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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.

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    Effects of Potassium or Sodium Supplementation on Mineral Homeostasis : A Controlled Dietary Intervention Study
    Humalda, Jelmer K. ; Yeung, Stanley M.H. ; Geleijnse, Johanna M. ; Gijsbers, Lieke ; Riphagen, Ineke J. ; Hoorn, Ewout J. ; Rotmans, Joris I. ; Vogt, Liffert ; Navis, Gerjan ; Bakker, Stephan J.L. ; Borst, Martin H. de - \ 2020
    Journal of Clinical Endocrinology and Metabolism 105 (2020)9. - ISSN 0021-972X - 11 p.
    calcium-phosphate metabolism - Diet controlled clinical trial - fibroblast growth factor 23 - nutrition - potassium - sodium

    CONTEXT: Although dietary potassium and sodium intake may influence calcium-phosphate metabolism and bone health, the effects on bone mineral parameters, including fibroblast growth factor 23 (FGF23), are unclear. OBJECTIVE: Here, we investigated the effects of potassium or sodium supplementation on bone mineral parameters. DESIGN, SETTING, PARTICIPANTS: We performed a post hoc analysis of a dietary controlled randomized, blinded, placebo-controlled crossover trial. Prehypertensive individuals not using antihypertensive medication (n = 36) received capsules containing potassium chloride (3 g/d), sodium chloride (3 g/d), or placebo. Linear mixed-effect models were used to estimate treatment effects. RESULTS: Potassium supplementation increased plasma phosphate (from 1.10 ± 0.19 to 1.15 ± 0.19 mmol/L, P = 0.004), in line with an increase in tubular maximum of phosphate reabsorption (from 0.93 ± 0.21 to 1.01 ± 0.20 mmol/L, P < 0.001). FGF23 decreased (114.3 [96.8-135.0] to 108.5 [93.5-125.9] RU/mL, P = 0.01), without change in parathyroid hormone and 25-hydroxy vitamin D3. Fractional calcium excretion decreased (from 1.25 ± 0.50 to 1.11 ± 0.46 %, P = 0.03) without change in plasma calcium. Sodium supplementation decreased both plasma phosphate (from 1.10 ± 0.19 to 1.06 ± 0.21 mmol/L, P = 0.03) and FGF23 (from 114.3 [96.8-135.0] to 108.7 [92.3-128.1] RU/mL, P = 0.02). Urinary and fractional calcium excretion increased (from 4.28 ± 1.91 to 5.45 ± 2.51 mmol/24 hours, P < 0.001, and from 1.25 ± 0.50 to 1.44 ± 0.54 %, P = 0.004, respectively). CONCLUSIONS: Potassium supplementation led to a decrease in FGF23, which was accompanied by increase in plasma phosphate and decreased calcium excretion. Sodium supplementation reduced FGF23, but this was accompanied by decrease in phosphate and increase in fractional calcium excretion. Our results indicate distinct effects of potassium and sodium intake on bone mineral parameters, including FGF23. CLINICAL TRIAL REGISTRATION NUMBER: NCT01575041.

    Vascular effects of sodium and potassium intake
    Gijsbers, Lieke - \ 2017
    Wageningen University. Promotor(en): J.M. Geleijnse; Pieter van 't Veer. - Wageningen : Wageningen University - ISBN 9789463436267 - 161
    sodium - potassium - vascular system - hypertension - blood pressure - mineral supplements - endothelium - blood vessels - heart rate - osmoregulation - human nutrition research - randomized controlled trials - cardiovascular diseases - natrium - kalium - vaatsysteem - hypertensie - bloeddruk - minerale supplementen - endotheel - bloedvaten - hartfrequentie - osmoregulatie - voedingsonderzoek bij de mens - gestuurd experiment met verloting - hart- en vaatziekten

    Cardiovascular diseases (CVD) are the main cause of death worldwide. Annually, about 17.5 million people die from CVD, accounting for ~30% of deaths worldwide. Elevated blood pressure (BP) is a major risk factor for CVD and the largest single contributor to global mortality. BP is a modifiable risk factor that is largely determined by lifestyle factors, including diet. Dietary minerals, in particular sodium and potassium, play an important role in BP regulation. While adverse effects of sodium and beneficial effects of potassium on BP have repeatedly been shown in human intervention studies, evidence on other vascular effects of these dietary minerals is still scarce. Therefore, we investigated the BP effects of sodium and potassium intake in healthy humans in a broader (patho)physiological context, focusing also on endothelial function, arterial stiffness, fluid regulation and heart rate.

