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.

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Baseline study Rangpur GEOPOTATO
Pronk, Annette ; Kessel, Geert ; Ahsan, Hasib ; Rahman, Md.M. ; Abdulla Hil, Shafi ; Islam, Nazrul ; Michielsen, Jean-Marie ; Hengsdijk, Huib - \ 2017
Wageningen : Wageningen University & Research (GEOPOTATO external report 4) - 42
Nutraceutical oleuropein supplementation prevents high fat diet-induced adiposity in mice
Stelt, I. van der; Hoek-van den Hil, E.F. ; Swarts, J.J.M. ; Vervoort, J.J.M. ; Hoving, L.L. ; Skaltsounis, L. ; Lemonakis, N. ; Andreadou, I. ; Schothorst, E.M. van; Keijer, J. - \ 2015
Journal of Functional Foods 14 (2015). - ISSN 1756-4646 - p. 702 - 715.
Oleuropein, a phenolic compound present in olives and extra virgin olive oils, is endowed with in vivo beneficial health effects and might be considered a functional food ingredient. Here, we investigated the health effects of neutraceutical oleuropein supplementation (0.59% w/w) on energy balance at the whole body and molecular level in mice fed a high fat diet (HFD). Oleuropein supplementation (HFD¿+¿O) prevented HFD-induced body weight gain resulting in a body weight that was comparable to that of normal fat diet (NFD)-fed mice. Furthermore, indirect calorimetric data, motoric movements, serum glucose and leptin levels, serum and hepatic lipid levels, adipocyte size and adipose tissue gene expression showed an improved health status compared to the control HFD-fed mice. In fact, it appeared indistinguishable between HFD¿+¿O-fed mice and NFD-fed mice. Initially, oleuropein might decrease intestinal energy uptake, while on the longer term weight maintenance could be related to an increased satiety signal. Our results indicate that oleuropein supplementation to a HFD can improve health by reducing adiposity.
Direct comparison of metabolic health effects of the flavonoids quercetin, hesperetin, epicatechin, apigenin and anthocyanins in high-fat-diet-fed mice
Hoek-van den Hil, E.F. ; Schothorst, E.M. van; Stelt, I. van der; Swarts, J.J.M. ; Vliet, M.A. van; Amolo, T. ; Vervoort, J.J.M. ; Venema, D.P. ; Hollman, P.C.H. ; Rietjens, I.M.C.M. ; Keijer, J. - \ 2015
Genes & Nutrition 10 (2015)4. - ISSN 1555-8932 - 13 p.
cardiovascular-disease - mediterranean diet - c57bl/6j mice - obese mice - bioavailability - polyphenols - inflammation - metaanalysis - cholesterol - prevention
Dietary flavonoid intake is associated with reduced risk of cardiovascular diseases, possibly by affecting metabolic health. The relative potency of different flavonoids in causing beneficial effects on energy and lipid metabolism has not been investigated. Effects of quercetin, hesperetin, epicatechin, apigenin and anthocyanins in mice fed a high-fat diet (HF) for 12 weeks were compared, relative to normal-fat diet. HF-induced body weight gain was significantly lowered by all flavonoids (17–29 %), but most by quercetin. Quercetin significantly lowered HF-induced hepatic lipid accumulation (71 %). Mesenteric adipose tissue weight and serum leptin levels were significantly lowered by quercetin, hesperetin and anthocyanins. Adipocyte cell size and adipose tissue inflammation were not affected. The effect on body weight and composition could not be explained by individual significant effects on energy intake, energy expenditure or activity. Lipid metabolism was not changed as measured by indirect calorimetry or expression of known lipid metabolic genes in liver and white adipose tissue. Hepatic expression of Cyp2b9 was strongly downregulated by all flavonoids. In conclusion, all flavonoids lowered parameters of HF-induced adiposity, with quercetin being most effective.
