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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Targeted vaccination against the bevacizumab binding site on VEGF using 3D-structured peptides elicits efficient antitumor activity
Wentink, Madelon Q. ; Hackeng, Tilman M. ; Tabruyn, Sebastien P. ; Puijk, Wouter C. ; Schwamborn, Klaus ; Altschuh, Daniele ; Meloen, Rob H. ; Schuurman, Teun ; Griffioen, Arjan W. ; Timmerman, Peter - \ 2016
Proceedings of the National Academy of Sciences of the United States of America 113 (2016)44. - ISSN 0027-8424 - p. 12532 - 12537.
Angiogenesis - Immunization - Peptide vaccines - Protein mimicry - VEGF

Therapeutic targeting of the VEGF signaling axis by the VEGFneutralizing monoclonal antibody bevacizumab has clearly demonstrated clinical benefit in cancer patients. To improve this strategy using a polyclonal approach, we developed a vaccine targeting VEGF using 3D-structured peptides that mimic the bevacizumab binding site. An in-depth study on peptide optimization showed that the antigen's 3D structure is essential to achieve neutralizing antibody responses. Peptide 1 adopts a clear secondary, native-like structure, including the typical cysteine-knot fold, as evidenced by CD spectroscopy. Binding and competition studies with bevacizumab in ELISA and surface plasmon resonance analysis revealed that peptide 1 represents the complete bevacizumab binding site, including the hairpin loop (β5-turn-β6) and the structure-supporting β2-α2-β3 loop. Vaccination with peptide 1 elicited high titers of cross-reactive antibodies to VEGF, with potent neutralizing activity. Moreover, vaccination-induced antisera displayed strong angiostatic and tumor-growth-inhibiting properties in a preclinical mouse model for colorectal carcinoma, whereas antibodies raised with peptides exclusively encompassing the β5-turn-β6 loop (peptides 15 and 20) did not. Immunization with peptide 1 or 7 (murine analog of 1) in combinationwith the potent adjuvant raffinose fatty acid sulfate ester (RFASE) showed significant inhibition of tumor growth in the B16F10 murine melanoma model. Based on these data, we conclude that this vaccination technology,which is currently being investigated in a phase I clinical trial (NCT02237638), can potentially outperform currently applied anti-VEGF therapeutics.

Smaakmodel Galia meloen voor betere communicatie binnen de keten
Verkerke, Wouter ; Hanenberg, Maike ; Steenbergen, Piet - \ 2015
Chocola maken van een Meloen
Peters, Sander - \ 2015
Meloen - Sequencing - veredeling - genetische diversiteit - Genomics

Sneller veredelen dankzij slimme combinatie van technieken. Veredelingsprogramma’s kunnen spectaculair worden versneld. Het ontwikkelen van een nieuw ras kost straks misschien nog maar twee jaar in plaats van vijf tot tien. Dat is te danken aan nieuwe slimme combinaties van state of the art moleculaire technieken.

Sneller veredelen dankzij slimme combinatie van technieken. Veredelingsprogramma’s kunnen spectaculair worden versneld. Het ontwikkelen van een nieuw ras kost straks misschien nog maar twee jaar in plaats van vijf tot tien. Dat is te danken aan nieuwe slimme combinaties van state of the art moleculaire technieken.

