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1. Chronic treatments with a 5-HT4 receptor agonist decrease amyloid pathology in the entorhinal cortex and learning and memory deficits in the 5xFAD mouse model of Alzheimer's disease

Author

Delphine Stephan, Patrizia Giannoni, Sylvie Claeysen, Michel Khrestchatisky, Evelyne Marchetti-Gauthier, François S. Roman, Stéphane D. Girard, Santiago Rivera, Martine Migliorati, Florence Gaven, Joël Bockaert, Kévin Baranger, Sarah Girot, Aix Marseille Université (AMU), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Détection, évaluation, gestion des risques CHROniques et éMErgents (CHROME) / Université de Nîmes (CHROME), Université de Nîmes (UNIMES), Vect-Horus, This work was supported by funding from the CNRS and Aix-Marseille Université, and by grants from the French National Agency for Research to SR and FR (MAD5 ANR-15-CE16-0006) and to MK (PREVENTAD ANR-11-MALZ-0007) and to the DHUNE project supported by A*MIDEX. This work was carried out thanks to the support of the A*MIDEX project (ANR-11-IDEX-0001-02) funded by the ‘‘Investissements d’Avenir’’ French government program, managed by the ANR. It was also supported by a grant from France Alzheimer to SR, and by La Fondation Vaincre Alzheimer grants to SR (#14776), and MK (#13745). Additional support was provided by CNRS, Inserm, University of Montpellier, and the French NationalAgency of Research (ADAMGUARD ANR-12-BSV4-0008) grants to JB and SC and by France Alzheimer and La Fondation Vaincre Alzheimergrants to SC (#12721). KB was granted a research associate fellowship by the French 'Fondation Plan Alzheimer' and postdoctoral support from the LABEX A*MIDEX 'Management des Talents' from Aix Marseille Université., ANR-15-CE16-0006,MAD5,Validation de MT5-MMP comme nouvelle cible thérapeutique dans la maladie d'Alzheimer et mécanismes d'action(2015), ANR-11-MALZ-0007,PREVENTAD,MMP-12 comme marqueur précoce et cible thérapeutique dans la progression de la maladie d'Alzheimer(2011), ANR-11-IDEX-0001,Amidex,INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE(2011), ANR-12-BSV4-0008,ADAMGUARD,Les réseaux protéiques associés aux récepteurs 5 HT4 : gardes rapprochées du trafic de l'ADAM10 et de l'APP(2012), Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2, Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Giannoni, Patrizia, Validation de MT5-MMP comme nouvelle cible thérapeutique dans la maladie d'Alzheimer et mécanismes d'action - - MAD52015 - ANR-15-CE16-0006 - AAPG2015 - VALID, Maladie d'Alzheimer et Maladies Apparentées - MMP-12 comme marqueur précoce et cible thérapeutique dans la progression de la maladie d'Alzheimer - - PREVENTAD2011 - ANR-11-MALZ-0007 - MALZ - VALID, INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE - - Amidex2011 - ANR-11-IDEX-0001 - IDEX - VALID, BLANC - Les réseaux protéiques associés aux récepteurs 5 HT4 : gardes rapprochées du trafic de l'ADAM10 et de l'APP - - ADAMGUARD2012 - ANR-12-BSV4-0008 - BLANC - VALID, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN ( NICN ), Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Génomique Fonctionnelle ( IGF ), Centre National de la Recherche Scientifique ( CNRS ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), Détection, évaluation, gestion des risques CHROniques et éMErgents (CHROME) / Université de Nîmes ( CHROME ), Université de Nîmes ( UNIMES ), Centre National de la Recherche Scientifique ( CNRS ) -Université de la Méditerranée - Aix-Marseille 2, Neurobiologie intégrative et adaptative ( NIA ), and Université de Provence - Aix-Marseille 1-Centre National de la Recherche Scientifique ( CNRS )

Subjects
0301 basic medicine, Agonist, medicine.medical_specialty, medicine.drug_class, Transgenic mouse model, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Internal medicine, medicine, Amyloid precursor protein, Dementia, Effects of sleep deprivation on cognitive performance, Neuroinflammation, Pharmacology, Olfactory tubing maze, Memory impairments, biology, Amyloidosis, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, 5-HT(4) receptor agonist, [ SDV.SP.PHARMA ] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Alzheimer's disease, medicine.disease, Entorhinal cortex, Pharmacotherapy, 3. Good health, 030104 developmental biology, Endocrinology, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [ SCCO.NEUR ] Cognitive science/Neuroscience, biology.protein, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Psychology, Neuroscience, 030217 neurology & neurosurgery
Abstract

International audience; Alzheimer's disease (AD) is the main cause of dementia and a major health issue worldwide. The complexity of the pathology continues to challenge its comprehension and the implementation of effective treatments. In the last decade, a number of possible targets of intervention have been pointed out, among which the stimulation of 5-HT4receptors (5-HT4Rs) seems very promising. 5-HT4R agonists exert pro-cognitive effects, inhibit amyloid-β peptide (Aβ) production and therefore directly and positively impact AD progression. In the present work, we investigated the effects of RS 67333, a partial 5-HT4R agonist, after chronic administration in the 5xFAD mouse model of AD. 5xFAD male mice and their wild type (WT) male littermates received either RS 67333 or vehicle solution i.p., twice a week, for 2 or 4 months. Cognitive performance was evaluated in a hippocampal-dependent behavioral task, the olfactory tubing maze (OTM). Mice were then sacrificed to evaluate the metabolism of the amyloid precursor protein (APP), amyloidosis and neuroinflammatory processes. No beneficial effects of RS 67333 were observed in 5xFAD mice after 2 months of treatment, while 5xFAD mice treated for 4 months showed better cognitive abilities compared to vehicle-treated 5xFAD mice. The beneficial effects of RS 67333 on learning and memory correlated with the decrease in both amyloid plaque load and neuroinflammation, more specifically in the entorhinal cortex. The most significant improvements in learning and memory and reduction of pathology stigmata were observed after the 4-month administration of RS 67333, demonstrating that treatment duration is important to alleviate amyloidosis and glial reactivity, particularly in the entorhinal cortex. These results confirm the 5-HT4R as a promising target for AD pathogenesis and highlight the need for further investigations to characterize fully the underlying mechanisms of action.

Published
2017

2. Serotonin transporter gene expression predicts the worsening of suicidal ideation and suicide attempts along a long-term follow-up of a Major Depressive Episode

Author

Jorge Lopez-Castroman, Thomas Desmidt, Karine Baumstarck, Pascale Mazzola-Pomietto, Emilie Olié, Philippe Courtet, Julia-Lou Consoloni, Marie-Noëlle Lefebvre, Pierre-Michel Llorca, Mocrane Abbar, El Chérif Ibrahim, Raoul Belzeaux, Jean Naudin, Jean-Michel Azorin, Wissam El-Hage, Xavier Zendjidjian, Emmanuel Haffen, Ludovic Samalin, Fondation FondaMental [Créteil], Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN ( NICN ), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique ( CNRS ), CIC-CPCET, Hôpital de la Timone [CHU - APHM] ( TIMONE ), Assistance Publique - Hôpitaux de Marseille ( APHM ), Neuropsychiatrie : recherche épidémiologique et clinique, Université Montpellier 1 ( UM1 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Institut de Neurosciences de la Timone ( INT ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Imagerie et cerveau, Université de Tours-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Neuro-Psycho Pharmacologie des Systèmes Dopimanégiques sous-corticaux - Clermont Auvergne ( NPsy-Sydo ), CHU Clermont-Ferrand-Université Clermont Auvergne ( UCA ), Service de psychiatrie adulte, Université de Nîmes ( UNIMES ) -Centre Hospitalier Régional Universitaire de Nîmes ( CHRU Nîmes ) -Hôpital Universitaire Carémeau [Nîmes], Centre Hospitalier Régional Universitaire de Nîmes (.), Cognition, Action, et Plasticité Sensorimotrice [Dijon - U1093] ( CAPS ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Aix Marseille Université ( AMU ), Pôle de psychiatrie, Assistance Publique - Hôpitaux de Marseille ( APHM ) -Hôpital Sainte-Marguerite [CHU - APHM] ( Hôpitaux Sud ) -CHU Marseille, Clinique Psychiatrique Universitaire [Tours], CHRU Tours, Pathologies du système nerveux : recherche épidémiologique et clinique, Université Montpellier 1 ( UM1 ) -IFR76-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Pôle de Psychiatrie Universitaire Solaris, Marseille, Hôpital Sainte-Marguerite [CHU - APHM] ( Hôpitaux Sud ), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), Assistance Publique - Hôpitaux de Marseille (APHM), 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), Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuro-Psycho Pharmacologie des Systèmes Dopimanégiques sous-corticaux (NPsy-Sydo), CHU Clermont-Ferrand-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Aix Marseille Université (AMU), Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud )-CHU Marseille, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Département Universitaire de Psychiatrie - [Hôpital Sainte Marguerite - APHM] (Hôpitaux Sud), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2, Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud )-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Oncology, Male, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Gene Expression, Suicide, Attempted, [ SDV.NEU.SC ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, 0302 clinical medicine, Surveys and Questionnaires, Gene expression, Pharmacology (medical), Longitudinal Studies, Prospective cohort study, Major depressive episode, Suicidal ideation, Serotonin transporter, ComputingMilieux_MISCELLANEOUS, Serotonin Plasma Membrane Transport Proteins, biology, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Middle Aged, 16. Peace & justice, 3. Good health, Psychiatry and Mental health, Neurology, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [ SCCO.NEUR ] Cognitive science/Neuroscience, Biomarker (medicine), Female, France, medicine.symptom, Adult, medicine.medical_specialty, Peripheral blood mononuclear cell, Polymorphism, Single Nucleotide, Suicidal Ideation, [ SDV.NEU.PC ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, 03 medical and health sciences, Internal medicine, medicine, Humans, Genetic Testing, RNA, Messenger, Biological Psychiatry, Pharmacology, Depressive Disorder, Major, Suicide attempt, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, 030227 psychiatry, ROC Curve, Case-Control Studies, biology.protein, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

The quest for biomarkers in suicidal behaviors has been elusive so far, despite their potential utility in clinical practice. One of the most robust biological findings in suicidal behaviors is the alteration of the serotonin transporter function in suicidal individuals. Our main objective was to investigate the predictive value of the serotonin transporter gene expression (SLC6A4) for suicidal ideation and as secondary, for suicide attempts in individuals with a major depressive episode (MDE). A 30-week prospective study was conducted on 148 patients with a MDE and 100 healthy controls including 4 evaluation times (0, 2, 8 and 30 weeks). Blood samples and clinical data were collected and SLC6A4 mRNA levels were measured from peripheral blood mononuclear cells using RT-qPCR. We first demonstrated the stability and reproducibility of SLC6A4 mRNA expression measures over time in healthy controls (F=0.658; p=0.579; η2=0.008; ICC=0.91, 95% CI [0.87-0.94]). Baseline SLC6A4 expression level (OR=0.563 [0.340-0.932], p=0.026) as well as early changes in SLC6A4 expression between baseline and the 2nd week (β=0.200, p=0.042) predicted the worsening of suicidal ideation (WSI) in the following 8 weeks. Moreover, changes in SLC6A4 expression between the 2nd and 8th weeks predicted the occurrence of a suicide attempt within 30 weeks (OR=10.976 [1.438-83.768], p=0.021). Altogether, the baseline level and the changes in SLC6A4 mRNA expression during a MDE might predict the WSI and the occurrence of suicidal attempts and could be a useful biomarker in clinical practice.

Published
2017

3. Use of LDL receptor-targeting peptide vectors for in vitro and in vivo cargo transport across the blood-brain barrier

Author

Molino, Yves, David, Marion, Varini, Karine, Jabès, Françoise, Gaudin, Nicolas, Fortoul, Aude, Bakloul, Karima, Masse, Maxime, Bernard, Anne, Drobecq, Lucile, Lécorché, Pascaline, Temsamani, Jamal, Jacquot, Guillaume, Khrestchatisky, Michel, Vect-Horus, Département génie civil et batiment ( DGCB ), ENTP, centre Lyonnais d'Acoustique ( CeLyA ), Université de Lyon, Centre de recherche en neurobiologie - neurophysiologie de Marseille ( CRN2M ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN ( NICN ), Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre National de la Recherche Scientifique ( CNRS ) -Université de la Méditerranée - Aix-Marseille 2, Département génie civil et batiment (DGCB), centre Lyonnais d'Acoustique (CeLyA), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS)

Subjects
CNS drug delivery, [ SDV ] Life Sciences [q-bio], intracellular trafficking, [SDV]Life Sciences [q-bio], lysosome, receptor-mediated transcytosis, lipids (amino acids, peptides, and proteins), endosome
Abstract

International audience; The blood-brain barrier (BBB) prevents the entry of many drugs into the brain and, thus, is a major obstacle in the treatment of CNS diseases. There is some evidence that the LDL receptor (LDLR) is expressed at the BBB and may participate in the transport of endogenous ligands from blood to brain, a process referred to as receptor-mediated transcytosis. We previously described a family of peptide vectors that were developed to target the LDLR. In the present study, in vitro BBB models that were derived from either wild-type and LDLR knockout animals (ldlr(-/-)) were used to validate the specific LDLR-dependent transcytosis of LDL via a nondegradative route. We next showed that LDLR-targeting peptide vectors, whether in fusion or chemically conjugated to an Ab Fc fragment, promote binding to apical LDLR and transendothelial transfer of the Fc fragment across BBB monolayers via the same route as LDL. Finally, we demonstrated in vivo that LDLR significantly contributes to the brain uptake of vectorized Fc. We thus provide further evidence that LDLR is a relevant receptor for CNS drug delivery via receptor-mediated transcytosis and that the peptide vectors we developed have the potential to transport drugs, including proteins or Ab based, across the BBB.-Molino, Y., David, M., Varini, K., Jabès, F., Gaudin, N., Fortoul, A., Bakloul, K., Masse, M., Bernard, A., Drobecq, L., Lécorché, P., Temsamani, J., Jacquot, G., Khrestchatisky, M. Use of LDL receptor-targeting peptide vectors for in vitro and in vivo cargo transport across the blood-brain barrier.

Published
2017

4. Pantethine Down-Regulates Leukocyte Recruitment and Inflammatory Parameters in a Mouse Model of Allergic Airway Inflammation

Author

Abou-Hamdan, Mhamad, Gharib, Bouchra, Bajenoff, Marc, Julia, Valerie, Reggi, Max, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Immunologie des muqueuses et inflammation, 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), 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 Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN ( NICN ), Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'Immunologie de Marseille - Luminy ( CIML ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de pharmacologie moléculaire et cellulaire ( IPMC ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Aix Marseille Université (AMU)-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), 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
[SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], [ SDV.OT ] Life Sciences [q-bio]/Other [q-bio.OT]
Abstract

International audience; Background: Migration of leukocytes into airways is the hallmark of allergic asthma. The aim of this study was to target the pathological process using pantethine, a pleiotropic natural compound which has been recently shown to down-regulate chemokine-driven T cell migration.& para;& para;Material/Methods: Mice were sensitized to the Leishmania LACK antigen, then treated or not treated with pantethine and exposed to LACK or saline aerosol. After sacrifice of the animals, cells in the bronchoalveolar lavage were analyzed and inflammatory parameters were determined to evaluate inflammation seriousness.& para;& para;Results: As compared to untreated animals, pantethine-treated animals displayed a moderated response to the allergen, as documented by decreased infiltration of inflammatory cells (all types), in addition to reduced levels of lung Th2 cytokines and circulating LACK-specific IgE.& para;& para;Conclusions: These data reveal the potential therapeutic importance of pantethine to moderate allergic asthma pathology. The compound has been previously shown to exert a broad range of protective activity in animals and in humans, with few or no adverse effects.

Published
2017

5. Optimization and in Vivo Validation of Peptide Vectors Targeting the LDL Receptor

Author

Nicolas Gaudin, Géraldine Ferracci, Jean-Daniel Malcor, Pascaline Lécorché, Mathieu Laurencin, Cedric Malicet, Guillaume Jacquot, Salvatore Cisternino, Vincent Dive, Marion David, Karine Varini, Fanny Gassiot, Maxime Masse, Michel Khrestchatisky, Aude Faucon, Maria Smirnova, Karima Abouzid, Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Université Pierre et Marie Curie - Paris 6 (UPMC), Optimisation Thérapeutique en Neuropsychopharmacologie (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Stress Cellulaire, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Département génie civil et batiment (DGCB), ENTP, centre Lyonnais d'Acoustique (CeLyA), Université de Lyon, Observatoire astronomique de Strasbourg, Observatoire astronomique de Strasbourg (ObAS), Université de Strasbourg (UNISTRA)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), 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)-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), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Agence Nationale de la Recherche, Fonds Unique Interministériel, Association Nationale de la Recherche et de la Technologie, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS), 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), Institut Cochin ( UMR_S567 / UMR 8104 ), 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 Pierre et Marie Curie - Paris 6 ( UPMC ), Institut des Sciences Chimiques de Rennes ( ISCR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Ecole Nationale Supérieure de Chimie de Rennes-Institut National des Sciences Appliquées ( INSA ) -Centre National de la Recherche Scientifique ( CNRS ), Variabilité de réponse aux psychotropes ( VariaPsy - U1144 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ), Centre de recherche en neurobiologie - neurophysiologie de Marseille ( CRN2M ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de génétique et de physiologie moléculaire et cellulaire ( CGPhiMC ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Département génie civil et batiment ( DGCB ), centre Lyonnais d'Acoustique ( CeLyA ), Observatoire astronomique de Strasbourg ( ObAS ), Université de Strasbourg ( UNISTRA ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ), Service d'Ingénierie Moléculaire des Protéines ( SIMOPRO ), Département Médicaments et Technologies pour la Santé ( DMTS ), Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN ( NICN ), Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)

Subjects
0301 basic medicine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Genetic Vectors, tissue distribution, Pharmaceutical Science, Peptide, CHO Cells, Biology, peptide vector, 03 medical and health sciences, Mice, Structure-Activity Relationship, 0302 clinical medicine, Cricetulus, Drug Delivery Systems, In vivo, Drug Discovery, Animals, LDLR knockout, Receptor, Peptide ligand, LDLR targeting, chemistry.chemical_classification, Mice, Knockout, medicinal chemistry based optimization, In vitro, Endocytosis, Peptide Fragments, Amino acid, High uptake, Mice, Inbred C57BL, 030104 developmental biology, chemistry, Biochemistry, Receptors, LDL, 030220 oncology & carcinogenesis, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, LDL receptor, Molecular Medicine
Abstract

International audience; Active targeting and delivery to pathophysiological organs of interest is of paramount importance to increase specific accumulation of therapeutic drugs or imaging agents while avoiding systemic side effects. We recently developed a family of new peptide ligands of the human and rodent LDL receptor (LDLR), an attractive cell-surface receptor with high uptake activity and local enrichment in several normal or pathological tissues (Malcor et al., J. Med. Chem. 2012, 55 (5), 2227). Initial chemical optimization of the 15-mer, all natural amino acid compound 1/VH411 (DSGL[CMPRLRGC]cDPR) and structure-activity relationship (SAR) investigation led to the cyclic 8 amino acid analogue compound 22/VH445 ([cMPRLRGC]c) which specifically binds hLDLR with a KD of 76 nM and has an in vitro blood half-life of ∼3 h. Further introduction of non-natural amino acids led to the identification of compound 60/VH4106 ([(d)-"Pen"M"Thz"RLRGC]c), which showed the highest KD value of 9 nM. However, this latter analogue displayed the lowest in vitro blood half-life (∼1.9 h). In the present study, we designed a new set of peptide analogues, namely, VH4127 to VH4131, with further improved biological properties. Detailed analysis of the hLDLR-binding kinetics of previous and new analogues showed that the latter all displayed very high on-rates, in the 10(6) s(-1.)M(-1) range, and off-rates varying from the low 10(-2) s(-1) to the 10(-1) s(-1) range. Furthermore, all these new analogues showed increased blood half-lives in vitro, reaching ∼7 and 10 h for VH4129 and VH4131, respectively. Interestingly, we demonstrate in cell-based assays using both VH445 and the most balanced optimized analogue VH4127 ([cM"Thz"RLRG"Pen"]c), showing a KD of 18 nM and a blood half-life of ∼4.3 h, that its higher on-rate correlated with a significant increase in both the extent of cell-surface binding to hLDLR and the endocytosis potential. Finally, intravenous injection of tritium-radiolabeled (3)H-VH4127 in wild-type or ldlr -/- mice confirmed their active LDLR targeting in vivo. Overall, this study extends our previous work toward a diversified portfolio of LDLR-targeted peptide vectors with validated LDLR-targeting potential in vivo.

