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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    Antibacterial prenylated isoflavonoids and stilbenoids : quantitative structure-activity relationships and mode of action
    Araya-Cloutier, Carla - \ 2017
    Wageningen University. Promotor(en): H. Gruppen, co-promotor(en): J.P. Vincken; H.M.W. den Besten. - Wageningen : Wageningen University - ISBN 9789463430364 - 200
    isoflavones - plant oestrogens - stilbenoids - regression analysis - computational chemistry - antibacterial agents - isoflavonen - plantenoestrogenen - stilbenoïden - regressieanalyse - computationele chemie - antibacteriële middelen

    Prenylated phenolic compounds, i.e. those bearing a C5-isoprenoid (prenyl) substituent, are abundant in plants from the Fabaceae (legume) family and are potential natural antibacterial agents against resistant pathogenic bacteria. To understand the antibacterial properties of these compounds, (quantitative) structure-activity relationships and mode of action of these molecules were investigated against Gram positive and negative bacteria.

    Compounds belonging to the flavonoid, isoflavonoid and stilbenoid classes were studied. Antibacterial activity was modulated by the (sub)class of phenolic compound, as well as by the configuration, position and number of prenyl groups. Prenylated isoflavones were found to be better antibacterials than prenylated pterocarpans and prenylated stilbenoids. It was also shown that chain prenylation increased the antibacterial activity more than pyran-ring prenylation. Diprenylated compounds were among the most active antibacterials with minimum inhibitory concentrations of less than 10 µg/mL against Listeria monocytogenes. The main molecular characteristics defining antibacterial activity were molecular shape (including flexibility and globularity) and hydrophobicity. Regarding the mode of action of these compounds, it was shown that prenylated phenolic compounds can disrupt the integrity of the membrane by permeabilization very quickly. Interestingly, some good antibacterial prenylated (iso)flavonoids showed good permeabilization capacity whereas others not (including diprenylated molecules), highlighting potential differences in their interactions with the bacterial membrane. Likewise, it was shown that Gram negative intrinsic resistance towards prenylated phenolic compounds is primarily due to the activity of efflux pump systems and that it can be overcome by using an efflux pump inhibitor in combination with antibacterial prenylated compounds. Last, in vitro production of prenylated phenolic compounds was performed with microbial prenyltransferase SrCloQ and novel C- and O-prenylated compounds were produced.

    The influence of phase II conjugation on the biological activity of flavonoids
    Beekmann, K. - \ 2016
    Wageningen University. Promotor(en): Ivonne Rietjens; Peter van Bladeren, co-promotor(en): L. Actis-Goretta. - Wageningen : Wageningen University - ISBN 9789462577640 - 171
    flavonoids - biological activity - in vitro - biosynthesis - peroxisomes - microarrays - daidzein - genistein - oestrogen receptors - isoflavones - quercetin - kaempferol - serine proteinases - threonine - flavonoïden - biologische activiteit - in vitro - biosynthese - peroxisomen - microarrays - daidzin - genisteïne - oestrogeenreceptoren - isoflavonen - quercetine - kaempferol - serine proteïnasen - threonine

    Flavonoid consumption is often correlated with a wide range of health effects, such as the prevention of cardiovascular diseases, neurodegenerative diseases, and diabetes. These effects are usually ascribed to the activity of the parent flavonoid aglycones, even though these forms of the flavonoids generally have a low systemic bioavailability. During uptake, flavonoids undergo phase II metabolism and are present in the systemic circulation nearly exclusively as conjugated metabolites. The aim of this thesis was to study the effect of conjugation on the biological activity of selected flavonoids towards different endpoints relevant for human health. To this end, conjugation with glucuronic acid was taken as the model type of conjugation because this modification is generally observed to be the most important metabolic conjugation reaction for flavonoids in man.

