Publications by authors named "Jim Kaput"

74 Publications

DNA Damage, n-3 Long-Chain PUFA Levels and Proteomic Profile in Brazilian Children and Adolescents.

Nutrients 2021 Jul 21;13(8). Epub 2021 Jul 21.

Department of Pediatrics, Medical School of Ribeirao Preto, University of Sao Paulo, Sao Paulo 14049-900, Brazil.

Fatty acids play a significant role in maintaining cellular and DNA protection and we previously found an inverse relationship between blood levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and DNA damage. The aim of this study was to explore differences in proteomic profiles, for 117 pro-inflammatory proteins, in two previously defined groups of individuals with different DNA damage and EPA and DHA levels. Healthy children and adolescents ( = 140) aged 9 to 13 years old in an urban area of Brazil were divided by k-means cluster test into two clusters of DNA damage (tail intensity) using the comet assay (cluster 1 = 5.9% ± 1.2 and cluster 2 = 13.8% ± 3.1) in our previous study. The cluster with higher DNA damage and lower levels of DHA (6.2 ± 1.6 mg/dL; 5.4 ± 1.3 mg/dL, = 0.003) and EPA (0.6 ± 0.2 mg/dL; 0.5 ± 0.1 mg/dL, < 0.001) presented increased expression of the proteins CDK8-CCNC, PIK3CA-PIK3R1, KYNU, and PRKCB, which are involved in pro-inflammatory pathways. Our findings support the hypothesis that low levels of n-3 long-chain PUFA may have a less protective role against DNA damage through expression of pro-inflammatory proteins, such as CDK8-CCNC, PIK3CA-PIK3R1, KYNU, and PRKCB.
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http://dx.doi.org/10.3390/nu13082483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8401971PMC
July 2021

Developing the Pathway to Personalized Health: The Potential of N-of-1 Studies for Personalizing Nutrition.

Authors:
Jim Kaput

J Nutr 2021 Oct;151(10):2863-2864

Vydiant, Folsom, CA, USA.

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http://dx.doi.org/10.1093/jn/nxab243DOI Listing
October 2021

Dietary patterns related to zinc and polyunsaturated fatty acids intake are associated with serum linoleic/dihomo-γ-linolenic ratio in NHANES males and females.

Sci Rep 2021 06 9;11(1):12215. Epub 2021 Jun 9.

Vydiant, Folsom, CA, USA.

Identifying dietary patterns that contribute to zinc (Zn) and fatty acids intake and their biomarkers that may have an impact on health of males and females. The present study was designed to (a) extract dietary patterns with foods that explain the variation of Zn and PUFAs intake in adult men and women; and (b) evaluate the association between the extracted dietary patterns with circulating levels of serum dihomo-γ-linolenic fatty acid (DGLA) or serum linoleic/dihomo-γ-linolenic (LA/DGLA) ratio in males and females. We used reduced rank regression (RRR) to extract the dietary patterns separated by sex in the NHANES 2011-2012 data. A dietary pattern with foods rich in Zn (1st quintile = 8.67 mg/day; 5th quintile = 11.11 mg/day) and poor in PUFAs (5th quintile = 15.28 g/day; 1st quintile = 18.03 g/day) was found in females (S-FDP2) and the same pattern, with foods poor in PUFAs (5th quintile = 17.6 g/day; 1st quintile = 20.7 g/day) and rich in Zn (1st quintile = 10.4 mg/day; 5th quintile = 12.9 mg/day) (S-MDP2), was found in males. The dietary patterns with foods rich in Zn and poor in PUFAs were negatively associated with serum LA/DGLA ratio. This is the first study to associate the LA/DGLA ratio with Zn and PUFAs related dietary patterns in males and females.
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http://dx.doi.org/10.1038/s41598-021-91611-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190411PMC
June 2021

Contribution of genetic ancestry and polygenic risk score in meeting vitamin B12 needs in healthy Brazilian children and adolescents.

Sci Rep 2021 06 7;11(1):11992. Epub 2021 Jun 7.

Department of Pediatrics and Department of Health Sciences, Ribeirão Preto Medical School, Nutrition and Metabolism Section, University of São Paulo, Avenida Bandeirantes, 3900, Bairro Monte Alegre, Ribeirão Preto, SP, 14040-900, Brazil.

Polymorphisms in genes related to the metabolism of vitamin B12 haven't been examined in a Brazilian population. To (a) determine the correlation between the local genetic ancestry components and vitamin B12 levels using ninety B12-related genes; (b) determine associations between these genes and their SNPs with vitamin B12 levels; (c) determine a polygenic risk score (PRS) using significant variants. This cross-sectional study included 168 children and adolescents, aged 9-13 years old. Total cobalamin was measured in plasma. Genotyping arrays and whole exome data were combined to yield ~ 7000 SNPs in 90 genes related to vitamin B12. The Efficient Local Ancestry Inference was used to estimate local ancestry for African (AFR), Native American, and European (EUR). The association between the genotypes and vitamin B12 levels were determined with generalized estimating equation. Vitamin B12 levels were driven by positive (EUR) and negative (AFR, AMR) correlations with genetic ancestry. A set of 36 variants were used to create a PRS that explained 42% of vitamin level variation. Vitamin B12 levels are influenced by genetic ancestry and a PRS explained almost 50% of the variation in plasma cobalamin in Brazilian children and adolescents.
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http://dx.doi.org/10.1038/s41598-021-91530-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184816PMC
June 2021

Metabolic Groups Related to Blood Vitamin Levels and Inflammatory Biomarkers in Brazilian Children and Adolescents.

