18 results on '"Chu-Van E"'
Search Results
2. Orchestration of Tryptophan-Kynurenine Pathway, Acute Decompensation, and Acute-on-Chronic Liver Failure in Cirrhosis
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Claria, J., Moreau, R., Fenaille, F., Amoros, A., Junot, C., Gronbaek, H., Coenraad, M.J., Pruvost, A., Ghettas, A., Chu-Van, E., Lopez-Vicario, C., Oettl, K., Caraceni, P., Alessandria, C., Trebicka, J., Pavesi, M., Deulofeu, C., Albillos, A., Gustot, T., Welzel, T.M., Fernandez, J., Stauber, R.E., Saliba, F., Butin, N., Colsch, B., Moreno, C., Durand, F., Nevens, F., Banares, R., Benten, D., Gines, P., Gerbes, A., Jalan, R., Angeli, P., Bernardi, M., Arroyo, V., EASL Clif Consortium, Grifols Chair European Fdn Study C, Clària, Joan, Moreau, Richard, Fenaille, Françoi, Amorós, Alex, Junot, Christophe, Gronbaek, Henning, Coenraad, Minneke J, Pruvost, Alain, Ghettas, Aurélie, Chu-Van, Emeline, López-Vicario, Cristina, Oettl, Karl, Caraceni, Paolo, Alessandria, Carlo, Trebicka, Jonel, Pavesi, Marco, Deulofeu, Carme, Albillos, Agustin, Gustot, Thierry, Welzel, Tania M, Fernández, Javier, Stauber, Rudolf E, Saliba, Faouzi, Butin, Noémie, Colsch, Benoit, Moreno, Christophe, Durand, Françoi, Nevens, Frederik, Bañares, Rafael, Benten, Daniel, Ginès, Pere, Gerbes, Alexander, Jalan, Rajiv, Angeli, Paolo, Bernardi, Mauro, Arroyo, Vicente, Grifols Chair, Partenaires INRAE, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Université Paris Diderot - Paris 7 (UPD7), Service de Pharmacologie et d'Immunoanalyse (SPI), Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Université Paris Saclay (COmUE), Aarhus University Hospital, Department of Gastroenterology and Hepatology, Leiden University Medical Center (LUMC), Institut National de la Recherche Agronomique (INRA), Medical University Graz, Department of Medical and Surgical Sciences, Universita degli Studi di Padova, San Giovanni Battista Hosp, Div Gastroenterol & Hepatol, Turin, Italy, Rheinische Friedrich-Wilhelms-Universität Bonn, Hospital Universitario, Université libre de Bruxelles (ULB), Goethe-Universität Frankfurt am Main, Hôpital Paul Brousse, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse, Université Catholique de Louvain = Catholic University of Louvain (UCL), Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Univ Hosp LMU Munich, Liver Ctr Munich, Dept Med 2, Munich, Germany, University College of London [London] (UCL), Universita di Padova, ICREA Academia Award, Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Universiteit Leiden-Universiteit Leiden, and Università degli Studi di Padova = University of Padua (Unipd)
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Liver Cirrhosis ,Male ,0301 basic medicine ,Cirrhosis ,Kynurenine pathway ,[SDV]Life Sciences [q-bio] ,medicine.medical_treatment ,severity ,Decompensated cirrhosis ,Systemic inflammation ,Gastroenterology ,Tryptophan -- blood ,chemistry.chemical_compound ,0302 clinical medicine ,hepatic-encephalopathy ,Prospective Studies ,Renal Insufficiency ,Indoleamine 2,3-dioxygenase ,Hepatic encephalopathy ,Kynurenine ,Liver Cirrhosis -- blood -- complications -- mortality -- physiopathology ,systemic inflammation ,Europe -- epidemiology ,Kynurenine -- blood ,Hepatic Encephalopathy -- blood -- complications ,Tryptophan ,Bacterial Infections -- blood -- complications ,Immunosuppression ,Bacterial Infections ,Sciences bio-médicales et agricoles ,Middle Aged ,Acute-On-Chronic Liver Failure -- blood -- etiology ,metabolomics ,3. Good health ,Europe ,chromatography ,Female ,030211 gastroenterology & hepatology ,medicine.symptom ,metabolomic ,medicine.medical_specialty ,indoleamine 2,3-dioxygenase ,Decompensated cirrhosi ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,organ failure ,Decompensation ,plasma ,Aged ,Inflammation ,Inflammation -- blood -- complications ,Renal Insufficiency -- blood -- complications ,Hepatology ,business.industry ,Acute-On-Chronic Liver Failure ,blockade ,medicine.disease ,mortality ,kynurenine ,030104 developmental biology ,chemistry ,Case-Control Studies ,Hepatic Encephalopathy ,business ,metabolism - Abstract
Systemic inflammation (SI) is involved in the pathogenesis of acute decompensation (AD) and acute-on-chronic liver failure (ACLF) in cirrhosis. In other diseases, SI activates tryptophan (Trp) degradation through the kynurenine pathway (KP), giving rise to metabolites that contribute to multiorgan/system damage and immunosuppression. In the current study, we aimed to characterize the KP in patients with cirrhosis, in whom this pathway is poorly known. The serum levels of Trp, key KP metabolites (kynurenine and kynurenic and quinolinic acids), and cytokines (SI markers) were measured at enrollment in 40 healthy subjects, 39 patients with compensated cirrhosis, 342 with AD (no ACLF) and 180 with ACLF, and repeated in 258 patients during the 28-day follow-up. Urine KP metabolites were measured in 50 patients with ACLF. Serum KP activity was normal in compensated cirrhosis, increased in AD and further increased in ACLF, in parallel with SI; it was remarkably higher in ACLF with kidney failure than in ACLF without kidney failure in the absence of differences in urine KP activity and fractional excretion of KP metabolites. The short-term course of AD and ACLF (worsening, improvement, stable) correlated closely with follow-up changes in serum KP activity. Among patients with AD at enrollment, those with the highest baseline KP activity developed ACLF during follow-up. Among patients who had ACLF at enrollment, those with immune suppression and the highest KP activity, both at baseline, developed nosocomial infections during follow-up. Finally, higher baseline KP activity independently predicted mortality in patients with AD and ACLF. Conclusion: Features of KP activation appear in patients with AD, culminate in patients with ACLF, and may be involved in the pathogenesis of ACLF, clinical course, and mortality., info:eu-repo/semantics/published
