Papers by Veronika Somoza
Ann N Y Acad Sci, 2008
Repeated mild heat shock treatment has been shown to have anti-aging effects on cellular mechanis... more Repeated mild heat shock treatment has been shown to have anti-aging effects on cellular mechanisms in vitro. Among these, the age-associated accumulation of advanced glycation end products (AGEs), such as N(epsilon)-(carboxymethyl)lysine (CML), has been demonstrated to be effectively prevented in glyoxal-exposed human skin fibroblasts following mild heat shock treatment. The biochemical mechanism responsible for this inhibition is not yet known. However, the involvement of heat shock proteins (HSPs) and the misfolded proteins degrading the ubiquitin-proteasome system have been hypothesized. As AGE-modified proteins are likely to be conformationally modified, we investigated whether treatment of human intestinal cells with casein-linked CML or nonprotein-linked CML affects the expression of HSPs and the ubiquitin-proteasome system by using matrix-assisted laser desorption/ionization-time-of-flight tandem mass spectroscopy (after protein separation by two-dimensional gel electrophoresis) and by Western blotting. Compared to nontreated control cells, expression of HSP90, HSP60, HSP70 chaperones, and the proteasome S26 ATPase subunit 2 were significantly upregulated in casein-CML and in CML-treated cells. Exposure of Caco-2 cells to beta-amyloid, a nonglycation product, revealed similar results. In conclusion, the results indicate that CML and casein-linked CML activate the expression of HSPs as well as the proteasome system, which are involved in the degradation of misfolded and possibly glycated proteins. Whether this mechanism is based on binding to cell surface receptors, such as the receptor for AGE, has to be clarified in future studies.
Food Hydrocolloids, May 1, 2009
The aim of the present study was to investigate the possible impact of the antioxidative activity... more The aim of the present study was to investigate the possible impact of the antioxidative activity and the altered technological properties of glycated caseinate on the oxidative stability of microencapsulated fish oil. Glucose, glucose syrup or dextrans were used for glycation of caseinate and the resulting blends were intensively characterised prior to their use for microencapsulation. After microencapsulation, hydroperoxide and propanal content of the encapsulated fish oil was monitored over a period of up to eight weeks. Heating in aqueous solution, but not dry heating, led to an increase in redox-active compounds in the caseinate-glucose syrup-based carrier matrix and in an increase in oxidative stability of the encapsulated oil. In contrast, microencapsulation in a dry-heated caseinate-glucose blend did not increase oxidative stability compared to the unheated carrier system although the content of redox-active Maillard reaction compounds was increased. Oil droplet size did not significantly change when using glycated caseinate and thus, neither an antioxidative effect of Maillard reaction products nor an improved emulsifying activity is responsible for the increase in oxidative stability. Results of the present study rather indicate that the molecular weight profile of the carrier matrix is one of the key determinants for the oxidative stability of the encapsulated oils.
Journal of Agricultural and Food Chemistry, Mar 1, 2011
Resveratrol, a nontoxic polyphenol, has been shown to inhibit tumor growth in a xenograft mouse m... more Resveratrol, a nontoxic polyphenol, has been shown to inhibit tumor growth in a xenograft mouse model of neuroblasoma. However, resveratrol is rapidly metabolized, mainly to its glucuronidated and sulfated derivatives. This study demonstrates that resveratrol alone, and not the glucuronidated or sulfated metabolites, is taken up into tumor cells, induces a rise in [Ca(2+)](i), and ultimately leads to a decrease in tumor cell viability. A new water-soluble resveratrol formulation was delivered directly at the site of the tumor in a neuroblastoma mouse model. The amount of unmodified resveratrol associated with the tumor increased more than 1000-fold. The increase of unmodified resveratrol associated with the tumor resulted in tumor regression. The number of residual tumor cells that remained viable also decreased as the ratio of the metabolites relative to unmodified resveratrol declined.