J Nutr Sci Vitaminol (Tokyo) 2020 ;66(6):515-525

Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo.

Certain B-vitamins and vitamin A may be involved in inflammatory pathways associated with homocysteine and omega-3 fatty acids. The aims of this study were (i) to determine whether different metabolic profiles of B-vitamins and vitamin A in Brazilian children and adolescents were positively or negatively related to homocysteine and omega-3 fatty acids using k-means clustering analysis, (ii) compare nutrient intakes and metabolites between the different metabolic profiles, (iii) evaluate if the statistically significant metabolites found between the metabolic groups, can predict the variation of leukotriene A4 hydrolase (LTA4H) levels, a biomarker of low-grade inflammation, in the total studied population. This cross-sectional study included 124 children and adolescents, aged 9-13 y old. Dietary intake was assessed by the food frequency questionnaire and 24-hour recall. Biomarkers for vitamins B2, B6, B12, folate and vitamin A were measured in plasma. Omega-3 fatty acids and homocysteine were measured in red blood cells (RBC). Two different metabolic profiles were found. Thirty of these individuals had overall average higher riboflavin, pyridoxal, and vitamin B12 plasma levels (metabolic group 1) compared to 94 individuals (group 2). Group 2 had lower dietary intake of vitamin B2, vitamin A, and vitamin B12 and higher RBC levels of homocysteine. EPA and DHA erythrocyte levels were not different between metabolic groups. Multiple linear regression analyses showed that blood cobalamin, riboflavin, pyridoxal and homocysteine combined, explained 9.0% of LTA4H levels variation in the total studied population. The metabolic group that had low plasma levels of riboflavin, pyridoxal, and cobalamin also had a lower dietary intake of B-vitamin and higher RBC homocysteine. The combined levels of the riboflavin, pyridoxal, cobalamin and homocysteine biomarkers can predict the variation of LTA4H in the total population studied, but it is not clear how this regulation occurs.
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http://dx.doi.org/10.3177/jnsv.66.515DOI Listing
August 2021

DNA methylation during human adipogenesis and the impact of fructose.

Genes Nutr 2020 Nov 26;15(1):21. Epub 2020 Nov 26.

The Microsoft Research - University of Trento Centre for Computational and Systems Biology, Piazza Manifattura 1, 38068, Rovereto, Italy.

Background: Increased adipogenesis and altered adipocyte function contribute to the development of obesity and associated comorbidities. Fructose modified adipocyte metabolism compared to glucose, but the regulatory mechanisms and consequences for obesity are unknown. Genome-wide methylation and global transcriptomics in SGBS pre-adipocytes exposed to 0, 2.5, 5, and 10 mM fructose, added to a 5-mM glucose-containing medium, were analyzed at 0, 24, 48, 96, 192, and 384 h following the induction of adipogenesis.

Results: Time-dependent changes in DNA methylation compared to baseline (0 h) occurred during the final maturation of adipocytes, between 192 and 384 h. Larger percentages (0.1% at 192 h, 3.2% at 384 h) of differentially methylated regions (DMRs) were found in adipocytes differentiated in the glucose-containing control media compared to adipocytes differentiated in fructose-supplemented media (0.0006% for 10 mM, 0.001% for 5 mM, and 0.005% for 2.5 mM at 384 h). A total of 1437 DMRs were identified in 5237 differentially expressed genes at 384 h post-induction in glucose-containing (5 mM) control media. The majority of them inversely correlated with the gene expression, but 666 regions were positively correlated to the gene expression.

Conclusions: Our studies demonstrate that DNA methylation regulates or marks the transformation of morphologically differentiating adipocytes (seen at 192 h), to the more mature and metabolically robust adipocytes (as seen at 384 h) in a genome-wide manner. Lower (2.5 mM) concentrations of fructose have the most robust effects on methylation compared to higher concentrations (5 and 10 mM), suggesting that fructose may be playing a signaling/regulatory role at lower concentrations of fructose and as a substrate at higher concentrations.
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http://dx.doi.org/10.1186/s12263-020-00680-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691080PMC
November 2020

Biomarker-based validity of a food frequency questionnaire estimating intake in Brazilian children and adolescents.

Int J Food Sci Nutr 2021 Mar 7;72(2):236-247. Epub 2020 Jul 7.

Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.

This study evaluated the validity of nutrient and food group intakes estimated by an FFQ against biomarkers. A 71-item semiquantitative FFQ was administered to 210 Brazilian children and adolescents aged 9-13 years. Intakes were correlated with biomarkers in plasma and red blood cells. Correlations between nutrients and their biomarkers were presented for animal protein, myristic acid (C14:0), EPA, DHA, β-carotene, folate, and vitamins B3, B5 and B6. Food groups and biomarkers were correlated as follows: fish products with EPA and DHA; milk and dairy with C14:0, pyridoxal 5'-phosphate and vitamin B12; total vegetables and dark green and orange vegetables with β-carotene; 5-methyltetrahydrofolate with green vegetables; and flour products with para-aminobenzoylglutamic acid. This FFQ is a valid tool for ranking Brazilian children and adolescents according to their intake of several nutrients and food groups.
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http://dx.doi.org/10.1080/09637486.2020.1786026DOI Listing
March 2021

DNA damage is inversely associated to blood levels of DHA and EPA fatty acids in Brazilian children and adolescents.

Food Funct 2020 Jun;11(6):5115-5121

Department of Pediatrics and Department of Health Sciences, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.

