Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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Comparative ecologic relationships of saturated fat, sucrose, food groups, and a Mediterranean food pattern score to 50-year coronary heart disease mortality rates among 16 cohorts of the Seven Countries Study
Kromhout, Daan ; Menotti, Alessandro ; Alberti-Fidanza, Adalberta ; Puddu, Paolo Emilio ; Hollman, Peter ; Kafatos, Anthony ; Tolonen, Hanna ; Adachi, Hisashi ; Jacobs, David R. - \ 2018
European Journal of Clinical Nutrition 72 (2018). - ISSN 0954-3007 - p. 1103 - 1110.

Background/objectives: We studied the ecologic relationships of food groups, macronutrients, eating patterns, and an a priori food pattern score (Mediterranean Adequacy Index: MAI) with long-term CHD mortality rates in the Seven Countries Study. Subjects/methods: Sixteen cohorts (12,763 men aged 40–59 years) were enrolled in the 1960s in seven countries (US, Finland, The Netherlands, Italy, Greece, former Yugoslavia: Croatia/Serbia, Japan). Dietary surveys were carried out at baseline and only in a subsample of each cohort. The average food consumption of each cohort was chemically analyzed for individual fatty acids and carbohydrates. Results: Ecologic correlations of diet were computed across cohorts for 50-year CHD mortality rates; 97% of men had died in cohorts with 50-year follow-up. CHD death rates ranged 6.7-fold among cohorts. At baseline, hard fat was greatest in northern Europe, olive oil in Greece, meat in the US, sweet products in northern Europe and the US, and fish in Japan. The MAI was high in Mediterranean and Japanese cohorts. The 50-year CHD mortality rates of the cohorts were closely positively ecologically correlated (r = 0.68–0.92) with average consumption of hard fat, sweet products, animal foods, saturated fat, and sucrose, but not with naturally occurring sugars. Vegetable foods, starch, and the a priori pattern MAI were inversely correlated (r = −0.59 to −0.91) with CHD mortality rates. Conclusions: Long-term CHD mortality rates had statistically significant ecologic correlations with several aspects of diet consumed in the 1960s, the traditional Mediterranean and Japanese patterns being rich in vegetable foods, and low in sweet products and animal foods.

Validating fatty acid intake as estimated by an FFQ : how does the 24 h recall perform as reference method compared with the duplicate portion?
Trijsburg, Laura ; Vries, Jeanne H.M. de; Hollman, Peter C.H. ; Hulshof, Paul J.M. ; ’t Veer, Pieter van; Boshuizen, Hendriek C. ; Geelen, Anouk - \ 2018
Public Health Nutrition 21 (2018)14. - ISSN 1368-9800 - p. 2568 - 2574.
Biomarker - Dietary assessment - Duplicate portion - Fatty acids - Measurement errors - Validity

Objective: To compare the performance of the commonly used 24 h recall (24hR) with the more distinct duplicate portion (DP) as reference method for validation of fatty acid intake estimated with an FFQ. Design: Intakes of SFA, MUFA, n-3 fatty acids and linoleic acid (LA) were estimated by chemical analysis of two DP and by on average five 24hR and two FFQ. Plasma n-3 fatty acids and LA were used to objectively compare ranking of individuals based on DP and 24hR. Multivariate measurement error models were used to estimate validity coefficients and attenuation factors for the FFQ with the DP and 24hR as reference methods. Setting: Wageningen, the Netherlands. Subjects: Ninety-two men and 106 women (aged 20–70 years). Results: Validity coefficients for the fatty acid estimates by the FFQ tended to be lower when using the DP as reference method compared with the 24hR. Attenuation factors for the FFQ tended to be slightly higher based on the DP than those based on the 24hR as reference method. Furthermore, when using plasma fatty acids as reference, the DP showed comparable to slightly better ranking of participants according to their intake of n-3 fatty acids (0·33) and n-3:LA (0·34) than the 24hR (0·22 and 0·24, respectively). Conclusions: The 24hR gives only slightly different results compared with the distinctive but less feasible DP, therefore use of the 24hR seems appropriate as the reference method for FFQ validation of fatty acid intake.

