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1.
Oncogene ; 32(9): 1202-6, 2013 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-22469986

RESUMO

Development of colon cancer is a multistep process that is regulated by intrinsic and extrinsic cellular signals. Extrinsic factors include molecular patterns that are derived from either pathogens (PAMPs) or cellular damage (DAMPs). These molecules can promote tumourigenesis by activation of the innate immune system, but the individual contribution of ligands and their receptors remains elusive. The receptor for advanced glycation end products (Rage) is a pattern recognition receptor that binds multiple ligands derived from a damaged cell environment such as Hmgb1 and S100 protein. Here we show that Rage signalling has a critical role in sporadic development of intestinal adenomas, as Apc(Min/+) Rage(-/-) mice are protected against tumourigenesis.


Assuntos
Adenoma/metabolismo , Neoplasias Intestinais/metabolismo , Receptores Imunológicos/metabolismo , Animais , Camundongos , Receptor para Produtos Finais de Glicação Avançada , Receptores de Reconhecimento de Padrão/metabolismo , Transdução de Sinais
2.
Cell Mol Life Sci ; 63(23): 2847-58, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17103110

RESUMO

Dietary quercetin intake is suggested to be health promoting, but this assumption is mainly based on mechanistic studies performed in vitro. Previously, we identified rat lung as a quercetin target tissue. To assess relevant in vivo health effects of quercetin, we analyzed mechanisms of effect in rat lungs of a chronic (41 weeks) 1% quercetin diet using whole genome microarrays. We show here that fatty acid catabolism pathways, like beta-oxidation and ketogenesis, are up-regulated by the long-term quercetin intervention. Up-regulation of genes (Hmgcs2, Ech1, Acox1, Pcca, Lpl and Acaa2) was verified and confirmed by quantitative real time PCR. In addition, free fatty acid levels were decreased in rats fed the quercetin diet, confirming that quercetin affects fatty acid catabolism. This in vivo study demonstrates for the first time that fatty acid catabolism is a relevant process that is affected in rats by chronic dietary quercetin.


Assuntos
Ácidos Graxos/metabolismo , Pulmão/metabolismo , Quercetina/farmacologia , Animais , Dieta , Regulação da Expressão Gênica/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Quercetina/administração & dosagem , Ratos , Ratos Endogâmicos F344
3.
J Biol Chem ; 275(33): 25805-13, 2000 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-10823823

RESUMO

Decreased phosphorylation of focal adhesion kinase and paxillin is associated with loss of focal adhesions and stress fibers and precedes the onset of apoptosis (van de Water, B., Nagelkerke, J. F., and Stevens, J. L. (1999) J. Biol. Chem. 274, 13328-13337). The cortical actin cytoskeletal network is also lost during apoptosis, yet little is known about the temporal relationship between altered phosphorylation of proteins that are critical in the regulation of this network and their potential cleavage by caspases during apoptosis. Adducins are central in the cortical actin network organization. Cisplatin caused apoptosis of renal proximal tubular epithelial cells, which was associated with the cleavage of alpha-adducin into a 74-kDa fragment; this was blocked by a general caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD-fmk). Hemagglutinin-tagged human alpha-adducin was cleaved into a similar 74-kDa fragment by caspase-3 in vitro but not by caspase-6 or -7. Asp-Arg-Val-Asp(29)-Glu, Asp-Ile-Val-Asp(208)-Arg, and Asp-Asp-Ser-Asp(633)-Ala were identified as the principal caspase-3 cleavage sites; Asp-Asp-Ser-Asp(633)-Ala was key in the formation of the 74-kDa fragment. Cisplatin also caused an increased phosphorylation of alpha-adducin and gamma-adducin in the MARCKS domain that preceded alpha-adducin cleavage and was associated with loss of adducins from adherens junctions; this was not affected by z-VAD-fmk. In conclusion, the data support a model in which increased phosphorylation of alpha-adducin due to cisplatin leads to dissociation from the cytoskeleton, a situation rendered irreversible by caspase-3-mediated cleavage of alpha-adducin at Asp-Asp-Ser-Asp(633)-Ala.


Assuntos
Apoptose , Proteínas de Ligação a Calmodulina/metabolismo , Caspases/metabolismo , Rim/metabolismo , Actinas/metabolismo , Clorometilcetonas de Aminoácidos/metabolismo , Animais , Antineoplásicos/farmacologia , Células COS , Proteínas de Transporte/metabolismo , Caspase 3 , Morte Celular , Cisplatino/farmacologia , Citoesqueleto/metabolismo , Relação Dose-Resposta a Droga , Células Epiteliais/metabolismo , Imunofluorescência , Humanos , Immunoblotting , L-Lactato Desidrogenase/metabolismo , Proteínas dos Microfilamentos/metabolismo , Fosforilação , Plasmídeos/metabolismo , Isoformas de Proteínas , Proteína Quinase C/química , Proteína Quinase C/metabolismo , Ratos , Serina/metabolismo , Fatores de Tempo , Transfecção
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