Author: "Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3)" / Topic: 0303 health sciences - Searchworks@Jio Institute Digital Library Search Results

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Start Over Author "Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3)" Topic 0303 health sciences

110 results on '"Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3)"'

1. Sostdc1 is expressed in all major compartments of developing and adult mammalian eyes

Author: Gabrielle Goldman, Marc Putterman, Fabien Guimiot, Thierry Jo Molina, Alexandre Moulin, Claudine Versaux-Botteri, Loïc Van Den Berghe, Francine Behar-Cohen, Alejandra Daruich, Eric Krejci, Matthieu P. Robert, Benoit Terris, Dominique Marchant, Christophe Klein, Maud Valensi, Laurent Jonet, Frederic Mascarelli, Dominique Bremond-Gignac, Marc Abitbol, EA no 2502 du ministère de la Recherche, de l'Enseignement Supérieur et la Technologie, Université Paris Descartes - Paris 5 (UPD5)-CERTO, Hormones, facteurs de croissance et physiopathologie vasculaire, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Développement, vieillissement et pathologie de la rétine, Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Ophthalmology, Université de Lausanne (UNIL), Biologie des Jonctions Neuromusculaires Normales et Pathologiques (U686), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), MINES ParisTech - École nationale supérieure des mines de Paris, Hôpital Robert Debré, Département de Pathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), CHU Necker - Enfants Malades [AP-HP], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), IFR 31 Louis Bugnard (IFR 31), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: Male, Pathology, medicine.medical_specialty, genetic structures, [SDV]Life Sciences [q-bio], Blotting, Western, Retinal Pigment Epithelium, In situ hybridization, Biology, 03 medical and health sciences, Cellular and Molecular Neuroscience, SOX2, medicine, Animals, Humans, In Situ Hybridization, ComputingMilieux_MISCELLANEOUS, Adaptor Proteins, Signal Transducing, Aged, 030304 developmental biology, 0303 health sciences, Retina, Retinal pigment epithelium, 030305 genetics & heredity, Wnt signaling pathway, Gene Expression Regulation, Developmental, Eye Diseases, Hereditary, Immunohistochemistry, eye diseases, Sensory Systems, Rats, 3. Good health, Disease Models, Animal, Ophthalmology, medicine.anatomical_structure, Child, Preschool, Eye development, RNA, Female, sense organs, PAX6, Immunostaining
Abstract: This study was conducted in order to study Sostdc1 expression in rat and human developing and adult eyes.Using the yeast signal sequence trap screening method, we identified the Sostdc1 cDNA encoding a protein secreted by the adult rat retinal pigment epithelium. We determined by in situ hybridization, RT-PCR, immunohistochemistry, and western blot analysis Sostdc1 gene and protein expression in developing and postnatal rat ocular tissue sections. We also investigated Sostdc1 immunohistolocalization in developing and adult human ocular tissues.We demonstrated a prominent Sostdc1 gene expression in the developing rat central nervous system (CNS) and eyes at early developmental stages from E10.5 days postconception (dpc) to E13 dpc. Specific Sostdc1 immunostaining was also detected in most adult cells of rat ocular tissue sections. We also identified the rat ocular embryonic compartments characterized by a specific Sostdc1 immunohistostaining and specific Pax6, Sox2, Otx2, and Vsx2 immunohistostaining from embryonic stages E10.5 to E13 dpc. Furthermore, we determined the localization of SOSTDC1 immunoreactivity in ocular tissue sections of developing and adult human eyes. Indeed, we detected SOSTDC1 immunostaining in developing and adult human retinal pigment epithelium (RPE) and neural retina (NR) as well as in several developing and adult human ocular compartments, including the walls of choroidal and scleral vessels. Of utmost importance, we observed a strong SOSTDC1 expression in a pathological ocular specimen of type 2 Peters' anomaly complicated by retinal neovascularization as well in the walls ofother pathological extra-ocular vessels. CONCLUSION: As rat Sostdc1 and human SOSTDC1 are dual antagonists of the Wnt/β-catenin and BMP signaling pathways, these results underscore the potential crucial roles of these pathways and their antagonists, such as Sostdc1 and SOSTDC1, in developing and adult mammalian normal eyes as well as in syndromic and nonsyndromic congenital eye diseases.
Published: 2019

2. Pancreatic preneoplastic lesions plasma signatures and biomarkers based on proteome profiling of mouse models

Author: Jérémy Nigri, Richard Tomasini, Frédéric Lopez, Frédéric Pont, Talal Al Saati, Aïcha El-Mrani, Pierre Cordelier, Julie Guillermet-Guibert, Véronique Gigoux, Marlène Dufresne, Laetitia Ligat, Romain Baer, Nathalie Saint-Laurent, Sébastien Déjean, Surfaces Cellulaires et Signalisation chez les Végétaux (SCSV), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie et Pathologie Digestive, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR 31 Louis Bugnard (IFR 31), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'anatomie et cytologie pathologiques [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Institut de Mathématiques de Toulouse UMR5219 (IMT), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), IFR 31 Louis Bugnard (IFR 31), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cancer Research, Pathology, medicine.medical_specialty, Proteome, endocrine system diseases, Colorectal cancer, pancreatic cancer, Protein Array Analysis, Pancreatic Intraepithelial Neoplasia, Mice, 03 medical and health sciences, Prostate cancer, proteomics, 0302 clinical medicine, [MATH.MATH-ST]Mathematics [math]/Statistics [math.ST], Biomarkers, Tumor, Animals, Medicine, Molecular Diagnostics, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, business.industry, Carcinoma in situ, ITIH, complement C3, medicine.disease, genetically engineered mouse model, Neoplasm Proteins, 3. Good health, Pancreatic Neoplasms, Disease Models, Animal, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer cell, biomarker, PanIN, Peptides, business, Pancreas, Liver cancer, Precancerous Conditions, Carcinoma in Situ, alpha-2-macroglobulin, Carcinoma, Pancreatic Ductal
Abstract: Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with a mortality that is almost identical to incidence. Because early detected PDAC is potentially curable, blood-based biomarkers that could detect currently developing neoplasia would improve patient survival and management. PDAC develops from pancreatic intraepithelial neoplasia (PanIN) lesions, graded from low grade (PanIN1) to high grade (PanIN3). We made the hypothesis that specific proteomic signatures from each precancerous stage exist and are detectable in plasma. Methods: We explored the peptide profiles of microdissected PanIN cells and of plasma samples corresponding to the different PanIN grade from genetically engineered mouse models of PDAC using capillary electrophoresis coupled to mass spectrometry (CE-MS) and Chip-MS/MS. Results: We successfully characterised differential peptides profiles from PanIN microdissected cells. We found that plasma from tumor-bearing mice and age-matched controls exhibit discriminative peptide signatures. We also determined plasma peptide signatures corresponding to low- and high-grade precancerous step present in the mice pancreas using the two mass spectrometry technologies. Importantly, we identified biomarkers specific of PanIN3. Conclusions: We demonstrate that benign and advanced PanIN lesions display distinct plasma peptide patterns. This strongly supports the perspectives of developing a non-invasive screening test for prediction and early detection of PDAC.
Published: 2015

3. First-in-man Phase 1 Clinical Trial of Gene Therapy for Advanced Pancreatic Cancer: Safety, Biodistribution, and Preliminary Clinical Findings

Author: Fabienne Vernejoul, Gérard Tiraby, Frédéric Martins, Naïma Hanoun, Laetitia Ligat, Hubert Lulka, Pierre Cordelier, Barbara Bournet, Aline Meulle, Sébastien Déjean, Odile Barbey, Rosine Guimbaud, Marion Gayral, Gilles Cambois, Marlène Dufresne, Philippe Otal, Louis Buscail, Fabian Gross, Frédéric Lopez, Frédéric Pont, Jérôme Torrisani, Nathalie Saint-Laurent, Alix Vignolle-Vidoni, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie et Pathologie Digestive, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de pharmacologie et de biologie structurale (IPBS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Surfaces Cellulaires et Signalisation chez les Végétaux (SCSV), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Mathématiques de Toulouse UMR5219 (IMT), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Plateforme GeT (Génome et Transcriptome), Génopole Toulouse, Institut National de la Recherche Agronomique (INRA), Laboratoire de Biothérapie, CHU Toulouse [Toulouse], Institut Claudius Regaud, CRLCC Institut Claudius Regaud, Department of Radiology, InvivoGen, INVIVOGEN, IFR 31 Louis Bugnard (IFR 31), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Génome et Transcriptome - Plateforme Génomique (GeT-PlaGe), Institut National de la Recherche Agronomique (INRA)-Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Module Biothérapies, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service Radiologie et imagerie médicale - Rangueil / Larrey [CHU Toulouse], Pôle imagerie médicale [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), and Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: Male, Endoscopic ultrasound, Oncology, medicine.medical_specialty, Genetic enhancement, medicine.medical_treatment, Phases of clinical research, Pharmacology, 03 medical and health sciences, 0302 clinical medicine, [MATH.MATH-ST]Mathematics [math]/Statistics [math.ST], Pancreatic cancer, Internal medicine, Drug Discovery, medicine, Genetics, Humans, Tissue Distribution, Adverse effect, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Aged, 030304 developmental biology, 0303 health sciences, Chemotherapy, medicine.diagnostic_test, business.industry, Genetic Therapy, Middle Aged, medicine.disease, Gemcitabine, 3. Good health, Pancreatic Neoplasms, Clinical trial, 030220 oncology & carcinogenesis, Molecular Medicine, Original Article, Female, business, medicine.drug
Abstract: This phase 1 trial was aimed to determine the safety, pharmacokinetics, and preliminary clinical activity of CYL-02, a nonviral gene therapy product that sensitizes pancreatic cancer cells to chemotherapy. CYL-02 was administrated using endoscopic ultrasound in 22 patients with pancreatic cancer that concomitantly received chemotherapy (gemcitabine). The maximum-tolerated dose (MTD) exceeded the maximal feasible dose of CYL-02 and was not identified. Treatment-related toxicities were mild, without serious adverse events. Pharmacokinetic analysis revealed a dose-dependent increase in CYL-02 DNA exposure in blood and tumors, while therapeutic RNAs were detected in tumors. No objective response was observed, but nine patients showed stable disease up to 6 months following treatment and two of these patients experienced long-term survival. Panels of plasmatic microRNAs and proteins were identified as predictive of gene therapy efficacy. We demonstrate that CYL-02 nonviral gene therapy has a favorable safety profile and is well tolerated in patients. We characterize CYL-02 biodistribution and demonstrate therapeutic gene expression in tumors. Treated patients experienced stability of disease and predictive biomarkers of response to treatment were identified. These promising results warrant further evaluation in phase 2 clinical trial.
Published: 2015
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4. Hypoxia Inhibits Cavin-1 and Cavin-2 Expression and Down-Regulates Caveolae in Adipocytes

Author: Claire Regazzetti, Yannick Le Marchand-Brustel, Philippe Gual, Karine Dumas, Philippe Valet, Pascal Peraldi, Jean-François Tanti, Faustine Pastor, S. Bonnafous, Soazig Le Lay, Sophie Giorgetti-Peraldi, Sandra Lacas-Gervais, Albert Tran, Mireille Cormont, Isabelle Dugail, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre méditerranéen de médecine moléculaire (C3M), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Joint Centre for Applied Electron Microscopy, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Signalisation moléculaire et obésité, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Stress Oxydant et Pathologies Métaboliques (SOPAM), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de recherche sur les obésités, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle Digestif, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Centre Hospitalier Universitaire de Nice (CHU Nice), Centre méditérannéen de médecine moléculaire (C3M), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and SOLETI, Raffaella
Subjects: Male, [SDV.BA] Life Sciences [q-bio]/Animal biology, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Adipose tissue, Mice, 0302 clinical medicine, Endocrinology, Caveolae, Adipocytes, RNA, Small Interfering, [SDV.BDD]Life Sciences [q-bio]/Development Biology, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, biology, [SDV.BA]Life Sciences [q-bio]/Animal biology, RNA-Binding Proteins, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, [SDV] Life Sciences [q-bio], [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, 030220 oncology & carcinogenesis, Female, RNA Interference, medicine.symptom, Signal Transduction, Cavin, medicine.medical_specialty, Down-Regulation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 03 medical and health sciences, Insulin resistance, 3T3-L1 Cells, Internal medicine, medicine, Animals, Humans, Gene silencing, Obesity, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, Insulin, Membrane Proteins, Phosphate-Binding Proteins, Hypoxia (medical), Hypoxia-Inducible Factor 1, alpha Subunit, medicine.disease, Mice, Inbred C57BL, Oxygen, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Insulin receptor, biology.protein, Carrier Proteins, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: During obesity, a hypoxic state develops within the adipose tissue, resulting in insulin resistance. To understand the underlying mechanism, we analyzed the involvement of caveolae because they play a crucial role in the activation of insulin receptors. In the present study, we demonstrate that in 3T3-L1 adipocytes, hypoxia induces the disappearance of caveolae and inhibits the expression of Cavin-1 and Cavin-2, two proteins necessary for the formation of caveolae. In mice, hypoxia induced by the ligature of the spermatic artery results in the decrease of cavin-1 and cavin-2 expression in the epididymal adipose tissue. Down-regulation of the expression of cavins in response to hypoxia is dependent on hypoxia-inducible factor-1. Indeed, the inhibition of hypoxia-inducible factor-1 restores the expression of cavins and caveolae formation. Expression of cavins regulates insulin signaling because the silencing of cavin-1 and cavin-2 impairs insulin signaling pathway. In human, cavin-1 and cavin-2 are decreased in the sc adipose tissue of obese diabetic patients compared with lean subjects. Moreover, the expression of cavin-2 correlates negatively with the homeostatic model assessment index of insulin resistance and glycated hemoglobin level. In conclusion, we propose a new mechanism in which hypoxia inhibits cavin-1 and cavin-2 expression, resulting in the disappearance of caveolae. This leads to the inhibition of insulin signaling and the establishment of insulin resistance.
Published: 2015

5. Muscle ectopic fat deposition contributes to anabolic resistance in obese sarcopenic old rats through e <scp>IF</scp> 2α activation

Author: Jean-Michel Chardigny, Jean-François Landrier, Joan Tordjman, Nicolas Tardif, Véronique Patrac, Yves Boirie, Stéphane Walrand, Jérôme Salles, Christophe Giraudet, Marie-Laure Collin, Christelle Guillet, Justine Bertrand-Michel, Sophie Reggio, Carole Migné, Unité de Nutrition Humaine (UNH), Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université-Institut National de la Recherche Agronomique (INRA), UMRS 872 équipe 7, Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, obésité et risque thrombotique (NORT), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), U 563, Institut Claude de Préval (ICP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Nutrition Clinique, CHU Clermont-Ferrand, ANR LIPAGE Project, Clermont Université-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Recherche Agronomique (INRA), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Clermont-Ferrand, Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ProdInra, Archive Ouverte, Unité de Nutrition Humaine ( UNH ), Institut National de la Recherche Agronomique ( INRA ) -Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Clermont Université, Centre de Recherche des Cordeliers ( CRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Nutrition, obésité et risque thrombotique ( NORT ), Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Institut National de la Santé et de la Recherche Médicale-Centre Hospitalier Universitaire de Purpan ( CHU Purpan ) - ( IFR 30 )
Subjects: Male, obesity, Aging, protein synthesis, Anabolism, muscle, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, Eukaryotic Initiation Factor-2, Adipose tissue, high-fat diet, sarcopenia, ceramide, elF2α signaling, eIF-2 Kinase, chemistry.chemical_compound, 0302 clinical medicine, Adipocyte, Myocyte, 0303 health sciences, Myogenesis, obésité, sensibilité à l'insuline, Adipose Tissue, Alimentation et Nutrition, Signal Transduction, medicine.medical_specialty, Ceramide, 030209 endocrinology & metabolism, Biology, Ceramides, Diet, High-Fat, 03 medical and health sciences, Insulin resistance, Downregulation and upregulation, sarcopenie, Internal medicine, eIF2α signaling, medicine, Food and Nutrition, Animals, Rats, Wistar, Muscle, Skeletal, 030304 developmental biology, Original Articles, Cell Biology, medicine.disease, Rats, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Disease Models, Animal, Endocrinology, chemistry, Insulin Resistance, muscle protein synthesis, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: Obesity and aging are characterized by decreased insulin sensitivity (IS) and muscle protein synthesis. Intramuscular ceramide accumulation has been implicated in insulin resistance during obesity. We aimed to measure IS, muscle ceramide level, protein synthesis, and activation of intracellular signaling pathways involved in translation initiation in male Wistar young (YR, 6-month) and old (OR, 25-month) rats receiving a low- (LFD) or a high-fat diet (HFD) for 10 weeks. A corresponding cellular approach using C2C12 myotubes treated with palmitate to induce intracellular ceramide deposition was taken. A decreased ability of adipose tissue to store lipids together with a reduced adipocyte diameter and a development of fibrosis were observed in OR after the HFD. Consequently, OR fed the HFD were insulin resistant, showed a strong increase in intramuscular ceramide level and a decrease in muscle protein synthesis associated with increased eIF2alpha phosphorylation. The accumulation of intramuscular lipids placed a lipid burden on mitochondria and created a disconnect between metabolic and regulating pathways in skeletal muscles of OR. In C2C12 cells, palmitate-induced ceramide accumulation was associated with a decreased protein synthesis together with upregulated eIF2alpha phosphorylation. In conclusion, a reduced ability to expand adipose tissues was found in OR, reflecting a lower lipid buffering capacity. Muscle mitochondrial activity was affected in OR conferring a reduced ability to oxidize fatty acids entering the muscle cell. Hence, OR were more prone to ectopic muscle lipid accumulation than YR, leading to decreased muscle protein anabolism. This metabolic change is a potential therapeutic target to counter sarcopenic obesity.
Published: 2014

6. The Intestinal Glucose–Apelin Cycle Controls Carbohydrate Absorption in Mice

Author: Isabelle Castan-Laurell, Bernard Masri, Estelle Wanecq, Yassine Sakar, Cédric Dray, Sylvain Galvani, Philippe Valet, Larry S. Barak, Anne Nègre-Salvayre, Robert Ducroc, Luc Garrigues, Danièle Daviaud, Bernard Monsarrat, Odile Burlet-Schiltz, Claire Vinel, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Department of Cell Biology, Duke University Medical Center, This work was funded by Inserm, Université Paris Diderot Paris 7 and Université Paul 19 Sabatier. Y.S. was a recipient of Fondation pour la Recherche Médicale (FRM)., Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Hormones, facteurs de croissance et physiopathologie vasculaire, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR 31 Louis Bugnard (IFR 31), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, [SDV]Life Sciences [q-bio], Mass Spectrometry, Intestinal absorption, Mice, Random Allocation, 0302 clinical medicine, AMP-activated protein kinase, Reference Values, Glucose homeostasis, Sodium-Glucose Transporter 1, ComputingMilieux_MISCELLANEOUS, Glucose Transporter Type 2, 0303 health sciences, Microscopy, Confocal, diabetes, biology, Gastroenterology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Immunohistochemistry, Apelin, apelin, Intercellular Signaling Peptides and Proteins, medicine.medical_specialty, mouse model, Blotting, Western, Carbohydrates, 030209 endocrinology & metabolism, Carbohydrate metabolism, 03 medical and health sciences, Internal medicine, medicine, Animals, 030304 developmental biology, Analysis of Variance, adipokine, Hepatology, Glucose transporter, Biological Transport, Mice, Inbred C57BL, Disease Models, Animal, Glucose, Endocrinology, Intestinal Absorption, biology.protein, GLUT2, Calorie intake, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Chromatography, Liquid
Abstract: International audience; BACKGROUND & AIMS: Glucose is absorbed into intestine cells via the sodium glucose transporter 1 (SGLT-1) and glucose transporter 2 (GLUT2); various peptides and hormones control this process. Apelin is a peptide that regulates glucose homeostasis and is produced by proximal digestive cells; we studied whether glucose modulates apelin secretion by enterocytes and the effects of apelin on intestinal glucose absorption. METHODS: We characterized glucose-related luminal apelin secretion in vivo and ex vivo by mass spectroscopy and immunologic techniques. The effects of apelin on (14)C-labeled glucose transport were determined in jejunal loops and in mice following apelin gavage. We determined levels of GLUT2 and SGLT-1 proteins and phosphorylation of AMPKα2 by immunoblotting. The net effect of apelin on intestinal glucose transepithelial transport was determined in mice. RESULTS: Glucose stimulated luminal secretion of the pyroglutaminated apelin-13 isoform ([Pyr-1]-apelin-13) in the small intestine of mice. Apelin increased specific glucose flux through the gastric epithelial barrier in jejunal loops and in vivo following oral glucose administration. Conversely, pharmacologic apelin blockade in the intestine reduced the increased glycemia that occurs following oral glucose administration. Apelin activity was associated with phosphorylation of AMPKα2 and a rapid increase of the GLUT2/SGLT-1 protein ratio in the brush border membrane. CONCLUSIONS: Glucose amplifies its own transport from the intestinal lumen to the bloodstream by increasing luminal apelin secretion. In the lumen, active apelin regulates carbohydrate flux through enterocytes by promoting AMPKα2 phosphorylation and modifying the ratio of SGLT-1:GLUT2. The glucose-apelin cycle might be pharmacologically handled to regulate glucose absorption and assess better control of glucose homeostasis.
Published: 2013