Pure epicatechin and inflammatory gene expression profiles in circulating immune cells in (pre) hypertensive adults; a randomized double-blind, placebo-controlled, crossover trial
Esser, D. ; Dower, J.I. ; Matualatupauw, J.C. ; Geleijnse, J.M. ; Kromhout, D. ; Hollman, P.C.H. ; Afman, L.A. - \ 2018
Homo sapiens - GSE84453 - PRJNA329219
Introduction: There is increasing evidence that consumption of cocoa products have a beneficial effect on cardio-metabolic health, but the underlying mechanisms remain unclear. Cocoa contains a complex mixture of flavan-3-ols. Epicatechin, a major monomeric flavan-3-ol, is considered to contribute to the cardio-protective effects of cocoa. We investigated effects of pure epicatechin supplementation on whole genome gene expression profiles of circulating immune cells. Methods: In a randomized, double blind, placebo-controlled cross-over trial, 37 (pre)hypertensive (40-80y) subjects received two 4-week interventions; epicatechin (100mg/day) or placebo with a wash-out period of 4-week between both interventions. Whole genome gene expression profiles of peripheral blood mononuclear cells were determined before and after both interventions. Results: After epicatechin supplementation 1180 genes were significantly regulated, of which 234 were also significantly regulated compared to placebo. Epicatechin supplementation up-regulated gene sets involved in transcription/translation and tubulin folding and down-regulated gene sets involved in inflammation. Only a few genes within these regulated gene sets were actually significantly changed upon epicatechin supplementation. Upstream regulators that were shown to be inhibited were classified as cytokine or inflammatory type molecules. Conclusion: Pure epicatechin supplementation modestly reduced gene expression related to inflammation signalling routes in circulating immune cells. These routes are known to play a role in cardiovascular health.
Pure flavonoid epicatechin and whole genome gene expression profiles in circulating immune cells in adults with elevated blood pressure: A randomised double-blind, placebo-controlled, crossover trial
Esser, Diederik ; Geleijnse, Johanna M. ; Matualatupauw, Juri C. ; Dower, James I. ; Kromhout, Daan ; Hollman, Peter C.H. ; Afman, Lydia A. - \ 2018
PLoS One 13 (2018)4. - ISSN 1932-6203 - 15 p.
Cocoa consumption has beneficial cardiometabolic effects, but underlying mechanisms remain unclear. Epicatechin, the cocoa major monomeric flavan-3-ol, is considered to contribute to these cardio-protective effects. We investigated effects of pure epicatechin supplementation on gene expression profiles of immune cells in humans. In a double blind, placebo-controlled cross-over trial, 32 (pre)hypertensive subjects aged 30 to 80, received two 4-week interventions, i.e. epicatechin (100mg/day) or placebo with a 4-week wash-out between interventions. Gene expression profiles of peripheral blood mononuclear cells were determined before and after both interventions. Epicatechin regulated 1180 genes, of which 234 differed from placebo. Epicatechin upregulated gene sets involved in transcription and tubulin folding and downregulated gene sets involved in inflammation, PPAR signalling and adipogenesis. Several negatively enriched genes within these gene sets were involved in insulin signalling. Most inhibited upstream regulators within the epicatechin intervention were cytokines or involved in inflammation. No upstream regulators were identified compared to placebo. Epicatechin, a cocoa flavan-3-ol, reduces gene expression involved in inflammation, PPAR-signalling and adipogenesis in immune cells. Effects were mild but our findings increase our understanding and provide new leads on how epicatechin rich products like cocoa may affect immune cells and exert cardiometabolic protective effects.
Baseline fatty acids, food groups, a diet score and 50-year all-cause mortality rates. An ecological analysis of the Seven Countries Study
Menotti, Alessandro ; Kromhout, Daan ; Puddu, Paolo Emilio ; Alberti-Fidanza, Adalberta ; Hollman, Peter ; Kafatos, Anthony ; Tolonen, Hanna ; Adachi, Hisashi ; Jacobs, David R. - \ 2017
Annals of medicine 49 (2017)8. - ISSN 0785-3890 - p. 718 - 727.
50-year follow-up - all-cause mortality - fatty acids - Seven Countries Study - socio-economic status
Objectives: This analysis deals with the ecologic relationships of dietary fatty acids, food groups and the Mediterranean Adequacy Index (MAI, derived from 15 food groups) with 50-year all-cause mortality rates in 16 cohorts of the Seven Countries Study. Material and methods: A dietary survey was conducted at baseline in cohorts subsamples including chemical analysis of food samples representing average consumptions. Ecologic correlations of dietary variables were computed across cohorts with 50-year all-cause mortality rates, where 97% of men had died. Results: There was a 12-year average age at death population difference between extreme cohorts. In the 1960s the average population intake of saturated (S) and trans (T) fatty acids and hard fats was high in the northern European cohorts while monounsaturated (M), polyunsaturated (P) fatty acids and vegetable oils were high in the Mediterranean areas and total fat was low in Japan. The 50-year all-cause mortality rates correlated (r= −0.51 to −0.64) ecologically inversely with the ratios M/S, (M + P)/(S + T) and vegetable foods and the ratio hard fats/vegetable oils. Adjustment for high socio-economic status strengthened (r= −0.62 to −0.77) these associations including MAI diet score. Conclusion: The protective fatty acids and vegetable oils are indicators of the low risk traditional Mediterranean style diets.KEY MESSAGESWe aimed at studying the ecologic relationships of dietary fatty acids, food groups and the Mediterranean Adequacy Index (MAI, derived from 15 food groups) with 50-year all-cause mortality rates in the Seven Countries Study.The 50-year all-cause mortality rates correlated (r = −0.51 to −0.64) ecologically inversely with the ratios M/S [monounsaturated (M) + polyunsaturated (P)]/[saturated (S) + trans (T)] fatty acids and vegetable foods and the ratio hard fats/vegetable oils. After adjustment for high socio-economic status, associations with the ratios strengthened (r = −0.62 to −0.77) including also the MAI diet score.The protective fatty acids and vegetable oils are indicators of the low risk traditional Mediterranean style diets.
BMI was found to be a consistent determinant related to misreporting of energy, protein and potassium intake using self-report and duplicate portion methods
Trijsburg, L.E. ; Geelen, M.M.E.E. ; Hollman, P.C.H. ; Hulshof, P.J.M. ; Feskens, E.J.M. ; Veer, P. van 't; Boshuizen, H.C. ; Vries, J.H.M. de - \ 2017
Public Health Nutrition 20 (2017)4. - ISSN 1368-9800 - p. 598 - 607.