Molecular nutrition & food research, Jan 12, 2015
The cytotoxic and genotoxic potential of phase II metabolites of resveratrol (RSV) was investigat... more The cytotoxic and genotoxic potential of phase II metabolites of resveratrol (RSV) was investigated in human colon cells with special emphasis on human topoisomerase (TOP) II. Cell-free screening of TOPII inhibition by the decatenation assay showed inhibitory potential for RSV (≥200 μM) and for the first time for the three human phase II metabolites RSV-3-sulfate (≥200 μM), RSV-3-glucuronide (≥100 μM) and RSV-disulfate (≥100 μM). Conjugation at the C4'-position (RSV-4'-sulfate and RSV-4'-glucuronide) resulted in loss of the inhibitory potential in this assay. Cell-based experiments with RSV and the most abundant metabolite in humans, RSV-3-Sulf, revealed no TOP poisoning in HT29 and Caco-2 cells up to 250 μM. Further, the phase II metabolite exhibited only minor effects in the comet assay and showed negligible cytotoxic effects and apoptotic potential after 1 h and 24 h of incubation. Fluorescence microscopy and HPLC-DAD analysis identified cellular uptake of RSV and of ...
Journal of Agricultural and Food Chemistry, 2015
The natural anti-inflammatory compound resveratrol (RES) is metabolized upon ingestion. After die... more The natural anti-inflammatory compound resveratrol (RES) is metabolized upon ingestion. After dietary-scale doses, plasma concentrations of sulfated and glucuronated metabolites in humans exceed those of RES. The aim of this in vitro study was to assess the effect of physiological concentrations (1 µM) of the most abundant RES metabolites (RES-3-O-sulfate, R3S; RES-disulfates, RdS; RES-3-O-glucuronide, R3G; RES-4'-O-glucuronide, R4G) on genes and proteins involved in immune cell chemotaxis and inflammation (IL-8, MIP-1b, MCP-1, CCR1, CCR2, CXCR2, SIRT1) in a cell model of lipopolysaccharide (LPS) activated U-937 macrophages. Levels of MCP-1 mRNA were comparably decreased after 3 h treatment with R3S and RdS by -24.7 ± 5.51% and -28.7 ± 19.2%. LPS-induced MCP-1 protein release was reduced after 3 h treatment by R3S (-20.8 ± 13.9%) and RdS (-25.7 ± 8.29%). After a 9 h treatment, RdS also inhibited IL-8 and MIP-1b protein release by -22.9 ± 3.57% and -20.1 ± 7.00%. Glucuronides showed differential effects after 6 h of treatment, with R4G up-regulating mRNA of MIP-1b (24.5 ± 14.8%), and R3G and R4G down-regulating CXCR2 surface protein compared to cells treated with LPS alone, by -5.33 ± 4.18% and -15.2 ± 5.99%, respectively. Contrary, R3G and R4G up-regulated SIRT1 mRNA by 22.7 ± 17.9% and 22.8 ± 16.9% in LPS-stimulated U-937 macrophages, showing anti-inflammatory properties. In conclusion, sulfated RES metabolites show an interesting beneficial potential for attenuating inflammatory immune processes.
Signal Transduction, 2005
Maillard reaction products (MRPs) and advanced glycation end-products (AGEs) correspond to modifi... more Maillard reaction products (MRPs) and advanced glycation end-products (AGEs) correspond to modified protein derivatives that are initially generated by non-enzymatic glycation between amino acids and reducing sugars in heat-treated foods and in vivo, respectively. Because lung tissue highly expresses the receptor for advanced glycation end-products (RAGE), we studied the impact of MRP/AGE-rich foods like bread crust (BC) and coffee extract (CE) on the proliferation and cell death induction using lung epithelial (H358) cells. Here, we showed that CE impairs the proliferation and viability of H358 cells at much higher extent than BC does. Particularly cell death induced by CE showed a concentration-dependent shift from apoptotic to necrotic features as estimated by caspase activation, phosphatidylserine exposure, leakage of the outer membrane, mitochondrial dysfunction and stress kinase activation. Moreover, CE at higher dose triggered the generation of reactive oxygen species thereby mediating caspase inhibition. Non-toxic concentrations of both foods only impaired the proliferation associated with an increased amount of cells in the S/G2 phase of the cell cycle, which did not depend on the over-expression of RAGE. From our data we conclude that MRP/AGE-rich foods mediate antiproliferative effects at moderate concentrations that might be important in physiological conditions like cancer prevention but contribute to cell death at higher levels in vitro.