7. Oxidized Low-Density Lipoproteins Trigger Endoplasmic Reticulum Stress in Vascular Cells

Author: Sanson, Marie, Augé, Nathalie, Vindis, Cécile, Muller, Carole, Bando, Yoshio, Thiers, Jean-Claude, Marachet, Marie-Agn&#232, s, Žarković, Kamelija, Sawa, Yoshiki, Salvayre, Robert, N&#232, gre-Salvayre, Anne, Simon, Marie Francoise, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Anatomy, Asahikawa Medical College, Département de biologie vasculaire, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Division of Pathology, University of Zagreb, Department of Surgery, Osaka University [Osaka], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], and University of Osaka
Subjects: MESH: Lipoproteins, LDL, Physiology, [SDV]Life Sciences [q-bio], Apoptosis, Endoplasmic Reticulum, MESH: Atherosclerosis, 0302 clinical medicine, MESH: Endothelial Cells, MESH: Proteins, Enzyme Inhibitors, MESH: Stress, Physiological, Endoplasmic Reticulum Chaperone BiP, Ketocholesterols, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Kinase, MESH: Ketocholesterols, Free Radical Scavengers, Cell biology, Lipoproteins, LDL, [SDV] Life Sciences [q-bio], Biochemistry, MESH: Enzyme Inhibitors, 030220 oncology & carcinogenesis, lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine, MESH: Oxygen, XBP1, KDEL, Cysteine Proteinase Inhibitors, In Vitro Techniques, MESH: Cysteine Proteinase Inhibitors, 03 medical and health sciences, MESH: Acetylcysteine, ER stress, apoptosis, ORP150, oxidized LDL, atherosclerosis, Lipid oxidation, Stress, Physiological, MESH: Endoplasmic Reticulum, Humans, HSP70 Heat-Shock Proteins, 030304 developmental biology, Aldehydes, MESH: Humans, ATF6, MESH: Apoptosis, Endoplasmic reticulum, JNK Mitogen-Activated Protein Kinases, MESH: Biological Markers, Endothelial Cells, Proteins, MESH: JNK Mitogen-Activated Protein Kinases, Atherosclerosis, Acetylcysteine, Oxygen, Chaperone (protein), MESH: Free Radical Scavengers, biology.protein, Unfolded protein response, MESH: Aldehydes, Biomarkers, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Oxidized low-density lipoproteins (oxLDLs) trigger various biological responses potentially involved in atherogenesis. Disturbing endoplasmic reticulum (ER) function results in ER stress and unfolded protein response, which tends to restore ER homeostasis but switches to apoptosis when ER stress is prolonged. We aimed to investigate whether ER stress is induced by oxLDLs and can be prevented by the ER-associated chaperone ORP150 (150-kDa oxygen-regulated protein). oxLDLs and the lipid oxidation products 7-ketocholesterol and 4-hydroxynonenal induce ER stress in human endothelial cells (HMEC-1), characterized by the activation of ER stress sensors (phosphorylation of Ire1α and PERK, nuclear translocation of ATF6) and of their subsequent pathways (eukaryotic initiation factor 2α phosphorylation, expression of XBP1/spliced XBP1, CHOP, and KDEL chaperones GRP78, GRP94, ORP150). ER stress was inhibited by the antioxidant N -acetylcysteine. In advanced atherosclerotic lesions, phospho-Ire1α, KDEL, and ORP150 staining were localized in lipid-rich areas with 4-hydroxynonenal adducts and CD68-positive macrophagic cells. By comparison, staining for 4-hydroxynonenal, phospho-Ire1α, KDEL, and ORP were faint and more diffuse in intimal hyperplasia. ER stress takes part in the apoptotic effect of oxLDLs, through the Ire1α/c-Jun N-terminal kinase pathway, as assessed by the protective effect of specific small interfering RNAs and c-Jun N-terminal kinase inhibitor. Forced expression of the chaperone ORP150 reduced both oxLDL-induced ER stress and apoptosis. ER stress markers and ORP150 chaperone are expressed in areas containing oxLDLs in atherosclerotic lesions and are induced by oxLDLs and oxidized lipids in cultured cells. The forced expression of ORP150 highlights its new protective role against oxLDL-induced ER stress and subsequent apoptosis.
Published: 2009

8. Reduced D2-mediated signaling activity and trans-synaptic upregulation of D1 and D2 dopamine receptors in mice overexpressing the dopamine transporter

Author: Marc G. Caron, Raul R. Gainetdinov, Bernard Masri, Valentina Ghisi, Amy J. Ramsey, Ali Salahpour, Hormones, facteurs de croissance et physiopathologie vasculaire, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Interdisciplinaire de Recherche Ions Lasers (CIRIL), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), and Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: medicine.medical_specialty, Quinpirole, Apomorphine, [SDV]Life Sciences [q-bio], Dopamine Plasma Membrane Transport Proteins, Mice, Transgenic, Article, [SCCO]Cognitive science, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Dopamine receptor D1, Dopamine, Internal medicine, Dopamine receptor D2, medicine, Animals, Enzyme Inhibitors, Extracellular Signal-Regulated MAP Kinases, Neurotransmitter, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Dopamine transporter, Mice, Knockout, Analysis of Variance, 0303 health sciences, biology, Receptors, Dopamine D2, [SCCO.NEUR]Cognitive science/Neuroscience, Receptors, Dopamine D1, Dopaminergic, Cell Biology, Benzazepines, Corpus Striatum, Up-Regulation, Mice, Inbred C57BL, alpha-Methyltyrosine, Endocrinology, nervous system, chemistry, Dopamine receptor, Dopamine Agonists, biology.protein, Proto-Oncogene Proteins c-akt, 030217 neurology & neurosurgery, Signal Transduction, medicine.drug
Abstract: The dopamine transporter (DAT) regulates the temporal and spatial actions of dopamine by reuptaking this neurotransmitter into the presynaptic neurons. We recently generated transgenic mice overexpressing DAT (DAT-tg) that have a 3-fold increase in DAT protein levels which results in a 40% reduction of the extracellular DA concentration in the striatum. The aim of this study was to examine the effect of this reduction in dopaminergic tone on postsynaptic responses mediated by dopamine receptors. We report here that DAT-tg mice have increased levels of striatal D1 (30%) and D2 (approximately 60%) dopamine receptors with D1 receptor signaling components not significantly altered, as evidenced by unaffected basal or stimulated levels of phospho-GluR1 (Ser845) and phospho-ERK2. However, the novel D2 mediated Akt signaling is markedly altered in DAT-tg animals. In particular, there is a 300% increase in the basal levels of phospho-Akt in the striatum of DAT-tg, reflecting the reduced extracellular dopamine tone in these animals. This increase in basal pAkt levels can be pharmacologically recapitulated by partial dopamine depletion in WT mice treated with the selective tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (alpha-MPT). Behaviorally, DAT-tg animals demonstrate an augmented synergistic interaction between up-regulated D1 and D2 receptors, which results in increased climbing behavior in transgenic mice after stimulation with either apomorphine or a co-administration of selective D1 and D2 receptor agonists. In sum, our study reveals that hypodopaminegia caused by up-regulation of DAT results in significant alterations at postsynaptic receptor function with most notable dysregulation at the level of D2 receptor signaling.
Published: 2009

9. Low dietary inorganic phosphate affects the brain by controlling apoptosis, cell cycle and protein translation

Author: George R. Beck, Anne-Catherine Prats, Yeon-Sook Lee, Jung-Taek Kwon, Kee-Ho Lee, Myung-Haing Cho, Gil-Hwan An, Soon-Kyung Hwang, Hua Jin, Dominique Morello, Department of Applied Chemistry, Chungju Campus, College of Natural Sciences, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), College of Human Ecology [Seoul] (HumEc), Seoul National University [Seoul] (SNU), Department of Medicine, National University of Singapore (NUS), Laboratoire d'Automatique, Génie Informatique et Signal (LAGIS), Université de Lille, Sciences et Technologies-Centrale Lille-Centre National de la Recherche Scientifique (CNRS), Dauphine Recherches en Management (DRM), Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Hormones, facteurs de croissance et physiopathologie vasculaire, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre de biologie du développement (CBD), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut für Anästhesiologie und Operative Intensivmedizin, University Hospital, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Phosphatase, Apoptosis, Mice, Transgenic, Biology, Biochemistry, Phosphates, Mice, 03 medical and health sciences, 0302 clinical medicine, Eukaryotic translation, Luciferases, Firefly, Animals, Initiation factor, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, Protein kinase B, Luciferases, Renilla, 030304 developmental biology, Brain Chemistry, 0303 health sciences, Nutrition and Dietetics, Sodium-Phosphate Cotransporter Proteins, Type III, Binding protein, Cell Cycle, EIF4E, Brain, Gene Expression Regulation, Developmental, Cell cycle, Diet, Internal ribosome entry site, Protein Biosynthesis, Proto-Oncogene Proteins c-akt, 030217 neurology & neurosurgery, Signal Transduction
Abstract: Inorganic phosphate (P(i)) plays a key role in diverse physiologic functions. In a previous study, we showed that high dietary P(i) perturbs brain growth through Akt/ERK signaling in developing mice. However, no study has investigated the response of the brain to low dietary P(i). In this study, we addressed this question by studying the effects of low dietary P(i) on the cerebrum of developing mice. Two-week-old weaned mice were fed with a low phosphate diet for 4 weeks. At the end of the study, their cerebrum was dissected and signals important for protein translation, apoptosis and cell cycle were examined. The low phosphate diet did not cause physiologically significant changes; it increased the protein expression of phosphatase and tensin homolog deleted on chromosome 10 but decreased Akt activity. In addition, expression of eukaryotic translation initiation factor binding protein coupled with increased complex formation of eukaryotic translation initiation factor 4E/eukaryotic translation initiation factor binding protein 1 was induced in the cerebrum by low phosphate, leading to reduced cap-dependent protein translation. Finally, low phosphate facilitated apoptosis and suppressed signals important for the cell cycle in the cerebrum of dual-luciferase reporter mice. In summary, our results showed that a low phosphate diet affects the brain by controlling protein translation, apoptosis and cell cycle in developing mice. Our results support the hypothesis that P(i) works as a stimulus capable of increasing or decreasing several pivotal genes for normal development and suggest that regulation of P(i) consumption is important in maintaining a healthy life.
Published: 2008

10. Critical Role for Sphingosine Kinase-1 in Regulating Survival of Neuroblastoma Cells Exposed to Amyloid-β Peptide

Author: Marie-Lise Maddelein, Virginie Garcia, Dimitri Pchejetski, Leyre Brizuela, Marie-Bernadette Delisle, Marie-Françoise Altié, A. Gomez-Brouchet, Olivier Cuvillier, Service d'anatomie pathologique et histologie-cytologie [Rangueil], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie et de biologie structurale (IPBS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Biologie du Fruit, Institut National de la Recherche Agronomique (INRA), and Institut des Maladies Métaboliques et Cardiovasculaires (I2MC)
Subjects: Programmed cell death, Ceramide, Cell Survival, Amyloid beta, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.medical_treatment, MESH: Insulin-Like Growth Factor I, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Line, Transforming Growth Factor beta1, MESH: Transforming Growth Factor beta1, Neuroblastoma, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, medicine, Humans, Gene silencing, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Insulin-Like Growth Factor I, MESH: Peptide Fragments, 030304 developmental biology, Pharmacology, 0303 health sciences, MESH: Humans, Amyloid beta-Peptides, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], biology, Sphingosine, Growth factor, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, MESH: Neuroblastoma, MESH: Phosphotransferases (Alcohol Group Acceptor), MESH: Amyloid beta-Peptides, Peptide Fragments, MESH: Cell Line, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Cell biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Phosphotransferases (Alcohol Group Acceptor), MESH: Cell Survival, Sphingosine kinase 1, chemistry, Cell culture, biology.protein, Molecular Medicine, [SDV.IB]Life Sciences [q-bio]/Bioengineering, 030217 neurology & neurosurgery
Abstract: International audience; We examined the role of sphingosine kinase-1 (SphK1), a critical regulator of the ceramide/sphingosine 1-phosphate (S1P) biostat, in the regulation of death and survival of SH-SY5Y neuroblastoma cells in response to amyloid beta (Abeta) peptide (25-35). Upon incubation with Abeta, SH-SY5Y cells displayed a marked down-regulation of SphK1 activity coupled with an increase in the ceramide/S1P ratio followed by cell death. This mechanism was redox-sensitive; N-acetylcysteine totally abrogated the down-regulation of SphK1 activity and strongly inhibited Abeta-induced cell death. SphK1 overexpression impaired the cytotoxicity of Abeta, whereas SphK1 silencing by RNA interference mimicked Abeta-induced cell death, thereby establishing a critical role for SphK1. We further demonstrated that SphK1 could mediate the well established cytoprotective action of insulin-like growth factor (IGF-I) against Abeta toxicity. A dominant-negative form of SphK1 or its pharmacological inhibition not only abrogated IGF-I-triggered stimulation of SphK1 but also hampered IGF-I protective effect. Similarly to IGF-I, the neuroprotective action of TGF-beta1 was also dependent on SphK1 activity; activation of SphK1 as well as cell survival were impeded by a dominant-negative form of SphK1. Taken together, these results provide the first illustration of SphK1 role as a critical regulator of death and survival of Abeta-treated cells.
Published: 2007

11. Longitudinal Analysis of Gene Expression in Porcine Skeletal Muscle After Post-Injection Local Injury

Author: Pierre-Louis Toutain, François Hatey, Pierre J. Ferré, Magali SanCristobal, Agnès Bonnet, Gwenola Tosser-Klopp, Laurence Liaubet, Didier Concordet, Emmanuelle Uro-Coste, Hervé P. Lefebvre, Physiologie et Toxicologie Expérimentales, Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Laboratoire de Génétique Cellulaire (LGC), Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Simon, Marie Francoise, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), and Régulations cellulaires: lipidoses et atherosclerose.
Subjects: Male, Pathology, Time Factors, MESH: Thymosin, Swine, [SDV]Life Sciences [q-bio], Muscle Proteins, MESH: Collagen Type I, Pharmaceutical Science, Post injection, MESH: Down-Regulation, MESH: Collagen, MESH: Fibronectins, Gene expression, MESH: Up-Regulation, Osteonectin, MESH: Animals, Pharmacology (medical), MESH: Swine, Oligonucleotide Array Sequence Analysis, MESH: Muscle, Skeletal, 0303 health sciences, 030302 biochemistry & molecular biology, MESH: Injections, Intramuscular, Pathophysiology, Up-Regulation, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Matrix Metalloproteinase 2, Molecular Medicine, Collagen, MESH: Osteonectin, Intramuscular injection, MESH: ras Proteins, Biotechnology, medicine.medical_specialty, Down-Regulation, Biology, Injections, Intramuscular, Collagen Type I, MESH: Gene Expression Profiling, MESH: Muscle Proteins, 03 medical and health sciences, medicine, Animals, Muscle, Skeletal, Pathological, 030304 developmental biology, Pharmacology, Gene Expression Profiling, MESH: Time Factors, Organic Chemistry, Skeletal muscle, MESH: Male, Fibronectins, Collagen Type I, alpha 1 Chain, Thymosin, MESH: Matrix Metalloproteinase 2, Gene expression profiling, MESH: Oligonucleotide Array Sequence Analysis, Time course, ras Proteins
Abstract: International audience; PURPOSE: The purpose of this study is to describe the time course of gene expression in a skeletal muscle local injury induced by an intramuscular (IM) injection, and to compare the dynamics of gene expression with pathological events. MATERIALS AND METHODS: Ten piglets received 4 IM injections of propylene glycol in the longissimus dorsi muscles 6 h, 2, 7, and 21 days before euthanasia, where control and injected muscle sites were sampled for RNA isolation and microscopic examination. The hybridization of nylon cDNA microarrays was carried out with radioactive probes obtained from the muscle RNA. RESULTS: 153 genes were found under- or over-expressed at least once among the investigated time-conditions. The eight most discriminant genes were also identified: Two genes (GTP-binding protein RAD and Ankyrin repeat domain protein) were over-expressed at 6 h and six genes between 2 and 21 days (Osteonectin, Fibronectin, Matrix metalloproteinase-2, Collagen alpha 1(I) chain, Collagen alpha 2(I) chain, and Thymosin beta-4). Necrosis, inflammation and regeneration were observed through both the dynamics of gene expression profiles and through the microscopic examinations. CONCLUSION: Our data demonstrate that several pathways are involved in post-injection muscle injury, and that necrosis, inflammation and regeneration are not sequential but occur in parallel.
Published: 2007

12. Adipose TriGlyceride Lipase (ATGL) and Hormone-Sensitive Lipase (HSL) protein expression is decreased in the obese insulin resistant state

Author: Carine Valle, Egbert F. Smit, Ellen E. Blaak, Peter Arner, Wim H. M. Saris, Johan W. E. Jocken, Dominique Langin, Cecilia Holm, Gabby B. Hul, Humane Biologie, RS: NUTRIM School of Nutrition and Translational Research in Metabolism, RS: NUTRIM - R1 - Metabolic Syndrome, Department of Human Biology, Nutrition and Toxicology, Maastricht University [Maastricht]-Research Institute Maastricht, Unité de recherche sur les obésités, IFR 31 Louis Bugnard (IFR 31), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Division of Diabetes, Metabolism, and Endocrinology, Lund University [Lund], Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], This study has received support from NUGENOB (Nutrient-Gene Interaction in Human Obesity, Implications for Dietary Guidelines) supported by the European Commission (Contract QLK1-CT-2000-00618), HEPADIP (Hepatic and Adipose Tissue and Functions in the Metabolic Syndrome) supported by the European Commission as an integrated project under the 6th Framework Programme (Contract LSHM-CT-2005- 018734), and Swedish Research Council Project 112 84., European Project: 32591,HEPADIP, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], University of Lund, Simon, Marie Francoise, Hepatic and adipose tissue and functions in the metabolic syndrome - HEPADIP - 32591 - OLD, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Biopsy, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Clinical Biochemistry, Adipose tissue, Hormone-sensitive lipase, MESH: Regression Analysis, Biochemistry, MESH: Lipase, MESH: Biopsy, 0302 clinical medicine, Endocrinology, Hyperinsulinemia, MESH: Obesity, MESH: Diet, Reducing, 2. Zero hunger, 0303 health sciences, MESH: Middle Aged, MESH: Sterol Esterase, MESH: Gene Expression Regulation, Enzymologic, Leptin, food and beverages, Middle Aged, MESH: Insulin Resistance, Adipose Tissue, MESH: Hyperinsulinism, Regression Analysis, Female, MESH: Adipose Tissue, Adult, medicine.medical_specialty, Diet, Reducing, 030209 endocrinology & metabolism, Biology, Gene Expression Regulation, Enzymologic, MESH: Weight Loss, 03 medical and health sciences, Insulin resistance, Hyperinsulinism, Internal medicine, Weight Loss, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Obesity, RNA, Messenger, MESH: RNA, Messenger, 030304 developmental biology, MESH: Humans, Insulin, Biochemistry (medical), MESH: Adult, Lipase, Sterol Esterase, medicine.disease, MESH: Male, Adipose triglyceride lipase, Insulin Resistance, MESH: Female
Abstract: International audience; AIM/HYPOTHESIS: Obesity is associated with increased triacylglycerol (TAG) storage in adipose tissue and insulin resistance. The mobilization of stored TAG is mediated by hormone-sensitive lipase (HSL) and the recently discovered adipose triglyceride lipase (ATGL). The aim of the present study was to examine whether ATGL and HSL mRNA and protein expression are altered in insulin-resistant conditions. In addition, we investigated whether a possible impaired expression could be reversed by a period of weight reduction. METHODS: Adipose tissue biopsies were taken from obese subjects (n = 44) with a wide range of insulin resistance, before and just after a 10-wk hypocaloric diet. ATGL and HSL protein and mRNA expression was determined by Western blot and quantitative RT-PCR, respectively. RESULTS: Fasting insulin levels and the degree of insulin resistance (using the homeostasis model assessment index for insulin resistance) were negatively correlated with ATGL and HSL protein expression, independent of age, gender, fat cell size, and body composition. Both mRNA and protein levels of ATGL and HSL were reduced in insulin-resistant compared with insulin-sensitive subjects (P < 0.05). Weight reduction significantly decreased ATGL and HSL mRNA and protein expression. A positive correlation between the decrease in leptin and the decrease in ATGL protein level after weight reduction was observed. Finally, ATGL and HSL mRNA and protein levels seem to be highly correlated, indicating a tight coregulation and transcriptional control. CONCLUSIONS: In obese subjects, insulin resistance and hyperinsulinemia are strongly associated with ATGL and HSL mRNA and protein expression, independent of fat mass. Data on weight reduction indicated that also other factors (e.g. leptin) relate to ATGL and HSL protein expression.
Published: 2007

