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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    Detection of peanut allergens in serum : circumventing the inhibitory effect of immunoglobulins
    Koppelman, Stef J. ; Witteveen, Michel ; JanssenDuijghuijsen, Lonneke ; Baumert, Joseph L. ; Witkamp, Renger F. ; Norren, Klaske van - \ 2020
    Allergy 75 (2020)7. - ISSN 0105-4538 - p. 1835 - 1836.
    allergens - food allergy - IgE - IgG4 - peanut
    Vitamin D, magnesium, calcium, and their interaction in relation to colorectal cancer recurrence and all-cause mortality
    Wesselink, Evertine ; Kok, Dieuwertje E. ; Bours, Martijn J.L. ; Wilt, Johannes H.W. De; Baar, Harm Van; Zutphen, Moniek Van; Geijsen, Anne M.J.R. ; Keulen, Eric T.P. ; Hansson, Bibi M.E. ; Ouweland, Jody Van Den; Witkamp, Renger F. ; Weijenberg, Matty P. ; Kampman, Ellen ; Duijnhoven, Fränzel J.B. Van - \ 2020
    American Journal of Clinical Nutrition 111 (2020)5. - ISSN 0002-9165 - p. 1007 - 1017.
    25(OH)D - all-cause mortality - calcium - colorectal cancer patients - interactions - magnesium - recurrence

    Background: Higher concentrations of 25-hydroxyvitamin D3 [25(OH)D3] at diagnosis are associated with a lower mortality risk in colorectal cancer (CRC) patients. However, magnesium and calcium are important in vitamin D metabolism. Objectives: We aimed to investigate 25(OH)D3, magnesium, or calcium and their interaction among patients with CRC in relation to recurrence and all-cause mortality. Methods: The study population included 1169 newly diagnosed stage I-III CRC patients from 2 prospective cohorts. Associations between 25(OH)D3 concentrations, magnesium or calcium intake through diet and/or supplements at diagnosis, and recurrence and all-cause mortality were evaluated using multivariable Cox proportional hazard models. The interaction between 25(OH)D3 and magnesium or calcium was assessed by investigating 1) joint compared with separate effects, using a single reference category; and 2) the effect estimates of 1 factor across strata of another. Results: Serum 25(OH)D3, calcium, and magnesium, alone and their interactions, were not associated with recurrence. Serum 25(OH)D3 concentrations seemed to be associated with all-cause mortality. An inverse association between magnesium intake (HRQ3 vs. Q1: 0.55; 95% CI: 0.32, 0.95 and HRQ4 vs. Q1: 0.65; 95% CI: 0.35, 1.21), but not calcium intake, and all-cause mortality was observed. When investigating the interaction between 25(OH)D3 and magnesium, we observed the lowest risk of all-cause mortality in patients with sufficient vitamin D concentrations (≥50 nmol/L) and a high magnesium intake (median split) (HR: 0.53; 95% CI: 0.31, 0.89) compared with patients who were vitamin D deficient (<50 nmol/L) and had a low magnesium intake. No interactions between calcium and vitamin D in relation to all-cause mortality were observed. Conclusions: Our findings suggest that the presence of an adequate status of 25(OH)D3 in combination with an adequate magnesium intake is essential in lowering the risk of mortality in CRC patients, yet the underlying mechanism should be studied. In addition, diet and lifestyle intervention studies are needed to confirm our findings. The COLON study was registered at as NCT03191110. The EnCoRe study was registered at as NTR7099.

    Fatty acids as cell signals in ingestive behaviors
    Figlewicz, Dianne P. ; Witkamp, Renger F. - \ 2020
    Physiology and Behavior 223 (2020). - ISSN 0031-9384

    Common dietary fatty acids, including palmitic acid, stearic acid, oleic acid, and polyunsaturated fatty acids, have been studied in the context of overall dietary fat and shown to impact on several types of behaviors, most prominently cognitive behaviors and ingestive behaviors. The independent effects of these fatty acids have been less well-delineated. Several studies implicate these common fatty acids in modulation of the CNS immune/inflammatory response as a key mediator of behavioral effects. However, signaling actions of the fatty acids to regulate cell structure and neuronal or synaptic function have been identified in numerous studies, and the relevance or contribution(s) of these to ingestive behavioral outcomes represent an area for future study. Finally, fatty acids are precursors of endocannabinoids and their structural congeners. Being highly dynamic and complex, the endocannabinoid system plays a key role ingestive behavior via cellular and synaptic mechanisms, thus representing another important area for future study.

    The association between circulating levels of vitamin D and inflammatory markers in the first 2 years after colorectal cancer diagnosis
    Wesselink, Evertine ; Balvers, Michiel ; Bours, Martijn J.L. ; Wilt, Johannes H.W. de; Witkamp, Renger F. ; Baar, Harm van; Geijsen, Anne J.M.R. ; Halteren, Henk van; Keulen, Eric T.P. ; Kok, Dieuwertje E. ; Kouwenhoven, Ewout A. ; Ouweland, Jody van den; Zutphen, Moniek van; Weijenberg, Matty P. ; Kampman, Ellen ; Duijnhoven, Fränzel J.B. van - \ 2020
    Therapeutic Advances in Gastroenterology 13 (2020). - ISSN 1756-283X
    25(OH)D - colorectal cancer - cytokines - inflammatory markers - interleukin 6

    Background: Calcitriol, the active form of vitamin D, may inhibit colorectal cancer (CRC) progression, which has been mechanistically linked to an attenuation of a pro-inflammatory state. The present study investigated the associations between circulating 25 hydroxy vitamin D3 (25(OH)D3) levels and inflammatory markers (IL10, IL8, IL6, TNFα and hsCRP) in the 2 years following CRC diagnosis. Methods: Circulating 25(OH)D3 levels and inflammatory markers were assessed at diagnosis, after 6, 12 and 24 months from 798 patients with sporadic CRC participating in two prospective cohort studies. Associations between 25(OH)D3 levels and individual inflammatory markers as well as a summary inflammatory z-score were assessed at each time point by multiple linear regression analyses. To assess the association between 25(OH)D3 and inflammatory markers over the course of 2 years, linear mixed model regression analyses were conducted. Results: Higher 25(OH)D3 levels were associated with lower IL6 levels at diagnosis, at 6 months after diagnosis and over the course of 2 years (β −0.06, 95% CI −0.08 to −0.04). In addition, 25(OH)D3 levels were inversely associated with the summary inflammatory z-score at diagnosis and over the course of 2 years (β −0.17, 95% CI −0.25 to −0.08). In addition, a significant inverse association between 25(OH)D3 levels and IL10 was found over the course of 2 years. Intra-individual analyses showed an inverse association between 25(OH)D3 and IL10, IL6 and TNFα. No statistically significant associations between 25(OH)D3 and IL8 and hsCRP levels were observed. Conclusions: Serum 25(OH)D3 levels were inversely associated with the summary inflammatory z-score and in particular with IL6 in the years following CRC diagnosis. This is of potential clinical relevance as IL6 has an important role in chronic inflammation and is also suggested to stimulate cancer progression. Further observational studies should investigate whether a possible 25(OH)D3-associated reduction of inflammatory mediators influences treatment efficacy and CRC recurrence.

    Chemotherapy and vitamin D supplement use are determinants of serum 25-hydroxyvitamin D levels during the first six months after colorectal cancer diagnosis
    Wesselink, Evertine ; Bours, Martijn J.L. ; Wilt, Johannes H.W. de; Aquarius, Michiel ; Breukink, Stephanie O. ; Hansson, Bibi ; Keulen, Eric T.P. ; Kok, Dieuwertje E. ; Ouweland, Jody van den; Roekel, Eline H. van; Snellen, Merel ; Winkels, Renate ; Witkamp, Renger F. ; Zutphen, Moniek van; Weijenberg, Matty P. ; Kampman, Ellen ; Duijnhoven, Fränzel J.B. van - \ 2020
    Journal of Steroid Biochemistry and Molecular Biology 199 (2020). - ISSN 0960-0760
    Changes over time - Colorectal cancer - Lifestyle and clinical determinants - Patients - serum 25(OH)D - Vitamin D

    Vitamin D metabolites, including 25-hydroxyvitamin D3 (25(OH)D3), may inhibit colorectal cancer (CRC) progression. Here we investigated cross-sectional and longitudinal associations of demographic, lifestyle and clinical characteristics with 25(OH)D3 serum concentrations in CRC patients at diagnosis and six months later. In 1201 newly-diagnosed stage I-III CRC patients, 25(OH)D3 levels were analysed twice. Multivariable linear regression was used to assess demographic, lifestyle and clinical determinants of 25(OH)D3 levels at diagnosis and six months later. Linear mixed models were used to assess characteristics associated with changes in 25(OH)D3 levels over time. Results of our study showed that vitamin D intake from diet or supplements, use of calcium supplements, BMI and disease stage were associated with 25(OH)D3 levels at both time points. Six months after diagnosis, gender and having received chemo- and/or radiotherapy were also associated with 25(OH)D3 levels. A stronger decrease in 25(OH)D3 levels was observed in patients who underwent chemotherapy, compared to surgery only (β-6.9 nmol/L 95 %CI -9.8; -4.0). Levels of 25(OH)D3 levels increased in patients using vitamin D supplements compared to non-users (β 4.0 nmol/L 95 %CI 1.2; 6.8). In conclusion, vitamin D supplement use and treatment appear to be important determinants of 25(OH)D3 levels during the first six months after CRC diagnosis, although the difference in 25(OH)D3 levels was minor. Identifier: NCT03191110

    Sulfide induced phosphate release from iron phosphates and its potential for phosphate recovery
    Wilfert, P. ; Meerdink, J. ; Degaga, B. ; Temmink, H. ; Korving, L. ; Witkamp, G.J. ; Goubitz, K. ; Loosdrecht, M.C.M. van - \ 2020
    Water Research 171 (2020). - ISSN 0043-1354
    Iron - Phosphate recovery - Sewage sludge - Sulfide

    Sulfide is frequently suggested as a tool to release and recover phosphate from iron phosphate rich waste streams, such as sewage sludge, although systematic studies on mechanisms and efficiencies are missing. Batch experiments were conducted with different synthetic iron phosphates (purchased Fe(III)P, Fe(III)P synthesized in the lab and vivianite, Fe(II)3(PO4)2*8H2O), various sewage sludges (with different molar Fe:P ratios) and sewage sludge ash. When sulfide was added to synthetic iron phosphates (molar Fe:S = 1), phosphate release was completed within 1 h with a maximum release of 92% (vivianite), 60% (purchased Fe(III)P) and 76% (synthesized Fe(III)P). In the latter experiment, rebinding of phosphate to Fe(II) decreased net phosphate release to 56%. Prior to the re-precipitation, phosphate release was very efficient (P released/S input) because it was driven by Fe(III) reduction and not by, more sulfide demanding, FeSx formation. This was confirmed in low dose sulfide experiments without significant FeSx formation. Phosphate release from vivianite was very efficient because sulfide reacts directly (1:1) with Fe(II) to form FeSx, without Fe(III) reduction. At the same time vivianite-Fe(II) is as efficient as Fe(III) in binding phosphate. From digested sewage sludge, sulfide dissolved maximally 30% of all phosphate, from the sludge with the highest iron content which was not as high as suggested in earlier studies. Sludge dewaterability (capillary suction test, 0.13 ± 0.015 g2(s2m4)−1) dropped significantly after sulfide addition (0.06 ± 0.004 g2(s2m4)−1). Insignificant net phosphate release (1.5%) was observed from sewage sludge ash. Overall, sulfide can be a useful tool to release and recover phosphate bound to iron from sewage sludge. Drawbacks -deterioration of the dewaterability and a net phosphate release that is lower than expected-need to be investigated.

    Development of a trained immunity and resilience model for testing of orally applied β-glucans
    Moerings, Bart ; Graaff, Priscilla de; Wichers, H.J. ; Garssen, Johan ; Witkamp, R.F. ; Debets, R. ; Mes, J.J. ; Bergenhenegouwen, Jeroen van; Govers, C.C.F.M. - \ 2019
    What moves wasting muscle? : Cancer cachexia; treatment, targets and translation
    Plas, Rogier Leendert Charles - \ 2019
    Wageningen University. Promotor(en): R.F. Witkamp; E. Kampman, co-promotor(en): K. van Norren. - Wageningen : Wageningen University - ISBN 9789463951586 - 139

    Cachexia is a common, serious and yet often under-recognised complication of cancer. Most obvious clinical manifestations of cachexia are loss of muscle mass, sometimes also including loss of fat mass and hence weight loss. This is driven by metabolic changes with or without a reduction in food intake, including elevated energy expenditure, excess catabolism and inflammation. Cachexia affects most patients with advanced stage cancer, with in some cancers more than 60% of all patients showing weight loss. Patients suffering from cachexia often also experience fatigue, muscle weakness and reduced response to cancer treatment. Conventional nutritional support is generally ineffective, the more so as anorexia often also develops in these patients. Together, these factors not only contribute to a reduced quality of life in these patients but are also assumed to be directly responsible for 20% of all cancer deaths. Thereby, aim of the current thesis was to get more insight into the processes driving this complex cachexia syndrome. Moreover, possible treatment targets and modalities were tested.

    In view of the variation in degree and clinical manifestations of cancer cachexia, variations in body composition and relative amounts of lean or fat mass are commonly occurring. To investigate possible consequences for the pharmacokinetics of cancer medication, associations between body composition and side-effects of chemotherapeutic treatment were studied in chapter 2. This was performed in a cohort of colon cancer patients receiving a treatment regimen consisting of capacetabine and oxaliplatin. Most patients [90%] experienced some side-effect during their treatment. Reductions in the dose of oxaliplatin were most common, while capecitabine treatment was usually not reduced. In contradiction to literature, we found that the amount of muscle mass, both absolute and relative to fat mass, was not associated with side-effects. However, we did find that the amount of fat infiltration in muscle tissue was associated with having more side-effects of the chemotherapy. Fat infiltration in muscle is a marker of poor muscle health. Therefore, our findings suggest that in our study population, not muscle quantity, but muscle functional quality is associated with side-effects of chemotherapy treatment.

    The complexity of the cachexia syndrome has thus far severely hampered the development of effective treatment regimens. General consensus exists that treatment should consist of a multi-modal program including nutrition, exercise and drugs. However, research on different treatment options in patients is difficult because of their situation and vulnerability. Therefore, animal studies are commonly used. In chapter 3 and 4, we studied effects of two treatment modalities for cachexia: nutrition (chapter 3) and training (chapter 4). To this end, we used the cancer cachexia model where C26 tumour cells are injected in the flank of a mouse to induce tumour development.

    In chapter 3, we studied the effects of a specific nutritional combination, high in protein, leucine and fish-oil, on circulating calcium levels in the C26 model. We found that the tumour increased calcium levels in the blood plasma. Moreover, plasma hypercalcemia was correlated with carcass mass and multiple organ masses. The specific nutritional combination was able to reduce the hypercalcemia. Subsequently, potential mechanisms underlying this effect were studied. Here, we focussed on the production of parathyroid hormone related protein (PTHrP) by the tumour cells that were used for the induction of cancer in the animals. PTHrP is a molecule well-known for its capacity of inducing hypercalcemia. We found that exposing the cells to the fish-oil component docosahexaenoic-acid (DHA) reduced their PTHrP production. Moreover, we also found that this was independent of cyclooxygenase-type 2 (COX-2), an enzyme involved in both DHA and PTHrP regulation. These results indicate that fish-oil, and specifically DHA, could be an important treatment component for reducing tumour-induced hypercalcemia.

    In chapter 4, we investigated the possible effects of an easily accessible exercise treatment modality; whole body vibration training for a period of 19 days, C26 mice daily underwent 15 minutes of whole body vibration training. Our main finding was that in the tumour bearing group, training shifted the muscle transcriptome, measured using a micro array, towards a pattern comparable to that obtained in control mice. On in-vivo cachexia outcomes, we found that the vibration training was not able to reduce body weight loss or muscle loss. Moreover, minimal effects were found on muscle function of the m. soleus. Despite that no major visible effects on body composition were found, the shift in muscle transcriptome seems promising and more studies into whole body vibration training as treatment component for cachexia seem warranted.

    In chapter 5, we studied to what extent the animal model that we used in chapter 3 and 4 mimics human cancer cachexia. This is important to assess the translatability of results from animal models to human patients. To do so, we compared publically available gene expression data, measured by micro-array or RNA-sequencing, in muscle tissue from different animal models with three human datasets. We found that there is no animal model outperforming other models in terms of similarity to the human datasets. Both on gene level and on pathway level, animal models not only displayed marked mutual and inter-study differences, but were also found to differ from human cachexia patients. Moreover, we found that on pathway level, different processes play different roles in different models. Unfortunately, due to the low number of human datasets, we were not able to draw firm conclusions based on this comparison. Therefore, upon appearance of additional well-described datasets, repetition of this comparison seems useful.

    Within the field of cancer cachexia research, large amounts of data are increasingly being generated. Potential for future research is to focus more on sharing and integrating data. By doing so, more thorough insight can be gained in the complex mechanisms driving cachexia allowing the design of more specific and personalized treatment strategies.

    Vlees is ongezond: hoe kan dat?
    Feskens, Edith ; Seidell, Jaap C. ; Roodenburg, A. ; Kampman, Ellen ; Witkamp, Renger ; Boekel, Tiny van - \ 2019

    Canadese onderzoekers zorgden eind september voor een shock. In het gerenommeerde blad Annals of Internal Medicine noemden zij het eten van rood vlees géén risico voor de volksgezondheid. Net nu we allemaal gewend zijn aan de gedachte dat minder vlees beter voor je is, was dat een tegenintuïtieve bevinding. Dick Veerman vroeg wetenschappers in Nederland en België om een reactie.

    Novel COX-2 products of n-3 polyunsaturated fatty acid-ethanolamine-conjugates identified in RAW264.7 macrophages
    Bus, Ian de; Zuilhof, Han ; Witkamp, Renger ; Balvers, Michiel ; Albada, Bauke - \ 2019
    Journal of Lipid Research 60 (2019)11. - ISSN 0022-2275 - p. 1829 - 1840.
    cyclooxygenase - cyclooxygenase 2 - fatty acid amides - fatty acid oxidation - high-performance liquid chromatography - inflammation - mass spectrometry - prostaglandins

    Cyclooxygenase 2 (COX-2) plays a key role in the regulation of inflammation by catalyzing the oxygenation of PUFAs to prostaglandins (PGs) and hydroperoxides. Next to this, COX-2 can metabolize neutral lipids, including endocannabinoid-like esters and amides. We developed an LC-HRMS-based human recombinant (h)COX-2 screening assay to examine its ability to also convert n-3 PUFA-derived N-acylethanolamines. Our assay yields known hCOX-2-derived products from established PUFAs and anandamide. Subsequently, we proved that eicosapentaenoylethanolamide (EPEA), the N-acylethanolamine derivative of EPA, is converted into PGE3-ethanolamide (PGE3-EA), and into 11-, 14-, and 18-hydroxyeicosapentaenoyl-EA (11-, 14-, and 18-HEPE-EA, respectively). Interestingly, we demonstrated that docosahexaenoylethanolamide (DHEA) is converted by hCOX-2 into the previously unknown metabolites, 13- and 16-hydroxy-DHEA (13- and 16-HDHEA, respectively). These products were also produced by lipopolysaccharide-stimulated RAW267.4 macrophages incubated with DHEA. No oxygenated DHEA metabolites were detected when the selective COX-2 inhibitor, celecoxib, was added to the cells, further underlining the role of COX-2 in the formation of the novel hydroxylated products. This work demonstrates for the first time that DHEA and EPEA are converted by COX-2 into previously unknown hydroxylated metabolites and invites future studies toward the biological effects of these metabolites.

    Receptomics, design of a microfluidic receptor screening technology
    Roelse, Margriet - \ 2019
    Wageningen University. Promotor(en): R.D. Hall; R.F. Witkamp, co-promotor(en): M.A. Jongsma. - Wageningen : Wageningen University - ISBN 9789463950817 - 193

    This thesis describes the development of a G Protein-Coupled Receptor (GPCR) screening technology that combines a receptor cell array (~300 spots) with microfluidics. This technology was developed for the purpose of sensing the taste of, or active components in complex samples. GPCR activation was monitored using a genetically encoded calcium indicator (GECI) which was based on a change in Förster Resonance Energy Transfer (FRET) between two fluorescent proteins linked by a calcium binding domain which, upon binding of calcium, induces a conformational change between the fluorophores. The receptor cell arrays were created by reverse transfection of printed plasmid DNA. The arrays were assembled in a flowcell, connected to a microfluidic system, and mounted on a stereo fluorescence microscope. This setup allowed for controlled and importantly, repeated sample exposure while monitoring the changes in intracellular calcium in real-time.

    GPCRs play an important role in many physiological or disease-related processes. These membrane proteins have evolved to sense a wide range of molecules that can be of either exogenous or endogenous origin. Their sensing mechanisms are complex and potentially involve many cellular signalling events depending the cell type. The introductory chapter of this thesis presents a brief overview of the GPCR types and their signalling pathways with a focus on taste signalling. This chapter also places the microfluidic receptomics technology within the framework of existing receptor screening technologies.

    The second chapter explores the general principles, setup and characterization of the microfluidic biosensor to measure GPCR activation via imaging of [Ca2+] changes in recombinant human HEK293 cells. These cells expressed a combination of the Neurokinin 1-receptor and Cameleon YC3.6 protein as calcium indicator. Here, a stable cell line was employed for robust expression with little variation

    Next to GPCRs, the system was also used for the detection of transient receptor potential channel Vanilloid 1 (TRPV1) ion channel activation by means of the Cameleon YC3.6 calcium sensor as is reported in Chapter 3. This assay was performed with LCMS fractions and whole extracts of chilli pepper fruits which led to the identification of new ion channel agonists. This chapter also discusses the possibility of coupling the receptomics assay directly to an LCMS as an additional on-line bioactivity detector. The general discussion of this thesis (Chapter 7) elaborates on this topic with additional perspectives on the feasibility of coupling the two systems.

    Chapter 4 provides an extensive technical characterization of the preparation and measurement of reverse transfected cell arrays using fluorescent proteins. The response of the Neurokinin 1-receptor in relation to its gene dose in reverse transfection was studied, as well as response reproducibility during repeated activations.