Quercetin tests negative for genotoxicity in transcriptome analyses of liver and small intestine of mice
Hil, E.F. van den; Schothorst, E.M. van; Stelt, I. van der; Keijer, J. ; Rietjens, I. - \ 2015
Food and Chemical Toxicology 81 (2015). - ISSN 0278-6915 - p. 34 - 39.
in-vivo - reverse mutation - bone-marrow - dna-damage - flavonoids - rats - cells - carcinogenicity - mutagenicity - polyphenols
Given the positive results of quercetin in in vitro genotoxicity studies, the in vivo genotoxic properties of this important dietary flavonoid warrant testing, especially considering possible high intake via widely available food supplements. Here, this was done by transcriptome analyses of the most relevant tissues, liver and small intestine, of quercetin supplemented mice. Quercetin (0.33%) supplemented to a high-fat diet was administered to mice during 12 weeks. Serum alanine aminotransferase and aspartate aminotransferase levels revealed no indications for hepatotoxicity. Microarray pathway analysis of liver and small intestine showed no regulation of genotoxicity related pathways. Analysis of DNA damage related genes also did not point at genotoxicity. Furthermore, a published classifier set of transcripts for identifying genotoxic compounds did not indicate genotoxicity. Only two transcripts of the classifier set were regulated, but in the opposite direction compared with the genotoxic compounds 2-acetylaminofluorene (2-AAF) and aflatoxin B1 (AFB1). Based on the weight of evidence of three different types of analysis, we conclude that supplementation with quercetin at ~350¿mg/kg bw/day for 12 weeks in mice showed no up-regulation of genotoxicity related pathways in liver and small intestine.
Quercetin tests negative for genotoxicity in transcriptome analyses of liver and small intestine of mice
Hil, E.F. van den; Schothorst, E.M. van; Stelt, I. van der; Keijer, J. ; Rietjens, I.M.C.M. - \ 2015
food toxicology
Given the positive results of quercetin in in vitro genotoxicity studies, the in vivo genotoxic properties of this important dietary flavonoid warrant testing, especially considering possible high intake via widely available food supplements. Here, this was done by transcriptome analyses of the most relevant tissues, liver and small intestine, of quercetin supplemented mice. Quercetin (0.33%) supplemented to a high-fat diet was administered to mice during 12 weeks. Serum alanine aminotransferase and aspartate aminotransferase levels revealed no indications for hepatotoxicity. Microarray pathway analysis of liver and small intestine showed no regulation of genotoxicity related pathways. Analysis of DNA damage related genes also did not point at genotoxicity. Furthermore, a published classifier set of transcripts for identifying genotoxic compounds did not indicate genotoxicity. Only two transcripts of the classifier set were regulated, but in the opposite direction compared with the genotoxic compounds 2-acetylaminofluorene (2-AAF) and aflatoxin B1 (AFB1). Based on the weight of evidence of three different types of analysis, we conclude that supplementation with quercetin at ~350 mg/kg bw/day for 12 weeks in mice showed no up-regulation of genotoxicity related pathways in liver and small intestine.
Unravelling mechanisms of dietary flavonoid-mediated health effects: effects on lipid metabolism and genotoxicity
Hoek-van den Hil, E.F. - \ 2015
Wageningen University. Promotor(en): Ivonne Rietjens; Jaap Keijer, co-promotor(en): Peter Hollman. - Wageningen : Wageningen University - ISBN 9789462573031 - 157
flavanoïden - flavonoïden - vetzuren - quercetine - flavonolen - lichaamsgewicht - lipidenmetabolisme - hart- en vaatziekten - lever - vetweefsel - gezondheid - genotoxiciteit - voeding - muizen - flavanoids - flavonoids - fatty acids - quercetin - flavonols - body weight - lipid metabolism - cardiovascular diseases - liver - adipose tissue - health - genotoxicity - nutrition - mice

Summary

Consumption of foods containing flavonoids is associated with a reduced risk of cardiovascular diseases (CVD), possibly by lipid-lowering effects. On the other hand, for one of these flavonoids, quercetin, also genotoxicity was shown especially in in vitro bioassays. Therefore, the first aim of this thesis was to identify mechanisms underlying potential beneficial health effects of flavonoids. The focus was on hepatic lipid metabolism and circulating lipids and a molecular and physiological approach was used. Secondly, we aimed to study the potential in vivo genotoxic effects of quercetin by transcriptome analyses in liver and small intestine, since these represent the tissues of first contact exposed to relatively high levels upon oral intake of flavonoids.

