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389 results on '"Institut de pharmacologie moléculaire et cellulaire ( IPMC )"'

1. Inhibition of effector antigen-specific T cells by intradermal administration of heme oxygenase-1 inducers

Author

Julien Pogu, Philippe Blancou, Maud Maquigneau, Frédéric Brau, Séverine Remy, Thomas Simon, Ignacio Anegon, Sylvie Pogu, Jean-François Fonteneau, Gilles Blancho, Eliane Piaggio, Nicolas Poirier, Bernard Vanhove, Centre de Recherche en Transplantation et Immunologie ( U1064 Inserm - CRTI - CHU Nantes ), Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Center for Vascular and Inflammatory Diseases [Baltimore, USA], University of Maryland School of Medicine [Baltimore], Immuno-Endocrinologie Cellulaire et Moléculaire [Nantes] ( IECM ), Université de Nantes ( UN ) -Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique ( ONIRIS ) -Institut National de la Recherche Agronomique ( INRA ), Institut de pharmacologie moléculaire et cellulaire ( IPMC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers, OSE Immunotherapeutics [Nantes], Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), ANR-10-IBHU-0005/10-IBHU-0005,CESTI (TSI-IHU),CESTI (TSI-IHU) ( 2010 ), ANR-11-LABX-0016/11-LABX-0016,IGO,Immunothérapies Grand Ouest ( 2011 ), ANR-10-IDEX-0001-02/10-IDEX-0001,PSL,PSL ( 2010 ), ANR-10-IDEX-0001-02/11-LABX-0043,DCBIOL,Biologie des cellules dendritiques ( 2010 ), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), University of Maryland School of Medicine, University of Maryland System-University of Maryland System, Immuno-Endocrinologie Cellulaire et Moléculaire [Nantes] (IECM), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation Progreffe, JDRF [5-2010-640], IMBIO network, Region Pays de la Loire, IHU-Cesti project, Investissements d'Avenir French, ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, Institut Curie-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-10-IBHU-0005/10-IBHU-0005,CESTI (TSI-IHU),CESTI (TSI-IHU)(2010), ANR-11-LABX-0016/11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), ANR-10-IDEX-0001-02/10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), ANR-10-IDEX-0001-02/11-LABX-0043,DCBIOL,Biologie des cellules dendritiques(2010), Bernardo, Elizabeth, Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID, Immuno-Endocrinologie Cellulaire et Moléculaire (IECM), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-Ecole Nationale Vétérinaire de Nantes-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and 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)

Subjects
CD4-Positive T-Lymphocytes, 0301 basic medicine, T-lymphocyte, Chemokine, T-Lymphocytes, T cell, Immunology, Antigen-Presenting Cells, Mice, Transgenic, T-Cell Antigen Receptor Specificity, [SDV.CAN]Life Sciences [q-bio]/Cancer, Autoimmunity, Autoantigens, Autoimmune Diseases, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigen, medicine, Animals, Humans, Immunology and Allergy, Hypersensitivity, Delayed, Intradermal injection, Antigens, Migration, biology, Effector, Diabetes, Dendritic cell, Papio anubis, Auto-immune encephalomyelitis, Delayed type hypersensitivity, 3. Good health, Heme oxygenase, 030104 developmental biology, medicine.anatomical_structure, Gene Expression Regulation, Heme oxygenase-1, biology.protein, Cytokines, Immunization, Myelin-Oligodendrocyte Glycoprotein, Tolerance, Monocyte-derived dendritic cells, CD8, T-Lymphocytes, Cytotoxic
Abstract

International audience; Developing protocols aimed at inhibiting effector T cells would be key for the treatment of T cell-dependent autoimmune diseases including type 1 autoimmune diabetes (T1D) and multiple sclerosis (MS). While heme oxygenase-1 (HO-1) inducers are clinically approved drugs for non-immune-related diseases, they do have immunosuppressive properties when administered systemically in rodents. Here we show that HO-1 inducers inhibit antigen-specific effector T cells when injected intradermally together with the T cell cognate antigens in mice. This phenomenon was observed in both a CD8 þ T cell-mediated model of T1D and in a CD4 þ T cell-dependent MS model. Intradermal injection of HO-1 in-ducers induced the recruitment of HO-1 þ monocyte-derived dendritic cell (MoDCs) exclusively to the lymph nodes (LN) draining the site of intradermal injection. After encountering HO-1 þ MoDCs, effector T-cells exhibited a lower velocity and a reduced ability to migrate towards chemokine gradients resulting in impaired accumulation to the inflamed organ. Intradermal co-injection of a clinically approved HO-1 inducer and a specific antigen to non-human primates also induced HO-1 þ MoDCs to accumulate in dermal draining LN and to suppress delayed-type hypersensitivity. Therefore, in both mice and non-human primates, HO-1 inducers delivered locally inhibited effector T-cells in an antigen-specific manner, paving the way for repositioning these drugs for the treatment of immune-mediated diseases.

Published
2017
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2. miR-600 Acts as a Bimodal Switch that Regulates Breast Cancer Stem Cell Fate through WNT Signaling

Author

Pascal Finetti, Claire Rioualen, François Bertucci, Bernard Mari, Julien Wicinski, Abigaelle Gros, Ricky Bhajun, Christophe Ginestier, Pascal Barbry, Olivier Cabaud, Guillaume Pinna, Daniel Birnbaum, Laurent Guyon, Ghislain Bidaut, Annick Harel-Bellan, Rita El Helou, Emmanuelle Charafe-Jauffret, Centre de Recherche en Cancérologie de Marseille ( CRCM ), Aix Marseille Université ( AMU ) -Institut Paoli-Calmettes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), Laboratoire de Biologie à Grande Échelle ( BGE - UMR S1038 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Grenoble Alpes [Saint Martin d'Hères]-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Institut de pharmacologie moléculaire et cellulaire ( IPMC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire Epigenetique et Cancer, Centre National de la Recherche Scientifique ( CNRS ), 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 Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS), 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 Nice Sophia Antipolis (1965 - 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), and Bidaut, Ghislain

Subjects
0301 basic medicine, Carcinogenesis, Cellular differentiation, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Bioinformatics, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], microRNA, medicine, Gene silencing, Humans, Wnt Signaling Pathway, lcsh:QH301-705.5, Wnt signaling pathway, Cell Differentiation, 3. Good health, Gene Expression Regulation, Neoplastic, Wnt Proteins, MicroRNAs, 030104 developmental biology, lcsh:Biology (General), Tumor progression, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Cancer research, Neoplastic Stem Cells, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Stem cell, Signal transduction, Stearoyl-CoA Desaturase, Signal Transduction
Abstract

Summary: Breast cancer stem cells (bCSCs) have been implicated in tumor progression and therapeutic resistance; however, the molecular mechanisms that define this state are unclear. We have performed two microRNA (miRNA) gain- and loss-of-function screens to identify miRNAs that regulate the choice between bCSC self-renewal and differentiation. We find that micro-RNA (miR)-600 silencing results in bCSC expansion, while its overexpression reduces bCSC self-renewal, leading to decreased in vivo tumorigenicity. miR-600 targets stearoyl desaturase 1 (SCD1), an enzyme required to produce active, lipid-modified WNT proteins. In the absence of miR-600, WNT signaling is active and promotes self-renewal, whereas overexpression of miR-600 inhibits the production of active WNT and promotes bCSC differentiation. In a series of 120 breast tumors, we found that a low level of miR-600 is correlated with active WNT signaling and a poor prognosis. These findings highlight a miR-600-centered signaling network that governs bCSC-fate decisions and influences tumor progression. : El Helou et al. identify miRNAs that are able to balance bCSC fate. They find that miR-600 silencing results in bCSC expansion, while its overexpression reduces bCSC self-renewal. miR-600 was further found to regulate WNT signaling through SCD1, and miR-600 expression correlates with clinical outcome.

Published
2017
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3. Selective Involvement of Serum Response Factor in Pressure-Induced Myogenic Tone in Resistance Arteries

Author

Retailleau, Kevin, Toutain, Bertrand, Galmiche, Guillaume, Fassot, Celine, Sharif-Naeini, Reza, Kauffenstein, Gilles, Mericskay, Mathias, Duprat, Fabrice, Li, Linda, Mérot, Jean, Lardeux, Aurelie, Pizard, Anne, Baudrie, Véronique, Jeunemaitre, Xavier, Feil, Robert, Göthert, Joachim, Lacolley, Patrick, Henrion, Daniel, Li, Zhenlin, Loufrani, Laurent, Grimaud, L., Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiologie de la Nutrition et du Comportement Alimentaire (PNCA), AgroParisTech-Institut National de la Recherche Agronomique (INRA), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), UMR915, Nutrition et athérome, Institut National de la Santé et de la Recherche Médicale (INSERM), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique [AP-HP Hôpital Européen Georges Pompidou, Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Eberhard Karls Universität Tübingen, Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Biologie Neurovasculaire et Mitochondriale Intégrée, Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Physiologie de la Nutrition et du Comportement Alimentaire ( PNCA ), Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech, Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut de pharmacologie moléculaire et cellulaire ( IPMC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Défaillance Cardiovasculaire Aiguë et Chronique ( DCAC ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lorraine ( UL ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Universitätsklinikum Essen [Universität Duisburg-Essen] ( Uniklinik Essen ), Centre Hospitalier Universitaire d'Angers ( CHU Angers ), PRES Université Nantes Angers Le Mans ( UNAM ), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Serum Response Factor, MESH : RNA, Messenger, Vasodilator Agents, MESH: Vascular Resistance, MESH : Actins, MESH : Blotting, Western, Filamin, Mechanotransduction, Cellular, Muscle, Smooth, Vascular, MESH : Mechanotransduction, Cellular, Mice, Contractile Proteins, 0302 clinical medicine, MESH: Protein Kinase Inhibitors, MESH: Animals, MESH: Myosin-Light-Chain Kinase, MESH : Patch-Clamp Techniques, MESH : p38 Mitogen-Activated Protein Kinases, 0303 health sciences, Microscopy, Confocal, MESH : Vasoconstrictor Agents, MESH : Gene Expression Regulation, Electrical impedance myography, MESH : Reverse Transcriptase Polymerase Chain Reaction, Arteries, MESH : Vascular Resistance, MESH : Arterial Pressure, MESH: Serum Response Factor, MESH: Vasoconstriction, MESH : Tail, MESH : Vasoconstriction, Cardiology and Cardiovascular Medicine, Tail, medicine.medical_specialty, Blotting, Western, MESH: Myography, MESH: Actins, MESH : Vasodilator Agents, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Serum response factor, MESH: Membrane Potentials, MESH: Blotting, Western, MESH: Contractile Proteins, RNA, Messenger, MESH : Microscopy, Confocal, Myosin-Light-Chain Kinase, MESH: Arteries, Phenylephrine, Dose-Response Relationship, Drug, MESH: Mechanotransduction, Cellular, MESH : Muscle, Smooth, Vascular, MESH : Protein Kinase Inhibitors, MESH: Vasodilator Agents, Endocrinology, Vasoconstriction, Vascular Resistance, Patch-Clamp Techniques, Time Factors, Contraction (grammar), Medizin, MESH : Dose-Response Relationship, Drug, 030204 cardiovascular system & hematology, MESH : Filamins, p38 Mitogen-Activated Protein Kinases, MESH: Mice, Knockout, Membrane Potentials, MESH: Dose-Response Relationship, Drug, MESH : Vasodilation, MESH : Calcium Signaling, MESH: Reverse Transcriptase Polymerase Chain Reaction, Vasoconstrictor Agents, MESH : Membrane Potentials, MESH: Microscopy, Confocal, MESH : Contractile Proteins, MESH: Filamins, Mice, Knockout, MESH : Myography, Reverse Transcriptase Polymerase Chain Reaction, MESH: Real-Time Polymerase Chain Reaction, Microfilament Proteins, MESH: Tail, MESH: Muscle, Smooth, Vascular, [ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH: Gene Expression Regulation, MESH: Myosin Light Chains, Vasodilation, MESH : Time Factors, medicine.drug, Myosin Light Chains, Myosin light-chain kinase, MESH : Microfilament Proteins, Filamins, MESH : Male, MESH: Arterial Pressure, MESH : Myosin Light Chains, MESH : Real-Time Polymerase Chain Reaction, Biology, Real-Time Polymerase Chain Reaction, MESH : Myosin-Light-Chain Kinase, MESH: Calcium Signaling, MESH: Vasodilation, MESH: Microfilament Proteins, MESH: Vasoconstrictor Agents, Internal medicine, MESH : Mice, MESH: Patch-Clamp Techniques, medicine, Animals, Arterial Pressure, Calcium Signaling, Patch clamp, Protein Kinase Inhibitors, MESH: Mice, Actin, MESH: RNA, Messenger, 030304 developmental biology, MESH: Time Factors, Myography, Actins, MESH : Arteries, MESH: Male, MESH: p38 Mitogen-Activated Protein Kinases, Gene Expression Regulation, MESH : Mice, Knockout, MESH : Serum Response Factor, MESH : Animals
Abstract

Objective— In resistance arteries, diameter adjustment in response to pressure changes depends on the vascular cytoskeleton integrity. Serum response factor (SRF) is a dispensable transcription factor for cellular growth, but its role remains unknown in resistance arteries. We hypothesized that SRF is required for appropriate microvascular contraction. Methods and Results— We used mice in which SRF was specifically deleted in smooth muscle or endothelial cells, and their control. Myogenic tone and pharmacological contraction was determined in resistance arteries. mRNA and protein expression were assessed by quantitative real-time PCR (qRT-PCR) and Western blot. Actin polymerization was determined by confocal microscopy. Stress-activated channel activity was measured by patch clamp. Myogenic tone developing in response to pressure was dramatically decreased by SRF deletion (5.9±2.3%) compared with control (16.3±3.2%). This defect was accompanied by decreases in actin polymerization, filamin A, myosin light chain kinase and myosin light chain expression level, and stress-activated channel activity and sensitivity in response to pressure. Contractions induced by phenylephrine or U46619 were not modified, despite a higher sensitivity to p38 blockade; this highlights a compensatory pathway, allowing normal receptor-dependent contraction. Conclusion— This study shows for the first time that SRF has a major part to play in the control of local blood flow via its central role in pressure-induced myogenic tone in resistance arteries.

Published
2013
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4. Long-Term Energy Deficit in Mice Causes Long-Lasting Hypothalamic Alterations after Recovery

Author

Carole Rovère, Odile Viltart, Ophélia Le Thuc, Mathieu Méquinion, Christophe Chauveau, David Alexandre, Pierre Hardouin, Sara Zgheib, Nicolas Chartrel, 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, Monash University [Clayton], Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Marrow Adiposity & Bone Lab - Adiposité Médullaire et Os - ULR 4490 (MABLab (ex-pmoi)), Université du Littoral Côte d'Opale (ULCO)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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, 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Université de Lille, CNRS, CHU Lille, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc], Institut de pharmacologie moléculaire et cellulaire [IPMC], Marrow Adiposity & Bone Lab - Adiposité Médullaire et Os - ULR 4490 [MABLab (ex-pmoi)], Différenciation et communication neuronale et neuroendocrine [DC2N], Physiopathologie des Maladies Osseuses Inflammatoires (PMOI) - ULR 4490, and Sciences Cognitives et Sciences Affectives (SCALab) - UMR 9193 [SCALab]

Subjects
0301 basic medicine, Leptin, Receptors, Neuropeptide, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Agouti-Related Protein, Animals, Body Weight, Cytokines, Disease Models, Animal, Eating, Female, Hypolipoproteinemias, Hypothalamic Hormones, Hypothalamus, Melanins, Mice, Mice, Inbred C57BL, Neuropeptide Y, Neuropeptides, Orexins, Pituitary Hormones, RNA, Messenger, Receptors, Leptin, Animal model, Anorexia nervosa, Anorexigenic peptides, Long-term energy deficit, Orexigenic peptides, Refeeding, 0302 clinical medicine, Endocrinology, ComputingMilieux_MISCELLANEOUS, Anorexia nervosa (differential diagnoses), Long lasting, medicine.medical_specialty, Neuropeptide, LeptinAnorexigenic peptides, 03 medical and health sciences, Cellular and Molecular Neuroscience, Internal medicine, medicine, Energy deficit, Endocrine and Autonomic Systems, business.industry, 030104 developmental biology, business, 030217 neurology & neurosurgery
Abstract

Although the short-term effects of fasting or energy deficit on hypothalamic neuropeptide circuitries are now better understood, the effects of long-term energy deficit and refeeding remain to be elucidated. We showed that after a long-term energy deficit, mice exhibited persistent hypoleptinemia following the refeeding period despite restoration of fat mass, ovarian activity, and feeding behavior. We aimed to examine the hypothalamic adaptations after 10 weeks of energy deficit and after 10 further weeks of nutritional recovery. To do so, we assessed the mRNA levels of the leptin receptor and the main orexigenic and anorexigenic peptides, and their receptors regulated by leptin. Markers of hypothalamic inflammation were assessed as leptin can also participate in this phenomenon. Long-term time-restricted feeding and separation induced significant increase in mRNA levels of hypothalamic orexigenic peptides, while both Y1 and Y5 receptor mRNAs were downregulated. No changes occurred in the mRNA levels of orexin (OX), melanin-concentrating hormone, pro-opiomelanocortin, 26RFa (26-amino acid RF-amide peptide), and their receptors despite an increase in the expression of melanocortin receptors (MC3-R and MC4-R) and OXR1 (OX receptor 1). The refeeding period induced an overexpression of leptin receptor mRNA in the hypothalamus. The other assessed mRNA levels were normalized except for Y2, Y5, MC3-R, and MC4-R, which remained upregulated. No convincing changes were observed in neuroinflammatory markers, even if interleukin-1β mRNA levels were increased in parallel with those of Iba1 (ionized calcium-binding adaptor molecule 1), a marker of microglial activation. Normalization of leptin-regulated functions and hypothalamic gene expressions in refed mice with low plasma leptin levels could be sustained by recalibration of hypothalamic sensitivity to leptin.