Published
2016

6. Profiling olfactory stem cells from living patients identifies miRNAs relevant for autism pathophysiology

Author

Karine Siquier-Pernet, Claire Rougeulle, Marylin Lepleux, Francois Feron, Bruno Gepner, Julien Fregeac, Yann Humeau, Laurence Colleaux, Anne Philippe, Lam Son Nguyen, Christelle Martin, Melanie Makhlouf, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Interdisciplinary Institute for Neuroscience (IINS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), ANDRA, Agence Nationale pour la Gestion des Déchets Radioactifs (ANDRA), LIttoral ENvironnement et Sociétés - UMR 7266 (LIENSs), Université de La Rochelle (ULR)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Parole et Langage (LPL), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Interdisciplinary Institute for Neuroscience, ANR-10-IBHU-0001/10-IBHU-0001,MMO (IHU-CANCER),MMO (IHU-CANCER)(2010), ANR-12-SAMA-0001,SAMENTA 2012 : EPI - ASD,Santé Mentales et Addictions (SAMENTA) Edition 2012 : 'Contributions des anomalies épigénomiques à l’étiologie des troubles autistiques', Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Laboratory of Molecular and pathophysiological bases of cognitive disorders, Sorbonne Université (SU), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-10-IBHU-0001,MMO (IHU-CANCER),Institut de Médecine Personnalisée du Cancer(2010), ANR-12-SAMA-0001,EPI-ASD,Contributions des anomalies épigénomiques à l'étiologie des troubles autistiques(2012), BMC, BMC, Instituts Hospitalo-Universitaires B - Institut de Médecine Personnalisée du Cancer - - MMO (IHU-CANCER)2010 - ANR-10-IBHU-0001 - IBHU - VALID, Santé Mentale et Addictions - Contributions des anomalies épigénomiques à l'étiologie des troubles autistiques - - EPI-ASD2012 - ANR-12-SAMA-0001 - SAMENTA - VALID, Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), 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 Interdisciplinaire de Neurosciences ( IINS ), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique ( CNRS ), Centre épigénétique et destin cellulaire ( EDC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN ( NICN ), Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), ANR-10-IBHU-0001/10-IBHU-0001,MMO (IHU-CANCER),MMO (IHU-CANCER) ( 2010 ), and Centre épigénétique et destin cellulaire (EDC)

Subjects
Male, 0301 basic medicine, Autism Spectrum Disorder, [SDV]Life Sciences [q-bio], Hippocampus, Transcriptome, Mice, 0302 clinical medicine, Neurodevelopmental disorder, 3' Untranslated Regions, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Neurons, MicroRNA, Autism spectrum disorders, Neural stem cell, [SDV] Life Sciences [q-bio], Adult Stem Cells, Psychiatry and Mental health, medicine.anatomical_structure, Organ Specificity, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Stem cell, Astrocyte, Adult stem cell, Adult, Genetic Vectors, Biology, Real-Time Polymerase Chain Reaction, Young Adult, 03 medical and health sciences, Olfactory Mucosa, Developmental Neuroscience, microRNA, medicine, Animals, Humans, Molecular Biology, [ SDV ] Life Sciences [q-bio], Olfactory mucosa stem cells, Research, Lentivirus, Fibroblasts, Neuron, medicine.disease, Human genetics, MicroRNAs, 030104 developmental biology, Astrocytes, Neuroscience, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Background Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders caused by the interaction between genetic vulnerability and environmental factors. MicroRNAs (miRNAs) are key posttranscriptional regulators involved in multiple aspects of brain development and function. Previous studies have investigated miRNAs expression in ASD using non-neural cells like lymphoblastoid cell lines (LCL) or postmortem tissues. However, the relevance of LCLs is questionable in the context of a neurodevelopmental disorder, and the impact of the cause of death and/or post-death handling of tissue likely contributes to the variations observed between studies on brain samples. Methods miRNA profiling using TLDA high-throughput real-time qPCR was performed on miRNAs extracted from olfactory mucosal stem cells (OMSCs) biopsied from eight patients and six controls. This tissue is considered as a closer tissue to neural stem cells that could be sampled in living patients and was never investigated for such a purpose before. Real-time PCR was used to validate a set of differentially expressed miRNAs, and bioinformatics analysis determined common pathways and gene targets. Luciferase assays and real-time PCR analysis were used to evaluate the effect of miRNAs misregulation on the expression and translation of several autism-related transcripts. Viral vector-mediated expression was used to evaluate the impact of miRNAs deregulation on neuronal or glial cells functions. Results We identified a signature of four miRNAs (miR-146a, miR-221, miR-654-5p, and miR-656) commonly deregulated in ASD. This signature is conserved in primary skin fibroblasts and may allow discriminating between ASD and intellectual disability samples. Putative target genes of the differentially expressed miRNAs were enriched for pathways previously associated to ASD, and altered levels of neuronal transcripts targeted by miR-146a, miR-221, and miR-656 were observed in patients’ cells. In the mouse brain, miR-146a, and miR-221 display strong neuronal expression in regions important for high cognitive functions, and we demonstrated that reproducing abnormal miR-146a expression in mouse primary cell cultures leads to impaired neuronal dendritic arborization and increased astrocyte glutamate uptake capacities. Conclusions While independent replication experiments are needed to clarify whether these four miRNAS could serve as early biomarkers of ASD, these findings may have important diagnostic implications. They also provide mechanistic connection between miRNA dysregulation and ASD pathophysiology and may open up new opportunities for therapeutic. Electronic supplementary material The online version of this article (doi:10.1186/s13229-015-0064-6) contains supplementary material, which is available to authorized users.

Published
2016

7. Systemic Lupus Erythematosus and Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Overlap Syndrome in Patients With Biopsy-Proven Glomerulonephritis

Author

Philippe Halfon, Laurent Chiche, Xavier Puéchal, Nathalie Bardin, Emmanuel Andrès, Vincent Vuiblet, Baptiste Hervier, Daniel Bertin, Laurent Daniel, Noémie Jourde-Chiche, Jean-Loup Pennaforte, Pierre-André Jarrot, Zahir Amoura, Bertrand Dussol, Eric Rondeau, Gilles Kaplanski, Benjamin Terrier, Mohamed Hamidou, Eric Daugas, Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Vascular research center of Marseille (VRCM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie de l'Endothelium, Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen [Fondation Ambroise Paré - Marseille], Service de médecine interne et d'immunologie clinique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Immunologie [Hôpital de la Conception - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION )-Centre National de la Recherche Scientifique (CNRS), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Médecine Interne, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP]-Université Paris Descartes - Paris 5 (UPD5), Institut E3M [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [APHP], Service de médecine interne [CHU Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC), Urgences néphrologiques et transplantation rénale [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Hôpital Bichat - Claude Bernard, CHU Cochin [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Aix Marseille Université (AMU), Hôpital Civil de Strasbourg, Héritages et Constructions dans le Texte et l'Image (HCTI), Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Institut Brestois des Sciences de l'Homme et de la Société (IBSHS), Université de Brest (UBO)-Université de Brest (UBO), Chirurgie urologique et transplantation rénale [Hôpital de la Conception - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Vascular research center of Marseille ( VRCM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ), Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ), Centre d'Immunologie de Marseille - Luminy ( CIML ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Matrice extracellulaire et dynamique cellulaire - UMR 7369 ( MEDyC ), Université de Reims Champagne-Ardenne ( URCA ) -SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne ( URCA ) -Université de Picardie Jules Verne ( UPJV ) -Université de Reims Champagne-Ardenne ( URCA ) -Université de Picardie Jules Verne ( UPJV ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance Publique - Hôpitaux de Marseille ( APHM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ) -Centre National de la Recherche Scientifique ( CNRS ), Aix Marseille Université ( AMU ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP]-Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Centre hospitalier universitaire de Nantes ( CHU Nantes ), Héritages et Constructions dans le Texte et l'Image ( HCTI ), Université de Bretagne Sud ( UBS ) -Université de Brest ( UBO ) -Maison des Sciences de l'Homme de Bretagne-Institut Brestois des Sciences de l'Homme et de la Société ( IBSHS ), Université de Brest ( UBO ) -Université de Brest ( UBO ), Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims ( CHU Reims ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ), Service de Département de médecine interne et immunologie clinique [CHU Pitié-Salpêtrière] (DMIIC), Institut Brestois des Sciences de l'Homme et de la Société (IBSHS), Université de Brest (UBO)-Université de Brest (UBO)-Université de Bretagne Sud (UBS)-Université de Brest (UBO), Institut National de la Santé et de la Recherche Médicale (INSERM) - Université de la Méditerranée - Aix-Marseille 2 - Aix Marseille Université (AMU), Hôpital Européen Marseille, Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Pitié-Salpêtrière [APHP], Laboratoire d'Anatomopathologie [Aix-Marseille], Assistance Publique - Hôpitaux de Marseille (APHM) - Hôpital de la Timone [CHU - APHM] (TIMONE) - CHU Marseille, Matrice extracellulaire et dynamique cellulaire (MEDyC), Université de Reims Champagne-Ardenne (URCA) - Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Immunologie [APHM-Hôpital de la Conception, Marseille], Assistance Publique - Hôpitaux de Marseille (APHM) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ) - Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Cochin [APHP] - Université Paris Descartes - Paris 5 (UPD5), CHU Tenon [APHP] - Assistance publique - Hôpitaux de Paris (AP-HP), Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), CHU Angers - Hôtel-Dieu de Nantes - Hôpital Laennec - Faculté de Médecine d'Angers - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS) - CHU Nantes, Hôpital Robert Debré - CHU Reims, Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Bichat - Claude Bernard [Paris] - Université Paris Diderot - Paris 7 (UPD7), Aix Marseille Université (AMU) - Assistance Publique - Hôpitaux de Marseille (APHM) - Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Institut Cochin, Université Sorbonne Paris Cité (USPC) - Université Paris Descartes - Paris 5 (UPD5) - Centre National de la Recherche Scientifique (CNRS) - Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), CHU Tenon [AP-HP], Université de Brest (UBO), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN ( NICN ), Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Université Pierre et Marie Curie - Paris 6 ( UPMC )

Subjects
Male, ANCA-ASSOCIATED VASCULITIS, Pathology, Anti-nuclear antibody, Biopsy, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Lupus nephritis, Kidney, Gastroenterology, Neutrophil extracellular traps, DISEASE, Glomerulonephritis, 0302 clinical medicine, immune system diseases, Lupus Erythematosus, Systemic, 10. No inequality, skin and connective tissue diseases, SJOGRENS-SYNDROME, medicine.diagnostic_test, Incidence, Overlap syndrome, General Medicine, 3. Good health, [SDV] Life Sciences [q-bio], ANTINUCLEAR ANTIBODY, Population Surveillance, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Female, CLINICAL-IMPLICATIONS, France, CRESCENTIC GLOMERULONEPHRITIS, Vasculitis, Research Article, Adult, medicine.medical_specialty, Adolescent, Antineutrophil cytoplasmic antibody-associated vasculitis, Observational Study, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, GRANULOPOIESIS SIGNATURES, CLASSIFICATION, Young Adult, 03 medical and health sciences, Internal medicine, NETTING NEUTROPHILS, medicine, Humans, Immune response, NEPHRITIS, Retrospective Studies, Anti-neutrophil cytoplasmic antibody, 030203 arthritis & rheumatology, Lupus erythematosus, [ SDV ] Life Sciences [q-bio], business.industry, medicine.disease, Antineutrophil cytoplasmic autoantibodies, business
Abstract

Supplemental Digital Content is available in the text, The aim of the study was to report the clinical, biological, and pathological characteristics of patients with glomerulonephritis (GN) secondary to systemic lupus erythematosus (SLE)/antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) overlap syndrome. A nationwide survey was conducted to identify cases of SLE/AAV overlap syndrome. Data were collected from SLE and AAV French research groups. Inclusion criteria were diagnosis of both SLE and AAV according to international classification criteria and biopsy-proven GN between 1995 and 2014. Additional cases were identified through a systematic literature review. A cohort of consecutive biopsy-proven GN was used to study the prevalence of overlapping antibodies and/or overlap syndrome. The national survey identified 8 cases of SLE/AAV overlap syndrome. All patients were female; median age was 40 years. AAV occurred before SLE (n = 3), after (n = 3), or concomitantly (n = 2). Six patients had rapidly progressive GN and 3/8 had alveolar hemorrhage. All patients had antinuclear antibodies (ANA); 7/8 had p-ANCA antimyeloperoxidase (MPO) antibodies. Renal biopsies showed lupus nephritis (LN) or pauci-immune GN. Remission was obtained in 4/8 patients. A literature review identified 31 additional cases with a similarly severe presentation. In the GN cohort, ANCA positivity was found in 30% of LN, ANA positivity in 52% of pauci-immune GN, with no correlation with pathological findings. The estimated prevalence for SLE/AAV overlap syndrome was 2/101 (2%). In patients with GN, SLE/AAV overlap syndrome may occur but with a low prevalence. Most patients have an aggressive renal presentation, with usually both ANA and anti-MPO antibodies. Further studies are needed to assess shared pathogenesis and therapeutic options.

Published
2016

8. Pantethine alters lipid composition and cholesterol content of membrane rafts, with down-regulation of cxcl12-induced t cell migration

Author

van Gijsel-Bonnello, Manuel, Acar, Niyazi, Molino, Yves, Bretillon, Lionel, Khrestchatisky, Michel, De Reggi, Max, Gharib, Bouchra, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Vect-Horus, Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN ( NICN ), Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), and 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 )

Subjects
lipid rafts, t cell migration, [ SDV.MHEP.PHY ] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], T-Lymphocytes, Down-Regulation, cell redox status, Lymphocyte Activation, Lipids, Chemokine CXCL12, Rats, Jurkat Cells, Cholesterol, Cell Movement, Pantetheine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Humans, Signal Transduction
Abstract

Pantethine, a natural low-molecular-weight thiol, shows a broad activity in a large range of essential cellular pathways. It has been long known as a hypolipidemic and hypocholesterolemic agent. We have recently shown that it exerts a neuroprotective action in mouse models of cerebral malaria and Parkinson's disease through multiple mechanisms. In the present study, we looked at its effects on membrane lipid rafts that serve as platforms for molecules engaged in cell activity, therefore providing a target against inappropriate cell response leading to a chronic inflammation. We found that pantethine-treated cells showed a significant change in raft fatty acid composition and cholesterol content, with ultimate downregulation of cell adhesion, CXCL12-driven chemotaxis, and transendothelial migration of various T cell types, including human Jurkat cell line and circulating effector T cells. The mechanisms involved include the alteration of the following: (i) CXCL12 binding to its target cells; (ii) membrane dynamics of CXCR4 and CXCR7, the two CXCL12 receptors; and (iii) cell redox status, a crucial determinant in the regulation of the chemokine system. In addition, we considered the linker for activation of T cells molecule to show that pantethine effects were associated with the displacement from the rafts of the acylated signaling molecules which had their palmitoylation level reduced.. In conclusion, the results presented here, together with previously published findings, indicate that due to its pleiotropic action, pantethine can downregulate the multifaceted process leading to pathogenic T cell activation and migration.

