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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    Mechanisms of Action of trans Fatty Acids
    Oteng, Antwi Boasiako ; Kersten, Sander - \ 2020
    Advances in Nutrition 11 (2020)3. - ISSN 2161-8313 - p. 697 - 708.
    cardiometabolic disease - cholesterogenesis - elaidic acid - ER stress - industrial trans fatty acid - inflammation - lipid metabolism - ruminant trans fatty acid

    Human studies have established a positive association between the intake of industrial trans fatty acids and the development of cardiovascular diseases, leading several countries to enact laws that restrict the presence of industrial trans fatty acids in food products. However, trans fatty acids cannot be completely eliminated from the human diet since they are also naturally present in meat and dairy products of ruminant animals. Moreover, bans on industrial trans fatty acids have not yet been instituted in all countries. The epidemiological evidence against trans fatty acids by far overshadows mechanistic insights that may explain how trans fatty acids achieve their damaging effects. This review focuses on the mechanisms that underlie the deleterious effects of trans fatty acids by juxtaposing effects of trans fatty acids against those of cis-unsaturated fatty acids and saturated fatty acids (SFAs). This review also carefully explores the argument that ruminant trans fatty acids have differential effects from industrial trans fatty acids. Overall, in vivo and in vitro studies demonstrate that industrial trans fatty acids promote inflammation and endoplasmic reticulum (ER) stress, although to a lesser degree than SFAs, whereas cis-unsaturated fatty acids are protective against ER stress and inflammation. Additionally, industrial trans fatty acids promote fat storage in the liver at the expense of adipose tissue compared with cis-unsaturated fatty acids and SFAs. In cultured hepatocytes and adipocytes, industrial trans fatty acids, but not cis-unsaturated fatty acids or SFAs, stimulate the cholesterol synthesis pathway by activating sterol regulatory element binding protein (SREBP) 2-mediated gene regulation. Interestingly, although industrial and ruminant trans fatty acids show similar effects on human plasma lipoproteins, in preclinical models, only industrial trans fatty acids promote inflammation, ER stress, and cholesterol synthesis. Overall, clearer insight into the molecular mechanisms of action of trans fatty acids may create new therapeutic windows for the treatment of diseases characterized by disrupted lipid metabolism.

    Mediterranean diet intervention alters the gut microbiome in older people reducing frailty and improving health status : The NU-AGE 1-year dietary intervention across five European countries
    Ghosh, Tarini Shankar ; Rampelli, Simone ; Jeffery, Ian B. ; Santoro, Aurelia ; Neto, Marta ; Capri, Miriam ; Giampieri, Enrico ; Jennings, Amy ; Candela, Marco ; Turroni, Silvia ; Zoetendal, Erwin G. ; Hermes, Gerben D.A. ; Elodie, Caumon ; Brugere, Corinne Malpuech ; Pujos-Guillot, Estelle ; Berendsen, Agnes M. ; Groot, Lisette C.P.G.M. De; Feskens, Edith J.M. ; Kaluza, Joanna ; Pietruszka, Barbara ; Bielak, Marta Jeruszka ; Comte, Blandine ; Maijo-Ferre, Monica ; Nicoletti, Claudio ; Vos, Willem M. de; Fairweather-Tait, Susan ; Cassidy, Aedin ; Brigidi, Patrizia ; Franceschi, Claudio ; O'Toole, Paul W. - \ 2020
    Gut 69 (2020)7. - ISSN 0017-5749
    ageing - diet - enteric bacterial microflora - inflammation - intestinal bacteria

    Objective: Ageing is accompanied by deterioration of multiple bodily functions and inflammation, which collectively contribute to frailty. We and others have shown that frailty co-varies with alterations in the gut microbiota in a manner accelerated by consumption of a restricted diversity diet. The Mediterranean diet (MedDiet) is associated with health. In the NU-AGE project, we investigated if a 1-year MedDiet intervention could alter the gut microbiota and reduce frailty. Design: We profiled the gut microbiota in 612 non-frail or pre-frail subjects across five European countries (UK, France, Netherlands, Italy and Poland) before and after the administration of a 12-month long MedDiet intervention tailored to elderly subjects (NU-AGE diet). Results: Adherence to the diet was associated with specific microbiome alterations. Taxa enriched by adherence to the diet were positively associated with several markers of lower frailty and improved cognitive function, and negatively associated with inflammatory markers including C-reactive protein and interleukin-17. Analysis of the inferred microbial metabolite profiles indicated that the diet-modulated microbiome change was associated with an increase in short/branch chained fatty acid production and lower production of secondary bile acids, p-cresols, ethanol and carbon dioxide. Microbiome ecosystem network analysis showed that the bacterial taxa that responded positively to the MedDiet intervention occupy keystone interaction positions, whereas frailty-associated taxa are peripheral in the networks. Conclusion: Collectively, our findings support the feasibility of improving the habitual diet to modulate the gut microbiota which in turn has the potential to promote healthier ageing.

