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Background The consumption of 2 g/d plant sterols (PS) reduces circulating low-density lipoprotein cholesterol (LDL-C) up to 10%. The degree of LDL-C lowering was associated with specific apolipoprotein E (APOE, rs429358) and cholesterol 7α-hydroxylase (CYP7A1, rs3808607) genosets in previous post hoc analyses of randomized controlled trials. However, since post-hoc analyses do not conform to the randomization model, there is a greater potential that the findings may be due to type I error, thus warranting validation through an a priori-designed intervention trial. Objective The GenePredict Plant Sterol study (GPS) was designed to validate associations of LDL-C lowering with specific APOE and CYP7A1 genosets through a priori recruitment of individuals carrying pre-specified genosets. Methods A two center, double-blind, placebo-controlled, randomized two-period crossover dietary intervention with 2 g/d of PS for 28 days with a minimum 28 day washout was undertaken from July 2017 to December 2019. A priori recruitment of individuals with slightly elevated LDL-C was based on genosets of APOE isoforms and CYP7A1 rs3808607. Randomization was performed with stratification by sex and genoset. Results The recruitment target of 64 participants with pre-specified genosets could not be reached, despite the screening of 477 individuals; 42 participants completed the intervention trial. Reductions in LDL-C were similar across all three genosets (-0.298 ±0.164, -0.357 ±0.115, -0.293 ±0.109 mmol/L, P = 0.0002 overall, P = 0.9126 for treatment*genoset), providing evidence that the shortfall in recruitment may not have stopped the trial from meeting the objective. Conclusions APOE and CYP7A1 genotypes did not influence the efficacy of LDL-C reductions upon dietary intervention with PS. Findings of previous post-hoc analyses could not be validated in a trial using a priori genotype-based recruitment. Obtaining adequate numbers of participants is challenging in trials using genoset-based recruitment, even for common variants.Trial Registration: Clinical Trials #NCT02765516 https://clinicaltrials.gov/ct2/show/NCT02765516.

International audience; ABSTRACT Background Blood lipid concentrations display high interindividual variability in response to dietary interventions, partly due to genetic factors. Existing studies have focused on single nucleotide polymorphisms (SNPs) analyzed individually, which only explain a limited fraction of the variability of these complex phenotypes. Objective We aimed to identify combinations of SNPs associated with the variability in LDL cholesterol and triglyceride (TG) concentration changes following 5 dietary interventions. Design In a multicenter randomized crossover trial, 92 participants with elevated waist circumference and low HDL cholesterol concentrations consumed 5 isoenergetic diets for 4 wk: a diet rich in saturated fatty acids (SFAs) from cheese, SFA from butter, monounsaturated fatty acids (MUFAs), n–6 polyunsaturated fatty acids (PUFAs), and a diet higher in carbohydrates (CHO). The association between 22 candidate SNPs in genes involved in lipid and bile acid metabolism and transport and changes in LDL cholesterol and TG concentrations was assessed with univariate statistics followed by partial least squares regression. Results Endpoint LDL cholesterol concentrations were significantly different (cheese: 3.18 ± 0.04, butter: 3.31 ± 0.04, MUFA: 3.00 ± 0.04, PUFA: 2.81 ± 0.04, CHO: 3.11 ± 0.04 mmol/L; P

Ammonia excretion in fish excretory epithelia is a complex interplay of multiple membrane transport proteins and mechanisms. Using the model system of zebrafish (Danio rerio) larvae, here we identified three paralogues of a novel ammonia transporter, hippocampus-abundant transcript 1 (DrHiat1), also found in most vertebrates. When functionally expressed in Xenopus laevis oocytes, DrHiat1a and DrHiat1b promoted methylamine uptake in a competitive manner with ammonia. In situ hybridization experiments showed that both transporters were expressed as early as the 4-cell stage in zebrafish embryos and could be identified in most tissues 4 days post-fertilization. Larvae experiencing morpholino-mediated knockdown of DrHiat1b exhibited significantly lower whole-body ammonia excretion rates compared with control larvae. Markedly decreased site-specific total ammonia excretion of up to 85% was observed in both the pharyngeal region (site of developing gills) and the yolk sac (region shown to have the highest NH4+ flux). This study is the first to identify DrHiat1b/DrHIAT1 in particular as an important contributor to ammonia excretion in larval zebrafish. Being evolutionarily conserved, these proteins are likely involved in multiple other general ammonia-handling mechanisms, making them worthy candidates for future studies on nitrogen regulation in fishes and across the animal kingdom.