Published
2015

9. When the nose must remain responsive: glutathione conjugation of the mammary pheromone in the newborn rabbit

Author

Gilles Sicard, Philippe Faure, Gérard Coureaud, Arièle Legendre, Yves Artur, Benoist Schaal, Hélène Tiesset, Jean-Marie Heydel, Catherine Potin, Ingrid Jakob, Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Agence Nationale de la Recherche [ANR-05-PNRA-1.E7-Aromalim], FEDER (fonds europeen de developpement regional), Regional Council of Burgundy (plan d'actions regional pour l'innovation), National Institute of Agronomy, Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN ( NICN ), Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Legendre, Arièle, Faure, Philippe, Coureaud, Gérard, and Heydel, Jean-Marie

Subjects
Vomeronasal organ, Physiology, Ingénierie des aliments, Stimulation, Pheromones, Behavioral Neuroscience, chemistry.chemical_compound, nursing, newborn, ODORANT-BINDING PROTEINS, [SDV.IDA]Life Sciences [q-bio]/Food engineering, Dinitrochlorobenzene, rabbit (Oryctolagus cuniculus), EXPRESSION PATTERNS, Acrolein, Receptor, Glutathione Transferase, GENE-EXPRESSION, glutathione transferases, [ SDV.IDA ] Life Sciences [q-bio]/Food engineering, perireceptor events, LOCALIZATION, mammary pheromone, Glutathione, Sensory Systems, Smell, medicine.anatomical_structure, Organ Specificity, Sex pheromone, Pheromone, Female, Rabbits, ENZYMES, olfaction, medicine.medical_specialty, Olfaction, Biology, Nose, Gene Expression Regulation, Enzymologic, Physiology (medical), Internal medicine, medicine, Food engineering, Animals, Lactation, Aldehydes, ALDEHYDE, Feeding Behavior, UDP-GLUCURONOSYLTRANSFERASE, xenobiotic-metabolizing enzymes, RAT OLFACTORY EPITHELIUM, S-TRANSFERASE, VOMERONASAL ORGAN, Nasal Mucosa, Endocrinology, chemistry, Animals, Newborn, Olfactory epithelium
Abstract

In insects, xenobiotic-metabolizing enzymes were demonstrated to regulate pheromones inactivation, clearing them from the olfactory periphery and keeping receptors ready for stimulation renewal. Here, we investigate whether similar processes could occur in mammals, focusing on the pheromonal communication between female rabbits and their newborns. Lactating rabbits emit in their milk a volatile aldehyde, 2-methylbut-2-enal, that elicits searching-grasping in neonates; called the mammary pheromone (MP), it is critical for pups which are constrained to find nipples within the 5 min of daily nursing. For newborns, it is thus essential to remain sensitive to this odorant during the whole nursing period to display several actions of sucking. Here, we show that the MP is enzymatically conjugated to glutathione in newborn olfactory epithelium (OE), in accordance with the high mRNA expression of glutathione transferases evidenced by quantitative reverse transcription-PCR. This activity in the nose is higher than in the liver and in OE of newborns compared with weanlings (no more responsive to the pheromone). Therefore, the results pinpoint the existence of a high level of MP-glutathione conjugation activity in the OE of young rabbits, especially in the developmental window where the perceptual sensitivity toward the MP is crucial for survival.

Published
2014

10. Chemical optimization of new ligands of the low-density lipoprotein receptor as potential vectors for central nervous system targeting

Author

Jean Martinez, Michel Khrestchatisky, Vincent Lisowski, Marion David, Franck Debarbieux, Patrick Vlieghe, Karima Abouzid, Aude Faucon, Nadine Payrot, Geneviève Rougon, Guillaume Jacquot, Nicolas Floquet, Jean-Daniel Malcor, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN ( NICN ), Centre National de la Recherche Scientifique ( CNRS ) -Université de la Méditerranée - Aix-Marseille 2, Centre de génétique et de physiologie moléculaire et cellulaire ( CGPhiMC ), Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Institut Cochin ( UMR_S567 / UMR 8104 ), 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 des Biomolécules Max Mousseron [Pôle Chimie Balard] ( IBMM ), Ecole Nationale Supérieure de Chimie de Montpellier ( ENSCM ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Biologie du Développement de Marseille ( IBDM ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), and 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)

Subjects
Models, Molecular, Magnetic Resonance Spectroscopy, Phage display, MESH: Transcytosis, MESH : Receptors, LDL, Peptide, Ligands, 01 natural sciences, MESH : Blood-Brain Barrier, MESH: Blood-Brain Barrier, MESH: Spinal Cord, Mice, MESH: Structure-Activity Relationship, MESH : Peptides, Cyclic, MESH : Structure-Activity Relationship, Drug Discovery, MESH: Ligands, MESH : Fluorescent Dyes, MESH: Animals, Receptor, chemistry.chemical_classification, MESH : Ligands, 0303 health sciences, MESH : Transcytosis, Chemistry, MESH: Fluorescent Dyes, Cell biology, Spinal Cord, Transcytosis, Biochemistry, Blood-Brain Barrier, Drug delivery, MESH: Oligopeptides, Molecular Medicine, Oligopeptides, MESH: Models, Molecular, MESH : Oligopeptides, MESH : Models, Molecular, MESH : Mice, Inbred C57BL, Biopanning, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 010402 general chemistry, Peptides, Cyclic, Structure-Activity Relationship, 03 medical and health sciences, MESH: Mice, Inbred C57BL, MESH : Mice, Animals, Humans, MESH: Mice, MESH: Peptides, Cyclic, Fluorescent Dyes, 030304 developmental biology, MESH: Humans, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, MESH: Magnetic Resonance Spectroscopy, MESH : Humans, MESH : Spinal Cord, 0104 chemical sciences, Mice, Inbred C57BL, Receptors, LDL, Docking (molecular), MESH: Receptors, LDL, LDL receptor, MESH : Magnetic Resonance Spectroscopy, MESH : Animals
Abstract

International audience; Drug delivery to the central nervous system is hindered by the presence of physiological barriers such as the blood-brain barrier. To accomplish the task of nutrient transport, the brain endothelium is endowed with various transport systems, including receptor-mediated transcytosis (RMT). This system can be used to shuttle therapeutics into the central nervous system (CNS) in a noninvasive manner. Therefore, the low-density lipoprotein receptor (LDLR) is a relevant target for delivering drugs. From an initial phage display biopanning, a series of peptide ligands for the LDLR was optimized leading to size reduction and improved receptor binding affinity with the identification of peptide 22 and its analogues. Further real-time biphoton microscopy experiments on living mice demonstrated the ability of peptide 22 to efficiently and quickly cross CNS physiological barriers. This validation of peptide 22 led us to explore its binding on the extracellular LDLR domain from an NMR-oriented structural study and docking experiments.

Published
2012

11. MAU-8 is a Phosducin-like Protein required for G protein signaling in C. elegans

Author

Caroline Lacoste, Cécile Iborra, Madeleine Erard-Garcia, Michael Seagar, Véronique Barthaux, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN ( NICN ), Centre National de la Recherche Scientifique ( CNRS ) -Université de la Méditerranée - Aix-Marseille 2, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Khrestchatisky, Michel, and Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2

Subjects
Embryo, Nonmammalian, Cell division, G protein, Protein subunit, Mutant, GTP-Binding Protein alpha Subunits, Gi-Go, Biology, medicine.disease_cause, 03 medical and health sciences, GTP-Binding Protein Regulators, 0302 clinical medicine, GTP-Binding Proteins, Microtubule, Heterotrimeric G protein, medicine, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], G protein signaling, Caenorhabditis elegans Proteins, Eye Proteins, Mitosis, Molecular Biology, 030304 developmental biology, 0303 health sciences, Mutation, GTP-Binding Protein beta Subunits, Neurotransmission, Intracellular Signaling Peptides and Proteins, PAR-5/14.3.3 proteins, Cell Biology, Phosphoproteins, Molecular biology, Cell biology, Centrosome, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], C. elegans, GTP-Binding Protein alpha Subunits, Gq-G11, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030217 neurology & neurosurgery, Signal Transduction, Developmental Biology
Abstract

The mau-8(qm57) mutation inhibits the function of GPB-2, a heterotrimeric G protein beta subunit, and profoundly affects behavior through the Galphaq/Galphao signaling network in C. elegans. mau-8 encodes a nematode Phosducin-like Protein (PhLP), and the qm57 mutation leads to the loss of a predicted phosphorylation site in the C-terminal domain of PhLP that binds the Gbetagamma surface implicated in membrane interactions. In developing embryos, MAU-8/PhLP localizes to the cortical region, concentrates at the centrosomes of mitotic cells and remains associated with the germline blastomere. In adult animals, MAU-8/PhLP is ubiquitously expressed in somatic tissues and germline cells. MAU-8/PhLP interacts with the PAR-5/14.3.3 protein and with the Gbeta subunit GPB-1. In mau-8 mutants, the disruption of MAU-8/PhLP stabilizes the association of GPB-1 with the microtubules of centrosomes. Our results indicate that MAU-8/PhLP modulates G protein signaling, stability and subcellular location to regulate various physiological functions, and they suggest that MAU-8 might not be limited to the Galphaq/Galphao network.

Published
2006

12. Influence of childhood maltreatment on prevalence, onset and persistence of psychiatric comorbidities and suicide attempts in bipolar disorders

Author

Grillault Laroche, D., Godin, O., Dansou, Y., Belzeaux, R., Aouizerate, B., Burté, T., Courtet, Philippe, Dubertret, C., Haffen, E., Llorca, P.M., Olié, Émilie, Roux, P., Polosan, M., Schwan, R., Leboyer, M., Bellivier, F., Marie-Claire, C., Etain, B., Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Henri Mondor [Créteil], Fondation FondaMental [Créteil], Assistance Publique - Hôpitaux de Marseille (APHM), Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier Charles Perrens [Bordeaux], Nutrition et Neurobiologie intégrée (NutriNeuro), Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux-Ecole nationale supérieure de chimie, biologie et physique-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre Hospitalier Princesse Grace, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), Université Paris Cité (UPCité), Hôpital Louis Mourier - AP-HP [Colombes], Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Centre d'Investigation Clinique de Besançon (Inserm CIC 1431), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), CHU Clermont-Ferrand, Université Clermont Auvergne (UCA), Centre Hospitalier de Versailles André Mignot (CHV), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Université de Lorraine (UL), Centre Psychothérapique de Nancy [Laxou] (CPN), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), ANR-10-COHO-0010,Psy-COH,FondaMental-Cohortes(2010), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2, AP-HP, Groupe Hospitalo-Universitaire AP-HP Nord, DMU ESPRIT, service de Psychiatrie et Addictologie, Hôpital Louis Mourier, Colombes, Inserm U1266, 178, rue des Renouillers, 92700 Colombes, France, UFR de Médecine Paris Nord, Université de Paris, 16, rue Henri Huchard, 75018 Paris, France., Groupe de Recherche en Psychologie Sociale (GRePS), Université Lumière - Lyon 2 (UL2), Praticien Hospitalier Universitaire, CPN Laxou, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Guerineau, Nathalie C., Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, Cohortes - FondaMental-Cohortes - - Psy-COH2010 - ANR-10-COHO-0010 - COHO - VALID, CHU Henri Mondor, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), and Hôpital Charles Perrens

Subjects
bipolar disorder, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, childhood trauma, [SDV]Life Sciences [q-bio], childhood maltreatment, prevalence, substance use, Suicide, Attempted, sequence, anxiety, comorbidities, Suicidal Ideation, [SDV] Life Sciences [q-bio], Psychiatry and Mental health, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, mental disorders, Humans, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Child Abuse, Child, network analysis, suicide, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

BackgroundPsychiatric comorbidities and suicide attempts are highly prevalent in Bipolar Disorders (BD). We examined the associations between childhood maltreatment, psychiatric comorbidities, and suicide attempts, in terms of lifetime prevalence, sequence of onset, and current symptoms.MethodsWe assessed 3,047 individuals with BD for suicide attempts, anxiety disorders, substance use disorders, and eating disorders. Participants completed a self-report for the assessment of childhood maltreatment. Associations between childhood maltreatment and characteristics of comorbidities (lifetime prevalence, current symptoms, and age at onset) were examined using logistic regressions and network analyses.ResultsPsychiatric comorbidities were frequent with a mean number per individual of 1.23 (SD = 1.4). Most comorbidities occurred prior to the onset of BD. Participants who reported higher levels of childhood maltreatment had more frequent and multiple comorbidities, which were also more currently active at inclusion. Childhood maltreatment did not decrease the age of onset of comorbidities, but was associated with a faster accumulation of comorbidities prior to the onset of BD. Logistic regression and network analyses showed that emotional abuse and sexual abuse might play a prominent role in the lifetime prevalence of psychiatric comorbidities and suicide attempts.ConclusionsChildhood maltreatment was associated with suicide attempts, and with frequent, multiple, and persistent psychiatric comorbidities that accumulated more rapidly prior to the onset of BD. Hence, childhood maltreatment should be systematically assessed in individuals with BD, in particular when the course of the disorder is characterized by a high comorbid profile or by a high suicidality.

Published
2022

13. TWEAK/Fn14 pathway modulates properties of a human microvascular endothelial cell model of blood brain barrier

Author

Stephan, Delphine, Sbai, Oualid, Wen, Jing, Couraud, Pierre-Olivier, Putterman, Chaim, Khrestchatisky, Michel, Desplat-Jégo, Sophie, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Rheumatology, Albert Einstein College of Medicine [New York], Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by a grant from the National Multiple Sclerosis Society (RG 4161-A-1), and by grants from the Agence Nationale de la Recherche (ANR-09-MNPS-030 and ANR-09-BIOT-015-01) to SDJ and MK., Albert Einstein College of Medicine, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN ( NICN ), Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and BMC, Ed.

Subjects
[SDV.IMM] Life Sciences [q-bio]/Immunology, Cell Survival, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Immunology, Models, Neurological, hCMEC/D3, lcsh:RC346-429, Receptors, Tumor Necrosis Factor, Cellular and Molecular Neuroscience, Neuroinflammation, CCL-2, Cell Line, Tumor, Human Umbilical Vein Endothelial Cells, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Humans, lcsh:Neurology. Diseases of the nervous system, ZO-1, HMEC, IL-8, Research, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Cytokine TWEAK, TNFSF12, Neurology, Blood-Brain Barrier, TWEAK Receptor, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Tumor Necrosis Factors, [SDV.IMM]Life Sciences [q-bio]/Immunology, Endothelium, Vascular, MMP-9, Signal Transduction
Abstract

Background The TNF ligand family member TWEAK exists as membrane and soluble forms and is involved in the regulation of various human inflammatory pathologies, through binding to its main receptor, Fn14. We have shown that the soluble form of TWEAK has a pro-neuroinflammatory effect in an animal model of multiple sclerosis and we further demonstrated that blocking TWEAK activity during the recruitment phase of immune cells across the blood brain barrier (BBB) was protective in this model. It is now well established that endothelial cells in the periphery and astrocytes in the central nervous system (CNS) are targets of TWEAK. Moreover, it has been shown by others that, when injected into mice brains, TWEAK disrupts the architecture of the BBB and induces expression of matrix metalloproteinase-9 (MMP-9) in the brain. Nevertheless, the mechanisms involved in such conditions are complex and remain to be explored, especially because there is a lack of data concerning the TWEAK/Fn14 pathway in microvascular cerebral endothelial cells. Methods In this study, we used human cerebral microvascular endothelial cell (HCMEC) cultures as an in vitro model of the BBB to study the effects of soluble TWEAK on the properties and the integrity of the BBB model. Results We showed that soluble TWEAK induces an inflammatory profile on HCMECs, especially by promoting secretion of cytokines, by modulating production and activation of MMP-9, and by expression of cell adhesion molecules. We also demonstrated that these effects of TWEAK are associated with increased permeability of the HCMEC monolayer in the in vitro BBB model. Conclusions Taken together, the data suggest a role for soluble TWEAK in BBB inflammation and in the promotion of BBB interactions with immune cells. These results support the contention that the TWEAK/Fn14 pathway could contribute at least to the endothelial steps of neuroinflammation.

Published
2013

14. Characterization of adenosine A2 receptors in peripheral blood mononuclear cells of patients with fibromuscular dysplasia

Author

Laurie Bruzzese, Régis Guieu, Marion Marlinge, Giovanna Mottola, Jean Ruf, Mohamed Chefrour, Nathalie Kipson, Bernard Vaisse, François Silhol, Patrick Mace, Gabrielle Sarlon, Christine Criado, Donato Vairo, Claire Guiol, Emmanuel Fenouillet, Anne Donnet, Hôpital de la Timone [CHU - APHM] (TIMONE), Aix-Marseille Université - Faculté de pharmacie (AMU PHARM), Aix Marseille Université (AMU), Centre recherche en CardioVasculaire et Nutrition (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHU de la Timone], Dysoxie, suractivité : aspects cellulaires et intégratifs thérapeutiques (DS-ACI / UMR MD2), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Service de l'Hypertension [AP-HM Hôpital de la Timone], 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), Département de Biochimie [Hôpital de la Timone - APHM], Aix-Marseille Université - Faculté de médecine (AMU MED), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0303 health sciences, Pathology, medicine.medical_specialty, Physiology, business.industry, [SDV]Life Sciences [q-bio], Fibromuscular dysplasia, 030204 cardiovascular system & hematology, medicine.disease, Adenosine, Peripheral blood mononuclear cell, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Internal Medicine, medicine, Cardiology and Cardiovascular Medicine, Receptor, business, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030304 developmental biology, medicine.drug
Abstract

International audience

Published
2020

15. Altered muscle membrane potential and redox status differentiates two subgroups of patients with chronic fatigue syndrome

Author

Emmanuel Fenouillet, Yves Jammes, Nabil Adjriou, Stanislas Rebaudet, Caroline Charpin, C. Stavris, Nathalie Kipson, Christine Criado, Régis Guieu, Frédérique Retornaz, fenouillet, emmanuel, Laboratoire de Physiopathologie Respiratoire (UPRES EA 2201), Université de la Méditerranée - Aix-Marseille 2-Institut Fédératif de Recherches Jean ROCHE (IFR 11)-Faculté de Médecine Nord, 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), Hôpital Européen [Fondation Ambroise Paré - Marseille], Dysoxie, suractivité : aspects cellulaires et intégratifs thérapeutiques (DS-ACI / UMR MD2), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU), Service de Rhumatologie, Assistance Publique - Hôpitaux de Marseille (APHM)-Institut du Mouvement et de l'appareil Locomoteur (IML), Assistance Publique - Hôpitaux de Marseille (APHM), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Centre Gérontologique Départemental de Marseille (CGD 13), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2