    These results led to a study of bitter taste receptors in relation to sensitivity-determining parameters such as sensor type and calcium buffering (Chapter 5). This chapter aimed to enhance the sensitivity and robustness of the receptor assay and showed proof of concept with bitter receptor arrays that performed in the same range as existing state-of-the-art platforms. Such bitter taste receptor arrays may be employed for future screenings of new bitter taste agonists or modulators and the identification of bitter principles in foods.

    Development of software and statistical models -the linear mixed model, as presented in Chapter 6- to analyse this new type of data showed that a spot-based comparison of sequentially-tested samples yielded the most reliable data and largely eliminated inter-spot differences in signal strength. The method could also visualize receptor specific differences between samples in the presence of a simulated host cell response. A host cell response, induced by ATP, was used to show that specific bitter receptor responses from compound spikes were cumulative to the host cell response and can be retrieved from a host cell response signal by means of comparative analysis.

    The general discussion (Chapter 7) critically discusses the advantages and limitations of this new micro-fluidics approach and details which additional developments are needed to advance the technology further. The receptomics technology as described in this thesis is argued to be complementary to microplate screening technologies and represents a new analytical paradigm. The microfluidics aspect and overall assay size reduction are more cost efficient and allow both a high content dynamics analysis as well as the development of novel applications such as direct identification of bioactive compounds by coupling of LCMS to receptomics.

    All in all, this thesis presents an enabling receptor screening technology that is based on new design principles. This receptomics technology offers novel applications and has potential in the bioactivity screening of crude extracts.

    A Diet Rich in Fish Oil and Leucine Ameliorates Hypercalcemia in Tumour-Induced Cachectic Mice
    Plas, Rogier L.C. ; Poland, Mieke ; Faber, Joyce ; Argilès, Josep ; Dijk, Miriam van; Laviano, Alessandro ; Meijerink, Jocelijn ; Witkamp, Renger F. ; Helvoort, Ardy van; Norren, Klaske van - \ 2019
    International Journal of Molecular Sciences 20 (2019)20. - ISSN 1661-6596
    cachexia - fish oil - hypercalcemia - leucine - PTHrP

    BACKGROUND: Dietary supplementation with leucine and fish oil rich in omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) has previously been shown to reduce cachexia-related outcomes in C26 tumour-bearing mice. To further explore associated processes and mechanisms we investigated changes in plasma Ca2+ levels, the involvement of parathyroid hormone related protein (PTHrP), and its possible interactions with cyclooxygenase 2 (COX-2). METHODS: CD2F1 mice were subcutaneously inoculated with C26 adenocarcinoma cells or sham treated and divided in: (1) controls, (2) tumour-bearing controls, and (3) tumour-bearing receiving experimental diets. After 20 days, body and organ masses and total plasma Ca2+ levels were determined. Furthermore, effects of DHA, EPA and leucine on production of PTHrP were studied in cultured C26 cells. RESULTS: The combination of leucine and fish oil reduced tumour-associated hypercalcemia. Plasma Ca2+ levels negatively correlated with carcass mass and multiple organ masses. DHA was able to reduce PTHrP production by C26 cells in vitro. Results indicate that this effect occurred independently of COX-2 inhibition. CONCLUSION: Our results suggest that cancer-related hypercalcemia may be ameliorated by a nutritional intervention rich in leucine and fish oil. The effect of fish oil possibly relates to a DHA-induced reduction of PTHrP excretion by the tumour.

    Nutritional impact on molecular and physiological adaptations to exercise : nutrition matters
    Knuiman, Pim - \ 2019
    Wageningen University. Promotor(en): R.F. Witkamp; M.T.E. Hopman, co-promotor(en): M.R. Mensink; J.A. Wouters. - Wageningen : Wageningen University - ISBN 9789463950060 - 191

    Skeletal muscle responds to exercise by a diversity of processes that collectively contribute to short-term and structural adaptations to the demanded performance capacities. There is common consensus that, in general, adequate nutrient availability during and after exercise is important to maximise skeletal muscle adaptation and ultimately performance. At the same time, several knowledge gaps remain regarding the precise mechanisms underlying these effects on adaptation, the most optimal nutrient composition in relation to type of exercise, optimal timing etc.

    This dissertation addresses some of these unsolved issues by studying the role of carbohydrates and proteins during adaptation following different forms of exercise. The first part (chapters 2 – 4) focusses on carbohydrate availability with resistance exercise, whereas the second part (chapters 5 - 7) specifically addresses the effects and potential of protein supplementation with endurance training. In chapter 2 we reviewed the existing literature regarding the role of skeletal muscle glycogen with endurance and resistance exercise. Based on this review we concluded that the role of muscle glycogen levels and/or carbohydrate availability on the skeletal muscle adaptive response to resistance exercise requires further scientific attention. To experimentally explore this, we assessed the impact of a pre-exercise meal that differed in macronutrient content on skeletal muscle glycogen levels and acute transcriptional level analysing specific mRNAs in the post-resistance exercise period in chapter 3. Specifically, after a glycogen depleting endurance exercise session in the morning, subjects received an isocaloric mixed meal containing different amounts of carbohydrates and fat 2 hours before a resistance exercise session in the afternoon, while ample protein was provided throughout the day. We hypothesized that some of the selected mRNAs associated with substrate metabolism and mitochondrial biogenesis would differ between the nutritional conditions, without any changes in proteolytic genes. The findings described in chapter 3 demonstrated that muscle mRNA responses related to exercise adaptation were minimally affected by the pre-exercise meals that differed in macronutrient composition. In chapter 4, derived from the same study, we describe the analysis of a number of plasma cytokine patterns during the day to investigate whether these mediators were affected by carbohydrate availability. We hypothesized that some selected cytokines would differ between nutritional conditions, whereas other circulating cytokines suggested to be involved in skeletal muscle adaptation would not respond differently. Our main finding was that a pre-exercise meal in general did not influence plasma cytokine responses in the post-resistance exercise period. Findings of chapter 3 and 4 contribute to the view that carbohydrate availability during resistance exercise is of minor importance when aiming for an acute positive skeletal muscle adaptive response. In addition, our data question the importance of carbohydrates as both substrate for resistance exercise and as modulator of the skeletal muscle response that underlies adaptation. Yet, at present it might be premature to change carbohydrate recommendations for individuals performing resistance exercise. Shifting our focus to proteins, we first reviewed the effects and possible underlying physiological mechanisms of protein supplementation on the adaptive response to endurance training in Chapter 5. To further explore these insights, we performed a double-blind randomised controlled trial with repeated measures to determine whether protein supplementation impacts the adaptive response to endurance training. In chapter 6 we provide proof-of-concept that protein supplementation elicited greater increases in VO2max and stimulated lean mass gain in response to prolonged endurance training. To our knowledge, this was the first double-blind randomised controlled trial with repeated measures showing that protein supplementation enhances the adaptive response to endurance training. These remarkable effects of protein on VO2max that were observed give rise to questions regarding their underlying mechanisms. To this end, we analysed the muscle transcriptome to gain insight into changes in the steady-state gene expression. In chapter 7, we demonstrated that prolonged endurance training changed expression of genes involved in extracellular matrix organisation, energy metabolism and oxidative phosphorylation. Changes in extracellular matrix organisation tended to be greater in the protein group than in the control group and these greater transcriptional changes may reflect the enhanced physiological adaptation as a result of protein supplementation.

    N-Eicosapentaenoyl Dopamine, A Conjugate of Dopamine and Eicosapentaenoic Acid (EPA), Exerts Anti-inflammatory Properties in Mouse and Human Macrophages
    Augimeri, Giuseppina ; Plastina, Pierluigi ; Gionfriddo, Giulia ; Rovito, Daniela ; Giordano, Cinzia ; Fazio, Alessia ; Barone, Ines ; Catalano, Stefania ; Andò, Sebastiano ; Bonofiglio, Daniela ; Meijerink, Jocelijn ; Witkamp, Renger - \ 2019
    Nutrients 11 (2019)9. - ISSN 2072-6643
    cyclooxygenase-2 - cytokines - endocannabinoid - inflammation - N-acyl dopamine - N-eicosapentaenoyl dopamine - polyunsaturated fatty acids (PUFAs)

    A large body of evidence suggests that dietary n-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), contribute to a reduced inflammatory tone thereby lowering the risk for several chronic and degenerative diseases. Different mechanisms have been proposed to explain these anti-inflammatory effects, including those involving endocannabinoids and endocannabinoid-like molecules. In this context, fatty acid amides (FAAs), conjugates of fatty acids with amines or amino acids, are an emerging class of compounds. Dopamine conjugates of DHA (N-docosahexaenoyl dopamine, DHDA) and EPA (N-eicosapentaenoyl dopamine, EPDA) have previously been shown to induce autophagy, apoptosis, and cell death in different tumor lines. Additionally, DHDA has displayed anti-inflammatory properties in vitro. Here, we tested the immune-modulatory properties of EPDA in mouse RAW 264.7 and human THP-1 macrophages stimulated with lipopolysaccharide (LPS). EPDA suppressed the production of monocyte chemoattractant protein-1 (MCP-1), and interleukin-6 (IL-6) in both cell lines, and nitric oxide (NO), and macrophage-inflammatory protein-3α (MIP3A) in RAW 264.7 macrophages. At a transcriptional level, EPDA attenuated cyclooxygenase-2 (COX-2) expression in both cell lines and that of MCP-1, IL-6, and interleukin-1β (IL-1β) in THP-1 macrophages. Although further research is needed to reveal whether EPDA is an endogenous metabolite, our data suggest that this EPA-derived conjugate possesses interesting immune-modulating properties.

    The Effect of Calcium Buffering and Calcium Sensor Type on the Sensitivity of an Array-Based Bitter Receptor Screening Assay.
    Roelse, M. ; Wehrens, H.R.M.J. ; Henquet, M.G.L. ; Witkamp, R.F. ; Hall, R.D. ; Jongsma, M.A. - \ 2019
    Chemical Senses 44 (2019)7. - ISSN 0379-864X - p. 497 - 505.
    The genetically encoded calcium sensor protein Cameleon YC3.6 has previously been applied for functional G protein–coupled receptor screening using receptor cell arrays. However, different types of sensors are available, with a wide range in [Ca2+] sensitivity, Hill coefficients, calcium binding domains, and fluorophores, which could potentially improve the performance of the assay. Here, we compared the responses of 3 structurally different calcium sensor proteins (Cameleon YC3.6, Nano140, and Twitch2B) simultaneously, on a single chip, at different cytosolic expression levels and in combination with 2 different bitter receptors, TAS2R8 and TAS2R14. Sensor concentrations were modified by varying the amount of calcium sensor DNA that was printed on the DNA arrays prior to reverse transfection. We found that ~2-fold lower concentrations of calcium sensor protein, by transfecting 4 times less sensor-coding DNA, resulted in more sensitive bitter responses. The best results were obtained with Twitch2B, where, relative to YC3.6 at the default DNA concentration, a 4-fold lower DNA concentration increased sensitivity 60-fold and signal strength 5- to 10-fold. Next, we compared the performance of YC3.6 and Twitch2B against an array with 11 different bitter taste receptors. We observed a 2- to 8-fold increase in sensitivity using Twitch2B compared with YC3.6. The bitter receptor arrays contained 300 spots and could be exposed to a series of 18 injections within 1 h resulting in 5400 measurements. These optimized sensor conditions provide a basis for enhancing receptomics calcium assays for receptors with poor Ca2+ signaling and will benefit future high-throughput receptomics experiments.
    Anti-inflammatory nutrition with high protein attenuates cardiac and skeletal muscle alterations in a pulmonary arterial hypertension model
    Vinke, Paulien ; Bowen, T.S. ; Boekschoten, Mark V. ; Witkamp, Renger F. ; Adams, Volker ; Norren, Klaske van - \ 2019
    Scientific Reports 9 (2019)1. - ISSN 2045-2322

    Pulmonary arterial hypertension (PAH) is characterized by remodelling of the pulmonary arteries and right ventricle (RV), which leads to functional decline of cardiac and skeletal muscle. This study investigated the effects of a multi-targeted nutritional intervention with extra protein, leucine, fish oil and oligosaccharides on cardiac and skeletal muscle in PAH. PAH was induced in female C57BL/6 mice by weekly injections of monocrotaline (MCT) for 8 weeks. Control diet (sham and MCT group) and isocaloric nutritional intervention (MCT + NI) were administered. Compared to sham, MCT mice increased heart weight by 7%, RV thickness by 13% and fibrosis by 60% (all p < 0.05) and these were attenuated in MCT + NI mice. Microarray and qRT-PCR analysis of RV confirmed effects on fibrotic pathways. Skeletal muscle fiber atrophy was induced (P < 0.05) by 22% in MCT compared to sham mice, but prevented in MCT + NI group. Our findings show that a multi-targeted nutritional intervention attenuated detrimental alterations to both cardiac and skeletal muscle in a mouse model of PAH, which provides directions for future therapeutic strategies targeting functional decline of both tissues.

    Anti-inflammatory nutrition with high protein attenuates cardiac and skeletal muscle alterations in a pulmonary arterial hypertension model
    Vinke, Paulien ; Bowen, T.S. ; Boekschoten, M.V. ; Witkamp, R.F. ; Adams, V. ; Norren, K. van; Hooiveld, G.J.E.J. - \ 2019
    Wageningen University
    Mus musculus - GSE125537 - PRJNA516702
    Background: Pulmonary arterial hypertension (PAH) is a progressive and fatal disease predominantly affecting women and characterized by right ventricular (RV) remodeling. PAH patients experience exercise intolerance and fatigue, often associated with functional decline of their cardiac and skeletal muscle. As treatment options for these disease manifestations are very limited, there is a need for novel therapeutic strategies. The present study used a pulmonary arterial hypertension model in female mice to investigate effects of a nutritional combination (containing extra protein, leucine, fish oil and oligosaccharides) presumably targeting pathways involved in cardiac and skeletal muscle remodeling. Methods: Pulmonary arterial hypertension was induced in female mice (C57/BL6) by weekly administration of monocrotaline (MCT; s.c. 600 mg/kg) during 8 weeks, using saline injection as control. During that period, one MCT group (MCT; n=9) and the sham group (Sham; n=9) received a control diet (standard AIN-93M) while a further MCT-treated group received the nutritional intervention (NI, isocaloric) (MCT+NI; n=10). Histological analyses were performed on the RV, tibialis anterior (TA), soleus and extensor digitorum longus (EDL) muscle. Microarray and qRT-PCR analysis for gene expression were performed in RV tissue, and protein analysis by Western blot in tibialis anterior material. Results: Compared to sham mice, MCT mice showed an increase in heart weight by 7%, RV thickness by 13% and fibrosis by 60% (all p<0.05), which were attenuated in MCT+NI mice. Gene Set Enrichment Analysis (GSEA) of array data from the RV confirmed upregulation of fibrotic pathways in the MCT-compared to sham-treated mice (P<0.05), which were downregulated in MCT+NI mice. In addition, skeletal muscle fiber cross-sectional area (CSA) of the tibialis anterior was reduced (P<0.05) by 22% in MCT compared to sham mice, but preserved in the MCT+NI group (1503 vs. 1178 vs 1495 µm2, respectively), with protein expression of the key E3 ligase MuRF1 also reduced by 30% compared to MCT mice alone (p<0.05). In the EDL, CSA was also reduced (p<0.05) by 28% in MCT compared to sham mice and preserved in the group receiving nutritional intervention (764 vs. 542 Vs.742 µm2). No effect of MCT or nutritional intervention was found in the soleus. Conclusions: A multi-compound supplemented nutrition significantly attenuated changes in both cardiac and skeletal muscle in a mouse model of PAH, providing directions for future therapeutic strategies targeting functional decline of both tissues
    The role of n-3 PUFA-derived fatty acid derivatives and their oxygenated metabolites in the modulation of inflammation
    Bus, Ian de; Witkamp, Renger ; Zuilhof, Han ; Albada, Bauke ; Balvers, Michiel - \ 2019
    Prostaglandins and Other Lipid Mediators 144 (2019). - ISSN 1098-8823
    Chemical probes - Endocannabinoid - Inflammation - Oxygenation - PUFA

    Notwithstanding the ongoing debate on their full potential in health and disease, there is general consensus that n-3 PUFAs play important physiological roles. Increasing dietary n-3 PUFA intake results in increased DHA and EPA content in cell membranes as well as an increase in n-3 derived oxylipin and -endocannabinoid concentrations, like fatty acid amides and glycerol-esters. These shifts are believed to (partly) explain the pharmacological and anti-inflammatory effects of n-3 PUFAs. Recent studies discovered that n-3 PUFA-derived endocannabinoids can be further metabolized by the oxidative enzymes CYP-450, LOX and COX, similar to the n-6 derived endocannabinoids. Interestingly, these oxidized n-3 PUFA derived endocannabinoids of eicosapentaenoyl ethanolamide (EPEA) and docosahexaenoyl ethanolamide (DHEA) have higher anti-inflammatory and anti-proliferative potential than their precursors. In this review, an overview of recently discovered n-3 PUFA derived endocannabinoids and their metabolites is provided. In addition, the use of chemical probes will be presented as a promising technique to study the n-3 PUFA and n-3 PUFA metabolism within the field of lipid biochemistry.

    Ionized and Total Magnesium Levels Change during Repeated Exercise in Older Adults
    Terink, Rieneke ; Balvers, M.G. ; Bongers, C.C.W.G. ; Eijsvogels, T.M.H. ; Witkamp, R.F. ; Mensink, M. ; Hopman, M.T. ; Klein Gunnewiek, J.M.T. - \ 2019
    Journal of Nutrition, Health and Aging 23 (2019)6. - ISSN 1279-7707 - p. 595 - 601.
    consecutive exercise days - micronutrients - Older adults - reference values

    Background: Magnesium is essential for health and performance. Sub-optimal levels have been reported for older persons. In addition, physical exercise is known to temporally decrease magnesium blood concentrations. Objective: To investigate these observations in conjunction we assessed total (tMg) and ionized magnesium (iMg) concentrations in plasma and whole blood, respectively, during 4 consecutive days of exercise in very old vital adults. Design: 68 participants (age 83.7±1.9 years) were monitored on 4 consecutive days at which they walked 30–40km (average ∼8 hours) per day at a self-determined pace. Blood samples were collected one or two days prior to the start of exercise (baseline) and every walking day immediately post-exercise. Samples were analysed for tMg and iMg levels. Results: Baseline tMg and iMg levels were 0.85±0.07 and 0.47±0.07 mmol/L, respectively. iMg decreased after the first walking day (−0.10±0.09 mmol/L, p<.001), increased after the second (+0.11±0.07 mmol/L, p<.001), was unchanged after the third and decreased on the final walking day, all compared to the previous day. tMg was only higher after the third walking day compared to the second walking day (p=.012). In 88% of the participants, iMg levels reached values considered to be sub-optimal at day 1, in 16% of the participants values were sub-optimal for tMg at day 2. Conclusion: Prolonged moderate intensity exercise caused acute effects on iMg levels in a degree comparable to that after a bout of intensive exercise. These effects were not associated with drop-out or health problems. After the second consecutive day of exercise, levels were returned to baseline values, suggesting rapid adaptation/resilience in this population.

    Capsaicin analogues derived from n-3 polyunsaturated fatty acids (PUFAs) reduce inflammatory activity of macrophages and stimulate insulin secretion by β-cells in vitro
    Cione, Erika ; Plastina, Pierluigi ; Pingitore, Attilio ; Perri, Mariarita ; Caroleo, Maria Cristina ; Fazio, Alessia ; Witkamp, Renger ; Meijerink, Jocelijn - \ 2019
    Nutrients 11 (2019)4. - ISSN 2072-6643
    Diabetes - Fatty acid amides - Inflammation - Obesity - PUFA - Vanillylamide

    In this study, two capsaicin analogues, N-eicosapentaenoyl vanillylamine (EPVA) and N-docosahexaenoyl vanillylamine (DHVA), were enzymatically synthesized from their corresponding n-3 long chain polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), both dietary relevant components. The compounds significantly reduced the production of some lipopolysaccharide (LPS)-induced inflammatory mediators, including nitric oxide (NO), macrophage-inflammatory protein-3α (CCL20) and monocyte chemoattractant protein-1 (MCP-1 or CCL2), by RAW264.7 macrophages. Next to this, only EPVA increased insulin secretion by pancreatic INS-1 832/13 β-cells, while raising intracellular Ca 2+ and ATP concentrations. This suggests that the stimulation of insulin release occurs through an increase in the intracellular ATP/ADP ratio in the first phase, while is calcium-mediated in the second phase. Although it is not yet known whether EPVA is endogenously produced, its potential therapeutic value for diabetes treatment merits further investigation.

    Drug use is associated with lower plasma magnesium levels in geriatric outpatients; possible clinical relevance
    Orten-Luiten, A.C.B. van; Janse, A. ; Verspoor, E. ; Brouwer-Brolsma, E.M. ; Witkamp, R.F. - \ 2019
    Clinical Nutrition 38 (2019)6. - ISSN 0261-5614 - p. 2668 - 2676.
    Adverse drug reaction - Cardiovascular disease - Diabetes - Drug-food interaction - Magnesium deficiency - Osteoporosis

    Background: Hypomagnesemia has been associated with diabetes, cardiovascular disease, and other disorders. Drug use has been suggested as one of the risk factors for low magnesium (Mg) levels. In the elderly population, prone to polypharmacy and inadequate Mg intake, hypomagnesemia might be relevant. Therefore, we aimed to investigate associations between drug use and plasma Mg. Methods: Cross-sectional data of 343 Dutch geriatric outpatients were analysed by Cox and linear regression, while adjusting for covariates. Drug groups were coded according to the Anatomical Therapeutic Chemical classification system; use was compared to non-use. Hypomagnesemia was defined as plasma Mg < 0.75 mmol/l and <0.70 mmol/l. Results: Prevalence of hypomagnesemia was 22.2% (Mg < 0.75 mmol/l) or 12.2% (Mg < 0.70 mmol/l); 67.6% of the patients used ≥5 medications (polypharmacy). The number of different drugs used was inversely linearly associated with Mg level (beta −0.01; p < 0.01). Fully adjusted Cox regression showed significant associations of polypharmacy with hypomagnesemia (Mg < 0.75 mmol/l) (prevalence ratio (PR) 1.81; 95%CI 1.08–3.14), proton pump inhibitors (PR 1.80; 95%CI 1.20–2.72), and metformin (PR 2.34; 95%CI 1.56–3.50). Moreover, stratified analyses pointed towards associations with calcium supplements (PR 2.26; 95%CI 1.20–4.26), insulins (PR 3.88; 95%CI 2.19–6.86), vitamin K antagonists (PR 2.01; 95%CI 1.05–3.85), statins (PR 2.44; 95%CI 1.31–4.56), and bisphosphonates (PR 2.97; 95%CI 1.65–5.36) in patients <80 years; selective beta blockers (PR 2.01; 95%CI 1.19–3.40) if BMI <27.0 kg/m2; and adrenergic inhalants in male users (PR 3.62; 95%CI 1.73–7.56). Linear regression supported these associations. Conclusion: As polypharmacy and several medications are associated with hypomagnesemia, Mg merits more attention, particularly in diabetes, cardiovascular disease, and in side-effects of proton pump inhibitors and calcium supplements.