Avenanthramides are phenolic compounds unique to oats and may contribute to health-promoting properties associated with oat consumption. This study used Xenopus laevis oocytes expressing the glucose transporters, glucose transporter 2 (GLUT2) or sodium-glucose transport protein 1 (SGLT1) and human Caco-2 cells models to investigate the effect of oat avenanthramides on human intestinal glucose transporters. The presence of avenanthramide reduced the glucose uptake in a dose-dependent manner in Caco-2 cells. Glucose uptake in oocytes expressing either GLUT2 or SGLT1 was nullified by oat avenanthramide. There was no significant difference between the inhibition potencies of avenanthramides C and B. Thus, our results suggest that avenanthramides may contribute to the antidiabetic properties of oats. PRACTICAL APPLICATIONS: The present research focus on the antidiabetic properties of avenanthramides, which are unique phenolic compounds found in oats. Inhibiting the activities of the glucose transport proteins expressed in the small intestine is a known strategy to improve the control of postprandial glucose level. We therefore examined the inhibitory effects of avenanthramides on two glucose transporters, glucose transporter 2 and sodium-glucose transport protein 1, predominantly found in the small intestine using the human small intestinal cell model Caco-2 cell line and by heterologously expressing these two transporters in the Xenopus laevis oocytes. Based on our results, we have confirmed for the first time that the glucose uptake is indeed inhibited by the presence of avenanthramides, suggesting the possibility of incorporating avenanthramides in foods to enhance postprandial glucose response, and ultimately improve the management of diabetes. Therefore, future research could consider utilizing this evidence in the development of diabetic-friendly functional foods or nutraceuticals containing avenanthramides.

Diets varying in SFA and MUFA content can impact glycaemic control; however, whether underlying differences in genetic make-up can influence blood glucose responses to these dietary fatty acids is unknown. We examined the impact of dietary oils varying in SFA/MUFA content on changes in blood glucose levels (primary outcome) and whether these changes were modified by variants in the stearoyl-CoA desaturase (SCD) gene (secondary outcome). Obese men and women participating in the randomised, crossover, isoenergetic, controlled-feeding Canola Oil Multicenter Intervention Trial II consumed three dietary oils for 6 weeks, with washout periods of ˜6 weeks between each treatment. Diets studied included a high SFA/low MUFA Control oil (36·6 % SFA/28·2 % MUFA), a conventional canola oil (6·2 % SFA/63·1 % MUFA) and a high-oleic acid canola oil (5·8 % SFA/74·7 % MUFA). No differences in fasting blood glucose were observed following the consumption of the dietary oils. However, when stratified by SCD genotypes, significant SNP-by-treatment interactions on blood glucose response were found with additive models for rs1502593 (P = 0·01), rs3071 (P = 0·02) and rs522951 (P = 0·03). The interaction for rs3071 remained significant (P = 0·005) when analysed with a recessive model, where individuals carrying the CC genotype showed an increase (0·14 (sem 0·09) mmol/l) in blood glucose levels with the Control oil diet, but reductions in blood glucose with both MUFA oil diets. Individuals carrying the AA and AC genotypes experienced reductions in blood glucose in response to all three oils. These findings identify a potential new target for personalised nutrition approaches aimed at improving glycaemic control.

Thermal processing not only disrupts cell membranes and cell walls, but also cleaves covalent bonds releasing low molecular phenolic. This study examined the impact of various heat treatments (100, 140, and 160°C) on the composition of phenolic acids and antioxidant activities in extracts obtained from defatted brewers spent grain (BSG) meal. Heating BSG at 160°C resulted in a 2-fold increase in total phenolic content [TPC, 172.98 ± 7.3 mg Gallic acid equivalent (GAE)/100 g defatted meal] and total flavonoid content [TFC, 16.15 ± 2.22 catechin equivalents (CE)/100 g defatted meal] compared to the untreated BSG extracts. The antioxidant activities of treated BSG extracts, determined by radical scavenging and ferric reducing antioxidant power (FRAP) were significantly (p < 0.5) higher than the corresponding untreated BSG extracts. Eleven phenolic acids were identified and quantified in BSG extracts by Ultra Performance Liquid Chromatography with Photodiode Array (UPLC-PDA). The amounts varied significantly (p < 0.05) depending on the degree of toasting BSG was subjected to. Chlorogenic acid, an ester of caffeic and quinic acid was the predominant phenolic acid present in all fractions. Significant (p < 0.05) increases in TPC, TFC, individual phenolic acids and antioxidant activity were observed in BSG extracts exposed to increasing oven temperatures. These results confirm the ability of heat processing to release bioactive phenolic from their bound forms thereby enhancing the phenolic acids and the digestibility of BSG meal in the intestinal tract.

The majority of the bioactive compounds present in canola seeds are phenolic compounds. They are present as aglycones, glycosides, monomers, polymerized structures, or as free or matrix-bound compounds. Conventional methods of extraction utilize an excessive amount of organic solvents and require high energy input. Current environmental issues associated with organic solvent disposal demand alternative methods for the extraction of phenolic compounds that are environmentally friendly and energy-efficient. Green technology has identified a number of alternative methods suitable for the extraction of phenolic compounds. This chapter will review those alternative green methods suitable for the extraction of phenolic compounds from canola and rapeseed. Such methods include ultrasonic extraction, microwave extraction, accelerated solvent extraction, subcritical water extraction, and supercritical fluid extraction.

