Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Sci Rep ; 7(1): 8063, 2017 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-28808239

RESUMO

The glucocorticoid receptor (GR) is a transcription factor of which the underlying gene regulatory mechanisms are complex and incompletely understood. The non-steroidal anti-inflammatory Compound A (CpdA), a selective GR modulating compound in various cell models, has been shown to favour GR-mediated gene repression but not GR-mediated gene activation. Shifting balances towards only a particular subset of GR gene regulatory events may be of benefit in the treatment of inflammatory diseases. We present evidence to support that the combination of CpdA with Dexamethasone (DEX), a classic steroidal GR ligand, can shape GR function towards a unique gene regulatory profile in a cell type-dependent manner. The molecular basis hereof is a changed GR phosphorylation status concomitant with a change in the GR cofactor recruitment profile. We subsequently identified and confirmed the orphan nuclear receptor SHP as a coregulator that is specifically enriched at GR when CpdA and DEX are combined. Combining CpdA with DEX not only leads to stronger suppression of pro-inflammatory gene expression, but also enhanced anti-inflammatory GR target gene expression in epithelial cells, making ligand combination strategies in future a potentially attractive alternative manner of skewing and fine-tuning GR effects towards an improved therapeutic benefit.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Dexametasona/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Receptores de Glucocorticoides/metabolismo , Células A549 , Animais , Linhagem Celular Tumoral , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Ligantes , Camundongos , Fosforilação/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/metabolismo , Ativação Transcricional/efeitos dos fármacos
2.
Neuroscience ; 242: 97-109, 2013 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-23545270

RESUMO

Glucocorticoid hormones exert crucial effects on the brain in relation to physiology, endocrine regulation, mood and cognition. Their two receptor types, glucocorticoid and mineralocorticoid receptors (GR and MR), are members of the nuclear receptor superfamily and act in large measure as transcription factors. The outcome of MR/GR action on the genome depends on interaction with members from different protein families, which are of crucial importance for cross-talk with other neuronal and hormonal signals that impinge on the glucocorticoid sensitive circuitry. Relevant interacting proteins include other transcription factors that may either tether the receptor to the DNA, or that bind in the vicinity of GR and MR to tune the transcriptional response. In addition, transcriptional coregulator proteins constitute the actual signal transduction pathway to the transcription machinery. We review the current evidence for involvement of individual coregulators in GR-dependent effects on stress responses, and learning and memory. We discuss the use of in vitro and in silico tools to predict those coregulators that are of importance for particular brain processes. Finally, we discuss the potential of selective receptor modulators that may only allow a subset of all interactions, thus allowing more selective targeting of glucocorticoid-dependent processes in the brain.


Assuntos
Encéfalo/fisiopatologia , Glucocorticoides/fisiologia , Transdução de Sinais/genética , Estresse Psicológico/genética , Estresse Psicológico/fisiopatologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Animais , Encéfalo/metabolismo , Regulação da Expressão Gênica/fisiologia , Humanos , Aprendizagem/fisiologia , Memória/fisiologia , Receptores Citoplasmáticos e Nucleares/fisiologia , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/fisiologia , Receptores de Mineralocorticoides/genética , Receptores de Mineralocorticoides/fisiologia
4.
J Immunol ; 166(2): 861-7, 2001 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-11145661

RESUMO

Release of allergic mediators from mast cells is enhanced by very late Ag (VLA)-5-mediated interaction of these cells with fibronectin. In this report, we show that VLA-5-mediated adhesion of bone marrow-derived mast cells to fibronectin can be induced by two different pathways: first, FcepsilonRI clustering, which depends on calmodulin activation and extracellular Ca(2+), and, second, by Mn(2+) stimulation, which is independent of calmodulin activation and antagonized by Ca(2+). Previous studies have shown the presence of several cation-binding domains in VLA-5 that are homologous to the calcium-binding EF-hands of calmodulin. To show a role for EF-hands of different proteins in VLA-5-mediated adhesion, we used calcium-like peptides (CALP), CALP1 and CALP2, designed to bind to EF-hands based on inverted hydropathy. CALP1 and, more potently, CALP2 inhibited FcepsilonRI-induced adhesion to fibronectin via different mechanisms. The target for the effects of CALP1 and 2 on FcepsilonRI-induced adhesion and degranulation was intracellular and likely involved calmodulin. Interestingly only CALP2 was able to inhibit Mn(2+)-induced calmodulin-independent adhesion by interfering with an extracellular target, which is probably VLA-5. We conclude that CALP1 and 2 can inhibit VLA-5-mediated adhesion of mast cells to fibronectin through binding to EF-hands of multiple proteins, and that these peptides can be used as lead compounds for the development of future therapy against allergy.


Assuntos
Células da Medula Óssea/metabolismo , Proteínas de Transporte/farmacologia , Motivos EF Hand/imunologia , Fibronectinas/metabolismo , Mastócitos/metabolismo , Oligopeptídeos/farmacologia , Peptídeos , Receptores de Fibronectina/fisiologia , Adjuvantes Imunológicos/síntese química , Adjuvantes Imunológicos/farmacologia , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Calmodulina/fisiologia , Proteínas de Transporte/síntese química , Proteínas de Transporte/metabolismo , Cátions Bivalentes/farmacologia , Adesão Celular/efeitos dos fármacos , Adesão Celular/imunologia , Degranulação Celular/efeitos dos fármacos , Degranulação Celular/imunologia , Espaço Extracelular/fisiologia , Fibronectinas/imunologia , Peptídeos e Proteínas de Sinalização Intercelular , Manganês/farmacologia , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Oligopeptídeos/síntese química , Oligopeptídeos/metabolismo , Receptores de IgE/fisiologia
5.
Bone Marrow Transplant ; 3(1): 69-75, 1988 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-3048473

RESUMO

In a retrospective study 17 patients were interviewed 1-5 years after bone marrow transplantation (BMT) about their emotional experiences and about the information and support given to them. In all patients the illness, the BMT and its consequences created severe emotional strain; their psychological state was closely linked to their physical condition. Yet, most patients showed a surprising emotional elasticity and affective adjustment. Although the patients were overwhelmingly positive about the information and support they had received, an important number of them felt inadequately prepared for the emotional and sexual problems they had to face in the first period after discharge. The results of this study have led to structural changes in the psychiatric and psychosocial approach to the BMT patients.


Assuntos
Transplante de Medula Óssea , Estresse Psicológico/etiologia , Atividades Cotidianas , Adaptação Psicológica , Adolescente , Adulto , Família , Feminino , Humanos , Masculino , Admissão do Paciente , Alta do Paciente , Complicações Pós-Operatórias/psicologia , Complicações Pós-Operatórias/reabilitação , Cuidados Pré-Operatórios , Estudos Retrospectivos , Apoio Social , Estresse Psicológico/psicologia
7.
Appl Opt ; 24(18): 2926, 1985 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-18223981
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...