Subjects
0301 basic medicine, medicine.medical_specialty, Thiobarbituric acid, Encephalomyelitis, lcsh:Medicine, Myalgic encephalomyelitis/chronic, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, Membrane Potentials, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Chronic fatigue syndrome, TBARS, Medicine, Humans, Muscle membrane, Exercise, Potassium outflow, Fatigue Syndrome, Chronic, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Muscle excitability, Research, lcsh:R, General Medicine, medicine.disease, Redox status, 030104 developmental biology, Endocrinology, chemistry, Myalgic encephalomyelitis/chronic fatigue syndrome, Oxidative stress, Flexor Digitorum Longus, business, Oxidation-Reduction, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background In myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), altered membrane excitability often occurs in exercising muscles demonstrating muscle dysfunction regardless of any psychiatric disorder. Increased oxidative stress is also present in many ME/CFS patients and could affect the membrane excitability of resting muscles. Methods Seventy-two patients were examined at rest, during an incremental cycling exercise and during a 10-min post-exercise recovery period. All patients had at least four criteria leading to a diagnosis of ME/CFS. To explore muscle membrane excitability, M-waves were recorded during exercise (rectus femoris (RF) muscle) and at rest (flexor digitorum longus (FDL) muscle). Two plasma markers of oxidative stress (thiobarbituric acid reactive substance (TBARS) and oxidation–reduction potential (ORP)) were measured. Plasma potassium (K+) concentration was also measured at rest and at the end of exercise to explore K+ outflow. Results Thirty-nine patients had marked M-wave alterations in both the RF and FDL muscles during and after exercise while the resting values of plasma TBARS and ORP were increased and exercise-induced K+ outflow was decreased. In contrast, 33 other patients with a diagnosis of ME/CFS had no M-wave alterations and had lower baseline levels of TBARS and ORP. M-wave changes were inversely proportional to TBARS and ORP levels. Conclusions Resting muscles of ME/CFS patients have altered muscle membrane excitability. However, our data reveal heterogeneity in some major biomarkers in ME/CFS patients. Measurement of ORP may help to improve the diagnosis of ME/CFS. Trial registration Ethics Committee “Ouest II” of Angers (May 17, 2019) RCB ID: number 2019-A00611-56

Published
2020

16. Target engagement and intracellular delivery of mono- and bivalent LDL receptor-binding peptide-cargo conjugates: Implications for the rational design of new targeted drug therapies

Author

Karine Varini, F. Gassiot, M. David, P. Lecorche, A. Faucon, B. Broc, M. Godard, Géraldine Ferracci, Michel Khrestchatisky, J. Temsamani, R. Sonnette, K. Abouzid, G. Jacquot, Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation (CEISAM), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Ingénierie des protéines (IP), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), and Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2

Subjects
Endosome, [SDV]Life Sciences [q-bio], Pharmaceutical Science, Peptide, CHO Cells, Endosomes, 02 engineering and technology, Ligands, 03 medical and health sciences, Cricetulus, Drug Delivery Systems, Animals, Humans, Tissue Distribution, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Rational design, 021001 nanoscience & nanotechnology, Endocytosis, In vitro, Cell biology, Protein Transport, Receptors, LDL, chemistry, Targeted drug delivery, Drug Design, LDL receptor, Peptides, 0210 nano-technology, Intracellular, Protein Binding, Conjugate
Abstract

Targeted delivery to specific tissues and subcellular compartments is of paramount importance to optimize therapeutic or diagnostic interventions while minimizing side-effects. Using recently identified LDL receptor (LDLR) -targeting small synthetic peptide-vectors conjugated to model cargos of different nature and size, we investigated in LDLR-expressing cells the impact of vector-cargo molecular engineering and coupling valency, as well as the cellular exposure duration on their target engagement and intracellular trafficking and delivery profiles. All vector-cargo conjugates evaluated were found to be delivered to late compartments together with the natural ligand LDL, although to varying extents and with different kinetics. Partial recycling together with the LDLR was also consistently observed. Under continuous cellular exposure, the extent of intracellular vector-cargo delivery primarily relies on their endosomal unloading potential. In this condition, the highest intracellular delivery potential was observed with a monovalent conjugate displaying a rather high LDLR dissociation rate. On the contrary, under transient cellular exposure followed by chase, low dissociation-rate bivalent conjugates revealed a higher intracellular delivery potential than the monovalent conjugate. This was shown to rely on their ability to undergo multiple endocytosis-recycling rounds, with limited release in the ligand-free medium. The absence of reciprocal competition with the natural ligand LDL on their respective intracellular trafficking was also demonstrated, which is essential in terms of potential safety liabilities. These results demonstrate that not only molecular engineering of new therapeutic conjugates of interest, but also the cellular exposure mode used during in vitro evaluations are critical to anticipate and optimize their delivery potential.

Published
2019

17. Influence of adjuvant chemotherapy on anti-Müllerian hormone in women below 35 years treated for early breast cancer

Author

Marion David, Marie Degremont, Agnès Loeb, Zena Khaznadar, Marianne Leheurteur, Anne Perdrix, Frédéric Di Fiore, Mathilde Saint-Ghislain, Florian Clatot, Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Centre de sociologie des organisations (Sciences Po, CNRS) (CSO), Sciences Po (Sciences Po)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Service d'Oncologie Médicale, CRLCC Haute Normandie-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Centre de sociologie des organisations (CSO), and Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2

Subjects
Anti-Mullerian Hormone, Counseling, Oncology, medicine.medical_treatment, 0302 clinical medicine, Limit of Detection, Medicine, Anthracyclines, Ovarian tissue cryopreservation, Age of Onset, Child, Ovarian Reserve, ComputingMilieux_MISCELLANEOUS, Early Detection of Cancer, media_common, Immunoassay, 030219 obstetrics & reproductive medicine, biology, Obstetrics and Gynecology, Anti-Müllerian hormone, 3. Good health, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Female, Taxoids, Adult, endocrine system, medicine.medical_specialty, Adolescent, media_common.quotation_subject, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Fertility, Young Adult, 03 medical and health sciences, Breast cancer, Internal medicine, Humans, Antineoplastic Agents, Alkylating, Retrospective Studies, Cryopreservation, Gynecology, Chemotherapy, urogenital system, business.industry, Ovary, Cancer, medicine.disease, Survival Analysis, Regimen, Reproductive Medicine, biology.protein, business, Biomarkers, Developmental Biology, Hormone
Abstract

The impact of chemotherapy on fertility appears to be of essential importance for the youngest cancer survivors. The aim of this study was to assess plasma anti-Mullerian hormone (AMH) evolution, using an automated sensitive AMH immunoassay in women younger than 35 years old before and after treatment with adjuvant chemotherapy for early breast cancer. We selected 54 women aged less than 35 years old, at the time of breast cancer diagnosis, who received chemotherapy between 2008 and 2014, and with plasma samples collected from the diagnosis, to 1 year, 3 years and 5 years post-diagnosis. The median AMH decreased markedly in the year after the diagnosis compared with the pretreatment values (P < 0.0001), and slightly increased 2 years later (P = 0.007, comparing 1-year and 3-years post-diagnosis concentrations), without any additional AMH recovery 5 years after diagnosis. This recovery did not reach age-dependent AMH expected values (P < 0.0001, comparing AMH measured values to AMH expected values). Addition of taxanes to an anthracyclines + alkylating-based regimen was associated with a worse AMH decrease (P = 0.007). Ovarian tissue cryopreservation before treatment did not influence the AMH recovery. These results highlight the necessity of fertility counselling before treatment, especially in women wanting children.

Published
2017

18. Impaired cortico-limbic functional connectivity in schizophrenia patients during emotion processing

Author

Pierre-Emmanuel Lazerges, Olivier Blin, Claire Boutet, Jean-Michel Azorin, Eric Fakra, Nematollah Jaafari, Magali Comte, Thierry Sage, Aïda Cancel, Fabien C Schneider, El Chérif Ibrahim, Jennifer T. Coull, Xavier Zendjidjian, Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Pôle de Psychiatrie, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), INSERM U1059, SAINBIOSE - Santé, Ingénierie, Biologie, Saint-Etienne (SAINBIOSE-ENSMSE), Centre Ingénierie et Santé (CIS-ENSMSE), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), CLINEA - Clinique de santé mentale, L'escale [Saint-Victoret, France], ORPEA Groupe, Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Laboratoire de neurosciences expérimentales et cliniques (LNEC), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pôle de psychiatrie, Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud )-CHU Marseille, COMBE, Isabelle, Institut de Neurosciences de la Timone ( INT ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Neurosciences Cognitives [Marseille] ( LNC ), Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Universitaire de Saint-Etienne ( CHU de Saint-Etienne ), Equipe NEMESIS - Centre de Recherches de l'Institut du Cerveau et de la Moelle épinière ( NEMESIS-CRICM ), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière ( CRICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de psychopathologie et psychologie médicale ( LPPM ), Université de Bourgogne ( UB ), Immunologie antivirale systémique et cérébrale, Université Paris-Sud - Paris 11 ( UP11 ) -IFR93-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN ( NICN ), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique ( CNRS ), Assistance Publique - Hôpitaux de Marseille ( APHM ) -Hôpital Sainte-Marguerite [CHU - APHM] ( Hôpitaux Sud ) -CHU Marseille, Microbes évolution phylogénie et infections ( MEPHI ), Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Clinical Investigation Centre (CIC-UPCET) and Department of Clinical Pharmacology, Centre investigation clinique - Unité de pharmacologie clinique et d'évaluations thérapeutiques ( CIC-UPCET ), Assistance Publique - Hôpitaux de Marseille ( APHM ) -Assistance Publique - Hôpitaux de Marseille ( APHM ), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), and Santé Ingénierie Biologie Saint-Etienne (SAINBIOSE)

Subjects
Cognitive Neuroscience, Experimental and Cognitive Psychology, Affect (psychology), Amygdala, behavioral disciplines and activities, 03 medical and health sciences, 0302 clinical medicine, mental disorders, medicine, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Prefrontal cortex, Anterior cingulate cortex, prefrontal cortex, medicine.diagnostic_test, Cognition, General Medicine, Original Articles, amygdala, medicine.disease, functional magnetic resonance imaging, 030227 psychiatry, Dorsolateral prefrontal cortex, schizophrenia, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, anterior cingulate cortex, medicine.anatomical_structure, nervous system, Schizophrenia, affect, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Functional magnetic resonance imaging, Psychology, Neuroscience, 030217 neurology & neurosurgery, psychological phenomena and processes
Abstract

International audience; Functional dysconnection is increasingly recognized as a core pathological feature in schizophrenia. Aberrant interactions between regions of the cortico-limbic circuitmay underpin the abnormal emotional processing associated with this illness. We used a functionalmagnetic resonance imaging paradigmdesigned to dissociate the various components of the corticolimbic circuit (i.e. a ventral automatic circuit that is intertwined with a dorsal cognitive circuit), to explore bottom-up appraisal as well as top-down control during emotion processing. In schizophrenia patients compared with healthy controls, bottom-up processes were associated with reduced interaction between the amygdala and both the anterior cingulate cortex (ACC) and the dorsolateral prefrontal cortex. Contrariwise, top-down control processes led to stronger connectivity between the ventral affective and the dorsal cognitive circuits, i.e. heightened interactions between the ventral ACC and the dorsolateral prefrontal cortex as well as between dorsal and ventral ACC. These findings offer a comprehensive view of the cortico-limbic dysfunction in schizophrenia. They confirmprevious results of impaired propagation of information between the amygdala and the prefrontal cortex and suggest a defective functional segregation in the dorsal cognitive part of the cortico-limbic circuit.

Published
2017

19. Discrimination and streaming of speech sounds based on differences in interaural and spectral cues

Author

Marion David, Nicolas Grimault, Mathieu Lavandier, Andrew J. Oxenham, ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), École Nationale des Travaux Publics de l'État (ENTPE), Ministère de l'Ecologie, du Développement Durable, des Transports et du Logement-École Nationale des Travaux Publics de l'État (ENTPE), Laboratoire Génie Civil et Bâtiment (LGCB), Neurosciences Sensorielles Comportement Cognition, Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Auditory Perception and Cognition Laboratory, University of Minnesota [Twin Cities], University of Minnesota System-University of Minnesota System, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2, Département génie civil et batiment (DGCB), ENTP, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), and University of Minnesota [Twin Cities] (UMN)

Subjects
Adult, Male, Time Factors, Acoustics and Ultrasonics, Computer science, Acoustics, Speech recognition, Speech sounds, Stimulus (physiology), behavioral disciplines and activities, 01 natural sciences, 050105 experimental psychology, Hearing, Arts and Humanities (miscellaneous), Phonetics, 0103 physical sciences, Humans, 0501 psychology and cognitive sciences, Sound Localization, 10. No inequality, 010301 acoustics, ComputingMilieux_MISCELLANEOUS, [SPI.ACOU]Engineering Sciences [physics]/Acoustics [physics.class-ph], Analysis of Variance, 05 social sciences, Middle Aged, Psychological and Physiological Acoustics, Stimulus Variability, Speech processing, [PHYS.MECA.ACOU]Physics [physics]/Mechanics [physics]/Acoustics [physics.class-ph], Noise, Acoustic Stimulation, Speech Perception, Spatial cues, Female, Cues, Perceptual Masking, psychological phenomena and processes
Abstract

Differences in spatial cues, including interaural time differences (ITDs), interaural level differences (ILDs) and spectral cues, can lead to stream segregation of alternating noise bursts. It is unknown how effective such cues are for streaming sounds with realistic spectro-temporal variations. In particular, it is not known whether the high-frequency spectral cues associated with elevation remain sufficiently robust under such conditions. To answer these questions, sequences of consonant-vowel tokens were generated and filtered by non-individualized head-related transfer functions to simulate the cues associated with different positions in the horizontal and median planes. A discrimination task showed that listeners could discriminate changes in interaural cues both when the stimulus remained constant and when it varied between presentations. However, discrimination of changes in spectral cues was much poorer in the presence of stimulus variability. A streaming task, based on the detection of repeated syllables in the presence of interfering syllables, revealed that listeners can use both interaural and spectral cues to segregate alternating syllable sequences, despite the large spectro-temporal differences between stimuli. However, only the full complement of spatial cues (ILDs, ITDs, and spectral cues) resulted in obligatory streaming in a task that encouraged listeners to integrate the tokens into a single stream.

Published
2017

20. Masking of Several Olfactory Notes by Infra-threshold Concentrations of 2,4,6-Trichloroanisole

Author

Sophie Tempere, E. Cuzange, G. de Revel, M.H. Schaaper, Gilles Sicard, Unité de Recherche Oenologie [Villenave d'Ornon], Institut National de la Recherche Agronomique (INRA)-Université de Bordeaux (UB)-Institut des Sciences de la Vigne et du Vin (ISVV), Quali-Bordeaux, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-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), Institut des Sciences de la Vigne et du Vin (ISVV)-Université de Bordeaux (UB)-Institut National de la Recherche Agronomique (INRA), and Unité de Recherche Oenologie [Villenave d'Ornon] (OENO)

Subjects
0301 basic medicine, 2,4,6-Trichloroanisole, [SDV]Life Sciences [q-bio], Stimulation, olfactory masking, cork taint, Sensory analysis, sensory analysis, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Perceived quality, dichorhinic stimulation, vitis vinifera, 0302 clinical medicine, analyse sensorielle, Wine, Psychophysical tests, wine profiling, Communication, chromatographie, business.industry, infra-threshold (subliminal) concentrations, Sensory Systems, 030104 developmental biology, oenologie, chemistry, Odor, chromatography, Cork taint, business, Psychology, Biological system, 030217 neurology & neurosurgery
Abstract

Introduction Among wine defects, 2,4,6-trichloroanisole has a specific impact on wine perception. In addition to giving to the wine an unpleasant odor, 2,4,6-trichloroanisole has a masking effect on notes. In this study, the specificity and efficacy of the masking effect of 2,4,6-trichloroanisole was tested at infra- and supra-threshold concentrations. A simplified model of a binary mixture was also studied for in-depth analysis of this phenomenon.Methods Techniques used included sensory analysis (odor profiling), psychophysical tests (threshold measurement and triangle test), chemical analyses (GC-MS), and a mono/dichorhinic stimulation paradigm, to test the hypothesis of peripheral interaction.Results The results revealed that TCA had a masking effect on a range of aromatic notes, even at infra-threshold concentrations. However, they also showed counteraction of odorant specificity by 2,4,6-trichloroanisole. The origin of this masking effect was also discussed. The results suggested that this interaction can be assumed to take place at receptor level.Conclusion This study provided experimental confirmation of the widespread idea that constituents in non-perceptible concentrations influence the perceived quality of mixtures of odorous compounds.Implications Moreover, this type of olfactory model may improve our understanding of combinatorial olfactory encoding at the peripheral level.

Published
2017

21. Global cerebral ischemia in rats leads to amnesia due to selective neuronal death followed by astroglial scar formation in the CA1 layer

Author

Guy Escoffier, Stéphane D. Girard, Kevin Sadelli, Maïna Brus, Michel Khrestchatisky, Antoine D. Veron, Jean-Claude Stamegna, François S. Roman, Nathalie Baril, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), and Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Four-vessel occlusion model, Neurogenesis, Cognitive Neuroscience, Ischemia, Amnesia, Experimental and Cognitive Psychology, Astrogliosis, Hippocampal formation, Brain Ischemia, Rats, Sprague-Dawley, Brain ischemia, 03 medical and health sciences, Behavioral Neuroscience, 0302 clinical medicine, Memory, medicine, Learning, Animals, Gliosis, CA1 Region, Hippocampal, Cell Proliferation, Neurons, Behavior, Cell Death, [SCCO.NEUR]Cognitive science/Neuroscience, Dentate gyrus, Association Learning, Global cerebral ischemia, medicine.disease, Magnetic Resonance Imaging, Rats, 030104 developmental biology, Astrocytes, medicine.symptom, Psychology, Neuroscience, 030217 neurology & neurosurgery
Abstract

International audience; Global Cerebral Ischemia (GCI) occurs following cardiac arrest or neonatal asphyxia and leads to harmful neurological consequences. In most cases, patients who survive cardiac arrest develop severe cognitive and motor impairments. This study focused on learning and memory deficits associated with brain neuroanatomical reorganization that appears after GCI. The four-vessel occlusion (4VO) model was performed to produce a transient GCI. Hippocampal lesions in ischemic rats were visualized using anatomical Magnetic Resonance Imaging (aMRI). Then, the learning and memory abilities of control and ischemic (bilaterally or unilaterally) rats were assessed through the olfactory associated learning task. Finally, a "longitudinal" histological study was carried out to highlight the cellular reorganizations occurring after GCI. We demonstrated that the imaging, behavioral and histological results are closely related. In fact, aMRI revealed the appearance of hyper-intense signals in the dorsal hippocampus at day 3 post-GCI. Consequently, we showed a rise in cell proliferation (Ki 67+cells) and endogenous neurogenesis especially in the dentate gyrus (DG) at day 3 post-GCI. Then, hyper-intense signals in the dorsal hippocampus were confirmed by strong neuronal losses in the CA1 layer at day 7 post-GCI. These results were linked with severe learning and memory impairments only in bilaterally ischemic rats at day 14 post-GCI. This amnesia was accompanied by huge astroglial and microglial hyperactivity at day 30 post-GCI. Finally, Nestin+cells and astrocytes gave rise to astroglial scars, which persisted 60days post-GCI. In the light of these results, the 4VO model appears a reliable method to produce amnesia in order to study and develop new therapeutic strategies.