Associations of individual single nucleotide polymorphisms (SNPs) in the human genes encoding for the ascorbic acid transporters SLC23A1 and SLC23A2 were reviewed. SNPs in both genes modify circulating ascorbic concentrations, the risks for various cancers, cardiovascular outcomes, inflammatory bowel disease, and ocular diseases. Disease associations are inconsistent and impact sizes are generally moderate. The impact sizes of SNPs on circulating ascorbic acid concentrations are moderate and reported changes did not alter the populations’ vitamin C status. Associations for the SLC23A1 and SLC23A2 genes are currently poorly validated, limiting their utility as diagnostic or predictive biomarkers.

Background: Variations in intestinal antioxidant membrane transporters are implicated in the initiation and progression of inflammatory bowel disease (IBD). Facilitated glucose transporter member 14 (GLUT14), encoded by the solute carrier family 2 member 14 (SLC2A14) gene, is a putative transporter for dehydroascorbic acid and glucose. Although information on the gene is limited, shorter and longer GLUT14 isoforms have been identified. We hypothesized that GLUT14 mediates glucose and dehydroascorbic acid uptake. If this function could be validated, then genetic variations may associate with IBD.Objective: This study aimed to determine the substrate(s) for the GLUT14 protein and interrogated genetic associations of SLC2A14 with IBD.Design: The uptake of radiolabeled substrates into Xenopus laevis oocytes expressing the 2 GLUT14 isoforms was assessed. Examination of gene-targeted genetic association in the Manitoba Inflammatory Bowel Disease Cohort Study was conducted through the genotyping of single nucleotide polymorphisms (SNPs) representing linkage blocks of the SLC2A14 gene.Results: Both GLUT14 isoforms mediated the uptake of dehydroascorbic acid and glucose into X. laevis oocytes. Three alleles in the SLC2A14 gene associated independently with IBD. The odds of having ulcerative colitis (UC) or Crohn disease (CD) were elevated in carriers of the SLC2A14 SNP rs2889504-T allele (OR: 3.60; 95% CI: 1.95, 6.64 and OR: 4.68; 95% CI: 2.78, 8.50, respectively). Similarly, the SNP rs10846086-G allele was associated with an increased risk of both UC and CD (OR: 2.91; 95% CI: 1.49, 5.68 and OR: 3.00; 95% CI: 1.55, 5.78, respectively). Moreover, the SNP rs12815313-T allele associated with increased susceptibility to CD and UC (OR: 2.12; 95% CI: 1.33, 3.36 and OR: 1.61; 95% CI: 1.01, 2.57, respectively).Conclusion: These findings strengthen the hypothesis that genetically determined local dysregulation of dietary vitamin C or antioxidants transport contributes to IBD development. These transporter proteins are targetable by dietary interventions, opening the avenue to a precision intervention for patients of specific genotypes with IBD. This trial was registered at clinicaltrials.gov as NCT03262649.

The literature on the iron requirements of exclusively breastfed infants contains conflicting data and contrary views.The purpose of this study was to summarize the evidence for both benefits and risks of daily oral iron supplementation with regard to hematologic, growth, cognitive parameters, and adverse effects in exclusively breastfed infants.Structured electronic searches were conducted using PubMed, Cochrane Library databases, and Google Scholar for randomized controlled trials (RCTs) involving daily iron supplementation in full-term healthy exclusively breastfed infants. Random- and fixed-effects models were used for calculating the pooled estimates.Four RCTs with 511 infants were included in the meta-analysis. Iron interventions had no significant effect on iron deficiency or iron deficiency anemia, serum ferritin level, or hemoglobin level. Iron interventions did result in a significant increase in Bayley psychomotor developmental indices in later life (mean difference [MD] = 7.00, confidence interval [95% CI] 0.99-13.01) and mean corpuscular volume (MD = 2.17 fL; 95% CI 0.99-3.35 fL). Iron supplementation was associated with slower growth during the exclusive breastfeeding period, but the long-term effect is unclear.Limited available evidence suggests that daily iron supplementation has beneficial effects on hematologic parameters and cognitive development, but may delay physical growth in healthy exclusively breastfed infants. There was no evidence to suggest that iron supplementation could cause other adverse effects.

Predictions of global increased temperature are for 1.8–4 °C by 2100. Increased temperature as an abiotic stress may exert a considerable influence on the levels of secondary metabolites in plants. These secondary metabolites may possibly exert biological activities beneficial in prevention or treatment of disorders linked to oxidative stress in human. Wheat secondary compounds in three Canadian and three Australian genotypes grown under controlled environments, in which the only changing parameter was temperature, were investigated. Kennedy and AC Navigator contained the highest amount of total phenolic acids among Australian and Canadian wheat genotypes, respectively. The total phenolic acids and total flavonoid contents of wheat genotypes increased following the increase of the growing temperature. In all the wheat genotypes, regardless of their growing temperatures, linoleic acid (C18:2n6) was measured as the main fatty acid. Significant increases in palmitic acid (C16:0) and oleic acid (C18:1n9) and significant decreases in linoleic acid (C18:2n6) and linolenic acid (C18:3n3) were observed at increased of growing temperature for all wheat genotypes. Growing temperature decreased campesterol content of wheat genotypes. Genotype and growing temperature significantly shifted the production of wheat secondary metabolites. This information might be used as a guide for breeding wheat varieties with higher antioxidant properties.