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- 2019
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3. L-Serine dietary supplementation is associated with clinical improvement of loss-of-function GRIN2B-related pediatric encephalopathy
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Soto D, Olivella M, Grau C, Armstrong-Moron J, Alcon C, Gasull X, Santos-Gómez A, Locubiche S, de Salazar MG, García-Díaz R, Gratacòs-Batlle E, Ramos-Vicente D, Chu-Van E, Colsch B, Fernández-Dueñas V, Ciruela F, Bayés À, Sindreu C, López-Sala A, Garcia-Cazorla A, and Altafaj X
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nervous system - Abstract
Autosomal dominant mutations in GRIN2B are associated with severe encephalopathy, but little is known about the pathophysiological outcomes and any potential therapeutic interventions. Genetic studies have described the association between de novo mutations of genes encoding the subunits of the N-methyl-d-aspartate receptor (NMDAR) and severe neurological conditions. Here, we evaluated a missense mutation in GRIN2B, causing a proline-to-threonine switch (P553T) in the GluN2B subunit of NMDAR, which was found in a 5-year-old patient with Rett-like syndrome with severe encephalopathy. Structural molecular modeling predicted a reduced pore size of the mutant GluN2B-containing NMDARs. Electrophysiological recordings in a HEK-293T cell line expressing the mutated subunit confirmed this prediction and showed an associated reduced glutamate affinity. Moreover, GluN2B(P553T)-expressing primary murine hippocampal neurons showed decreased spine density, concomitant with reduced NMDA-evoked currents and impaired NMDAR-dependent insertion of the AMPA receptor subunit GluA1 at stimulated synapses. Furthermore, the naturally occurring coagonist d-serine restored function to GluN2B(P553T)-containing NMDARs. l-Serine dietary supplementation of the patient was hence initiated, resulting in the increased abundance of d-serine in the plasma and brain. The patient has shown notable improvements in motor and cognitive performance and communication after 11 and 17 months of l-serine dietary supplementation. Our data suggest that l-serine supplementation might ameliorate GRIN2B-related severe encephalopathy and other neurological conditions caused by glutamatergic signaling deficiency.
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- 2019
4. Increasing plant protein in the diet induces changes in the plasma metabolome that may be beneficial for metabolic health. A randomized crossover study in males.
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Lépine G, Mariotti F, Tremblay-Franco M, Courrent M, Verny MA, David J, Mathé V, Jame P, Anchisi A, Lefranc-Millot C, Perreau C, Guérin-Deremaux L, Chollet C, Castelli F, Chu-Van E, Huneau JF, Rémond D, Pickering G, Fouillet H, and Polakof S
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- Adult, Humans, Male, Middle Aged, Young Adult, Blood Glucose metabolism, Cardiometabolic Risk Factors, Cross-Over Studies, Fasting blood, Insulin Resistance, Postprandial Period physiology, Metabolome physiology, Plant Proteins, Dietary administration & dosage
- Abstract
Background & Aim: Dietary shifts replacing animal protein (AP) with plant protein (PP) sources have been associated with lowering cardiometabolic risk (CMR), but underlying mechanisms are poorly characterized. This nutritional intervention aims to characterize the metabolic changes induced by diets containing different proportions of AP and PP sources in males at CMR., Design: This study is a 4-week, crossover, randomized, controlled-feeding trial in which 19 males with CMR followed two diets providing either 36 % for the control diet (CON-D) or 64 % for the flexitarian diet (FLEX-D) of total protein intake from PP sources. Plasma nontargeted metabolomes (LC-MS method) were measured in the fasted state and after a high-fat challenge meal at the end of each intervention arm. Lipogenesis and protein synthesis fluxes, flow-mediated dilatation (FMD) and gluco-lipidic responses were assessed after the challenge meal. Data were analyzed with mixed models, and univariate and multivariate models for metabolomics data., Results: In both arms CMR improved with time, with decreased body weight (-0.9 %), insulin resistant (-34 %, HOMA-IR, Homeostatic Model Assessment for Insulin Resistance) and low-density lipoproteins (LDL)-cholesterol (-11 %). Diet had no effect on FMD or metabolic fluxes, but a trend (0.05
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- 2024
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5. Nontargeted urine metabolomic analysis of acute intermittent porphyria reveals novel interactions between bile acids and heme metabolism: New promising biomarkers for the long-term management of patients.