Annals of the New York Academy of Sciences, 2008
Free Radical Biology and Medicine, 2014
Free radicals and oxidative stress are important factors in the biology of aging and responsible ... more Free radicals and oxidative stress are important factors in the biology of aging and responsible for the development of age-related diseases. One way to reduce the formation of free radicals is to boost the antioxidative system by nutrition. Heat treatment of food promote the Maillard reaction which is responsible for their characteristic color and taste. During the Maillard reaction reducing sugars react with proteins in a non-enzymatic way leading to the formation of advanced glycation end products (AGEs). As an AGE-rich source our group used bread crust (BCE) to investigate the effect of AGEs on the antioxidant defense. It is well known that the NF-kB pathway is activated by treatment of cells with AGEs. Therefore for stimulation with the BCE we used the macrophage reporter cell line RAW/NF-kB/SEAPorter™. Amino acid analysis and LC-MS/MS by Orbitrap Velo was used to determine the bioactive compounds in the soluble BCE. The radical scavenging effect was conducted by the DPPH-assay. BCE induced the NF-kB pathway in RAW/NF-kB/SEAPorter™ cells and also showed a concentration-dependent antioxidative capacity by the DPPH-assay. With the LC/MS and amino acid analyses, we identified the presence of gliadin in BCE confirmed by using specific gliadin antibodies. By immunoprecipitation (IP) with an antibody against γ-gliadin and western blot probing against the AGE carboxymethyllysine (CML) the presence of AGE-gliadin in BCE was confirmed. Stimulation of the RAW/NF-kB/SEAPorter™ cells with the γ-gliadin depleted fractions did not activate the NF-kB pathway. CML-modified gliadin in the BCE is a bioactive compound of the bread crust which is responsible for the antioxidative capacity and for the induction of the NF-kB pathway in mouse macrophages.
British Journal of Nutrition, 2008
PLoS ONE, 2013
Infant formula-feeding is associated with reduced insulin sensitivity. In rodents and healthy hum... more Infant formula-feeding is associated with reduced insulin sensitivity. In rodents and healthy humans, advanced glycation end product (AGE)-rich diets exert diabetogenic effects. In comparison with human breast-milk, infant formulas contain high amounts of AGEs. We assessed the role of AGEs in infant-formula-consumption-associated insulin resistance. Total plasma levels of N(ε)-(carboxymethyl)lysine (CML), AGEs-associated fluorescence (λ(ex) = 370 nm/λ(em) = 445 nm), soluble adhesion molecules, markers of micro- binflammation (hsCRP), oxidative stress (malondialdehyde, 8-isoprostanes) and leptinemia were determined, and correlated with insulin sensitivity in a cross-sectional study in 166 healthy term infants aged 3-to-14 months, subdivided according to feeding regimen (breast-milk- vs. infant formula-fed) and age (3-to-6-month-olds, 7-to-10-month-olds, and 11-to-14-month-old infants). Effects of the consumption of low- vs. high-CML-containing formulas were assessed. 36 infants aged 5.8 ± 0.3 months were followed-up 7.5 ± 0.3 months later. Cross-sectional study: 3-to-6-month-olds and 7-to-10-month-old formula-fed infants presented higher total plasma CML levels and AGEs-associated fluorescence (p<0.01, both), while only the 3-to-6-month-olds displayed lower insulin sensitivity (p<0.01) than their breast-milk-fed counterparts. 3-to-6-month-olds fed low-CML-containing formulas presented lower total plasma CML levels (p<0.01), but similar insulin sensitivity compared to those on high-CML-containing formulas. Markers of oxidative stress and inflammation, levels of leptin and adhesion molecules did not differ significantly between the groups. Follow-up study: at initial investigation, the breast-milk-consuming infants displayed lower total plasma CML levels (p<0.01) and AGEs-associated fluorescence (p<0.05), but higher insulin sensitivity (p<0.05) than the formulas-consuming infants. At follow-up, the groups did not differ significantly in either determined parameter. In healthy term infants, high dietary load with CML does not play a pathophysiological role in the induction of infant formula-associated insulin resistance. Whether a high load of AGEs in early childhood affects postnatal programming remains to be elucidated.