Published
2016
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5. ADAM30 Downregulates APP-Linked Defects Through Cathepsin D Activation in Alzheimer's Disease

Author

Pierre Dourlen, Yves Lemoine, Amandine Flaig, Frédéric Checler, Anne Marie Ayral, Jean-Charles Lambert, Kris Gevaert, Mathias Laga, Fanny Eysert, Tiago Mendes, David M. A. Mann, Linda Chami, Anne Sophie Hérard, Thierry Delzescaux, Franck Lafont, Florie Demiautte, Franck Hansmannel, Benoit Deprez, Charlotte Delay, David Hot, Florence Leroux, Bart Dermaut, Philippe Amouyel, Ludovic Huot, Yoann Sottejeau, Florence Pasquier, Nicolas Souedet, Florent Letronne, Charlotte Bauer, Marc Dhenain, Marie Lesaffre, Geoffroy Laumet, Nicolas Malmanche, David Tulasne, Claudine Berr, Rebecca Deprez, Julie Dumont, Elisabeth Werkmeister, Michel E. Vandenberghe, Jean Jacques Hauw, Julien Chapuis, Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, 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, Droit et Santé, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), 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), Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB), Universiteit Gent = Ghent University (UGENT), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Médicaments et molécules pour agir sur les Systèmes Vivants - U 1177 (M2SV), 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, Institut de pharmacologie moléculaire et cellulaire (IPMC), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Mécanismes de la Tumorigénèse et Thérapies Ciblées - UMR 8161 (M3T), 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 National de la Recherche Scientifique (CNRS), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), 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)-Centre National de la Recherche Scientifique (CNRS), Réseau International des Instituts Pasteur (RIIP), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service d'Hépato-gastro-entérologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CEA [Fontenay-aux-Roses] (UGRA / SETA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Institute of Brain, Behaviour and Mental Health, University of Manchester [Manchester], Hérard, Anne-Sophie, Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), CDithem Platform, IGM, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), 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 National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Fédératif de Recherche 142, Institut Fédératif de Recherche, Center for Medical Genetics [Ghent], Ghent University Hospital, Département de neurologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neuropathologie Raymond Escourolle, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Division of Neuroscience and Experimental Psychology [Salford, UK], University of Manchester [Manchester]-Salford Royal NHS Foundation Trust [Salford, UK], Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Dept Med Prot Res, Flanders Institute for Biotechnology, Département Imagerie et Simulation pour le Contrôle (DISC), Laboratoire d'Intégration des Systèmes et des Technologies (LIST), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Laboratoire des Maladies Neurodégénératives - UMR 9199 [LMN], Institut de pharmacologie moléculaire et cellulaire [IPMC], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc], Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL], Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD], Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE], Nutrition-Génétique et Exposition aux Risques Environnementaux [NGERE], CEA [Fontenay-aux-Roses] [UGRA / SETA], and Institut de biologie de Lille - IBL [IBLI]

Subjects
0301 basic medicine, Patch-Clamp Techniques, ADAM, A Disintegrin and Metalloproteinase Domain, lcsh:Medicine, Cathepsin D, COFRADIC, combined fractional diagonal chromatography, ALPHA-SECRETASE, Mice, 0302 clinical medicine, Pepstatins, Amyloid precursor protein, BRAIN, RNA, Small Interfering, Tissues and Organs (q-bio.TO), GENE-EXPRESSION, lcsh:R5-920, ROLES, IRS4, insulin receptor substrate 4, P3 peptide, Brain, Long-term potentiation, General Medicine, AMYLOID PRECURSOR PROTEIN, Alpha secretase, BACE, Beta-site APP cleaving enzyme 1, Neurons and Cognition (q-bio.NC), [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], RNA Interference, Macrolides, LTP, lcsh:Medicine (General), GKAP1, G kinase-anchoring protein 1, Research Paper, Genetically modified mouse, Amyloid, CTSD, cathepsin D, Down-Regulation, Mice, Transgenic, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, TD2, Type 2 diabetes, Alzheimer Disease, APP, amyloid precursor protein, Cell Line, Tumor, Animals, Humans, Secretion, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Amino Acid Sequence, TRANSGENIC MOUSE MODEL, Amyloid beta-Peptides, PLA, proximity ligation assay, lcsh:R, LTP, long term potentiation, Biology and Life Sciences, Quantitative Biology - Tissues and Organs, ADAM30, DEGRADATION, CamKIIα, Ca2 +/calmodulin-dependent protein kinase II alpha, Molecular biology, Mice, Inbred C57BL, MICE, ADAM Proteins, 030104 developmental biology, HEK293 Cells, Metabolism, Microscopy, Fluorescence, Quantitative Biology - Neurons and Cognition, FOS: Biological sciences, COGNITIVE DECLINE, biology.protein, Alzheimer, BSA, bovine serum albumin, MMP, metalloproteinase, INHIBITORS, Lysosomes, APP, MRI, magnetic resonance imaging, 030217 neurology & neurosurgery
Abstract

Although several ADAMs (A disintegrin-like and metalloproteases) have been shown to contribute to the amyloid precursor protein (APP) metabolism, the full spectrum of metalloproteases involved in this metabolism remains to be established. Transcriptomic analyses centred on metalloprotease genes unraveled a 50% decrease in ADAM30 expression that inversely correlates with amyloid load in Alzheimer's disease brains. Accordingly, in vitro down- or up-regulation of ADAM30 expression triggered an increase/decrease in Aβ peptides levels whereas expression of a biologically inactive ADAM30 (ADAM30mut) did not affect Aβ secretion. Proteomics/cell-based experiments showed that ADAM30-dependent regulation of APP metabolism required both cathepsin D (CTSD) activation and APP sorting to lysosomes. Accordingly, in Alzheimer-like transgenic mice, neuronal ADAM30 over-expression lowered Aβ42 secretion in neuron primary cultures, soluble Aβ42 and amyloid plaque load levels in the brain and concomitantly enhanced CTSD activity and finally rescued long term potentiation alterations. Our data thus indicate that lowering ADAM30 expression may favor Aβ production, thereby contributing to Alzheimer's disease development., Highlights • By transcriptomic analyses, low levels of ADAM30 expression was observed in the brain of AD cases (compared with controls). • Activation of cathepsin D by ADAM30 is required to modulate the APP metabolism in vitro, i.e. decrease in Ab secretion. • In AD-like mice, neuronal ADAM30 expression led to lower soluble Aβ42, amyloid plaques and to rescue long term potentiation The amyloid precursor protein (APP) processing is central in the etiology of Alzheimer's disease (AD). Characterizing the actors of this metabolism is thus an important challenge. We searched for proteins involved in the APP processing and we selected the A disintegrin-like and metalloprotease 30 (ADAM30). Our results revealed an axis in APP metabolism pathway through an ADAM30-dependent cathepsin D activation. When activated following ADAM30 expression, a decrease in Aβ secretion occurred in vitro and in vivo. ADAM30 under-expression observed in AD brains and thus the impairment of the ADAM30-dependent pathway may favor Aβ peptide production and, ultimately, AD development.

Published
2016
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6. Functional characterization of the AFF (AF4/FMR2) family of RNA-binding proteins: insights into the molecular pathology of FRAXE intellectual disability

Author

Mireille Melko, Samantha Zongaro, Jozef Gecz, Dominique Douguet, Barbara Bardoni, Céline Verheggen, Mounia Bensaid, Institut de pharmacologie moléculaire et cellulaire ( IPMC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Montpellier ( UM ), Department of Genetic Medicine Women's and Children's, University of Adelaide, Université Côte d'Azur ( UCA ), Institut de pharmacologie moléculaire et cellulaire (IPMC), 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), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)

Subjects
MESH : Cell Line, MESH : Molecular Sequence Data, MESH: Sequence Homology, Amino Acid, Gene Expression, RNA-binding protein, MESH: Amino Acid Sequence, MESH: Gene Order, Exon, 0302 clinical medicine, MESH : Protein Transport, Genes, Reporter, Transcription (biology), Gene Order, Genetics (clinical), Genetics, 0303 health sciences, MESH : Amino Acid Sequence, MESH : Sequence Alignment, RNA-Binding Proteins, General Medicine, MESH : Genes, Reporter, Phenotype, MESH : Sequence Homology, Amino Acid, DNA-Binding Proteins, Protein Transport, MESH : Fragile X Syndrome, 030220 oncology & carcinogenesis, RNA splicing, MESH : RNA Splicing, MESH : DNA-Binding Proteins, Intranuclear Space, MESH: Fragile X Syndrome, MESH: Protein Transport, MESH: Gene Expression, RNA Splicing, Molecular Sequence Data, MESH : RNA-Binding Proteins, MESH: Sequence Alignment, MESH: Intranuclear Space, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Cell Line, 03 medical and health sciences, MESH : Fibroblasts, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : HeLa Cells, Amino Acid Sequence, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, Gene, 030304 developmental biology, MESH: Molecular Sequence Data, MESH: Humans, MESH : Gene Order, Sequence Homology, Amino Acid, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, MESH: Genes, Reporter, MESH : Humans, Alternative splicing, RNA, Fibroblasts, MESH: Cell Line, MESH : Gene Expression, MESH: RNA-Binding Proteins, MESH : Intranuclear Space, MESH: Fibroblasts, Fragile X Syndrome, MESH: HeLa Cells, MESH: RNA Splicing, Sequence Alignment, MESH: DNA-Binding Proteins, HeLa Cells
Abstract

International audience; The AFF (AF4/FMR2) family of genes includes four members: AFF1/AF4, AFF2/FMR2, AFF3/LAF4 and AFF4/AF5q31. AFF2/FMR2 is silenced in FRAXE intellectual disability, while the other three members have been reported to form fusion genes as a consequence of chromosome translocations with the myeloid/lymphoid or mixed lineage leukemia (MLL) gene in acute lymphoblastic leukemias (ALLs). All AFF proteins are localized in the nucleus and their role as transcriptional activators with a positive action on RNA elongation was primarily studied. We have recently shown that AFF2/FMR2 localizes to nuclear speckles, subnuclear structures considered as storage/modification sites of pre-mRNA splicing factors, and modulates alternative splicing via the interaction with the G-quadruplex RNA-forming structure. We show here that similarly to AFF2/FMR2, AFF3/LAF4 and AFF4/AF5q31 localize to nuclear speckles and are able to bind RNA, having a high apparent affinity for the G-quadruplex structure. Interestingly, AFF3/LAF4 and AFF4/AF5q31, like AFF2/FMR2, modulate, in vivo, the splicing efficiency of a mini-gene containing a G-quadruplex structure in one alternatively spliced exon. Furthermore, we observed that the overexpression of AFF2/3/4 interferes with the organization and/or biogenesis of nuclear speckles. These findings fit well with our observation that enlarged nuclear speckles are present in FRAXE fibroblasts. Furthermore, our findings suggest functional redundancy among the AFF family members in the regulation of splicing and transcription. It is possible that other members of the AFF family compensate for the loss of AFF2/FMR2 activity and as such explain the relatively mild to borderline phenotype observed in FRAXE patients.

Published
2011
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7. Adrenal Cortex Remodeling and Functional Zona Glomerulosa Hyperplasia in Primary Aldosteronism

Author

Arndt Benecke, Xavier Jeunemaitre, Estelle Louiset, José-Felipe Golib Dzib, Pierre-François Plouin, Sheerazed Boulkroun, Tchao Meatchi, Enzo Lalli, Laurence Amar, Benoit Samson-Couterie, Hervé Lefebvre, Maria-Christina Zennaro, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Institut des Hautes Etudes Scientifiques (IHES), IHES, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Institut de Recherche Interdisciplinaire [Villeneuve d'Ascq] (IRI), Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Droit et Santé-Université de Lille, Sciences et Technologies, Service de génétique [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), Institut des Hautes Etudes Scientifiques ( IHES ), Différenciation et communication neuronale et neuroendocrine ( DC2N ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), UNIROUEN - UFR Santé, Normandie Université ( NU ) -Normandie Université ( NU ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Institut de pharmacologie moléculaire et cellulaire ( IPMC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Université Côte d'Azur ( UCA ), Institut de Recherche Interdisciplinaire [Villeneuve d'Ascq] ( IRI ), Université de Lille, Sciences et Technologies-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA), Université de Lille, Sciences et Technologies-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), and Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)

Subjects
Male, MESH : Steroid 11-beta-Hydroxylase, MESH : Immunohistochemistry, MESH : Adrenal Cortex Neoplasms, MESH: Adrenal Cortex Neoplasms, MESH : Adrenal Cortex, chemistry.chemical_compound, 0302 clinical medicine, Primary aldosteronism, MESH : Female, Aldosterone, In Situ Hybridization, 0303 health sciences, MESH: Middle Aged, Adrenal cortex, MESH : In Situ Hybridization, Middle Aged, MESH : Adult, Hyperplasia, Immunohistochemistry, MESH : Hyperaldosteronism, MESH: Hyperaldosteronism, medicine.anatomical_structure, Female, Zona Glomerulosa, Adenoma, Adult, medicine.medical_specialty, MESH: Zona Glomerulosa, medicine.drug_class, MESH : Male, 030209 endocrinology & metabolism, Biology, MESH: Aldosterone Synthase, 03 medical and health sciences, MESH: In Situ Hybridization, MESH : Hyperplasia, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Internal medicine, Hyperaldosteronism, Internal Medicine, medicine, Cytochrome P-450 CYP11B2, Humans, MESH : Middle Aged, Steroid 11-beta-hydroxylase, 030304 developmental biology, MESH : Aldosterone Synthase, MESH: Adenoma, MESH: Humans, MESH : Aldosterone, MESH: Hyperplasia, MESH : Humans, MESH: Aldosterone, MESH: Immunohistochemistry, MESH: Adult, medicine.disease, Adrenal Cortex Neoplasms, MESH: Male, Endocrinology, MESH : Adenoma, chemistry, Mineralocorticoid, Zona glomerulosa, Adrenal Cortex, Steroid 11-beta-Hydroxylase, MESH: Adrenal Cortex, MESH : Zona Glomerulosa, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, MESH: Steroid 11-beta-Hydroxylase
Abstract

International audience; Primary aldosteronism is the most common form of secondary hypertension with hypokalemia and suppressed renin-angiotensin system caused by autonomous aldosterone production. Our aim was to compare zona glomerulosa (ZG) structure and function between control adrenals and the peritumoral tissue from patients operated on for aldosterone-producing adenoma. ZG morphology and CYP11B1, CYP11B2, and disabled 2 expression were studied in 15 control adrenals and 25 adrenals with aldosterone-producing adenoma. A transcriptome analysis was done using publicly available data sets. In control adrenals, ZG was discontinuous, and CYP11B2 expression was focal or partly continuous and localized to 3 structures, foci, megafoci, and aldosterone-producing cell clusters. CYP11B2 expression was restricted to a limited number of ZG cells expressing Dab2 but not CYP11B1; aldosterone-producing cell clusters were composed of cells with an intermediate phenotype expressing CYP11B2 but not disabled 2 or CYP11B1. In peritumoral tissue, large remodeling of the adrenal cortex was observed with increased nodulation and decreased vascularization that were not correlated with CYP11B2 expression. In 17 out of 25 adrenals, hyperplasia of adjacent ZG was observed with persistent expression of CYP11B2 that was extended to the entire ZG. In all of the adrenals from patients with aldosterone-producing adenoma, CYP11B2 expression was present in foci, megafoci, and aldosterone-producing cell clusters. Transcriptome profiling indicates a close relationship between peritumoral and control adrenal cortex. In conclusion, adrenal cortex remodeling, reduced vascularization, and ZG hyperplasia are major features of adrenals with aldosterone-producing adenoma. Transcriptional phenotyping is not in favor of this being an intermediate step toward the formation of aldosterone-producing adenoma.

