The role of oxidative stress in neurodegenerative diseases and potential antioxidant therapies.

Objectives: The central nervous system (CNS) is essential for homeostasis and controls the physiological functions of the body. However, the biochemical characteristics of the CNS make it especially vulnerable to oxidative damage (OS). This phenomenon compromises correct CNS functioning, leading to neurodegeneration and neuronal death. Contents: OS plays a crucial role in the physiopathology of neurodegenerative diseases. It is involved in multiple mechanisms of nucleic acid, protein, and lipid oxidation, thereby contributing to progressive brain damage. These mechanisms include mitochondrial dysfunction; excessive production of reactive oxygen and nitrogen species; deficiency of antioxidant defenses; protein oligomerization; cytokine production and inflammatory response; blood-brain barrier abnormalities; and proteasome dysfunction. All these dysfunctions are involved in the pathogenesis of neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, or amyotrophic lateral sclerosis. Summary and outlook: A curative treatment is currently not available. Research is focused on the search for therapies that reduce oxidative damage and delay disease progression. In the recent years, researchers have focused their attention on the effects of antioxidant therapies.

Urinary metals and metal mixtures and oxidative stress biomarkers in an adult population from Spain: The Hortega Study.

INTRODUCTION: Few studies have investigated the role of exposure to metals and metal mixtures on oxidative stress in the general population. OBJECTIVES: We evaluated the cross-sectional association of urinary metal and metal mixtures with urinary oxidative stress biomarkers, including oxidized to reduced glutathione ratio (GSSG/GSH), malondialdehyde (MDA), and 8­oxo­7,8­dihydroguanine (8-oxo-dG), in a representative sample of a general population from Spain (Hortega Study). METHODS: Urine antimony (Sb), barium (Ba), cadmium (Cd), chromium (Cr), cobalt (Co), copper (Cu), molybdenum (Mo), vanadium (V) and zinc (Zn) were measured by ICPMS in 1440 Hortega Study participants. RESULTS: The geometric mean ratios (GMRs) of GSSG/GSH comparing the 80th to the 20th percentiles of metal distributions were 1.15 (95% confidence intervals [95% CI]: 1.03-1.27) for Mo, 1.17 (1.05-1.31) for Ba, 1.23 (1.04-1.46) for Cr and 1.18 (1.00-1.40) for V. For MDA, the corresponding GMRs (95% CI) were 1.13 (1.03-1.24) for Zn and 1.12 (1.02-1.23) for Cd. In 8-oxo-dG models, the corresponding GMR (95% CI) were 1.12 (1.01-1.23) for Zn and 1.09 (0.99-1.20) for Cd. Cr for GSSG/GSH and Zn for MDA and 8-oxo-dG drove most of the observed associations. Principal component (PC) 1 (largely reflecting non-essential metals) was positively associated with GSSG/GSH. The association of PC2 (largely reflecting essential metals) was positive for GSSG/GSH but inverse for MDA. CONCLUSIONS: Urine Ba, Cd, Cr, Mo, V and Zn were positively associated with oxidative stress measures at metal exposure levels relevant for the general population. The potential health consequences of environmental, including nutritional, exposure to these metals warrants further investigation.

Obesity indexes and total mortality among elderly subjects at high cardiovascular risk: the PREDIMED study.