13. Apelin receptors: From signaling to antidiabetic strategy

Author: Carline Chaves-Almagro, Philippe Valet, Claude Knauf, Cédric Dray, Isabelle Castan-Laurell, Bernard Masri, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Hormones, facteurs de croissance et physiopathologie vasculaire, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3)
Subjects: medicine.medical_specialty, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Adipokine, Type 2 diabetes, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Bioinformatics, Receptors, G-Protein-Coupled, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Animals, Humans, Hypoglycemic Agents, Amino Acid Sequence, Obesity, Receptor, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, G protein-coupled receptor, Apelin receptor, Pharmacology, 0303 health sciences, Lipid metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, Apelin, Endocrinology, Diabetes Mellitus, Type 2, Intercellular Signaling Peptides and Proteins, Signal transduction, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Signal Transduction
Abstract: The G protein-coupled receptor APJ and its cognate ligand, apelin, are widely expressed throughout human body. They are implicated in different key physiological processes such as angiogenesis, cardiovascular functions, fluid homeostasis and energy metabolism regulation. On the other hand, this couple ligand-receptor is also involved in the development and progression of different pathologies including diabetes, obesity, cardiovascular disease and cancer. Recently, a new endogenous peptidic ligand of APJ, named Elabela/Toddler, has been identified and shown to play a crucial role in embryonic development. Whereas nothing is yet known regarding Elabela/Toddler functions in adulthood, apelin has been extensively described as a beneficial adipokine regarding to glucose and lipid metabolism and is endowed with anti-diabetic and anti-obesity properties. Indeed, there is a growing body of evidence supporting apelin signaling as a novel promising therapeutic target for metabolic disorders (obesity, type 2 diabetes). In this review, we provide an overview of the pharmacological properties of APJ and its endogenous ligands. We also report the activity of peptidic and non-peptidic agonists and antagonists targeting APJ described in the literature. Finally, we highlight the important role of this signaling pathway in the control of energy metabolism at the peripheral level and in the central nervous system in both physiological conditions and during obesity or diabetes.
Published: 2015

14. Regulation of Autophagy by Sphingosine Kinase 1 and Its Role in Cell Survival during Nutrient Starvation

Author: Grégory Lavieu, Stéphane Carpentier, Joëlle Botti, Giusy Sala, Riccardo Ghidoni, Thierry Levade, Patrice Codogno, Francesca Scarlatti, Glycobiologie et signalisation cellulaire, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Biochemistry and Molecular Biology, San Paolo Medical School, Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Codogno, Patrice
Subjects: MESH: Ubiquitin-Activating Enzymes, Apoptosis, Ubiquitin-Activating Enzymes, Autophagy-Related Protein 7, Biochemistry, chemistry.chemical_compound, MESH: RNA, Small Interfering, Enzyme Inhibitors, RNA, Small Interfering, 2. Zero hunger, 0303 health sciences, biology, Hydrolysis, TOR Serine-Threonine Kinases, 030302 biochemistry & molecular biology, Cell biology, Phosphotransferases (Alcohol Group Acceptor), MESH: Cell Survival, Sphingosine kinase 1, MESH: Enzyme Inhibitors, Protein kinase B signaling, MESH: Phospholipase D, Beclin-1, Female, RNA Interference, MESH: Membrane Proteins, MESH: Hydrolysis, Programmed cell death, Ceramide, MESH: Adenine, MESH: Cell Line, Tumor, Cell Survival, Blotting, Western, Green Fluorescent Proteins, MESH: RNA Interference, Lactosylceramides, Breast Neoplasms, MESH: Starvation, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Ceramides, 03 medical and health sciences, MESH: Green Fluorescent Proteins, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Autophagy, Phospholipase D, Humans, MESH: Autophagy, MESH: Blotting, Western, MESH: Lactosylceramides, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Protein Kinases, Molecular Biology, Protein kinase B, 030304 developmental biology, MESH: Humans, Sphingosine, MESH: Apoptosis Regulatory Proteins, Adenine, MESH: Apoptosis, Membrane Proteins, Cell Biology, MESH: Phosphotransferases (Alcohol Group Acceptor), MESH: Ceramides, Sphingolipid, chemistry, Starvation, Cancer research, biology.protein, Apoptosis Regulatory Proteins, Protein Kinases, MESH: Female, MESH: Breast Neoplasms
Abstract: The sphingolipid ceramide induces macroautophagy (here called autophagy) and cell death with autophagic features in cancer cells. Here we show that overexpression of sphingosine kinase 1 (SK1), an enzyme responsible for the production of sphingosine 1-phosphate (S1P), in MCF-7 cells stimulates autophagy by increasing the formation of LC3-positive autophagosomes and the rate of proteolysis sensitive to the autophagy inhibitor 3-methyladenine. Autophagy was blocked in the presence of dimethylsphingosine, an inhibitor of SK activity, and in cells expressing a catalytically inactive form of SK1. In SK1(wt)-overexpressing cells, however, autophagy was not sensitive to fumonisin B1, an inhibitor of ceramide synthase. In contrast to ceramide-induced autophagy, SK1(S1P)-induced autophagy is characterized by (i) the inhibition of mammalian target of rapamycin signaling independently of the Akt/protein kinase B signaling arm and (ii) the lack of robust accumulation of the autophagy protein Beclin 1. In addition, nutrient starvation induced both the stimulation of autophagy and SK activity. Knocking down the expression of the autophagy protein Atg7 or that of SK1 by siRNA abolished starvation-induced autophagy and increased cell death with apoptotic hallmarks. In conclusion, these results show that SK1(S1P)-induced autophagy protects cells from death with apoptotic features during nutrient starvation.
Published: 2006

15. Production of Lysophosphatidic Acid in Blister Fluid: Involvement of a Lysophospholipase D Activity

Author: Josette Fauvel, Madie Fanguin, Sandra Grès, Hugues Chap, Jean-Pierre Salles, Jean-Sébastien Saulnier-Blache, Clotilde Cariven, Bertrand Perret, Juliette Mazereeuw-Hautier, Service de Dermatologie, CHU Toulouse [Toulouse], Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche sur les obésités, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Dermatologie [CHU Toulouse], Pôle Clinique des Voies respiratoires [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Saulnier-Blache, Jean Sébastien
Subjects: Keratinocytes, Male, wound healing, MESH: Multienzyme Complexes, Biochemistry, chemistry.chemical_compound, Blister, 0302 clinical medicine, MESH: Aged, 80 and over, Cell Movement, Lysophosphatidic acid, Pyrophosphatases, Receptors, Lysophosphatidic Acid, Keratinocyte migration, Receptor, skin and connective tissue diseases, MESH: Cell Movement, Cells, Cultured, Aged, 80 and over, MESH: Aged, 0303 health sciences, MESH: Middle Aged, biology, integumentary system, MESH: Comparative Study, Middle Aged, lysophospholipase D, MESH: Keratinocytes, 3. Good health, Cell biology, Phosphodiesterase I, 030220 oncology & carcinogenesis, Female, lipids (amino acids, peptides, and proteins), biological phenomena, cell phenomena, and immunity, Autotaxin, MESH: Cells, Cultured, Adult, blister fluid, medicine.medical_specialty, skin, MESH: Glycoproteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Dermatology, Article, MESH: Lysophospholipids, MESH: Blister, 03 medical and health sciences, Phospholipase A2, Multienzyme Complexes, Internal medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Platelet activation, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, Aged, Glycoproteins, 030304 developmental biology, MESH: Humans, Phosphoric Diester Hydrolases, Glucose-6-Phosphate Isomerase, MESH: Adult, Cell Biology, [SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology, MESH: Male, Endocrinology, chemistry, biology.protein, Alkylglycerophosphoethanolamine phosphodiesterase, Lysophospholipids, Wound healing, MESH: Phosphoric Diester Hydrolases, MESH: Female, lysophosphatidic acid, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, MESH: Autocrine Motility Factor
Abstract: Lysophosphatidic acid (LPA) is present in abundance in serum resulting from platelet activation and is also found in other biological fluids. LPA controls numerous cellular responses and plays a role in specific functions such as wound healing, especially in the skin. Nevertheless, its presence in the skin has never been investigated. Since re-epithelialization occurs after blister rupture, we tested the presence of endogenous LPA in blister fluid and investigated a possible mechanism for its biosynthesis and biological functions. Using a radioenzymatic assay, LPA was detected in 33 blister fluids originating from 24 bullous dermatoses, and at higher concentrations than in plasma. In parallel, blister fluids contained a lysophospholipase D (LPLD) activity but no detectable phospholipase A2 activity. The expressions of the LPLD autotaxin (ATX) and of LPA1-receptor (LPA1-R) were greatly increased in blister skin when compared with normal skin. Finally, LPA was found to have a positive effect on the migration of cultured keratinocytes. These results show that LPA is present in blister fluid synthesized by the LPLD ATX. Due to its ability to enhance keratinocyte migration, LPA in blister fluid could, via the LPA1-R, play an important role in re-epithelialization occurring after blister rupture.
Published: 2005
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16. Site specific alterations of adipose tissue mitochondria in 3′-azido-3′-deoxythymidine (AZT)-treated rats: An early stage in lipodystrophy?

Author: Louis Casteilla, Dominique Breilh, Sylvie Caspar-Bauguil, Jean-Baptiste Gordien, Bénédicte Salin, Stéphanie Hagry, Yvette Fernandez, Audrey Carrière, Jacques Schaeffer, Michel Rigoulet, Anne Galinier, Luc Pénicaud, Bertrand Beauvoit, Catherine Deveaud, Métabolisme Plasticité et Mitochondrie [lié à l'ex IFR 31] (LMPM), IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, medicine.medical_specialty, Mitochondrial DNA, Anti-HIV Agents, [SDV]Life Sciences [q-bio], Adipose tissue, White adipose tissue, Mitochondrion, Weight Gain, medicine.disease_cause, DNA, Mitochondrial, Biochemistry, Electron Transport Complex IV, 03 medical and health sciences, chemistry.chemical_compound, Internal medicine, Adipocyte, Pyruvic Acid, medicine, Animals, Citrate synthase, Rats, Wistar, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Pharmacology, 0303 health sciences, biology, 030306 microbiology, HIV-Associated Lipodystrophy Syndrome, medicine.disease, Mitochondria, Rats, 3. Good health, Oxidative Stress, Endocrinology, Adipose Tissue, Liver, chemistry, biology.protein, Lipodystrophy, Oxidation-Reduction, Zidovudine, Oxidative stress
Abstract: Although it is well accepted that treatment with nucleoside reverse transcriptase inhibitors (NRTIs) modifies fat metabolism and fat distribution in humans, the mechanisms underlying these modifications are not yet known. The present investigation examines the effects of chronic oral administration of 3'-azido-3'-deoxythymidine (AZT) on the mitochondrial metabolism and the redox status management of rat white adipose tissues originating from two anatomical sites, as well as of the rat liver. Results showed that AZT treatment induced differential effects on the mitochondrial functions depending on the anatomical localisation. Indeed, in inguinal adipose tissue, a significant decrease in the cytochrome c oxidase activity and in the mitochondrial DNA (mtDNA) content was observed, whereas the activity of citrate synthase, a mitochondrial protein exclusively encoded by the nucleus, was not affected. In contrast, no significant change in these parameters could be detected for epididymal tissue and for liver. In parallel, no oxidative stress could be detected after treatment, for both white adipose tissues and for liver, even though treated liver exhibited several modifications in redox management. Taken together, these data demonstrate differential mitochondrial effects of AZT on subcutaneous versus visceral white adipose tissue. Moreover, the decrease in mitochondrial oxidative capacity of inguinal adipocyte consecutive to AZT treatment is not primarily due to an oxidative stress per se, but rather to a depletion of the mtDNA content per cell.
Published: 2005

17. Apelin (65–77) Activates Extracellular Signal-Regulated Kinases via a PTX-Sensitive G Protein

Author: Bernard Masri, Bernard Knibiehler, Honoré Mazarguil, Hicham Lahlou, Yves Audigier, Hormones, facteurs de croissance et physiopathologie vasculaire, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées
Subjects: MAPK/ERK pathway, Indoles, Time Factors, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Mitogen-activated protein kinase kinase, Biochemistry, Receptors, G-Protein-Coupled, Maleimides, Mice, 0302 clinical medicine, Cricetinae, Protein Isoforms, Virulence Factors, Bordetella, Enzyme Inhibitors, Phosphorylation, ComputingMilieux_MISCELLANEOUS, Genes, Dominant, Mitogen-Activated Protein Kinase 1, Apelin Receptors, 0303 health sciences, Mitogen-Activated Protein Kinase 3, Kinase, Recombinant Proteins, 3. Good health, Apelin, Intercellular Signaling Peptides and Proteins, Mitogen-Activated Protein Kinases, Plasmids, Protein Binding, Signal Transduction, Immunoblotting, Biophysics, Receptors, Cell Surface, CHO Cells, Biology, Transfection, Pertussis toxin, 03 medical and health sciences, Adipokines, GTP-Binding Proteins, Animals, Endothelium, Molecular Biology, Monomeric GTP-Binding Proteins, 030304 developmental biology, Apelin receptor, G protein-coupled receptor, Flavonoids, G protein-coupled receptor kinase, Dose-Response Relationship, Drug, Receptors, Dopamine D2, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Cyclic AMP-Dependent Protein Kinases, Molecular biology, Peptide Fragments, Protein Structure, Tertiary, Enzyme Activation, Pertussis Toxin, Type C Phospholipases, Mutation, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Carrier Proteins, 030217 neurology & neurosurgery
Abstract: We report here that apelin (65–77) induces activation of extracellular-regulated kinases (ERKs) in Chinese hamster ovary (CHO) cells expressing the msr/apj receptor. This concentration-dependent activation was transient, peaking at 5 min. Pretreatment of CHO cells with pertussis toxin fully abrogated ERK phosphorylation, whereas overexpression of the β-adrenergic receptor kinase-1 C-terminal fragment did not alter ERK activation. Transfection with a dominant-negative mutant of Ras was without effect on ERK activation, whereas an inhibitor of many protein kinase C isoforms, GF109203X, strongly decreased it. These results demonstrate that stimulation of the murine msr/apj receptor promotes ERK activation via the α subunit of a pertussis toxin-sensitive protein in a Ras-independent pathway.
Published: 2002

18. Expression of the murine msr/apj receptor and its ligand apelin is upregulated during formation of the retinal vessels

Author: François Malecaze, Yves Audigier, Bernard Knibiehler, Bernard Masri, Magali Saint-Geniez, Hormones, facteurs de croissance et physiopathologie vasculaire, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Embryology, medicine.medical_specialty, Endothelium, [SDV]Life Sciences [q-bio], Receptors, Cell Surface, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Ligands, Receptors, G-Protein-Coupled, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Adipokines, Downregulation and upregulation, Internal medicine, medicine, Animals, Receptor, [SDV.BDD]Life Sciences [q-bio]/Development Biology, In Situ Hybridization, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, G protein-coupled receptor, Apelin Receptors, 0303 health sciences, Retina, Receptors, Dopamine D2, Gene Expression Regulation, Developmental, Retinal Vessels, Retinal, Ligand (biochemistry), Up-Regulation, Apelin, Cell biology, Mice, Inbred C57BL, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Endocrinology, medicine.anatomical_structure, chemistry, 030220 oncology & carcinogenesis, cardiovascular system, Intercellular Signaling Peptides and Proteins, Carrier Proteins, Developmental Biology
Abstract: We have recently identified a new G protein-coupled receptor, msr/apj, whose transcripts are detected in the endothelium of the primary blood vessels and the newly forming heart (Mech. Dev. 1999;84:199). Its expression during formation of the embryonic vasculature incited us to investigate whether expression of the receptor also increased during the formation of retinal vessels, which occurs postnatally in the mouse. Interestingly, msr/apj transcripts are indeed associated with the forming vessels and trace the centrifugal extension of the superficial vasculature. We also show that expression of the endogenous ligand apelin is upregulated at the leading edge of vessel formation.
Published: 2002

19. Synthesis, antioxidant and cytoprotective evaluation of potential antiatherogenic phenolic hydrazones. A structure–activity relationship insight

Author: Florence Bedos-Belval, Chantal Carayon, Corinne Vanucci-Bacqué, Corinne Bernis, Anne Nègre-Salvayre, Michel Baltas, Caroline Camaré, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées
Subjects: Antioxidant, DPPH, Cell Survival, Ultraviolet Rays, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Pharmaceutical Science, Hydrazone, Protective Agents, 01 natural sciences, Biochemistry, Antioxidants, 03 medical and health sciences, chemistry.chemical_compound, Mice, Structure-Activity Relationship, Phenols, Superoxides, Phenolic antioxidants, Drug Discovery, medicine, TBARS, Structure–activity relationship, Organic chemistry, Animals, [CHIM]Chemical Sciences, MTT assay, Lipoprotein oxidation, Arylhydrazones, Molecular Biology, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, 010405 organic chemistry, Superoxide, Organic Chemistry, Hydrazones, Endothelial Cells, Atherosclerosis, 0104 chemical sciences, Lipoproteins, LDL, chemistry, Oxidative stress, Molecular Medicine, LDL oxidation, Oxidation-Reduction
Abstract: International audience; A novel series of hydrazones derived from substituted benzaldehydes have been synthesized as potential antiatherogenic agents. Several methods were used for exploring their antioxidant and cytoprotective properties, such as their scavenging effect on 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical, the inhibition of superoxide anion (O2radical dot−) generation and the measurement of cell-induced low-density lipoprotein oxidation (monitored by the formation of TBARS). The cytoprotective efficacy was also evaluated by measuring the cell viability (monitored by the MTT assay) in the presence of cytotoxic oxidized LDL. In this report, we discuss the relationship between the chemical structure of phenolic hydrazones and their antioxidant and cytoprotective activities, for subsequent application as antiatherogenic agents. This SAR study confirms that the phenolic frame is not the only prerequisite for antioxidant activity and N-methylbenzothiazole hydrazone moiety magnifies the dual required properties in two most interesting derivatives.
Published: 2014

