Advances in Autism Research
compiled by Teresa Binstock for ARI
April 2008
Autism, oxidative stress, and nutrients
Elevated oxidative stress in autistic children is well documented. Most of the citations regarding nutrients describe benefits of supplements in regard to reducing oxidative stress. However, an important lesson is that increasing the dose of a given supplement (eg, vitamin E) can have adverse effects. Furthermore, some studies suggest that antioxidant supplementation is more effective for individuals with increased oxidative stress than for healthy individuals. Again, some citations convey the limits and risks of excessive use of antioxidants (eg, 3). Nonetheless, many and perhaps most peer-reviewed studies convey that supplements can help reduce elevated oxidative stress.
1. Oxidative susceptibility of unfractionated serum or plasma: response to antioxidants in vitro and to antioxidant supplementation
Atkin MA, Gasper A, Ullegaddi R, Powers HJ.
Clin Chem. 2005 Nov;51(11):2138-44.
http://www.clinchem.org/cgi/reprint/51/11/2138
BACKGROUND: The susceptibility of plasma lipids to oxidation is thought to be a factor contributing to atherogenic risk. Various groups have studied the in vitro oxidizability of isolated LDL and examined the effects of conventional antioxidants. The drawbacks associated with the isolation of LDL for evaluation of in vitro oxidizability, however, have limited the application of this measurement in large-scale studies. METHODS: We developed and evaluated an assay that can be used to directly assess the oxidative susceptibility of unfractionated serum or plasma lipids, obviating the need for isolation of lipoprotein fractions. Oxidative conditions were initiated in vitro with cuprous chloride and 2,2'-azobis(2-amidinopropane) hydrochloride. The effects of antioxidants added in vitro, and as an oral supplement, were monitored by conjugated diene formation. RESULTS: The addition of ascorbic acid (0-50 micromol/L) in vitro elicited a dose-dependent protective effect, increasing the lag time to oxidation (P < 0.001). In contrast, alpha-tocopherol demonstrated prooxidant behavior at increasing concentrations (0-50 micromol/L), although we observed a decrease in the maximum rate of oxidation. Our findings are supported by the results from plasma samples of participants in a randomized antioxidant (vitamins C and E) intervention study after acute ischemic stroke. The group receiving vitamins C and E for 14 days showed an increased lag time to plasma lipid oxidation in vitro compared with the nonsupplemented group (P < 0.05). CONCLUSION: The susceptibility of unfractionated plasma or serum lipids to oxidation in vitro offers an alternative to LDL for evaluating the efficacy of antioxidant regimens.
PMID: 16123150
2. Antioxidant supplementation reduces inter-individual variation in markers of oxidative damage
Volkovová K et al.
Free Radic Res. 2005 Jun;39(6):659-66.
The aim of this study was to examine the effect of antioxidant supplementation on oxidative damage and chromosome stability in middle-aged men, smokers and non-smokers. A total of 124 men aged 48+/-6 years from Bratislava and from the rural population near Bratislava were investigated; 64 men (22 smokers and 42 non-smokers) were supplemented for 12 weeks with antioxidants, while 60 (25 smokers and 35 non-smokers) were given placebo. The daily antioxidant supplementation consisted of vitamin C (100 mg), vitamin E (100 mg), ss-carotene (6 mg), and selenium (50 microg). Samples of blood were taken on two occasions: At the beginning and at the end of the supplementation trial. Concentrations of dietary antioxidants, ferric reducing ability, malondialdehyde as an indicator of lipid peroxidation in plasma, micronuclei and chromosome aberrations in lymphocytes were measured. Antioxidant supplementation significantly increased the levels of vitamin C, ss-carotene, a-tocopherol and selenium in plasma. The overall antioxidant status of plasma measured as ferric reducing ability of plasma (FRAP) increased significantly (p<0.001) after antioxidant supplementation as well. The increase in antioxidant parameters after supplementation were consistently more pronounced in non-smokers than in smokers. There was a significant decrease of malondialdehyde concentration in the non-smokers, while in smokers the decrease of malondialdehyde concentration was not significant. Antioxidant supplementation did not affect the proportion of lymphocytes with micronuclei or the total number of micronuclei; however, there was a significant positive correlation (p<0.001) between the malondialdehyde concentration at the beginning of the supplementation trial and the difference in number of cells with micronuclei before and after the supplementation. The percent of cells with chromosome aberrations decreased significantly after antioxidant supplementation in smokers. These results indicate that a combined antioxidant supplementation (a) is effective even at very moderate doses; (b) significantly diminishes oxidative damage to lipids when it is high initially; and (c) is effective in decreasing chromosomal instability in lymphocytes of middle-aged men.
PMID: 16036344
3. Life-long vitamin C supplementation in combination with cold exposure does not affect oxidative damage or lifespan in mice, but decreases expression of antioxidant protection genes
Selman C et al.
Mech Ageing Dev. 2006 Dec;127(12):897-904.
Oxidative stress is suggested to be central to the ageing process, with endogenous antioxidant defence and repair mechanisms in place to minimize damage. Theoretically, supplementation with exogenous antioxidants might support the endogenous antioxidant system, thereby reducing oxidative damage, ageing-related functional decline and prolonging life- and health-span. Yet supplementation trials with antioxidants in animal models have had minimal success. Human epidemiological data are similarly unimpressive, leading some to question whether vitamin C, for example, might have pro-oxidant properties in vivo. We supplemented cold exposed (7+/-2 degrees C) female C57BL/6 mice over their lifespan with vitamin C (ascorbyl-2-polyphosphate), widely advocated and self administered to reduce oxidative stress, retard ageing and increase healthy lifespan. No effect on mean or maximum lifespan following vitamin C treatment or any significant impact on body mass, or on parameters of energy metabolism was observed. Moreover, no differences in hepatocyte and lymphocyte DNA oxidative damage or hepatic lipid peroxidation was seen between supplemented and control mice. Using a DNA macroarray specific for oxidative stress-related genes, we found that after 18 months of supplementation, mice exhibited a significantly reduced expression of several genes in the liver linked to free-radical scavenging, including Mn-superoxide dismutase. We confirmed these effects by Northern blotting and found additional down-regulation of glutathione peroxidase (not present on macroarray) in the vitamin C treated group. We suggest that high dietary doses of vitamin C are ineffective at prolonging lifespan in mice because any positive benefits derived as an antioxidant are offset by compensatory reductions in endogenous protection mechanisms, leading to no net reduction in accumulated oxidative damage.
PMID: 17092545
4. Oxidative stress and antioxidant deficiencies in asthma: potential modification by diet
Misso NL, Thompson PJ.
Redox Rep. 2005;10(5):247-55.
The lungs of asthmatic patients are exposed to oxidative stress due to the generation of reactive oxygen and nitrogen species as a consequence of chronic airway inflammation. Increased concentrations of NO*, H2O2 and 8-isoprostane have been measured in exhaled breath and induced sputum of asthmatic patients. O2*-, NO*, and halides interact to form highly reactive species such as peroxynitrite and HOBr, which in turn cause nitration and bromination of protein tyrosine residues. Oxidative stress may also reduce glutathione levels and cause inactivation of antioxidant enzymes such as superoxide dismutase, with a consequent increase in apoptosis, shedding of airway epithelial cells and airway remodelling. The oxidant/antioxidant equilibrium in asthmatic patients may be further perturbed by low dietary intakes of the antioxidant vitamins C and E, selenium and flavonoids, with a consequent lowering of the concentrations of these and other non-dietary antioxidants such as bilirubin and albumin in plasma and airway epithelial lining fluid. Although supplementation with vitamins C and E appears to offer protection against the adverse effects of ozone, recent randomised, placebo-controlled trials of vitamin C or E supplements for patients with mild asthma have not shown significant benefits over standard therapy. However, genetic variation in glutathione S-transferase may influence the susceptibility of asthmatic individuals to oxidative stress and the extent to which they are likely to benefit from antioxidant supplementation. Long-term prospective trials are required to determine whether modification of dietary intake will benefit asthma patients and reduce the socio-economic burden of asthma in the community.
PMID: 16354413
5. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism
James SJ et al.
Am J Clin Nutr. 2004 Dec;80(6):1611-7.
http://www.ajcn.org/cgi/reprint/80/6/1611
BACKGROUND: Autism is a complex neurodevelopmental disorder that usually presents in early childhood and that is thought to be influenced by genetic and environmental factors. Although abnormal metabolism of methionine and homocysteine has been associated with other neurologic diseases, these pathways have not been evaluated in persons with autism. OBJECTIVE: The purpose of this study was to evaluate plasma concentrations of metabolites in the methionine transmethylation and transsulfuration pathways in children diagnosed with autism. DESIGN: Plasma concentrations of methionine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), adenosine, homocysteine, cystathionine, cysteine, and oxidized and reduced glutathione were measured in 20 children with autism and in 33 control children. On the basis of the abnormal metabolic profile, a targeted nutritional intervention trial with folinic acid, betaine, and methylcobalamin was initiated in a subset of the autistic children. RESULTS: Relative to the control children, the children with autism had significantly lower baseline plasma concentrations of methionine, SAM, homocysteine, cystathionine, cysteine, and total glutathione and significantly higher concentrations of SAH, adenosine, and oxidized glutathione. This metabolic profile is consistent with impaired capacity for methylation (significantly lower ratio of SAM to SAH) and increased oxidative stress (significantly lower redox ratio of reduced glutathione to oxidized glutathione) in children with autism. The intervention trial was effective in normalizing the metabolic imbalance in the autistic children. CONCLUSIONS: An increased vulnerability to oxidative stress and a decreased capacity for methylation may contribute to the development and clinical manifestation of autism.
