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1.
Apoptosis ; 12(8): 1407-18, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17440815

RESUMO

BACKGROUND: Hyperhomocysteinaemia (HHC) is thought to be a risk factor for cardiovascular disease including heart failure. While numerous studies have analyzed the role of homocysteine (Hcy) in the vasculature, only a few studies investigated the role of Hcy in the heart. Therefore we have analyzed the effects of Hcy on isolated cardiomyocytes. METHODS: H9c2 cells (rat cardiomyoblast cells) and adult rat cardiomyocytes were incubated with Hcy and were analyzed for cell viability. Furthermore, we determined the effects of Hcy on intracellular mediators related to cell viability in cardiomyocytes, namely NOX2, reactive oxygen species (ROS), mitochondrial membrane potential (DeltaPsi (m)) and ATP concentrations. RESULTS: We found that incubation of H9c2 cells with 0.1 mM D,L-Hcy (= 60 microM L-Hcy) resulted in an increase of DeltaPsi (m) as well as ATP concentrations. 1.1 mM D,L-Hcy (= 460 microM L-Hcy) induced reversible flip-flop of the plasma membrane phospholipids, but not apoptosis. Incubation with 2.73 mM D,L-Hcy (= 1.18 mM L-Hcy) induced apoptosis and necrosis. This loss of cell viability was accompanied by a thread-to-grain transition of the mitochondrial reticulum, ATP depletion and nuclear NOX2 expression coinciding with ROS production as evident from the presence of nitrotyrosin residues. Notably, only at this concentration we found a significant increase in S-adenosylhomocysteine which is considered the primary culprit in HHC. CONCLUSION: We found concentration-dependent effects of Hcy in cardiomyocytes, varying from induction of reversible flip-flop of the plasma membrane phospholipids, to apoptosis and necrosis.


Assuntos
Apoptose/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Homocisteína/farmacologia , Fluidez de Membrana/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Animais , Caspase 3/metabolismo , Membrana Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Homocisteína/análise , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Cardíacas/efeitos dos fármacos , Modelos Biológicos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/patologia , NADPH Oxidase 2 , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Necrose/induzido quimicamente , Fosfolipídeos/metabolismo , Processamento de Proteína Pós-Traducional , Ratos , S-Adenosil-Homocisteína/análise , S-Adenosilmetionina/análise
2.
J Clin Pathol ; 60(2): 167-72, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16837630

RESUMO

BACKGROUND: Clinical outcome in patients with diffuse large B cell lymphomas (DLBCL) is highly variable and poorly predictable. Microarray studies showed that patients with DLBCL with a germinal centre B cell-like (GCB) phenotype have a better prognosis than those with an activated B cell-like (ABC) phenotype. The BMI1 proto-oncogene was identified as one of the genes present in the signature of the ABC type of DLBCL, associated with a poor prognosis. OBJECTIVES: (1) To investigate, in primary nodal DLBCL, the expression of BMI1 and its association with clinical outcome and DLBCL signature; (2) to look for an association between BMI1 expression and the expression of its putative downstream targets p14ARF and p16INK4a. RESULTS: BMI1 expression was found to be associated with poor clinical outcome, but not clearly with an ABC-like phenotype of DLBCL. Expression of BMI1 was frequently, but not always, related to low levels of expression of p14ARF and p16INK4a. CONCLUSION: Expression of BMI1 is associated with an unfavourable clinical outcome of primary nodal DLBCL.


Assuntos
Biomarcadores Tumorais/metabolismo , Linfoma de Células B/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Feminino , Humanos , Técnicas Imunoenzimáticas , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/genética , Complexo Repressor Polycomb 1 , Prognóstico , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Análise de Sobrevida , Proteína Supressora de Tumor p14ARF/metabolismo
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