Dietary omega-3 polyunsaturated fatty acids (n-3 PUFA), including alpha-linolenic acid (ALA) and preformed longer chain PUFA (LCPUFA, particularly docosahexaenoic acid, DHA) differ in their egg LCPUFA enrichment efficiency. However, mechanisms leading to these differences are unclear. To this end, omega-3 PUFA contents in different lipid classes, including triacylglycerol (TAG) and total phospholipid (PL) in yolk, liver and adipose, as well as the expression of key hepatic enzymes in lipid metabolism were evaluated in laying hens in response to changes in dietary supply. Seventy Lohmann hens (n=10/treatment) consumed either a control diet (0.03% total omega-3 PUFA), or the control with supplementation (0.20%, 0.40% and 0.60% total omega-3 PUFA) from either flaxseed oil or algal product, as sources of ALA (precursor) or DHA (preformed), respectively. The study was arranged in a completely randomized design, and data were analyzed using the Proc Mixed procedure of SAS. ALA accumulated as a function of intake (P

The SLC2A14 gene encodes for GLUT14, an orphan member of the facilitated membrane glucose transporter family, which was originally described to be exclusively expressed in human testis. However, genetic variations in SLC2A14 are associated with chronic diseases such as Alzheimer’s disease and Inflammatory Bowel Disease, which cannot be explained by a strictly testicular expression. Therefore we analyzed available information on the SLC2A14 gene to update knowledge of the locus and its encoded products. This report presents an expanded SLC2A14 gene locus and a more diverse tissue expression, concurring with the existing evidence for disease associations. The exon utilization is tissue specific, with major expression in testis. When the 2 major testicular protein isoforms were expressed in mammalian cells, they located to the plasmalemma membrane, providing early evidence that GLUT14 could function as a membrane transporter.

Background Dairy intake has been associated with varying impacts on circulating cholesterol concentrations across nutritional epidemiology and intervention studies, with findings attributed mainly to differences in the nature of dairy products consumed or study designs. The contribution of the genomic architecture to such observations has yet to be revealed. Objective We assessed the impact of multiple common genetic variations in cholesterol-related genes on responses of serum cholesterol to the recommended amount of dairy product intake in Canada. Methods In a multicenter, randomized crossover design, 101 normolipidemic adults (n = 29 men and 72 women), with a mean ± SD age of 41.7 ± 16.7 y and a body mass index (BMI, in kg/m(2)) of 25.9 ± 4.3 consumed 3 servings/d of dairy [375 mL 1% milk-fat (MF) milk, 175 g 1.5% MF yogurt, and 30 g of 34% MF cheese] or energy-matched control products (juice, cashews, and cookies) provided within a prudent background diet for 4 wk each, separated by a 4- to 8-wk washout period. Serum lipid variables were determined by standard enzymatic methods by using an autoanalyzer. Candidate single nucleotide polymorphisms were assessed by TaqMan genotyping assay. Results The responsiveness of serum total cholesterol (TC) and LDL cholesterol to the dairy compared with the control diet was associated with individuals' genotypes. The cholesterol transport gene ATP-binding cassette subfamily G, member 5 (ABCG5) rs6720173-GG homozygotes had higher concentrations of TC (+0.18 mmol/L; P = 0.0118) and LDL cholesterol (+0.17 mmol/L; P = 0.0056) relative to C-allele carriers (-0.07 and -0.06 mmol/L, respectively). The bile acid synthesis gene cholesterol 7α-hydroxylase (CYP7A1) rs3808607-G-allele carriers had higher TC (+0.20 to +0.28 mmol/L; P = 0.0026) and LDL cholesterol (+0.19 mmol/L for GT genotype; P = 0.0260) relative to TT homozygotes (-0.11 and -0.03 mmol/L, respectively). In addition, the cholesterol synthesis gene 7-dehydrocholesterol reductase (DHCR7) rs760241-A-allele carriers had higher LDL cholesterol (+0.26 mmol/L; P = 0.0399) relative to GG homozygotes (+0.06 mmol/L). Conclusion Genetic variations in ABCG5, CYP7A1, and DHCR7 may contribute to differing responses of serum cholesterol to dairy intake among healthy adults. This trial was registered at clinicaltrials.gov as NCT01444326.