PMID: 15585776
6. Urinary catecholamines in children with attention deficit hyperactivity disorder (ADHD): modulation by a polyphenolic extract from pine bark (pycnogenol)
Nutr Neurosci. 2007 Jun-Aug;10(3-4):151-7.
Dvoráková M et al.
Our study tested the hypothesis that treatment with a potent polyphenol complex not only reduces hyperactivity of children, but also catecholamine excretion and oxidative stress. Urine catecholamine concentrations were measured in attention deficit hyperactivity disorder (ADHD) children and healthy controls. ADHD children received either placebo (PL) or Pycnogenol (Pyc), a bioflavonoid extract from the pine bark, for one month. The study was performed in a randomized, double-blind, PL controlled design. Concentrations of catecholamines were higher in urine of ADHD patients compared to those of healthy children. Moreover, noradrenaline (NA) concentrations positively correlated with degree of hyperactivity of ADHD children. In ADHD patients, adrenaline (A) and NA concentrations positively correlated with plasma levels of oxidized glutathione. The treatment of ADHD children with Pyc caused decrease of dopamine (D) and trend of A and NA decrase and increased GSH/GSSG ratio. In conclusion, the data provide further evidence for the overactivity of the noradrenergic system in ADHD and demonstrate that A release may be increased, as well. Treatment of ADHD children with Pyc normalized catecholamine concentrations, leading to less hyperactivity, and, consequently, to reduced oxidative stress.
PMID: 18019397
7. Effect of polyphenolic extract, Pycnogenol, on the level of 8-oxoguanine in children suffering from attention deficit/hyperactivity disorder
Chovanová Z et al.
Free Radic Res. 2006 Sep;40(9):1003-10.
The purpose of this randomized, double-blind and placebo controlled study was to test the effect of polyphenolic extract of pine bark Pycnogenol (Pyc) on the level of oxidized purines represented by 8-oxo-7,8-dihydroguanine (8-oxoG) and on the total antioxidant status (TAS) in children with attention deficit/hyperactivity disorder (ADHD).We have found significantly increased damage to DNA in ADHD children when compared to controls. 8-oxoG was significantly lower after 1 month of Pyc administration in comparison to the beginning state and to placebo group. TAS in ADHD children was lower in comparison to controls. After Pyc administration, TAS was elevated but statistically significant increase was recorded after 1 month of termination of Pyc application. Improvement of DNA damage and TAS after Pyc administration is associated with the improvement of attention in ADHD children.In conclusion, Pycnogenol(R) administration reduces oxidative damage to DNA, normalizes TAS and improves attention of ADHD children. Explanation of mutual relation between oxidative damage to DNA, TAS and symptoms of ADHD and mechanism of Pyc's action needs further investigations.
PMID: 17015282
8. Treatment of ADHD with French maritime pine bark extract, Pycnogenol
Trebatická J et al.
Eur Child Adolesc Psychiatry. 2006 Sep;15(6):329-35.
Attention Deficit/Hyperactivity Disorder (ADHD) is the most common psychiatric disorder in children. Pycnogenol, an extract from the bark of the French maritime pine, consisting of phenolic acids, catechin, taxifolin and procyanidins, has shown improvement of ADHD in case reports and in an open study. Aim of the present study was to evaluate the effect of Pycnogenol on ADHD symptoms. Sixty-one children were supplemented with 1 mg/kg/day Pycnogenol or placebo over a period of 4 weeks in a randomised, placebo-controlled, doubleblind study. Patients were examined at start of trial, 1 month after treatment and 1 month after end of treatment period by standard questionnaires: CAP (Child Attention Problems) teacher rating scale, Conner's Teacher Rating Scale (CTRS), the Conner's Parent Rating Scale (CPRS) and a modified Wechsler Intelligence Scale for children. Results show that 1-month Pycnogenol administration caused a significant reduction of hyperactivity, improves attention and visual-motoric coordination and concentration of children with ADHD. In the placebo group no positive effects were found. One month after termination of Pycnogenol administration a relapse of symptoms was noted. Our results point to an option to use Pycnogenol as a natural supplement to relieve ADHD symptoms of children.
PMID: 16699814
9. Pycnogenol inhibits macrophage oxidative burst, lipoprotein oxidation, and hydroxyl radical-induced DNA damage
Nelson AB et al.
Drug Dev Ind Pharm. 1998 Feb;24(2):139-44.
Pycnogenol (procyanidins extracted from Pinus maritima) has been reputed as a potent free-radical scavenger and an antioxidant phytochemical. We previously reported that pycnogenol prevents vascular endothelial cells from injury induced by an organic oxidant t-butyl hydroperoxide. In this study, we determined the effects of pycnogenol on (a) oxidative burst of macrophages, (b) oxidation of plasma low density lipoprotein (LDL), and (c) hydroxyl radical-induced breakage of plasmid DNA. Pycnogenol was incubated with J774 murine macrophages at 37 degrees C and 5% CO2 and oxidative burst was triggered by zymosan. The intensity of fluorescence was measured. Pycnogenol exhibited a concentration-dependent inhibition of oxidative burst. CuSO4 was used to oxidize human plasma LDL and the formation of thiobarbituric acid reactive substances (TBARS) was determined. Co-incubation with pycnogenol resulted in a concentration-dependent inhibition of LDL oxidation. Exposure of pBR322 plasmid DNA to iron/ascorbic acid system resulted in cleavage/damage of DNA by hydroxyl radical, measured by agarose gel electrophoresis. Pycnogenol significantly minimized this cleavage. The results indicate that pycnogenol exhibits an extensive antioxidant effect in all three in vitro systems.
PMID: 15605443
10. A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology
Rohdewald P.
Int J Clin Pharmacol Ther. 2002 Apr;40(4):158-68.
OBJECTIVES: An increasing body of evidence indicates that Pycnogenol (PYC), a standardized extract of French maritime pine bark, has favorable pharmacological properties. This is a review of studies with both PYC and components of the preparation, that have helped to elucidate target sites and possible mechanisms for activity in men. METHODS: Studies appearing in peer reviewed literature, as well as results presented at international meetings not yet available as published papers, are included in this review. Additional data from published sources in German and French languages that are not widely available are also included. RESULTS: Chemical identification studies showed that PYC is primarily composed of procyanidins and phenolic acids. Procyanidins are biopolymers of catechin and epicatechin subunits which are recognized as important constituents in human nutrition. PYC contains a wide variety of procyanidins that range from the monomeric catechin and taxifolin to oligomers with 7 or more flavonoid subunits. The phenolic acids are derivatives of benzoic and cinnamic acids. The ferulic acid and taxifolin components are rapidly absorbed and excreted as glucuronides or sulphates in men, whereas procyanidins are absorbed slowly and metabolized to valerolactones which are excreted as glucuronides. PYC has low acute and chronic toxicity with mild unwanted effects occurring in a small percentage of patients following oral administration. Clinical studies indicate that PYC is effective in the treatment of chronic venous insufficiency and retinal micro-hemorrhages. PYC protects against oxidative stress in several cell systems by doubling the intracellular synthesis of anti-oxidative enzymes and by acting as a potent scavenger of free radicals. Other anti-oxidant effects involve a role in the regeneration and protection of vitamin C and E. Anti-inflammatory activity has been demonstrated in vitro and in vivo in animals. Protection against UV-radiation-induced erythema was found in a clinical study following oral intake of PYC. In asthma patients symptom scores and circulating leukotrienes are reduced and lung function is improved. Immunomodulation has been observed in both animal models as well as in patients with Lupus erythematosus. PYC antagonizes the vasoconstriction caused by epinephrine and norepinephrine by increasing the activity of endothelial nitric oxide synthase. Dilation of the small blood vessels has been observed in patients with cardiovascular disease, whereas in smokers, PYC prevents smoking-induced platelet aggregation and reduces the concentration of thromboxane. The ability to inhibit angiotensin-converting enzyme is associated with a mild antihypertensive effect. PYC relieves premenstrual symptoms, including abdominal pain and this action may be associated with the spasmolytic action of some phenolic acids. An improvement in cognitive function has been observed in controlled animal experiments and these findings support anecdotal reports of improvement in ADHD patients taking PYC supplements. CONCLUSIONS: There is much evidence showing that PYC has beneficial effects on physiological functions. Results from ongoing clinical research are required to confirm and extend previous observations.
PMID: 11996210
11. Vitamin E, oxidative stress, and inflammation
Singh U et al.
Annu Rev Nutr. 2005;25:151-74.