    One-carbon metabolites, B-vitamins and associations with systemic inflammation and angiogenesis biomarkers among colorectal cancer patients: Results from the ColoCare Study
    Kiblawi, Rama ; Holowatyj, Andreana N. ; Gigic, Biljana ; Brezina, Stefanie ; Geijsen, Anne J.M.R. ; Ose, Jennifer ; Lin, Tengda ; Hardikar, Sheetal ; Himbert, Caroline ; Warby, Christy A. ; Böhm, Jürgen ; Bours, Martijn J.L. ; Duijnhoven, Fränzel J.B. Van; Gumpenberger, Tanja ; Kok, Dieuwertje E. ; Koole, Janna L. ; Roekel, Eline H. Van; Schrotz-King, Petra ; Ulvik, Arve ; Gsur, Andrea ; Habermann, Nina ; Weijenberg, Matty P. ; Ueland, Per Magne ; Schneider, Martin ; Ulrich, Alexis ; Ulrich, Cornelia M. ; Playdon, Mary - \ 2020
    The British journal of nutrition 123 (2020)10. - ISSN 0007-1145 - p. 1187 - 1200.
    B-vitamins - colorectal cancer - CRPangiogenesis - folate - folic acid - inflammation - One-carbon metabolism - Vitamin B

    B-vitamins involved in one-carbon metabolism have been implicated in the development of inflammation- A nd angiogenesis-related chronic diseases, such as colorectal cancer. Yet, the role of one-carbon metabolism in inflammation and angiogenesis among colorectal cancer patients remains unclear.The objective of this study was to investigate associations of components of one-carbon metabolism with inflammation and angiogenesis biomarkers among newly diagnosed colorectal cancer patients (n=238) in the prospective ColoCare Study, Heidelberg.We cross-sectionally analyzed associations between 12 B-vitamins and one-carbon metabolites and 10 inflammation and angiogenesis biomarkers from pre-surgery serum samples using multivariable linear regression models. We further explored associations among novel biomarkers in these pathways with Spearman partial correlation analyses. We hypothesized that pyridoxal-5'-phosphate (PLP) is inversely associated with inflammatory biomarkers.We observed that PLP was inversely associated with CRP (r=-0.33, plinear<0.0001), SAA (r=-0.23, plinear=0.003), IL-6 (r=-0.39, plinear <0.0001), IL-8 (r=-0.20, plinear=0.02) and TNFα (r=-0.12, plinear=0.045). Similar findings were observed for 5-methyl-tetrahydrofolate and CRP (r=-0.14), SAA (r=-0.14) and TNFα (r=-0.15) among colorectal cancer patients. Folate catabolite apABG was positively correlated with IL-6 (r= 0.27, plinear<0.0001) and pABG was positively correlated with IL-8 (r= 0.21, plinear<0.0001), indicating higher folate utilization during inflammation.Our data support the hypothesis of inverse associations between PLP and inflammatory biomarkers among colorectal cancer patients. A better understanding of the role and inter-relation of PLP and other one-carbon metabolites with inflammatory processes among colorectal carcinogenesis and prognosis could identify targets for future dietary guidance for colorectal cancer patients.

