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 clinicaltrials.gov as NCT03191110. The EnCoRe study was registered at trialregister.nl 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. ClinicalTrials.gov 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.
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