References of "De Tullio, Pascal"
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See detailAn Easy, Convenient Cell and Tissue Extraction Protocol for Nuclear Magnetic Resonance Metabolomics.
Matheus, Nicolas ULg; Hansen, Sylvain ULg; Rozet, Eric ULg et al

in Phytochemical analysis : PCA (in press)

INTRODUCTION: As a complement to the classic metabolomics biofluid studies, the visualisation of the metabolites contained in cells or tissues could be a very powerful tool to understand how the local ... [more ▼]

INTRODUCTION: As a complement to the classic metabolomics biofluid studies, the visualisation of the metabolites contained in cells or tissues could be a very powerful tool to understand how the local metabolism and biochemical pathways could be affected by external or internal stimuli or pathologies. Therefore, extraction and/or lysis is necessary to obtain samples adapted for use with the current analytical tools (liquid NMR and MS). These extraction or lysis work-ups are often the most labour-intensive and rate-limiting steps in metabolomics, as they require accuracy and repeatability as well as robustness. Many of the procedures described in the literature appear to be very time-consuming and not easily amenable to automation. OBJECTIVE: To find a fast, simplified procedure that allows release of the metabolites from cells and tissues in a way that is compatible with NMR analysis. METHODS: We assessed the use of sonication to disrupt cell membranes or tissue structures. Both a vibrating probe and an automated bath sonicator were explored. RESULTS: The application of sonication as the disruption procedure led to reproducible NMR spectral data compatible with metabolomics studies. This method requires only a small biological tissue or cell sample, and a rapid, reduced work-up was applied before analysis. The spectral patterns obtained are comparable with previous, well-described extraction protocols. CONCLUSION: The rapidity and the simplicity of this approach could represent a suitable alternative to the other protocols. Additionally, this approach could be favourable for high- throughput applications in intracellular and intratissular metabolite measurements. Copyright (c) 2014 John Wiley & Sons, Ltd. [less ▲]

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See detailSperm Motility and Lactate production at different sperm concentrations
Ponthier, Jérôme ULg; De Tullio, Pascal ULg; Blommaert, Didier ULg et al

in Journal of Equine Veterinary Science (2014, January), 34(1), 75-76

Lactate production is associated with total spermatozoa concentration. It negatively affects preservation of total and progressive motility, showing an effect of by-products of anaerobic metabolism on ... [more ▼]

Lactate production is associated with total spermatozoa concentration. It negatively affects preservation of total and progressive motility, showing an effect of by-products of anaerobic metabolism on long-term storage. Moreover, our data show that non-progressive motile spermatozoa are highly associated to lactate concentration, and thus, anaerobic glycolysis. More studies are required to determine relative contributions of aerobiosis and anaerobiosis to spermatozoa motility under different storage conditions. [less ▲]

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See detailDevelopment of Thiophenic Analogues of Benzothiadiazine Dioxides as New Powerful Potentiators of 2-Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic Acid (AMPA) Receptors
Francotte, Pierre ULg; Goffin, Eric ULg; Fraikin, Pierre et al

in Journal of Medicinal Chemistry (2013), 56(20), 7838-7850

On the basis of the results obtained in previous series of AMPA potentiators belonging to 3,4-dihydro-2H-benzo- and 3,4-dihydro-2H-pyrido-1,2,4-thiadiazine 1,1-dioxides, the present work focuses on the ... [more ▼]

On the basis of the results obtained in previous series of AMPA potentiators belonging to 3,4-dihydro-2H-benzo- and 3,4-dihydro-2H-pyrido-1,2,4-thiadiazine 1,1-dioxides, the present work focuses on the design of original isosteric 3,4-dihydro-2H-thieno-1,2,4-thiadiazine 1,1-dioxides. Owing to the sulfur position, three series of compounds were developed and their activity as AMPA potentiators was characterized. In each of the developed series, potent compounds were discovered. After screening the selected active compounds on a safety in vivo test, 6-chloro-4-ethyl-3,4-dihydro-2H-thieno[2,3-e]-1,2,4-thiadiazine 1,1-dioxide (24) appeared as the most promising compound and was further evaluated. Its effects on long-term potentiation in vivo and on AMPA-mediated noradrenaline release were measured to predict its potential cognitive enhancing properties. Finally, an object recognition test performed in mice revealed that 24 was able to significantly enhance cognition, after oral administration, at doses as low as 0.3 mg/kg. This study validates the interest of the isosteric replacement of the benzene or pyridine nuclei by the thiophene nucleus in the ring-fused thiadiazine dioxides class of AMPA potentiators. [less ▲]

