Jayne V. Woodside

Antioxidants in health and disease

Free radical production occurs continuously in all cells as part of normal cellular function. However, excess free radical production originating from endogenous or exogenous sources might play a role in many diseases. Antioxidants prevent free radical induced tissue damage by preventing the formation of radicals, scavenging them, or by promoting their decomposition. This article reviews the basic chemistry of free radical formation in the body, the consequences of free radical induced tissue damage, and the function of antioxidant defence systems, with particular reference to the development of atherosclerosis.

Methionine synthase D919G polymorphism is a significant but modest determinant of circulating homocysteine concentrations

Elevation in plasma homocysteine concentration has been associated with vascular disease and neural tube defects. Methionine synthase is a vitamin B12‐dependent enzyme that catalyses the remethylation of homocysteine to methionine. Therefore, defects in this enzyme may result in elevated homocysteine levels. One relatively common polymorphism in the methionine synthase gene (D919G) is an A to G transition at bp 2,756, which converts an aspartic acid residue believed to be part of a helix involved in co‐factor binding to a glycine. We have investigated the effect of this polymorphism on plasma homocysteine levels in a working male population (n = 607) in which we previously described the relationship of the C677T “thermolabile” methylenetetrahydrofolate reductase (MTHFR) polymorphism with homocysteine levels. We found that the methionine synthase D919G polymorphism is significantly (P = 0.03) associated with homocysteine concentration, and the DD genotype contributes to a moderate increase in homocysteine levels across the homocysteine distribution (OR = 1.58, DD genotype in the upper half of the homocysteine distribution, P = 0.006). Unlike thermolabile MTHFR, the homocysteine‐elevating effects of the methionine synthase polymorphism are independent of folate and B12 levels; however, the DD genotype has a larger homocysteine‐elevating effect in individuals with low B6 levels. This polymorphism may, therefore, make a moderate, but significant, contribution to clinical conditions that are associated with elevated homocysteine. Genet. Epidemiol. 17:298–309, 1999.

Dietary patterns and breast cancer risk: a systematic review and meta-analysis

BACKGROUND Dietary patterns, which represent whole-diet and possible food and nutrient interactions, have been linked to the risk of various cancers. However, the associations of these dietary patterns with breast cancer remain unclear. OBJECTIVE We critically appraised the literature and conducted meta-analyses to pool the results of studies to clarify the relation between dietary patterns and breast cancer risk. DESIGN MEDLINE and EMBASE were searched for relevant articles that identified common dietary patterns published up to November 2009. Multivariable-adjusted odds ratios (ORs) comparing highest and lowest categories of dietary pattern scores and multivariable-adjusted ORs for a 20th-percentile increase in dietary pattern scores were combined by using random-effects meta-analyses. RESULTS Case-control and cohort studies were retrieved that identified prudent/healthy (n = 18), Western/unhealthy (n = 17), and drinker (n = 4) dietary patterns. There was evidence of a decrease in the risk of breast cancer in the highest compared with the lowest categories of prudent/healthy dietary patterns (OR = 0.89; 95% CI: 0.82, 0.99; P = 0.02) in all studies and in pooled cohort studies alone. An increase in the risk of breast cancer was shown for the highest compared with the lowest categories of a drinker dietary pattern (OR = 1.21; 95% CI: 1.04, 1.41; P = 0.01). There was no evidence of a difference in the risk of breast cancer between the highest and the lowest categories of Western/unhealthy dietary patterns (OR = 1.09; 95% CI: 0.98, 1.22; P = 0.12). CONCLUSION The results of this systematic review and meta-analysis indicate that some dietary patterns may be associated with breast cancer risk.

