References of "Frederick, Raphael"
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See detailIntestinal Sucrase as a Novel Target Contributing to the Regulation of Glycemia by Prebiotics.
Neyrinck, Audrey M.; Pachikian, Barbara; Taminiau, Bernard ULg et al

in PLoS ONE (2016), 11(8),

Inulin-type fructans (ITF) are known for their capacity to modulate gut microbiota, energy metabolism and to improve glycemia in several animal models of obesity, and in humans. The potential contribution ... [more ▼]

Inulin-type fructans (ITF) are known for their capacity to modulate gut microbiota, energy metabolism and to improve glycemia in several animal models of obesity, and in humans. The potential contribution of ITF as modulators of sugar digestion by host enzymes has not been evaluated yet. A sucrose challenge has been performed on naive mice fed a standard diet supplemented with or without native chicory inulin (Fibruline 5%) for 3 weeks. The area under the curve of glycemia as well as sucrase activity in the small intestine were lowered after inulin treatment. Pyrosequencing of the 16S rRNA gene confirmed important changes in gut microbiota (mostly in favor of Blautia genus) due to inulin extract supplementation. Interestingly, the suppressive effect of inulin extract on postprandial glycemia also occurred when inulin was directly added to the sucrose solution, suggesting that the effect on sucrose digestion did not require chronic inulin administration. In vitro tests confirmed a direct inhibition of sucrase enzyme by the inulin extract, thereby suggesting that native chicory inulin, in addition to its well-known prebiotic effect, is also able to decrease the digestibility of carbohydrates, a phenomenon that can contribute in the control of post prandial glycemia. We may not exclude that the sucrose escaping the digestion could also contribute to the changes in the gut microbiota after a chronic treatment with inulin. [less ▲]

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See detailImpact de l’inuline sur l’activité des disaccharidases intestinales : une nouvelle cible contribuant à l’effet hypoglycémiant des prébiotiques
Neyrinck, Audrey M.; Theulier, Pauline; Jouret, Alexandra et al

Conference (2014, December)

Introduction et but de l’étude: Il est établi que l’administration de prébiotiques de type fructanes permet de diminuer la glycémie chez l’homme –un effet ayant abouti à une allégation par l’EFSA- et dans ... [more ▼]

Introduction et but de l’étude: Il est établi que l’administration de prébiotiques de type fructanes permet de diminuer la glycémie chez l’homme –un effet ayant abouti à une allégation par l’EFSA- et dans différents modèles murins d’obésité. Les mécanismes moléculaires sous-jacents restent à démontrer, et jusqu'à présent, sont évoqués une modulation de l'expression de gènes clés régulateurs du métabolisme énergétique, une modulation de la fonction endocrine de l'intestin et un changement de la sensibilité à l'insuline. Nous avons testé l’hypothèse selon laquelle l’inuline issue de la racine de chicorée change la digestibilité du saccharose, et avons mis en relation cet effet avec la modulation du microbiote intestinal. Matériel et méthodes: Un test de tolérance orale au saccharose (TTOS) a été réalisé sur des souris nourries avec un régime standard. Après 6h de jeune, les souris ont été gavées soit avec une solution de saccharose (3 g.kg-1) supplémentée avec de l’inuline (Fibruline® 5%), soit avec du saccharose seul. La glycémie et l’insulinémie ont été suivies durant 2h. Un TTOS a été appliqué également chez des souris préalablement nourries durant 20 jours avec l’inuline (5% dans un régime standard). L’activité des disaccharidases de la bordure en brosse ainsi que la composition du microbiote intestinal par pyroséquençage et par PCR quantitative de l’ADNr16S caecal ont été évaluées. L’activité de l’a-glucosidase a été évaluée in vitro en présence ou non d’inuline. Résultats et Analyse statistique: La glycémie et la réponse insulinémique sont significativement plus faibles 2h après le challenge avec la solution de saccharose lorsque l’inuline est ajoutée à la solution de gavage. L’analyse in vitro ne permet pas de mettre en évidence un effet inhibiteur direct de l’inuline sur l’a-glucosidase. Après 20 jours de supplémentation en inuline, l’aire sous la courbe (AUC) pour la glycémie lors de l’OTTS diminue significativement chez les souris ayant reçu l’inuline alors que les taux d’insuline sont inchangés. Par ailleurs, l’activité des disaccharidases (maltase, lactase, sucrase) est plus faible après la supplémentation chronique en inuline. En parallèle, une analyse de l’ARNr 16S révèle des changements bactériens importants au niveau du contenu caecal un mois après l’administration d’inuline, en ce compris une augmentation du nombre de Bifidobactéries. Conclusion: L’inuline est capable de diminuer la digestibilité de glucides indépendamment d’un changement de la composition du microbiote. L’arrivée de ces glucides au niveau du (caeco-)colon pourrait participer aux changement bactériens observés après une supplémentation chronique en inuline. En outre, l’administration d’inuline exerce un effet hypoglycémiant qui ne s’accompagne pas d’un changement des taux d’insuline, suggérant une amélioration de la sensibilité à l’insuline; cet effet pourrait s’expliquer en partie la baisse d’activité des disaccharidases. Ces résultats renforcent l’intérêt de l’ingestion de prébiotique de type inuline dans le contexte des désordres glucidiques associés ou non à l’obésité (diabète). [less ▲]

