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BACKGROUND: Physical exercise influences homocysteine (Hcy) concentrations, cognitive function and the metabolic profile. The purpose of this study was to investigate the influence of regular physical exercise on Hcy levels, the metabolic profile and cognitive function in healthy elderly males before and after an endurance exercise program. METHODS: Forty-five healthy and sedentary volunteers were randomized into 2 groups: (1) a control group asked not to change their normal everyday activities and not to start any regular physical exercise program and (2) an experimental group trained at a heart rate intensity corresponding to ventilatory threshold 1 (VT-1) for 60 min/day 3 times weekly on alternate days for 6 months using a cycle ergometer. All volunteers underwent cognitive evaluations, blood sample analyses and ergospirometric assessments. RESULTS: A significant improvement in cognitive function was observed in the experimental group compared with the control group (p < 0.05). No significant changes in Hcy levels were observed in the experimental group (p > 0.05), but there was a significant increase in peak oxygen consumption and workload at VT-1 as well as a significant improvement in cholesterol, triglycerides, HDL, glucose, alkaline phosphatase, urea, T3, T4 and prostate-specific antigen compared with the control group (p < 0.05). CONCLUSION: The data suggest that a physical exercise program does not reduce Hcy levels in healthy elderly males, although it improves the cardiovascular and metabolic profile as well as cognitive function.
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Fabry Disease, an X-linked inborn error of metabolism, is characterized by progressive renal insufficiency, with cardio and cerebrovascular involvement. Homocysteine (Hcy) is considered a risk factor for vascular diseases, but the mechanisms by which it produces cardiovascular damage are still poorly understood. Regarding the vascular involvement in FD patients, the analysis of factors related to thromboembolic events could be useful to improving our understanding of the disease. The aim of this study was to evaluate plasma Hcy and other parameters involved in the methionine cycle, as well as oxidative stress markers. The sample consisted of a group of 10 male FD patients and a control group of 8 healthy individuals, paired by age. Venous blood was collected for Hcy determination, molecular analysis, identification of thiobarbituric acid reactive substances, total glutathione and antioxidant enzymes activity, as well as vitamins quantification. Comparative analysis of FD patients versus the control group indicated hyperhomocysteinemia in 8 of the 10 FD patients, as well as a significant increase in overall glutathione levels and catalase activity. It is inferred that FD patients, apart from activation of the antioxidant system, present increased levels of plasma Hcy, although this is probably unrelated to common alterations in the methionine cycle.
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OBJETIVO: Homocisteína e a sepse estão ambos associados à inflamação e ativação endotelial. O objetivo desse estudo foi verificar se o nível plasmático de homocisteína está relacionado à gravidade do quadro séptico. MÉTODOS: Estudo clínico, prospectivo e observacional, incluindo pacientes com sepse grave ou choque séptico com menos de 48 horas de instalação da disfunção orgânica. Os níveis de homocisteína foram determinados no dia da inclusão no estudo e nos dias 3, 7, 14. A associação entre homocisteína com o escore Sequential Organ Failure Assessment (SOFA) foi avaliada pelo teste de Sperman e com mortalidade pelo teste de Mann-Whitney. Os resultados foram considerados significativos se p<0,05. RESULTADOS: Foram incluídos 21 pacientes e feitas 60 coletas para avaliação da homocisteina total (mediana de 6,92 (5,27 - 9,74 μmol/l). O teste de correlação Spearman não mostrou associação entre homocisteina e SOFA (r = -0,15 e p = 0,26). Também não foi encontrada correlação da medida de homocisteína na data de admissão do estudo e a diferença do SOFA obtido no 3º dia e o SOFA da admissão (deltaSOFA) (r = 0,04 e p = 0,87). A variação da homocisteína do 3º dia e a admissão no estudo (deltaHmc) e a variação do SOFA no mesmo período não estavam correlacionadas (r = -0,11 e p = 0,66). A homocisteina da admissão não se correlacionou com mortalidade na UTI (p=0,46) ou com a mortalidade hospitalar.(p=0,13). Mesmo quando foi utilizado o deltaHmc não houve correlação (p=012 e p=0,99, respectivamente). CONCLUSÃO: O nível basal de homocisteína ou sua variação nos primeiros dias da disfunção não estiveram relacionadas com a piora dos parâmetros funcionais dos sistemas orgânicos ou mortalidade nos pacientes sépticos.