Circulating lipids are important CVD-related risk markers, which are in general determined with commercially available enzyme-based assays. However, the usual enzyme in these assays, peroxidase, has previously been reported to be inhibited by flavonoids. Therefore, we have studied in chapter 2 whether these assays can adequately be used in flavonoid research. We observed that various flavonoid aglycones interfere with peroxidase used in triglycerides (TG) and free fatty acids (FFA) enzymatic assays, reporting incorrect lower TG and FFA levels than actually present. Furthermore, addition of metabolites such as isorhamnetin or quercetin-3-O-glucuronide, the major metabolite of quercetin in human and rat plasma, to murine serum also resulted in a significant reduction of the detected TG levels, while a trend was seen towards reduced FFA levels. It can be concluded that when applying these biochemical assays, vigilance is needed and alternative analytical methods assessing FFA or TG levels should preferably be applied for studying the biological effects of flavonoids on TG and FFA levels.

In chapter 3 mechanistic and physiological effects of quercetin on hepatic lipid metabolism were studied. C57BL/6JOlaHsd male adult mice received a mild high-fat (30 en%) diet without or with supplementation of 0.33% (w/w) quercetin for 12 weeks. Gas chromatography and 1H-NMR were used to quantitatively measure serum lipid profiles. Whole genome microarray analysis of liver tissue was used to identify potential mechanisms underlying altered circulating lipid levels by quercetin supplementation. Body weight, energy intake and hepatic lipid accumulation did not differ significantly between the quercetin and the control group. In serum of quercetin-fed mice, TG levels were decreased by 14% (p<0.001) and total poly unsaturated fatty acids (PUFA) levels were increased by 13% (p<0.01). Levels of palmitic acid, oleic acid, and linoleic acid were all decreased by 9-15% (p<0.05) in quercetin-fed mice. Both palmitic acid and oleic acid can be oxidized by omega-oxidation. Gene expression profiling showed indeed that quercetin increased hepatic lipid metabolism, especially omega-oxidation. At the gene level, this was reflected by the up-regulation of cytochrome P450 (Cyp) 4a10, Cyp4a14, Cyp4a31 and Acyl-CoA thioesterase 3 (Acot3). Two relevant regulators, cytochrome P450 oxidoreductase (Por, rate limiting for cytochrome P450 activities) and the transcription factor constitutive androstane receptor (Car; official symbol Nr1i3) were also up- regulated in the quercetin-fed mice. We concluded that quercetin intake increased hepatic lipid omega-oxidation and lowered corresponding circulating lipid levels, which may contribute to potential beneficial effects of quercetin on CVD.

Subsequently, in chapter 4 effects of quercetin supplementation were studied in mice given a high-fat (40 en%) background diet. The set-up of the experiment was the same as in chapter 3, with the exception of the background diet that was used, which was different in fat content and composition. This high-fat diet-induced body weight gain, and serum and hepatic lipid accumulation, which are all known risk factors for CVD. The aim of this study was to investigate the effects and underlying molecular mechanisms of the effects of the flavonoid quercetin on hepatic lipid metabolism in mice given this high-fat diet background. C57BL/6JOlaHsd male adult mice received the high-fat diet without or with supplementation of 0.33% (w/w) quercetin for 12 weeks. Body weight gain was 29% lower in quercetin fed mice versus control mice (p<0.01), while the energy intake was not significantly different. Quercetin supplementation lowered high-fat diet-induced hepatic lipid accumulation to 29% of the amount present in the control mice (p<0.01). 1H-NMR serum lipid profiling revealed that the supplementation also significantly lowered high-fat diet-induced increases in serum lipid levels. Global gene expression profiling of liver showed that cytochrome P450 2b (Cyp2b) genes, key target genes of the transcription factor Car, were down-regulated. However, the induction of omega-oxidation observed by quercetin supplementation to a mild high-fat (30en%) diet (chapter 3), was not observed this time with the high-fat (40en%) diet. Cumulatively, quercetin decreased high-fat diet-induced body weight gain, hepatic lipid accumulation and serum lipid levels. This was accompanied by regulation of cytochrome P450 2b genes in liver, which are considered to be under transcriptional control of CAR. The quercetin effects are likely dependent on the fat content and composition of the diet.