This study aimed to investigate the association between DNA damage and blood levels of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), retinol, beta-carotene and riboflavin in Brazilian children and adolescents. Subjects (n = 140) were healthy boys and girls aged 9 to 13 years in Ribeirão Preto (SP, Brazil). Data collection included anthropometry, assessment of energy intake and blood sampling. DNA damage was evaluated by single-cell gel electrophoresis (comet assay). Principal component analysis (PCA) was used to verify associations between blood concentrations of vitamins, polyunsaturated fatty acids and DNA damage. Multiple regression analyses, k-means cluster, and analysis of covariance (ANCOVA), adjusted for confounding variables such as age, sex, energy intake, body mass index and total cholesterol (when needed), were applied to confirm the associations. PCA explained 69.4% of the inverse relationships between DNA damage and blood levels of DHA, EPA, retinol, and beta-carotene. Results were confirmed by ANCOVA and multiple regression analyses for DHA and EPA. In conclusion, omega-3-fatty acids were inversely associated with DNA damage in Brazilian children and adolescents and may be a protective factor against the development of future diseases.
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http://dx.doi.org/10.1039/c9fo02551kDOI Listing
June 2020

Metabo groups in response to micronutrient intervention: Pilot study.

Food Sci Nutr 2020 Jan 19;8(1):683-693. Epub 2019 Dec 19.

Department of Pediatrics and Department of Health Sciences Faculty of Medicine of Ribeirão Preto University of São Paulo São Paulo Brazil.

Micronutrients and their metabolites are cofactors in proteins involved in lipid metabolism. The present study was a subproject of the Harmonized Micronutrient Project (ClinTrials.gov # NCT01823744). Twenty participants were randomly selected from 136 children and adolescents that consumed a daily dose of 12 vitamins and 5 minerals supplementation for 6 weeks. The 20 individuals were divided into two pools of 10 individuals, according to their lipid profile at baseline (Pool 1 with lower triglycerides, LDL, and VLDL). The individuals were analyzed at baseline, after 6 weeks of daily supplementation, and after 6 weeks of a washout period in relation to anthropometric, body composition, food intake, lipid profile, micronutrient levels, and iTRAQ proteomic data. Genetic ancestry and its association with vitamin serum levels were also determined. After supplementation, LDL levels decreased while alpha-tocopherol and pantothenic acid levels increased in pool 2; lipid profiles in pool 1 did not change but had higher plasma levels of pantothenic acid, pyridoxal, and pyridoxic acid. In pool 2, expression of some proteins increased, and expression of other ones decreased after intervention, while in pool 1, the same proteins responded inversely or did not change their levels. Plasma alpha-tocopherol and Native American genetic ancestry explained a significant fraction of LDL plasma levels at baseline and in response to the intervention. After intervention, changes in expression of alpha-1 antitrypsin, haptoglobin, Ig alpha-1 chain C region, plasma protease C1 inhibitor, alpha-1-acid glycoprotein 1, fibrinogen alpha, beta, and gamma-chain in individuals in pool 2 may be associated with levels of LDL and vitamin E. Vitamin E and Native American genetic ancestry may also be implicated in changes of vitamin E and LDL levels. The results of this pilot study must be validated in future studies with larger sample size or in in vitro studies.
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http://dx.doi.org/10.1002/fsn3.1357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977437PMC
January 2020

Vitamin B2 and Folate Concentrations are Associated with ARA, EPA and DHA Fatty Acids in Red Blood Cells of Brazilian Children and Adolescents.

Nutrients 2019 Dec 2;11(12). Epub 2019 Dec 2.

Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Bandeirantes Avenue, 3900, Ribeirão Preto 14049-900, Brazil.

Vitamins B2, B6, B12, and folate are essential for methylation reactions and possibly influence the transport of polyunsaturated fatty acids in plasma and red blood cells (RBC). Associations between B-vitamin biomarkers and fatty acid (FA) profile were analyzed in Brazilian children and adolescents. This cross-sectional study included 249 children and adolescents, aged 9-13 years old. Dietary intake was assessed by the food frequency questionnaire and the healthy eating index (HEI). Biomarkers for vitamins B2, B6, B12, and folate were measured in plasma. The FA profile and the metabolites of one-carbon metabolism were measured in RBC. Associations were tested with multiple linear regression models. An increase of 1 nmol/L in vitamin B2 was associated with an increase of 0.19 mg/dL of EPA, 0.20 mg/dL of ARA, and 0.25 mg/dL of DHA in RBC. An increase of 1 ng/mL in plasma folate was associated with an increase of 0.14 mg/dL of EPA, 0.22 mg/dL of ARA, and 0.21 mg/dL of DHA in RBC. These findings highlight the importance of an adequate intake of vitamin B2 and folate in childhood, since they may improve the FA profile in RBCs and may help prevent cardiovascular disease.
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http://dx.doi.org/10.3390/nu11122918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950420PMC
December 2019

Lessons from application of data science strategies in nutritional research.

Authors:
Jim Kaput

Am J Clin Nutr 2020 01;111(1):4-5

Vydiant, Sacramento, CA, USA.

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http://dx.doi.org/10.1093/ajcn/nqz284DOI Listing
January 2020

Impact of multi-micronutrient supplementation on lipidemia of children and adolescents.

Clin Nutr 2020 07 18;39(7):2211-2219. Epub 2019 Oct 18.

Lipid Metabolism, Nestlé Research, EPFL Innovation Park, 1015, Switzerland; Institute of Clinical Chemistry, Inselspital, Bern University Hospital, Bern, Switzerland. Electronic address:

Background: Micronutrient supplementation has been extensively explored as a strategy to improve health and reduce risk of chronic diseases. Fat-soluble vitamins like A and E with their antioxidant properties and mechanistic interactions with lipoproteins, have potentially a key impact on lipid metabolism and lipidemia.