Dietary Intake of Fruits and Vegetables Improves Microvascular Function in Hypertensive Subjects in a Dose-Dependent Manner

Background— Observational evidence has consistently linked increased fruit and vegetable consumption with reduced cardiovascular morbidity; however, there is little direct trial evidence to support the concept that fruit and vegetable consumption improves vascular function. This study assessed the dose-dependent effects of a fruit and vegetable intervention on arterial health in subjects with hypertension. Methods and Results— After a 4-week run-in period during which fruit and vegetable intake was limited to 1 portion per day, participants were randomized to consume either 1, 3, or 6 portions daily for the next 8 weeks. Endothelium-dependent and -independent arterial vasodilator responses were assessed by venous occlusion plethysmography in the brachial circulation before and after intervention. Compliance was monitored with serial contemporaneous 4-day food records and by measuring concentrations of circulating dietary biomarkers. A total of 117 volunteers completed the 12-week study. Participants in the 1-, 3-, and 6-portions/d groups reported consuming on average 1.1, 3.2, and 5.6 portions of fruit and vegetables, respectively, and serum concentrations of lutein and &bgr;-cryptoxanthin increased across the groups in a dose-dependent manner. For each 1-portion increase in reported fruit and vegetable consumption, there was a 6.2% improvement in forearm blood flow responses to intra-arterial administration of the endothelium-dependent vasodilator acetylcholine (P=0.03). There was no association between increased fruit and vegetable consumption and vasodilator responses to sodium nitroprusside, an endothelium-independent vasodilator. Conclusions— The present study illustrates that among hypertensive volunteers, increased fruit and vegetable consumption produces significant improvements in an established marker of endothelial function and cardiovascular prognosis.

Effect of phytoestrogen and antioxidant supplementation on oxidative DNA damage assessed using the comet assay

Antioxidant species may act in vivo to decrease oxidative damage to DNA, protein and lipids thus reducing the risk of coronary heart disease and cancer. Phytoestrogens are plant compounds which are a major component of traditional Asian diets and which may be protective against certain hormone-dependent cancers (breast and prostate) and against coronary heart disease. They may also be able to function as antioxidants, scavenging potentially harmful free radicals. In this study, the effects of the isoflavonoids (a class of phytoestrogen) genistein and equol on hydrogen peroxide-mediated DNA damage in human lymphocytes were determined using alkaline single-cell gel electrophoresis (the comet assay). Treatment with hydrogen peroxide significantly increased the levels of DNA strand breaks. Pre-treatment of the cells with both genistein and equol offered protection against this damage at concentrations within the physiological range. This protection was greater than that offered by addition of the known antioxidant vitamins ascorbic acid and alpha-tocopherol, or the compounds 17beta-oestradiol and Tamoxifen which have similar structures to isoflavonoids and are known to have weak antioxidant properties. These findings are consistent with the hypothesis that phytoestrogens can, under certain conditions, function as antioxidants and protect against oxidatively-induced DNA damage.

Vegetarian diets, low-meat diets and health: a review

OBJECTIVE To review the epidemiological evidence for vegetarian diets, low-meat dietary patterns and their association with health status in adults. DESIGN Published literature review focusing primarily on prospective studies and meta-analyses examining the association between vegetarian diets and health outcomes. RESULTS Both vegetarian diets and prudent diets allowing small amounts of red meat are associated with reduced risk of diseases, particularly CHD and type 2 diabetes. There is limited evidence of an association between vegetarian diets and cancer prevention. Evidence linking red meat intake, particularly processed meat, and increased risk of CHD, cancer and type 2 diabetes is convincing and provides indirect support for consumption of a plant-based diet. CONCLUSIONS The health benefits of vegetarian diets are not unique. Prudent plant-based dietary patterns which also allow small intakes of red meat, fish and dairy products have demonstrated significant improvements in health status as well. At this time an optimal dietary intake for health status is unknown. Plant-based diets contain a host of food and nutrients known to have independent health benefits. While vegetarian diets have not shown any adverse effects on health, restrictive and monotonous vegetarian diets may result in nutrient deficiencies with deleterious effects on health. For this reason, appropriate advice is important to ensure a vegetarian diet is nutritionally adequate especially for vulnerable groups.

Bilirubin and coronary heart disease risk in the Prospective Epidemiological Study of Myocardial Infarction (PRIME)

