Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Clin Invest ; 122(4): 1377-92, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22406537

RESUMO

In Alzheimer disease (AD), amyloid ß peptide (Aß) accumulates in plaques in the brain. Receptor for advanced glycation end products (RAGE) mediates Aß-induced perturbations in cerebral vessels, neurons, and microglia in AD. Here, we identified a high-affinity RAGE-specific inhibitor (FPS-ZM1) that blocked Aß binding to the V domain of RAGE and inhibited Aß40- and Aß42-induced cellular stress in RAGE-expressing cells in vitro and in the mouse brain in vivo. FPS-ZM1 was nontoxic to mice and readily crossed the blood-brain barrier (BBB). In aged APPsw/0 mice overexpressing human Aß-precursor protein, a transgenic mouse model of AD with established Aß pathology, FPS-ZM1 inhibited RAGE-mediated influx of circulating Aß40 and Aß42 into the brain. In brain, FPS-ZM1 bound exclusively to RAGE, which inhibited ß-secretase activity and Aß production and suppressed microglia activation and the neuroinflammatory response. Blockade of RAGE actions at the BBB and in the brain reduced Aß40 and Aß42 levels in brain markedly and normalized cognitive performance and cerebral blood flow responses in aged APPsw/0 mice. Our data suggest that FPS-ZM1 is a potent multimodal RAGE blocker that effectively controls progression of Aß-mediated brain disorder and that it may have the potential to be a disease-modifying agent for AD.


Assuntos
Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/metabolismo , Benzamidas/uso terapêutico , Modelos Animais de Doenças , Fármacos Neuroprotetores/uso terapêutico , Fragmentos de Peptídeos/metabolismo , Receptores Imunológicos/antagonistas & inibidores , Envelhecimento/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/genética , Animais , Benzamidas/farmacologia , Benzamidas/toxicidade , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células CHO/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Cricetinae , Cricetulus , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/toxicidade , Fragmentos de Peptídeos/genética , Desempenho Psicomotor/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada , Proteínas Recombinantes de Fusão/metabolismo , Bibliotecas de Moléculas Pequenas
2.
J Clin Invest ; 119(11): 3437-49, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19841542

RESUMO

Activated protein C (APC) is a signaling protease with anticoagulant activity. Here, we have used mice expressing a mutation in superoxide dismutase-1 (SOD1) that is linked to amyotrophic lateral sclerosis (ALS) to show that administration of APC or APC analogs with reduced anticoagulant activity after disease onset slows disease progression and extends survival. A proteolytically inactive form of APC with reduced anticoagulant activity provided no benefit. APC crossed the blood-spinal cord barrier in mice via endothelial protein C receptor. When administered after disease onset, APC eliminated leakage of hemoglobin-derived products across the blood-spinal cord barrier and delayed microglial activation. In microvessels, motor neurons, and microglial cells from SOD1-mutant mice and in cultured neuronal cells, APC transcriptionally downregulated SOD1. Inhibition of SOD1 synthesis in neuronal cells by APC required protease-activated receptor-1 (PAR1) and PAR3, which inhibited nuclear transport of the Sp1 transcription factor. Diminished mutant SOD1 synthesis by selective gene excision within endothelial cells did not alter disease progression, which suggests that diminished mutant SOD1 synthesis in other cells, including motor neurons and microglia, caused the APC-mediated slowing of disease. The delayed disease progression in mice after APC administration suggests that this approach may be of benefit to patients with familial, and possibly sporadic, ALS.


Assuntos
Fibrinolíticos/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Microglia/enzimologia , Neurônios Motores/enzimologia , Proteína C/farmacologia , Superóxido Dismutase/metabolismo , Esclerose Lateral Amiotrófica/tratamento farmacológico , Animais , Barreira Hematoencefálica/metabolismo , Linhagem Celular , Núcleo Celular/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Endotélio/metabolismo , Fibrinolíticos/uso terapêutico , Masculino , Camundongos , Microglia/citologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Proteína C/uso terapêutico , Receptores de Superfície Celular/metabolismo , Receptores Ativados por Proteinase/metabolismo , Fator de Transcrição Sp1/metabolismo , Medula Espinal/irrigação sanguínea , Medula Espinal/enzimologia , Superóxido Dismutase/genética
3.
J Exp Med ; 204(2): 253-8, 2007 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-17242164

RESUMO

Compelling evidence suggests that the epithelial cell-derived cytokine thymic stromal lymphopoietin (TSLP) may initiate asthma or atopic dermatitis through a dendritic cell-mediated T helper (Th)2 response. Here, we describe how TSLP might initiate and aggravate allergic inflammation in the absence of T lymphocytes and immunoglobulin E antibodies via the innate immune system. We show that TSLP, synergistically with interleukin 1 and tumor necrosis factor, stimulates the production of high levels of Th2 cytokines by human mast cells (MCs). We next report that TSLP is released by primary epithelial cells in response to certain microbial products, physical injury, or inflammatory cytokines. Direct epithelial cell-mediated, TSLP-dependent activation of MCs may play a central role in "intrinsic" forms of atopic diseases and explain the aggravating role of infection and scratching in these diseases.


Assuntos
Citocinas/metabolismo , Células Epiteliais/metabolismo , Hipersensibilidade/etiologia , Imunidade Inata/imunologia , Mastócitos/imunologia , Análise de Variância , DNA Complementar/genética , Ensaio de Imunoadsorção Enzimática , Humanos , Reação em Cadeia da Polimerase , Receptores de Citocinas/metabolismo , Linfopoietina do Estroma do Timo
4.
J Med Chem ; 47(7): 1605-8, 2004 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-15027850

RESUMO

From the discovery of competitive hexapeptide inhibitors, potent and selective HCV NS3 protease macrocyclic inhibitors have been identified. Structure-activity relationship studies were performed focusing on optimizing the N-terminal carbamate and the aromatic substituent on the (4R)-hydroxyproline moiety. Inhibitors meeting the potency criteria in the cell-based assay and with improved oral bioavailability in rats were identified. BILN 2061 was selected as the best compound, the first NS3 protease inhibitor reported with antiviral activity in man.


Assuntos
Antivirais/síntese química , Carbamatos/síntese química , Hepacivirus/enzimologia , Compostos Heterocíclicos/síntese química , Inibidores de Proteases/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Animais , Antivirais/química , Antivirais/farmacologia , Disponibilidade Biológica , Carbamatos/química , Carbamatos/farmacologia , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Injeções Intravenosas , Prolina/química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Ratos , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...