References of "De Tullio, Pascal"
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See detailNMR in the Pharmaceutical and Biomedical areas for identification and quantification of drugs and metabolomics applications
LAMBERT, Vincent ULg; Dufour, Gilles ULg; Chiap, Patrice ULg et al

Conference (2014, June 23)

Nuclear Magnetic Resonance (NMR) is probably, with mass spectrometry, the most powerful analytical tool for the structural determination of organic compounds. For a long time and due to technical ... [more ▼]

Nuclear Magnetic Resonance (NMR) is probably, with mass spectrometry, the most powerful analytical tool for the structural determination of organic compounds. For a long time and due to technical limitations, the main applications of NMR were focused on chemistry (organic, inorganic and medicinal chemistry) or biochemistry (i.e. proteins and proteins ligands analysis). Indeed, despite of very interesting potential in terms of structural information, reproducibility, specificity, quantification, NMR suffered of a lack of sensitivity and sometime of resolution in the case of complex mixture analysis in comparison with other technics. However, since several years, important technical improvements such as huge increase in sensitivity, hyphenation of NMR with LC system, automation and development of 2D and presaturation sequences have opened new putative applications for NMR, specifically in the pharmaceutical and biomedical areas. Then, beside the mass and chromatographic technics classically used for drug analysis, NMR represents an interesting and complementary tool for many applications. In this presentation, we will describe some NMR applications related to the pharma area. Starting from the identification of xenobiotic metabolites by coupling LC-SPE-NMR data with LC-MS/MS results, quantification of cyclodextrines in complex media, identification of illicit compounds, we will finish with our recent metabolomics NMR developments. [less ▲]

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See detailInhibition of PDH Kinase as a new therapeutic target for Age-related Macular Degeneration (AMD)
Arslan, Deniz ULg; Pirotte, Bernard ULg; De Tullio, Pascal ULg et al

Poster (2014, June)

Metabolomics is one of the most recent technologies in the world of Omics sciences. It aims at studying metabolome, which is composed of small molecular weight organic molecules (called metabolites) of a ... [more ▼]

Metabolomics is one of the most recent technologies in the world of Omics sciences. It aims at studying metabolome, which is composed of small molecular weight organic molecules (called metabolites) of a cell, an organism or a biological system. This approach gives rise to a growing number of applications in many areas, such as biomarkers discovery, clinical studies, drug efficacy and toxicity evaluation, diagnostic tools, quality control. One of the most interesting features of metabolomics is its capability to extract biochemical information reflecting biological events and then to be a powerful tool in the knowledge of the aetiology of some pathologies. Indeed, it is clear that every disease could alter more or less drastically the metabolic profile of the patients. Then a metabolomics approach could highlight the biochemical pathways affected and could allow the identification of new putative therapeutic strategies or targets that could be useful in a new drug discovery strategy. As proteomics, metabolomics approach represents a new and powerful tool for Medicinal Chemistry. Age-related Macular Degeneration (AMD) is a leading cause of vision loss in the western world among people aged 50 or older. 90% of all vision loss due to AMD results from the exudative form, which is characterized by choroidal neovascularization (CNV). Age-related changes that induce pathologic CNV are incompletely understood. A successful application of anti-VEGF approaches in the clinic is obviously a turning point in AMD treatment. Nevertheless, despite such important advances, critical issues remain to be addressed. To better understand the aetiology of this pathology, we used and improved a murine model of laser-induced choroidal neovascularization and applied a 1H NMR metabolomics study. This approach leads to the emergence of different putative biomarkers and to the validation of the CNV model for an experimental study of AMD. Among these “biomarkers”, lactate appears to be clearly involved in the development of AMD. The modulation of their plasma concentration by treatment of the animals with synthetic compounds and more specifically Pyruvate DesHydrogenase Kinase inhibitors (PDHK) significantly decrease the impact of laser induced CNV. Starting from these results, the development of new PDHK inhibitors could open the way to innovative treatment opportunities in AMD disease. [less ▲]

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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 (2014)

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 detailBlocking lipid synthesis overcomes tumor re-growth and metastasis after anti-angiogenic therapy withdrawal.
Sounni, Nor Eddine ULg; Cimino, Jonathan ULg; BLACHER, Silvia ULg et al

in Cell Metabolism (2014), 20

The molecular mechanisms responsible for the failure of antiangiogenic therapies and how tumors adapt to these therapies are unclear. Here, we applied transcriptomic, proteomic, and metabolomic approaches ... [more ▼]

The molecular mechanisms responsible for the failure of antiangiogenic therapies and how tumors adapt to these therapies are unclear. Here, we applied transcriptomic, proteomic, and metabolomic approaches to preclinical models and provide evidence for tumor adaptation to vascular endothelial growth factor blockade through a metabolic shift toward carbohydrate and lipid metabolism in tumors. During sunitinib or sorafenib treatment, tumor growth was inhibited and tumors were hypoxic and glycolytic. In sharp contrast, treatment withdrawal led to tumor regrowth, angiogenesis restoration, moderate lactate production, and enhanced lipid synthesis. This metabolic shift was associated with a drastic increase in metastatic dissemination. Interestingly, pharmacological lipogenesis inhibition with orlistat or fatty acid synthase downregulation with shRNA inhibited tumor regrowth and metastases after sunitinib treatment withdrawal. Our data shed light on metabolic alterations that result in cancer adaptation to antiangiogenic treatments and identify key molecules involved in lipid metabolism as putative therapeutic targets. [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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