The effect of polyphenolic extract from pine bark,Pycnogenol® on the level of glutathione in children suffering from attention deficit hyperactivity disorder (ADHD)

Abstract

Attention deficit hyperactivity disorder (ADHD) belongs to the neurodevelopmental disorders characterized by impulsivity, distractibility and hyperactivity. In the pathogenesis of ADHD genetic and non-genetic factors play an important role. It is assumed that one of non-genetic factors should be oxidative stress. Pycnogenol^®, an extract from the pine bark, consists of bioflavonoids, catechins, procyanidins and phenolic acids. Pycnogenol^® acts as powerful antioxidant, chelating agent; it stimulates the activities of some enzymes, like SOD, eNOS, and exhibits other biological activities.

Aim: The aim of this randomized, double-blind, placebo-controlled trial was to investigate the influence of administered Pycnogenol^® or placebo on the level of reduced (GSH) and oxidized (GSSG) glutathione in children suffering from ADHD and on total antioxidant status (TAS). This is the first investigation of the redox glutathione state in relation to ADHD.

Results: One month of Pycnogenol^® administration (1 mg/kg body weight/day) caused a significant decrease in GSSG and a highly significant increase in GSH levels as well as improvement of GSH/GSSG ratio in comparison to a group of patients taking a placebo. TAS in children with ADHD was decreased in comparison with reference values. Pycnogenol^® administration normalizes TAS of ADHD children.     

Regulatory roles of thioredoxin in oxidative stress-induced cellular responses

Abstract

Thioredoxin (TRX) is a small ubiquitous and multifunctional protein having a redox-active dithiol/disulfide within the conserved active site sequence –Cys–Gly–Pro–Cys–. TRX is induced by a variety of oxidative stimuli, including UV irradiation, inflammatory cytokines and chemical carcinogens, and has been shown to play crucial roles in the regulation of cellular responses such as gene expression, cell proliferation and apoptosis. Overexpression of TRX protects cells from cytotoxicity elicited by oxidative stress in both in vitro and in vivo models. The regulatory mechanism of TRX expression and activity is also being elucidated. Recently, TRX binding protein-2 (TBP-2)/vitamin D3 up-regulated protein 1 (VDUP1) was identified as a negative regulator of TRX. The analysis of TRX promoter region has revealed putative regulatory elements responsible for oxidative stress. Thus, the modulation of TRX functions may be a new therapeutic strategy for the treatment of oxidative stress-mediated diseases.     

Dietary supplementation with (R)-α-lipoic acid reverses the age-related accumulation of iron and depletion of antioxidants in the rat cerebral cortex

Abstract

Accumulation of divalent metal ions (e.g. iron and copper) has been proposed to contribute to heightened oxidative stress evident in aging and neurodegenerative disorders. To understand the extent of iron accumulation and its effect on antioxidant status, we monitored iron content in the cerebral cortex of F344 rats by inductively coupled plasma atomic emission spectrometry (ICP-AES) and found that the cerebral iron levels in 24–28-month-old rats were increased by 80% (p<0.01) relative to 3-month-old rats. Iron accumulation correlated with a decline in glutathione (GSH) and the GSH/GSSG ratio, indicating that iron accumulation altered antioxidant capacity and thiol redox state in aged animals. Because (R)-α-Lipoic acid (LA) is a potent chelator of divalent metal ions in vitro and also regenerates other antioxidants, we monitored whether feeding LA (0.2% [w/w]; 2 weeks) could lower cortical iron and improve antioxidant status. Results show that cerebral iron levels in old LA-fed animals were lower when compared to controls and were similar to levels seen in young rats. Antioxidant status and thiol redox state also improved markedly in old LA-fed rats versus controls. These results thus show that LA supplementation may be a means to modulate the age-related accumulation of cortical iron content, thereby lowering oxidative stress associated with aging.     