Background β-Glucan, a soluble fiber with viscous property, has a documented cholesterol-lowering effect. The molecular weight (MW) of β-glucan, which contributes to viscosity, and an individual's genotype might influence the cholesterol-lowering efficacy of β-glucan. Objectives This study was designed to determine whether the cholesterol-lowering efficacy of barley β-glucan varied as a function of MW and the daily dose consumed. Our second aim was to determine whether any gene-diet interactions are associated with the cholesterol-lowering efficacy of β-glucan. Methods In a randomized controlled crossover trial, 30 mildly hypercholesterolemic adults [12 men and 18 women, aged 27-78 y; body mass index (in kg/m(2)): 20-40; total cholesterol (TC): 5.0-8.0 mmol/L; LDL cholesterol: 2.7-5.0 mmol/L] were randomly assigned to receive a breakfast that contained either barley β-glucan at 3 g high MW (HMW)/d, 5 g low MW (LMW)/d, or 3 g LMW/d or a control diet, each for 5 wk. The washout period between the phases was 4 wk. Fasting blood samples were collected at the start and end of each phase for blood lipid analysis and genotyping. Results Consumption of 3 g HMW β-glucan/d lowered TC by -0.12 mmol/L (95% CI: -0.24, -0.006 mmol/L) compared with the control diet (P= 0.0046), but the LMW β-glucan, at either 3 g/d or 5 g/d, did not change serum cholesterol concentrations. This effect of HMW β-glucan was associated with gene-diet interaction, whereby individuals with the single nucleotide polymorphism (SNP) rs3808607-G allele (GG or GT) of the cytochrome P450 family 7 subfamily A member 1 gene (CYP7A1) had greater responses to 3 g HMW β-glucan/d in lowering TC than TT carriers (P= 0.0006). Conclusions The HMW β-glucan rather than LMW β-glucan reduced circulating TC effectively in mildly hypercholesterolemic adults. The cholesterol-lowering effect of β-glucan may also be determined by the genetic characteristics of an individual. These data show that individuals carrying theCYP7A1SNP rs3808607-G allele are more responsive to the cholesterol-lowering effect of β-glucan with HMW than TT carriers. This trial was registered atclinicaltrials.govasNCT01408719.

Adequate plasma, cellular, and tissue vitamin C concentrations are required for maintaining optimal health through suppression of oxidative stress and optimizing functions of certain enzymes that require vitamin C as a cofactor. Polymorphisms in the vitamin C transporter genes, compromising genes encoding sodium-dependent ascorbate transport proteins, and also genes encoding facilitative transporters of dehydroascorbic acid, are associated with plasma and tissue cellular ascorbate status and hence cellular redox balance. This review summarizes our current knowledge of the links between variations in vitamin C transporter genes and common chronic diseases. We conclude that emerging genetic knowledge has a good likelihood of defining future personalized dietary recommendations and interventions; however, further validations through biological studies as well as controlled dietary trials are required to identify predictive and actionable genetic biomarkers. We further advocate the need to consider genetic variation of vitamin C transporters in future clinical and epidemiologic studies on common complex diseases.

Phenolic compounds in beer are derived from grains and hops during processing and production. Thus, the total phenolic content (TPC) of beer extracts, from selected Canadian and foreign commercial, and laboratory produced beers were examined and ranged from 3.72 ± 0.23 to 13.73 ± 0.49 mg GAE/100 mL beer. The total flavonoid content (TFC) of the same beer extracts varied from 0.82 ± 0.02 to 5.28 ± 0.04 mg CE/100 mL beer. Of particular interest were the hydroxycinnamic acids (HCAs) and derivatives in beer extracts because of their antioxidant properties. Main HCAs and a key derivative of ferulic acid, 4-vinylguaiacol (4-VG), were identified in beer extracts by high performance liquid chromatography (HPLC). Significant variations in TPC, TFC, HCAs and 4-VG content were observed among the beer extracts. Antioxidant activities of beer extracts, determined by radical scavenging and ferric-reducing assays, were positively correlated (p 0.05). The positive correlation of 4-VG with ABTS radical cation scavenging and reducing power assays is reported first time. These findings suggest that phenolic compounds and a key derivative of the hydroxycinnamic acid, 4-VG, may have the protective role in the beer as an antioxidant.

Whole grain consumption is associated with reduced risk of type 2 diabetes, and the underlying mechanism might be related to the actions of polyphenols. Dietary polyphenols contribute to low glycemic indices through inhibition of intestinal glucose transport proteins. This study has two objectives: (1) to evaluate how the contents of phenolic acids in wheat vary by genetic background and growth condition and (2) to evaluate how these changes translate into physiologic relevance by investigating cellular glucose transporter inhibitions. Phenolic acids were extracted from wheat varieties grown at different locations over two crop years. The degree of inhibition of glucose uptake into human Caco-2E cells was determined. Free and bound phenolic acid extracts of all wheat genotypes inhibited glucose uptake. Degree of glucose uptake inhibitions positively correlated with the contents of free and bound phenolic acids, and the correlation coefficients were R2=0.91 and R2=0.89, respectively. Genotype and environment influenced the content of free and bound phenolic acids which linearly translated to the degree of glucose uptake inhibition in a model of intestinal absorption (P<0.05). Results of this work mechanistically support the hypothesis that dietary phenols positively influence the glycemic index and therefore the health properties of whole grain consumption.