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See detailEffect of head-to-head addition in vinyl acetate controlled radical polymerization: why is Co(acac)2-mediated polymerization so much better?
Morin, Aurélie N.; Detrembleur, Christophe ULg; Jérôme, Christine ULg et al

in Macromolecules (2013), 46(11), 4303-4312

The controlled polymerization of vinyl acetate has been recently achieved by several techniques, but PVAc with targeted Mn and low dispersity up to very high monomer conversions and high degrees of ... [more ▼]

The controlled polymerization of vinyl acetate has been recently achieved by several techniques, but PVAc with targeted Mn and low dispersity up to very high monomer conversions and high degrees of polymerization was only obtained with Co(acac)2 as controlling agent in the so-called CMRP, a type of organometallic mediated radical polymerization (OMRP). Other techniques (including ATRP, ITP, TERP, and RAFT/MADIX) have shown a more or less pronounced slowdown in the polymerization kinetics, which was attributed to the higher strength of the C−X bond between the radical PVAc chain and the trapping agent (X) in the dormant species and to a consequent slower reactivation after a less frequent head-to-head monomer addition. The reason for the CMRP exception is clarified by the present contribution. First, a detailed investigation by 1H, 13C and multiplicity-edited HSQC and DEPT-135 NMR of the PVAc obtained by CMRP, in comparison with a regular polymer made by free radical polymerization under the same conditions, has revealed that Co(acac)2 does not significantly alter the fraction of head-to-head sequences in the polymer backbone and that there is no accumulation of Co(acac)2-capped chains with a head-to-head ω end. Hence, both dormant chains (following the head-to-head and the head-to-tail monomer additions) must be reactivated at similar rates. A DFT study shows that this is possible because the dormant chains are stabilized not only by the C−Co σ bond but also by formation of a chelate ring through coordination of the ω monomer carbonyl group. The head-to-head dormant chain contains an inherently stronger C−Co bond but forms a weaker 6-membered chelate ring, whereas the weaker C−Co bond in the head-to-tail dormant chain is compensated by a stronger 5-membered chelate ring. Combination of the two effects leads to similar activation enthalpies, as verified by DFT calculations using a variety of local, gradient-corrected, hybrid and “ad hoc” functionals (BPW91, B3PW91, BPW91*, M06 and M06L). While the BDE(C−X) of model H-VAc−X molecules [X = Cl, I, MeTe, EtOC(S)S and Co(acac)2] are functional dependent, the BDE difference between head-to-head and head-to-tail dormant chain models is almost functional insensitive, with values of 5−9 kcal/mol for the ATRP, ITP and TERP models, 3−6 for the RAFT/MADIX model, and around zero for CMRP. [less ▲]

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See detailIdentification of methylenecyclopropyl acetic acid in serum of European horses with atypical myopathy
Votion, Dominique ULg; van Galen, G; Sweetan et al

in Equine Veterinary Journal (2013)

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See detailAge-related Macular Degeneration Study: A Metabolomics Approach
LAMBERT, Vincent ULg; Hansen, Sylvain ULg; Rousseau, Réjanne et al

Conference (2013, May 23)

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See detailMEASURING VARIABILITY SOURCES IN NMR METABOLOMIC STUDIES
Rozet, Eric ULg; De Tullio, Pascal ULg; Hubert, Philippe ULg et al

Conference (2013, May 13)

Due to the huge amount of information available in NMR spectra obtained from the analysis of metabolomic experiments, multivariate analysis such as Principal Component Analysis (PCA) are required to ... [more ▼]

