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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Reducing viral contamination from finger pads: handwashing is more effective than alcohol-based hand disinfectants
Tuladhar, E. ; Hazeleger, W.C. ; Koopmans, M. ; Zwietering, M.H. ; Duizer, E. - \ 2015
Journal of Hospital Infection 90 (2015)3. - ISSN 0195-6701 - p. 226 - 234.
feline calicivirus - murine norovirus - foodborne viruses - norwalk virus - in-vivo - inactivation - sanitizer - surrogate - efficacy - food
Background - Hand hygiene is important for interrupting transmission of viruses through hands. Effectiveness of alcohol-based hand disinfectant has been shown for bacteria but their effectiveness in reducing transmission of viruses is ambiguous. Aim - To test efficacy of alcohol hand disinfectant against human enteric and respiratory viruses and to compare efficacy of an alcohol-based hand disinfectant and handwashing with soap and water against norovirus. Methods - Efficacies of a propanol and an ethanol-based hand disinfectant against human enteric and respiratory viruses were tested in carrier tests. Efficacy of an alcohol-based hand disinfectant and handwashing with soap and water against noroviruses GI.4, GII.4, and MNV1 were tested using finger pad tests. Findings - The alcohol-based hand disinfectant reduced the infectivity of rotavirus and influenza A virus completely within 30 s whereas poliovirus Sabin 1, adenovirus type 5, parechovirus 1, and MNV1 infectivity were reduced 3.0 ± 0.4 log10) was significantly higher than treating hands with alcohol (2.8 ± 1.5 log10). Washing with soap and water for 30 s removed genomic copies of MNV1 (>5 log10), noroviruses GI.4 (>6 log10), and GII.4 (4 log10) completely from all finger pads. Treating hands with propanol-based hand disinfectant showed little or no reduction to complete reduction with mean genomic copy reduction of noroviruses GI.4, GII.4, and MNV1 being >2.6, >3.3, and >1.2 log10 polymerase chain reaction units respectively. Conclusions - Washing hands with soap and water is better than using alcohol-based hand disinfectants in removing noroviruses from hands. Keywords: Carrier test; Enteric virus; Finger pad test; Foodborne viruses; Hand disinfection; Norovirus; Respiratory viruses
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.
Oral administration of Lactobacillus plantarum 299v modulates gene expression in the ileum of pigs: prediction of crosstalk between intestinal immune cells and sub-mucosal adipocytes
Hulst, M.M. ; Gross, G. ; Liu, Yapin ; Hoekman, A.J.W. ; Niewold, T. ; Meulen, J. van der; Smits, M.A. - \ 2015
Genes & Nutrition 10 (2015)3. - ISSN 1555-8932 - 13 p.
kappa-b - functional-analysis - in-vivo - inhibition - immunoglobulins - identification - adipogenesis - macrophages - metabolism - activation
To study host–probiotic interactions in parts of the intestine only accessible in humans by surgery (jejunum, ileum and colon), pigs were used as model for humans. Groups of eight 6-week-old pigs were repeatedly orally administered with 5 × 1012 CFU Lactobacillus plantarum 299v (L. plantarum 299v) or PBS, starting with a single dose followed by three consecutive daily dosings 10 days later. Gene expression was assessed with pooled RNA samples isolated from jejunum, ileum and colon scrapings of the eight pigs per group using Affymetrix porcine microarrays. Comparison of gene expression profiles recorded from L. plantarum 299v-treated pigs with PBS-treated pigs indicated that L. plantarum 299v affected metabolic and immunological processes, particularly in the ileum. A higher expression level of several B cell-specific transcription factors/regulators was observed, suggesting that an influx of B cells from the periphery to the ileum and/or the proliferation of progenitor B cells to IgA-committed plasma cells in the Peyer’s patches of the ileum was stimulated. Genes coding for enzymes that metabolize leukotriene B4, 1,25-dihydroxyvitamin D3 and steroids were regulated in the ileum. Bioinformatics analysis predicted that these metabolites may play a role in the crosstalk between intestinal immune cells and sub-mucosal adipocytes. Together with regulation of genes that repress NFKB- and PPARG-mediated transcription, this crosstalk may contribute to tempering of inflammatory reactions. Furthermore, the enzyme adenosine deaminase, responsible for the breakdown of the anti-inflammatory mediator adenosine, was strongly down-regulated in response to L. plantarum 299v. This suggested that L. plantarum 299v-regulated production of adenosine by immune cells like regulatory T cells may also be a mechanism that tempers inflammation in the ileum, and perhaps also in other parts of the pig’s body.