Published
2017

22. Hsc70 chaperone activity is required for the cytosolic slow axonal transport of synapsin

Author

Jichao Sun, Utpal Das, Archan Ganguly, Ghislaine Caillol, Lina Wang, Subhojit Roy, John R. Yates, Xuemei Han, Daniel Gitler, Jonathan Loi, Christophe Leterrier, University of California [San Diego] (UC San Diego), University of California (UC), University of Wisconsin-Madison, Ben-Gurion University of the Negev (BGU), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), and Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Male, Proteomics, Multiprotein complex, Immunoprecipitation, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Regulator, macromolecular substances, Biology, Transfection, Axonal Transport, Hippocampus, Models, Biological, Article, Mass Spectrometry, 03 medical and health sciences, 0302 clinical medicine, Slow axonal transport, Animals, Humans, Cytosolic transport, Protein Interaction Maps, Research Articles, Mice, Knockout, Neurons, Microscopy, HSC70 Heat-Shock Proteins, Cell Biology, Synapsin, Synapsins, Cell biology, Rats, Cytosol, Kinetics, 030104 developmental biology, HEK293 Cells, nervous system, Multiprotein Complexes, Axoplasmic transport, Female, 030217 neurology & neurosurgery
Abstract

Using proteomics, live microscopy, and superresolution microscopy, Ganguly et al. offer insight into the molecular composition of cytosolic cargo complexes conveyed in slow axonal transport, identifying the heat shock protein Hsc70 as a major regulator of this transport., Soluble cytosolic proteins vital to axonal and presynaptic function are synthesized in the neuronal soma and conveyed via slow axonal transport. Our previous studies suggest that the overall slow transport of synapsin is mediated by dynamic assembly/disassembly of cargo complexes followed by short-range vectorial transit (the “dynamic recruitment” model). However, neither the composition of these complexes nor the mechanistic basis for the dynamic behavior is understood. In this study, we first examined putative cargo complexes associated with synapsin using coimmunoprecipitation and multidimensional protein identification technology mass spectrometry (MS). MS data indicate that synapsin is part of a multiprotein complex enriched in chaperones/cochaperones including Hsc70. Axonal synapsin–Hsc70 coclusters are also visualized by two-color superresolution microscopy. Inhibition of Hsc70 ATPase activity blocked the slow transport of synapsin, disrupted axonal synapsin organization, and attenuated Hsc70–synapsin associations, advocating a model where Hsc70 activity dynamically clusters cytosolic proteins into cargo complexes, allowing transport. Collectively, our study offers insight into the molecular organization of cytosolic transport complexes and identifies a novel regulator of slow transport.

Published
2017

23. Impact of learning and training on wine expertise: a review

Author

Gilles Sicard, Sophie Tempere, G. de Revel, Unité de Recherche Oenologie [Villenave d'Ornon] (OENO), Institut National de la Recherche Agronomique (INRA)-Université de Bordeaux (UB)-Institut des Sciences de la Vigne et du Vin (ISVV), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Unité de Recherche Oenologie [Villenave d'Ornon]

Subjects
0301 basic medicine, 030109 nutrition & dietetics, Process (engineering), media_common.quotation_subject, Cognition, 04 agricultural and veterinary sciences, 040401 food science, Applied Microbiology and Biotechnology, 03 medical and health sciences, 0404 agricultural biotechnology, Categorization, Perception, [SDV.IDA]Life Sciences [q-bio]/Food engineering, Psychophysics, Quality (business), [SPI.GPROC]Engineering Sciences [physics]/Chemical and Process Engineering, Wine tasting, Psychology, Food Science, media_common, Mental image, Cognitive psychology
Abstract

International audience; Experts are able to conduct both analytical and holistic tasks involved in evaluating wine quality. Although there is no standard for wine-tasting training, a number of papers have reported on experts' ability to discriminate among and categorize wines, highlighting a process involving perceptual clues and cognitive processing. This review focuses on the influence of different training tasks on tasting and olfactory abilities. Moreover, recent researches in psychophysics and neurosciences demonstrated the potential functionality of mental imagery. The ability to create mental images may play an important role in discrimination and categorization, but is dependent on preliminary perceptual, attentional, and semantic training.

Published
2019

24. Clinical association of mixed connective tissue disease and granulomatosis with polyangiitis: a case report and systematic screening of anti-U1RNP and anti-PR3 auto-antibody double positivity in ten European hospitals

Author

A. Tubery, Xavier Bossuyt, Pascale Chretien, Catherine Johanet, Françoise Fortenfant, Daniela Lakomy, Isabelle Abreu, Nicole Fabien, Sophie Desplat-Jégo, Claire Daien, Bernard Combe, Thierry Vincent, Sophie Hue, Service de Rhumatologie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Service d'immunologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Physiopathologie et traitement des maladies du foie, Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Paul Brousse, Centre des Matériaux des Mines d'Alès (C2MA), IMT - MINES ALES (IMT - MINES ALES), and Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)

Subjects
Male, medicine.medical_specialty, Pathology, IgA Vasculitis, Myeloblastin, Immunology, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Mixed connective tissue disease, Weight Loss, Prevalence, medicine, Retrospective analysis, Humans, Mass Screening, cardiovascular diseases, Autoantibodies, Mixed Connective Tissue Disease, 030203 arthritis & rheumatology, biology, business.industry, Anca vasculitis, Granulomatosis with Polyangiitis, Retrospective cohort study, Middle Aged, Ribonucleoproteins, Small Nuclear, medicine.disease, Dermatology, Hospitals, 3. Good health, Europe, Asthenia, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Antibody, Vasculitis, business, Granulomatosis with polyangiitis, Microscopic polyangiitis
Abstract

International audience; We report here the case of a 50-years-old man treated for mixed ă connective tissue disease (MCTD) positive for anti-U1 ribonucleoprotein ă (U1RNP) antibodies who secondarily developed a granulomatosis with ă polyangiitis (GPA) associated with anti-proteinase 3 anti-neutrophil ă cytoplasmic antibodies (PR3-ANCA). We then evaluated the frequency of ă the association between anti-U1RNP and anti-PR3-ANCA antibodies by a ă systematic retrospective study in ten European hospitals. Overall, out ă of 11,921 samples analyzed for both auto-antibodies, 18 cases of ă anti-U1RNP and anti-PR3-ANCA double positivity were found and only one ă patient presented with both MCTD and GPA symptoms. Our retrospective ă analysis indicates that anti-U1RNP and anti-PR3-ANCA antibodies double ă positivity is infrequent and very rarely associated with both MTCD and ă GPA. Our observation describes for the first time the coexistence of ă MTCD and severe GPA in a Caucasian patient. Association of anti-U1RNP ă and ANCA antibodies was rarely reported in the literature. Eleven cases ă of MCTD and ANCA vasculitis have been reported to date, with only two ă cases with anti-PR3-ANCA association, and only one vasculitis. The seven ă other cases reported in the literature presented with an association of ă MCTD and microscopic polyangiitis which appears to be a more frequent ă presentation than MTCD associated with GPA.

Published
2016

25. Differential expression of vitamin D-associated enzymes and receptors in brain cell subtypes

Author

Delphine Stephan, Xiangyang Cui, Véréna Landel, Francois Feron, Darryl W. Eyles, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Queensland Brain Institute, University of Queensland, Brisbane 4072, Australia, FERON, Francois, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE), and China Agricultural University (CAU)

Subjects
0301 basic medicine, Male, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Clinical Biochemistry, Kidney, Biochemistry, Calcitriol receptor, Hippocampus, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Vitamin D, Receptor, Vitamin D3 24-Hydroxylase, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Cerebral Cortex, Neurons, Microglia, Cell biology, medicine.anatomical_structure, Liver, Molecular Medicine, Cholestanetriol 26-Monooxygenase, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroglia, medicine.medical_specialty, Cell type, Protein Disulfide-Isomerases, Biology, 03 medical and health sciences, Paracrine signalling, Internal medicine, medicine, Animals, Rats, Wistar, Autocrine signalling, Molecular Biology, 25-Hydroxyvitamin D3 1-alpha-Hydroxylase, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Endothelial Cells, Cell Biology, Steroid hormone, 030104 developmental biology, chemistry, Animals, Newborn, Receptors, Calcitriol, Cholecalciferol, 030217 neurology & neurosurgery
Abstract

Accumulating evidence indicates that the active form of vitamin D, 1,25(OH)2D3, can be considered as a neurosteroid. However, the cerebral expression of vitamin D-associated enzymes and receptors remains controversial. With the idea of carrying out a comparative study in mind, we compared the transcript expression of Cyp27a1, Cyp27b1, Cyp24a1, Vdr and Pdia3 in purified cultures of astrocytes, endothelial cells, microglia, neurons and oligodendrocytes. We observed that endothelial cells and neurons can possibly transform the inactive cholecalciferol into 25(OH)D3. It can then be metabolised into 1,25(OH)2D3, by neurons or microglia, before being transferred to astrocytes where it can bind to VDR and initiate gene transcription or be inactivated when in excess. Alternatively, 1,25(OH)2D3 can induce autocrine or paracrine rapid non-genomic actions via PDIA3 whose transcript is abundantly expressed in all cerebral cell types. Noticeably, brain endothelial cells appear as a singular subtype as they are potentially able to transform cholecalciferol into 25(OH)D3 and exhibit a variable expression of Pdia3, according to 1,25(OH)2D3 level. Altogether, our data indicate that, within the brain, vitamin D may trigger major auto-/paracrine non genomic actions, in addition to its well documented activities as a steroid hormone.

Published
2018

26. Correction to: Current research into brain barriers and the delivery of therapeutics for neurological diseases: a report on CNS barrier congress London, UK, 2017

Author

Alan W. Stitt, Birger Brodin, Gert Fricker, Margareta Hammarlund-Udenaes, Hazel C. Jones, Pieter J. Gaillard, Heiko Manninga, Matthew Campbell, Roosmarijn E. Vandenbroucke, Carl I. Webster, Krzysztof B. Wicher, John Greenwood, Markus Schwaninger, Michel Khrestchatisky, Ignacio A. Romero, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)

Subjects
Central Nervous System, 0301 basic medicine, Viral vectors, Published Erratum, BLOOD, Blood-retinal barrier, Neurologi, Review, THERAPY, lcsh:RC346-429, 570 Life sciences, 0302 clinical medicine, Neuroinflammation, Medicine and Health Sciences, Medicine, Blood csf barrier, Blood–retinal barrier, ComputingMilieux_MISCELLANEOUS, Blood-brain barrier, 0303 health sciences, MicroRNA, General Medicine, TARGET, Neurology, Blood-Brain Barrier, Current (fluid), medicine.medical_specialty, education, Blood–brain barrier, 03 medical and health sciences, Cellular and Molecular Neuroscience, INFLAMMATION, Developmental Neuroscience, Journal Article, Animals, Humans, Psychiatry, Intensive care medicine, lcsh:Neurology. Diseases of the nervous system, 030304 developmental biology, Final version, Liposomal technology, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, Biology and Life Sciences, Correction, Protein capsules, Blood–CSF barrier, MODEL, 030104 developmental biology, ENDOTHELIUM, Blood-CSF barrier, Drug delivery, Antibody therapy, Nervous System Diseases, business, 030217 neurology & neurosurgery
Abstract

This is a report on the CNS barrier congress held in London, UK, March 22–23rd 2017 and sponsored by Kisaco Research Ltd. The two 1-day sessions were chaired by John Greenwood and Margareta Hammarlund-Udenaes, respectively, and each session ended with a discussion led by the chair. Speakers consisted of invited academic researchers studying the brain barriers in relation to neurological diseases and industry researchers studying new methods to deliver therapeutics to treat neurological diseases. We include here brief reports from the speakers.After publication of the article [1], it has been brought to our attention that there are some errors in the formatting of names in the final version of the article.

Published
2018

27. αII Spectrin Forms a Periodic Cytoskeleton at the Axon Initial Segment and Is Required for Nervous System Function

Author

Juan A. Oses-Prieto, Chuansheng Zhang, Matthew N. Rasband, Joshua Lalonde, Claire Yu-Mei Huang, Alma L. Burlingame, Christophe Leterrier, Jeffrey L. Noebels, Tammy Szu-Yu Ho, Baylor College of Medicine (BCM), Baylor University, University of California [San Francisco] (UC San Francisco), University of California (UC), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of California [San Francisco] (UCSF), University of California, and Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2

Subjects
0301 basic medicine, Nervous system, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Action Potentials, Neurodegenerative, Inbred C57BL, Medical and Health Sciences, Hippocampus, axon initial segment, Mice, Chlorocebus aethiops, Ankyrin, 2.1 Biological and endogenous factors, Spectrin, Axon, Aetiology, Research Articles, Cells, Cultured, Cytoskeleton, chemistry.chemical_classification, axon, Node of Ranvier, Cultured, General Neuroscience, Neurodegeneration, EPB41, Cell biology, medicine.anatomical_structure, Neurological, COS Cells, node of Ranvier, Cells, 1.1 Normal biological development and functioning, macromolecular substances, Biology, 03 medical and health sciences, ankyrin, Underpinning research, Ranvier's Nodes, medicine, Animals, Neurology & Neurosurgery, Psychology and Cognitive Sciences, Neurosciences, medicine.disease, Axon initial segment, Axons, Mice, Inbred C57BL, 030104 developmental biology, chemistry, Neuroscience, Gene Deletion
Abstract

Spectrins form a submembranous cytoskeleton proposed to confer strength and flexibility to neurons and to participate in ion channel clustering at axon initial segments (AIS) and nodes of Ranvier. Neuronal spectrin cytoskeletons consist of diverse β subunits and αII spectrin. Although αII spectrin is found in neurons in both axonal and somatodendritic domains, using proteomics, biochemistry, and superresolution microscopy, we show that αII and βIV spectrin interact and form a periodic AIS cytoskeleton. To determine the role of spectrins in the nervous system, we generatedSptan1f/fmice for deletion of CNS αII spectrin. We analyzed αII spectrin-deficient mice of both sexes and found that loss of αII spectrin causes profound reductions in all β spectrins. αII spectrin-deficient mice die before 1 month of age and have disrupted AIS and many other neurological impairments including seizures, disrupted cortical lamination, and widespread neurodegeneration. These results demonstrate the importance of the spectrin cytoskeleton both at the AIS and throughout the nervous system.SIGNIFICANCE STATEMENTSpectrin cytoskeletons play diverse roles in neurons, including assembly of excitable domains such as the axon initial segment (AIS) and nodes of Ranvier. However, the molecular composition and structure of these cytoskeletons remain poorly understood. Here, we show that αII spectrin partners with βIV spectrin to form a periodic cytoskeleton at the AIS. Using a new αII spectrin conditional knock-out mouse, we show that αII spectrin is required for AIS assembly, neuronal excitability, cortical lamination, and to protect against neurodegeneration. These results demonstrate the broad importance of spectrin cytoskeletons for nervous system function and development and have important implications for nervous system injuries and diseases because disruption of the spectrin cytoskeleton is a common molecular pathology.

Published
2017

28. The nano-architecture of the axonal cytoskeleton

Author

Christophe Leterrier, Subhojit Roy, Pankaj Dubey, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), and Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS)

Subjects
Neurons, 0301 basic medicine, Nano architecture, Future studies, Extramural, General Neuroscience, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Biology, Axonal Transport, Axons, Microscopy, Electron, 03 medical and health sciences, 030104 developmental biology, Live cell imaging, Form and function, Architecture, Axonal cytoskeleton, Animals, Humans, Neuronal cytoskeleton, Neuroscience, Cytoskeleton, Actin
Abstract

International audience; The cytoskeleton is a cellular shapeshifter. Like these creatures of mythology and speculative fiction, the cytoskeleton can alter its physical form and shape to accommodate the immediate needs of the cell. Indeed, many a rapt student has watched the cytoskeleton of a dividing cell seemingly miraculously transform into an organized mitotic spindle and then dissolve into an indiscrete mass, right before their eyes. The extreme polarization of neurons (that is, their fundamental asymmetry, arising due to the presence of elongated processes), along with their lifelong plasticity, creates unique demands on the cytoskeleton. A remarkable example is the axon, which can grow to enormous lengths and must generate and maintain its form and function throughout life — a burden that rests largely on the cytoskeleton. The axonal cytoskeleton has three major constituents: microtubules, neurofilaments and actin (BOX 1). Each is unique, associating with its own set of binding proteins and performing specialized roles within the axon. Most of these cytoskeletal proteins are synthesized in the neu­ ronal soma and are transported along the axon. Such transport is a constitutive phenomenon that occurs throughout the life of the neuron. Thus, the axonal cytoskeleton is best understood by considering both its anatomical organization and its dynamics (including axonal transport). Given the complex morphology and physiology of neurons, the field of neurobiology has traditionally been at the forefront of adopting new optical techno­ logies as they arise. Advances in microscopy now allow us to observe cells with unprecedented spatial resolu­ tion and to follow dynamic processes with exquisite temporal detail 1. For example, super­resolution strat­ egies that circumvent the diffraction limit of optical microscopy appeared more than ten years ago (BOX 2) and have been used to reveal aspects of neuronal organ­ ization down to the scale of macromolecular com­ plexes 2. These techniques have provided key insights into the organization and function of the axonal cytoskeleton — and in particular the organization of actin and microtubules — revealing how it builds the axon and maintains its intricate architecture. Focusing on the cytoskeleton within the axon initial segment (AIS) and the more distal axon shaft, in this Review, we highlight these recent discoveries and place them in the context of earlier findings, giving the reader a tentative vision of the future. Overview of the axonal cytoskeleton The history of cytoskeletal research is essentially the pursuit of tools and techniques that allowed an ever­ closer view of this elaborate structure, a quest that continues to this day. Early studies by 17th­century microscopy pioneers highlighted a network of 'neu­ rofibrils' , which we now know were most likely neuro­ filaments 3. With the advent of electron microscopy, two types of fibrils were seen in axons: filaments measuring approximately 10 nm in diameter, corresponding to neurofilaments, and others measuring approximately 20–30 nm in diameter, corresponding to structures that eventually came to be known as microtubules 4,5. Abstract | The corporeal beauty of the neuronal cytoskeleton has captured the imagination of generations of scientists. One of the easiest cellular structures to visualize by light microscopy, its existence has been known for well over 100 years, yet we have only recently begun to fully appreciate its intricacy and diversity. Recent studies combining new probes with super-resolution microscopy and live imaging have revealed surprising details about the axonal cytoskeleton and, in particular, have discovered previously unknown actin-based structures. Along with traditional electron microscopy, these newer techniques offer a nanoscale view of the axonal cytoskeleton, which is important for our understanding of neuronal form and function, and lay the foundation for future studies. In this Review, we summarize existing concepts in the field and highlight contemporary discoveries that have fundamentally altered our perception of the axonal cytoskeleton.