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the Western world. Its incidence has also been increasing lately in developing countries. Several lines of evidence support a role for oxidative stress and inflammation in atherogenesis. Oxidation of lipoproteins is a hallmark in atherosclerosis. Oxidized low-density lipoprotein induces inflammation as it induces adhesion and influx of monocytes and influences cytokine release by monocytes. A number of proinflammatory cytokines such as interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) modulate monocyte adhesion to endothelium. C-reactive protein (CRP), a prototypic marker of inflammation, is a risk marker for CVD and it could contribute to atherosclerosis. Hence, dietary micronutrients having anti-inflammatory and antioxidant properties may have a potential beneficial effect with regard to cardiovascular disease. Vitamin E is a potent antioxidant with anti-inflammatory properties. Several lines of evidence suggest that among different forms of vitamin E, alpha-tocopherol (AT) has potential beneficial effects with regard to cardiovascular disease. AT supplementation in human subjects and animal models has been shown to decrease lipid peroxidation, superoxide (O2-) production by impairing the assembly of nicotinamide adenine dinucleotide phosphate (reduced form) oxidase as well as by decreasing the expression of scavenger receptors (SR-A and CD36), particularly important in the formation of foam cells. AT therapy, especially at high doses, has been shown to decrease the release of proinflammatory cytokines, the chemokine IL-8 and plasminogen activator inhibitor-1 (PAI-1) levels as well as decrease adhesion of monocytes to endothelium. In addition, AT has been shown to decrease CRP levels, in patients with CVD and in those with risk factors for CVD. The mechanisms that account for nonantioxidant effects of AT include the inhibition of protein kinase C, 5-lipoxygenase, tyrosine-kinase as well as cyclooxygenase-2. Based on its antioxidant and anti-inflammatory activities, AT (at the appropriate dose and form) could have beneficial effects on cardiovascular disease in a high-risk population.
PMID: 16011463
12. Oxidative stress in subjects affected by celiac disease
Odetti P et al.
Free Radic Res. 1998 Jul;29(1):17-24.
In order to study the role of oxidative stress in celiac disease, protein carbonyl groups, thiobarbituric acid-reactive substance and pentosidine were evaluated in the plasma of nine patients with asymptomatic celiac disease and in a control group (n = 25). Plasma alpha-tocopherol, retinol and lipids were determined in the same samples. The levels of markers of oxidative stress derived from both protein (carbonyl groups) and lipids (thiobarbituric acid-reactive substances) were significantly higher in celiac disease patients, whereas lipoproteins and alpha-tocopherol were significantly lower. These data indicate that in celiac disease, even when asymptomatic, a redox imbalance persists; this is probably caused by an absorption deficiency, even if slight. Dietary supplementation with antioxidant molecules may offer some benefit and deserves further investigation.
PMID: 9733018
13. Red wine consumption increases antioxidant status and decreases oxidative stress in the circulation of both young and old humans
Micallef M et al.
Nutr J. 2007 Sep 24;6:27.
BACKGROUND: Red wine contains a naturally rich source of antioxidants, which may protect the body from oxidative stress, a determinant of age-related disease. The current study set out to determine the in vivo effects of moderate red wine consumption on antioxidant status and oxidative stress in the circulation. METHODS: 20 young (18-30 yrs) and 20 older (>or= 50 yrs) volunteers were recruited. Each age group was randomly divided into treatment subjects who consumed 400 mL/day of red wine for two weeks, or control subjects who abstained from alcohol for two weeks, after which they crossed over into the other group. Blood samples were collected before and after red wine consumption and were used for analysis of whole blood glutathione (GSH), plasma malondialdehyde (MDA) and serum total antioxidant status. RESULTS: Results from this study show consumption of red wine induced significant increases in plasma total antioxidant status (P < 0.03), and significant decreases in plasma MDA (P < 0.001) and GSH (P < 0.004) in young and old subjects. The results show that the consumption of 400 mL/day of red wine for two weeks, significantly increases antioxidant status and decreases oxidative stress in the circulation CONCLUSION: It may be implied from this data that red wine provides general oxidative protection and to lipid systems in circulation via the increase in antioxidant status.
PMID: 17888186
14. High concentration of antioxidants N-acetylcysteine and mitoquinone-Q induces intercellular adhesion molecule 1 and oxidative stress by increasing intracellular glutathione
Mukherjee TK et al.
J Immunol. 2007 Feb 1;178(3):1835-44.
http://www.jimmunol.org/cgi/reprint/178/3/1835
In endothelial cells, the intracellular level of glutathione is depleted during offering protection against proinflammatory cytokine TNF-alpha-induced oxidative stress. Administration of anti-inflammatory drugs, i.e., N-acetylcysteine (NAC) or mitoquinone-Q (mito-Q) in low concentrations in the human pulmonary aortic endothelial cells offered protection against depletion of reduced glutathione and oxidative stress mediated by TNF-alpha. However, this study addressed that administration of NAC or mito-Q in high concentrations resulted in a biphasic response by initiating an enhanced generation of both reduced glutathione and oxidized glutathione and enhanced production of reactive oxygen species, along with carbonylation and glutathionylation of the cellular proteins. This study further addressed that IkappaB kinase (IKK), a phosphorylation-dependent regulator of NF-kappaB, plays an important regulatory role in the TNF-alpha-mediated induction of the inflammatory cell surface molecule ICAM-1. Of the two catalytic subunits of IKK (IKKalpha and IKKbeta), low concentrations of NAC and mito-Q activated IKKalpha activity, thereby inhibiting the downstream NF-kappaB and ICAM-1 induction by TNF-alpha. High concentrations of NAC and mito-Q instead caused glutathionylation of IKKalpha, thereby inhibiting its activity that in turn enhanced the downstream NF-kappaB activation and ICAM-1 expression by TNF-alpha. Thus, establishing IKKalpha as an anti-inflammatory molecule in endothelial cells is another focus of this study. This is the first report that describes a stressful situation in the endothelial cells created by excess of antioxidative and anti-inflammatory agents NAC and mito-Q, resulting in the generation of reactive oxygen species, carbonylation and glutathionylation of cellular proteins, inhibition of IKKalpha activity, and up-regulation of ICAM-1expression.
PMID: 17237434
15. Physiological dose of lycopene suppressed oxidative stress and enhanced serum levels of immunoglobulin M in patients with Type 2 diabetes mellitus: a possible role in the prevention of long-term complications
Neyestani TR et al.
J Endocrinol Invest. 2007 Nov;30(10):833-8.
OBJECTIVE: This study was undertaken to evaluate the antioxidant effects of lycopene in physiological doses and its possible effects on the immune response in patients with Type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: A total of 35 patients with T2DM of both sexes aged 54+/-9 yr were enrolled in a double-blind placebo-controlled clinical trial conducted for 2 months. After a 2-week lycopene-free diet washout period, patients were allocated to either lycopene supplementation group (10 mg/day) (no.=16) or placebo group (no.=19), which were age- and sex matched. Patients were instructed to keep their diet and physical activity as unchanged as possible. RESULTS: While dietary intake of energy and body weight did not change, the ratio of serum total antioxidant capacity (TAC) to malondialdehyde (MDA) increased significantly in the lycopene group compared to the placebo group (p=0.007). Though a statistically significant increase in serum concentrations of lycopene (p<0.001) was not accompanied by enhanced delayed-type hypersensitivity response, a significant negative correlation was found between serum levels of lycopene and immunoglobulin (Ig)G (r=-0.338, p=0.008). Interestingly, variations of serum levels of lycopene directly correlated with those of IgM (r=0.466, p=0.005). There was an insignificant decrement in serum anti-oxidized LDL IgG levels in the lycopene group. CONCLUSIONS: Lycopene, probably by increasing TAC and inhibiting MDA-LDL formation, may attenuate T cell-dependent adaptive (pro-atherogenic) immune response. Meanwhile, with enhancement of innate immunity and hence prevention of ox-LDL uptake by macrophage and foam cell formation, lycopene may be effective in prevention of long-term diabetic complications, notably cardiovascular disease.
PMID: 18075285
16. Coenzyme Q10 (ubiquinol-10) supplementation improves oxidative imbalance in children with trisomy 21
Miles MV et al.
Pediatr Neurol. 2007 Dec;37(6):398-403.
Endogenous coenzyme Q10 is an essential cofactor in the mitochondrial respiratory chain, a potent antioxidant, and a potential biomarker for systemic oxidative status. Evidence of oxidative stress was reported in individuals with trisomy 21. In this study, 14 children with trisomy 21 had significantly increased (P < 0.0001) plasma ubiquinone-10 (the oxidized component of coenzyme Q10) compared with 12 age- and sex-matched healthy children (historical controls). Also, the mean ratio of ubiquinol-10 (the biochemically reduced component):total coenzyme Q10 was significantly decreased (P < 0.0001). After 3 months of ubiquinol-10 supplementation (10 mg/kg/day) to 10 patients with trisomy 21, the mean ubiquinol-10:total coenzyme Q10 ratio increased significantly (P < 0.0001) above baseline values, and 80% of individual ratios were within normal range. No significant or unexpected adverse effects were reported by participants. To our knowledge, this is the first study to indicate that the pro-oxidant state in plasma of children with trisomy 21, as assessed by ubiquinol-10:total coenzyme Q10 ratio, may be normalized with ubiquinol-10 supplementation. Further studies are needed to determine whether correction of this oxidant imbalance improves clinical outcomes of children with trisomy 21.