Bright fluorescent Streptococcus pneumoniae for live cell imaging of host-pathogen interactions
Kjos, M. ; Aprianto, R. ; Fernandes, V.E. ; Andrew, P.W. ; Strijp, J.A.G. van; Nijland, R. ; Veening, J.W. - \ 2015
Journal of Bacteriology 197 (2015)5. - ISSN 0021-9193 - p. 807 - 818.
epithelial-cells - gene-expression - pneumococcal virulence - bacillus-subtilis - in-vivo - protein - capsule - colonization - disease - invasion
Streptococcus pneumoniae is a common nasopharyngeal resident in healthy people, but at the same time one of the major causes of infectious diseases such as pneumonia, meningitis and sepsis. The shift from commensal to pathogen and its interaction with host cells is poorly understood. One of the major limitations for research on pneumococcal-host interactions is the lack of suitable tools for live cell imaging. To address this issue, we developed a generally applicable strategy to create genetically stable, highly fluorescent bacteria. Our strategy relies on fusing superfolder green fluorescent protein (GFP) or a far-red fluorescent protein (RFP) to the abundant histone-like protein HlpA. Due to efficient translation and limited cellular diffusion of these fusions, the cells are 25-fold brighter than the currently best available imaging S. pneumoniae strain. These novel bright pneumococcal strains are fully virulent and the GFP-reporter can be used for in situ imaging in mouse tissue. We used our reporter strains to study the effect of the polysaccharide capsule, a major pneumococcal virulence factor, on different stages of infection. By dual-color live cell imaging experiments, we show that unencapsulated pneumococci adhere significantly better to human lung epithelial cells compared to encapsulated strains, in line with previous data obtained by classical approaches. We also confirm with live cell imaging that the capsule protects pneumococci from neutrophil phagocytosis, demonstrating the versatility and usability of our reporters. The described imaging tools will pave the way for live cell imaging of pneumococcal infection and help understand the mechanisms of pneumococcal pathogenesis.
Molecular and functional characterization of the scavenger receptor CD36 in zebrafish and common carp
Fink, I.R. ; Benard, E.L. ; Hermsen, G.J. ; Meijer, A.H. ; Forlenza, M. ; Wiegertjes, G. - \ 2015
Molecular Immunology 63 (2015)2. - ISSN 0161-5890 - p. 381 - 393.
toll-like receptors - salmon salmo-salar - cyprinus-carpio - density-lipoprotein - neutrophilic granulocytes - monoclonal-antibodies - accessory molecules - innate immunity - gene family - in-vivo
CD36 is a scavenger receptor which has been studied closely in mammals where it is expressed by many different cell types and plays a role in highly diverse processes, both homeostatic and pathologic. It is among other things important in the innate immune system, in angiogenesis, and in clearance of apoptotic cells, and it is also involved in lipid metabolism and atherosclerosis. Recently, in the cephalochordate amphioxus a primitive CD36 family member was described, which was present before the divergence of CD36 from other scavenger receptor B family members, SCARB1 and SCARB2. Not much is known on the Cd36 molecule in teleost fish. We therefore studied Cd36 in both zebrafish and common carp, two closely related cyprinid fish species. Whereas a single cd36 gene is present in zebrafish, carp has two cd36 genes, and all show conserved synteny compared to mammalian CD36. The gene expression of carp cd36 is high in brain, ovary and testis but absent in immune organs. Although in mammals CD36 expression in erythrocytes, monocytes and macrophages is high, gene expression studies in leukocyte subtypes of adult carp and zebrafish larvae, including thrombocytes and macrophages provided no indication for any substantial expression of cd36 in immune cell types. Surprisingly, analysis of the cd36 promoter region does show the presence of several binding sites for transcription factors known to regulate immune responses. Overexpression of carp cd36 locates the receptor on the cell surface of mammalian cell lines consistent with the predicted topology of cyprinid Cd36 with a large extracellular domain, two transmembrane domains, and short cytoplasmic tails at both ends. Gene expression of cd36 is down-regulated during infection of zebrafish with Mycobacterium marinum, whereas knockdown of cd36 in zebrafish larvae led to higher bacterial burden upon such infection. We discuss the putative role for Cd36 in immune responses of fish in the context of other members of the scavenger receptor class B family.