    In Chapter 2, the effects of sodium and potassium supplementation on BP and arterial stiffness were examined by means of a randomized placebo-controlled crossover trial. Thirty-six untreated Dutch individuals with mildly elevated BP on a fully controlled diet that was relatively low in sodium (2-3 g/d) and potassium (2-3 g/d) received capsules with sodium (3 g/d), potassium (3 g/d) or placebo, for 4 weeks each, in random order. After each intervention, fasting office BP, 24-h ambulatory BP and measures of arterial stiffness were assessed. The results of this study showed that increased sodium intake strongly raised office and ambulatory systolic BP (7-8 mmHg) whereas increased potassium intake lowered systolic BP (3-4 mmHg). Potassium supplementation increased ambulatory HR, but office HR was not affected. Measures of arterial stiffness were not materially affected by increased sodium or potassium intake, possibly due to the relatively short intervention period.

    In the same study we investigated the effects of increased sodium and potassium intake on the functional measure of endothelial function (flow-mediated dilation), and on a comprehensive set of biomarkers of endothelial dysfunction and low-grade inflammation (Chapter 3). Four weeks of supplemental sodium had no effect on brachial flow-mediated dilation, or on the blood biomarkers of endothelial dysfunction and low-grade inflammation, except for an increase in serum endothelin-1 (a biomarker of endothelial dysfunction). Potassium supplementation improved flow-mediated dilation by 1.2% and tended to lower the low-grade inflammation marker interleukin-8. This suggests that potassium may beneficially influence vascular health by improving endothelial function.

    In a post-hoc analysis of the same study in 35 untreated individuals, the humoral effects of supplemental sodium and potassium were assessed using a panel of markers that are involved in osmoregulation and volume regulation (Chapter 4). Results showed that supplemental sodium increased plasma natriuretic peptides and plasma copeptin, and suppressed the renin-angiotensin system. Supplemental potassium decreased plasma MR-pro-ANP, increased plasma copeptin, and stimulated the renin-angiotensin system. These findings suggest that the mineral-induced changes in BP elicit several counter regulatory mechanisms to maintain volume homeostasis.

    In Chapter 5, the effect of potassium supplementation on heart rate was assessed in a meta-analysis of 22 randomized, placebo-controlled trials in healthy adults. Overall, increasing potassium intake by 2-3 g/d for at least two weeks did not affect resting heart rate. 24-h Ambulatory heart rate was not significantly affected in subgroup analysis of 4 RCTs, including ours. Other subgroup analyses for characteristics of the study and study population also showed no significant effects, and there was no evidence for a dose-response relationship. These results suggest that increasing potassium intake is not expected to adversely affect heart rate in apparently healthy adults.

    In Chapter 6, BP associations for sodium and potassium intake using different dietary assessment methods were examined. Data of 993 healthy Dutch adults not on antihypertensive medication were analyzed using a cross-sectional approach. Sodium and potassium intake were estimated from two non-consecutive 24-h urinary samples (considered as the gold standard), two non-consecutive web-based 24-h recalls, and a validated 180-item food frequency questionnaire (FFQ). This study showed no significant associations of sodium intake with BP, regardless of the dietary assessment method used. Potassium intake estimated from 24-h urine and FFQ was inversely associated with BP (~1.5 mmHg reduction per 1 g/d increment). This suggests that dietary assessment methods in cross-sectional studies may be inadequate for estimating the association of sodium intake with BP, but may yield reliable results for potassium intake.

    As discussed in Chapter 7, the studies presented in this thesis indicate that increasing sodium intake from a recommended level to a level that is common in Western societies for four weeks strongly raises BP in individuals with an untreated mildly elevated BP. The results for endothelial function and arterial stiffness are inconclusive, and hence more (longer-term) studies are warranted. Increasing the intake of potassium lowers BP and improves endothelial function, even in individuals on a relatively low-sodium diet. Both sodium and potassium intake affected fluid parameters, likely indicating that compensatory responses are stimulated to maintain body fluid balance. Although in our RCT ambulatory heart rate was increased after supplemental potassium, the meta-analysis showed that increasing potassium intake is unlikely to affect heart rate in apparently healthy adults. When evaluating the effectiveness of sodium and potassium intake on cardiovascular health, results obtained from observational studies should be interpreted with caution, particularly for sodium intake.

    Around the world people consume on average 9-12 g of salt and 2-4 g of potassium on a daily basis. A more optimal intake of sodium and potassium can be achieved through adherence to dietary guidelines and product reformulation by food industry. This could reduce BP by more than 10 mmHg and lower the number of cardiovascular deaths by at least one-quarter in Western populations.