    Trained Immunity: Linking Obesity and Cardiovascular Disease across the Life-Course?
    Bekkering, Siroon ; Saner, Christoph ; Riksen, Niels P. ; Netea, Mihai G. ; Sabin, Matthew A. ; Saffery, Richard ; Stienstra, Rinke ; Burgner, David P. - \ 2020
    Trends in Endocrinology & Metabolism 31 (2020)5. - ISSN 1043-2760 - p. 378 - 389.
    atherosclerosis - cardiovascular disease - inflammation - obesity - trained immunity

    Obesity, a chronic inflammatory disease, is the most prevalent modifiable risk factor for cardiovascular disease. The mechanisms underlying inflammation in obesity are incompletely understood. Recent developments have challenged the dogma of immunological memory occurring exclusively in the adaptive immune system and show that the innate immune system has potential to be reprogrammed. This innate immune memory (trained immunity) is characterized by epigenetic and metabolic reprogramming of myeloid cells following endogenous or exogenous stimulation, resulting in enhanced inflammation to subsequent stimuli. Trained immunity phenotypes have now been reported for other immune and non-immune cells. Here, we provide a novel perspective on the putative role of trained immunity in mediating the adverse cardiovascular effects of obesity and highlight potential translational pathways.

    HILPDA Uncouples Lipid Droplet Accumulation in Adipose Tissue Macrophages from Inflammation and Metabolic Dysregulation
    Dierendonck, Xanthe A.M.H. van; Rosa Rodriguez, Montserrat A. de la; Georgiadi, Anastasia ; Mattijssen, Frits ; Dijk, Wieneke ; Weeghel, Michel van; Singh, Rajat ; Borst, Jan Willem ; Stienstra, Rinke ; Kersten, Sander - \ 2020
    Cell Reports 30 (2020)6. - ISSN 2211-1247 - p. 1811 - 1822.e6.
    ATGL - fatty acid metabolism - Hilpda - inflammation - lipid droplets - macrophages - obesity

    Obesity leads to a state of chronic, low-grade inflammation that features the accumulation of lipid-laden macrophages in adipose tissue. Here, we determined the role of macrophage lipid-droplet accumulation in the development of obesity-induced adipose-tissue inflammation, using mice with myeloid-specific deficiency of the lipid-inducible HILPDA protein. HILPDA deficiency markedly reduced intracellular lipid levels and accumulation of fluorescently labeled fatty acids. Decreased lipid storage in HILPDA-deficient macrophages can be rescued by inhibition of adipose triglyceride lipase (ATGL) and is associated with increased oxidative metabolism. In diet-induced obese mice, HILPDA deficiency does not alter inflammatory and metabolic parameters, despite markedly reducing lipid accumulation in macrophages. Overall, we find that HILPDA is a lipid-inducible, physiological inhibitor of ATGL-mediated lipolysis in macrophages and uncouples lipid storage in adipose tissue macrophages from inflammation and metabolic dysregulation. Our data question the contribution of lipid droplet accumulation in adipose tissue macrophages in obesity-induced inflammation and metabolic dysregulation.

    Mice Deficient in the IL-1β Activation Genes Prtn3, Elane, and Casp1 Are Protected Against the Development of Obesity-Induced NAFLD
    Mirea, Andreea Manuela ; Stienstra, Rinke ; Kanneganti, Thirumala Devi ; Tack, Cees J. ; Chavakis, Triantafyllos ; Toonen, Erik J.M. ; Joosten, Leo A.B. - \ 2020
    Inflammation Research 43 (2020). - ISSN 0360-3997 - p. 1054 - 1064.
    IL-1 beta - inflammation - neutrophil serine proteases - obesity

    Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. Inflammatory pathways contribute to disease pathogenesis; however, regulation of the underlying mechanism is not completely understood. IL-1β, a pro-inflammatory cytokine, participates in the development and progression of NAFLD. To become bioactive, IL-1β requires enzymatic processing. Mechanisms that activate IL-1β include the classical NLRP3 inflammasome-caspase-1 and the neutrophil serine proteases, neutrophil elastase, and proteinase-3. Several studies have shown that both caspase-1 and the neutrophil serine proteases are important for NAFLD development. However, it is unknown whether these pathways interact and if they have a synergistic effect in promoting NAFLD. In the present study, we developed a novel and unique mouse model by intercrossing caspase-1/11 knockout mice with neutrophil elastase/proteinase-3 double knockout mice. Subsequently, these mice were examined regarding the development of high-fat diet–induced NAFLD. Our results show that mice deficient in caspase-1, neutrophil elastase, and proteinase-3 were protected from developing diet-induced weigh gain, liver steatosis, and adipose tissue inflammation when compared with controls. We conclude that pathways that process pro-IL-1β to bioactive IL-1β play an important role in promoting the development of NAFLD and obesity-induced inflammation. Targeting these pathways could have a therapeutic potential in patients with NAFLD.