Physiology & Behavior, 2012
Maillard reaction products (MRPs) are generated upon thermal processing of foods, modifying their... more Maillard reaction products (MRPs) are generated upon thermal processing of foods, modifying their colour and flavour. We asked whether aroma compounds generated via Maillard-type reactions modulate the in vivo effects of MRP-rich diets (MRPD). Male Wistar rats were fed for 3weeks either with a standard rat chow, an aroma compounds containing MRPD comprising 25% bread crust, or an aroma-extracted MRPD. In contrast to standard rat chow, consumption of MRPDs affected glucose control, induced hyper-leptinemia and hyper-adiponectinemia. Plasma adipokines were significantly higher in rats on aroma containing MRPD in comparison with those consuming aroma-extracted MRPD. Consumption of both MRPDs significantly increased the expression of the insulin receptor in the olfactory bulb, and mildly in the hypothalamus. Administration of the aroma containing MRPD significantly increased the leptin receptor expression in the olfactory bulb, and in the hypothalamus. Under both MRPDs, strong expression of c-fos indicated an increased neuronal activity in the olfactory bulb. Neuronal activity in brain areas involved in the central regulation of food intake and energy homeostasis was more pronounced in rats fed by the aroma containing MRPD. In conclusion, short-term consumption of a MRPD fortified with bread crust, particularly if containing solvent extractable volatile aroma compounds, affected the leptin-induced central signalling of anorexigenic/orexigenic hormones, and the neuronal activity in the central nervous system. Behavioural changes and altered glucose control were more evident in rats on the aroma containing MRPD. Our data suggest that volatile aroma compounds in foods might affect endocrine signalling and neuronal regulation of metabolism.
Molecular Pharmacology, 2009
The phytoestrogen resveratrol has putative health-promoting effects and is present in several die... more The phytoestrogen resveratrol has putative health-promoting effects and is present in several dietary constituents. Resveratrol is metabolized extensively in the gut epithelium, resulting in the formation of hydrophilic glucuronic acid and sulfate conjugates. These polar resveratrol conjugates need specific transporters to cross the cell membrane. We show here that vectorial transport of some of these metabolites is mediated by multidrug resistance protein 3 (MRP3, ABCC3) and/or breast cancer resistance protein (BCRP, ABCG2) located in the basolateral and apical membranes of enterocytes, respectively. In vitro, MRP3 transports resveratrol-glucuronide (Res-3-G). The absence of Mrp3 in mice results in altered disposition of Res-3-G and its parent compound resveratrol, leading to a reduced This work was supported by the Nederlandse Organisatie voor Gezondheidsonderzoek en Zorginnovatie [TOP Grant 40-00812-98-07-028].