Published
2017

29. Study of gene expression alteration in male androgenetic alopecia: evidence of predominant molecular signaling pathways

Author

Marion C. Bonnet, S. Scalvino, Armand Bensussan, Joanna Wdzieczak-Bakala, J-C. Choulot, Laurence Michel, M. Hocquaux, A. Patatian, Z. Hamidou, E. Lati, S. Ly Ka So, P. Reygagne, J. Pouch, E. Loing, Francette Jean-Louis, B. Ducos, P. Benech, S. Bianovici, Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre de Santé Sabouraud, Hair Disease Center, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire BIO-EC, Institut de biologie de l'ENS Paris (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), laboratoire GENEX, Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Ales Groupe, International Flavors and Fragrances-Lucas Meyer Cosmetics, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), laboratoire GENEX (GENEX), Benech, Philippe, and Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS)

Subjects
Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Transcriptome, Transforming Growth Factor beta, Gene expression, male androgenetic alopecia, Vitamin D, Wnt Signaling Pathway, reproductive and urinary physiology, integumentary system, Mast cell granule, Wnt signaling pathway, Catenins, Up-Regulation, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Bone Morphogenetic Proteins, Hair Follicle, Signal Transduction, Adult, Genetic Markers, medicine.medical_specialty, DNA, Complementary, education, Down-Regulation, Dermatology, Biology, behavioral disciplines and activities, 03 medical and health sciences, Internal medicine, medicine, Humans, development, 25-Hydroxyvitamin D3 1-alpha-Hydroxylase, Analysis of Variance, Gene Expression Profiling, Alopecia, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Hair follicle, signaling pathways, Hairless, body regions, 030104 developmental biology, Hair loss, Endocrinology, inflammation, Case-Control Studies, Scalp, Cancer research, gene expression
Abstract

BACKGROUND: Male androgenetic alopecia (AGA) is the most common form of hair loss in men and is characterized by a distinct pattern of progressive hair loss starting from the frontal area and the vertex of the scalp. Although several genetic risk loci have been identified, relevant genes for AGA remain to be defined. OBJECTIVES: Herein, molecular biomarkers associated with premature AGA were identified through gene expression analysis using cDNA generated from scalp vertex biopsies of hairless/bald men with premature AGA and healthy volunteers. RESULTS: This monocentric study reveals that genes encoding mast cell granule enzymes, inflammatory and immunoglobulin-associated immune mediators were significantly over-expressed in AGA. In contrast, under-expressed genes appear to be associated with the Wnt/β-catenin and BMP/TGF-β signaling pathways. Although involvement of these pathways in hair follicle regeneration is well-described, functional interpretation of the transcriptomic data highlights different events that account for their inhibition. In particular, one of these events depends on the dysregulated expression of proopiomelanocortin (POMC), as confirmed by RT-qPCR and immunohistochemistry. In addition, lower expression of CYP27B1 in AGA subjects supports the notion that changes in vitamin D metabolism contributes to hair loss. CONCLUSION: This study provides compelling evidence for distinct molecular events contributing to alopecia that may pave way for new therapeutic approaches. This article is protected by copyright. All rights reserved.

Published
2017

30. Binding to RNA regulates Set1 function

Author

Luciano, Pierre, Jeon, Jongcheol, El-kaoutari, Abdessamad, Challal, Drice, Bonnet, Amandine, Barucco, Mara, Candelli, Tito, Jourquin, Frederic, Lesage, Pascale, Kim, Jaehoon, Libri, Domenico, Géli, Vincent, 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), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Pathologie et virologie moléculaire (PVM (UMR_7151)), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Genome Instability and Carcinogenesis, 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 Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), and Pathologie et virologie moléculaire

Subjects
Set1, [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV]Life Sciences [q-bio], RNA binding, H3K4 methylation, transcription, Article
Abstract

International audience; The Set1 family of histone H3 lysine 4 (H3K4) methyltransferases is highly conserved from yeast to human. Here we show that the Set1 complex (Set1C) directly binds RNA in vitro through the regions that comprise the double RNA recognition motifs (dRRM) and N-SET domain within Set1 and its subunit Spp1. To investigate the functional relevance of RNA binding, we performed UV RNA crosslinking (CRAC) for Set1 and RNA polymerase II in parallel with ChIP-seq experiments. Set1 binds nascent transcripts through its dRRM. RNA binding is important to define the appropriate topology of Set1C distribution along transcription units and correlates with the efficient deposition of the H3K4me3 mark. In addition, we uncovered that Set1 binds to different classes of RNAs to levels that largely exceed the levels of binding to the general population of transcripts, suggesting the Set1 persists on these RNAs after transcription. This class includes RNAs derived from SET1, Ty1 retrotransposons, specific transcription factors genes and snRNAs (small nuclear RNAs). We propose that Set1 modulates adaptive responses, as exemplified by the post-transcriptional inhibition of Ty1 retrotransposition.

Published
2017

31. Identification of LRP-1 as an endocytosis and recycling receptor for B1-integrin in thyroid cancer cells

Author

Theret, Louis, Jeanne, Albin, Langlois, Benoît, Hachet, Cathy, David, Marion, Khrestchatisky, Michel, Devy, Jérome, Hervé, Emonard, Almagro, Sébastien, Dedieu, Stéphane, Université de Reims Champagne-Ardenne (URCA), Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Reliable and efficient component based software engineering (TRISKELL), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2, Biologie moléculaire et cellulaire de la différenciation, Université Joseph Fourier - Grenoble 1 (UJF)-Institut Albert Bonniot-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Signalisation et Récepteurs Matriciels (SiRMa), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Inria Rennes – Bretagne Atlantique, Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), and Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé)

Subjects
LRP-1, cancer, endocytosis, β1-integrin, lipids (amino acids, peptides, and proteins), [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, recycling, Research Paper
Abstract

International audience; LRP-1 is a large endocytic receptor mediating the clearance of various molecules from the extracellular matrix. LRP-1 was reported to control focal adhesion turnover to optimize the adhesion-deadhesion balance to support invasion. To better understand how LRP-1 coordinates cell-extracellular matrix interface, we explored its ability to regulate cell surface integrins in thyroid carcinomas. Using an antibody approach, we demonstrated that β1-integrin levels were increased at the plasma membrane under LRP1 silencing or upon RAP treatment, used as LRP-1 antagonist. Our data revealed that LRP-1 binds with both inactive and active β1-integrin conformations and identified the extracellular ligand-binding domains II or IV of LRP-1 as sufficient to bind β1-integrin. Using a recombinant β1-integrin, we demonstrated that LRP-1 acts as a regulator of β1-integrin intracellular traffic. Moreover, RAP or LRP-1 blocking antibodies decreased up to 36% the number of β1-integrin-containing endosomes. LRP-1 blockade did not significantly affect the levels of β1-integrin-containing lysosomes while decreasing localization of β1-integrin within Rab-11 positive vesicles. Overall, we identified an original molecular process in which LRP-1 acts as a main regulator of β1-integrin internalization and recycling in thyroid cancer cells.

Published
2017

32. An αII Spectrin-Based Cytoskeleton Protects Large-Diameter Myelinated Axons from Degeneration

Author

Claire Yu-Mei Huang, Christophe Leterrier, Matthew N. Rasband, Chuansheng Zhang, Daniel R. Zollinger, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2, and Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Male, node of Ranvier, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, degeneration, macromolecular substances, Biology, 03 medical and health sciences, Mice, Ranvier's Nodes, medicine, Animals, Spectrin, Axon, Large diameter, Cytoskeleton, Actin, Research Articles, axon, Node of Ranvier, General Neuroscience, Axon initial segment, Axons, Cell biology, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, nervous system, Female, NODAL, Demyelinating Diseases
Abstract

Axons must withstand mechanical forces, including tension, torsion, and compression. Spectrins and actin form a periodic cytoskeleton proposed to protect axons against these forces. However, because spectrins also participate in assembly of axon initial segments (AISs) and nodes of Ranvier, it is difficult to uncouple their roles in maintaining axon integrity from their functions at AIS and nodes. To overcome this problem and to determine the importance of spectrin cytoskeletons for axon integrity, we generated mice with αII spectrin-deficient peripheral sensory neurons. The axons of these neurons are very long and exposed to the mechanical forces associated with limb movement; most lack an AIS, and some are unmyelinated and have no nodes. We analyzed αII spectrin-deficient mice of both sexes and found that, in myelinated axons, αII spectrin forms a periodic cytoskeleton with βIV and βII spectrin at nodes of Ranvier and paranodes, respectively, but that loss of αII spectrin disrupts this organization.Avil-cre;Sptan1f/fmice have reduced numbers of nodes, disrupted paranodal junctions, and mislocalized Kv1 K+channels. We show that the density of nodal βIV spectrin is constant among axons, but the density of nodal αII spectrin increases with axon diameter. Remarkably,Avil-cre;Sptan1f/fmice have intact nociception and small-diameter axons, but severe ataxia due to preferential degeneration of large-diameter myelinated axons. Our results suggest that nodal αII spectrin helps resist the mechanical forces experienced by large-diameter axons, and that αII spectrin-dependent cytoskeletons are also required for assembly of nodes of Ranvier.SIGNIFICANCE STATEMENTA periodic axonal cytoskeleton consisting of actin and spectrin has been proposed to help axons resist the mechanical forces to which they are exposed (e.g., compression, torsion, and stretch). However, until now, no vertebrate animal model has tested the requirement of the spectrin cytoskeleton in maintenance of axon integrity. We demonstrate the role of the periodic spectrin-dependent cytoskeleton in axons and show that loss of αII spectrin from PNS axons causes preferential degeneration of large-diameter myelinated axons. We show that nodal αII spectrin is found at greater densities in large-diameter myelinated axons, suggesting that nodes are particularly vulnerable domains requiring a specialized cytoskeleton to protect against axon degeneration.

Published
2017

33. Developmental trajectories of handwriting characteristics in children and adults with ASD

Author

Godde, Anaïs, TSAO, Raphaële, Gepner, Bruno, Tardif, Carole, Centre de Recherche en Psychologie de la Connaissance, du Langage et de l'Émotion (PsyCLÉ), Aix Marseille Université (AMU), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), and Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
handwriting quality, [SCCO.PSYC]Cognitive science/Psychology, autism spectrum disorder, developmental trajectory, speed production
Abstract

International audience; Dans le trouble du spectre de l'autisme, la présence de difficultés d'écriture manuscrite est connue mais encore peu étudiée dans la littérature. L'objectif de cette recherche est donc double : caractériser l'écriture manuscrite chez des enfants et des adultes avec TSA et évaluer son évolution avec l'âge. Sur le premier point, les résultats mettent en lumière l'existence de difficultés au niveau de la qualité et de la vitesse de production chez les enfants et les adultes avec TSA. Sur le second point, les trajectoires de développement montrent bien un retard pour la population avec TSA mais indiquent une évolution similaire de la qualité des tracés et de la vitesse à celle de la population contrôle de même âge réel. Ces données incitent à repérer précocement ces difficultés d'écriture pour tenter d'y remédier. Abstract Handwriting difficulties in autism spectrum disorder (ASD) are well known but only very little studied. The aim of the current study was twofold: 1) to characterize handwriting in children and adults with ASD and 2) to evaluate its evolution with age. Our results first showed difficulties on quality and speed production in both children and adults with ASD and second delayed developmental trajectories in ASD population albeit highligting a similar evolution of handwriting quality and speed compared to control subjects of the same age. These observations encourage early identification of handwriting difficulties to try to cure them.

Published
2017

34. Reducing Information’s Speed Improves Verbal Cognition and Behavior in Autism: A 2-Cases Report

Author

Bruno Gepner, Thomas Arciszewski, Laura Latzko, Carole Tardif, Centre de Recherche en Psychologie de la Connaissance, du Langage et de l'Émotion (PsyCLÉ), Aix Marseille Université (AMU), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2, and Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, medicine.medical_specialty, Adolescent, Autism Spectrum Disorder, media_common.quotation_subject, Audiology, behavioral disciplines and activities, 03 medical and health sciences, Presentation, Nonverbal communication, [SCCO]Cognitive science, 0302 clinical medicine, Cognition, Temporal theory, medicine, Humans, 0501 psychology and cognitive sciences, Language Development Disorders, ComputingMilieux_MISCELLANEOUS, media_common, Socioemotional selectivity theory, business.industry, Verbal Behavior, Communication, 05 social sciences, medicine.disease, Test (assessment), Autism spectrum disorder, Child, Preschool, Pediatrics, Perinatology and Child Health, [SCCO.PSYC]Cognitive science/Psychology, Autism, business, 030217 neurology & neurosurgery, 050104 developmental & child psychology
Abstract

According to the temporal theory of autism spectrum disorders (ASDs), audiovisual changes in environment, particularly those linked to facial and verbal language, are often too fast to be faced, perceived, and/or interpreted online by many children with ASD, which could help explain their facial, verbal, and/or socioemotional interaction impairments. Our goal here was to test for the first time the impact of slowed-down audiovisual information on verbal cognition and behavior in 2 boys with ASD and verbal delay. Using 15 experimental sessions during 4 months, both boys were presented with various stimuli (eg, pictures, words, sentences, cartoons) and were then asked questions or given instructions regarding stimuli. The audiovisual stimuli and instructions/questions were presented on a computer's screen and were always displayed twice: at real-time speed (RTS) and at slowed-down speed (SDS) using the software Logiral. We scored the boys’ verbal cognition performance (ie, ability to understand questions/instructions and answer them verbally/nonverbally) and their behavioral reactions (ie, attention, verbal/nonverbal communication, social reciprocity), and analyzed the effects of speed and order of the stimuli presentation on these factors. According to the results, both participants exhibited significant improvements in verbal cognition performance with SDS presentation compared with RTS presentation, and they scored better with RTS presentation when having SDS presentation before rather than after RTS presentation. Behavioral reactions were also improved in SDS conditions compared with RTS conditions. This initial evidence of a positive impact of slowed-down audiovisual information on verbal cognition should be tested in a large cohort of children with ASD and associated speech/language impairments.

Published
2017

35. Assessment of the anti-feeding and insecticidal effects of the combination of dinotefuran, permethrin and pyriproxyfen (Vectra((R)) 3D) against Triatoma infestans on rats

Author

Tahir, D., Davoust, B., Varloud, M., Berenger, J. -M., Raoult, Didier, Almeras, L., Parola, Philippe, Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), INSB-INSB-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2

Subjects
[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Trypanosoma cruzi, rat model, efficacy, ectoparasiticide, Triatoma infestans
Abstract

International audience; This study, based on the rat model, was designed to explore the anti-feeding and insecticidal efficacy of a topical ectoparasiticide, dinotefuran-permethrin-pyriproxyfen (DPP), against Triatoma infestans (Hemiptera: Reduviidae), a vector of Trypanosoma cruzi (Trypanosomatida: Trypanosomatidae), for which dogs are domestic reservoir hosts. Twenty rats were divided into two equal groups: untreated and treated. Each rat was exposed under sedation to 16 T.infestans of mixed life stages for 1h on days 1, 7, 14, 21 and 28 post-treatment. The anti-feeding and insecticidal effects of DPP were estimated after 1h of exposure. Insecticidal efficacy was also assessed after incubation of the insects for 24h post-exposure. Anti-feeding efficacy was 96.7, 84.7, 80.5, 81.5 and 42.6% on days 1, 7, 14, 21 and 28, respectively. Insecticidal efficacy evaluated at 1 and 24h after exposure on days 1, 7, 14, 21 and 28 was 100, 91.2, 82.5, 80.0 and 29.1, and 100, 100, 100, 96.0 and 49.9%, respectively. This study demonstrates that a single administration of DPP spot-on treatment at a dose equivalent to the minimal recommended dose in rats has a powerful effect against T.infestans starting from day1 that lasts for at least 3weeks.

Published
2017

36. A Patient-Specific Stem Cell Model to Investigate the Neurological Phenotype Observed in Ataxia-Telangiectasia

Author

Romal Stewart, Ratneswary Sutharsan, Alan Mackay-Sim, Francois Feron, Martin F. Lavin, Gautam Wali, Chris T. Perry, STFC Rutherford Appleton Laboratory (RAL), Science and Technology Facilities Council (STFC), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Eskitis Institute for Cell and Molecular Therapies, Griffith University [Brisbane], and FERON, Francois

Subjects
0301 basic medicine, Nasal cavity, Pathology, medicine.medical_specialty, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Neurogenesis, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Biology, medicine.disease, 3. Good health, 03 medical and health sciences, Olfactory mucosa, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Ataxia-telangiectasia, medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Olfactory ensheathing glia, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cellular model, Stem cell, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, Adult stem cell
Abstract

The molecular pathogenesis of ataxia-telangiectasia (A-T) is not yet fully understood, and a versatile cellular model is required for in vitro studies. The occurrence of continuous neurogenesis and easy access make the multipotent adult stem cells from the olfactory mucosa within the nasal cavity a potential cellular model. We describe an efficient method to establish neuron-like cells from olfactory mucosa biopsies derived from A-T patients for the purpose of studying the cellular and molecular aspects of this debilitating disease.