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Lefebvre T, Eguether T, Thévenot E, Poli A, Chu-Van E, Krasniqi P, Schmitt C, Talbi N, Nicolas G, Puy H, Junot C, Lamazière A, Castelli F, Gouya L, and Fenaille F
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Acute intermittent porphyria is an inherited error of heme synthesis. The underlying pathophysiology, involving mainly hepatic heme synthesis, is poorly understood despite its occurrence, and the severity of acute porphyria attack is still difficult to control. A better understanding of the interactions between heme synthesis and global metabolism would improve the management of AIP patients. An untargeted metabolomic analysis was performed on the urine of 114 patients with overt AIP and asymptomatic carriers using liquid chromatography coupled to high-resolution mass spectrometry. The collected data were analyzed by combining univariate and multivariate analyses. A total of 239 metabolites were annotated in urine samples by matching chromatographic and mass spectral characteristics with those from our chemical library. Twenty-six metabolites, including porphyrin precursors, intermediates of tryptophan or glycine metabolism and, unexpectedly, bile acids, showed significant concentration differences between the phenotypic groups. Dysregulation of bile acid metabolism was confirmed by targeted quantitative analysis, which revealed an imbalance in favor of hydrophobic bile acids associated with changes in conjugation, which was more pronounced in the severe phenotype. Using a random forest model, the cholic acid/chenodeoxycholic acid ratio enables the differential classification of severe patients from other patients with a diagnostic accuracy of 84%. The analysis of urine samples revealed significant modifications in the metabolome of AIP patients. Alteration in bile acids provides new insights into the pathophysiology of chronic complications, such as primary liver cancer, while also providing new biomarker candidates for predicting the most severe phenotypes., (© 2024 SSIEM.)
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- 2024
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6. Concordant inter-laboratory derived concentrations of ceramides in human plasma reference materials via authentic standards.
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Torta F, Hoffmann N, Burla B, Alecu I, Arita M, Bamba T, Bennett SAL, Bertrand-Michel J, Brügger B, Cala MP, Camacho-Muñoz D, Checa A, Chen M, Chocholoušková M, Cinel M, Chu-Van E, Colsch B, Coman C, Connell L, Sousa BC, Dickens AM, Fedorova M, Eiríksson FF, Gallart-Ayala H, Ghorasaini M, Giera M, Guan XL, Haid M, Hankemeier T, Harms A, Höring M, Holčapek M, Hornemann T, Hu C, Hülsmeier AJ, Huynh K, Jones CM, Ivanisevic J, Izumi Y, Köfeler HC, Lam SM, Lange M, Lee JC, Liebisch G, Lippa K, Lopez-Clavijo AF, Manzi M, Martinefski MR, Math RGH, Mayor S, Meikle PJ, Monge ME, Moon MH, Muralidharan S, Nicolaou A, Nguyen-Tran T, O'Donnell VB, Orešič M, Ramanathan A, Riols F, Saigusa D, Schock TB, Schwartz-Zimmermann H, Shui G, Singh M, Takahashi M, Thorsteinsdóttir M, Tomiyasu N, Tournadre A, Tsugawa H, Tyrrell VJ, van der Gugten G, Wakelam MO, Wheelock CE, Wolrab D, Xu G, Xu T, Bowden JA, Ekroos K, Ahrends R, and Wenk MR
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- Humans, Calibration, Mass Spectrometry methods, Lipidomics methods, Reproducibility of Results, Ceramides blood, Reference Standards, Laboratories standards
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In this community effort, we compare measurements between 34 laboratories from 19 countries, utilizing mixtures of labelled authentic synthetic standards, to quantify by mass spectrometry four clinically used ceramide species in the NIST (National Institute of Standards and Technology) human blood plasma Standard Reference Material (SRM) 1950, as well as a set of candidate plasma reference materials (RM 8231). Participants either utilized a provided validated method and/or their method of choice. Mean concentration values, and intra- and inter-laboratory coefficients of variation (CV) were calculated using single-point and multi-point calibrations, respectively. These results are the most precise (intra-laboratory CVs ≤ 4.2%) and concordant (inter-laboratory CVs < 14%) community-derived absolute concentration values reported to date for four clinically used ceramides in the commonly analyzed SRM 1950. We demonstrate that calibration using authentic labelled standards dramatically reduces data variability. Furthermore, we show how the use of shared RM can correct systematic quantitative biases and help in harmonizing lipidomics. Collectively, the results from the present study provide a significant knowledge base for translation of lipidomic technologies to future clinical applications that might require the determination of reference intervals (RIs) in various human populations or might need to estimate reference change values (RCV), when analytical variability is a key factor for recall during multiple testing of individuals., (© 2024. The Author(s).)
