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    ABSTRACT: Intake of the essential micronutrient selenium (Se) has health implications. This work addressed whether some effects of Se on gene expression are exerted through microRNAs (miRNA). Human colon adenocarcinoma cells (Caco-2) were grown in Se-deficient or Se-adequate medium for 72 h. RNA was extracted and subjected to analysis of 737 miRNA using microarray technology. One hundred and forty-five miRNA were found to be expressed in Caco-2 cells. Twelve miRNA showed altered expression after Se depletion: miR-625, miR-492, miR-373*, miR-22, miR-532-5p, miR-106b, miR-30b, miR-185, miR-203, miR1308, miR-28-5p, miR-10b. These changes were validated by quantitative real-time PCR (RT-qPCR). Transcriptomic analysis showed that Se depletion altered expression of 50 genes including selenoproteins GPX1, SELW, GPX3, SEPN1, SELK, SEPSH2 and GPX4. Pathway analysis identified arachidonic acid metabolism, glutathione metabolism, oxidative stress, positive acute phase response proteins and respiration of mitochondria as Se-sensitive pathways. Bioinformatic analysis identified 13 transcripts as targets for the Se-sensitive miRNA; three were predicted to be recognised by miR-185. Silencing of miR-185 increased GPX2 and SEPSH2 expression. We propose that miR-185 plays a role in up-regulation of GPX2 and SEPHS2 expression. In the case of SEPHS2 this may contribute to maintaining selenoprotein synthesis. The data indicate that micronutrient supply can regulate the cell miRNA expression profile.
    Molecular Nutrition & Food Research 12/2013; 57(12). DOI:10.1002/mnfr.201300168
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    ABSTRACT: Breast cancer (BC) is one of the most common cancers in women. Evidence suggests that genetic variation in antioxidant enzymes could influence BC risk, but to date the relationship between selenoproteins and BC risk remains unclear. In this report, a study population including 975 Danish cases and 975 controls matched for age and hormone replacement therapy (HRT) use was genotyped for five functional single nucleotide polymorphisms (SNPs) in SEPP1, GPX1, GPX4 and the antioxidant enzyme SOD2 genes. The influence of genetic polymorphisms on breast cancer risk was assessed using conditional logistic regression. Additionally pre-diagnosis erythrocyte GPx (eGPx) activity was measured in a sub-group of the population. A 60% reduction in risk of developing overall BC and ductal BC was observed in women who were homozygous Thr carriers for SEPP1 rs3877899. Additionally, Leu carriers for GPX1 Pro198Leu polymorphism (rs1050450) were at ∼2 fold increased risk of developing a non-ductal BC. Pre-diagnosis eGPx activity was found to depend on genotype for rs713041 (GPX4), rs3877899 (SEPP1), and rs1050450 (GPX1) and on HRT use. Moreover, depending on genotype and HRT use, eGPx activity was significantly lower in women who developed BC later in life compared with controls. Furthermore, GPx1 protein levels increased in human breast adenocarcinoma MCF7 cells exposed to β-estradiol and sodium selenite.In conclusion, our data provide evidence that SNPs in SEPP1 and GPX1 modulate risk of BC and that eGPx activity is modified by SNPs in SEPP1, GPX4 and GPX1 and by estrogens. Our data thus suggest a role of selenoproteins in BC development.
    PLoS ONE 09/2013; 8(9):e73316. DOI:10.1371/journal.pone.0073316
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    ABSTRACT: Functional near infrared spectroscopy (NIRS) is a non-invasive optical imaging technique used to monitor cerebral blood flow (CBF) and by proxy neuronal activation. The use of NIRS in nutritional intervention studies is a relatively novel application of this technique, with only a small, but growing, number of trials published to date. These trials-in which the effects on CBF following administration of dietary components such as caffeine, polyphenols and omega-3 polyunsaturated fatty acids are assessed-have successfully demonstrated NIRS as a sensitive measure of change in hemodynamic response during cognitive tasks in both acute and chronic treatment intervention paradigms. The existent research in this area has been limited by the constraints of the technique itself however advancements in the measurement technology, paired with studies endeavoring increased sophistication in number and locations of channels over the head should render the use of NIRS in nutritional interventions particularly valuable in advancing our understanding of the effects of nutrients and dietary components on the brain.
    Frontiers in Human Neuroscience 08/2013; 7:473. DOI:10.3389/fnhum.2013.00473
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    ABSTRACT: There is an increasing body of evidence suggesting that metal homeostasis is dysregulated in the pathology of Alzheimer's disease (AD). Although expression levels of several transporters belonging the SLC30 family, which comprises predominantly zinc transporters, have been studied in the AD brain, SLC30A10 (ZnT10) has not been studied in this context. To determine if dysregulated expression of ZnT10, which may transport both Zn and Mn, could be a factor that contributes to AD, we investigated if there were differences in ZnT10 mRNA levels in specimens of frontal cortex from AD patients and controls and also if brain tissue from the APP/PS1 transgenic (Tg) mouse model showed abnormal levels of ZnT10 mRNA expression. Our results show that ZnT10 is significantly (P<0.01) decreased in the frontal cortex in AD. Furthermore, we observed a significant decrease in ZnT10 mRNA levels in the APP/PS1-Tg mice compared with wild-type controls (P<0.01). Our results suggest that this dysregulation in ZnT10 could further contribute to disease progression.