20. Antibacterial and Antifungal Activities of Vasostatin-1, the N-terminal Fragment of Chromogranin A

Author: Karine Lugardon, Yannick Goumon, Dominique Aunis, Angelo Corti, Marie-Hélène Metz-Boutigue, Philippe Bulet, Roselyne Raffner, Agnès F. Delmas, Biologie de la communication cellulaire, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), San Raffaele Scientific Institute, Vita-Salute San Raffaele University and Center for Translational Genomics and Bioinformatics, Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Lugardon, K, Raffner, R, Goumon, Y, Corti, Angelo, Delmas, A, Bulet, P, Aunis, D, and Metz Boutigue, Mh
Subjects: endocrine system, Neutrophils, [SDV]Life Sciences [q-bio], Molecular Sequence Data, 030209 endocrinology & metabolism, Peptide, Biology, Biochemistry, law.invention, Structure-Activity Relationship, 03 medical and health sciences, 0302 clinical medicine, Immune system, Anti-Infective Agents, In vivo, law, Chromogranins, Animals, Humans, Amino Acid Sequence, Molecular Biology, Peptide sequence, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Innate immune system, Bacteria, Fungi, Chromogranin A, Cell Biology, Peptide Fragments, Recombinant Proteins, Anti-Bacterial Agents, Rats, chemistry, Recombinant DNA, biology.protein, Cattle, Antibacterial activity
Abstract: International audience; Vasostatin-1, the natural N-terminal 1-76 chromogranin A (CGA)-derived fragment in bovine sequence, has been purified from chromaffin secretory granules and identified by sequencing and matrix-assisted laser desorption time-of-flight mass spectrometry. This peptide, which displays antibacterial activity against Gram-positive bacteria at micromolar concentrations, is also able to kill a large variety of filamentous fungi and yeast cells in the 1-10 microM range. We have found that the C-terminal moiety of vasostatin-1 is essential for the antifungal activity, and shorter active peptides have been synthesized. In addition, from the comparison with the activity displayed by related peptides (human recombinant and rat synthetic fragments), we could determine that antibacterial and antifungal activities have different structural requirements. To assess for such activities in vivo, CGA and CGA-derived fragments were identified in secretory material released from human polymorphonuclear neutrophils upon stimulation. Vasostatin-1, which is stored in a large variety of cells (endocrine, neuroendocrine, and neurons) and which is liberated from stimulated chromaffin and immune cells upon stress, may represent a new component active in innate immunity.
Published: 2000

21. A signaling cascade mediated by ceramide, src and PDGFRβ coordinates the activation of the redox-sensitive neutral sphingomyelinase-2 and sphingosine kinase-1

Author: Yusuf A. Hannun, Nathalie Augé, Christelle Coatrieux, Anne Nègre-Salvayre, Christel Cinq-Frais, Marie-Hélène Grazide, Robert Salvayre, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Stony Brook University [SUNY] (SBU), State University of New York (SUNY), Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medicine, State University of New York (SUNY)-State University of New York (SUNY), and Simon, Marie Francoise
Subjects: Ceramide, [SDV]Life Sciences [q-bio], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, medicine.disease_cause, Ceramides, Cell Line, Receptor, Platelet-Derived Growth Factor beta, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Sphingosine, medicine, Animals, Humans, Sphingosine-1-phosphate, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Dose-Response Relationship, Drug, Cell Biology, Hydrogen Peroxide, Oxidants, Sphingolipid, Mice, Mutant Strains, Cell biology, Enzyme Activation, Oxidative Stress, Phosphotransferases (Alcohol Group Acceptor), Sphingomyelin Phosphodiesterase, src-Family Kinases, chemistry, Sphingosine kinase 1, biology.protein, Signal transduction, Lysophospholipids, 030217 neurology & neurosurgery, Oxidative stress, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Proto-oncogene tyrosine-protein kinase Src, Signal Transduction
Abstract: International audience; Stress-inducing agents, including oxidative stress, generate the sphingolipid mediators ceramide (Cer) and sphingosine-1-phosphate (S1P) that are involved in stress-induced cellular responses. The two redox-sensitive neutral sphingomyelinase-2 (nSMase2) and sphingosine kinase-1 (SK1) participate in transducing stress signaling to ceramide and S1P, respectively; however, whether these key enzymes are coordinately regulated is not known. We investigated whether a signaling link coordinates nSMase2 and SK1 activation by H2O2. In mesenchymal cells, H2O2 elicits a dose-dependent biphasic effect, mitogenic at low concentration (5μM), and anti-proliferative and toxic at high concentration (100μM). Low H2O2 concentration triggered activation of nSMase2 and SK1 through a nSMase2/Cer-dependent signaling pathway that acted upstream of activation of SK1. Further results implicated src and the trans-activation of PDGFRβ, as supported by the blocking effect of specific siRNAs, pharmacological inhibitors, and genetically deficient cells for nSMase2, src and SK1. The H2O2-induced src/PDGFRβ/SK1 signaling cascade was impaired in nSMase2-deficient fro/fro cells and was rescued by exogenous C2Cer that activated src/PDGFRβ/SK1. Thus, the results define a nSMase2/SK1 signaling pathway implicated in the mitogenic response to low oxidative stress. On the other hand, high oxidative stress induced inhibition of SK1. The results also showed that the toxicity of high H2O2 concentration was comparable in control and nSMase2-deficient cells. Taken together the results identify a tightly coordinated nSMase2/SK1 pathway that mediates the mitogenic effects of H2O2 and may sense the degree of oxidative stress.
Published: 2013

22. Protein Disulfide Isomerase Modification and Inhibition Contribute to ER Stress and Apoptosis Induced by Oxidized Low Density Lipoproteins

Author: Corinne Bernis, Pauline Larroque-Cardoso, Carole Muller, Françoise Guéraud, Elodie Mucher, Cécile Vindis, Nathalie Augé, Caroline Camaré, Jan Bandemer, Anne Nègre-Salvayre, Robert Salvayre, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), ToxAlim (ToxAlim), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, INSERM, Universite of Toulouse, Fondation pour la Recherche Medicale [DCV2007040927], ANR Blanc SVSE1 'CARINA', Prévention et promotion de la cancérogénèse par les aliments (ToxAlim-PPCA), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Simon, Marie Francoise, and Régulations cellulaires: lipidoses et atherosclerose.
Subjects: MESH: Oxidation-Reduction, [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, MESH: Lipoproteins, LDL, Physiology, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Apoptosis, ATHEROGENESIS, Endoplasmic Reticulum, medicine.disease_cause, Biochemistry, MESH: Dose-Response Relationship, Drug, Lipid peroxidation, chemistry.chemical_compound, 0302 clinical medicine, MESH: Structure-Activity Relationship, ATHEROSCLEROTIC LESIONS, ENDOPLASMIC-RETICULUM STRESS, Protein disulfide-isomerase, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, General Environmental Science, 0303 health sciences, OXIDATIVE MODIFICATION, MESH: Oxidative Stress, biology, U937 Cells, Cell biology, [SDV] Life Sciences [q-bio], Lipoproteins, LDL, 030220 oncology & carcinogenesis, POTENTIAL ROLE, SURVIVAL, lipids (amino acids, peptides, and proteins), Oxidation-Reduction, MESH: Cells, Cultured, inorganic chemicals, Protein Disulfide-Isomerases, MESH: U937 Cells, Structure-Activity Relationship, 03 medical and health sciences, INFLAMMATION, MESH: Endoplasmic Reticulum, medicine, Humans, MESH: Protein Disulfide-Isomerases, LIPID-PEROXIDATION PRODUCTS, Molecular Biology, 030304 developmental biology, MESH: Humans, Dose-Response Relationship, Drug, Endoplasmic reticulum, MESH: Apoptosis, Cell Biology, nervous system diseases, body regions, Oxidative Stress, chemistry, CELL-DEATH, Chaperone (protein), Unfolded protein response, biology.protein, General Earth and Planetary Sciences, Pyridoxamine, LDL-INDUCED APOPTOSIS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Oxidative stress
Abstract: Aims: Protein disulfide isomerase (PDI) is an abundant endoplasmic reticulum (ER)-resident chaperone and oxidoreductase that catalyzes formation and rearrangement (isomerization) of disulfide bonds, thereby participating in protein folding. PDI modification by nitrosative stress is known to increase protein misfolding, ER stress, and neuronal apoptosis. As LDL oxidation and ER stress may play a role in atherogenesis, this work was designed to investigate whether PDI was inactivated by oxLDLs, thereby participating in oxLDL-induced ER stress and apoptosis. Results: Preincubation of human endothelial HMEC-1 and of macrophagic U937 cells with toxic concentration of oxLDLs induced PDI inhibition and modification, as assessed by 4-HNE-PDI adducts formation. PDI inhibition by bacitracin potentiated ER stress (increased mRNA expression of CHOP and sXBP1) and apoptosis induced by oxLDLs. In contrast, increased PDI activity by overexpression of an active wild-type PDI was associated with reduced oxLDL-induced ER stress and toxicity, whereas the overexpression of a mutant inactive form was not protective. These effects on PDI were mimicked by exogenous 4-HNE and prevented by the carbonyl-scavengers N-acetylcysteine and pyridoxamine, which reduced CHOP expression and toxicity by oxLDLs. Interestingly, 4-HNE-modified PDI was detected in the lipid-rich areas of human advanced atherosclerotic lesions. Innovation and Conclusions: PDI modification by oxLDLs or by reactive carbonyls inhibits its enzymatic activity and potentiates both ER stress and apoptosis by oxLDLs. PDI modification by lipid peroxidation products in atherosclerotic lesions suggests that a loss of function of PDI may occur in vivo, and may contribute to local ER stress, apoptosis, and plaque progression. Antioxid. Redox Signal. 18, 731-742.
Published: 2013

23. Mechanisms of human smooth muscle cell proliferation and transplant vasculopathy induced by HLA class I antibodies: in vitro and in vivo studies.: Antibody-induced transplant vasculopathy

Author: Anne Nègre-Salvayre, Mogens Thomsen, Magali Trayssac, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, M. T. was funded by a Ph.D. fellowship from Ministère de l'Enseignement Supérieur et de la Recherche. This work was also supported by INSERM (Institut National de la Santé Et de la Recherche Médicale), Agence de la Biomédecine and University Paul Sabatier Toulouse III., Service de biochimie, PRES Université de Toulouse, Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3)
Subjects: Graft Rejection, Isoantigens, Vascular smooth muscle, medicine.drug_class, [SDV]Life Sciences [q-bio], Myocytes, Smooth Muscle, Immunology, Vasculopathy, Human leukocyte antigen, Monoclonal antibody, Antibodies, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, In vivo, medicine, Animals, Humans, Immunology and Allergy, Myocyte, Vascular Diseases, Mesenteric arteries, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, 030304 developmental biology, 0303 health sciences, biology, Histocompatibility Antigens Class I, Antibodies, Monoclonal, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, In vitro, Signaling, 3. Good health, Animal models, Disease Models, Animal, medicine.anatomical_structure, Smooth muscle cells, biology.protein, Antibody, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract: International audience; Vascular smooth muscle cells (SMC) play an important role in the pathophysiology of transplant vasculopathy (TV), a major cause of late death in patients receiving an organ transplant. In this review we describe the proliferative effect in vitro and in vivo of HLA class I antibodies on human SMC. We have developed an experimental model using segments of human mesenteric arteries transplanted in the position of the infrarenal aorta in immunodeficient mice (SCID/beige). Weekly injections of transplanted mice with a monoclonal antibody towards HLA class I provoked typical lesions of TV after 6 weeks in the human graft while transplanted mice receiving an irrelevant antibody did not develop any significant lesion. In vitro, the anti-HLA antibodies were mitogenic to SMC and we showed that they activate a stress-induced signaling pathway implicating matrix metalloproteinases (MMP) and neutral sphingomyelinase 2 (nSMase-2). The proliferative effect of anti-HLA antibodies could be blocked by pharmacological inhibitors or by siRNA. Administration of pharmacological inhibitors diminished the development of TV in grafted mice injected with anti-HLA antibodies demonstrating an important role of the MMP/nSMase-2 pathway in antibody-induced TV. This observation opens new perspectives for the management of TV in clinical settings.
Published: 2012

24. In vivo effects of glucose and insulin on secretion and gene expression of glucagon in rats

Author: Nadim Kassis, Luc Pénicaud, Christophe Magnan, Alain Ktorza, M C Laury, Marc Gilbert, J. Philippe, Laboratoire de physiopathologie de la nutrition (LPN), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Métabolisme Plasticité et Mitochondrie [lié à l'ex IFR 31] (LMPM), IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)
Subjects: Blood Glucose, endocrine system, medicine.medical_specialty, medicine.medical_treatment, Glucagon Measurement, 030209 endocrinology & metabolism, Hypoglycemia, Arginine, Glucagon, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Internal medicine, medicine, Hyperinsulinemia, Animals, Insulin, RNA, Messenger, Rats, Wistar, ComputingMilieux_MISCELLANEOUS, gamma-Aminobutyric Acid, 030304 developmental biology, 0303 health sciences, Chemistry, Glucagon secretion, nutritional and metabolic diseases, medicine.disease, Rats, Glucose, medicine.anatomical_structure, Gene Expression Regulation, Female, Pancreas, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Hyperinsulinism, hormones, hormone substitutes, and hormone antagonists
Abstract: We investigated the effects of insulin and glucose on the control of secretion and gene expression of glucagon in vivo in rats. Animals were studied during 1) a 48-h period of either glucose infusion (hyperglycemia plus hyperinsulinemia; HG-HI rats) or insulin infusion (euglycemia plus hyperinsulinemia; EG-HI rats), and 2) a prolonged postinfusion period in both groups. In HG-HI rats, elevation of plasma insulin and glucose concentrations by about 7 and 5 times, respectively, resulted in a decline in glucagon levels, which fell significantly within 6 h and remained low thereafter, whereas these levels were unchanged in EG-HI rats. Glucagon messenger RNA levels and pancreatic glucagon content were not significantly affected in either HG-HI or EG-HI rats. After cessation of infusions, hypoglycemia occurred in both group of rats. In HG-HI rats, hypoglycemia lasted for about 36 h without any surge in the plasma glucagon level, whereas in EG-HI rats it was transient (approximately 1 h) and stimulated glucagon secretion. In both groups the pancreatic alpha-cell was unresponsive to arginine during the postinfusion period. In conclusion, although a role of intraislet insulin cannot be excluded, glucagon gene expression is insensitive to changes in plasma glucose and insulin concentrations. In contrast, hyperglycemia/hyperinsulinemia, not hyperinsulinemia alone, lowers glucagon secretion and affects the alpha-cell responsiveness to hypoglycemia.
Published: 1995

25. Serotonin 5-HT2A receptor-mediated hypertrophy is negatively regulated by caveolin-3 in cardiomyoblasts and neonatal cardiomyocytes

Author: Cécile Vindis, Christelle Villeneuve, Angelo Parini, Anne Nègre-Salvayre, Jeanne Mialet-Perez, Catherine Ordener, Romina D'Angelo, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Microscopie Confocale & Cytométrie (E22 M2C), ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Simon, Marie Francoise, Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées
Subjects: Male, MESH: Signal Transduction, Caveolin 3, [SDV]Life Sciences [q-bio], MESH: Myoblasts, Cardiac, MESH: Myocytes, Cardiac, TRPC1, Mice, 0302 clinical medicine, Caveolae, Myocyte, Myocytes, Cardiac, Receptor, Serotonin, 5-HT2A, MESH: Animals, MESH: Gene Silencing, MESH: Caveolin 3, Receptor, ComputingMilieux_MISCELLANEOUS, Mice, Inbred C3H, 0303 health sciences, NFAT, MESH: Gene Expression Regulation, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Cell biology, Protein Transport, MESH: Caveolae, Cardiology and Cardiovascular Medicine, Myoblasts, Cardiac, Protein Binding, Signal Transduction, Serotonin, MESH: Protein Transport, MESH: Rats, Cardiomegaly, Biology, Cell Line, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Animals, MESH: Protein Binding, Gene Silencing, MESH: Mice, Inbred C3H, MESH: Mice, Molecular Biology, 5-HT receptor, 030304 developmental biology, G protein-coupled receptor, MESH: Receptor, Serotonin, 5-HT2A, MESH: Male, Rats, MESH: Cell Line, Disease Models, Animal, Gene Expression Regulation, MESH: Serotonin, MESH: Cardiomegaly, MESH: Disease Models, Animal, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; The serotonin 5-HT(2A) receptor belongs to the G-protein-coupled receptors (GPCRs) superfamily and mediates the hypertrophic response to serotonin (5-HT) in cardiac myocytes. At present the regulatory mechanisms of 5-HT(2A) receptor-induced myocyte hypertrophy are not fully understood. The localization and the compartmentation of GPCRs within specialized membrane microdomains are known to modulate their signalling pathway. Therefore, we hypothesized that caveolae microdomains and caveolin-3, the predominant isoform of cardiac caveolae, might be regulators of 5-HT(2A) receptor signalling. We demonstrate that 5-HT(2A) receptors interact with caveolin-3 upon 5-HT stimulation and traffic into caveolae membrane microdomains. We provide evidence that caveolin-3 knockdown abolishes the redistribution of 5-HT(2A) receptors into caveolae and enhances 5-HT(2A) receptor-induced myocyte hypertrophic markers such as cell size, protein synthesis and ANF gene expression. Importantly, we demonstrate that caveolin-3 and caveolae structures are negative regulators of 5-HT(2A) receptor-induced nuclear factor of activated T cells (NFAT) transcriptional activation. Taken together, our data demonstrate that caveolin-3 and caveolae microdomains are important regulators of the hypertrophic response induced by 5-HT(2A) receptors. These findings thus open new insights to target heart hypertrophy under the enhanced serotonin system. This article is part of a Special Issue entitled "Local Signaling in Myocytes".
Published: 2012

26. A physiological increase of insulin in the olfactory bulb decreases detection of a learned aversive odor and abolishes food odor-induced sniffing behavior in rats

Author: Chloé Hegoburu, Tristan Jaillard, A.K. Julliard, Claude Duchamp, Belkacem Messaoudi, Cyril Dégletagne, Pascaline Aimé, Marc Thevenet, Samuel Garcia, Anne Lorsignol, Anne-Marie Mouly, Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Pathology an Cell Biolgy, Columbia University [New York], Métabolisme Plasticité et Mitochondrie [lié à l'ex IFR 31] (LMPM), IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), STROMALab, Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM), Écophysiologie, Comportement, Conservation, Laboratoire d'Ecologie des Hydrosystèmes Naturels et Anthropisés (LEHNA), Université de Lyon-Université de Lyon-École Nationale des Travaux Publics de l'État (ENTPE)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École Nationale des Travaux Publics de l'État (ENTPE)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École Nationale des Travaux Publics de l'État (ENTPE)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École Nationale des Travaux Publics de l'État (ENTPE), Neurosciences Sensorielles Comportement Cognition, Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre Européen des Sciences du Goût, and Centre National de la Recherche Scientifique (CNRS)
Subjects: Olfactory system, Blood Glucose, Male, Anatomy and Physiology, medicine.medical_treatment, [SDV]Life Sciences [q-bio], lcsh:Medicine, Energy homeostasis, Behavioral Neuroscience, stress, 0302 clinical medicine, Sniffing, Insulin, lcsh:Science, odor-fear conditioning, 2. Zero hunger, 0303 health sciences, plethysmograph, Multidisciplinary, biology, Behavior, Animal, Animal Models, Olfactory Bulb, Sensory Systems, Smell, fear, Sensory Perception, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Research Article, olfaction, medicine.medical_specialty, emotion, Endocrine System, 03 medical and health sciences, Model Organisms, Internal medicine, Diabetes mellitus, medicine, Avoidance Learning, Animals, Rats, Wistar, Biology, 030304 developmental biology, DNA Primers, Injections, Intraventricular, Olfactory System, Base Sequence, Endocrine Physiology, lcsh:R, medicine.disease, Olfactory bulb, Rats, Insulin receptor, ultrasonic vocalizations, Endocrinology, Odor, Food, Cellular Neuroscience, Odorants, biology.protein, Rat, lcsh:Q, Molecular Neuroscience, [SDE.BE]Environmental Sciences/Biodiversity and Ecology, Physiological Processes, Energy Metabolism, 030217 neurology & neurosurgery, respiration, Neuroscience
Abstract: International audience; Insulin is involved in multiple regulatory mechanisms, including body weight and food intake, and plays a critical role in metabolic disorders such as obesity and diabetes. An increasing body of evidence indicates that insulin is also involved in the modulation of olfactory function. The olfactory bulb (OB) contains the highest level of insulin and insulin receptors (IRs) in the brain. However, a role for insulin in odor detection and sniffing behavior remains to be elucidated. Using a behavioral paradigm based on conditioned olfactory aversion (COA) to isoamyl-acetate odor, we demonstrated that an intracerebroventricular (ICV) injection of 14 mU insulin acutely decreased olfactory detection of fasted rats to the level observed in satiated animals. In addition, whereas fasted animals demonstrated an increase in respiratory frequency upon food odor detection, this effect was absent in fasted animals receiving a 14 mU insulin ICV injection as well as in satiated animals. In parallel, we showed that the OB and plasma insulin levels were increased in satiated rats compared to fasted rats, and that a 14 mU insulin ICV injection elevated the OB insulin level of fasted rats to that of satiated rats. We further quantified insulin receptors (IRs) distribution and showed that IRs are preferentially expressed in the caudal and lateral parts of the main OB, with the highest labeling found in the mitral cells, the main OB projection neurons. Together, these data suggest that insulin acts on the OB network to modulate olfactory processing and demonstrate that olfactory function is under the control of signals involved in energy homeostasis regulation and feeding behaviors.
Published: 2012