Vitamin C is essential to prevent scurvy in humans and is implicated in the primary prevention of common and complex diseases such as coronary heart disease, stroke, and cancer. This chapter reviews the latest knowledge about dietary vitamin C in human health with an emphasis on studies of the molecular mechanisms of vitamin C maintenance as well as gene-nutrient interactions modifying these relationships. Epidemiological evidence indicates 5% prevalence for vitamin C deficiency and 13% prevalence for suboptimal status even in industrialized countries. The daily intake (dose) and the corresponding systemic concentrations (response) are related in a saturable relationship, and low systemic vitamin C concentrations in observational studies are associated with negative health outcomes. However, there is no evidence that vitamin C supplementation impacts the risks for all-cause mortality, impaired cognitive performance, reduced quality of life, the development of eye diseases, infections, cardiovascular disease, and cancers. This might be related to the fact that prevention would not be realized by supplementation in populations already adequately supplied through dietary sources. Recent genetic association studies indicate that the dietary intake might not be the sole determinant of systemic concentrations, since variations in genes participating in redox homeostasis and vitamin C transport had been associated with lowered plasma concentrations. However, impact sizes are generally low and these phenomena might only affect individual of suboptimal dietary supply.

Vitamin C is essential to prevent scurvy in humans and is implicated in the primary prevention of common and complex diseases such as coronary heart disease, stroke, and cancer. This chapter reviews the latest knowledge about dietary vitamin C in human health with an emphasis on studies of the molecular mechanisms of vitamin C maintenance as well as gene-nutrient interactions modifying these relationships. Epidemiological evidence indicates 5% prevalence for vitamin C deficiency and 13% prevalence for suboptimal status even in industrialized countries. The daily intake (dose) and the corresponding systemic concentrations (response) are related in a saturable relationship, and low systemic vitamin C concentrations in observational studies are associated with negative health outcomes. However, there is no evidence that vitamin C supplementation impacts the risks for all-cause mortality, impaired cognitive performance, reduced quality of life, the development of eye diseases, infections, cardiovascular disease, and cancers. This might be related to the fact that prevention would not be realized by supplementation in populations already adequately supplied through dietary sources. Recent genetic association studies indicate that the dietary intake might not be the sole determinant of systemic concentrations, since variations in genes participating in redox homeostasis and vitamin C transport had been associated with lowered plasma concentrations. However, impact sizes are generally low and these phenomena might only affect individual of suboptimal dietary supply.

Recent work suggests that plant sterol (PS) consumption may lower triglyceride (TG) concentrations; however, human clinical trial evidence is inconsistent. We associated SNP r5882 in cholesteryl ester transfer protein with changes in TG concentrations following PS consumption (2 g/day for 4 weeks) in a dual-centre, single-blind, randomized, crossover trial. TG concentrations were lowered in homozygotes for the minor G-allele of rs5882 (–0.46 ± 0.13 mmol/L, p = 0.002, n = 10); there was no effect in the A-allele carriers.

Background: Benefits of plant sterols (PS) for cholesterol loweringare compromised by large variability in efficacy across individuals.High fractional cholesterol synthesis measured by deuterium incor-poration has been associated with nonresponse to PS consumption;however, prospective studies that show this association have yet tobe conducted.Objective: Thegoalwastotestwhetherthelathosterol-to-cholesterolratio (L:C), a surrogate marker of endogenous cholesterol synthesis,serves as an a priori predictor of cholesterol lowering in response toPS consumption.Design: Sixty-three mildly hypercholesterolemic adults who werepreselected as possessing either high endogenous cholesterol synthe-sis [HS;n = 24;L:C = 2.036 0.39mmol/mmol(mean 6 SD)]orlowendogenous cholesterol synthesis [LS; n = 39; L:C = 0.99 6 0.28mmol/mmol (mean 6 SD)] on the basis of baseline L:C consumed2 g PS/d or a placebo for 28 d with the use of a dual-center, single-blind, randomized crossover design. Plasma lipid and noncholesterolsterol concentrations were measured at the end of each phase.Results: PS consumption lowered total cholesterol (TC; 20.25 60.05 mmol/L; P , 0.0001) and LDL cholesterol (20.17 6 0.04mmol/L; P , 0.0001) overall. Specifically, LS individuals respondedto PS treatment with a reduction in TC (20.40 6 0.07 mmol/L; P ,0.0001) and LDL cholesterol (20.29 6 0.05 mmol/L; P = 0.0002),whereas HS individuals failed to show cholesterol lowering (TC:20.09 6 0.09 mmol/L; P = 0.2843; LDL cholesterol: 20.05 60.07 mmol/L; P = 0.4917). The odds of LS participants respondingwith cholesterol lowering better thanthe mean cholesterol lowering inall participants to PS consumption were 4.25 (95% CI: 1.242, 14.556;P = 0.0211) for TC and 3.36 (95% CI: 1.112, 10.161; P = 0.0317) forLDL cholesterol, which was higher than for HS participants.Conclusions: The L:C ratio predicts the extent of reduction incirculating TC and LDL cholesterol in response to PS consumption.Cholesterol synthesis assessment may thus have a use in identifyingresponders and nonresponders to PS therapy. This trial was regis-tered at clinicaltrials.govas NCT01131832. Am J Clin Nutr doi:10.3945/ajcn.114.095356.Keywords cholesterol lowering, interindividual variability, non-cholesterol sterols, plant sterols, randomized controlled trialINTRODUCTIONPlant sterols (PS)

