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1. Immunotherapy in MSI/dMMR tumors in the perioperative setting: The IMHOTEP trial

Author

Clélia Coutzac, Frederic Bibeau, Meher Ben Abdelghani, Thomas Aparicio, Romain Cohen, Elodie Coquan, Olivier Dubreuil, Ludovic Evesque, François Ghiringhelli, Stefano Kim, Samuel Lesourd, Cindy Neuzillet, Jean-Marc Phelip, Guillaume Piessen, Philippe Rochigneux, Emmanuelle Samalin, Emilie Soularue, Yann Touchefeu, David Tougeron, Aziz Zaanan, Christelle de la Fouchardière, Département cancer environnement (Centre Léon Bérard - Lyon), Centre Léon Bérard [Lyon], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Anatomie pathologique [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Paul Strauss, CRLCC Paul Strauss, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Groupe Hospitalier Diaconesses Croix Saint-Simon, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Service d'oncogénétique [Centre georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Centre Eugène Marquis (CRLCC), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Hôpital Claude Huriez [Lille], CHU Lille, Centre de Recherche en Cancérologie de Marseille (CRCM), 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), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut du Cancer de Montpellier (ICM), Institut Mutualiste de Montsouris (IMM), Nantes Université (Nantes Univ), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Amgen, Bristol-Myers Squibb, BMS, Pfizer, AstraZeneca, Bayer, Roche, Sanofi, Meso Scale Diagnostics, MSD, Les Laboratories Pierre Fabre, MSD France, Ministère des Affaires Sociales et de la Santé, Institut National Du Cancer, INCa: PHRC-K 2019 Inca-DGOS_14333, PRT-K 2020–15324, Servier, Institut Servier, CC declares a consulting and advisory board for Amgen, Servier, and received honoria from Servier, Amgen. TA received honoraria from Servier, Pierre fabre, Amgen, AstraZeneca and declares consulting for Bioven, Servier, SIRTEC, MSD. RC received honoraria from MSD Oncology, Pierre Fabre, and Bristol-Myers Squibb, declares consulting from Exeliom Biosciences, Enterome Bioscience and received research funding from Servier Institute. OD received honoraria from Amgen, Sanofi, Merck Serono, MSD, Servier, Ipsen, Keocyt and declares consulting for Merck Serono, Sanofi, MSD, AstraZeneca, Novartis. LE declares consulting for BMS and Servier. FG declares research grant from Roche, AstraZeneca and consulting for Astrazenca, Roche, Sanofi, BMS, MSD, Merck-Serono, Amgen. EL declares consulting for Roche, Servier, Ipsen, Bayer, BTG, MSD. CN received honoraria from Amgen, AstraZeneca, Baxter, Bristol-Myers Squibb, Fresenius Kabi, Incyte Biosciences, Merck, MSD, Mylan, Novartis, Nutricia, Pierre Fabre, Roche, Sanofi, Servier and research funding from Roche. ES received honoraria from Servier, Amgen, Merck Serono, MSD, Pierre Fabre Oncology BMS, Sanofi, Research funding from Bayer, and declares consulting for Pierre Fabre Oncology. YT declares honoraria from MSD, Astra Zeneca, Bayer, Amgen, Servier, Ipsen, Pierre Fabre, AAA and consulting for Merck. DT received honoraria from Amgen, Roche, Sanofi, Bristol-Myers Squibb, Merck Serono, MSD, Bristol-Myers Squibb, Servier/Pfizer, Ipsen, research funding from AstraZeneca, SERVIER, Roche, MSD, BTG, and declares consulting for Sanofi, MSD, Pierre Fabre, and AstraZeneca. A.Z. declares consulting and/or advisory boards for Amgen, Lilly, Merck, Roche, Sanofi, Servier, Baxter, MSD, Pierre Fabre, Havas Life, Alira Health, Zymeworks, and Daiichi. CDLF received honoraria from Amgen, Astra- Zeneca, Bayer, Bristol-Myers Squibb, Eisai, Incyte Biosciences, Ipsen, Lilly, Merck Serono, MSD, Pierre Fabre Oncologie, Pfizer, Roche, Sanofi-Aventis, Servier. FB, MBZ, SK, EC, PR and ES declares no conflicts of interests., and This study is supported by a grant from the French Ministry of Health and the French National Cancer Institute (PHRC-K 2019 Inca-DGOS_14333 and PRT-K 2020–15324). It is also carried out with the support of MSD France. The opinions expressed in this article are those of the authors and do not necessarily reflect those of MSD France.

Subjects
Hepatology, MSI/dMMR, [SDV]Life Sciences [q-bio], Gastroenterology, Immune checkpoint inhibitor, DNA Mismatch Repair, Colorectal cancer, Perioperative immunotherapy, Antineoplastic Agents, Immunological, Endometrial cancer, Neoplasms, Humans, Immunologic Factors, Microsatellite Instability, Immunotherapy, Prospective Studies, Colorectal Neoplasms, Gastric cancer, Immune Checkpoint Inhibitors
Abstract

International audience; Background: Immune checkpoint inhibitors (ICI) targeting Programmed death-1 (PD-1) have shown their efficacy in advanced MSI/dMMR (microsatellite instability/deficient mismatch repair) tumors. The MSI/dMMR status predicts clinical response to ICI. The promising results evaluating ICI in localized MSI/dMMR tumors in neoadjuvant setting need to be confirmed in MSI/dMMR solid tumors. The aim of the IMHOTEP trial is to assess the efficacy of neoadjuvant anti-PD-1 treatment in MSI/dMMR tumors regarding the pathological complete response rate. Methods: This study is a prospective, multicenter, phase II study including 120 patients with localized MSI/dMMR carcinomas suitable for curative surgery. A single dose of pembrolizumab will be administered before the surgery planned 6 weeks later. Primary objective is to evaluate the efficacy of neoadjuvant pembrolizumab according to pathological complete tumor response. Secondary objectives are to assess safety, recurrence-free survival and overall survival. Ancillary studies will assess molecular and immunological biomarkers predicting response/resistance to ICI. First patient was enrolled in December 2021. Discussion: The IMHOTEP trial will be one of the first clinical trial investigating perioperative ICI in localized MSI/dMMR in a tumor agnostic setting. Assessing neoadjuvant anti-PD-1 is mandatory to improve MSI/dMMR patient's outcomes. The translational program will explore potential biomarker to improve our understanding of immune escape and response in this ICI neoadjuvant setting.

Published
2022

2. Microvascular assessment of fascio-cutaneous flaps by ultrasound: A large animal study

Author

Guillaume, Goudot, Yanis, Berkane, Eloi, de Clermont-Tonnerre, Claire, Guinier, Irina, Filz von Reiterdank, Antonia, van Kampen, Korkut, Uygun, Curtis L, Cetrulo, Basak E, Uygun, Anahita, Dua, Alexandre G, Lellouch, Harvard Medical School [Boston] (HMS), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Pontchaillou [Rennes], Université de Rennes (UR), Shriners Hospitals for Children [Boston], Massachusetts General Hospital [Boston, MA, USA], and GG was funded by the Federation Française de Cardiologie and the Institut Servier. YB was funded by CHU de Rennes, Fondation des Gueules Cassées and Shriners Children Boston (#84308-BOS-22). Shriners Hospitals partially funded this work for Children grant #85127-BOS-20 (BU) and 85015-BOS-23 (KU, CC, AL). AK was funded by the American Heart Association Postdoctoral Fellowship Award. The US. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick, MD 21702–5014, is the awarding and administering acquisition office. This work was supported by the Office of Assistant Secretary of Defense for Health Affairs through the Reconstructive Transplant Research Program, Technology Development Award under Awards No. W81XWH-19-1-0440 (CC, KU), W81XWH-17-1-0680 (KU, CC, AL), W81XWH-21-RTRP-IIRA (CC, AL). Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. This material is partially based upon work supported by the National Science Foundation under Grant No. EEC 1941543. Partial support from the US National Institutes of Health (R01EB028782) is gratefully acknowledged.

Subjects
pig, Physiology, Physiology (medical), [SDV]Life Sciences [q-bio], microvascularization, MV-Flow, Microvascular flow imaging, microcirculation, flap surgery, vascularity index
Abstract

Objectives: Blood perfusion quality of a flap is the main prognostic factor for success. Microvascular evaluation remains mostly inaccessible. We aimed to evaluate the microflow imaging mode, MV-Flow, in assessing flap microvascularization in a pig model of the fascio-cutaneous flap.Methods: On five pigs, bilateral saphenous fascio-cutaneous flaps were procured on the superficial femoral vessels. A conventional ultrasound evaluation in pulsed Doppler and color Doppler was conducted on the ten flaps allowing for the calculation of the saphenous artery flow rate. The MV-Flow mode was then applied: for qualitative analysis, with identification of saphenous artery collaterals; then quantitative, with repeated measurements of the Vascularity Index (VI), percentage of pixels where flow is detected relative to the total ultrasound view area. The measurements were then repeated after increasing arterial flow by clamping the distal femoral artery.Results: The MV-Flow mode allowed a better follow-up of the saphenous artery’s collaterals and detected microflows not seen with the color Doppler. The VI was correlated to the saphenous artery flow rate (Spearman rho of 0.64; p = 0.002) and allowed to monitor the flap perfusion variations.Conclusion: Ultrasound imaging of microvascularization by MV-Flow mode and its quantification by VI provides valuable information in evaluating the microvascularization of flaps.