Due to the huge amount of information available in NMR spectra obtained from the analysis of metabolomic experiments, multivariate analysis such as Principal Component Analysis (PCA) are required to understand the influence of treatments over the metabolites [1]. However, many experiments in metabolomics studies have more complexes variability structures than simply comparing several treatments: they may include time effects, biological effects such as diet or hormonal status, and other blocking factors or variability sources: samples stability, age of the individuals, pH of a buffer, days of acquisition, and so on. Metabolomic data analysis needs to extract from the spectral data matrix the variations linked to a change indicated in the factor of interest. However other sources of variability may impair this objective. This stresses the importance to discover the sources of variability of the spectral metabolomic data using appropriate methodology. Classically, to analyze such data analysis of variance (ANOVA) or multivariate ANOVA (MANOVA) [2] is used. However direct application of these methodologies to NMR spectra obtained from structured metabolomics studies is inappropriate or impossible. More complex data analyses methodologies are required to understand the importance of the various factors implied in the experiments and to provide a measure of their variance components. Three related methodologies have been proposed to achieve this: ASCA [3], ANOVA-PCA [4] and AComDim [5]. The ASCA and ANOVA-PCA methodologies combine first an analysis of variance step (ANOVA) and then a PCA step. The AComDim one adds to the output of the ANOVA-PCA step a multi-block analysis. In this presentation, the usefulness and applicability of these advanced techniques to data analysis of NMR metabolomic spectra are provided to highlight the increase of knowledge gained and the estimation of main sources of variability arising in an experimental setup. Two NMR databases will be used [6]. The first one concerns human serum analyzed by 1H-NMR where three random factors are present: day of measurement (3 days), sample (2 samples per individual) and replication of analyses as well as two fixed controlled factors, time of measurement after thawing (2 times) and two protein suppression methods for the spectral pre-treatment. The second database is about the 1H-NMR analyses of rats’ urine where two different concentrations of citrate and of hippurate were deliberately added and three other sources of variability are present: urine pool diluted or not diluted, repetitions of analyses, days of analyses (three days), as well as two different spectral pre-treatment procedures. [less ▲]

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See detailIdentification and structure elucidation of four cannabimimetic compounds in seized products
Denooz, Raphaël ULg; VAN HEUGEN, Jean-Claude ULg; Frederich, Michel ULg et al

in Journal of Analytical Toxicology (2013), 37(2), 56-63

Since 2008, herbal mixtures with synthetic cannabinoid compounds have been sold as incense throughout the world. Although these new drugs are labeled as not for human consumption, these products are ... [more ▼]

Since 2008, herbal mixtures with synthetic cannabinoid compounds have been sold as incense throughout the world. Although these new drugs are labeled as not for human consumption, these products are smoked for their cannabis-like effects. This study reports the structural and spectral elucidation of four cannabimimetic compounds seized in Belgium: (4-methoxyphenyl)-1-(pentyl-1H-indol-3-yl)methanone (RCS-4), 1-(5-fluoropentyl)-3-(1-naphtoyl)indole (AM-2201), 2-(2-chlorophenyl)-1-(1-pentylindol-3-yl)ethanone (JWH-203) and 4-ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-210). Laboratory investigations were conducted by liquid chromatography (LC)–ultraviolet spectroscopy, high-resolution accurate mass detection and nuclear magnetic resonance (NMR) analysis. This combined analytical approach allowed the detection of illicit compounds for which reference materials were not available. To facilitate identification and to complete existing databases, ultraviolet spectra and NMR data of all seized products are presented. Additionally, LC–quadrupole time-of-flight data were recorded to provide absolute identification. [less ▲]

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See detailApplication de la résonance magnétique nucléaire (RMN) en toxicologie judiciaire
Denooz, Raphaël ULg; Frederich, Michel ULg; Charlier, Corinne ULg et al

in Acta Clinica Belgica (2013), 68(6), 470

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See detailTriphenylphosphonium salts of 1,2,4-benzothiadiazine 1,1-dioxides related to diazoxide targeting mitochondrial ATP-sensitive potassium channels
Constant-Urban, C.; Charif, M.; Goffin, Eric ULg et al

in Bioorganic & Medicinal Chemistry Letters (2013), 23

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See detailEffects of diazoxide, benzothiadiazine and benzopyrane derivatives on mitochondrial proton and electron leaks of cardiomyocytes (H9C2 cell line).
Mouithys-Mickalad, Ange ULg; Ceusters, Justine ULg; Charef, M et al

Poster (2013)