The heat shock transcription factor PsHSF1 of Phytophthora sojae is required for oxidative stress tolerance and detoxifying the plant oxidative burst
Sheng, Yuting ; Wang, Yonglin ; Meijer, H.J.G. ; Yang, Xinyu ; Hua, C. ; Ye, Wenwu ; Tao, Kai ; Liu, Xiaoyun ; Govers, F. ; Wang, Yuanchao - \ 2015
Environmental Microbiology 17 (2015)4. - ISSN 1462-2912 - p. 1351 - 1364.
signal-transduction - in-vivo - pathogen - infestans - expression - sequence - defense - laccase - binding - yeast
In the interaction between plant and microbial pathogens, reactive oxygen species (ROS) rapidly accumulate upon pathogen recognition at the infection site and play a central role in plant defence. However, the mechanisms that plant pathogens use to counteract ROS are still poorly understood especially in oomycetes, filamentous organisms that evolved independently from fungi. ROS detoxification depends on transcription factors (TFs) that are highly conserved in fungi but much less conserved in oomycetes. In this study, we identified the TF PsHSF1 that acts as a modulator of the oxidative stress response in the soybean stem and root rot pathogen Phytophthora sojae. We found that PsHSF1 is critical for pathogenicity in P.¿sojae by detoxifying the plant oxidative burst. ROS produced in plant defence can be detoxified by extracellular peroxidases and laccases which might be regulated by PsHSF1. Our study extends the understanding of ROS detoxification mechanism mediated by a heat shock TF in oomycetes.
Gene expression profiles in zebrafish (Danio rerio) liver after acute exposure to okadaic acid
Zhang, N. ; Li, H.Y. ; Liu, J.S. ; Yang, W.D. - \ 2014
Environmental Toxicology and Pharmacology 37 (2014)2. - ISSN 1382-6689 - p. 791 - 802.
dinoflagellate prorocentrum-lima - protein phosphatase inhibition - in-vivo - activator protein-1 - abc transporter - carcinoma-cells - microcystin-lr - tumor promoter - marine toxins - growth-factor
Okadaic acid (OA), a main component of diarrheic shellfish poisoning (DSP) toxins, is a strong and specific inhibitor of the serine/threonine protein phosphatases PP1 and PP2A. However, not all of the OA-induced effects can be explained by this phosphatase inhibition, and controversial results on OA are increasing. To provide clues on potential mechanisms of OA other than phosphatase inhibition, here, acute toxicity of OA was evaluated in zebrafish, and changes in gene expression in zebrafish liver tissues upon exposure to OA were observed by microarray. The i.p. ED50 (6 h) of OA on zebrafish was 1.54 mu g OA/g body weight (bw). Among the genes analyzed on the zebrafish array, 55 genes were significantly up-regulated and 36 down-regulated in the fish liver tissue upon exposure to 0.176 mu g OA/g bw (low-dose group, LD) compared with the low ethanol control (LE). However, there were no obvious functional clusters for them. On the contrary, fish exposure to 1.760 mu g OA/g bw (high-dose group, HD) yielded a great number of differential expressed genes (700 up and 285 down) compared with high ethanol control (HE), which clustered in several functional terms such as p53 signaling pathway, Wnt signaling pathway, glutathione metabolism and protein processing in endoplasmic reticulum, etc. These genes were involved in protein phosphatase activity, translation factor activity, heat shock protein binding, as well as transmembrane transporter activity. Our findings may give some useful information on the pathways of OA-induced injury in fish. (C) 2014 Elsevier B.V. All rights reserved.
Regulation of Acetate Kinase Isozymes and Its Importance for MixedAcid Fermentation in Lactococcus lactis
Puri, P. ; Goel, A. ; Bochynska, A. ; Poolman, B. - \ 2014
Journal of Bacteriology 196 (2014)7. - ISSN 0021-9193 - p. 1386 - 1393.
streptococcus-lactis - escherichia-coli - methanosarcina-thermophila - lysine acetylation - membrane-proteins - product formation - light-scattering - in-vivo - metabolism - phosphate
Acetate kinase (ACK) converts acetyl phosphate to acetate along with the generation of ATP in the pathway for mixed-acid fermentation in Lactococcus lactis. The reverse reaction yields acetyl phosphate for assimilation purposes. Remarkably, L. lactis has two ACK isozymes, and the corresponding genes are present in an operon. We purified both enzymes (AckA1 and AckA2) from L. lactis MG1363 and determined their oligomeric state, specific activities, and allosteric regulation. Both proteins form homodimeric complexes, as shown by size exclusion chromatography and static light-scattering measurements. The turnover number of AckA1 is about an order of magnitude higher than that of AckA2 for the reaction in either direction. The K-m values for acetyl phosphate, ATP, and ADP are similar for both enzymes. However, AckA2 has a higher affinity for acetate than does AckA1, suggesting an important role under acetate-limiting conditions despite the lower activity. Fructose-1,6-bisphosphate, glyceraldehyde- 3-phosphate, and phospho-enol-pyruvate inhibit the activities of AckA1 and AckA2 to different extents. The allosteric regulation of AckA1 and AckA2 and the pool sizes of the glycolytic intermediates are consistent with a switch from homolactic to mixed-acid fermentation upon slowing of the growth rate.