In chapter 5 we investigated whether flavonoids from other flavonoid subclasses can exert the same effects as we observed for quercetin. Effects of quercetin, hesperetin, epicatechin, apigenin and anthocyanins, in C57BL/6JOlaHsd male adult mice fed a high-fat diet for 12 weeks were compared, relative to a normal-fat diet. High-fat diet-induced body weight gain was significantly lowered by all flavonoids (17-29%), but most by quercetin. Quercetin significantly lowered high-fat diet-induced hepatic lipid accumulation (by 71%). High-fat diet-induced increases of mesenteric adipose tissue weight and serum leptin levels were significantly lowered by quercetin, hesperetin, and anthocyanins. Adipocyte cell size and adipose tissue inflammation were not affected.

The effects on body weight and adiposity could not be explained by individual significant differences in energy intake, energy expenditure, nor by differences in activity. Lipid metabolism was not changed as measured by indirect calorimetry or expression of known lipid metabolic genes in liver and white adipose tissue. Hepatic expression of Cyp2b9 was strongly down-regulated by all flavonoids. Overall, all five flavonoids lowered parameters of high-fat diet-induced adiposity, with quercetin being most effective.

Next to the beneficial health effects of flavonoids, the safety of flavonoids is under discussion, mainly because of potential genotoxic effects found for quercetin in vitro. Therefore, in chapter 6 the in vivo genotoxicity of this flavonoid was studied by transcriptome analyses in two tissues, small intestine and liver, where the highest exposure to quercetin is expected. This is especially of interest in view of high intake by widely available food supplements. Quercetin (0.33%) supplemented to a high-fat diet was administered to C57BL/6JOlaHsd male adult mice during 12 weeks. Serum alanine aminotransferase and aspartate aminotransferase levels revealed no indications for hepatotoxicity. General microarray pathway analysis of liver and small intestinal tissue samples showed no regulation of genotoxicity related pathways. In addition, analysis of DNA damage pathways in these tissues did also not point at genotoxicity. Furthermore, comparison with a published classifier set of transcripts for identifying genotoxic compounds did not reveal any similarities in the regulation of these classifier set by quercetin. Available microarray datasets of known genotoxic liver carcinogens, 2-acetylaminofluorene and aflatoxin B1 in mice were taken along as positive controls for comparison, and indeed showed genotoxic properties (regulation of genotoxic related genes) in the analyses. This transcriptomic analysis showed that supplementation with quercetin at ~350 mg/kg bw/day for 12 weeks did not induce genotoxicity in liver and small intestine.

In conclusion, we have shown in vivo efficacy of flavonoids reflected by effects on metabolic health parameters, including hepatic lipid metabolism. These effects on hepatic lipid metabolism seemed to be related or influenced by the transcription factor CAR. The dietary contexts appeared to modify the health effects. The five studied flavonoids in general showed the same effects, with quercetin being the most effective. No genotoxicity of quercetin was found by transcriptome analyses in liver and small intestine. Overall, we have obtained indications for beneficial health effects of flavonoids in mice, which makes it interesting to study if these effects can be extrapolated to humans to further explore their potential as functional compounds of dietary flavonoid intake.

Quercetin decreases high-fat diet induced bodyweight gain and accumulation of hepatic and circulating lipids in mice
Schothorst, E.M. van; Hil, E.F. van den; Keijer, J. - \ 2014
human nutrition and health - GSE51343 - PRJNA222808
Dietary flavonoids may protect against cardiovascular diseases (CVD). Increased circulating lipid levels and hepatic lipid accumulation are known risk factors for CVD. The aim of this study was to investigate the effects and underlying molecular mechanisms of the flavonoid quercetin on hepatic lipid metabolism in mice with high-fat diet induced body weight gain and hepatic lipid accumulation. Adult male mice received a 40 energy% high-fat diet without or with supplementation of 0.33 % (w/w) quercetin for 12 weeks. Body weight gain was 29 % lower in quercetin fed mice (p < 0.01), while the energy intake was not significantly different. Quercetin supplementation lowered hepatic lipid accumulation to 29 % of the amount present in the control mice (p < 0.01). 1H nuclear magnetic resonance serum lipid profiling revealed that the supplementation significantly lowered serum lipid levels. Global gene expression profiling of liver showed that cytochrome P450 2b (Cyp2b) genes, key target genes of the transcription factor constitutive androstane receptor (Car; official symbol Nr1i3), were downregulated. Quercetin decreased high-fat diet induced body weight gain, hepatic lipid accumulation and serum lipid levels. This was accompanied by regulation of cytochrome P450 2b genes in liver, which are possibly under transcriptional control of CAR. The quercetin effects are likely dependent on the fat content of the diet.
