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1.
Int J Alzheimers Dis ; 2010: 864625, 2010 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-20981353

RESUMO

Mice transgenic for production of excessive or mutant forms of beta-amyloid differ from patients with Alzheimer's disease in the degree of inflammation, oxidative damage, and alteration of intermediary metabolism, as well as the paucity or absence of neuronal atrophy and cognitive impairment. Previous observers have suggested that differences in inflammatory response reflect a discrepancy in the state of the locus coeruleus (LC), loss of which is an early change in Alzheimer's disease but which is preserved in the transgenic mice. In this paper, we extend these observations by examining the effects of the LC on markers of oxidative stress and intermediary metabolism. We compare four groups: wild-type or Tg2576 Aß transgenic mice injected with DSP4 or vehicle. Of greatest interest were metabolites different between ablated and intact transgenics, but not between ablated and intact wild-type animals. The Tg2576_DSP4 mice were distinguished from the other three groups by oxidative stress and altered energy metabolism. These observations provide further support for the hypothesis that Tg2576 Aß transgenic mice with this ablation may be a more congruent model of Alzheimer's disease than are transgenics with an intact LC.

2.
Toxicol Pathol ; 37(3): 280-92, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19380839

RESUMO

Drug-induced nephrotoxicity is a major concern, since many pharmacological compounds are filtered through the kidneys for excretion into urine. To discover biochemical biomarkers useful for early identification of nephrotoxicity, metabolomic experiments were performed on Sprague-Dawley Crl:CD (SD) rats treated with the nephrotoxins gentamicin, cisplatin, or tobramycin. Using a combination of gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS), a global, nontargeted metabolomics analysis was performed on urine and kidney samples collected after one, five, and twenty-eight dosing days. Increases in polyamines and amino acids were observed in urine from drug-treated rats after a single dose, and prior to observable histological kidney damage and conventional clinical chemistry indications of nephrotoxicity. Thus, these metabolites are potential biomarkers for the early detection of drug-induced nephrotoxicity. Upon prolonged dosing, nephrotoxin-induced changes included a progressive loss of amino acids in urine, concomitant with a decrease in amino acids and nucleosides in kidney tissue. A nephrotoxicity prediction model, based on the levels of branched-chain amino acids in urine, distinguished nephrotoxin-treated samples from vehicle-control samples, with 100%, 93%, and 70% accuracy at day 28, day 5, and day 1, respectively. Thus, this panel of biomarkers may provide a noninvasive method to detect kidney injury long before the onset of histopathological kidney damage.


Assuntos
Rim/química , Metabolômica , Toxinas Biológicas/análise , Animais , Biomarcadores/análise , Biomarcadores/urina , Cromatografia Líquida/métodos , Cisplatino/análise , Diagnóstico Precoce , Feminino , Cromatografia Gasosa-Espectrometria de Massas/métodos , Gentamicinas/análise , Rim/patologia , Masculino , Espectrometria de Massas , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Tobramicina/análise
3.
Bioanalysis ; 1(9): 1645-63, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21083109

RESUMO

The identification of biomarkers of drug-induced kidney injury is an area of intensive focus in drug development. Traditional markers of renal function, including blood urea nitrogen and serum creatinine, are not region-specific and only increase significantly after substantial kidney injury. Therefore, more sensitive markers of kidney injury are needed. The ideal biomarkers will identify nephrotoxicity early in the drug-discovery process, resulting in decreased development costs and safer drugs. Metabolomics, the study of the small biochemicals present in a biological sample, has become a promising player in the nephrotoxicity arena. In this review, we describe the current status of the identification of metabolic biomarkers for drug-induced kidney toxicity screening. Many of these markers have been confirmed across multiple studies and can detect nephrotoxicity earlier than the traditional clinical chemistry and histopathology methods. Upon further validation, such markers will offer clear benefits for the pharmaceutical industry and regulatory agencies.


Assuntos
Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/diagnóstico , Biomarcadores Farmacológicos/análise , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Rim/efeitos dos fármacos , Metabolômica/métodos , Animais , Biomarcadores Farmacológicos/metabolismo , Desenho de Fármacos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Diagnóstico Precoce , Feminino , Humanos , Testes de Função Renal , Masculino , Camundongos , Ratos
4.
Mol Biol Cell ; 17(7): 2942-51, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16624863

RESUMO

Cajal bodies (CBs) are subnuclear bodies that are widespread in eukaryotes, being found in mammals, many other vertebrates and in all plant species so far examined. They are mobile structures, moving, fusing, and budding within the nucleus. Here we describe a screen for Arabidopsis mutants with altered CBs and describe mutants that have smaller Cajal bodies (ncb-2, ncb-3), lack them altogether (ncb-1), have increased numbers of CBs (pcb) or have flattened CBs (ccb). We have identified the gene affected in the ncb mutants as a distant homolog of the vertebrate gene that encodes coilin (At1g13030) and have termed the resulting protein Atcoilin. A T-DNA insertional mutant in this gene (ncb-4) also lacks Cajal bodies. Overexpression of Atcoilin cDNA in ncb-1 restores Cajal bodies, which recruit U2B'' as in the wild type, but which are, however, much larger than in the wild type. Thus we have shown that At1g13030 is required for Cajal body formation in Arabidopsis, and we hypothesize that the level of its expression is correlated with Cajal body size. The Atcoilin gene is unaffected in pcb and ccb, suggesting that other genes can also affect CBs.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Corpos Enovelados/genética , Genes de Plantas/fisiologia , Proteínas Nucleares/metabolismo , Sequência de Aminoácidos , Arabidopsis/metabolismo , Arabidopsis/ultraestrutura , Proteínas de Arabidopsis/genética , Núcleo Celular/metabolismo , Núcleo Celular/ultraestrutura , Corpos Enovelados/metabolismo , Corpos Enovelados/ultraestrutura , Análise Mutacional de DNA , Expressão Gênica , Dados de Sequência Molecular , Mutagênese Insercional , Proteínas Nucleares/genética , Proteínas de Ligação a RNA
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