المؤلفون: Sandra Lacas-Gervais, Baharia Mograbi, Amine Belaid, Christophe Duranton, Marc Cougnon, Sébastien Giraud, Christian Frelin, Didier F. Pisani, Michel Tauc, Nicolas Melis, Nicolas Blondeau, Paul Vigne, Konstantina Fragaki, Stephan M. Huber, Thierry Hauet, Isabelle Rubera

المساهمون: Physiologie cellulaire et moléculaire des systèmes intégrés (PCMSI), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Service de Biochimie [Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut de Biologie Valrose (IBV), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), University of Konstanz, Centre Commun de Microscopie Appliquée (CCMA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Service de génétique médicale, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Neurobiologie Vasculaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), Transport Ionique Aspects Normaux et Pathologiques (TIANP), CNRS

المصدر: Journal of the American Society of Nephrology
Journal of the American Society of Nephrology, American Society of Nephrology, 2017, 28 (3), pp.811-822. ⟨10.1681/ASN.2016010012⟩

مصطلحات موضوعية: 0301 basic medicine, MESH: Cell Death, Male, Swine, [SDV]Life Sciences [q-bio], MESH: Cell Hypoxia, Respiratory chain, DHPS, Mitochondrion, MESH: Kidney Transplantation, Mixed Function Oxygenases, Mice, 0302 clinical medicine, Peptide Initiation Factors, Deoxyhypusine synthase, MESH: Animals, MESH: Peptide Initiation Factors, MESH: Swine, Cells, Cultured, MESH: Treatment Outcome, Kidney, biology, Cell Death, Chemistry, renal cell biology, RNA-Binding Proteins, General Medicine, Deoxyhypusine Hydroxylase, MESH: Mixed Function Oxygenases, Cell Hypoxia, Cell biology, Mitochondria, medicine.anatomical_structure, Treatment Outcome, Nephrology, 030220 oncology & carcinogenesis, Female, MESH: Cells, Cultured, Programmed cell death, MESH: Rats, MESH: Mitochondria, ischemia, cell survival, 03 medical and health sciences, MESH: Mice, Inbred C57BL, medicine, Gene silencing, Animals, MESH: Lysine, Rats, Wistar, MESH: Mice, hypoxia, Lysine, transplant outcomes, MESH: Rats, Wistar, Kidney Transplantation, MESH: Male, Rats, Mice, Inbred C57BL, 030104 developmental biology, MESH: RNA-Binding Proteins, Basic Research, biology.protein, MESH: Female

الوصف: International audience; The eukaryotic initiation factor 5A (eIF5A), which is highly conserved throughout evolution, has the unique characteristic of post-translational activation through hypusination. This modification is catalyzed by two enzymatic steps involving deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). Notably, eIF5A may be involved in regulating the lifespan of Drosophila during long-term hypoxia. Therefore, we investigated the possibility of a link between eIF5A hypusination and cellular resistance to hypoxia/anoxia. Pharmacologic targeting of DHPS by N1-guanyl-1,7-diaminoheptane (GC7) or RNA interference-mediated inhibition of DHPS or DOHH induced tolerance to anoxia in immortalized mouse renal proximal cells. Furthermore, GC7 treatment of cells reversibly induced a metabolic shift toward glycolysis as well as mitochondrial remodeling and led to downregulated expression and activity of respiratory chain complexes, features characteristic of mitochondrial silencing. GC7 treatment also attenuated anoxia-induced generation of reactive oxygen species in these cells and in normoxic conditions, decreased the mitochondrial oxygen consumption rate of cultured cells and mice. In rats, intraperitoneal injection of GC7 substantially reduced renal levels of hypusinated eIF5A and protected against ischemia-reperfusion-induced renal injury. Finally, in the preclinical pig kidney transplant model, intravenous injection of GC7 before kidney removal significantly improved graft function recovery and late graft function and reduced interstitial fibrosis after transplant. This unconventional signaling pathway offers an innovative therapeutic target for treating hypoxic-ischemic human diseases and organ transplantation.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2d6458b8364eefd67670a482c6116d32Test
https://europepmc.org/articles/PMC5328152Test/