Published
2010
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8. Transcriptional repression of microRNA genes by PML-RARA increases expression of key cancer proteins in acute promyelocytic leukemia

Author

Bernard Mari, Elodie Portales-Casamar, Bruno Cassinat, Evelyne Friederich, Christine Chomienne, Khalil Arar, Pascal Barbry, Thomas Maurin, Anne Saumet, Manuella Bouttier, Laurent Vallar, Guillaume Vetter, Charles-Henri Lecellier, Wyeth W. Wasserman, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Cytoskeleton and Cell Plasticity Lab, Université du Luxembourg (Uni.lu), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), University of British Columbia (UBC), Institut de pharmacologie moléculaire et cellulaire (IPMC), 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), Centre de Recherche Public Santé, CRP-Santé Luxembourg, Sigma-Proligo, Granulopoiese et Processus Leucemiques (UMR_S_718), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Université du Luxembourg ( Uni.lu ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), University of British Columbia ( UBC ), Institut de pharmacologie moléculaire et cellulaire ( IPMC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Granulopoiese et Processus Leucemiques, and Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )

Subjects
Oncogene Proteins, Fusion, Transcription, Genetic, Retinoic acid, MESH : Leukemia, Promyelocytic, Acute, MESH : Oncogene Proteins, Fusion, Biochemistry, chemistry.chemical_compound, 0302 clinical medicine, Leukemia, Promyelocytic, Acute, MESH : Tumor Markers, Biological, MESH : Homeodomain Proteins, RNA, Neoplasm, MESH : Tretinoin, Regulation of gene expression, 0303 health sciences, Gene Expression Regulation, Leukemic, Myeloid leukemia, Hematology, MESH : Arsenic, 3. Good health, MESH : Antineoplastic Agents, Leukemia, 030220 oncology & carcinogenesis, MESH: Cell Adhesion Molecules, MESH: Gene Expression Regulation, Leukemic, medicine.drug, Acute promyelocytic leukemia, MESH: Cell Line, Tumor, Immunology, Antineoplastic Agents, Tretinoin, Biology, MESH : Cell Adhesion Molecules, Arsenic, 03 medical and health sciences, Cell Line, Tumor, MESH: Arsenic, MESH: Homeodomain Proteins, microRNA, Biomarkers, Tumor, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Homeodomain Proteins, MESH: Tretinoin, MESH: Humans, MESH : Cell Line, Tumor, MESH: Transcription, Genetic, MESH : Humans, MESH : Transcription, Genetic, Cell Biology, MESH: RNA, Neoplasm, medicine.disease, MESH : MicroRNAs, MicroRNAs, MESH : RNA, Neoplasm, MESH : Gene Expression Regulation, Leukemic, chemistry, Retinoic acid receptor alpha, MESH: Tumor Markers, Biological, Cancer research, MESH: Antineoplastic Agents, Cell Adhesion Molecules, MESH: MicroRNAs, MESH: Leukemia, Promyelocytic, Acute, MESH: Oncogene Proteins, Fusion
Abstract

Micro(mi)RNAs are small noncoding RNAs that orchestrate many key aspects of cell physiology and their deregulation is often linked to distinct diseases including cancer. Here, we studied the contribution of miRNAs in a well-characterized human myeloid leukemia, acute promyelocytic leukemia (APL), targeted by retinoic acid and trioxide arsenic therapy. We identified several miRNAs transcriptionally repressed by the APL-associated PML-RAR oncogene which are released after treatment with all-trans retinoic acid. These coregulated miRNAs were found to control, in a coordinated manner, crucial pathways linked to leukemogenesis, such as HOX proteins and cell adhesion molecules whose expressions are thereby repressed by the chemotherapy. Thus, APL appears linked to transcriptional perturbation of miRNA genes, and clinical protocols able to successfully eradicate cancer cells may do so by restoring miRNA expression. The identification of abnormal miRNA biogenesis in cancer may therefore provide novel biomarkers and therapeutic targets in myeloid leukemias.

Published
2009
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9. Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype

Author

Catherine Heurteaux, Nicolas Guy, Malika El Yacoubi, Susanne Thümmler, Guillaume Lucas, Jean-Marie Vaugeois, Nicolas Blondeau, Marc Borsotto, Guy Debonnel, Xiao-Dong Peng, Gabriella Gobbi, Michel Lazdunski, Catherine Widmann, Florence Noble, Institut de pharmacologie moléculaire et cellulaire ( IPMC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Child Psychiatry, McGill University, Neuropsycho-pharmacologie expérimentale, Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Centre National de la Recherche Scientifique ( CNRS ), Pharmacochimie moléculaire et structurale, Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -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 de pharmacologie moléculaire et cellulaire (IPMC), 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), McGill University = Université McGill [Montréal, Canada], Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Serotonin, medicine.medical_specialty, Genotype, Drug Resistance, Pharmacology, Biology, Neurotransmission, Synaptic Transmission, Mice, 03 medical and health sciences, chemistry.chemical_compound, Potassium Channels, Tandem Pore Domain, 0302 clinical medicine, Corticosterone, Fluoxetine, Internal medicine, medicine, Animals, Neurotransmitter, Depression (differential diagnoses), 030304 developmental biology, Mice, Knockout, Analysis of Variance, Depressive Disorder, 0303 health sciences, Behavior, Animal, Pyramidal Cells, General Neuroscience, Antidepressive Agents, Potassium channel, 3. Good health, Phenotype, Endocrinology, chemistry, Antidepressant, Gene Deletion, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery, medicine.drug
Abstract

Depression is a devastating illness with a lifetime prevalence of up to 20%. The neurotransmitter serotonin or 5-hydroxytryptamine (5-HT) is involved in the pathophysiology of depression and in the effects of antidepressant treatments. However, molecular alterations that underlie the pathology or treatment of depression are still poorly understood. The TREK-1 protein is a background K+ channel regulated by various neurotransmitters including 5-HT. In mice, the deletion of its gene (Kcnk2, also called TREK-1) led to animals with an increased efficacy of 5-HT neurotransmission and a resistance to depression in five different models and a substantially reduced elevation of corticosterone levels under stress. TREK-1–deficient (Kcnk2−/−) mice showed behavior similar to that of naive animals treated with classical antidepressants such as fluoxetine. Our results indicate that alterations in the functioning, regulation or both of the TREK-1 channel may alter mood, and that this particular K+ channel may be a potential target for new antidepressants.

Published
2006
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10. Evidence for Constitutive Microbiota-Dependent Short-Term Control of Food Intake in Mice: Is There a Link with Inflammation, Oxidative Stress, Endotoxemia, and GLP-1?

Author

Selma Ben Fradj, Emmanuelle Nédélec, Juliette Salvi, Mélanie Fouesnard, Marine Huillet, Gaëtan Pallot, Céline Cansell, Clara Sanchez, Catherine Philippe, Vincent Gigot, Aleth Lemoine, Doriane Trompier, Thomas Henry, Virginie Petrilli, Benedicte F. Py, Hervé Guillou, Nicolas Loiseau, Sandrine Ellero-Simatos, Jean-Louis Nahon, Carole Rovère, Jacques Grober, Gaelle Boudry, Véronique Douard, Alexandre Benani, Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut de pharmacologie moléculaire et cellulaire (IPMC), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-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), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Toxicologie Intégrative & Métabolisme (ToxAlim-TIM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), This work was supported by the French ‘‘Investissements d’Avenir’’ program, project ISITE-BFC (contract National Research Agency (ANR)-15-IDEX-0003), by the ANR (contract ANR-21-CE14-0033), by the Re´gion Bourgogne and FEDER program (contract 2019-6200FEO047S00409) toA.B., by the INRAE grant ‘‘Action Prioritaire du De´partement Alimentation Humaine’’ to A.B., G.B., and V.D., by the Medisite Foundation and the French government, managed by the ANR, through the UCAJEDI Investments in the Future project (contract ANR-15-IDEX-01) to C.C., C.S.,J.L.N., and C.R., by the LABEX SIGNALIFE program (contract ANR-11-LABX-0028-01) to J.L.N. and C.R., and by the Fondation pour la Recherche Me´dicale (contract DEQ20170336744) to V.P., ANR-15-IDEX-0003,BFC,ISITE ' BFC(2015), ANR-21-CE14-0033,MicroFlamEAT,Rôle de la réponse inflammatoire microgliale postprandiale dans le contrôle cérébral du comportement alimentaire(2021), ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), 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), Université Bourgogne Franche-Comté [COMUE] (UBFC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), 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-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Montpellier (UM), Physiologie de la Nutrition et du Comportement Alimentaire (PNCA (UMR 0914)), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Département cancer environnement (Centre Léon Bérard - Lyon), Centre Léon Bérard [Lyon], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Institut Agro Dijon, and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)

Subjects
food intake, Physiology, [SDV]Life Sciences [q-bio], satiety, Clinical Biochemistry, eating disorders, digestive system, Biochemistry, Eating, Mice, Glucagon-Like Peptide 1, Mice, Inbred NOD, Appetite Depressants, microbiota, Animals, energy homeostasis, Molecular Biology, General Environmental Science, Inflammation, digestive, oral, and skin physiology, Cell Biology, Endotoxemia, Oxidative Stress, gut, General Earth and Planetary Sciences, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

International audience; AIMS: Although prebiotics, probiotics, and fecal transplantation can alter the sensation of hunger and/or feeding behavior, the role of the constitutive gut microbiota in the short-term regulation of food intake during normal physiology is still unclear. RESULTS: An antibiotic-induced microbiota depletion study was designed to compare feeding behavior in conventional and microbiota-depleted mice. Tissues were sampled to characterize the time profile of microbiota-derived signals in mice during consumption of either standard or high-fat food for 1 hour. Pharmacological and genetic tools were used to evaluate the contribution of postprandial endotoxemia and inflammatory responses in the short-term regulation of food intake. We observed constitutive microbial and macronutrient-dependent control of food intake at the time scale of a meal, i.e., within 1 hour of food introduction. Specifically, microbiota depletion increased food intake and the microbiota-derived anorectic effect became significant during the consumption of high-fat but not standard food. This anorectic effect correlated with a specific postprandial microbial metabolic signature and did not require postprandial endotoxemia or an NLRP3 (NOD-, LRR- and Pyrin domain-containing protein 3)-inflammasome mediated inflammatory response. Innovation and Conclusion: These findings show that the gut microbiota controls host appetite at the time scale of a meal under normal physiology. Interestingly, a microbiota-derived anorectic effect develops specifically with a high-fat meal, indicating that gut microbiota activity is involved in the satietogenic properties of foods.

Published
2022
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11. Idealized multiple-timescale model of cortical spreading depolarization initiation and pre-epileptic hyperexcitability caused by NaV1.1/SCN1A mutations

Author

Louisiane Lemaire, Mathieu Desroches, Martin Krupa, Massimo Mantegazza, Mathématiques pour les Neurosciences (MATHNEURO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Bernstein Center for Computational Neuroscience [Berlin], Humboldt University Of Berlin, Laboratoire Jean Alexandre Dieudonné (LJAD), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut de pharmacologie moléculaire et cellulaire (IPMC), and Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Applied Mathematics, Modeling and Simulation, [MATH.MATH-DS]Mathematics [math]/Dynamical Systems [math.DS], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Agricultural and Biological Sciences (miscellaneous)
Abstract

NaV1.1 (SCN1A) is a voltage-gated sodium channel mainly expressed in GABAergic neurons. Loss of function mutations of NaV1.1 lead to epileptic disorders, while gain of function mutations cause a migraine in which cortical spreading depolarizations (CSDs) are involved. It is still debated how these opposite effects initiate two different manifestations of neuronal hyperactivity: epileptic seizures and CSD. To investigate this question, we previously built a conductance-based model of two neurons (GABAergic and pyramidal), with dynamic ion concentrations (Lemaire et al. in PLOS Comput. Biol. 17(7):e1009239, 2021). When implementing either NaV1.1 migraine or epileptogenic mutations, ion concentration modifications acted as slow processes driving the system to the corresponding pathological firing regime. However, the large dimensionality of the model complicated the exploitation of its implicit multi-timescale structure. Here, we substantially simplify our biophysical model to a minimal version more suitable for bifurcation analysis. The explicit timescale separation allows us to apply slow-fast theory, where slow variables are treated as parameters in the fast singular limit. In this setting, we reproduce both pathological transitions as dynamic bifurcations in the full system. In the epilepsy condition, we shift the spike-terminating bifurcation to lower inputs for the GABAergic neuron, to model an increased susceptibility to depolarization block. The resulting failure of synaptic inhibition triggers hyperactivity of the pyramidal neuron. In the migraine scenario, spiking-induced release of potassium leads to the abrupt increase of the extracellular potassium concentration. This causes a dynamic spike-terminating bifurcation of both neurons, which we interpret as CSD initiation.

Published
2023
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12. Predicting hERG repolarization power at 37°C from recordings at room temperature

Author

Barbara B. R. Oliveira‐Mendes, Malak Alameh, Jérôme Montnach, Béatrice Ollivier, Solène Gibaud, Sylvain Feliciangeli, Florian Lesage, Flavien Charpentier, Gildas Loussouarn, Michel De Waard, Isabelle Baró, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), LabEx Ion Channels Science and Therapeutics [France], Institut du Thorax [Nantes], Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice (CHU Nice), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)

Subjects
[SDV]Life Sciences [q-bio], Molecular Medicine, Medicine (miscellaneous)
Abstract

International audience; Dear Editor, Loss-of-function and gain-of-function mutations in the KCNH2 gene cause long and short-QT syndromes (LQTS or SQTS), respectively, predisposing to life-threatening F I G U R E 1 Repolarization power of wild-type (WT) hERG as a function of temperature. A simplified and optimized action potential was applied (AP-clamp) by an automated patch clamp system in 384-well plates on HEK293 cells stably expressing hERG. (A) Mean (± SEM) current recordings during AP-clamp at various temperatures (in pA, n = 194, 211, 114 and 172 cells at 22-37 • C, respectively). Dashed line: AP time course (voltage scale: right Y axis). (B) Mean (± SEM) current recordings during AP-clamp at 27 • C for AP of various durations (see inset for APs; for currents: n = 168−254 for Time x 0.5 to x 5). The small inward current observed in (A) and (B), when the AP is returning to resting values, is attributed to contamination of the intracellular solution by the extracellular Tyrode solution, intrinsic to the cell catch process in the automated patch clamp (see supplementary information). (C) Mean (± SEM) time integral of the recorded currents: repolarization power, at various temperatures versus time factor (n = 155−232, 168−254, 79−133 and 144−173 at 22-37 • C, respectively). Horizontal dashed line: repolarization power at 37 • C: 22.3 pA.s. (D) As in (B), at 27 • C, after time and current corrections using various factors from 1.5 to 3 on the respective recordings. For example, for the recordings obtained during the AP of 2 x duration, the time was divided by 2 and the current multiplied by 2. Note the overlap of the current corrected by the factor of 2 at 27 • C (black) with the reference current obtained during the standard AP at 37 • C (red).

Published
2023
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13. Dysfonction mitochondriale et défaillance de la mitophagie dans la maladie d’Alzheimer

Author

Loan Vaillant-Beuchot, Frédéric Checler, Arnaud Mary, Mounia Chami, Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Chemistry, [SDV]Life Sciences [q-bio], General Medicine, ComputingMilieux_MISCELLANEOUS, 030217 neurology & neurosurgery, General Biochemistry, Genetics and Molecular Biology, 030304 developmental biology
Abstract

International audience; No abstract available

Published
2021
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14. Dkk3 is a component of the genetic circuitry regulating aldosterone biosynthesis in the adrenal cortex

Author

Sascha Bandulik, Abeer El Wakil, Nicolas Guy, Maria-Christina Zennaro, Jacques Barhanin, Christof Niehrs, Saïd Bendahhou, Enzo Lalli, Richard Warth, Bernard Mari, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Medical Cell Biology, Universität Regensburg (UR), Laboratoire de PhysioMédecine Moléculaire (LP2M), 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), Ion Channel Science and Therapeutics, Laboratories of Excellence, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Department of Molecular Embryology, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Institute of Molecular Biology, Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie moléculaire et cellulaire ( IPMC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Université Côte d'Azur ( UCA ), University of Regensburg, Laboratoire de PhysioMédecine Moléculaire ( LP2M ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Paris Descartes - Paris 5 ( UPD5 ), and DKFZ

Subjects
Aldosterone synthase, Male, medicine.medical_specialty, 030209 endocrinology & metabolism, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Primary aldosteronism, Internal medicine, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Renin–angiotensin system, Hyperaldosteronism, Genetics, medicine, Animals, Cluster Analysis, Gene Silencing, Molecular Biology, Aldosterone, Genetics (clinical), 030304 developmental biology, Adaptor Proteins, Signal Transducing, Mice, Knockout, 0303 health sciences, biology, Adrenal gland, Adrenal cortex, Gene Expression Profiling, General Medicine, medicine.disease, Phenotype, medicine.anatomical_structure, Endocrinology, chemistry, Gene Expression Regulation, Zona glomerulosa, biology.protein, Adrenal Cortex, Intercellular Signaling Peptides and Proteins, Calcium, Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Primary aldosteronism (PA, autonomous aldosterone production from the adrenal cortex) causes the most common form of secondary arterial hypertension (HT), which is also the most common curable form of HT. Recent studies have highlighted an important role of mutations in genes encoding potassium channels in the pathogenesis of PA, both in human disease and in animal models. Here, we have exploited the unique features of the hyperaldosteronemic phenotype of Kcnk3 null mice, which is dependent on sexual hormones, to identify genes whose expression is modulated in the adrenal gland according to the dynamic hyperaldosteronemic phenotype of those animals. Genetic inactivation of one of the genes identified by our strategy, dickkopf-3 (Dkk3), whose expression is increased by calcium influx into adrenocortical cells, in the Kcnk3 null background results in the extension of the low-renin, potassium-rich diet insensitive hyperaldosteronemic phenotype to the male sex. Compound Kcnk3/Dkk3 animals display an increased expression of Cyp11b2, the rate-limiting enzyme for aldosterone biosyntheis in the adrenal zona glomerulosa (ZG). Our data show that Dkk3 can act as a modifier gene in a mouse model for altered potassium channel function and suggest its potential involvement in human PA syndromes.

