[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: SCOPE: 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. METHODS AND RESULTS: 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. CONCLUSION: Genetic variation in UGT1A1, CBG, ABCG2, and ABCC2 influences isoflavone metabolism so may affect benefits of dietary consumption.
[Show abstract][Hide abstract] ABSTRACT: DNA methylation patterns change as individuals grow older, and DNA methylation appears susceptible to modification by the diet. Thus DNA methylation may be a mechanism through which diet can affect aging and longevity. We propose that effects on DNA methylation also contribute to the extension in lifespan observed in response to dietary restriction. Relationships between diet-induced changes in DNA methylation and parallel effects on aging and/or lifespan could, of course, be purely associative. Proof of these ideas requires experimental model systems in which it is possible to manipulate genome methylation status and to measure effects on aging and/or lifespan. Commonly-used short-lived and genetically-malleable metazoan species, such as Caenorhabditis elegans and Drosophila, are not suitable for such studies; the C. elegans genome is not methylated, and DNA methylation in Drosophila is dissimilar from mammalian DNA methylation, occurring at cytosines at sites other than in CpG sequences. The honeybee provides a potentially unique and tractable model for such studies. Female larval development into the long-lived queen phenotype or short-lived worker is determined purely by diet (royal jelly) through an effect on DNA methylation, and honeybee DNA methylation mirrors that of the mammalian genome. Mammalian cell lines and biochemical approaches offer complementary tools to address specific components of hypotheses relating to effects of diet on aging through DNA methylation in a more targeted manner. Our studies using mammalian cell lines are revealing effects of Sirt1 on DNA methylation, and indicate that Sirt1 and resveratrol affect the expression of different sets of genes.
[Show abstract][Hide abstract] ABSTRACT: Zn is essential to the structure and function of numerous proteins and enzymes so requires tight homeostatic control at both the systemic and cellular level. Two families of Zn transporters - ZIP (SLC39) and ZnT (SLC30) - contribute to Zn homeostasis. There are at least 10 members of the human ZnT family, and the expression profile and regulation of each varies depending on tissue type. Little is known about the role and expression pattern of ZnT10; however in silico data predict restricted expression to foetal tissue. We show a differential expression profile for ZnT10 in adult human tissue by RT-qPCR and detect highest levels of expression in small intestine, liver and brain tissues. We present data revealing the functional activity of ZnT10 to be in the efflux direction. Using a plasmid construct to express ZnT10 with an N-terminal FLAG-epitope tag, we reveal subcellular localisation in a neuroblastoma cell line (SH-SY5Y) to be at the Golgi apparatus under standard conditions of culture, with trafficking to the plasma membrane observed at higher extracellular Zn concentrations. We demonstrate down-regulation by Zn of ZnT10 mRNA levels in cultured intestinal and neuroblastoma cell lines and demonstrate reduced transcription from the ZnT10 promoter at an elevated extracellular Zn concentration. These features of ZnT10 localisation, regulation and function, together with the discovery that ZnT10 is expressed a high levels in brain tissue, indicate that ZnT10 has a role in regulating Zn homeostasis in the brain so may have relevance to the development of neurodegenerative disease.
[Show abstract][Hide abstract] ABSTRACT: The importance of variation in total volume of physical activity or moderate- to vigorous-intensity physical activity (MVPA) to development of body fatness in childhood is unclear, and it is unclear if physical activity has a greater influence on adiposity in boys than girls.
To assess relationships between 2-year changes in objectively measured physical activity, sedentary behavior, and adiposity in English children.
Prospective cohort study, set in Northeast England, of a socioeconomically representative sample of 403 children. Measures were change in accelerometer-determined physical activity and sedentary behavior from age 7 to 9 years (data collected 2006/2007 and 2008/2009; analyzed in 2010) and concurrent change in adiposity (fat mass index derived from bioelectric impedance) and change in BMI Z-score.
Decline in MVPA was associated with a greater increase in fat mass index in boys but not girls. Declining MVPA was associated with increased BMI Z-score in boys but not girls. Increased sedentary behavior was not associated with increased BMI Z-score in either gender.
Avoiding mid-late childhood reductions in MVPA may reduce excessive fat gain, although such strategies may have greater impact on boys than girls.
American journal of preventive medicine 05/2012; 42(5):445-51.
[Show abstract][Hide abstract] 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 01/2012;
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