As misreporting, mostly under-reporting, of dietary intake is a generally known problem in nutritional research, we aimed to analyse the association between selected determinants and the extent of misreporting by the duplicate portion method (DP), 24 h recall (24hR) and FFQ by linear regression analysis using the biomarker values as unbiased estimates.

For each individual, two DP, two 24hR, two FFQ and two 24 h urinary biomarkers were collected within 1·5 years. Also, for sixty-nine individuals one or two doubly labelled water measurements were obtained. The associations of basic determinants (BMI, gender, age and level of education) with misreporting of energy, protein and K intake of the DP, 24hR and FFQ were evaluated using linear regression analysis. Additionally, associations between other determinants, such as physical activity and smoking habits, and misreporting were investigated.

The Netherlands.

One hundred and ninety-seven individuals aged 20–70 years.

Higher BMI was associated with under-reporting of dietary intake assessed by the different dietary assessment methods for energy, protein and K, except for K by DP. Men tended to under-report protein by the DP, FFQ and 24hR, and persons of older age under-reported K but only by the 24hR and FFQ. When adjusted for the basic determinants, the other determinants did not show a consistent association with misreporting of energy or nutrients and by the different dietary assessment methods.

As BMI was the only consistent determinant of misreporting, we conclude that BMI should always be taken into account when assessing and correcting dietary intake.
Variability in quercetin action
Schothorst, E.M. van; Bunschoten, J.E. ; Stelt, I. van der; Hollman, P.C.H. ; Rietjens, I.M.C.M. ; Keijer, J. - \ 2016
quercetin action
Does epicatechin contribute to the acute vascular function effects of dark chocolate? A randomized, crossover study
Dower, James I. ; Geleijnse, Marianne ; Kroon, Paul A. ; Philo, Mark ; Mensink, Marco ; Kromhout, Daan ; Hollman, Peter C.H. - \ 2016
Molecular Nutrition & Food Research 60 (2016)11. - ISSN 1613-4125 - p. 2379 - 2386.
Chocolate - Epicatechin - Flavan-3-ol - Randomized controlled trial - Vascular function

Scope: Cocoa, rich in flavan-3-ols, improves vascular function, but the contribution of specific flavan-3-ols is unknown. We compared the effects of pure epicatechin, a major cocoa flavan-3-ol, and chocolate. Methods and results: In a randomized crossover study, twenty healthy men (40-80 years) were supplemented with: (1) 70g dark chocolate (150 mg epicatechin) with placebo capsules; (2) pure epicatechin capsules (2 × 50 mg epicatechin) with 75g white chocolate; and (3) placebo capsules with 75 g white chocolate (0 mg epicatechin). Vascular function (flow-mediated dilation (FMD) and augmentation index (AIx)) were measured before and 2 hours after interventions. Epicatechin metabolites time-profiles were measured in blood to calculate the bioavailability. Pure epicatechin did not significantly improve FMD (+0.75%; p = 0.10) or AIx (-2.2%; p = 0.23) compared to placebo. Dark chocolate significantly improved FMD (+0.96%; p = 0.04) and AIx (-4.6%; p = 0.02). Differences in improvements in FMD (+ 0.21%; p = 0.65) or Aix (-2.4%; p = 0.20) between pure epicatechin and dark chocolate were not significant. The bioavailability of epicatechin did not differ between pure epicatechin and dark chocolate (p = 0.14). Conclusions: Despite differences in epicatechin dose, improvements in vascular function after pure epicatechin and chocolate were similar and the bioavailability did not differ, suggesting a role for epicatechin.

Dietary epicatechin intake and 25-year risk of cardiovascular mortality: the Zutphen Elderly Study
Dower, J.I. ; Geleijnse, J.M. ; Hollman, P.C.H. ; Soedamah-Muthu, S.S. ; Kromhout, D. - \ 2016
American Journal of Clinical Nutrition 104 (2016)1. - ISSN 0002-9165 - p. 58 - 64.
cardiovascular disease - cocoa - epicatechin - flavan-3-ols - tea
Background: Prospective cohort studies have shown that the consumption of cocoa and tea is associated with lower risk of cardiovascular diseases (CVDs), and cocoa and tea have been shown to improve CVD risk factors in randomized controlled trials. Cocoa and tea are major dietary sources of the flavan-3-ol epicatechin.

Objective: We investigated the associations of dietary epicatechin intake with 25-y CVD mortality in elderly Dutch men.