Published
2012
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15. Combining affinity purification and mass spectrometry to define the network of the nuclear proteins interacting with the N-terminal region of FMRP

Author

Félicie Kieffer, Fahd Hilal, Anne-Sophie Gay, Delphine Debayle, Marie Pronot, Gwénola Poupon, Iliona Lacagne, Barbara Bardoni, Stéphane Martin, Carole Gwizdek, Martin, Stephane, Explorer des stratégies innovantes pour restaurer la fonction synaptique et les comportements sociocognitifs dans un modèle murin exprimant une mutation récurrente du syndrome du X fragile chez l'humain - - InnoVinFXS2020 - ANR-20-CE16-0006 - AAPG2020 - VALID, Centres d'excellences - Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie - - SIGNALIFE2011 - ANR-11-LABX-0028 - LABX - VALID, Idex UCA JEDI - - UCA JEDI2015 - ANR-15-IDEX-0001 - IDEX - VALID, Institut de pharmacologie moléculaire et cellulaire (IPMC), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-20-CE16-0006,InnoVinFXS,Explorer des stratégies innovantes pour restaurer la fonction synaptique et les comportements sociocognitifs dans un modèle murin exprimant une mutation récurrente du syndrome du X fragile chez l'humain(2020), ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), and ANR-15-IDEX-0001,UCA JEDI,Idex UCA JEDI(2015)

Subjects
[SDV] Life Sciences [q-bio], [SCCO]Cognitive science, [SDV]Life Sciences [q-bio], [SCCO] Cognitive science, Biochemistry, Genetics and Molecular Biology (miscellaneous), Molecular Biology, Biochemistry
Abstract

Fragile X-Syndrome (FXS) represents the most common inherited form of intellectual disability and the leading monogenic cause of Autism Spectrum Disorders. In most cases, this disease results from the absence of expression of the protein FMRP encoded by the FMR1 gene (Fragile X messenger ribonucleoprotein 1). FMRP is mainly defined as a cytoplasmic RNA-binding protein regulating the local translation of thousands of target mRNAs. Interestingly, FMRP is also able to shuttle between the nucleus and the cytoplasm. However, to date, its roles in the nucleus of mammalian neurons are just emerging. To broaden our insight into the contribution of nuclear FMRP in mammalian neuronal physiology, we identified here a nuclear interactome of the protein by combining subcellular fractionation of rat forebrains with pull‐ down affinity purification and mass spectrometry analysis. By this approach, we listed 55 candidate nuclear partners. This interactome includes known nuclear FMRP-binding proteins as Adar or Rbm14 as well as several novel candidates, notably Ddx41, Poldip3, or Hnrnpa3 that we further validated by target‐specific approaches. Through our approach, we identified factors involved in different steps of mRNA biogenesis, as transcription, splicing, editing or nuclear export, revealing a potential central regulatory function of FMRP in the biogenesis of its target mRNAs. Therefore, our work considerably enlarges the nuclear proteins interaction network of FMRP in mammalian neurons and lays the basis for exciting future mechanistic studies deepening the roles of nuclear FMRP in neuronal physiology and the etiology of the FXS.

Published
2022
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16. Lipoprotein-associated and secreted phospholipases A₂ in cardiovascular disease: roles as biological effectors and biomarkers

Author

Mallat, Ziad, Lambeau, Gérard, Tedgui, Alain, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de pharmacologie moléculaire et cellulaire ( IPMC ), Université Nice Sophia Antipolis ( UNS ), and Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
MESH: Inflammation, MESH: Group IV Phospholipases A2, MESH : Atherosclerosis, MESH : Polymorphism, Genetic, Lipoproteins, enzymes, MESH : Group VI Phospholipases A2, MESH : Lipoproteins, MESH: Prognosis, MESH: Atherosclerosis, Group VI Phospholipases A2, MESH : Group IV Phospholipases A2, Predictive Value of Tests, MESH: Polymorphism, Genetic, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH: Group VI Phospholipases A2, Humans, MESH : Predictive Value of Tests, ComputingMilieux_MISCELLANEOUS, Inflammation, MESH : Inflammation, MESH : Prognosis, MESH: Humans, Polymorphism, Genetic, Group IV Phospholipases A2, MESH : Humans, MESH: Biological Markers, MESH: Lipoproteins, Atherosclerosis, Prognosis, MESH: Predictive Value of Tests, MESH : Biological Markers, [SDV.IMM]Life Sciences [q-bio]/Immunology, Biomarkers
Abstract

International audience

Published
2010
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17. Fluorescent‐ and tagged‐protoxin II peptides: potent markers of the Na v 1.7 channel pain target

Author

Claude Zoukimian, Jérôme Montnach, Patrick Delmas, Nancy Osorio, Michel De Waard, Céline Marionneau, Sophie Burel, Massimo Mantegazza, Rachid Boukaiba, Sébastien Nicolas, Rémy Béroud, Michel Partiseti, Stephan De Waard, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Smartox Biotechnology, Institut de pharmacologie moléculaire et cellulaire (IPMC), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Sanofi-Aventis R&D, SANOFI Recherche, ANR-16-CE92-0013,Progress DHF,Mécanismes de la progression de la dysfonction diastolique vers l'insuffisance cardiaque(2016), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-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)-Aix Marseille Université (AMU), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
0301 basic medicine, Gene isoform, pain target, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Protoxin II, Peptide, Gating, 03 medical and health sciences, 0302 clinical medicine, Automated patch clamp, voltage-gated sodium channel, automated patchclamp, Receptor, Nav1.7, cellular distribution, Pharmacology, chemistry.chemical_classification, pull-down, Sodium channel, cell line, 030104 developmental biology, chemistry, Cell culture, Biotinylation, biotinylated analogue, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Biophysics, fluorescent analogue, 030217 neurology & neurosurgery
Abstract

Background and purpose Protoxin II (ProTx II) is a high affinity gating modifier that is thought to selectively block the Nav 1.7 voltage-dependent Na+ channel, a major therapeutic target for the control of pain. We aimed at producing ProTx II analogues entitled with novel functionalities for cell distribution studies and biochemical characterization of its Nav channel targets. Experimental approach We took advantage of the high affinity properties of the peptide, combined to its slow off rate, to design a number of new tagged analogues useful for imaging and biochemistry purposes. We used high-throughput automated patch-clamp to identify the analogues best matching the native properties of ProTx II and validated them on various Nav -expressing cells in pull-down and cell distribution studies. Key results Two of the produced ProTx II analogues, Biot-ProTx II and ATTO488-ProTx II, best recapitulate the pharmacological properties of unlabelled ProTx II, while other analogues remain high affinity blockers of Nav 1.7. The biotinylated version of ProTx II efficiently works for the pull-down of several Nav isoforms tested in a concentration-dependent manner, while the fluorescent ATTO488-ProTx II specifically labels the Nav 1.7 channel over other Nav isoforms tested in various experimental conditions. Conclusions and implications The properties of these ProTx II analogues as tools for Nav channel purification and cell distribution studies pave the way for a better understanding of ProTx II channel receptors in pain and their pathophysiological implications in sensory neuronal processing. The new fluorescent ProTx II should also reveal itself useful for the design of new drug screening strategies.

Published
2021
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18. Sublingual vaccination and delivery systems

Author

Claire Monge, Bernard Verrier, Evelyne Colomb, A.L. Paris, F. Anjuère, Laboratoire de Biologie Tissulaire et d'ingénierie Thérapeutique UMR 5305 (LBTI), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
Protective immunity, [SDV]Life Sciences [q-bio], First line, Administration, Sublingual, Pharmaceutical Science, 02 engineering and technology, Buccal mucosa, 03 medical and health sciences, Vaccine administration, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Humans, Medicine, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, Adverse effect, Patient compliance, Immunity, Mucosal, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Vaccines, 0303 health sciences, business.industry, Vaccination, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, 021001 nanoscience & nanotechnology, 3. Good health, [CHIM.POLY]Chemical Sciences/Polymers, [SDV.SP.PG]Life Sciences [q-bio]/Pharmaceutical sciences/Galenic pharmacology, Immunization, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Immunology, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, 0210 nano-technology, business
Abstract

International audience; Most infectious agents use mucosal tissues as entry portals, thus, mucosae are frequently defined as a first line of defense against pathogens. Mucosal protection generally operates through antibody-mediated and cytotoxic Tcell responses which can be triggered by mucosal vaccines. Sublingual vaccination provides many advantages such as systemic and mucosal responses (both locally and at remote mucosal sites), besides being a needle-free administration route with high patient compliance and limited adverse effects. Buccal mucosa complexity nonetheless represents a challenge for vaccine administration, hence, many efforts were recently deployed to improve vaccine components, mucoadhesion and/or penetration. Several innovative approaches indeed confirmed that a robust and protective immunity can be achieved by sublingual vaccines. This review will then specify the most recent delivery systems and improvements developed to increase sublingual vaccines efficiency. We will focus our description on the immune mechanisms involved and the requirements for optimal sublingual immunization and mucosal protection.

Published
2021
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19. A novel microduplication in <scp> INPP5A </scp> segregates with schizophrenia spectrum disorder in the family of a patient with both childhood onset schizophrenia and autism spectrum disorder

Author

Małgorzata Drozd, Maria Capovilla, Florence Askenazy, Susanne Thümmler, Arnaud Fernandez, Barbara Bardoni, Hôpitaux Pédiatriques de Nice Lenval (CHU-Lenval), Centre Hospitalier Universitaire de Nice (CHU Nice), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
0301 basic medicine, inositol pathway, INPP5A, MESH: Pedigree, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, CNV, Central nervous system, Dendritic spine morphogenesis, 030105 genetics & heredity, MESH: Phenotype, behavioral disciplines and activities, MESH: Child Development Disorders, Pervasive, MESH: Brain, 03 medical and health sciences, Neurodevelopmental disorder, MESH: Child, mental disorders, Gene duplication, Genetics, medicine, MESH: Animals, childhood-onset schizophrenia, MESH: Inositol Polyphosphate 5-Phosphatases, MESH: Mice, Gene, Genetics (clinical), MESH: Adolescent, MESH: Autism Spectrum Disorder, MESH: Humans, business.industry, MESH: Genetic Predisposition to Disease, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, MESH: Adult, medicine.disease, neurodevelopmental disorder, MESH: Male, Pathophysiology, MESH: Siblings, 030104 developmental biology, medicine.anatomical_structure, MESH: Young Adult, Autism spectrum disorder, Schizophrenia, MESH: Disease Models, Animal, business, MESH: Female, MESH: Schizophrenia, Childhood
Abstract

Childhood-Onset Schizophrenia (COS) is a very rare and severe psychiatric disorder defined by adult schizophrenia symptoms occurring before the age of 13. We report a microduplication in the 10q26.3 region including part of the Inositol Polyphosphate-5-Phosphatase A (INPP5A) gene that segregates with Schizophrenia Spectrum Disorders (SSDs) in the family of a female patient affected by both COS and Autism Spectrum Disorder (ASD). Phenotyping and genotyping (including CGH-array) were performed for mother, healthy sister, and affected child according to the GenAuDiss protocol (NCT02565524). The duplication size is 324 kb and is present in a patient with COS and in her mother with SSD, but not in the patient's healthy sister. INPP5A encodes a membrane-associated 43 kDa type I inositol 1,4,5-trisphosphate (InsP3) 5-phosphatase. This protein is found both in mouse and human brains and we found that its Drosophila homologue 5PtaseI is specifically expressed in the central nervous system. Hydrolyzed products from InsP3 5-phosphatases mobilize intracellular calcium, which is relevant for dendritic spine morphogenesis in neurons and altered in both schizophrenia and ASD. These may constitute arguments in favor of this gene alteration in the pathophysiology of COS.

Published
2021
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20. Non-canonical miRNA-RNA base-pairing impedes tumor suppressor activity of miR-16

Author

Anaïs M Quéméner, Laura Bachelot, Marc Aubry, Stéphane Avner, Delphine Leclerc, Gilles Salbert, Florian Cabillic, Didier Decaudin, Bernard Mari, Frédéric Mouriaux, Marie-Dominique Galibert, David Gilot, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-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 Curie [Paris], Institut de pharmacologie moléculaire et cellulaire (IPMC), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Ligue Nationale Contre le Cancer, French Ministry of Research, Fondation ARC pour la Recherche, AVIESAN Plan Cancer, Région Bretagne, University of Rennes 1, CNRS, Ministère de la Recherche et de l’Enseignement Supérieur, Rennes Métropole, and Chard-Hutchinson, Xavier

Subjects
[SDV] Life Sciences [q-bio], Adult, Uveal Neoplasms, MicroRNAs, Ecology, Health, Toxicology and Mutagenesis, [SDV]Life Sciences [q-bio], Humans, Plant Science, Cyclin D3, Biochemistry, Genetics and Molecular Biology (miscellaneous), Base Pairing, Melanoma
Abstract

Uveal melanoma (UM), the most common primary intraocular tumor in adults, has been extensively characterized by omics technologies during the last 5 yr. Despite the discovery of gene signatures, the molecular actors driving cancer aggressiveness are not fully understood, and UM is still associated with very poor overall survival (OS) at the metastatic stage. By defining the miR-16 interactome, we revealed that miR-16 mainly interacts via non-canonical base-pairing to a subset of RNAs, promoting their expression levels. Consequently, the canonical miR-16 activity, involved in the RNA decay of oncogenes, such ascyclin D3, is impaired. This non-canonical base-pairing can explain both the derepression of miR-16 targets and the promotion of oncogene expression observed in patients with poor OS in two cohorts. miR-16 activity, assessment using our RNA signature, discriminates the patient’s OS as effectively as current methods. To the best of our knowledge, this is the first time that a predictive signature has been composed of genes belonging to the same mechanism (miR-16) in UM. Altogether, our results strongly suggest that UM is a miR-16 disease.

Published
2022
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21. Microgliosis: a double-edged sword in the control of food intake

Author

Juliette Salvi, Pierre Andreoletti, Etienne Audinat, Eglantine Balland, Selma Ben Fradj, Mustapha Cherkaoui‐Malki, Tony Heurtaux, Fabienne Liénard, Emmanuelle Nédélec, Carole Rovère, Stéphane Savary, Anne Véjux, Doriane Trompier, Alexandre Benani, Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire Bio-PeroxIL. Biochimie du peroxysome, inflammation et métabolisme lipidique [Dijon] (BIO-PEROXIL), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Monash university, Institut de pharmacologie moléculaire et cellulaire (IPMC), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Luxembourg Center of Neuropathology (LCNP), University of Luxembourg [Luxembourg], Agence Nationale de la Recherche., ANR-21-CE14-0033,MicroFlamEAT,Rôle de la réponse inflammatoire microgliale postprandiale dans le contrôle cérébral du comportement alimentaire(2021), Guerineau, Nathalie C., and Rôle de la réponse inflammatoire microgliale postprandiale dans le contrôle cérébral du comportement alimentaire - - MicroFlamEAT2021 - ANR-21-CE14-0033 - AAPG2021 - VALID

Subjects
food intake, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Cell Biology, eating disorders, Biochemistry, lipids, inflammation, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Microglia, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], hypothalamus, Molecular Biology, energy homeostasis
Abstract

State-of-the-Art review.; International audience; Maintaining energy balance is essential for survival and health. This physiological function is controlled by the brain, which adapts food intake to energy needs. Indeed, the brain constantly receives a multitude of biological signals that are derived from digested foods, or that originate from the gastrointestinal tract, energy stores (liver and adipose tissues), and from other metabolically active organs (muscles). These signals, which include circulating nutrients, hormones, and neuronal inputs from the periphery, collectively provide information on the overall energy status of the body. In the brain, several neuronal populations can specifically detect these signals. Nutrient-sensing neurons are found in discrete brain areas and are highly enriched in the hypothalamus. In turn, specialized brain circuits coordinate homeostatic responses acting mainly on appetite, peripheral metabolism, activity and arousal. Accumulating evidence shows that hypothalamic microglial cells located at the vicinity of these circuits can influence the brain control of energy balance. However, microglial cells could have opposite effects on energy balance, i.e., homeostatic or detrimental, and the conditions for this shift are not totally understood yet. One hypothesis relies on the extent of microglial activation, and nutritional lipids can considerably change it.

Published
2022
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22. NK Cell and Fibroblast-Mediated Regulation of Skin Squamous Cell Carcinoma Invasion by CLEC2A Is Compromised in Xeroderma Pigmentosum

Author

Alain Sarasin, Miguel Basante, Thierry Magnaldo, Maria Goncalves-Maia, Estelle Cosson, Yannick Gache, Veronique M. Braud, Sébastien Schaub, Emie Salavagione, M.-F. Avril, Margot Muller, Françoise Bernerd, CNRS UMR7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Université Côte d'Azur (UCA), Institut de pharmacologie moléculaire et cellulaire (IPMC), 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), L'OREAL, Research & Innovation, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Biologie Valrose (IBV), 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), Institut Gustave Roussy (IGR), Intégrité du génome et cancers (IGC), Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Saclay, ANR-15-IDEX-0001,UCA JEDI,Idex UCA JEDI(2015), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Université Côte d'Azur (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)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
Male, 0301 basic medicine, Skin Neoplasms, Biopsy, [SDV]Life Sciences [q-bio], Cell, Cell Communication, Biochemistry, 0302 clinical medicine, Cancer-Associated Fibroblasts, Tumor Microenvironment, Child, Immunologic Surveillance, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Skin, Aged, 80 and over, education.field_of_study, integumentary system, 3. Good health, DNA-Binding Proteins, Killer Cells, Natural, medicine.anatomical_structure, Child, Preschool, 030220 oncology & carcinogenesis, Carcinoma, Squamous Cell, Female, Receptors, NK Cell Lectin-Like, Adult, Xeroderma pigmentosum, Adolescent, Primary Cell Culture, Population, Dermatology, Biology, Young Adult, 03 medical and health sciences, Skin Squamous Cell Carcinoma, medicine, Humans, Lectins, C-Type, Neoplasm Invasiveness, Fibroblast, education, Molecular Biology, Aged, Xeroderma Pigmentosum, Tumor microenvironment, Gene Expression Profiling, Infant, Newborn, Infant, Cell Biology, medicine.disease, Coculture Techniques, 030104 developmental biology, Cell culture, Cancer cell, Cancer research
Abstract

The ability of cancer cells to invade and disseminate can be affected by components of the surrounding microenvironment. To identify dermal components that regulate the growth of epidermal carcinomas, we studied the genetic disease called xeroderma pigmentosum that bears mutations in genes involved in the nucleotide excision repair of DNA. Patients with xeroderma pigmentosum are more prone to develop cutaneous tumors than the general population and their dermal fibroblasts display the features of dermal cancer-associated fibroblasts, which promote the invasion of keratinocytes. Here, we report that 3-dimensional dermal cultures of fibroblasts from healthy donors but not from patients with xeroderma pigmentosum complementation group C express CLEC2A, which is the ligand of the activating NK cell receptor NKp65. A similar loss of CLEC2A was observed in sporadic dermal cancer-associated fibroblasts and upon the culture of fibroblasts with cutaneous squamous cell carcinoma-conditioned medium. Using an innovative 3-dimensional organotypic skin culture model that contain NK cells in addition to fibroblasts and squamous cell carcinoma cells, we unveiled a key role of CLEC2A that orchestrates a crosstalk between fibroblasts and NK cells, thereby leading to the control of squamous cell carcinoma invasion. These findings indicate that CLEC2A-expressing dermal fibroblasts play a major role in immune surveillance of the skin.

