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We investigated the role of oxidative stress and the inflammasome in trauma-induced axon degeneration and vision loss using a mouse model. The left eyes of male mice were exposed to over-pressure air waves. Wild-type C57Bl/6 mice were fed normal, high-vitamin-E (VitE), ketogenic or ketogenic-control diets. Mice lacking the ability to produce vitamin C (VitC) were maintained on a low-VitC diet. Visual evoked potentials (VEPs) and retinal superoxide levels were measured in vivo. Tissue was collected for biochemical and histological analysis. Injury increased retinal superoxide, decreased SOD2, and increased cleaved caspase-1, IL-1α, IL-1β, and IL-18 levels. Low-VitC exacerbated the changes and the high-VitE diet mitigated them, suggesting that oxidative stress led to the increase in IL-1α and activation of the inflammasome. The injury caused loss of nearly 50% of optic nerve axons at 2 weeks and astrocyte hypertrophy in mice on normal diet, both of which were prevented by the high-VitE diet. The VEP amplitude was decreased after injury in both control-diet and low-VitC mice, but not in the high-VitE-diet mice. The ketogenic diet also prevented the increase in superoxide levels and IL-1α, but had no effect on IL-1β. Despite this, the ketogenic diet preserved optic nerve axons, prevented astrocyte hypertrophy, and preserved the VEP amplitude. These data suggest that oxidative stress induces priming and activation of the inflammasome pathway after neurotrauma of the visual system. Further, blocking the activation of the inflammasome pathway may be an effective post-injury intervention.
Vitamin E includes several tocopherol isoforms, which may reduce lung cancer risk, but past studies evaluating the association between vitamin E intake and lung cancer risk were inconsistent. We prospectively investigated the associations between tocopherol intake from diet and from supplements with lung cancer risk among 72,829 Chinese female nonsmokers aged 40-70 years and participating in the Shanghai Women's Health Study (SWHS). Dietary and supplement tocopherol exposure was assessed by a validated food-frequency questionnaire at baseline and reassessed for change in intake during follow-up. Cox proportional hazards models with time-dependent covariates were used to calculate multivariate-adjusted hazard ratios (HRs) and 95% confidence interval (CIs) for lung cancer. After 12.02 years of follow-up, 481 women were diagnosed with lung cancer. Total dietary tocopherol was inversely associated with lung cancer risk among women meeting dietary guidelines for adequate intake (AI) of tocopherol (14 mg/day or more: HR: 0.78; 95% CI 0.60-0.99; compared with the category less than AI). The protective association between dietary tocopherol intake and lung cancer was restricted to women exposed to side-stream smoke in the home and workplace [HR = 0.53 (0.29-0.97), p-trend = 0.04]. In contrast, vitamin E supplement use was associated with increased lung cancer risk (HR: 1.33; 95% CI: 1.01-1.73), more so for lung adenocarcinoma risk (HR: 1.79; 95% CI: 1.23-2.60). In summary, dietary tocopherol intake may reduce the risk of lung cancer among female nonsmokers; however, supplements may increase lung adenocarcinoma risk and requires further investigation.
© 2014 UICC.
Asthma and allergic lung disease occur as complex environmental and genetic interactions. Clinical studies of asthma indicate a number of protective dietary factors, such as vitamin E, on asthma risk. However, these studies have had seemingly conflicting outcomes. In this perspective, we discuss opposing regulatory effects of tocopherol isoforms of vitamin E, mechanisms for tocopherol isoform regulation of allergic lung inflammation, association of vitamin E isoforms with outcomes in clinical studies, and how the variation in global prevalence of asthma may be explained, at least in part, by vitamin E isoforms.
OBJECTIVES - Key antioxidants, vitamins C and E, are necessary for normal brain development and neuronal function. In this study, we depleted both of these vitamins in two mouse models to determine if oxidative stress due to combined vitamin C and E dietary deficiency altered their neurological phenotype. The first model lacked both alleles for the Gulonolactone oxidase gene (Gulo(-/-)) and therefore was unable synthesize vitamin C. To obtain an additional cellular deficiency of vitamin C, the second model also lacked one allele for the cellular vitamin C transporter gene (Gulo(-/-)/SVCT2(+/-)).