Succes van een nieuwe tomaat staat of valt bij oordeel Bleiswijkse proefpanel
Hanenberg, Maike - \ 2015
Bleiswijk – "Onderzoeker kwaliteit glasgroente en fruit". Zo omschrijft Maike Hanenberg haar functie bij het smaakteam Bleiswijk van Wageningen UR Glastuinbouw. In het laboratorium, bij het proefkassencomplex vlak naast de A12, doet zij een boekje open over smaakproeven. De biologe, met als specialisatie voeding en menselijke gezondheid, legt uit hoe het proeven van kasgroente en -fruit in zijn werk gaat. "Bij een opdracht voor een teler of een zaadveredelingsbedrijf gaat er via de mail een oproep naar leden van het smaakpanel. Vijftig mensen worden dan opgeroepen voor een smaakproef. Proevers beseffen zelf niet hoe belangrijk zij zijn. Maar de opdrachtgevers gebruiken de informatie écht." Het Bleiswijkse panel proefde de afgelopen tijd vooral tomaten, paprika's, en aardbeien. Maar ook dingen als asperges, meloen, boerenkool, aubergine en -auw- Spaanse pepers stonden op het menu. Tot exotische groente als zeekraal aan toe. De proevers geven alleen aan of iets wel of niet lekker is. Daarnaast is een expertteam actief met door het smaakteam getrainde proevers die gedetailleerder kunnen ingaan op de smaak. Hanenberg zou blij zijn met meer proevers in het smaakpanel. "In de toekomst gaan we grotere proeven organiseren. En de vorm verandert, steeds vaker vragen we om ook visueel' te beoordelen. Het liefst zou ik met een smaakproef op locatie willen gaan," zegt de onderzoekster. "Het geeft een ander beeld als je eens een nieuwe groep mensen laat proeven, bijvoorbeeld bij een evenement." Naast de smaakproefresultaten meet Hanenberg ook andere aspecten van groente en fruit, zoals houdbaarheid en hoeveelheid suikers. "Er is zo veel meer mogelijk met marketing in de groente- en fruitsector. Maar de basis ligt hier, namelijk: goede smaak. Italiaanse tomaten zouden lekkerder zijn dan de onze, maar dat is allemaal een kwestie van beleving."
Mogelijkheden voor smaakmodel meloen ter discussie op Fruit Logistica
Verkerke, W. - \ 2012
Wageningen UR Glastuinbouw
Pharmacological and toxicological assessment of a potential GnRH vaccine in young-adult male pigs
Turkstra, J.A. ; Staay, F.J. van der; Stockhofe-Zurwieden, N. ; Woelders, H. ; Meloen, R.H. ; Schuurman, T. - \ 2011
Vaccine 29 (2011)21. - ISSN 0264-410X - p. 3791 - 3801.
gonadotropin-releasing-hormone - follicle-stimulating-hormone - advanced prostate-cancer - white-tailed deer - active immunization - testicular function - boar taint - efficient immunocastration - fsh-secretion - male rats
Active immunization against gonadotrophin-releasing hormone (GnRH) is successfully applied to prevent boar taint in pork. In men, GnRH immunization could be an alternative to hormone therapy in patients with prostate cancer. In this study, a new GnRH vaccine formulation (a modified GnRH peptide conjugate formulated with CoVaccine adjuvant) was investigated for its pharmacological efficacy and safety in young-adult male pigs. Immunization resulted in castrate-like plasma testosterone levels in all treated pigs from week 8 until the end of the study, 30 weeks after the first immunization. Testosterone depletion retarded testes growth, reduced the relative weight of the testes and accessory sex organs, and reduced sperm counts and motility. There was no clinically relevant toxicity. Typical vaccination-related adverse reactions, such as swelling at the injection site and fever, were considered acceptable. We conclude that this GnRH vaccine efficiently and rapidly reduced serum testosterone levels, without inducing chronic toxic effects, and therefore could be applicable in both veterinary and human medicine
Bladvlekkenziekte weer toenemend probleem door vochtiger klimaat
Paternotte, S.J. ; Arkesteijn, M. - \ 2010
Onder Glas 7 (2010)8. - p. 23 - 23.
plantenziekteverwekkers - bladvlekkenziekte - mycosphaerella - vruchtgroenten - klimaatregeling - luchtkwaliteit - gewasbescherming - afwijkingen, planten - glastuinbouw - groenten - plant pathogens - leaf spotting - fruit vegetables - air conditioning - air quality - plant protection - plant disorders - greenhouse horticulture - vegetables
Bladvlekkenziekte kan bij behalve komkommer ook bij meloen, augurk en courgette schade aan het gewas en de vrucht aanrichten. Vooral in de jaren tachtig was dit een probleem. De laatste jaren is er weer een toename, die te maken zou kunnen hebben met energiebesparende maatregelen als meer schermen en minder stoken, waardoor een vochtiger klimaat ontstaat.