Design: We used data from the Zutphen Elderly Study, which was a prospective cohort study of 774 men aged 65–84 y in 1985. Epicatechin intake was estimated 4 times in 15 y with the use of the crosscheck dietary history method. Time-dependent Cox proportional hazards models were used to investigate repeated measures of epicatechin intake in relation to 25-y CVD mortality.

Results: Mean intake of epicatechin was 15.2 ± 7.7 mg/d, and the major dietary sources were tea (51%), apples (28%), and cocoa (7%). During 25 y of follow-up, 329 men died from CVD, 148 died from coronary heart disease (CHD), and 72 men died from stroke. Risk of CHD mortality was 38% lower in men in the top tertile of epicatechin intake than in men in the bottom tertile of epicatechin intake (HR: 0.62; 95% CI: 0.39, 0.98). Epicatechin intake was also significantly associated with 46% lower risk of CVD mortality in men with prevalent CVD (HR: 0.54; 95% CI: 0.31, 0.96) but not in men who were free of CVD.

Conclusions: We show, for the first time to our knowledge, that epicatechin intake is inversely related to CHD mortality in elderly men and to CVD mortality in prevalent cases of CVD. More studies are needed before conclusions can be drawn
A risk assessment-driven quantitative comparison of gene expression profiles in PBMCs and white adipose tissue of humans and rats after isoflavone supplementation
Velpen, V. van der; Veer, P. van 't; Islam, M.A. ; Braak, C.J.F. ter; Leeuwen, F.X.R. ; Afman, L.A. ; Hollman, P.C.H. ; Schouten, A. ; Geelen, M.M.E.E. - \ 2016
Food and Chemical Toxicology 95 (2016). - ISSN 0278-6915 - p. 203 - 210.
Risk assessment - Gene expression - Species and tissue differences - Quantitative evaluation - Isoflavones - Multivariate model
Quantitative insight into species differences in risk assessment is expected to reduce uncertainty and variability related to extrapolation from animals to humans. This paper explores quantification and comparison of gene expression data between tissues and species from intervention studies with isoflavones.

Gene expression data from peripheral blood mononuclear cells (PBMCs) and white adipose tissue (WAT) after 8wk isoflavone interventions in postmenopausal women and ovariectomized F344 rats were used. A multivariate model was applied to quantify gene expression effects, which showed 3–5-fold larger effect sizes in rats compared to humans. For estrogen responsive genes, a 5-fold greater effect size was found in rats than in humans. For these genes, intertissue correlations (r = 0.23 in humans, r = 0.22 in rats) and interspecies correlation in WAT (r = 0.31) were statistically significant. Effect sizes, intertissue and interspecies correlations for some groups of genes within energy metabolism, inflammation and cell cycle processes were significant, but weak.

Quantification of gene expression data reveals differences between rats and women in effect magnitude after isoflavone supplementation. For risk assessment, quantification of gene expression data and subsequent calculation of intertissue and interspecies correlations within biological pathways will further strengthen knowledge on comparability between tissues and species.
Dietary epicatechnin and quercetin in cardiovascular health and disease
Dower, J.I. - \ 2016
University. Promotor(en): Daan Kromhout; Marianne Geleijnse, co-promotor(en): Peter Hollman. - Wageningen : Wageningen University - ISBN 9789462577862 - 164 p.
cardiovascular disorders - cardiovascular diseases - epicatechin - quercetin - epidemiological surveys - genome analysis - chocolate - hart- en vaatstoornissen - hart- en vaatziekten - epicatechine - quercetine - epidemiologische onderzoeken - genoomanalyse - chocolade

Epidemiological studies showed that the consumption of flavonoid-rich foods such as cocoa and tea is associated with a lower risk of cardiovascular disease (CVD). Randomised controlled trials (RCTs) showed that cocoa and tea improved markers of cardiometabolic health including blood pressure, endothelial function, insulin resistance, arterial stiffness and inflammation.

Cocoa is particularly rich in the flavan-3-ol epicatechin and tea is the main dietary source of epicatechin and of the major flavonol quercetin. However, evidence on the individual roles of epicatechin and quercetin in the health effects of cocoa and tea is still scarce. Therefore, we estimated the strength of the association between epicatechin intake and CVD mortality in a prospective cohort study. Furthermore, we also investigated the effects of epicatechin and quercetin on markers of cardiometabolic health and gene expression, by means of two RCTs.

In Chapter 2, the association between epicatechin intake and CVD mortality was studied using data from the Zutphen Elderly Study, a cohort of 744 elderly Dutch men. During 25 years of follow-up, 329 men died from CVD and 148 from coronary heart disease (CHD). Results from this study showed that men in the highest tertile of epicatechin intake had a 38% lower risk of CHD mortality compared to men in the lowest tertile. For men with prevalent CVD, the risk of CVD mortality was 46% lower for men in the highest tertile of intake, compared to men in the lowest tertile. This is the first epidemiological study to have investigated the association between epicatechin intake and CVD mortality. Hence, more and larger cohort studies are required to confirm this association, possibly with a focus on populations with a high risk of CVD.