Effects of maternal nutrition on immune competence and microbiota composition of piglets
Greeff, A. de; Vastenhouw, S.A. ; Bikker, P. ; Bossers, A. ; Bree, F.M. de; Schokker, D. ; Roubos-van den Hil, P.J. ; Ramaekers, P. ; Smits, M.A. ; Rebel, J.M.J. - \ 2014
In: Book of abstracts of the 65th Annual Meeting of the European Association for Animal Production. - Wageningen Academic Publishers - ISBN 9789086862481 - p. 125 - 125.
Quercetin decreases high-fat diet induced body weight gain and accumulation of hepatic and circulating lipids in mice
Hoek-van den Hil, E.F. ; Schothorst, E.M. van; Stelt, I. van der; Swarts, J.J.M. ; Venema, D.P. ; Sailer, M. ; Vervoort, J.J.M. ; Hollman, P.C.H. ; Rietjens, I. ; Keijer, J. - \ 2014
Genes & Nutrition 9 (2014). - ISSN 1555-8932 - 8 p.
cardiovascular-disease - gene-expression - c57bl/6j mice - acid - risk - hepatocytes - metabolism - flavonoids - obesity - women
Dietary flavonoids may protect against cardiovascular diseases (CVD). Increased circulating lipid levels and hepatic lipid accumulation are known risk factors for CVD. The aim of this study was to investigate the effects and underlying molecular mechanisms of the flavonoid quercetin on hepatic lipid metabolism in mice with high-fat diet induced body weight gain and hepatic lipid accumulation. Adult male mice received a 40 energy% high-fat diet without or with supplementation of 0.33 % (w/w) quercetin for 12 weeks. Body weight gain was 29 % lower in quercetin fed mice (p <0.01), while the energy intake was not significantly different. Quercetin supplementation lowered hepatic lipid accumulation to 29 % of the amount present in the control mice (p <0.01). 1H nuclear magnetic resonance serum lipid profiling revealed that the supplementation significantly lowered serum lipid levels. Global gene expression profiling of liver showed that cytochrome P450 2b (Cyp2b) genes, key target genes of the transcription factor constitutive androstane receptor (Car; official symbol Nr1i3), were downregulated. Quercetin decreased high-fat diet induced body weight gain, hepatic lipid accumulation and serum lipid levels. This was accompanied by regulation of cytochrome P450 2b genes in liver, which are possibly under transcriptional control of CAR. The quercetin effects are likely dependent on the fat content of the diet.
Thermoneutrality results in prominent diet-induced body weight differences in C57BL/6J mice, not paralleled by diet-induced metabolic differences
Hoevenaars, F.P.M. ; Bekkenkamp-Grovenstein, M. ; Janssen, R.J.R.J. ; Heil, S.G. ; Bunschoten, A. ; Hoek-van den Hil, E.F. ; Snaas-Alders, S.H. ; Teerds, K.J. ; Schothorst, E.M. van; Keijer, J. - \ 2014
Molecular Nutrition & Food Research 58 (2014)4. - ISSN 1613-4125 - p. 799 - 807.