Monitoring health by values of acute phase proteins
Gruys, E. ; Toussaint, M.J.M. ; Niewold, T.A. ; Koopmans, S.J. ; Dijk, E. van; Meloen, R.H. - \ 2006
Acta Histochemica 108 (2006)3. - ISSN 0065-1281 - p. 229 - 232.
dependent adaptive dichotomy - c-reactive protein - infection - disease
A systemic acute phase reaction may develop during infection and inflammation, due to the action of peripherally liberated proinflammatory cytokines. Hepatic metabolism changes, and negative and positive acute phase proteins (APPs) can be measured in the blood: the APPs therefore represent appropriate analytes to assess health. White they are non-specific markers, their levels change with biological effects and this can be used to assess nutritional. deficits and reactive processes, especially when positive and negative acute phase variables are combined in an index. Unfortunately, at present, no comprehensive, easy-to-use and cheap system is available to assess various acute phase proteins in serum or blood samples. Protein micro-array technology may satisfy this need; it will permit simultaneous analysis of numerous analytes in the same small volume sample and enable integration of information derived from systemic reactivity and nutrition with disease-specific variables. Applying such technology may help to address health problems in many countries.
GnRH tandem peptides for inducing an immunogenic response to GnRH-I without cross-reactivity to other GnRH isoforms
Turkstra, J.A. ; Schaaper, W.M.M. ; Oonk, H.B. ; Meloen, R.H. - \ 2005
Vaccine 23 (2005)41. - ISSN 0264-410X - p. 4915 - 4920.
gonadotropin-releasing-hormone - follicle-stimulating-hormone - active immunization - luteinizing-hormone - breast-cancer - 2nd isoform - brain - secretion - growth - form
Gonadotropin releasing hormone (GnRH) occurs in various isoforms in mammals, i.e. GnRH-I (mammalian GnRH), GnRH-II (chicken GnRH-II), GnRH-III (salmon GnRH) and two forms of lamprey GnRH. The function of the latter four molecules have only been partially investigated. Also not much is known about the physiological effects of GnRH-I immunization on the function of these GnRH isoforms. In order to avoid possible harmful side-effects due to undesired neutralization of GnRH isoforms, GnRH-I specificity of antibodies raised against a panel of alternative GnRH antigens was determined. The results show that GnRH antigens can be designed which generate antibodies that specifically bind GnRH-I, without cross-reacting with other GnRH isoforms.
Novel rabies virus-neutralizing epitope recognized by human monoclonal antibody: Fine mapping and escape mutant analysis
Marissen, W.E. ; Kramer, R.A. ; Rice, A. ; Weldon, W.C. ; Niezgoda, M. ; Faber, M. ; Slootstra, J.W. ; Meloen, R.H. ; Clijsters-van der Horst, M. ; Visser, T.J. ; Jongeneelen, M. ; Thijsse, S. ; Throsby, M. ; Kruif, J. de; Rupprecht, C.E. ; Dietzschold, B. ; Goudsmit, J. ; Bakker, A.B.H. - \ 2005
Journal of Virology 79 (2005)8. - ISSN 0022-538X - p. 4672 - 4678.