    A review of scientific literature published until early 2012 reveals that metabolic conjugation can affect the biological activity of flavonoids in different ways. Conjugation can increase, decrease, inverse or not affect the biological activity, depending on the flavonoid, the type and position of conjugation, the endpoint studied, and the assay system used. Based on the literature reviewed it is concluded that the effect of conjugation has to be studied on a case-by-case basis.

    As the research on the biological activity of biologically relevant flavonoid conjugates is often hampered by the generally low commercial availability and high prices of these conjugates, a simple and versatile method for the biosynthesis of metabolically relevant flavonoid conjugates is described. Using this method, relevant conjugates can be prepared from different flavonoid substrates in sufficient quantities for in vitro bioassays. Further, an efficient strategy for the identification of these flavonoid conjugates by LC-MS and 1H-NMR using MetIDB (Metabolite Identification Database), a publicly accessible database of predicted and experimental 1H-NMR spectra of flavonoids, is presented.

    To study the effect of conjugation on the biological activities of flavonoids, several different assay systems and endpoints were used to study the activity of different flavonoids and their conjugates. The effects of quercetin, kaempferol, and their main plasma conjugates quercetin-3-O-glucuronide and kaempferol-3-O-glucuronide (K-3G) on different endpoints related to peroxisome proliferator-activated receptor (PPAR)-γ were studied. PPAR-γ activation is reported to have positive health effects related to adipogenesis, insulin resistance and inflammation. The presented results show that the flavonoid aglycones increased PPAR-γ mediated gene expression in a stably transfected reporter gene cell line, and that glucuronidation diminished this effect. These observed increases in reporter gene expression were accompanied by increased PPAR-γ receptor-mRNA expression upon exposure to kaempferol, an effect that was also reduced by glucuronidation. Using the cell-free Microarray Assay for Real-time Coregulator-Nuclear receptor Interaction (MARCoNI) it was demonstrated that, unlike the known PPAR-γ agonist rosiglitazone, neither the flavonoid aglycones nor the conjugates are agonistic ligands of the PPAR-γ receptor. Supporting the hypothesis that the tested compounds have a different mode of action from normal LBD agonism, quercetin appeared to synergistically increase the effect of rosiglitazone in the reporter gene assay. The modes of action behind the observed effects remain to be elucidated and might include effects on protein kinase activities affecting expression of the PPAR-γ receptor, or posttranscriptional modifications of PPAR-γ.

    Another type of nuclear receptor known to be targeted by certain flavonoids are the estrogen receptor (ER)α- and ERβ. ERs are the main targets of estrogenic compounds, and upon their activation different transcriptional responses with opposite effects on cell proliferation and apoptosis are elicited; ERα activation stimulates cell proliferation, while ERβ activation causes apoptosis and reduces ERα mediated induction of cell proliferation. Using the MARCoNI assay, the intrinsic estrogenic effects of the two main dietary isoflavones daidzein and genistein, and their plasma conjugates daidzein-7-O-glucuronide and genistein-7-O-glucuronide on the ligand induced coregulator binding of ERα- and ERβ-LBD were studied and compared to the effect of the positive control 17β-estradiol (E2). The results show that the tested isoflavone compounds are less potent agonists of ERα- and ERβ-LBD than E2, although they modulate the LBD-coregulator interactions in a manner similar to E2. Genistein is shown to be a more potent agonist than daidzein for both receptor subtypes. While in the MARCoNI assay genistein had a strong preference for ERβ-LBD activation over ERα-LBD activation, daidzein had a slight preference for ERα-LBD activation over ERβ-LBD activation. Glucuronidation reduced the intrinsic agonistic activities of both daidzein and genistein to induce ERα-LBD and ERβ-LBD - coregulator interactions and increased their average half maximal effective concentrations (EC50s) by 8 to 4,400 times. The results presented further show that glucuronidation changed the preferential activation of genistein from ERβ-LBD to ERα-LBD and increased the preferential activation of daidzein for ERα-LBD; this is of special interest given that ERβ activation, which is counteracting the possible adverse effects of ERα activation, is considered one of the supposedly beneficial modes of action of isoflavones.