Molecular Nutrition & Food Research, 2007
High mobility group box protein 1 (HMGB1) is a ubiquitous nuclear protein that can be actively re... more High mobility group box protein 1 (HMGB1) is a ubiquitous nuclear protein that can be actively released from the cell in certain conditions thereby mediating cytokine-like function. While nuclear HMGB1 modulates the transcriptional activity of cells, extracellular HMGB1 partially acts via binding to the receptor for advanced glycation end products (RAGE), which is highly expressed in lung tissue. Therefore, we studied the impact of food-derived advanced glycation end products (AGEs), the Maillard reaction products, on the lung expression of HMGB1. Feeding rats with AGE-rich diet, containing either bread crust or coffee beverage, resulted in an upregulation of HMGB1 mRNA and protein especially in those animals receiving bread crust diet. The expression of RAGE was not influenced. Moreover, we revealed a positive correlation between an increased lung AGE level and HMGB1 protein expression in both animal groups receiving either bread crust or coffee extract but not in the control group. In contrast, the ageing-related AGE accumulation was not associated with an increased level of HMGB1 protein in lung tissue from senescent (100 wk) compared to young-adult (24 wk) rats. Our data suggest a physiological role of food- but not ageing-associated AGEs in the regulation of the HMGB1 expression in lung.
Molecular Nutrition & Food Research, 2010
The manuscript reviews beneficial aspects of food processing with main focus on cooking/heat trea... more The manuscript reviews beneficial aspects of food processing with main focus on cooking/heat treatment, including other food-processing techniques (e.g. fermentation). Benefits of thermal processing include inactivation of food-borne pathogens, natural toxins or other detrimental constituents, prolongation of shelf-life, improved digestibility and bioavailability of nutrients, improved palatability, taste, texture and flavour and enhanced functional properties, including augmented antioxidants and other defense reactivity or increased antimicrobial effectiveness. Thermal processing can bring some unintentional undesired consequences, such as losses of certain nutrients, formation of toxic compounds (acrylamide, furan or acrolein), or of compounds with negative effects on flavour perception, texture or colour. Heat treatment of foods needs to be optimized in order to promote beneficial effects and to counteract, to the best possible, undesired effects. This may be achieved more effectively/sustainably by consistent fine-tuning of technological processes rather than within ordinary household cooking conditions. The most important identified points for further study are information on processed foods to be considered in epidemiological work, databases should be built to estimate the intake of compounds from processed foods, translation of in-vitro results to in-vivo relevance for human health should be worked on, thermal and non-thermal processes should be optimized by application of kinetic principles.
Journal of Food Science, 2010
In cruciferous vegetables, myrosinase metabolizes the relatively inactive glucosinolates into iso... more In cruciferous vegetables, myrosinase metabolizes the relatively inactive glucosinolates into isothiocyanates and other products that have the ability to increase detoxification enzyme expression. Thus, maintaining myrosinase activity during food preparation may be critical to receiving the maximum benefit of consumption of Brussels sprouts or other cruciferous vegetables. To test the importance of maintaining myrosinase activity for maximizing bioactivity, experimental diets containing 20% unblanched (active myrosinase) or 20% blanched (inactivated myrosinase) freezedried Brussels sprouts and a nutrient-matched control diet were evaluated in vitro and in vivo for their ability to induce detoxification enzymes. Treatment of immortalized HepG2 human hepatoma cells with the unblanched Brussels sprout diet caused a greater increase quinone activity compared to the blanched Brussels sprout diet. C3H/HeJ mice fed the unblanched Brussels sprout diets for 2 wk had significantly higher plasma sulforaphane concentrations. Liver expression of CYP1A1 and epoxide hydrolase, measured using real-time PCR, was correlated with the plasma concentration of sulforaphane. In the lung, expression of epoxide hydrolase, thioredoxin reductase, UDP glucuronosyltransferase, quinone reductase, heme oxygenase, CYP1A1, CYP1A2, and CYP1B1 were also correlated with the plasma concentration of sulforaphane. Together these data demonstrate that, as predicted by the in vitro experiment, in vivo exposure to Brussels sprouts with active myrosinase resulted in greater induction of both phase I and phase II detoxification enzymes in the liver and the lungs that correlated with plasma sulforaphane concentrations.