high-level expression - postexposure prophylaxis - glycoprotein - pathogenicity - determinant - virulence - mice - igg
Anti-rabies virus immunoglobulin combined with rabies vaccine protects humans from lethal rabies infections. For cost and safety reasons, replacement of the human or equine polyclonal immunoglobulin is advocated, and the use of rabies virus-specific monoclonal antibodies (MAbs) is recommended. We produced two previously described potent rabies virus-neutralizing human MAbs, CR57 and CRJB, in human PER.C6 cells. The two MAbs competed for binding to rabies virus glycoprotein. Using CR57 and a set of 15-mer overlapping peptides covering the glycoprotein ectodomain, a neutralization domain was identified between amino acids (aa) 218 and 240. The minimal binding region was identified as KLCGVL (aa 226 to 231), with key residues K-CGV- identified by alanine replacement scanning. The critical binding region of this novel nonconformational rabies virus epitope is highly conserved within rabies viruses of genotype 1. Subsequently, we generated six rabies virus variants escaping neutralization by CR57 and six variants escaping CRJB. The CR57 escape mutants were only partially covered by CRJB, and all CRJB-resistant variants completely escaped neutralization by CR57. Without exception, the CR57-resistant variants showed a mutation at key residues within the defined minimal binding region, while the CRJB escape viruses showed a single mutation distant from the CR57 epitope (N182D) combined with mutations in the CR57 epitope. The competition between CR57 and CRJB, the in vitro escape profile, and the apparent overlap between the recognized epitopes argues against including both CR57 and CRJB in a MAb cocktail aimed at replacing classical immunoglobulin preparations.
Effects of GnRH immunization in sexually mature pony stallions
Turkstra, J.A. ; Meer, F.J.U.M. ; Knaap, J. ; Rottier, P.J.M. ; Teerds, K.J. ; Colenbrander, B. ; Meloen, R.H. - \ 2005
Animal Reproduction Science 86 (2005)3-4. - ISSN 0378-4320 - p. 247 - 259.
hormone-releasing-hormone - active immunization - efficient immunocastration - equine castration - immunoneutralization - complications - cryptorchid - parameters - vaccine - peptide
Immunization against gonadotrophin releasing hormone (GnRH) was studied as an alternative for the commonly used surgical castration in stallions. Two GnRH vaccines comprising non-mineral oil adjuvants were evaluated for their potential to induce high antibody titers directed against GnRH and subsequent effects on reproductive characteristics. Twelve sexually mature male hemicastrated Shetland ponies were assigned to three groups. Group 1 and 2 were injected with 1 mg peptide equivalent of G6k-GnRH-tandem-dimer conjugated to ovalbumin (OVA) in CoVaccine¿ HT adjuvant (GnRH/CoVaccine) and in Carbopol (GnRH/Carbopol), respectively, and group 3 was injected with CoVaccine¿ HT adjuvant without antigen (controls). After immunization no adverse effects were observed with respect to the injections sites or general health. Two weeks after the second vaccination antibody titers against GnRH increased rapidly in all animals of the GnRH/CoVaccine group, at the same time reducing serum testosterone levels maximally for the further duration of the experiment. In the GnRH/Carbopol group antibody responses and effects on testosterone levels were intermediate in two stallions and not apparent in the remaining stallions of this group. Semen evaluation showed that from 2 weeks after the second immunization onwards, sperm motility was affected in all stallions treated with GnRH/CoVaccine and one stallion treated with GnRH/Carbopol. Seven weeks after the second immunization, no semen could be collected from two stallions, one of each group, due to suppressed libido. Histological examination of the testes, 15 weeks after the initial immunization, demonstrated reduction in seminiferous tubuli diameters in all stallions of the GnRH/CoVaccine group and one stallion of the GnRH/Carbopol group. Furthermore, spermatogenesis was extremely disorganized in these stallions, as indicated by absence of the lumen in the seminiferous tubules, the absence of spermatozoa and spermatids in the tubular cross-sections and the impossibility to determine the stage of the tubular cross-sections. Testis size was also substantially reduced in three out of four stallions treated with GnRH/CoVaccine
Antifungal activity of synthetic peptides derived from Impatiens balsamina antimicrobial peptides Ib-AMP1 and Ib-AMP4
Thevissen, K. ; Francois, E.J.A. ; Sijtsma, L. ; Amerongen, A. van; Schaaper, W.M.M. ; Meloen, R. ; Posthuma-Trumpie, G.A. ; Broekaert, W.F. ; Cammue, B.P.A. - \ 2005
Peptides 26 (2005)7. - ISSN 0196-9781 - p. 1113 - 1119.