    The Use of Proton Pump Inhibitors May Increase Symptoms of Muscle Function Loss in Patients with Chronic Illnesses
    Vinke, Paulien ; Wesselink, Evertine ; Orten-Luiten, Wout van; Norren, Klaske van - \ 2020
    International Journal of Molecular Sciences 21 (2020)1. - ISSN 1661-6596
    cachexia - cancer - COPD - heart failure - inflammation - magnesium - microbiota - proton pump inhibitors - sarcopenic obesity - vitamin D

    Long-term use of proton pump inhibitors (PPIs) is common in patients with muscle wasting-related chronic diseases. We explored the hypothesis that the use of PPIs may contribute to a reduction in muscle mass and function in these patients. Literature indicates that a PPI-induced reduction in acidity of the gastrointestinal tract can decrease the absorption of, amongst others, magnesium. Low levels of magnesium are associated with impaired muscle function. This unwanted side-effect of PPIs on muscle function has been described in different disease backgrounds. Furthermore, magnesium is necessary for activation of vitamin D. Low vitamin D and magnesium levels together can lead to increased inflammation involved in muscle wasting. In addition, PPI use has been described to alter the microbiota's composition in the gut, which might lead to increased inflammation. However, PPIs are often provided together with nonsteroidal anti-inflammatory drugs (NSAIDs), which are anti-inflammatory. In the presence of obesity, additional mechanisms could further contribute to muscle alterations. In conclusion, use of PPIs has been reported to contribute to muscle function loss. Whether this will add to the risk factor for development of muscle function loss in patients with chronic disease needs further investigation.

    Deletion of haematopoietic Dectin-2 or CARD9 does not protect from atherosclerosis development under hyperglycaemic conditions
    Thiem, Kathrin ; Hoeke, Geerte ; Zhou, Enchen ; Hijmans, Anneke ; Houben, Tom ; Boels, Margien G. ; Mol, Isabel M. ; Lutgens, Esther ; Shiri-Sverdlov, Ronit ; Bussink, Johan ; Kanneganti, Thirumala D. ; Boon, Mariëtte R. ; Stienstra, Rinke ; Tack, Cees J. ; Rensen, Patrick C.N. ; Netea, Mihai G. ; Berbée, Jimmy F.P. ; Diepen, Janna A. van - \ 2020
    Diabetes & Vascular Disease Research 17 (2020)1. - ISSN 1479-1641 - p. 1 - 12.
    Atherosclerosis - C-type lectin receptors - CARD9 - Dectin-2 - hyperglycaemia - inflammation - monocytes/macrophages

    Background: C-type lectin receptors, including Dectin-2, are pattern recognition receptors on monocytes and macrophages that mainly recognize sugars and sugar-like structures present on fungi. Activation of C-type lectin receptors induces downstream CARD9 signalling, leading to the production of cytokines. We hypothesized that under hyperglycaemic conditions, as is the case in diabetes mellitus, glycosylated protein (sugar-like) structures activate C-type lectin receptors, leading to immune cell activation and increased atherosclerosis development. Methods: Low-density lipoprotein receptor-deficient mice were lethally irradiated and transplanted with bone marrow from control wild-type, Dectin-2−/− or Card9−/− mice. After 6 weeks of recovery, mice received streptozotocin injections (50 mg/g BW; 5 days) to induce hyperglycaemia. After an additional 2 weeks, mice were fed a Western-type diet (0.1% cholesterol) for 10 weeks. Results and Conclusion: Deletion of haematopoietic Dectin-2 reduced the number of circulating Ly6Chi monocytes, increased pro-inflammatory cytokine production, but did not affect atherosclerosis development. Deletion of haematopoietic CARD9 tended to reduce macrophage and collagen content in atherosclerotic lesions, again without influencing the lesion size. Deletion of haematopoietic Dectin-2 did not influence atherosclerosis development under hyperglycaemic conditions, despite some minor effects on inflammation. Deletion of haematopoietic CARD9 induced minor alterations in plaque composition under hyperglycaemic conditions, without affecting lesion size.