In Chapter 3, the chronic effects of pure epicatechin and quercetin on markers of cardiometabolic health were investigated by means of a RCT. Thirty-seven apparently healthy men and women aged 40–80 years consumed (-)-epicatechin (100 mg/d), quercetin-3-glucoside (160 mg/d), or placebo capsules for 4 weeks, in random order. Markers of cardiometabolic health were measured before and after each 4-week intervention. The results of this study showed that epicatechin improved insulin resistance and had a borderline significant effect on endothelial function. This suggests that epicatechin contributes to the cardioprotective effects of cocoa and tea, however, larger long-term RCTs are required to confirm these effects. Pure quercetin supplementation did not affect any of these markers of cardiometabolic health.

Using data from the same study, we investigated the effects of supplementation of pure epicatechin and quercetin on a comprehensive set of biomarkers of endothelial dysfunction and inflammation (Chapter 4). With the exception of sE-selectin (a biomarker of endothelial dysfunction), epicatechin supplementation did not beneficially influence any of the biomarkers, suggesting a lack of evidence for a role of epicatechin in inflammation. Quercetin also lowered sE-selectin as well as the inflammatory biomarker IL-1β and the overall z-score for inflammation. This suggests that quercetin may contribute to the cardioprotective effects of tea by reducing inflammation and possibly by improving endothelial function.

In the same study, the effects of pure epicatechin supplementation on whole genome gene expression profiles of circulating immune cells were also assessed (Chapter 5). Pure epicatechin supplementation modestly reduced gene expression related to inflammation signalling routes in circulating immune cells – routes which are known to play a role in cardiovascular health. However, there was no evidence that epicatechin affected pathways related to insulin resistance or endothelial function.

To directly compare the acute effects of pure epicatechin and epicatechin from dark chocolate on vascular function, we carried out an acute RCT in 20 apparently healthy men aged 40-80 years (Chapter 6). On three separate occasions, subjects consumed: 1) 70g dark chocolate (150 mg epicatechin) with two placebo capsules; 2) two pure epicatechin capsules (100 mg epicatechin) with 75g white chocolate and 3) two placebo capsules with 75g white chocolate (0 mg epicatechin). Endothelial function and arterial stiffness were measured before and two hours after each intervention. To determine epicatechin bioavailability, epicatechin metabolites were measured in blood samples taken at repeated intervals over a period of 8 hours. There was no significant difference in improvement in endothelial function or arterial stiffness between pure epicatechin and dark chocolate. There was also no difference in bioavailability of pure epicatechin and epicatechin from dark chocolate, when standardised per 100 mg of epicatechin. This suggests that epicatechin may contribute to the vascular effects of cocoa and that the bioavailability of pure epicatechin and epicatechin from dark chocolate is similar.

In the general discussion, the main findings of this thesis were first summarised. Methodological considerations related to cohort studies, such as the assessment of flavonoid intake and the possibility of residual confounding were also discussed. Issues related to the relevance of cardiometabolic markers in RCTs and the effect of cocoa flavan-3-ol bioavailability were addressed. Finally, suggestions for future research were put forward.

In conclusion, the results of this thesis suggest that epicatechin contributes to the cardioprotective effects of cocoa and tea. Epicatechin intake was inversely related to CHD mortality in elderly men, and to CVD mortality in men with prevalent CVD. The cardioprotective effects of epicatechin are likely mediated through improvements in insulin resistance and possibly endothelial function. In contrast, quercetin is unlikely to play a major role in the cardioprotective effects of tea. Results for quercetin from cohort studies are inconclusive, and based on the results of our chronic RCT, quercetin did not affect vascular function or insulin resistance, but may help to lower inflammation. Evidence of the role that individual flavonoids play in the aetiology of CVD is still limited. More studies with pure flavonoids are required to elucidate their role.

The 7th International Conference on Polyphenols and Health
Hollman, P.C.H. - \ 2016
Nutrition Bulletin 41 (2016)1. - ISSN 1471-9827 - p. 92 - 95.
Gene expression profiling in human precision cut liver slices in response to the FXR agonist obeticholic acid
IJssennagger, Noortje ; Janssen, A.W.F. ; Milona, Alexandra ; Ramos Pittol, J.M. ; Hollman, D.A.A. ; Mokry, Michal ; Betzel, Bark ; Berends, F.J. ; Janssen, I.M. ; Mil, S.W.C. van; Kersten, Sander - \ 2016
Journal of Hepatology (2016). - ISSN 0168-8278 - p. 1158 - 1166.
Farnesoid X receptor - Gene expression profiling - Human liver slices - Obeticholic acid

