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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    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.

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