Background Classic coronary heart disease risk factors fail to explain the large coronary heart disease incidence gradient between Northern Ireland and France. The Prospective Epidemiological Study of Myocardial Infarction (PRIME), a multicentre prospective study of 10 593 men, aims to investigate novel risk factors in these populations. We tested the hypothesis that higher bilirubin, a bile pigment possessing antioxidant properties, is associated with decreased coronary heart disease risk. Methods Bilirubin was measured in 216 participants who had developed coronary heart disease at 5-year follow-up and in 434 matched controls. Results Bilirubin was significantly lower in cases (geometric mean 7.95 μmol/l; interquartile range 5.32–12.33 μmol/l) compared with controls (9.07; 6.16–12.76; P = 0.005). Conditional logistic regression, adjusted for classical and putative risk factors, showed a U-shaped pattern, with coronary heart disease risk significantly lower for bilirubin in the third and fourth fifths, compared with the first. Additionally, there was a significant quadratic relationship between coronary heart disease risk and fifths of bilirubin concentration (χ2 = 6.80, df = 2; P = 0.035). Conclusions These findings suggest that bilirubin is a novel coronary heart disease risk marker in middle-aged men, with a U-shaped relationship observed between bilirubin concentration and coronary heart disease risk. Eur J Cardiovasc Prev Rehabil 14: 79-84

Fruit and vegetable intake and risk of cardiovascular disease

A high intake of fruit and vegetables (FV) has been shown to be associated with reduced risk of a number of chronic diseases, including CVD. This review aims to provide an overview of the evidence that increased FV intake reduces risk of CVD, focusing on studies examining total FV intake. This evidence so far available is largely based on prospective cohort studies, with meta-analyses demonstrating an association between increased FV intake and reduced risk of both CHD and stroke. Controlled intervention trials examining either clinical or cardiovascular risk factor endpoints are scarce. However, such trials have shown that an increase in FV consumption can lower blood pressure and also improve microvascular function, both of which are commensurate with a reduced risk of CVD. The effects of increased FV consumption on plasma lipid levels, risk of diabetes and body weight have yet to be firmly established. In conclusion, evidence that FV consumption reduces the risk of CVD is so far largely confined to observational epidemiology, with further intervention studies required.

Do phytoestrogens reduce the risk of breast cancer and breast cancer recurrence? What clinicians need to know

Oestrogen is an important determinant of breast cancer risk. Oestrogen-mimicking plant compounds called phytoestrogens can bind to oestrogen receptors and exert weak oestrogenic effects. Despite this activity, epidemiological studies suggest that the incidence of breast cancer is lower in countries where the intake of phytoestrogens is high, implying that these compounds may reduce breast cancer risk, and possibly have an impact on survival. Isoflavones and lignans are the most common phytoestrogens in the diet. In this article, we present findings from human observational and intervention studies related to both isoflavone and lignan exposure and breast cancer risk and survival. In addition, the clinical implications of these findings are examined in the light of a growing dietary supplement market. An increasing number of breast cancer patients seek to take supplements together with their standard treatment in the hope that these will either prevent recurrence or treat their menopausal symptoms. Observational studies suggest a protective effect of isoflavones on breast cancer risk and the case may be similar for increasing lignan consumption although evidence so far is inconsistent. In contrast, short-term intervention studies suggest a possible stimulatory effect on breast tissue raising concerns of possible adverse effects in breast cancer patients. However, owing to the dearth of human studies investigating effects on breast cancer recurrence and survival the role of phytoestrogens remains unclear. So far, not enough clear evidence exists on which to base guidelines for clinical use, although raising patient awareness of the uncertain effect of phytoestrogens is recommended.

Influence of 5-HT2C receptor and leptin gene polymorphisms, smoking and drug treatment on metabolic disturbances in patients with schizophrenia.

BACKGROUND Obesity and metabolic syndrome are significant problems for patients taking antipsychotic drugs. Evidence is emerging of genetic risk factors. AIMS To investigate the influence of two candidate genes, smoking and drug treatment on obesity and metabolic syndrome in patients with schizophrenia. METHOD Patients (n=134) were assessed for measures of obesity, other factors contributing to metabolic syndrome, and two genetic polymorphisms (5-HT(2C) receptor -759C/T and leptin -2548A/G). RESULTS Neither genotype nor smoking was significantly associated with measures of obesity. However, both leptin genotype and smoking were significantly associated with metabolic syndrome. Significant interaction occurred between the genetic polymorphisms for effects on obesity, whereby a genotype combination increased risk. Drug treatment showed significant effects on measures of obesity and triglyceride concentrations; risperidone was associated with lower values than olanzapine or clozapine. CONCLUSIONS The findings suggest interacting genetic risk factors and smoking influence development of metabolic syndrome in patients on antipsychotic drugs.