A pathologist's prognosis for ‘redox reaction’ profiles

Summary

The acute respiratory distress syndrome continues to be a major medical problem. Despite recent advances in treatment, such as the use of nitrogen monoxide (NO), extracorporeal membrane oxygenation (ECMO) and specialized ventilatory techniques in maintaining adequate oxygenation, mortality still remains high. The presence of activated neutrophils coupled with high inspired oxygen concentrations provide conditions that favour increased oxidative stress and this has focused attention on the possible role of free radical species in both the initiation and propagation of ARDS. Although there is evidence implicating increased free radical activity in ARDS, much of this is from animal models and the role of intervention in such processes has not been established. Although antioxidant therapy has been suggested as a possible treatment for ARDS the current literature is less than convincing. We examine the available data from human studies and suggest possible further studies and future therapeutic goals.     

Hydroxyl radical oxidation of guanosine 5′-triphosphate (GTP): requirement for a GTP–Cu(II) complex

Abstract

Levels of oxidized guanosine base in DNA have become a hallmark biomarker in assessing oxidative stress implicated in a variety of disease and toxin-induced states. However, there is evidence that the guanosine in the nucleotide triphosphate pool (GTP) is more susceptible to oxidation than guanosine residues incorporated into nucleic acids and this causes a substantial amount of the oxidized product, 8-oxoguanosine 5′-triphosphate (oxo⁸GTP), to accumulate in cell-free and in cell-culture preparations. Electron paramagnetic resonance (EPR) spectroscopy and direct EPR analysis of free radical production by copper sulfate and L-ascorbic acid demonstrates that the hydroxyl radical (HO^?) is produced via oxidation of Cu⁺ to Cu²⁺ while in a complex with GTP. This HO^? production is dependent on the availability of oxygen and the presence of GTP in the reaction milieu. Verification of free radical-mediated production of oxo⁸GTP is presented using HPLC with electrochemical detection and matrix-assisted laser desorption/ionization linear time-of-flight mass spectrometry (MALDI-LTOF-MS). The sum of these results is presented in a novel mechanism of GTP oxidation by Cu²⁺ and L-ascorbic acid. A better understanding of the chemistry involved in this oxidative modification of GTP facilitates a more comprehensive understanding of its potential physiological consequences.     

Photochemiluminescent detection of antiradical activity. V. Application in combination with the hydrogen peroxide-initiated chemiluminescence of blood plasma proteins to evaluate antioxidant homeostasis in humans

Abstract

Disturbance of the steady state between pro- and antioxidants in tissues is an important aetiopathogenetic factor. Two methods - (i) photosensitized chemiluminescence for detection of antiradical activity and (ii) hydrogen peroxide-initiated chemiluminescence of plasma proteins (CLP) and erythrocytes (CLE) - were tested in 136 healthy donors and 82 patients with untreated breast tumours for their applicability to detecting disturbances in antioxidant homeostasis in humans. The total antiradical capacity of water-soluble substances (ACW) and its urate-independent proportion (ACU) were lower (P <0.05) and CLP higher (P <0.001) in smokers in comparison to non-smokers. A significant negative correlation was found between the content of ascorbate in plasma and the intensity of CLP: r = 0.39, P <0.001. A significant reduction in ACU and increased values of CLP and CLE were seen according to the stage of disease in breast cancer patients. On the basis of these observations and model experiments we suggest that hydrogen peroxide-initiated chemiluminescence can serve as a parameter of oxidative modification of blood components and, in combination with the antioxidant parameters, can be used to describe the antioxidant homeostasis in humans and possibly to have value as a predictor of disease states.     

Atherothrombosis and oxidative stress: the connection and correlation in diabetes

Abstract

Background: Hyperglycaemia-induced depletion of reduced glutathione (GSH) causes erythrocyte oxidative stress (EOS), which leads to vascular events including exacerbation of thrombotic events evidenced by changes in D-dimer level. It would, therefore, appear that there is a complex link between GSH and D-dimer, which are part of an emerging array of biomarkers associated with diabetes. The objective of this study was to investigate evidence of correlation between levels of plasma D-dimer and erythrocyte GSH in diabetes disease progression.