Published
2022

3. Targeting the DNA damage response in immuno-oncology: developments and opportunities

Author

Christopher J. Lord, Philippe Pasero, Mathieu Rouanne, Roman M. Chabanon, Jean-Charles Soria, Sophie Postel-Vinay, Programme ATIP - Avenir, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hôpital Foch [Suresnes], The institute of cancer research [London], Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Institut Gustave Roussy (IGR), Université Paris-Saclay, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), AstraZeneca, Roche, Association pour la Recherche sur le Cancer, ARC: PGA1 RF 20190208576, Boehringer Ingelheim, Merck KGaA, Ligue Contre le Cancer: INCa-DGOS-INSERM_12551, Cancéropôle Ile de France: 2017-1-EMERG-72, Fondation Bettencourt Schueller, Fondation des Treilles, The authors thank Y. L. Lin and H. Técher for their careful reading of the manuscript and insightful comments. The work in the laboratory of S.P.-V. is supported by programme grants from ATIP-Avenir INSERM / La Ligue Nationale Contre le Cancer, SIRIC SOCRATE-2 (INCa-DGOS-INSERM_12551), Cancéropôle Ile-de-France (2017-1-EMERG-72) and Association pour la Recherche contre le Cancer (ARC PGA1 RF 20190208576). R.M.C. received funding from Fondation Bettencourt-Schueller, Fondation des Treilles, Fondation Philanthropia-Lombard Odier, Institut Servier, and Cancéropôle Ile-De-France., and R.M.C., M.R. and P.P. have no conflicts of interest or financial interests to disclose. C.J.L. is a named inventor on patents describing the use of DNA repair inhibitors and stands to gain from their use as part of the Institute of Cancer Research Rewards to Inventor scheme. C.J.L. has received research funding from AstraZeneca, Merck KGaA, Artios and Pfizer, has received consultancy and/or advisory fees from Astra Zeneca, Merck KGaA, Artios, Tango and GLG, and is a shareholder of OviBio and Tango. J.-C.S. has received consultancy fees from Relay Therapeutics, is a shareholder of AstraZeneca, Gritstone and Daiichi Sankyo, and is a member of the Hookipa board of directors. S.P.-V. has received research funding from Merck KGaA, Boehringer Ingelheim and Roche for unrelated research projects. As part of the Drug Development Department (DITEP), S.P.-V. is a principal investigator or a subinvestigator on clinical trials by Abbvie, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, Aveo, Bayer Healthcare AG, Bbb Technologies BV, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Chugai Pharmaceutical Co., Clovis Oncology, Daiichi Sankyo, Debiopharm S.A., Eisai, Eli Lilly, Exelixis, Forma, Gamamabs, Genentech Inc., Glaxosmithkline, H3 Biomedicine Inc., Hoffmann La Roche AG, Innate Pharma, Iris Servier, Janssen Cilag, Kyowa Kirin Pharmaceutical Development Inc., Loxo Oncology, Lytix Biopharma AS, Medimmune, Menarini Ricerche, Merck Sharp & Dohme-Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology NV, Oncoethix, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Pfizer, PharmaMar, Pierre Fabre, Roche, Sanofi Aventis, Taiho Pharma, Tesaro Inc. and Xencor. S.P.-V. has participated in advisory boards for Merck KGaA.

Subjects
Antigenicity, DNA damage, General Mathematics, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Cancer immunotherapy, Medical Oncology, Genomic Instability, 03 medical and health sciences, 0302 clinical medicine, Immune system, Targeted therapies, Immunity, Adjuvanticity, Neoplasms, medicine, Animals, Humans, 030304 developmental biology, 0303 health sciences, business.industry, Applied Mathematics, Immunogenicity, Immunotherapy, 3. Good health, 030220 oncology & carcinogenesis, Cancer research, Immunogenic cell death, Tumour immunology, business, DNA Damage
Abstract

International audience; Immunotherapy has revolutionized cancer treatment and substantially improved patient outcome with regard to multiple tumour types. However, most patients still do not benefit from such therapies, notably because of the absence of pre-existing T cell infiltration. DNA damage response (DDR) deficiency has recently emerged as an important determinant of tumour immunogenicity. A growing body of evidence now supports the concept that DDR-targeted therapies can increase the antitumour immune response by (1) promoting antigenicity through increased mutability and genomic instability, (2) enhancing adjuvanticity through the activation of cytosolic immunity and immunogenic cell death and (3) favouring reactogenicity through the modulation of factors that control the tumour–immune cell synapse. In this Review, we discuss the interplay between the DDR and anticancer immunity and highlight how this dynamic interaction contributes to shaping tumour immunogenicity. We also review the most innovative preclinical approaches that could be used to investigate such effects, including recently developed ex vivo systems. Finally, we highlight the therapeutic opportunities presented by the exploitation of the DDR–anticancer immunity interplay, with a focus on those in early-phase clinical development.

Published
2021

4. Mitral valve repair based on intraoperative objective measurement

Author

P.-J. Cottinet, Jean-Fabien Capsal, Daniel Grinberg, Florent Ganet, Minh Quyen Le, David Audigier, Young Joon Kwon, Miguel Angel Fernández, Jean-François Obadia, Laboratoire de Génie Electrique et Ferroélectricité (LGEF), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA), Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Mount Sinai Health System, COmputational Mathematics for bio-MEDIcal Applications (COMMEDIA), Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jacques-Louis Lions (LJLL (UMR_7598)), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), The author thank the support from the 'Fulbright' program, 'Federation Française de Cardiologie', 'Philippe Foundation', and 'Institut Servier' Doctoral Fellowship program., and Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)

Subjects
0301 basic medicine, medicine.medical_specialty, medicine.medical_treatment, lcsh:Medicine, Article, 03 medical and health sciences, [SPI]Engineering Sciences [physics], 0302 clinical medicine, Internal medicine, Prolapse, medicine, Humans, New device, lcsh:Science, Heart Valve Prosthesis Implantation, Mitral valve repair, Multidisciplinary, business.industry, lcsh:R, Objective measurement, Experimental data, Mitral Valve Insufficiency, Reproducibility of Results, Equipment Design, Implantation, Chordal force distribution, 030104 developmental biology, Equipment and Supplies, Tension, Cardiology, Chordae Tendineae, Mitral Valve, lcsh:Q, business, 030217 neurology & neurosurgery, Mitral valve surgery
Abstract

In this paper, we propose a very innovative designed system that enables optimal length adjustment during transapical neochordae implantation for mitral valve repair, increasing accuracy and reproducibility of neochordae length adjustment. Also, such a new device allowed real-time measurement and recording of chordae tension, producing original physiological data. To the best of our knowledge, the tension of chordae had never been measured previously as precisely, especially in in vivo human clinical trials. Preliminary experimental data have been collected on 10 selected patients, giving us the opportunity to assess for the first time the tension applied on the chordae implanted in beating human hearts. The final goal of our measuring device is to provide reliable objective intraoperative data to improve the understanding of changes occurring after mitral valve repair (MVR). This novel measuring instrument may bring change in the paradigm of MVR by allowing repair with strong objective and quantitative, instead of qualitative anatomical analysis.

Published
2019

5. What do MITRA-FR and COAPT teach us about the percutaneous treatment of secondary mitral regurgitation?

Author

Erwan Donal, Jean-François Obadia, Daniel Grinberg, Hospices Civils de Lyon (HCL), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Federation Francaise de Cardiologie, Philippe Foundation, Institut Servier Doctoral Fellowship program, Fulbright Program, Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Heart Valve Prosthesis Implantation, medicine.medical_specialty, Mitral regurgitation, Percutaneous, business.industry, Mitral Valve Insufficiency, 030204 cardiovascular system & hematology, 3. Good health, Surgery, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Mitral Valve, [SDV.IB]Life Sciences [q-bio]/Bioengineering, 030212 general & internal medicine, Cardiology and Cardiovascular Medicine, business, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2019

6. Modulation of large dense core vesicle insulin content mediates rhythmic hormone release from pancreatic beta cells over the 24h cycle

Author

Aurore Quinault, Quan Zhang, Philippe Lefebvre, Catherine Dacquet, Geoffrey Denwood, Luc Penicaud, Coralie Spiegelhalter, Marianne Rodriguez, Corinne Leloup, Stephan C. Collins, Nadia Messaddeq, Collins, Stephan, 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), Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford [Oxford], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherches Internationales Servier [Suresnes] (IRIS), Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), The authors acknowledge the scientific and financial support from the Institut Servier. AQ was hired through a contract with Servier (contract 130717/ZA/NM)., University of Oxford, Récepteurs nucléaires, maladies cardiovasculaires et diabète (EGID), Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)

Subjects
0301 basic medicine, Physiology, medicine.medical_treatment, Gene Expression, lcsh:Medicine, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biochemistry, Mice, Endocrinology, 0302 clinical medicine, Insulin-Secreting Cells, Insulin Secretion, Medicine and Health Sciences, Insulin, lcsh:Science, Proinsulin, Secretory Pathway, Multidisciplinary, Organic Compounds, Chemistry, Monosaccharides, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Cell biology, Circadian Oscillators, Circadian Rhythms, medicine.anatomical_structure, Cell Processes, Physical Sciences, Alimentation et Nutrition, Beta cell, Research Article, Insulin processing, Materials Science, Material Properties, Carbohydrates, Capacitance, 030209 endocrinology & metabolism, Carbohydrate metabolism, Exocytosis, 03 medical and health sciences, Genetics, medicine, Animals, Food and Nutrition, Secretion, Diabetic Endocrinology, Endocrine Physiology, Secretory Vesicles, Pancreatic islets, Organic Chemistry, lcsh:R, Chemical Compounds, Neurosciences, Biology and Life Sciences, Cell Biology, Glucagon, Hormones, Mice, Inbred C57BL, MicroRNAs, Glucose, 030104 developmental biology, Neurons and Cognition, lcsh:Q, Chronobiology
Abstract

International audience; The rhythmic nature of insulin secretion over the 24h cycle in pancreatic islets has been mostly investigated using transcriptomics studies showing that modulation of insulin secretion over this cycle is achieved via distal stages of insulin secretion. We set out to measure β-cell exocytosis using in depth cell physiology techniques at several time points. In agreement with the activity and feeding pattern of nocturnal rodents, we find that C57/Bl6J islets in culture for 24h exhibit higher insulin secretion during the corresponding dark phase than in the light phase (Zeitgeber Time ZT20 and ZT8, respectively, in vivo). Glucose-induced insulin secretion is increased by 21% despite normal intracellular Ca2+ transients and depolarization-evoked exocytosis, as measured by whole-cell capacitance measurements. This paradox is explained by a 1.37-fold increase in beta cell insulin content. Ultramorphological analyses show that vesicle size and density are unaltered, demonstrating that intravesicular insulin content per granule is modulated over the 24h cycle. Proinsulin levels did not change between ZT8 and ZT20. Islet glucagon content was inversely proportional to insulin content indicating that this unique feature is likely to support a physiological role. Microarray data identified the differential expression of 301 transcripts, of which 26 are miRNAs and 54 are known genes (including C2cd4b, a gene previously involved in insulin processing, and clock genes such as Bmal1 and Rev-erbα). Mouse β-cell secretion over the full course of the 24h cycle may rely on several distinct cellular functions but late night increase in insulin secretion depends solely on granule insulin content.