    Milk and dairy consumption and risk of cardiovascular diseases and all-cause mortality : dose–response meta-analysis of prospective cohort studies
    Guo, Jing ; Astrup, Arne ; Lovegrove, Julie A. ; Gijsbers, Lieke ; Givens, David I. ; Soedamah-Muthu, Sabita S. - \ 2017
    European Journal of Epidemiology 32 (2017)4. - ISSN 0393-2990 - p. 269 - 287.
    All-cause mortality - Cardiovascular disease - Dairy - Dose–response meta-analysis - Fermented dairy - Milk
    With a growing number of prospective cohort studies, an updated dose–response meta-analysis of milk and dairy products with all-cause mortality, coronary heart disease (CHD) or cardiovascular disease (CVD) have been conducted. PubMed, Embase and Scopus were searched for articles published up to September 2016. Random-effect meta-analyses with summarised dose–response data were performed for total (high-fat/low-fat) dairy, milk, fermented dairy, cheese and yogurt. Non-linear associations were investigated using the spine models and heterogeneity by subgroup analyses. A total of 29 cohort studies were available for meta-analysis, with 938,465 participants and 93,158 mortality, 28,419 CHD and 25,416 CVD cases. No associations were found for total (high-fat/low-fat) dairy, and milk with the health outcomes of mortality, CHD or CVD. Inverse associations were found between total fermented dairy (included sour milk products, cheese or yogurt; per 20 g/day) with mortality (RR 0.98, 95% CI 0.97–0.99; I2 = 94.4%) and CVD risk (RR 0.98, 95% CI 0.97–0.99; I2 = 87.5%). Further analyses of individual fermented dairy of cheese and yogurt showed cheese to have a 2% lower risk of CVD (RR 0.98, 95% CI 0.95–1.00; I2 = 82.6%) per 10 g/day, but not yogurt. All of these marginally inverse associations of totally fermented dairy and cheese were attenuated in sensitivity analyses by removing one large Swedish study. This meta-analysis combining data from 29 prospective cohort studies demonstrated neutral associations between dairy products and cardiovascular and all-cause mortality. For future studies it is important to investigate in more detail how dairy products can be replaced by other foods.
    Dairy consumption and risk of stroke: A systematic review and updated dose-response meta-analysis of prospective cohort studies
    Goede, J. de; Soedamah-Muthu, S.S. ; Pan, An ; Gijsbers, L. ; Geleijnse, J.M. - \ 2016
    Journal of the American Heart Association 5 (2016). - ISSN 2047-9980
    dairy products - meta‐analysis - prospective cohort study - stroke - systematic review
    Background
    A higher milk consumption may be associated with a lower stroke risk. We conducted a comprehensive systematic review and dose–response meta‐analysis of milk and other dairy products in relation to stroke risk.

    Methods and Results
    Through a systematic literature search, prospective cohort studies of dairy foods and incident stroke in stroke‐free adults were identified. Random‐effects meta‐analyses with summarized dose–response data were performed, taking into account sources of heterogeneity, and spline models were used to systematically investigate nonlinearity of the associations. We included 18 studies with 8 to 26 years of follow‐up that included 762 414 individuals and 29 943 stroke events. An increment of 200 g of daily milk intake was associated with a 7% lower risk of stroke (relative risk 0.93; 95% CI 0.88–0.98; P=0.004; I2=86%). Relative risks were 0.82 (95% CI 0.75–0.90) in East Asian and 0.98 (95% CI 0.95–1.01) in Western countries (median intakes 38 and 266 g/day, respectively) with less but still considerable heterogeneity within the continents. Cheese intake was marginally inversely associated with stroke risk (relative risk 0.97; 95% CI 0.94–1.01 per 40 g/day). Risk reductions were maximal around 125 g/day for milk and from 25 g/day onwards for cheese. Based on a limited number of studies, high‐fat milk was directly associated with stroke risk. No associations were found for yogurt, butter, or total dairy.

    Conclusions
    Milk and cheese consumption were inversely associated with stroke risk. Results should be placed in the context of the observed heterogeneity. Future epidemiological studies should provide more details about dairy types, including fat content. In addition, the role of dairy in Asian populations deserves further attention.
    Potassium supplementation and heart rate : A meta-analysis of randomized controlled trials
    Gijsbers, L. ; Molenberg, Famke ; Bakker, S.J.L. ; Geleijnse, J.M. - \ 2016
    Nutrition, Metabolism & Cardiovascular Diseases 26 (2016)8. - ISSN 0939-4753 - p. 674 - 682.
    Blood pressure - BP - Heart rate - HR - Meta-analysis - Potassium - Randomized controlled trial - Randomized controlled trials - RCT