    Effect of pore size distribution and particle size of porous metal oxides on phosphate adsorption capacity and kinetics
    Suresh Kumar, Prashanth ; Korving, Leon ; Keesman, Karel J. ; Loosdrecht, Mark C.M. van; Witkamp, Geert Jan - \ 2019
    Chemical Engineering Journal 358 (2019). - ISSN 1385-8947 - p. 160 - 169.
    Adsorption kinetics - Diffusion - Particle size - Phosphate adsorption - Pore size distribution - Porous metal oxide

    Phosphate is a vital nutrient but its presence in surface waters even at very low concentrations can lead to eutrophication. Adsorption is often suggested as a step for reducing phosphate down to very low concentrations. Porous metal oxides can be used as granular adsorbents that have a high surface area and hence a high adsorption capacity. But from a practical point of view, these adsorbents also need to have good adsorption kinetics. The surface area of such adsorbents comes from pores of varying pore size and the pore size distribution (PSD) of the adsorbents can affect the phosphate adsorption kinetics. In this study, the PSD of 4 different adsorbents was correlated with their phosphate adsorption kinetics. The adsorbents based on iron and aluminium (hydr)oxide were grinded and the adsorption performance was studied as a function of their particle size. This was done to identify diffusion limitations due to the PSD of the adsorbents. The phosphate adsorption kinetics were similar for small particles of all the adsorbents. For larger particles, the adsorbents having pores larger than 10 nm (FSP and DD6) showed faster adsorption than adsorbents with smaller pores (GEH and CFH). Even though micropores (pores < 2 nm) contributed to a higher portion of the adsorbent surface area, pores bigger than 10 nm were needed to increase the rate of adsorption.

    Identification of hydroxytyrosyl oleate, a derivative of hydroxytyrosol with anti-inflammatory properties, in olive oil by-products
    Plastina, Pierluigi ; Benincasa, Cinzia ; Perri, Enzo ; Fazio, Alessia ; Augimeri, Giuseppina ; Poland, Mieke ; Witkamp, Renger ; Meijerink, Jocelijn - \ 2019
    Food Chemistry 279 (2019). - ISSN 0308-8146 - p. 105 - 113.
    COX-2 - Hydroxytyrosyl ester - Inflammation - Macrophages - NO - Olive mill waste water - Olive oil - PGE

    Hydroxytyrosyl esters with short, medium and long acyl chains were evaluated for their ability to reduce nitric oxide (NO) production by lipopolysaccharide-stimulated RAW264.7 macrophages. Among the compounds tested, C18 esters, namely hydroxytyrosyl stearate (HtySte) and hydroxytyrosyl oleate (HtyOle), were found to decrease NO production in a concentration-dependent manner, while the other compounds, including the parent hydroxytyrosol, were ineffective in the tested concentration range (0.5–5 μM). Further study of the potential immune-modulating properties of HtyOle revealed a significant and concentration-dependent suppression of prostaglandin E2 production. At a transcriptional level, HtyOle inhibited the expression of inducible NO synthase, cyclooxygenase-2 and interleukin-1β. Moreover, HtyOle was identified for the first time in olive oil by-products by means of high performance liquid chromatography coupled with mass spectrometry. By contrast, HtyOle was not found in intact olives. Our results suggest that HtyOle is formed during oil processing and represents a significant form in which hydroxytyrosol occurs.

    Plasma citrulline concentration, a marker for intestinal functionality, reflects exercise intensity in healthy young men
    Kartaram, Shirley ; Mensink, Marco ; Teunis, Marc ; Schoen, Eric ; Witte, Gerrit ; Janssen Duijghuijsen, Lonneke ; Verschuren, Martie ; Mohrmann, Karin ; M'Rabet, Laura ; Knipping, Karen ; Wittink, Harriet ; Helvoort, Ardy van; Garssen, Johan ; Witkamp, Renger ; Pieters, Raymond ; Norren, Klaske van - \ 2019
    Clinical Nutrition 38 (2019)5. - ISSN 0261-5614 - p. 2251 - 2258.
    Citrulline - Exercise intensity - Glutamine - Intestinal fatty acid binding protein - Intestinal function

    Background & aims: Plasma citrulline concentration is considered to be a marker for enterocyte metabolic mass and to reflect its reduction as may occur during intestinal dysfunction. Strenuous exercise can act as a stressor to induce small intestinal injury. Our previous studies suggest that this comprises the intestinal ability to produce citrulline from a glutamine-rich protein bolus. In this study we investigated the effects of different exercise intensities and hydration state on citrulline and iFABP levels following a post-exercise glutamine bolus in healthy young men. Methods: Fifteen healthy young men (20–35 yrs, VO2 max 56.9 ± 3.9 ml kg−1 min−1) performed in a randomly assigned cross-over design, a rest (protocol 1) and four cycle ergometer protocols. The volunteers cycled submaximal at different percentages of their individual pre-assessed maximum workload (Wmax): 70% Wmax in hydrated (protocol 2) and dehydrated state (protocol 3), 50% Wmax (protocol 4) and intermittent 85/55% Wmax in blocks of 2 min (protocol 5). Immediately after 1 h exercise or rest, subjects were given a glutamine bolus with added alanine as an iso-caloric internal standard (7.5 g of each amino acid). Blood samples were collected before, during and after rest or exercise, up to 24 h post onset of the experiment. Amino acids and urea were analysed as metabolic markers, creatine phosphokinase and iFABP as markers of muscle and intestinal damage, respectively. Data were analysed using a multilevel mixed linear statistical model. p values were corrected for multiple testing. Results: Citrulline levels already increased before glutamine supplementation during normal hydrated exercise, while this was not observed in the dehydrated and rest protocols. The low intensity exercise protocol (50% Wmax) showed the highest increase in citrulline levels both during exercise (43.83 μmol/L ± 2.63 (p < 0.001)) and after glutamine consumption (50.54 μmol/L ± 2.62) compared to the rest protocol (28.97 μmol/L ± 1.503 and 41.65 μmol/L ± 1.96, respectively, p < 0.05). However, following strenuous exercise at 70% Wmax in the dehydrated state, citrulline levels did not increase during exercise and less after the glutamine consumption when compared to the resting condition and hydrated protocols. In line with this, serum iFABP levels were the highest with the strenuous dehydrated protocol (1443.72 μmol/L ± 249.9, p < 0.001), followed by the high intensity exercise at 70% Wmax in the hydrated condition. Conclusions: Exercise induces an increase in plasma citrulline, irrespective of a glutamine bolus. The extent to which this occurs is dependent on exercise intensity and the hydration state of the subjects. The same holds true for both the post-exercise increase in citrulline levels following glutamine supplementation and serum iFABP levels. These data indicate that citrulline release during exercise and after an oral glutamine bolus might be dependent on the intestinal health state and therefore on intestinal functionality. Glutamine is known to play a major role in intestinal physiology and the maintenance of gut health and barrier function. Together, this suggests that in clinical practice, a glutamine bolus to increase citrulline levels after exercise might be preferable compared to supplementing citrulline itself. To our knowledge this is the first time that exercise workload-related effects on plasma citrulline are reported in relation to intestinal damage.

    Feeding mitochondria: Potential role of nutritional components to improve critical illness convalescence
    Wesselink, E. ; Koekkoek, W.A.C. ; Grefte, S. ; Witkamp, R.F. ; Zanten, A.R.H. van - \ 2019
    Clinical Nutrition 38 (2019)3. - ISSN 0261-5614 - p. 982 - 995.
    ATP - Bio-energetic failure - Electron chain complex - Enzyme Q10 - Melatonin - Micronutrients

    Persistent physical impairment is frequently encountered after critical illness. Recent data point towards mitochondrial dysfunction as an important determinant of this phenomenon. This narrative review provides a comprehensive overview of the present knowledge of mitochondrial function during and after critical illness and the role and potential therapeutic applications of specific micronutrients to restore mitochondrial function. Increased lactate levels and decreased mitochondrial ATP-production are common findings during critical illness and considered to be associated with decreased activity of muscle mitochondrial complexes in the electron transfer system. Adequate nutrient levels are essential for mitochondrial function as several specific micronutrients play crucial roles in energy metabolism and ATP-production. We have addressed the role of B vitamins, ascorbic acid, α-tocopherol, selenium, zinc, coenzyme Q10, caffeine, melatonin, carnitine, nitrate, lipoic acid and taurine in mitochondrial function. B vitamins and lipoic acid are essential in the tricarboxylic acid cycle, while selenium, α-tocopherol, Coenzyme Q10, caffeine, and melatonin are suggested to boost the electron transfer system function. Carnitine is essential for fatty acid beta-oxidation. Selenium is involved in mitochondrial biogenesis. Notwithstanding the documented importance of several nutritional components for optimal mitochondrial function, at present, there are no studies providing directions for optimal requirements during or after critical illness although deficiencies of these specific micronutrients involved in mitochondrial metabolism are common. Considering the interplay between these specific micronutrients, future research should pay more attention to their combined supply to provide guidance for use in clinical practise. Revision number: YCLNU-D-17-01092R2.

    Side-effects related to adjuvant CAPOX treatment for colorectal cancer are associated with intermuscular fat area, not with total skeletal muscle or fat, a retrospective observational study
    Plas, R.L.C. ; Norren, K. van; Baar, H. van; Aller, C. van; Bakker, M. de; Botros, N. ; Witkamp, R.F. ; Haringhuizen, A. ; Kampman, E. ; Winkels, R.M. - \ 2018
    JCSM Clinical Reports 3 (2018)1. - ISSN 2521-3555 - 13 p.
    Aims Chemotherapeutic treatment is regularly accompanied by side‐effects. Hydrophilic chemotherapeutics such as capecitabine and oxaliplatin (CAPOX), often used in colorectal cancer treatment, predominantly accumulate in non adipose tissues. Therefore the aim of this paper was to investigate whether body composition and fat infiltration inthe muscle (muscle attenuation and intermuscular‐adipose‐tissue [IMAT] content) are associated with chemotherapy induced toxicities. Methods In this retrospective observational study, we collected data from 115 colorectal cancer patients receiving adjuvant CAPOX chemotherapy between 2006 and 2015. Information on cancer characteristics were obtained from the Netherlands Cancer Registry. Diagnostic CT scans were retrieved to assess cross‐sectional areas of skeletal muscle and adipose tissue at the third lumbar vertebrae. Information on dose‐limiting toxicity [DLT] and relative administered dose (as % of BSA‐based‐planned‐dose) were retrieved from medical charts. Associations between body composition,muscle quality and chemotherapy‐induced toxicities were determined using Cox‐regression and linear‐regression analyses. Results We found that DLT incidence was 90% in our cohort: 50% had their dose reduced, 30% their next cyclepostponed, 4% a full treatment stop and 6% was hospitalized at their first DLT. Most common were reductions in oxaliplatin dose whilst keeping the capecitabine dose constant. Cox regression analysis indicated no association between body composition or muscle quality and DLT during the first treatment cycle or time to the first DLT. Multiple linear regression showed that higher IMAT‐index and IMAT muscle percentage were associated with a lower relative administered dose of oxaliplatin. Conclusions In conclusion; only IMAT, not skeletal or fat area was associated with dose‐limiting toxicities among these CRC patients who received CAPOX treatment.
    Release of major peanut allergens from their matrix under various pH and simulated saliva conditions—Ara h2 and ara h6 are readily bio-accessible
    Koppelman, Stef J. ; Smits, Mieke ; Tomassen, Monic ; Jong, Govardus A.H. De; Baumert, Joe ; Taylor, Steve L. ; Witkamp, Renger ; Veldman, Robert Jan ; Pieters, Raymond ; Wichers, Harry - \ 2018
    Nutrients 10 (2018)9. - ISSN 2072-6643
    Allergen - Arachis hypogaea - Bio-accessibility - Peanut - Saliva

    The oral mucosa is the first immune tissue that encounters allergens upon ingestion of food. We hypothesized that the bio-accessibility of allergens at this stage may be a key determinant for sensitization. Light roasted peanut flour was suspended at various pH in buffers mimicking saliva. Protein concentrations and allergens profiles were determined in the supernatants. Peanut protein solubility was poor in the pH range between 3 and 6, while at a low pH (1.5) and at moderately high pHs (>8), it increased. In the pH range of saliva, between 6.5 and 8.5, the allergens Ara h2 and Ara h6 were readily released, whereas Ara h1 and Ara h3 were poorly released. Increasing the pH from 6.5 to 8.5 slightly increased the release of Ara h1 and Ara h3, but the recovery remained low (approximately 20%) compared to that of Ara h2 and Ara h6 (approximately 100% and 65%, respectively). This remarkable difference in the extraction kinetics suggests that Ara h2 and Ara h6 are the first allergens an individual is exposed to upon ingestion of peanut-containing food. We conclude that the peanut allergens Ara h2 and Ara h6 are quickly bio-accessible in the mouth, potentially explaining their extraordinary allergenicity.

    Understanding and improving the reusability of phosphate adsorbents for wastewater effluent polishing
    Suresh Kumar, Prashanth ; Ejerssa, Wondesen Workneh ; Wegener, Carita Clarissa ; Korving, Leon ; Dugulan, Achim Iulian ; Temmink, Hardy ; Loosdrecht, Mark C.M. van; Witkamp, Geert-Jan - \ 2018
    Water Research 145 (2018). - ISSN 0043-1354 - p. 365 - 374.
    Calcium adsorption - Phosphate adsorption - Regeneration - Reusability - Surface precipitation - Wastewater effluent

    Phosphate is a vital nutrient for life but its discharge from wastewater effluents can lead to eutrophication. Adsorption can be used as effluent polishing step to reduce phosphate to very low concentrations. Adsorbent reusability is an important parameter to make the adsorption process economically feasible. This implies that the adsorbent can be regenerated and used over several cycles without appreciable performance decline. In the current study, we have studied the phosphate adsorption and reusability of commercial iron oxide based adsorbents for wastewater effluent. Effects of adsorbent properties like particle size, surface area, type of iron oxide, and effects of some competing ions were determined. Moreover the effects of regeneration methods, which include an alkaline desorption step and an acid wash step, were studied. It was found that reducing the adsorbent particle size increased the phosphate adsorption of porous adsorbents significantly. Amongst all the other parameters, calcium had the greatest influence on phosphate adsorption and adsorbent reusability. Phosphate adsorption was enhanced by co-adsorption of calcium, but calcium formed surface precipitates such as calcium carbonate. These surface precipitates affected the adsorbent reusability and needed to be removed by implementing an acid wash step. The insights from this study are useful in designing optimal regeneration procedures and improving the lifetime of phosphate adsorbents used for wastewater effluent polishing.

    Changes in iron metabolism during prolonged repeated walking exercise in middle-aged men and women
    Terink, Rieneke ; Haaf, D. ten; Bongers, C.W.G. ; Balvers, M.G.J. ; Witkamp, R.F. ; Mensink, M. ; Eijsvogels, T.M.H. ; Klein Gunnewiek, J.M.T. ; Hopman, M.T.E. - \ 2018
    European Journal of Applied Physiology 118 (2018)11. - ISSN 1439-6319 - p. 2349 - 2357.
    Fe - Hb - Hp - Repetitive exercise

    Purpose: The aim of the present study was to assess the effect of prolonged and repeated exercise on iron metabolism in middle-aged adults and to compare differences between sexes. Methods: 50 male (58.9 ± 9.9 year) and 48 female (50.9 ± 11.2 year) individuals were monitored on 4 consecutive days at which they walked on average 8 h and 44 min per day at a self-determined pace. Blood samples were collected 1 or 2 days prior to the start of the exercise (baseline) and every day immediately post-exercise. Samples were analysed for iron, ferritin, haemoglobin, and haptoglobin concentrations. Results: Plasma iron decreased across days, while ferritin increased across days (both p < 0.001). Haptoglobin showed a decrease (p < 0.001) after the first day and increased over subsequent days (p < 0.001). Haemoglobin did not change after the first day, but increased during subsequent days (p < 0.05). At baseline, 8% of the participants had iron concentrations below minimum reference value (10 µmol/L), this increased to 43% at day 4. There was an interaction between sex and exercise days on iron (p = 0.028), ferritin (p < 0.001) and haemoglobin levels (p = 0.004), but not on haptoglobin levels. Conclusion: This study showed decreases in iron, increases in ferritin, a decrease followed by increases in haptoglobin and no change followed by increases in haemoglobin. This is most likely explained by (foot strike) haemolysis, inflammation, and sweat and urine losses. These processes resulted in iron levels below minimum reference value in a large number of our participants.

    Let thy food be thy medicine….when possible
    Witkamp, Renger F. ; Norren, Klaske van - \ 2018
    European Journal of Pharmacology 836 (2018). - ISSN 0014-2999 - p. 102 - 114.
    Food-drug interactions - Inflammation - Nutrition - Sarcopenia, Cachexia, Food-Pharma

    There is no evidence that Hippocrates, although being credited for it, ever literally stated ‘let thy food be thy medicine and thy medicine be thy food’. However, yet in line with Hippocrates’ philosophy, we are currently witnessing a reappraisal of the complementarity of nutrition and pharmacology. Recent studies not only underline the therapeutic potential of lifestyle interventions, but are also generating valuable insights in the complex and dynamic transition from health to disease. Next to this, nutritional biology can significantly contribute to the discovery of new molecular targets. It is clear that most of the current top-selling drugs used in chronic cardio-metabolic diseases modulate relatively late-stage complications, which generally indicate already longer existing homeostatic imbalances. Pharmacologists are increasingly aware that typical multifactorial disorders require subtle, multiple target pharmacological approaches, instead of the still often dominating ‘one disease - one target - one drug’ paradigm. This review discusses the recent developments in the pharma-nutrition interface and shows some relevant mechanisms, including receptors and other targets, and examples from clinical practice. The latter includes inflammatory diseases and progressive loss of muscle function. The examples also illustrate the potential of targeted combinations of medicines with nutrition and (or) other life-style interventions, to increase treatment efficacy and (or) reduce adverse effects. More attention to a potentially negative outcome of drug-food combinations is also required, as shown by the example of food-drug interactions. Together, the developments at the food-pharma interface underline the demand for intensified collaboration between the disciplines, in the clinic and in science.

    Mitochondrial dynamics in cancer-induced cachexia
    Ende, Miranda van der; Grefte, Sander ; Plas, Rogier ; Meijerink, Jocelijn ; Witkamp, Renger F. ; Keijer, Jaap ; Norren, Klaske van - \ 2018
    Biochimica et Biophysica Acta - Reviews on Cancer 1870 (2018)2. - ISSN 0304-419X - p. 137 - 150.
    Animal models - Cancer-induced cachexia - Mitochondria - Mitochondrial dynamics - Muscle

    Cancer-induced cachexia has a negative impact on quality of life and adversely affects therapeutic outcomes and survival rates. It is characterized by, often severe, loss of muscle, with or without loss of fat mass. Insight in the pathophysiology of this complex metabolic syndrome and direct treatment options are still limited, which creates a research demand. Results from recent studies point towards a significant involvement of muscle mitochondrial networks. However, data are scattered and a comprehensive overview is lacking. This paper aims to fill existing knowledge gaps by integrating published data sets on muscle protein or gene expression from cancer-induced cachexia animal models. To this end, a database was compiled from 94 research papers, comprising 11 different rodent models. This was combined with four genome-wide transcriptome datasets of cancer-induced cachexia rodent models. Analysis showed that the expression of genes involved in mitochondrial fusion, fission, ATP production and mitochondrial density is decreased, while that of genes involved ROS detoxification and mitophagy is increased. Our results underline the relevance of including post-translational modifications of key proteins involved in mitochondrial functioning in future studies on cancer-induced cachexia.

    In vitro anti-inflammatory and radical scavenging properties of chinotto (Citrus myrtifolia Raf.) essential oils
    Plastina, Pierluigi ; Apriantini, Astari ; Meijerink, Jocelijn ; Witkamp, Renger ; Gabriele, Bartolo ; Fazio, Alessia - \ 2018
    Nutrients 10 (2018)6. - ISSN 2072-6643
    Antioxidant - Citrus - Inflammation - Macrophages - Nitric oxide

    Chinotto (Citrus myrtifolia Raf.) is a widely diffused plant native from China and its fruits have a wide-spread use in confectionary and drinks. Remarkably, only little has been reported thus far on its bioactive properties, in contrast to those of the taxonomically related bergamot (Citrus bergamia Risso). The present study aimed to investigate potential in vitro anti-inflammatory and radical scavenging properties of chinotto essential oils (CEOs) and to establish to what extent their composition and bioactivities are dependent on maturation. Essential oil from half ripe chinotto (CEO2) reduced the production of nitric oxide (NO) and the expression of inflammatory genes, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), cytokines, including interleukin-1β (IL-1β) and interleukin-6 (IL-6), and chemokine monocyte chemotactic protein-1 (MCP-1) by lipopolysaccharide (LPS)-stimulated RAW264,7 macrophages. Limonene, linalool, linalyl acetate, and γ-terpinene were found to be the main components in CEO2. Moreover, CEO2 showed high radical scavenging activity measured as Trolox equivalents (TE) against both 2,2′-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS). These findings show that chinotto essential oil represents a valuable part of this fruit and warrants further in vivo studies to validate its anti-inflammatory potential.