    Akkermansia muciniphila reduces Porphyromonas gingivalis-induced inflammation and periodontal bone destruction
    Huck, Olivier ; Mulhall, Hannah ; Rubin, George ; Kizelnik, Zev ; Iyer, Radha ; Perpich, John D. ; Haque, Nasreen ; Cani, Patrice D. ; Vos, Willem M. de; Amar, Salomon - \ 2020
    Journal of Clinical Periodontology 47 (2020)2. - ISSN 0303-6979 - p. 202 - 212.
    infection - inflammation - periodontitis - probiotic

    Aim: Akkermansia muciniphila is a beneficial gut commensal, whose anti-inflammatory properties have recently been demonstrated. This study aimed to evaluate the effect of A. muciniphila on Porphyromonas gingivalis elicited inflammation. Material and Methods: In lean and obese mice, A. muciniphila was administered in P. gingivalis-induced calvarial abscess and in experimental periodontitis model (EIP). Bone destruction and inflammation were evaluated by histomorphometric analysis. In vitro, A. muciniphila was co-cultured with P. gingivalis, growth and virulence factor expression was evaluated. Bone marrow macrophages (BMMϕ) and gingival epithelial cells (TIGK) were exposed to both bacterial strains, and the expression of inflammatory mediators, as well as tight junction markers, was analysed. Results: In a model of calvarial infection, A. muciniphila decreased inflammatory cell infiltration and bone destruction. In EIP, treatment with A. muciniphila resulted in a decreased alveolar bone loss. In vitro, the addition of A. muciniphila to P. gingivalis-infected BMMϕ increased anti-inflammatory IL-10 and decreased IL-12. Additionally, A. muciniphila exposure increases the expression of junctional integrity markers such as integrin-β1, E-cadherin and ZO-1 in TIGK cells. A. muciniphila co-culture with P. gingivalis reduced gingipains mRNA expression. Discussion: This study demonstrated the protective effects of A. muciniphila administration and may open consideration to its use as an adjunctive therapeutic agent to periodontal treatment.

    Whole Grain Wheat Consumption Affects Postprandial Inflammatory Response in a Randomized Controlled Trial in Overweight and Obese Adults with Mild Hypercholesterolemia in the Graandioos Study
    Hoevenaars, Femke P.M. ; Esser, Diederik ; Schutte, Sophie ; Priebe, Marion G. ; Vonk, Roel J. ; Brink, Willem J. van den; Kamp, Jan Willem van der; Stroeve, Johanna H.M. ; Afman, Lydia A. ; Wopereis, Suzan - \ 2019
    The Journal of Nutrition 149 (2019)12. - ISSN 0022-3166 - p. 2133 - 2144.
    (compromised) healthy subjects - challenge test - composite biomarkers - inflammation - liver - metabolic health - phenotypic flexibility - resilience - whole grain wheat

    BACKGROUND: Whole grain wheat (WGW) consumption is associated with health benefits in observational studies. However, WGW randomized controlled trial (RCT) studies show mixed effects. OBJECTIVES: The health impact of WGW consumption was investigated by quantification of the body's resilience, which was defined as the "ability to adapt to a standardized challenge." METHODS: A double-blind RCT was performed with overweight and obese (BMI: 25-35 kg/m2) men (n = 19) and postmenopausal women (n = 31) aged 45-70 y, with mildly elevated plasma total cholesterol (>5 mmol/L), who were randomly assigned to either 12-wk WGW (98 g/d) or refined wheat (RW). Before and after the intervention a standardized mixed-meal challenge was performed. Plasma samples were taken after overnight fasting and postprandially (30, 60, 120, and 240 min). Thirty-one biomarkers were quantified focusing on metabolism, liver, cardiovascular health, and inflammation. Linear mixed-models evaluated fasting compared with postprandial intervention effects. Health space models were used to evaluate intervention effects as composite markers representing resilience of inflammation, liver, and metabolism. RESULTS: Postprandial biomarker changes related to liver showed decreased alanine aminotransferase by WGW (P = 0.03) and increased β-hydroxybutyrate (P = 0.001) response in RW. Postprandial changes related to inflammation showed increased C-reactive protein (P = 0.001), IL-6 (P = 0.02), IL-8 (P = 0.007), and decreased IL-1B (P = 0.0002) in RW and decreased C-reactive protein (P < 0.0001), serum amyloid A (P < 0.0001), IL-8 (P = 0.02), and IL-10 (P < 0.0001) in WGW. Health space visualization demonstrated diminished inflammatory (P < 0.01) and liver resilience (P < 0.01) by RW, whereas liver resilience was rejuvenated by WGW (P < 0.05). CONCLUSIONS: Twelve-week 98 g/d WGW consumption can promote liver and inflammatory resilience in overweight and obese subjects with mildly elevated plasma cholesterol. The health space approach appeared appropriate to evaluate intervention effects as composite markers. This trial was registered at as NCT02385149.