Published
2018

7. Soluble Siglec-5 associates to PSGL-1 and displays anti-inflammatory activity

Author

Pepin, Marion, Mezouar, Soraya, Pegon, Julie, Muczynski, Vincent, Adam, Frédéric, Bianchini, Elsa P, Bazaa, Amine, Proulle, Valerie, Rupin, Alain, Paysant, Jerome, Panicot-Dubois, Laurence, Christophe, Olivier D., Dubois, Christophe, Lenting, Peter J, Denis, Cécile V, Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Université Paris-Sud - Paris 11 (UP11)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vascular research center of Marseille (VRCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Service d'hématologie, immunologie biologiques et cytogénétique, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Institut de Recherches Internationales Servier [Suresnes] (IRIS), The study was financially supported by a PhD-research grant from Institut Servier & Association Nationale de la Recherche Technique (Contrat CIFRE) to JPe, and an Inserm-Poste d’Accueil-grant (# ASC13101LSA) to MP., Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Anti-Inflammatory Agents/pharmacology, E-SELECTIN LIGAND-1, [SDV]Life Sciences [q-bio], Anti-Inflammatory Agents, MESH: Membrane Glycoproteins/genetics, MESH: Antigens, Differentiation, Myelomonocytic/metabolism, MESH: Lectins/metabolism, MESH: Antigens, CD/pharmacology, MESH: Leukocytes, Mononuclear/drug effects, Lectins, MESH: Animals, MYELOID CELLS, MESH: E-Selectin/metabolism, NEUTROPHILS, IN-VIVO, MESH: Inflammation/drug therapy, Membrane Glycoproteins, MESH: Inflammation/chemically induced, MESH: Inflammation/pathology, MESH: Membrane Glycoproteins/metabolism, MESH: Leukocyte Rolling/physiology, P-Selectin, Female, E-Selectin, MESH: Leukocytes, Mononuclear/metabolism, CD33-RELATED SIGLECS, VON-WILLEBRAND-FACTOR, MESH: Lectins/pharmacology, Antigens, Differentiation, Myelomonocytic, MESH: Antigens, Differentiation, Myelomonocytic/pharmacology, MESH: Tumor Necrosis Factor-alpha/toxicity, GLYCOPROTEIN LIGAND, MESH: Antigens, CD/metabolism, Article, MESH: Mice, Inbred C57BL, Antigens, CD, Animals, Humans, Leukocyte Rolling, Protein Interaction Domains and Motifs, MESH: Antigens, Differentiation, Myelomonocytic/genetics, SIALIC-ACID, Inflammation, MESH: Protein Interaction Domains and Motifs, MESH: Humans, Tumor Necrosis Factor-alpha, MESH: Lectins/genetics, MESH: Solubility, Mice, Inbred C57BL, Disease Models, Animal, Solubility, Leukocytes, Mononuclear, MESH: Antigens, CD/genetics, IMMUNE-SYSTEM, MESH: Disease Models, Animal, MESH: Female, MESH: P-Selectin/metabolism
Abstract

International audience; Interactions between endothelial selectins and the leukocyte counter-receptor PSGL1 mediates leukocyte recruitment to inflammation sites. PSGL1 is highly sialylated, making it a potential ligand for Siglec-5, a leukocyte-receptor that recognizes sialic acid structures. Binding assays using soluble Siglec-5 variants (sSiglec-5/C4BP and sSiglec-5/Fc) revealed a dose- and calcium-dependent binding to PSGL1. Pre-treatment of PSGL1 with sialidase reduced Siglec-5 binding by 79 ± 4%. In confocal immune-fluorescence assays, we observed that 50% of Peripheral Blood Mononuclear Cells (PBMCs) simultaneously express PSGL1 and Siglec-5. Duolink-proximity ligation analysis demonstrated that PSGL1 and Siglec-5 are in close proximity (

Published
2016

8. Amotl1 mediates sequestration of the Hippo effector Yap1 downstream of Fat4 to restrict heart growth

Author

Chiara V. Ragni, Jean-François Le Garrec, Jean-Christophe Olivo-Marin, Laurent Guillemot, Tatiana P. Resende, Alain Trouvé, Sigolène M. Meilhac, Helen McNeill, Lisa Kitasato, Nicolas Diguet, Marta Novotova, Nicolas Charon, Alexandre Dufour, Sorin Pop, Caroline Badouel, URA 2578, Centre National de le Recherche Scientifique, UPMC - Institut de Formation Doctorale (IFD ), Université Pierre et Marie Curie - Paris 6 (UPMC), Département de Biologie du Développement et Cellules souches - Department of Developmental and Stem Cell Biology, Institut Pasteur [Paris], Institute of Molecular Physiology and Genetics, Slovak Academy of Science [Bratislava] (SAS), Universidade do Porto, Analyse d'images biologiques - Biological Image Analysis (BIA), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre de Mathématiques et de Leurs Applications (CMLA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Samuel Lunenfeld Research Institute, Mount Sinai Hospital [Toronto, Canada] (MSH), This work was supported by grants from VEGA [2/0110/15] to M.N. and from the Institut Pasteur [PTR335], ANR [11-JSV2-00601], FRM [DPC20111122997], CNRS [PEPS BMI] to S.M.M. C.V.R. was funded by the MESR and ARC, N.D. and L.K. by the Fondation Lefoulon-Delalande, L.K. by the Institut Servier and S.M.M. is an INSERM research scientist. T.P.R. is funded by the FCT [SFRH/BPD/80588/2011] and INEB [NORTE-07-0124-FEDER-000005] to P. Pinto-do-Ó., ANR-11-JSV2-0006,cardiopol,Polarité des cellules du myocarde au cours de la formation des chambres cardiaques(2011), Institut Pasteur [Paris] (IP), Bases Génétiques, Moléculaires et Cellulaires du Développement (BGMCD), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institute of Molecular Physiology and Genetics (IMPG), Universidade do Porto = University of Porto, and Analyse d'Images Quantitative (AIQ)

Subjects
0301 basic medicine, animal structures, Science, Heart growth, General Physics and Astronomy, Cardiomegaly, Cell Cycle Proteins, Biology, Models, Biological, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Mice, Downregulation and upregulation, Animals, Transcription factor, Angiopoietin-Like Protein 1, Adaptor Proteins, Signal Transducing, Cell Proliferation, YAP1, Hippo signaling pathway, Multidisciplinary, Kinase, Cadherin, Effector, fungi, Gene Expression Regulation, Developmental, Membrane Proteins, Heart, YAP-Signaling Proteins, General Chemistry, Desmosomes, Cadherins, Phosphoproteins, Cell biology, Rats, body regions, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, 030104 developmental biology, Animals, Newborn, sense organs, Protein Binding, Signal Transduction
Abstract

Although in flies the atypical cadherin Fat is an upstream regulator of Hippo signalling, the closest mammalian homologue, Fat4, has been shown to regulate tissue polarity rather than growth. Here we show in the mouse heart that Fat4 modulates Hippo signalling to restrict growth. Fat4 mutant myocardium is thicker, with increased cardiomyocyte size and proliferation, and this is mediated by an upregulation of the transcriptional activity of Yap1, an effector of the Hippo pathway. Fat4 is not required for the canonical activation of Hippo kinases but it sequesters a partner of Yap1, Amotl1, out of the nucleus. The nuclear translocation of Amotl1 is accompanied by Yap1 to promote cardiomyocyte proliferation. We, therefore, identify Amotl1, which is not present in flies, as a mammalian intermediate for non-canonical Hippo signalling, downstream of Fat4. This work uncovers a mechanism for the restriction of heart growth at birth, a process which impedes the regenerative potential of the mammalian heart., Growth of the mammalian heart is controlled by Hippo signalling but how this is regulated is unclear. Here, the authors show that Fat4 (an atypical cadherin) acts upstream of Hippo signalling and Fat4 mutant mice have thicker myocardium, which is mediated by the scaffold Amot1 and transcription factor Yap1.