    Many flavonoids are reported to be inhibitors of protein kinases. To study the effect of conjugation on the inhibition of serine/threonine protein kinases by flavonoids, kaempferol and its main plasma conjugate K-3G were selected as model compounds. Protein kinases are involved in a wide range of physiological processes by controlling signaling cascades and regulating protein functions; modulation of their activities can have a wide range of biological effects. The inhibitory effects of kaempferol, K-3G, and the broad-specificity protein kinase inhibitor staurosporine on the phosphorylation activity of recombinant protein kinase A (PKA) and of a lysate prepared from the hepatocellular carcinoma cell line HepG2 were studied using a microarray platform that determines the phosphorylation of 141 putative serine/threonine phosphorylation sites derived from human proteins. The results reveal that glucuronidation reduces the intrinsic potency of kaempferol to inhibit the phosphorylation activity of PKA and HepG2 lysate on average about 16 and 3.5 times, respectively. It is shown that the inhibitory activity of K-3G in the experiments conducted was not caused by deconjugation to the aglycone. Furthermore, the results show that kaempferol and K-3G, unlike the broad-specificity protein kinase inhibitor staurosporine, did not appear to inhibit all protein kinases present in the HepG2 lysate to a similar extent, indicating that kaempferol selectively targets protein kinases, a characteristic that appeared not to be affected by glucuronidation. The fact that K-3G appeared to be only a few times less potent than kaempferol implies that K-3G does not necessarily need to be deconjugated to the aglycone to exert potential inhibitory effects on protein kinases.

    The results obtained in the present thesis support the conclusion that glucuronidation of flavonoids does not necessarily abolish their activity and that flavonoid glucuronides may be biologically active themselves, albeit at higher concentrations than the parent aglycones. In line with the conclusions from the earlier literature review, an updated literature review on the effect of conjugation on the biological activity of flavonoids concludes that that the effect of conjugation on the biological activity of flavonoids depends on the type and position of conjugation, the endpoint studied and the assay system used. Based on the results described and the literature reviewed in this thesis, several recommendations and perspectives for future research are formulated. Several methodological considerations are formulated that need to be taken into account when studying the biological activity of flavonoids and their conjugates to avoid confounding results. Further, the relevance of the gut microbiome for flavonoid bioactivity is highlighted, and considerations regarding the pharmacokinetics and pharmacodynamics of flavonoids in vivo are formulated. Altogether, it can be concluded that circulating flavonoid conjugates may exert biological activities themselves, and that understanding these is a prerequisite to successfully elucidate the mechanisms of action behind the biological activities linked to flavonoid consumption.

    Improvement of risk assessment by integrating toxicological and epidemiological approaches: the case of isoflavones
    Islam, M.A. - \ 2015
    Wageningen University. Promotor(en): Ivonne Rietjens; Rolaf van Leeuwen; Tinka Murk. - Wageningen : Wageningen University - ISBN 9789462574649 - 174
    isoflavones - glucosides - soyabeans - toxic substances - bioavailability - biomarkers - human nutrition research - risk-benefit analysis - gene expression - isoflavonen - glucosiden - sojabonen - toxische stoffen - biologische beschikbaarheid - biomarkers - voedingsonderzoek bij de mens - risico-baten analyse - genexpressie

    Improvement of risk assessment by integrating toxicological and epidemiological approaches: the case of isoflavones

    PhD-thesis Mohammed Ariful Islam

    This thesis describes the results of a research project that aimed at the improvement of the risk/benefit assessment of soy isoflavones (SIF) by combining toxicological and epidemiological methods. The toxicological studies were carried out at the Department of Toxicology and part of the results were compared with the outcome of human intervention studies, that were carried out in parallel research project at the Division of Human Nutrition. In Chapter 1 it is explained why we considered such an integrated “tox-epi” approach to be useful for the prediction of possible effects of SIF in humans on the basis of animal data. SIF are constituents of soy based supplements, which became more and more popular in Western societies over the last decades, because of their putative beneficial health effects, that were related to the SIF present in these supplements. In spite of the long and safe history of soy consumption by the East and the South-East Asian population, the benefit and safety of soy have been challenged in recent years and concerns have been raised about possible adverse health effects. These concerns focussed primarily on the weak estrogenic and proliferative effects of SIF. Chapter 1 also provides some background information on the individual SIF, their structural similarity with the steroid hormone estradiol (E2) and their interaction with the estrogen receptors ERα and ERβ.