    Increasing quality of life in pulmonary arterial hypertension : is there a role for nutrition?
    Vinke, Paulien ; Jansen, Suzanne M. ; Witkamp, Renger F. ; Norren, Klaske van - \ 2018
    Heart Failure Reviews 23 (2018)5. - ISSN 1382-4147 - p. 711 - 722.
    Deficiencies - Exercise - Lifestyle - Nutrition - Pulmonary arterial hypertension - Review

    Pulmonary arterial hypertension (PAH) is a progressive disease primarily affecting the pulmonary vasculature and heart. PAH patients suffer from exercise intolerance and fatigue, negatively affecting their quality of life. This review summarizes current insights in the pathophysiological mechanisms underlying PAH. It zooms in on the potential involvement of nutritional status and micronutrient deficiencies on PAH exercise intolerance and fatigue, also summarizing the potential benefits of exercise and nutritional interventions. Pubmed/Medline, Scopus, and Web of Science were searched for publications on pathophysiological mechanisms of PAH negatively affecting physical activity potential and nutritional status, and for potential effects of interventions involving exercise or nutritional measures known to improve exercise intolerance. Pathophysiological processes that contribute to exercise intolerance and impaired quality of life of PAH patients include right ventricular dysfunction, inflammation, skeletal muscle alterations, and dysfunctional energy metabolism. PAH-related nutritional deficiencies and metabolic alterations have been linked to fatigue, exercise intolerance, and endothelial dysfunction. Available evidence suggests that exercise interventions can be effective in PAH patients to improve exercise tolerance and decrease fatigue. By contrast, knowledge on the prevalence of micronutrient deficiencies and the possible effects of nutritional interventions in PAH patients is limited. Although data on nutritional status and micronutrient deficiencies in PAH are scarce, the available knowledge, including that from adjacent fields, suggests that nutritional intervention to correct deficiencies and metabolic alterations may contribute to a reduction of disease burden.

    Associations of hyperosmolar medications administered via nasogastric or nasoduodenal tubes and feeding adequacy, food intolerance and gastrointestinal complications amongst critically ill patients : A retrospective study
    Wesselink, Evertine ; Koekkoek, Kristine W.A.C. ; Looijen, Martijn ; Blokland, Dick A. van; Witkamp, Renger F. ; Zanten, Arthur R.H. van - \ 2018
    Clinical Nutrition ESPEN 25 (2018). - ISSN 2405-4577 - p. 78 - 86.
    Diarrhea - Enteral feeding - Enteral feeding intolerance - Gastric residual volume - Gastro-intestinal symptoms - Hyperosmolar medications - Tube feeding

    Background: Adequate nutrition is essential during critical illness. However, providing adequate nutrition is often hindered by gastro-intestinal complications, including feeding intolerance. It is suggested that hyperosmolar medications could be causally involved in the development of gastro-intestinal complications. The aims of the present study were 1) to determine the osmolality of common enterally administered dissolved medications and 2) to study the associations between nasogastric and nasoduodenal administered hyperosmolar medications and nutritional adequacy as well as food intolerance and gastro-intestinal symptoms. Methods: This retrospective observational cohort study was performed in a medical-surgical ICU in the Netherlands. Adult critically ill patients receiving enteral nutrition and admitted for a minimum ICU duration of 7 days were eligible. The osmolalities of commonly used enterally administrated medications were measured using an osmometer. Patients were divided in two groups: Use of hyperosmolar medications (>500 mOsm/kg) on at least one day during the first week versus none. The associations between the use of hyperosmolar medications and nutritional adequacy were assessed using multiple logistic regression analysis. The associations between hyperosmolar medication and food intolerance as well as gastrointestinal symptoms were assessed using ordinal logistic regression. Results: In total 443 patients met the inclusion criteria. Of the assessed medications, only three medications were found hyperosmolar. We observed no associations between the use of hyperosmolar medications and nutritional adequacy in the first week of ICU admission (caloric intake β −0.27 95%CI –1.38; 0.83, protein intake β 0.32 95%CI –0.90; 1.53). In addition, no associations were found for enteral feeding intolerance, diarrhea, obstipation, gastric residual volume, nausea and vomiting in ICU patients receiving hyperosmolar medications via a nasogastric tube. A subgroup analysis of patients on duodenal feeding showed that postpyloric administration of hyperosmolar medications was associated with increased risk of diarrhea (OR 138.7 95%CI 2.33; 8245). Conclusions: Our results suggest that nasogastric administration of hyperosmolar medication via a nasogastric tube does not affect nutritional adequacy, development of enteral feeding intolerance and other gastro-intestinal complications during the first week after ICU admission. During nasoduodenal administration an increased diarrhea incidence may be encountered.

    The effect of exercise on intestinal integrity and protein permeability
    Janssen Duijghuijsen, L.M. ; Keijer, J. ; Mensink, M.R. ; Bastiaan-Net, S. ; Mes, J.J. ; Luiking, Yvette ; Wichers, H.J. ; Witkamp, R.F. ; Norren, K. van - \ 2018
    Calcium imaging of GPCR activation using arrays of reverse transfected HEK293 cells in a microfluidic system
    Roelse, Margriet ; Henquet, Maurice G.L. ; Verhoeven, Harrie A. ; Ruijter, Norbert C.A. De; Wehrens, Ron ; Lenthe, Marco S. Van; Witkamp, Renger F. ; Hall, Robert D. ; Jongsma, Maarten A. - \ 2018
    Sensors 18 (2018)2. - ISSN 1424-8220
    Cameleon YC3.6 - Cell array - GPCR - Microfluidics - NK1 receptor - Reverse transfection
    Reverse-transfected cell arrays in microfluidic systems have great potential to perform large-scale parallel screening of G protein-coupled receptor (GPCR) activation. Here, we report the preparation of a novel platform using reverse transfection of HEK293 cells, imaging by stereo-fluorescence microscopy in a flowcell format, real-time monitoring of cytosolic calcium ion fluctuations using the fluorescent protein Cameleon and analysis of GPCR responses to sequential sample exposures. To determine the relationship between DNA concentration and gene expression, we analyzed cell arrays made with variable concentrations of plasmid DNA encoding fluorescent proteins and the Neurokinin 1 (NK1) receptor. We observed pronounced effects on gene expression of both the specific and total DNA concentration. Reverse transfected spots with NK1 plasmid DNA at 1% of total DNA still resulted in detectable NK1 activation when exposed to its ligand. By varying the GPCR DNA concentration in reverse transfection, the sensitivity and robustness of the receptor response for sequential sample exposures was optimized. An injection series is shown for an array containing the NK1 receptor, bitter receptor TAS2R8 and controls. Both receptors were exposed 14 times to alternating samples of two ligands. Specific responses remained reproducible. This platform introduces new opportunities for high throughput screening of GPCR libraries.
    The role of fatty acids and their endocannabinoid-like derivatives in the molecular regulation of appetite
    Witkamp, Renger F. - \ 2018
    Molecular Aspects of Medicine 64 (2018). - ISSN 0098-2997 - p. 45 - 67.
    Intake, absorption and synthesis of fatty acids, including those produced by the intestinal microbiota are tightly monitored via specific receptors and, indirectly through their conversion into a variety of signalling molecules. The resulting information is integrated and translated to different physiological processes, including the regulation of appetite and satiation. Direct chemosensing of fatty acids takes place via interaction with free fatty acid (FFA) and other receptors. These are present in the oronasal cavity and along the entire gastrointestinal tract, in various other tissues, and, for some receptors also in brain. Results from early studies have suggested differences between fatty acids in their ability to induce the release of satiety hormones or their short-term effects on food-intake. However, more recent findings indicate that this has limited impact on long-term energy intake. Similarly, pharmacological strategies for appetite control via modulation of peripheral fatty acid binding receptors have not met their expectations. Regarding the psychobiology of eating behaviour, there has been a shift towards emphasising the importance of food reward and the cephalic phase response. Lipid-rich foods are highly energy dense. During evolution this has stimulated the development of reward mechanisms, in which fatty acids, in conjunction with carbohydrates, are major triggers. Fatty acids are also precursors of endocannabinoids and their structural congeners. The endocannabinoid system (ECS) plays a pivotal role in the homeostatic and non-homeostatic regulation of eating behaviour. In the brain it links to different endocrine and neuronal pathways, including dopaminergic circuits in the mesocorticolimbic system such as the ventral tegmental area and the nucleus accumbens, which are crucial for hedonic eating. Despite the vast progress made in the field of neurobiology it is clear that eating behaviour, one of our strongest instincts, still possess major scientific challenges. The failure, already a decade ago, of the cannabinoid-receptor type 1 (CB1) blockers for treatment of overweight and its complications may serve as an illustration that 'single-target' approaches to modulate, or even understand-, over- or undereating are very unrealistic.
    Fish oil LC-PUFAs do not affect blood coagulation parameters and bleeding manifestations : Analysis of 8 clinical studies with selected patient groups on omega-3-enriched medical nutrition
    Jeansen, Stephanie ; Witkamp, Renger F. ; Garthoff, Jossie A. ; Helvoort, Ardy van; Calder, Philip C. - \ 2018
    Clinical Nutrition 37 (2018)3. - ISSN 0261-5614 - p. 948 - 957.
    Bleeding - Coagulation - DHA - EPA - LC-PUFA - Omega-3

    Background & aims: The increased consumption of fish oil enriched-products exposes a wide diversity of people, including elderly and those with impaired health to relatively high amounts of n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs). There is an ongoing debate around the possible adverse effects of n-3 LC-PUFAs on bleeding risk, particularly relevant in people with a medical history of cardiovascular events or using antithrombotic drugs. Methods: This analysis of 8 clinical intervention studies conducted with enteral medical nutrition products containing fish oil as a source of n-3 LC-PUFAs addresses the occurrence of bleeding-related adverse events and effects on key coagulation parameters (Prothrombin Time [PT], (activated) and Partial Thromboplastin Time [(a)PTT]). Results: In all the patients considered (over 600 subjects treated with the active product in total), with moderate to severe disease, with or without concomitant use of antithrombotic agents, at home or in an Intensive Care Unit (ICU), no evidence of increased risk of bleeding with use of n-3 LC-PUFAs was observed. Furthermore there were no statistically significant changes from baseline in measured coagulation parameters. Conclusion: These findings further support the safe consumption of n-3 LC-PUFAs, even at short-term doses up to 10 g/day of eicosapentaenoic acid + docosahexaenoic acid (EPA + DHA) or consumed for up to 52 weeks above 1.5 g/day, in selected vulnerable and sensitive populations such as subjects with gastrointestinal cancer or patients in an ICU. We found no evidence to support any concern raised with regards to the application of n-3 LC-PUFAs and the potentially increased risk for the occurrence of adverse bleeding manifestations in these selected patient populations consuming fish oil enriched medical nutrition.

    Eat your way to health
    Witkamp, R.F. - \ 2017
    A tomato with your coffee?
    Witkamp, R.F. ; Kleef, E. van; Zeinstra, G.G. - \ 2017
    ‘Bepaal per patiënt de optimale combinatie van voeding en farma’
    Witkamp, R.F. - \ 2017
    Food reward from a behavioural and (neuro)physiological perspective
    Bruijn, Suzanne E.M. - \ 2017
    Wageningen University. Promotor(en): C. de Graaf; R.F. Witkamp, co-promotor(en): G. Jager. - Wageningen : Wageningen University - ISBN 9789463436748 - 154
    food - physiological functions - feeding behaviour - food preferences - perception - hormones - responses - neurohormonal control - stomach bypass - gastric bypass - satiety - voedsel - fysiologische functies - voedingsgedrag - voedselvoorkeuren - perceptie - hormonen - reacties - neurohormonale controle - maag bypass - buik bypass - verzadigdheid

    Food reward is an important driver of food intake and triggers consumption of foods for pleasure, so-called hedonic eating, even in the absence of any energy deficits. Hedonic eating can trigger overeating and may therefore lead to obesity. Given the rise in obesity rates and the health risks associated with being obese, hedonic eating and food reward are important phenomena to study. This thesis aimed to add on to the existing knowledge on food reward. The phenomenon was approached from a behavioural, sensory and (neuro)physiological perspective in healthy, lean and in obese gastric bypass populations.

    For the behavioural perspective, the main outcome measure used in this thesis was food preferences. To be able to study food preferences for four macronutrient and two taste categories, a new food preference task was developed. In chapter 2, the development and validation of the Macronutrient and Taste Preference Ranking Task (MTPRT) were described. The MTPRT uses a ranking method to determine preferences for four macronutrient (high-carbohydrate, high-fat, high-protein, low-energy) and two taste (sweet and savoury) categories.

    For the sensory and physiological perspective, focus was put on the endocannabinoid system (ECS): a neuromodulatory system that plays a role in food reward. To gain more insight into this role, the effect of ECS modulation with pharmacological challenges on sensory perception of sweet taste and on food preferences were studied, as well as endocannabinoid responses to food intake. In chapter 3 it was shown that inhaling Cannabis with low doses of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) does not alter sweet taste intensity perception and liking in humans, nor does it affect food preferences. Vice versa, in chapter 4 it was found that liking of a food taste does not affect endocannabinoid responses to food intake, after controlling for expectations. When palatability of the food is unknown until the first bite, response of endocannabinoids, ghrelin and pancreatic polypeptide did not differ between a palatable and a neutral food across anticipatory, consummatory and post-ingestive phases of food intake. Endocannabinoid and ghrelin plasma concentrations decreased after food intake, which suggests an orexigenic function for endocannabinoids.

    In chapters 5, 6 and 7, studies with patients who underwent Roux-en-Y gastric bypass surgery were described. These studies were intended to gain more insight into alterations in food reward in relation to (morbid) obesity and in response to surgical treatment by RYGB surgery.

    First, in chapter 5 food preferences were assessed before, and at two months and one year after RYGB. It was shown that patients have decreased preference for high-carbohydrate and high-fat foods, and increased preference for low-energy foods after compared with before surgery. In addition, liking ratings for the high-carbohydrate and high-fat foods were decreased after RYGB surgery, whereas liking of low-energy products changed minimally. Potential mechanisms behind these alterations in food preferences include changes in neural processing of food cues and changes in appetite-related gut hormones.

    In chapter 6, it was shown that alterations in food preferences after RYGB surgery are indeed related to changes in neural activation in response to food cues. With regards to the appetite-related hormones it was shown that plasma concentrations of the endocannabinoid anandamide were increased after compared with before surgery. Plasma concentrations of other endocannabinoids and ghrelin did not change. Moreover, changes in endocannabinoid or ghrelin concentrations did not correlate with changes in food preferences or neural response to food cues. Together, these results suggest that changes in neural processing of food cues contribute to changes in food preferences towards low-energy foods, and provide a first indication that the endocannabinoid system does not seem to play a role in this process.

    To gain more insight into behavioural responses to food cues, a response-inhibition paradigm was used in chapter 7, in which response-inhibition to high-energy and low-energy food cues was assessed during brain imaging. The behavioural data did not show differences in performance when comparing before and two months after RYGB surgery. The brain imaging data showed that activation in reward-related brain areas was decreased in response to both high- and low-energy food pictures after RYGB surgery. Also, prefrontal brain areas were more activated in response to the high-energy pictures, which suggests improved response inhibition.

    In conclusion, the findings in this thesis show that modulating the ECS with low doses of THC and CBD does not influence sweet taste perception and liking and food preferences, and vice versa, food taste liking in the absence of expectations does not affect endocannabinoid responses to food intake. With regards to RYGB surgery it was uncovered that changes in food preferences after RYGB surgery are related to altered brain reward processing, but no relation with changes in endocannabinoid tone was found. The success of RYGB surgery and the changes in food choice might in part be caused by an improved inhibitory response to high-energy foods.

    Eet jezelf gezond
    Witkamp, R.F. - \ 2017
    Eet jezelf gezond
    Witkamp, R.F. - \ 2017
    Public health relevance of drug–nutrition interactions
    Péter, Szabolcs ; Navis, Gerjan ; Borst, Martin H. de; Schacky, Clemens von; Orten-Luiten, Anne Claire B. van; Zhernakova, Alexandra ; Witkamp, Renger F. ; Janse, André ; Weber, Peter ; Bakker, Stephan L.J. ; Eggersdorfer, Manfred - \ 2017
    European Journal of Nutrition 56 (2017)suppl. 2. - ISSN 1436-6207 - p. 23 - 36.
    Drug–nutrient interactions - Health benefits - Microbiota - Micronutrient deficiency - Public health
    The public health relevance of drug–nutrition interactions is currently highly undervalued and overlooked. This is particularly the case for elderly persons where multi-morbidity and consequently polypharmacy is very common. Vitamins and other micronutrients have central functions in metabolism, and their interactions with drugs may result in clinically relevant physiological impairments but possibly also in positive effects. On 12 April 2016, the University Medical Center Groningen (The Netherlands), as part of its Healthy Ageing program, organized a workshop on the public health relevance of drug–nutrient interactions. In this meeting, experts in the field presented results from recent studies on interactions between pharmaceuticals and nutrients, and discussed the role of nutrition for elderly, focusing on those persons receiving pharmaceutical treatment. This paper summarizes the proceedings of the symposium and provides an outlook for future research needs and public health measures. Since food, pharma and health are closely interconnected domains, awareness is needed in the medical community about the potential relevance of drug–nutrition interactions. Experts and stakeholders should advocate for the integration of drug–nutrition evaluations in the drug development process. Strategies for the individual patients should be developed, by installing drug review protocols, screening for malnutrition and integrating this topic into the general medical advice.
    The role of hypothalamic inflammation, the hypothalamic–pituitary–adrenal axis and serotonin in the cancer anorexia–cachexia syndrome
    Norren, Klaske van; Dwarkasing, Jvalini T. ; Witkamp, Renger F. - \ 2017
    Current Opinion in Clinical Nutrition and Metabolic Care 20 (2017)5. - ISSN 1363-1950 - p. 396 - 401.
    PURPOSE OF REVIEW: In cancer patients, the development of cachexia (muscle wasting) is frequently aggravated by anorexia (loss of appetite). Their concurrence is often referred to as anorexia–cachexia syndrome. This review focusses on the recent evidence underlining hypothalamic inflammation as key driver of these processes. Special attention is given to the involvement of hypothalamic serotonin. RECENT FINDINGS: The anorexia–cachexia syndrome is directly associated with higher mortality in cancer patients. Recent reports confirm its severe impact on the quality of life of patients and their families.Hypothalamic inflammation has been shown to contribute to muscle and adipose tissue loss in cancer via central hypothalamic interleukine (IL)1β-induced activation of the hypothalamic–pituitary–adrenal axis. The resulting release of glucocorticoids directly stimulates catabolic processes in these tissues via activation of the ubiquitin–proteosome pathway. Next to this, hypothalamic inflammation has been shown to reduce food intake in cancer by triggering changes in orexigenic and anorexigenic responses via upregulation of serotonin availability and stimulation of its signalling pathways in hypothalamic tissues. This combination of reduced food intake and stimulation of tissue catabolism represents a dual mechanism by which hypothalamic inflammation contributes to the development and maintenance of anorexia and cachexia in cancer. SUMMARY: Hypothalamic inflammation is a driving force in the development of the anorexia-cachexia syndrome via hypothalamic–pituitary–adrenal axis and serotonin pathway activation.
    Beta-blocker use and fall risk in older individuals : Original results from two studies with meta-analysis
    Ham, Annelies C. ; Dijk, S.C. van; Swart, Karin M.A. ; Enneman, Anke W. ; Zwaluw, Nikita L. van der; Brouwer-Brolsma, Elske M. ; Schoor, Natasja M. van; Zillikens, M.C. ; Lips, Paul ; Groot, Lisette C.P.G.M. de; Hofman, Albert ; Witkamp, Renger F. ; Uitterlinden, André G. ; Stricker, Bruno H. ; Velde, Nathalie van der - \ 2017
    British Journal of Clinical Pharmacology 83 (2017)10. - ISSN 0306-5251 - p. 2292 - 2302.
    CYP2D6 - Falls - Meta-analysis - β-blockers

    Aims: To investigate the association between use of β-blockers and β-blocker characteristics - selectivity, lipid solubility, intrinsic sympathetic activity (ISA) and CYP2D6 enzyme metabolism - and fall risk. Methods: Data from two prospective studies were used, including community-dwelling individuals, n = 7662 (the Rotterdam Study) and 2407 (B-PROOF), all aged ≥55 years. Fall incidents were recorded prospectively. Time-varying β-blocker use was determined using pharmacy dispensing records. Cox proportional hazard models adjusted for age and sex were applied to determine the association between β-blocker use, their characteristics - selectivity, lipid solubility, ISA and CYP2D6 enzyme metabolism - and fall risk. The results of the studies were combined using meta-analyses. Results: In total 2917 participants encountered a fall during a total follow-up time of 89529 years. Meta-analysis indicated no association between use of any β-blocker, compared to nonuse, and fall risk, hazard ratio (HR) = 0.97 [95% confidence interval (CI) 0.88-1.06]. Use of a selective β-blocker was also not associated with fall risk, HR = 0.92 (95%CI 0.83-1.01). Use of a nonselective β-blocker was associated with an increased fall risk, HR = 1.22 (95%CI 1.01-1.48). Other β-blocker characteristics including lipid solubility and CYP2D6 enzyme metabolism were not associated with fall risk. Conclusion: Our study suggests that use of a nonselective β-blocker, contrary to selective β-blockers, is associated with an increased fall risk in an older population. In clinical practice, β-blockers have been shown effective for a variety of cardiovascular indications. However, fall risk should be considered when prescribing a β-blocker in this age group, and the pros and cons for β-blocker classes should be taken into consideration.

    Wat moet je doen en laten als je gezonder wilt worden?
    Witkamp, R.F. - \ 2017
    Universiteit van Nederland
    Slik jij de praatjes van afslankguru’s als zoete koek? Ken jij alle dieten uit je hoofd? Renger Witkamp, hoogleraar Voeding en Farmacologie (Wageningen UR) bekijkt al deze hypes met een nuchtere en wetenschappelijke blik. Na dit praatje kun je alles wat je voorgeschoteld krijgt in de media over je gezondheid beter in perspectief plaatsen.
    'Leefstijl vaker inzetten als medicijn'
    Witkamp, R.F. - \ 2017

    Gezonde voeding en beweging moeten vaker worden ingezet als ‘medicijn’ tegen chronische aandoeningen. Zieken krijgen dan niet alleen pillen, maar ook groente, fruit, fietsen en wandelen op recept. Dat schrijven deskundigen van onder meer WUR in het rapport Kennissynthese voeding als behandeling van chronische ziekte, dat ze hebben gemaakt in opdracht van ZonMW.