Published
2020
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23. Serum cytokines associated with behavior: A cross-sectional study in 5-year-old children

Author

Susana Barbosa, Anne Forhan, Olfa Khalfallah, Barbara Heude, Nicolas Glaichenhaus, Laetitia Davidovic, Cédric Galéra, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), and Fondation de France AAP Autisme et neurodeveloppement (France)

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Cross-sectional study, Emotions, Immunology, Population, Logistic regression, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, 03 medical and health sciences, Behavioral Neuroscience, 0302 clinical medicine, Surveys and Questionnaires, Internal medicine, medicine, Humans, HEALTHY, education, Children, Emotion, Problem Behavior, Behavior, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, education.field_of_study, Penalized regression, Endocrine and Autonomic Systems, business.industry, Mental Disorders, Confounding, Strengths and Difficulties Questionnaire, Mother–child cohort, 3. Good health, Cross-Sectional Studies, 030104 developmental biology, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Prosocial behavior, Child, Preschool, Cohort, Cytokines, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Psychosocial, 030217 neurology & neurosurgery
Abstract

International audience; Nearly 10% of 5-year-old children experience social, emotional or behavioral problems and are at increased risk of developing mental disorders later in life. While animal and human studies have demonstrated that cytokines can regulate brain functions, it is unclear whether individual cytokines are associated with specific behavioral dimensions in population-based pediatric samples. Here, we used data and biological samples from 786 mother-child pairs participating to the French national mother-child cohort EDEN. At the age of 5, children were assessed for behavioral difficulties using the Strengths and Difficulties Questionnaire (SDQ) and had their serum collected. Serum samples were analyzed for levels of well-characterized effector or regulatory cytokines. We then used a penalized logistic regression method (Elastic Net), to investigate associations between serum levels of cytokines and each of the five SDQ-assessed behavioral dimensions after adjustment for relevant covariates and confounders, including psychosocial variables. We found that interleukin (IL)-6, IL-7, and IL-15 were associated with increased odds of problems in prosocial behavior, emotions, and peer relationships, respectively. In contrast , eight cytokines were associated with decreased odds of problems in one dimension: IL-8, IL-10, and IL-17A with emotional problems, Tumor Necrosis Factor (TNF)-α with conduct problems, CC motif chemokine Ligand (CCL)2 with hyperactivity/inattention, C-X-C motif chemokine Ligand (CXCL)10 with peer problems, and CCL3 and IL-16 with abnormal prosocial behavior. Without implying causation, these associations support the notion that cytokines regulate brain functions and behavior and provide a rationale for launching longitudinal studies.

Published
2020
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24. Ciliary melanin‐concentrating hormone receptor 1 (MCHR1) is widely distributed in the murine CNS in a sex‐independent manner

Author

Daniella S. Battagello, Jozélia G. Ferreira, Bianca S. M. Bono, Melissa J. Chee, Antoine Roger Adamantidis, Jean-Louis Nahon, Luciane V. Sita, Lívia Clemente Motta-Teixeira, Françoise Presse, Marianne O. Klein, Jackson C. Bittencourt, Giovanne B. Diniz, Jessica C. G. Duarte, Université Côte d'Azur (UCA), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
Male, 0301 basic medicine, Neuropeptide, Biology, Rats, Sprague-Dawley, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Kisspeptin, Neurochemical, Animals, Rats, Long-Evans, Cilia, Receptors, Somatostatin, Receptor, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, Sex Characteristics, Tyrosine hydroxylase, HIPOCAMPU DE ANIMAL, Brain, Rats, Cell biology, Melanin-concentrating hormone receptor, Olfactory bulb, Mice, Inbred C57BL, 030104 developmental biology, nervous system, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Calretinin, 030217 neurology & neurosurgery
Abstract

Melanin-concentrating hormone (MCH) is a ubiquitous vertebrate neuropeptide predominantly synthesized by neurons of the diencephalon that can act through two G protein-coupled receptors, called MCHR1 and MCHR2. The expression of Mchr1 has been investigated in both rats and mice, but its synthesis remains poorly described. After identifying an antibody that detects MCHR1 with high specificity, we employed immunohistochemistry to map the distribution of MCHR1 in the CNS of rats and mice. Multiple neurochemical markers were also employed to characterize some of the neuronal populations that synthesize MCHR1. Our results show that MCHR1 is abundantly found in a subcellular structure called the primary cilium, which has been associated, among other functions, with the detection of free neurochemical messengers present in the extracellular space. Ciliary MCHR1 was found in a wide range of areas, including the olfactory bulb, cortical mantle, striatum, hippocampal formation, amygdala, midline thalamic nuclei, periventricular hypothalamic nuclei, midbrain areas, and in the spinal cord. No differences were observed between male and female mice, and interspecies differences were found in the caudate-putamen nucleus and the subgranular zone. Ciliary MCHR1 was found in close association with several neurochemical markers, including tyrosine hydroxylase, calretinin, kisspeptin, estrogen receptor, oxytocin, vasopressin, and corticotropin-releasing factor. Given the role of neuronal primary cilia in sensing free neurochemical messengers in the extracellular fluid, the widespread distribution of ciliary MCHR1, and the diverse neurochemical populations who synthesize MCHR1, our data indicate that nonsynaptic communication plays a prominent role in the normal function of the MCH system.

Published
2020
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25. Guidelines: Anaesthesia in the context of COVID-19 pandemic

Author

Lionel Velly, Etienne Gayat, Hervé Quintard, Emmanuel Weiss, Audrey De Jong, Philippe Cuvillon, Gérard Audibert, Julien Amour, Marc Beaussier, Matthieu Biais, Sébastien Bloc, Marie Pierre Bonnet, Pierre Bouzat, Gilles Brezac, Claire Dahyot-Fizelier, Souhayl Dahmani, Mathilde de Queiroz, Sophie Di Maria, Claude Ecoffey, Emmanuel Futier, Thomas Geeraerts, Haithem Jaber, Laurent Heyer, Rim Hoteit, Olivier Joannes-Boyau, Delphine Kern, Olivier Langeron, Sigismond Lasocki, Yoan Launey, Frederic le Saché, Anne Claire Lukaszewicz, Axel Maurice-Szamburski, Nicolas Mayeur, Fabrice Michel, Vincent Minville, Sébastien Mirek, Philippe Montravers, Estelle Morau, Laurent Muller, Jane Muret, Karine Nouette-Gaulain, Jean Christophe Orban, Gilles Orliaguet, Pierre François Perrigault, Florence Plantet, Julien Pottecher, Christophe Quesnel, Vanessa Reubrecht, Bertrand Rozec, Benoit Tavernier, Benoit Veber, Francis Veyckmans, Hélène Charbonneau, Isabelle Constant, Denis Frasca, Marc-Olivier Fischer, Catherine Huraux, Alice Blet, Marc Garnier, Assistance Publique - Hôpitaux de Marseille (APHM), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Université Sorbonne Paris Nord, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service d'Anesthésie et Réanimation [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Cardiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Mutualiste de Montsouris (IMM), Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Equipe 1 : EPOPé - Épidémiologie Obstétricale, Périnatale et Pédiatrique (CRESS - U1153), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Neuro-imagerie fonctionnelle et métabolique (ANTE-INSERM U836, équipe 5), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Pharmacologie des anti-infectieux (PHAR), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anesthésie-réanimation, Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service d'anesthésie réanimation chirurgicale [Rennes], Hôpital Pontchaillou-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Clermont-Ferrand, CHU Toulouse [Toulouse], Service Anesthésie - Réanimation [Bordeaux], CHU Bordeaux [Bordeaux], Physiopathologie et Pharmacologie Clinique de la Douleur, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Anesthésie-Réanimation [AP-HP Hôpitaux Saint-Louis Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Clinique Juge - Clinique du sport [Marseille], Pôle d'Anesthésie-Réanimation [CHU Rangueil], CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Hôpital de Rangueil, Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'anesthésie - réanimation chirurgicale [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Département d'Anesthésie Réanimation, 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), Unité de réanimation médicale [CHU de Carémeau, Nîmes], Institut Curie [Paris], Réanimation Médico-Chirurgicale, Service d'Anesthésie Réanimation, CHU Necker - Enfants Malades [AP-HP], Département d'anesthésie-réanimation[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier], Mitochondries, stress oxydant et protection musculaire (Strasbourg), Mitochondrie, stress oxydant et protection musculaire (MSP), Université de Strasbourg (UNISTRA)-Université de Strasbourg (UNISTRA), Physiopathologie et Epidemiologie de l'Insuffisance Respiratoire, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Nantes (CHU Nantes), Service de soins intensifs [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Groupe d’Anesthésie-Réanimation Chirurgie cardio-thoracique et vasculaire [Toulouse], Clinique Pasteur [Toulouse], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Poitiers - Faculté de Médecine et de Pharmacie, Université de Poitiers, Département d'anesthésiologie [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), Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Sorbonne Université (SU), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Rennes (UR)-Hôpital Pontchaillou, Université de Rennes (UR)-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 de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Pôle Anesthésie Réanimation [CHU de Toulouse], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Biomarqueurs CArdioNeuroVASCulaires (BioCANVAS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Histoire et Cultures de l'Antiquité et du Moyen Âge (HISCANT-MA), Université de Lorraine (UL), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Emergency Department, Université Bordeaux Segalen - Bordeaux 2-Hôpital Pellegrin - Bordeaux, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM), Anaesthesiology, Robert Debré Hospital, Service d'anesthésie réanimation chirurgicale, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie mitochondriale, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherches sur les Herbivores - UMR 1213 (UMRH), Institut National de la Recherche Agronomique (INRA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Laboratoire d'Anesthésiologie, Université Pierre et Marie Curie - Paris 6 (UPMC), and Department of Anesthesia, Burn and Critical Care, University Hospitals Saint-Louis - Lariboisière, AP-HP, Paris, France.

Subjects
Infection prevention and control, [SDV]Life Sciences [q-bio], Psychological intervention, Airway management, Context (language use), Critical Care and Intensive Care Medicine, Article, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, 030202 anesthesiology, Informed consent, Personal protective equipment, Pandemic, Health care, Medicine, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Modalities, SARS-CoV-2, business.industry, COVID-19, 030208 emergency & critical care medicine, General Medicine, Guideline, 3. Good health, Anesthesiology and Pain Medicine, Universal precautions, Anesthesia, Viruses, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract

Objectives The world is currently facing an unprecedented healthcare crisis caused by the COVID-19 pandemic. The objective of these guidelines is to produce a framework to facilitate the partial and gradual resumption of intervention activity in the context of the COVID-19 pandemic. Methods The group has endeavoured to produce a minimum number of recommendations to highlight the strengths to be retained in the 7 predefined areas: (1) protection of staff and patients; (2) benefit/risk and patient information; (3) preoperative assessment and decision on intervention; (4) modalities of the preanaesthesia consultation; (5) specificity of anaesthesia and analgesia; (6) dedicated circuits and (7) containment exit type of interventions. Results The SFAR Guideline panel provides 51 statements on anaesthesia management in the context of COVID-19 pandemic. After one round of discussion and various amendments, a strong agreement was reached for 100% of the recommendations and algorithms. Conclusion We present suggestions for how the risk of transmission by and to anaesthetists can be minimised and how personal protective equipment policies relate to COVID-19 pandemic context.

Published
2020
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26. Allergy Evaluation of Hypersensitivity to Platinum Salts and Taxanes: A Six-Year Experience

Author

Johana Pradelli, Michèle Ben Hayoun, Philippe Follana, Julien Duquesne, Charles-Hugo Marquette, Jacques Boutros, Paul Verdoire, Anne-Claire Frin, Sylvie Leroy, Jonathan Benzaquen, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), 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), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
medicine.medical_specialty, Allergy, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Drug allergy, Drug Hypersensitivity, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Humans, Immunology and Allergy, 030212 general & internal medicine, Platinum, Skin Tests, Chemotherapy, Taxane, business.industry, medicine.disease, Carboplatin, 3. Good health, Oxaliplatin, Pharmaceutical Preparations, 030228 respiratory system, chemistry, Cohort, Salts, Taxoids, business, Anaphylaxis, medicine.drug
Abstract

Background Hypersensitivity reactions (HSRs) to platinum salts (PS) and taxanes (TX) are a challenge to cancer management. Allergy evaluation based on skin tests (ST) and graded challenges can provide a diagnosis of an allergy to a suspected drug and indicate possible treatment with alternative same-class drugs. Objective This study aimed to estimate the negative predictive value of ST in the diagnosis of HSRs to TX and PS. Methods This multicenter study prospectively enrolled patients with a suspected HSR to PS and TX. ST were performed for chemotherapy, drugs of the same pharmacological class, and other agents (latex or cotreatments). For patients with negative ST, a graded challenge was performed by the cancer teams trained in allergy management. Results A total of 119 consecutive patients were included during a 6-year period. ST results were positive for 58% of the cohort: for TX in 7 patients and for PS in 62 patients. Other agents were responsible for 4.2% of cases. Skin cross-reactivity was 50% for TX and 30% for PS. A graded challenge was performed in 14 patients for TX and in 50 patients for PS. Negative predictive values (NPVs) for ST were 100% for TX and 92% for PS, with NPVs for individuals PS of 100% for cisplatin, 89% for oxaliplatin, and 87% for carboplatin. Conclusions ST to PS or TX offered a high NPV, making allergy evaluation a key element in the management of patients with cancer. Graded challenges can be safely performed by oncology teams trained in anaphylaxis management.

Published
2020
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27. Pierre Chardin, un pionnier de la découverte des gènes et protéines de la superfamille Ras

Author

Alfred Wittinghofer, Jean de Gunzburg, Hélène Barelli, Ahmed Zahraoui, Françoise Moreau-Gachelin, Jacques Camonis, Bruno Goud, Institut de pharmacologie moléculaire et cellulaire (IPMC), 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), Institut Curie [Paris], Transduction du signal et oncogénèse, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), PSL Univ, Inst Curie, CNRS UMR 144, F-75005 Paris, France, Max Planck Institute of Molecular Plant Physiology (MPI-MP), Max-Planck-Gesellschaft, Système membranaires, photobiologie, stress et détoxication (SMPSD), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Biologie Cellulaire et Cancer, and Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, [SDV]Life Sciences [q-bio], 030220 oncology & carcinogenesis, General Medicine, Biology, Molecular biology, ComputingMilieux_MISCELLANEOUS, General Biochemistry, Genetics and Molecular Biology, 030304 developmental biology
Abstract

International audience; No abstract available

Published
2020
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28. Combattre l’accident vasculaire cérébral en inhibant une enzyme liée à la voie de synthèse des polyamines

Author

Nicolas Blondeau, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
chemistry.chemical_classification, 0303 health sciences, business.industry, [SDV]Life Sciences [q-bio], Polyamine synthesis, General Medicine, Pharmacology, medicine.disease, General Biochemistry, Genetics and Molecular Biology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Text mining, Enzyme, chemistry, Medicine, business, Stroke, ComputingMilieux_MISCELLANEOUS, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

International audience; No abstract available

Published
2021
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29. Single Subcutaneous Injection of Lysophosphatidyl-Choline Evokes ASIC3-Dependent Increases of Spinal Dorsal Horn Neuron Activity

Author

Ludivine Pidoux, Kevin Delanoe, Julie Barbier, Fabien Marchand, Eric Lingueglia, Emmanuel Deval, DEVAL, Emmanuel, Douleur articulaire chronique : vers de nouvelles cibles moléculaires. - - JOINT-PAIN2017 - ANR-17-CE16-0018 - AAPG2017 - VALID, Laboratoires d'excellence - Canaux ioniques d'intérêt thérapeutique - - ICST2011 - ANR-11-LABX-0015 - LABX - VALID, Institut de pharmacologie moléculaire et cellulaire (IPMC), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), ANR-17-CE16-0018,JOINT-PAIN,Douleur articulaire chronique : vers de nouvelles cibles moléculaires.(2017), and ANR-11-LABX-0015,ICST,Canaux ioniques d'intérêt thérapeutique(2011)

Subjects
TRPV1, Cellular and Molecular Neuroscience, spinal cord neurons, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, pain, lysophosphatidyl-choline, Molecular Biology, acid-sensing ion channel 3, sodium channel
Abstract

Lysophosphatidyl-choline (LPC), a member of the phospholipid family, is an emerging player in pain. It is known to modulate different pain-related ion channels, including Acid-Sensing Ion Channel 3 (ASIC3), a cationic channel mainly expressed in peripheral sensory neurons. LPC potentiates ASIC3 current evoked by mild acidifications, but can also activate the channel at physiological pH. Very recently, LPC has been associated to chronic pain in patients suffering from fibromyalgia or osteoarthritis. Accordingly, repetitive injections of LPC within mouse muscle or joint generate both persistent pain-like and anxiety-like behaviors in an ASIC3-dependent manner. LPC has also been reported to generate acute pain behaviors when injected intraplantarly in rodents. Here, we explore the mechanism of action of a single cutaneous injection of LPC by studying its effects on spinal dorsal horn neurons. We combine pharmacological, molecular and functional approaches including in vitro patch clamp recordings and in vivo recordings of spinal neuronal activity. We show that a single cutaneous injection of LPC exclusively affects the nociceptive pathway, inducing an ASIC3-dependent sensitization of nociceptive fibers that leads to hyperexcitabilities of both high threshold (HT) and wide dynamic range (WDR) spinal neurons. ASIC3 is involved in LPC-induced increase of WDR neuron’s windup as well as in WDR and HT neuron’s mechanical hypersensitivity, and it participates, together with TRPV1, to HT neuron’s thermal hypersensitivity. The nociceptive input induced by a single LPC cutaneous rather induces short-term sensitization, contrary to previously described injections in muscle and joint. If the effects of peripheral LPC on nociceptive pathways appear to mainly depend on peripheral ASIC3 channels, their consequences on pain may also depend on the tissue injected. Our findings contribute to a better understanding of the nociceptive signaling pathway activated by peripheral LPC via ASIC3 channels, which is an important step regarding the ASIC3-dependent roles of this phospholipid in acute and chronic pain conditions.