    Chapter 2 describes the differences between rats and humans in the conversion of the three major soy isoflavone glucosides, daidzin, genistin and glycitin, and their aglycones in a series of in vitro models. Results of studies in a Caco-2 transwell model confirmed that deconjugation of the isoflavone glucosides is essential for their transport across the intestinal barrier. It was shown that both rat and human intestinal S9 fractions were able to deconjugate the glucosides, and that intestinal enzymes plaid an important role in this deconjugation reaction. It was demonstrated that in the rat lactase phlorizin hydrolase, glucocerebrosidase, and cytosolic broad-specificity β-glucosidase contribute significantly to this deconjugation, and that in humans deconjugation mainly appeared to occur through the activity of broad-specificity β-glucosidase. Species difference in glucuronidation and sulfation were smaller than for the deconjugation reaction, and it was shown that 7-O-glucuronides were the major metabolites for all the three isoflavone aglycones. The in vitro results also indicated that glucuronidation in rats might be more efficient than in humans, again pointing towards species differences in the metabolism of isoflavone glycosides between rats and humans. It was also shown that the reconjugation reaction has a larger catalytic efficiency than the deconjugation of the glucosides, which corroborates that the detection of aglycones in the systemic circulation is unlikely.

    It has been reported in literature that following administration of SIF to humans or animals, these compounds are mainly (~98%) present in the systemic circulation in their conjugated form (i.e. as glucuronide and sulphate) of which the estrogenic potency is not yet clear. Chapter 3 provides evidence that in an intact cellular model the major SIF glucuronide metabolites in blood, genistein-7-O-glucuronide (GG) and daidzein-7-O-glucuronide (DG), only become estrogenic after deconjugation. The estrogenic potencies of genistein (Ge), daidzein (Da), GG and DG were determined using stably transfected U2OS-ERα, U2OS-ERβ reporter gene cells and proliferation was tested in T47D-ERβ and in T47D breast cancer cells. In all these assays the estrogenic potency of the aglycones was significantly higher than that of their corresponding glucuronides. UPLC analysis revealed that in the in vitro cell line assays, 0.2-1.6% of the glucuronides were deconjugated to their corresponding aglycones. It was also found that, under similar experimental conditions, rat breast tissue S9 fraction was about 30 times more potent in deconjugating these glucuronides than human breast tissue S9 fraction. The results presented in Chapter 3 confirm that SIF glucuronides are not estrogenic as such when tested in an intact cellular model system, and that the small fraction of aglycones account for the observed estrogenic effects. They also provide evidence for a significant species difference in the metabolism of SIF.

    In Chapters 4 and 5 of this thesis, two rat studies are described, that were performed to further elucidate important modes of action underlying biological effects of SIF and to facilitate an interspecies comparison of the effects observed in rats with those observed in human intervention studies. In these studies inbred ovariectomized Fischer344 rats were used, as an animal model for (post)menopausal women. In the first study described in Chapter 4, two dose levels (i.e. 2 and 20 mg/kg bw) were used to characterise plasma bioavailability, urinary and faecal concentrations of SIF and to investigate changes in gene expression in peripheral blood mononuclear cells (PBMC). The low dose was in line with the type of dosing relevant for human supplement use. Animals were dosed at 0 and 48 hr and sacrificed 4 hr after the last dose. A clear dose dependent increase of SIF concentrations in plasma, urine and faeces was observed, together with a strong correlation in changes in gene expression between the two dose groups. In the transcriptomic analysis, all estrogen responsive genes (ERG) and related biological pathways (BPs) that were found to be affected by the SIF treatment were regulated in both dose groups in the same direction, and indicate possible beneficial effects of SIF. However, most of the common genes in PBMC of rats and of (post)menopausal women, exposed to a comparable dose of the same supplement, were regulated in opposite direction. Thus based on these results no correlation was found between the changes in gene expression in rats and humans, leading to the conclusion that rats might not be a suitable model for humans.