BACKGROUND: Different indexes of regional adiposity have been proposed for identifying persons at higher risk of death. Studies specifically assessing these indexes in large cohorts are scarce. It would also be interesting to know whether a dietary intervention may counterbalance the adverse effects of adiposity on mortality. METHODS: We assessed the association of four different anthropometric indexes (waist-to-height ratio (WHtR), waist circumference (WC), body mass index (BMI) and height) with all-cause mortality in 7447 participants at high cardiovascular risk from the PREDIMED trial. Forty three percent of them were men (55 to 80 years) and 57% were women (60 to 80 years). All of them were initially free of cardiovascular disease. The recruitment took place in 11 recruiting centers between 2003 and 2009. RESULTS: After adjusting for age, sex, smoking, diabetes, hypertension, intervention group, family history of coronary heart disease, and leisure-time physical activity, WC and WHtR were found to be directly associated with a higher mortality after 4.8 years median follow-up. The multivariable-adjusted HRs for mortality of WHtR (cut-off points: 0.60, 0.65, 0.70) were 1.02 (0.78-1.34), 1.30 (0.97-1.75) and 1.55 (1.06-2.26). When we used WC (cut-off points: 100, 105 and 110 cm), the multivariable adjusted Hazard Ratios (HRs) for mortality were 1.18 (0.88-1.59), 1.02 (0.74-1.41) and 1.57 (1.19-2.08). In all analyses, BMI exhibited weaker associations with mortality than WC or WHtR. The direct association between WHtR and overall mortality was consistent within each of the three intervention arms of the trial. CONCLUSIONS: Our study adds further support to a stronger association of abdominal obesity than BMI with total mortality among elderly subjects at high risk of cardiovascular disease. We did not find evidence to support that the PREDIMED intervention was able to counterbalance the harmful effects of increased adiposity on total mortality. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN35739639.

Relación del estrés oxidativo y la pérdida de peso obtenida en pacientes obesos mórbidos mediante cirugía bariátrica con la técnica del cruce duodenal / Relationship of oxidative stress and weight loss achieved in morbid obese patients by means of bariatric surgery using the duodenal switch technique

Introducción: El estrés oxidativo, presente de forma evidente en los obesos mórbidos, es un indicador del estado inflamatorio crónico que representa la obesidad y posible nexo de unión con sus comorbilidades, algunas de las cuales son un importante factor de riesgo para el desarrollo de enfermedades cardiovasculares, por lo que la atenuación de su intensidad se ha convertido en un objetivo terapéutico. Material y método: Hemos intervenido de forma consecutiva, mediante la técnica quirúrgica del cruce duodenal, a 28 pacientes afectos de obesidad mórbida, realizando un estudio del estrés oxidativo presente en ellos mediante la determinación de productos de oxidación molecular y de antioxidantes, en el preoperatorio y a lo largo de un año tras la cirugía. Se ha controlado la evolución ponderal y la evolución de las comorbilidades presentes. Resultados: Los pacientes de la serie presentaron una media de edad de 43 ± 1 años y un IMC medio de 50,3. El 82% presentó comorbilidad asociada. Tras la cirugía todos los pacientes perdieron peso de forma progresiva a lo largo del periodo estudiado, con mejoría paralela de las comorbilidades y disminución progresiva de los valores del EO y mejoría de los sistemas antioxidantes, siendo los valores de EO al finalizar el estudio similares a los de la población normal. Conclusión: La pérdida de peso obtenida consigue una mejora de las comorbilidades y de los valores de estrés oxidativo de modo que al final del estudio los resultados obtenidos son similares a los de la población normal (AU)

INTRODUCTION: Oxidative stress (OS), which is overtly present in morbid obesity, is an indicator of a chronic inflammatory state associated to obesity and possibly related with the associated comorbidities, some of which represent an important risk factor for the occurrence of cardiovascular diseases, so that decreasing its intensity has become a treatment priority. MATERIALS AND METHODS: he have consecutively performed the duodenal crossing surgical technique in 28 patients suffering from morbidobesity, assessing the level of oxidative stress by the determination of the products of molecular oxidation and antioxidants before the surgery and throughout one year after the surgery. Weight evolution and the progression of the comorbidities already present were assessed. RESULTS: the mean age of the patients in this series was 43 ± 1 years and the mean BMI 50.3. 82% had associated comorbidities. After the surgery, all the patients progressively lost weight throughout the study period, with a parallel improvement of the comorbidities and a progressive decrease in OS values and improvement of the antioxidant systems, the OS values being similar to those of a normal population at the end of the study. CONCLUSION: The weight loss achieved allows improving the comorbidities and the oxidative stress values so that at the end of the study the results obtained are similar to those of a normal population (AU)

[Oxidative stress; a comparative study between normal and morbid obesity group population]. / Estrés oxidativo; estudio comparativo entre un grupo de población normal y un grupo de población obesa mórbida.