Published
2022
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30. Analysis of the Equilibrium Phase in Immune-Controlled Tumors Provides Hints for Designing Better Strategies for Cancer Treatment

Author

Kevin Atsou, Sokchea Khou, Fabienne Anjuère, Véronique M. Braud, Thierry Goudon, COmplex Flows For Energy and Environment (COFFEE), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jean Alexandre Dieudonné (LJAD), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), and Institut de pharmacologie moléculaire et cellulaire (IPMC)

Subjects
Cancer Research, Oncology, equilibrium phase, drug response, cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, immunotherapy, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, mathematical oncology
Abstract

International audience; When it comes to improving cancer therapies, one challenge is to identify key biological parameters that prevent immune escape and maintain an equilibrium state characterized by a stable subclinical tumor mass, controlled by the immune cells. Based on a space and size structured partial differential equation model, we developed numerical methods that allow us to predict the shape of the equilibrium at low cost, without running simulations of the initial-boundary value problem. In turn, the computation of the equilibrium state allowed us to apply global sensitivity analysis methods that assess which and how parameters influence the residual tumor mass. This analysis reveals that the elimination rate of tumor cells by immune cells far exceeds the influence of the other parameters on the equilibrium size of the tumor. Moreover, combining parameters that sustain and strengthen the antitumor immune response also proves more efficient at maintaining the tumor in a long-lasting equilibrium state. Applied to the biological parameters that define each type of cancer, such numerical investigations can provide hints for the design and optimization of cancer treatments.

Published
2022
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31. Early Life Exposure to Tumor Necrosis Factor Induces Precocious Sensorimotor Reflexes Acquisition and Increases Locomotor Activity During Mouse Postnatal Development

Author

Cristina Paraschivescu, Susana Barbosa, Juliette Van Steenwinckel, Pierre Gressens, Nicolas Glaichenhaus, Laetitia Davidovic, Institut de pharmacologie moléculaire et cellulaire (IPMC), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Davidovic, Laetitia

Subjects
behavior, Cognitive Neuroscience, neurodevelopmental disorders, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, TNF, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BDD.EO] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Behavioral Neuroscience, Neuropsychology and Physiological Psychology, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, cytokine, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, reflex acquisition
Abstract

International audience; Inflammation appears as a cardinal mediator of the deleterious effect of early life stress exposure on neurodevelopment. More generally, immune activation during the perinatal period, and most importantly elevations of pro-inflammatory cytokines levels could contribute to psychopathology and neurological deficits later in life. Cytokines are also required for normal brain function in homeostatic conditions and play a role in neurodevelopmental processes. Despite these latter studies, whether pro-inflammatory cytokines such as Tumor Necrosis Factor (TNF) impact neurodevelopmental trajectories and behavior during the immediate postnatal period remains to be elucidated. To address this issue, we have injected mouse pups daily with recombinant TNF from postnatal day (P)1 to P5. This yielded a robust increase in peripheral and central TNF at P5, and also an increase of additional pro-inflammatory cytokines. Compared to control pups injected with saline, mice injected with TNF acquired the righting and the acoustic startle reflexes more rapidly and exhibited increased locomotor activity 2 weeks after birth. Our results extend previous work restricted to adult behaviors and support the notion that cytokines, and notably TNF, modulate early neurodevelopmental trajectories.

Published
2021
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32. Report from the 28th Meeting on Toxinology, 'Toxins: What’s up, Doc?', Organized by the French Society of Toxinology on 28–29 November 2022

Author

Pascale Marchot, Évelyne Benoit, Ziad Fajloun, Sylvie Diochot, Architecture et fonction des macromolécules biologiques (AFMB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO) (SIMoS), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), SIMOPRO, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Azm Center for research in biotechnology and its applications [TRIPOLI], Université Libanaise, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and 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)

Subjects
Toxinomics, Health, Toxicology and Mutagenesis, Medical application, Neuromuscular junction, Toxin structure–function relationship, Deep learning, Bacterial toxin, Toxin receptor–target, Toxicology, Toxin tracking, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Marine toxin, Plant toxin, Toxin structure, Animal toxin
Abstract

International audience; The French Society of Toxinology (SFET) organized its 28th annual meeting on 28–29 November 2022 (RT28). The central theme of this meeting was “Toxins: What’s up, Doc?”, emphasizing the latest findings on animal, bacterial, algal, plant and fungal toxins through sessions dedicated to deep learning, toxin tracking and toxinomic advances, shared by ca. 80 participants. The abstracts of the 10 invited and 11 selected lectures and 15 posters, along with the names of the Best Oral Communication and Best Poster awardees, are presented in this report.

Published
2023
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33. SWI/SNF chromatin remodeler complex within the reward pathway is required for behavioral adaptations to stress

Author

L. Amar, C. Vernochet, Philippe Faure, A. C. Compagnion, S. Bhattacharya, Fabio Marti, François Tronche, Peter Vanhoutte, J. Barik, S. Karaki, M. Yaniv, R. Durand de Cuttoli, Estefani Saint-Jour, C. Baranowski, Sébastien Parnaudeau, A. Zayed, Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL), Institut Pasteur [Paris] (IP), Université Côte d'Azur (UCA), Institut de pharmacologie moléculaire et cellulaire (IPMC), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), This work was supported by a Sorbonne Université grant (Emergence to FT), the Labex BioPsy (to FT and SP), the Foundation for MedicalResearch (FRM Equipe grant DEQ20140329552 to FT), the Institut National du Cancer (TABAC grant to PF, JB and FT), and the Agence Nationale de la Recherche (ANR3053NEUR3143830 to FT, ANR-14-CE35-0029-01 to SP, and ANR-15-CE16-0017 to JB and PV), ANR-14-CE35-0029,PsyCoStress,Glucocorticoids and Psychiatric Disorders: Mechanisms of Stress Induced Cognitive Deficits(2014), ANR-15-CE16-0017,GLAD,Rôle des heteromères formés par les récepteurs dopamine-glutamate et de signalisation dépendante du calcium nucléaire associée dans l'addiction(2015), AMAR, LAURENCE, Appel à projets générique - Glucocorticoids and Psychiatric Disorders: Mechanisms of Stress Induced Cognitive Deficits - - PsyCoStress2014 - ANR-14-CE35-0029 - Appel à projets générique - VALID, Rôle des heteromères formés par les récepteurs dopamine-glutamate et de signalisation dépendante du calcium nucléaire associée dans l'addiction - - GLAD2015 - ANR-15-CE16-0017 - AAPG2015 - VALID, This work was supported by a Sorbonne Université grant (Emergence), the Labex BioPsy, the Foundation for Medical Research (FRM Equipe grant DEQ20140329552), the INCA (TABAC grant to PF, JB and FT), and the Agence Nationale de la Recherche (ANR3053NEUR31438301, ANR-14-CE35-0029-01 and ANR-15-CE16-0017)., amar, laurence, Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
Heterochromatin, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Biology, Medium spiny neuron, General Biochemistry, Genetics and Molecular Biology, Chromatin remodeling, Social defeat, Mice, 03 medical and health sciences, 0302 clinical medicine, Reward, Cell Line, Tumor, Animals, Epigenetics, 030304 developmental biology, Adenosine Triphosphatases, 0303 health sciences, Multidisciplinary, SMARCA4 Gene, General Chemistry, Chromatin Assembly and Disassembly, Chromatin, SWI/SNF, Cell biology, [SDV] Life Sciences [q-bio], 030217 neurology & neurosurgery
Abstract

Stress exposure is a cardinal risk factor for most psychiatric diseases. Preclinical and clinical studies point to changes in gene expression involving epigenetic modifications within mesocorticolimbic brain circuits. Brahma (BRM) and Brahma-Related-Gene-1 (BRG1) are ATPase subunits of the SWI/SNF complexes involved in chromatin remodeling, a process essential to enduring plastic changes in gene expression. Here, we show that repeated social defeat induces changes in BRG1 nuclear distribution. The inactivation of the Brg1/Smarca4 gene within dopamine-innervated regions or the constitutive inactivation of the Brm/Smarca2 gene leads to resilience to repeated social defeat and decreases the behavioral responses to cocaine without impacting midbrain dopamine neurons activity. Within striatal medium spiny neurons Brg1 gene inactivation reduces the expression of stress- and cocaine-induced immediate early genes, increases levels of heterochromatin and at a global scale decreases chromatin accessibility. Altogether these data demonstrate the pivotal function of SWI/SNF complexes in behavioral and transcriptional adaptations to salient environmental challenges.

Published
2021
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34. Decoding Of Nanopore-Sequenced Synthetic DNA Storing Digital Images

Author

Marc Antonini, Pascal Barbry, Raja Appuswamy, Eva Gil San Antonio, Melpomeni Dimopoulou, Laboratoire d'Informatique, Signaux, et Systèmes de Sophia Antipolis (I3S), 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), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), and Eurecom [Sophia Antipolis]

Subjects
Computer science, business.industry, 020207 software engineering, 02 engineering and technology, Nanopore, Digital image, [INFO.INFO-LG]Computer Science [cs]/Machine Learning [cs.LG], Synthetic DNA, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], 0202 electrical engineering, electronic engineering, information engineering, 020201 artificial intelligence & image processing, Computer vision, Artificial intelligence, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, ComputingMilieux_MISCELLANEOUS, Decoding methods
Abstract

International audience

Published
2021
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35. Linotrins: Omega-3 oxylipins featuring an E,Z,E conjugated triene motif are present in the plant kingdom and alleviate inflammation in LPS-challenged microglial cells

Author

Laurence Balas, Sujit Kumar Dey, Sophie Béraud-Dufour, Dean Edward Riechers, Olivia Augusta Landau, Justine Bertrand-Michel, Thierry Durand, Nicolas Blondeau, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), 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), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), University of Illinois [Chicago] (UIC), University of Illinois System, Plateau MetaToul-LIPIDOMIQUE = MetaToul-Lipidomics, MetaToul-MetaboHUB, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), 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-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 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), 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 des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Pharmacology, Inflammation, Lipopolysaccharides, Linolenic acid, [SDV]Life Sciences [q-bio], Organic Chemistry, alpha-Linolenic Acid, Total synthesis, General Medicine, Conjugated triene, Drug Discovery, Humans, Microglial cell, Microglia, Oxylipins, Cytokine
Abstract

International audience; Alpha-linolenic acid (ALA), an essential omega-3 polyunsaturated fatty acid found in plants, exertsneuroprotection and anti-inflammatory effects in chronic and acute CNS disease models. However, theunderlying mechanisms are not yet understood. Since ALA is not incorporated into the brain, theobserved health benefits may result from some of its metabolites. The putative formation of dihydroxylatedALA derivatives (called linotrins) was recently shown in vitro in the presence of lipoxygenases.However, the in vitro biosynthesis of linotrins was neither stereoselective nor quantitatively efficient forstudying their physiological roles as enantiomeric pure forms. Herein, we report the first stereocontrolledsynthesis that features regio- and stereoselective hydrometalations of alkynes for assemblingthe sensitive E,Z,E-conjugated trienes, as well as LC-MS investigations that provide evidence oflinotrins occurrence in plants. Moreover, strong anti-inflammatory effects on microglia highlight thepotential physiological importance of linotrins and open new perspectives in search of CNS therapeutics.

Published
2021
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36. Un marché d’échange de lipides

Author

Bruno Antonny, Bruno Mesmin, Joëlle Bigay, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
0303 health sciences, Chemistry, Cholesterol, [SDV]Life Sciences [q-bio], Endoplasmic reticulum, 030302 biochemistry & molecular biology, Steroid Metabolism, General Medicine, High Cholesterol Levels, General Biochemistry, Genetics and Molecular Biology, Cell biology, 03 medical and health sciences, chemistry.chemical_compound, lipids (amino acids, peptides, and proteins), Cholesterol metabolism, Phosphatidylinositol, OSBP, Cellular compartment, 030304 developmental biology
Abstract

International audience; Cholesterol is synthesized in the endoplasmic reticulum (RE) and then transported to cellular compartments whose functions require high cholesterol levels. Here, we describe the mechanism by which cholesterol is transported from the RE to the trans-Golgi network (TGN) by the protein OSBP (Oxysterol-Binding Protein). OSBP has two complementary activities. First, it tethers the RE to the TGN by forming a contact site where the two membranes are about twenty nanometers away. Then, it exchanges RE cholesterol for a TGN lipid, phosphatidylinositol 4-phosphate (PI4P). Eventually, PI4P is hydrolyzed at the RE, making the exchange cycle irreversible. Thus, OSBP is at the center of a lipid exchange market where a transported cholesterol “costs” a PI4P. Antiviral or anti-cancer molecules target OSBP, suggesting the importance of the OSBP cycle in different physiopathological contexts. The general principles of this cycle are shared by other lipid-transfer proteins; Le cholestérol est synthétisé dans le réticulum endoplasmique (RE) puis transporté vers les compartiments cellulaires dont la fonction en nécessite un taux élevé. Nous décrivons ici le mécanisme de transport du cholestérol du RE vers le réseau trans golgien (TGN) par la protéine OSBP (oxysterol binding protein). Celle-ci présente deux activités complémentaires : elle arrime les deux compartiments, RE et TGN, en formant un site de contact où les deux membranes sont à une vingtaine de nanomètres de distance ; puis elle échange le cholestérol du RE avec un lipide présent dans le TGN, le phosphatidylinositol 4-phosphate (PI4P). Dans le RE, le PI4P est hydrolysé, rendant le cycle d’échange irréversible. OSBP est donc au cœur d’un marché d’échange de lipides dans lequel un cholestérol transporté « coûte » un PI4P. Des molécules à activités antivirales ou anticancéreuses ont pour cible OSBP, suggérant une importance dans différents contextes physiopathologiques du cycle d’OSBP, dont les bases générales sont partagées par d’autres protéines transporteurs de lipides.

Published
2020
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37. Anti-PLA2R1 Antibodies Containing Sera Induce In Vitro Cytotoxicity Mediated by Complement Activation

Author

Kévin Zorzi, Vincent L.M. Esnault, Gérard Lambeau, Cécile Courivaud, Barbara Seitz-Polski, Noémie Jourde-Chiche, Thomas Crepin, Guillaume Dolla, Christine Payré, Hajar Ouahmi, M. Lateb, Mohamad Zaidan, Bertrand Knebelmann, Vesna Brglez, Sonia Boyer-Suavet, Institut de pharmacologie moléculaire et cellulaire (IPMC), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Département de Néphrologie - Hôpital Pasteur [Nice], Hôpital Pasteur [Nice] (CHU), Centre Hospitalier Universitaire de Nice (CHU Nice), Néphrologie [CHU Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Service de Néphrologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de néphrologie et transplantation rénale [Hôpital de la Conception - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Hôpital l'Archet, Fondation pour la Recherche Médicale (FRMING20140129210, SPF20150934219, FDT201805005509, and DEQ20180339193), and the Fondation du Rein (award and grant FdR 2018/FRM/G.L), ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), ANR-17-CE17-0012,MNaims,Dissection moléculaire de la glomérulonéphrite extramembraneuse liée à PLA2R1: vers l'identification de nouveaux biomarqueurs cliniques(2017), HAL AMU, Administrateur, Centres d'excellences - Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie - - SIGNALIFE2011 - ANR-11-LABX-0028 - LABX - VALID, Dissection moléculaire de la glomérulonéphrite extramembraneuse liée à PLA2R1: vers l'identification de nouveaux biomarqueurs cliniques - - MNaims2017 - ANR-17-CE17-0012 - AAPG2017 - VALID, Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)

Subjects
Cytotoxicity, Immunologic, Male, 0301 basic medicine, PROGNOSIS, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Autoantigens, Glomerulonephritis, Membranous, Immunoglobulin G, Epitope, Cohort Studies, Epitopes, Complement inhibitor, 0302 clinical medicine, SUBCLASS, BINDING, Immunology and Allergy, Prospective Studies, Cytotoxicity, Complement Activation, biology, Podocytes, Chemistry, General Medicine, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], Titer, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Rabbits, Antibody, Rituximab, Research Article, lcsh:Immunologic diseases. Allergy, DOMAIN-CONTAINING 7A, IGG4, Adult, [SDV.IMM] Life Sciences [q-bio]/Immunology, Article Subject, Cell Survival, Immunology, GLOMERULAR-DISEASES, PHOSPHOLIPASE-A2 RECEPTOR AUTOANTIBODIES, 03 medical and health sciences, GLOMERULONEPHRITIS, Animals, Humans, Aged, Autoantibodies, Receptors, Phospholipase A2, Complement System Proteins, Molecular biology, Complement system, HEK293 Cells, 030104 developmental biology, MEMBRANOUS NEPHROPATHY, biology.protein, Alternative complement pathway, lcsh:RC581-607
Abstract

The phospholipase A2 receptor (PLA2R1) is the major autoantigen in idiopathic membranous nephropathy (MN). However, the pathogenic role of anti-PLA2R1 autoantibodies is unclear. Our aim was to evaluate the in vitro cytotoxicity of anti-PLA2R1 antibodies mediated by complement. Forty-eight patients with PLA2R1-related MN from the prospective cohort SOURIS were included. Anti-PLA2R1 titer, epitope profile, and anti-PLA2R1 IgG subclasses were characterized by ELISA. Cell cytotoxicity was evaluated by immunofluorescence in HEK293 cells overexpressing PLA2R1 incubated with patient or healthy donor sera in the presence or absence of rabbit complement or complement inhibitors. Mean cytotoxicity of anti-PLA2R1 sera for HEK293 cells overexpressing PLA2R1 was 2±2%, which increased to 24±6% after addition of rabbit complement (p<0.001) (n=48). GVB-EDTA, which inhibits all complement activation pathways, completely blocked cell cytotoxicity, whereas Mg-EGTA, which only inhibits the classical and lectin pathways, highly decreased suggesting a limited role of the alternative pathway. A higher diversity of IgG subclasses beyond IgG4 and high titer of total IgG anti-PLA2R1 were associated with increased cytotoxicity (p=0.01 and p=0.03 respectively). In a cohort of 37 patients treated with rituximab, high level of complement-mediated cytotoxicity was associated with less and delayed remission at month 6 after rituximab therapy (5/12 vs. 20/25 (p=0.03) in 8.5 months±4.4 vs. 4.8±4.0 (p=0.02)). Kaplan-Meier analysis demonstrated that high level of cytotoxicity (≥40%) (p=0.005), epitope spreading (defined by immunization beyond the immunodominant CysR domain) (p=0.002), and high titer of anti-PLA2R1 total IgG (p=0.01) were factors of poor renal prognosis. Anti-PLA2R1 antibodies containing sera can induce in vitro cytotoxicity mediated by complement activation, and the level of cytotoxicity increases with the diversity and the titer of anti-PLA2R1 IgG subclasses. These patients with high level of complement-mediated cytotoxicity could benefit from adjuvant therapy using complement inhibitor associated with rituximab to induce earlier remission and less podocyte injury.

