Alterations in lipid profile and enzymes paraoxonase and butyrylcholinesterase in CBS-deficient patients

Homocystinuria is an inborn error of metabolism most frequently caused by cystathionine β-synthase (CBS) deficiency. Homocysteine (Hcy), methionine (Met) and other metabolites of Hcy accumulate in the body of affected patients, leading to clinical manifestations such as dislocation of the optic lents, osteoporosis, mental retardation, and thromboembolism. Despite the fact that thromboembolism represent the major cause of morbidity and the most frequent cause of death in CBS-deficient patients, the cause of cardiovascular changes found in homocystinuria remain unclear. In this work, we evaluated the lipid profile (total cholesterol, HDL cholesterol, LDL cholesterol, oxidized LDL cholesterol, apolipoprotein A-1) and the activities of the enzymes paraoxonase (PON1) and butyrylcholinesterase (BuChE) in plasma of patients with homocystinuria due CBS deficiency, at diagnosis and during the treatment. It was verified a significant decrease in HDL cholesterol and apolipoprotein A1 levels in the both groups of CBS-deficient patients (at diagnosis and under treatment) when compared to controls. PON1 activity was also significantly lower in the both groups of CBS-deficient patients when compared to controls which may be related with an Hcy-dependent oxidation of any group important to catalytic activity of the enzyme that favors the atherogenesis. BuChE activity was significantly increased only in CBS-deficient patients at diagnosis and it is known that this enzymatic activity is positively associated with cardiovascular risk factors. Evaluated together, our results demonstrated that treated or not CBS-deficient patients presented important alterations in lipid metabolism. This work contributes to the understanding of the responsible mechanisms of vascular lesions in CBS-deficient patients.Apoio: CNPq, FAPERGS, CAPES, FIPE/HCP

Increased oxidative damage in carriers of the germline TP53 p.R337H mutation

Germline mutations in TP53 are the underlying defect of Li-Fraumeni Syndrome (LFS) and Li-Fraumeni-like (LFL) Syndrome, autosomal dominant disorders characterized by predisposition to multiple early onset cancers. In Brazil, a variant form of LFS/LFL is commonly detected because of the high prevalence of a founder mutation at codon 337 in TP53 (p.R337H). The p53 protein exerts multiple roles in the regulation of oxidative metabolism and cellular anti-oxidant defense systems. Herein, we analyzed the redox parameters in blood samples from p.R337H mutation carriers (C, n = 17) and non-carriers (NC, n = 17). We identified a significant increase in erythrocyte GPx activity and in plasma carbonyl content,an indicator of protein oxidative damage, in mutation carriers compared to non-carriers (P = 0.048 and P = 0.035, respectively). Mutation carriers also showed a four-fold increase in plasma malondialdehyde levels, indicating increased lipid peroxidation (NC = 40.2060.71, C = 160.560.88, P,0.0001). Finally, carriers showed increased total antioxidant status but a decrease in plasma ascorbic acid content. The observed imbalance could be associated with deregulated cell bioenergetics and/or with increased inflammatory stress, two effects that may result from loss of wild-type p53 function. These findings provide the first evidence that oxidative damage occurs in carriers of a germline TP53 mutation, and these may have important implications regarding our understanding of the mechanisms responsible for germline TP53 p.R337H mutation-associated carcinogenesis

Globotriaosylceramide is correlated with oxidative stress and inflammation in Fabry patients treated with enzyme replacement therapy

AbstractFabry disease is an X-linked inborn error of glycosphingolipid catabolism due to deficient activity of α-galactosidase A that leads to accumulation of the enzyme substrates, mainly globotriaosylceramide (Gb3), in body fluids and lysosomes of many cell types. Some pathophysiology hypotheses are intimately linked to reactive species production and inflammation, but until this moment there is no in vivo study about it. Hence, the aim of this study was to investigate oxidative stress parameters, pro-inflammatory cytokines and Gb3 levels in Fabry patients under treatment with enzyme replacement therapy (ERT) and finally to establish a possible relation between them. We analyzed urine and blood samples of patients under ERT (n=14) and healthy age-matched controls (n=14). Patients presented decreased levels of antioxidant defenses, assessed by reduced glutathione (GSH), glutathione peroxidase (GPx) activity and increased superoxide dismutase/catalase (SOD/CAT) ratio in erythrocytes. Concerning to the damage to biomolecules (lipids and proteins), we found that plasma levels of malondialdehyde (MDA) and protein carbonyl groups and di-tyrosine (di-Tyr) in urine were increased in patients. The pro-inflammatory cytokines IL-6 and TNF-α were also increased in patients. Urinary Gb3 levels were positively correlated with the plasma levels of IL-6, carbonyl groups and MDA. IL-6 levels were directly correlated with di-Tyr and inversely correlated with GPx activity. This data suggest that pro-inflammatory and pro-oxidant states occur, are correlated and seem to be induced by Gb3 in Fabry patients

A prevalência das malformações cardíacas na Síndrome de Goldenhar (Espectro Óculo-aurículo-vertebral) / The prevalence of cardiac malformations in Goldenhar's Syndrome (Ocululo-auriculo-vertebral spectrum)

Síndrome de Goldenhar (espectro óculo-aurículo-vertebral) é uma microssomia craniofacial envolvendo os dois primeiros arcos faríngeos, devendo atender aos critérios morfológicos de Feigold e Baum que incluem malformações auriculares, vertebrais e dermoides epibulbares. Outras anomalias podem estar presentes, merecendo destaque as cardíacas devido os possíveis prognósticos negativos, sendo relevante ao pediatra conhecer a prevalência delas. Para a realização desta revisão, foram profundamente analisados trabalhos nas bases Scielo, PubMed e BVS. Estudos relevantes na área mostram frequência média de malformações cardíacas em pacientes com síndrome de Goldenhar de 32%, índice que se encaixa na grande variabilidade estatística (entre 5% e 58%). As anomalias mais prevalentes frente aos estudos e assim ordenados são: defeitos do tipo conotruncal/defeitos de saída, defeitos de septo, e outros defeitos, sendo alguns de seus subtipos bem descritos quanto a indicação de cirurgia cardíaca e risco de morte nos primeiros dois anos de vida. A principal malformação encontrada é a tetralogia de Fallot, e dentre as menos prevalentes, mas bem relatadas, tem-se a dextrocardia. É importante a avaliação precoce desses pacientes para diagnóstico e seguimento, sendo de grande valia os achados ecocardiográficos aliados à clínica

Envolvimento da via PLC no mecanismo de ação do T4 sobre a fosforilação das proteínas do citoesqueleto de córtex cerebral de ratos

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Efeito da homocisteína sobre a fosforilação dos filamentos intermediários de hipocampo de ratos

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