Published
2016

9. Public T cell receptors confer high-avidity CD4 responses to HIV controllers

Author

Pierre de Truchis, Mathieu Claireaux, Alexandre Nouël, Lisa A. Chakrabarti, Moran Galperin, Samia Hendou, Daniela Benati, Pierre Lechat, Brigitte Lemercier, Annick Lim, Fernando Arenzana-Seisdedos, Olivier Lambotte, Jean-François Delfraissy, Kristy-Anne Campbell, Jamie Rossjohn, Stephanie Gras, Faroudy Boufassa, Madhura Mukhopadhyay, Pathogénie Virale - Viral Pathogenesis, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University [Clayton], Département d'Immunologie - Department of Immunology, Institut Pasteur [Paris] (IP), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institute of Infection and Immunity, Cardiff University, This work was supported by ANRS, Sidaction, the Pasteur Institute, the Australian Research Council (ARC), and the National Health and Medical Research Council of Australia (NHMRC). L.A. Chakrabarti is supported by grants grants from ANRS (EP36-8) and Agence Nationale de la Recherche (ANR PD1VAX), S. Gras is supported by an ARC Future Fellowship (FF120100416), and J. Rossjohn by an NHMRC Australia Fellowship (AF50). D. Benati was the recipient of postdoctoral fellowships from ANRS, the Fondation pour la Recher- che Médicale, and the Institut Servier. M. Galperin is the recipient of an ANRS doctoral fellowship. M. Mukhopadhyay is a scholar in the Pasteur - Paris University (PPU) International PhD program., ANR-14-CE16-0029,PD1VAX,Une nouvelle stratégie de vaccination par vecteur ADN PD1 pour mimer les réponses spécifiques de Gag trouvées chez les contrôleurs spontanés du VIH(2014), Pathogénie Virale, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Pham, Cécile, and Appel à projets générique - Une nouvelle stratégie de vaccination par vecteur ADN PD1 pour mimer les réponses spécifiques de Gag trouvées chez les contrôleurs spontanés du VIH - - PD1VAX2014 - ANR-14-CE16-0029 - Appel à projets générique - VALID

Subjects
0301 basic medicine, Adult, CD4-Positive T-Lymphocytes, Adoptive cell transfer, CD4 antigen, Receptors, Antigen, T-Cell, chemical and pharmacologic phenomena, HIV Infections, Biology, gag Gene Products, Human Immunodeficiency Virus, Epitope, HIV Long-Term Survivors, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Immune system, L Cells, Antigen, Antiretroviral Therapy, Highly Active, Animals, Humans, HLA-DR Antigen, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Immunity, Cellular, T-cell receptor, HIV, Adoptive Transfer, CD4 Antigens, Genes, T-Cell Receptor alpha, Genes, T-Cell Receptor beta, HLA-DR Antigens, L Cells (Cell Line), Middle Aged, HIV-1, Medicine (all), hemic and immune systems, General Medicine, Virology, 3. Good health, 030104 developmental biology, chemistry, Immunology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, CD8, 030215 immunology, Research Article
Abstract

International audience; The rare patients who are able to spontaneously control HIV replication in the absence of therapy show signs of a particularly efficient cellular immune response. To identify the molecular determinants that underlie this response, we characterized the T cell receptor (TCR) repertoire directed at Gag293, the most immunoprevalent CD4 epitope in the HIV-1 capsid. HIV controllers from the ANRS CODEX cohort showed a highly skewed TCR repertoire that was characterized by a predominance of TRAV24 and TRBV2 variable genes, shared CDR3 motifs, and a high frequency of public clonotypes. The most prevalent public clonotypes generated TCRs with affinities at the higher end of values reported for naturally occurring TCRs. The high-affinity Gag293-specific TCRs were cross-restricted by up to 5 distinct HLA-DR alleles, accounting for the expression of these TCRs in HIV controllers of diverse genetic backgrounds. Transfer of these TCRs to healthy donor CD4+ T cells conferred high antigen sensitivity and polyfunctionality, thus recapitulating key features of the controller CD4 response. Transfer of a high-affinity Gag293-specific TCR also redirected CD8+ T cells to target HIV-1 capsid via nonconventional MHC II restriction. Together, these findings indicate that TCR clonotypes with superior functions are associated with HIV control. Amplification or transfer of such clonotypes may contribute to immunotherapeutic approaches aiming at a functional HIV cure.

Published
2016

10. Synthesis and anticancer activity of new pyrrolocarbazoles and pyrrolo-β-carbolines

Author

Marie Laronze, Amélie Lansiaux, Stéphane Léonce, J.-Y. Laronze, Olivier Lozach, Christian Bailly, Pierre Renard, Michel Boisbrun, Laurent Meijer, Bruno Pfeiffer, Janos Sapi, Isolement, structure, transformations et synthèse de substances naturelles (ISTSSN), Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, Mer et santé (MS), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Génétique moléculaire et approches thérapeutiques des hémopathies malignes, IRCL-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Indoles, Stereochemistry, Clinical Biochemistry, Carbazoles, DNA Footprinting, Pharmaceutical Science, Antineoplastic Agents, Tumor cells, Nucleic Acid Denaturation, 010402 general chemistry, 01 natural sciences, Biochemistry, Chemical synthesis, Glycogen Synthase Kinase 3, Inhibitory Concentration 50, Mice, Structure-Activity Relationship, chemistry.chemical_compound, Cell Line, Tumor, CDC2 Protein Kinase, Drug Discovery, Animals, Pyrroles, Enzyme Inhibitors, Imide, Cytotoxicity, Molecular Biology, Glycogen Synthase Kinase 3 beta, Molecular Structure, 010405 organic chemistry, Cell Cycle, Organic Chemistry, Temperature, Titrimetry, Biological activity, DNA, Leukemia L1210, 3. Good health, 0104 chemical sciences, DNA Topoisomerases, Type I, chemistry, Lactam, Molecular Medicine, Topoisomerase I Inhibitors, Carbolines
Abstract

'Bended' 1, 3 or 'linear' 2 pyrrolidino-fused (aza)carbazoles were prepared and screened towards a few cancer-related targets. Whereas 'bended' derivatives 1 and 3 proved to be weakly toxic, several members of the 'linear' family strongly interact with DNA, especially derivative 28a.

Published
2005

11. Structure–Activity Relationships of Human Urotensin II and Related Analogues on Rat Aortic Ring Contraction

Author

Gervaise Loirand, Pierre Renard, Pierre Pacaud, Jérôme Leprince, David Chatenet, Hubert Vaudry, Marie-Christine Tonon, Christophe Dubessy, Elizabeth Scalbert, Bernard Calas, Céline Marionneau, Bruno Pfeiffer, Patricia Labarrère, Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP 23), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, Les Laboratoires SERVIER, and Institut de Recherche Servier

Subjects
Male, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Aorta, Thoracic, Peptide, MESH: Amino Acid Sequence, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, MESH: Dose-Response Relationship, Drug, chemistry.chemical_compound, MESH: Structure-Activity Relationship, 0302 clinical medicine, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Drug Discovery, Vasoconstrictor Agents, MESH: Animals, MESH: Peptide Fragments, Receptor, chemistry.chemical_classification, Alanine, 0303 health sciences, Biological activity, General Medicine, Amino acid, Biochemistry, MESH: Rats, Stereochemistry, Urotensins, MESH: Aorta, Thoracic, Molecular Sequence Data, In Vitro Techniques, Structure-Activity Relationship, MESH: Vasoconstrictor Agents, 03 medical and health sciences, Animals, Humans, Amino Acid Sequence, Rats, Wistar, 030304 developmental biology, MESH: In Vitro Techniques, Pharmacology, MESH: Humans, MESH: Molecular Sequence Data, MESH: Urotensins, Dose-Response Relationship, Drug, MESH: Rats, Wistar, Peptide Fragments, MESH: Male, In vitro, Rats, chemistry, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Urotensin-II, 030217 neurology & neurosurgery, Cysteine
Abstract

International audience; The sequence of human urotensin II (UII) has been recently established as H-Glu-Thr-Pro-Asp-Cys-Phe-Trp-Lys-Tyr-Cys-Val-OH, and it has been reported that UII is the most potent mammalian vasoconstrictor peptide identified so far. A series of UII analogues was synthesized, and the contractile activity of each compound was studied in vitro using de-endothelialised rat aortic rings. Replacement of each amino acid by an L-alanine or by a D-isomer showed that the N- and C-terminal residues flanking the cyclic region of the amidated peptide were relatively tolerant to substitution. Conversely, replacement of any residue of the cyclic region significantly reduced the contractile activity of the molecule. The octapeptide UII(4-11) was 4 times more potent than UII, indicating that the C-terminal region of the molecule possesses full biological activity. Alanine or D-isomer substitutions in UII(4-11) or in UII(4-11)-NH2, respectively, showed a good correlation with the results obtained for UII-NH2. Disulfide bridge disruption or replacement of the cysteine residues by their D-enantiomers markedly reduced the vasoconstrictor effect of UII and its analogues. In contrast, acetylation of the N-terminal residue of UII and UII-NH2 enhanced the potency of the peptide. Finally, monoiodination of the Tyr6 residue in UII(4-11) increased by 5 fold the potency of the peptide in the aortic ring bioassay. This structure-activity relationship study should provide useful information for the rational design of selective and potent UII receptor agonists and antagonists.

Published
2003

12. Cdk5 induces constitutive activation of 5-HT6 receptors to promote neurite growth

Author

Fabrice Raynaud, Martial Séveno, Philippe Marin, Millan Mark, Séverine Morisset-Lopez, Paul Déléris, Séverine Chaumont-Dubel, Fanny Duhr, Joël Bockaert, Clotilde Mannoury la Cour, Institut de Génomique Fonctionnelle (IGF), 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), Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), and INSTITUT SERVIER

Subjects
Agonist, Calcium Channels, L-Type, medicine.drug_class, [SDV]Life Sciences [q-bio], Primary Cell Culture, CDC42, Molecular neuroscience, Biology, Ligands, Hippocampus, Piperazines, Rats, Sprague-Dawley, Mice, Cell Line, Tumor, Neurites, medicine, Animals, Humans, Gene silencing, Inverse agonist, Phosphorylation, cdc42 GTP-Binding Protein, Receptor, Molecular Biology, Sulfonamides, Kinase, Cyclin-dependent kinase 5, Gene Expression Regulation, Developmental, Cell Differentiation, Cyclin-Dependent Kinase 5, Cell Biology, Rats, Cell biology, nervous system, Receptors, Serotonin, Mutation, Signal Transduction
Abstract

International audience; The serotonin6 receptor (5-HT6R) is a promising target for treating cognitive deficits of schizophrenia often linked to alterations of neuronal development. This receptor controls neurodevelopmental processes, but the signaling mechanisms involved remain poorly understood. Using a proteomic strategy, we show that 5-HT6Rs constitutively interact with cyclin-dependent kinase 5 (Cdk5). Expression of 5-HT6Rs in NG108-15 cells induced neurite growth and expression of voltage-gated Ca2+ channels, two hallmarks of neuronal differentiation. 5-HT6R–elicited neurite growth was agonist independent and prevented by the 5-HT6R antagonist SB258585, which behaved as an inverse agonist. Moreover, it required receptor phosphorylation at Ser350 by Cdk5 and Cdc42 activity. Supporting a role of native 5-HT6Rs in neuronal differentiation, neurite growth of primary neurons was reduced by SB258585, by silencing 5-HT6R expression or by mutating Ser350 into alanine. These results reveal a functional interplay between Cdk5 and a G protein–coupled receptor to control neuronal differentiation.