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- 2024
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7. Metabolomics Analysis of Rabbit Plasma after Ocular Exposure to Vapors of Sulfur Mustard.
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Bouhlel J, Caffin F, Gros-Désormeaux F, Douki T, Benoist JF, Castelli FA, Chu-Van E, Piérard C, Junot C, and Fenaille F
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Sulfur mustard (SM) is a highly potent alkylating vesicant agent and remains a relevant threat to both civilians and military personnel. The eyes are the most sensitive organ after airborne SM exposure, causing ocular injuries with no antidote or specific therapeutics available. In order to identify relevant biomarkers and to obtain a deeper understanding of the underlying biochemical events, we performed an untargeted metabolomics analysis using liquid chromatography coupled to high-resolution mass spectrometry of plasma samples from New Zealand white rabbits ocularly exposed to vapors of SM. Metabolic profiles (332 unique metabolites) from SM-exposed (n = 16) and unexposed rabbits (n = 8) were compared at different time intervals from 1 to 28 days. The observed time-dependent changes in metabolic profiles highlighted the profound dysregulation of the sulfur amino acids, the phenylalanine, the tyrosine and tryptophan pathway, and the polyamine and purine biosynthesis, which could reflect antioxidant and anti-inflammatory activities. Taurine and 3,4-dihydroxy-phenylalanine (Dopa) seem to be specifically related to SM exposure and correspond well with the different phases of ocular damage, while the dysregulation of adenosine, polyamines, and acylcarnitines might be related to ocular neovascularization. Additionally, neither cysteine, N-acetylcysteine, or guanine SM adducts were detected in the plasma of exposed rabbits at any time point. Overall, our study provides an unprecedented view of the plasma metabolic changes post-SM ocular exposure, which may open up the development of potential new treatment strategies.
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- 2024
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8. Uveitic glaucoma-like features in Yap conditional knockout mice.
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Bitard J, Grellier EK, Lourdel S, Filipe HP, Hamon A, Fenaille F, Castelli FA, Chu-Van E, Roger JE, Locker M, and Perron M
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Glaucoma is a multifactorial neurodegenerative disease characterized by the progressive and irreversible degeneration of the optic nerve and retinal ganglion cells. Despite medical advances aiming at slowing degeneration, around 40% of treated glaucomatous patients will undergo vision loss. It is thus of utmost importance to have a better understanding of the disease and to investigate more deeply its early causes. The transcriptional coactivator YAP, an important regulator of eye homeostasis, has recently drawn attention in the glaucoma research field. Here we show that Yap conditional knockout mice (Yap cKO), in which the deletion of Yap is induced in both Müller glia (i.e. the only retinal YAP-expressing cells) and the non-pigmented epithelial cells of the ciliary body, exhibit a breakdown of the aqueous-blood barrier, accompanied by a progressive collapse of the ciliary body. A similar phenotype is observed in human samples that we obtained from patients presenting with uveitis. In addition, aged Yap cKO mice harbor glaucoma-like features, including deregulation of key homeostatic Müller-derived proteins, retinal vascular defects, optic nerve degeneration and retinal ganglion cell death. Finally, transcriptomic analysis of Yap cKO retinas pointed to early-deregulated genes involved in extracellular matrix organization potentially underlying the onset and/or progression of the observed phenotype. Together, our findings reveal the essential role of YAP in preserving the integrity of the ciliary body and retinal ganglion cells, thereby preventing the onset of uveitic glaucoma-like features., (© 2024. The Author(s).)
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- 2024
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9. Development of an Untargeted Metabolomics Strategy to Study the Metabolic Rewiring of Dendritic Cells upon Lipopolysaccharide Activation.
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Michieletto J, Delvaux A, Chu-Van E, Junot C, Fenaille F, and Castelli FA
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Dendritic cells (DCs) are essential immune cells for defense against external pathogens. Upon activation, DCs undergo profound metabolic alterations whose precise nature remains poorly studied at a large scale and is thus far from being fully understood. The goal of the present work was to develop a reliable and accurate untargeted metabolomics workflow to get a deeper insight into the metabolism of DCs when exposed to an infectious agent (lipopolysaccharide, LPS, was used to mimic bacterial infection). As DCs transition rapidly from a non-adherent to an adherent state upon LPS exposure, one of the leading analytical challenges was to implement a single protocol suitable for getting comparable metabolomic snapshots of those two cellular states. Thus, a thoroughly optimized and robust sample preparation method consisting of a one-pot solvent-assisted method for the simultaneous cell lysis/metabolism quenching and metabolite extraction was first implemented to measure intracellular DC metabolites in an unbiased manner. We also placed special emphasis on metabolome coverage and annotation by using a combination of hydrophilic interaction liquid chromatography and reverse phase columns coupled to high-resolution mass spectrometry in conjunction with an in-house developed spectral database to identify metabolites at a high confidence level. Overall, we were able to characterize up to 171 unique meaningful metabolites in DCs. We then preliminarily compared the metabolic profiles of DCs derived from monocytes of 12 healthy donors upon in vitro LPS activation in a time-course experiment. Interestingly, the resulting data revealed differential and time-dependent activation of some particular metabolic pathways, the most impacted being nucleotides, nucleotide sugars, polyamines pathways, the TCA cycle, and to a lesser extent, the arginine pathway.