Assessing the susceptibility of amylose-lysophosphatidylcholine complexes to amylase by the use of iodine
Ahmadi-Abhari, S. ; Woortman, A.J.J. ; Hamer, R.J. ; Loos, K. - \ 2014
Starch-Stärke 66 (2014)5-6. - ISSN 0038-9056 - p. 576 - 581.
wheat-starch - chain-length - inclusion complexes - fatty-acids - in-vivo - digestion - binding - digestibility - microscopy - property
The formation of amylose-lysophosphatidylcholine (LPC) inclusion complexes renders amylose less susceptible to amylase digestion. In order to better understand this phenomenon on a structural level, the complexation of 9% wheat starch suspensions with 0, 2, 3, and 5% exogenous LPC was developed in RVA. Amylose-LPC inclusion complexes were isolated after 15, 30, 60, 120, and 240min in vitro digestion of the wheat starch suspensions to quantify the amount of non-complexed amylose by spectrophotometry. The samples were dissolved in DMSO containing 0.5% LiBr and exposed to iodine. In addition, parts of the digesta were defatted and subjected to the same procedure to elucidate the total amount of amylose that remained undigested. In this way, more insight was obtained into the protective effect of amylose-LPC complex formation on digestion of starch. This study confirms that the amylose susceptibility to amylolysis decreases in the presence of LPC. Higher LPC concentrations not only induced the formation of more amylose inclusion complexes but also resulted in more stable complexes which remained undigested as well as longer amylose chains after enzyme hydrolysis, due to the presence of LPC inside the amylose helix. In addition, a higher melting enthalpy of the amylose-LPC complexes in the digesta demonstrates the protective effect of LPC during enzyme hydrolysis.
Zebrafish enpp1 mutants exhibit pathological mineralization, mimicking features of generalized arterial calcification of infancy (GACI) and pseudoxanthoma elasticum (PXE)
Apschner, A. ; Huitema, L.F.A. ; Ponsioen, B. ; Peterson-Maduro, J. ; Schulte-Merker, S. - \ 2014
Disease Models & Mechanisms 7 (2014)7. - ISSN 1754-8411 - p. 811 - 822.
homozygous missense mutation - in-vivo - ectopic calcification - vertebral bodies - bone-formation - danio-rerio - osteopontin - osteoclasts - expression - osteoblasts
In recent years it has become clear that, mechanistically, biomineralization is a process that has to be actively inhibited as a default state. This inhibition must be released in a rigidly controlled manner in order for mineralization to occur in skeletal elements and teeth. A central aspect of this concept is the tightly controlled balance between phosphate, a constituent of the biomineral hydroxyapatite, and pyrophosphate, a physiochemical inhibitor of mineralization. Here, we provide a detailed analysis of a zebrafish mutant, dragonfish (dgf), which is mutant for ectonucleoside pyrophosphatase/phosphodiesterase 1 (Enpp1), a protein that is crucial for supplying extracellular pyrophosphate. Generalized arterial calcification of infancy (GACI) is a fatal human disease, and the majority of cases are thought to be caused by mutations in ENPP1. Furthermore, some cases of pseudoxanthoma elasticum (PXE) have recently been linked to ENPP1. Similar to humans, we show here that zebrafish enpp1 mutants can develop ectopic calcifications in a variety of soft tissues – most notably in the skin, cartilage elements, the heart, intracranial space and the notochord sheet. Using transgenic reporter lines, we demonstrate that ectopic mineralizations in these tissues occur independently of the expression of typical osteoblast or cartilage markers. Intriguingly, we detect cells expressing the osteoclast markers Trap and CathepsinK at sites of ectopic calcification at time points when osteoclasts are not yet present in wild-type siblings. Treatment with the bisphosphonate etidronate rescues aspects of the dgf phenotype, and we detected deregulated expression of genes that are involved in phosphate homeostasis and mineralization, such as fgf23, npt2a, entpd5 and spp1 (also known as osteopontin). Employing a UAS-GalFF approach, we show that forced expression of enpp1 in blood vessels or the floorplate of mutant embryos is sufficient to rescue the notochord mineralization phenotype. This indicates that enpp1 can exert its function in tissues that are remote from its site of expression.