METHODS - The experimental treatment was 16 weeks of vitamin E deprivation followed by 3 weeks of vitamin C deprivation. Mice were assessed for motor coordination deficits, vitamin levels, and oxidative stress biomarkers.
RESULTS - In the first model, defects in motor performance were more apparent in both vitamin C-deficient groups (VE+VC-, VE-VC-) compared to vitamin C-supplemented groups (VE+VC+, VE-VC+) regardless of vitamin E level. Analysis of brain cortex and liver confirmed decreases of at least 80% for each vitamin in mice on deficient diets. Vitamin E deficiency doubled oxidative stress biomarkers (F2-isoprostanes and malondialdehyde). In the second model, Gulo(-/-)/SVCT2(+/-) mice on the doubly deficient diets showed deficits in locomotor activity, Rota-rod performance, and other motor tasks, with no concomitant change in anxiety or spatial memory.
DISCUSSION - Vitamin E deficiency alone caused a modest oxidative stress in brain that did not affect motor performance. Adding a cellular deficit in vitamin C to dietary deprivation of both vitamins significantly impaired motor performance.
BACKGROUND - Epidemiologic studies on the relationship between vitamin intake and liver cancer risk are sparse and inconsistent.
METHODS - We evaluated vitamin intake from diet and supplements and risk of liver cancer in 132,837 women and men from China who were recruited into the Shanghai Women's Health Study from 1997 to 2000 or the Shanghai Men's Health Study from 2002 to 2006. In-person interviews, using a validated food-frequency questionnaire, were conducted to collect data on dietary habits. Follow-up consisted of in-person surveys and record linkage. Hazard ratios and 95% confidence intervals were estimated using Cox proportional hazard models with adjustment for potential confounders to compare liver cancer risk among participants with high vs low vitamin intake. All statistical tests were two-sided.
RESULTS - After excluding the first 2 years of follow-up, 267 participants (including 118 women and 149 men) developed liver cancer during an average of 10.9 (Shanghai Women's Health Study) or 5.5 (Shanghai Men's Health Study) years of follow-up. Dietary vitamin E intake was inversely associated with liver cancer risk (P(trend) = .01), as was vitamin E supplement use (hazard ratio = 0.52, 95% confidence interval = 0.30 to 0.90). This association was consistent among participants with and without self-reported liver disease or a family history of liver cancer. Vitamin C and multivitamin use was associated with increased risk among participants with self-reported liver disease or family history of liver cancer, whereas intake of vitamin C and other vitamins from dietary sources was unrelated to liver cancer risk.
CONCLUSIONS - Vitamin E intake, either from diet or supplements, may reduce the risk of liver cancer.
Both environmental and genetic factors impact lipid traits. Environmental modifiers of known genotype-phenotype associations may account for some of the "missing heritability" of these traits. To identify such modifiers, we genotyped 23 lipid-associated variants identified previously through genome-wide association studies (GWAS) in 2,435 non-Hispanic white, 1,407 non-Hispanic black, and 1,734 Mexican-American samples collected for the National Health and Nutrition Examination Surveys (NHANES). Along with lipid levels, NHANES collected environmental variables, including fat-soluble macronutrient serum levels of vitamin A and E levels. As part of the Population Architecture using Genomics and Epidemiology (PAGE) study, we modeled gene-environment interactions between vitamin A or vitamin E and 23 variants previously associated with high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. We identified three SNP × vitamin A and six SNP × vitamin E interactions at a significance threshold of p < 2.2 × 10(-3). The most significant interaction was APOB rs693 × vitamin E (p = 8.9 × 10(-7)) for LDL-C levels among Mexican-Americans. The nine significant interaction models individually explained 0.35-1.61% of the variation in any one of the lipid traits. Our results suggest that vitamins A and E may modify known genotype-phenotype associations; however, these interactions account for only a fraction of the overall variability observed for HDL-C, LDL-C, and TG levels in the general population.