Background: Mitochondria are double membrane- organelles that play a central role in cellular metabolism, calcium homeostasis and redox signaling. They have been also considered as main producers of ... [more ▼]

Background: Mitochondria are double membrane- organelles that play a central role in cellular metabolism, calcium homeostasis and redox signaling. They have been also considered as main producers of adenosine triphosphate (ATP) and reactive oxygen species (ROS). In many cancer cells those organelles become dysfunctional leading to a shift of energy metabolism from oxidative phosphorylation to active glycolysis and an increase of ROS generation. According to Warberg’ theory, cancer damage might occur at the mitochondrial level, affecting tiny structures within each cell implicated in the energy production through ATP. New insight is that mitochondria might be a good therapeutic target for metabolic syndromes, ischemia/reperfusion injury and organs transplantation. Therefore, search for novel molecules able to keep mitochondria functional are of relevant interest. Methodology: Cardiomyocytes (H9C2 cells) were from ATCC (USA) and grown till confluence. The basal cellular respiratory rate, proton and electron leaks as well as ATP production were measured with the High Resolution Oxygraphy (Oroboros, Austria). All compounds: diazoxide (DIAZ), diazoxide –related analogs (1: BPDZ-259, 2: BPDZ-444), and benzopyran derivatives (3: BPDZ-490, 4: BPDZ-711) were tested at final concentration of 10-5 M, except when specified and compared to control samples (cells with or without DMSO). Results and conclusion: The basal respiratory rate of H9C2 cells (5x106/mL) was changed depending on the chemical structure of the tested compounds: e.g. compound 3 strongly enhanced the routine respiration, while 4 displayed a marked lowering effect. In contrast, the addition of similar concentration of benzothiadiazin derivatives (1, 2) had no effect on routine respiration but also on the other respiratory parameters such as oligomycin-induced leak and ATP production. Similar profile was obtained with the reference molecule: diazoxide. Overall, our findings indicate that both diazoxide-like analogues (1 and 2) and diazoxide were without significant effect on basal respiration, ATP production, even on maximal respiration. Interestingly, two derivatives show opposite effects: compound 3 behaves as a uncoupling agent and the other one (4) exhibits a real lowering effect on respiration but that was reversible. The latter effect might be of interest if this kind of molecules could be used for further use as an agent for organ conservation during transplantation. Our results also demonstrate that diazoxide, a well-known Mito-KATP opener, did not exert its effect beside of clinical situation like ischemia/reperfusion injury. [less ▲]

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See detailLaser-induced choroidal neovascularization model to study age-related macular degeneration in mice.
LAMBERT, Vincent ULg; Lecomte, Julie ULg; Hansen, Sylvain ULg et al

in Nature Protocols (2013), 8(11), 2197-2211

The mouse model of laser-induced choroidal neovascularization (CNV) has been used extensively in studies of the exudative form of age-related macular degeneration (AMD). This experimental in vivo model ... [more ▼]

The mouse model of laser-induced choroidal neovascularization (CNV) has been used extensively in studies of the exudative form of age-related macular degeneration (AMD). This experimental in vivo model relies on laser injury to perforate Bruch's membrane, resulting in subretinal blood vessel recruitment from the choroid. By recapitulating the main features of the exudative form of human AMD, this assay has served as the backbone for testing antiangiogenic therapies. This standardized protocol can be applied to transgenic mice and can include treatments with drugs, recombinant proteins, antibodies, adenoviruses and pre-microRNAs to aid in the search for new molecular regulators and the identification of novel targets for innovative treatments. This robust assay requires 7-14 d to complete, depending on the treatment applied and whether immunostaining is performed. This protocol includes details of how to induce CNV, including laser induction, lesion excision, processing and different approaches to quantify neoformed vasculature. [less ▲]

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See detailAMPA receptor positive allosteric modulators: a patent review
Pirotte, Bernard ULg; Francotte, Pierre ULg; Goffin, Eric ULg et al

in Expert Opinion on Therapeutic Patents (2013), 23

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See detailSéminaire des chercheurs Télévie 2013
Cimino, Jonathan ULg; Sounni, Nor Eddine ULg; Calligaris, David ULg et al

Poster (2012, December 10)

