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11 results on '"Theraptosis S.A."'

1. Consistent Osteoblastic Differentiation of Human Mesenchymal Stem Cells with Bone Morphogenetic Protein 4 and Low Serum

Author

Luc Sensebé, Frédéric Deschaseaux, Pierre Layrolle, Alain Langonné, Jérôme Sohier, Philippe Rosset, Thomas Cordonnier, Micro et Nanomédecines Biomimétiques, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Theraptosis Research Laboratory, Theraptosis S.A., Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe de recherche clinique en Odontologie (ERT1051), Université de Nantes (UN), Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes] (INSERM U1238), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Etablissement Français du Sang Centre-Atlantique (EA3855), EFS, Micro et Nanomédecines Biomimétiques (MINT), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université Bretagne Loire (UBL)

Subjects
Adult, Serum, Ceramics, Biomedical Engineering, Medicine (miscellaneous), Bioengineering, Bone Morphogenetic Protein 4, Bone morphogenetic protein, Regenerative medicine, 03 medical and health sciences, Mice, 0302 clinical medicine, Osteogenesis, medicine, Animals, Humans, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Aged, Cell Proliferation, Aged, 80 and over, 0303 health sciences, Osteoblasts, Tissue Scaffolds, Chemistry, Gene Expression Profiling, Mesenchymal stem cell, Cell Differentiation, Mesenchymal Stem Cells, Middle Aged, Alkaline Phosphatase, Flow Cytometry, In vitro, 3. Good health, Cell biology, Bone morphogenetic protein 7, Bone morphogenetic protein 6, medicine.anatomical_structure, Bone morphogenetic protein 4, Gene Expression Regulation, 030220 oncology & carcinogenesis, Immunology, Bone marrow
Abstract

Providing fully mature and functional osteoblasts is challenging for bone tissue engineering and regenerative medicine. Such cells could be obtained from multipotent bone marrow mesenchymal stem cells (MSCs) after induction by different osteogenic factors. However, there are some discrepancies in results, notably due to the use of sera and to the type of osteogenic factor. In this study, we compared the osteogenic differentiation of bone marrow MSCs induced by dexamethasone (Dex) or bone morphogenetic proteins (BMPs) by assessing phenotypes in vitro and functional osteoblasts in vivo. Reducing the content of fetal calf serum from 10% to 2% significantly increased the mineral deposition and expression of osteoblastic markers during osteogenesis. In comparison to Dex condition, the addition of BMP4 greatly improved the differentiation of MSCs into fully mature osteoblasts as seen by high expression of Osterix. These results were confirmed in different supportive matrixes, plastic flasks, or biphasic calcium phosphate biomaterials. In contrast to Dex-derived osteoblasts, BMP4-derived osteoblasts from MSCs were significantly able to produce new bone in subcutis of nude mice in accordance with in vitro results. In conclusion, we describe a convenient ex vivo method to produce consistently mature functional osteoblasts from human MSCs with use of BMP4 and low serum.

Published
2011
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2. Targeting neonatal ischemic brain injury with a pentapeptide-based irreversible caspase inhibitor

Author

G Debret, Alain Lacampagne, Catherine I. Rousset, Pierre Gressens, S Holifanjaniaina, R Casimir, Etienne Jacotot, Xinhua Wang, M Bezault, D. Chauvier, J-M Rauzier, Jean Mariani, M Smirnova, Henrik Hagberg, Sylvain Renolleau, Leslie Schwendimann, Stefan Matecki, Ylva Carlsson, Christiane Charriaut-Marlangue, Eric Bernard, P Rustin, A-P Trichet, M Hébert, Johan Hoebeke, S Ankri, Theraptosis S.A., Neurobiologie des processus adaptatifs (NPA), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Service de réanimation néonatale et pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP]-Sorbonne Université (SU), Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Centre for the developing brain, Imperial College London, Department of Physiology, University of Gothenburg (GU), Immunologie et chimie thérapeutiques (ICT), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique Théorique de la Matière Condensée (LPTMC), Department of Obstetrics & Gynaecology, Sahlgrenska University Hospital, Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Charles Foix (UEF), Hôpital Charles Foix Ivry/Seine, French Ministry of Research, Inserm, Foundation Grace de Monaco, ANVAR, MRC, Univesity Pari s7, Premup, Medical Research Council UK, MRC Sweden, ALF-LUA, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sahlgrenska University Hospital [Gothenburg], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Charles Foix [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Cancer Research, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Immunology, Excitotoxicity, Ischemia, Apoptosis, ischemia, Pharmacology, Cysteine Proteinase Inhibitors, medicine.disease_cause, Pentapeptide repeat, Neuroprotection, 03 medical and health sciences, Cellular and Molecular Neuroscience, Mice, 0302 clinical medicine, In vivo, medicine, Animals, Caspase, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Binding Sites, biology, Safety pharmacology, Cytochromes c, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, medicine.disease, Caspase Inhibitors, caspase inhibitor, 3. Good health, Rats, perinatal brain damage, Disease Models, Animal, Neuroprotective Agents, Animals, Newborn, Caspases, Hypoxia-Ischemia, Brain, biology.protein, Quinolines, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Original Article, neuroprotection, Oligopeptides, 030217 neurology & neurosurgery
Abstract