27. A key role for matrix metalloproteinases and neutral sphingomyelinase-2 in transplant vasculopathy triggered by anti-HLA antibody

Author: Anne Nègre-Salvayre, Magali Trayssac, Jean-Claude Thiers, Lionel Rostaing, Sylvain Galvani, Nassim Kamar, Hans-Willi Krell, Robert Salvayre, Mogens Thomsen, Federico Sallusto, Denis Calise, Nathalie Augé, Service de biochimie, PRES Université de Toulouse, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Roche Diagnostics GmbH, Service de néphrologie, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Simon, Marie Francoise, Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Département de Néphrologie et Transplantation d'organes [CHU Toulouse], Pôle Urologie - Néphrologie - Dialyse - Transplantations - Brûlés - Chirurgie plastique - Explorations fonctionnelles et physiologiques [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Néphrologie, dialyse et transplantation [Hôpital de Rangueil, Toulouse], Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)
Subjects: Matrix metalloproteinase inhibitor, [SDV]Life Sciences [q-bio], MESH: Piperazines, MESH: Antibodies, Anti-Idiotypic, Constriction, Pathologic, Mice, SCID, Matrix metalloproteinase, Muscle, Smooth, Vascular, Piperazines, Organ transplantation, Mice, MESH: Matrix Metalloproteinase 14, 0302 clinical medicine, HLA Antigens, MESH: Neointima, MESH: RNA, Small Interfering, MESH: Animals, RNA, Small Interfering, MESH: Mice, SCID, MESH: HLA Antigens, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, Aniline Compounds, biology, Arteries, MESH: Muscle, Smooth, Vascular, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Antibodies, Anti-Idiotypic, 3. Good health, Sphingomyelin Phosphodiesterase, MESH: Models, Animal, Models, Animal, MESH: Vascular Diseases, Matrix Metalloproteinase 2, Antibody, Cardiology and Cardiovascular Medicine, Sphingomyelin, MESH: Cells, Cultured, medicine.medical_specialty, Anti-HLA antibody, In Vitro Techniques, Matrix Metalloproteinase Inhibitors, Benzylidene Compounds, MESH: Aniline Compounds, 03 medical and health sciences, Immune system, MESH: Constriction, Pathologic, Neointima, Physiology (medical), MESH: Vascular Grafting, Matrix Metalloproteinase 14, medicine, Animals, Humans, Vascular Diseases, MESH: Mice, MESH: Arteries, 030304 developmental biology, Immunosuppressive treatment, Hyperplasia, MESH: Humans, MESH: Hyperplasia, business.industry, MESH: Matrix Metalloproteinase 2, Disease Models, Animal, Pyrimidines, MESH: Sphingomyelin Phosphodiesterase, MESH: Pyrimidines, Immunology, biology.protein, Vascular Grafting, MESH: Benzylidene Compounds, MESH: Disease Models, Animal, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract: Background— Outcomes for organ transplantation are constantly improving because of advances in organ preservation, surgical techniques, immune clinical monitoring, and immunosuppressive treatment preventing acute transplant rejection. However, chronic rejection including transplant vasculopathy still limits long-term patient survival. Transplant vasculopathy is characterized by progressive neointimal hyperplasia leading to arterial stenosis and ischemic failure of the allograft. This work sought to decipher the manner in which the humoral immune response, mimicked by W6/32 anti-HLA antibody, contributes to transplant vasculopathy. Methods and Results— Studies were performed in vitro on cultured human smooth muscle cells, ex vivo on human arterial segments, and in vivo in a model consisting of human arterial segments grafted into severe combined immunodeficiency/beige mice injected weekly with anti-HLA antibodies. We report that anti-HLA antibodies are mitogenic for smooth muscle cells through a signaling mechanism implicating matrix metalloproteinases (MMPs) (membrane type 1 MMP and MMP2) and neutral sphingomyelinase-2. This mitogenic signaling and subsequent DNA synthesis are blocked in smooth muscle cells silenced for MMP2 or for neutral sphingomyelinase-2 by small interfering RNAs, in smooth muscle cells transfected with a vector coding for a dominant-negative form of membrane type 1 MMP, and after treatment by pharmacological inhibitors of MMPs (Ro28-2653) or neutral sphingomyelinase-2 (GW4869). In vivo, Ro28-2653 and GW4869 reduced the intimal thickening induced by anti-HLA antibodies in human mesenteric arteries grafted into severe combined immunodeficiency/beige mice. Conclusions— These data highlight a crucial role for MMP2 and neutral sphingomyelinase-2 in vasculopathy triggered by a humoral immune response and open new perspectives for preventing transplant vasculopathy with the use of MMP and neutral sphingomyelinase inhibitors, in addition to conventional immunosuppression.
Published: 2011

28. Lipid-Induced Peroxidation in the Intestine Is Involved in Glucose Homeostasis Imbalance in Mice

Author: Aurélie Waget, Matteo Serino, Jean-Claude Thiers, Gaelle Payros, Rémy Burcelin, Amélie Lacombe, Serge Luquet, Jessica Denom, Myriam Masseboeuf, Catherine Kabani, Céline Cruciani-Guglielmacci, Nicolas Marsollier, Anne Nègre-Salvayre, Christophe Magnan, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), RB is the recipient of a grant from the European Association for the Study of Diabetes (EASD) and Amylin. CM is the recipient of funding from the 'Agence Nationale de la Recherche' (France): ANR-07-PHYSIO, Simon, Marie Francoise, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)
Subjects: Central Nervous System, Anatomy and Physiology, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Guanidines, Jejunum, Lipid peroxidation, chemistry.chemical_compound, Mice, 0302 clinical medicine, Endocrinology, Integrative Physiology, Glucose homeostasis, Homeostasis, Insulin, Intestinal Mucosa, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Multidisciplinary, Intestines, medicine.anatomical_structure, Medicine, Research Article, medicine.medical_specialty, Science, Endocrine System, Biology, Neurological System, 03 medical and health sciences, Insulin resistance, Internal medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Obesity, 030304 developmental biology, Nutrition, Diabetic Endocrinology, Endocrine Physiology, medicine.disease, Vagus nerve, Oxidative Stress, Glucose, chemistry, Metabolic Disorders, Duodenum, Lipid Peroxidation, Insulin Resistance, Physiological Processes, Digestive System, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; BACKGROUND: Daily variations in lipid concentrations in both gut lumen and blood are detected by specific sensors located in the gastrointestinal tract and in specialized central areas. Deregulation of the lipid sensors could be partly involved in the dysfunction of glucose homeostasis. The study aimed at comparing the effect of Medialipid (ML) overload on insulin secretion and sensitivity when administered either through the intestine or the carotid artery in mice. METHODOLOGY/PRINCIPAL FINDINGS: An indwelling intragastric or intracarotid catheter was installed in mice and ML or an isocaloric solution was infused over 24 hours. Glucose and insulin tolerance and vagus nerve activity were assessed. Some mice were treated daily for one week with the anti-lipid peroxidation agent aminoguanidine prior to the infusions and tests. The intestinal but not the intracarotid infusion of ML led to glucose and insulin intolerance when compared with controls. The intestinal ML overload induced lipid accumulation and increased lipid peroxidation as assessed by increased malondialdehyde production within both jejunum and duodenum. These effects were associated with the concomitant deregulation of vagus nerve. Administration of aminoguanidine protected against the effects of lipid overload and normalized glucose homeostasis and vagus nerve activity. CONCLUSIONS/SIGNIFICANCE: Lipid overload within the intestine led to deregulation of gastrointestinal lipid sensing that in turn impaired glucose homeostasis through changes in autonomic nervous system activity.
Published: 2011

29. Antiatherogenic Effect of Bisvanillyl-Hydralazone, a New Hydralazine Derivative with Antioxidant, Carbonyl Scavenger, and Antiapoptotic Properties

Author: Marie-Hélène Grazide, Nadji Belkheiri, Koji Uchida, Benaissa Bouguerne, Cécile Vindis, Robert Salvayre, Florence Bedos-Belval, Hubert Duran, Michel Baltas, Anne Nègre-Salvayre, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Food and Biodynamics, Graduate School of Bioagricultural Sciences-Nagoya University, Université Fédérale Toulouse Midi-Pyrénées, Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP)
Subjects: Male, Antioxidant, Physiology, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Apoptosis, 030204 cardiovascular system & hematology, medicine.disease_cause, Biochemistry, Antioxidants, Lipid peroxidation, Protein Carbonylation, chemistry.chemical_compound, Mice, 0302 clinical medicine, [CHIM] Chemical Sciences, Hydrogen peroxide, Cells, Cultured, Chemokine CCL2, ComputingMilieux_MISCELLANEOUS, General Environmental Science, Chelating Agents, chemistry.chemical_classification, Mice, Knockout, 0303 health sciences, Superoxide, Hydralazine, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Plaque, Atherosclerotic, 3. Good health, Lipoproteins, LDL, lipids (amino acids, peptides, and proteins), medicine.drug, Bisvanillyl-Hydralazone, Proteasome Endopeptidase Complex, 03 medical and health sciences, medicine, Cell Adhesion, [CHIM]Chemical Sciences, Animals, Humans, Molecular Biology, 030304 developmental biology, Reactive oxygen species, Antiapoptotic Properties, Guaiacol, Endothelial Cells, Cell Biology, Atherosclerosis, Enzyme Activation, Oxidative Stress, chemistry, Hydralazine Derivative, General Earth and Planetary Sciences, Lipid Peroxidation, Reactive Oxygen Species, Carbonyl Scavenger, Oxidative stress, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Lipoprotein, Foam Cells
Abstract: International audience; Reactive oxygen species (ROS) generated within the vascular wall trigger low-density lipoprotein (LDL) oxidation, lipid peroxidation, and carbonyl stress that are involved in atherogenesis. We recently reported that the antihypertensive drug, hydralazine, exhibits carbonyl scavenger and antiatherogenic properties, but only moderate antioxidant activity, so that high concentrations are required for inhibiting LDL oxidation. We aimed to develop agents sharing both antioxidant and carbonyl scavenger properties. We have synthesized a new hydralazine derivative, the bisvanillyl-hydralazone (BVH). BVH strongly inhibited LDL oxidation induced by copper and by human endothelial cells (HMEC-1), and prevented the formation of macrophagic foam cells. BVH reduced both the extracellular generation of ROS (superoxide anion and hydrogen peroxide) induced by oxidized LDL (oxLDL), as well as intracellular oxidative stress and proteasome activation, NFkappaB activation, and oxLDL-mediated proinflammatory signaling. In parallel, BVH prevented the carbonyl stress induced by oxLDL on cellular proteins, and blocked the apoptotic cascade as assessed by the inhibition of Bid cleavage, cytochrome C release, and DEVDase activation. Lastly, BVH prevented atherogenesis and carbonyl stress in apoE(-/-) mice. In conclusion, BVH is the prototype of a new class of antioxidant and carbonyl scavenger agents designed for new therapeutical approaches in atherosclerosis.
Published: 2011

30. Mechanism of Bactericidal Activity of Microcin L in Escherichia coli and Salmonella enterica

Author: Marie Cottenceau, Natacha Morin, Sophie Sablé, Isabelle Lanneluc, Anne Marie Pons, Nathalie Connil, Hormones, facteurs de croissance et physiopathologie vasculaire, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), LIttoral ENvironnement et Sociétés - UMRi 7266 (LIENSs), Université de La Rochelle (ULR)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Microbiologie Signaux et Microenvironnement (LMSM), Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Normandie Université (NU)
Subjects: Microbial Sensitivity Tests, medicine.disease_cause, Microbiology, 03 medical and health sciences, Bacteriocin, Bacteriocins, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], medicine, Escherichia coli, Inner membrane, Pharmacology (medical), Mechanisms of Action: Physiological Effects, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Antibacterial agent, Pharmacology, 0303 health sciences, biology, 030306 microbiology, Salmonella enterica, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Microcin, biology.organism_classification, Enterobacteriaceae, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Enteritis, Anti-Bacterial Agents, Infectious Diseases, Biochemistry, Bacterial outer membrane
Abstract: For the first time, the mechanism of action of microcin L (MccL) was investigated in live bacteria. MccL is a gene-encoded peptide produced by Escherichia coli LR05 that exhibits a strong antibacterial activity against related Enterobacteriaceae , including Salmonella enterica serovars Typhimurium and Enteritidis. We first subcloned the MccL genetic system to remove the sequences not involved in MccL production. We then optimized the MccL purification procedure to obtain large amounts of purified microcin to investigate its antimicrobial and membrane properties. We showed that MccL did not induce outer membrane permeabilization, which indicated that MccL did not use this way to kill the sensitive cell or to enter into it. Using a set of E. coli and Salmonella enterica mutants lacking iron-siderophore receptors, we demonstrated that the MccL uptake required the outer membrane receptor Cir. Moreover, the MccL bactericidal activity was shown to depend on the TonB protein that transduces the proton-motive force of the cytoplasmic membrane to transport iron-siderophore complexes across the outer membrane. Using carbonyl cyanide 3-chlorophenylhydrazone, which is known to fully dissipate the proton-motive force, we proved that the proton-motive force was required for the bactericidal activity of MccL on E. coli . In addition, we showed that a primary target of MccL could be the cytoplasmic membrane: a high level of MccL disrupted the inner membrane potential of E. coli cells. However, no permeabilization of the membrane was detected.
Published: 2011

31. Effects of a high-fat diet on energy metabolism and ROS production in rat liver

Author: Anne Galinier, Hervé Dubouchaud, Nellie Taleux, Karine Couturier, Cécile Cottet-Rousselle, Louis Casteilla, Anne Athias, Xavier Leverve, Guillaume Vial, Bioenergétique fondamentale et appliquée ( LBFA ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Métabolisme, plasticité et mitochondrie, Université Paul Sabatier - Toulouse 3 ( UPS ) -IFR31-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Métabolisme Plasticité et Mitochondrie [lié à l'ex IFR 31] (LMPM), IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Hamant, Sarah
Subjects: Mitochondrial ROS, Male, Transcription, Genetic, MESH : Reactive Oxygen Species, Mitochondria, Liver, MESH : Hepatocytes, Mitochondrion, Oxidative Phosphorylation, MESH: Hepatocytes, 0302 clinical medicine, MESH: Membrane Potential, Mitochondrial, Citrate synthase, MESH: Animals, Beta oxidation, MESH : Electron Transport, 2. Zero hunger, Membrane Potential, Mitochondrial, 0303 health sciences, MESH : Rats, Adenine nucleotide translocator, MESH: Energy Metabolism, MESH: Reactive Oxygen Species, Lipids, Biochemistry, Liver, MESH: Dietary Fats, Mitochondrial matrix, 030220 oncology & carcinogenesis, Body Composition, MESH : Oxidative Phosphorylation, ATP–ADP translocase, MESH: Mitochondria, Liver, MESH: Rats, MESH : Body Composition, MESH : Male, Oxidative phosphorylation, Biology, MESH : Rats, Wistar, Electron Transport, 03 medical and health sciences, MESH: Oxidative Phosphorylation, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Rats, Wistar, MESH: Electron Transport, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Hepatology, MESH: Transcription, Genetic, MESH : Transcription, Genetic, MESH : Liver, MESH : Lipids, MESH: Body Composition, MESH: Rats, Wistar, MESH: Lipids, Dietary Fats, MESH: Male, Rats, MESH : Energy Metabolism, MESH : Membrane Potential, Mitochondrial, MESH : Mitochondria, Liver, biology.protein, Hepatocytes, MESH : Animals, Energy Metabolism, Reactive Oxygen Species, MESH : Dietary Fats, MESH: Liver
Abstract: International audience; BACKGROUND & AIMS: A high-fat diet affects liver metabolism, leading to steatosis, a complex disorder related to insulin resistance and mitochondrial alterations. Steatosis is still poorly understood since diverse effects have been reported, depending on the different experimental models used. METHODS: We hereby report the effects of an 8 week high-fat diet on liver energy metabolism in a rat model, investigated in both isolated mitochondria and hepatocytes. RESULTS: Liver mass was unchanged but lipid content and composition were markedly affected. State-3 mitochondrial oxidative phosphorylation was inhibited, contrasting with unaffected cytochrome content. Oxidative phosphorylation stoichiometry was unaffected, as were ATPase and adenine nucleotide translocator proteins and mRNAs. Mitochondrial acylcarnitine-related H(2)O(2) production was substantially higher and the mitochondrial quinone pool was smaller and more reduced. Cellular consequences of these mitochondrial alterations were investigated in perifused, freshly isolated hepatocytes. Ketogenesis and fatty acid-dependent respiration were lower, indicating a lower β-oxidation rate contrasting with higher RNA contents of CD36, FABP, CPT-1, and AcylCoA dehydrogenases. Concomitantly, the cellular redox state was more reduced in the mitochondrial matrix but more oxidized in the cytosol: these opposing changes are in agreement with a significantly higher in situ mitochondrial proton motive force. CONCLUSIONS: A high-fat diet results in both a decrease in mitochondrial quinone pool and a profound modification in mitochondrial lipid composition. These changes appear to play a key role in the resulting inhibition of fatty acid oxidation and of mitochondrial oxidative-phosphorylation associated with an increased mitochondrial ROS production. Mitochondrial quinone pool could have prospects as a crucial event, potentially leading to interesting therapeutic perspectives.
Published: 2011