PMID: 18021919
17. Almond consumption reduces oxidative DNA damage and lipid peroxidation in male smokers
Li N et al.
J Nutr. 2007 Dec;137(12):2717-22.
http://jn.nutrition.org/cgi/content/full/137/12/2717
Smoking increases the risk of several chronic diseases associated with elevated oxidative stress status. Almonds are a good source of antioxidant nutrients and may diminish smoking-related biomarkers of oxidative stress. We investigated whether almond consumption decreases biomarkers of oxidative stress in young male smokers. We conducted a randomized, crossover clinical trial with 60 healthy male soldiers (18-25 y) who were habitual smokers (5-20 cigarettes/d) and supplemented their diet with 84 g almonds or 120 g pork (to control for calories) daily for 4 wk with a 4-wk washout period between treatment periods. In addition, 30 healthy nonsmoking men were provided the same daily serving of pork as reference comparison. Blood and urine were collected and assessed for biomarkers of oxidative stress. Baseline values of urinary 8-hydroxy-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) and peripheral lymphocyte DNA strand breaks were significantly higher by 185, 64, and 97% in smokers than nonsmokers, whereas activities of plasma superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase were significantly lower by 15, 10, and 9%, respectively. After the almond intervention, serum alpha-tocopherol, SOD, and GPX increased significantly in smokers by 10, 35, and 16%, respectively and 8-OHdG, MDA, and DNA strand breaks decreased significantly by 28, 34, and 23%. In smokers, after almond supplementation, the concentration of 8-OHdG remained significantly greater than in nonsmokers by 98%. These results suggest almond intake can enhance antioxidant defenses and diminish biomarkers of oxidative stress in smokers.
PMID: 18029489
18. The relationship between dose of vitamin E and suppression of oxidative stress in humans
Roberts LJ 2nd et al.
Free Radic Biol Med. 2007 Nov 15;43(10):1388-93.
The oxidation hypothesis of atherogenesis has been the focus of much research over the past 2 decades. However, randomized placebo-controlled trials evaluating the efficacy of vitamin E in preventing cardiovascular events in aggregate have failed to show a beneficial effect. Implicit in these trials is that the dose of vitamin E tested effectively suppressed oxidative stress status but this was never determined. We defined the dose-dependent effects of vitamin E (RRR-alpha-tocopherol) to suppress plasma concentrations of F2-isoprostanes, a biomarker of free radical-mediated lipid peroxidation, in participants with polygenic hypercholesterolemia and enhanced oxidative stress, a population at risk for cardiovascular events. A time-course study was first performed in participants supplemented with 3200 IU/day of vitamin E for 20 weeks. A dose-ranging study was then performed in participants supplemented with 0, 100, 200, 400, 800, 1600, or 3200 IU/day of vitamin E for 16 weeks. In the time-course study, maximum suppression of plasma F2-isoprostane concentrations did not occur until 16 weeks of supplementation. In the dose-ranging study there was a linear trend between the dosage of vitamin E and percentage reduction in plasma F2-isoprostane concentrations which reached significance at doses of 1600 IU (35+/-2%, p<0.035) and 3200 IU (49+/-10%, p<0.005). This study provides information on the dosage of vitamin E that decreases systemic oxidant stress in vivo in humans and informs the planning and evaluation of clinical studies that assess the efficacy of vitamin E to mitigate disease.
PMID: 17936185
19. Lipoic acid and N-acetyl cysteine decrease mitochondrial-related oxidative stress in Alzheimer disease patient fibroblasts
Moreira PI et al.
J Alzheimers Dis. 2007 Sep;12(2):195-206.
In this study, we evaluated the effect of lipoic acid (LA) and N-acetyl cysteine (NAC) on oxidative [4-hydroxy-2-nonenal, N(epsilon)-(carboxymethyl)lysine and heme oxygenase-1] and apoptotic (caspase 9 and Bax) markers in fibroblasts from patients with Alzheimer disease (AD) and age-matched and young controls. AD fibroblasts showed the highest levels of oxidative stress, and the antioxidants, lipoic acid (1 mM) and/or N-acetyl cysteine (100 microM) exerted a protective effect as evidenced by decreases in oxidative stress and apoptotic markers. Furthermore, we observed that the protective effect of LA and NAC was more pronounced when both agents were present simultaneously. AD-type changes could be generated in control fibroblasts using N-methylprotoporphyrin to inhibit cytochrome oxidase assembly indicating that the the oxidative damage observed was associated with mitochondrial dysfunction. The effects of N-methylprotoporphyrine were reversed or attenuated by both lipoic acid and N-acetyl cysteine. These data suggest mitochondria are important in oxidative damage that occurs in AD. As such, antioxidant therapies based on lipoic acid and N-acetyl cysteine supplementation may be promising.
PMID: 17917164
20. The effect of alpha-tocopherol on the oxidative stress and antioxidants in idiopathic IgA nephropathy
Ong-ajyooth L et al.
J Med Assoc Thai. 2006 Nov;89 Suppl 5:S164-70.
OBJECTIVE: Nearly 25% of IgA nephropathy patients progress to end-stage renal disease over a 20-25 year follow-up period. IgA containing immune complex stimulates oxygen free radical production by mesangial cells in vitro, which may mediate glomerular injury in this disorder. Therefore, we studied whether dietary supplementation with the antioxidant agent, vitamin E, attenuates renal damage in patients with IgA nephropathy. MATERIAL AND METHOD: Twenty-eight patients with idiopathic IgA nephropathy were supplemented with vitamin E 400 mg/day for 6 months. Antioxidant enzymes, glutathione, plasma malondialdehyde (MDA), and renal function were studied after 3 and 6 months therapy. RESULT: The result of the study showed high plasma MDA and significant reduction after therapy (1.15 +/- 0.45 VS 0.86 +/- 0.30 microM, p < 0.0001). The RBC vitamin E was also elevated statistically significantly (5.07 +/- 2.42 VS 15.70 +/- 3.37 microM, p < 0.001). Glutathione peroxidase activities were decreased (38.52 +/- 15.53 VS 23.97 +/- 7.63 U/gHb, p < 0.001). Glutathione was also decreased (44.80 +/- 9.70 VS 32.45 +/- 6.74 mg/dl, p < 0.05) but there were no changes in red cell catalase and superoxide dismutase activities. Creatinine clearance, proteinuria, urine N-acetyl glucosaminidase and beta2-microglobulin also showed no improvement. CONCLUSION: Our data demonstrated the particular group of IgA nephropathy patients with low vitamin E level and high oxidative stress had significant reduction of oxidative stress after vitamin E therapy.
PMID: 17718258
21. Genetic susceptibility of newborn daughters to oxidative stress
Decordier I et al.
Toxicol Lett. 2007 Jul 30;172(1-2):68-84.
A central question in risk assessment is whether newborns' susceptibility to mutagens is different from that of adults. Therefore we investigated whether genotype and/or the DNA strand break repair phenotype in combination with the MN assay would allow estimation of the relative sensitivity of a newborn as compared to his mother for oxidative DNA damage. We compared the in vitro genetic susceptibility for H2O2 in PBMC of 17 mother-newborn daughter pairs taking into account genotypes for relevant DNA repair (hOGG1, XRCC1, XRCC3, XPD) and folate metabolism (MTHFR) polymorphisms. After in vitro challenge with H2O2 the repair capacity was assessed by the Comet assay and chromosome/genome mutations by the cytokinesis-block MN assay. No statistically significant differences were found between mothers and their newborn daughters either for initial DNA damage or for residual DNA damage. Mothers showed higher background frequencies of MN as compared to their newborn daughters, due to the age factor. This was confirmed by significantly higher frequencies of MN observed in mothers versus newborn daughters for several genotypes. No genotype with a significant effect on DNA repair capacity in newborns was identified. Concerning MN frequencies, however, newborns carrying the variant XRCC3(241) genotype might be at higher risk for the induction of MN by oxidative stress. Multivariate analysis revealed a significant protective effect of maternal antioxidant supplementation during pregnancy against oxidative DNA damage in newborns in terms of MN frequencies. However, these conclusions might not be extrapolable to other types of DNA damage and need confirmation in a study on a larger population.
PMID: 17614221
22. Nutritional intervention in brain aging: reducing the effects of inflammation and oxidative stress
Lau FC et al.
Subcell Biochem. 2007;42:299-318.
It is estimated that by the year 2050 the elderly (aged 65 or older) population will double the population of children (aged 0-14) for the first time in history. The expansion of the elderly population has already taken a toll on health care systems. In order to alleviate the health care costs and increase the quality of living in the aging population, it is crucial to explore methods that may retard or reverse the deleterious effects of aging. Inflammation and oxidative stress play important roles in brain aging. Inflammatory markers, as well as cellular and molecular oxidative damage, increase during normal brain aging. This increase is accompanied by the concomitant decline in cognitive and motor performance in the elderly population, even in the absence of neurodegenerative diseases. Epidemiological studies have shown that consumption of diets rich in antioxidant and anti-inflammatory agents, such as those found in fruits and vegetables, may lower the risk of developing age-related neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Research from our laboratory suggests that dietary supplementation with fruit or vegetable extracts can decrease the age-enhanced vulnerability to oxidative stress and inflammation. Additional research suggests that the polyphenolic compounds found in fruits such as blueberries may exert their beneficial effects through signal transduction and neuronal communication. Thus, nutritional intervention may exert therapeutic protection against age-related deficits and neurodegenerative diseases.