Published
2017

37. MT5-MMP Promotes Alzheimer's Pathogenesis in the Frontal Cortex of 5xFAD Mice and APP Trafficking in vitro

Author

Baranger, Kévin, Bonnet, Amandine E, Girard, Stéphane D, Paumier, Michel, García-González, Laura, Elmanaa, Wejdane, Bernard, Anne, Charrat, Eliane, Stephan, Delphine, Bauer, Charlotte, Moschke, Katrin, Lichtenthaler, Stefan F, Roman, François S, Checler, Frédéric, Khrestchatisky, Michel, Rivera, Santiago, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-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 (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-11-IDEX-0001,Amidex,INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE(2011), ANR-11-LABX-0009,DISTALZ,Développement de stratégies innovantes pour une approche transdisciplinaire de la maladie d'Alzheime(2011), ANR-15-CE16-0006,MAD5,Validation de MT5-MMP comme nouvelle cible thérapeutique dans la maladie d'Alzheimer et mécanismes d'action(2015), European Project: FEDER, 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), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), ANR-11-IDEX-0001-02/11-IDEX-0001,AMIDEX,AMIDEX(2011), and ANR-11-LABX-0009/11-LABX-0009,DISTALZ,Développement de stratégies innovantes pour une approche transdisciplinaire de la maladie d'Alzheime(2011)

Subjects
Matrix metalloproteinase, Amyloid precursor protein, [SDV]Life Sciences [q-bio], Amyloid beta peptide, Transgenic mice, ddc:610, Endosomes, Neuroscience, Original Research, Learning and memory
Abstract

International audience; We previously reported that deficiency of membrane-type five matrix metalloproteinase (MT5-MMP) prevents amyloid pathology in the cortex and hippocampus of 5xFAD mice, and ameliorates the functional outcome. We have now investigated whether the integrity of another important area affected in Alzheimer's disease (AD), the frontal cortex, was also preserved upon MT5-MMP deficiency in 4-month old mice at prodromal stages of the pathology. We used the olfactory H-maze (OHM) to show that learning impairment associated with dysfunctions of the frontal cortex in 5xFAD was prevented in bigenic 5xFAD/MT5-MMP(-/-) mice. The latter exhibited concomitant drastic reductions of amyloid beta peptide (Aβ) assemblies (soluble, oligomeric and fibrillary) and its immediate precursor, C99. Simultaneously, astrocyte reactivity and tumor necrosis factor alpha (TNF-α) levels were also lowered. Moreover, MT5-MMP deficiency induced a decrease in N-terminal soluble fragments of amyloid precursor protein (APP), including soluble APPα (sAPPα), sAPPβ and the MT5-MMP-linked fragment of 95 kDa, sAPP95. However, the lack of MT5-MMP did not affect the activity of β- and γ-secretases. In cultured HEKswe cells, transiently expressed MT5-MMP localized to early endosomes and increased the content of APP and Aβ40 in these organelles, as well as Aβ levels in cell supernatants. This is the first evidence that the pro-amyloidogenic features of MT5-MMP lie, at least in part, on the ability of the proteinase to promote trafficking into one of the amyloidogenic subcellular loci. Together, our data further support the pathogenic role of MT5-MMP in AD and that its inhibition improves the functional and pathological outcomes, in this case in the frontal cortex. These data also support the idea that MT5-MMP could become a novel therapeutic target in AD.

Published
2017

38. Changes in SK channel expression in the basal ganglia after partial nigrostriatal dopamine lesions in rats: Functional consequences

Author

Nathalie Turle-Lorenzo, Thierry Deltheil, Christiane Mourre, Gaëlle Guiraudie-Capraz, Marianne Amalric, Christine Manrique, Jeremy Camon, Sabrine Aidi-Knani, Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neurosciences intégratives et adaptatives (LNIA), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), and Amalric, Marianne

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Small-Conductance Calcium-Activated Potassium Channels, Dopamine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Parkinson's disease, Gene Expression, Substantia nigra, Striatum, Calcium-activated potassium channel, Apamin, Basal Ganglia, SK channel, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, Parkinsonian Disorders, Internal medicine, Basal ganglia, medicine, Animals, Homeostasis, Rats, Wistar, Oxidopamine, Pharmacology, Reaction time, Pars compacta, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Corpus Striatum, Rats, 3. Good health, Substantia Nigra, Subthalamic nucleus, 030104 developmental biology, Endocrinology, chemistry, nervous system, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroscience, 030217 neurology & neurosurgery, medicine.drug
Abstract

International audience; Parkinson's disease (PD) is a progressive neurodegenerative disease originating from the loss of dopa-mine (DA) neurons in the substantia nigra pars compacta (SNC). The small-conductance calcium-activated potassium (SK) channels play an essential role in the regulation of midbrain DA neuron activity patterns, as well as excitability of other types of neurons of the basal ganglia. We therefore questioned whether the SK channel expression in the basal ganglia is modified in parkinsonian rats and how this could impact behavioral performance in a reaction time task. We used a rat model of early PD in which the progressive nigrostriatal DA degeneration was produced by bilateral infusions of 6-hydroxydopamine (6-OHDA) into the striatum. In situ hybridization of SK2 and SK3 mRNA and binding of iodinated apamin (SK2/SK3 blocker) were performed at 1, 8 or 21 days postsurgery in sham and 6-OHDA lesion groups. A significant decrease of SK3 channel expression was found in the SNC of lesioned animals at the three time points, with no change of SK2 channel expression. Interestingly, an upregulation of SK2 mRNA and apamin binding was found in the subthalamic nucleus (STN) at 21 days postlesion. These results were confirmed using quantitative real time polymerase chain reaction (qRT-PCR) approach. Functionally, the local infusion of apamin into the STN of parkinsonian rats enhanced the akinetic deficits produced by nigrostriatal DA lesions in a reaction time task while apamin infusion into the SNC had an opposite effect. These effects disappear when the positive modulator of SK channels (CyPPA) is co-administered with apamin. These findings suggest that an upregulation of SK2 channels in the STN may underlie the physiological adjustment to increased subthalamic excitability following partial DA denervation.

Published
2017

39. Regulation of Neuroinflammation: What Role for the Tumor Necrosis Factor-Like Weak Inducer of Apoptosis/Fn14 Pathway?

Author

Boulamery, Audrey, Desplat-Jégo, Sophie, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), ANR-11-IDEX-0001-02/11-IDEX-0001,AMIDEX,AMIDEX(2011), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), ANR-11-IDEX-0001,Amidex,INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE(2011), DESPLAT-JEGO, Sophie, and INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE - - Amidex2011 - ANR-11-IDEX-0001 - IDEX - VALID

Subjects
tumor necrosis factor-like weak inducer of apoptosis, [SDV.IMM] Life Sciences [q-bio]/Immunology, Mini Review, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Immunology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Fn14, neuropsychiatric systemic lupus erythematosus, central nervous system, multiple sclerosis, stroke, neuroinflammation, glioma, [SDV.IMM]Life Sciences [q-bio]/Immunology
Abstract

International audience; Observed in many central nervous system diseases, neuroinflammation (NI) proceeds from peripheral immune cell infiltration into the parenchyma, from cytokine secretion and from oxidative stress. Astrocytes and microglia also get activated and proliferate. NI manifestations and consequences depend on its context and on the acute or chronic aspect of the disease. The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/Fn14 pathway has been involved in chronic human inflammatory pathologies such as neurodegenerative, autoimmune, or malignant diseases. New data now describe its regulatory effects in tissues or fluids from patients with neurological diseases. In this mini-review, we aim to highlight the role of TWEAK/Fn14 in modulating NI in multiple sclerosis, neuropsychiatric systemic lupus erythematosus, stroke, or glioma. TWEAK/Fn14 can modulate NI by activating canonical and non-canonical nuclear factor-κB pathways but also by stimulating mitogen-activated protein kinase signaling. These downstream activations are associated with (i) inflammatory cytokine, chemokine and adhesion molecule expression or release, involved in NI propagation, (ii) matrix-metalloproteinase 9 secretion, implicated in blood–brain barrier disruption and tissue remodeling, (iii) astrogliosis and microgliosis, and (iv) migration of tumor cells in glioma. In addition, we report several animal and human studies pointing to TWEAK as an attractive therapeutic target.

Published
2017

40. From Blood to Lesioned Brain: An In Vitro Study on Migration Mechanisms of Human Nasal Olfactory Stem Cells

Author

Girard, Stéphane D., Virard, Isabelle, Lacassagne, Emmanuelle, Paumier, Jean-Michel, Lahlou, Hanae, Jabes, Françoise, Molino, Yves, Stephan, Delphine, Baranger, Kevin, Belghazi, Maya, Deveze, Arnaud, Khrestchatisky, Michel, Nivet, Emmanuel, Roman, François S., Féron, François, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neurosciences intégratives et adaptatives (LNIA), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Vect-Horus, Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biomécanique Appliquée (LBA UMR T24), Aix Marseille Université (AMU)-Université Gustave Eiffel, ANR-09-PEXT-0005,ADHOC,modèles de co-viabilité biodiversité marine et pêcheries(2009), ANR-11-IDEX-0001,Amidex,INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE(2011), Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2, Aix Marseille Université (AMU)-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR), ANR-09-PEXT-0005,ADHOC(2009), ANR-11-IDEX-0001-02/11-IDEX-0001,AMIDEX,AMIDEX(2011), FERON, Francois, La 6ème extinction - modèles de co-viabilité biodiversité marine et pêcheries - - ADHOC2009 - ANR-09-PEXT-0005 - La 6ème extinction - VALID, and INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE - - Amidex2011 - ANR-11-IDEX-0001 - IDEX - VALID

Subjects
lcsh:Internal medicine, Article Subject, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], lcsh:RC31-1245, Research Article
Abstract

International audience; Stem cell-based therapies critically rely on selective cell migration toward pathological or injured areas. We previously demonstrated that human olfactory ectomesenchymal stem cells (OE-MSCs), derived from an adult olfactory lamina propria, migrate specifically toward an injured mouse hippocampus after transplantation in the cerebrospinal fluid and promote functional recoveries. However, the mechanisms controlling their recruitment and homing remain elusive. Using an in vitro model of blood-brain barrier (BBB) and secretome analysis, we observed that OE-MSCs produce numerous proteins allowing them to cross the endothelial wall. Then, pan-genomic DNA microarrays identified signaling molecules that lesioned mouse hippocampus overexpressed. Among the most upregulated cytokines, both recombinant SPP1/ osteopontin and CCL2/MCP-1 stimulate OE-MSC migration whereas only CCL2 exerts a chemotactic effect. Additionally, OE-MSCs express SPP1 receptors but not the CCL2 cognate receptor, suggesting a CCR2-independent pathway through other CCR receptors. These results confirm that OE-MSCs can be attracted by chemotactic cytokines overexpressed in inflamed areas and demonstrate that CCL2 is an important factor that could promote OE-MSC engraftment, suggesting improvement for future clinical trials.

Published
2017

41. Metabolic changes and inflammation in cultured astrocytes from the 5xFAD mouse model of Alzheimer’s disease: Alleviation by pantethine

Author

Manuel van Gijsel-Bonnello, Kévin Baranger, Philippe Benech, Santiago Rivera, Michel Khrestchatisky, Max de Reggi, Bouchra Gharib, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2, Institut de neurophysiopathologie (INP), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), ANR-11-MALZ-0007,PREVENTAD,MMP-12 comme marqueur précoce et cible thérapeutique dans la progression de la maladie d'Alzheimer(2011), ANR-15-CE16-0006,MAD5,Validation de MT5-MMP comme nouvelle cible thérapeutique dans la maladie d'Alzheimer et mécanismes d'action(2015), ANR-11-IDEX-0001,Amidex,INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE(2011), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Cell Survival, Cells, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Messenger, Citric Acid Cycle, Interleukin-1beta, Gene Expression, lcsh:Medicine, Mice, Transgenic, alpha Subunit, Transgenic, Pentose Phosphate Pathway, 03 medical and health sciences, Mice, Amyloid beta-Protein Precursor, 0302 clinical medicine, Alzheimer Disease, Presenilin-1, Metabolomics, Animals, RNA, Messenger, lcsh:Science, Cells, Cultured, Inflammation, Multidisciplinary, Cultured, Animal, lcsh:R, Correction, Hypoxia-Inducible Factor 1, alpha Subunit, Disease Models, Animal, 030104 developmental biology, Astrocytes, Disease Models, Pantetheine, RNA, lcsh:Q, Hypoxia-Inducible Factor 1, Glycolysis, 030217 neurology & neurosurgery
Abstract

International audience; Astrocytes play critical roles in central nervous system homeostasis and support of neuronal function. A better knowledge of their response may both help understand the pathophysiology of Alzheimer's disease (AD) and implement new therapeutic strategies. We used the 5xFAD transgenic mouse model of AD (Tg thereafter) to generate astrocyte cultures and investigate the impact of the genotype on metabolic changes and astrocytes activation. Metabolomic analysis showed that Tg astrocytes exhibited changes in the glycolytic pathway and tricarboxylic acid (TCA) cycle, compared to wild type (WT) cells. Tg astrocytes displayed also a prominent basal inflammatory status, with accentuated reactivity and increased expression of the inflammatory cytokine interleukin-1 beta (IL-1β). Compensatory mechanisms were activated in Tg astrocytes, including: i) the hexose monophosphate shunt with the consequent production of reducing species; ii) the induction of hypoxia inducible factor-1 alpha (HIF-1α), known to protect against amyloid-β (Aβ) toxicity. Such events were associated with the expression by Tg astrocytes of human isoforms of both amyloid precursor protein (APP) and presenilin-1 (PS1). Similar metabolic and inflammatory changes were induced in WT astrocytes by exogenous Aβ peptide. Pantethine, the vitamin B5 precursor, known to be neuroprotective and anti-inflammatory, alleviated the pathological pattern in Tg astrocytes as well as WT astrocytes treated with Aß. In conclusion, our data enlighten the dual pathogenic/protective role of astrocytes in AD pathology and the potential protective role of pantethine.

Published
2017

42. Molecular determinism of specific anosmia to 2-bromo-4-methylphenol

Author

Tempere, Sophie, Schaaper, Marie-Hélène, LYTRA, Georgia, Barbe, Jean-Christophe, Riquier, Laurent, MARION, Stéphanie, De Revel, Gilles, Sicard, Gilles, Unité de Recherche Oenologie [Villenave d'Ornon], Institut National de la Recherche Agronomique (INRA)-Université de Bordeaux (UB)-Institut des Sciences de la Vigne et du Vin (ISVV), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche Oenologie [Villenave d'Ornon] (OENO), and Institut des Sciences de la Vigne et du Vin (ISVV)-Université de Bordeaux (UB)-Institut National de la Recherche Agronomique (INRA)

Subjects
analyse sensorielle, hyposmie, phénotype, detection threshold, oenologie, [SDV]Life Sciences [q-bio], structure-odour relationship, 2-bromo-4-methylphenol, composé olfactif, anosmia, sensory analysis
Abstract

Several studies have revealed considerable variations in human chemosensory capacities. Considerable interindividual differences in sensitivity to various odorants and specific hyposmias are well known. Many chemical studies have focused on elucidating structure-odour relationships on the basis of detection threshold measurements. The basic idea of quantitative structure-activity relationship studies is that a molecule's structure provides information about its biological activity. In a recent sensory assay of 2-bromo-4-methylphenol, Barbe et al. (2014) highlighted a noticeable bimodal distribution of individual sensitivity with large interindividual differences. The aim of the present study was to investigate the link between the chemical structure of 2-bromo-4-methylphenol and this bimodal distribution. The olfactory phenotypes for a selection of six structurally related halogenated compounds were compared using detection thresholds determination. This study revealed that specific anosmia for 2-bromo-4-methylphenol was apparently linked to the halogenated substitution position.

Published
2017

43. Tissue inhibitor of matrix metalloproteinases-1 loaded poly(lactic-co-glycolic acid) nanoparticles for delivery across the blood–brain barrier

Author

Bojja Sreedhar, Mayank Chaturvedi, Michel Khrestchatisky, Leszek Kaczmarek, Yves Molino, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), and Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS)

Subjects
protein delivery, Chemistry, Pharmaceutical, RBCEC culture, brain delivery, Pharmaceutical Science, Polysorbates, Matrix metalloproteinase, chemistry.chemical_compound, Drug Delivery Systems, Polylactic Acid-Polyglycolic Acid Copolymer, International Journal of Nanomedicine, Drug Discovery, Nanotechnology, sustained release, health care economics and organizations, BBB penetration, Cells, Cultured, Original Research, Cultured, General Medicine, Endothelial stem cell, PLGA, Chemistry, medicine.anatomical_structure, Nanomedicine, Biochemistry, Blood-Brain Barrier, Drug delivery, Materials science, Cells, education, Biophysics, Bioengineering, Blood–brain barrier, Cell Line, Biomaterials, Surface-Active Agents, In vivo, medicine, Animals, Lactic Acid, Tissue Inhibitor of Metalloproteinase-1, [SCCO.NEUR]Cognitive science/Neuroscience, Organic Chemistry, technology, industry, and agriculture, Endothelial Cells, Penetration (firestop), In vitro, Rats, chemistry, PLGA nanoparticles, Delayed-Action Preparations, Pharmaceutical, drug delivery, Nanoparticles, Polyglycolic Acid
Abstract

Mayank Chaturvedi,1 Yves Molino,2 Bojja Sreedhar,3 Michel Khrestchatisky,4 Leszek Kaczmarek1 1Laboratory of Neurobiology, Nencki Institute, Warsaw, Poland; 2Vect-Horus, Marseille, France; 3Indian Institute of Chemical Technology, Hyderabad, India; 4Aix-Marseille Université, CNRS, NICN, UMR7259, Marseille, France Aim: The aim of this study was to develop poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) for delivery of a protein – tissue inhibitor of matrix metalloproteinases 1 (TIMP-1) – across the blood–brain barrier (BBB) to inhibit deleterious matrix metalloproteinases (MMPs). Materials and methods: The NPs were formulated by multiple-emulsion solvent-evaporation, and for enhancing BBB penetration, they were coated with polysorbate 80 (Ps80). We compared Ps80-coated and uncoated NPs for their toxicity, binding, and BBB penetration on primary rat brain capillary endothelial cell cultures and the rat brain endothelial 4 cell line. These studies were followed by in vivo studies for brain delivery of these NPs. Results: Results showed that neither Ps80-coated nor uncoated NPs caused significant opening of the BBB, and essentially they were nontoxic. NPs without Ps80 coating had more binding to endothelial cells compared to Ps80-coated NPs. Penetration studies showed that TIMP-1 NPs + Ps80 had 11.21%±1.35% penetration, whereas TIMP-1 alone and TIMP-1 NPs without Ps80 coating did not cross the endothelial monolayer. In vivo studies indicated BBB penetration of intravenously injected TIMP-1 NPs + Ps80. Conclusion: The study demonstrated that Ps80 coating of NPs does not cause significant toxic effects to endothelial cells and that it can be used to enhance the delivery of protein across endothelial cell barriers, both in vitro and in vivo. Keywords: PLGA nanoparticles, drug delivery, protein delivery, sustained release, brain delivery, BBB penetration, RBCEC culture

Published
2014

44. Effect of pantethine on ovarian tumor progression and choline metabolism

Author

Marie-France Penet, Balaji Krishnamachary, Flonne Wildes, Yelena Mironchik, Delia Mezzanzanica, Franca Podo, Max DE REGGI, Bouchra Gharib, Zaver M Bhujwalla, Johns Hopkins University School of Medicine [Baltimore], Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de résonance magnétique biologique et médicale (CRMBM), and Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, medicine.medical_specialty, Cancer Research, Orthotopic model, choline metabolism, Ovary, Biology, lcsh:RC254-282, Metastasis, 03 medical and health sciences, Ovarian tumor, chemistry.chemical_compound, 0302 clinical medicine, In vivo, Internal medicine, medicine, metastasis, Pantethine, Original Research, Phosphocholine, Ascites, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, ovarian cancer, chemistry, Oncology, Tumor progression, 030220 oncology & carcinogenesis, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], high-resolution MRS, Ovarian cancer
Abstract

International audience; Epithelial ovarian cancer remains the leading cause of death from ă gynecologic malignancy among women in developed countries. New ă therapeutic strategies evaluated with relevant preclinical models are ă urgently needed to improve survival rates. Here, we have assessed the ă effect of pantethine on tumor growth and metabolism using magnetic ă resonance imaging and high-resolution proton magnetic resonance ă spectroscopy (MRS) in a model of ovarian cancer. To evaluate treatment ă strategies, it is important to use models that closely mimic tumor ă growth in humans. Therefore, we used an orthotopic model of ovarian ă cancer where a piece of tumor tissue, derived from an ovarian tumor ă xenograft, is engrafted directly onto the ovary of female mice, to ă maintain the tumor physiological environment. Treatment with pantethine, ă the precursor of vitamin B5 and active moiety of coenzyme A, was started ă when tumors were similar to 100 mm(3) and consisted of a daily i.p. ă injection of 750 mg/kg in saline. Under these conditions, no side ă effects were observed. High-resolution H-1 MRS was performed on treated ă and control tumor extracts. A dual-phase extraction method based on ă methanol/chloroform/water was used to obtain lipid and water-soluble ă fractions from the tumors. We also investigated effects on metastases ă and ascites formation. Pantethine treatment resulted in slower tumor ă progression, decreased levels of phosphocholine and phosphatidylcholine, ă and reduced metastases and ascites occurrence. In conclusion, pantethine ă represents a novel potential, well-tolerated, therapeutic tool in ă patients with ovarian cancer. Further in vivo preclinical studies are ă needed to confirm the beneficial role of pantethine and to better ă understand its mechanism of action.