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See detailSynthesis, crystal structures and electronic properties of isomers of chloro-pyridinylvinyl-1H-indoles.
Moineaux, Laurence; Laurent, Sophie; Reniers, Jeremy et al

in European journal of medicinal chemistry (2012), 54

Three isomers of chloro-3-(2-pyridin-3-ylvinyl)-1H-indole were synthesized and tested as inhibitors of human tryptophan 2,3-dioxygenase (hTDO). The crystal structures of two of them were solved by X-ray ... [more ▼]

Three isomers of chloro-3-(2-pyridin-3-ylvinyl)-1H-indole were synthesized and tested as inhibitors of human tryptophan 2,3-dioxygenase (hTDO). The crystal structures of two of them were solved by X-ray diffraction. The solubility of the molecules also was determined experimentally. The molecular electrostatic potentials and dipole moments of the three isomers were calculated by ab initio quantum mechanics (HF/6-311G). The single crystal X-ray analyses reveal non-planar structures. This non-coplanarity is retained during docking of the compounds into a model of hTDO, the molecular target of this series. The position of the Cl atom does not significantly affect the electronic delocalization. Nevertheless, the position of the Cl atom produces a local variation of bond lengths inducing different dipole moments for these isomers. Variations in dipole moments are consistent with the different melting points and crystal packings. Differences in aqueous solubilities are best explained by subtle changes in H-bonds resulting from different accessibilities of the indole NH's due to steric effects of the Cl substituent. The non-coplanarity plays an important role in the crystalline packing of the molecules in contrast to the position of the Cl. This study leads to a better understanding of the structural and electronic characteristics of this chemical series and can potentially help to better understand their inhibitory activity. [less ▲]

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See detailIndol-2-yl ethanones as novel indoleamine 2,3-dioxygenase (IDO) inhibitors.
Dolusic, Eduard; Larrieu, Pierre; Blanc, Sébastien et al

in Bioorganic & Medicinal Chemistry (2011), 19(4), 1550-61

Indoleamine 2,3-dioxygenase (IDO) is a heme dioxygenase which has been shown to be involved in the pathological immune escape of diseases such as cancer. The synthesis and structure-activity relationships ... [more ▼]

Indoleamine 2,3-dioxygenase (IDO) is a heme dioxygenase which has been shown to be involved in the pathological immune escape of diseases such as cancer. The synthesis and structure-activity relationships (SAR) of a novel series of IDO inhibitors based on the indol-2-yl ethanone scaffold is described. In vitro and in vivo biological activities have been evaluated, leading to compounds with IC(50) values in the micromolar range in both tests. Introduction of small substituents in the 5- and 6-positions of the indole ring, indole N-methylation and variations of the aromatic side chain are all well tolerated. An iron coordinating group on the linker is a prerequisite for biological activity, thus corroborating the virtual screening results. [less ▲]