Séminaire des chercheurs Télévie 2013

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See detailMétabolomique et Chimie Médicinale, vers la découverte de nouvelles cibles thérapeutiques : application à la dégénérescence maculaire liée à l'âge (DMLA)
De Tullio, Pascal ULg

Conference (2012, May 25)

La métabolomique est une des sciences « omiques » les plus récemment développées. Elle consiste en l’étude de l’ensemble des composés de petit poids moléculaire (métabolites) présents dans une cellule, un ... [more ▼]

La métabolomique est une des sciences « omiques » les plus récemment développées. Elle consiste en l’étude de l’ensemble des composés de petit poids moléculaire (métabolites) présents dans une cellule, un organe, un organisme ou plus globalement un biofluide et qui constitue le métabolome. Elle s’inscrit dans la continuité de la génomique, de la transcriptomique et de la protéomique puisqu’elle étudie l’ensemble des composés de fonctionnement « terminaux » des organismes et permet de relier une modification du métabolisme à une ou plusieurs cascades biochimiques. Or, toute pathologie entraîne ou est liée inévitablement à un disfonctionnement plus ou moins important du métabolisme et donc doit modifier le profil du métabolome par des changements de concentration et l’apparition ou la disparition de certains métabolites particuliers. L’application de la métabolomique à l’étude d’une pathologie permettrait donc, en principe, de mettre en lumière des voies biologiques affectées ou modifiées par cette même pathologie. Et en ce sens, la métabolomique, tout comme la protéomique et dans une moindre mesure la génomique, identifie des cibles thérapeutiques potentielles, nouvelles ou non. En effet, en partant du principe que l’amélioration symptomatique de toute maladie est représentée par le retour à un état de fonctionnement « normal » de l’organisme affecté, c’est à dire à un profil de métabolisme « sain », il apparaît évident que moduler en ce sens les voies biochimiques identifiées par la métabolomique peut constituer une approche thérapeutique originale. Dans sa recherche de nouveaux médicaments, la Chimie Médicinale est bien entendu très « demandeuse » de nouvelles cibles ou d’approches pharmacologiques novatrices et donc la métabolomique représente un outil tout à fait intéressant pour les pharmacochimistes. Une étude métabolomique est caractérisée par différentes étapes. Elle débute par une sélection et une collecte contrôlée des échantillons à analyser (échantillons « pathologiques » et « sains »). Elle se poursuit par la préparation et l’analyse des échantillons de manière à obtenir le profil métabolique le plus complet, ce qui est en général réalisé via l’utilisation de la RMN ou de la spectrométrie de masse. Les données obtenues doivent ensuite être préparées (post-processing) pour l’analyse statistique discriminante finale (i.e. PCA ; ICA, PLS-DA…). Cette analyse doit permettre la discrimination des groupes « sain » et « malade » et l’identification des molécules entraînant cette discrimination, molécules souvent nommées « biomarqueurs ». Ces biomarqueurs peuvent ensuite être reliés à différentes voies biochimiques. La dégénérescence maculaire liée à l’âge (DMLA) est la principale cause de perte de vision dans le monde occidental. Elle est notamment caractérisée par une néovascularisation choroïdienne (NVC). Malgré le développement de nouvelles thérapies, les mécanismes moléculaires et les changements métaboliques sous-jacents à cette pathologie sont toujours mal compris. C’est pourquoi nous avons décidé d’étudier la DMLA par le biais d’une approche métabolomique basée à la fois sur l’étude de sera de patients atteints de DMLA et sur un modèle murin de NVC induite au laser. L’analyse des échantillons humains et murins a été menée par RMN du proton et a conduit à la distinction claire de deux groupes chez la souris (induites au laser ou non) et chez l’humain (patients atteints de DMLA ou sains). Chose remarquable, les « biomarqueurs » discriminants sont identiques dans l’étude clinique humaine et dans le modèle expérimental animal. Leur modulation permet une amélioration sensible des effets de l’impact laser chez la souris, laissant par la même entrevoir une possibilité de traitement efficace chez l’homme. Cette approche a donc permis non seulement d’identifier des voies biochimiques impliquées dans la pathologie et donc d’ouvrir de nouveaux axes de recherche pour une meilleure compréhension de l’étiologie de la pathologie mais également de proposer des solutions thérapeutiques potentielles novatrices. [less ▲]

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