International audience; Brain protection of the newborn remains a challenging priority and represents a totally unmet medical need. Pharmacological inhibition of caspases appears as a promising strategy for neuroprotection. In a translational perspective, we have developed a pentapeptide-based group II caspase inhibitor, TRP601/ORPHA133563, which reaches the brain, and inhibits caspases activation, mitochondrial release of cytochrome c, and apoptosis in vivo. Single administration of TRP601 protects newborn rodent brain against excitotoxicity, hypoxia–ischemia, and perinatal arterial stroke with a 6-h therapeutic time window, and has no adverse effects on physiological parameters. Safety pharmacology investigations, and toxicology studies in rodent and canine neonates, suggest that TRP601 is a lead compound for further drug development to treat ischemic brain damage in human newborns.

Published
2011

3. 3D environment on human mesenchymal stem cells differentiation for bone tissue engineering

Author

Jérôme Sohier, Pierre Layrolle, Thomas Cordonnier, Luc Sensebé, Julien Gaillard, Philippe Rosset, Alain Langonné, Ecosystèmes montagnards (UR EMGR), Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Models for the performance analysis and the control of networks (MAESTRO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Theraptosis Research Laboratory, Theraptosis S.A., Etablissement Français du Sang Centre-Atlantique (EA3855), EFS, Université de Nantes - UFR Odontologie, Université de Nantes (UN), Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Université de Nantes - UFR Odontologie (UFR Odonto), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), STROMALab, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS)

Subjects
Calcium Phosphates, Bone sialoprotein, Sialoglycoproteins, Cellular differentiation, Biomedical Engineering, Biophysics, Bone Morphogenetic Protein 2, Bioengineering, Bone and Bones, Biomaterials, Extracellular matrix, 03 medical and health sciences, Imaging, Three-Dimensional, 0302 clinical medicine, Tissue engineering, Integrin-Binding Sialoprotein, Humans, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, 030304 developmental biology, 0303 health sciences, Osteoblasts, Tissue Engineering, biology, Reverse Transcriptase Polymerase Chain Reaction, Mesenchymal stem cell, Biomaterial, Cell Differentiation, Mesenchymal Stem Cells, Alkaline Phosphatase, Cell biology, Durapatite, biology.protein, Polystyrenes, Stem cell, 030217 neurology & neurosurgery, Biomedical engineering
Abstract

In this work a novel method was developed to create a three dimensional environment at a cellular level for bone tissue engineering. Biphasic calcium phosphate (BCP) particles of 140-200 microm were used in association with human mesenchymal stem cells (hMSCs). The cells seeded on these particles adhered and proliferated more rapidly in the first day of culture compared to culture on plastic. Analyses of hMSCs cultured without osteogenic factors on BCP particles revealed an abundant extracellular matrix production forming 3-dimensional (3D) hMSCs/BCP particles constructs after few days. Bone morphogenetic 2 (BMP-2), bone sialoprotein (BSP) and ALP gene expression using real time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) confirmed that expression profiles were modified by the culture substrate while the addition of osteogenic medium enhanced bone markers expression. These results indicate that BCP particles alone are able to induce an osteoblastic differentiation of hMSCs that might be of interest for bone tissue engineering.

