Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Respir Res ; 11: 41, 2010 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-20412595

RESUMO

BACKGROUND: We analyzed serial concentrations of multiple inflammatory mediators from serum and induced sputum obtained from patients with stable COPD and controls. The objective was to determine which proteins could be used as reliable biomarkers to assess COPD disease state and severity. METHODS: Forty-two subjects; 21 with stable COPD and 21 controls, were studied every 2 weeks over a 6-week period. Serum and induced sputum were obtained at each of 3 visits and concentrations of 19 serum and 22 sputum proteins were serially assessed using multiplex immunoassays. We used linear mixed effects models to test the distribution of proteins for an association with COPD and disease severity. Measures of within- and between-subject coefficients of variation were calculated for each of the proteins to assess reliability of measurement. RESULTS: There was significant variability in concentrations of all inflammatory proteins over time, and variability was greater for sputum proteins (median intra-subject coefficient of variation 0.58) compared to proteins measured in serum (median intra-subject coefficient of variation 0.32, P = 0.03). Of 19 serum proteins and 22 sputum proteins tested, only serum CRP, myeloperoxidase and VEGF and sputum IL-6, IL-8, TIMP-1, and VEGF showed acceptable intra and inter-patient reliability and were significantly associated with COPD, the severity of lung function impairment, and dyspnea. CONCLUSIONS: Levels of many serum and sputum biomarkers cannot be reliably ascertained based on single measurements. Multiple measurements over time can give a more reliable and precise estimate of the inflammatory burden in clinically stable COPD patients.


Assuntos
Mediadores da Inflamação/metabolismo , Análise Serial de Proteínas , Doença Pulmonar Obstrutiva Crônica/imunologia , Idoso , Biomarcadores/sangue , Biomarcadores/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Imunoensaio , Mediadores da Inflamação/sangue , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Análise Serial de Proteínas/métodos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Escarro/imunologia , Fatores de Tempo
2.
Bioorg Med Chem Lett ; 20(5): 1693-6, 2010 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-20138512

RESUMO

Here we report on the discovery of a series of maleimides which have high potency and good selectivity for GSK-3beta. The incorporation of polar groups afforded compounds with good bioavailability. The most potent compound 34 has an IC(50) of 0.6nM for GSK-3beta, over 100-fold selectivity against a panel of other kinases, and shows efficacy in rat osteoporosis models. The X-ray structure of GSK-3beta protein with 34 bound revealed the binding mode of the template and provided insights for future optimization opportunities.


Assuntos
Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Indóis/química , Maleimidas/química , Inibidores de Proteínas Quinases/química , Administração Oral , Animais , Sítios de Ligação , Cristalografia por Raios X , Modelos Animais de Doenças , Descoberta de Drogas , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Indóis/síntese química , Indóis/farmacocinética , Maleimidas/síntese química , Maleimidas/farmacocinética , Camundongos , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Ratos , Relação Estrutura-Atividade
3.
Science ; 303(5655): 229-32, 2004 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-14716014

RESUMO

The development of osteoporosis involves the interaction of multiple environmental and genetic factors. Through combined genetic and genomic approaches, we identified the lipoxygenase gene Alox15 as a negative regulator of peak bone mineral density in mice. Crossbreeding experiments with Alox15 knockout mice confirmed that 12/15-lipoxygenase plays a role in skeletal development. Pharmacologic inhibitors of this enzyme improved bone density and strength in two rodent models of osteoporosis. These results suggest that drugs targeting the 12/15-lipoxygenase pathway merit investigation as a therapy for osteoporosis.


Assuntos
Araquidonato 12-Lipoxigenase/genética , Araquidonato 12-Lipoxigenase/metabolismo , Araquidonato 15-Lipoxigenase/genética , Araquidonato 15-Lipoxigenase/metabolismo , Densidade Óssea/genética , Animais , Densidade Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Diferenciação Celular , Células Cultivadas , Cruzamentos Genéticos , Inibidores Enzimáticos/farmacologia , Feminino , Fluorenos/farmacologia , Perfilação da Expressão Gênica , Ligação Genética , Rim/metabolismo , Inibidores de Lipoxigenase , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Camundongos Transgênicos , Análise de Sequência com Séries de Oligonucleotídeos , Osteoblastos/citologia , Osteoblastos/metabolismo , Osteoblastos/fisiologia , Osteogênese , Osteoporose/enzimologia , Polimorfismo Genético , Locos de Características Quantitativas , Ratos , Receptores Citoplasmáticos e Nucleares/metabolismo , Células Estromais/metabolismo , Fatores de Transcrição/metabolismo
4.
J Cell Biochem ; 88(2): 267-73, 2003 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-12520525