Journal of Agricultural and Food Chemistry, 2011
Resveratrol, a nontoxic polyphenol, has been shown to inhibit tumor growth in a xenograft mouse m... more Resveratrol, a nontoxic polyphenol, has been shown to inhibit tumor growth in a xenograft mouse model of neuroblasoma. However, resveratrol is rapidly metabolized, mainly to its glucuronidated and sulfated derivatives. This study demonstrates that resveratrol alone, and not the glucuronidated or sulfated metabolites, is taken up into tumor cells, induces a rise in [Ca(2+)](i), and ultimately leads to a decrease in tumor cell viability. A new water-soluble resveratrol formulation was delivered directly at the site of the tumor in a neuroblastoma mouse model. The amount of unmodified resveratrol associated with the tumor increased more than 1000-fold. The increase of unmodified resveratrol associated with the tumor resulted in tumor regression. The number of residual tumor cells that remained viable also decreased as the ratio of the metabolites relative to unmodified resveratrol declined.
Journal of Agricultural and Food Chemistry, 2009
A number of 3(2H)-furanones are synthesized by fruits and have been found in cooked foodstuffs, w... more A number of 3(2H)-furanones are synthesized by fruits and have been found in cooked foodstuffs, where they impart flavor and odor because of their low perception thresholds. They show genotoxic properties in model studies but are also ranked among the antioxidants and anticarcinogens. This study examined the efficiency of intestinal absorption and metabolic conversion of 3(2H)-furanones by using Caco-2 cell monolayers as an intestinal epithelial cell model. The permeability of each agent was measured in both the apical to basal and basal to apical directions. 2,5-Dimethyl-4-methoxy-3(2H)-furanone (DMMF) showed the highest absorption rate in all experiments, while similar amounts of 4-hydroxy-2,5-dimethyl-3(2H)-furanone (HDMF), 4-hydroxy-2(or 5)-ethyl-5(or 2)-methyl-3(2H)-furanone (HEMF), and 4-hydroxy-5-methyl-3(2H)-furanone (HMF) were taken up. HDMF-glucoside was almost not absorbed but was hydrolyzed to a small extent. The transport of 3(2H)-furanones could not be saturated even at levels of 500 microM and occurred in both directions. Because the uptake was only slightly reduced by apical hyperosmolarity, passive diffusion by paracellular transport is proposed.
Journal of Agricultural and Food Chemistry, 2007
Epithelial buccal cells (KB) were exposed to orange juice or orange juice fractions containing ei... more Epithelial buccal cells (KB) were exposed to orange juice or orange juice fractions containing either the dry matter (DM), the volatile compounds (aqueous distillate, AD), or individual nonvolatile or volatile components. Intracellular formation of the pro-inflammatory cytokine IL-6 was analyzed by flow cytometry. Exposure to whole orange juice resulted in an increase in IL-6 formation of 23% compared to nontreated control cells, whereas treatment of the cells with either DM or AD resulted in a 22 or 1% increase, respectively. Dose-response experiments revealed that exposure of the cells to a 2- or 4-fold concentrated AD resulted in an increased IL-6 formation, whereas an inhibiting effect was measured after treatment of the cells with an 8-fold concentrated AD. These results indicated the presence of pro- as well as anti-inflammatory compounds in the aqueous distillate. To identify the active principles, volatile compounds present in the AD-treated cells were analyzed by GC-MS. In particular, limonene, linalool, and alpha-terpineol were shown to be present in significant amounts. Subsequent studies on the IL-6 formation revealed that limonene had a stimulating effect and alpha-terpineol had an inhibiting effect, whereas linalool had no effect. This anti-inflammatory effect of alpha-terpineol on IL-6 formation was verified by quantitative real-time reverse transcription Polymerase Chain Reaction experiments in which alpha-terpineol inhibited the gene expression of the IL-6 receptor.
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Papers by Veronika Somoza