Published
2010

4. A flavivirus protein M-derived peptide directly permeabilizes mitochondrial membranes, triggers cell death and reduces human tumor growth in nude mice

Author

Dominique Rebouillat, Olivier Chaloin, Nelly Buron, Sylviane Muller, Magali Brabant, Sylvie Dupont, Alain Langonne, Jean Paul Briand, David Chauvier, Catherine Brenner, Hervé Lecoeur, Myriam Lassalle, Mathieu Porceddu, Olivier Deas, Richard Casimir, Annie Borgne-Sanchez, Etienne Jacotot, Ludwig Baux, Theraptosis Research Laboratory, Theraptosis S.A., Immunologie et chimie thérapeutiques (ICT), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS), Department of Reproductive Biology, and Imperial College London

Subjects
Cancer Research, Programmed cell death, Amino Acid Motifs, Molecular Sequence Data, Clinical Biochemistry, Cell, Mice, Nude, Pharmaceutical Science, Peptide, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, Mitochondrion, Permeability, Mice, Viral Proteins, 03 medical and health sciences, Transduction (genetics), 0302 clinical medicine, Cell Line, Tumor, medicine, Animals, Humans, Amino Acid Sequence, Cell Proliferation, 030304 developmental biology, Membrane Potential, Mitochondrial, Pharmacology, chemistry.chemical_classification, 0303 health sciences, Cell Death, Flavivirus, Biochemistry (medical), Cell Biology, Survival Analysis, Xenograft Model Antitumor Assays, Molecular biology, Mitochondria, Protein Structure, Tertiary, 3. Good health, Protein M, medicine.anatomical_structure, Ectodomain, chemistry, Apoptosis, 030220 oncology & carcinogenesis, Mitochondrial Membranes, tat Gene Products, Human Immunodeficiency Virus, Mitochondrial Swelling, Peptides
Abstract

International audience; Dengue viruses belong to the Flavivirus family and are responsible for hemorrhagic fever in Human. Dengue virus infection triggers apoptosis especially through the expression of the small membrane (M) protein. Using isolated mitochondria, we found that synthetic peptides containing the C-terminus part of the M ectodomain caused apoptosis-related mitochondrial membrane permeabilization (MMP) events. These events include matrix swelling and the dissipation of the mitochondrial transmembrane potential (DeltaPsi(m)). Protein M Flavivirus sequence alignments and helical wheel projections reveal a conserved distribution of charged residues. Moreover, when combined to the cell penetrating HIV-1 Tat peptide transduction domain (Tat-PTD), this sequence triggers a caspase-dependent cell death associated with DeltaPsi(m) loss and cytochrome c release. Mutational approaches coupled to functional screening on isolated mitochondria resulted in the selection of a protein M derived sequence containing nine residues with potent MMP-inducing properties on isolated mitochondria. A chimeric peptide composed of a Tat-PTD linked to the 9-mer entity triggers MMP and cell death. Finally, local administration of this chimeric peptide induces growth inhibition of xenograft prostate PC3 tumors in immuno-compromised mice, and significantly enhances animal survival. Together, these findings support the notion of using viral genomes as valuable sources to discover mitochondria-targeted sequences that may lead to the development of new anticancer compounds.

Published
2009

5. Broad-spectrum caspase inhibitors: from myth to reality?

Author

Etienne Jacotot, D Chauvier, S Ankri, Christiane Charriaut-Marlangue, R Casimir, Theraptosis Research Laboratory, Theraptosis S.A., Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC) - Centre National de la Recherche Scientifique (CNRS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Hydrocarbons, Fluorinated, MESH: Benzyl Compounds, MESH: Neurons, Computational biology, Amino Acid Chloromethyl Ketones, Mice, 03 medical and health sciences, Broad spectrum, 0302 clinical medicine, Benzyl Compounds, Animals, Humans, MESH: Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Enzyme Inhibitors, Molecular Biology, MESH: Mice, 030304 developmental biology, Neurons, 0303 health sciences, Caspase inhibitors, MESH: Caspases, MESH: Humans, Chemistry, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, MESH: Amino Acid Chloromethyl Ketones, Cell Biology, Caspase Inhibitors, Cathepsins, MESH: Hydrocarbons, Fluorinated, MESH: Enzyme Inhibitors, MESH: Cathepsins, Quinolines, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030217 neurology & neurosurgery, MESH: Quinolines
Published
2007