    Kennissynthese voeding als behandeling van chronische ziekten
    Witkamp, Renger ; Navis, Gerjan ; Boer, Jolanda ; Plat, Jogchum ; Assendelft, Pim ; Vries, Jeanne de; Dekker, Louise ; Seves, Marije ; Pot, Gerda - \ 2017
    Wageningen : Wageningen Universiteit - 70
    Deze kennissynthese richt zicht op voeding als therapeutische optie, dat wil zeggen: het specifiek inzetten van voedingsmaatregelen teneinde het beloop van chronische ziekten gunstig te beïnvloeden. Het begrip voeding wordt in dit verband gedefinieerd als ‘voedingsmiddelen zoals ook beschreven in de Richtlijnen Goede Voeding’. Dit betekent dat de medische voeding (dieetvoeding voor medisch gebruik) hier niet is meegenomen. De synthese is uitgevoerd in opdracht van ZonMW, door een team van deskundigen van Wageningen Universiteit en Research (WUR), het Universitair Medisch Centrum Groningen (UMCG), het Rijksinstituut voor Volksgezondheid en Milieu (RIVM) en het RadboudUMC. Tijdens de uitvoering zijn vertegenwoordigers van verschillende universiteiten en medische centra, voedingskundigen, artsen, diëtisten en andere zorgprofessionals, patiëntenverenigingen, gezondheidsfondsen en industrie geconsulteerd. Daarnaast zijn bestaande richtlijnen en voedingsadviezen in kaart gebracht en is gekeken naar wetenschapsagenda’s.
    Effect of pore size distribution on iron oxide coated granular activated carbons for phosphate adsorption – Importance of mesopores
    Suresh Kumar, Prashanth ; Prot, Thomas ; Korving, Leon ; Keesman, Karel J. ; Dugulan, Iulian ; Loosdrecht, Mark C.M. van; Witkamp, Geert Jan - \ 2017
    Chemical Engineering Journal 326 (2017). - ISSN 1385-8947 - p. 231 - 239.
    Adsorption affinity - Iron coating - Mesopores - Non Local Density Functional Theory (NLDFT) - Oxidized activated carbon

    Adsorption is often suggested for to reach very low phosphate levels in municipal wastewater effluent and even to recover phosphate. Adsorbent performance is usually associated with surface area but the exact role of the pore size distribution (PSD) is unclear. Here, we show the effect of the PSD on phosphate adsorption. Granular activated carbons (GACs) with varying PSDs were treated with potassium permanganate followed by reaction with ferric chloride to form iron oxide coated GACs (Fe-GACs). Energy dispersive X-ray and kinetics experiments confirmed that manganese anchored on the GAC is important for subsequent iron attachment. Mössbauer spectroscopy showed presence of ferrihydrite in Fe-GAC. Transmission electron microscopy showed that the iron oxide particles are not present in the micropores of the GACs. Phosphate adsorption isotherms were performed with the Fe-GACs and adsorption at lower phosphate concentrations correlated with the porous area of >3 nm of the adsorbents, a high fraction of which is contributed by mesopores. These results show that high surface areas of GACs resulting from micropores do not contribute to adsorption at low phosphate concentrations. This can be explained by the micropores being difficult to coat with iron oxide nanoparticles, but in addition the diffusion of phosphate into these pores could also be hindered. It is therefore recommended to use backbones having high mesoporous areas. This information is useful for developing adsorbents particularly for applications treating low phosphate concentrations, for e.g. in municipal wastewater effluent polishing.

    Docosahexaenoyl serotonin emerges as most potent inhibitor of IL-17 and CCL-20 released by blood mononuclear cells from a series of N-acyl serotonins identified in human intestinal tissue
    Wang, Ya ; Balvers, Michiel G.J. ; Hendriks, Henk F.J. ; Wilpshaar, Tessa ; Heek, Tjarda van; Witkamp, Renger F. ; Meijerink, Jocelijn - \ 2017
    Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids 1862 (2017)9. - ISSN 1388-1981 - p. 823 - 831.
    CCL-20 - Docosahexaenoyl serotonin - Endocannabinoids - IL-17 - Inflammatory bowel disease (IBD) - Th17

    Fatty acid amides (FAAs), conjugates of fatty acids with ethanolamine, mono-amine neurotransmitters or amino acids are a class of molecules that display diverse functional roles in different cells and tissues. Recently we reported that one of the serotonin-fatty acid conjugates, docosahexaenoyl serotonin (DHA-5-HT), previously found in gut tissue of mouse and pig, attenuates the IL-23-IL-17 signaling axis in LPS-stimulated mice macrophages. However, its presence and effects in humans remained to be elucidated. Here, we report for the first time its identification in human intestinal (colon) tissue, along with a series of related N-acyl serotonins. Furthermore, we tested these fatty acid conjugates for their ability to inhibit the release of IL-17 and CCL-20 by stimulated human peripheral blood mononuclear cells (PBMCs). Serotonin conjugates with palmitic acid (PA-5-HT), stearic acid (SA-5-HT) and oleic acid (OA-5-HT) were detected in higher levels than arachidonoyl serotonin (AA-5-HT) and DHA-5-HT, while eicosapentaenoyl serotonin (EPA-5-HT) could not be quantified. Among these, DHA-5-HT was the most potent in inhibiting IL-17 and CCL-20, typical Th17 pro-inflammatory mediators, by Concanavalin A (ConA)-stimulated human PBMCs. These results underline the idea that DHA-5-HT is a gut-specific endogenously produced mediator with the capacity to modulate the IL-17/Th17 signaling response. Our findings may be of relevance in relation to intestinal inflammatory diseases like Crohn's disease and Ulcerative colitis.

    Decrease in ionized and total magnesium blood concentrations in endurance athletes following an exercise bout restores within hours-potential consequences for monitoring and supplementation
    Terink, Rieneke ; Balvers, Michiel G.J. ; Hopman, Maria T. ; Witkamp, Renger F. ; Mensink, Marco ; Klein Gunnewiek, J.M.T. - \ 2017
    International Journal of Sport Nutrition & Exercise Metabolism 27 (2017)3. - ISSN 1526-484X - p. 164 - 170.
    Blood analysis - Micronutrients - Status monitoring

    Magnesium is essential for optimal sport performance, generating an interest to monitor its status in athletes. However, before measuring magnesium status in blood could become routine, more insight into its diurnal fluctuations and effects of exercise itself is necessary. Therefore, we measured the effect of an acute bout of exercise on ionized (iMg) and total plasma magnesium (tMg) in blood obtained from 18 healthy well-trained endurance athletes (age, 31.1 ± 8.1 yr.; VO2max, 50.9 ± 7.5 ml/kg/min) at multiple time points, and compared this with a resting situation. At both days, 7 blood samples were taken at set time points (8:30 fasted, 11:00, 12:30, 13:30, 15:00, 16:00, 18:30). The control day was included to correct for a putative diurnal fluctuation of magnesium. During the exercise day, athletes performed a 90 min bicycle ergometer test (70% VO2max) between 11:00 and 12:30. Whole blood samples were analyzed for iMg and plasma for tMg concentrations. Both concentrations decreased significantly after exercise (0.52 ± 0.04-0.45 ± 0.03 mmol/L and 0.81 ± 0.07-0.73 ± 0.06 mmol/L, respectively, p <.001) while no significant decline was observed during that time-interval on control days. Both, iMg and tMg, returned to baseline, on average, 2.5 hr after exercise. These findings suggest that timing of blood sampling to analyze Mg status is important. Additional research is needed to establish the recovery time after different types of exercise to come to a general advice regarding the timing of magnesium status assessment in practice.

    Endocannabinoids derived from n-3 PUFAs - Formation, release and possible roles in inflammation and obesity
    Wang, Ya - \ 2017
    Wageningen University. Promotor(en): R.F. Witkamp, co-promotor(en): J. Meijerink; J.-P. Vincken. - Wageningen : Wageningen University - ISBN 9789463432016 - 195
    polyunsaturated fats - health promotion - obesity - inflammation - cannabinoids - neurology - energy restricted diets - meervoudig onverzadigde vetten - gezondheidsbevordering - obesitas - ontsteking - cannabinoïden - neurologie - energiearme diëten

    The fatty acid composition of our daily diet is considered a major determinant of long-term health risk and the development of disease. Several lines of evidence point toward a state of chronic ‘low-grade’ inflammation as an overarching process that is modulated by fatty acids and their different metabolites. Diets rich in omega-3 polyunsaturated fatty acids (PUFAs), among which docosahexaenoic acid (22:6n-3; DHA) have been found to be associated with a reduction of inflammatory activity. However, the mechanisms underlying these immune-modulatory effects of n-3 PUFAs are only partly known. Earlier data from our group and from other labs have provided evidence for an as yet largely unexplored mechanism involving the formation of DHA-derived fatty acid amides. Fatty acid amides (FAAs) are a group of lipids formed from fatty acids and biogenic amines, which are widely occurring in nature. An increasing number of FAAs, including conjugates of fatty acids with neurotransmitters and mono-amines, have been detected as endogenous molecules in different cells and tissues. However, their bioactivities have remained largely unknown so far.

    In the first experimental part (chapter 2 and 3) of this thesis, we explored the immune-modulatory profiles of two relatively unknown DHA-derived FAAs conjugates with dopamine and serotonin, respectively. In chapter 2, we enzymatically synthesised the dopamine conjugate of DHA, N-docosahexaenoyl dopamine (DHDA), and demonstrated that DHDA significantly suppressed the production of several mediators involved in (neuro-)inflammation. We showed that these immune-modulatory effects involved the enzyme cyclooxygenase-2 (COX-2), as its gene-expression and (or) production of its metabolite PGE2 were down-regulated by DHDA in both activated macrophages as well as microglia. Additionally, the immune-modulatory activities of DHDA were compared with those of N-arachidonoyl dopamine (NADA) and similar potencies were found in the cell types tested. In chapter 3, we investigated the effects of docosahexaenoyl serotonin (DHA-5-HT), the serotonin conjugate of DHA on inflammatory processes in human PBMCs. By comparing the immune-modulatory potencies of 6 serotonin-conjugates with palmitic acid (PA-5-HT), stearic acid (SA-5-HT), oleic acid (OA-5-HT), arachidonic acid (AA-5-HT), eicosapentaenoic acid (EPA-5-HT) and docosahexaenoic acid (DHA-5-HT), DHA-5-HT turned out to exert the strongest inhibitory effects on the production of IL-17 from ConA-stimulated human PBMCs. Furthermore, DHA-5-HT concentration-dependently inhibited the production of IL-17 and CCL-20, two important Th17 mediators involved in the pathogenesis of IBD. Also, we demonstrated the in vivo presence of N-acyl serotonins in human intestine. Taken together, we revealed the immune-modulatory effects of two n-3 PUFA-derived fatty acid amides with thus far largely unknown functions and showed that these compounds were far more potent than its parent compound DHA. These findings were shown not only for innate inflammatory processes in stimulated mouse macrophages, but were also found to be present in human PBMCs and likely involved the adaptive CD4+ Th17 response.

    In order to study the effects of dietary omega-3 fatty acids on endocannabinoid tone in relation to obesity and metabolic health, a parallel-designed, randomized human study was conducted in the second part of the thesis. In this 12 weeks intervention hundred men and women with abdominal obesity were assigned to either a Western type energy restricted (ER) diet, a Targeted ER diet or a control group. The two ER diet groups were both subjected to energy restriction but their diets differed in nutrient composition. The traditional, more Western-style diet (Western ER diet) included both saturated as well as unsaturated fats, whereas the Targeted ER diet was amongst others enriched with monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs). This intervention resulted in significant weight loss and significant improvements of metabolic parameters in both energy restriction (ER) dietary intervention groups. In chapter 4, we revealed that the two weight loss regimes (ER-diets) with different fatty acid composition did not significantly affect fasting peripheral levels of AEA and 2-AG in both plasma and abdominal adipose tissues. By contrast, plasma DHEA was found to be significantly decreased in the Western ER group compared with the Targeted ER group. Additionally, circulating EC-related compounds DHEA, DHAGly, PEA and SEA were significantly decreased in the Western ER diet group after intervention. Furthermore, decreased levels of DHEA were positively associated with body weight reduction. In chapter 5, by performing a high calorie mixed meal test (MMT) before and after the intervention, we found that postprandial AEA and 2-AG levels were significantly reduced in the targeted ER group upon the intervention. By contrast, the DHA-derived compounds DHEA and DHAGly showed a significant increase in the Targeted ER group after 12 weeks of intervention. Additionally, all measured endocannabinoids and related compounds, with the exception of 2-AG, showed a similar characteristic time curve in response to the MMT, with EC levels reaching their highest concentration as early as 5 minutes after food intake (T=10min in experiment).

    In conclusion, we showed here that two largely unknown amidated DHA conjugates are more potent mediators of inflammatory processes than their parent compound DHA. These findings support our previously proposed idea that DHA-derived FAAs play a role in the underlying mechanism of the beneficial health effects of DHA. We further uncovered that a combination of ER and n-3 PUFAs in the diet alters the postprandial endocannabinoid tone. Given the fact that the endocannabinoid system (ECS) plays an important role in both the central and peripheral regulation of food intake and energy homeostasis, these findings provide new insights in the potentially mechanisms involved in an over-activated endocannabinoid system during obesity.

    Optimal nutrition and the ever-changing dietary landscape : a conference report
    Shao, A. ; Drewnowski, A. ; Willcox, D.C. ; Krämer, L. ; Lausted, C. ; Eggersdorfer, M. ; Mathers, J. ; Bell, J.D. ; Randolph, R.K. ; Witkamp, R. ; Griffiths, J.C. - \ 2017
    European Journal of Nutrition 56 (2017)suppl.1. - ISSN 1436-6207 - 21 p.
    Aging - Big data - Bioactives - Biomarkers - Dietary patterns - Dietary supplements - Longevity - Micronutrients - Obesity - Overfed - Phytonutrients - Sarcopenic obesity - Systems approaches - Undernourished - Wellness

    The field of nutrition has evolved rapidly over the past century. Nutrition scientists and policy makers in the developed world have shifted the focus of their efforts from dealing with diseases of overt nutrient deficiency to a new paradigm aimed at coping with conditions of excess—calories, sedentary lifestyles and stress. Advances in nutrition science, technology and manufacturing have largely eradicated nutrient deficiency diseases, while simultaneously facing the growing challenges of obesity, non-communicable diseases and aging. Nutrition research has gone through a necessary evolution, starting with a reductionist approach, driven by an ambition to understand the mechanisms responsible for the effects of individual nutrients at the cellular and molecular levels. This approach has appropriately expanded in recent years to become more holistic with the aim of understanding the role of nutrition in the broader context of dietary patterns. Ultimately, this approach will culminate in a full understanding of the dietary landscape—a web of interactions between nutritional, dietary, social, behavioral and environmental factors—and how it impacts health maintenance and promotion.

    Tomaatje bij de koffie?
    Witkamp, Renger ; Vet, Emely de; Immink, Victor ; Kleef, Ellen van; Zeinstra, Gertrude - \ 2017

    Wie alleen ’s avonds groenten eet, krijgt er te weinig van binnen. Onderzoekers zoeken daarom nieuwe manieren om groenten aan de man te krijgen. En het werkt. Vergaderaars blijken bijvoorbeeld best bereid hun koekje bij de koffie in te ruilen voor snoeptomaatjes. ‘Als er groenten voorhanden zijn, willen mensen die graag eten.’

    N-Docosahexaenoyl Dopamine, an Endocannabinoid-like Conjugate of Dopamine and the n-3 Fatty Acid Docosahexaenoic Acid, Attenuates Lipopolysaccharide-Induced Activation of Microglia and Macrophages via COX-2
    Wang, Ya ; Plastina, Pierluigi ; Vincken, Jean Paul ; Jansen, Renate ; Balvers, Michiel ; Klooster, Jean Paul ten; Gruppen, Harry ; Witkamp, Renger ; Meijerink, Jocelijn - \ 2017
    ACS Chemical Neuroscience 8 (2017)3. - ISSN 1948-7193 - p. 548 - 557.
    cyclooxygenase-2 - Endocannabinoids - interleukin-6 - N-arachidonoyl dopamine - N-docosahexaenoyl dopamine - prostaglandin E

    Several studies indicate that the n-3 long-chain polyunsaturated fatty acid docosahexaenoic acid (DHA) contributes to an attenuated inflammatory status in the development of neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease. To explain these effects, different mechanisms are being proposed, including those involving endocannabinoids and related signaling molecules. Many of these compounds belong to the fatty acid amides, conjugates of fatty acids with biogenic amines. Conjugates of DHA with ethanolamine or serotonin have previously been shown to possess anti-inflammatory and potentially neuroprotective properties. Here, we synthesized another amine conjugate of DHA, N-docosahexaenoyl dopamine (DHDA), and tested its immune-modulatory properties in both RAW 264.7 macrophages and BV-2 microglial cells. N-Docosahexaenoyl dopamine significantly suppressed the production of nitric oxide (NO), the cytokine interleukin-6 (IL-6), and the chemokines macrophage-inflammatory protein-3α (CCL20) and monocyte chemoattractant protein-1 (MCP-1), whereas its parent compounds, dopamine and DHA, were ineffective. Further exploration of potential effects of DHDA on key inflammatory mediators revealed that cyclooxygenase-2 (COX-2) mRNA level and production of prostaglandin E2 (PGE2) were concentration-dependently inhibited in macrophages. In activated BV-2 cells, PGE2 production was also reduced, without changes in COX-2 mRNA levels. In addition, DHDA did not affect NF-kB activity in a reporter cell line. Finally, the immune-modulatory activities of DHDA were compared with those of N-arachidonoyl dopamine (NADA) and similar potencies were found in both cell types. Taken together, our data suggest that DHDA, a potentially endogenous endocannabinoid, may be an additional member of the group of immune-modulating n-3 fatty acid-derived lipid mediators.

    Micronutrient Intakes in 553 Dutch Elite and Sub-Elite Athletes: Prevalence of Low and High Intakes in Users and Non-Users of Nutritional Supplements
    Wardenaar, Floris ; Brinkmans, Naomi ; Ceelen, Ingrid ; Rooij, Bo Van; Mensink, Marco ; Witkamp, Renger ; Vries, Jeanne De - \ 2017
    Nutrients 9 (2017)2. - ISSN 2072-6643
    This study investigated whether athletes meet micronutrient recommendations and whether the adequacy of their intake is related to the use of dietary supplements, sport nutrition products or a combination. Micronutrient intakes of 553 Dutch (sub-) elite athletes were assessed using web-based 24-h dietary recalls with accompanying nutritional supplement questionnaires. In the majority of both users and non-users of dietary supplements, vitamin D intake was below the estimated average requirement (AR) if supplements were not included in the analysis. Including dietary supplements improved vitamin D intake, but still a part of the athletes, both men and women, reported an intake below the AR. Non-users of dietary supplements were particularly at risk for low intakes of vitamins B1, B2, B3 and vitamins A, C and selenium. Mean iron intake was reported below the AR in a substantial group of women, both users and non-users. The use of sport nutrition products contributed only slightly to micronutrient intake. A small prevalence of athletes using dietary supplements showed intakes of some micronutrients above the Upper Level. In conclusion, both users and non-users of nutritional supplements reported inadequate intake of micronutrients. For most micronutrients, use of nutritional supplements does not completely compensate for intakes below AR. Athletes should consider making better food choices and the daily use of a low-dosed multivitamin supplement. View Full-Text
    Macronutrient Intakes in 553 Dutch Elite and Sub-Elite Endurance, Team, and Strength Athletes: Does Intake Differ between Sport Disciplines?
    Wardenaar, Floris ; Brinkmans, Naomi ; Ceelen, Ingrid ; Rooij, Bo Van; Mensink, Marco ; Witkamp, Renger ; Vries, Jeanne De - \ 2017
    Nutrients 9 (2017)2. - ISSN 2072-6643
    Web-based 24-h dietary recalls and questionnaires were obtained from 553 Dutch well-trained athletes. The total energy and macronutrient intake was compared between discipline-categories (endurance, team, and strength) within gender, and dietary inadequacy, i.e., too low or high intakes, according to selected recommendations and guidelines, was evaluated by applying a probability approach. On average, 2.83 days per person were reported with a mean energy intake of 2566–2985 kcal and 1997–2457 kcal per day, for men and women, respectively. Between disciplines, small differences in the mean intake of energy and macronutrients were seen for both men and women. Overall, 80% of the athletes met the suggested lower-limit sport nutrition recommendation of 1.2 g·kg−1 of protein per day. The carbohydrate intake of 50%–80% of athletes was between 3 and 5 g·kg−1 bodyweight, irrespective of the category of their discipline. This can be considered as low to moderate, in view of their daily total exercise load (athletes reported on average ~100 minutes per day). In conclusion, only small differences in the mean energy and macronutrient intake between elite endurance, strength, and team sport athletes, were found. The majority of the athletes were able to meet the generally accepted protein recommendation for athletes, of 1.2 g·kg−1. However, for most athletes, the carbohydrate intake was lower than generally recommended in the existing consensus guidelines on sport nutrition. This suggests that athletes could either optimize their carbohydrate intake, or that average carbohydrate requirements merit a re-evaluation.
    Endurance exercise increases intestinal uptake of the peanut allergen Ara h 6 after peanut consumption in humans
    Janssen Duijghuijsen, Lonneke M. ; Norren, Klaske Van; Grefte, Sander ; Koppelman, Stef J. ; Lenaerts, Kaatje ; Keijer, Jaap ; Witkamp, Renger F. ; Wichers, Harry J. - \ 2017
    Nutrients 9 (2017)1. - ISSN 2072-6643
    Allergen - Ara h 6 - Endurance exercise - Food-dependent exercise-induced anaphylaxis - Intestinal permeability

    Controlled studies on the effect of exercise on intestinal uptake of protein are scarce and underlying mechanisms largely unclear. We studied the uptake of the major allergen Ara h 6 following peanut consumption in an exercise model and compared this with changes in markers of intestinal permeability and integrity. Ten overnight-fasted healthy non-allergic men (n = 4) and women (n = 6) (23 ± 4 years) ingested 100 g of peanuts together with a lactulose/rhamnose (L/R) solution, followed by rest or by 60 min cycling at 70% of their maximal workload. Significantly higher, though variable, levels of Ara h 6 in serum were found during exercise compared to rest (Peak p = 0.03, area under the curve p = 0.006), with individual fold changes ranging from no increase to an increase of over 150-fold in the uptake of Ara h 6. Similarly, uptake of lactulose (2-18 fold change, p = 0.0009) and L/R ratios (0.4-7.9 fold change, p = 0.04) were significantly increased which indicates an increase in intestinal permeability. Intestinal permeability and uptake of Ara h 6 were strongly correlated (r = 0.77, p <0.0001 for lactulose and Ara h 6). Endurance exercise after consumption may lead to increased paracellular intestinal uptake of food proteins.