The molecular background of iron excretion into breast milk has not been determined in humans. We determined the expression of known iron transporters in mRNA extracted from human milk fat globules to deduce which known transporters are responsible for iron excretion into human milk.The expression of iron transporters in mRNA from human milk fat globules and mouse mammary epithelial cell lines was determined by quantitative real-time polymerase chain reaction.The expression of the transferrin receptor 1 (TFRC), divalent metal transporter 1 (SLC11A2), transferrin (TF), and lactoferrin (LTF) was confirmed in RNA isolated from the human milk fat globule. Similar expression was observed in the mouse mammary epithelial cell line HC11 in resting and lactating phenotypes. No iron export protein could be determined in the RNA isolated from fat globules in human breast milk and a human mammary epithelial cell line.The lack of iron exporters in the human mammary epithelia, in conjunction with the presence of lactoferrin suggests that transmembrane transport is not a major route of iron excretion into human milk.

Background: SLC22A23 is an orphan gene in the SLC22 family of organic membrane transporters, and its single-nucleotide polymorphism rs17309827-T was recently nominally associated with intestinal inflammation in a genome-wide association study. Other polymorphisms in the SLC22A23 gene have been associated with diseases with an inflammatory component, and polymorphisms in related genes in the SLC22 family have been repeatedly associated with inflammatory bowel disease (IBD). Objective: In a candidate-gene study using a well-phenotyped, highly monitored, Manitoban white cohort, we investigated whether variations in SLC22A23 were associated with intestinal inflammation. Design: Selected genetic variations were genotyped by using fluorescentbased assays or a polymerase chain reaction‐restriction fragment length polymorphism analysis in 160 individuals with Crohn disease, 149 individuals with ulcerative colitis, and 142 healthy control subjects to determine genetic associations. Results: Homozygocity for single-nucleotide polymorphisms rs4959235-TTand rs950318-GG was associated with IBD, whereby 6% of patients (18 of 311 cases) carried these genotypes, but they were not seen in healthy controls. Conclusion: Associations reported in this article add to the emerging evidence that SLC22A23 variants could modify IBD risk. However, the biology of the gene and impact of variations on the gene’s functions need to be tested to validate a causative role. Am J Clin Nutr doi: 10.3945/ajcn.113.080549.

The two membrane transporters Slc23a1 and Slc23a2 mediate ascorbic acid uptake into cells. We recently determined the key role of Slc23a1 in renal re-absorption of ascorbic acid in a knockout mouse model. However, the renal spatial and temporal expression patterns of murine Slc23a1 and Slc23a2 are not defined. This study utilizes database evidence combined with experimental confirmation via in-situ hybridization to define the spatial and temporal expression of Slc23a1 in the murine kidney. Slc23a1 is expressed in the early proximal tubule, but not in its precursors during embryonic development, and exclusive proximal tubular expression persists throughout the animal’s lifetime. In contrast, Slc23a2 is uniformly expressed in metabolic cell types such as stromal cells. The expression patterns appear to be conserved from rodent lineages to humans.

IntroductionLifestyle factors, such as diet, physical activity and sleep, are associated with the development of many chronic diseases. The objective of The Manitoba Personalized Lifestyle Research study is to understand how these lifestyle factors interact with each other and with other factors, such as an individual’s genetics and gut microbiome, to influence health.MethodsAn observational study of adults, with extensive phenotyping by objective health and lifestyle assessments, and retrospective assessment of early life experiences, with retrospective and prospective utilisation of secondary data from administrative health records.Study populationA planned non-random convenience sample of 840 Manitobans aged 30–46 recruited from the general population, stratified by sex (equal men and women), body mass index (BMI; 60% of participants with a BMI>25 kg/m2) and geography (25% from rural areas). These stratifications were selected based on Manitoba demographics.MeasurementsLifestyle factors assessed will include dietary pattern, physical activity, cardiovascular fitness, and sleep. Factors such as medical history, socioeconomic status, alcohol and tobacco consumption, cognition, stress, anxiety, and early life experiences will also be documented. A maternal survey will be performed. Body composition and bone density will be measured by dual energy X-ray absorptiometry. Blood pressure, pulse wave velocity, and augmentation index will be measured on two consecutive days. Chronic disease risk biomarkers will be measured in blood and urine samples. DNA will be extracted for genetic analysis. A faecal sample will be collected for microbiome analysis. Participants may provide their Manitoba personal health information number to link their study data with administrative health records.Ethics and disseminationEthics approval has been obtained from the University of Manitoba Health Research Ethics Board (protocol # HS18951; 05/01/2016). Data analysis, release of results and publication of manuscripts are scheduled to start in early 2019. Additional information atwww.TMPLR.ca.Trial registration numberNCT03674957; Pre-results.