6. Targeted Vpr-derived Peptides Reach Mitochondria to Induce Apoptosis of aVb3-Expressing Endothelial Cells

Author

Pierre Rustin, Etienne Jacotot, Dominique Rebouillat, J. Brière, Hervé Lecoeur, Déas O, Deniaud A, Myriam Lassalle, Johan Hoebeke, Lena Edelman, Christine Péchoux, D. Chauvier, Magali Brabant, Roux P, Brenner C, Dupont S, Baux L, Alain Langonne, J. P. Briand, A. Borgne-Sanchez, Laboratoire de génétique et biologie cellulaire (LGBC), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Theraptosis Research Laboratory, Theraptosis S.A., Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Dynamique (Plate-Forme) (PFID), Institut Pasteur [Paris], Unité de recherche génomique et physiologie de la lactation (GPL), Institut National de la Recherche Agronomique (INRA), Immunologie et chimie thérapeutiques (ICT), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS), 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), Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique et Physiologie de la Lactation (GPL), Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut Pasteur [Paris] (IP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-École Pratique des Hautes Études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)

Subjects
[SDV]Life Sciences [q-bio], Apoptosis, MESH: Amino Acid Sequence, Mitochondrion, APOPTOSE, Mitochondrial apoptosis-induced channel, MESH: Dose-Response Relationship, Drug, Mice, 0302 clinical medicine, MESH: Mitochondrial Membranes, ENDOTHELIAL CELLS, BIOLOGIE CELLULAIRE, MESH: Animals, MESH: Endothelial Cells, Peptide sequence, Inbred BALB C, 0303 health sciences, Mice, Inbred BALB C, biology, MESH: Peptides, Cytochrome c, Adenine nucleotide translocator, PEPTIDES, Cell biology, Mitochondria, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], MESH: Integrin alphaVbeta3, MESH: Cell Survival, 030220 oncology & carcinogenesis, MESH: Permeability, Mitochondrial Membranes, Mitochondrial fission, Drug, CELLULAR TRAFFICKING APOPTOSIS, Voltage-dependent anion channel, MESH: Gene Products, vpr, MESH: Mitochondria, Cell Survival, Integrin, Molecular Sequence Data, MESH: Mice, Inbred BALB C, PTP, Permeability, Dose-Response Relationship, 03 medical and health sciences, Gene Products, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [INFO]Computer Science [cs], Amino Acid Sequence, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: Molecular Sequence Data, MESH: Humans, Dose-Response Relationship, Drug, MESH: Apoptosis, Gene Products, vpr, vpr, Cell Biology, Integrin alphaVbeta3, biology.protein, Lysosomes, MESH: Lysosomes
Abstract

International audience; The HIV-1 encoded apoptogenic protein Vpr induces mitochondrial membrane permeabilization (MMP) via interactions with the voltage-dependent anion channel (VDAC) and the adenine nucleotide translocator (ANT). We have designed a peptide, TEAM-VP, composed of two functional domains, one a tumor blood vessel RGD-like 'homing' motif and the other an MMP-inducing sequence derived from Vpr. When added to isolated mitochondria, TEAM-VP interacts with ANT and VDAC, reduces oxygen consumption and overcomes Bcl-2 protection to cause inner and outer MMP. TEAM-VP specifically recognizes cell-surface expressed alpha(V)beta(3) integrins, internalizes, temporarily localizes to lysosomes and progressively co-distributes with the mitochondrial compartment with no sign of lysosomal membrane permeabilization. Finally TEAM-VP reaches mitochondria of angiogenic endothelial cells to induce mitochondrial fission, dissipation of the mitochondrial transmembrane potential (DeltaPsi(m)), cytochrome c release and apoptosis hallmarks. Hence, this chimeric peptide constitutes the first example of a virus-derived mitochondriotoxic compound as a candidate to kill selectively tumor neo-endothelia.