plant defensins - fungal growth - mechanism - proteins
Seeds of Impatiens balsamina contain a set of related antimicrobial peptides (Ib-AMPs). We have produced a synthetic variant of Ib-AMP1, oxidized to the bicyclic native conformation, which was fully active on yeast and fungal strains; and four linear 20-mer Ib-AMP variants, including two all-d forms. We show that the all-d variants are as active on yeast and fungal strains as native peptides. In addition, fungal growth inhibition nor salt-dependency of Ib-AMP4 could be improved by more than two-fold via replacement of amino acid residues by arginine or tryptophan. Native Ib-AMPs showed no hemolytic nor toxic activity up to a concentration of 100 µM. All these data demonstrate the potential of the native Ib-AMPs to combat fungal infections.
Identification of an interleukin-15 alpha receptor-binding site on human interleukin-15
Bernard, J. ; Harb, C. ; Mortier, E. ; Quemener, A. ; Meloen, R.H. ; Vermot-Desroches, C. ; Wijdeness, J. ; Dijken, J.P. van; Grotzinger, J. ; Slootstra, J.W. ; Plet, A. ; Jacques, Y. - \ 2004
Journal of Biological Chemistry 279 (2004)23. - ISSN 0021-9258 - p. 24313 - 24322.
cell growth-factor - alpha-chain - il-2 receptor - 3-dimensional structure - sequence alignment - il-15r-alpha chain - natural-killer - beta-chain - in-vivo - protein
To identify the epitopes in human Interleukin-15 (IL-15) that are responsible for binding to the interleukin-15 receptor -chain, antibody as well as receptor mapping by peptide scanning and site-directed mutagenesis was used. By peptide scanning, we identified four regions in IL-15: the first one (85CKECEELEEKN95) is located in the C-D loop and is recognized by a set of non-inhibitory antibodies. The second region (102SFVHIVQMFIN112) is located in helix D and is recognized by two antibodies that are inhibitory of IL-15 bio-activity, but not of IL-15 binding to IL-15R. The two remaining regions react with a recombinant soluble form of the IL-15R: the first (44LLELQVISL52, peptide 1) corresponds to a sequence located in the B helix and the second (64ENLII68, peptide 2) to a sequence located in helix C. The latter is also contained in the epitope recognized by an antibody (mAb B-E29) that prevents IL-15 binding to IL-15R. By site directed mutagenesis, we confirmed that residues present in peptide 1 (L45, E46, V49, S51, L52) and peptide 2 (L66 and I67) are involved in the binding of IL-15 to IL-15R. Furthermore, the results presented indicate that residues in the second peptide (E64, N65, I68) participate in IL-2R recruitment. This finding could have implications on the dynamic of receptor assembly. These results also indicate that the modes of interaction of IL-15 and IL-2 with their respective {alpha) chains are not completely analogous. Finally, some of the IL-15 mutants generated in this study displayed agonist or antagonist properties and may be useful as therapeutic agents.
An in vitro screening assay based on synthetic prion protein peptides for identification of fibril-interfering compounds
Boshuizen, R.S. ; Langeveld, J.P.M. ; Salmona, M. ; Williams, A. ; Meloen, R.H. ; Langendijk, J.P. - \ 2004
Analytical Biochemistry 333 (2004)2. - ISSN 0003-2697 - p. 372 - 380.