The effect of feruloylated arabinoxylan mono- and oligosaccharides (FAXmo) on mammalianα-glucosidase and glucose transporters was investigated using human Caco-2 cells, rat intestinal acetone powder, andXenopus laevisoocytes. The isolated FAXmo from wheat aleurone and corn bran were identified to have degree of polymerization (DP) of 4 and 1, respectively, by HPLC-MS. Both FAXmo extracts were effective inhibitors of sucrase and maltase functions of theα-glucosidase. The IC50 for FAXmo extracts on Caco-2 cells and rat intestinalα-glucosidase was 1.03–1.65 mg/mL and 2.6–6.5 mg/mL, respectively. Similarly, glucose uptake in Caco-2 cells was inhibited up to 40%. The inhibitory effect of FAXmo was dependent on their ferulic acid (FA) content (R= 0.95). Sodium independent glucose transporter 2 (GLUT2) activity was completely inhibited by FAXmo in oocytes injected to express GLUT2. Our results suggest that ferulic acid and feruloylated arabinoxylan mono-/oligosaccharides have potential for use in diabetes management.

The results of ultrasonic bleaching prove effectiveness in reducing chlorophyll content in cold‐pressed hempseed oil and suggest its potential for prolonging the shelf‐life.

Two novel imaging agents trastuzumab-Cy5.5-CHX-A''1 and cetuximab-Cy7-CHX-A''2, bearing both a chelating moiety (CHX-A'') for sequestering metallic radionuclides ((86)Y or (111)In) and the near infrared dye Cy5.5/Cy7, were prepared by a novel modular synthetic strategy as examples of dual-labeled, antibody-based imaging probe library. Fluorescent microscopy illustrated that 1 and 2 strongly bind to HER2-expressing cancer cells (e.g., NIH3T3-HER2(+), SKOV-3) and to EGFR-expressing cancer cells (e.g., A431), respectively, thereby demonstrating that the functionality of the targeting moiety is conserved. Hence, the described novel synthesis strategy can be applied to engineer other tumor-targeted monoclonal antibody based probes for multimodality imaging.

Previous observational studies suggest that vitamin C may reduce risk of colorectal cancer. Vitamin C transport is facilitated by membrane bound sodium-dependent transporters, SVCT1 (encoded by SLC23A1) and SVCT2 (encoded by SLC23A2). To investigate if common genetic variants in these two genes are associated with risk of colorectal tumor development, we conducted a case-control study of 656 Caucasian advanced distal colorectal adenoma cases and 665 Caucasian sigmoidoscopy-negative controls nested within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The analysis of common single nucleotide polymorphisms in SLC23A1 revealed no association. For SLC23A2, overall, there was no association with haplotypes, but two SNPs located in intron 8 and exon 11 could be associated (odds ratio = 0.49, 95% confidence interval = 0.25-0.95 for haplotype G-C vs. haplotype C-C). The findings should be confirmed in follow-up studies, and further investigation is required to probe the functional basis of this finding.

Ligand size and valency strongly influence the receptor uptake and clearance of tumor angiogenesis imaging agents. The structures of successful imaging agents exhibit a high degree of variability, encompassing small monovalent arginine-glycine-aspartic acid (RGD)-containing peptides, multivalent RGD-oligomers, and a monoclonal antibody against integrin alpha-v-beta-3 (alpha-v-beta-3). We have pursued a nanoscale approach to imaging of angiogenesis using rationally designed polyamidoamine (PAMAM) dendrimers covalently adorned with RGD-cyclopeptides. An orthogonal oxime-ligation strategy was applied to chemoselectively effect conjugation of the PAMAM dendrimers with RGD-cyclopeptides for targeting alpha vbeta 3. Fluorescent dyes for optical imaging and chelates for gadolinium-based magnetic resonance (MR) imaging were subsequently appended to create robust multimodal macromolecular imaging agents. Fluorescence microscopy revealed selective binding of the resulting RGD peptide-bearing dendrimer with empty chelates to alpha-v-beta-3-expressing cells, but somewhat reduced selectivity was observed following Gd(III) complexation. The expected incomplete saturation of chelates with Gd(III) ions permitted radiometal complexation, and an in vivo tissue distribution of the resulting agent in M21 melanoma tumor-bearing mice showed mostly renal and reticuloendothelial accumulation, with the tumor:blood ratio peaking (3.30+/-0.03) at 2 h postinjection.