Subjects and methods: A cohort of 69 subjects were selected based on medical history plus clinical findings and equally divided into control, prediabetes and diabetes groups, matched for age and sex. Plasma D-dimer and erythrocyte reduced glutathione (GSH) were determined and separated into quartiles as a means of indicating disease severity. Statistical analysis was by Pearson's correlation coefficient.

Results: Of the three groups, only the diabetes group showed any correlation between GSH and D-dimer. Of importance is that for increasing GSH, the second quartile range of GSH (xbar ± SD = 45 ± 22 mg/100ml) showed a statistically significant negative correlation for ranked D-dimer (xbar ± SD = 1055 ± 828 μg/l; r = ?0.88; P < 0.02). The fourth quartile GSH range (xbar ± SD = 79 ± 40 mg/100 ml) showed a statistically significant positive correlation with D-dimer (xbar ± SD = 1055 ± 828 μg/l; r = 0.91; P < 0.02). Thus, within the diabetes group only, the increasing level of oxidative stress as measured by GSH first indicates a reduction in D-dimer followed by a rise in D-dimer, which led to the proposal of a two-part process of atherosclerosis that reconciles previous contradictory findings.

Conclusions: This study provides not only evidence of a correlation between oxidative stress level and fibrinolysis in diabetes, but also an explanation of why previous studies have found both hypo- or hyperfibrinolysis associated with diabetes.     

The role of oxidative stress in an equine model of human asthma

Abstract

Equine recurrent airway obstruction (RAO) is a naturally occurring respiratory disease in horses with many similarities to human asthma and, as a result, has been used as an animal model of this disease. Oxidative stress has been demonstrated to occur in a range of respiratory diseases in human beings including asthma. Quantitatively, horses have a greater non-enzymatic antioxidant capacity in the pulmonary epithelial lining fluid compared to human beings due to high ascorbic acid concentrations, which reflects their ability to synthesise ascorbic acid. Consequently, a greater oxidative load is likely to be required to induce oxidative stress in horses compared to human beings. Induction of acute neutrophilic airway inflammation in RAO horses by exposure to organic dust does not result in marked pulmonary oxidative stress. However, with a more prolonged inflammatory response, the antioxidant capacity is depleted and oxidative stress occurs. Despite the clear evidence of oxidative stress in RAO, there is currently limited data linking oxidative stress with a causal role in the development of the pathophysiological features of RAO, namely airway obstruction, airway hyper-responsiveness, airway inflammation and mucus accumulation. However, pathways do exist whereby oxidants could potentially augment the production of important mediators in RAO. Further work is required to ascertain the benefits of antioxidant supplementation in RAO and to determine the role of oxidative stress in the pathogenesis of the disease. Given the similarities with human asthma, results from RAO horses could enhance the understanding of the role of oxidative stress in human asthma.     

The acute phase protein haptoglobin and its relation to oxidative status in piglets undergoing weaning-induced stress

Abstract

Haptoglobin (Hp) prevents the hemoglobin driven generation of hydroxyl radicals and lipid peroxides. Hp can reduce the neutrophil respiratory burst and is an antioxidative molecule in its own right. We aimed to evaluate Hp concentrations, oxidative stress and antioxidative capacity in blood during weaning and to characterise potential relationships between these parameters. Two batches of 10 piglets each (2 trials) weaned at the age of 27–30 days were fed a starter feed mix ad libitum. Blood samples were taken 1 week before weaning and at weekly intervals thereafter. Oxidative stress was monitored via the D-ROM^® system, antioxidative capacity was measured with the TEAC assay and Hp concentrations were measured by ELISA. Neutrophil phagocytic activity and oxidative burst were examined via flow-cytometry. Body weights were recorded weekly. Hp concentrations were increased in both trials post-weaning (P < 0.01); oxidative stress and oxidative burst were elevated in trial I (P < 0.005). In trial I, Hp and ROM values returned to baseline levels at 6 weeks post-weaning. The piglets in trial II showed respiratory symptoms and maintained elevated Hp concentrations. ROM values and Hp were related (r = 0.58; P < 0.01). Hp and body weight gain were inversely related post-weaning.