32. Pathological aspects of lipid peroxidation

Author: Giuseppe Poli, José C. E. Serrano, Giovanni E. Mann, Reinald Pamplona, János Fehér, Nathalie Augé, Victoria Ayala, Gabriella Lengyel, Werner Siems, Rainer Brenke, Shlomo Sasson, Kamelija Zarkovic, Robert Salvayre, Guy Cohen, Jordi Boada, Tilman Grune, Anne Nègre-Salvayre, Sarah J. Chapple, Richard C.M. Siow, Manuel Portero-Otin, Ingrid Wiswedel, Yael Riahi, Neven Zarkovic, Ofer Shamni, Huveyda Basaga, Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Metabolic Pathophysiology Research GroupDepartment of Basic Medical Sciences, Universitat de Lleida, Biological Sciences and Bioengineering Program, Sabanci University [Istanbul], Departament de Medicina Experimental, Hufeland Hospital, Cardiovascular Division, King‘s College London, The Hebrew University of Jerusalem (HUJ), 2nd Department of Medicine, Semmelweis University [Budapest], Institute of Biological Chemistry and Nutrition, University of Hohenheim, Department of Clinical and Biological Sciences, San Luigi Hospital-University of Turin, Department of Pharmacology, The Hebrew University of Jerusalem (HUJ)-Institute for Drug Research, Cités, Territoires, Environnement et Sociétés (CITERES), Université de Tours-Centre National de la Recherche Scientifique (CNRS), Research Institute of Physiotherapy and Gerontology, Institute of Medical Education Bad Harzburg-KortexMed Institute of Medical Education Bad Harzburg, Department of Pathological Biochemistry, Medical Faculty of the Otto-von-Guericke-University, Department of Neuropathology, University of Zagreb-Clinical Hospital Center Zagreb, Rudjer Boskovic Institute, Centre National de la Recherche Scientifique (CNRS)-Université de Tours (UT), Rudjer Boskovic Institute [Zagreb], Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université de Tours, Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Università degli studi di Torino = University of Turin (UNITO)-San Luigi Hospital
Subjects: Aging, [SDV]Life Sciences [q-bio], Bioinformatics, medicine.disease_cause, Biochemistry, MESH: Lipid Peroxidation, MESH: Atherosclerosis, MESH: Neurodegenerative Diseases, Lipid peroxidation, chemistry.chemical_compound, Liver disease, 0302 clinical medicine, Neoplasms, MESH: Aging, MESH: Animals, MESH: Neoplasms, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, MESH: Oxidative Stress, Liver Diseases, Fatty liver, Neurodegenerative Diseases, General Medicine, 3. Good health, lipid peroxidation, 4-hydroxynonenal, medicine.medical_specialty, MESH: Diabetes Mellitus, MESH: Liver Diseases, oxidative stress, oxidative homeostasis, ROS, 4-Hydroxynonenal, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, liver disease, atherosclerosis, redox equilibrium, cell signalling, oxidized phospholipids, oxysterol, diabetes, 4-hydroxydodecadienal, pre-eclampsia, HELLP syndrome, IUGR, glutathione, redox signaling, Nrf2, antioxidant enzymes, foetal endothelium, renal diseases, lymphoedema, hyperglycaemia, advanced glycation end-products, cancer, Oxysterol, Biology, 03 medical and health sciences, Internal medicine, Diabetes mellitus, Diabetes Mellitus, medicine, Animals, Humans, 030304 developmental biology, MESH: Humans, Atherosclerosis, medicine.disease, Oxidative Stress, Endocrinology, chemistry, Ageing, Lipid Peroxidation, 030217 neurology & neurosurgery, Oxidative stress, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Lipid peroxidation (LPO) product accumulation in human tissues is a major cause of tissular and cellular dysfunction that plays a major role in ageing and most age-related and oxidative stress-related diseases. The current evidence for the implication of LPO in pathological processes is discussed in this review. New data and literature review are provided evaluating the role of LPO in the pathophysiology of ageing and classically oxidative stress-linked diseases, such as neurodegenerative diseases, diabetes and atherosclerosis (the main cause of cardiovascular complications). Striking evidences implicating LPO in foetal vascular dysfunction occurring in pre-eclampsia, in renal and liver diseases, as well as their role as cause and consequence to cancer development are addressed.
Published: 2010

33. Proteasomal degradation of retinoid X receptor alpha reprograms transcriptional activity of PPARgamma in obese mice and humans

Author: François Pattou, Julie Dumont, Emmanuel Bouchaert, Alain Ktorza, Philippe Lefebvre, Catherine Dacquet, Aurore Guédin, Luc Pénicaud, Yacir Benomar, Audrey Langlois, Bruno Lefebvre, Louis Casteilla, Bart Staels, Nathalie Hennuyer, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Division of Meabolic Diseases, Institut de Recherches Servier, Métabolisme Plasticité et Mitochondrie [lié à l'ex IFR 31] (LMPM), IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Thérapie cellulaire du diabète, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Division of Metabolic Diseases, Derudas, Marie-Hélène, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Transcription, Genetic, Peroxisome proliferator-activated receptor, Mice, Obese, White adipose tissue, MESH: Thiazolidinediones, MESH: Retinoid X Receptor alpha, Mice, 0302 clinical medicine, MESH: Obesity, MESH: Animals, MESH: Mice, Obese, chemistry.chemical_classification, 0303 health sciences, MESH: Proteasome Endopeptidase Complex, General Medicine, MESH: Gene Expression Regulation, MESH: Insulin Resistance, Adipose Tissue, Signal transduction, Ubiquitin Thiolesterase, MESH: Adipose Tissue, Research Article, Agonist, medicine.medical_specialty, Proteasome Endopeptidase Complex, medicine.drug_class, 030209 endocrinology & metabolism, Retinoid X receptor, Biology, Rosiglitazone, 03 medical and health sciences, Downregulation and upregulation, Internal medicine, 3T3-L1 Cells, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Obesity, MESH: Mice, 030304 developmental biology, Thyroid hormone receptor, Retinoid X Receptor alpha, MESH: Humans, Retinoid X receptor alpha, MESH: Transcription, Genetic, MESH: Ubiquitin Thiolesterase, MESH: 3T3-L1 Cells, MESH: Male, PPAR gamma, Endocrinology, chemistry, Gene Expression Regulation, MESH: PPAR gamma, Thiazolidinediones, Insulin Resistance
Abstract: International audience; Obese patients have chronic, low-grade inflammation that predisposes to type 2 diabetes and results, in part, from dysregulated visceral white adipose tissue (WAT) functions. The specific signaling pathways underlying WAT dysregulation, however, remain unclear. Here we report that the PPARgamma signaling pathway operates differently in the visceral WAT of lean and obese mice. PPARgamma in visceral, but not subcutaneous, WAT from obese mice displayed increased sensitivity to activation by its agonist rosiglitazone. This increased sensitivity correlated with increased expression of the gene encoding the ubiquitin hydrolase/ligase ubiquitin carboxyterminal esterase L1 (UCH-L1) and with increased degradation of the PPARgamma heterodimerization partner retinoid X receptor alpha (RXRalpha), but not RXRbeta, in visceral WAT from obese humans and mice. Interestingly, increased UCH-L1 expression and RXRalpha proteasomal degradation was induced in vitro by conditions mimicking hypoxia, a condition that occurs in obese visceral WAT. Finally, PPARgamma-RXRbeta heterodimers, but not PPARgamma-RXRalpha complexes, were able to efficiently dismiss the transcriptional corepressor silencing mediator for retinoid and thyroid hormone receptors (SMRT) upon agonist binding. Increasing the RXRalpha/RXRbeta ratio resulted in increased PPARgamma responsiveness following agonist stimulation. Thus, the selective proteasomal degradation of RXRalpha initiated by UCH-L1 upregulation modulates the relative affinity of PPARgamma heterodimers for SMRT and their responsiveness to PPARgamma agonists, ultimately activating the PPARgamma-controlled gene network in visceral WAT of obese animals and humans.
Published: 2010

34. Immune reactivity to type VII collagen: implications for gene therapy of recessive dystrophic epidermolysis bullosa

Author: José E. Mejía, Catherine Prost-Squarcioni, Alain Hovnanian, Zulma G. Vitezica, P Loiseau, Valérie Pendaries, C Leroux, Matthias Titeux, Christine Bodemer, Audrey Décha, Géraldine Gasc, U 563, Institut Claude de Préval (ICP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Département d'Immunologie et Histocompatibilité, Partenaires INRAE, Tissus animaux, nutrition, digestion, écosystème et métabolisme (TANDEM), Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-École nationale supérieure agronomique de Toulouse [ENSAT], Centre de Référence sur les Maladies Génétiques à Expression Cutanée, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Centre de Référence des Maladies Bulleuses Auto-immunes Ile de France, Université Paris Nord (Paris 13), Département de génétique, Institut Curie [Paris], ProdInra, Migration, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-École nationale supérieure agronomique de Toulouse [ENSAT]
Subjects: Epidermolysis bullosa acquisita, Pathology, medicine.medical_specialty, Collagen Type VII, Genetic enhancement, [SDV]Life Sciences [q-bio], ESSAI CLINIQUE, EPIDERMOLYSE BULLEUSE DYSTROPHIQUE, Enzyme-Linked Immunosorbent Assay, [INFO] Computer Science [cs], Validation Studies as Topic, Sensitivity and Specificity, 03 medical and health sciences, 0302 clinical medicine, Immune system, IMMUNE RESPONSE, Anchoring fibrils, Genetics, medicine, Humans, [INFO]Computer Science [cs], TYPE VII COLLAGEN, Molecular Biology, Gene, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Immunity, Cellular, business.industry, ELISPOT, REACTION IMMUNITAIRE, Genodermatosis, CLINICAL TRIAL, medicine.disease, COLLAGENE TYPE VII, 3. Good health, Epidermolysis Bullosa Dystrophica, [SDV] Life Sciences [q-bio], chemistry, SYSTEME IMMUNITAIRE, 030220 oncology & carcinogenesis, Immunology, Mutation, Molecular Medicine, business, Glycoprotein, DYSTROPHIC EPIDERMOLYSIS BULLOSA
Abstract: International audience; Recessive dystrophic epidermolysis bullosa (RDEB) is a severe genodermatosis caused by loss-of-function mutations in COL7A1 encoding type VII collagen, the component of anchoring fibrils. As exogenous type VII collagen may elicit a deleterious immune response in RDEB patients during upcoming clinical trials of gene therapies or protein replacement therapies, we developed enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunosorbent spot (ELISPOT) assays to analyze B- and T-cell responses, to the full-length type VII collagen. The ELISA was highly sensitive and specific when tested against sera from 41 patients with epidermolysis bullosa acquisita (EBA), and the IFN-g ELISPOT detected a cellular response that correlated with ongoing EBA manifestations. Both tests were next applied to assess the risk of an immune response to type VII collagen in seven RDEB patients with a range of type VII collagen expression profiles. Immune responses against type VII collagen were dependent on the expression of type VII collagen protein, and consequently on the nature and position of the respective COL7A1 mutations. These immunologic tests will be helpful for the selection of RDEB patients for future clinical trials aiming at restoring type VII collagen expression, and in monitoring their immune response to type VII collagen after treatment.
Published: 2010

35. Human multipotent adipose-derived stem cells differentiate into functional brown adipocytes

Author: Christian Dani, Luc Pénicaud, Mamen Carmona, Jean Galitzky, Louis Casteilla, Christian Elabd, Gérard Ailhaud, Ez-Zoubir Amri, Karsten Kristiansen, Chiara Chiellini, Olivia Cochet, Rasmus K. Petersen, Anne Bouloumié, Institute of Developmental Biology and Cancer (IBDC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Métabolisme Plasticité et Mitochondrie [lié à l'ex IFR 31] (LMPM), IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Biochemistry and Molecular Biology, University of Southern Denmark (SDU), Department of Biology [Copenhagen], Faculty of Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Simon, Marie Francoise, Université Nice Sophia Antipolis (1965 - 2019) (UNS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)
Subjects: Male, medicine.medical_specialty, Adipose Tissue, White, Blotting, Western, Cell Respiration, Adipose tissue, 030209 endocrinology & metabolism, White adipose tissue, Biology, Ion Channels, Cell Line, Mitochondrial Proteins, Rosiglitazone, 03 medical and health sciences, chemistry.chemical_compound, Oxygen Consumption, 0302 clinical medicine, Adipocyte, Internal medicine, Brown adipose tissue, medicine, Humans, Uncoupling protein, Cells, Cultured, Uncoupling Protein 1, 030304 developmental biology, PRDM16, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, Multipotent Stem Cells, Cell Differentiation, Cell Biology, Thermogenin, Adipocytes, Brown, Endocrinology, medicine.anatomical_structure, chemistry, Child, Preschool, Receptors, Adrenergic, beta-3, Androgens, Molecular Medicine, Thiazolidinediones, Stem cell, Developmental Biology
Abstract: In contrast to the earlier contention, adult humans have been shown recently to possess active brown adipose tissue with a potential of being of metabolic significance. Up to now, brown fat precursor cells have not been available for human studies. We have shown previously that human multipotent adipose-derived stem (hMADS) cells exhibit a normal karyotype and high self-renewal ability; they are known to differentiate into cells that exhibit the key properties of human white adipocytes, that is, uncoupling protein two expression, insulin-stimulated glucose uptake, lipolysis in response to β-agonists and atrial natriuretic peptide, and release of adiponectin and leptin. Herein, we show that, upon chronic exposure to a specific PPARγ but not to a PPARβ/δ or a PPARα agonist, hMADS cell-derived white adipocytes are able to switch to a brown phenotype by expressing both uncoupling protein one (UCP1) and CIDEA mRNA. This switch is accompanied by an increase in oxygen consumption and uncoupling. The expression of UCP1 protein is associated to stimulation of respiration by β-AR agonists, including β3-AR agonist. Thus, hMADS cells represent an invaluable cell model to screen for drugs stimulating the formation and/or the uncoupling capacity of human brown adipocytes that could help to dissipate excess caloric intake of individuals. Disclosure of potential conflicts of interest is found at the end of this article.
Published: 2009

36. Somatostatin receptor scintigraphy screening in advanced hepatocarcinoma: A multi-center French study

Author: Christiane Susini, Véronique Moullart, Christian Duhamel, Rachida Lebtahi, Jean Claude Barbare, Séverine Hommel, Alexis Hugentobler, Eric Nguyen-Khac, Jean Louis Dupas, Thomas Aparicio, B. Tramier, Céline Lobry, Jean Paul Joly, Isabelle Ollivier, Jean François Cadranel, Service d'Hépato-Gastroentérologie, CHU Amiens-Picardie, Service d'Hépato-Gastro-Enterologie et Nutrition [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service d'hépato-gastro-entérologie, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Médecine Nucléaire [Amiens], Service de médecine nucléaire [CHU Caen], Service de Médecine Nucléaire [Paris 18eme], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Biologie et Pathologie Digestive, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Hospitalier du Havre, Service d'Hépato-Gastroentérologie [CHU Rouen], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CH Laennec de Creil, Service d'Hépato-Gastroentérologie CH Compiègne, CH COMPIEGNE, Service de Biostatistiques, Simon, Marie Francoise, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, CHU Caen, and Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN)
Subjects: Adult, Male, Cancer Research, medicine.medical_specialty, Cirrhosis, Carcinoma, Hepatocellular, Octreotide, Scintigraphy, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, parasitic diseases, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Somatostatin receptor 2, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Receptors, Somatostatin, Receptor, Radionuclide Imaging, 030304 developmental biology, Aged, Neoplasm Staging, Pharmacology, Prothrombin time, Aged, 80 and over, 0303 health sciences, medicine.diagnostic_test, Somatostatin receptor scintigraphy, business.industry, Indium Radioisotopes, Liver Neoplasms, Middle Aged, medicine.disease, Immunohistochemistry, 3. Good health, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Multivariate Analysis, Molecular Medicine, France, Radiopharmaceuticals, Nuclear medicine, business, Somatostatin, medicine.drug
Abstract: International audience; BACKGROUND: Somatostatin receptor scintigraphy (SRS) has been reported for receptor (SSTR) screening in advanced hepatocarcinoma (aHC) prior to somatostatin analogue treatment. AIMS: To evaluate SSTR screening with SRS in aHC patients. RESULTS: Seventy aHC patients (63 men) aged 65 +/- 11 y were included, with alcohol, viral or other causes cirrhosis in 35 (50%), 23 (33%), 12 (17%) cases respectively. CLIP score was 2.7 +/- 1.7, with more than three nodules in 37 (53%) cases. Largest nodule measured 7.6 +/- 4.5 cm. Median alpha-fetoprotein was 574 UI/mL. SRS was positive in 25/70 (35.7%) livers and 7/17 (41.2%) metastatic sites. Positive SRS patients differed from others for tumor size (9.2 +/- 4 vs. 6.7 +/- 4.6 cm, p = 0.03), prothrombin time (PT) (75.2 +/- 15.2 vs. 61.9 +/- 19%, p = 0.005), albumin (34.1 +/- 5.9 vs. 30.5 +/- 7.2 g/L, p = 0.04) and Child-Pugh (6.7 +/- 1.8 vs. 7.7 +/- 2.3, p = 0.04). After multivariate analysis, only PT was associated with positive SRS (p = 0.028). Immunohistochemistry was positive for SSTR2s in 6/7 tumors (SRS uptake in 5/6 cases). METHODS: SRS was performed prior treatment, with images at 4, 24 and 48 h. For seven tumors, SSTR2 subtype was detected immunohistochemically. CONCLUSIONS: In advanced hepatocarcinoma, we report SRS uptake in 35.7% of livers and 41.2% of metastatic sites. SRS value in screening patients for somatostatin analogue treatment remains to be assessed.
Published: 2009

37. Specific Requirements for V{gamma}9V{delta}2 T Cell Stimulation by a Natural Adenylated Phosphoantigen

Author: Frédéric Pont, Jayati Mookerjee-Basu, Suzanne Peyrottes, Christian Périgaud, Corinne Rolland, Hélène Martin, Christian Davrinche, Eric Champagne, Pierre Vantourout, Laurent O. Martinez, Bertrand Perret, Xavier Collet, Departement /u563 : Lipoproteines et Mediateurs Lipidiques, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateau Technique de Spectrométrie de Masse, Institut Claude de Préval (ICP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Departement /u563 : Immunologie et Maladies infectieuses, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Association pour la Recherche sur le Cancer (ARC contracts #3711-3913-4847), Ligue Nationale contre le Cancer (#R07002BBA). Inserm (Avenir), FRM, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Eric, Champagne
Subjects: Adenosine monophosphate, Lymphoma, B-Cell, T cell, T-Lymphocytes, Immunology, Antigen presentation, Isopentenyl pyrophosphate, Antigen-Presenting Cells, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Adenosine Triphosphate, Hemiterpenes, Organophosphorus Compounds, Antigen, Cell Line, Tumor, nucleotide antigens, medicine, Immunology and Allergy, Humans, Receptor, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, Cells, Cultured, 030304 developmental biology, 0303 health sciences, Diphosphonates, phosphoantigens, Receptors, Antigen, T-Cell, gamma-delta, Adenosine Monophosphate, antigen presentation, medicine.anatomical_structure, chemistry, Biochemistry, Cell culture, Gamma-delta T cells, Cancer cell, 030215 immunology
Abstract: 1 pages; International audience; Human Vgamma9Vdelta2 T lymphocytes recognize phosphorylated alkyl Ags. Isopentenyl pyrophosphate (IPP) was previously proposed as the main Ag responsible for Vgamma9Vdelta2 T cell activation by cancer cells. However, triphosphoric acid 1-adenosin-5;-yl ester 3-(3-methylbut-3-enyl) ester (ApppI), a metabolite in which the isopentenyl moiety is linked to ATP, was reported in cells activated with aminobisphosphonates. The contribution of this compound to tumor-stimulatory activity was thus examined. ApppI induces selective expansion of Vgamma9Vdelta2 T cells from PBMCs. In the absence of APCs, however, ApppI has little stimulatory activity on Vgamma9Vdelta2 T cells, and optimal activation with ApppI requires addition of a nucleotide pyrophosphatase releasing IPP plus AMP. Thus, ApppI has no intrinsic stimulatory activity. Nevertheless, stimulation by ApppI is strengthened by the presence of APCs. Moreover, in contrast to IPP, ApppI can be efficiently pulsed on dendritic cells as well as on nonprofessional APCs. Pulsed APCs display stable and phosphatase-resistant stimulatory activity, indicative of Ag modification. HPLC analysis of tumor cell extracts indicates that latent phosphoantigenic activity is stored intracellularly in the Vgamma9Vdelta2 cell-sensitive tumor Daudi and can be activated by a nucleotide pyrophosphatase activity. The presence of ApppI in Daudi cell extracts was demonstrated by mass spectrometry. Nucleotidic Ags such as ApppI are thus a storage form of phosphoantigen which may represent a major source of phosphoantigenic activity in tumor cells. The unique properties of ApppI may be important for the design of Ags used in anticancer immunotherapeutic protocols using Vgamma9Vdelta2 cells.
Published: 2009