    PLoS ONE 05/2013; 8(5):e65475. DOI:10.1371/journal.pone.0065475
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    ABSTRACT: Previous (mainly population-based) studies have suggested the health benefits of the elective, lifelong inclusion of whole-grain foods in the diet, forming the basis for public health recommendations to increase whole grain consumption. Currently, there is limited evidence to assess how public health recommendations can best result in longer-term improvements in dietary intake. The present study aimed to assess the impact of a previous 16-week whole-grain intervention on subsequent, elective whole grain consumption in free-living individuals. Participants completed a postal FFQ 1, 6 and 12 months after the end of the whole-grain intervention study period. This FFQ included inputs for whole-grain foods commonly consumed in the UK. Whole grain consumption was significantly higher (approximately doubled) in participants who had received whole-grain foods during the intervention (P< 0·001) compared with the control group who did not receive whole-grain foods during the intervention. This increased whole grain consumption was lower than whole grain intake levels required by participants during the intervention period between 60 and 120 g whole grains/d. Aside from a significant increase (P< 0·001) in NSP consumption compared with control participants (mean increase 2-3 g/d), there were no obvious improvements to the pattern of foods of the intervention group. The results of the present study suggest that a period of direct exposure to whole-grain foods in non-habitual whole-grain food consumers may benefit subsequent, elective dietary patterns of whole grain consumption. These findings may therefore aid the development of future strategies to increase whole grain consumption for public health and/or food industry professionals.
    The British journal of nutrition 02/2013; 110(5):1-6. DOI:10.1017/S0007114512006034
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    ABSTRACT: BACKGROUND: An understanding of causal relations between diet and health is hindered by the lack of robust biological markers of food exposure. OBJECTIVE: We aimed to develop a data-driven procedure to discover urine biomarkers indicative of habitual exposure to different foods. DESIGN: The habitual diet of 68 participants was assessed by using 4 food-frequency questionnaires over 3 mo, and participants were assigned to different consumption-frequency classes for 58 dietary components. Flow infusion electrospray-ionization mass spectrometry followed by supervised multivariate data analysis was used to determine whether the chemical composition of urine was related to specific differences in the consumption levels of each food. RESULTS: Foods were eaten habitually in 1 of 5 basic patterns differing in range and distribution of consumption frequency. Overnight, 24-h, and fasting urine samples proved useful for biomarker lead discovery with habitual citrus exposure used as a paradigm. Exposure level discrimination robustness improved linearly as urine samples from low-frequency citrus consumers were compared with urine samples from participants reporting increasingly higher intakes. For all foods, distinctiveness and consumption-frequency range influenced the likelihood that differential dietary exposure could be detected. Model output statistics indicated foods for which biomarker lead discovery was feasible. Metabolites proposed previously as acute intake biomarkers of citrus (proline betaine), oily fish (methylhistidine), coffee (dihydrocaffeic acid derivatives), and tomato (phenolic metabolites) were also biomarkers of habitual exposure. A significance threshold in modeling output statistics was determined to guide the discovery of potential biomarkers for other foods. CONCLUSION: This data-driven strategy can identify urinary metabolites associated with habitual exposure to specific foods. This trial has the UK registration number 4349 and was registered at isrtcn.org as CCT-NAPN-A13175.
    American Journal of Clinical Nutrition 12/2012; 97(2). DOI:10.3945/ajcn.112.048033
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    ABSTRACT: Genetic variation in relevant enzymes and transporters may contribute to discordant observations concerning health outcomes of dietary isoflavone consumption, so we examined the association of the UGT1A1*28 promoter polymorphism and of other SNPs with isoflavone metabolites in urine. We genotyped prospectively for polymorphisms in UGT1A1 (UGT1A1*28), LPH (666G>A), CBG (1368T>A), ABCG2 (421C>A), and ABCC2 (1249G>A) to select 100 women (18–50 years) to receive a commercial soy supplement as a single dose and collect all urine over 24 h for analysis by RP-HPLC. We observed large differences in isoflavone recovery (mean 39%, eightfold variation) and metabolites. Glucuronides were the major metabolites (72% of total). UGT1A1*28 was associated only with percentage of glycitein as sulphate (positive; p = 0.046), but excluding five participants with both minor alleles of CBG and ABCG2 uncovered additional associations with percentage of glycitein as glucuronide (negative; p = 0.028), combined isoflavones as sulphate (positive; p = 0.035) and sulphate-to-glucuronide ratio for combined isoflavones (positive; p = 0.036). CBG1368T>A, ABCG2 421C>A, and ABCC2 1249G>A were also associated with differences in isoflavone metabolites in urine. Genetic variation in UGT1A1, CBG, ABCG2, and ABCC2 influences isoflavone metabolism so may affect benefits of dietary consumption.