    Editorial : Diet, Inflammation and Colorectal Cancer
    Gessani, Sandra ; Duijnhoven, Fränzel J. Van; Moreno-Aliaga, Maria Jesus - \ 2019
    Frontiers in Immunology 10 (2019). - ISSN 1664-3224
    colorectal cancer - diet - dietary factors - inflammation - obesity
    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.

    Cold Induced Depot-Specific Browning in Ferret Aortic Perivascular Adipose Tissue
    Reynés, Bàrbara ; Schothorst, Evert M. van; Keijer, Jaap ; Ceresi, Enzo ; Oliver, Paula ; Palou, Andreu - \ 2019
    Frontiers in Physiology 10 (2019). - ISSN 1664-042X
    adipose tissue - browning - cardiovascular disease - cold exposure - inflammation - thermogenesis

    Brown adipose tissue is responsible for facultative thermogenesis to produce heat and increase energy expenditure in response to proper stimuli, e.g., cold. Acquisition of brown-like features (browning) in perivascular white adipose tissue (PVAT) may protect against obesity/cardiovascular disease. Most browning studies are performed in rodents, but translation to humans would benefit from a closer animal model. Therefore, we studied the browning response of ferret thoracic aortic PVAT (tPVAT) to cold. We performed global transcriptome analysis of tPVAT of 3-month-old ferrets acclimatized 1 week to 22 or 4°C, and compared the results with those of inguinal subcutaneous adipose tissue. Immunohistochemistry was used to visualize browning. Transcriptome data revealed a stronger cold exposure response of tPVAT, including increased expression of key brown/brite markers, compared to subcutaneous fat. This translated into a clear white-to-brown remodeling of tPVAT, with the appearance of multilocular highly UCP1-stained adipocytes. The pathway most affected by cold exposure in tPVAT was immune response, characterized by down-regulation of immune-related genes, with cardio protective implications. On the other hand, subcutaneous fat responded to cold by increasing energy metabolism based on increased expression of fatty acid oxidation and tricarboxylic acid cycle genes, concordant with lower inguinal adipose tissue weight in cold-exposed animals. Thus, ferret tPVAT responds to cold acclimation with a strong induction of browning and immunosuppression compared to subcutaneous fat. Our results present ferrets as an accessible translational animal model displaying functional responses relevant for obesity and cardiovascular disease prevention.

    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.

    Optogenetic control shows that kinetic proofreading regulates the activity of the T cell receptor
    Yousefi, O.S. ; Günther, Matthias ; Hörner, Maximilian ; Chalupsky, Julia ; Wess, Maximilian ; Brandl, Simon M. ; Smith, Robert W. ; Fleck, Christian ; Kunkel, Tim ; Zurbriggen, Matias D. ; Höfer, Thomas ; Weber, Wilfried ; Schamel, Wolfgang W.A. - \ 2019
    eLife 8 (2019). - ISSN 2050-084X
    A. thaliana - dynamics - human - immunology - inflammation - ligand-receptor - optogenetics - signaling - T cells

    The immune system distinguishes between self and foreign antigens. The kinetic proofreading (KPR) model proposes that T cells discriminate self from foreign ligands by the different ligand binding half-lives to the T cell receptor (TCR). It is challenging to test KPR as the available experimental systems fall short of only altering the binding half-lives and keeping other parameters of the interaction unchanged. We engineered an optogenetic system using the plant photoreceptor phytochrome B (PhyB) as a ligand to selectively control the dynamics of ligand binding to the TCR by light. This opto-ligand-TCR system was combined with the unique property of PhyB to continuously cycle between the binding and non-binding states under red light, with the light intensity determining the cycling rate and thus the binding duration. Mathematical modeling of our experimental datasets showed that indeed the ligand-TCR interaction half-life is the decisive factor for activating downstream TCR signaling, substantiating KPR.