Objective: The impact of micronutrients on lipid metabolism requires further investigation including characterization of plasma lipidome following supplementation and any cause-effect on circulating lipids.

Design: In this study, we elucidate the effect and associations of a multi-micronutrient intervention in Brazilian children and teens with lipoprotein alterations and lipid metabolism.

Results: Our analysis suggests a combination of short and long-term impact of supplementation on lipid metabolism, potentially mediated primarily by α-tocopherol (vitamin E) and retinol (vitamin A). Among the lipid classes, levels of phospholipids, lysophospholipids, and cholesterol esters were impacted the most along with differential incorporation of stearic, palmitic, oleic and arachidonic acids. Integrated analysis with proteomic data suggested potential links to supplementation-mediated alterations in protein levels of phospholipases and pyruvate dehydrogenase kinase 1 (PDK1).

Conclusions: Associations between the observed differences in lipidemia, total triglyceride, and VLDL-cholesterol levels suggest that micronutrients may play a role in reducing these risk factors for cardiovascular disease in children. This would require further investigation.
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http://dx.doi.org/10.1016/j.clnu.2019.09.010DOI Listing
July 2020

Targeting the delivery of dietary plant bioactives to those who would benefit most: from science to practical applications.

Eur J Nutr 2019 Nov 22;58(Suppl 2):65-73. Epub 2019 Oct 22.

INRA, UNH, Unité de Nutrition Humaine, CRNH Auvergne, Université Clermont Auvergne, Clermont-Ferrand, France.

Background: A healthy diet and optimal lifestyle choices are amongst the most important actions for the prevention of cardiometabolic diseases. Despite this, it appears difficult to convince consumers to select more nutritious foods. Furthermore, the development and production of healthier foods do not always lead to economic profits for the agro-food sector. Most dietary recommendations for the general population represent a "one-size-fits-all approach" which does not necessarily ensure that everyone has adequate exposure to health-promoting constituents of foods. Indeed, we now know that individuals show a high variability in responses when exposed to specific nutrients, foods, or diets.

Purpose: This review aims to highlight our current understanding of inter-individual variability in response to dietary bioactives, based on the integration of findings of the COST Action POSITIVe. We also evaluate opportunities for translation of scientific knowledge on inter-individual variability in response to dietary bioactives, once it becomes available, into practical applications for stakeholders, such as the agro-food industry. The potential impact from such applications will form an important impetus for the food industry to develop and market new high quality and healthy foods for specific groups of consumers in the future. This may contribute to a decrease in the burden of diet-related chronic diseases.
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http://dx.doi.org/10.1007/s00394-019-02075-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851046PMC
November 2019

A proteomic signature that reflects pancreatic beta-cell function.

PLoS One 2018 30;13(8):e0202727. Epub 2018 Aug 30.

Institute of Food and Health, UCD School of Agriculture and Food Science, University College Dublin, Belfield, Ireland University College Dublin, Dublin, Republic of Ireland.

Aim: Proteomics has the potential to enhance early identification of beta-cell dysfunction, in conjunction with monitoring the various stages of type 2 diabetes onset. The most routine method of assessing pancreatic beta-cell function is an oral glucose tolerance test, however this method is time consuming and carries a participant burden. The objectives of this research were to identify protein signatures and pathways related to pancreatic beta-cell function in fasting blood samples.

Methods: Beta-cell function measures were calculated for MECHE study participants who completed an oral glucose tolerance test and had proteomic data (n = 100). Information on 1,129 protein levels was obtained using the SOMAscan assay. Receiver operating characteristic curves were used to assess discriminatory ability of proteins of interest. Subsequent in vitro experiments were performed using the BRIN-BD11 pancreatic beta-cell line. Replication of findings were achieved in a second human cohort where possible.

Results: Twenty-two proteins measured by aptamer technology were significantly associated with beta-cell function/HOMA-IR while 17 proteins were significantly associated with the disposition index (p ≤ 0.01). Receiver operator characteristic curves determined the protein panels to have excellent discrimination between low and high beta-cell function. Linear regression analysis determined that beta-endorphin and IL-17F have strong associations with beta-cell function/HOMA-IR, β = 0.039 (p = 0.005) and β = -0.027 (p = 0.013) respectively. Calcineurin and CRTAM were strongly associated with the disposition index (β = 0.005 and β = 0.005 respectively, p = 0.012). In vitro experiments confirmed that IL-17F modulated insulin secretion in the BRIN-BD11 cell line, with the lower concentration of 10 ng/mL significantly increasing glucose stimulated insulin secretion (p = 0.043).

Conclusions: Early detection of compromised beta-cell function could allow for implementation of nutritional and lifestyle interventions before progression to type 2 diabetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202727PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117012PMC
February 2019

A computationally driven analysis of the polyphenol-protein interactome.

Sci Rep 2018 02 2;8(1):2232. Epub 2018 Feb 2.

Nestle Institute of Health Sciences, Lausanne, Switzerland.

