RESUMO
Glutathione synthetase deficiency (GSSD) is a rare inborn error of glutathione metabolism with autosomal recessive inheritance. The severe form of the disease is characterized by acute metabolic acidosis, usually present in the neonatal period with hemolytic anemia and progressive encephalopathy. A case of a male newborn infant who had severe metabolic acidosis with high anion gap, hemolytic anemia, and hyperbilirubinemia is reported. A high level of 5-oxoproline was detected in his urine and a diagnosis of generalized GSSD was made. DNA sequence analysis revealed the infant to be compound heterozygous with two mutations, c.738dupG in exon 8 of GSS gene resulting in p.S247fs and a repetitive sequence in exon 3 of GSS gene. Treatment after diagnosis of GSSD included supplementation with antioxidants and oral sodium hydrogen bicarbonate. However, he maintained a variable degree of metabolic acidosis and succumbed shortly after his parents requested discontinuation of therapy because of dismal prognosis and medical futility when he was 18 days old.
Assuntos
Humanos , Masculino , Recém-Nascido , Erros Inatos do Metabolismo dos Aminoácidos/genética , Glutationa Sintase/deficiência , Mutação , Acidose/etiologia , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Ácido Glutâmico/análise , Glutationa Sintase/genética , Glutationa Sintase/metabolismo , Piroglutamato Hidrolase/deficiência , Piroglutamato Hidrolase/genética , Análise de Sequência de DNA/métodosRESUMO
Previously, we demonstrated that galangin (3,5,7-trihydroxyflavone) protects human keratinocytes against ultraviolet B (UVB)-induced oxidative damage. In this study, we investigated the effect of galangin on induction of antioxidant enzymes involved in synthesis of reduced glutathione (GSH), and investigated the associated upstream signaling cascades. By activating nuclear factor-erythroid 2-related factor (Nrf2), galangin treatment significantly increased expression of glutamate-cysteine ligase catalytic subunit (GCLC) and glutathione synthetase (GSS). This activation of Nrf2 depended on extracellular signal-regulated kinases (ERKs) and protein kinase B (AKT) signaling. Inhibition of GSH in galangin-treated cells attenuated the protective effect of galangin against the deleterious effects of UVB. Our results reveal that galangin protects human keratinocytes by activating ERK/AKT-Nrf2, leading to elevated expression of GSH-synthesizing enzymes.
Assuntos
Humanos , Domínio Catalítico , MAP Quinases Reguladas por Sinal Extracelular , Glutamato-Cisteína Ligase , Glutationa Sintase , Glutationa , Queratinócitos , Proteínas Proto-Oncogênicas c-aktRESUMO
BACKGROUND: Exposure to ethanol abuse and severe oxidative stress are risk factors for hepatocarcinoma. The aim of this study was to evaluate the effects of S-adenosylmethionine (SAMe) and its combinations with taurine and/or betaine on the level of glutathione (GSH), a powerful antioxidant in the liver, in acute hepatotoxicity induced by ethanol. METHODS: To examine the effects of SAMe and its combinations with taurine and/or betaine on ethanol-induced hepatotoxicity, AML12 cells and C57BL/6 mice were pretreated with SAMe, taurine, and/or betaine, followed by ethanol challenge. Cell viability was detected with an MTT assay. GSH concentration and mRNA levels of GSH synthetic enzymes were measured using GSH reductase and quantitative real-time reverse transcriptase-PCR. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were measured with commercially available kits. RESULTS: Pretreatment of SAMe, with or without taurine and/or betaine, attenuated decreases in GSH levels and mRNA expression of the catalytic subunit of glutamate-cysteine ligase (GCL), the rate-limiting enzyme for GSH synthesis, in ethanol-treated cells and mice. mRNA levels of the modifier subunit of GCL and glutathione synthetase were increased in mice treated with SAMe combinations. SAMe, taurine, and/or betaine pretreatment restored serum ALT and AST levels to control levels in the ethanol-treated group. CONCLUSIONS: Combinations of SAMe with taurine and/or betaine have a hepatoprotective effect against ethanol-induced liver injury by maintaining GSH homeostasis.
Assuntos
Animais , Camundongos , Alanina Transaminase , Aspartato Aminotransferases , Betaína , Domínio Catalítico , Sobrevivência Celular , Etanol , Glutamato-Cisteína Ligase , Glutationa Sintase , Glutationa , Homeostase , Fígado , Estresse Oxidativo , Oxirredutases , Fatores de Risco , RNA Mensageiro , S-Adenosilmetionina , TaurinaRESUMO
Pyroglutamic acid (also known as 5-oxoproline) is an organic acid intermediate of the gamma-glutamyl cycle. Accumulation of pyroglutamic acid is a rare cause of high anion gap metabolic acidosis. In the pediatric population, the congenital form of pyroglutamic acidemia has been extensively described. However, there are scarce reports of the acquired form of this condition in children. The urine test for organic acids confirms the diagnosis of pyroglutamic acidemia. We report the case of a 16-month-old girl who developed transient 5-oxoprolinemia associated with malnutrition and the use of acetaminophen and ampicillin for the treatment of acute otitis media and abdominal pain. The patient received 21-hour course of n-acetylcysteine with improvement of metabolic acidosis. This report highligts the need of considering pyroglutamic acidemia in the differencial diagnosis for high anion gap metabolic acidosis in pediatric patients with malnutrition and other risk factors...
Assuntos
Humanos , Glutationa Sintase/deficiência , Cetose , Ácido PirrolidonocarboxílicoAssuntos
Humanos , Catalase/genética , Enzimas/farmacocinética , Genoma Humano , Glutationa Peroxidase/genética , Glutationa Sintase/genética , Superóxido Dismutase/genética , Antioxidantes/farmacocinética , Cromossomos Humanos/efeitos dos fármacos , Cromossomos Humanos/enzimologia , Cromossomos Humanos/genética , Monoaminoxidase/genética , NADP/genética , Oxidantes/antagonistas & inibidores , Óxido Nítrico Sintase/genética , Peroxidase/genética , Xantina Desidrogenase/genéticaRESUMO
Se estandarizaron las técnicas de actividad de g -glutamil cisteil sintetasa y glutatión sintetasa con el objetivo de estudiar los pacientes con deficiencia congénita de glutatión reducido. Los valores normales encontrados en nuestro laboratorio no presentaron diferencias significativas con los señalados por otros autores. Se estudiaron varios miembros de una familia con deficiencia de glutatión reducido. Los estudios bioquímicos excluyeron la posible deficiencia de glucosa-6-fosfato deshidrogenasa. En el propósito y un hermano (G.D.R.) se encontró deficiencia de glutatión sintetasa. Ambos presentan una anemia hemolítica congénita no esferocítica, con hemólisis crónica e íctero que se exacerba en el transcurso de procesos infecciosos y también litiasis vesicular. Ninguno presentó acidosis metabólica ni trastornos neurológicos progresivos, por lo que ambos son portadores de la forma benigna de la enfermedad. En el padre y otro hermano, los resultados del estudio hematológico y bioquímico indican que posiblemente son heterocigóticos para la deficiencia de esta enzima. Esta es la primera familia con deficiencia de glutatión sintetasa encontrada en nuestra población