OBJECTIVE: To determine the level of oxidative stress in morbid obese patients by comparing their results to those of a normal population. MATERIAL AND METHODS: We have studied the metabolites most representative of OS, both in the blood (MDA, 8-oxo-dG, GSSG and the ratio GSSG/GSH) and in the urine (8-oxo-dG), as well as the GSH antioxidant. A descriptive analysis of the sample was performed. The Kolmogorv-Smirnov test was used to assess whether the distribution of the different metabolites was normal. In the case of normal distribution, the Student's t test was used to compare the means, the Mann-Whitney U test was used for non-parametric data, with a significance level of p < 0.05 for hypothesis contrast. RESULTS: There were 28 patients in each group, without statistically significant differences regarding age and gender. The group of patients with morbid obesity presented an average BMI of 50.1 ± 4 and 23.9 ± 6 in the group with normal weight. 67.8% of the patients with morbid obesity had other comorbidities. There were no associated pathologies in the control group. All the values for the different OS metabolites were higher in the group of patients with morbid obesity than in the control group, whereas the activity of the antioxidant systems (GSH) was lower in the group with morbid obesity. CONCLUSION: The figures of OS metabolites obtained in the group of patients with morbid obesity confirm the presence of OS in obesity at a pathological level given the differences obtained in the group of normal population.

Objetivo: Determinar el grado de Estrés Oxidativo en pacientes obesos mórbidos comparando los resultados con los de una población normal. Material y método: Hemos estudiado los metabolitos más representativos del EO, tanto en sangre (MDA, 8-oxo-dG, GSSG y la relación GSSG/GSH) como en orina (8-oxo-dG), así como el antioxidante GSH. Realizamos un análisis descriptivo de la muestra. Se realizó la prueba de Kolmogorv-Smirnov para evaluar si la distribución de los distintos metabolitos seguía un modelo de normalidad. En los casos de distribución normal, se empleó la T de Student para comparar medias, utilizando la U de Mann-Whitney para los datos no paramétricos, utilizando en los contrastes de hipótesis el nivel de significación p < 0,05. Resultados: Los pacientes fueron 28 en cada grupo, sin diferencias estadísticamente significativas en cuanto a edad y sexo. El grupo de pacientes con obesidad mórbida presentó un IMC medio de 50,1 ± 4 y de 23,9 ± 6 el grupo normopeso. Un 67,8% de los pacientes obesos mórbidos presentaron comorbilidades. No había patología asociada en el grupo control. Todos los valores de los distintos metabolitos de EO fueron más elevados en el grupo de obesos mórbidos que en el grupo control mientras que la actividad de los sistemas antioxidantes (GSH) fue menor en el grupo de obesos mórbidos. Conclusión: Los valores de los metabolitos de EO obtenidos en el grupo de obesos mórbidos confirma la presencia de EO en la obesidad, de un modo que se puede considerar patológico dadas las diferencias obtenidas en el grupo de población normal.

[Relationship of oxidative stress and weight loss achieved in morbid obese patients by means of bariatric surgery using the duodenal switch technique]. / Relación del estrés oxidativo y la pérdida de peso obtenida en pacientes obesos mórbidos mediante cirugía bariátrica con la técnica del cruce duodenal.