Published
2006

7. Peptido-targeting of the mitochondrial transition pore complex for therapeutic apoptosis induction

Author

Johan Hoebeke, Sylviane Muller, Catherine Brenner, Jean-Paul Briand, Aurélien Deniaud, Etienne Jacotot, Immunopathologie et immunointervention thérapeutique, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie et chimie thérapeutiques (ICT), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut de RadioAstronomie Millimétrique (IRAM), Centre National de la Recherche Scientifique (CNRS), Academia Sinica Institute of Astronomy and Astrophysics (ASIAA), Academia Sinica, Laboratoire Biodiversité et Fonctionnement des Ecosystèmes (LBFE), Université Paul Verlaine - Metz (UPVM), Laboratoire de Chimie et Applications (LCA), Theraptosis Research Laboratory, Theraptosis S.A., Laboratoire de génétique et biologie cellulaire (LGBC), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Université Pierre et Marie Curie - Paris 6 (UPMC) - IFR58 - Institut National de la Santé et de la Recherche Médicale (INSERM), Cancéropôle du Grand Est - Centre National de la Recherche Scientifique (CNRS), Institute of Astronomy and Astrophysics (ASIAA Sinica), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ) - École pratique des hautes études (EPHE) - Centre National de la Recherche Scientifique (CNRS), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)

Subjects
MESH: Signal Transduction, Pore complex, Aging, Apoptosis, Mitochondrion, Mitochondrial Membrane Transport Proteins, MESH: Neurodegenerative Diseases, 0302 clinical medicine, Drug Delivery Systems, Neoplasms, Drug Discovery, Homeostasis, MESH: Aging, MESH: Animals, MESH: Neoplasms, 0303 health sciences, MESH: Oxidative Stress, MESH: Peptides, Liver Diseases, Neurodegeneration, Neurodegenerative Diseases, MESH: Mitochondrial Membrane Transport Proteins, Cell biology, Mitochondria, MESH: Homeostasis, Reperfusion Injury, Intermembrane space, Signal Transduction, Programmed cell death, MESH: Liver Diseases, Stereochemistry, MESH: Mitochondria, MESH: Drug Delivery Systems, Biology, 03 medical and health sciences, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Pharmacology, MESH: Humans, Mitochondrial Permeability Transition Pore, MESH: Apoptosis, medicine.disease, Cytosol, Oxidative Stress, Mitochondrial permeability transition pore, MESH: Reperfusion Injury, Peptides, 030217 neurology & neurosurgery
Abstract

The permeability transition pore (PTPC), a polyprotein complex, participates in the mitochondrial homeostasis as well as in the mitochondrial phase of the intrinsic pathway of apoptosis. It integrates multiple death signals including alterations of the intracellular milieu, translocation of pro-apoptotic members of the Bax/Bcl-2 family, p53, and viral proteins. As a consequence, PTPC can act as a coordinator of the pro-apoptotic mitochondrial membrane permeabilization process and the release of pro-apoptotic intermembrane space proteins into the cytosol. Moreover, the deregulation of PTPC has been involved in several major human pathologies such as cancer, neurodegeneration, ischemia/reperfusion, aging, as well as hepatotoxicity. Therefore, PTPC has emerged as a promising potential therapeutic target. Here, we will review the current knowledge concerning the two opposite functions of the PTPC and its implication in various pathologies. We will discuss the possibility to target this complex with peptides to modulate apoptosis in an innovative therapeutic perspective.

Published
2006

8. Upstream control of apoptosis by caspase-2 in serum-deprived primary neurons

Author

Jean-Claude Martinou, Dominique Rebouillat, D. Chauvier, Jean Mariani, Etienne Jacotot, Hervé Lecoeur, Alain Langonne, A. Borgne-Sanchez, Theraptosis Research Laboratory, Theraptosis S.A., Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Department of Cell Biology, Sciences III, University of Geneva [Switzerland], Université Pierre et Marie Curie - Paris 6 (UPMC) - Centre National de la Recherche Scientifique (CNRS), and Université de Genève = University of Geneva (UNIGE)