    Nutritional Supplement Use by Dutch Elite and Sub-Elite Athletes: Does Receiving Dietary Counselling Make a Difference?
    Wardenaar, F.C. ; Ceelen, I.J.M. ; Dijk, J.W. van; Hangelbroek, R.W.J. ; Roy, L. van; Pouw, B. van der; Vries, J.H.M. de; Mensink, M.R. ; Witkamp, R.F. - \ 2017
    International Journal of Sport Nutrition & Exercise Metabolism 27 (2017)1. - ISSN 1526-484X - p. 32 - 42.
    The use of nutritional supplements is highly prevalent among athletes. In this cross-sectional study we assessed the prevalence of nutritional supplement use by a large group of Dutch competitive athletes in relation to dietary counselling. A total of 778 athletes (407 males and 371 females) completed a web-based questionnaire about the use of nutritional supplements. Log-binomial regression models were applied to estimate crude and adjusted prevalence ratios (PR) for the use of individual nutritional supplements in athletes receiving dietary counselling as compared to athletes not receiving dietary counselling. Of the athletes 97.2% had used nutritional supplements at some time during their sports career, whereas 84.7% indicated having used supplements during the last 4 weeks. The top ranked supplements used over the last 4 weeks from dietary supplements, sport nutrition products and ergogenic supplements were multivitamin and mineral preparations (42.9%), isotonic sports drinks (44.1%) and caffeine (13.0%). After adjustment for elite status, age, and weekly exercise duration, dietary counselling was associated with a higher prevalence of the use of vitamin D, recovery drinks, energy bars, isotonic drinks with protein, dextrose, beta-alanine, and sodium bicarbonate. In contrast, dietary counselling was inversely associated with the use of combivitamins, calcium, vitamin E, vitamin B2, retinol, energy drinks and BCAA and other amino acids. In conclusion, almost all athletes had used nutritional supplements at some time during their athletic career. Receiving dietary counselling seemed to result in better informed choices with respect to the use of nutritional supplements related to performance, recovery, and health.
    Evaluation of dietary intake and nutritional supplement use of elite and sub-elite Dutch athletes : Dutch Sport Nutrition and Supplement Study
    Wardenaar, Floris C. - \ 2017
    Wageningen University. Promotor(en): Renger Witkamp, co-promotor(en): Marco Mensink; Jeanne de Vries. - Wageningen : Wageningen University - ISBN 9789463430326 - 189
    food intake - food supplements - athletes - nutrition - sport - dietary guidelines - netherlands - voedselopname - voedselsupplementen - atleten - voeding - sport - dieetrichtlijnen - nederland

    Background: Well-trained elite athletes differ from the general population in being considerably more physically active and by other lifestyle characteristics including intensive training routines and periodisation of their training programs. Hence, adequate intake of energy and nutrients is of great importance to this population to ensure optimal performance and recovery during training or competition and also to minimize health risks. A consistent dietary intake pattern, in line with the sport-specific recommendations can be difficult to achieve for this group. The specific recommendations are formulated for nutritional intake during and after training or within competition. However, a large variation is seen in dietary intake by athletes. Therefore, the question arises as to what extent athletes meet recommendations and use nutritional supplements in an optimal manner.

    Aims: First, to investigate dietary intake and nutritional supplement use by well-trained Dutch athletes and compare these intakes with recommendations both for the general population and sport nutrition recommendations, which are based on expert consensus. Second, to provide an up-to-date overview of nutrient intake levels in a diverse and relatively large group of Dutch elite and sub-elite athletes practicing sports at the highest competitive level.

    Methods: As part of this thesis 24-hour recalls and questionnaires were used to gain insight into dietary intake and nutritional supplement use (n=553). To validate our methods, 24-hour nitrogen urine excretions were obtained in a subsample of our athletic population (n=47). A questionnaire was used to 1) investigate the prevalence of nutritional supplement use in a large sample of the athletic population (n=778) and 2) investigate the prevalence of nutritional supplement use in a large sample of the Dutch general population (n=1544). Finally, food intake during an ultramarathon was monitored (n=4) and questioned using a food frequency questionnaire (n=41).

    Results: Our validation study showed that 24-hour recalls and accompanying questionnaires underestimated protein intake in young elite athletes to the same extent as reported for non- athlete populations. Notwithstanding this, the method was considered suitable for ranking athletes according to their protein intake as needed in epidemiological studies. It was found that most athletes were able to meet the estimated average requirement (EAR) for carbohydrate and protein. Regarding sport nutrition recommendations, most of the athletes met protein (1.2 g/kg) but not carbohydrate recommendations (5 g/kg). No major differences in carbohydrate and protein intake were seen between sports categories (i.e. endurance, team and strength athletes). Athletes were at risk of too low intake levels of several micronutrients, especially when they did not use dietary supplements (i.e. vitamin D, vitamin A, vitamin B1 and B2 in men and women, and iron in women), whereas users of supplements showed a slightly elevated risk of intake levels exceeding the upper intake level (UL). This was in particular the case for vitamin B3. Our investigations in ultramarathon runners showed that these athletes did not reach sports nutrition recommendations from their habitual diet. In men and women, habitual mean carbohydrate (CHO) intake was lower than recommended, as was mean protein intake by women. CHO intake during the race was <60 g/h in 75% of the athletes. A large variation in nutrient and fluid intake was seen. This may be related to a high incidence of GI distress (82% of the runners reported GI complaints, but severe GI distress was low). Use of dietary supplements and sport nutrition products in the general population was reported by two-thirds of all respondents. Thirty-three percent reported the use of sport nutrition products. One could question whether the use of these energy containing sport nutrition products fits all respondents’ physical activity needs. Furthermore, it was shown that almost all athletes (97%) have used nutritional supplements some time during their athletic careers. Additionally, receiving dietary counselling seems to result in better choices with respect to nutritional supplement use.

    Conclusion: On a population level and with respect to the existing sport nutrition recommendations, nutritional intake in well-trained Dutch competitive athletes was low to moderate for carbohydrate intake and sufficient for protein intake. Suboptimal consumption of micronutrients was reported based on comparison with the estimated average requirement (EAR) for several micronutrients, especially for vitamin D. The use of dietary supplements adds to dietary intake. However, not all athletes consume these types of products, and day to day compliance in supplement users is low. Athletes are advised to focus on the selection of whole food carbohydrate-rich products with a high nutrient density and to consume a large variety of products containing both fat-soluble and water-soluble vitamins. When athletes experience difficulties in following these recommendations, the advice could be to use a low dose multivitamin (50-100% RDA).

    Adaptation of exercise-induced stress in well-trained healthy young men
    Janssen Duijghuijsen, L.M. ; Keijer, J. ; Mensink, M.R. ; Lenaerts, Kaatje ; Ridder, L.O. ; Nierkens, Stefan ; Kartaram, Shirley ; Verschuren, Martie C.M. ; Pieters, Raymond ; Bas, Richard ; Witkamp, R.F. ; Wichers, H.J. ; Norren, K. van - \ 2017
    Experimental Physiology 102 (2017)1. - ISSN 0958-0670 - p. 86 - 99.
    Strenuous exercise induces different stress-related physiological changes, potentially including changes in intestinal barrier function. In the Protégé Study (ISRCTN14236739; we determined the test-retest repeatability in responses to exercise in well-trained individuals.
    Eleven well-trained males (27±4 years old) completed an exercise protocol that consisted of intensive cycling intervals, followed by an overnight fast and an additional 90 min cycling phase at 50% Wmax the next morning. The day before (rest), and immediately after the exercise protocol (exercise) a lactulose/rhamnose solution was ingested. Markers of energy metabolism, lactulose/rhamnose ratio, several cytokines and potential stress-related markers were measured at rest and during exercise. In addition, untargeted urine metabolite profiles were obtained. The complete procedure (Test) was repeated one week later (Retest) to assess repeatability.
    Metabolic effect parameters with regard to energy metabolism and urine metabolomics were similar for both the Test and Retest period, underlining comparable exercise load. Following exercise, intestinal permeability (one hour plasma lactulose/rhamnose ratio), serum interleukin-6, interleukin-10, fibroblast growth factor-21, and muscle creatine kinase levels were only significantly increased compared to rest during the first test and not when the test was repeated.
    Responses to strenuous exercise in well-trained young men, as indicated by intestinal markers and myokines, show adaptation in Test-Retest outcome. This might be due to a carry-over effect of the defense mechanisms triggered during the Test. This finding has implications for the design of studies aimed at evaluating physiological responses to exercise.
    CYP2C9 genotypes modify benzodiazepine-related fall risk: Original results from three studies with meta-analysis
    Ham, A.C. ; Ziere, Gijsbertus ; Broer, Linda ; Wijngaarden, J.P. van; Zwaluw, N.L. van der; Brouwer, E.M. ; Dhonukshe-Rutten, R.A.M. ; Groot, C.P.G.M. de; Witkamp, R.F. - \ 2017
    Journal of the American Medical Directors Association 18 (2017)1. - ISSN 1525-8610 - p. 88.e1 - 88.e15.
    To investigate whether the CYP2C9*2 and *3 variants modify benzodiazepine-related fall risk.
    Three prospective studies; the Rotterdam Study, B-PROOF, and LASA.
    Community-dwelling individuals living in or near five Dutch cities.
    There were 11,485 participants aged ≥55 years.
    Fall incidents were recorded prospectively. Benzodiazepine use was determined using pharmacy dispensing records or interviews. Cox proportional hazard models adjusted for age and sex were applied to determine the association between benzodiazepine use and fall risk stratified for CYP2C9 genotype and comparing benzodiazepine users to nonusers. The results of the three studies were combined applying meta-analysis. Within benzodiazepine users, the association between genotypes and fall risk was also assessed.
    Three thousand seven hundred five participants (32%) encountered a fall during 91,996 follow-up years, and 4% to 15% (depending on the study population) used benzodiazepines. CYP2C9 variants had frequencies of 13% for the *2 allele and 6% for the *3 allele. Compared to nonusers, current benzodiazepine use was associated with an 18% to 36% increased fall risk across studies with a combined hazard ratio (HR) = 1.26 (95% confidence interval [CI], 1.13; 1.40). CYP2C9*2 or *3 allele variants modified benzodiazepine-related fall risk. Compared to nonusers, those carrying a CYP2C9*2 or *3 allele and using benzodiazepines had a 45% increased fall risk (HR, 1.45 95% CI, 1.21; 1.73), whereas CYP2C9*1 homozygotes using benzodiazepines had no increased fall risk (HR, 1.14; 95% CI, 0.90; 1.45). Within benzodiazepine users, having a CYP2C9*2 or *3 allele was associated with an increased fall risk (HR, 1.35; 95% CI, 1.06; 1.72). Additionally, we observed an allele dose effect; heterozygous allele carriers had a fall risk of (HR = 1.30; 95% CI, 1.05; 1.61), and homozygous allele carriers of (HR = 1.91 95% CI, 1.23; 2.96).
    CYP2C9*2 and *3 allele variants modify benzodiazepine-related fall risk. Those using benzodiazepines and having reduced CYP2C9 enzyme activity based on their genotype are at increased fall risk. In clinical practice, genotyping might be considered for elderly patients with an indication for benzodiazepine use. However, because the exact role of CYP2C9 in benzodiazepine metabolism is still unclear, additional
    Detection of peanut allergen in human blood after consumption of peanuts is skewed by endogenous immunoglobulins
    Janssen Duijghuijsen, L.M. ; Wichers, H.J. ; Norren, K. van; Keijer, J. ; Baumert, J.L. ; Jong, Govardus A.H. De; Witkamp, R.F. ; Koppelman, S.J. - \ 2017
    Journal of Immunological Methods 440 (2017). - ISSN 0022-1759 - p. 52 - 57.
    Some studies have suggested that allergens may appear in the circulation after ingestion of allergenic food
    sources. The reported levels of allergen in serum, however, are low, and conclusions between studies differ.
    Here, we investigated factors that determine the detection of allergens in serum after consumption of peanuts.
    Ten healthy volunteers ingested 100 g of light-roasted peanuts. Serumsampleswere taken at regular intervals for
    six hours. A double monoclonal sandwich ELISAwas used to analyse the presence and quantity of the major peanut
    allergen Ara h 6 in serum.
    In 4 out of 10 subjects, no Ara h 6 could be detected. Purified Ara h 6 thatwas digested in vitrowas still reactive in
    the ELISA, rejecting the possibility that digestion leads to small peptides that could not be detected. Spiking of purified
    Ara h 6 in baseline serum showed that the pre-ingestion serum of these four subjects partially prevented
    Ara h 6 to react in the ELISA, with a reduction of reactivity of up to 3 orders of magnitude or more. Pre-ingestion
    serum of the other six subjects did not show such an effect. The reduction of reactivity of Ara h 6 coincided with
    high titres of IgG and IgG4, and removal of IgG from pre-ingestion serum abolished this effect completely, indicating
    that IgG and IgG4 inhibited the reactivity of Ara h6 in the ELISA.
    Weconclude that some individuals have IgG and IgG4 against food allergens in their blood, which interfereswith
    detection of such food allergens in serum. Because this effect does not occur for each individual, the possibility of
    such interference should be taken into considerationwhen interpreting immunochemical studies on the absorption
    of food allergens in serum.
    Intraileal casein infusion increases plasma concentrations of amino acids in humans : A randomized cross over trial
    Ripken, Dina ; Avesaat, Mark van; Troost, F.J. ; Masclee, A.A. ; Witkamp, R.F. ; Hendriks, Henk F. - \ 2017
    Clinical Nutrition 36 (2017)1. - ISSN 0261-5614 - p. 143 - 149.
    Amino acid absorption - Ileal brake - Protein

    Background: Activation of the ileal brake by casein induces satiety signals and reduces energy intake. However, adverse effects of intraileal casein administration have not been studied before. These adverse effects may include impaired amino acid digestion, absorption and immune activation. Objective: To investigate the effects of intraileal infusion of native casein on plasma amino acid appearance, immune activation and gastrointestinal (GI) symptoms. Design: A randomized single-blind cross over study was performed in 13 healthy subjects (6 male; mean age 26 ± 2.9 years; mean body mass index 22.8 ± 0.4 kg/m-2), who were intubated with a naso-ileal feeding catheter. Thirty minutes after intake of a standardized breakfast, participants received an ileal infusion, containing either control (C) consisting of saline, a low-dose (17.2 kcal) casein (LP) or a high-dose (51.7 kcal) of casein (HP) over a period of 90 min. Blood samples were collected for analysis of amino acids (AAs), C-reactive protein (CRP), pro-inflammatory cytokines and oxylipins at regular intervals. Furthermore, GI symptom questionnaires were collected before, during and after ileal infusion. Results: None of the subjects reported any GI symptoms before, during or after ileal infusion of C, LP and HP. Plasma concentrations of all AAs analyzed were significantly increased after infusion of HP as compared to C (p <0.001), and most AAs were increased after infusion of LP (p <0.001). In total, 12.49 ± 1.73 and 3.18 ± 0.87 g AAs were found in plasma after intraileal infusion of HP and LP, corresponding to 93 ± 13% (HP) and 72 ± 20% (LP) of AAs infused as casein, respectively. Ileal casein infusion did not affect plasma concentrations of CRP, IL-6, IL-8, IL-1β and TNF-α. Infusion of HP resulted in a decreased concentration of 11,12-dihydroxyeicosatrienoic acid whereas none of the other oxylipins analyzed were affected. Conclusions: A single intraileal infusion of native casein results in a concentration and time dependent increase of AAs in plasma, suggesting an effective digestion and absorption of AAs present in casein. Also, ileal infusion did not result in immune activation nor in GI symptoms. NCT01509469.

    Self-Reported Use and Reasons among the General Population for Using Sports Nutrition Products and Dietary Supplements
    Wardenaar, Floris ; Dool, Remko Van Den; Ceelen, Ingrid ; Witkamp, Renger ; Mensink, Marco - \ 2016
    Sports Medicine 4 (2016)2. - ISSN 0112-1642
    The purpose of the present study was to determine the prevalence of dietary supplements (DS’s) and sport nutrition product (SNPs) among the general population, to identify differences for gender, age, and exercise frequency, and to determine the main reasons for use. The study was designed as a web-based questionnaire in a representative sample (n = 1544) of the Dutch population. Sixty-two percent (n = 957) of the respondents reported having used DS’s, SNPs, or both in the last twelve months. Women and older people reported the highest DS use. The highest use of SNPs was reported by regular exercising men and younger people with improving sporting performance as their main objective. Most frequently reported DS’s were multivitamins (28%) and vitamin C (19%)—for SNPs, energy drinks (22%) and isotonic drinks (19%). Health considerations were the most important motivation (DS’s 90% and SNPs 52%), but also performance was substantially reported (DS’s 14% and SNPs 35%). A substantial group of sedentary respondents also reported the use of SNPs. This study confirms that DS’s, SNPs, or both are widely used among the general population. Both health as performance are important reasons for use. It can be questioned whether the use of SNPs fits all respondents’ physical activity needs. View Full-Text
    TNFalpha and IL-6 induced anorexia: effects on serotonin turnover
    Dwarkasing, Jvalini ; Witkamp, Renger ; Boekschoten, Mark ; Laak, M.C. ter; Flik, G. ; Norren, Klaske van - \ 2016
    Wageningen University
    GSE69151 - Mus musculus - GSE69151 - Mus musculus - PRJNA284645
    Anorexia can occur as a serious complication of chronic disease. Increasing evidence suggests that inflammation plays a major role, along with a hypothalamic dysregulation characterized by locally elevated serotonin levels. The present study was undertaken to further explore the connections between peripheral inflammation, anorexia and hypothalamic serotonin metabolism and signaling pathways. We studied transcriptomic changes and serotonergic activity in the hypothalamus of mice after an intraperitoneal injection with TNFα, IL-6 or a combination of TNFα and IL-6.
    Docosahexaenoyl Serotonin, an endogenously formed n-3 fatty acid-serotonin conjugate, has anti-inflammatory properties by attenuating IL23–IL17 signalling in macrophages
    Poland, M.C.R. ; Klooster, Jean Paul ten; Wang, Zheng ; Pieters, Raymond ; Boekschoten, M.V. ; Witkamp, R.F. ; Meijerink, J. - \ 2016
    Wageningen University
    Mus musculus - GSE87369 - PRJNA344499
    Conjugates of fatty acids and amines, including endocannabinoids, are known to play important roles as endogenous signalling molecules. Among these, the ethanolamine conjugate of the n-3 poly unsaturated long chain fatty acid (PUFA) docosahexaenoic acid (22:6n-3) (DHA) was shown to possess strong anti-inflammatory properties. Previously, we identified the serotonin conjugate of DHA, docosahexaenoyl serotonin (DHA-5-HT), in intestinal tissues and showed that its levels are markedly influenced by intake of n-3 PUFAs. However, its biological roles remain to be elucidated. Here, we show that DHA-5-HT possesses potent anti-inflammatory properties by attenuating the IL-23-IL-17 signalling cascade in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Transcriptome analysis revealed that DHA-5-HT down-regulates LPS-induced genes, particularly those involved in generating a CD4 + Th17 response. Hence, levels of PGE2, IL-6, IL-1β, and IL-23, all pivotal macrophage-produced mediators driving the activation of pathogenic Th17 cells in a concerted way, were found to be significantly suppressed by concentrations as low as 100–500 nM DHA-5-HT. Furthermore, DHA-5-HT inhibited the ability of RAW264.7 cells to migrate and downregulated chemokines like MCP-1, CCL-20, and gene-expression of CCL-22 and of several metalloproteinases. Gene set enrichment analysis (GSEA) suggested negative overlap with gene sets linked to inflammatory bowel disease (IBD) and positive overlap with gene sets related to the Nrf2 pathway. The specific formation of DHA-5-HT in the gut, combined with increasing data underlining the importance of the IL-23-IL-17 signalling pathway in the aetiology of many chronic inflammatory diseases merits further investigation into its potential as therapeutic compound in e.g. IBD or intestinal tumorigenesis.
    Geneesmiddelgebruik, ondervoeding en deficiënties bij ouderen
    Orten-Luiten, A.C.B. van; Janse, A. ; Witkamp, R.F. - \ 2016
    MFM- praktijkgerichte nascholing over farmacotherapie (2016)editie 2. - ISSN 0168-7670
    Over het effect van geneesmiddelgebruik op de voedingsstatus bij ouderen is relatief weinig bekend. Ondanks de hoge prevalentie van ondervoeding en deficiënties in deze kwetsbare leeftijdsgroep, worden de klinische gevolgen van voedingstekorten bij oudere patiënten vaak niet opgemerkt, of gezien als symptomen van ouderdom of comorbiditeit. Daarnaast is in geneesmiddelonderzoek evaluatie van voeding-geneesmiddelinteracties (VGI's) niet verplicht. Vijf verschillende klassen van VGI's worden besproken: het effect van nutriënten, voeding of voedingstoestand op geneesmiddelwerking en het effect van geneesmiddelgebruik op voedingstoestand of deficiënties, met de focus op vitamine D, foliumzuur, magnesium en vitamine B12. Deze systematische benadering van VGI's is een tool voor uitbreiding van dit kennisgebied in onderzoek en implementatie van deze materie in de praktijk.
    Intestinal epithelial integrity depends on mitochondrial energy production
    Janssen Duijghuijsen, L.M. ; Grefte, Sander ; Norren, K. van; Boer, V.C.J. de; Dartel, D.A.M. van; Witkamp, R.F. ; Wichers, H.J. ; Keijer, J. - \ 2016
    intestinal epithelial integrity - mitochondrial energy production
    Drug-Nutrition Interactions in Older People
    Orten-Luiten, A.C. van; Janse, A. ; Witkamp, R. - \ 2016
    In: Food for the Aging Population: Second Edition Elsevier Inc. Academic Press - ISBN 9780081003480 - p. 203 - 222.
    Adverse drug reaction - Deficiency - Elderly - Food-drug interactions - Frail - Medication - Micronutrients - Minerals - Nutrients - Polypharmacy - Vitamins
    Although both malnutrition and polypharmacy in elderly populations are relevant clinical issues, relatively little is known about their mutual relationship through drug-nutrition interactions (DNIs). To address this knowledge gap, DNIs are discussed, captured in a framework of five classes: the impact of food, nutrients, and nutrition status on drug action, and vice versa, the impact of drug use on nutrition status.
    Intestinal epithelial integrity depends on mitochondrial energy production
    Janssen Duijghuijsen, L.M. ; Grefte, Sander ; Norren, K. van; Boer, V.C.J. de; Dartel, D.A.M. van; Witkamp, R.F. ; Wichers, H.J. ; Keijer, J. - \ 2016
    The noncaloric sweetener rebaudioside a stimulates glucagon-like peptide 1 release and increases enteroendocrine cell numbers in 2-dimensional mouse organoids derived from different locations of the intestine
    Wielen, Nikkie van der; Klooster, Jean Paul ten; Muckenschnabl, Susanne ; Pieters, Raymond ; Hendriks, Henk F.J. ; Witkamp, Renger F. ; Meijerink, Jocelijn - \ 2016
    The Journal of Nutrition 146 (2016)12. - ISSN 0022-3166 - p. 2429 - 2435.
    Duodenum - GLP-1 - Glucagon-like peptide 1 - Gut hormone - Ileum - Jejunum - Minigut - Organoids - Peptide YY - Stevia

    Background: Glucagon-like peptide 1 (GLP-1) contributes to satiety and plays a pivotal role in insulin secretion and glucose homeostasis. Similar to GLP-1, peptide YY (PYY) and cholecystokinin also influence food intake. The secretion of these hormones by enteroendocrine cells along the intestine is modulated by nutrients. Preparations from the Stevia rebaudiana plant, including rebaudioside A, are increasingly being used as noncaloric sweeteners. Objective: We investigated the effects of rebaudioside A on enteroendocrine cells by assessing both cell numbers as well as their secretory capacity in an organoid model. Methods: A 2-dimensional organoid model derived from duodenal, jejunal, and ileal crypts of a C57BL/6J mouse was developed and characterized with the use of gene expression and immunofluorescence. We stimulated these organoids with 10 mmol/L rebaudioside A for 1 h and measured their GLP-1, PYY, and cholecystokinin release. We also analyzed the effects of rebaudioside A on gene expression in enteroendocrine cells after an 18-h incubation. Results: The 2-dimensional organoids contained crypt cells and differentiated villus cells, including enterocytes and goblet and enteroendocrine cells. These enteroendocrine cells stained positive for GLP-1, PYY, and serotonin. The cultured 2-dimensional organoids maintained their location-specific gene expression patterns. Compared with the control, rebaudioside A induced GLP-1 secretion 1.7-fold in the duodenum (P <0.01), 2.2-fold in the jejunum (P <0.01), and 4.3-fold in the ileum (P <0.001). PYY release was increased by rebaudioside A 3-fold in the ileumcompared with the control (P <0.05). Long-term (18-h) stimulation with the sweetener induced the expression of the enteroendocrine-specific markers chromogranin A, glucagon, Pyy, and cholecystokinin 3.5- (P <0.001), 3.5- (P <0.001), 3.8- (P <0.05), and 6.5-fold (P <0.001), respectively. Conclusions: These results show novel ex vivo effects of rebaudioside A on enteroendocrine cells of the mouse small intestine and highlight potentially new applications for rebaudioside A in metabolic diseases.