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- 2023
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10. Chronic Consumption of Cocoa Rich in Procyanidins Has a Marginal Impact on Gut Microbiota and on Serum and Fecal Metabolomes in Male Endurance Athletes.
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Tabone M, García-Merino JA, Bressa C, Rocha Guzman NE, Herrera Rocha K, Chu Van E, Castelli FA, Fenaille F, and Larrosa M
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- Athletes, Feces, Humans, Male, Metabolome, Catechin, Gastrointestinal Microbiome, Proanthocyanidins
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Cocoa is used in the sports world as a supplement, although there is no consensus on its use. We investigated the effect of cocoa intake on intestinal ischemia (intestinal fatty acid-binding protein (I-FABP)), serum lipopolysaccharide (LPS) levels, gastrointestinal symptoms, and gut microbiota in endurance athletes during their training period on an unrestricted diet. We also performed a metabolomics analysis of serum and feces after a bout of exercise before and after supplementation. Cocoa consumption had no effect on I-FABP, LPS, or gastrointestinal symptoms. Cocoa intake significantly increased the abundance of Blautia and Lachnospira genera and decreased the abundance of the Agathobacter genus, which was accompanied by elevated levels of polyphenol fecal metabolites 4-hydroxy-5-(phenyl)-valeric acid and O-methyl-epicatechin- O -glucuronide. Our untargeted approach revealed that cocoa had no significant effects on serum and fecal metabolites and that its consumption had little impact on the metabolome after a bout of physical exercise.
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- 2022
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11. ProMetIS, deep phenotyping of mouse models by combined proteomics and metabolomics analysis.
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Imbert A, Rompais M, Selloum M, Castelli F, Mouton-Barbosa E, Brandolini-Bunlon M, Chu-Van E, Joly C, Hirschler A, Roger P, Burger T, Leblanc S, Sorg T, Ouzia S, Vandenbrouck Y, Médigue C, Junot C, Ferro M, Pujos-Guillot E, de Peredo AG, Fenaille F, Carapito C, Herault Y, and Thévenot EA
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- Adaptor Proteins, Signal Transducing, Animals, Female, Liver, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Myxovirus Resistance Proteins, Phenotype, Plasma, Disease Models, Animal, Metabolomics, Proteomics
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Genes are pleiotropic and getting a better knowledge of their function requires a comprehensive characterization of their mutants. Here, we generated multi-level data combining phenomic, proteomic and metabolomic acquisitions from plasma and liver tissues of two C57BL/6 N mouse models lacking the Lat (linker for activation of T cells) and the Mx2 (MX dynamin-like GTPase 2) genes, respectively. Our dataset consists of 9 assays (1 preclinical, 2 proteomics and 6 metabolomics) generated with a fully non-targeted and standardized approach. The data and processing code are publicly available in the ProMetIS R package to ensure accessibility, interoperability, and reusability. The dataset thus provides unique molecular information about the physiological role of the Lat and Mx2 genes. Furthermore, the protocols described herein can be easily extended to a larger number of individuals and tissues. Finally, this resource will be of great interest to develop new bioinformatic and biostatistic methods for multi-omics data integration., (© 2021. The Author(s).)
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- 2021
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12. Activation of Vitamin D Receptor Pathway Enhances Differentiating Capacity in Acute Myeloid Leukemia with Isocitrate Dehydrogenase Mutations.
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Sabatier M, Boet E, Zaghdoudi S, Guiraud N, Hucteau A, Polley N, Cognet G, Saland E, Lauture L, Farge T, Sahal A, Pancaldi V, Chu-Van E, Castelli F, Bertoli S, Bories P, Récher C, Boutzen H, Mansat-De Mas V, Stuani L, and Sarry JE
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Relapses and resistance to therapeutic agents are major barriers in the treatment of acute myeloid leukemia (AML) patients. These unfavorable outcomes emphasize the need for new strategies targeting drug-resistant cells. As IDH mutations are present in the preleukemic stem cells and systematically conserved at relapse, targeting IDH mutant cells could be essential to achieve a long-term remission in the IDH mutant AML subgroup. Here, using a panel of human AML cell lines and primary AML patient specimens harboring IDH mutations, we showed that the production of an oncometabolite (R)-2-HG by IDH mutant enzymes induces vitamin D receptor-related transcriptional changes, priming these AML cells to differentiate with pharmacological doses of ATRA and/or VD. This activation occurs in a CEBPα-dependent manner. Accordingly, our findings illuminate potent and cooperative effects of IDH mutations and the vitamin D receptor pathway on differentiation in AML, revealing a novel therapeutic approach easily transferable/immediately applicable to this subgroup of AML patients.