PURPOSE - To determine if short-term Age-Related Eye Disease Study (AREDS) antioxidant and zinc supplementation affects biomarkers of oxidative stress, possibly serving as a predictor of their efficacy.
DESIGN - Prospective interventional case series.
METHODS - Nineteen subjects, 12 with intermediate or advanced age-related macular degeneration (AMD) (AREDS categories 3 or 4) and 7 non-AMD controls, were admitted to the Vanderbilt General Clinical Research Center and placed on a controlled diet for 7 days. Antioxidant and zinc supplements were stopped 2 weeks prior to study enrollment. Dietary supplementation with 500 mg vitamin C, 400 IU vitamin E, 15 mg β-carotene, 80 mg zinc oxide, and 2 mg cupric oxide per day was instituted on study day 2. Blood was drawn on study days 2 and 7, and plasma concentrations of cysteine (Cys), cystine (CySS), glutathione (GSH), isoprostane (IsoP), and isofuran (IsoF) were determined.
RESULTS - Short-term AREDS supplementation significantly lowered mean plasma levels of CySS in participants on a regulated diet (P = .034). No significant differences were observed for Cys, GSH, IsoP, or IsoF. There were no significant differences between AMD patients and controls.
CONCLUSIONS - This pilot interventional study shows that a 5-day course of antioxidant and zinc supplements can modify plasma levels of CySS, suggesting that this oxidative stress biomarker could help predict how likely an individual is to benefit from AREDS supplementation. Further, CySS may be useful for the evaluation of new AMD therapies, particularly those hypothesized to affect redox status.
Copyright © 2012 Elsevier Inc. All rights reserved.
In the Shandong Intervention Trial, 2 weeks of antibiotic treatment for Helicobacter pylori reduced the prevalence of precancerous gastric lesions, whereas 7.3 years of oral supplementation with garlic extract and oil (garlic treatment) or vitamin C, vitamin E, and selenium (vitamin treatment) did not. Here we report 14.7-year follow-up for gastric cancer incidence and cause-specific mortality among 3365 randomly assigned subjects in this masked factorial placebo-controlled trial. Conditional logistic regression was used to estimate the odds of gastric cancer incidence, and the Cox proportional hazards model was used to estimate the relative hazard of cause-specific mortality. All statistical tests were two-sided. Gastric cancer was diagnosed in 3.0% of subjects who received H pylori treatment and in 4.6% of those who received placebo (odds ratio = 0.61, 95% confidence interval = 0.38 to 0.96, P = .032). Gastric cancer deaths occurred among 1.5% of subjects assigned H pylori treatment and among 2.1% of those assigned placebo (hazard ratio [HR] of death = 0.67, 95% CI = 0.36 to 1.28). Garlic and vitamin treatments were associated with non-statistically significant reductions in gastric cancer incidence and mortality. Vitamin treatment was associated with statistically significantly fewer deaths from gastric or esophageal cancer, a secondary endpoint (HR = 0.51, 95% CI = 0.30 to 0.87; P = .014).
Over the past several decades, investigations in humans and animal models of heart failure (HF) have provided substantial evidence that oxidative stress is increased in HF and contributes to disease progression. The high metabolic activity of cardiac myocytes makes these cells active sources of reactive oxygen species. Work in cell and animal models clearly demonstrates that oxidative stress activates processes such as changes in gene expression and cell death that are now accepted components of myocardial remodeling and HF. Antioxidants prevent progressive remodeling and even improve cardiac function in animal models of HF. It is therefore disappointing that to date no antioxidant strategy has translated to a therapeutic in the HF clinic. Possible explanations, including inadequate appreciation of the critical disease-modifying sources of reactive oxygen species, the choice of the wrong antioxidant strategy, or incomplete understanding of individual variability in human antioxidant defenses in this brief review.