INTRODUCTION: Oxidative stress (OS), which is overtly present in morbid obesity, is an indicator of a chronic inflammatory state associated to obesity and possibly related with the associated comorbidities, some of which represent an important risk factor for the occurrence of cardiovascular diseases, so that decreasing its intensity has become a treatment priority. MATERIALS AND METHODS: he have consecutively performed the duodenal crossing surgical technique in 28 patients suffering from morbid obesity, assessing the level of oxidative stress by the determination of the products of molecular oxidation and antioxidants before the surgery and throughout one year after the surgery. Weight evolution and the progression of the comorbidities already present were assessed. RESULTS: the mean age of the patients in this series was 43 ± 1 years and the mean BMI 50.3. 82% had associated comorbidities. After the surgery, all the patients progressively lost weight throughout the study period, with a parallel improvement of the comorbidities and a progressive decrease in OS values and improvement of the antioxidant systems, the OS values being similar to those of a normal population at the end of the study. CONCLUSION: The weight loss achieved allows improving the comorbidities and the oxidative stress values so that at the end of the study the results obtained are similar to those of a normal population.

Introducción: El estrés oxidativo, presente de forma evidente en los obesos mórbidos, es un indicador del estado inflamatorio crónico que representa la obesidad y posible nexo de unión con sus comorbilidades, algunas de las cuales son un importante factor de riesgo para el desarrollo de enfermedades cardiovasculares, por lo que la atenuación de su intensidad se ha convertido en un objetivo terapéutico. Material y método: Hemos intervenido de forma consecutiva, mediante la técnica quirúrgica del cruce duodenal, a 28 pacientes afectos de obesidad mórbida, realizando un estudio del estrés oxidativo presente en ellos mediante la determinación de productos de oxidación molecular y de antioxidantes, en el preoperatorio y a lo largo de un año tras la cirugía. Se ha controlado la evolución ponderal y la evolución de las comorbilidades presentes. Resultados: Los pacientes de la serie presentaron una media de edad de 43 ± 1 años y un IMC medio de 50,3. El 82% presentó comorbilidad asociada. Tras la cirugía todos los pacientes perdieron peso de forma progresiva a lo largo del periodo estudiado, con mejoría paralela de las comorbilidades y disminución progresiva de los valores del EO y mejoría de los sistemas antioxidantes, siendo los valores de EO al finalizar el estudio similares a los de la población normal. Conclusión: La pérdida de peso obtenida consigue una mejora de las comorbilidades y de los valores de estrés oxidativo de modo que al final del estudio los resultados obtenidos son similares a los de la población normal. Palabras clave: estrés oxidativo, obesidad, obesidad mórbida, cruce duodenal, pérdida de peso.

Oxidative stress and antioxidant enzyme values in lymphomonocytes after an oral unsaturated fat load test in familial hypercholesterolemic subjects.

Oxidative stress (OS) has been observed in conditions affecting the cardiovascular system. Familial hypercholesterolemia (FH) is associated with an increased risk of premature coronary heart disease. In the postprandial state, circulating lipids and lipoproteins can modulate OS status. Our aim was to study the response of lymphomonocyte OS status and reactive oxygen species by-products after an oral unsaturated fat load test (OFLT) in those with FH and to compare this response with that obtained in normolipidemic, normoglycemic subjects. We studied 12 patients with FH and 20 healthy controls. In both groups, lymphomonocyte, oxidized/reduced glutathione ratio, and malondialdehyde were determined at baseline and at 2, 4, 6, and 8 hours after an OFLT. Fasting urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine and isoprostane were measured using standard procedures. In both groups, oxidized/reduced glutathione ratio and malondialdehyde significantly decreased in the postprandial state after the OFLT. Both parameters were significantly higher in the FH group at baseline and during all the postprandial points, but the reduction from the baseline levels was significantly higher in the FH group than in the control group. Urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine was significantly increased in the FH group compared with the healthy control group, indicating a higher fasting OS status. We conclude that subjects with FH exhibited OS levels that were higher than in controls before and after an OFLT, but the improvement in the OS status after the unsaturated fat load was significantly higher in subjects with FH.

Associations of the FTO rs9939609 and the MC4R rs17782313 polymorphisms with type 2 diabetes are modulated by diet, being higher when adherence to the Mediterranean diet pattern is low.