Background & Aims: The bile acid-activated farnesoid X receptor (FXR) is a nuclear receptor regulating bile acid, glucose and cholesterol homeostasis. Obeticholic acid (OCA), a promising drug for the treatment of non-alcoholic steatohepatitis (NASH) and type 2 diabetes, activates FXR. Mouse studies demonstrated that FXR activation by OCA alters hepatic expression of many genes. However, no data are available on the effects of OCA in the human liver. Here we generated gene expression profiles in human precision cut liver slices (hPCLS) after treatment with OCA. Methods: hPCLS were incubated with OCA for 24. h. Wild-type or FXR-/- mice received OCA or vehicle by oral gavage for 7. days. Results: Transcriptomic analysis showed that well-known FXR target genes, including NR0B2 (SHP), ABCB11 (BSEP), SLC51A (OSTα) and SLC51B (OSTβ), and ABCB4 (MDR3) are regulated by OCA in hPCLS. Ingenuity pathway analysis confirmed that 'FXR/RXR activation' is the most significantly changed pathway upon OCA treatment. Comparison of gene expression profiles in hPCLS and mouse livers identified 18 common potential FXR targets. ChIP-sequencing in mouse liver confirmed FXR binding to IR1 sequences of Akap13, Cgnl1, Dyrk3, Pdia5, Ppp1r3b and Tbx6. Conclusions: Our study shows that hPCLS respond to OCA treatment by upregulating well-known FXR target genes, demonstrating its suitability to study FXR-mediated gene regulation. We identified six novel bona-fide FXR target genes in both mouse and human liver. Finally, we discuss a possible explanation for changes in high or low density lipoprotein observed in NASH and primary biliary cholangitis patients treated with OCA based on the genomic expression profile in hPCLS.

Abstract P407: Epicatechin intake and markers of glucose and insulin metabolism: the Zutphen elderly study
Obura, M. ; Dower, J.I. ; Kromhout, D. ; Hollman, P.C.H. ; Geleijnse, J.M. ; Soedamah-Muthu, S.S. ; Goede, J. de - \ 2015
European Journal of Epidemiology 30 (2015)6. - ISSN 0393-2990 - p. 915 - 915.
epidemiology - diabetes
Background: Consumption of flavonoid-rich foods like cocoa and tea
is associated with a reduced risk of type 2 diabetes and improved
glycemic control. Cocoa and tea are both important dietary sources of
the flavonoid epicatechin. Our objective therefore was to examine
whether dietary epicatechin intake is associated with markers of
glucose and insulin metabolism.
Methods: We conducted a prospective study in 437 men from the
Zutphen Elderly Study aged 65–84 years at baseline (1985), free of
diabetes and cancer. Dietary epicatechin and other nutrients were
assessed at baseline using a validated cross-check dietary history
method. Glucose and insulin areas under the curve (AUC) were
determined in response to an oral glucose tolerance test (OGTT)
performed in 1990. Homeostasis model assessment of insulin resistance
(HOMA-IR) as well as Matsuda index were calculated from
fasting glucose (mmol/l) and insulin (mU/l) levels. Glycated hemoglobin
(HbA1c) was measured in 1993. Adjusted means and 95 %
confidence intervals (95 % CI) across quintiles of epicatechin intake
and trend analysis were calculated using multivariable linear regression.
Models were adjusted for age, BMI, socioeconomic status,
family history of diabetes, lifestyle (smoking, physical activity and
alcohol consumption), dietary factors (total energy and dietary fiber)
and cardiovascular disease.
Results: The median intake of epicatechin in the highest quintile (Q5)
was 26.6 mg/day compared to 5.5 mg/day in the lowest quintile (Q1).
Tea contributed 50 % of epicatechin intake, followed by apples
(29 %), cocoa (8 %) and red wine (2 %). Epicatechin intake was not
associated with any of the markers of glucose and insulin metabolism
(p trends[0.05 for all). The adjusted mean (95 % CI) for HbA1c (%)
was 4.9 (4.7–5.1) in Q1 and 4.7 (4.5–4.9) in Q5 (p trend = 0.32). The
adjusted means (95 % CI) for Q1 and Q5 were 90.5 (81.4–100.6)and
93.4 (83.6–104.4) (p trend = 0.52) for the Matsuda index, 891
(842–942) and 882 (832–935) (p trend = 0.94) for glucoseAUC
(mmol/L min), 4777 (4323–5279) and 4995 (4498.8–5547.4)
(p trend = 0.86) for insulinAUC (mU/L min) and 2.3 (2.0–2.5) and
2.1 (1.9–2.4) (p trend = 0.29) for HOMA-IR. There was no interaction
with age, family history of diabetes, smoking status and BMI.
Excluding men with cardiovascular disease (n = 57) did not alter the
associations.
Conclusions: In Dutch elderly non-diabetic men, epicatechin intake
was not associated with markers of glucose and insulin metabolism.
Effects of sodium and potassium supplementation on endothelial function and inflammation in untreated (pre)hypertensives: a fully controlled dietary intervention study
Gijsbers, L. ; Dower, J.I. ; Schalkwijk, C.G. ; Kusters, Y.H.A.M. ; Bakker, S.J. ; Hollman, P.C.H. ; Geleijnse, J.M. - \ 2015
Journal of Hypertension 33 (2015)S1. - ISSN 0263-6352 - p. e72 - e72.
OBJECTIVE:
High sodium and low potassium have been associated with detrimental effects on blood pressure. However, the role of these minerals in endothelial dysfunction and low-grade inflammation, which may predispose to cardiovascular disease, has not yet been established. We performed a randomized placebo-controlled crossover study to examine the effects of sodium and potassium supplementation on endothelial function and inflammation in untreated (pre)hypertensive adults.