    Background and aims: Increasing the intake of potassium has been shown to lower blood pressure, but whether it also affects heart rate (HR) is largely unknown. We therefore assessed the effect of potassium supplementation on HR in a meta-analysis of randomized controlled trials. Methods and results: We searched PubMed (1966-October 2014) for randomized, placebo-controlled trials in healthy adults with a minimum duration of two weeks in which the effect of increased potassium intake on HR was assessed. In addition, reference lists from meta-analysis papers on potassium and blood pressure were hand-searched for publications. Two investigators independently extracted the data. We performed random effects meta-analyses, subgroup and meta-regression analyses for characteristics of the study (e.g. design, intervention duration, potassium dose and salt type, change in potassium excretion, sodium excretion during intervention) and study population (e.g. gender, age, hypertensive status, pre-study HR, pre-study potassium excretion). A total of 22 trials (1086 subjects), with a median potassium dose of 2.5 g/day (range: 0.9-4.7 g/day), and median intervention duration of 4 weeks (range: 2-24 weeks) were included. The meta-analysis showed no overall effect of increased potassium intake on HR (0.19 bpm, 95% CI: -0.44, 0.82). Stratified analyses yielded no significant effects of potassium intake on HR in subgroups, and there was no evidence for a dose-response relationship in meta-regression analyses. Conclusion: A chronic increase in potassium intake with supplemental doses of 2-3 g/day is unlikely to affect HR in apparently healthy adults.

    Consumption of dairy foods and diabetes incidence: a dose-response meta-analysis of observational studies
    Gijsbers, L. ; Ding, E.L. ; Malik, Vasanti ; Goede, J. de; Geleijnse, J.M. ; Soedamah-Muthu, S.S. - \ 2016
    American Journal of Clinical Nutrition 103 (2016)4. - ISSN 0002-9165 - p. 1111 - 1124.
    dairy - milk - yoghurt - type 2 diabetes - cheese
    BACKGROUND: A growing number of cohort studies suggest a potential role of dairy consumption in type 2 diabetes (T2D) prevention. The strength of this association and the amount of dairy needed is not clear. OBJECTIVE: We performed a meta-analysis to quantify the associations of incident T2D with dairy foods at different levels of intake. DESIGN: A systematic literature search of the PubMed, Scopus, and Embase databases (from inception to 14 April 2015) was supplemented by hand searches of reference lists and correspondence with authors of prior studies. Included were prospective cohort studies that examined the association between dairy and incident T2D in healthy adults. Data were extracted with the use of a predefined protocol, with double data-entry and study quality assessments. Random-effects meta-analyses with summarized dose-response data were performed for total, low-fat, and high-fat dairy, (types of) milk, (types of) fermented dairy, cream, ice cream, and sherbet. Nonlinear associations were investigated, with data modeled with the use of spline knots and visualized via spaghetti plots. RESULTS: The analysis included 22 cohort studies comprised of 579,832 individuals and 43,118 T2D cases. Total dairy was inversely associated with T2D risk (RR: 0.97 per 200-g/d increment; 95% CI: 0.95, 1.00; P = 0.04; I2 = 66%), with a suggestive but similar linear inverse association noted for low-fat dairy (RR: 0.96 per 200 g/d; 95% CI: 0.92, 1.00; P = 0.072; I2 = 68%). Nonlinear inverse associations were found for yogurt intake (at 80 g/d, RR: 0.86 compared with 0 g/d; 95% CI: 0.83, 0.90; P < 0.001; I2 = 73%) and ice cream intake (at ∼10 g/d, RR: 0.81; 95% CI: 0.78, 0.85; P < 0.001; I2 = 86%), but no added incremental benefits were found at a higher intake. Other dairy types were not associated with T2D risk. CONCLUSION: This dose-response meta-analysis of observational studies suggests a possible role for dairy foods, particularly yogurt, in the prevention of T2D. Results should be considered in the context of the observed heterogeneity.
    Effects of potassium supplementation on markers of osmoregulation and volume regulation: results of a fully controlled dietary intervention study
    Riphagen, I.J. ; Gijsbers, L. ; Gastel, M.D. van; Kema, I.P. ; Gansevoort, R.T. ; Navis, G. ; Bakker, S.J.L. ; Geleijnse, J.M. - \ 2016
    Journal of Hypertension 34 (2016)2. - ISSN 0263-6352 - p. 215 - 220.
    OBJECTIVE: Lifestyle measures including dietary sodium restriction and increased potassium intake are recognized to lower blood pressure (BP). Potassium was found to be effective in reducing BP at higher levels of sodium intake, but to have little effect when sodium intake is restricted. The humoral mechanisms underlying these sodium intake dependent effects of potassium are unknown. We investigated the effects of potassium supplementation on top of a fully controlled sodium-restricted diet on markers of osmoregulation and volume regulation. METHODS: In this post-hoc analysis, we included 35 (pre)hypertensive individuals participating in a randomized, double-blind, placebo-controlled crossover trial. Individuals received capsules containing sodium [3.0 g (130 mmol)/day], potassium [2.8 g (72 mmol)/day], or placebo for three four-week periods. Linear mixed-effect models were used to estimate the effects of potassium supplementation compared with placebo. Skewed data were ln-transformed before analysis. RESULTS: Increased potassium intake was associated with a significant decrease in 24-h BP (-3.6/-1.6 mmHg). Furthermore, we found a significant decrease in ln MR-proANP {-0.08 [95% confidence interval (95% CI)] (-0.15, -0.01) pmol/l, P = 0.03} and significant increases in 24-h heart rate [2.5 (0.9, 4.0) bpm, P = 0.002], ln plasma copeptin [0.11 (0.01, 0.20) pmol/l, P = 0.02], ln renin [0.34 (0.08, 0.60) μIU/ml, P = 0.01], and ln aldosterone [0.14 (0.07, 0.22) nmol/l, P < 0.001] compared with placebo. CONCLUSIONS: We found that potassium has BP-lowering effects during sodium restriction. These BP-lowering effects, however, seem mitigated by several counter regulatory mechanisms (i.e. increased secretion of vasopressin, stimulation of RAAS, and increased heart rate) that were activated to maintain volume homeostasis and counterbalance the decrease in BP.
    Encapsulated sodium supplementation of 4weeks does not alter salt taste preferences in a controlled low sodium and low potassium diet
    Bolhuis, Dieuwerke P. ; Gijsbers, Lieke ; Jager, Ilse de; Geleijnse, Johanna M. ; Graaf, Kees de - \ 2015
    Food Quality and Preference 46 (2015). - ISSN 0950-3293 - p. 58 - 65.
    Potassium intake - Salt preference - Salt taste responses - Saltiness intensity - Sodium intake