PMID: 17612057
23. The evidence basis for coenzyme Q therapy in oxidative phosphorylation disease
Haas RH.
Mitochondrion. 2007 Jun;7 Suppl:S136-45. Epub 2007 Mar 30.
The evidence supporting a treatment benefit for coenzyme Q10 (CoQ10) in primary mitochondrial disease (mitochondrial disease) whilst positive is limited. Mitochondrial disease in this context is defined as genetic disease causing an impairment in mitochondrial oxidative phosphorylation (OXPHOS). There are no treatment trials achieving the highest Level I evidence designation. Reasons for this include the relative rarity of mitochondrial disease, the heterogeneity of mitochondrial disease, the natural cofactor status and easy 'over the counter availability' of CoQ10 all of which make funding for the necessary large blinded clinical trials unlikely. At this time the best evidence for efficacy comes from controlled trials in common cardiovascular and neurodegenerative diseases with mitochondrial and OXPHOS dysfunction the etiology of which is most likely multifactorial with environmental factors playing on a background of genetic predisposition. There remain questions about dosing, bioavailability, tissue penetration and intracellular distribution of orally administered CoQ10, a compound which is endogenously produced within the mitochondria of all cells. In some mitochondrial diseases and other commoner disorders such as cardiac disease and Parkinson's disease low mitochondrial or tissue levels of CoQ10 have been demonstrated providing an obvious rationale for supplementation. This paper discusses the current state of the evidence supporting the use of CoQ10 in mitochondrial disease.
PMID: 17485245
24. Coenzyme Q, oxidative stress and aging
Sohal RS, Forster MJ.
Mitochondrion. 2007 Jun;7 Suppl:S103-11. Epub 2007 Mar 30.
Coenzyme Q (CoQ) has three well-characterized functions in mitochondria, namely (i) transfer of reducing equivalents in the electron transport chain, (ii) generation of superoxide anion radical, O2*-, and (iii) quenching of free radicals. The main purpose of this review is to discuss the effects of CoQ10 intake for relatively prolonged periods on mitochondrial respiratory capacity, indicators of oxidative stress, and life span of animals, in context of the broader issue of whether or not the overall progression of the aging process can be modified by CoQ10 administration. Comparative studies on different mammalian species have indicated that the rate of mitochondrial superoxide anion radical generation is directly correlated with mitochondrial CoQ9 content and inversely related to amounts of CoQ10, particularly the CoQ10 bound to mitochondrial membrane proteins. Contrary to the historical view, dietary supplementation of mice and rats with CoQ10 has been demonstrated to augment the endogenous CoQ content (CoQ9 + CoQ10) in mitochondria and homogenates of various tissues, albeit to varying extent. Ingestion of CoQ10 results in the elevation of endogenous CoQ9, the predominant homologue in mice and rats. In our studies, there was no indication of a discernable effect of CoQ10 intake reflecting enhancement of mitochondrial respiratory activity, antioxidant capacity and pro-oxidant potentiation or prolongation of life span. The possibility that CoQ10 intake affects certain other biological functions by as yet unelucidated mechanisms cannot be ruled out as CoQ has been shown to broadly alter gene expression in mice.
PMID: 17482528
25. Garlic oil prevents tributyltin-induced oxidative damage in vivo and in vitro
Liu HG, Xu LH.
J Food Prot. 2007 Mar;70(3):716-21.
Tributyltin (TBT) can be transported to the human body by contaminated seafood. Presently, there is no known effective strategy to eliminate TBT's toxic effects from contaminated food. The present study was conducted to investigate the ability of garlic oil (GO) to prevent TBT-induced oxidative damage in vivo as well as in vitro. The results follow: both reactive oxygen species (ROS) production and malondialdehyde content decreased in mice pretreated with GO, the number of cells with damaged DNA in unprotected mice increased significantly compared with that in GO-protected mice (comet assay), and the alleviation of the depletion of cortical thymocytes and damage to nucleoli and mitochondria in GO-protected mice was observed. In human FL (human amniotic cells; American Type Culture Collection) cell studies, TBT-induced intracellular ROS generation was significantly inhibited after FL cells were pretreated with GO, and the TBT-induced cytotoxic effects were also prevented by GO. The results led to the first observation that GO was effective in reducing TBT-induced oxidative damage both in vivo and in vitro. The possible protective mechanism may stem from the considerable ability of GO to scavenge ROS. We conclude that GO could be an effective agent or food supplement in reducing the toxicity of TBT.
PMID: 17388064
26. Zinc supplementation decreases incidence of infections in the elderly: effect of zinc on generation of cytokines and oxidative stress
Prasad AS et al.
Am J Clin Nutr. 2007 Mar;85(3):837-44.
http://www.ajcn.org/cgi/content/full/85/3/837
BACKGROUND: Zinc deficiency, cell-mediated immune dysfunction, susceptibility to infections, and increased oxidative stress have been observed in elderly subjects (ie, those >55 y old). Zinc is an effective antiinflammatory and antioxidant agent. OBJECTIVES: The primary objective was to determine the effect of zinc on the incidence of total infections in healthy elderly subjects. The secondary objective was to determine the effect of zinc on cytokines and oxidative stress markers. DESIGN: A randomized, double-blind, placebo-controlled trial of zinc supplementation was conducted in elderly subjects. Fifty healthy subjects of both sexes aged 55-87 y and inclusive of all ethnic groups were recruited for this study from a senior center. The zinc-supplemented group received zinc gluconate (45 mg elemental Zn/d) orally for 12 mo. Incidence of infections during the supplementation period was documented. The generation of inflammatory cytokines, T helper 1 and T helper 2 cytokines, and oxidative stress markers and the plasma concentrations of zinc were measured at baseline and after supplementation. RESULTS: Compared with a group of younger adults, at baseline the older subjects had significantly lower plasma zinc, higher ex vivo generation of inflammatory cytokines and interleukin 10, and higher plasma oxidative stress markers and endothelial cell adhesion molecules. The incidence of infections and ex vivo generation of tumor necrosis factor alpha and plasma oxidative stress markers were significantly lower in the zinc-supplemented than in the placebo group. Plasma zinc and phytohemagglutin-induced interleukin 2 mRNA in isolated mononuclear cells were significantly higher in the zinc-supplemented than in the placebo group. CONCLUSIONS: After zinc supplementation, the incidence of infections was significantly lower, plasma zinc was significantly higher, and generation of tumor necrosis factor alpha and oxidative stress markers was significantly lower in the zinc-supplemented than in the placebo group.
PMID: 17344507
27. The role of N-acetylcysteine treatment on anti-oxidative status in patients with type II diabetes mellitus
Ozkilic AC et al.
J Basic Clin Physiol Pharmacol. 2006;17(4):245-54.
The development of diabetic complications has usually been attributed to the nonenzymic glycation of tissue proteins. Only recently, however, have researchers examined the possible role on free radicals in the pathogenesis of diabetes. In the present study, glutathione (GSH) and major antioxidant enzyme levels in plasma of patients with type II diabetes mellitus were assessed both before and after 3 months of N-acetylcysteine (NAC) therapy. Thirty-two diabetic patients were examined as well as fifteen healthy controls. Before treatment with NAC, glutathione peroxidase (GPx), catalase (CAT), and (GSH) levels of diabetic patients and control subjects showed no significant differences, whereas glutathione S-transferase (GST) levels were higher in type II diabetic patients. Following 3 months of Following NAC supplementation, GSH, GST, and CAT levels were found to be similar to the levels before treatment. On the other hand, GPx activity was significantly lower compared with the values before treatment. According to this finding, NAC treatment could have a positive effect on GPx values in type II diabetic patients showing abnormally high values.
PMID: 17338280
28. Effect of melatonin on the oxidative stress in erythrocytes of healthy young and elderly subjects
Kedziora-Kornatowska K et al.
J Pineal Res. 2007 Mar;42(2):153-8.
The disturbances in pro- and antioxidant balance may play an important role in the pathomechanism of aging. The pineal hormone melatonin, which exerts effective antioxidative properties, is suggested to be involved in the aging process. The aim of this study was to compare the oxidative stress in erythrocytes of healthy young adults and elderly people, and to determine the influence of melatonin supplementation on measured parameters in both examined groups. The malondialdehyde (MDA) and reduced glutathione levels as well as Cu-Zn superoxide dismutase (SOD-1), catalase, glutathione peroxidase (GSH-Px), glutathione S-transferase (GST) and glutathione reductase (GR) activities in erythrocytes and morning serum melatonin concentration in 14 healthy young adults and 14 healthy elderly people at baseline and after the 30th day of melatonin (5 mg daily) supplementation were determined. A significant age effect on increasing the MDA level and decreasing SOD-1, GSH-Px and GR activities as well as melatonin concentration was observed. Melatonin supplementation resulted in a significant increase in melatonin concentration, SOD-1 and GR activities and a decrease in the MDA level in both examined groups. These data indicate an age-related augmentation of oxidative stress in erythrocytes and the improvement of erythrocytic antioxidative defense by melatonin administration. These results might suggest melatonin supplementation to prevent age-related diseases and to prolong the lifespan and improve the quality of life of elderly people.