adipose-tissue - mitochondrial-function - obesity - fat - thermogenesis - models - health - gene - induction - disease
Scope Mice are usually housed at 20–24°C. At thermoneutrality (28°C) larger diet-induced differences in obesity are seen. We tested whether this leads to large differences in metabolic health parameters. Methods and results We performed a 14-wk dietary intervention in C57BL/6J mice at 28°C and assessed adiposity and metabolic health parameters for a semipurified low fat (10 energy%) diet and a moderate high fat (30 energy%) diet. A large and significant diet-induced differential increase in body weight, adipose tissue mass, adipocyte size, serum leptin level, and, to some extent, cholesterol level was observed. No adipose tissue inflammation was seen. No differential effect of the diets on serum glucose, free fatty acids, triacylglycerides, insulin, adiponectin, resistin, PAI-1, MMP-9, sVCAM-1, sICAM-1, sE-selectin, IL-6, ApoE, fibrinogen levels, or HOMA index was observed. Also in muscle no differential effect on mitochondrial density, mitochondrial respiratory control ratio, or mRNA expression of metabolic genes was found. Finally, in liver no differential effect on weight, triacylglycerides level, aconitase/citrate synthase activity ratio was seen. Conclusion Low fat diet and moderate high fat diet induce prominent body weight differences at thermoneutrality, which is not paralleled by metabolic differences. Our data rather suggest that thermoneutrality alters metabolic homeostasis.
Quercetin induces hepatic lipid omega-oxidation and lowers serum lipid levels in mice [Mus Musculus]
Schothorst, E.M. van; Keijer, J. ; Bunschoten, J.E. ; Hil, E.F. van den; Rietjens, I.M.C.M. ; Hollman, P.C.H. - \ 2013
human nutrition and health - GSE39140 - PRJNA170118
Elevated circulating lipid levels are known risk factors for cardiovascular diseases (CVD). In order to examine the effects of quercetin on hepatic lipid metabolism and detailed serum lipid profiles, mice received a mild-high-fat diet without (control) or with supplementation of 0.33% (w/w) quercetin for 12 weeks. Gas chromatography and 1H nuclear magnetic resonance were used to measure quantitatively serum lipid profiles and whole genome microarray analysis was used to identify the responsible mechanisms in liver. There were no significant differences found in mean body weight, energy intake and hepatic lipid accumulation between the quercetin and control group. In serum of quercetin-fed mice, TG levels were decreased with 15%, poly unsaturated fatty acids (PUFA) were increased with 14% and saturated fatty acids were decreased. Palmitic acid, oleic acid, and linoleic acid were all decreased in quercetin-fed mice by 9-15%. Both palmitic acid and oleic acid can be oxidized by omega-oxidation. Indeed, gene expression profiling showed that quercetin increased hepatic lipid metabolism, especially omega-oxidation. At the gene level, this was reflected by the up regulation of cytochrome P450 (Cyp) 4a10, Cyp4a14, Cyp4a31 and Acyl-CoA thioesterase 3 (Acot3). Two relevant regulators, Cytochrome P450 oxidoreductase (Por, rate limiting for cytochrome P450s) and the transcription factor Constitutive androstane receptor (Car; official symbol Nr1i3) were also up regulated in the quercetin-fed mice. We conclude that quercetin intake increased hepatic lipid omega-oxidation and lowered corresponding circulating lipid levels, a process that may involve Por and Car, and results in a potential beneficial CVD preventive effect.
Quercetin induces hepatic lipid omega-oxidation and lowers serum lipid levels in mice
Hoek-van den Hil, E.F. ; Keijer, J. ; Bunschoten, A. ; Vervoort, J. ; Stankova, B. ; Bekkenkamp, M. ; Herreman, L. ; Venema, D.P. ; Hollman, P.C.H. ; Tvrzicka, E. ; Rietjens, I. ; Schothorst, E.M. van - \ 2013
Quercetin induces hepatic lipid omega-oxidation and lowers serum lipid levels in mice
Hoek-van den Hil, E.F. ; Keijer, J. ; Bunschoten, A. ; Vervoort, J.J.M. ; Stankova, B. ; Bekkenkamp, M. ; Herreman, L. ; Venema, D.P. ; Hollman, P.C.H. ; Tvrzicka, E. ; Rietjens, I. ; Schothorst, E.M. van - \ 2013
In: Annals of Nutrition & Metabolism : Abstracts of the 20th International Congress of Nutrition. - Munich : Karger - ISBN 9783318025163 - p. 149 - 149.