Published
2016

45. Stimulation of 5-HT2C Receptors Improves Cognitive Deficits Induced by Human Tryptophan Hydroxylase 2 Loss of Function Mutation

Author

Adeline Etiévant, Francis Lemay, Stella Manta, Guy Escoffier, François S. Roman, François Y. Doré, Jean Levasseur-Moreau, Jean-Martin Beaulieu, Thomas Del’Guidice, Morgane Lemasson, 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), Institut cellule souche et cerveau / Stem Cell and Brain Research Institute (SBRI), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie intégrative et adaptative (NIA), Université de Provence - Aix-Marseille 1-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), Institut cellule souche et cerveau (SBRI), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), and Institut cellule souche et cerveau (U846 Inserm - UCBL1)

Subjects
Agonist, medicine.drug_class, Perseveration, Mice, Transgenic, Reversal Learning, Motor Activity, Tryptophan Hydroxylase, Piperazines, 5-Hydroxytryptophan, Mice, Cognition, Serotonin Agents, Dopamine Uptake Inhibitors, Reward, Avoidance Learning, Receptor, Serotonin, 5-HT2C, medicine, Animals, Humans, Maze Learning, Pharmacology, TPH2, Methylphenidate, [SCCO.NEUR]Cognitive science/Neuroscience, Cognitive flexibility, Tryptophan hydroxylase, Olfactory Perception, medicine.disease, Psychiatry and Mental health, Schizophrenia, Pyrazines, Mutation, Original Article, medicine.symptom, Cognition Disorders, Psychology, Neuroscience, Serotonin 5-HT2 Receptor Agonists, medicine.drug
Abstract

International audience; Polymorphisms in the gene encoding the serotonin synthesis enzyme Tph2 have been identified in mental illnesses, including bipolar disorder, major depression, autism, schizophrenia, and ADHD. Deficits in cognitive flexibility and perseverative behaviors are shared common symptoms in these disorders. However, little is known about the impact of Tph2 gene variants on cognition. Mice expressing a human TPH2 variant (Tph2-KI) were used to investigate cognitive consequences of TPH2 loss of function and pharmacological treatments. We applied a recently developed behavioral assay, the automated H-maze, to study cognitive functions in Tph2-KI mice. This assay involves the consecutive discovery of three different rules: a delayed alternation task, a non-alternation task, and a delayed reversal task. Possible contribution of locomotion, reward, and sensory perception were also investigated. The expression of loss-of-function mutant Tph2 in mice was associated with impairments in reversal learning and cognitive flexibility, accompanied by perseverative behaviors similar to those observed in human clinical studies. Pharmacological restoration of 5-HT synthesis with 5-hydroxytryptophan or treatment with the 5-HT(2C) receptor agonist CP809.101 reduced cognitive deficits in Tph2-KI mice and abolished perseveration. In contrast, treatment with the psychostimulant methylphenidate exacerbated cognitive deficits in mutant mice. Results from this study suggest a contribution of TPH2 in the regulation of cognition. Furthermore, identification of a role for a 5-HT(2) receptor agonist as a cognition-enhancing agent in mutant mice suggests a potential avenue to explore for the personalized treatment of cognitive symptoms in humans with reduced 5-HT synthesis and TPH2 polymorphisms.

Published
2013

46. Reprogramming of Human Fibroblasts to Pluripotency with Lineage Specifiers

Author

Carme Cortina, Yuriko Hishida, Juan Carlos Izpisua Belmonte, Laia Miquel, Ignacio Sancho-Martinez, Sachin Kumar, Emmanuel Nivet, Concepcion Rodriguez Esteban, Tomoaki Hishida, Yun Xia, Nuria Montserrat, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Dept Genet & Plant Breeding, Chaudhary Charan Singh University, Laboratoire de Chimie Physique D'Orsay (LCPO), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Chaudhary Charan Singh University [Meerut], and Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Pluripotent Stem Cells, Lineage (genetic), Somatic cell, Cells, GATA3 Transcription Factor, Biology, Small Interfering, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, SOX2, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Genetics, Humans, Cell Lineage, Transgenes, Induced pluripotent stem cell, 030304 developmental biology, 0303 health sciences, Cultured, Guided Tissue Regeneration, SOXB1 Transcription Factors, Gene Expression Profiling, fungi, Computational Biology, Cell Biology, Cell Dedifferentiation, Fibroblasts, Cell biology, Gene expression profiling, Gene Expression Regulation, KLF4, embryonic structures, RNA, Molecular Medicine, biological phenomena, cell phenomena, and immunity, Reprogramming, Octamer Transcription Factor-3, 030217 neurology & neurosurgery
Abstract

International audience; Since the initial discovery that OCT4, SOX2, KLF4, and c-MYC overexpression sufficed for the induction of pluripotency in somatic cells, methodologies replacing the original factors have enhanced our understanding of the reprogramming process. However, unlike in mouse, OCT4 has not been replaced successfully during reprogramming of human cells. Here we report on a strategy to accomplish this replacement. Through a combination of transcriptome and bioinformatic analysis we have identified factors previously characterized as being lineage specifiers that are able to replace OCT4 and SOX2 in the reprogramming of human fibroblasts. Our results show that it is possible to replace OCT4 and SOX2 simultaneously with alternative lineage specifiers in the reprogramming of human cells. At a broader level, they also support a model in which counteracting lineage specification networks underlies the induction of pluripotency.

Published
2013
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47. Evidence for Early Cognitive Impairment Related to Frontal Cortex in the 5XFAD Mouse Model of Alzheimer's Disease

Author

Michel Khrestchatisky, Marlyse Jacquet, Evelyne Marchetti, Anne Bernard, Cyrielle Gauthier, François S. Roman, Kévin Baranger, Guy Escoffier, Stéphane D. Girard, Santiago Rivera, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), and Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS)

Subjects
Genetically modified mouse, Transgene, Mice, Transgenic, Inbred C57BL, Transgenic, Presenilin, Amyloid beta-Protein Precursor, Mice, Olfaction Disorders, Alzheimer Disease, Glial Fibrillary Acidic Protein, Presenilin-1, Reaction Time, Animals, Humans, Medicine, Memory impairment, Cognitive Dysfunction, Maze Learning, Analysis of Variance, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, General Neuroscience, Age Factors, Cognition, General Medicine, medicine.disease, Magnetic Resonance Imaging, Frontal Lobe, Mice, Inbred C57BL, Psychiatry and Mental health, Clinical Psychology, Frontal lobe, Gliosis, Mutation, Geriatrics and Gerontology, Alzheimer's disease, medicine.symptom, business, Neuroscience
Abstract

International audience; The frontal cortex is a brain structure that plays an important role in cognition and is known to be affected in Alzheimer's disease (AD) in humans. Over the past years, transgenic mouse models have been generated to recapitulate the main features of this disease, including cognitive impairments. This study investigates frontal cortex dependent learning abilities in one of the most early-onset transgenic murine model of AD, the 5XFAD mice. We compared frontal performance of 2-, 4-, and 6-month-old 5XFAD mice with their wild-type littermates using a newly developed automated device, the olfactory H-maze, in which mice have to discover three different rules consecutively according to the delayed reaction paradigm. We report early cognitive deficits related to frontal cortex appearing in 4-month-old 5XFAD mice before hippocampal-dependent learning and memory impairment, in relation with neuropathologic processes such as strong gliosis and emerging amyloid plaques. The present results demonstrate that the olfactory H-maze is a very sensitive and simple experimental paradigm that allows assessment of frontal functions in transgenic mice and should be useful to test pre-clinical therapeutic approaches to alter the course of AD.

Published
2013

48. Conversion of human fibroblasts to angioblast-like progenitor cells

Author

Francesca S. Boscolo, Fred H. Gage, Ignacio Sancho-Martinez, Aitor Aguirre, Nuria Montserrat, Sergio Ruiz, Krystal Moon, Cécile Volle-Challier, Louise C. Laurent, Concepcion Rodriguez, Julian Pulecio, Rathi D Thiagarajan, Juan Carlos Izpisua Belmonte, Ahmet M. Denli, Ilir Dubova, Yun Xia, Caroline Pendaries, Jean-Marc Herbert, Emmanuel Nivet, Mo Li, Leo Kurian, Jeanne F. Loring, Françoise Bono, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), SANOFI Recherche, Laboratoire de Chimie Physique D'Orsay (LCPO), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Technology, Somatic cell, Cellular differentiation, Messenger, Fluorescent Antibody Technique, Angioblast, Medical and Health Sciences, Biochemistry, Mice, 0302 clinical medicine, Smooth Muscle, Cell Movement, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Cells, Cultured, 0303 health sciences, Cultured, Blotting, Reverse Transcriptase Polymerase Chain Reaction, Stem Cells, Cell Differentiation, Biological Sciences, Flow Cytometry, Cellular Reprogramming, Cell biology, Endothelial stem cell, Stem cell, Western, Reprogramming, Biotechnology, Cells, Blotting, Western, Myocytes, Smooth Muscle, Neovascularization, Physiologic, Biology, Real-Time Polymerase Chain Reaction, Article, 03 medical and health sciences, Vascular, Animals, Humans, Cell Lineage, RNA, Messenger, Endothelium, Progenitor cell, Physiologic, Molecular Biology, Neovascularization, Cell Proliferation, 030304 developmental biology, Progenitor, Myocytes, Cell Biology, Fibroblasts, Molecular biology, RNA, Endothelium, Vascular, Biomarkers, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Lineage conversion of one somatic cell type into another constitutes an attractive approach for research and clinical use. Lineage conversion can proceed in a direct manner, in the absence of proliferation and multipotent progenitor generation, or in an indirect manner, by the generation of expandable multipotent progenitor states. Here we report on the development of a combined reprogramming methodology that, transitioning through a plastic intermediate state, allows for the generation of human mesodermal progenitor cells while circumventing the traditional hallmarks of pluripotency. Converted mesodermal progenitor cells demonstrated bi-potent differentiation potential and were able to generate endothelial and smooth muscle lineages. Importantly, human fibroblasts can be converted into angioblast-like progenitor cells by non-integrative approaches. Differentiated angioblast-like cells exhibit neo-angiogenesis and anastomosis in vivo. The methodology for indirect lineage conversion to angioblast-like cells described here adds to the armamentarium of reprogramming approaches aimed at the clinical treatment of ischemic pathologies.

Published
2013

49. Olfactory stem cells reveal MOCOS as a new player in autism spectrum disorders

Author

Féron, François-Xavier, Gepner, B, Lacassagne, E, Stephan, S, Mesnage, M, Blanchard, M, Boulanger, N, Tardif, C, Devèze, A, Rousseau, Sylvain, Suzuki, K, Belmonte, Jc, Khrestchatisky, M, Nivet, E, Erard-Garcia, M, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Investigations Cliniques en Biothérapie (CBT 1409), INSERM, Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Psychologie de la Connaissance, du Langage et de l'Émotion (PsyCLÉ), Aix Marseille Université (AMU), Département ORL, Assistance Publique - Hôpitaux de Marseille (APHM), Département Anesthésie, Gene Expression Laboratory, The Salk Institute for Biological Studies, Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Systèmes d'élevage méditerranéens et tropicaux (UMR SELMET), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Réponse immunitaire et developpement chez les insectes (RIDI - UPR 9002), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'ORL, CHU Nord, Laboratoire de Biomécanique Appliquée (LBA UMR T24), Aix Marseille Université (AMU)-Université Gustave Eiffel-Aix Marseille Université (AMU)-Université Gustave Eiffel, Neurobiologie intégrative et adaptative (NIA), Université de Provence - Aix-Marseille 1-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2, 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 Strasbourg (UNISTRA)-Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-Aix Marseille Université (AMU)-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-Aix Marseille Université (AMU)-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-Aix Marseille Université (AMU), and Tardif, Carole

Subjects
Adult, Male, Autism Spectrum Disorder, [SDV]Life Sciences [q-bio], autism spectrum disorders, [SHS.PSY]Humanities and Social Sciences/Psychology, MOCOS, Olfactory Receptor Neurons, [SHS.PSY] Humanities and Social Sciences/Psychology, Mice, Olfactory Mucosa, stem cells, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], neurotransmission, Caenorhabditis elegans, ComputingMilieux_MISCELLANEOUS, Mice, Inbred C57BL, Sulfurtransferases, autism spectrum disorders, neurotransmission , MOCOS, stem cells, [SCCO.PSYC] Cognitive science/Psychology, [SCCO.PSYC]Cognitive science/Psychology, Original Article, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], France
Abstract

International audience; With an onset under the age of 3 years, autism spectrum disorders (ASDs) are now understood as diseases arising from pre-and/or early postnatal brain developmental anomalies and/or early brain insults. To unveil the molecular mechanisms taking place during the misshaping of the developing brain, we chose to study cells that are representative of the very early stages of ontogenesis, namely stem cells. Here we report on MOlybdenum COfactor Sulfurase (MOCOS), an enzyme involved in purine metabolism, as a newly identified player in ASD. We found in adult nasal olfactory stem cells of 11 adults with ASD that MOCOS is downregulated in most of them when compared with 11 age-and gender-matched control adults without any neuropsychiatric disorders. Genetic approaches using in vivo and in vitro engineered models converge to indicate that altered expression of MOCOS results in neurotransmission and synaptic defects. Furthermore, we found that MOCOS misexpression induces increased oxidative-stress sensitivity. Our results demonstrate that altered MOCOS expression is likely to have an impact on neurodevelopment and neurotransmission, and may explain comorbid conditions, including gastrointestinal disorders. We anticipate our discovery to be a fresh starting point for the study on the roles of MOCOS in brain development and its functional implications in ASD clinical symptoms. Moreover, our study suggests the possible development of new diagnostic tests based on MOCOS expression, and paves the way for drug screening targeting MOCOS and/or the purine metabolism to ultimately develop novel treatments in ASD.

Published
2016

50. Vitamin D and cognition in older adults: international consensus ă guidelines

Author

Katherine L. Tucker, Olivier Beauchet, Duygu Gezen-Ak, Pascal Millet, Selma Yilmazer, Allan V. Kalueff, Tammy Scott, Erdinç Dursun, David Llewellyn, Thomas J. Littlejohns, Francois Feron, Cédric Annweiler, Service de médecine interne et gérontologie clinique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Mémoire de Ressources et de Recherche, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Département de Médecine Interne et Gérontologie clinique, Centre Hospitalier Universitaire d'Angers (CHU Angers), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), EA Pharmaceuticals and Analytical Methods for Neglected diseases and counterfeit Drugs, and Université Bordeaux Segalen - Bordeaux 2

Subjects
Aged, 80 and over, Consensus, 030214 geriatrics, Consensus Development Conferences as Topic, 030209 endocrinology & metabolism, Vitamin D Deficiency, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Neuropsychology and Physiological Psychology, Alzheimer Disease, Humans, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Geriatrics and Gerontology, Vitamin D, Cognition Disorders, Biological Psychiatry, ComputingMilieux_MISCELLANEOUS, Aged
Abstract

International audience; Background. Hypovitaminosis D, a common condition in older adults, is ă associated with brain changes and dementia. Given the fast growing ă contribution of literature in this research field, clear guidance is ă needed for clinicians and researchers. Methods. International experts ă met at the invitational summit on ``Vitamin D and cognition in older ă adults'' in Boston, MA, July 2013. Based upon literature and expert ă opinion, the task force focused on key questions on the role of vitamin ă D in Alzheimer disease and related disorders. Each question was ă discussed and voted using a Delphi-like approach. Results. Experts ă reached agreement that hypovitaminosis D increases the risk of cognitive ă decline and dementia in older adults, may alter the clinical ă presentation as a consequence of related comorbidities, but should not ă be used thus far as a diagnostic or prognostic biomarker of Alzheimer ă disease due to lack of specificity and insufficient evidence. ă Hypovitaminosis D should be screened in this population because of its ă high prevalence and supplemented, if necessary, but this advice was not ă specific to cognition. Conclusions. The task force agreed on 5 ă overarching principles related to vitamin D and cognition in older ă adults.

Published
2016

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