    Iron Status of Kenyan Pregnant Women after Adjusting for Inflammation Using BRINDA Regression Analysis and Other Correction Methods
    Mwangi, Martin N. ; Echoka, Elizabeth ; Knijff, Marthe ; Kaduka, Lydia ; Werema, Brenda G. ; Kinya, Frida M. ; Mutisya, Richard ; Muniu, Erastus M. ; Demir, Ayşe Y. ; Verhoef, Hans ; Bourdet-Sicard, Raphaelle - \ 2019
    Nutrients 11 (2019)2. - ISSN 2072-6643
    acute-phase proteins - C-reactive protein - ferritin - inflammation - Kenya - pregnant women - α1-acid glycoprotein

    Serum ferritin concentration is the preferred biomarker to assess population iron status in the absence of inflammation. Interpretation of this biomarker is complicated in populations with a high burden of infection, however, because inflammation increases serum ferritin concentration independently of iron status. We aimed to compare estimates of iron status of Kenyan pregnant women, with circulating ferritin concentrations adjusted for inflammation using newly proposed methods by the BRINDA project, or using previously proposed adjustment methods. We re-analyzed data from pregnant Kenyan women living in a rural area where malaria is highly endemic (n = 470) or in an urban area (n = 402). As proposed by the BRINDA group, we adjusted individual ferritin concentration by internal regression for circulating concentrations of C-reactive protein (CRP) and α₁-acid glycoprotein (AGP). Other adjustment methods comprised: (a) arithmetic correction factors based on CRP or AGP; (b) exclusion of subjects with inflammation (CRP >5 mg/L or AGP >1 g/L); and (c) higher ferritin cut-off value (<30 μg/L). We additionally adjusted for Plasmodium infection as appropriate. Lastly, we assessed iron status without adjustment for inflammation. All correction methods increased prevalence of iron deficiency compared to the unadjusted estimates. This increase was more pronounced with the internal regression correction method. The iron deficiency prevalence estimate increased from 53% to 87% in rural Kisumu study and from 30% to 41% in the urban Nairobi study after adjusting for inflammation (CRP and AGP) using the BRINDA internal regression method. When we corrected for both inflammation and Plasmodium infection using the regression correction, it resulted in lower prevalence estimates compared to uninfected women. Application of linear regression methods to adjust circulating ferritin concentration for inflammation leads to markedly decreased point estimates for ferritin concentration and increased estimates for the prevalence of iron deficiency in pregnancy.

    The relationship of habitual diet with esophageal inflammation and integrity in eosinophilic esophagitis
    Kroon, Marlou L.A. de; Warners, Marijn J. ; Ampting, Marleen T.J. van; Harthoorn, Lucien F. ; Bredenoord, Arjan J. ; Doorn, Mylene van; Kok, Melanie ; Rhijn, Bram D. van; Eussen, Simone R.B.M. ; Vlieg-Boerstra, Berber J. - \ 2019
    Allergy 74 (2019)5. - ISSN 0105-4538 - p. 1005 - 1009.
    adults - eosinophilic esophagitis - esophageal mucosal integrity - habitual dietary intake - inflammation
    Bovine lactoferrin enhances TLR7-mediated responses in plasmacytoid dendritic cells in elderly women : Results from a nutritional intervention study with bovine lactoferrin, GOS and Vitamin D
    Splunter, Marloes van; Perdijk, Olaf ; Fick-Brinkhof, Henriëtte ; Feitsma, Anouk L. ; Floris-Vollenbroek, Esther G. ; Meijer, Ben ; Brugman, Sylvia ; Savelkoul, Huub F.J. ; Hoffen, Els van; Neerven, R.J.J. van - \ 2018
    Frontiers in Immunology 9 (2018). - ISSN 1664-3224
    aging - bovine lactoferrin - GOS - inflammation - mDCs - pDCs - TLR stimulation - Vitamin D