Polyphenol-rich foods are part of many nutritional interventions aimed at improving health and preventing cardiometabolic diseases (CMDs). Polyphenols have oxidative, inflammatory, and/or metabolic effects. Research into the chemistry and biology of polyphenol bioactives is prolific but knowledge of their molecular interactions with proteins is limited. We mined public data to (i) identify proteins that interact with or metabolize polyphenols, (ii) mapped these proteins to pathways and networks, and (iii) annotated functions enriched within the resulting polyphenol-protein interactome. A total of 1,395 polyphenols and their metabolites were retrieved (using Phenol-Explorer and Dictionary of Natural Products) of which 369 polyphenols interacted with 5,699 unique proteins in 11,987 interactions as annotated in STITCH, Pathway Commons, and BindingDB. Pathway enrichment analysis using the KEGG repository identified a broad coverage of significant pathways of low specificity to particular polyphenol (sub)classes. When compared to drugs or micronutrients, polyphenols have pleiotropic effects across many biological processes related to metabolism and CMDs. These systems-wide effects were also found in the protein interactome of the polyphenol-rich citrus fruits, used as a case study. In sum, these findings provide a knowledgebase for identifying polyphenol classes (and polyphenol-rich foods) that individually or in combination influence metabolism.
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http://dx.doi.org/10.1038/s41598-018-20625-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797150PMC
February 2018

Validation of the Brazilian Healthy Eating Index-Revised Using Biomarkers in Children and Adolescents.

Nutrients 2018 Jan 30;10(2). Epub 2018 Jan 30.

Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Bandeirantes Avenue, 3900, Ribeirão Preto 14049-900, Brazil.

The Brazilian Healthy Eating Index-Revised (BHEI-R) can be used to determine overall dietary patterns. We assessed the BHEI-R scores in children and adolescents, aged from 9 to 13 years old, and associated its component scores with biomarkers of health and dietary exposure. Three 24-h recalls were used to generate BHEI-R. Biomarkers were analyzed in plasma and red blood cells. Correlation tests, agreement, and covariance analyses were used to associate BHEI-R components with biomarkers. Data from 167 subjects were used. The strongest correlations were between fruits, vegetables and legumes with omega-6 and omega-3 fatty acids, and β-carotene intakes. Milk and dairy correlated with plasma retinol and pyridoxine. All components rich in vegetable and animal protein sources correlated with plasma creatine. Total BHEI-R scores were positively associated with intakes of omega-6, omega-3, fiber and vitamin C, and inversely associated with energy and saturated fat intakes of individuals. Plasma β-carotene and riboflavin biomarkers were positively associated with total BHEI-R. An inadequate food consumption pattern was captured by both biomarkers of health and dietary exposure. BHEI-R was validated for the above dietary components and can be associated with metabolomics and nutritional epidemiological data in future pediatric studies.
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http://dx.doi.org/10.3390/nu10020154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852730PMC
January 2018

Clinical and Vitamin Response to a Short-Term Multi-Micronutrient Intervention in Brazilian Children and Teens: From Population Data to Interindividual Responses.

Mol Nutr Food Res 2018 03 22;62(6):e1700613. Epub 2018 Feb 22.

School of Pharmaceutical Science of Ribeirao Preto, University of São Paulo, Ribeirao Preto, Brazil.

Scope: Micronutrients are in small amounts in foods, act in concert, and require variable amounts of time to see changes in health and risk for disease. These first principles are incorporated into an intervention study designed to develop new experimental strategies for setting target recommendations for food bioactives for populations and individuals.

Methods And Results: A 6-week multivitamin/mineral intervention is conducted in 9-13 year olds. Participants (136) are (i) their own control (n-of-1); (ii) monitored for compliance; (iii) measured for 36 circulating vitamin forms, 30 clinical, anthropometric, and food intake parameters at baseline, post intervention, and following a 6-week washout; and (iv) had their ancestry accounted for as modifier of vitamin baseline or response. The same intervention is repeated the following year (135 participants). Most vitamins respond positively and many clinical parameters change in directions consistent with improved metabolic health to the intervention. Baseline levels of any metabolite predict its own response to the intervention. Elastic net penalized regression models are identified, and significantly predict response to intervention on the basis of multiple vitamin/clinical baseline measures.

Conclusions: The study design, computational methods, and results are a step toward developing recommendations for optimizing vitamin levels and health parameters for individuals.
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http://dx.doi.org/10.1002/mnfr.201700613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6120145PMC
March 2018

Proposed guidelines to evaluate scientific validity and evidence for genotype-based dietary advice.

Genes Nutr 2017 15;12:35. Epub 2017 Dec 15.

Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre + (MUMC+), Maastricht, The Netherlands.

Nutrigenetic research examines the effects of inter-individual differences in genotype on responses to nutrients and other food components, in the context of health and of nutrient requirements. A practical application of nutrigenetics is the use of personal genetic information to guide recommendations for dietary choices that are more efficacious at the individual or genetic subgroup level relative to generic dietary advice. Nutrigenetics is unregulated, with no defined standards, beyond some commercially adopted codes of practice. Only a few official nutrition-related professional bodies have embraced the subject, and, consequently, there is a lack of educational resources or guidance for implementation of the outcomes of nutrigenetic research. To avoid misuse and to protect the public, personalised nutrigenetic advice and information should be based on clear evidence of validity grounded in a careful and defensible interpretation of outcomes from nutrigenetic research studies. Evidence requirements are clearly stated and assessed within the context of state-of-the-art 'evidence-based nutrition'. We have developed and present here a draft framework that can be used to assess the strength of the evidence for scientific validity of nutrigenetic knowledge and whether 'actionable'. In addition, we propose that this framework be used as the basis for developing transparent and scientifically sound advice to the public based on nutrigenetic tests. We feel that although this area is still in its infancy, minimal guidelines are required. Though these guidelines are based on semi-quantitative data, they should stimulate debate on their utility. This framework will be revised biennially, as knowledge on the subject increases.
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http://dx.doi.org/10.1186/s12263-017-0584-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732517PMC
December 2017

Metabolic Differences between Dogs of Different Body Sizes.