Evaluation of nonspreading Rift Valley fever virus as a vaccine vector using influenza virus hemagglutinin as a model antigen
Oreshkova, N. ; Cornelissen, L.A.H.M. ; Haan, C.A.M. de; Moormann, R.J.M. ; Kortekaas, J.A. - \ 2014
Vaccine 32 (2014)41. - ISSN 0264-410X - p. 5323 - 5329.
rna recombination - rhesus macaques - in-vivo - protein - replication - epitope - nss
Virus replicon particles are capable of infection, genome replication and gene expression, but are unable to produce progeny virions, rendering their use inherently safe. By virtue of this unique combination of features, replicon particles hold great promise for vaccine applications. We previously developed replicon particles of Rift Valley fever virus (RVFV) and demonstrated their high efficacy as a RVFV vaccine in the natural target species. We have now investigated the feasibility of using this nonspreading RVFV (NSR) as a vaccine vector using influenza virus hemagglutinin as a model antigen. NSR particles were designed to express either the full-length hemagglutinin of influenza A virus H1N1 (NSR-HA) or the respective soluble ectodomain (NSR-sHA). The efficacies of the two NSR vector vaccines, applied via either the intramuscular or the intranasal route, were evaluated. A single vaccination with NSR-HA protected all mice from a lethal challenge dose, while vaccination with NSR-sHA was not protective. Interestingly, whereas intramuscular vaccination elicited superior systemic immune responses, intranasal vaccination provided optimal clinical protection.
Anti-inflammatory properties of the medicinal mushroom Cordyceps militaris might be related to its linear (1¿3)-ß-D-glucan.
Smiderle, F.R. ; Baggio, C.H. ; Borato, D.G. ; Santana-Filho, A.P. ; Sassaki, G.L. ; Iacomini, M. ; Griensven, L.J.L.D. van - \ 2014
PLoS One 9 (2014)10. - ISSN 1932-6203
formalin test - in-vivo - fruiting bodies - beta-glucans - congo-red - polysaccharides - mice - macrophages - extract - complex
The Ascomycete Cordyceps militaris, an entomopathogenic fungus, is one of the most important traditional Chinese medicines. Studies related to its pharmacological properties suggest that this mushroom can exert interesting biological activities. Aqueous (CW and HW) and alkaline (K5) extracts containing polysaccharides were prepared from this mushroom, and a ß-D-glucan was purified. This polymer was analysed by GC-MS and NMR spectrometry, showing a linear chain composed of ß-D-Glcp (1¿3)-linked. The six main signals in the 13C-NMR spectrum were assigned by comparison to reported data. The aqueous (CW, HW) extracts stimulated the expression of IL-1ß, TNF-a, and COX-2 by THP-1 macrophages, while the alkaline (K5) extract did not show any effect. However, when the extracts were added to the cells in the presence of LPS, K5 showed the highest inhibition of the pro-inflammatory genes expression. This inhibitory effect was also observed for the purified ß-(1¿3)-D-glucan, that seems to be the most potent anti-inflammatory compound present in the polysaccharide extracts of C. militaris. In vivo, ß-(1¿3)-D-glucan also inhibited significantly the inflammatory phase of formalin-induced nociceptive response, and, in addition, it reduced the migration of total leukocytes but not the neutrophils induced by LPS. In conclusion, this study clearly demonstrates the anti-inflammatory effect of ß-(1¿3)-D-glucan.
Xenogeneic therapeutic cancer vaccines as breakers of immune tolerance for clinical application: to use or not to use?
Strioga, M.M. ; Darinskas, A. ; Pasukoniene, V. ; Mlynska, A. ; Ostapenko, V. ; Schijns, V.E.J.C. - \ 2014
Vaccine 32 (2014)32. - ISSN 0264-410X - p. 4015 - 4024.
prostatic acid-phosphatase - advanced melanoma patients - oral malignant-melanoma - dendritic cell vaccine - human tumor-antigens - dna vaccine - t-cells - adaptive immunity - human tyrosinase - in-vivo
Accumulation of firm evidence that clinically apparent cancer develops only when malignant cells manage to escape immunosurveillance led to the introduction of tumor immunotherapy strategies aiming to reprogramm the cancer-dysbalanced antitumor immunity and restore its capacity to control tumor growth. There are several immunotherapeutical strategies, among which specific active immunotherapy or therapeutic cancer vaccination is one of the most promising. It targets dendritic cells (DCs) which have a unique ability of inducing naive and central memory T cell-mediated immune response in the most efficient manner. DCs can be therapeutically targeted either in vivo/in situ or by ex vivo manipulations followed by their re-injection back into the same patient. The majority of current DC targeting strategies are based on autologous or allogeneic tumor-associated antigens (TAAs) which possess various degrees of inherent tolerogenic potential. Therefore still limited efficacy of various tumor immunotherapy approaches may be attributed, among various other mechanisms, to the insufficient immunogenicity of self-protein-derived TAAs. Based on such an idea, the use of homologous xenogeneic antigens, derived from different species was suggested to overcome the natural immune tolerance to self TAAs. Xenoantigens are supposed to differ sufficiently from self antigens to a degree that renders them immunogenic, but at the same time preserves an optimal homology range with self proteins still allowing xenoantigens to induce cross-reactive T cells. Here we discuss the concept of xenogeneic vaccination, describe the cons and pros of autologous/allogeneic versus xenogeneic therapeutic cancer vaccines, present the results of various pre-clinical and several clinical studies and highlight the future perspectives of integrating xenovaccination into rapidly developing tumor immunotherapy regimens.