    The effect of endurance exercise on intestinal integrity in well-trained healthy men
    Janssen Duijghuijsen, Lonneke ; Mensink, Marco ; Lenaerts, Kaatje ; Fiedorowicz, Ewa ; Dartel, Dorien A.M. van; Mes, Jurriaan J. ; Luiking, Yvette C. ; Keijer, Jaap ; Wichers, Harry J. ; Witkamp, Renger F. ; Norren, Klaske van - \ 2016
    Physiological Reports 4 (2016)20. - ISSN 2051-817X
    Amino acids - betacasomorphin-7 - citrulline - dipeptidylpeptidase-4 - exercise - intestinal permeability

    Exercise is one of the external factors associated with impairment of intestinal integrity, possibly leading to increased permeability and altered absorption. Here, we aimed to examine to what extent endurance exercise in the glycogen-depleted state can affect intestinal permeability toward small molecules and protein-derived peptides in relation to markers of intestinal function. Eleven well-trained male volunteers (27 ± 4 years) ingested 40 g of casein protein and a lactulose/rhamnose (L/R) solution after an overnight fast in resting conditions (control) and after completing a dual – glycogen depletion and endurance – exercise protocol (first protocol execution). The entire procedure was repeated 1 week later (second protocol execution). Intestinal permeability was measured as L/R ratio in 5 h urine and 1 h plasma. Five-hour urine excretion of betacasomorphin-7 (BCM7), postprandial plasma amino acid levels, plasma fatty acid binding protein 2 (FABP-2), serum pre-haptoglobin 2 (preHP2), plasma glucagon-like peptide 2 (GLP2), serum calprotectin, and dipeptidylpeptidase-4 (DPP4) activity were studied as markers for excretion, intestinal functioning and recovery, inflammation, and BCM7 breakdown activity, respectively. BCM7 levels in urine were increased following the dual exercise protocol, in the first as well as the second protocol execution, whereas 1 h-plasma L/R ratio was increased only following the first exercise protocol execution. FABP2, preHP2, and GLP2 were not changed after exercise, whereas calprotectin increased. Plasma citrulline levels following casein ingestion (iAUC) did not increase after exercise, as opposed to resting conditions. Endurance exercise in the glycogen depleted state resulted in a clear increase of BCM7 accumulation in urine, independent of DPP4 activity and intestinal permeability. Therefore, strenuous exercise could have an effect on the amount of food-derived bioactive peptides crossing the epithelial barrier. The health consequence of increased passage needs more in depth studies.

    Docosahexaenoyl serotonin, an endogenously formed n-3 fatty acid-serotonin conjugate has anti-inflammatory properties by attenuating IL-23–IL-17 signaling in macrophages
    Poland, Mieke ; Klooster, Jean Paul ten; Wang, Zheng ; Pieters, Raymond ; Boekschoten, Mark ; Witkamp, Renger ; Meijerink, Jocelijn - \ 2016
    Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids 1861 (2016)12. - ISSN 1388-1981 - p. 2020 - 2028.
    Acyl serotonines - DHA - DHA-5-HT - Endocannabinoids - Intestine - Nrf2

    Conjugates of fatty acids and amines, including endocannabinoids, are known to play important roles as endogenous signaling molecules. Among these, the ethanolamine conjugate of the n-3 poly unsaturated long chain fatty acid (PUFA) docosahexaenoic acid (22:6n-3) (DHA) was shown to possess strong anti-inflammatory properties. Previously, we identified the serotonin conjugate of DHA, docosahexaenoyl serotonin (DHA-5-HT), in intestinal tissues and showed that its levels are markedly influenced by intake of n-3 PUFAs. However, its biological roles remain to be elucidated. Here, we show that DHA-5-HT possesses potent anti-inflammatory properties by attenuating the IL-23-IL-17 signaling cascade in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Transcriptome analysis revealed that DHA-5-HT down-regulates LPS-induced genes, particularly those involved in generating a CD4+ Th17 response. Hence, levels of PGE2, IL-6, IL-1β, and IL-23, all pivotal macrophage-produced mediators driving the activation of pathogenic Th17 cells in a concerted way, were found to be significantly suppressed by concentrations as low as 100–500 nM DHA-5-HT. Furthermore, DHA-5-HT inhibited the ability of RAW264.7 cells to migrate and downregulated chemokines like MCP-1, CCL-20, and gene-expression of CCL-22 and of several metalloproteinases. Gene set enrichment analysis (GSEA) suggested negative overlap with gene sets linked to inflammatory bowel disease (IBD) and positive overlap with gene sets related to the Nrf2 pathway. The specific formation of DHA-5-HT in the gut, combined with increasing data underlining the importance of the IL-23-IL-17 signaling pathway in the etiology of many chronic inflammatory diseases merits further investigation into its potential as therapeutic compound in e.g. IBD or intestinal tumorigenesis.

    Moderate alcohol consumption after a mental stressor attenuates the endocrine stress response
    Schrieks, I.C. ; Joosten, M.M. ; Klöpping-Ketelaars, W.A.A. ; Witkamp, R.F. ; Hendriks, H.F.J. - \ 2016
    Alcohol 57 (2016). - ISSN 0741-8329 - p. 29 - 34.
    Alcohol - Cortisol - Immune system - Psychological stress - Trier Social Stress Test

    Alcohol is often consumed to reduce tension and improve mood when exposed to stressful situations. Previous studies showed that moderate alcohol consumption may reduce stress when alcohol is consumed prior to a stressor, but data on the effect of alcohol consumption after a mental stressor is limited. Therefore, our objective was to study whether moderate alcohol consumption immediately after a mental stressor attenuates the stress response. Twenty-four healthy men (age 21–40 y, BMI 18–27 kg/m2) participated in a placebo-controlled trial. They randomly consumed 2 cans (660 mL, ∼26 g alcohol) of beer or alcohol-free beer immediately after a mental stressor (Stroop task and Trier Social Stress Test). Physiological and immunological stress response was measured by monitoring heart rate and repeated measures of the hypothalamic-pituitary-adrenal axis (HPA-axis), white blood cells and a set of cytokines. After a mental stressor, cortisol and adrenocorticotropic hormone (ACTH) concentrations were 100% and 176% more reduced at 60 min (P = 0.012 and P = 0.001, respectively) and 92% and 60% more reduced at 90 min (P

    Analysis of omega-3 fatty acid derived N-acylethanolamines in biological matrices
    Witkamp, Renger F. ; Balvers, Michiel - \ 2016
    In: Endocannabinoid signaling: Methods and Protocols / Maccarrone, Mauro, Humana Press Inc. (Methods in Molecular Biology ) - ISBN 9781493935376 - p. 27 - 40.
    Docosahexaenoylethanolamide - Eicosapentaenoylethanolamide - Endocannabinoids - LC-MS - N-3 fatty acids - Solid phase extraction

    The adequate quantification of endocannabinoids can be complex due to their low endogenous levels and structural diversity. Therefore, advanced analytical approaches, such as LC-MS, are used to measure endocannabinoids in plasma, tissues, and other matrices. Recent work has shown that endocannabinoids that are synthesized from n-3 fatty acids, such as docosahexaenoylethanolamide (DHEA) and eicosapentaenoylethanolamide (EPEA), have anti-inflammatory and anti-tumorigenic properties and stimulate synapse formation in neurites. Here, an LC-MS based method for the quantification of n-3 endocannabinoids DHEA and EPEA which is also suited to measure a wider spectrum of endocannabinoids is described. The chapter contains a step-by-step protocol for the analysis of n-3 endocannabinoids in plasma, including sample collection and solid phase extraction, LC-MS analysis, and data processing. Modifications to the protocol that allow quantifying n-3 endocannabinoids in tissues and cell culture media will also be discussed. Finally, conditions that alter endocannabinoid concentrations are briefly discussed.

    Vivianite as an important iron phosphate precipitate in sewage treatment plants
    Wilfert, P. ; Mandalidis, A. ; Dugulan, A.I. ; Goubitz, K. ; Korving, L. ; Temmink, H. ; Witkamp, G.J. ; Loosdrecht, M.C.M. Van - \ 2016
    Water Research 104 (2016). - ISSN 0043-1354 - p. 449 - 460.
    Iron - Mössbauer spectroscopy - Phosphorus - Sewage - Sewage sludge - Vivianite

    Iron is an important element for modern sewage treatment, inter alia to remove phosphorus from sewage. However, phosphorus recovery from iron phosphorus containing sewage sludge, without incineration, is not yet economical. We believe, increasing the knowledge about iron-phosphorus speciation in sewage sludge can help to identify new routes for phosphorus recovery. Surplus and digested sludge of two sewage treatment plants was investigated. The plants relied either solely on iron based phosphorus removal or on biological phosphorus removal supported by iron dosing. Mössbauer spectroscopy showed that vivianite and pyrite were the dominating iron compounds in the surplus and anaerobically digested sludge solids in both plants. Mössbauer spectroscopy and XRD suggested that vivianite bound phosphorus made up between 10 and 30% (in the plant relying mainly on biological removal) and between 40 and 50% of total phosphorus (in the plant that relies on iron based phosphorus removal). Furthermore, Mössbauer spectroscopy indicated that none of the samples contained a significant amount of Fe(III), even though aerated treatment stages existed and although besides Fe(II) also Fe(III) was dosed. We hypothesize that chemical/microbial Fe(III) reduction in the treatment lines is relatively quick and triggers vivianite formation. Once formed, vivianite may endure oxygenated treatment zones due to slow oxidation kinetics and due to oxygen diffusion limitations into sludge flocs. These results indicate that vivianite is the major iron phosphorus compound in sewage treatment plants with moderate iron dosing. We hypothesize that vivianite is dominating in most plants where iron is dosed for phosphorus removal which could offer new routes for phosphorus recovery.

    Increased hypothalamic serotonin turnover in inflammation-induced anorexia
    Dwarkasing, J.T. ; Witkamp, R.F. ; Boekschoten, M.V. ; Laak, M.C. ter; Heins, M.S. ; Norren, K. van - \ 2016
    BMC Neuroscience 17 (2016)1. - ISSN 1471-2202

    Background: Anorexia can occur as a serious complication of disease. Increasing evidence suggests that inflammation plays a major role, along with a hypothalamic dysregulation characterized by locally elevated serotonin levels. The present study was undertaken to further explore the connections between peripheral inflammation, anorexia and hypothalamic serotonin metabolism and signaling pathways. First, we investigated the response of two hypothalamic neuronal cell lines to TNFα, IL-6 and LPS. Next, we studied transcriptomic changes and serotonergic activity in the hypothalamus of mice after intraperitoneal injection with TNFα, IL-6 or a combination of TNFα and IL-6. Results: In vitro, we showed that hypothalamic neurons responded to inflammatory mediators by releasing cytokines. This inflammatory response was associated with an increased serotonin release. Mice injected with TNFα and IL-6 showed decreased food intake, associated with altered expression of inflammation-related genes in the hypothalamus. In addition, hypothalamic serotonin turnover showed to be elevated in treated mice. Conclusions: Overall, our results underline that peripheral inflammation reaches the hypothalamus where it affects hypothalamic serotoninergic metabolism. These hypothalamic changes in serotonin pathways are associated with decreased food intake, providing evidence for a role of serotonin in inflammation-induced anorexia.

    Nutrient-induced glucagon like peptide-1 release is modulated by serotonin
    Ripken, Dina ; Wielen, Nikkie van der; Wortelboer, Heleen M. ; Meijerink, Jocelijn ; Witkamp, Renger F. ; Hendriks, Henk F.J. - \ 2016
    Journal of Nutritional Biochemistry 32 (2016). - ISSN 0955-2863 - p. 142 - 150.
    GLP-1 - Nutrients - Rebaudioside A - Serotonin - Small intestine

    Glucagon like peptide-1 (GLP-1) and serotonin are both involved in food intake regulation. GLP-1 release is stimulated upon nutrient interaction with G-protein coupled receptors by enteroendocrine cells (EEC), whereas serotonin is released from enterochromaffin cells (ECC). The central hypothesis for the current study was that nutrient-induced GLP-1 release from EECs is modulated by serotonin through a process involving serotonin receptor interaction. This was studied by assessing the effects of serotonin reuptake inhibition by fluoxetine on nutrient-induced GLP-1, PYY and CCK release from isolated pig intestinal segments. Next, serotonin-induced GLP-1 release was studied in enteroendocrine STC-1 cells, where effects of serotonin receptor inhibition were studied using specific and non-specific antagonists.Casein (1% w/v), safflower oil (3.35% w/v), sucrose (50 mM) and rebaudioside A (12.5 mM) stimulated GLP-1 release from intestinal segments, whereas casein only stimulated PYY and CCK release. Combining nutrients with fluoxetine further increased nutrient-induced GLP-1, PYY and CCK release.Serotonin release from intestinal tissue segments was stimulated by casein and safflower oil while sucrose and rebaudioside A had no effect. The combination with fluoxetine (0.155 μM) further enhanced casein and safflower oil induced-serotonin release.Exposure of ileal tissue segments to serotonin (30 μM) stimulated GLP-1 release whereas it did not induce PYY and CCK release. Serotonin (30 and 100 μM) also stimulated GLP-1 release from STC-1 cells, which was inhibited by the non-specific 5HT receptor antagonist asenapine (1 and 10 μM). These data suggest that nutrient-induced GLP-1 release is modulated by serotonin through a receptor mediated process.

    Intestinal nutrient sensing : a gut feeling for food
    Wielen, N. van der - \ 2016
    Wageningen University. Promotor(en): Renger Witkamp, co-promotor(en): Jocelijn Meijerink; Henk F.J. Hendriks. - Wageningen : Wageningen University - ISBN 9789462576995 - 200
    obesity - hormones - intestines - gastrointestinal hormones - pancreozymin - vasoactive intestinal peptide - sensing - in vivo experimentation - animal models - in vitro - gastric bypass - food - weight reduction - stevia rebaudiana - release - obesitas - hormonen - darmen - maagdarmhormonen - pancreozymine - vasoactief intestinaal peptide - aftasten - in vivo experimenten - diermodellen - in vitro - buik bypass - voedsel - gewichtsvermindering - stevia rebaudiana - vrijgeven

    The alarming increase in obesity rates creates an urgent need for effective prevention and treatment strategies. The most effective treatment for obesity today is bariatric surgery. Bariatric surgery comprises a number of different procedures having in common that they induce weight loss and alter gut hormone release. Gut hormones are well known for their effects on food intake behavior and their role in weight loss after bariatric surgery is undeniable. In addition, the therapeutic use of GLP-1 (Glucagon-Like Peptide-1) analogues including liraglutide in type II diabetes and obesity is on the rise. This underlines why gut hormones are considered promising targets for the development of new treatment strategies against obesity and its comorbidities.

    The secretion of gut hormones, among which GLP-1, is influenced by nutrient ingestion. The interactions of dietary components or their breakdown products with receptors and transporters located on the enteroendocrine cells of the intestinal tract can induce their release, a process called intestinal nutrient sensing. In this thesis, we aimed to further elucidate intestinal nutrient sensing mechanisms on a cellular level. First, the regional expression of several gut nutrient sensing related genes along the intestinal tract was assessed in three commonly studied species, namely mouse, pig and man. Gene expression of receptors, transporters and peptides involved in nutrient sensing shows a distinctive distribution pattern along the small intestine, which is in the distal small intestine highly similar between the species. Subsequently, we sought to investigate if this expression was changed after a weight loss inducing bariatric procedure. By whole transcriptome analysis, we showed that upper gastrointestinal tissue expression of genes associated with nutrient sensing was hardly changed. In contrast, a considerable reduction in inflammatory pathways was observed.

    Next, we sought to investigate the effects of the non-caloric sweetener rebaudioside A. This Stevia rebaudiana-derived compound was approved on the European market in 2011. As there is still some controversy about the effects of sweeteners in general on GLP-1 release, we investigated the effects of this specific sweetener. Because of the short half-life of GLP-1, the effect of nutrient stimulation was mainly studied in ex vivo and in vitro models in which local intestinal hormone release could be determined. A two dimensional gut model using intestinal organoids derived from murine intestinal crypts was developed to study location-specific hormone secretion. Rebaudioside A was found to induce GLP-1 and PYY release ex vivo from porcine intestinal tissue and in two dimensional organoids. This induction of the release was specific for the intestinal location, with the ileum being most potently stimulated by rebaudioside A. Moreover, prolonged exposure to rebaudioside A increased enteroendocrine cell numbers in two dimensional organoids. When studying the underlying mechanism in enteroendocrine STC-1 cells, we concluded that rebaudioside A-induced GLP-1 release was independent of the sweet taste receptor.

    The studies presented in this thesis add to our understanding the role of receptors and other molecular structures that are likely to be involved in nutrient sensing and the modulation of gut hormone release. What we know now is that several factors play a role in gut hormone release. This includes not only the nature and dose of the active compound(s), but also the location and timing of its (their) interactions with receptors and other targets along the gastrointestinal tract. We have shown that rebaudioside A may be a potential compound to induce gut hormone release in vivo, especially when applied to the distal small intestine. Therefore, rebaudioside A may be a promising compound to influence food intake, possibly most potent when delivered in the ileum.

    Small intestinal targets involved in food intake regulation : 'from nutrient to satiety signal'
    Ripken, D. - \ 2016
    Wageningen University. Promotor(en): Renger Witkamp; H.F.J. Hendriks. - Wageningen : Wageningen University - ISBN 9789462576438 - 180
    obesity - preventive nutrition - small intestine - ileum - duodenum - jejunum - satiety - appetite control - food intake - safflower oil - vagus nerve - casein - stevia rebaudiana - sucrose - macronutrients - serotonin - animal models - human feeding - obesitas - preventieve voeding - dunne darm - ileum - duodenum - jejunum - verzadigdheid - eetlustcontrole - voedselopname - saffloerolie - nervus vagus - caseïne - stevia rebaudiana - sucrose - macronutriënten - serotonine - diermodellen - humane voeding

    Background and aim: The worldwide increasing prevalence of overweight and obesity raises concerns for health. There is a clear need for preventive strategies, because current preventative interventions have proven to be unsuccessful in the long term. New strategies may be developed based on targets in the small intestine by activating satiety signals. The thesis aimed to investigate small intestinal targets contributing to food intake regulation. These targets included serotonin, the vagal nerve and the intestinal brake mechanism.

    Methods: The effects of ileal stimulation with safflower oil (lipid mixture), casein (protein), sucrose (carbohydrate) and rebaudioside A (non-caloric sweetener) on GLP-1 and PYY release were investigated by applying an porcine ex vivo intestinal segment model. The same model was also used to investigate if serotonin is involved in (non-)nutritional-induced GLP-1 and PYY release.

    The contribution to satiation of GLP-1 and CCK receptors at the vagal nerve, was studied by investigating the effects of GLP-1 and CCK receptor antagonists on ad libitum food intake in a pig model of subdiaphragmatic vagotomy.

    Two placebo controlled randomized crossover studies were performed in healthy volunteers to investigate the effects of small intestinal macronutrient delivery on ad libitum food intake and satiety signals. The first study compared the effects of duodenal, jejunal and ileal casein delivery on ad libitum food intake and satiety signals. The second study investigated if ileal delivery of all three macronutrients results in activation of satiety signals and reduction in ad libitum food intake. In addition, it was investigated if ileal delivery of native casein is efficiently digested and absorbed and does not result in adverse effects. In both studies the nutrients were delivered to the small intestine by inserting a nasointestinal feeding tube in healthy volunteers.