J Nutr Metab 2017 26;2017:4535710. Epub 2017 Oct 26.

Nestlé Institute of Health Sciences, Lausanne, Switzerland.

Introduction: The domesticated dog, , has been selectively bred to produce extreme diversity in phenotype and genotype. Dogs have an immense diversity in weight and height. Specific differences in metabolism have not been characterized in small dogs as compared to larger dogs.

Objectives: This study aims to identify metabolic, clinical, and microbiota differences between small and larger dogs.

Methods: Gas chromatography/mass spectrometry, liquid chromatography/tandem mass spectrometry, clinical chemistry analysis, dual-energy X-ray absorptiometry, and 16S pyrosequencing were used to characterize blood metabolic, clinical, and fecal microbiome systems, respectively. Eighty-three canines from seven different breeds, fed the same kibble diet for 5 weeks, were used in the study.

Results: 449 metabolites, 16 clinical parameters, and 6 bacteria (at the genus level) were significantly different between small and larger dogs. Hierarchical clustering of the metabolites yielded 8 modules associated with small dog size.

Conclusion: Small dogs had a lower antioxidant status and differences in circulating amino acids. Some of the amino acid differences could be attributed to differences in microflora. Additionally, analysis of small dog metabolites and clinical parameters reflected a network which strongly associates with kidney function.
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http://dx.doi.org/10.1155/2017/4535710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684564PMC
October 2017

A 48-Hour Vegan Diet Challenge in Healthy Women and Men Induces a BRANCH-Chain Amino Acid Related, Health Associated, Metabolic Signature.

Mol Nutr Food Res 2018 02 28;62(3). Epub 2017 Dec 28.

Nestle Institute of Health Sciences (NIHS), Lausanne, Switzerland.

Scope: Research is limited on diet challenges to improve health. A short-term, vegan protein diet regimen nutritionally balanced in macronutrient composition compared to an omnivorous diet is hypothesized to improve metabolic measurements of blood sugar regulation, blood lipids, and amino acid metabolism.

Methods And Results: This randomized, cross-over, controlled vegan versus animal diet challenge is conducted on 21 (11 female,10 male) healthy participants. Fasting plasma is measured during a 3 d diet intervention for clinical biochemistry and metabonomics. Intervention diet plans meet individual caloric needs. Meals are provided and supervised. Diet compliance is monitored.

Conclusions: The vegan diet lowers triglycerides, insulin and homeostatic model assessment (HOMA-IR), bile acids, elevated magnesium levels, and changed branched-chain amino acids (BCAAs) metabolism (p < 0.05), potentiating insulin and blood sugar control after 48 h. Cholesterol control improves significantly in the vegan versus omnivorous diets. Plasma amino acid and magnesium concentrations positively correlate with dietary amino acids. Polyunsaturated fatty acids and dietary fiber inversely correlate with insulin, HOMA-IR, and triglycerides. Nutritional biochemistries, BCAAs, insulin, and HOMA-IR are impacted by sexual dimorphism. A health-promoting, BCAA-associated metabolic signature is produced from a short-term, healthy, controlled, vegan diet challenge when compared with a healthy, controlled, omnivorous diet.
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http://dx.doi.org/10.1002/mnfr.201700703DOI Listing
February 2018

Ancestors' dietary patterns and environments could drive positive selection in genes involved in micronutrient metabolism-the case of cofactor transporters.

Genes Nutr 2017 4;12:28. Epub 2017 Oct 4.

The Microsoft Research, University of Trento Centre for Computational Systems Biology (COSBI), piazza Manifattura 1, 38068 Rovereto, TN Italy.

Background: During evolution, humans colonized different ecological niches and adopted a variety of subsistence strategies that gave rise to diverse selective pressures acting across the genome. Environmentally induced selection of vitamin, mineral, or other cofactor transporters could influence micronutrient-requiring molecular reactions and contribute to inter-individual variability in response to foods and nutritional interventions.

Methods: A comprehensive list of genes coding for transporters of cofactors or their precursors was built using data mining procedures from the HGDP dataset and then explored to detect evidence of positive genetic selection. This dataset was chosen since it comprises several genetically diverse worldwide populations whom ancestries have evolved in different environments and thus lived following various nutritional habits and lifestyles.

Results: We identified 312 cofactor transporter (CT) genes involved in between-cell or sub-cellular compartment distribution of 28 cofactors derived from dietary intake. Twenty-four SNPs distributed across 14 CT genes separated populations into continental and intra-continental groups such as African hunter-gatherers and farmers, and between Native American sub-populations. Notably, four SNPs were located in with one being a known eQTL of the NCKX3 protein.

Conclusions: These findings could support the importance of considering individual's genetic makeup along with their metabolic profile when tailoring personalized dietary interventions for optimizing health.
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http://dx.doi.org/10.1186/s12263-017-0579-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628472PMC
October 2017

Sexual Dimorphism, Age, and Fat Mass Are Key Phenotypic Drivers of Proteomic Signatures.

J Proteome Res 2017 11 4;16(11):4122-4133. Epub 2017 Oct 4.

Nestlé Institute of Health Sciences , 1015 Lausanne, Switzerland.