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See detailDiscovery and preliminary SARs of keto-indoles as novel indoleamine 2,3-dioxygenase (IDO) inhibitors.
Dolusic, Eduard; Larrieu, Pierre; Blanc, Sebastien et al

in European journal of medicinal chemistry (2011), 46(7), 3058-65

Indoleamine 2,3-dioxygenase (IDO) is an important new therapeutic target for the treatment of cancer. With the aim of discovering novel IDO inhibitors, a virtual screen was undertaken and led to the ... [more ▼]

Indoleamine 2,3-dioxygenase (IDO) is an important new therapeutic target for the treatment of cancer. With the aim of discovering novel IDO inhibitors, a virtual screen was undertaken and led to the discovery of the keto-indole derivative 1a endowed with an inhibitory potency in the micromolar range. Detailed kinetics were performed and revealed an uncompetitive inhibition profile. Preliminary SARs were drawn in this series and corroborated the putative binding orientation as suggested by docking. [less ▲]

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See detailPyrazolo[4,3-c]isoquinolines as potential inhibitors of NF-kappaB activation.
Mortier, Jeremie; Frederick, Raphael; Ganeff, Corinne et al

in Biochemical Pharmacology (2010), 79(10), 1462-72

In this work, we aimed to build a 3D-model of NIK and to study the binding of pyrazolo[4,3-c]isoquinolines with a view to highlight the structural elements responsible for their inhibitory potency ... [more ▼]

In this work, we aimed to build a 3D-model of NIK and to study the binding of pyrazolo[4,3-c]isoquinolines with a view to highlight the structural elements responsible for their inhibitory potency. However, in the course of this work, we unexpectedly found that the pyrazolo[4,3-c]isoquinolines initially reported as NIK inhibitors were neither inhibitors of this enzyme nor of the alternative NF-kappaB pathway, but were in fact inhibitors of another kinase, the TGF-beta activated kinase 1 (TAK1) which is involved in the classical NF-kappaB pathway. [less ▲]

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See detailNF-kappaB inducing kinase (NIK) inhibitors: identification of new scaffolds using virtual screening.
Mortier, Jeremie; Masereel, Bernard; Remouchamps, Caroline ULg et al

in Bioorganic & Medicinal Chemistry Letters (2010), 20(15), 4515-20

As a wide variety of pro-inflammatory cytokines are involved in the development of rheumatoid arthritis (RA), there is an urgent need for the discovery of novel therapeutic strategies. Among these, the ... [more ▼]

As a wide variety of pro-inflammatory cytokines are involved in the development of rheumatoid arthritis (RA), there is an urgent need for the discovery of novel therapeutic strategies. Among these, the inhibition of the NF-kappaB inducing kinase (NIK), a key enzyme of the NF-kappaB alternative pathway activation, represents a potential interesting approach. In fact, NIK is involved downstream of many tumor necrosis factor receptors (TNFR) like CD40, RANK or LTbetaR, implicated in the pathogenesis of RA. But, up to now, the number of reported putative NIK inhibitors is extremely limited. In this work, we report a virtual screening (VS) study combining various filters including high-throughput docking using a 3D-homology model and ranking by using different scoring functions. This work led to the identification of two molecular fragments, 4H-isoquinoline-1,3-dione (5) and 2,7-naphthydrine-1,3,6,8-tetrone (6) which inhibit NIK with an IC(50) value of 51 and 90 microM, respectively. This study opens new perspectives in the field of the NF-kappaB alternative pathway inhibition. [less ▲]

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See detailSynthèse de b-cyclodextrines modifiées
Bertolla, Carine; Piette, Marie ULg; Evrard, Brigitte ULg et al

Poster (2003, May)

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