Immunomodulatory Properties of Streptococcus and Veillonella Isolates from the Human Small Intestine Microbiota
Bogert, B. van den; Meijerink, M. ; Zoetendal, E.G. ; Wells, J.M. ; Kleerebezem, M. - \ 2014
PLoS One 9 (2014)12. - ISSN 1932-6203 - 20 p.
segmented filamentous bacteria - tight junction proteins - patch dendritic cells - gut microbiota - lactobacillus-plantarum - ly6c(hi) monocytes - genome sequence - oral tolerance - immune-system - in-vivo
The human small intestine is a key site for interactions between the intestinal microbiota and the mucosal immune system. Here we investigated the immunomodulatory properties of representative species of commonly dominant small-intestinal microbial communities, including six streptococcal strains (four Streptococcus salivarius, one S. equinus, one S. parasanguinis) one Veillonella parvula strain, one Enterococcus gallinarum strain, and Lactobacillus plantarum WCFS1 as a bench mark strain on human monocyte-derived dendritic cells. The different streptococci induced varying levels of the cytokines IL-8, TNF-a, and IL-12p70, while the V. parvula strain showed a strong capacity to induce IL-6. E. gallinarum strain was a potent inducer of cytokines and TLR2/6 signalling. As Streptococcus and Veillonella can potentially interact metabolically and frequently co-occur in ecosystems, immunomodulation by pair-wise combinations of strains were also tested for their combined immunomodulatory properties. Strain combinations induced cytokine responses in dendritic cells that differed from what might be expected on the basis of the results obtained with the individual strains. A combination of (some) streptococci with Veillonella appeared to negate IL-12p70 production, while augmenting IL-8, IL-6, IL-10, and TNF-a responses. This suggests that immunomodulation data obtained in vitro with individual strains are unlikely to adequately represent immune responses to mixtures of gut microbiota communities in vivo. Nevertheless, analysing the immune responses of strains representing the dominant species in the intestine may help to identify immunomodulatory mechanisms that influence immune homeostasis.
Nutritional aspects of metabolic inflammation in relation to health-insights from transcriptomic biomarkers in PBMC of fatty acids and polyphenols
Afman, L.A. ; Milenkovic, D. ; Roche, H. - \ 2014
Molecular Nutrition & Food Research 58 (2014)8. - ISSN 1613-4125 - p. 1708 - 1720.
blood mononuclear-cells - gene-expression profiles - fish-oil supplementation - improves insulin sensitivity - randomized controlled-trial - coronary-artery-disease - adipose-tissue - postmenopausal women - nlrp3 inflammasome - in-vivo
Recent research has highlighted potential important interaction between metabolism and inflammation, within the context of metabolic health and nutrition, with a view to preventing diet-related disease. In addition to this, there is a paucity of evidence in relation to accurate biomarkers that are capable of reflecting this important biological interplay or relationship between metabolism and inflammation, particularly in relation to diet and health. Therefore the objective of this review is to highlight the potential role of transcriptomic approaches as a tool to capture the mechanistic basis of metabolic inflammation. Within this context, this review has focused on the potential of peripheral blood mononuclear cells transcriptomic biomarkers, because they are an accessible tissue that may reflect metabolism and subacute chronic inflammation. Also these pathways are often dysregulated in the common diet-related diseases obesity, type 2 diabetes, and cardiovascular disease, thus may be used as markers of systemic health. The review focuses on fatty acids and polyphenols, two classes of nutrients/nonnutrient food components that modulate metabolism/inflammation, which we have used as an example of a proof-of-concept with a view to understanding the extent to which transcriptomic biomarkers are related to nutritional status and/or sensitive to dietary interventions. We show that both nutritional components modulate inflammatory markers at the transcriptomic level with the capability of profiling pro- and anti-inflammatory mechanisms in a bidirectional fashion; to this end transcriptomic biomarkers may have potential within the context of metabolic inflammation. This transcriptomic biomarker approach may be a sensitive indicator of nutritional status and metabolic health.