Subjects
Serum, caspase-2, neuronal apoptosis, Cancer Research, Programmed cell death, Neurite, Cell Survival, Clinical Biochemistry, Caspase 2, Pharmaceutical Science, Apoptosis, Mitochondrion, serum deprivation, Models, Biological, Mice, 03 medical and health sciences, 0302 clinical medicine, checkpoint, Neurotrophic factors, Animals, Humans, Enzyme Inhibitors, Cells, Cultured, Caspase, bcl-2-Associated X Protein, 030304 developmental biology, Neurons, Pharmacology, 0303 health sciences, biology, Cytochrome c, Biochemistry (medical), Cytochromes c, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Cell Biology, Cell biology, Enzyme Activation, mitochondria, Protein Transport, Bax, biology.protein, RNA Interference, Peptides, [SDV.NEU.SC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, 030217 neurology & neurosurgery
Abstract

During development as well as in pathological situations, neurons that fail to find appropriate targets or neurotrophic factors undergo cell death. Using primary cortical neurons subjected to acute serum-deprivation (SD), we have examined caspases activation, mitochondrial dysfunction and cell death parameters. Among a panel of metabolic, signaling and caspases inhibitors only those able to interfere with caspase-2 like activity protect primary neurons against SD-induced cell death. In situ detection and subcellular fractionation demonstrate a very early activation of cytosolic caspase-2, which controls Bax cleavage, relocalization and mitochondrial membrane permeabilization (MMP). Both z-VDVAD-fmk and a siRNA specific for caspase-2 abolish Bax changes, mitochondrial membranes permeabilization, as well as cytochrome c release-dependent activation of caspase-9/caspase-3, nuclear alterations, phosphatidylserine exposure, neurites dismantling and neuronal death. Hence, caspase-2 is an early checkpoint for apoptosis initiation in primary neurons subjected to serum deprivation.

Published
2005

9. Dynamic analysis of apoptosis in primary cortical neurons by fixed- and real-time cytofluorometry

Author

Hervé Lecoeur, Jean Mariani, Alain Langonne, Etienne Jacotot, Dominique Rebouillat, Bernard Brugg, D. Chauvier, Lena Edelman, Theraptosis Research Laboratory, Theraptosis S.A., Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Technologie cellulaire anti-tumorale, Institut Pasteur [Paris] (IP), and Institut Pasteur [Paris]

Subjects
Cancer Research, cerebellum, Clinical Biochemistry, Pharmaceutical Science, Apoptosis, Mitochondrion, Flow cytometry, Membrane Potentials, cell counts, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, medicine, Fluorescence microscope, Animals, Caspase, 030304 developmental biology, Pharmacology, Membrane potential, Cerebral Cortex, Neurons, 0303 health sciences, biology, medicine.diagnostic_test, MPTP, naturally occurring cell death, Biochemistry (medical), [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Cell Biology, Flow Cytometry, Cell biology, Mitochondria, medicine.anatomical_structure, chemistry, biology.protein, Neuron, 030217 neurology & neurosurgery
Abstract

We describe here a cytofluorometric technology for the characterization of decision, execution, and degradation steps of neuronal apoptosis. Multiparametric flow cytometry was developped and combined to detailled fluorescence microscopy observations to establish the chronology and hierarchy of death-related events: neuron morphological changes, mitochondrial transmembrane potential (Δ Ψ m ) collapse, caspase-3 and -9 activation, phosphatidyl-serine exposure, nuclear dismantling and final plasma membrane permeabilization. Moreover, we developped a reliable real-time flow cytometric monitoring of Δ Ψ m and plasma membrane integrity in response to neurotoxic insults including MPTP treatment. Taking advantage of recently developped specific fluorescent probes and a third generation pan-caspase inhibitor, this integrated approach will be pertinent to study the cell biology of neuronal apoptosis and to characterize new neuro-toxic/protective molecules.