OBJECTIVE: Homocysteine and sepsis are both associated with inflammation and endothelial activation. Therefore this study was aimed to evaluate if the plasma homocystein level is related with the septic patient clinical severity. METHODS: Severe sepsis or septic shock patients, with less than 48 hours from organ dysfunction start, were admitted to this prospective observational study. Homocysteine levels were determined by the time of study admission and then on the Days 3, 7 and 14. The homocysteine association with the Sequential Organ Failure Assessment (SOFA) score was evaluated using the Sperman test, and its association with mortality using the Mann-Whitney test. A p<0.05 value was considered statistically significant. RESULTS: Twenty one patients were enrolled, and 60 blood samples were collected to measure total homocysteine [median 6.92 (5.27 - 9.74 μmol/L)]. The Sperman correlation test showed no association between homocysteine and SOFA ( r=0.15 and p=0.26). Also no correlation was found for the homocysteine level by the study admission time and the difference between the Day 3 SOFA score versus by study admission (deltaSOFA) (r=0.04 and p=0.87). Homocysteine variation between the Day 3 and the study admission (deltaHmc) and SOFA score variation in the same period were not correlated (r=-0.11 and p=0.66). Homocysteine by the study admission was not correlated with death in intensive care unit rate (p= 0.46) or in-hospital death rate (p = 0.13). This was also true for deltaHmc (p=0.12 and p=0.99, respectively). CONCLUSION: Baseline homocysteine levels and its variations within the first dysfunction days were not related with septic patients' worsened organ function parameters or mortality.
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OBJECTIVE: Homocysteine and sepsis are both associated with inflammation and endothelial activation. Therefore this study was aimed to evaluate if the plasma homocystein level is related with the septic patient clinical severity. METHODS: Severe sepsis or septic shock patients, with less than 48 hours from organ dysfunction start, were admitted to this prospective observational study. Homocysteine levels were determined by the time of study admission and then on the Days 3, 7 and 14. The homocysteine association with the Sequential Organ Failure Assessment (SOFA) score was evaluated using the Sperman test, and its association with mortality using the Mann-Whitney test. A p<0.05 value was considered statistically significant. RESULTS: Twenty one patients were enrolled, and 60 blood samples were collected to measure total homocysteine [median 6.92 (5.27 - 9.74 µmol/L)]. The Sperman correlation test showed no association between homocysteine and SOFA ( r=0.15 and p=0.26). Also no correlation was found for the homocysteine level by the study admission time and the difference between the Day 3 SOFA score versus by study admission (deltaSOFA) (r=0.04 and p=0.87). Homocysteine variation between the Day 3 and the study admission (deltaHmc) and SOFA score variation in the same period were not correlated (r=-0.11 and p=0.66). Homocysteine by the study admission was not correlated with death in intensive care unit rate (p= 0.46) or in-hospital death rate (p = 0.13). This was also true for deltaHmc (p=0.12 and p=0.99, respectively). CONCLUSION: Baseline homocysteine levels and its variations within the first dysfunction days were not related with septic patients' worsened organ function parameters or mortality.