BACKGROUND: Although the fat mass and obesity (FTO) and melanocortin-4 receptor (MC4R) genes have been consistently associated with obesity risk, the association between the obesity-risk alleles with type 2 diabetes is still controversial. In some recent meta-analyses in which significant results have been reported, the associations disappeared after adjustment for body mass index (BMI). However gene-diet interactions with dietary patterns have not been investigated. Our main aim was to analyze whether these associations are modulated by the level of adherence to the Mediterranean Diet (MedDiet). METHODS: Case-control study in 7,052 high cardiovascular risk subjects (3,430 type 2 diabetes cases and 3,622 non-diabetic subjects) with no differences in BMI. Diet was assessed by validated questionnaires. FTO-rs9939609 and MC4R-rs17782313 were determined. An aggregate genetic score was calculated to test additive effects. Gene-diet interactions were analyzed. RESULTS: Neither of the polymorphisms was associated with type 2 diabetes in the whole population. However, we found consistent gene-diet interactions with adherence to the MedDiet both for the FTO-rs9939609 (P-interaction=0.039), the MC4R-rs17782313 (P-interaction=0.009) and for their aggregate score (P-interaction=0.006). When adherence to the MedDiet was low, carriers of the variant alleles had higher type 2 diabetes risk (OR=1.21, 95%CI: 1.03-1.40; P=0.019 for FTO-rs9939609 and OR=1.17, 95%CI:1.01-1.36; P=0.035 for MC4R-rs17782313) than wild-type subjects. However, when adherence to the MedDiet was high, these associations disappeared (OR=0.97, 95%CI: 0.85-1.16; P=0.673 for FTO-rs9939609 and OR=0.89, 95%CI:0.78-1.02; P=0.097 for MC4R-rs17782313). These gene-diet interactions remained significant even after adjustment for BMI. As MedDiet is rich in folate, we also specifically examined folate intake and detected statistically significant interaction effects on fasting plasma glucose concentrations in non-diabetic subjects. However these findings should be interpreted with caution because folate intake may simply reflect a healthy dietary pattern. CONCLUSIONS: These novel results suggest that the association of the FTO-rs9939609 and the MC4R-rs17782313 polymorphisms with type 2 diabetes depends on diet and that a high adherence to the MedDiet counteracts the genetic predisposition.

Increased oxidative stress levels and normal antioxidant enzyme activity in circulating mononuclear cells from patients of familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is a clinical condition with high risk for developing atherosclerosis. Increased oxidative stress (OS) and FH have been related to atherosclerosis, but no data are available on levels of OS and antioxidant enzyme activity in circulating mononuclear cells (CMCs) from FH patients. Circulating mononuclear cells are important mediators in atherosclerosis development, and chronically increased blood OS present in FH can induce modification in CMC activity. The objective of the study was to analyze the OS levels in CMCs from FH patients and controls. We have selected 30 nonrelated FH index patients and 30 normoglycemic and normocholesterolemic controls matched by age, sex, body mass index, abdominal circumference, and homeostasis model assessment index. Production of free radicals was analyzed by measurement of xanthine oxidase activity in plasma, reduced and oxidized glutathione (GSH and GSSG, respectively), and malonyldialdehyde in levels CMCs. Antioxidant status was analyzed by measuring antioxidant enzyme activity as superoxide dismutase, catalase, and glutathione peroxidase. We have found that FH patients showed significantly higher xanthine oxidase and malonyldialdehyde enzyme activities, as well as increased GSSG and lower GSH values resulting in a higher GSSG/GSH ratio. These data indicate a higher free radical production in plasma and increased OS levels in CMCs from patients than from controls. No significant differences were found in superoxide dismutase, catalase, and glutathione peroxidase activities between both groups. These data show an important alteration of OS regulation in FH and the absence of antioxidant response in CMCs mediated by some of the major antioxidant enzymes.