Regulação da Expressão Gênica , Proteína Jagged-1/genética , Músculo Liso Vascular/metabolismo , RNA/genética , Receptor Notch1/genética , Aneurisma da Aorta Torácica/metabolismo , Aneurisma da Aorta Torácica/patologia , Apoptose , Western Blotting , Proliferação de Células , Regulação para Baixo , Feminino , Homeostase , Humanos , Proteína Jagged-1/biossíntese , Masculino , Músculo Liso Vascular/patologia , Fenótipo , Reação em Cadeia da Polimerase , Receptor Notch1/biossíntese , Estudos Retrospectivos , Transdução de Sinais
2.
Eur J Prev Cardiol ; 25(1_suppl): 51-58, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29708036

RESUMO

Background Sporadic non-syndromic thoracic aortic aneurysms (SNSTAAs) are less well understood than familial non-syndromic or syndromic ones. Here, we focused on morphologic and molecular changes of the extracellular matrix of the tunica media of SNSTAAs. Design Single centre design. Methods Surgical media samples from seven SNSTAAs and seven controls underwent quantitative polymerase chain reaction, proteomics-bioinformatics, immunoblotting, histology and immunohistochemistry analysis. Results A down-regulation of Decorin mRNA with unchanged protein levels associated with a remarkable increase of collagen fibres. A reduced and distorted network of elastic fibres partnered with an attenuated expression of microfibril-associated glycoprotein1 despite the rise of MFAP2 gene-encoded mRNA levels. An increasingly proteolysed paxillin (55 kDa PXN), a focal adhesion protein, combined with an upregulated 62 kDa PXN holoprotein, without changes in amount and phosphorylation of focal adhesion kinase (pp125FAK). The upregulation of SPOCK2-encoded Testican2 proteoglycan and of ectodysplasin (EDA) protein was coupled with a down-regulation of EDA2 receptor (EDA2R). Conclusions Several tunica media extracellular matrix-related changes favour SNSTAA development. A steady level of decorin and a microfibril-associated glycoprotein1 protein shortage cause the assembly of structurally defective collagen and elastic fibres. Up-regulation of PXN holoproteins perturbs PXN/pp125FAK interaction and focal adhesion functioning. Testican2 up-regulation suppresses the membrane-type matrix metalloproteinase inhibiting activities of other SPOCK family members thus enhancing extracellular matrix proteolysis. Finally, the altered EDA•EDA2R signalling would impact on the remodelling of SNSTAA tunica media. Altogether, our results pave the way to a deeper molecular understanding of SNSTAAs necessary to identify their early diagnostic biochemical markers.


Assuntos
Aneurisma da Aorta Torácica/genética , Decorina/genética , Matriz Extracelular/metabolismo , Adesões Focais/metabolismo , Regulação da Expressão Gênica , Proteoglicanas/genética , Receptor Xedar/genética , Aneurisma da Aorta Torácica/metabolismo , Aneurisma da Aorta Torácica/patologia , Decorina/biossíntese , Matriz Extracelular/patologia , Humanos , Immunoblotting , Imuno-Histoquímica , Reação em Cadeia da Polimerase , Proteoglicanas/biossíntese , RNA/genética , Receptor Xedar/biossíntese
4.
J Appl Genet ; 46(1): 93-104, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15741670

RESUMO

Recent evidence indicates an important role of inflammation pathways, airways remodeling and epithelium activation in asthma genetics. In particular, transcriptome studies have detected differentially expressed genes involved in eosinophil apoptosis, the arginase pathway, response to allergens or interleukins, and to inhaled corticosteroids. Candidate gene and genome wide studies have localized genetic regions involved in the disease, such as the A1AR and CLCA1 genes (chromosome 1), IL-1RN and DPP10 (2q14), HLA-G and TNF-a (6p21), GPRA (7p14), FceRI and GSTP1 (11q13), NOS1, IFNG, STAT6, VDR, and other genes (12q13-26), PHF11 and flanking genes (13q14), AACT and PTGDR (14q), and ADAM33 (20p13). The role of these and other genetic determinants has to be confirmed in future, preferably longitudinal, studies.


Assuntos
Asma/genética , Perfilação da Expressão Gênica , Alérgenos , Antiasmáticos/uso terapêutico , Mapeamento Cromossômico , Predisposição Genética para Doença , Genoma Humano , Humanos
5.
Genet. mol. biol ; 22(3): 291-4, Sept. 1999. tab
Artigo em Inglês | LILACS | ID: lil-272833

RESUMO

Realizou-se a análise de 79 pacientes provenientes do Sul do Brasil para duas mutaçöes raras da fibrose cística (CF), R1162X e 2183AA G; dentre estes pacientes, 49 eram nascidos no Estado do Paraná (PR) e 30 eram nascidos no Estado de Santa Catarina (SC). Para a mutaçäo 2183AA G, dois alelos foram detectados entre os pacientes de SC e um alelo entre os pacientes do PR. Quando estes pacientes foram classificados de acordo com a origem étnica, 14 por cento dos alelos detectados entre os pacientes de origem italiana eram portadores da mutaçäo R1162X e 7 por cento da mutaçäo 2183AA G. Estas mutaçöes, juntamente com a mutaçäo delta F508, também foram analisadas em uma amostra de 270 indivíduos normais de origem italiana näo-consangüíneos, os quais eram nascidos no Estado do PR. Nessa amostra foram detectados dois alelos delta F508 e um alelo 2183AA G. As freqüências das mutaçöes delta F508, R1162X e 2183AA G näo mostraram desvio estatístico significativo daquelas freqüências observadas no norte da Itália. Nossos resultados demonstram que é importante incluir estas mutaçöes no conjunto de mutaçöes a serem pesquisadas nos pacientes com FC do sul do Brasil, especialmente quando estes pacientes tiverem origem italiana.


Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Adulto , Pessoa de Meia-Idade , População Branca , Fibrose Cística/genética , Frequência do Gene , Brasil , Genética Populacional , Mutação/genética , Reação em Cadeia da Polimerase
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