stained amyloid fibrils - congo red - thioflavine-t - branched polyamines - alzheimers-disease - molecular-cloning - dextran sulfate - cultured-cells - scrapie - prp
Transmissible spongiform encephalopathies are neurodegenerative diseases and are considered to be caused by malformed prion proteins accumulated into fibrillar structures that can then aggregate to form larger deposits or amyloid plaques. The identification of fibril-interfering compounds is of therapeutic and prophylactic interest. A robust and easy-to-perform, high-throughput, in vitro fluorescence assay was developed for the detection of such compounds. The assay was based on staining with the fluorescent probe thioflavin S in polystyrene microtiter plates to determine the amyloid state of synthetic peptides, representing a putative transmembrane domain of human and mouse prion protein. In determining optimal test conditions, it was found that drying peptides from phosphate buffer prior to staining resulted in good reproducibility with an interassay variation coefficient of 8%. Effects of thioflavin S concentration and staining time were established. At optimal thioflavin S concentration of 0.2 mg/ml, the fluorescence signals of thioflavin S with five different prion protein-based fibrillogenic peptides, as well as peptide Aß(1¿42), were found to show a peptide-dependent linear correlation within a peptide concentration range of 10¿400 ¿M. The ability of the assay to identify compounds that interfere with fibril formation and/or dissociate preformed fibrils was demonstrated for tetracyclic compounds by preceding coincubation with human prion protein peptide huPrP106¿126
Discovery and in vivo evaluation of new melanocortin-4 receptor-selective peptides
Nijenhuis, W.A.J. ; Kruijtzer, J.A.W. ; Wanders, N. ; Vrinten, D.H. ; Garner, K.M. ; Schaaper, W.M.M. ; Meloen, R.H. ; Gispen, W.H. ; Liskamp, R.M. ; Adan, R.A.H. - \ 2003
Peptides 24 (2003)2. - ISSN 0196-9781 - p. 271 - 280.
melanocyte-stimulating hormone - alpha-melanotropin action - agouti-related protein - evaluation in-vitro - biological evaluation - molecular-cloning - inverse agonist - msh analogs - amino-acid - rat
The melanocortin-4 receptor (MC4R) is involved in several physiological processes, including body weight regulation and grooming behaviour in rats. It has also been suggested that the MC4R mediates the effects of melanocortin ligands on neuropathic pain. Selective compounds are needed to study the exact role of the MC4R in these different processes. We describe here the development and evaluation of new melanocortin compounds that are selective for the MC4R as compared with the other centrally expressed receptors, MC3R and MC5R. First, a library of 18 peptides, in which a melanocortin-based sequence was systematically point-mutated, was screened for binding to and activity on the MC3R, MC4R and MC5R. Compound Ac-Nle-Gly-Lys-Image-Phe-Arg-Trp-Gly-NH2 (JK1) appeared to be the most selective MC4R compound, based on affinity. This compound is 90- and 110-fold selective for the MC4R as compared to the MC3R and MC5R, respectively. Subsequent modification of JK1 yielded compound Ac-Nle-Gly-Lys-Image-Nal(2)-Arg-Trp-Gly-NH2 (JK7), a selective MC4R antagonist with 34-fold MC4R/MC3R and 109-fold MC4R/MC5R selectivity. The compounds were active in vivo as determined in a grooming assay and a model for neuropathic pain in rats. Intravenous (i.v.) injections suggested that they were able to pass the blood¿brain barrier. The compounds identified here will be useful in further research on the physiological roles of the MC4R.
Multidrug-resistant tumor cells remain sensitive to a recombinant interleukin-4-Pseudomonas exotoxin, except when overexpressing the multidrug resistance protein MRP1
Jong, M.C. de; Scheffer, G.L. ; Broxterman, H.J. ; Hooijberg, J.H. ; Slootstra, J.W. ; Meloen, R.H. ; Kreitman, R.J. ; Husain, S.R. ; Joshi, B.H. ; Puri, R.K. ; Scheper, R.J. - \ 2003
Clinical Cancer Research 9 (2003)13. - ISSN 1078-0432 - p. 5009 - 5017.