PMID: 17286747
29. Melatonin for Insomnia in Children With Autism Spectrum Disorders
Andersen IM et al.
J Child Neurol. 2008 Jan 8 [Epub ahead of print]
We describe our experience in using melatonin to treat insomnia, a
common sleep concern, in children with autism spectrum disorders. One
hundred seven children (2-18 years of age) with a confirmed diagnosis
of autism spectrum disorders who received melatonin were identified by
reviewing the electronic medical records of a single pediatrician. All
parents were counseled on sleep hygiene techniques. Clinical response
to melatonin, based on parental report, was categorized as (1) sleep no
longer a concern, (2) improved sleep but continued parental concerns,
(3) sleep continues to be a major concern, and (4) worsened sleep. The
melatonin dose varied from 0.75 to 6 mg. After initiation of melatonin,
parents of 27 children (25%) no longer reported sleep concerns at
follow-up visits. Parents of 64 children (60%) reported improved sleep,
although continued to have concerns regarding sleep. Parents of 14
children (13%) continued to report sleep problems as a major concern,
with only 1 child having worse sleep after starting melatonin (1%), and
1 child having undetermined response (1%). Only 3 children had mild
side-effects after starting melatonin, which included morning
sleepiness and increased enuresis. There was no reported increase in
seizures after starting melatonin in children with pre-existing
epilepsy and no new-onset seizures. The majority of children were
taking psychotropic medications. Melatonin appears to be a safe and
well-tolerated treatment for insomnia in children with autism spectrum
disorders. Controlled trials to determine efficacy appear warranted.
PMID: 18182647
30. Role of the melatonin system in the control of sleep: therapeutic implications
Pandi-Perumal SR et al.
CNS Drugs. 2007;21(12):995-1018.
The circadian rhythm of pineal melatonin secretion, which is
controlled by the suprachiasmatic nucleus (SCN), is reflective of
mechanisms that are involved in the control of the sleep/wake cycle.
Melatonin can influence sleep-promoting and sleep/wake
rhythm-regulating actions through the specific activation of MT(1)
(melatonin 1a) and MT(2) (melatonin 1b) receptors, the two major
melatonin receptor subtypes found in mammals. Both receptors are highly
concentrated in the SCN. In diurnal animals, exogenous melatonin
induces sleep over a wide range of doses. In healthy humans, melatonin
also induces sleep, although its maximum hypnotic effectiveness, as
shown by studies of the timing of dose administration, is influenced by
the circadian phase. In both young and elderly individuals with primary
insomnia, nocturnal plasma melatonin levels tend to be lower than those
in healthy controls. There are data indicating that, in affected
individuals, melatonin therapy may be beneficial for ameliorating
insomnia symptoms. Melatonin has been successfully used to treat
insomnia in children with attention-deficit hyperactivity disorder or
autism, as well as in other neurodevelopmental disorders in which sleep
disturbance is commonly reported. In circadian rhythm sleep disorders,
such as delayed sleep-phase syndrome, melatonin can significantly
advance the phase of the sleep/wake rhythm. Similarly, among shift
workers or individuals experiencing jet lag, melatonin is beneficial
for promoting adjustment to work schedules and improving sleep quality.
The hypnotic and rhythm-regulating properties of melatonin and its
agonists (ramelteon, agomelatine) make them an important addition to
the armamentarium of drugs for treating primary and secondary insomnia
and circadian rhythm sleep disorders.
PMID: 18020480
31. Abnormal melatonin synthesis in autism spectrum disorders
Melke J et al.
Mol Psychiatry. 2008 Jan;13(1):90-8. Epub 2007 May 15.
http://www.nature.com/mp/journal/v13/n1/pdf/4002016a.pdf
Melatonin is produced in the dark by the pineal gland and is a key
regulator of circadian and seasonal rhythms. A low melatonin level has
been reported in individuals with autism spectrum disorders (ASD), but
the underlying cause of this deficit was unknown. The ASMT gene,
encoding the last enzyme of melatonin synthesis, is located on the
pseudo-autosomal region 1 of the sex chromosomes, deleted in several
individuals with ASD. In this study, we sequenced all ASMT exons and
promoters in individuals with ASD (n=250) and compared the allelic
frequencies with controls (n=255). Non-conservative variations of ASMT
were identified, including a splicing mutation present in two families
with ASD, but not in controls. Two polymorphisms located in the
promoter (rs4446909 and rs5989681) were more frequent in ASD compared
to controls (P=0.0006) and were associated with a dramatic decrease in
ASMT transcripts in blood cell lines (P=2 x 10(-10)). Biochemical
analyses performed on blood platelets and/or cultured cells revealed a
highly significant decrease in ASMT activity (P=2 x 10(-12)) and
melatonin level (P=3 x 10(-11)) in individuals with ASD. These results
indicate that a low melatonin level, caused by a primary deficit in
ASMT activity, is a risk factor for ASD. They also support ASMT as a
susceptibility gene for ASD and highlight the crucial role of melatonin
in human cognition and behavior.
PMID: 17505466
32. Randomized controlled trial of melatonin for children with autistic spectrum disorders and sleep problems
Garstang J, Wallis M.
Child Care Health Dev. 2006 Sep;32(5):585-9.
BACKGROUND: Melatonin is often used for autistic children with
sleep disorders, despite a lack of published evidence in this
population. METHODS: A randomized, placebo-controlled double-blind
crossover trial of melatonin was undertaken in 11 children with
autistic spectrum disorder (ASD). RESULTS: Seven children completed the
trial. Sleep latency was 2.6 h [95% confidence intervals (CI)
2.28-2.93] baseline, 1.91 h (95% CI 1.78-2.03) with placebo and 1.06 h
(95% CI 0.98-1.13) with melatonin. Wakings per night were 0.35 (95% CI
0.18-0.53) baseline, 0.26 (95% CI 0.20-0.34) with placebo and 0.08 (95%
CI 0.04-0.12) with melatonin. Total sleep duration was 8.05 h (95% CI
7.65-8.44) baseline, 8.75 h (95% CI 8.56-8.98) with placebo and 9.84 h
(95% CI 9.68-9.99) with melatonin. CONCLUSIONS: Although the study was
small owing to recruitment difficulties, it still provides evidence of
effectiveness of melatonin in children with sleep difficulties and ASD,
which we predict a larger study would confirm.
PMID: 16919138
33. An open-label study of controlled-release melatonin in treatment of sleep disorders in children with autism
Giannotti F et al.
J Autism Dev Disord. 2006 Aug;36(6):741-52.
Long-term effectiveness of controlled-release melatonin in 25
children, aged 2.6-9.6 years with autism without other coexistent
pathologies was evaluated openly. Sleep patterns were studied using
Children's Sleep Habits Questionnaire (CSHQ) and sleep diaries at
baseline, after 1-3-6 months melatonin treatment and 1 month after
discontinuation. Sleep diary and CSHQ showed a more problematic sleep
in autistic children compared with controls. During treatment sleep
patterns of all children improved. After discontinuation 16 children
returned to pre-treatment score, readministration of melatonin was
again effective. Treatment gains were maintained at 12 and 24-month
follow-ups. No adverse side effects were reported. In conclusion,
controlled-release melatonin may provide an effective and
well-tolerated treatment for autistic children with chronic sleep
disorders.
PMID: 16897403
34. Nocturnal excretion of 6-sulphatoxymelatonin in children and adolescents with autistic disorder
Tordjman S et al.
Biol Psychiatry. 2005 Jan 15;57(2):134-8.
BACKGROUND: Many studies in autistic disorder report sleep problems and
altered circadian rhythms, suggesting abnormalities in melatonin
physiology. Additionally, melatonin, a pineal gland hormone produced
from serotonin, is of special interest in autistic disorder given
reported alterations in central and peripheral serotonin neurobiology.
METHODS: Nocturnal urinary excretion of 6-sulphatoxymelatonin was
measured by radioimmunoassay in groups of children and adolescents with
autistic disorder (n = 49) and normal control individuals (n = 88)
matched on age, sex, and Tanner stage of puberty. RESULTS: Nocturnal
6-sulphatoxymelatonin excretion rate was significantly and
substantially lower in patients with autism than in normal controls
(mean +/- SEM, .75 +/- .11 vs. 1.80 +/- .17 microg/hr, p =.0001), and
was significantly negatively correlated with severity of autistic
impairments in verbal communication and play (p < .05). CONCLUSIONS:
These findings indicate clearly that nocturnal production of melatonin
is reduced in autism. Further research is warranted in order to
understand the mechanisms underlying the lower melatonin production, to
assess the impact of altered melatonin on the pathophysiology and
behavioral expression of autistic disorder, and to determine the
utility of melatonin administration in individuals with autism.
PMID: 15652871
35. Effects of alpha-tocopherol and mixed tocopherol supplementation on markers of oxidative stress and inflammation in type 2 diabetes
Wu JH et al.
Clin Chem. 2007 Mar;53(3):511-9.