Isoflavone supplement composition and equol producer status affect gene expression in adipose tissue: a double-blind, randomized, placebo-controlled crossover trial in postmenopausal women
Velpen, V. van der; Geelen, A. ; Hollman, P.C.H. ; Schouten, E.G. ; Veer, P. van 't; Afman, L.A. - \ 2014
American Journal of Clinical Nutrition 100 (2014)5. - ISSN 0002-9165 - p. 1269 - 1277.
in-vivo - glucose-metabolism - lipid-metabolism - soy isoflavones - phytoestrogens - profiles - protein - macrophage - insights - genotype
Background: Isoflavone supplements, consumed by women experiencing menopausal symptoms, are suggested to have positive effects on menopause-related adiposity and cardiovascular disease risk profile, but discussions about their safety are still ongoing. Objective: The objective was to study the effects of an 8-wk consumption of 2 different isoflavone supplements compared with placebo on whole-genome gene expression in the adipose tissue of postmenopausal women. Design: This double-blind, randomized, placebo-controlled crossover intervention consisted of 2 substudies, one with a low-genistein (LG) supplement (56% daidzein + daidzin, 16% genistein + genistin, and 28% glycitein + glycitin) and the other with a high-genistein (HG) supplement (49% daidzein + daidzin, 41% genistein + genistin, and 10% glycitein + glycitin). Both supplements provided ~100 mg isoflavones/d (aglycone equivalents). After the 8-wk isoflavone and placebo period, whole-genome arrays were performed in subcutaneous adipose tissue of postmenopausal women (n = 26 after LG, n = 31 after HG). Participants were randomized by equol-producing phenotype, and data analysis was performed per substudy for equol producers and nonproducers separately. Results: Gene set enrichment analysis showed downregulation of expression of energy metabolism–related genes after LG supplementation (n = 24) in both equol-producing phenotypes and oppositely regulated expression for equol producers (down) and nonproducers (up) after HG supplementation (n = 31). Expression of inflammation-related genes was upregulated in equol producers but downregulated in nonproducers, independent of supplement type. Only 4.4–7.0% of the genes with significantly changed expression were estrogen responsive. Body weight, adipocyte size, and plasma lipid profile were not affected by isoflavone supplementation. Conclusions: Effects of isoflavones on adipose tissue gene expression were influenced by supplement composition and equol-producing phenotype, whereas estrogen-responsive effects were lacking. LG isoflavone supplementation resulted in a caloric restriction–like gene expression profile for both producer phenotypes and pointed toward a potential beneficial effect, whereas both supplements induced anti-inflammatory gene expression in equol producers.
Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise
Catoire, M. ; Alex, S. ; Paraskevopulos, N. ; Mattijssen, F.B.J. ; Mensink, M.R. ; Kersten, A.H. - \ 2014
Proceedings of the National Academy of Sciences of the United States of America 111 (2014)11. - ISSN 0027-8424 - p. E1043 - E1052.
human skeletal-muscle - angiopoietin-like protein-4 - lipoprotein-lipase - adipose-tissue - insulin-resistance - postprandial triacylglycerol - endurance exercise - in-vivo - expression - receptor
Physical activity increases energy metabolism in exercising muscle. Whether acute exercise elicits metabolic changes in nonexercising muscles remains unclear. We show that one of the few genes that is more highly induced in nonexercising muscle than in exercising human muscle during acute exercise encodes angiopoietin-like 4 (ANGPTL4), an inhibitor of lipoprotein lipase-mediated plasma triglyceride clearance. Using a combination of human, animal, and in vitro data, we show that induction of ANGPTL4 in nonexercising muscle is mediated by elevated plasma free fatty acids via peroxisome proliferator-activated receptor-d, presumably leading to reduced local uptake of plasma triglyceride-derived fatty acids and their sparing for use by exercising muscle. In contrast, the induction of ANGPTL4 in exercising muscle likely is counteracted via AMP-activated protein kinase (AMPK)-mediated down-regulation, promoting the use of plasma triglycerides as fuel for active muscles. Our data suggest that nonexercising muscle and the local regulation of ANGPTL4 via AMPK and free fatty acids have key roles in governing lipid homeostasis during exercise.