Published
2014

13. Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro

Author

Henrik Hagberg, Idoia Lara Celador, Tifenn Le Charpentier, Vibol Chhor, Carina Mallard, Marie-Virgine Oré, Vincent Degos, Etienne Jacotot, Sophie Lebon, Karin Sävman, Bobbi Fleiss, Julien Josserand, Pierre Gressens, Neuronal Stress and Aging (NSA), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-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 de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Wellcome Trust [WT094823MA], Inserm, Universite Paris 7, Fondation Leducq, Fondation Grace de Monaco, Fondation Roger de Spoelberch, PremUP, Fondation des gueules cassees, Institut Servier, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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), 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)-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)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and 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)-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)

Subjects
Lipopolysaccharides, Male, Macrophage, M1-M2, Fluorescent Antibody Technique, Gene Expression, Mice, Behavioral Neuroscience, M1–M2, 0302 clinical medicine, Neuroinflammation, Drug-screening, SOCS3, TLR4, Cerebral Cortex, Neurons, 0303 health sciences, Microglia, Cell Polarity, Immunohistochemistry, Phenotype, Neuroprotection, Cell biology, medicine.anatomical_structure, Cytokines, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Chemokines, medicine.symptom, Cell Survival, Primary Cell Culture, Immunology, Inflammation, Lipopolysaccharide, Biology, Real-Time Polymerase Chain Reaction, Article, 03 medical and health sciences, medicine, Animals, 030304 developmental biology, Endocrine and Autonomic Systems, Regeneration (biology), Interleukins, Toll-Like Receptor 4, Neuronal cell death, RNA, 030217 neurology & neurosurgery
Abstract

Highlight ► A unique catalogue of phenotype markers and neuronotoxic effects of polarised primary microglia, as a comparative tool to screen neurotherapies., Microglia mediate multiple facets of neuroinflammation, including cytotoxicity, repair, regeneration, and immunosuppression due to their ability to acquire diverse activation states, or phenotypes. Modulation of microglial phenotype is an appealing neurotherapeutic strategy but a comprehensive study of classical and more novel microglial phenotypic markers in vitro is lacking. The aim of this study was to outline the temporal expression of a battery of phenotype markers from polarised microglia to generate an in vitro tool for screening the immunomodulatory potential of novel compounds. We characterised expression of thirty-one macrophage/microglial phenotype markers in primary microglia over time (4, 12, 36, and 72 h), using RT-qPCR or multiplex protein assay. Firstly, we selected Interleukin-4 (IL-4) and lipopolysaccharide (LPS) as the strongest M1–M2 polarising stimuli, from six stimuli tested. At each time point, markers useful to identify that microglia were M1 included iNOS, Cox-2 and IL-6 and a loss of M2a markers. Markers useful for quantifying M2b-immunomodulatory microglia included, increased IL-1RA and SOCS3 and for M2a-repair and regeneration, included increased arginase-1, and a loss of the M1 and M2b markers were discriminatory. Additional markers were regulated at fewer time points, but are still likely important to monitor when assessing the immunomodulatory potential of novel therapies. Further, to facilitate identification of how novel immunomodulatory treatments alter the functional affects of microglia, we characterised how the soluble products from polarised microglia affected the type and rate of neuronal death; M1/2b induced increasing and M2a-induced decreasing neuronal loss. We also assessed any effects of prior activation state, to provide a way to identify how a novel compound may alter phenotype depending on the stage of injury/insult progression. We identified generally that a prior M1/2b reduced the ability of microglia to switch to M2a. Altogether, we have characterised a profile of phenotype markers and a mechanism of assessing functional outcome that we can use as a reference guide for first-line screening of novel immunomodulatory therapies in vitro in the search for viable neuroprotectants.

Published
2013

14. Synthesis, biological activity and quantitative structure-activity relationships of N-substituted-3,4-dihydro-2H-1-benzopyran derivatives

Author

Luc Morin-Allory, Bruno Pfeiffer, M.‐C. Viaud, Christophe Marot, G. Guillaumet, Marie-Claire Rettori, Corinne Comoy, Institut de Chimie Organique et Analytique (ICOA), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Orléans (UO)-Institut de Chimie du CNRS (INC), Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), and INSTITUT SERVIER

Subjects
0303 health sciences, [CHIM.ORGA]Chemical Sciences/Organic chemistry, 010405 organic chemistry, Stereochemistry, Organic Chemistry, Clinical Biochemistry, Pharmaceutical Science, Quantitative structure, Biological activity, 01 natural sciences, Biochemistry, 0104 chemical sciences, 3. Good health, Benzopyran, 03 medical and health sciences, chemistry.chemical_compound, chemistry, Drug Discovery, Molecular Medicine, Receptor, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

Synthesis of N -substituted-3,4-dihydro-2 H -1-benzopyran derivatives which have a potential affinity for the 5-HT 1A receptor is reported. The comparison between the experimental values of binding and the prediction of Q.S.A.R. studies is described.

Published
1996

15. Acute food deprivation reduces expression of diazepam-binding inhibitor, the precursor of the anorexigenic octadecaneuropeptide ODN, in mouse glial cells

Author

Schouft, Marie-Thérèse, Fontaine, Marc, Scalbert, Elisabeth, Malagon, Maria, Gandolfo, Pierrick, Desrues, Laurence, Cellier, Eric, Decker, Annick, Clerens, Stefan, Vandesande, Frans, Do-Rego, C., Beauvillain, C., Baroncini, Marc, Balment, Richard, Dujardin, Cynthia, Tollemer, Helene, BRUZZONE, FEDERICA, Tollemer, Hélène, Do-Régo, Jean, Simonnet, Guy, VALLARINO, MAURO, Beauvillain, Jean, Costentin, Jean, Do-Régo, Jean-Claude, Beauvillain, Jean-Claude, Chartrel, C, Alvear-Perez, P, Iturrioz, X., Reaux-Le Goazigo, A., Audinot, V., Chomarat, C, Coge, C, Nosjean, O., Rodriguez, M., Galizzi, J., Goazigo, R., Chomarat, P., Coge, F., Chartrel, Nicolas, Alonzeau, Jessy, Alexandre, David, Jeandel, Jean, Alvear-Perez, Rodrigo, Boutin, Jean, Anouar, Youssef, Llorens-Cortes, Catherine, Jeandel, Lydie, Carlier, Ludovic, Ségalas-Milazzo, Isabelle, Guilhaudis, Laure, Oulyadi, Hassan, Davoust, Daniel, Dubessy, Christophe, Scalbert, Elizabeth, Pfeiffer, Bruno, Renard, Pierre, Lihrmann, Isabelle, Pacaud, Pierre, Chevrier, Lucie, De Brevern, Alexandre, Hernandez, Eva, Guedj, Anne Marie, de Roux, Nicolas, Cholez, V, Debuysscher, V, Bourgeais, B, Boudot, B, Tron, F., Brassart, B., Regnier, A., Bissac, E, Pecnard, E, Gouilleux, F., Lassoued, K, Gouilleux-Gruart, V, Cholez, E, Bourgeais, J, Boudot, C., Gouilleux, V, Chuquet, Julien, Lecrux, Clotilde, Chatenet, David, Chazalviel, Laurent, Roussel, Simon, MacKenzie, Eric, Touzani, Omar, Tonon, M.C, Li, S., Leprince, J�r�me, Tonon, M.C., Compère, M, Lanfray, D, Castel, Hélène, Morin, M., Leprince, Jérôme, Dureuil, B, Vaudry, Hubert, Pelletier, G., Tonon, Marie-Christine, Compère, V., Morin, F., Dureuil, D, Vaudry, V, inconnu, Inconnu, Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Différenciation et communication neuronale et neuroendocrine (DC2N), Chercheur indépendant, Laboratoire de l'intégration, du matériau au système (IMS), Centre National de la Recherche Scientifique (CNRS)-Institut Polytechnique de Bordeaux-Université Sciences et Technologies - Bordeaux 1, University of Córdoba [Córdoba], Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, UMR 5287, Homéostasie-Allostasie-Pathologie-Réhabilitation, Centre National de la Recherche Scientifique (CNRS), Neuropsycho-pharmacologie expérimentale, Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 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), Laboratoire de Physique et Physiologie Intégratives de l'Arbre Fruitier et Forestier (PIAF), Institut National de la Recherche Agronomique (INRA)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherches Servier, Centre de Recherches de Croissy, ESPE de l'Académie d'Amiens, Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Equipe de Chimie Organique et Biologie Structurale (ECOBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA), Université Henri Poincaré - Nancy 1 (UHP), Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, Les Laboratoires SERVIER, Institut de Recherche Servier, Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bioinformatique génomique et moléculaire ((U 726)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Service des Maladies Métaboliques et Endocriniennes, Hôpital Universitaire Carémeau [Nîmes], Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP 23), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Henri Becquerel-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), 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), STMicroelectronics, Génétique, immunothérapie, chimie et cancer (GICC), UMR 6239 CNRS [2008-2011] (GICC UMR 6239 CNRS), Université de Tours-Centre National de la Recherche Scientifique (CNRS), Matrice extracellulaire et régulations cellulaires (MERC), Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Institut Armand Frappier (INRS-IAF), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), Neurodégénérescence : modèles et stratégies thérapeutiques (NMST), Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Aix-Marseille Université - Faculté de pharmacie (AMU PHARM), Aix Marseille Université (AMU), IRCELYON-Ingéniérie, du matériau au réacteur (ING), Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Télécom SudParis (TSP), Université Sciences et Technologies - Bordeaux 1-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille 2 - Faculté de Médecine -Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), 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)-CHU Pitié-Salpêtrière [APHP], CHU Rouen, Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-CRLCC Henri Becquerel-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PSL Research University (PSL)-Centre National de la Recherche Scientifique (CNRS)-Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PSL Research University (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie Organique Fine (IRCOF), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université Le Havre Normandie (ULH), Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), and 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)