BACKGROUND: Vitamin E isomers may protect against atherosclerosis. The aim of this study was to compare the effects of supplementation with either alpha-tocopherol (alphaT) or mixed tocopherols rich in gamma-tocopherol (gammaT) on markers of oxidative stress and inflammation in patients with type 2 diabetes. METHODS: In a double-blind, placebo-controlled trial, 55 patients with type 2 diabetes were randomly assigned to receive (500 mg/day) (a) alphaT, (b) mixed tocopherols, or (c) placebo for 6 weeks. Cellular tocopherols, plasma and urine F(2)-isoprostanes, erythrocyte antioxidant enzyme activities, plasma inflammatory markers, and ex vivo assessment of eicosanoid synthesis were analyzed pre- and postsupplementation. RESULTS: Neutrophil alphaT and gammaT increased (both P <0.001) with mixed tocopherol supplementation, whereas alphaT (P <0.001) increased and gammaT decreased (P <0.005) after alphaT supplementation. Both alphaT and mixed tocopherol supplementation resulted in reduced plasma F(2)-isoprostanes (P <0.001 and P = 0.001, respectively) but did not affect 24-h urinary F(2)-isoprostanes or erythrocyte antioxidant enzyme activities. Neither alphaT nor mixed tocopherol supplementation affected plasma C-reactive protein, interleukin 6, tumor necrosis factor-alpha, or monocyte chemoattractant protein-1. Stimulated neutrophil leukotriene B(4) production decreased significantly in the mixed tocopherol group (P = 0.02) but not in the alphaT group (P = 0.15). CONCLUSIONS: The ability of tocopherols to reduce systemic oxidative stress suggests potential benefits of vitamin E supplementation in patients with type 2 diabetes. In populations with well-controlled type 2 diabetes, supplementation with either alphaT or mixed tocopherols rich in gammaT is unlikely to confer further benefits in reducing inflammation.
PMID: 17272491
36. Antioxidant supplementation lowers exercise-induced oxidative stress in young overweight adults
Vincent HK et al.
Obesity (Silver Spring). 2006 Dec;14(12):2224-35. free online
http://www.obesityresearch.org/cgi/reprint/14/12/2224
OBJECTIVE: To determine whether antioxidant (AOX) supplementation attenuates post-exercise oxidative stress and contributors to oxidative stress (inflammation, blood lipids) in overweight young adults. RESEARCH METHODS AND PROCEDURES: This was a randomized, double-blind, controlled study. Overweight (BMI, 33.2 +/- 1.9 kg/m(2)) and comparative normal-weight (BMI, 21.9 +/- 0.5 kg/m(2)) adults 18 to 30 years old (total N = 48) were enrolled. Participants received either daily antioxidant (AOX) treatment (800 IU of vitamin E, 500 mg of vitamin C, 10 mg of beta-carotene) or placebo (PL) for 8 weeks for a total of four groups. All participants completed a standardized 30-minute cycle exercise bout at baseline and 8 weeks. Exercise-induced changes in lipid hydroperoxide (DeltaPEROX), C-reactive protein (DeltaCRP), interleukin-6 (DeltaIL-6), cholesterol subfractions, triglycerides, total AOX status (DeltaTAS), and adiponectin were assessed. RESULTS: Exercise-induced DeltaPEROX was lower in the overweight-AOX group (0.09 nM/kg per min) compared with PL-treated overweight and normal-weight groups (0.98, 0.53 nM/kg per min) by 8 weeks (p < 0.05). Adiponectin was increased in both overweight and normal-weight AOX groups (22.1% vs. 3.1%; p < 0.05) but reduced in PL groups. DeltaIL-6, Deltatotal cholesterol, and Deltalow-density lipoprotein-cholesterol concentrations during exercise were lower in the AOX-treated groups compared with PL groups (all p < 0.05). After controlling for BMI, the Deltatotal cholesterol, Deltalow-density lipoprotein-cholesterol, Deltaadiponectin, and DeltaTAS explained 59.1% of the variance of the regression model of the DeltaPEROX by 8 weeks (total model R(2) = 0.600; p = 0.015). DISCUSSION: AOX lowers exercise-induced oxidative stress in overweight adults. Inflammatory and lipid markers may also be attenuated with AOX. Further studies are needed to determine whether AOX may be used in cardiovascular disease prevention in the overweight population.
PMID: 17189550
37. Oxidative stress and genetic and epidemiologic determinants of oxidant injury in childhood asthma
Ercan H et al.
J Allergy Clin Immunol. 2006 Nov;118(5):1097-104.
BACKGROUND: The factors contributing to the oxidant/antioxidant imbalance in asthma are incompletely understood. OBJECTIVE: To determine the factors associated with oxidative stress including asthma severity and the genotype of the antioxidant enzymes. METHODS: A total of 196 children with mild asthma, 116 children with moderate-severe asthma, and 2 healthy control groups (187 and 68 children) were included in the study. Plasma levels of malondialdehyde were measured as the indicator of oxidative stress, and reduced glutathione levels as the indicator of antioxidant defense. Children were genotyped for null variants of glutathione S transferase (GST) T1 and GSTM1, and ile105val variant of GSTP1. Risk factors were analyzed with multivariate logistic regression. RESULTS: Systemic levels of malondialdehyde increased and reduced glutathione levels decreased significantly from healthy controls to patients with mild asthma and then to patients with moderate-severe asthma (P < .001 for each). Multivariate logistic regression identified asthma and asthma severity as independent factors associated with oxidative stress (odds ratio between 17 and 56; P < .001). Children with asthma with GSTP1 val/val genotype had higher malondialdehyde and lower glutathione levels compared with other genotypes (P = .023 and P = .014, respectively). GSTP1 val/val genotype was independently associated with asthma severity (odds ratio, 4.210; 95% CI, 1.581-11.214; P = .004). CONCLUSION: Our study indicates the presence of a strong oxidative stress in children with asthma that increases with the severity of the disease. In this population, val/val genotype at GSTP1 ile105val locus may be an important factor in determining the degree of oxidant injury. CLINICAL IMPLICATIONS: Children with asthma with val/val genotype at GSTP1 ile105val locus may be good candidates for supplemental antioxidant therapy.
PMID: 17088135
38. Prevention of oxidative stress-mediated neuropathology and improved clinical outcome by adjunctive use of a combination of antioxidants and omega-3 fatty acids in schizophrenia
Mahadik SP et al.
Int Rev Psychiatry. 2006 Apr;18(2):119-31.
Schizophrenia is associated with a broad range of neurodevelopmental, structural and behavioral abnormalities that often progress with or without treatment. Evidence indicates that such neurodevelopmental abnormalities may result from defective genes and/or non-genetic factors such as pre-natal and neonatal infections, birth complications, famines, maternal malnutrition, drug and alcohol abuse, season of birth, sex, birth order and life style. Experimentally, these factors have been found to cause the cellular metabolic stress that often results in oxidative stress, such as increased cellular levels of reactive oxygen species (ROS) over the antioxidant capacity. This can trigger the oxidative cell damage (i.e., DNA breaks, protein inactivation, altered gene expression, loss of membrane lipid-bound essential polyunsaturated fatty acids [EPUFAs] and often apoptosis) contributing to abnormal neural growth and differentiation. The brain is preferentially susceptible to oxidative damage since it is under very high oxygen tension and highly enriched in ROS susceptible proteins, lipids and poor DNA repair. Evidence is increasing for increased oxidative stress and cell damage in schizophrenia. Furthermore, treatments with some anti-psychotics together with the lifestyle and dietary patterns, that are pro-oxidant, can exacerbate the oxidative cell damage and trigger progression of neuropathology. Therefore, adjunctive use of dietary antioxidants and EPUFAs, which are known to regulate the growth factors and neuroplasticity, can effectively improve the clinical outcome. The dietary supplementation of either antioxidants or EPUFAs, particularly omega-3 has already been found to improve some psychopathologies. However, a combination of antioxidants and omega-3 EPUFAs, particularly in the early stages of illness, when brain has high degree of neuroplasticity, potentially may be even more effective for long-term improved clinical outcome of schizophrenia.
PMID: 16777666
39. Relationship between aging and susceptibility of erythrocytes to oxidative damage: in view of nutraceutical interventions
Marotta F et al.
Rejuvenation Res. 2006 Summer;9(2):227-30.
Twelve (12) healthy elderly subjects were divided into two groups: (a) those given an antioxidant/NO-modulating fermented papaya preparation (FPP) 9 g/day for 4 weeks, and (b) a placebo group. No protein/lipid distribution in erythrocytes (RBC) membranes was noted among different ages and treatments. Higher RBC concentration of malondialdehyde and nitric oxide synthase were found in the elderly (p < 0.05 versus "young" controls), whereas superoxide dismutase was unaltered. Such abnormalities were prevented by FPP supplementation (p < 0.01). RBC and RBC ghosts showed an enhanced susceptibility to lipid peroxidation by using cumene hydroperoxide (p < 0.01 versus young) but FPP supplementation significantly protected intact RBC (p < 0.05). These preliminary data suggest that nutraceuticals with antioxidant/NO-regulating properties significantly protect from RBC oxidative damage, and are potential weapons for the aging process and chronic and degenerative diseases.