Published
2004

10. HIV-1 Tat protein directly induces mitochondrial membrane permeabilization and inactivates cytochrome c oxidase

Author

Olivier Chaloin, Etienne Daniel Francois Jacotot, Pierre Rustin, Mathieu Porceddu, Alain Langonne, Aurélien Deniaud, Magali Brabant, Catherine Brenner, Hervé Lecoeur, S. Muller, J-J Brière, J. P. Briand, Christine Péchoux, Nelly Buron, Dominique Rebouillat, Ralph El-Khoury, A. Borgne-Sanchez, Immunophysiologie et Parasitisme Intracellulaire, Institut Pasteur [Paris] (IP), Theraptosis S.A., Theraptosis SA, Mitologics SAS, Hôpital Robert Debré, Immunologie et chimie thérapeutiques (ICT), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS), Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-IFR2-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), Unité de recherche génomique et physiologie de la lactation (GPL), Institut National de la Recherche Agronomique (INRA), Laboratoire de génétique et biologie cellulaire (LGBC), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Signalisation et physiopathologie cardiaque, Université Paris-Sud - Paris 11 (UP11)-IFR141-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM UMR676, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Laboratoire de Biochimie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Department of Reproductive Biology, Imperial College London, French Ministry of Research, ANVAR, Sidaction, AFM, Ammi, CNRS, Inserm, CRITT Ile de France, Institut Pasteur [Paris], CNRS FRE 2445, Centre National de la Recherche Scientifique (CNRS), Génomique et Physiologie de la Lactation (GPL), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Pansiot, Sylvie, Laboratoire de génétique et biologie cellulaire, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Centre National de la Recherche Scientifique (CNRS), and Jacotot, E

Subjects
Cancer Research, Cytochrome, Virologie, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Mitochondrion, 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid, medicine.disease_cause, MESH: 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid, Oxidative Phosphorylation, chemistry.chemical_compound, Mice, 0302 clinical medicine, membrane mitochondriale, MESH: Mitochondrial Membranes, MESH: Membrane Potential, Mitochondrial, cytochrome c oxidase, MESH: Animals, Membrane Potential, Mitochondrial, 0303 health sciences, Mice, Inbred BALB C, cytochrome c oxydase, biology, Cytochrome c, microscopie électronique, Brain, Cytochromes c, MESH: Cytochromes c, 3. Good health, Mitochondria, protéine virale, HIV-1, Tat, mitochondria, Liver, Proto-Oncogene Proteins c-bcl-2, mitochondrie, DIDS, MESH: Permeability, Mitochondrial Membranes, Original Article, tat Gene Products, Human Immunodeficiency Virus, MESH: Myocardium, Viral protein, MESH: Mitochondria, Immunology, MESH: Mice, Inbred BALB C, polarographie, potentiel transmembranaire, Oxidative phosphorylation, spectrophotométrie, spectrofluorométrie, Permeability, Electron Transport Complex IV, 03 medical and health sciences, Cellular and Molecular Neuroscience, MESH: Brain, MESH: Electron Transport Complex IV, MESH: Oxidative Phosphorylation, Virology, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], medicine, Cytochrome c oxidase, Animals, Humans, MESH: Mice, technique elisa, 030304 developmental biology, MESH: tat Gene Products, Human Immunodeficiency Virus, MESH: Humans, Ion Transport, synthèse de protéine, perméabilité cellulaire, Myocardium, Cell Biology, Molecular biology, MESH: Ion Transport, chemistry, MESH: Proto-Oncogene Proteins c-bcl-2, biology.protein, virus de l'immunodéficience humaine, 030217 neurology & neurosurgery, MESH: Liver
Abstract

International audience; The Trans-activator protein (Tat) of human immunodeficiency virus (HIV) is a pleiotropic protein involved in different aspects of AIDS pathogenesis. As a number of viral proteins Tat is suspected to disturb mitochondrial function. We prepared pure synthetic full-length Tat by native chemical ligation (NCL), and Tat peptides, to evaluate their direct effects on isolated mitochondria. Submicromolar doses of synthetic Tat cause a rapid dissipation of the mitochondrial transmembrane potential (ΔΨ(m)) as well as cytochrome c release in mitochondria isolated from mouse liver, heart, and brain. Accordingly, Tat decreases substrate oxidation by mitochondria isolated from these tissues, with oxygen uptake being initially restored by adding cytochrome c. The anion-channel inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) protects isolated mitochondria against Tat-induced mitochondrial membrane permeabilization (MMP), whereas ruthenium red, a ryanodine receptor blocker, does not. Pharmacologic inhibitors of the permeability transition pore, Bax/Bak inhibitors, and recombinant Bcl-2 and Bcl-XL proteins do not reduce Tat-induced MMP. We finally observed that Tat inhibits cytochrome c oxidase (COX) activity in disrupted mitochondria isolated from liver, heart, and brain of both mouse and human samples, making it the first described viral protein to be a potential COX inhibitor.