Mosquito and Drosophila entomobirnaviruses suppress dsRNA- and siRNA-induced RNAi
Cleef, K.W.R. van; Mierlo, J.T. van; Miesen, P. ; Overheul, G.J. ; Fros, J.J. ; Schuster, S. ; Marklewitz, M. ; Pijlman, G.P. ; Junglen, S. ; Rij, R.P. van - \ 2014
Nucleic Acids Research 42 (2014)13. - ISSN 0305-1048 - p. 8732 - 8744.
bursal disease virus - double-stranded-rna - capsid protein vp3 - intrinsic antiviral immunity - pancreatic necrosis virus - mammalian-cells - adult drosophila - nodamura virus - animal virus - in-vivo
RNA interference (RNAi) is a crucial antiviral defense mechanism in insects, including the major mosquito species that transmit important human viruses. To counteract the potent antiviral RNAi pathway, insect viruses encode RNAi suppressors. However, whether mosquito-specific viruses suppress RNAi remains unclear. We therefore set out to study RNAi suppression by Culex Y virus (CYV), a mosquito-specific virus of the Birnaviridae family that was recently isolated from Culex pipiens mosquitoes. We found that the Culex RNAi machinery processes CYV double-stranded RNA (dsRNA) into viral small interfering RNAs (vsiRNAs). Furthermore, we show that RNAi is suppressed in CYV-infected cells and that the viral VP3 protein is responsible for RNAi antagonism. We demonstrate that VP3 can functionally replace B2, the well-characterized RNAi suppressor of Flock House virus. VP3 was found to bind long dsRNA as well as siRNAs and interfered with Dicer-2-mediated cleavage of long dsRNA into siRNAs. Slicing of target RNAs by pre-assembled RNA-induced silencing complexes was not affected by VP3. Finally, we show that the RNAi-suppressive activity of VP3 is conserved in Drosophila X virus, a birnavirus that persistently infects Drosophila cell cultures. Together, our data indicate that mosquito-specific viruses may encode RNAi antagonists to suppress antiviral RNAi.
DON shares a similar mode of action as the ribotoxic stress inducer anisomycin while TBTO shares ER stress patterns with the ER stress inducer Thapsigargin based on comparative gene expression profiling in Jurkat T cells
Schmeits, P.C.J. ; Katika, M.R. ; Peijnenburg, A.A.C.M. ; Loveren, H. van; Hendriksen, P.J.M. - \ 2014
Toxicology Letters 224 (2014)3. - ISSN 0378-4274 - p. 395 - 406.
tri-n-butyltin - unfolded protein response - tributyltin-oxide tbto - mouse thymoma cells - deoxynivalenol don - induced apoptosis - plasma-membrane - ribosomal-rna - in-vivo - activation
Previously, we studied the effects of deoxynivalenol (DON) and tributyltin oxide (TBTO) on whole genome mRNA expression profiles of human T lymphocyte Jurkat cells. These studies indicated that DON induces ribotoxic stress and both DON and TBTO induced ER stress which resulted into T-cell activation and apoptosis. The first goal of the present study was to provide final proof for these mode of actions by comparing the effects of 6 h exposure to DON and TBTO on mRNA expression to those of positive controls of ribotoxic stress (anisomycin), ER stress (thapsigargin) and T cell activation (ionomycin). Genes affected by anisomycin and the majority of genes affected by thapsigargin were affected in the same direction by DON and TBTO, respectively, confirming the expected modes of action. Pathway analysis further sustained that DON induces ribotoxic stress and both DON and TBTO induce unfolded protein response (UPR), ER stress, T cell activation and apoptosis. The second goal was to assess whether DON and/or TBTO affect other pathways above those detected before. TBTO induced groups of genes that are involved in DNA packaging and heat shock response that were not affected by thapsigargin. DON did not affect other genes than anisomycin indicating the effect of DON to be restricted to ribotoxic stress. This study also demonstrates that comparative gene expression analysis is a very promising tool for the identification of modes of action of immunotoxic compounds.
Reprogrammed metabolism of cancer cells as a potential therapeutic target
Keijer, J. ; Dartel, D.A.M. van - \ 2014
Current Pharmaceutical Design 20 (2014)15. - ISSN 1381-6128 - p. 2580 - 2594.
activated protein-kinase - fatty-acid synthase - hypoxia-inducible factor-1 - beta-phenylethyl isothiocyanate - permeability transition pore - human prostate-cancer - double-edged-sword - in-vivo - energy-metabolism - mitochondrial-function
Metabolism in cancer cells is reprogrammed. Cancer cells largely depend on glycolysis for ATP production. The metabolic alterations in cancer cells facilitate resistance to cell death as well as biosynthesis of nucleotides and lipids, building blocks for growth. The reprogrammed metabolism is increasingly seen as a target in cancer therapy. This review describes the metabolic reprogramming of cancer cells and illustrates how this is related to cell cycle and apoptosis resistance. Is also describes various scenarios for targeting cancer cell metabolism and highlights options for interventions with nutrition and bioactive food components.
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