permuted interleukin 4-toxin - fibroblast-growth-factor - breast-carcinoma cells - p-glycoprotein - drug-resistance - cancer-cells - antitumor-activity - membrane-vesicles - atpase activity - il-4 receptors
Tumor cells may become resistant to conventional anticancer drugs through the occurrence of transmembrane transporter proteins such as P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2), or members of the multidrug resistance-associated protein family (MRP1¿MRP5; ABCC1¿ABCC5). In this report, we studied whether tumor cells that are cytostatic drug resistant because of overexpression of one of the above mentioned proteins are sensitive to a new anticancer agent, interleukin-4 toxin (IL-4 toxin). IL-4 toxin is a fusion protein composed of circularly permuted IL-4 and a truncated form of Pseudomonas exotoxin (PE) [IL-4(38¿37)-PE38KDEL]. Ninety-six-h cytotoxicity assays and 10-day clonogenic assays showed that drug-selected multidrug resistant (MDR) tumor cells that overexpress P-glycoprotein or breast cancer resistance proteins are still sensitive to IL-4 toxin. Also, tumor cells transfected with cDNA for MRP2¿5 showed no resistance, or marginal resistance, only to the toxin as compared with the parent cells. In contrast, MRP1-overexpressing cells, both drug selected and MRP1 transfected, are clearly resistant to IL-4 toxin with resistance factors of 4.3 to 8.4. MRP1-overexpressing cells were not resistant to PE itself. IL-4 toxin resistance in MRP1-overexpressing cells could be reversed by the MRP1 inhibitors probenecid or MK571 and were not affected by glutathione depletion by DL-buthionine-S,R-sulfoximine. In a transport assay using plasma membrane vesicles prepared from MRP1-overexpressing cells, IL-4 toxin and IL-4, but not PE, inhibited the translocation of the known MRP1 substrate 17ß-estradiol 17-(ß-D-glucuronide) (E217ßG). These data suggest that MRP1-overexpressing cells are resistant to IL-4 toxin because of extrusion of this agent by MRP1. Still, the results of this study demonstrate that IL-4 toxin effectively kills most MDR tumor cells and, therefore, represents a promising anticancer drug.
Functional analysis of synthetic insectatachykinin analogs on recombinant neurokinin receptor expressing cell lines
Torfs, H. ; Akerman, K.E. ; Nachman, R.J. ; Oonk, H.B. ; Detheux, M. ; Poels, J. ; Loy, T. van; Loof, A. ; Meloen, R.H. ; Vassart, G. ; Parmentier, M. ; Broeck, J. van den - \ 2002
Peptides 23 (2002)11. - ISSN 0196-9781 - p. 1999 - 2005.
tachykinin-related peptides - insect neuropeptides - urechis-unicinctus - myotropic peptides - echiuroid worm - identification - vertebrate - homology - family - cockroach
The activity of a series of synthetic tachykinin-like peptide analogs was studied by means of microscopic calcium imaging on recombinant neurokinin receptor expressing cell lines. A C-terminal pentapeptide (FTGMRa) is sufficient for activation of the stomoxytachykinin receptor (STKR) expressed in Schneider 2 cells. Replacement of amino acid residues at the position of the conserved phenylalanine (F) or arginine (R) residues by alanine (A) results in inactive peptides (when tested at 1 ¿M), whereas A-replacements at other positions do not abolish the biological activity of the resulting insectatachykinin-like analogs. Calcium imaging was also employed to compare the activity of C-terminally substituted tachykinin analogs on three different neurokinin receptors. The results indicate that the major pharmacological and evolutionary difference between tachykinin-related agonists for insect (STKR) and human (NK1 and NK2) receptors resides in the C-terminal amino acid residues (R versus M). A single C-terminal amino acid change can turn an STKR-agonist into an NK-agonist and vice versa
Functional mimicry of a discontinuous antigenic site by a designed synthetic peptide
Villen, J. ; Borras, E. ; Schaaper, W.M.M. ; Meloen, R.H. ; Davila, M. ; Domingo, E. ; Giralt, E. ; Andreu, D. - \ 2002
ChemBioChem 3 (2002)39509. - ISSN 1439-4227 - p. 175 - 182.