PMID: 16706649
40. Involvement of selenoprotein P in protection of human astrocytes from oxidative damage
Steinbrenner H et al.
Free Radic Biol Med. 2006 May 1;40(9):1513-23.
Selenoprotein P (SeP) is a highly glycosylated, selenium-rich plasma protein. Aside from its role as selenium carrier protein, an antioxidative function of SeP has been suggested. Astrocytes, which detoxify reactive oxygen species in the brain, were described as potential target cells of SeP. We investigated the expression of SeP in human astrocytes and its involvement in the protection of these cells against tert-butyl hydroperoxide (t-BHP)-induced oxidative damage. We show that primary human astrocytes and the human astrocytoma cell line MOG-G-CCM express SeP as an unglycosylated protein, which is not secreted. SeP expression in astrocytes is constitutive. Preincubation of astrocytes with hepatocyte-derived SeP mimicks the protective effect of low-molecular-weight selenocompounds such as sodium selenite or selenomethionine against oxidative damage, shielding astrocytes from t-BHP-induced cytotoxicity. Selenium supplementation of astrocytes counteracts oxidative stress via an increase in expression and activity of the selenoenzyme cytosolic glutathione peroxidase (cGPx). Furthermore, specific downregulation of SeP expression by small interfering RNA decreases cell viability of human astrocytes and makes them more susceptible to t-BHP-induced cytotoxicity. Our results implicate an antioxidant activity of constitutively expressed SeP in selenium-deficient astrocytes, while during adequate selenium supply the enhanced protection against oxidative stress is exerted by cGPx.
PMID: 16632112
41. Oxidative stress: a bridge between Down's syndrome and Alzheimer's disease
Zana M et al.
Neurobiol Aging. 2007 May;28(5):648-76. Epub 2006 Apr 19.
Besides the genetic, biochemical and neuropathological analogies between Down's syndrome (DS) and Alzheimer's disease (AD), there is ample evidence of the involvement of oxidative stress (OS) in the pathogenesis of both disorders. The present paper reviews the publications on DS and AD in the past 10 years in light of the "gene dosage" and "two-hit" hypotheses, with regard to the alterations caused by OS in both the central nervous system and the periphery, and the main pipeline of antioxidant therapeutic strategies. OS occurs decades prior to the signature pathology and manifests as lipid, protein and DNA oxidation, and mitochondrial abnormalities. In clinical settings, the assessment of OS has traditionally been hampered by the use of assays that suffer from inherent problems related to specificity and/or sensitivity, which explains some of the conflicting results presented in this work. For DS, no scientifically proven diet or drug is yet available, and AD trials have not provided a satisfactory approach for the prevention of and therapy against OS, although most of them still need evidence-based confirmation. In the future, a balanced up-regulation of endogenous antioxidants, together with multiple exogenous antioxidant supplementation, may be expected to be one of the most promising treatment methods.
PMID: 16624449
42. Effects of antioxidant supplementation on postprandial oxidative stress and endothelial dysfunction: a single-blind, 15-day clinical trial in patients with untreated type 2 diabetes, subjects with impaired glucose tolerance, and healthy controls
Neri S et al.
Clin Ther. 2005 Nov;27(11):1764-73.
BACKGROUND: Increased generation of reactive oxygen species (ROS) and oxidative stress may be of crucial importance in the pathogenesis of endothelial damage. Furthermore, there is understood to be a relationship between endothelial damage, glycemic control, disorders of lipid metabolism, and coagulative hemostatic disorders. OBJECTIVE: This study investigated within- and between-group changes in various circulating markers of oxidation-reduction balance and endothelial function after a balanced moderate-fat meal with and without antioxidant supplementation in patients with early-stage, untreated type 2 diabetes mellitus; subjects with impaired glucose tolerance (IGT); and healthy controls. METHODS: In this single-blind, controlled clinical study, groups of patients with type 2 diabetes and subjects with IGT were identified and compared with a group of healthy controls. All groups followed a controlled, well-balanced diet for 10 days before and throughout the study. Before and after consumption of a standardized moderate-fat meal, plasma levels of oxidants (malondialdehyde, 4-hydroxynonenal, oxidized low-density lipoprotein), the antioxidant glutathione peroxidase, and markers of endothelial function (NO, endothelin-1, von Willebrand factor [vWF], vascular cell adhesion molecule-1 [VCAM-1]) were determined. These measures were then reassessed after 15 days of standard antioxidant treatment consisting of a thiol-containing antioxidant (N-acetylcysteine 600 g/d), a bound antioxidant (vitamin E 300 g/d), and an aqueous phase antioxidant (vitamin C 250 mg/d). The efficacy of antioxidant treatment in reversing abnormalities in oxidation-reduction balance after a moderate-fat meal was assessed by evaluating changes in plasma levels of ROS on the morning of the 16th day following an overnight fast. Safety was monitored in terms of adverse events, vital signs, physical findings, and laboratory values. RESULTS: The study included 46 patients with type 2 diabetes (23 men, 23 women; mean [SD] age, 41 [3] years; mean body mass index [BMI], 24 [2] kg/m(2)), 46 with IGT (23 men, 23 women; mean age, 39 [3] years; mean BMI, 23 [3] kg/m(2)), and 46 control subjects (23 men, 23 women; mean age, 40 [1] years; mean BMI, 22 [1] kg/m(2)). Before supplementation, all 3 groups had significantly increased levels of oxidants, vWF, and VCAM-1 (all, P < 0.001) and significantly decreased levels of antioxidants and NO (both, P < 0.001) after consumption of a moderate-fat meal. After 15 days of antioxidant treatment, significant improvements in these measures were seen in all groups (P < 0.05). CONCLUSIONS: This study showed changes in oxidation-reduction balance, NO bioavailability, and nonthrombogenic endothelial factors after a moderate-fat meal in patients with type 2 diabetes and those with IGT, but these postprandial changes were reverse in all subjects after 15 days of standard antioxidant supplementation. These findings suggest that the use of anti-oxidants may have decreased oxidative stress in these subjects.
PMID: 16368447
43. Garlic supplementation prevents oxidative DNA damage in essential hypertension
Dhawan V, Jain S.
Mol Cell Biochem. 2005 Jul;275(1-2):85-94.
Oxygen-free radicals and other oxygen/nitrogen species are constantly generated in the human body. Most are intercepted by antioxidant defences and perform useful metabolic roles, whereas others escape to damage biomolecules like DNA, lipids and proteins. Garlic has been shown to contain antioxidant phytochemicals that prevent oxidative damage. These include unique water-soluble organosulphur compounds, lipid-soluble organosulphur compounds and flavonoids. Therefore, in the present study, we have tried to explore the antioxidant effect of garlic supplementation on oxidative stress-induced DNA damage, nitric oxide (NO) and superoxide generation and on the total antioxidant status (TAS) in patients of essential hypertension (EH). Twenty patients of EH as diagnosed by JNC VI criteria (Group I) and 20 age and sex-matched normotensive controls (Group II) were enrolled in the study. Both groups were given garlic pearls (GP) in a dose of 250 mg per day for 2 months. Baseline samples were taken at the start of the study, i.e. 0 day, and thereafter 2 months follow-up. 8-Hydroxy-2'-deoxyguanosine (8-OHdG), lipids, lipid peroxidation (MDA), NO and antioxidant vitamins A, E and C were determined. A moderate decline in blood pressure (BP) and a significant reduction in 8-OHdG, NO levels and lipid peroxidation were observed in Group I subjects with GP supplementation. Further, a significant increase in vitamin levels and TAS was also observed in this group as compared to the control subjects. These findings point out the beneficial effects of garlic supplementation in reducing blood pressure and counteracting oxidative stress, and thereby, offering cardioprotection in essential hypertensives.
PMID: 16335787
44. Oxidative stress and ageing: is ageing a cysteine deficiency syndrome?
Dröge W.
Philos Trans R Soc Lond B Biol Sci. 2005 Dec 29;360(1464):2355-72.
http://journals.royalsociety.org/content/l70078673710x66k/fulltext.pdf
Reactive oxygen species (ROS) are constantly produced in biological tissues and play a role in various signalling pathways. Abnormally high ROS concentrations cause oxidative stress associated with tissue damage and dysregulation of physiological signals. There is growing evidence that oxidative stress increases with age. It has also been shown that the life span of worms, flies and mice can be significantly increased by mutations which impede the insulin receptor signalling cascade. Molecular studies revealed that the insulin-independent basal activity of the insulin receptor is increased by ROS and downregulated by certain antioxidants. Complementary clinical studies confirmed that supplementation of the glutathione precursor cysteine decreases insulin responsiveness in the fasted state. In several clinical trials, cysteine supplementation improved skeletal muscle functions, decreased the body fat/lean body mass ratio, decreased plasma levels of the inflammatory cytokine tumour necrosis factor alpha (TNF-alpha), improved immune functions, and increased plasma albumin levels. As all these parameters degenerate with age, these findings suggest: (i) that loss of youth, health and quality of life may be partly explained by a deficit in cysteine and (ii) that the dietary consumption of cysteine is generally suboptimal and everybody is likely to have a cysteine deficiency sooner or later.
PMID: 16321806
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