RESUMO

Our recent studies have shown that the vitamin D analog Ro-26-9228 restores bone mineral density without inducing hypercalcemia in osteopenic rats. Our ex vivo experiments demonstrated that the analog upregulated gene expression in trabecular bone but not in the duodenum of female rats. We examined the mechanism for the tissue selectivity of Ro-26-9228 in Caco-2, a human cell line of intestinal origin, and hFOB, and a human fetal osteoblast cell line. We found that the abilities of Ro-26-9228 and the natural hormone, 1,25-dihydroxyvitamin D(3) (1,25D(3)) to induce VDRE-reporter gene expression in transiently transfected human osteoblasts are similar. In contrast, in Caco-2 cells, Ro-26-9228 induces 40-fold less reporter gene expression than 1,25D(3) does. We also examined the abilities of the vitamin D receptor (VDR)-ligand complexes from these two cell lines to interact with partners of transcription (glucocorticoid receptor-interacting protein, VDR-interacting protein, and retinoid X receptor), in pull-down assays. These assays revealed that 1,25D(3) induces similar levels of interaction of these co-factors with VDR from both osteoblasts and intestinal cells. In contrast, Ro-26-9228 induces significant interaction of VDR from osteoblast cells with these co-factors, but less of VDR from Caco-2 cells. These results suggest that the cellular environment of intestinal cells, unlike that of osteoblasts, represses the ability of VDR-Ro-26-9228 complexes to interact with transcription partners.


Assuntos
Receptores de Calcitriol/efeitos dos fármacos , Transativadores , Vitamina D/análogos & derivados , Vitamina D/farmacologia , Animais , Células CACO-2 , Feto , Regulação da Expressão Gênica/efeitos dos fármacos , Ribonucleoproteínas Nucleares Heterogêneas Grupo U/metabolismo , Humanos , Complexo Mediador , Proteínas Nucleares/metabolismo , Osteoblastos/metabolismo , Ratos , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Fatores de Transcrição , Ativação Transcricional/efeitos dos fármacos
5.
Endocrinology ; 143(5): 1625-36, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-11956143

RESUMO

We have examined several analogs of 1alpha,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] in an animal model of osteoporosis (ovariectomized rats) to identify a compound with a greater therapeutic range than 1,25-(OH)(2)D(3) for treatment of this bone disease. Here, we report that one analog, Ro-26-9228, had a bone-protecting effect but did not induce hypercalcemia at a wide concentration range. Analysis of biochemical markers and the bone histomorphometry of analog-treated rats suggested that Ro-26-9228 acted by inhibiting bone resorption and increasing the number of differentiated osteoblasts. To determine the basis for the segregation between hypercalcemia and bone-protecting action, we examined gene expression in tissues that regulate calcium homeostasis. We found that 1,25-(OH)(2)D(3) induced 24-hydroxylase mRNA expression in the duodena of ovariectomized rats, but Ro-26-9228 did not. Furthermore, in the duodena of intact animals, 1,25-(OH)(2)D(3) induced a significant increase in calbindin D 9K and plasma membrane calcium pump 1 mRNAs, but Ro-26-9228 had no effect on these mRNAs. On the other hand, the osteoblast-specific gene products osteocalcin and osteopontin were significantly up-regulated in trabecular bone by both the natural hormone and Ro-26-9228. Further investigation of gene-regulatory events in trabecular bone revealed that both 1,25-(OH)(2)D(3) and Ro-26-9228 up-regulated TGF beta1 and beta2 mRNAs. We concluded that the unique properties of Ro-26-9228 include preferential gene regulation in osteoblasts over duodenum and effective induction of growth factors in bone.


Assuntos
Doenças Ósseas Metabólicas/tratamento farmacológico , Doenças Ósseas Metabólicas/patologia , Vitamina D/uso terapêutico , Animais , Ligação Competitiva/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/metabolismo , Células CACO-2 , Calcitriol/uso terapêutico , Cálcio/sangue , Cálcio/urina , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Osteoporose/prevenção & controle , Ovariectomia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Gênica/genética , Transfecção , Vitamina D/análogos & derivados , Vitamina D/farmacocinética , Vitamina D/fisiologia , Vitamina D/toxicidade , Proteína de Ligação a Vitamina D/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...