DESIGN AND METHOD:
During the study, subjects were on a fully controlled diet that contained on average 2.4 g of sodium and 2.3 g of potassium per day for a 2500 kcal intake. After one-week run-in, subjects were randomized to ingest capsules with supplemental sodium (3 g/d), supplemental potassium (3 g/d), or placebo, for four weeks each, in random order. After each intervention period, brachial artery flow-mediated dilation, and circulating biomarkers of endothelial function (e.g. nitric oxide, endothelin-1, cellular adhesion molecules) and inflammation (e.g. tumor necrosis factor-α, C-reactive protein, interleukins) were measured.

RESULTS:
Of 37 randomized subjects, 36 completed the study. Subjects had a mean pre-treatment blood pressure of 145/81 mmHg. Sodium supplementation increased serum endothelin-1 by 0.24 pg/ml (95% CI: 0.03, 0.45), but had no effect on other endothelial or inflammatory biomarkers, or flow-mediated dilation. Potassium supplementation reduced interleukin-8 levels by 0.28 pg/ml (95% CI: 0.03, 0.53), without affecting other circulating biomarkers. Flow-mediated dilation was 1.16% (95% CI: 0.37, 1.96) higher after potassium supplementation than after placebo, with 83% of the subjects showing an improvement (Figure).

CONCLUSIONS:
Sodium and potassium supplementation had little impact on circulating endothelial and inflammatory biomarkers, and only for potassium an effect on flow-mediated dilation was observed. This study suggests different actions for sodium and potassium in the pathophysiological processes leading to cardiovascular disease.(Figure is included in full-text article.).
Reply to H Schroeter et al. : Letter to the Editor
Dower, J.I. ; Geleijnse, J.M. ; Kromhout, D. ; Hollman, P.C.H. - \ 2015
American Journal of Clinical Nutrition 102 (2015). - ISSN 0002-9165 - p. 976 - 977.
Supplementation of the Pure Flavonoids Epicatechin and Quercetin Affects Some Biomarkers of Endothelial Dysfunction and Inflammation in (Pre)Hypertensive Adults: A Randomized Double-Blind, Placebo-Controlled, Crossover Trial
Dower, J.I. ; Geleijnse, J.M. ; Gijsbers, L. ; Schalkwijk, C.G. ; Kromhout, D. ; Hollman, P.C.H. - \ 2015
The Journal of Nutrition 145 (2015)7. - ISSN 0022-3166 - p. 1459 - 1463.
Background: Consumption of flavonoid-rich foods such as cocoa and tea may reduce cardiovascular disease risk. The flavonoids epicatechin (in cocoa and tea) and quercetin (in tea) probably play a role by reducing endothelial dysfunction and inflammation, 2 main determinants of atherosclerosis. Objective: We studied the effects of supplementation of pure epicatechin and quercetin on biomarkers of endothelial dysfunction and inflammation. Methods: Thirty-seven apparently healthy (pre)hypertensive men and women (40–80 y) participated in a randomized, double-blind, placebo-controlled crossover trial. Participants ingested (-)-epicatechin (100 mg/d), quercetin-3-glucoside (160 mg/d), or placebo capsules for a period of 4 wk, in random order. Plasma biomarkers of endothelial dysfunction and inflammation were measured at the start and end of each 4-wk intervention period. The differences in changes over time between the intervention and placebo periods (¿intervention - ¿placebo) were calculated and tested with a linear mixed model for repeated measures. Results: Epicatechin changed ¿epicatechin - ¿placebo for soluble endothelial selectin (sE-selectin) by -7.7 ng/mL (95% CI: -14.5, -0.83; P = 0.03) but did not significantly change this difference (-0.30; 95% CI: -0.61, 0.01; P = 0.06) for the z score for endothelial dysfunction. Quercetin changed ¿quercetin - ¿placebo for sE-selectin by -7.4 ng/mL (95% CI: -14.3, -0.56; P = 0.03), that for IL-1ß by -0.23 pg/mL (95% CI: -0.40, -0.06; P = 0.009), and that for the z score for inflammation by -0.33 (95% CI: -0.60, -0.05; P = 0.02). Conclusions: In (pre)hypertensive men and women, epicatechin may contribute to the cardioprotective effects of cocoa and tea through improvements in endothelial function. Quercetin may contribute to the cardioprotective effects of tea possibly by improving endothelial function and reducing inflammation. This trial was registered at clinicaltrials.gov as NCT01691404.
Effects of sodium and potassium supplementation on endothelial function: a fully controlled dietary intervention study
Gijsbers, L. ; Dower, J.I. ; Schalkwijk, C.G. ; Kusters, Y.H.A.M. ; Bakker, S.J.A. ; Hollman, P.C.H. ; Geleijnse, J.M. - \ 2015
British Journal of Nutrition 114 (2015)9. - ISSN 0007-1145 - p. 1419 - 1426.