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- 2021
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13. Multiplatform metabolomics for an integrative exploration of metabolic syndrome in older men.
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Comte B, Monnerie S, Brandolini-Bunlon M, Canlet C, Castelli F, Chu-Van E, Colsch B, Fenaille F, Joly C, Jourdan F, Lenuzza N, Lyan B, Martin JF, Migné C, Morais JA, Pétéra M, Poupin N, Vinson F, Thevenot E, Junot C, Gaudreau P, and Pujos-Guillot E
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- Aged, Aged, 80 and over, Humans, Male, Metabolic Syndrome blood, Metabolomics methods, Aging metabolism, Metabolic Syndrome metabolism, Metabolome
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Background: Metabolic syndrome (MetS), a cluster of factors associated with risks of developing cardiovascular diseases, is a public health concern because of its growing prevalence. Considering the combination of concomitant components, their development and severity, MetS phenotypes are largely heterogeneous, inducing disparity in diagnosis., Methods: A case/control study was designed within the NuAge longitudinal cohort on aging. From a 3-year follow-up of 123 stable individuals, we present a deep phenotyping approach based on a multiplatform metabolomics and lipidomics untargeted strategy to better characterize metabolic perturbations in MetS and define a comprehensive MetS signature stable over time in older men., Findings: We characterize significant changes associated with MetS, involving modulations of 476 metabolites and lipids, and representing 16% of the detected serum metabolome/lipidome. These results revealed a systemic alteration of metabolism, involving various metabolic pathways (urea cycle, amino-acid, sphingo- and glycerophospholipid, and sugar metabolisms…) not only intrinsically interrelated, but also reflecting environmental factors (nutrition, microbiota, physical activity…)., Interpretation: These findings allowed identifying a comprehensive MetS signature, reduced to 26 metabolites for future translation into clinical applications for better diagnosing MetS., Funding: The NuAge Study was supported by a research grant from the Canadian Institutes of Health Research (CIHR; MOP-62842). The actual NuAge Database and Biobank, containing data and biologic samples of 1,753 NuAge participants (from the initial 1,793 participants), are supported by the Fonds de recherche du Québec (FRQ; 2020-VICO-279753), the Quebec Network for Research on Aging, a thematic network funded by the Fonds de Recherche du Québec - Santé (FRQS) and by the Merck-Frost Chair funded by La Fondation de l'Université de Sherbrooke. All metabolomics and lipidomics analyses were funded and performed within the metaboHUB French infrastructure (ANR-INBS-0010). All authors had full access to the full data in the study and accept responsibility to submit for publication., Competing Interests: Declaration of Competing Interest All authors declare they have no conflict of interest., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)
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- 2021
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14. Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia.
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Stuani L, Sabatier M, Saland E, Cognet G, Poupin N, Bosc C, Castelli FA, Gales L, Turtoi E, Montersino C, Farge T, Boet E, Broin N, Larrue C, Baran N, Cissé MY, Conti M, Loric S, Kaoma T, Hucteau A, Zavoriti A, Sahal A, Mouchel PL, Gotanègre M, Cassan C, Fernando L, Wang F, Hosseini M, Chu-Van E, Le Cam L, Carroll M, Selak MA, Vey N, Castellano R, Fenaille F, Turtoi A, Cazals G, Bories P, Gibon Y, Nicolay B, Ronseaux S, Marszalek JR, Takahashi K, DiNardo CD, Konopleva M, Pancaldi V, Collette Y, Bellvert F, Jourdan F, Linares LK, Récher C, Portais JC, and Sarry JE
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- Acute Disease, Aminopyridines pharmacology, Animals, Cell Line, Tumor, Doxycycline pharmacology, Drug Resistance, Neoplasm drug effects, Enzyme Inhibitors pharmacology, Epigenesis, Genetic drug effects, Glycine analogs & derivatives, Glycine pharmacology, HL-60 Cells, Humans, Isocitrate Dehydrogenase antagonists & inhibitors, Isocitrate Dehydrogenase metabolism, Isoenzymes antagonists & inhibitors, Isoenzymes genetics, Isoenzymes metabolism, Leukemia, Myeloid drug therapy, Leukemia, Myeloid metabolism, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Mitochondria drug effects, Mitochondria metabolism, Oxadiazoles pharmacology, Oxidative Phosphorylation drug effects, Piperidines pharmacology, Pyridines pharmacology, Triazines pharmacology, Xenograft Model Antitumor Assays methods, Mice, Drug Resistance, Neoplasm genetics, Isocitrate Dehydrogenase genetics, Leukemia, Myeloid genetics, Mitochondria genetics, Mutation
- Abstract
Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, and susceptibility to mitochondrial inhibitors in cancer cells. Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) harboring an IDH mutation displayed an enhanced mitochondrial oxidative metabolism. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurred through the increase in electron transport chain complex I activity, mitochondrial respiration, and methylation-driven CEBPα-induced fatty acid β-oxidation of IDH1 mutant cells. While IDH1 mutant inhibitor reduced 2-HG oncometabolite and CEBPα methylation, it failed to reverse FAO and OxPHOS. These mitochondrial activities were maintained through the inhibition of Akt and enhanced activation of peroxisome proliferator-activated receptor-γ coactivator-1 PGC1α upon IDH1 mutant inhibitor. Accordingly, OxPHOS inhibitors improved anti-AML efficacy of IDH mutant inhibitors in vivo. This work provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDH mutant inhibitors., Competing Interests: Disclosures: B. Nicolay reported "other" from Agios Pharmaceuticals outside the submitted work and is an employee and shareholder of Agios Pharmaceuticals. J.R. Marszalek reported a patent to IACS-010759 issued. K. Takahashi reported personal fees from Celgene during the conduct of the study; and personal fees from Symbio Pharmaceuticals, GSK, and Novartis outside the submitted work. C.D. DiNardo reported personal fees from Agios Pharmaceuticals, Celgene, and AbbVie outside the submitted work. M. Konopleva reported "other" from Amgen, Kisoji, and Reata Pharmaceutical; and grants from AbbVie, Genentech, and Stemline Therapeutics, F. Hoffman La-Roche, Forty Seven, Eli Lilly, Cellectis, Calithera, Ablynx, Agios, Ascentage, Astra Zeneca, Rafael Pharmaceutical, and Sanofi outside the submitted work. In addition, M. Konopleva had a patent to Novartis pending (62/993,166), a patent to Eli Lilly issued, and a patent to Reata Pharmaceutical issued (7,795,305 B2 CDDO). C. Récher reported grants from Celgene, Amgen, Novartis, Jazz, AbbVie, Astellas, MaatPharma, Agios, Daiichi-Sankyo, and Roche; personal fees from Incyte, Macrogenics, Otsuka, Janssen, Pfizer, and Takeda; and non-financial support from Sanofi and Gilead outside the submitted work. No other disclosures were reported., (© 2021 Stuani et al.)
- Published
- 2021
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15. Effect of gut microbiota on depressive-like behaviors in mice is mediated by the endocannabinoid system.
- Author
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Chevalier G, Siopi E, Guenin-Macé L, Pascal M, Laval T, Rifflet A, Boneca IG, Demangel C, Colsch B, Pruvost A, Chu-Van E, Messager A, Leulier F, Lepousez G, Eberl G, and Lledo PM
- Subjects
- Animals, Disease Models, Animal, Fatty Acids metabolism, Fecal Microbiota Transplantation, Lactobacillus physiology, Male, Mice, Mice, Inbred C57BL, Neurogenesis drug effects, Behavior, Animal, Depression complications, Endocannabinoids pharmacology, Gastrointestinal Microbiome physiology, Stress, Psychological complications
- Abstract
Depression is the leading cause of disability worldwide. Recent observations have revealed an association between mood disorders and alterations of the intestinal microbiota. Here, using unpredictable chronic mild stress (UCMS) as a mouse model of depression, we show that UCMS mice display phenotypic alterations, which could be transferred from UCMS donors to naïve recipient mice by fecal microbiota transplantation. The cellular and behavioral alterations observed in recipient mice were accompanied by a decrease in the endocannabinoid (eCB) signaling due to lower peripheral levels of fatty acid precursors of eCB ligands. The adverse effects of UCMS-transferred microbiota were alleviated by selectively enhancing the central eCB or by complementation with a strain of the Lactobacilli genus. Our findings provide a mechanistic scenario for how chronic stress, diet and gut microbiota generate a pathological feed-forward loop that contributes to despair behavior via the central eCB system.
- Published
- 2020
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16. Inhibition of Lysosome Membrane Recycling Causes Accumulation of Gangliosides that Contribute to Neurodegeneration.
- Author
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Boutry M, Branchu J, Lustremant C, Pujol C, Pernelle J, Matusiak R, Seyer A, Poirel M, Chu-Van E, Pierga A, Dobrenis K, Puech JP, Caillaud C, Durr A, Brice A, Colsch B, Mochel F, El Hachimi KH, Stevanin G, and Darios F
- Subjects
- Animals, Autophagy drug effects, Female, Glutamic Acid pharmacology, Humans, Induced Pluripotent Stem Cells cytology, Induced Pluripotent Stem Cells metabolism, Lysosomes drug effects, Mice, Mice, Knockout, Neurons cytology, Neurons metabolism, Proteins genetics, Proteins metabolism, Spastic Paraplegia, Hereditary metabolism, Spastic Paraplegia, Hereditary pathology, Zebrafish metabolism, Zebrafish Proteins deficiency, Zebrafish Proteins genetics, Gangliosides metabolism, Intracellular Membranes metabolism, Lysosomes metabolism
- Abstract
Lysosome membrane recycling occurs at the end of the autophagic pathway and requires proteins that are mostly encoded by genes mutated in neurodegenerative diseases. However, its implication in neuronal death is still unclear. Here, we show that spatacsin, which is required for lysosome recycling and whose loss of function leads to hereditary spastic paraplegia 11 (SPG11), promotes clearance of gangliosides from lysosomes in mouse and human SPG11 models. We demonstrate that spatacsin acts downstream of clathrin and recruits dynamin to allow lysosome membrane recycling and clearance of gangliosides from lysosomes. Gangliosides contributed to the accumulation of autophagy markers in lysosomes and to neuronal death. In contrast, decreasing ganglioside synthesis prevented neurodegeneration and improved motor phenotype in a SPG11 zebrafish model. Our work reveals how inhibition of lysosome membrane recycling leads to the deleterious accumulation of gangliosides, linking lysosome recycling to neurodegeneration., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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17. Low-Protein Diet Induces IRE1α-Dependent Anticancer Immunosurveillance.