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Both oxidative/nitrosative stress and alterations in DNA methylation are observed during carcinogenesis of different tumor types, but no clear correlation between these events has been demonstrated until now. Melanoma cell lines were previously established after submitting the nontumorigenicmelanocyte lineage, melan-a, to cycles of anchorage blockade. In this work, increased intracellular oxidative species and nitric oxide levels, as well as alterations in the DNA methylation, were observed after melan-a detachment, which were also associated with a decrease in intracellular homocysteine (Hcy), an element in the methionine (universal methyl donor) cycle. This alteration was accompanied by increase in glutathione (GSH) levels and methylated DNA content. Furthermore, a significant increase in dnmt1 and 3b expression was identified along melan-a anchorage blockade. L(G)-Nitro-L-arginine methyl esther (L-NAME), known as a nitric oxide synthase (NOS) inhibitor, and N-acetyl-L-cysteine (NAC) prevented the increase in global DNA methylation, as well as the increase in dnmt1 and 3b expression, observed during melan-a detachment. Interestingly, both L-NAME and NAC did not inhibit nitric oxide (NO) production in these cells, but abrogated superoxide anion production during anchorage blockade. In conclusion, oxidative stress observed during melanocyte anchorage blockade seems to modulate DNA methylation levels and may directly contribute to the acquisition of an anoikis-resistant phenotype through an epigenetic mechanism.
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Transformación Celular Neoplásica/genética , Metilación de ADN , Melanocitos/metabolismo , Estrés Oxidativo , Acetilcisteína/farmacología , Animales , Anoicis/genética , Adhesión Celular/efectos de los fármacos , Técnicas de Cultivo de Célula/métodos , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/metabolismo , Células Cultivadas/citología , Células Cultivadas/efectos de los fármacos , Células Cultivadas/metabolismo , Cisteína/metabolismo , Metilación de ADN/efectos de los fármacos , Regulación de la Expresión Génica , Glutatión/metabolismo , Homocisteína/metabolismo , Peroxidación de Lípido , Melanocitos/efectos de los fármacos , Melanocitos/patología , Ratones , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/metabolismo , Sefarosa/farmacología , Superóxidos/metabolismo , Tripsina/farmacologíaRESUMEN
BACKGROUND: An increased concentration of plasma homocysteine (Hcy) has toxic effects on vascular endothelium. This seems to be a risk factor of cardiovascular disease, premature stroke and venous thrombosis. The risk is higher in coincidence with other factors like chronic diseases and familiar hypercholesterolemia. The aim of our study was to evaluate plasma Hcy concentration in patients with juvenile idiopathic arthritis (JIA) and its correlation with methotrexate (MTX) therapy, serum folate and B12 vitamin, and hyperlipidemia. METHODS: Fifty-one patients (37 females; mean age 11.3 years, range 2.3-17 years) with JIA and 52 healthy controls (42 females; mean age 12.5 years; range 3-18 years) were included in the study. Thirty-two patients were using weekly MTX (mean doses: 0.1-1 mg/kg). For statistical analysis both JIA and control groups were distributed in three subgroups according to age (3 - 7, 8 - 12 and 13 - 18 years). The laboratory investigation included measurement of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), plasma Hcy, serum folate, vitamin B12, triglycerides, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL). For data analysis, we considered raised Hcy values >or= 12.56 micromol/L, which corresponds to the 90th percentile observed in the control group. RESULTS: The mean plasma Hcy concentration was 9.3 +/- 3.16 micromol/L in JIA patients and 8.9 +/- 2.42 micromol/L in healthy controls (p = 0.615). Higher concentration of Hcy was observed in the subgroup of 13 - 18 years (patients and controls, p < 0.001). We did not find correlation between MTX use and plasma Hcy concentration. With regard to vitamin B12 concentration, we detected normal values in both patients and controls while serum folate concentration was higher in patients (p < 0.001). With regard to the lipidogram, lower concentration of HDL was found in patients (p = 0.007) and higher levels of VLDL (p = 0.014) and triglycerides (p = 0.001) were observed in controls. We did not observe correlation among plasma Hcy concentration, clinical findings, ESR and CRP. CONCLUSION: JIA patients do not present significant increased concentration of Hcy despite the use of MTX, probably due to the folate supplementation. The mild abnormalities in the lipidogram may reflect a current concern with diet and health.