Validated protein biomarkers are needed for assessing health trajectories, predicting and subclassifying disease, and optimizing diagnostic and therapeutic clinical decision-making. The sensitivity, specificity, accuracy, and precision of single or combinations of protein biomarkers may be altered by differences in physiological states limiting the ability to translate research results to clinically useful diagnostic tests. Aptamer based affinity assays were used to test whether low abundant serum proteins differed based on age, sex, and fat mass in a healthy population of 94 males and 102 females from the MECHE cohort. The findings were replicated in 217 healthy male and 377 healthy female participants in the DiOGenes consortium. Of the 1129 proteins in the panel, 141, 51, and 112 proteins (adjusted p < 0.1) were identified in the MECHE cohort and significantly replicated in DiOGenes for sexual dimorphism, age, and fat mass, respectively. Pathway analysis classified a subset of proteins from the 3 phenotypes to the complement and coagulation cascades pathways and to immune and coagulation processes. These results demonstrated that specific proteins were statistically associated with dichotomous (male vs female) and continuous phenotypes (age, fat mass), which may influence the identification and use of biomarkers of clinical utility for health diagnosis and therapeutic strategies.
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http://dx.doi.org/10.1021/acs.jproteome.7b00501DOI Listing
November 2017

Propelling the paradigm shift from reductionism to systems nutrition.

Genes Nutr 2017 25;12. Epub 2017 Jan 25.

CREA-NUT, Food & Nutrition Research Centre, Rome, Italy.

The complex physiology of living organisms represents a challenge for mechanistic understanding of the action of dietary bioactives in the human body and of their possible role in health and disease. Animal, cell, and microbial models have been extensively used to address questions that could not be pursued experimentally in humans, posing an additional level of complexity in translation of the results to healthy and diseased metabolism. The past few decades have witnessed a surge in development of increasingly sensitive molecular techniques and bioinformatic tools for storing, managing, and analyzing increasingly large datasets. Application of such powerful means to molecular nutrition research led to a major leap in study designs and experimental approaches yielding experimental data connecting dietary components to human health. Scientific journals bear major responsibilities in the advancement of science. As primary actors of dissemination to the scientific community, journals can impose rigid criteria for publishing only sound, reliable, and reproducible data. Journal policies are meant to guide potential authors to adopt the most updated standardization guidelines and shared best practices. Such policies evolve in parallel with the evolution of novel approaches and emerging challenges and therefore require constant updating. We highlight in this manuscript the major scientific issues that led to formulating new, updated journal policies for , a journal which targets the growing field of nutritional systems biology interfacing personalized nutrition and preventive medicine, with the ultimate goal of promoting health and preventing or treating disease. We focus here on relevant issues requiring standardization in nutrition research. We also introduce new sections on human genetic variation and nutritional bioinformatics which follow the evolution of nutritional science into the twenty-first century.
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http://dx.doi.org/10.1186/s12263-016-0549-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5264346PMC
January 2017

High-throughput method for the quantitation of metabolites and co-factors from homocysteine-methionine cycle for nutritional status assessment.

Bioanalysis 2016 Sep;8(18):1937-49

Nestlé Institute of Health Sciences SA, Campus EPFL, Innovation Quarter, CH-1015 Lausanne, Switzerland.

Aim: There is increasing interest in the profiling and quantitation of methionine pathway metabolites for health management research. Currently, several analytical approaches are required to cover metabolites and co-factors.

Results: We report the development and the validation of a method for the simultaneous detection and quantitation of 13 metabolites in red blood cells. The method, validated in a cohort of healthy human volunteers, shows a high level of accuracy and reproducibility.

Conclusion: This high-throughput protocol provides a robust coverage of central metabolites and co-factors in one single analysis and in a high-throughput fashion. In large-scale clinical settings, the use of such an approach will significantly advance the field of nutritional research in health and disease.
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http://dx.doi.org/10.4155/bio-2016-0112DOI Listing
September 2016

Systems view of adipogenesis via novel omics-driven and tissue-specific activity scoring of network functional modules.

Sci Rep 2016 07 7;6:28851. Epub 2016 Jul 7.

The Microsoft Research - University of Trento Centre for Computational and Systems Biology, Piazza Manifattura 1, 38068 Rovereto, Italy.

The investigation of the complex processes involved in cellular differentiation must be based on unbiased, high throughput data processing methods to identify relevant biological pathways. A number of bioinformatics tools are available that can generate lists of pathways ranked by statistical significance (i.e. by p-value), while ideally it would be desirable to functionally score the pathways relative to each other or to other interacting parts of the system or process. We describe a new computational method (Network Activity Score Finder - NASFinder) to identify tissue-specific, omics-determined sub-networks and the connections with their upstream regulator receptors to obtain a systems view of the differentiation of human adipocytes. Adipogenesis of human SBGS pre-adipocyte cells in vitro was monitored with a transcriptomic data set comprising six time points (0, 6, 48, 96, 192, 384 hours). To elucidate the mechanisms of adipogenesis, NASFinder was used to perform time-point analysis by comparing each time point against the control (0 h) and time-lapse analysis by comparing each time point with the previous one. NASFinder identified the coordinated activity of seemingly unrelated processes between each comparison, providing the first systems view of adipogenesis in culture. NASFinder has been implemented into a web-based, freely available resource associated with novel, easy to read visualization of omics data sets and network modules.
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http://dx.doi.org/10.1038/srep28851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4935943PMC
July 2016

A network analysis of cofactor-protein interactions for analyzing associations between human nutrition and diseases.

Sci Rep 2016 Jan 18;6:19633. Epub 2016 Jan 18.

The Microsoft Research - University of Trento Centre for Computational and Systems Biology (COSBI), Rovereto (TN), Italy.