    During aging the immune system is dysregulated. Especially plasmacytoid dendritic cells (pDCs) and myeloid DCs (mDCs) have reduced Toll like receptor (TLR)-mediated responses resulting in increased susceptibility to infections. Consumption of bovine lactoferrin (bLF) has been shown to reduce infections with viruses. Galacto-oligosacharides (GOS) and Vitamin D are associated with reduced pro-inflammatory cytokine levels in serum, and increased TLR7/8 responses, respectively. A double-blind placebo-controlled nutritional intervention study in elderly women was performed, to investigate the potential of bLF, GOS, and Vitamin D to restore TLR responsiveness of pDCs and mDCs and to reduce inflammatory markers in serum. The nutritional intervention group (n = 15) received bLF for 3 weeks, followed by 3 weeks of bLF + GOS, and subsequently 3 weeks of bLF + GOS + Vitamin D. The placebo group (n = 15) received maltodextrin for 9 weeks. Every 3 weeks, blood was collected and TLR responses of pDCs and mDCs, and inflammation-related markers in serum were measured. After 3 weeks of bLF supplementation, increased TLR7/8 and TLR1/2 responses were observed in pDCs of the nutritional intervention group compared to the placebo group. When the effects of the entire nutritional intervention were investigated, increased TLR1/2 mediated responses in mDCs were observed, and in serum sVCAM tended to decrease. Finally, based on the RAND-36 questionnaire physical function tended to improve in the intervention group. Since especially TLR7-mediated responses in pDCs were enhanced after bLF supplementation compared to placebo, this suggests that bLF may contribute to antiviral responses mediated by pDC in elderly women.

    Associations among High-Quality Protein and Energy Intake, Serum Transthyretin, Serum Amino Acids and Linear Growth of Children in Ethiopia
    Tessema, Masresha ; Gunaratna, Nilupa S. ; Brouwer, Inge D. ; Donato, Katherine ; Cohen, Jessica L. ; McConnell, Margaret ; Belachew, Tefera ; Belayneh, Demissie ; Groote, Hugo De - \ 2018
    Nutrients 10 (2018)11. - ISSN 2072-6643
    energy intake - Ethiopia - inflammation - linear growth - protein intake - protein quality - serum IGF-1 - serum transthyretin

    Limited evidence is available on the associations of high-quality protein and energy intake, serum transthyretin (TTR), serum amino acids and serum insulin-like growth factor-1 (IGF-1) with linear growth of young children. Data collected during the baseline of a randomized control trial involving rural Ethiopian children aged 6⁻35 months (n = 873) were analyzed to evaluate the associations among height/length-for-age z-scores, dietary intakes, and these biomarkers (i.e., serum level of TTR, IGF-1, tryptophan and lysine, and inflammation). The prevalence of stunting was higher for children >23 months (38%) than ≤23 months (25%). The prevalence of inflammation was 35% and of intestinal parasites 48%. Three-quarters of the children were energy deficient, and stunted children had lower daily energy intake that non-stunted children (p < 0.05). Intakes of tryptophan, protein, and energy, and serum levels of tryptophan and IGF-1 were positively correlated with the linear growth of children. Controlling for inflammation, intestinal parasites, and sociodemographic characteristics, daily tryptophan (b = 0.01, p = 0.001), protein (b = 0.01, p = 0.01) and energy (b = 0.0003, p = 0.04) intakes and serum TTR (b = 2.58, p = 0.04) and IGF-1 (b = 0.01, p = 0.003) were positively associated with linear growth of children. Linear growth failure in Ethiopian children is likely associated with low quality protein intake and inadequate energy intake. Nutrition programs that emphasize improved protein quantity and quality and energy intake may enhance the linear growth of young children and need to be further investigated in longitudinal and interventional studies.

    Environmental Signals Influencing Myeloid Cell Metabolism and Function in Diabetes
    Ratter, Jacqueline M. ; Tack, Cees J. ; Netea, Mihai G. ; Stienstra, Rinke - \ 2018
    Trends in Endocrinology & Metabolism 29 (2018)7. - ISSN 1043-2760 - p. 468 - 480.
    diabetes - immunometabolism - inflammation - macrophages

    The environment induces metabolic reprogramming of immune cells via specific signaling pathways. Recent studies have revealed that changes in cell metabolism affect key immune cell functions including cytokine production and migration. In diabetes, these functions are either insufficiently or excessively activated, translating into diabetes-associated complications, including increased susceptibility to infection and accelerated cardiovascular disease. Diabetes alters the abundance of environmental signals, including glucose, insulin, and lipids. Subsequently, changes in environmental signals drive metabolic reprogramming, impair immune cell function, and ultimately contribute to diabetes-associated complications. We review here recent studies on changes in innate immune cell metabolism, especially in myeloid cells, that are driven by environmental signals relevant to diabetes, and discuss therapeutic perspectives of targeting metabolism of immune cells in diabetes.

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