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BACKGROUND: Congenital heart defects are the result of incomplete heart development and, like many diseases, have been associated with high homocysteine concentration. METHODS: We evaluated homocysteine, folic acid and vitamin B(12) concentrations, and the mutations 677C>T and 1298A>C in MTHFR, 844ins68 in CBS and 2756A>G in MTR genes in 58 patients with congenital heart defects, 38 control subjects, and mothers of 49 patients and 26 controls. RESULTS: Control and patients presented normal range concentrations for homocysteine (7.66 +/- 3.16 microM and 6.95 +/- 3.12 microM, respectively), folic acid (8.31 +/- 3.00 ng/mL and 11.84 +/- 10.74 ng/mL) and vitamin B(12,) (613.56 +/- 307.57 pg/mL and 623.37 +/- 303.12 pg/mL), which did not differ among groups. For the mothers studied, homocysteine and vitamin B(12) concentrations also did not differ between groups. However, folic acid concentrations of mothers showed significant difference, the highest values being in the group of patients. No difference was found in allele frequencies among all groups studied. CONCLUSIONS: In the studied groups, high homocysteine seems not to be correlated with congenital heart defects, as well as folic acid and vitamin B(12). The mutations studied, in isolation, were not related to congenital heart defects, but high concentration of maternal homocysteine is associated with the presence of three or four mutated alleles.
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5-Metiltetrahidrofolato-Homocisteína S-Metiltransferasa/genética , Ligasas de Carbono-Nitrógeno/genética , Cistationina betasintasa/genética , Cardiopatías Congénitas/genética , Homocisteína/sangre , Adulto , Alelos , Preescolar , Femenino , Ácido Fólico/sangre , Frecuencia de los Genes , Cardiopatías Congénitas/enzimología , Humanos , Masculino , Mutación , Vitamina B 12/sangreRESUMEN
BACKGROUND: Helicobacter pylori gastritis may lead to impairment of the production of pepsinogen and acid, which are essential to cobalamin absorption. In turn, cobalamin deficiency leads to hyperhomocysteinaemia, a risk factor for cardio and cerebrovascular diseases. AIM: To evaluate the effect of H pylori eradication on plasma homocysteine levels in elderly patients. PATIENTS: Sixty-two H pylori-positive elderly patients with cobalamin deficiency were prospectively studied. METHODS: Homocysteine and cobalamin concentrations were determined before, 6 and 12 months after H pylori eradication. RESULTS: Corpus atrophy was observed in a few patients; otherwise, in most of them, the degree of corpus gastritis was moderate to severe. The initial homocysteine mean (SD) levels decreased from 41.0 (27.1) to 21.6 (10.1) micromol/l at the 6 month follow-up (p<0.001) and to 13.1 (3.8) micromol/l 12 months after H pylori eradication (p<0.001). Conversely, initial cobalamin mean levels increased from 145.5 (48.7) pmol/l to 209.8 (87.1) pmol/l and to 271.2 (140.8) pmol/l, 6 and 12 months after treatment, respectively (p<0.001 for both). Although the erythrocyte mean corpuscular volume was within reference intervals, it decreased significantly 6 (p = 0.002) and 12 (p<0.001) months after treatment. CONCLUSIONS: The results of the current study demonstrated that the eradication of H pylori in elderly patients with cobalamin deficiency is followed by increasing of cobalamin and decreasing of homocysteine blood levels.
