Jean Herman

University of Leuven, Louvain, Flanders, Belgium

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Publications (10)44.64 Total impact

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    ABSTRACT: Wheat bran extract (WBE), containing arabinoxylan-oligosaccharides that are potential prebiotic substrates, has been shown to modify bacterial colonic fermentation in human subjects and to beneficially affect the development of colorectal cancer (CRC) in rats. However, it is unclear whether these changes in fermentation are able to reduce the risk of developing CRC in humans. The aim of the present study was to evaluate the effects of WBE on the markers of CRC risk in healthy volunteers, and to correlate these effects with colonic fermentation. A total of twenty healthy subjects were enrolled in a double-blind, cross-over, randomised, controlled trial in which the subjects ingested WBE (10 g/d) or placebo (maltodextrin, 10 g/d) for 3 weeks, separated by a 3-week washout period. At the end of each study period, colonic handling of NH3 was evaluated using the biomarker lactose[15N, 15N']ureide, colonic fermentation was characterised through a metabolomics approach, and the predominant microbial composition was analysed using denaturing gradient gel electrophoresis. As markers of CRC risk, faecal water genotoxicity was determined using the comet assay and faecal water cytotoxicity using a colorimetric cell viability assay. Intake of WBE induced a shift from urinary to faecal 15N excretion, indicating a stimulation of colonic bacterial activity and/or growth. Microbial analysis revealed a selective stimulation of Bifidobacterium adolescentis. In addition, WBE altered the colonic fermentation pattern and significantly reduced colonic protein fermentation compared with the run-in period. However, faecal water cytotoxicity and genotoxicity were not affected. Although intake of WBE clearly affected colonic fermentation and changed the composition of the microbiota, these changes were not associated with the changes in the markers of CRC risk.
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    ABSTRACT: ScopeIn vitro and animal studies have shown differential colonic fermentation of structurally different prebiotics. We evaluated the impact of 2 structurally different prebiotics (wheat bran extract (WBE, containing arabinoxylan-oligosaccharides) and oligofructose)) on colonic fermentation and markers of bowel health in healthy volunteers.Methods and resultsNineteen healthy subjects completed a double-blind, cross-over RCT. Interventions with WBE, oligofructose or placebo for 2 weeks (week 1: 15g/day; week 2: 30g/day), were separated by 2-week wash-out periods. At the end of each study period, colonic fermentation was characterized through a metabolomics approach. Fecal water genotoxicity and cytotoxicity were determined using the comet and WST-1 assay, respectively, as parameters of gut health.Cluster analysis revealed differences in effects of WBE and oligofructose on colonic fermentation. WBE, but not oligofructose, reduced fecal p-cresol (p = 0.009) and isovaleric acid concentrations (p = 0.022), markers of protein fermentation. Fecal water cytotoxicity was significantly lower after intake of WBE (p = 0.015). Both WBE- and oligofructose-intake tended to reduce fecal water genotoxicity compared to placebo (WBE: p = 0.060; oligofructose: p = 0.057). Changes in fermentation were not related to changes in fecal water toxicity.Conclusion Structurally different prebiotics affect colonic fermentation and gut health in a different way.This article is protected by copyright. All rights reserved
    Molecular Nutrition & Food Research 11/2014; 58(11). DOI:10.1002/mnfr.201400298 · 4.91 Impact Factor
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    ABSTRACT: An efficient and practical strategy for the synthesis of (3R,4s,5S)-4-(2-hydroxyethyl) piperidine-3,4,5-triol and its N-alkyl derivatives 8a-f, starting from the d-glucose, is reported. The chiral pool methodology involves preparation of the C-3-allyl-α-d-ribofuranodialdose 10, which was converted to the C-5-amino derivative 11 by reductive amination. The presence of C-3-allyl group gives an easy access to the requisite hydroxyethyl substituted compound 13. Intramolecular reductive aminocyclization of C-5 amino group with C-1 aldehyde provided the γ-hydroxyethyl substituted piperidine iminosugar 8a that was N-alkylated to get N-alkyl derivatives 8b-f. Iminosugars 8a-f were screened against glycosidase enzymes. Amongst synthetic N-alkylated iminosugars, 8b and 8c were found to be α-galactosidase inhibitors while 8d and 8e were selective and moderate α-mannosidase inhibitors. In addition, immunomodulatory activity of compounds 8a-f was examined. These results were substantiated by molecular docking studies using AUTODOCK 4.2 programme.
    Bioorganic & Medicinal Chemistry 10/2014; 22(21). DOI:10.1016/j.bmc.2014.09.034 · 2.95 Impact Factor
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    ABSTRACT: A series of novel pyrimidine analogues were synthesized and evaluated for immunosuppressive activity in the Mixed Lymphocyte Reaction assay, which is well-known as the in vitro model for in vivo rejection after organ transplantation. Systematic variation of the substituents at positions 2, 4 and 6 of the pyrimidine scaffold led to the discovery of 2-benzylthio-5-cyano-6-(4-methoxyphenyl)-4-morpholinopyrimidine with an IC(50) value of 1.6μM in the MLR assay.
    Bioorganic & medicinal chemistry 01/2013; 21(5). DOI:10.1016/j.bmc.2012.12.032 · 2.82 Impact Factor