    Results: All macronutrients and rebaudioside A stimulated GLP-1 and PYY release from ileal tissue segments. Protein and fat stimulated serotonin release. Inhibiting the reuptake of serotonin resulted in enhanced nutrient induced GLP-1, PYY and CCK release. Serotonin stimulated GLP-1 release from enteroendocrine cells via a serotonin receptor mediated process.

    Results of the in vivo pig study showed that antagonism of the CCK receptor increased food intake in both vagotomized and sham operated pigs. Blocking the GLP-1 receptor did not affect food intake in both groups.

    The human studies showed that ileal protein delivery inhibited food intake and activated satiety signals as compared to duodenal or jejunal protein delivery. Also, ileal delivery of small quantities (51.7 kcal) of each macronutrient decreased food intake and activated satiety signals. In addition, it was shown that ileal delivery of native casein resulted in a time and concentration depended increase in plasma concentrations of amino acids and did not result in activation of immune responses nor in gastrointestinal complaints.

    Conclusions: The data presented in this thesis show that ileal delivery of all macronutrients results in activation of satiety signals and reduction of food intake. Stimulation of the ileum resulted in the strongest activation of satiety signals and inhibition of food intake compared to duodenal and jejunal stimulation. Besides direct nutrient-receptor interaction, the ileum senses (non-)nutritional stimuli via serotonin mediated processes resulting in GLP-1 release. In conclusion, these results demonstrate that targeting the ileum with small amounts of macronutrients is safe and has potential as a weight management strategy.

    Fatty acids, endocannabinoids and inflammation
    Witkamp, Renger - \ 2016
    European Journal of Pharmacology 785 (2016). - ISSN 0014-2999 - p. 96 - 107.
    COX2 - Eicosanoids - Endocannabinoids - Fatty acids - Inflammation - PUFAS

    From their phylogenetic and pharmacological classification it might be inferred that cannabinoid receptors and their endogenous ligands constitute a rather specialised and biologically distinct signalling system. However, the opposite is true and accumulating data underline how much the endocannabinoid system is intertwined with other lipid and non-lipid signalling systems. Endocannabinoids per se have many structural congeners, and these molecules exist in dynamic equilibria with different other lipid-derived mediators, including eicosanoids and prostamides. With multiple crossroads and shared targets, this creates a versatile system involved in fine-tuning different physiological and metabolic processes, including inflammation. A key feature of this 'expanded' endocannabinoid system, or 'endocannabinoidome', is its subtle orchestration based on interactions between a relatively small number of receptors and multiple ligands with different but partly overlapping activities. Following an update on the role of the 'endocannabinoidome' in inflammatory processes, this review continues with possible targets for intervention at the level of receptors or enzymes involved in formation or breakdown of endocannabinoids and their congeners. Although its pleiotropic character poses scientific challenges, the 'expanded' endocannabinoid system offers several opportunities for prevention and therapy of chronic diseases. In this respect, successes are more likely to come from 'multiple-target' than from 'single-target' strategies.

    Vitamin D deficiency as adverse drug reaction? A cross-sectional study in Dutch geriatric outpatients
    Orten-Luiten, A.C.B. van; Janse, A. ; Dhonukshe-Rutten, R.A.M. ; Witkamp, R.F. - \ 2016
    European Journal of Clinical Pharmacology (2016). - ISSN 0031-6970 - p. 605 - 614.
    Adverse drug reaction - Drug-food interaction - Elderly - Polypharmacy - Vitamin D

    Purpose: Adverse drug reactions as well as vitamin D deficiency are issues of public health concern in older people. However, relatively little is known about the impact of drug use on vitamin D status. Our primary aim is to explore associations between drug use and vitamin D status in older people. Furthermore, prevalences of drug use and vitamin D deficiency are estimated. Methods: In a population of 873 community-dwelling Dutch geriatric outpatients, we explored the cross-sectional relationships of polypharmacy (≥5 medications concomitantly used), severe polypharmacy (≥10 medications), and use of twenty-one specific drug groups, with serum 25-hydroxyvitamin D (25(OH)D) by analysis of covariance. Results: Overall prevalence of polypharmacy was 65 %, of severe polypharmacy 22 %. Depending on the cut-off value, prevalence of vitamin D deficiency was 49 % (

    Hypothalamic inflammation and food intake regulation during chronic illness
    Dwarkasing, J.T. ; Marks, D.L. ; Witkamp, R.F. ; Norren, K. van - \ 2016
    Peptides 77 (2016). - ISSN 0196-9781 - p. 60 - 66.
    Anorexia is a common symptom in chronic illness. It contributes to malnutrition and strongly affects survival and quality of life. A common denominator of many chronic diseases is an elevated inflammatory status, which is considered to play a pivotal role in the failure of food-intake regulating systems in the hypothalamus. In this review, we summarize findings on the role of hypothalamic inflammation on food intake regulation involving hypothalamic neuropeptide Y (NPY) and pro-opiomelanocortin (POMC). Furthermore, we outline the role of serotonin in the inability of these peptide based food-intake regulating systems to respond and adapt to changes in energy metabolism during chronic disease.
    Bridging the seen and the unseen: A systems pharmacology view of herbal medicine
    Schroen, Y. ; Wang, Mel ; Wietmarschen, Herman A. van; Witkamp, R.F. ; Hankemeier, Thomas ; Fan, Tai-Ping - \ 2015
    Science 350 (2015)6262. - ISSN 0036-8075 - p. S66 - S69.
    Omega-3 Polyunsaturated N-Acylethanolamines: A Link Between Diet and Cellular Biology
    Meijerink, Jocelijn ; Balvers, Michiel ; Plastina, Pierluigi ; Witkamp, Renger - \ 2015
    In: The Endocannabinoidome / Di Marzo, V., Wang, J., Elsevier Inc. Academic Press - ISBN 9780124201262 - p. 15 - 32.
    COX - DHA - DHEA - Diet - EPA - EPEA - Fatty acid amide - Fish oil - Inflammation - N-3 PUFAs

    The "endocannabinoidome" encompasses the dynamic network of endocannabinoid-like mediators and their often-redundant metabolic enzymes and "promiscuous" targets. Together, they constitute a versatile mechanism to fine-tune homeostasis. The relative concentration of its mediators is for an important part determined by the availability of their precursor molecules. Among these, several polyunsaturated fatty acids (PUFAs) are (-in)directly dependent on dietary supply. Fatty acid amides constitute an important subclass within the endocannabinoidome. These also include a number of conjugates of n-3 fatty acids, of which the biological activity largely remains to be elucidated. Most is known about the ethanolamides of DHA (DHEA) and EPA (EPEA). In particular, DHEA possesses anti-inflammatory properties, and studies indicate that it stimulates neurogenesis in brain. Both EPEA and DHEA induce apoptosis and are antiproliferative in certain tumor cell lines. Although these compounds bind to cannabinoid receptors, effects found thus far seem to take place via nonreceptor mechanisms mainly.

    Vitamin D, inflammation, and colorectal cancer progression : A review of mechanistic studies and future directions for epidemiological studies
    Harten-Gerritsen, Suzanne van; Balvers, Michiel G.J. ; Witkamp, Renger F. ; Kampman, Ellen ; Duijnhoven, F.J.B. van - \ 2015
    Cancer Epidemiology Biomarkers & Prevention 24 (2015)12. - ISSN 1055-9965 - p. 1820 - 1828.

    Survival from colorectal cancer is positively associated with vitamin D status. However, whether this association is causal remains unclear. Inflammatory processes may link vitamin D to colorectal cancer survival, and therefore investigating inflammatory markers as potential mediators may be a valuable next step. This review starts with an overview of inflammatory processes suggested to be involved in colorectal cancer progression and regulated by vitamin D. Next, we provide recommendations on how to study inflammatory markers in future epidemiologic studies on vitamin D and colorectal cancer survival. Mechanistic studies have shown that calcitriol-active form of vitamin D- influences inflammatory processes involved in cancer progression, including the enzyme cyclooxygenase 2, the NF-κB pathway, and the expression of the cytokines TNFα, IL1β, IL6, IL8, IL17, and TGFβ1. Based on this and taking into account methodologic issues, we recommend to include analysis of specific soluble peptides and proteins, such as cytokines, in future epidemiologic studies on this issue. VitaminDand the markers should preferably be measured at multiple time points during disease progression or recovery and analyzed using mediation analysis. Including these markers in epidemiologic studies may help answer whether inflammation mediates a causal relationship between vitamin D and colorectal cancer survival. Cancer Epidemiol Biomarkers Prev; 24(12); 1820-8.

    Effects of mood inductions by meal ambiance and moderate alcohol consumption on endocannabinoids and N-acylethanolamines in humans : A randomized crossover trial
    Schrieks, I.C. ; Ripken, Dina ; Stafleu, Annette ; Witkamp, R.F. ; Hendriks, Henk F.J. - \ 2015
    PLoS ONE 10 (2015)5. - ISSN 1932-6203 - 15 p.

    Background: The endocannabinoid system is suggested to play a regulatory role in mood. However, the response of circulating endocannabinoids (ECs) to mood changes has never been tested in humans. In the present study, we examined the effects of mood changes induced by ambiance and moderate alcohol consumption on plasma ECs 2-arachidonoylglycerol (2-AG), anandamide (AEA), and some N-acylethanolamine (NAE) congeners in humans. Methods: Healthy women (n = 28) participated in a randomized cross-over study. They consumed sparkling white wine (340 mL; 30 g alcohol) or alcohol-free sparkling white wine (340 mL;

    Tolerability and safety of souvenaid in patients with mild Alzheimer's disease : Results of multi-center, 24-week, open-label extension study
    Olde Rikkert, Marcel G.M. ; Verhey, Frans R. ; Blesa, Rafael ; Arnim, Christine A.F. Von; Bongers, Anke ; Harrison, John ; Sijben, John ; Scarpini, Elio ; Vandewoude, Maurits F.J. ; Vellas, Bruno ; Witkamp, Renger ; Kamphuis, Patrick J.G.H. ; Scheltens, Philip - \ 2015
    Journal of Alzheimers Disease 44 (2015)2. - ISSN 1387-2877 - p. 471 - 480.
    Alzheimer's disease - clinical trial - dietary management - intervention studies - long-term - medical nutrition therapy - memory - patient adherence - safety

    Background: The medical food Souvenaid, containing the specific nutrient combination Fortasyn Connect, is designed to improve synapse formation and function in patients with Alzheimer's disease (AD). Two double-blind randomized controlled trials (RCT) with Souvenaid of 12 and 24 week duration (Souvenir I and Souvenir II) showed that memory performance was improved in drug-naïve mild AD patients, whereas no effects on cognition were observed in a 24-week RCT (S-Connect) in mild to moderate AD patients using AD medication. Souvenaid was well-tolerated in all RCTs. Objective: In this 24-week open-label extension (OLE) study to the 24-week Souvenir II RCT, long-term safety and intake adherence of the medical food Souvenaid was evaluated. Methods: Patients with mild AD (n = 201) received Souvenaid once-daily during the OLE. Main outcome parameters were safety and product intake adherence. The memory domain z-score from a revised neuropsychological test battery was continued as exploratory parameter. Results: Compared to the RCT, a similar (low) incidence and type of adverse events was observed, being mainly (68.3%) of mild intensity. Pooled data (RCT and OLE) showed that 48-week use of Souvenaid was well tolerated with high intake adherence (96.1%). Furthermore, a significant increase in the exploratory memory outcome was observed in both the active-active and control-active groups during Souvenaid intervention. Conclusion: Souvenaid use for up to 48-weeks was well tolerated with a favorable safety profile and high intake adherence. The findings in this OLE study warrant further investigation toward the long-term safety and efficacy of Souvenaid in a well-controlled, double-blind RCT.

    Moderate alcohol consumption stimulates food intake and food reward of savoury foods
    Schrieks, I.C. ; Stafleu, Annette ; Griffioen-Roose, Sanne ; Graaf, Kees de; Witkamp, R.F. ; Boerrigter-Rijneveld, Rianne ; Hendriks, H.F.J. - \ 2015
    Appetite 89 (2015). - ISSN 0195-6663 - p. 77 - 83.
    Alcohol consumption - Appetite - Food intake - Food reward - Liking - Wanting

    The aim of this study was to investigate whether food reward plays a role in the stimulating effect of moderate alcohol consumption on subsequent food intake. In addition, we explored the role of oral and gut sensory pathways in alcohol's effect on food reward by modified sham feeding (MSF) or consumption of a preload after alcohol intake.In a single-blind crossover design, 24 healthy men were randomly assigned to either consumption of vodka/orange juice (20 g alcohol) or orange juice only, followed by consumption of cake, MSF of cake or no cake. Food reward was evaluated by actual food intake measured by an ad libitum lunch 45 min after alcohol ingestion and by behavioural indices of wanting and liking of four food categories (high fat, low fat, sweet and savoury).Moderate alcohol consumption increased food intake during the ad libitum lunch by 11% (+338 kJ, P = 0.004). Alcohol specifically increased intake (+127 kJ, P

    Waarom kun je door blijven eten terwijl je eigenlijk al vol zit?
    Witkamp, R.F. - \ 2015
    Universiteit van Nederland
    voedselconsumptie - overeten - voedingsgedrag - fysiologie - neurofysiologie - verslaving - biologie - food consumption - overeating - feeding behaviour - physiology - neurophysiology - addiction - biology
    Je hebt al een amuse, voorgerecht, hoofdgerecht en toetje op, en dan is-ie daar ineens: de kaasplank. Hoe is het mogelijk dat je door kunt blijven eten terwijl je al vol zit? Renger Witkamp, hoogleraar Voeding en Farmacologie (Wageningen UR), legt je uit wat hier de verklaring voor is en waarom dat ooit nuttig was.
    Hoe kan je je eetlust remmen?
    Witkamp, R.F. - \ 2015
    Universiteit van Nederland
    eetlust - eetlustremmers - cannabis - voeding en gezondheid - voedingsfysiologie - fysiologie - voedselonderzoek - appetite - anorexiants - cannabis - nutrition and health - nutrition physiology - physiology - food research
    Denk je bij cannabis aan het krijgen van een vreetkick? Na dit college van Renger Witkamp (Wageningen UR) snap je wat het verband tussen die twee is en hoe we die kennis kunnen gebruiken om je eetlust te remmen. Klinkt goed, toch? Er is alleen één groot probleem. Welk? Dat hoor je in dit college.
    Hoe kun je te dik en toch gezond zijn?
    Witkamp, R.F. - \ 2015
    Universiteit van Nederland
    overgewicht - lichaamsgewicht - quetelet index - obesitas - gezondheid - volksgezondheid - buikvet - lichaamsvet - fysiologie - overweight - body weight - body mass index - obesity - health - public health - abdominal fat - body fat - physiology
    Je kijkt naar beneden en ziet dat er zich in de loop der jaren wat vet is gaan ophopen rondom je middel. Waarom is het gevaarlijk om juist daar teveel vet te hebben? Renger Witkamp (Wageningen UR) legt uit hoe het nu precies zit met de gevaren van die extra kilootjes en of het per definitie ongezond is om wat dikker te zijn.
    Bestaat de ideale afslankpil?
    Witkamp, R.F. - \ 2015
    Universiteit van Nederland
    gezondheid - lichaamsgewicht - gewichtsvermindering - gewichtsverliezen - farmacologie - health - body weight - weight reduction - weight losses - pharmacology
    Wie de ideale afslankpil bedenkt, zal daar ver-schrik-ke-lijk rijk mee worden. Renger Witkamp, hoogleraar Voeding en Farmacologie (Wageningen UR) brengt je op de hoogte van allerlei (bizarre!) pogingen in de afgelopen decennia om te komen tot die pil. Zit er een pil bij die jij zou overwegen om te nemen?
    Wat moet je doen en laten als je gezonder wilt
    Witkamp, R.F. - \ 2015
    Universiteit van Nederland
    diëten - voeding en gezondheid - voedselwetenschappen - fysiologie - voedselproducten - gezondheidsvoedsel - gezondheidsbevordering - voedingsonderzoek - diets - nutrition and health - food sciences - physiology - food products - health foods - health promotion - nutrition research
    Slik jij de praatjes van afslankguru's als zoete koek? Ken jij alle diëten uit je hoofd? Renger Witkamp, hoogleraar Voeding en Farmacologie (Wageningen UR) bekijkt al deze hypes met een nuchtere en wetenschappelijke blik. Na dit praatje kun je alles wat je voorgeschoteld krijgt in de media over je gezondheid beter in perspectief plaatsen.
    Validation of web-based, multiple 24-h recalls combined with nutritional supplement intake questionnaires against nitrogen excretions to determine protein intake in Dutch elite athletes
    Wardenaar, F.C. ; Steennis, J. ; Geelen, I.J.M. ; Mensink, M.R. ; Witkamp, R.F. ; Vries, J.H.M. de - \ 2015
    The British journal of nutrition 114 (2015)12. - ISSN 0007-1145 - p. 2083 - 2092.
    Information on dietary composition is vitally important for elite athletes to optimise their performance and recovery, which requires valid tools. The aim of the present study was to investigate the validity of assessing protein intake using three web-based 24-h recalls and questionnaires, by comparing these with three urinary N excretions on the same day. A total of forty-seven Dutch elite top athletes, both disabled and non-disabled, aged between 18 and 35 years, with a BMI of 17·5–31 kg/m2, exercising >12 h/week were recruited. Estimated mean dietary protein intake was 109·6 (SD 33·0) g/d by recalls and questionnaires v. 141·3 (SD 38·2) g/d based on N excretions in urine; the difference was 25·5 (SD 21·3) % between the methods (P
    Hypothalamic regulation of food intake during cancer
    Dwarkasing, J.T. - \ 2015
    Wageningen University. Promotor(en): Renger Witkamp, co-promotor(en): Klaske van Norren; Mark Boekschoten. - Wageningen : Wageningen University - ISBN 9789462575486 - 147
    hypothalamische regulatie - anorexia - eetlustcontrole - voedselopname - cancer - chronische ziekten - diermodellen - muizen - serotonine - hypothalamic regulation - anorexia - appetite control - food intake - cancer - chronic diseases - animal models - mice - serotonin

    Appetite is often reduced in patients with chronic illness, including cancer.

    Cancer anorexia, loss of appetite, frequently co-exists with cachexia, and the combined clinical picture is known as anorexia-cachexia syndrome. In patients suffering from this syndrome, anorexia considerably contributes to the progression of cachexia, and strongly impinges on quality of life. Inflammatory processes in the hypothalamus are considered to play a crucial role in the development of disease-related anorexia.

    The main aim of this thesis was to further elucidate crucial processes involved in the pathogenesis of anorexia in cancer. To investigate mechanisms specifically involved in cancer anorexia, we used two tumour mouse models with opposing food intake behaviours: a C26-colon adenocarcinoma model with increased food intake and a Lewis lung carcinoma model with decreased food intake. In both models, tumour-induced cachexia (body wasting) was strongly present. The contrast in food intake behaviour between tumour-bearing (TB) mice in response to growth of the two different tumours was used to distinguish processes involved in cachexia from those specifically involved in anorexia.

    The hypothalamus was used for transcriptomic analysis (Affymetrix chips). We found expression of genes involved in serotonin signalling in the hypothalamus to be differentially regulated between the two tumour models. Furthermore, transcriptional activity of genes involved in serotonin signalling were inversely associated with food intake behaviour. Surprisingly, we also found a strong increase in gene expression of NPY and AgRP, potent orexigenic neuropeptides, in both models, meaning that their expression did not reflect food intake behaviour. However, NPY has also been described to regulate energy storage. Therefore, we hypothesized that this upregulation of NPY/AgRP corresponded to weight loss, which was severe in both tumour models.

    Using hypothalamic cell lines we further explored how serotonin might act on food intake regulatory pathways. We showed that serotonin was able to inhibit neuronal NPY secretion, while not affecting gene expression. Inflammatory markers IL-6 and TNFα were also measured in plasma and it was found that C26 TB mice had a lower inflammatory response than LL TB mice. These differences in inflammatory response could be implicated in the differences in feeding behaviour and serotonin signalling between C26 and LL TB mice. We therefore investigated the direct influence of inflammation on hypothalamic serotonin turnover and its contribution to the development of anorexia. To this end, different doses of TNF and IL-6 were administered by injection to healthy mice, inducing an acute inflammatory response. The injected cytokine doses were estimated from their corresponding plasma levels measured in tumour bearing (TB) mice. Also in this cytokine induced-anorexia model, where anorexia was exclusively induced by an inflammatory response, serotonin metabolism in the hypothalamus was affected. Both TNF and IL-6 increased hypothalamic serotonin turnover while also inducing anorectic behaviour. Furthermore, the effect of cytokines on increasing serotonin turnover was supported by in vitro experiments with hypothalamic neuronal cell lines.

    In conclusion, we identified hypothalamic serotonin signalling to play a major role in the decrease in food intake during cancer. Serotonin signalling itself is modulated by inflammatory mediators. Therefore, hypothalamic inflammation is an important trigger in the failure of hypothalamic food-intake regulation, probably by affecting serotonergic signalling, which acts as an upstream modulator of various orexigenic and anorexigenic systems.

    Nutrient Intake by Ultramarathon Runners: Can They Meet Recommendations?
    Wardenaar, F.C. ; Vries, J.H.M. de; Witkamp, R.F. ; Mensink, M.R. - \ 2015
    International Journal of Sport Nutrition & Exercise Metabolism 25 (2015)4. - ISSN 1526-484X - p. 375 - 386.
    Purpose: The objective of this study was to investigate whether ultramarathon runners were able to meet nutrition recommendations during a training period and on a competition day. Methods: In preparation for a 60 or 120 km ultramarathon covering a varied terrain, male and female ultramarathon runners (n=68, age 46.5±7.1 y) reported habitual dietary intake during three independent days using a web-based 24-hour recall and questionnaires. The diet was assessed using probability of inadequacy or by qualitative evaluation using reference dietary intakes or sports nutrition recommendations. A small group of 120 km runners (n=4) was observed continuously during the race. After the race, 60 km runners (n=41) received a questionnaire to assess dietary intake and gastrointestinal (GI) distress on the race day. Spearman rank correlation coefficients (r) were applied to investigate the association between intake and general GI distress symptoms. Results: In men and women, habitual mean carbohydrate (CHO) intake was lower than recommended, as was mean protein intake by women. CHO intake during the race was
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