High Na and low K intakes have adverse effects on blood pressure, which increases the risk for CVD. The role of endothelial dysfunction and inflammation in this pathophysiological process is not yet clear. In a randomised placebo-controlled cross-over study in untreated (pre)hypertensives, we examined the effects of Na and K supplementation on endothelial function and inflammation. During the study period, subjects were provided with a diet that contained 2·4 g/d of Na and 2·3 g/d of K for a 10 460 kJ (2500 kcal) intake. After 1-week run-in, subjects received capsules with supplemental Na (3·0 g/d), supplemental K (2·8 g/d) or placebo, for 4 weeks each, in random order. After each intervention, circulating biomarkers of endothelial function and inflammation were measured. Brachial artery flow-mediated dilation (FMD) and skin microvascular vasomotion were assessed in sub-groups of twenty-two to twenty-four subjects. Of thirty-seven randomised subjects, thirty-six completed the study. Following Na supplementation, serum endothelin-1 was increased by 0·24 pg/ml (95 % CI 0·03, 0·45), but no change was seen in other endothelial or inflammatory biomarkers. FMD and microvascular vasomotion were unaffected by Na supplementation. K supplementation reduced IL-8 levels by 0·28 pg/ml (95 % CI 0·03, 0·53), without affecting other circulating biomarkers. FMD was 1·16 % (95 % CI 0·37, 1·96) higher after K supplementation than after placebo. Microvascular vasomotion was unaffected. In conclusion, a 4-week increase in Na intake increased endothelin-1, but had no effect on other endothelial or inflammatory markers. Increased K intake had a beneficial effect on FMD and possibly IL-8, without affecting other circulating endothelial or inflammatory biomarkers.
Comparison of duplicate portion and 24 h recall as reference methods for validating a FFQ using urinary markers as the estimate of true intake
Trijsburg, L.E. ; Vries, J.H.M. de; Boshuizen, H.C. ; Hulshof, P.J.M. ; Hollman, P.C.H. ; Veer, P. van 't; Geelen, A. - \ 2015
British Journal of Nutrition 114 (2015)8. - ISSN 0007-1145 - p. 1304 - 1312.
As FFQ are subject to measurement error, associations between self-reported intake by FFQ and outcome measures should be adjusted by correction factors obtained from a validation study. Whether the correction is adequate depends on the characteristics of the reference method used in the validation study. Preferably, reference methods should (1) be unbiased and (2) have uncorrelated errors with those in the FFQ. The aim of the present study was to assess the validity of the duplicate portion (DP) technique as a reference method and compare its validity with that of a commonly used reference method, the 24 h recall (24hR), for protein, K and Na using urinary markers as the unbiased reference method. For 198 subjects, two DP, two FFQ, two urinary biomarkers and between one and fifteen 24hR (web based and/or telephone based) were collected within 1·5 years. Multivariate measurement error models were used to estimate bias, error correlations between FFQ and DP or 24hR, and attenuation factors of these methods. The DP was less influenced by proportional scaling bias (0·58 for protein, 0·72 for K and 0·52 for Na), and correlated errors between DP and FFQ were lowest (protein 0·28, K 0·17 and Na 0·19) compared with the 24hR. Attenuation factors (protein 0·74, K 0·54 and Na 0·43) also indicated that the DP performed better than the 24hR. Therefore, the DP is probably the best available reference method for FFQ validation for nutrients that currently have no generally accepted recovery biomarker.
Potential Health Impact of Environmentally Released Micro- and Nanoplastics in the Human Food Production Chain: Experiences from Nanotoxicology
Bouwmeester, H. ; Hollman, P.C.H. ; Peters, R.J.B. - \ 2015
Environmental Science and Technology 49 (2015). - ISSN 0013-936X - p. 8932 - 8947.
mytilus-edulis l. - persistent organic pollutants - field-flow fractionation - plastic marine debris - particle-size - hydrodynamic chromatography - drug-delivery - polystyrene nanoparticles - engineered nanomaterials - placopecten-magellanicus
High concentrations of plastic debris have been observed in the oceans. Much of the recent concern has focused on microplastics in the marine environment. Recent studies of the size distribution of the plastic debris suggested that continued fragmenting of microplastics into nanosized particles may occur. In this review we assess the current literature on the occurrence of environmentally released micro- and nanoplastics in the human food production chain and their potential health impact. The currently used analytical techniques introduce a great bias in the knowledge, since they are only able to detect plastic particles well above the nanorange. We discuss the potential use of the very sensitive analytical techniques that have been developed for the detection and quantification of engineered nanoparticles. We recognize three possible toxic effects of plastic particles: first due to the plastic particles themselves, second to the release of persistent organic pollutant adsorbed to the plastics, and third to the leaching of additives of the plastics. The limited data on microplastics in foods do not predict adverse effect of these pollutants or additives. Potential toxic effects of microplastic particles will be confined to the gut. The potential human toxicity of nanoplastics is poorly studied. Based on our experiences in nanotoxicology we prioritized future research questions.
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