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    ABSTRACT: Protein fermentation results in production of metabolites such as ammonia, amines and indolic, phenolic and sulfur-containing compounds. In vitro studies suggest that these metabolites might be toxic. However, human and animal studies do not consistently support these findings. We modified protein fermentation in healthy subjects to assess the effects on colonic metabolism and parameters of gut health, and to identify metabolites associated with toxicity. After a 2-week run-in period with normal protein intake (NP), 20 healthy subjects followed an isocaloric high protein (HP) and low protein (LP) diet for 2 weeks in a cross-over design. Protein fermentation was estimated from urinary p-cresol excretion. Fecal metabolite profiles were analyzed using GC-MS and compared using cluster analysis. DGGE was used to analyze microbiota composition. Fecal water genotoxicity and cytotoxicity were determined using the Comet assay and the WST-1-assay, respectively, and were related to the metabolite profiles. Dietary protein intake was significantly higher during the HP diet compared to the NP and LP diet. Urinary p-cresol excretion correlated positively with protein intake. Fecal water cytotoxicity correlated negatively with protein fermentation, while fecal water genotoxicity was not correlated with protein fermentation. Heptanal, 3-methyl-2-butanone, dimethyl disulfide and 2-propenyl ester of acetic acid are associated with genotoxicity and indole, 1-octanol, heptanal, 2,4-dithiapentane, allyl-isothiocyanate, 1-methyl-4-(1-methylethenyl)-benzene, propionic acid, octanoic acid, nonanoic acid and decanoic acid with cytotoxicity. This study does not support a role of protein fermentation in gut toxicity. The identified metabolites can provide new insight into colonic health. ClinicalTrial.gov NCT01280513.
    PLoS ONE 12/2012; 7(12):e52387. DOI:10.1371/journal.pone.0052387 · 3.53 Impact Factor
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    ABSTRACT: A series of 5-substituted 2'-deoxyuridine monophosphate analogues has been synthesized and evaluated as potential inhibitors of mycobacterial ThyX, a novel flavin-dependent thymidylate synthase in Mycobacterium tuberculosis. A systematic SAR study led to the identification of compound 5a, displaying an IC(50) value against mycobacterial ThyX of 0.91 μM. This derivative lacks activity against the classical mycobacterial thymidylate synthase ThyA (IC(50) > 50 μM) and represents the first example of a selective mycobacterial FDTS inhibitor.
    Journal of Medicinal Chemistry 06/2011; 54(13):4847-62. DOI:10.1021/jm2004688 · 5.48 Impact Factor
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    ABSTRACT: Herein we describe the synthesis and in vitro and in vivo activity of thiazolo[5,4-d]pyrimidines as a novel class of immunosuppressive agents, useful for preventing graft rejection after organ transplantation. This research resulted in the discovery of a series of compounds with potent activity in the mixed lymphocyte reaction (MLR) assay, which is well-known as the in vitro model for in vivo rejection after organ transplantation. The most potent congeners displayed IC(50) values of less than 50 nM in this MLR assay and hence are equipotent to cyclosporin A, a clinically used immunosuppressive drug. One representative of this series was further evaluated in a preclinical animal model of organ transplantation and showed excellent in vivo efficacy. It validates these compounds as new promising immunosuppressive drugs.
    Journal of Medicinal Chemistry 01/2011; 54(2):655-68. DOI:10.1021/jm101254z · 5.48 Impact Factor
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    ABSTRACT: Screening of a pteridine-based compound library led to the identification of compounds exhibiting immunosuppressive as well as anti-inflammatory activity. Optimization afforded a series of 2-amino-4-N-piperazinyl-6-(3,4-dimethoxyphenyl)pteridine analogues. The most potent congeners in this series displayed low nM IC(50) values in the Mixed Lymphocyte Reaction (MLR) assay. In addition, these compounds also have potent anti-inflammatory activity as measured in the Tumor Necrosis Factor (TNF) assay.
    Bioorganic & medicinal chemistry letters 01/2011; 21(1):145-9. DOI:10.1016/j.bmcl.2010.11.053 · 2.65 Impact Factor
  • Gastroenterology 01/2011; 140(5). DOI:10.1016/S0016-5085(11)62253-1 · 12.82 Impact Factor
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    ABSTRACT: Besides TNF, activated T cells play a central role in the pathogenesis of inflammatory bowel diseases such as Crohn's disease. New therapies are still awaited to cure these often debilitating diseases. Natural occurring pteridines such as tetrahydrobiopterin (BH4) and neopterin have been reported to have immune modulating activities. Starting from a pteridine scaffold library, we intended to select compounds with potent in vitro inhibitory effects on T cells and to evaluate in vivo efficacy of selected compounds on trinitrobenzenesulphonate (TNBS) colitis in mice. Compound 4AZA1378 was selected because it potently inhibits human T cell proliferation at low nM concentrations (IC50 4 nM) while an almost 50-fold higher concentration was needed to inhibit LPS-induced TNF production. Mice treated with 4AZA1378 had less severe signs of colitis after TNBS rectal administration, with a more rapid weight recovery. Myeloperoxidase (MPO) activity and intralesional cytokine production were lower in mice of the treated groups. Furthermore anti-TNBS antibody responses were completely inhibited by treatment with 4AZA1378. In conclusion, we identified a pteridine analogue 4AZA1378 with immunosuppressive activity and a strong remission-inducing effect in TNBS colitis, supporting further pre-clinical and clinical development of this novel molecule for treatment of inflammatory diseases.
    Clinical Immunology 02/2007; 122(1):53-61. DOI:10.1016/j.clim.2006.09.007 · 3.99 Impact Factor