- Author
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Rubio-Patiño C, Bossowski JP, De Donatis GM, Mondragón L, Villa E, Aira LE, Chiche J, Mhaidly R, Lebeaupin C, Marchetti S, Voutetakis K, Chatziioannou A, Castelli FA, Lamourette P, Chu-Van E, Fenaille F, Avril T, Passeron T, Patterson JB, Verhoeyen E, Bailly-Maitre B, Chevet E, and Ricci JE
- Subjects
- Animals, Antigen-Presenting Cells immunology, Cell Line, Tumor, Colorectal Neoplasms diet therapy, Colorectal Neoplasms immunology, Endoribonucleases genetics, Female, Lymphocyte Depletion, Lymphoma diet therapy, Lymphoma immunology, Melanoma, Experimental diet therapy, Melanoma, Experimental immunology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Protein Serine-Threonine Kinases genetics, RNA Helicases metabolism, Signal Transduction, CD8-Positive T-Lymphocytes immunology, Diet, Protein-Restricted, Endoribonucleases metabolism, Immunologic Surveillance, Neoplasms, Experimental diet therapy, Neoplasms, Experimental immunology, Protein Serine-Threonine Kinases metabolism, Unfolded Protein Response immunology
- Abstract
Dietary restriction (DR) was shown to impact on tumor growth with very variable effects depending on the cancer type. However, how DR limits cancer progression remains largely unknown. Here, we demonstrate that feeding mice a low-protein (Low PROT) isocaloric diet but not a low-carbohydrate (Low CHO) diet reduced tumor growth in three independent mouse cancer models. Surprisingly, this effect relies on anticancer immunosurveillance, as depleting CD8
+ T cells, antigen-presenting cells (APCs), or using immunodeficient mice prevented the beneficial effect of the diet. Mechanistically, we established that a Low PROT diet induces the unfolded protein response (UPR) in tumor cells through the activation of IRE1α and RIG1 signaling, thereby resulting in cytokine production and mounting an efficient anticancer immune response. Collectively, our data suggest that a Low PROT diet induces an IRE1α-dependent UPR in cancer cells, enhancing a CD8-mediated T cell response against tumors., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2018
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18. Detection of secondary biomarker of met-eGH as a strategy to screen for somatotropin misuse in horseracing.
- Author
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Bailly-Chouriberry L, Chu-Van E, Pinel G, Garcia P, Popot MA, André-Fontaine G, Bonnaire Y, and Le Bizec B
- Subjects
- Animals, Antibody Specificity, Biomarkers blood, Biosensing Techniques, Blotting, Western methods, Enzyme-Linked Immunosorbent Assay methods, Recombinant Proteins immunology, Doping in Sports prevention & control, Growth Hormone immunology, Horses immunology, Immunoglobulin G blood, Methionine immunology
- Abstract
Since the Australian commercialisation of the recombinant equine growth hormone (reGH) in 1998 (EquiGen-5), Bresagen), this reGH, which differs only from eGH by an additional methionine at the N-terminal end (met-eGH), is worldwide suspected to be administered to racehorses as a doping agent. Indeed, the use of this biological drug is considered as a threat to horseracing since it acts both on growth, development or reproductive functions, and on the improvement of performances. In this work, we describe two reliable techniques based on surface plasmon resonance biosensor immunoassay (SPR-BIA) and solid-phase enzyme-linked immunosorbent assay (ELISA) as new, rapid and efficient long-term screening methods applicable to horseracing antidoping analysis. The ELISA and SPR-BIA tests were applied to octanoic acid purified IgGs from serum/plasma samples collected on two thoroughbreds treated with recombinant equine growth hormone for a period of two weeks. The first kinetic study of serum/plasma antibodies raised as a consequence of recombinant equine growth hormone administrations, which allows the detection from eight days up to 200 days after the beginning of the treatment, was performed. In order to trace the occurrence of anti-reGH antibodies in routine analysis and to monitor the animal level exposure to this forbidden molecule, a random population study was conducted on 233 post-race horses.
- Published
- 2008
- Full Text
- View/download PDF
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