    Preference for saltiness is learned by oral exposure to salt taste; however, some data suggest a role for bodily sodium and potassium levels on salt taste preferences as well. The objective was to investigate whether encapsulated sodium and potassium supplementation lead to altered salt taste responses among adults with high blood pressure on a low sodium and low potassium diet. Twenty-six participants with untreated upper-range prehypertension or stage 1 hypertension were on a fully controlled low sodium and low potassium diet (both targeted at 2 g/day) for 13 weeks. Participants received capsules with sodium (3 g/d), potassium (3 g/d), or placebo, for 4 weeks each, in randomized order in a double blind crossover design. Sensory evaluation was done before and after each supplementation period and involved ratings of pleasantness and intensity in different salt (NaCl) concentrations in food and water, desire-to-eat salty food, and detection threshold for NaCl. Neither sodium supplementation nor potassium supplementation led to alterations in salt taste responses in food and water, and did not affect detection threshold (P= 0.59). There was no clear role for sodium or potassium supplementation on desire-to-eat salty food. In addition, we did not find effects of reduced oral exposure to salt over weeks, through the sodium-reduced diet, on salt taste preferences, in contrast to earlier studies. In conclusion, the results of this study suggest preference for saltiness is independent of changes in bodily sodium or potassium levels.

    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.).
    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
    The 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.
    Effects of the pure flavonoids epicatechin and quercetin on vascular function and cardiometabolic health: a randomized double-blind, placebo-controlled, crossover trial
    Dower, J.I. ; Geleijnse, J.M. ; Gijsbers, L. ; Zock, P.L. ; Kromhout, D. ; Hollman, P.C.H. - \ 2015
    American Journal of Clinical Nutrition 101 (2015)5. - ISSN 0002-9165 - p. 914 - 921.
    homeostasis model assessment - reduces blood-pressure - flavanol-rich cocoa - insulin-resistance - dark chocolate - cardiovascular-disease - hypertensive subjects - endothelial function - plasma epicatechin - catechin contents
    BACKGROUND: Prospective cohort studies showed inverse associations between the intake of flavonoid-rich foods (cocoa and tea) and cardiovascular disease (CVD). Intervention studies showed protective effects on intermediate markers of CVD. This may be due to the protective effects of the flavonoids epicatechin (in cocoa and tea) and quercetin (in tea). OBJECTIVE: We investigated the effects of supplementation of pure epicatechin and quercetin on vascular function and cardiometabolic health. DESIGN: Thirty-seven apparently healthy men and women aged 40-80 y with a systolic blood pressure (BP) between 125 and 160 mm Hg at screening were enrolled in a randomized, double-blind, placebo-controlled, crossover trial. CVD risk factors were measured before and after 4 wk of daily flavonoid supplementation. Participants received (-)-epicatechin (100 mg/d), quercetin-3-glucoside (160 mg/d), or placebo capsules for 4 wk in random order. The primary outcome was the change in flow-mediated dilation from pre- to postintervention. Secondary outcomes included other markers of CVD risk and vascular function. RESULTS: Epicatechin supplementation did not change flow-mediated dilation significantly (1.1% absolute; 95% CI: -0.1%, 2.3%; P = 0.07). Epicatechin supplementation improved fasting plasma insulin (¿ insulin: -1.46 mU/L; 95% CI: -2.74, -0.18 mU/L; P = 0.03) and insulin resistance (¿ homeostasis model assessment of insulin resistance: -0.38; 95% CI: -0.74, -0.01; P = 0.04) and had no effect on fasting plasma glucose. Epicatechin did not change BP (office BP and 24-h ambulatory BP), arterial stiffness, nitric oxide, endothelin 1, or blood lipid profile. Quercetin-3-glucoside supplementation had no effect on flow-mediated dilation, insulin resistance, or other CVD risk factors. CONCLUSIONS: Our results suggest that epicatechin may in part contribute to the cardioprotective effects of cocoa and tea by improving insulin resistance. It is unlikely that quercetin plays an important role in the cardioprotective effects of tea. This study was registered at clinicaltrials.gov as NCT01691404.
    Effects of sodium and potassium supplementation on blood pressure and arterial stiffness: a fully controlled dietary intervention study
    Gijsbers, L. ; Dower, J.I. ; Mensink, M.R. ; Siebelink, A.E. ; Bakker, S.J.L. ; Geleijnse, J.M. - \ 2015