Subjects
Leptin, Male, Transcription, Genetic, MESH: Sequence Homology, Amino Acid, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Receptors, G-Protein-Coupled, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, MESH: Neuropeptides, Energy homeostasis, MESH: Down-Regulation, MESH: Ependyma, Mice, 0302 clinical medicine, Endocrinology, Lateral Ventricles, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Insulin, MESH: Animals, MESH: Proline-Rich Protein Domains, MESH: Peptide Fragments, MESH: Lateral Ventricles, Diazepam Binding Inhibitor, 2. Zero hunger, 0303 health sciences, MESH: Ranidae, MESH: Receptors, Kisspeptin-1, Fasting, medicine.anatomical_structure, Hypothalamus, Neuroglia, MESH: Neuroglia, Ependyma, Diazepam binding inhibitor, Injections, Intraperitoneal, MESH: Injections, Intraperitoneal, Protein Binding, MESH: Protein Transport, medicine.medical_specialty, MESH: Rats, Central nervous system, Down-Regulation, Neuropeptide, MESH: Fasting, MESH: Insulin, Biology, 03 medical and health sciences, Internal medicine, medicine, Animals, MESH: Protein Binding, Molecular Biology, MESH: Mice, Third Ventricle, MESH: RNA, Messenger, 030304 developmental biology, MESH: Transcription, Genetic, Neuropeptides, MESH: Time Factors, MESH: Rats, Wistar, MESH: Leptin, MESH: Hypothalamus, Peptide Fragments, MESH: Male, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, MESH: Diazepam Binding Inhibitor, 030217 neurology & neurosurgery, MESH: Third Ventricle
Abstract

In the central nervous system of mammals, the gene encoding diazepam-binding inhibitor (DBI) is exclusively expressed in glial cells. Previous studies have shown that central administration of a DBI processing product, the octadecaneuropeptide ODN, causes a marked inhibition of food consumption in rodents. Paradoxically, however, the effect of food restriction on DBI gene expression has never been investigated. Here, we show that in mice, acute fasting dramatically reduces DBI mRNA levels in the hypothalamus and the ependyma bordering the third and lateral ventricles. I.p. injection of insulin, but not of leptin, selectively stimulated DBI expression in the lateral ventricle area. These data support the notion that glial cells, through the production of endozepines, may relay peripheral signals to neurons involved in the central regulation of energy homeostasis.

Published
2010

16. Rebeccamycin derivatives as dual DNA damaging agents and potent checkpoint kinase 1 inhibitors

Author

Marie -Paule Hildebrand, Olivier Lozach, Laurent Meijer, Michelle Prudhomme, Christelle Marminon, Roy M. Golsteyn, Pascale Moreau, Marie-Hélène David-Cordonnier, Fabrice Anizon, Bruno Pfeiffer, Alain Pierré, Paul Peixoto, Synthèse et étude de systèmes à intêret biologique (SEESIB), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), 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), Association EURATOM-CEA (CEA/DSM/DRFC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de recherches Paul Pascal (CRPP), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biogenèse membranaire (LBM), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Botanique, Faculté des Sciences Pharmaceutiques et Biologiques, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-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), Laboratoire de Matériaux Catalytiques et Catalyse en Chimie Organique (LMCCCO), Université Montpellier 1 (UM1)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS), Institut des Matériaux Jean Rouxel (IMN), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Ecole Polytechnique de l'Université de Nantes (EPUN), Université de Nantes (UN)-Université de Nantes (UN), Département de Recherche sur la Fusion Contrôlée (DRFC), Service de Recherche en Hémato-Immunologie (SRHI - UMR_E 05), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7), Service d'hématologie clinique, Hôpital Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, Institut de Recherches Servier, SERVIER, Les Laboratoires SERVIER, Institut de Recherche Servier, Division Recherche et Cancérologie, Institut de recherches sur la catalyse (IRC), Centre National de la Recherche Scientifique (CNRS), Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Maladies a Prions et Systeme Immunitaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Nantes (UN)-Université de Nantes (UN)-Ecole Polytechnique de l'Université de Nantes (EPUN), Université de Nantes (UN)-Université de Nantes (UN)-Institut de Chimie du CNRS (INC)-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), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), and Université Paris Diderot - Paris 7 (UPD7)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
DNA damage, Rebeccamycin, Stereochemistry, Carbazoles, Antineoplastic Agents, Topoisomerase-I Inhibitor, Indolocarbazole, 03 medical and health sciences, chemistry.chemical_compound, Mice, Structure-Activity Relationship, 0302 clinical medicine, medicine, Structure–activity relationship, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, CHEK1, DNA Cleavage, Protein Kinase Inhibitors, 030304 developmental biology, Cell Proliferation, Pharmacology, 0303 health sciences, biology, Topoisomerase, DNA, 3. Good health, chemistry, Biochemistry, 030220 oncology & carcinogenesis, Checkpoint Kinase 1, biology.protein, Molecular Medicine, Drug Screening Assays, Antitumor, Topoisomerase I Inhibitors, Protein Kinases, medicine.drug, DNA Damage
Abstract

Rebeccamycin is an indolocarbazole class inhibitor of topoisomerase I. In the course of structure-activity relationship studies on rebeccamycin derivatives, we have synthesized analogues with the sugar moiety attached to either one or both indole nitrogens. Some analogues, especially those with substitutions at the 6' position of the carbohydrate moiety exhibit potent inhibitory activity toward Checkpoint kinase 1 (Chk1), a kinase that has a major role in the G2/M checkpoint in response to DNA damage. Some of these compounds retained a genotoxic activity either through intercalation into the DNA and/or by topoisomerase I-mediated DNA cleavage. We explored the structure-activity relationship between these compounds and their multiple targets. These rebeccamycin derivatives represent a novel class of potential antitumor agents that have a dual effect and might selectively induce the death of cancer cells.

Published
2008

17. Analysis of cyclin B1 and CDK activity during apoptosis induced by camptothecin treatment

Author

M. Mahé, S. Léonce, Aurélie Studeny, John A. Hickman, Laurent Meijer, Isabelle Naime, R. M. Golsteyn, I. Versteege, A. Borgne, M. Magdalena Rodriguez, Pigments R&D, Merck & Co. Inc, Institut de Recherches Servier, Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, Division Recherche et Cancérologie, Centre de Recherche de Croissy, Institut de Recherche Servier, Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Analyse et de Mathématiques Appliquées (LAMA), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Fédération de Recherche Bézout-Université Paris-Est Marne-la-Vallée (UPEM), Biomécanique et génie biomédical (BIM), Centre National de la Recherche Scientifique (CNRS), Departamen to de Quimica, Centro de Investigacio´n y de Estudios Avanzados del IPN, Departament de Quimica, Universitat de Girona, Universitat de Girona (UdG), Laboratoire de Génie Electrique de Grenoble (G2ELab), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS), Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), SERVIER, Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Est Marne-la-Vallée (UPEM)-Fédération de Recherche Bézout-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), and Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cancer Research, Cyclin E, Cyclin D, Cyclin A, MESH: HT29 Cells, Cyclin B, Fluorescent Antibody Technique, Apoptosis, MESH: Cell Cycle, MESH: Base Sequence, 0302 clinical medicine, MESH: Fluorescent Antibody Technique, 0303 health sciences, biology, Cell Cycle, Cyclin-Dependent Kinases, 3. Good health, Cell biology, MESH: Cyclin-Dependent Kinases, 030220 oncology & carcinogenesis, MESH: Camptothecin, Electrophoresis, Polyacrylamide Gel, RNA Interference, HT29 Cells, MESH: DNA Primers, MESH: Antineoplastic Agents, Phytogenic, MESH: RNA Interference, CDK-activating kinase, 03 medical and health sciences, Cyclin-dependent kinase, Genetics, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cyclin B1, Molecular Biology, 030304 developmental biology, DNA Primers, MESH: Humans, Base Sequence, MESH: Apoptosis, MESH: Cyclin A, MESH: Cyclin B, Antineoplastic Agents, Phytogenic, MESH: Cyclin E, Cyclin E1, biology.protein, Camptothecin, Cyclin A2, MESH: Electrophoresis, Polyacrylamide Gel
Abstract

We have studied the role of cyclins and cyclin-dependent kinase (CDK) activity in apoptosis induced by camptothecin (CPT). In this model, 22% of the cells stain for annexin-V at 24 h and then proceed to be 93% positive by 72 h. This time window permits the analysis of cyclins in cells that are committed to apoptosis but not yet dead. We provide evidence that cyclin protein levels and then associated kinase levels increase after CPT treatment. Strikingly, cyclin B1 and cyclin E1 proteins are present at the same time in CPT treated HT29 cells. Although cyclin B1 and E1 CDK complexes are activated in CPT treated cells, only the cyclin B1 complex is required for apoptosis since reduction of cyclin B1 by RNAi or roscovitine treatment reduces the number of annexin-V-stained cells. We have detected poorly organized chromosomes and phosphorylated histone H3 epitopes at the time of maximum cyclin B1/CDK kinase activity in CPT-treated cells, which suggests that these cells enter a mitotic catastrophe. Understanding which CDKs are required for apoptosis may allow us to better adapt CDK inhibitors for use as anti-cancer compounds.