    Molecular Nutrition & Food Research 12/2012; 56(12). DOI:10.1002/mnfr.201200287
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    ABSTRACT: Background Observational studies report that higher intake of dietary fi bre (a heterogeneous mix including non-starch polysaccharides and resistant starches) is associated with reduced risk of colorectal cancer, but no randomised trials with prevention of colorectal cancer as a primary endpoint have been done. We assessed the eff ect of resistant starch on the incidence of colorectal cancer. Methods In the CAPP2 study, individuals with Lynch syndrome were randomly assigned in a two-by-two factorial design to receive 600 mg aspirin or aspirin placebo or 30 g resistant starch or starch placebo, for up to 4 years. Randomisation was done with a block size of 16. Post-intervention, patients entered into double-blind follow-up; participants and investigators were masked to treatment allocation. The primary endpoint for this analysis was development of colorectal cancer in participants randomly assigned to resistant starch or resistant-starch placebo with both intention-to-treat and per-protocol analyses. This study is registered, ISRCTN 59521990. Findings 463 patients were randomly assigned to receive resistant starch and 455 to receive resistant-starch placebo. At a median follow-up 52·7 months (IQR 28·9–78·4), 53 participants developed 61 primary colorectal cancers (27 of 463 participants randomly assigned to resistant starch, 26 of 455 participants assigned to resistant-starch placebo). Intention-to-treat analysis of time to fi rst colorectal cancer showed a hazard ratio (HR) of 1·40 (95% CI 0·78–2·56; p=0·26) and Poisson regression accounting for multiple primary events gave an incidence rate ratio (IRR) of 1·15 (95% CI 0·66–2·00; p=0·61). For those completing 2 years of intervention, per-protocol analysis yielded a HR of 1·09 (0·55–2·19, p=0·80) and an IRR of 0·98 (0·51–1·88, p=0·95). No information on adverse events was gathered during post-intervention follow-up. Interpretation Resistant starch had no detectable eff ect on cancer development in carriers of hereditary colorectal cancer. Dietary supplementation with resistant starch does not emulate the apparently protective eff ect of diets rich in dietary fi bre against colorectal cancer.
    The Lancet Oncology 12/2012; DOI:10.1016/S1470-2045(12)70475-8
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    ABSTRACT: Changes in DNA methylation across the life course may contribute to the ageing process. We hypothesised that some effects of dietary restriction to extend lifespan and/or mitigate against features of ageing result from changes in DNA methylation, so we determined if genes that respond to dietary restriction also show age-related changes in DNA methylation. In support of our hypothesis, the intersection of lists of genes compiled from published sources that (1) were differentially expressed in response to dietary restriction and (2) showed altered methylation with increased age was greater than expected. We also hypothesised that some effects of Sirt1, which may play a pivotal role in beneficial effects of dietary restriction, are mediated through DNA methylation. We thus measured effects of Sirt1 overexpression and knockdown in a human cell line on DNA methylation and expression of a panel of eight genes that respond to dietary restriction and show altered methylation with age. Six genes were affected at the level of DNA methylation, and for six expressions were affected. In further support of our hypothesis, we observed by DNA microarray analysis that genes showing differential expression in response to Sirt1 knockdown were over-represented in the complied list of genes that respond to dietary restriction. The findings reveal that Sirt1 has effects on DNA methylation across the genome and affects, in particular, the expression of genes that respond to dietary restriction. Sirt1-mediated effects on DNA methylation and, consequently, gene expression may thus be one of the mechanisms underlying the response to dietary restriction.
    Age 11/2012; 35(5). DOI:10.1007/s11357-012-9485-8
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    ABSTRACT: Increased dietary intake of Selenium (Se) has been suggested to lower prostate cancer mortality, but supplementation trials have produced conflicting results. Se is incorporated into 25 selenoproteins. The aim of this work was to assess whether risk of prostate cancer is affected by genetic variants in genes coding for selenoproteins, either alone or in combination with Se status. 248 cases and 492 controls from an EPIC-Heidelberg nested case-control study were subjected to two-stage genotyping with an initial screening phase in which 384 tagging-SNPs covering 72 Se-related genes were determined in 94 cases and 94 controls using the Illumina Goldengate methodology. This analysis was followed by a second phase in which genotyping for candidate SNPs identified in the first phase was carried out in the full study using Sequenom. Risk of high-grade or advanced stage prostate cancer was modified by interactions between serum markers of Se status and genotypes for rs9880056 in SELK, rs9605030 and rs9605031 in TXNRD2, and rs7310505 in TXNRD1. No significant effects of SNPs on prostate cancer risk were observed when grade or Se status was not taken into account. In conclusion, the risk of high-grade or advanced-stage prostate cancer is significantly altered by a combination of genotype for SNPs in selenoprotein genes and Se status. The findings contribute to explaining the biological effects of selenium intake and genetic factors in prostate cancer development and highlight potential roles of thioredoxin reductases and selenoprotein K in tumour progression.
    PLoS ONE 11/2012; 7(11):e48709. DOI:10.1371/journal.pone.0048709
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