    Journal of Human Hypertension 29 (2015). - ISSN 0950-9240 - p. 592 - 598.
    We performed a randomised, placebo-controlled, crossover study to examine the effects of sodium and potassium supplementation on blood pressure (BP) and arterial stiffness in untreated (pre)hypertensive individuals. During the study, subjects were on a fully controlled diet that was relatively low in sodium and potassium. After a 1-week run-in period, subjects received capsules with supplemental sodium (3¿g¿d-1, equals 7.6¿g¿d-1 of salt), supplemental potassium (3¿g¿d-1) or placebo, for 4 weeks each, in random order. Fasting office BP, 24-h ambulatory BP and measures of arterial stiffness were assessed at baseline and every 4 weeks. Of 37 randomized subjects, 36 completed the study. They had a mean pre-treatment BP of 145/81¿mm¿Hg and 69% had systolic BP greater than or equal to140¿mm¿Hg. Sodium excretion was increased by 98 mmol per 24¿h and potassium excretion by 63 mmol per 24¿h during active interventions, compared with placebo. During sodium supplementation, office BP was significantly increased by 7.5/3.3¿mm¿Hg, 24-h BP by 7.5/2.7¿mm¿Hg and central BP by 8.5/3.6¿mm¿Hg. During potassium supplementation, 24-h BP was significantly reduced by 3.9/1.6¿mm¿Hg and central pulse pressure by 2.9¿mm¿Hg. Pulse wave velocity and augmentation index were not significantly affected by sodium or potassium supplementation. In conclusion, increasing the intake of sodium caused a substantial increase in BP in subjects with untreated elevated BP. Increased potassium intake, on top of a relatively low-sodium diet, had a beneficial effect on BP. Arterial stiffness did not materially change during 4-week interventions with sodium or potassium.
    Combining an in vitro reporter gene assay with metabolomics to identify tomato phytochemicals responsible for inducing electrophile-responsive element (EpRE)-mediated gene transcription
    Eekelen, H.D.L.M. van; Gijsbers, L. ; Maliepaard, C.A. ; Vreeburg, R.A.M. ; Finkers, H.J. ; Tikunov, Y.M. ; Gomez Roldan, M.V. ; Haan, L.H.J. de; Vos, R.C.H. de; Aarts, J.M.M.J.G. ; Rietjens, I. ; Bovy, A.G. - \ 2015
    Metabolomics 11 (2015)2. - ISSN 1573-3882 - p. 302 - 311.
    solanum-lycopersicon - mass-spectrometry - fruit - expression - health - metabolism - flavonoids - lycopene - deglycosylation - polyphenols
    The electrophile-responsive element (EpRE) is a transcriptional enhancer involved in cancer-chemoprotective gene expression effects of certain dietary compounds. In this study we measured the ability of extracts of glycosidase treated tomato fruits from 97 different accessions to induce EpRE-mediated luciferase expression using EpRE-LUX reporter cells and analyzed the same extracts using LC–MSbased untargeted metabolomics profiling. We were able to pinpoint those tomato compounds that were most correlated with EpRE-mediated luciferase induction, by combining reporter gene assay data with the metabolic profiles of the same extracts. Flavonoids were the compounds showing the strongest positive correlation with EpRE-LUX activity. These results were validated using a transgenic tomato line accumulating high levels of flavonoids. Results obtained corroborated that flavonoids are an important determinant of the ability of tomato fruit extracts to induce EpRE-mediated beneficial health effects. Overall, these results indicate that combining untargeted metabolomics with reporter gene assays provides a powerful tool for nutritionists, plant breeders and food chemists towards identification of potential health-beneficial constituents of tomato fruits, as well as of other crops and products derived thereof.
    Effects of Sodium and Potassium Supplementation on Blood Pressure and Arterial Stiffness in Untreated (Pre)Hypertensives
    Gijsbers, L. ; Dower, J.I. ; Mensink, M.R. ; Geleijnse, J.M. - \ 2014
    Effects of Sodium and Potassium Supplementation on Blood Pressure and Arterial Stiffness in Untreated (Pre)Hypertensives on a Low-Sodium, Low-Potassium Diet
    Gijsbers, L. ; Dower, J.I. ; Mensink, M.R. ; Geleijnse, J.M. - \ 2014
    Circulation 129 (2014). - ISSN 0009-7322