Published
2019
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38. Mammalian Mechanoelectrical Transduction: Structure and Function of Force-Gated Ion Channels

Author

Dominique Douguet, Eric Honoré, Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie moléculaire et cellulaire (IPMC), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and Honoré, Eric

Subjects
0303 health sciences, [SDV]Life Sciences [q-bio], PIEZO1, Mechanoelectrical transduction, Depolarization, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Gating, Biology, General Biochemistry, Genetics and Molecular Biology, Autonomic regulation, Structure and function, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Mechanosensitive channels, Neuroscience, ComputingMilieux_MISCELLANEOUS, 030217 neurology & neurosurgery, Ion channel, 030304 developmental biology
Abstract

The conversion of force into an electrical cellular signal is mediated by the opening of different types of mechanosensitive ion channels (MSCs), including TREK/TRAAK K2P channels, Piezo1/2, TMEM63/OSCA, and TMC1/2. Mechanoelectrical transduction plays a key role in hearing, balance, touch, and proprioception and is also implicated in the autonomic regulation of blood pressure and breathing. Thus, dysfunction of MSCs is associated with a variety of inherited and acquired disease states. Significant progress has recently been made in identifying these channels, solving their structure, and understanding the gating of both hyperpolarizing and depolarizing MSCs. Besides prototypical activation by membrane tension, additional gating mechanisms involving channel curvature and/or tethered elements are at play.

Published
2019
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39. La fonction d’un long ARN non codant décodée dans la fibrose pulmonaire idiopathique

Author

Grégoire Savary, Nicolas Pottier, Christelle Cauffiez, Bernard Mari, Impact de l'environnement chimique sur la santé humaine - ULR 4483 (IMPECS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de pharmacologie moléculaire et cellulaire (IPMC), 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)-Centre National de la Recherche Scientifique (CNRS), CNRS, Université de Lille, IMPact de l'Environnement Chimique sur la Santé humaine (IMPECS) - EA 4483, Impact de l'environnement chimique sur la santé humaine - ULR 4483 [IMPECS], and Université Nice Sophia Antipolis (... - 2019) (UNS)

Subjects
0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, business.industry, [SDV]Life Sciences [q-bio], 030220 oncology & carcinogenesis, Medicine, General Medicine, business, ComputingMilieux_MISCELLANEOUS, General Biochemistry, Genetics and Molecular Biology, 030304 developmental biology
Abstract

International audience

Published
2019
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40. High-Dose Rituximab and Early Remission in PLA2R1-Related Membranous Nephropathy

Author

Hanna Debiec, Christelle Zaghrini, Alessandra Rosenthal, Michel Ticchioni, Karine Dahan, Gérard Lambeau, Alexandra Rousseau, Barbara Seitz-Polski, Vincent L.M. Esnault, Marine Andreani, Ghislaine Bernard, Pierre Ronco, Sylvia Benzaken, Departement d'immunologie, hôpital de l'Archet, CHU de Nice, Département de Néphrologie - Hôpital Pasteur [Nice], Hôpital Pasteur [Nice] (CHU), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Service de Néphrologie et Dialyses [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département d'Immunologie, Centre Hospitalier Universitaire de Nice (CHU de Nice)-Groupe hospitalier l'Archet (Nice), Laboratoire Immunologie [Nice], Hôpital de l'Archet-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)

Subjects
Male, medicine.medical_specialty, Epidemiology, 030232 urology & nephrology, Nice, Early remission, Critical Care and Intensive Care Medicine, Glomerulonephritis, Membranous, Gastroenterology, Cohort Studies, Epitopes, 03 medical and health sciences, 0302 clinical medicine, Membranous nephropathy, Interquartile range, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Internal medicine, medicine, Immunologic Factors, Humans, Prospective Studies, ComputingMilieux_MISCELLANEOUS, Aged, 030304 developmental biology, computer.programming_language, Epitope spreading, 0303 health sciences, Transplantation, business.industry, Receptors, Phospholipase A2, Remission Induction, Editorials, Original Articles, Middle Aged, 16. Peace & justice, medicine.disease, 3. Good health, Nephrology, Cohort, Female, Rituximab, business, computer, medicine.drug, Cohort study
Abstract

BACKGROUND AND OBJECTIVES: Different rituximab protocols are used to treat membranous nephropathy. We compared two rituximab protocols in patients with membranous nephropathy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Twenty-eight participants from the NICE cohort received two infusions of 1-g rituximab at 2-week intervals, whereas 27 participants from the Prospective Randomized Multicentric Open Label Study to Evaluate Rituximab Treatment for Membranous Nephropathy (GEMRITUX) cohort received two infusions of 375 mg/m(2) at 1-week interval. We measured serum rituximab levels and compared remission at month 6 and before any treatment modification and analyzed factors associated with remission and relapses. RESULTS: Remissions occurred in 18 (64%) versus eight (30%) from the NICE and GEMRITUX cohort (P=0.02) at month 6, respectively, and in 24 (86%) versus 18 (67%) participants (P=0.12) before treatment modification, respectively. Median time to remission was 3 [interquartile range (IQR), 3–9] and 9 [IQR, 6–12] months for NICE and GEMRITUX cohorts respectively (P=0.01). Participants from the NICE cohort had higher circulating level of rituximab and lower CD19 counts (3.3 µg/L [IQR, 0.0–10.8] versus 0.0 [IQR, 0.0–0.0] P

Published
2019
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41. Does Intraneuronal Accumulation of Carboxyl-terminal Fragments of the Amyloid Precursor Protein Trigger Early Neurotoxicity in Alzheimer’s Disease?

Author

Inger Lauritzen, Raphaëlle Pardossi-Piquard, Frédéric Checler, Anaïs Bécot, Alexandre Bourgeois, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
Genetically modified mouse, [SDV]Life Sciences [q-bio], C-terminal APP fragments, memory-related behavior, Amyloid beta-Protein Precursor, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Extracellular, Amyloid precursor protein, medicine, Animals, Humans, Senile plaques, C99, Neuroinflammation, 030304 developmental biology, 0303 health sciences, dimerization, biology, synaptic dysfunction, Chemistry, Autophagy, Neurotoxicity, Alzheimer's disease, medicine.disease, animal models, Peptide Fragments, Cell biology, C83, endolysosomalautophagic dysfunction, Neurology, biology.protein, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Antibody, brain network alterations, 030217 neurology & neurosurgery
Abstract

Background: Alzheimer’s disease (AD) is associated with extracellular accumulation and aggregation of amyloid β (Aβ) peptides ultimately seeding in senile plaques. Recent data show that their direct precursor C99 (βCTF) also accumulates in AD-affected brain as well as in AD-like mouse models. C99 is consistently detected much earlier than Aβ, suggesting that this metabolite could be an early contributor to AD pathology. C99 accumulates principally within endolysosomal and autophagic structures and its accumulation was described as both a consequence and one of the causes of endolysosomalautophagic pathology, the occurrence of which has been documented as an early defect in AD. C99 was also accompanied by C99-derived C83 (αCTF) accumulation occurring within the same intracellular organelles. Both these CTFs were found to dimerize leading to the generation of higher molecular weight CTFs, which were immunohistochemically characterized in situ by means of aggregate-specific antibodies. Discussion: Here, we discuss studies demonstrating a direct link between the accumulation of C99 and C99-derived APP-CTFs and early neurotoxicity. We discuss the role of C99 in endosomal-lysosomalautophagic dysfunction, neuroinflammation, early brain network alterations and synaptic dysfunction as well as in memory-related behavioral alterations, in triple transgenic mice as well as in newly developed AD animal models. Conclusion: This review summarizes current evidence suggesting a potential role of the β -secretasederived APP C-terminal fragment C99 in Alzheimer’s disease etiology

Published
2019
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42. Group IIA secreted phospholipase A2 (PLA2G2A) augments adipose tissue thermogenesis

Author

Gérard Lambeau, Mladen Savikj, Qingming Dong, Erin J. Stephenson, Christine Payré, Heather S. Smallwood, Edwards A. Park, Michael S. Kuefner, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden, Department of Anatomy, College of Graduate Studies and Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, Illinois, USA, Department of Pharmacology, The University of Tennessee Health Science Center, Memphis, Tennessee, USA, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
Male, medicine.medical_specialty, Transgene, [SDV]Life Sciences [q-bio], Adipose Tissue, White, Adipose tissue, Biochemistry, Group II Phospholipases A2, 03 medical and health sciences, Mice, 0302 clinical medicine, Phospholipase A2, Adipose Tissue, Brown, Internal medicine, Brown adipose tissue, Genetics, medicine, Citrate synthase, Animals, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Uncoupling Protein 1, 030304 developmental biology, PRDM16, Mice, Knockout, 0303 health sciences, biology, Chemistry, Biological Transport, Thermogenesis, Thermogenin, Mitochondria, Mice, Inbred C57BL, medicine.anatomical_structure, Endocrinology, biology.protein, Female, Energy Metabolism, 030217 neurology & neurosurgery, Biotechnology
Abstract

Group IIA secreted phospholipase A2 (PLA2G2A) hydrolyzes glycerophospholipids at the sn-2 position resulting in the release of fatty acids and lysophospholipids. C57BL/6 mice do not express Pla2g2a due to a frameshift mutation (wild-type [WT] mice). We previously reported that transgenic expression of human PLA2G2A in C57BL/6 mice (IIA+ mice) protects against weight gain and insulin resistance, in part by increasing total energy expenditure. Additionally, we found that brown and white adipocytes from IIA+ mice have increased expression of mitochondrial uncoupling markers, such as uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor-gamma coactivator, and PR domain containing 16, suggesting that the energy expenditure phenotype might be due to an increased thermogenic capacity in adipose tissue. Here, we further characterize the impact of PLA2G2A on thermogenic mechanisms in adipose tissue. Metabolic analysis of WT and IIA+ mice revealed that even when housed within their thermoneutral zone, IIA+ mice have elevated energy expenditure compared to WT littermates. Increased energy expenditure in IIA+ mice is associated with increased citrate synthase activity in brown adipose tissue (BAT) and increased mitochondrial respiration in both brown and white adipocytes. We also observed that direct addition of recombinant PLA2G2A enzyme to in vitro cultured adipocytes results in the marked induction of UCP1 protein expression. Finally, we report that PLA2G2A induces the expression of numerous transcripts related to energy substrate transport and metabolism in BAT, suggestive of an increase in substrate flux to fuel BAT activity. These data demonstrate that PLA2G2A enhances adipose tissue thermogenesis, in part, through elevated substrate delivery and increased mitochondrial content in BAT.

Published
2021
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43. Involvement of ASIC1a channels in the spinal processing of pain information by deep projection neurons

Author

Kevin Delanoe, Eric Lingueglia, Romain Veltz, Ludivine Pidoux, Ariane Delrocq, Perrine Inquimbert, Emmanuel Deval, Magda Chafai, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
0303 health sciences, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Chronic pain, Iberiotoxin, medicine.disease, Apamin, Spinal cord, Inhibitory postsynaptic potential, Potassium channel, 03 medical and health sciences, chemistry.chemical_compound, Electrophysiology, 0302 clinical medicine, medicine.anatomical_structure, chemistry, Neuroplasticity, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroscience, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Dorsal horn of the spinal cord is an important crossroad of pain neuraxis, especially for the neuronal plasticity mechanisms that can lead to chronic pain states. Windup is a well-known spinal pain facilitation process initially described several decades ago, but which exact mechanism is still not fully understood. Here, we combine bothex vivoandin vivoelectrophysiological recordings of spinal neurons with computational modelling to demonstrate a role for ASIC1a-containing channels in the windup process. Spinal application of the ASIC1a inhibitory venom peptides mambalgin-1 and psalmotoxin-1 (PcTx1) significantly reduces the ability of deep wide dynamic range (WDR) neurons to develop windupin vivo. All deep WDR-like neurons recorded from spinal slices exhibit an ASIC current with biophysical and pharmacological characteristics consistent with functional expression of ASIC1a/ASIC2 heteromeric channels. A computational model of WDR neuron supplemented with heteromeric ASIC1a/ASIC2 channel parameters accurately reproduces the experimental data, further supporting a positive contribution of these channels to windup. It also predicts a calcium-dependent windup decrease for elevated ASIC conductances, a phenomenon that was experimentally validated using either a combination of calcium-activated potassium channel inhibitory peptides (apamin and iberiotoxin), or the Texas coral snake ASIC-activating toxin (MitTx). This study demonstrates a possible dual contribution to windup of calcium permeable ASIC1a/ASIC2 channels in deep laminae projecting neurons, promoting it upon moderate channel activity, but ultimately leading to calcium-dependent windup inhibition associated to potassium channels when activity increases.

Published
2021
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44. DHA-containing phospholipids control membrane fusion and transcellular tunnel dynamics

Author

Meng-Chen Tsai, Lucile Fleuriot, Sébastien Janel, David Gonzalez-Rodriguez, Camille Morel, Amel Mettouchi, Delphine Debayle, Stéphane Dallongeville, Jean-Christophe Olivo-Marin, Bruno Antonny, Frank Lafont, Emmanuel Lemichez, Hélène Barelli, Institut de pharmacologie moléculaire et cellulaire (IPMC), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Toxines bactériennes - Bacterial Toxins, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), 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)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et Physique - Approche Multi-échelle des Milieux Complexes (LCP-A2MC), Université de Lorraine (UL), Analyse d'images biologiques - Biological Image Analysis (BIA), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), This work was supported by a grant from the Fondation pour la Recherche Médicale (Convention DEQ20180339156 Equipes FRM 2018), the Agence Nationale de la Recherche (ANR-11-LABX-0028-01, ANR-15-CE18-0016, ANR 10-EQPX-04-01, ANR-10-INBS-04 and ANR-10-LABX-62-IBEID) and FEDER 12001407, and partially by grants from the France-BioImaging infrastructure (ANR-10-INBS-04) and the Labex IBEID (ANR-10-LABX-62-IBEID). M.-C.T. was supported by a PhD fellowship from the Labex Signalife PhD Programme and by the Fondation pour la Recherche Médicale (Contrat FDT201904008135)., ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), ANR-15-CE18-0016,TransEndotheliaTunnel,Vers la prévention de dysfonctions vasculaires et la délivrance de médicaments au travers des endothelia(2015), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), DELARUE, NADINE, Centres d'excellences - Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie - - SIGNALIFE2011 - ANR-11-LABX-0028 - LABX - VALID, Vers la prévention de dysfonctions vasculaires et la délivrance de médicaments au travers des endothelia - - TransEndotheliaTunnel2015 - ANR-15-CE18-0016 - AAPG2015 - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, and Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID

Subjects
Docosahexaenoic Acids, Transendothelial cell macroaperture, [SDV]Life Sciences [q-bio], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Membrane Fusion, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Animals, Humans, Endothelium, Large-scale membrane dynamics, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Phospholipids, Polyunsaturated phospholipids, Actin cytoskeleton, Cell Membrane, Endothelial Cells, Cell Biology, Bacterial toxin, [SDV] Life Sciences [q-bio], DHA, Docosahexaenoic acid, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, lipids (amino acids, peptides, and proteins)
Abstract

Metabolic studies and animal knockout models point to the critical role of polyunsaturated docosahexaenoic acid (22:6, DHA)-containing phospholipids (DHA-PLs) in physiology. Here, we investigated the impact of DHA-PLs on the dynamics of transendothelial cell macroapertures (TEMs) triggered by RhoA inhibition-associated cell spreading. Lipidomic analyses showed that human umbilical vein endothelial cells (HUVECs) subjected to a DHA diet undergo a 6-fold enrichment in DHA-PLs at the plasma membrane (PM) at the expense of monounsaturated oleic acid-containing PLs (OA-PLs). Consequently, DHA-PL enrichment at the PM induces a reduction in cell thickness and shifts cellular membranes towards a permissive mode of membrane fusion for transcellular tunnel initiation. We provide evidence that a global homeostatic control of membrane tension and cell cortex rigidity minimizes overall changes of TEM area through a decrease of TEM size and lifetime. Conversely, low DHA-PL levels at the PM lead to the opening of unstable and wider TEMs. Together, this provides evidence that variations of DHA-PL levels in membranes affect cell biomechanical properties.