Published
2006

18. Structure−Activity Relationships of a Novel Series of Urotensin II Analogues: Identification of a Urotensin II Antagonist

Author

Cédric Boularan, Christophe Dubessy, Bruno Pfeiffer, Hubert Vaudry, Pierre Pacaud, Isabelle Lihrmann, David Chatenet, Elizabeth Scalbert, Marie-Christine Tonon, Pierre Renard, Jérôme Leprince, Institut Armand Frappier (INRS-IAF), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, Les Laboratoires SERVIER, Institut de Recherche Servier, Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroendocrinologie cellulaire et moléculaire, and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Rats, Stereochemistry, Urotensins, Vasodilator Agents, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Cricetinae, Peptide, CHO Cells, MESH: Receptors, G-Protein-Coupled, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, In Vitro Techniques, MESH: Radioligand Assay, Receptors, G-Protein-Coupled, Radioligand Assay, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, Cricetulus, 0302 clinical medicine, MESH: Structure-Activity Relationship, MESH: Cricetulus, MESH: CHO Cells, Cricetinae, Drug Discovery, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Animals, Humans, Structure–activity relationship, MESH: Animals, Receptor, MESH: Peptide Fragments, 030304 developmental biology, chemistry.chemical_classification, MESH: In Vitro Techniques, 0303 health sciences, MESH: Humans, MESH: Urotensins, Rational design, Antagonist, Biological activity, Peptide Fragments, Cyclic peptide, Rats, MESH: Vasodilator Agents, chemistry, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Molecular Medicine, Urotensin-II, 030217 neurology & neurosurgery
Abstract

International audience; Urotensin II (U-II) is a potent vasoconstrictor peptide which has been identified as the endogenous ligand for the orphan G protein-coupled receptor GPR14 now renamed UT receptor. As the C-terminal cyclic hexapeptide of U-II (U-II(4-11), H-Asp-Cys-Phe-Trp-Lys-Tyr-Cys-Val-OH) possesses full biological activity, we have synthesized a series of U-II(4-11) analogues and measured their binding affinity on hGPR14-transfected CHO cells and their contractile activity on de-endothelialized rat aortic rings. The data indicate that a free amino group and a functionalized side-chain at the N-terminal extremity of the peptide are not required for biological activity. In addition, the minimal chemical requirement at position 9 of U-II(4-11) is the presence of an aromatic moiety. Most importantly, replacement of the Phe6 residue by cyclohexyl-Ala (Cha) led to an analogue, [Cha6]U-II(4-11), that was devoid of agonistic activity but was able to dose-dependently suppress the vasoconstrictor effect of U-II on rat aortic rings. These new pharmacological data, by providing further information regarding the structure-activity relationships of U-II analogues, should prove useful for the rational design of potent and nonpeptidic UT receptor agonists and antagonists.

Published
2006

19. Structure-activity relationships and structural conformation of a novel urotensin II-related peptide. Peptides 2004. Proceedings of the 3rd International and 28th European Symposium, pp 804-805

Author

Chatenet, David, Leprince, Jérôme, Dubessy, Christophe, Carlier, Ludovic, Boularan, Cedric, Milazzo-Segalas, Isabelle, Guilhaudis, Laure, Oulyadi, Hassan, Davoust, Daniel, Scalbert, Elisabeth, Pfeiffer, Bruno, Renard, Pierre, Pacaud, Pierre, Lihrmann, Isabelle, Tonon, Marie Christine, Vaudry, Hubert, Institut Armand Frappier (INRS-IAF), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Différenciation et communication neuronale et neuroendocrine (DC2N), Equipe de Chimie Organique et Biologie Structurale (ECOBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU), Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, Les Laboratoires SERVIER, Institut de Recherche Servier, Physiopathologie et pharmacologie cellulaires et moléculaires, and Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2005

20. Structure–activity relationships and structural conformation of a novel urotensin II-related peptide

Author

Hassan Oulyadi, Cédric Boularan, Pierre Renard, Pierre Pacaud, Isabelle Ségalas-Milazzo, Laure Guilhaudis, Isabelle Lihrmann, David Chatenet, Jérôme Leprince, Christophe Dubessy, Bruno Pfeiffer, Hubert Vaudry, Daniel Davoust, Ludovic Carlier, Elizabeth Scalbert, Marie-Christine Tonon, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroendocrinologie cellulaire et moléculaire, Université de Nantes (UN), Université de Picardie Jules Verne (UPJV), Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Equipe de Chimie Organique et Biologie Structurale (ECOBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU), Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, Les Laboratoires SERVIER, Institut de Recherche Servier, Institut du thorax, and Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Models, Molecular, Protein Conformation, Physiology, Stereochemistry, Peptide Hormones, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Molecular Sequence Data, Peptide, MESH: Amino Acid Sequence, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Urotensin-II receptor, Biochemistry, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, MESH: Protein Conformation, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Animals, Humans, MESH: Animals, Amino Acid Sequence, Receptor, MESH: Peptide Fragments, MESH: Organ Specificity, 030304 developmental biology, chemistry.chemical_classification, Alanine, 0303 health sciences, MESH: Humans, MESH: Molecular Sequence Data, Intracellular Signaling Peptides and Proteins, Rational design, Antagonist, Biological activity, Peptide Fragments, 3. Good health, chemistry, Organ Specificity, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, MESH: Peptide Hormones, Urotensin-II, 030217 neurology & neurosurgery, MESH: Models, Molecular
Abstract

Urotensin II (UII) has been described as the most potent vasoconstrictor peptide and recognized as the endogenous ligand of the orphan G protein-coupled receptor GPR14. Recently, a UII-related peptide (URP) has been isolated from the rat brain and its sequence has been established as H-Ala- Cys-Phe-Trp-Lys-Tyr-Cys- Val-OH. In order to study the structure–function relationships of URP, we have synthesized a series of URP analogs and measured their binding affinity on h GPR14-transfected cells and their contractile activity in a rat aortic ring bioassay. Alanine substitution of each residue of URP significantly reduced the binding affinity and the contractile activity of the peptides, except for the Ala 8 -substituted analog that retained biological activity. Most importantly, d -scan of URP revealed that [ d -Trp 4 ]URP abrogated and [ d -Tyr 6 ]URP partially suppressed the UII-evoked contractile response. [Orn 5 ]URP, which had very low agonistic efficacy, was the most potent antagonist in this series. The solution structure of URP has been determined by 1 H NMR spectroscopy and molecular dynamics. URP exhibited a single conformation characterized by an inverse γ-turn comprising residues Trp-Lys-Tyr which plays a crucial role in the biological activity of URP. These pharmacological and structural data should prove useful for the rational design of non-peptide ligands as potential GPR14 agonists and antagonists.

Published
2004

21. Nouveaux dérivés de [3,4-a:3,4-c]carbazole, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent

Author

Prudhomme, Michelle, Hugon, Bernadette, Anizon, Fabrice, Hickman, John, Pierré, Alain, Renard, Pierre, Pfeiffer, Bruno, Synthèse et étude de systèmes à intêret biologique (SEESIB), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Division Recherche et Cancérologie, Institut de Recherches Servier, Les Laboratoires SERVIER, Institut de Recherche Servier, Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, and Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Published
2002

22. Nouveaux dérivés de [3,4-c]carbazole et de pyrido[2,3-b]pyrrolo[3,4-e]indole, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent

Author

Prudhomme, Michelle, Hugon, Bernadette, Anizon, Fabrice, Hickman, John, Pierré, Alain, Renard, Pierre, Pfeiffer, Bruno, Synthèse et étude de systèmes à intêret biologique (SEESIB), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Division Recherche et Cancérologie, Institut de Recherches Servier, Les Laboratoires SERVIER, Institut de Recherche Servier, Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, and Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)

Published
2002

23. Structure-activity relationship of human urotensin II. Peptides 2002, Proceedings of the 27th European Peptide Symposium, pp176-177

Author

Labarrère, Patricia, Chatenet, David, Marionneau, Clémence, Leprince, Jérôme, Scalbert, Elisabeth, Chavanieu, Alain, Pfeiffer, Bruno, Renard, Pierre, Pacaud, Pierre, Vaudry, Hubert, Calas, Bernard, Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP 23), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, Les Laboratoires SERVIER, Institut de Recherche Servier, Institut du thorax, and Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2002

24. Nouveaux dérivés d'hydroxyalkyle indolocarbazole, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent

Author

Prudhomme, Michelle, Marminon, Christelle, Moreau, Pascale, Hickman, John, Pierré, Alain, Pfeiffer, Bruno, Renard, Pierre, G. Bizot-Espiart, J., Synthèse et étude de systèmes à intêret biologique (SEESIB), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Division Recherche et Cancérologie, Institut de Recherches Servier, Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, Les Laboratoires SERVIER, Institut de Recherche Servier, and Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Published
2001

25. Nouveaux dérivés de pyrido-pyrido-pyrrolo[3,2-g]pyrrolo[3,4-e]-indole et pyrido-pyrrolo[2,3-a]pyrrolo[3,4-c]carbazole, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent

Author

Prudhomme, Michelle, Marminon, Christelle, Routier, S., Coudert, G., Merour, J.-Y., Hickman, John, Pierré, Alain, Renard, Pierre, Pfeiffer, Bruno, Synthèse et étude de systèmes à intêret biologique (SEESIB), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Division Recherche et Cancérologie, Institut de Recherches Servier, Les Laboratoires SERVIER, Institut de Recherche Servier, Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, and Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)

Published
2001

26. Synthesis and in Vitro Evaluation of New 8-Amino-1,4-benzoxazine Derivatives as Neuroprotective Antioxidants

Author

Lockhart Brian, Maurice-Bernard Fleury, Bruno Pfeiffer, Martine Largeron, Cibles Thérapeutiques et conception de médicaments (CiTCoM - UMR 8038), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Institut de Recherches Servier, Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, and Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Antioxidant, Stereochemistry, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Substituent, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 010402 general chemistry, medicine.disease_cause, Hippocampus, 01 natural sciences, Neuroprotection, Chemical synthesis, Antioxidants, Cell Line, Benzophenones, Mice, Structure-Activity Relationship, chemistry.chemical_compound, Oxazines, Drug Discovery, medicine, Animals, Structure–activity relationship, [CHIM]Chemical Sciences, Spiro Compounds, Cytotoxicity, ComputingMilieux_MISCELLANEOUS, Neurons, Psychotropic Drugs, Cell Death, Molecular Structure, 010405 organic chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, In vitro, Benzoxazines, 0104 chemical sciences, 3. Good health, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, Oxidative Stress, Neuroprotective Agents, Biochemistry, chemistry, Nerve Degeneration, Molecular Medicine, Oxidative stress
Abstract

A series of new 8-amino-1,4-benzoxazine derivatives 5a-o was synthesized and examined for their intrinsic cytotoxicity and their capacity to inhibit oxidative stress-mediated neuronal degeneration in neuronal cell cultures. In particular, substituent effects at the 3- and 8-positions of the 1,4-benzoxazine ring were investigated by in vitro evaluation. In this aim, 3-alkyl substituents seemed to be essential for efficient neuroprotective activity. Furthermore, within the subseries of substituted 3-alkyl benzoxazines, the most active derivatives were those bearing an 8-benzylamino substituent. From the combined results of both toxicity and neuroprotection expressed in terms of the safety index, 8-benzylamino-substituted-3-alkyl-1,4-benzoxazines were identified as the most promising compounds, owing to their potent neuroprotective activity without the manifestation of intrinsic cytotoxicity.