    In Chapter 5 an animal experiment is described, in which rats received a dose of 2 mg SIF/kg body weight per day for a period of eight weeks. This dosing regimen was similar as that of the parallel human intervention study. Changes in gene expression in different target (i.e. breast (BT), uterus (UT) and sternum (ST)) and non-target (i.e. peripheral blood mononuclear cells (PBMC), adipose (AT) and liver (LT)) tissues were compared. Rank-rank scattered plots did not show any correlation in gene expression changes among different tissues. Out of 87 estrogen responsive genes (ERG), only 19 were found to be significantly regulated (p<0.05) in different tissues. The significantly regulated ERG were mostly found in LT, AT and UT. Surprisingly, no ERG were significantly regulated in BT and ST, although these are considered to be important estrogen sensitive target tissues. No correlation was observed with the changes in gene expression in the PBMC of two rat studies. Correlation was also not seen in the changes of gene expression in PBMC and adipose tissue between rat and humans.

    In Chapter 6 the results of the research project described in this thesis are evaluated. It was the aim of thesestudies to contribute to theimprovement ofthe risk and/or benefit assessment of SIF for humans, by using in vitro and in vivo animal and human models, and gene expression data in various animal and human tissues, as early biomarkers of effects of exposure to SIF. Although important information has been gathered on the metabolism and the estrogenic activity of SIF and their aglycones, we were not able to predict possible effects in human target tissues based on the results of changes in gene expression in target tissues obtained in the 8 weeks rat study. Possibly aged rats might be a more appropriate model than young ovariectomized rats.

    Separation of isoflavones form okara : process mechanisms & synthesis
    Jankowiak, L. - \ 2014
    Wageningen University. Promotor(en): Remko Boom, co-promotor(en): Atze Jan van der Goot. - Wageningen : Wageningen University - ISBN 9789462570641 - 184
    sojaproducten - isoflavonen - extractie - bijproducten - soyabean products - isoflavones - extraction - byproducts

    By-product utilisation, more efficient use of resources, and more sustainable processing have become of the utmost importance for society and the food industry. During soymilk production, a by-product called okara is produced in great quantities. Despite being a by-product, okara contains many nutrients, which could be utilised for human consumption. Isoflavones are one example of the components present in soy, which are also found in okara. Isoflavones are a subclass of flavonoids, a group of the many polyphenols that exist, and are believed to have a positive effect in the prevention of hormone related cancers, cardiovascular disease, osteoporosis and obesity. One of the main challenges when extracting isoflavones from okara are their low concentration in okara and the strong water binding capacity of the biopolymer matrix of okara. Besides, isoflavones comprise several classes of components having different properties with respect to for example their solubility. This makes the separation and purification of those components in a cost-efficient manner with a non-toxic solvent route challenging.

    The aim of this thesis is to provide insight for the development of a polyphenol separation process on the case of okara. The presence of a partly solid matrix and its impact on the separation process was investigated, and the opportunities and challenges for isoflavone separation from okara are presented in this thesis. By means of this case, the applicability of a process synthesis methodology for separation processes was investigated.