38. Cell therapy based on adipose tissue-derived stromal cells promotes physiological and pathological wound healing

Author: Teni Ebrahimian, M. Benderitter, Béatrice Cousin, Louis Casteilla, Radia Tamarat, Claire Squiban, P. Gourmelon, Mireille André, F. Pouzoulet, V. Buard, Laboratoire de Radiopathologie et Thérapies Expérimentales, Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Métabolisme Plasticité et Mitochondrie [lié à l'ex IFR 31] (LMPM), IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Service de RadioBiologie et d'Epidémiologie (IRSN/DRPH/SRBE), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and ATHENA, Irsn
Subjects: green fluorescent protein, Male, Pathology, wound healing, radiation exposure, wound closure, capillary, Mice, 0302 clinical medicine, Genes, Reporter, Models, genetics, endothelium cell, Cells, Cultured, viscoelasticity, pathophysiology, 0303 health sciences, Cultured, integumentary system, C57BL mouse, keratinocyte growth factor, interphase, alpha actin, reporter gene, [SDV] Life Sciences [q-bio], Endothelial stem cell, secretion, priority journal, 030220 oncology & carcinogenesis, Cardiology and Cardiovascular Medicine, Keratinocyte, medicine.medical_specialty, cytokeratin 14, Cells, Neovascularization, Physiologic, keratinocyte, perfusion, animal tissue, 03 medical and health sciences, vascularization, epidermis, Cell Lineage, Progenitor cell, Physiologic, Reporter, mouse, vasculotropin, animal model, adipose tissue derived stromal cell, capillary density, Mice, Inbred C57BL, Genes, Regional Blood Flow, cell therapy, Stromal Cells, Wound healing, transplantation, collagen, Keratinocytes, Vascular Endothelial Growth Factor A, Time Factors, Angiogenesis, Cell Transplantation, [SDV]Life Sciences [q-bio], Dermatologic Surgical Procedures, Adipose tissue, Inbred C57BL, Cell therapy, Cell Fusion, angiogenesis, blood flow, animal, time, Skin, article, Cell Differentiation, laser Doppler flowmetry, adipose tissue, dermis, medicine.anatomical_structure, stroma cell, Models, Animal, skin injury, Stromal cell, Fibroblast Growth Factor 7, animal experiment, Green Fluorescent Proteins, Biology, blood, medicine, Animals, controlled study, fluorescence in situ hybridization, Neovascularization, 030304 developmental biology, CD31 antigen, cytokeratin 5, cell culture, nonhuman, Endothelial Cells, Capillaries, vasculotropin A, protein blood level, epithelization, cytology, metabolism
Abstract: Objective— We hypothesized that adipose tissue may contain progenitors cells with cutaneous and angiogenic potential. Methods and Results— Adipose tissue-derived stroma cells (ADSCs) were administrated to skin punched wounds of both nonirradiated and irradiated mice (20 Gy, locally). At day14, ADSCs promoted dermal wound healing and enhanced wound closure, viscolesticity, and collagen tissue secretion in both irradiated and nonirradiated mice. Interestingly, GFP-positive ADSCs incorporated in dermal and epidermal tissue in vivo and expressed epidermal markers K5 and K14. Cultured ADSCs in keratinocyte medium have been shown to differentiate into K5- and K14-positive cells and produced high levels of KGF. At Day 7, ADSCs also improved skin blood perfusion assessed by laser Doppler imaging, capillary density, and VEGF plasma levels in both irradiated and nonirradiated animals. GFP-positive ADSCs incorporated into capillary structures in vivo and expressed the endothelial cell marker CD31. Finally, in situ interphase fluorescence hybridization showed that a small number of ADSCs have the potential to fuse with endogenous keratinocytes. Conclusion— ADSCs participate in dermal wound healing in physiological and pathological conditions by their ability to promote reepithelialization and angiogenesis. Hence, adipose lineage cells represent a new cell source for therapeutic dermal wound healing.
Published: 2009

39. The p.Asp216His TOR1A allele effect is not found in the French population

Author: Alain Calender, Nicolas Molinari, Gwenaëlle Collod-Béroud, Fabienne Clot, Arnaud Blanchard, Mélissa Yana Frédéric, Gaetan Lesca, Laura Cif, Alexandra Durr, Alexis Brice, Claire-Marie Dhaenens, Mireille Claustres, Bernard Sablonnière, Sylvie Tuffery-Giraud, Marie Vidailhet, Maria Martinez, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Centre de Biologie-Pathologie, UF de Neurobiologie-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Service de Génétique Moléculaire et Clinique, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Neurochirurgie [Hôpital Gui de Chauliac], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier], Fédération des Maladies du Système Nerveux, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département d'Information Médicale, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), M.Y.F. is supported by a grant from AFM (Association Française contre les Myopathies). This work was financially supported by the LFCD-AMADYS and INSERM Dystonia National Network and Gis Maladies Rares., Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), COLLOD-BEROUD, Gwenaëlle, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Université Montpellier 1 (UM1), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Universitaire de Lille (CHU de Lille), U837, Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, U 563, Institut Claude de Préval (ICP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Analyse des Systèmes et Biométrie (ASB), Institut National de la Recherche Agronomique (INRA), and UFR Médecine
Subjects: Pathology, medicine.medical_specialty, Population, DNA Mutational Analysis, DYT1, [SDV.GEN] Life Sciences [q-bio]/Genetics, TOR1A, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Medicine, SNP, Humans, Histidine, Allele, education, Allele frequency, Alleles, 030304 developmental biology, Genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, education.field_of_study, Aspartic Acid, business.industry, population studies, genetic modifiers, Penetrance, Human genetics, Neurology, Dystonic Disorders, Mutation (genetic algorithm), movement disorders, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, dystonia, Neurology (clinical), France, business, 030217 neurology & neurosurgery, Dystonic disorder, Molecular Chaperones
Abstract: International audience; DYT1 dystonia are one of the exceptions in human genetics with its unique and recurrent mutation (c.907delGAG). In this rare movement disorder, the mutation is associated with incomplete penetrance as well as great clinical variability, making this disease a benchmark to search for genetic modifiers. Recently, Risch et al. have demonstrated the implication of the rs1801968 SNP in disease penetrance. We attempted to replicate this result in an exhaustive DYT1 French population with no success. Our results argue that the rs1801968 H allele effect is not part of the modifiers in the French population of DYT1 patients and that others have to be identified in our population.
Published: 2009

40. Small, dense HDL3 particles attenuates apoptosis in endothelial cells: Pivotal role of apolipoprotein A-I

Author: Robert Salvayre, Anne Nègre-Salvayre, Kerry-Anne Rye, Martine Couturier, Patrice Thérond, Juliana A. de Souza, Cécile Vindis, Anatol Kontush, M. John Chapman, S. Chantepie, Dyslipoproteinémies et athérosclerose : Génétique, métabolisme et thérapeutique, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Heart Research Institute, Department of Biochemistry, Université Paris Descartes - Paris 5 (UPD5), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR14-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Régulations cellulaires: lipidoses et atherosclerose., IFR 31 Louis Bugnard ( IFR 31 ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Apolipoprotein B, [SDV]Life Sciences [q-bio], Immunoblotting, anti-oxidative activity, Apoptosis, 030204 cardiovascular system & hematology, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Sphingosine, Annexin, Humans, HDL particle heterogeneity, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, reactive oxygen species, 0303 health sciences, Apolipoprotein A-I, biology, Caspase 3, Cholesterol, Cytochrome c, Cytochromes c, Endothelial Cells, nutritional and metabolic diseases, Lipoproteins, HDL3, Articles, Cell Biology, Cytoprotection, Molecular biology, Cell biology, Lipoproteins, LDL, chemistry, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], anti-apoptotic activity, sphingosine-1-phosphate, biology.protein, Molecular Medicine, Density gradient ultracentrifugation, lipids (amino acids, peptides, and proteins), [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Lysophospholipids, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, BH3 Interacting Domain Death Agonist Protein, Lipoprotein
Abstract: International audience; Abstract Plasma high-density lipoprotein (HDL) protect endothelial cells against apoptosis induced by oxidatively modified low-density lipoprotein (oxLDL). The specific component(s) of HDL implicated in such cytoprotection remain(s) to be identified. Human microvascular endothelial cells (HMEC-1) were incubated with mildly oxLDL in the presence or absence of each of five physicochemically-distinct HDL subpopulations fractionated from normolipidemic human plasma (n=7) by isopycnic density gradient ultracentrifugation. All HDL subfractions protected HMEC-1 against oxLDL-induced primary apoptosis as revealed by nucleic acid staining, annexin V binding, quantitative DNA fragmentation, inhibition of caspase-3 activity, and reduction of cytoplasmic release of cytochrome c and apoptosis-inducing factor. Small, dense HDL3c displayed twofold superior intrinsic cytoprotective activity (as determined by mitochondrial dehydrogenase activity) relative to large, light HDL2b on a per particle basis (p
Published: 2009

41. Adult stromal cells derived from human adipose tissue provoke pancreatic cancer cell death both in vitro and in vivo

Author: Louis Buscail, Emmanuel Ravet, Jean-Marie Péron, Philippe Bourin, Ismahane Touil, Sandrine Poglio, Louis Casteilla, Mélanie Bertuzzi, Mireille André, Jean-Louis Grolleau, Jean-Pierre Chavoin, Pierre Cordelier, Fabienne De Toni, Hubert Lulka, Béatrice Cousin, Luc Pénicaud, Métabolisme Plasticité et Mitochondrie [lié à l'ex IFR 31] (LMPM), IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Chirurgie plastique, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Laboratoire de thérapie cellulaire (EFS-PM), Etablissement Français du Sang, This work has been supported by grants from Region Midi-Pyrenees, Ligue Nationale Contre le Cancer and Cancrople Grand Sud-Ouest (EMERGEANCE)., Développement et Communication Chimique chez les Insectes ( DCCI ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Chirurgie plastique - brûlés [CHU Toulouse], Pôle Urologie - Néphrologie - Dialyse - Transplantations - Brûlés - Chirurgie plastique - Explorations fonctionnelles et physiologiques [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Développement et Communication Chimique chez les Insectes (DCCI), and Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Pathology, medicine.medical_specialty, Stromal cell, Science, Cell, Oncology/Gastrointestinal Cancers, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Adenocarcinoma, Metastasis, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Pancreatic tumor, Pancreatic cancer, Cell Line, Tumor, medicine, Humans, 030304 developmental biology, Cell Proliferation, 0303 health sciences, Multidisciplinary, Cell Death, Cell growth, G1 Phase, Cell Biology, medicine.disease, Coculture Techniques, 3. Good health, Pancreatic Neoplasms, medicine.anatomical_structure, Adipose Tissue, 030220 oncology & carcinogenesis, Culture Media, Conditioned, Cancer cell, Cancer research, Physiology/Integrative Physiology, Medicine, Stromal Cells, Research Article
Abstract: 1932-6203 (Electronic) Journal Article Research Support, Non-U.S. Gov't; International audience; BACKGROUND: Normal tissue homeostasis is maintained by dynamic interactions between epithelial cells and their microenvironment. Disrupting this homeostasis can induce aberrant cell proliferation, adhesion, function and migration that might promote malignant behavior. Indeed, aberrant stromal-epithelial interactions contribute to pancreatic ductal adenocarcinoma (PDAC) spread and metastasis, and this raises the possibility that novel stroma-targeted therapies represent additional approaches for combating this malignant disease. The aim of the present study was to determine the effect of human stromal cells derived from adipose tissue (ADSC) on pancreatic tumor cell proliferation. PRINCIPAL FINDINGS: Co-culturing pancreatic tumor cells with ADSC and ADSC-conditioned medium sampled from different donors inhibited cancer cell viability and proliferation. ADSC-mediated inhibitory effect was further extended to other epithelial cancer-derived cell lines (liver, colon, prostate). ADSC conditioned medium induced cancer cell necrosis following G1-phase arrest, without evidence of apoptosis. In vivo, a single intra-tumoral injection of ADSC in a model of pancreatic adenocarcinoma induced a strong and long-lasting inhibition of tumor growth. CONCLUSION: These data indicate that ADSC strongly inhibit PDAC proliferation, both in vitro and in vivo and induce tumor cell death by altering cell cycle progression. Therefore, ADSC may constitute a potential cell-based therapeutic alternative for the treatment of PDAC for which no effective cure is available.
Published: 2009

42. Interleukin-6 deficiency fails to prevent chronic rejection after aortic allografts in apolipoprotein E-deficient mice

Author: Denis Calise, Nicole Therville, Jean Claude Thiers, Bruno Ségui, Hervé Benoist, Mogens Thomsen, Talal Al Saati, Houda Yacoub-Youssef, Nelly Blaes, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de microchirurgie, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Plateau technique d'histopathologie expérimentale, Institut Claude de Préval (ICP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Simon, Marie Francoise
Subjects: Graft Rejection, Apolipoprotein E, MESH: Vascular Resistance, 030204 cardiovascular system & hematology, MESH: Mice, Knockout, Mice, 0302 clinical medicine, Isoantibodies, Deficient mouse, MESH: Animals, Aorta, Dominance (genetics), Mice, Knockout, 0303 health sciences, biology, MESH: Aorta, MESH: Apolipoproteins E, 3. Good health, Titer, medicine.anatomical_structure, Mice, Inbred DBA, Antibody, Cardiology and Cardiovascular Medicine, Pulmonary and Respiratory Medicine, medicine.medical_specialty, T cell, MESH: Graft Rejection, 03 medical and health sciences, Apolipoproteins E, Internal medicine, medicine, MESH: Transplantation, Homologous, Animals, Transplantation, Homologous, Interleukin 6, MESH: Mice, 030304 developmental biology, Transplantation, MESH: Mice, Inbred DBA, Interleukin-6, Cell growth, business.industry, MESH: Interleukin-6, MESH: Isoantibodies, Endocrinology, Immunology, biology.protein, Vascular Resistance, Surgery, business
Abstract: International audience; BACKGROUND: Chronic vascular rejection (CVR) is characterized by an intimal thickening in the arteries of allografts due to immunoinflammatory reactions and smooth muscle cell proliferation. Interleukin 6 (IL-6) levels are increased in patients with graft rejection, however the role of IL-6 in CVR is not known. We investigated if IL-6 deficiency in the recipient could prevent CVR after an aortic allograft. METHODS: Donor aortas from wild-type DBA/2 mice were transplanted into C57BL/6 recipients, either wild-type mice or mice deficient for IL-6 (IL-6(-/-)), apolipoprotein E (ApoE(-/-)), or both (IL-6(-/-)ApoE(-/-)). Alloantibody titers were determined at Day 30, 60, or 90 after grafting. The grafts were examined for CVR lesions by morphometry and immunohistology. RESULTS: All recipient allografts displayed lesions typical for CVR. The lesions were larger in IL-6-deficient strains, and significantly so in IL-6(-/-)ApoE(-/-) recipients. Early immunoglobulin (Ig) G1 alloantibody deposits were observed in the grafts of ApoE-deficient strains and late IgG2a deposits in the grafts of IL-6-deficient strains. A rapid and sustained type 1 helper T cell (Th1; IgG2a) alloresponse in IL-6(-/-) mice, and a strong type 2 helper T cell (Th2; IgG1) response in ApoE(-/-) mice were observed. IL-6(-/-)ApoE(-/-) mice displayed the highest alloantibody titer, with a Th1 dominance. CONCLUSIONS: Unexpectedly, IL-6 deficiency in the recipient mice did not prevent CVR lesions but even aggravated them in IL-6(-/-)ApoE(-/-) recipients. This was associated with increased local and systemic alloresponses.
Published: 2009

43. Involvement of hippocampal CA3 KATP channels in contextual memory

Author: Bernard Frances, Ambre M. Bertholet, Alexandre Betourne, Robert J. French, Anne Lorsignol, Luc Pénicaud, Hélène Halley, Zhong-Ping Feng, Jean-Michel Lassalle, Elodie Labroue, Hong Shuo Sun, Centre de Recherches sur la Cognition Animale [Toulouse] ( CRCA ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National de la Recherche Scientifique ( CNRS ), Métabolisme, plasticité et mitochondrie, Université Paul Sabatier - Toulouse 3 ( UPS ) -IFR31-Centre National de la Recherche Scientifique ( CNRS ), Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherches sur la Cognition Animale (CRCA), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Métabolisme Plasticité et Mitochondrie [lié à l'ex IFR 31] (LMPM), IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut des sciences du cerveau de Toulouse. (ISCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Grant #03340 from ACI 'Neurosciences intégratives et computationnelles', the Paul Sabatier University and the Centre National de la Recherche Scientifique. The Canadian Institutes of Health Research.
Subjects: Male, medicine.medical_specialty, Mouse, Tolbutamide, Protein subunit, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, Hippocampus, Morris water navigation task, CA3, Hippocampal formation, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Memory, Internal medicine, Diazoxide, medicine, Animals, KATP channels, Fear conditioning, Potassium Channels, Inwardly Rectifying, 030304 developmental biology, Mice, Knockout, Pharmacology, 0303 health sciences, Fear, Contextual memory, Potassium channel, Mice, Inbred C57BL, Endocrinology, Psychology, Neuroscience, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Locomotion, 030217 neurology & neurosurgery, medicine.drug
Abstract: International audience; This paper evaluates the involvement of hippocampal ATP-sensitive potassium channels (K(ATP)) in learning and memory. After confirming expression of the Kir6.2 subunit in the CA3 region of C57BL/6J mice, we performed intra-hippocampal pharmacological injections of specific openers and blockers of K(ATP) channels. The opener diazoxide, the blocker tolbutamide, or a mixture of both, were bilaterally injected in the CA3 region before we subjected the animals to a fear conditioning paradigm. Diazoxide strongly impaired contextual memory of mice at both doses tested. This impairment was specifically reversed by co-injecting the blocker tolbutamide. Moreover, we studied the mnemonic abilities of mice deleted for the Kir6.2 subunit. These mice were backcrossed to C57BL/6J mice and tested in two learning paradigms. We found a significant impairment of contextual and tone memories in the Kir6.2 knock-out mice when compared with heterozygous or wild-type animals. Furthermore, these animals were also slightly impaired in a spatial version of the Morris water maze task. Our data suggest a specific involvement of hippocampal K(ATP) Kir6.2/SUR1 channels in memory processes
Published: 2009

44. Brain glucagon-like peptide 1 signaling controls the onset of high-fat diet-induced insulin resistance and reduces energy expenditure