Quercetin induces hepatic lipid omega-oxidation and lowers serum lipid levels in mice
Hoek-van den Hil, E.F. ; Keijer, J. ; Bunschoten, A. ; Vervoort, Jacques ; Stankova, B. ; Bekkenkamp-Grovestein, M. ; Herreman, L. ; Venema, D.P. ; Hollman, P.C.H. ; Tvrzicka, E. ; Rietjens, I. ; Schothorst, E.M. van - \ 2013
PLoS ONE 8 (2013)1. - ISSN 1932-6203 - 10 p.
fatty-acid oxidation - cytochrome-p450 reductase - liver-disease - receptor car - metabolism - dietary - rat - flavonoids - risk - hydroxylases
Elevated circulating lipid levels are known risk factors for cardiovascular diseases (CVD). In order to examine the effects of quercetin on lipid metabolism, mice received a mild-high-fat diet without (control) or with supplementation of 0.33% (w/w) quercetin for 12 weeks. Gas chromatography and 1H nuclear magnetic resonance were used to quantitatively measure serum lipid profiles. Whole genome microarray analysis of liver tissue was used to identify possible mechanisms underlying altered circulating lipid levels. Body weight, energy intake and hepatic lipid accumulation did not differ significantly between the quercetin and the control group. In serum of quercetin-fed mice, triglycerides (TG) were decreased with 14% (p
Resolving 3D-domain swapping of human IL-10 prevents extensive multimerisation and increases yield
Westerhof, L.B. ; Wilbers, R.H.P. ; Roosien, J. ; Bakker, J. ; Schots, A. - \ 2012
In: Molecular farming: plants as production platform for high value proteins. - Warsaw : - p. 27 - 27.
Heterologous expression platforms of biopharmaceutical proteins have been significantly improved over the last decade. Further improvement can be established by examining the intrinsic properties of proteins. Interleukin-10 (IL-10) is an anti-inflammatory cytokine with a short half-life that plays an important role in re-establishing immune homeostasis. This homodimeric protein of 36 kDa has significant therapeutic potential to treat inflammatory and autoimmune diseases. We have shown that the major production bottleneck of human IL-10 is not protein instability as previously suggested, but extensive multimerisation due to its intrinsic 3D domain swapping characteristic. Extensive multimerisation of human IL-10 could be visualised as granules in planta. On the other hand, mouse IL-10 hardly multimerised, which could be largely attributed to its glycosylation. By introducing a short glycine-serine-linker between the fourth and fifth alpha helix of human IL-10 a stable monomeric form of IL-10 (hIL-10mono) was created that no longer multimerised and increased yield up to 20-fold. However, hIL-10mono no longer had the ability to reduce pro-inflammatory cytokine secretion from lipopolysaccharide-stimulated macrophages. Forcing dimerisation restored biological activity. This was achieved by fusing human IL-10mono to the C-terminal end of constant domains 2 and 3 of human immunoglobulin A (Fca), a natural dimer. Stable dimeric forms of IL-10, like Fca-IL-10, may not only be a better format for improved production, but also a more suitable format for medical applications.
3D Domain Swapping Causes Extensive Multimerisation of Human Interleukin-10 When Expressed In Planta
Westerhof, L.B. ; Wilbers, R.H.P. ; Roosien, J. ; Velde, J. van de; Goverse, A. ; Bakker, J. ; Schots, A. - \ 2012
PLoS ONE 7 (2012)10. - ISSN 1932-6203 - 10 p.
crystal-structure - transgenic tobacco - escherichia-coli - interferon-gamma - receptor - reveals - il-10 - csf - disease - cytosol
Heterologous expression platforms of biopharmaceutical proteins have been significantly improved over the last decade. Further improvement can be established by examining the intrinsic properties of proteins. Interleukin-10 (IL-10) is an anti-inflammatory cytokine with a short half-life that plays an important role in re-establishing immune homeostasis. This homodimeric protein of 36 kDa has significant therapeutic potential to treat inflammatory and autoimmune diseases. In this study we show that the major production bottleneck of human IL-10 is not protein instability as previously suggested, but extensive multimerisation due to its intrinsic 3D domain swapping characteristic. Extensive multimerisation of human IL-10 could be visualised as granules in planta. On the other hand, mouse IL-10 hardly multimerised, which could be largely attributed to its glycosylation. By introducing a short glycine-serine-linker between the fourth and fifth alpha helix of human IL-10 a stable monomeric form of IL-10 (hIL-10mono) was created that no longer multimerised and increased yield up to 20-fold. However, hIL-10mono no longer had the ability to reduce pro-inflammatory cytokine secretion from lipopolysaccharide-stimulated macrophages. Forcing dimerisation restored biological activity. This was achieved by fusing human IL-10mono to the C-terminal end of constant domains 2 and 3 of human immunoglobulin A (Fca), a natural dimer. Stable dimeric forms of IL-10, like Fca-IL-10, may not only be a better format for improved production, but also a more suitable format for medical applications.