    In chapter 2, the use of ethanol and water was investigated as relatively non-toxic solvents for extraction of the isoflavones. High extraction yields were obtained with 50-70% ethanol. However, different optima in the range of 0%-100% ethanol were obtained dependent on the isoflavone group, which highly differ in hydrophobicity. The glucosides had an optimum at 50%-60% ethanol, the malonyl-glucosides between 30% and 60% ethanol, and the aglycone yield increased monotonously with the ethanol concentration. The solvent choice does not just determine the yield of isoflavones in the extract, but also the swelling of the matrix, important for the separation of the solvent and the okara, and the purity in the extract. While finding a good solvent for a range of components is one issue, a second challenge in the utilisation of okara is its high moisture content, because this limits the ethanol concentrations that can be used in the extraction solvent when extracting the crude okara. Nevertheless, the same extraction yields were obtained as with the dried material, which led to the conclusion that drying of the starting material, being an energy intensive operation, should be omitted.

    The consequences of using the wet, non-dried okara were evaluated using an exergy analysis. The use of the water in okara poses a challenge if a high fraction of a co-solvent such as ethanol is needed, since that increases the total liquid-to solid ratio. Therefore, we conceptually designed the extraction process and evaluated the efficiency and sustainability of different options (chapter 3). Exergy analysis can quantify and combine effects of solvent consumption and physical energy thermodynamically. In addition, it can indicate the resource efficiency of a process and can be used to compare streams with different solvents such as ethanol and water. Often used for process optimisation, we investigated the use of exergy for process synthesis, which delivered the information for further process design and decision-making. A drying step was found to be less detrimental than an increased solvent use. The use of ethanol, its loss and distillation, and the loss of the extracted residue were identified as the most inefficient steps within the conceptual process, and with this, guidelines were given how to improve the systems sustainability.

    The analysis performed in chapter 3 showed that a significant step towards better sustainability is made when ethanol is fully omitted as solvent in the extraction step. Furthermore, it was shown in chapter 2 that part of the isoflavones are rather water soluble due to their glucosidic nature. Therefore, the extraction and solubilisation of isoflavones in water was investigated in detail in chapter 4. Besides, the co-extraction of proteins in the water environment and their effect on the isoflavone extraction was investigated. The temperature did not influence the extraction, but an increased liquid-to-solid ratio and the pH did have a clear influence on the extraction yield. Okara may also contain the less polar aglycones, which are in general not present naturally in the soybeans, but which are products of hydrolysis of the glycosides due to certain processing conditions. The ionisation (dissociation) of the components at higher pH can modify their solubility and interaction with the matrix; therefore, by adjusting the pH the aglycones could be solubilised in water as well.

    Further purification based on affinity separation was shown to be more feasible with water as solvent, since a water-ethanol mixture would be such a good solvent that the adsorption on the column would be hindered. The common way of regenerating such components includes the use of another solvent than is used for extraction, leading to an additional evaporation step. The higher affinity of isoflavones in an aqueous environment to a resin, and the possibility to omit an additional preparation step demonstrated the suitability of water as solvent in the primary extraction step: the extracts are more suitable for chromatographic purification, while ethanol or aqueous ethanol could be used as eluent. This demonstrates that it is important not to design a processing step by itself, but to optimise an internally coherent processing system as a whole.

    Chapter 5 reports on the adsorption of the isoflavones on polyvinyl polypyrrolidone (PVPP) with special regards to the effect of proteins that are co-suspended in the extract. The adsorption efficiency was only negatively influenced when accounting for the isoflavones that are lost with protein that precipitates at lower pH. The affinity of the isoflavone groups could be described with constant partition coefficients resulting from a simple model. Furthermore, the adsorption of the isoflavones onto PVPP with the entire okara matrix present at floating pH could be described with a model using the partition coefficients describing the affinity to the PVPP and to the matrix. The model suggests that it is possible to ‘pull’ the isoflavones from the okara by concurrent adsorption of the isoflavones to an adsorption resin that is present in the same solution, thus increasing both yield and purity.

    The three main isoflavone groups present in okara behave differently throughout the entire study, due to their different properties. The order of their adsorption affinities was the reverse of their water extractability. A more sustainable integrated recovery process can be designed for polyphenolic components, by identifying the right balance between the polarity and hydrophobicity of the component of interest, the solvent, and the adsorbent.