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Infecciones por Helicobacter/sangre , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori , Homocisteína/sangre , Deficiencia de Vitamina B 12/microbiología , Anciano , Anciano de 80 o más Años , Autoanticuerpos/sangre , Femenino , Estudios de Seguimiento , Gastrinas/sangre , Gastritis/sangre , Gastritis/tratamiento farmacológico , Gastritis/microbiología , Gastritis/patología , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/patología , Humanos , Factor Intrinseco/inmunología , Masculino , Persona de Mediana Edad , Células Parietales Gástricas/inmunología , Pepsinógeno A/sangre , Estudios Prospectivos , Deficiencia de Vitamina B 12/sangreRESUMEN
BACKGROUND: Gaucher disease (GD) is the most common glycosphingolipidosis resulting in accumulation of glucoceramide. The most effective treatment for this disease is enzyme replacement therapy (ERT) which involves recombinant enzyme infusion. Enzymatic deficiency in GD patients may induce a cascade of events culminating in secondary effects such as the production of reactive oxygen species (ROS). We investigated the relationship between ROS and GD by analyzing blood oxidative stress markers in GD patients submitted to ERT at different stages during the treatment. METHODS: Blood were collected before and just after enzyme infusion. Red blood cell catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD) and total glutathione (tGSH), and plasma thiobarbituric acid reactive substances (TBARS) were assayed by spectrophotometry. Homocysteine concentrations and related polymorphisms were also studied. Control individuals matched for sex and age were also analyzed. RESULTS: Concentrations of homocysteine and TBARS, and GPx enzyme activity were not different in ERT-treated GD patients. CAT activity was higher while SOD was lower in patients compared to controls. No variations in any of these parameters were found before and just after ERT. Regarding tGSH, a significant increase was observed in GD patients after infusion. Genotypic frequencies studied did not differ from controls or other Brazilian samples. CONCLUSION: ERT-treated GD patients show an improvement in antioxidant capacity, which is further increased just after recombinant enzyme infusion.
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Biomarcadores/sangre , Enfermedad de Gaucher/sangre , Estrés Oxidativo , Adolescente , Adulto , Catalasa/sangre , Niño , Terapia Enzimática , Enzimas/genética , Femenino , Enfermedad de Gaucher/genética , Enfermedad de Gaucher/terapia , Frecuencia de los Genes , Genotipo , Glutatión/sangre , Glutatión Peroxidasa/sangre , Homocisteína/sangre , Humanos , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Proteínas Recombinantes/uso terapéutico , Superóxido Dismutasa/sangre , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Factores de TiempoRESUMEN
BACKGROUND: Cystathionine beta-synthase (CBS) deficiency is the most common cause of homocystinuria. However, no data are available concerning the molecular basis of this disease in Brazilian populations. METHODS: We studied 14 Brazilian patients from 11 unrelated families using a combined screening approach, involving restriction analysis, single-strand conformational polymorphism (SSCP) scanning, and sequencing. RESULTS: All patients presented homocysteine levels higher than 200 mumol/l before the beginning of treatment. The most common CBS gene mutations, p.G307S (c.919G > A) and p.I278T (c.833T > C), were evaluated and the allele c.919A was not found. One allele with the c.844 ins68 (4.5%) in the CBS gene was found. Three families (6 patients) presented the allele c.833 C (13.6%), without the insertion in the heterozygous state. SSCP scanning and sequencing showed 3 alleles p.T191M (13.64%) in 2 families. One allele with a novel mutation was found in exon 4 (c.168T > A) of the CBS gene (4.5%). We also analyzed c.677C > T and c.1298A > C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and the 2756A > G polymorphism in the methionine synthase (MTR) gene. The frequencies of mutated alleles were: 50% c.677T and 18.2% c.1298C for MTHFR, and 27.3% c.2756G for MTR. CONCLUSION: In spite of the high level of racial mixing in the country, Brazilian homocystinuric patients did not present a high prevalence of the most common mutations described in the literature.