Published
1999

27. Synthesis of novel orthoalkylaminophenol derivatives as potent neuroprotective agents in vitro

Author

Lockhart Brian, Anne Neudorffer, Martine Largeron, Maurice-Bernard Fleury, Bruno Pfeiffer, Ronan Larget, Institut de Recherches Servier, Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, Cibles Thérapeutiques et conception de médicaments (CiTCoM - UMR 8038), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)

Subjects
Antioxidant, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Pharmaceutical Science, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 010402 general chemistry, Aminophenols, 01 natural sciences, Biochemistry, Chemical synthesis, Neuroprotection, Hippocampus, Antioxidants, Cell Line, Mice, Drug Discovery, medicine, Animals, Vitamin E, [CHIM]Chemical Sciences, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 010405 organic chemistry, Chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, In vitro, 0104 chemical sciences, 3. Good health, Neuroprotective Agents, Cell culture, Molecular Medicine
Abstract

A series of orthoalkylaminophenol derivatives was synthesized and tested in vitro with respect to their neuroprotective effect. Some of these compounds exhibited a potent antioxidant activity close to that of standard alpha-tocopherol.

Published
1999

28. Design and synthesis of imidazoline derivatives active on glucose homeostasis in a rat model of type II diabetes. 1. Synthesis and biological activities of N-benzyl-N'-(arylalkyl)-2-(4',5'-dihydro-1'H-imidazol-2'-yl)piperazines

Author

Jean Jacques Godfroid, P. Renard, E. Touboul, Bruno Pfeiffer, G. Le Bihan, B. Guardiola-Lemaitre, Luc Pénicaud, T. Bellahsene, Xuan Wang, Georges Dive, D. Manechez, Alain Ktorza, A. Lamouri, Frédéric Rondu, CAN-FOR, National Institute of Advanced Science and Technology, Centre d'Ingénierie des Protéines, Université de Liège, Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, Métabolisme Plasticité et Mitochondrie [lié à l'ex IFR 31] (LMPM), IFR 31 Louis Bugnard (IFR 31), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de physiopathologie de la nutrition (LPN), and Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Blood Glucose, Male, Models, Molecular, medicine.medical_specialty, Adrenergic receptor, Imidazoline receptor, 010402 general chemistry, 01 natural sciences, Chemical synthesis, Piperazines, Receptors, Adrenergic, alpha-2, In vivo, Internal medicine, Diabetes mellitus, Drug Discovery, medicine, Animals, Homeostasis, Glucose homeostasis, Rats, Wistar, B cell, ComputingMilieux_MISCELLANEOUS, 010405 organic chemistry, Chemistry, Imidazoles, Glucose Tolerance Test, Streptozotocin, medicine.disease, Rats, 0104 chemical sciences, 3. Good health, Disease Models, Animal, medicine.anatomical_structure, Endocrinology, Diabetes Mellitus, Type 2, Drug Design, Molecular Medicine, Cattle, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, medicine.drug
Abstract

The physiopathology of non-insulin-dependent diabetes mellitus is associated with a dysfunction in the regulation of insulin secretion. The alpha 2-adrenoceptors have been reported to be involved in this alteration, although alpha 2-antagonists containing an imidazoline ring may stimulate insulin secretion independently of alpha 2-adrenoceptor blockage. Recently, a new "imidazoline-binding site" involved in the control of K(+)-ATP channels in the B cell has been proposed. In the course of searching for new antidiabetic agents, 1-alkyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)-4-benzylpiperazines, 1-benzyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)-4-alkylpiperazines, and 1-benzyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)-4-benzylpiperazines have been designed and evaluated as potential adrenoceptor antagonists. Pharmacological evaluation was performed in vivo using glucose tolerance tests performed on a rat model of type II diabetes obtained by injection of a low dose (35 mg/kg) of streptozotocin (STZ). For some compounds, binding experiments were performed on alpha 2 adrenoceptors and I1 and I2 imidazoline-binding sites. The biological and physicochemical data have been combined with molecular modeling studies to establish structure-activity relationships. The most active compound was 1-(2',4'-dichlorobenzyl)-2-(4',5'-dihydro-1'H-imidazol-2'-yl)- 4-methylpiperazine (7f); intraperitoneal administration (100 mumol/kg) of 7f strongly improved glucose tolerance in STZ diabetic rats. This effect seemed at least partly mediated by a significant increase of insulin secretion. Other compounds of the same family (7b, 16f, 23b) have also shown potent activity. We found no correlation between in vivo antihyperglycemic properties and in vitro affinities for alpha 2-adrenoceptors or I1, and I2 binding sites. These compounds can be considered as antihyperglycemic agents potentially useful for treatment of type II diabetes and are currently under complementary investigation.

Published
1997

29. Effect of S-21663 (PMS 812), an imidazoline derivative, on glucose tolerance and insulin secretion in a rat model of type II diabetes

Author

Wang, X., Rondu, F., Lamouri, A., Dokhan, R., Marc, S., Touboul, E., Pfeiffer, B., Manechez, D., Renard, P., Guardiola-Lemaitre, B., Godfroid, J. J., Ktorza, Alain, Pénicaud, Luc, CAN-FOR, National Institute of Advanced Science and Technology, Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, Laboratoire de physiopathologie de la nutrition (LPN), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), 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), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut de recherches Servier ( INSTITUT DE RECHERCHES SERVIER ), Laboratoire de physiopathologie de la nutrition ( LPN ), Université Paris Diderot - Paris 7 ( UPD7 ) -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 ), and Delon, Viviane

Subjects
Male, Dose-Response Relationship, Drug, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, Imidazoles, Glucose Tolerance Test, Diabetes Mellitus, Experimental, Rats, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Disease Models, Animal, Animals, Insulin, Rats, Wistar, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, ComputingMilieux_MISCELLANEOUS
Abstract

International audience; We have studied the activity of S-21663 (PMS 812), a new imidazoline derivative, in a rat model of Type II diabetes obtained by i.v. injection of a low dose (35 mg/kg) of streptozotocin, using glucose tolerance tests. Glucose tolerance and insulin secretion were measured as the delta G and the delta l, i.e., the respective increase in glycemia and insulinemia over 30 min after the glucose load. The rate of glucose disappearance was calculated as the K coefficient and the insulin response to glucose as the delta l/delta G. After i.p. injection of S-21663, delta G (millimoles per liter per minute) was decreased (71.7 +/- 10.1 vs. 112.6 +/- 15.1; P < .05), whereas K was increased (3.3 +/- 0.3 vs. 1.5 +/- 0.1; P < .05). Insulin secretion was also largely improved (delta l/delta G: 90.9 +/- 22.2 vs. 18.3 +/- 2.6; P < .05). Oral administration of the product was almost as efficient as i.p. injection. Chronic treatment (15 days) increased the efficiency. Insulin secretion measured in vitro at both 2.8 and 16.6 mM glucose was quadrupled by S-21663 (100 microM). S-21663 binds neither to alpha-2 adrenoceptors nor to known imidazoline binding sites. S-21663 can be considered as a potential hypoglycemic agent in Type II diabetes.

Published
1996

31. [Cardiovascular risk factors in type 2 diabetes].

Author

Lesobre B

Subjects
Diabetes Mellitus, Type 2 blood, Female, Humans, Hyperglycemia complications, Hyperglycemia physiopathology, Insulin blood, Male, Risk Factors, Cardiovascular Diseases etiology, Diabetes Mellitus, Type 2 complications, Diabetic Angiopathies etiology
Abstract

Morbidity and mortality through coronary atherosclerosis are higher in Type 2 diabetic patients than in nondiabetic subjects, roughly by a factor of 2 in males and 3 in females. Methodological problems in attempting to weigh the relative effects of each factor make it difficult to accurately interpret the numerous epidemiological data already available. Three issues are discussed here:--Do diabetics have more "classic" risk factors than nondiabetics? The incidence of hypertension, lipid disorders, and even smoking is practically consistently higher in diabetics, with "diabetic" lipid disorders (decreased HDL cholesterol and hypertriglyceridemia) topping the list.--Do diabetics have specific risk factors which could explain the observed increase in coronary morbidity and mortality? The answer would appear to be yes, as patent microalbuminuria--between 30 and 300 mg/24 hours--is found, as well as retinopathy and an increase in fibrinogen and PAI1 plasminogen activator inhibitor. Recent genetic studies have highlighted the role of Lp (a), and particularly that of angiotensin converting-enzyme gene polymorphism (DD allele).--What are the respective roles of hyperglycalmia and elevated levels of circulating insulin? In contrast to the importance of insulin in nondiabetics as demonstrated in longitudinal studies, insulin appears to play a marginal or even nil role in diabetics once the disease is established. It is probably glycaemia itself which remains the fundamental factor, even though the mechanisms leading from hyperglycemia to macrovascular complications remain unknown.

Published
1994

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