    The investigated process synthesis methodology, and the design options that followed by applying this methodology are discussed in detail in chapter 6. A simplified simultaneous extraction-adsorption separation process, which resulted from the process synthesis is presented. Two base case flow diagrams that can be investigated in depths are further discussed in chapter 7.

    Since the relevant properties and phenomena underlying the results presented in this thesis are quite generic, they can be translated to other separation processes, and the same approach can be used to develop more sustainable separation processes for polyphenols or other useful compounds from other food-by-products. By using the sustainability and efficiency as a prime objective within process design in combination with a good understanding of the underlying phenomena of the system, a new step in process design can be made: Sustainable process development requires proper understanding of the complex systems we are dealing with, the matrix itself, but also the thermodynamic behaviour of the components, and their behaviour in the matrix and during processing.

    Molecular effects of isoflavone supplementation : human intervention studies and quantitative models for risk assessment
    Velpen, V. van der - \ 2014
    Wageningen University. Promotor(en): Pieter van 't Veer; Evert Schouten, co-promotor(en): Anouk Geelen; Lydia Afman. - Wageningen : Wageningen UR - ISBN 9789461739520 - 153
    isoflavonen - voedselsupplementen - risicoschatting - genexpressie - blootstellingsbepaling - menopauze - isoflavones - food supplements - risk assessment - gene expression - exposure assessment - menopause

    Background: Risk assessment can potentially be improved by closely linked experiments in the disciplines of epidemiology and toxicology. This was explored for isoflavones in a case study. For isoflavones potential beneficial health effects have been suggested, but discussions on their safety are ongoing as well.

    Aims and methods: Effects of isoflavone supplements on gene expression were studied in white blood cells (PBMCs) and adipose tissue, among postmenopausal women in two human intervention studies. To advance risk assessment, the dose response relation between intake and blood levels was studied with a log-linear regression model as well as the comparability of the human gene expression profiles with results from a rat experiment using multivariate analysis.

    Results: In both PBMCs and adipose tissue, changes in gene expression profiles pointed at effects of isoflavones on energy metabolism, inflammation and cell cycle; these effects were modified by supplement composition and equol-producing phenotype. Hypothesized estrogen-responsive effects were not observed. For the intake range of 0-100mg/day, the plasma concentrations of daidzein, equol, genistein and total isoflavones were quantified, interindividual variation. Expression of estrogen-responsive gene profiles and other biological pathways could be quantitatively compared between PBMCs and adipose tissue, as well as between humans and rats. en nog iets

    Conclusion: Effects of isoflavone supplementation on gene expression in PBMCs and adipose tissue of postmenopausal women suggest mainly beneficial effects of a dose of ~100mg/day. The absence of a clear estrogen-like response suggested a limited role of the estrogen receptor in isoflavone induced gene expression in postmenopausal women. The trials and quantitative models provide important tools[AG1] that enable further exploration of intertissue and interspecies comparability and advancing the use of transcriptomics in assessing risks and benefits.

    Modelling data from human and animal studies provide important possibilities for further exploration of intertissue and interspecies similarities and for the use of transcriptomics in improving risk assessment.

    Processing of raw materials for the isolation of phytoestrogens : report on session 2 workpackage 5 : second open plenary Phytohealth meeting : 27th-30th October 2004, Hersonissos, Crete, Greece
    Schroot, J.H. - \ 2004
    Wageningen : Agrotechnology & Food Sciences Group (Report / wageningen UR, Agrotechnology & Food Innovations 307) - ISBN 9789067548717 - 66
    plantenoestrogenen - isoflavonen - lignanen - voedselverwerking - houdbaarheid (kwaliteit) - biologische beschikbaarheid - eu regelingen - plant oestrogens - isoflavones - lignans - food processing - keeping quality - bioavailability - eu regulations
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