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Homocistinuria/sangre , Homocistinuria/genética , 5-Metiltetrahidrofolato-Homocisteína S-Metiltransferasa/genética , Adolescente , Adulto , Alelos , Brasil , Niño , Preescolar , Cistationina betasintasa/deficiencia , Cistationina betasintasa/genética , Exones/genética , Femenino , Homocisteína/sangre , Homocistinuria/enzimología , Humanos , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Mutación/genética , Polimorfismo Conformacional Retorcido-SimpleRESUMEN
Associations between specific alleles of genes encoding enzymes in the methionine/homocysteine pathway and plasma homocysteine levels have been examined in different populations. In the present study, we determined polymorphisms of MTHFR A222V (677C > T), MTHFR E429A (1298A > C), MTRR I22M (66A > G), MTR D919G (2756A > G), and CBS 844ins68 and total plasma homocysteine levels (tHcy) among 154 mothers of children with Down syndrome (DS) and 158 control mothers from Brazil. Homocysteine levels were higher among DS mothers compared to control groups (10.437 vs. 8.600 respectively, P = 0.002). Only the 677T allele was associated with altered levels of tHcy in the case group (F((2,153)) = 5.300; P = 0.006), primarily when homozygous. In the control group, the association of the TT genotype with higher levels of tHcy showed borderline significance (F((2,157)) = 2.974; P = 0.054). All genotype distributions were similar in the two groups (P > 0.05), but the frequency of the 677T allele in the case group was significantly higher (chi(2) = 3.862; DF = 1; P = 0.049; OR = 1.437 (1.001-2.062)). Although the 677T allele is associated with increased homocysteine levels, its presence has only a modest impact as an independent risk factor for DS. All the other polymorphisms did not show an association with risk for the syndrome, when evaluated separately (P > 0.05). However, when the presence of 677T, 1298C, 2756G, 66G, and 844ins68 alleles were evaluated together, the mothers of children with DS tend to have a higher number of uncommon alleles than the mothers with no previous affected child.
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Síndrome de Down/genética , Enzimas/genética , Homocisteína/metabolismo , Polimorfismo Genético , 5-Metiltetrahidrofolato-Homocisteína S-Metiltransferasa/genética , 5-Metiltetrahidrofolato-Homocisteína S-Metiltransferasa/metabolismo , Adolescente , Adulto , Alelos , Estudios de Casos y Controles , Cistationina betasintasa/genética , Cistationina betasintasa/metabolismo , Enzimas/metabolismo , Salud de la Familia , Femenino , Ferredoxina-NADP Reductasa/genética , Ferredoxina-NADP Reductasa/metabolismo , Frecuencia de los Genes , Genotipo , Homocisteína/sangre , Humanos , Desequilibrio de Ligamiento , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/metabolismo , Madres , Factores de RiesgoRESUMEN
Hyperhomocysteinemia was initially related to cardiovascular diseases; but homocysteine (Hcy) metabolism disturbances have more recently associated with a wide range of pathophysiological conditions including age-related diseases, disrupted circadian rhythms and gynaecological disorders. Since in many cases we do not know to what extent animal models are physiologically similar to human ones, this study aimed to track spontaneous variations in rat plasma Hcy concentrations during different physiological processes such as life cycle, 24 hours and estrous cycle. Plasma total Hcy concentrations were accessed by HPLC. Plasma Hcy concentration varied with age and newborns had the lowest values (2.94 +/- 0.47 micromol/L). Rats aged 10 days presented concentration similar to 3 month old animals (6.87 +/- 0.67 and 8.29 +/- 1.55 micromol/L respectively). Values decreased to 6.42 +/- 1.65 micromol/L at 6 months and 4.87 +/- 0.81 micromol/L at 28 months. Concerning circadian variations in Hcy concentration cosinor analysis showed acrophase in young rats at 1:09 pm, but no plasma Hcy circadian variations in aged rats. Female rats showed changes in Hcy concentration during the estrous cycle with higher values during the diestrous I (10.61 +/- 1.81 micromol/L) compared with the estrous (8.47 +/- 1.86 micromol/L) and diestrous II (7.68 +/- 1.58 micromol/L) phases. In conclusion, plasma Hcy concentration varied spontaneously with ontogenic development and during the estrous cycle and presented a circadian rhythm variation in young rats.