mouth-disease virus - monoclonal-antibodies - bioactive peptides - canine parvovirus - natural host - hiv-1 gp120 - protection - vaccines - epitopes - protein
Functional reproduction of the discontinuous antigenic site D of foot-and-mouth disease virus (FMDV) has been achieved by means of synthetic peptide constructions that integrate each of the three protein loops that define the antigenic site into a single molecule. The site D mimics were designed on the basis of the X-ray structure of FMDV type C-S8c1 with the aid of molecular dynamics, so that the five residues assumed to be involved in antigenic recognition are located on the same face of the molecule, exposed to solvent and defining a set of native-like distances and angles. The designed site D mimics are disulfide-linked heterodimers that consist of a larger unit containing VP2(71-84), followed by a polyproline module and by VP3(52-62), and a smaller unit corresponding to VP1(188-194) (VP=viral protein). Guinea pig antisera to the peptides recognized the viral particle and competed with site D-specific monoclonal antibodies, while inoculation with a simple (not covalently joined to one another) admixture of the three VP1-VP3 sequences yielded no detectable virus-specific serum conversion. Similar results have been reproduced in two bovines. Antisera to the peptides also moderately neutralize FMDV in cell cultures and partially protect guinea pigs against challenge with the virus. These results demonstrate functional mimicry of the discontinuous site D by the peptides, which are therefore obvious candidates for a multicomponent, peptide-based vaccine against FMDV
A peptide mimic of an antigenic loop of alpha-human chorionic gonadotropin hormone: solution structure and interaction with a llama V-HH domain
Ferrat, G. ; Renisio, J.G. ; Morelli, X. ; Slootstra, J.W. ; Meloen, R. ; Cambillau, C. ; Darbon, H. - \ 2002
Biochemical Journal 366 (2002). - ISSN 0264-6021 - p. 415 - 422.
crystal-structure - antibody fragment - soft docking - complex - protein - recognition - nmr
The X-ray structure of a ternary complex between human chorionic gonadotropin hormone (hCG) and two Fvs recognizing its alpha and beta subunits has been recently determined. The Fvs recognize the elongated hCG molecule by its two ends, one being the Leu-12-Cys-29 loop of the alpha subunit. We have designed and synthesized a 17-amino-acid peptide (named PepH14) derived from the sequence of this antigenic loop with the purpose of mimicking its three-dimensional structure and its affinity for antibodies. We have determined the solution structure of PepH14 by homonuclear NMR spectroscopy and derived distance restraints. Comparison of this structure with that of the corresponding antigenic loop of alpha-hCG reveals strong conformational similarities. In particular, the two pairs of residues that establish crucial contacts with the Fv fragment share the same conformation in PepH14 and in the authentic hormone loop. We propose a three-dimensional model of interaction of PepH14 with a llama V-HH (V-HH-H14) fragment cloned from a single-chain llama immunoglobulin raised against alpha-hCG. This model has been constrained by the chemical shift variations of the H14 (HN)-H-1 and N-15 resonances monitored upon binding with PepH14. Mapping of the backbone chemical shift variations on the V-HH structure determined by NMR indicates that PepH14 binds to V-HH-H14 and forms a complex using the three complementary determining regions (CDRs). They define a shallow groove encompassing residues Thr-31, Ala-56, Tyr-59 and Trp-104 which have been shown to be in conformational exchange [Renisio, Perez, Czisch, Guenneugues, Bornet, Frenken, Cambillau and Darbon (2002) Proteins 47, 546-555] and also Phe-37 and Ala-50. This groove is close to the hydrophobic interface area observed between VH and VL domains in Fvs from classical antibodies, which explains the rather lateral binding of PepH14 on the V-HH.
Performance and hormone levels of immunocastrated, surgically castrated and intact male pigs fed ad libitum high- and low-energy diets
Zeng, X.Y. ; Turkstra, J.A. ; Jongbloed, A.W. ; Diepen, J.T.M. van; Meloen, R.H. ; Oonk, H.B. ; Guo, D.Z. ; Wiel, D.F.M. van de - \ 2002
Livestock Production Science 77 (2002). - ISSN 0301-6226 - p. 1 - 11.
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