The involvement of vitamins and other micronutrients in intermediary metabolism was elucidated in the mid 1900's at the level of individual biochemical reactions. Biochemical pathways remain the foundational knowledgebase for understanding how micronutrient adequacy modulates health in all life stages. Current daily recommended intakes were usually established on the basis of the association of a single nutrient to a single, most sensitive adverse effect and thus neglect interdependent and pleiotropic effects of micronutrients on biological systems. Hence, the understanding of the impact of overt or sub-clinical nutrient deficiencies on biological processes remains incomplete. Developing a more complete view of the role of micronutrients and their metabolic products in protein-mediated reactions is of importance. We thus integrated and represented cofactor-protein interaction data from multiple and diverse sources into a multi-layer network representation that links cofactors, cofactor-interacting proteins, biological processes, and diseases. Network representation of this information is a key feature of the present analysis and enables the integration of data from individual biochemical reactions and protein-protein interactions into a systems view, which may guide strategies for targeted nutritional interventions aimed at improving health and preventing diseases.
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http://dx.doi.org/10.1038/srep19633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4726080PMC
January 2016

Systems-Level Nutrition Approaches to Define Phenotypes Resulting from Complex Gene-Environment Interactions.

Authors:
Jim Kaput

Nestle Nutr Inst Workshop Ser 2016 14;84:1-13. Epub 2016 Jan 14.

High-throughput metabolomic, proteomic, and genomic technologies have delivered 21st-century data showing that humans cannot be randomized into groups: individuals are genetically and biochemically distinct. Gene-environment interactions caused by unique dietary and lifestyle factors contribute to the heterogeneity in physiologies observed in human studies. The risk factors determined for populations (i.e. the population-attributable risk) cannot be applied to the individual. Developing individual risk/benefit factors in light of the genetic diversity of human populations, the complexity of foods, culture and lifestyle, and the variety in metabolic processes that lead to health or disease are significant challenges for personalizing dietary advice for healthy or diseased individuals.
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http://dx.doi.org/10.1159/000436947DOI Listing
October 2016

Human nutrition, environment, and health.

Genes Nutr 2015 Sep;10(5):489

Nestlé Institute of Health Sciences, Lausanne, Switzerland,

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http://dx.doi.org/10.1007/s12263-015-0489-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549339PMC
September 2015

Fructose Alters Intermediary Metabolism of Glucose in Human Adipocytes and Diverts Glucose to Serine Oxidation in the One-Carbon Cycle Energy Producing Pathway.

Metabolites 2015 Jun 16;5(2):364-85. Epub 2015 Jun 16.

Current Address: Nestle Institute of Health Sciences, 1015 Lausanne, Switzerland.

Increased consumption of sugar and fructose as sweeteners has resulted in the utilization of fructose as an alternative metabolic fuel that may compete with glucose and alter its metabolism. To explore this, human Simpson-Golabi-Behmel Syndrome (SGBS) preadipocytes were differentiated to adipocytes in the presence of 0, 1, 2.5, 5 or 10 mM of fructose added to a medium containing 5 mM of glucose representing the normal blood glucose concentration. Targeted tracer [1,2-13C2]-d-glucose fate association approach was employed to examine the influence of fructose on the intermediary metabolism of glucose. Increasing concentrations of fructose robustly increased the oxidation of [1,2-13C2]-d-glucose to 13CO2 (p < 0.000001). However, glucose-derived 13CO2 negatively correlated with 13C labeled glutamate, 13C palmitate, and M+1 labeled lactate. These are strong markers of limited tricarboxylic acid (TCA) cycle, fatty acid synthesis, pentose cycle fluxes, substrate turnover and NAD+/NADP+ or ATP production from glucose via complete oxidation, indicating diminished mitochondrial energy metabolism. Contrarily, a positive correlation was observed between glucose-derived 13CO2 formed and 13C oleate and doses of fructose which indicate the elongation and desaturation of palmitate to oleate for storage. Collectively, these results suggest that fructose preferentially drives glucose through serine oxidation glycine cleavage (SOGC pathway) one-carbon cycle for NAD+/NADP+ production that is utilized in fructose-induced lipogenesis and storage in adipocytes.
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http://dx.doi.org/10.3390/metabo5020364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4495377PMC
June 2015

The genomics of micronutrient requirements.

Genes Nutr 2015 Jul 19;10(4):466. Epub 2015 May 19.

Department of Pediatrics, Faculty of Medicine, Nutrition and Metabolism, University of São Paulo, Bandeirantes Avenue, HCFMRP Campus USP, 3900, Ribeirão Preto, SP, 14049-900, Brazil,

Healthy nutrition is accepted as a cornerstone of public health strategies for reducing the risk of noncommunicable conditions such as obesity, cardiovascular disease, and related morbidities. However, many research studies continue to focus on single or at most a few factors that may elicit a metabolic effect. These reductionist approaches resulted in: (1) exaggerated claims for nutrition as a cure or prevention of disease; (2) the wide use of empirically based dietary regimens, as if one fits all; and (3) frequent disappointment of consumers, patients, and healthcare providers about the real impact nutrition can make on medicine and health. Multiple factors including environment, host and microbiome genetics, social context, the chemical form of the nutrient, its (bio)availability, and chemical and metabolic interactions among nutrients all interact to result in nutrient requirement and in health outcomes. Advances in laboratory methodologies, especially in analytical and separation techniques, are making the chemical dissection of foods and their availability in physiological tissues possible in an unprecedented manner. These omics technologies have opened opportunities for extending knowledge of micronutrients and of their metabolic and endocrine roles. While these technologies are crucial, more holistic approaches to the analysis of physiology and environment, novel experimental designs, and more sophisticated computational methods are needed to advance our understanding of how nutrition influences health of individuals.
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http://dx.doi.org/10.1007/s12263-015-0466-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4434349PMC
July 2015
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