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Busanello E.N.B.,Federal University of Rio Grande do Sul | Lobato V.G.A.,Federal University of Rio Grande do Sul | Zanatta A.,Federal University of Rio Grande do Sul | Borges C.G.,Federal University of Rio Grande do Sul | And 8 more authors.
Cerebellum | Year: 2014

Zellweger syndrome (ZS) and some peroxisomal diseases are severe inherited disorders mainly characterized by neurological symptoms and cerebellum abnormalities, whose pathogenesis is poorly understood. Biochemically, these diseases are mainly characterized by accumulation of pristanic acid (Prist) and other fatty acids in the brain and other tissues. In this work, we evaluated the in vitro influence of Prist on redox homeostasis by measuring lipid, protein, and DNA damage, as well as the antioxidant defenses and the activities of aconitase and α-ketoglutarate dehydrogenase in cerebellum of 30-day-old rats. The effect of Prist on DNA damage was also evaluated in blood of these animals. Some parameters were also evaluated in cerebellum from neonatal rats and in cerebellum neuronal cultures. Prist significantly increased malondialdehyde (MDA) levels and carbonyl formation and reduced sulfhydryl content and glutathione (GSH) concentrations in cerebellum of young rats. It also caused DNA strand damage in cerebellum and induced a high micronuclei frequency in blood. On the other hand, this fatty acid significantly reduced α-ketoglutarate dehydrogenase and aconitase activities in rat cerebellum. We also verified that Prist-induced increase of MDA levels was totally prevented by melatonin and attenuated by α-tocopherol but not by the nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester, indicating the involvement of reactive oxygen species in this effect. Cerebellum from neonate rats also showed marked alterations of redox homeostasis, including an increase of MDA levels and a decrease of sulfhydryl content and GSH concentrations elicited by Prist. Finally, Prist provoked an increase of dichlorofluorescein (DCFH) oxidation in cerebellum-cultivated neurons. Our present data indicate that Prist compromises redox homeostasis in rat cerebellum and blood and inhibits critical enzymes of the citric acid cycle that are susceptible to free radical attack. The present findings may contribute to clarify the pathogenesis of the cerebellar alterations observed in patients affected by ZS and some peroxisomal disorders in which Prist is accumulated. © 2014, Springer Science+Business Media New York. Source


dos Santos Mello M.,Federal University of Rio Grande do Sul | Ribas G.S.,Servico de Genetica Medica do Hospital de Clinicas de Porto Alegre | Wayhs C.A.Y.,Servico de Genetica Medica do Hospital de Clinicas de Porto Alegre | Hammerschmidt T.,Servico de Genetica Medica do Hospital de Clinicas de Porto Alegre | And 7 more authors.
Molecular and Cellular Biochemistry | Year: 2015

3-hydroxy-3-methylglutaric aciduria (HMGA; OMIM 246450) is a rare autosomal recessive disorder, caused by the deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase (4.1.3.4), which results in the accumulation of 3-hydroxy-3-methylglutaric (HMG) and 3-methylglutaric (MGA) acids in tissues and biological fluids of affected individuals. Recent in vivo and in vitro animal studies have demonstrated that the accumulation of these metabolites can disturb the cellular redox homeostasis, which can contribute to the neurological manifestations presented by the patients. So, in the present work, we investigated oxidative stress parameters in plasma and urine samples from HMGA patients, obtained at the moment of diagnosis of this disorder and during therapy with low-protein diet and L-carnitine supplementation. It was verified that untreated HMGA patients presented higher levels of urinary di-tyrosine and plasma thiobarbituric acid-reactive substances (TBA-RS), which are markers of protein and lipid oxidative damage, respectively, as well as a reduction of the urinary antioxidant capacity. Treated HMGA patients also presented an increased protein oxidative damage, as demonstrated by their higher concentrations of plasma protein carbonyl groups and urinary di-tyrosine, as well as by the reduction of total sulfhydryl groups in plasma, in relation to controls. On the other hand, HMGA patients under therapy presented normal levels of TBA-RS and urinary antioxidant capacity, which can be related, at least in part, to the antioxidant and antiperoxidative effects exerted by L-carnitine. The results of this work are the first report showing that a redox imbalance occurs in patients with HMGA what reinforces the importance of the antioxidant therapy in this disorder. © 2015, Springer Science+Business Media New York. Source


Vanzin C.S.,Federal University of Rio Grande do Sul | Manfredini V.,Federal University of Pampa | Marinho A.E.,Federal University of Pampa | Biancini G.B.,Federal University of Rio Grande do Sul | And 5 more authors.
Gene | Year: 2014

High blood levels of homocysteine (Hcy) are found in patients affected by homocystinuria, a genetic disorder caused by deficiency of cystathionine β-synthase (CBS) activity, as well as in nutritional deficiencies (vitamin B12 or folate) and in abnormal renal function. We previously demonstrated that lipid and protein oxidative damage is increased and the antioxidant defenses diminished in plasma of CBS-deficient patients, indicating that oxidative stress is involved in the pathophysiology of this disease. In the present work, we extended these investigations by evaluating DNA damage through the comet assay in peripheral leukocytes from CBS-deficient patients, as well as by analyzing of the in vitro effect of Hcy on DNA damage in white blood cells. We verified that DNA damage was significantly higher in the CBS-deficient patients under treatment based on a protein-restricted diet and pyridoxine, folic acid, betaine and vitamin B12 supplementation, when compared to controls. Furthermore, the in vitro study showed a concentration-dependent effect of Hcy inducing DNA damage. Taken together, the present data indicate that DNA damage occurs in treated CBS-deficient patients, possibly due to high Hcy levels. © 2014 Elsevier B.V. Source

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