Author: Eric Sabatier, Luc Pénicaud, Afifa Ait-Belgnaoui, Aurélie Waget, Alexandre Benani, Natacha Godet, Sophie Rastrelli, Rémy Burcelin, Marc Uldry, Claude Knauf, Cendrine Cabou, Philippe Valet, André Colom, Cédric Dray, Patrice D. Cani, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unit of Pharmacokinetics, Metabolism, Nutrition, and Toxicology (PMNT-73/69), Université Catholique de Louvain = Catholic University of Louvain (UCL), Neuro-Gastroentérologie et Nutrition (NGN), Institut National de la Recherche Agronomique (INRA)-Ecole supérieure d'agriculture de Purpan (ESAP), Métabolisme Plasticité et Mitochondrie [lié à l'ex IFR 31] (LMPM), IFR 31 Louis Bugnard (IFR 31), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Dana-Farber Cancer Institute [Boston], Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole supérieure d'agriculture de Purpan (ESAP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Catholique de Louvain (UCL), Ecole supérieure d'agriculture de Purpan (ESAP)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)
Subjects: Blood Glucose, Male, MESH: Signal Transduction, [SDV]Life Sciences [q-bio], Messenger, Nitric Oxide Synthase Type II, Type 2 diabetes, Inbred C57BL, Proglucagon, MESH: Carbon Dioxide, Ion Channels, Mice, 0302 clinical medicine, Endocrinology, Glucagon-Like Peptide 1, Hyperinsulinemia, Glycolysis, MESH: Animals, MESH: Oxygen Consumption, MESH: Peptide Fragments, 0303 health sciences, MESH: Muscle, Skeletal, digestive, oral, and skin physiology, MESH: Energy Metabolism, MESH: Mitochondrial Proteins, Skeletal, Glucagon-like peptide-1, MESH: Motor Activity, MESH: Body Temperature Regulation, [SDV] Life Sciences [q-bio], MESH: Insulin Resistance, MESH: Dietary Fats, MESH: Hyperinsulinism, Muscle, MESH: Nitric Oxide Synthase Type II, MESH: Physical Endurance, hormones, hormone substitutes, and hormone antagonists, Type 2, Body Temperature Regulation, Signal Transduction, MESH: Diabetes Mellitus, Type 2, medicine.medical_specialty, endocrine system, 030209 endocrinology & metabolism, Biology, Motor Activity, Mitochondrial Proteins, 03 medical and health sciences, Insulin resistance, Oxygen Consumption, MESH: Mice, Inbred C57BL, Internal medicine, Diabetes mellitus, Hyperinsulinism, Glucose Intolerance, medicine, Diabetes Mellitus, Animals, MESH: Mice, MESH: Glucose Intolerance, 030304 developmental biology, MESH: RNA, Messenger, MESH: Glucagon-Like Peptide 1, Carbon Dioxide, medicine.disease, Dietary Fats, Peptide Fragments, MESH: Male, Basal (medicine), MESH: Proglucagon, MESH: Ion Channels, MESH: Brain Stem, Physical Endurance, MESH: Blood Glucose, RNA, Insulin Resistance, Energy Metabolism, Thermogenesis, Brain Stem
Abstract: International audience; Glucagon-like peptide-1 (GLP-1) is a peptide released by the intestine and the brain. We previously demonstrated that brain GLP-1 increases glucose-dependent hyperinsulinemia and insulin resistance. These two features are major characteristics of the onset of type 2 diabetes. Therefore, we investigated whether blocking brain GLP-1 signaling would prevent high-fat diet (HFD)-induced diabetes in the mouse. Our data show that a 1-month chronic blockage of brain GLP-1 signaling by exendin-9 (Ex9), totally prevented hyperinsulinemia and insulin resistance in HFD mice. Furthermore, food intake was dramatically increased, but body weight gain was unchanged, showing that brain GLP-1 controlled energy expenditure. Thermogenesis, glucose utilization, oxygen consumption, carbon dioxide production, muscle glycolytic respiratory index, UCP2 expression in muscle, and basal ambulatory activity were all increased by the exendin-9 treatment. Thus, we have demonstrated that in response to a HFD, brain GLP-1 signaling induces hyperinsulinemia and insulin resistance and decreases energy expenditure by reducing metabolic thermogenesis and ambulatory activity.
Published: 2008

45. Potent activation of FGF-2 IRES-dependent mechanism of translation during brain development

Author: Leonel Prado-Lourenco, Sylvie Audigier, Anne-Catherine Prats, Caroline Conte, Irma Gabriela Gonzalez-Herrera, Janique Guiramand, Max Récasens, Catherine Cohen-Solal, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Hormones, facteurs de croissance et physiopathologie vasculaire, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: protein synthesis, MESH: Neurons, FGF-2, Fibroblast growth factor, Mice, 0302 clinical medicine, IRES, MESH: Electrical Synapses, Protein biosynthesis, MESH: Animals, Cells, Cultured, Neurons, 0303 health sciences, MESH: Culture Media, Conditioned, Brain, Translation (biology), Cell biology, medicine.anatomical_structure, MESH: Models, Animal, Receptors, Glutamate, MESH: Protein Biosynthesis, Models, Animal, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Fibroblast Growth Factor 2, Astrocyte, MESH: Cells, Cultured, MESH: Mice, Transgenic, Mice, Transgenic, Biology, MESH: Receptors, Glutamate, Article, 03 medical and health sciences, MESH: Brain, Electrical Synapses, medicine, Animals, RNA, Messenger, Molecular Biology, development, MESH: Mice, 030304 developmental biology, MESH: RNA, Messenger, Messenger RNA, MESH: Fibroblast Growth Factor 2, Molecular biology, neuron, MESH: Astrocytes, Internal ribosome entry site, Astrocytes, Culture Media, Conditioned, Protein Biosynthesis, Forebrain, Neuron, MESH: Ribosomes, Ribosomes, 030217 neurology & neurosurgery
Abstract: International audience; Fibroblast growth factor-2 (FGF-2) plays a fundamental role in brain functions. This role may be partly achieved through the control of its expression at the translational level via an internal ribosome entry site (IRES)-dependent mechanism. Transgenic mice expressing a bicistronic mRNA allowed us to study in vivo and ex vivo where this translational mechanism operates. Along brain development, we identified a stringent spatiotemporal regulation of FGF-2 IRES activity showing a peak at post-natal day 7 in most brain regions, which is concomitant with neuronal maturation. At adult age, this activity remained relatively high in forebrain regions. By the enrichment of this activity in forebrain synaptoneurosomes and by the use of primary cultures of cortical neurons or cocultures with astrocytes, we showed that this activity is indeed localized in neurons, is dependent on their maturation, and correlates with endogenous FGF-2 protein expression. In addition, this activity was regulated by astrocyte factors, including FGF-2, and spontaneous electrical activity. Thus, neuronal IRES-driven translation of the FGF-2 mRNA may be involved in synapse formation and maturation.
Published: 2008

46. Pharmacological Characterization of Membrane-Expressed Human Trace Amine-Associated Receptor 1 (TAAR1) by a Bioluminescence Resonance Energy Transfer cAMP Biosensor

Author: Bernard Masri, Jonathan D. Violin, Raul R. Gainetdinov, Ali Salahpour, Robert J. Lefkowitz, Marc G. Caron, Tatyana D. Sotnikova, Xiao-Dong Zhang, Amy J. Ramsey, Larry S. Barak, Department of Cell Biology, Duke University Medical Center, College of Information and Electrical Engineering [Beijing] (CIEE), China Agricultural University (CAU), Hormones, facteurs de croissance et physiopathologie vasculaire, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), and Howard Hughes Medical Institute (HHMI)
Subjects: Dextroamphetamine, Time Factors, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Cell Survival, [SDV]Life Sciences [q-bio], Biosensing Techniques, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Article, Cell Line, Receptors, G-Protein-Coupled, Cell membrane, 03 medical and health sciences, 0302 clinical medicine, TAAR1, Phenethylamines, Cyclic AMP, Fluorescence Resonance Energy Transfer, medicine, Guanine Nucleotide Exchange Factors, Humans, Receptor, Trace amine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, G protein-coupled receptor, Pharmacology, 0303 health sciences, Cell Membrane, Förster resonance energy transfer, medicine.anatomical_structure, Biochemistry, Molecular Medicine, Guanine nucleotide exchange factor, Signal transduction, 030217 neurology & neurosurgery, Signal Transduction
Abstract: Trace amines are neurotransmitters whose role in regulating invertebrate physiology has been appreciated for many decades. Recent studies indicate that trace amines may also play a role in mammalian physiology by binding to a novel family of G protein-coupled receptors (GPCRs) that are found throughout the central nervous system. A major obstacle impeding the careful pharmacological characterization of trace amine associated receptors (TAARs) is their extremely poor membrane expression in model cell systems, and a molecular basis for this phenomenon has not been determined. In the present study, we show that the addition of an asparagine-linked glycosylation site to the N terminus of the human trace amine associated receptor 1 (TAAR1) is sufficient to enable its plasma membrane expression, and thus its pharmacological characterization with a novel cAMP EPAC (exchange protein directly activated by cAMP) protein based bioluminescence resonance energy transfer (BRET) biosensor. We applied this novel cAMP BRET biosensor to evaluate the activity of putative TAAR1 ligands. This study represents the first comprehensive investigation of the membrane-expressed human TAAR1 pharmacology. Our strategy to express TAARs and to identify their ligands using a cAMP BRET assay could provide a foundation for characterizing the functional role of trace amines in vivo and suggests a strategy to apply to groups of poorly expressing GPCRs that have remained difficult to investigate in model systems.
Published: 2008

47. Exercise-induced lipid mobilization in subcutaneous adipose tissue is mainly related to natriuretic peptides in overweight men

Author: Max Lafontan, Fabien Pillard, I. Harant, Michel Berlan, Claire Thalamas, Isabelle de Glisezinski, François Crampes, Cedric Moro, Marie-Adeline Marques, Eva Klimcakova, Unité de recherche sur les obésités, IFR 31 Louis Bugnard (IFR 31), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Pharmacologie Clinique [CHU Toulouse], Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service d'exploration de la fonction respiratoire et de médecine du sport, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut de médecine moléculaire de Rangueil (I2MR), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Endocrinologie, maladies métaboliques et nutrition [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Laboratoire des Adaptations de l'Organisme à l'Exercice Musculaire, Institut de minéralogie et de physique des milieux condensés (IMPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Physique du Globe de Paris (IPG Paris)-Centre National de la Recherche Scientifique (CNRS), Franco-czech Laboratory for clinical research on obesity, Charles University [Prague] (CU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie de l'adipocyte, physiologie du tissu adipeux et obésités, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut Louis Bugnard-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Pharmacocinétique et de Toxicologie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pharmacologie Clinique, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, CHU Toulouse [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Recherche sur les obésités, CHU Toulouse [Toulouse]-Laboratoire, CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Université Pierre et Marie Curie - Paris 6 (UPMC)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Franco-Czech Laboratory for Clinical Research on Obesity, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut Louis Bugnard-Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Pharmacocinétique et de Toxicologie clinique [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], and CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse]
Subjects: Blood Glucose, Glycerol, Male, Sympathetic nervous system, Physiology, MESH: Atrial Natriuretic Factor, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Adipose tissue, 030204 cardiovascular system & hematology, Overweight, MESH: Dose-Response Relationship, Drug, Propanolamines, 0302 clinical medicine, Atrial natriuretic peptide, Insulin, Medicine, MESH: Double-Blind Method, MESH: Lipid Mobilization, 0303 health sciences, Cross-Over Studies, Lipid Mobilization, MESH: Adrenergic beta-Antagonists, MESH: Thiophenes, medicine.anatomical_structure, medicine.symptom, Atrial Natriuretic Factor, Adult, medicine.medical_specialty, Microdialysis, Adrenergic beta-Antagonists, Subcutaneous Fat, Physical exercise, Thiophenes, MESH: Insulin, MESH: Cross-Over Studies, 03 medical and health sciences, MESH: Subcutaneous Fat, Double-Blind Method, MESH: Glycerol, Physiology (medical), Internal medicine, Humans, Phentolamine, MESH: Overweight, Exercise, MESH: Propanolamines, Adrenergic alpha-Antagonists, Pancreatic hormone, 030304 developmental biology, MESH: Humans, Dose-Response Relationship, Drug, business.industry, MESH: Phentolamine, MESH: Adult, MESH: Male, Endocrinology, MESH: Exercise, MESH: Blood Glucose, MESH: Adrenergic alpha-Antagonists, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Involvement of sympathetic nervous system and natriuretic peptides in the control of exercise-induced lipid mobilization was compared in overweight and lean men. Lipid mobilization was determined using local microdialysis during exercise. Subjects performed 35-min exercise bouts at 60% of their maximal oxygen consumption under placebo or after oral tertatolol [a β-adrenergic receptor (AR) antagonist]. Under placebo, exercise increased dialysate glycerol concentration (DGC) in both groups. Phentolamine (α-AR antagonist) potentiated exercise-induced lipolysis in overweight but not in lean subjects; the α2-antilipolytic effect was only functional in overweight men. After tertatolol administration, the DGC increased similarly during exercise no matter which was used probe in both groups. Compared with the control probe under placebo, lipolysis was reduced in lean but not in overweight men treated with the β-AR blocker. Tertatolol reduced plasma nonesterified fatty acids and insulin concentration in both groups at rest. Under placebo or tertatolol, the exercise-induced changes in plasma nonesterified fatty acids, glycerol, and insulin concentrations were similar in both groups. Exercise promoted a higher increase in catecholamine and ANP plasma levels after tertatolol administration. In conclusion, the major finding of our study is that in overweight men, in addition to an increased α2-antilipolytic effect, the lipid mobilization in subcutaneous adipose tissue that persists during exercise under β-blockade is not dependent on catecholamine action. On the basis of correlation findings, it seems to be related to a concomitant exercise-induced rise in plasma ANP when exercise is performed under tertatolol intake and a decrease in plasma insulin.
Published: 2008

48. High reproducibility of two-dimensional liquid chromatography using pH-driven fractionation with a pressure-resistant electrode

Author: Daniel Gonzalez-Dunia, Frédéric Pont, Elsa Suberbielle, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateau Technique de Spectrométrie de Masse, Institut Claude de Préval (ICP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées
Subjects: Proteomics, Two-dimensional liquid chromatography, MESH: Hydrogen-Ion Concentration, Non-porous silica, Chromatogram comparison, Clinical Biochemistry, Analytical chemistry, MESH: Vero Cells, Fractionation, 01 natural sciences, Biochemistry, pH meter, High-performance liquid chromatography, Analytical Chemistry, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Chlorocebus aethiops, Animals, Sample preparation, Peak concordance, MESH: Animals, Vero Cells, 030304 developmental biology, 0303 health sciences, Reproducibility, Chromatography, Chemistry, MESH: Proteomics, 010401 analytical chemistry, PF2D, Reverse phase high-performance liquid chromatography, Reproducibility of Results, Cell Biology, General Medicine, Repeatability, Reversed-phase chromatography, Hydrogen-Ion Concentration, MESH: Cercopithecus aethiops, 0104 chemical sciences, MESH: Reproducibility of Results, Two-dimensional chromatography, HPLC, MESH: Chromatography, Liquid, Chromatofocusing, Chromatography, Liquid
Abstract: International audience; Automated two-dimensional liquid chromatography using the PF2D system from Beckman Coulter provides a fractionation platform well suited for differential proteomic studies. To date, the reliability and reproducibility of PF2D has not been accurately tested. Here, we used an optimized software and a pressure-resistant pH electrode, allowing a precise and reproducible control of the pH limits for each fraction during PF2D. We tested the reliability of this improved system by performing several rounds of fractionation using the same protein extract. Three UV maps were generated, leading to 54 chromatograms and more than 3000 protein peaks. Using semi-automated software for peak-to-peak comparison between 2D-LC chromatograms, we demonstrate that the peak concordance is very high. The rates of concordance were higher in the second dimension repeatability tests, indicating that the limiting factors for 2D-LC reproducibility rely on the pI fractionation and sample preparation steps. The reproducibility between maps was closely related to pH curves similarities, further stressing the need of careful pH adjustment and precise electrode calibration.
Published: 2008

49. Metabolic syndrome features small, apolipoprotein A-I-poor, triglyceride-rich HDL3 particles with defective anti-apoptotic activity

Author: Juliana A. de Souza, Carlos V. Serrano, Anatol Kontush, M. John Chapman, Anne Nègre-Salvayre, S. Chantepie, Cécile Vindis, Robert Salvayre, Boris Hansel, P. Thérond, Eric Bruckert, Heart Institute, Universidade de São Paulo = University of São Paulo (USP), Dyslipoproteinémies et athérosclerose : Génétique, métabolisme et thérapeutique, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de biochimie, Université Paris Descartes - Paris 5 (UPD5), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Simon, Marie Francoise, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of São Paulo (USP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of São Paulo ( USP ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR14-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Régulations cellulaires: lipidoses et atherosclerose., IFR 31 Louis Bugnard ( IFR 31 ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), and CHU Pitié-Salpêtrière [APHP]
Subjects: Male, MESH: Lipoproteins, LDL, Apolipoprotein B, medicine.medical_treatment, MESH: Apolipoprotein A-I, MESH : Reactive Oxygen Species, Apoptosis, 030204 cardiovascular system & hematology, medicine.disease_cause, chemistry.chemical_compound, 0302 clinical medicine, MESH: Metabolic Syndrome X, MESH : Particle Size, MESH: Endothelial Cells, Metabolic Syndrome, 0303 health sciences, MESH: Middle Aged, MESH: Reactive Oxygen Species, Middle Aged, MESH : Triglycerides, Lipoproteins, LDL, MESH: Insulin Resistance, MESH : Cholesterol, HDL, Cholesteryl ester, lipids (amino acids, peptides, and proteins), MESH : Apolipoprotein A-I, MESH: Cholesterol, HDL, MESH : Insulin Resistance, MESH : Lipoproteins, LDL, Cardiology and Cardiovascular Medicine, MESH: Triglycerides, medicine.medical_specialty, MESH : Male, MESH : Metabolic Syndrome X, Biology, 03 medical and health sciences, Insulin resistance, Internal medicine, medicine, Humans, MESH : Middle Aged, MESH: Particle Size, Particle Size, Triglycerides, 030304 developmental biology, MESH: Humans, Apolipoprotein A-I, MESH : Endothelial Cells, Insulin, MESH: Apoptosis, MESH : Humans, Cholesterol, HDL, Hypertriglyceridemia, Endothelial Cells, medicine.disease, MESH: Male, Endocrinology, chemistry, biology.protein, Insulin Resistance, Metabolic syndrome, Reactive Oxygen Species, MESH : Apoptosis, Oxidative stress, Lipoprotein
Abstract: International audience; The metabolic syndrome (MetS) phenotype is typically characterized by visceral obesity, insulin resistance, atherogenic dyslipidemia involving hypertriglyceridemia and subnormal levels of high density lipoprotein-cholesterol (HDL-C), oxidative stress and elevated cardiovascular risk. The potent antioxidative activity of small HDL3 is defective in MetS [Hansel B, et al. J Clin Endocrinol Metab 2004;89:4963-71]. We evaluated the functional capacity of small HDL3 particles from MetS subjects to protect endothelial cells from apoptosis induced by mildly oxidized low-density lipoprotein (oxLDL). MetS subjects presented an insulin-resistant obese phenotype, with hypertriglyceridemia, elevated apolipoprotein B and insulin levels, but subnormal HDL-C concentrations and chronic low grade inflammation (threefold elevation of C-reactive protein). When human microvascular endothelial cells (HMEC-1) were incubated with oxLDL (200 microg apolipoprotein B/ml) in the presence or absence of control HDL subfractions (25 microg protein/ml), small, dense HDL3b and 3c significantly inhibited cellular annexin V binding and intracellular generation of reactive oxygen species. The potent anti-apoptotic activity of small HDL3c particles was reduced (-35%; p
Published: 2008

50. Dynamin 2 mutations cause sporadic centronuclear myopathy with neonatal onset

Author: Michèle Mayer, Svetlana Maugenre, Jorge A. Bevilacqua, Ana Lia Taratuto, Marc Bitoun, Norma B. Romero, Pascale Guicheney, Emmanuelle Uro-Coste, Fabiana Lubieniecki, Claude Cances, Soledad Monges, Bernard Prudhon, Michel Fardeau, Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Universidad de Chile = University of Chile [Santiago] (UCHILE), Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Departement of neuropathology, FLENI Institute for Neurological Research, Neuropaediatrics, Garrahan National Paediatric Hospital, Pathology, Département de Pédiatrie [CHU Toulouse], CHU Toulouse [Toulouse], Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Coeur, Muscle et Vaisseaux, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of Chile [Santiago], Reference center for neuromuscular disease, CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Heterozygote, Pathology, medicine.medical_specialty, Adolescent, [SDV]Life Sciences [q-bio], Mutation, Missense, Facial Muscles, Ophthalmoparesis, Dynamin II, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Age of Onset, Centronuclear myopathy, Child, Muscle, Skeletal, Autosomal dominant centronuclear myopathy, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Dynamin, Leg, 0303 health sciences, Muscle Weakness, Ophthalmoplegia, business.industry, Infant, Newborn, Facial weakness, Infant, Muscle weakness, medicine.disease, Electrophysiology, DNM2, Breast Feeding, Neonatal hypotonia, Neurology, Child, Preschool, Mutation, Muscle Hypotonia, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Myopathies, Structural, Congenital
Abstract: We report four heterozygous dynamin 2 (DNM2) mutations in five centronuclear myopathy patients aged 1 to 15 years. They all presented with neonatal hypotonia with weak suckling. Thereafter, their phenotype progressively improved. All patients demonstrated muscle weakness prominent in the lower limbs, and most of them also presented with facial weakness, open mouth, arched palate, ptosis, and ophthalmoparesis. Electrophysiology showed only myopathic changes, and muscle biopsies showed central nuclei and type 1 fiber hypotrophy and predominance. Our results expand the phenotypic spectrum of dynamin 2-related centronuclear myopathy from the classic mild form to the more severe neonatal phenotype.
Published: 2007

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