Interference of flavonoids with enzymatic assays for the determination of free fatty acid and triglyceride levels
Hoek-van den Hil, E.F. ; Beekmann, K. ; Keijer, J. ; Hollman, P.C.H. ; Rietjens, I. ; Schothorst, E.M. van - \ 2012
Analytical and Bioanalytical Chemistry 402 (2012)3. - ISSN 1618-2642 - p. 1389 - 1392.
dietary flavonoids - thyroid peroxidase - quercetin - metabolites - rats - myeloperoxidase - polyphenols - inhibition - oxidation - cells
Flavonoids are bioactive food compounds with potential lipid-lowering effects. Commercially available enzymatic assays are widely used to determine free fatty acid (FFA) and triglyceride (TG) levels both in vivo in plasma or serum and in vitro in cell culture medium or cell lysate. However, we have observed that various flavonoids interfere with peroxidases used in these enzymatic assays, resulting in incorrect lower FFA and TG levels than actually present. Furthermore, addition of isorhamnetin or the major metabolite of the flavonoid quercetin in human and rat plasma, quercetin-3-O-glucuronide, to murine serum also resulted in a significant reduction of the detected TG levels, while a trend was seen for FFA levels. It is concluded that when applying these assays, vigilance is needed and alternative analytical methods, directly assessing FFA or TG levels, should be used for studying the biological effects of flavonoids on FFA and TG levels.
Anti-diarrhoeal aspects of fermented soya beans
Roubos-van den Hil, P.J. ; Nout, M.J.R. - \ 2011
In: Soybean and Health / El-Shemy, H.A., Rijeka, Croatia : InTech - ISBN 9789533075358 - p. 383 - 406.
Risico's van toxische stoffen in ons dagelijks leven: het versc hil tussen risico en risico, oftewel: Hazard en Risk
Murk, Tinka - \ 2011
Bioactivity of tempe by inhibiting adhesion of ETEC to intestinal cells, as influenced by fermentation substrates and starter pure cultures
Roubos-van den Hil, P.J. ; Nout, M.J.R. ; Meulen, J. van der; Gruppen, H. - \ 2010
Food Microbiology 27 (2010)5. - ISSN 0740-0020 - p. 638 - 644.
enterotoxigenic escherichia-coli - in-vitro digestibility - soya bean tempe - rhizopus-oligosporus - food - soybeans - bacteria - diarrhea - quality - growth
Soya bean tempe is known for its bioactivity in reducing the severity of diarrhoea in piglets. This bioactivity is caused by an inhibition of the adhesion of enterotoxigenic Escherichia coli (ETEC) to intestinal cells. In this paper, we assessed the bioactive effect of soya tempe on a range of ETEC target strains, as well as the effect of a range of cereal and leguminous substrates and starter pure cultures. Soya bean tempe extracts strongly inhibited the adhesion of ETEC strains tested. All tempe made from other leguminous seeds were as bioactive as soya bean tempe, whereas tempe made from cereals showed no bioactivity. Using soya beans as substrate, fermentation with several fungi (Mucor, Rhizopus spp. and yeasts) as well as Bacillus spp. resulted in bioactive tempe, whereas fermentation with lactobacilli showed no bioactivity. The active component is releasedor formed during the fermentation and is not present in microbial biomass and only partly in unfermented substrates. The bioactivity being not specific for a single ETEC strain, makes the bioactive tempe relevant for applications in animal husbandry.
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