    Introduction: We performed a 12-week randomized placebo-controlled crossover study to examine the effects of sodium and potassium supplementation on blood pressure (BP) and arterial stiffness in untreated (pre)hypertensive individuals on a low-sodium, low-potassium diet. Methods: During the study, subjects were on a fully controlled diet that provided on average 2.4 g/d of sodium (equals 6 g/d of salt) and 2.2 g/d of potassium. After a 1-week run-in period, 37 subjects received capsules with supplemental sodium (3 g/d, equals 7.5 g/d of salt), supplemental potassium (3 g/d), or placebo, for four weeks each (not separated by wash-out), in random order. Fasting office BP, 24-h ambulatory BP, and measures of arterial stiffness (SphygmoCor®) were assessed at baseline and after each treatment. Results: Subjects had a mean pre-treatment BP of 145/81 mmHg and 68% (25 of 37) had systolic BP (SBP) =140 mmHg. In 36 subjects who completed the study, sodium supplementation increased urinary sodium by 97.6 mmol/24h (2.2 g/d) and potassium supplementation increased urinary potassium by 62.9 mmol/24h (2.5 g/d), compared to placebo (Table). Sodium supplementation significantly increased office BP by 7.5/3.3 mmHg, 24-h BP by 7.0/2.1 mmHg and central BP by 8.5/3.6 mmHg. Potassium supplementation significantly reduced 24-h BP by 4.0/1.7 mmHg. Measures of arterial stiffness did not change. Conclusion: Increasing the intake of sodium has a strong adverse effect on BP in untreated (pre)hypertensive individuals. Increased potassium intake, however, lowers BP even when people are on a reduced sodium diet. Short-term changes in sodium and potassium intake have little effect on arterial stiffness
    Correlation between activation of PPAR¿ and resistin downregulation in a mouse adipocyte cell line by a series of thiazolidinediones.
    Sotiriou, A. ; Blaauw, R.H. ; Meijer, C. ; Gijsbers, L.H. ; Burg, B. van der; Vervoort, J. ; Rietjens, I.M.C.M. - \ 2013
    Toxicology in Vitro 27 (2013)5. - ISSN 0887-2333 - p. 1425 - 1432.
    insulin-resistance - adipose-tissue - antihyperglycemic agents - expression - receptor - glucose - metabolism - mechanisms - biology - obesity
    The present study shows significant correlations between the EC50 for PPAR¿ activation in a reporter gene cell line and resistin downregulation in mouse adipocytes, and between the IC50 for resistin downregulation and the already published minimum effective dose for antihyperglycemic activity in a mouse model. These correlations indicate that PPAR¿ mediated downregulation of resistin might promote insulin sensitivity and that downregulation of resistin in mouse adipocytes provides an adequate and possibly more direct bioassay for screening of newly developed antihyperglycemic compounds. Because of the higher throughput of the PPAR¿ the resistin downregulation assays seems most suitable to be used as a second tier in a tiered screening strategy.
    Induction of Peroxisome Proliferator-Activated Receptor ¿ (PPAR¿)-Mediated Gene Expression by Tomato (Solanum lycopersicum L.) Extracts
    Gijsbers, L. ; Eekelen, H.D.L.M. van; Haan, L.H.J. de; Swier, J.M. ; Heijink, N.L. ; Kloet, S.K. ; Bovy, A.G. ; Keijer, J. ; Rietjens, I.M.C.M. ; Aarts, J.M.M.J.G. - \ 2013
    Journal of Agricultural and Food Chemistry 61 (2013)14. - ISSN 0021-8561 - p. 3419 - 3427.
    improves insulin sensitivity - ppar-gamma - plasma-concentrations - hypertensive patients - blood-pressure - food-products - beta-carotene - cancer cells - fruit - lycopene
    Since beneficial effects related to tomato consumption partially overlap with those related to peroxisome proliferator-activated receptor ¿ (PPAR¿) activation, our aim was to test extracts of tomato fruits and tomato components, including polyphenols and isoprenoids, for their capacity to activate PPAR¿ using the PPAR¿2 CALUX reporter cell line. Thirty tomato compounds were tested; seven carotenoids and three polyphenols induced PPAR¿2-mediated luciferase expression. Two extracts of tomato, one containing deglycosylated phenolic compounds and one containing isoprenoids, also induced PPAR¿2-mediated expression at physiologically relevant concentrations. Furthermore, enzymatically hydrolyzed extracts of seven tomato varieties all induced PPAR¿-mediated expression, with a 1.6-fold difference between the least potent and the most potent variety. The two most potent varieties had high flavonoid content, while the two least potent varieties had low flavonoid content. These data indicate that extracts of tomato are able to induce PPAR¿-mediated gene expression in vitro and that some tomato varieties are more potent than others.
    In vitro reporter gene assays for assessment of PPAR- and Nrf2-mediated health effects of tomato and its bioactive constituents
    Gijsbers, L. - \ 2013
    Wageningen University. Promotor(en): Ivonne Rietjens; Jaap Keijer, co-promotor(en): Jac Aarts. - S.l. : s.n. - ISBN 9789461735096 - 159
    solanum lycopersicum - tomaten - assays - bioactieve verbindingen - biologische activiteit - reporter-genen - genexpressie - solanum lycopersicum - tomatoes - assays - bioactive compounds - biological activity - reporter genes - gene expression