Published
2012

11. Use of Human Cancer Cell Lines Mitochondria to Explore the Mechanisms of BH3 Peptides and ABT-737-Induced Mitochondrial Membrane Permeabilization

Author

Pierre Rustin, Christine Péchoux, Magali Brabant, Diana Desgué, Etienne Jacotot, Nelly Buron, Myriam Lassalle, Mathieu Porceddu, Annie Borgne-Sanchez, Cindy Racoeur, Theraptosis S.A., Mitologics SAS, Hôpital Robert Debré, Unité de recherche génomique et physiologie de la lactation (GPL), Institut National de la Recherche Agronomique (INRA), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Department of Reproductive Biology, and Imperial College London

Subjects
Non-Clinical Medicine/Research Methods, [SDV]Life Sciences [q-bio], Mitochondrion, Mitochondrial apoptosis-induced channel, Piperazines, Membrane Potentials, Nitrophenols, Mice, 0302 clinical medicine, BIOLOGIE CELLULAIRE, Inner mitochondrial membrane, Mice, Inbred BALB C, Sulfonamides, 0303 health sciences, Multidisciplinary, biology, Cytochrome c, Cell Biology/Cellular Death and Stress Responses, CANCER, Mitochondria, 3. Good health, Cell biology, PROTEINE BCL-2, Gene Expression Regulation, Neoplastic, Cross-Linking Reagents, Proto-Oncogene Proteins c-bcl-2, Biochemistry, mitochondrie, protéine, 030220 oncology & carcinogenesis, Mitochondrial Membranes, Medicine, Female, Biotechnology/Protein Chemistry and Proteomics, Biochemistry/Drug Discovery, biological phenomena, cell phenomena, and immunity, Bacterial outer membrane, Research Article, Science, Oncology/Oncology Agents, Permeability, 03 medical and health sciences, Cell Line, Tumor, Proto-Oncogene Proteins, Animals, Humans, [INFO]Computer Science [cs], 030304 developmental biology, apoptose, Biphenyl Compounds, Peptide Fragments, CYTOCHROME-C RELEASE, BCL-2 FAMILY PROTEINS, MIMETIC ABT-737, OUTER-MEMBRANE, CASPASE ACTIVATION, BAX, APOPTOSIS, DEATH, INHIBITORS, DOMAINS, membrane cellulaire, Apoptosis, Cancer cell, biology.protein, Apoptosome, humain
Abstract

International audience; Current limitations of chemotherapy include toxicity on healthy tissues and multidrug resistance of malignant cells. A number of recent anti-cancer strategies aim at targeting the mitochondrial apoptotic machinery to induce tumor cell death. In this study, we set up protocols to purify functional mitochondria from various human cell lines to analyze the effect of peptidic and xenobiotic compounds described to harbour either Bcl-2 inhibition properties or toxic effects related to mitochondria. Mitochondrial inner and outer membrane permeabilization were systematically investigated in cancer cell mitochondria versus non-cancerous mitochondria. The truncated (t-) Bid protein, synthetic BH3 peptides from Bim and Bak, and the small molecule ABT-737 induced a tumor-specific and OMP-restricted mitochondrio-toxicity, while compounds like HA-14.1, YC-137, Chelerythrine, Gossypol, TW-37 or EM20-25 did not. We found that ABT-737 can induce the Bax-dependent release of apoptotic proteins (cytochrome c, Smac/Diablo and Omi/HtrA2 but not AIF) from various but not all cancer cell mitochondria. Furthermore, ABT-737 addition to isolated cancer cell mitochondria induced oligomerization of Bax and/or Bak monomers already inserted in the mitochondrial membrane. Finally immunoprecipatations indicated that ABT-737 induces Bax, Bak and Bim desequestration from Bcl-2 and Bcl-xL but not from Mcl-1L. This study investigates for the first time the mechanism of action of ABT-737 as a single agent on isolated cancer cell mitochondria. Hence, this method based on MOMP (mitochondrial outer membrane permeabilization) is an interesting screening tool, tailored for identifying Bcl-2 antagonists with selective toxicity profile against cancer cell mitochondria but devoid of toxicity against healthy mitochondria.

Published
2010

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