Published
2021
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45. Blockade of pro-fibrotic response mediated by the miR-143/-145 cluster prevents targeted therapy-induced phenotypic plasticity and resistance in melanoma

Author

Couralet M, Caroline Lacoux, C.M. Mounier, Frédéric Larbret, Irondelle M, Christophe Girard, Berestjuk I, Diazzi S, Bernard Mari, Carminati A, Alberto Baeri, Marcel Deckert, Jean-Christophe Marine, Lise Lefèvre, Oskar Marín-Béjar, Marin Truchi, Margaux Lecacheur, Sophie Tartare-Deckert, Julien Fassy, Georges Vassaux, Centre méditerranéen de médecine moléculaire (C3M), 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), Institut de pharmacologie moléculaire et cellulaire (IPMC), 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), Leuven Center for Cancer Biology (VIB-KU-CCB), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), FHU OncoAge - Pathologies liées à l’âge [CHU Nice] (OncoAge), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Université Côte d'Azur (UCA), Girard, christophe, Université Nice Sophia Antipolis (... - 2019) (UNS), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)

Subjects
[SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, biology, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology, Actin cytoskeleton, Targeted therapy, Extracellular matrix, Focal adhesion, 03 medical and health sciences, Crosstalk (biology), 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Downregulation and upregulation, 030220 oncology & carcinogenesis, biology.protein, Cancer research, medicine, Myofibroblast, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, 030304 developmental biology, Fascin
Abstract

Lineage dedifferentiation towards a mesenchymal-like state is a common mechanism of adaptive response and resistance to targeted therapy in melanoma. Yet, the transcriptional network driving this phenotypic plasticity remains elusive. Remarkably, this cellular state displays myofibroblast and fibrotic features and escapes MAPK inhibitors (MAPKi) through extracellular matrix (ECM) remodeling activities. Here we show that the anti-fibrotic drug Nintedanib/BIBF1120 is active to normalize the fibrous ECM network, enhance the efficacy of MAPK-targeted therapy and delay tumor relapse in a pre-clinical model of melanoma. We also uncovered the molecular networks that regulate the acquisition of this resistant phenotype and its reversion by Nintedanib, pointing the miR-143/-145 pro-fibrotic cluster as a driver of the therapy-resistant mesenchymal-like phenotype. Upregulation of the miR-143/-145 cluster under BRAFi/MAPKi therapy was observed in melanoma cells in vitro and in vivo and was associated with an invasive/undifferentiated profile of resistant cells. The 2 mature miRNAs generated from this cluster, miR-143-3p and miR-145-5p collaborated to mediate phenotypic transition towards a drug resistant undifferentiated mesenchymal-like state by targeting Fascin actin-bundling protein 1 (FSCN1), modulating the dynamic crosstalk between the actin cytoskeleton and the ECM through the regulation of focal adhesion dynamics as well as contributing to a fine-tuning of mechanotransduction pathways. Our study brings insights into a novel miRNA-mediated regulatory network that contributes to non-genetic adaptive drug resistance and provides proof-of-principle that preventing MAPKi-induced pro-fibrotic stromal response is a viable therapeutic opportunity for patients on targeted therapy.

Published
2021
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46. Arf6 is necessary for senseless expression in response to wingless signalling during Drosophila wing development

Author

Pascal P. Thérond, Julien Marcetteau, Tamás Matusek, Frédéric Luton, 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)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), and 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)

Subjects
animal structures, QH301-705.5, Science, [SDV]Life Sciences [q-bio], Armadillo, Regulator, Wnt1 Protein, Signalling, General Biochemistry, Genetics and Molecular Biology, Adherens junction, 03 medical and health sciences, Transduction (genetics), Wnt, 0302 clinical medicine, biology.animal, Animals, Drosophila Proteins, Biology (General), Arf6, Wnt Signaling Pathway, 030304 developmental biology, 0303 health sciences, biology, fungi, Wnt signaling pathway, LRP6, Cell biology, Wingless, Pangolin, Drosophila, Signal transduction, General Agricultural and Biological Sciences, 030217 neurology & neurosurgery, Transcription Factors, Research Article
Abstract

Wnt signalling is a core pathway involved in a wide range of developmental processes throughout the metazoa. In vitro studies have suggested that the small GTP binding protein Arf6 regulates upstream steps of Wnt transduction, by promoting the phosphorylation of the Wnt co-receptor, LRP6, and the release of β-catenin from the adherens junctions. To assess the relevance of these previous findings in vivo, we analysed the consequence of the absence of Arf6 activity on Drosophila wing patterning, a developmental model of Wnt/Wingless signalling. We observed a dominant loss of wing margin bristles and Senseless expression in Arf6 mutant flies, phenotypes characteristic of a defect in high level Wingless signalling. In contrast to previous findings, we show that Arf6 is required downstream of Armadillo/β-catenin stabilisation in Wingless signal transduction. Our data suggest that Arf6 modulates the activity of a downstream nuclear regulator of Pangolin activity in order to control the induction of high level Wingless signalling. Our findings represent a novel regulatory role for Arf6 in Wingless signalling., Summary: Arf6 is necessary for the patterning of the wing margin by Wingless in Drosophila melanogaster, acting downstream of stabilized Armadillo but upstream or at the level of Pangolin activity.

Published
2021

47. MT5‐MMP controls APP and β‐CTF/C99 metabolism through proteolytic‐dependent and ‐independent mechanisms relevant for Alzheimer's disease

Author

Anne Bernard, Kévin Baranger, Nicolas Jullien, Jean-Michel Paumier, Michel Khrestchatisky, Dominika Pilat, Delphine Stephan, Emmanuel Nivet, Laura García-González, Laurence Louis, Santiago Rivera, Frédéric Checler, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), ANR-17-EURE-0029,nEURo*AMU,Marseille NeuroSchool, une formation d'excellence(2017), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Université Nice Sophia Antipolis (... - 2019) (UNS), and 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)

Subjects
0301 basic medicine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Peptide, Matrix metalloproteinase, medicine.disease_cause, Biochemistry, Pathogenesis, Amyloid beta-Protein Precursor, Mice, 0302 clinical medicine, Amyloid precursor protein, chemistry.chemical_classification, 0303 health sciences, Mutation, Metalloproteinase, biology, Chemistry, 3. Good health, Cell biology, medicine.anatomical_structure, amyloid beta precursor protein, lysosome, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], metalloproteinase, Biotechnology, Matrix Metalloproteinases, Membrane-Associated, secretase, Amyloid beta, Mice, Transgenic, Cell Line, 03 medical and health sciences, Alzheimer Disease, Lysosome, Genetics, medicine, Animals, Humans, endosome, scavenger, Molecular Biology, 030304 developmental biology, Amyloid beta-Peptides, HEK 293 cells, Peptide Fragments, Mice, Inbred C57BL, α-CTF/C83, HEK293 Cells, proteasome, 030104 developmental biology, Proteasome, Proteolysis, biology.protein, Amyloid Precursor Protein Secretases, Amyloid precursor protein secretase, 030217 neurology & neurosurgery
Abstract

International audience; Abbreviations: 3xTG, transgenic mice expressing human APP, MAPT, and PSEN1 genes with three familial mutations; 5xFAD, transgenic mice expressing human APP and PSEN1 genes with five familial mutations; AD, Alzheimer's disease; ADAM, a disintegrin and metalloprotease; APP, amyloid protein precursor; Aβ, beta-amyloid peptide; BACE-1, beta-site APP-cleaving enzyme-1; C3, BACE-1 inhibitor IV; C99/C83, APP CTF of 99/83 amino acids; CAT-, deletion of the catalytic domain; CTF, C-terminal fragment; DAPT, γ-secretase inhibitor; EXT-, deletion of the extracellular domain; GFP, green fluorescent protein; HEKswe, human embryonic kidney cells carrying the APP Swedish mutation; HPX-, deletion of the hemopexin domain; HRP, horseradish peroxidase enzyme; IC-, deletion of the intracytoplasmic domain; MMP, matrix metalloproteinase; MT1/5-MMP, membrane-type 1/5 matrix metalloproteinase; MT1/5Δ-MMP, catalytically inactive MT1-MMP or MT5-MMP; MTT, 3-(4,5-Dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide; PSEN 1(2), presenilin 1 and 2; qPCR, quantitative polymerase chain reaction; RFP, red fluorescent protein; RXP03, MMP inhibitor; sAPP95, soluble amyloid protein precursor fragment generated by MT5-MMP; sAPPFL, full-length soluble amyloid protein precursor; sAPPα/β, soluble APPα/β; Tf, transferrin; TIMP, tissue inhibitor of MMPs; TIMP-1Δ, inactive TIMP-1; TM/IC-, deletion of the transmembrane and intracytoplasmic domains.

Published
2021
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48. Nanoscale architecture of a VAP-A-OSBP tethering complex at membrane contact sites

Author

Joëlle Bigay, Aurélie Di Cicco, Eugenio de la Mora, Bruno Mesmin, Daniel Lévy, Bruno Antonny, John Manzi, Romain Gautier, Joël Polidori, Manuela Dezi, Daniel Castaño-Díez, Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), and University of Basel (Unibas)

Subjects
0301 basic medicine, Science, General Physics and Astronomy, behavioral disciplines and activities, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Organelle, OSBP, Multidisciplinary, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Chemistry, Endoplasmic reticulum, General Chemistry, Golgi apparatus, Small molecule, humanities, Transmembrane protein, 030104 developmental biology, Membrane, symbols, Biophysics, Cryoelectron tomography, Plant lipid transfer proteins, 030217 neurology & neurosurgery
Abstract

Membrane contact sites (MCS) are subcellular regions where two organelles appose their membranes to exchange small molecules, including lipids. Structural information on how proteins form MCS is scarce. We designed an in vitro MCS with two membranes and a pair of tethering proteins suitable for cryo-tomography analysis. It includes VAP-A, an ER transmembrane protein interacting with a myriad of cytosolic proteins, and oxysterol-binding protein (OSBP), a lipid transfer protein that transports cholesterol from the ER to the trans Golgi network. We show that VAP-A is a highly flexible protein, allowing formation of MCS of variable intermembrane distance. The tethering part of OSBP contains a central, dimeric, and helical T-shape region. We propose that the molecular flexibility of VAP-A enables the recruitment of partners of different sizes within MCS of adjustable thickness, whereas the T geometry of the OSBP dimer facilitates the movement of the two lipid-transfer domains between membranes., Membrane contact sites (MCS) are subcellular regions where two organelles appose their membranes to exchange small molecules, including lipids. Here authors designed an in vitro MCS suitable for cryotomography and sub-tomogram analysis which sheds light on the recruitment of proteins of different sizes within MCS of adjustable thickness.

Published
2021
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49. Simultaneous Pharmacologic Inhibition of Yes-Associated Protein 1 and Glutaminase 1 via Inhaled Poly(Lactic-co-Glycolic) Acid-Encapsulated Microparticles Improves Pulmonary Hypertension

Author

Thomas Bertero, Abhinav P. Acharya, Wei Sun, Nilay Mitash, Ricardo Pineda, Stephen Y. Chan, Lloyd D. Harvey, Melanie Königshoff, Chen Shan C. Woodcock, Ying Tang, Steven R. Little, Yi Yin Tai, Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
Male, Time Factors, Benzeneacetamides, Vasodilation, 030204 cardiovascular system & hematology, Pharmacology, Mechanotransduction, Cellular, Vascular Medicine, Rats, Sprague-Dawley, chemistry.chemical_compound, 0302 clinical medicine, Vascular stiffness, Polylactic Acid-Polyglycolic Acid Copolymer, Pulmonary Biology, pulmonary hypertension, Vascular Disease, Medicine, Enzyme Inhibitors, Lung, Glycolic acid, Cells, Cultured, Original Research, 0303 health sciences, Drug Carriers, Monocrotaline, Glutaminase, nanoparticle, Intracellular Signaling Peptides and Proteins, 3. Good health, Drug Combinations, Cardiology and Cardiovascular Medicine, Drug Compounding, Hypertension, Pulmonary, Vascular Remodeling, Yes associated protein 1, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Administration, Inhalation, Thiadiazoles, Animals, Humans, Particle Size, 030304 developmental biology, mechanotransduction, therapy, Cellular metabolism, business.industry, Hemodynamics, Verteporfin, YAP-Signaling Proteins, Metabolism, medicine.disease, Pulmonary hypertension, Disease Models, Animal, chemistry, Delayed-Action Preparations, Ventricular Function, Right, business, metabolism
Abstract

Background Pulmonary hypertension (PH) is a deadly disease characterized by vascular stiffness and altered cellular metabolism. Current treatments focus on vasodilation and not other root causes of pathogenesis. Previously, it was demonstrated that glutamine metabolism, as catalyzed by GLS1 (glutaminase 1) activity, is mechanoactivated by matrix stiffening and the transcriptional coactivators YAP1 (yes‐associated protein 1) and transcriptional coactivator with PDZ‐binding motif (TAZ), resulting in pulmonary vascular proliferation and PH. Pharmacologic inhibition of YAP1 (by verteporfin) or glutaminase (by CB‐839) improved PH in vivo. However, systemic delivery of these agents, particularly YAP1 inhibitors, may have adverse chronic effects. Furthermore, simultaneous use of pharmacologic blockers may offer additive or synergistic benefits. Therefore, a strategy that delivers these drugs in combination to local lung tissue, thus avoiding systemic toxicity and driving more robust improvement, was investigated. Methods and Results We used poly(lactic‐co‐glycolic) acid polymer‐based microparticles for delivery of verteporfin and CB‐839 simultaneously to the lungs of rats suffering from monocrotaline‐induced PH. Microparticles released these drugs in a sustained fashion and delivered their payload in the lungs for 7 days. When given orotracheally to the rats weekly for 3 weeks, microparticles carrying this drug combination improved hemodynamic (right ventricular systolic pressure and right ventricle/left ventricle+septum mass ratio), histologic (vascular remodeling), and molecular markers (vascular proliferation and stiffening) of PH. Importantly, only the combination of drug delivery, but neither verteporfin nor CB‐839 alone, displayed significant improvement across all indexes of PH. Conclusions Simultaneous, lung‐specific, and controlled release of drugs targeting YAP1 and GLS1 improved PH in rats, addressing unmet needs for the treatment of this deadly disease.

Published
2021
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50. High Dimensional Imaging Mass Cytometry Panel to Visualize the Tumor Immune Microenvironment Contexture

Author

Roxane Elaldi, Patrice Hemon, Luciana Petti, Estelle Cosson, Belinda Desrues, Anne Sudaka, Gilles Poissonnet, Ellen Van Obberghen-Schilling, Jacques-Olivier Pers, Veronique M. Braud, Fabienne Anjuère, Aïda Meghraoui-Kheddar, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Centre Antoine Lacassagne, Nice, France, ANR-19-P3IA-0002,3IA@cote d'azur,3IA Côte d'Azur(2019), BRAUD, Veronique, 3IA Côte d'Azur - - 3IA@cote d'azur2019 - ANR-19-P3IA-0002 - P3IA - VALID, 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), and 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)

Subjects
0301 basic medicine, Skin Neoplasms, Tissue imaging, [SDV]Life Sciences [q-bio], Immune microenvironment, Immunology, imaging mass cytometry, High dimensional, Workflow, Extracellular matrix, 03 medical and health sciences, panel design, 0302 clinical medicine, Immune system, Biomarkers, Tumor, Tumor Microenvironment, Methods, Humans, Immunology and Allergy, Mass cytometry, Image Cytometry, tumor immune microenvironment, Tumor microenvironment, Chemistry, biomarkers, RC581-607, Immunohistochemistry, [SDV] Life Sciences [q-bio], 030104 developmental biology, Tumor progression, 030220 oncology & carcinogenesis, Carcinoma, Squamous Cell, Disease Progression, Cancer research, immune therapies, Immunologic diseases. Allergy
Abstract

The integrative analysis of tumor immune microenvironment (TiME) components, their interactions and their microanatomical distribution is mandatory to better understand tumor progression. Imaging Mass Cytometry (IMC) is a high dimensional tissue imaging system which allows the comprehensive and multiparametric in situ exploration of tumor microenvironments at a single cell level. We describe here the design of a 39-antibody IMC panel for the staining of formalin-fixed paraffin-embedded human tumor sections. We also provide an optimized staining procedure and details of the experimental workflow. This panel deciphers the nature of immune cells, their functions and their interactions with tumor cells and cancer-associated fibroblasts as well as with other TiME structural components known to be associated with tumor progression like nerve fibers and tumor extracellular matrix proteins. This panel represents a valuable innovative and powerful tool for fundamental and clinical studies that could be used for the identification of prognostic biomarkers and mechanisms of resistance to current immunotherapies.

Published
2021
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