    The consumption of food products with health-promoting properties, such as for example margarines with plant sterols, fruit juice enriched with calcium and cereals with (soluble) fibre, has increased rapidly during the last years. The present thesis provides proof-of-principle that reporter gene assays are effective tools to investigate the effects of functional foods and food compounds on gene expression pathways.

    In order to test fruits and vegetables for selected functions in reporter gene assays, extraction methods for vegetables and fruits are needed which result in extracts suitable for testing in cell-based assays. In this thesis, methods are described to prepare three different tomato extracts, containing 1) apolar compounds such as isoprenoids, 2) semi-polar compounds, such as flavonoid glycosides and 3) deglycosylated semi-polar compounds such as flavonoid aglycones. All three tomato extracts were compatible with cell-physiological and cell culture conditions.

    Next, the three tomato extracts and individual tomato compounds were tested for their capacity to induce EpRE-mediated, PPARγ-mediated and PPARα-mediated gene expression using three reporter gene assays; the previously described EpRE-LUX assay and the newly developed PPARγ CALUX and PPARα CALUX assays. Both flavonoid glycosides and the tomato extract containing semi-polar compounds were unable to induce EpRE-mediated, PPARγ-mediated and PPARα-mediated gene expression, while the tomato extract containing deglycosylated semi-polar compounds, as well as individual flavonoid aglycones were able to induce EpRE-mediated, PPARγ-mediated and PPARα-mediated gene expression. Some individual isoprenoids and the tomato extract containing apolar compounds were also inducing PPARγ-mediated and PPARα-mediated gene expression, but not EpRE-mediated gene expression.

    To assess differences between tomato varieties, extracts containing deglycosylated semi-polar compounds were generated from fruits of different tomato varieties. These were then tested for their capacity to induce EpRE-mediated (97 varieties), PPARγ-mediated (7 varieties) and PPARα-mediated (7 varieties) gene expression. The extracts of these varieties were all able to induce both EpRE-mediated, PPARγ-mediated and PPARα-mediated gene expression. For EpRE-mediated gene expression, a 3-fold difference was found between the least potent and the most potent variety; for PPARγ-mediated gene expression, this difference was 1.6-fold, and for PPARα-mediated gene expression this was 1.7-fold.

    Metabolomics profiles of the 97 extracts were generated in order to identify phytochemicals responsible for the differences in potency of the 97 tomato varieties to induce EpRE-mediated gene expression. The flavonoid aglycone quercetin was identified as one of the main compounds responsible for the ability of tomato extracts to induce EpRE-mediated gene expression using multivariate analysis that combined the reporter gene assay data with metabolite profiles of the same tomato extracts. In addition, yet unidentified compounds correlated with the response in the EpRE-LUX assay and these compounds may also contribute to the observed induction of EpRE-mediated gene expression.

    In conclusion, the work presented in this thesis provides proof-of-principle that reporter gene assays can be implemented for screening bioactive food compounds as well as whole fruit and vegetable extracts for their capacity to induce gene expression through specific health-related transcription factor.It was shown that reporter gene assays are able to pick up differences in activation of these transcription factors induced by different varieties of tomato. Furthermore, this thesis provides proof-of-principle that active ingredients contributing to the activity of the whole tomato extracts could be identified by combining reporter gene assays and metabolite profiling. Our results indicate that combining multiple reporter gene assays and metabolomics profiling, is useful in fast screening of larger numbers of food items and food compounds. Therefore, the use of reporter gene assays as a first tier in a tiered approach aiming at supporting health claims will limit the number of animal studies and human studies needed, by enabling the ranking and selection of highly promising food items or constituents for further in vivo testing.

    Development and validation of two stable reporter cell lines for PPAR¿-mediated modulation of gene expression
    Haan, L.H.J. de; Gijsbers, L. ; Man, H. ; Kloet, S.K. ; Keijer, J. ; Rietjens, I.M.C.M. ; Burg, B. van der; Aarts, J.M.M.J.G. - \ 2012
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