RESUMO
A human neuroblastoma cell line, IMR-32, was used as an in vitro model system to study the effects of arsenic trioxide (As(2)O(3)) on aggressive human neuroblastoma. From 0.5 micro M, As(2)O(3) exhibited a dose-dependent inhibition of IMR-32 proliferation. At concentrations of 1.5 micro M or higher, As(2)O(3) up-regulated caspase 3, leading to cellular apoptosis. However, neurofilament-200 kDa and tyrosine hydroxylase were not up-regulated, implying minimal neuronal differentiation. Concomitantly, TrkA was down-regulated and TrkB up-regulated. Pre-treatment with the protein kinase C (PKC) inhibitor Ro-31-8220 partially blocked As(2)O(3)-mediated apoptosis, meaning that As(2)O(3) might signal through PKC activation. The results suggest that As(2)O(3) might be potentially useful in neuroblastoma.
Assuntos
Apoptose/efeitos dos fármacos , Arsenicais/farmacologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Óxidos/farmacologia , Trióxido de Arsênio , Western Blotting , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Inibidores do Crescimento/farmacologia , Humanos , Indóis/farmacologia , Neuroblastoma/enzimologia , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Proteínas de Neurofilamentos/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Receptor trkA/metabolismo , Receptor trkB/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
Bone mineral density (BMD), an important risk factor for osteoporosis, is a complex trait likely affected by multiple genes. The linkage and/or association of 13 polymorphic loci of seven candidate genes (estrogen receptor alpha [ERalpha] and beta [ERbeta], calcium-sensing receptor, vitamin D receptor, collagen type 1alpha1, low-density lipoprotein [LDL] receptor-related protein 5 [LRPS], and transforming growth factor beta1) were evaluated in 177 southern Chinese pedigrees of 674 subjects, with each pedigree identified through a proband having a BMD Z score of -1.28 or less at the hip or spine. A suggestive linkage was detected between the IVS1-351A/G polymorphism of ERalpha and spine BMD, and between the 1082G/A, 1730G/A, and D14S1026 polymorphisms of ERbeta and BMD at both spine and hip. The quantitative transmission disequilibrium test (QTDT) detected total family association between 1730G/A of ERbeta and BMD at spine and hip; between D14S1026 of ERbeta and hip BMD; and between the 266A/G and 2220C/T polymorphisms of LRP5 and hip BMD. Similar total family associations were detected when only the females were analyzed. In addition, the IVS1-397T/C polymorphism of ERalpha was associated with spine BMD, and the 266A/G and 2220C/T polymorphisms of LRP5 were associated with femoral neck BMD in the females. A within-family association was detected with the IVS1-397T/C polymorphism of ERalpha, and the 266A/G and 2220C/T polymorphisms of LRP5 in the females. The effect of each polymorphism on BMD variance ranged from 1% to 4%. In conclusion, ERalpha, ERbeta and LRP5 are important candidate genes determining BMD variation, especially in females.
Assuntos
Densidade Óssea/genética , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Ligação Genética , Proteínas Relacionadas a Receptor de LDL/genética , Adulto , Idoso , Povo Asiático/genética , Colágeno Tipo I/genética , Cadeia alfa 1 do Colágeno Tipo I , Feminino , Frequência do Gene , Humanos , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Masculino , Pessoa de Meia-Idade , Linhagem , Polimorfismo Genético , Receptores de Calcitriol/genética , Receptores de Detecção de Cálcio/genética , Fator de Crescimento Transformador beta/genéticaRESUMO
OBJECTIVE: Thyrotoxic periodic paralysis (TPP) is a complication of hyperthyroidism association with recurrent, reversible episodes of muscle weakness. Increased sodium-potassium ATPase (Na/K-ATPase) pump activity is postulated to contribute to the hypokalaemic paralytic attacks in TPP. The aim of this study was to determine the genetic predisposition to TPP in relation to Na/K-ATPase genes. DESIGN: A case-control association study. PATIENTS: Ninety-nine male Chinese TPP patients were compared to 84 male Graves' disease (GD) patients without TPP and 100 normal male controls. MEASUREMENT: A total of 1500 base pairs upstream of the transcriptional start site of the five Na/K-ATPase genes that are expressed in the skeletal muscles, namely ATP1A1, ATP1A2, ATP1B1, ATP1B2 and ATP1B4, were sequenced in all subjects for mutations or polymorphisms. The single nucleotide polymorphisms (SNPs) of the coding regions of the five genes were also studied for association with TPP. RESULTS: No mutations were detected in the 5' regions of the five genes in any of the patients studied. There was no difference in the distribution of SNPs and SNP haplotypes in the upstream and coding region of these genes between the three groups of subjects. CONCLUSION: No association between the polymorphisms of ATP1A1, ATP1A2, ATP1B1, ATP1B2 and ATP1B4 genes and TPP could be detected.
Assuntos
Paralisia Periódica Hipopotassêmica/genética , Polimorfismo de Nucleotídeo Único/genética , ATPase Trocadora de Sódio-Potássio/genética , Adenosina Trifosfatases/genética , Adulto , Sequência de Bases , Estudos de Casos e Controles , Proteínas de Transporte de Cátions/genética , Moléculas de Adesão Celular Neuronais/genética , Frequência do Gene , Doença de Graves/genética , Haplótipos , Humanos , Paralisia Periódica Hipopotassêmica/enzimologia , Masculino , Mutação , Subunidades Proteicas/genéticaRESUMO
A human neuroblastoma cell line IMR-32 was used as an in vitro model to examine three naturally occurring retinoic acid (RA) isomers, 9-cis (9c), 13-cis (13c) and all-trans (AT) RA, in mediating growth differentiation and neuronal differentiation. All RA isomers inhibited cellular proliferation, with 13c-RA being most effective. Cyclic AMP-responsive-element-binding-protein (CREB) was activated during RA treatment. AT-RA was a better differentiating agent in inducing the highest expression of the neurotrophic factor receptor TrkA. After prolonged RA treatment, the expression of RA receptors (RARs) was comparable for the three isomers, but retinoid X receptors (RXRs) were differentially regulated. These results imply that distinctive molecular pathways might be involved in the in vitro differentiation of neuroblastoma with different RA isomers.