المؤلفون: Sébastien Giraud, Marc Cougnon, Nicolas Melis, Christophe Duranton, Thierry Hauet, Michel Tauc, Isabelle Rubera

المصدر: Toxicology Letters. 259:S12-S13

مصطلحات موضوعية: Activation pathway, business.industry, Cancer research, Acute kidney injury, Medicine, General Medicine, Toxicology, business, medicine.disease, medicine.disease_cause, EIF5A, Oxidative stress

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::b5b62efca0b2dc5e5a976289c791cb79Test
https://doi.org/10.1016/j.toxlet.2016.07.064Test

المؤلفون: Saïd Bendahhou, Serena Giuliano, Nicolas Melis, Christophe Duranton, Isabelle Rubera, Michel Tauc, Marc Cougnon

المساهمون: Physiologie cellulaire et moléculaire des systèmes intégrés (PCMSI), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Biologie et pathologies des cellules mélanocytaires : de la pigmentation cutanée aux mélanomes, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Unité associée de Physiopathologie respiratoire des ruminants, Institut National de la Recherche Agronomique (INRA)

المصدر: British Journal of Pharmacology
British Journal of Pharmacology, Wiley, 2014, 171 (15), pp.3716-3727. ⟨10.1111/bph.12726⟩

مصطلحات موضوعية: congenital, hereditary, and neonatal diseases and abnormalities, chloride channel, Cell Survival, [SDV]Life Sciences [q-bio], Glycine, Cystic Fibrosis Transmembrane Conductance Regulator, Context (language use), Pharmacology, Bioinformatics, Cystic fibrosis, Benzoates, Cell Line, cystic fibrosis, 03 medical and health sciences, Mice, 0302 clinical medicine, Chlorides, Cricetinae, inhibitors, CaCC, medicine, Animals, Viability assay, Patch clamp, CFTR, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, biology, Cell growth, business.industry, chloride conductance, VSORC, respiratory system, patch-clamp, medicine.disease, Research Papers, Cystic fibrosis transmembrane conductance regulator, 3. Good health, whole-cell, Hydrazines, Cell culture, Chloride channel, biology.protein, Thiazolidines, business, 030217 neurology & neurosurgery

الوصف: Background and Purpose For decades, inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel have been used as tools to investigate the role and function of CFTR conductance in cystic fibrosis research. In the early 2000s, two new and potent inhibitors of CFTR, CFTRinh-172 and GlyH-101, were described and are now widely used to inhibit specifically CFTR. However, despite some evidence, the effects of both drugs on other types of Cl−-conductance have been overlooked. In this context, we explore the specificity and the cellular toxicity of both inhibitors in CFTR-expressing and non–CFTR-expressing cells. Experimental Approach Using patch-clamp technique, we tested the effects of CFTRinh-172 and GlyH-101 inhibitors on three distinct types of Cl− currents: the CFTR-like conductance, the volume-sensitive outwardly rectifying Cl− conductance (VSORC) and finally the Ca2+-dependent Cl− conductance (CaCC). We also explored the effect of both inhibitors on cell viability using live/dead and cell proliferation assays in two different cell lines. Key Results We confirmed that these two compounds were potent inhibitors of the CFTR-mediated Cl− conductance. However,GlyH-101 also inhibited the VSORC conductance and the CaCC at concentrations used to inhibit CFTR. The CFTRinh-172 did not affect the CaCC but did inhibit the VSORC, at concentrations higher than 5 µM. Neither inhibitor (20 µM; 24 h exposure) affected cell viability, but both were cytotoxic at higher concentrations. Conclusions and Implications Both inhibitors affected Cl− conductances apart from CFTR. Our results provided insights into their use in mouse models.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::764f07701149dd18ba475c86b79036a8Test
https://hal.archives-ouvertes.fr/hal-02918173Test

المؤلفون: Marc Cougnon, Isabelle Rubera, Baharia Mograbi, Nicolas Melis, Christophe Duranton, Michel Tauc

المساهمون: Physiologie cellulaire et moléculaire des systèmes intégrés (PCMSI), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)

المصدر: Cell Death and Disease
Cell Death and Disease, Nature Publishing Group, 2013, 4 (10), pp.e817-e817. ⟨10.1038/cddis.2013.355⟩
Cell Death & Disease

مصطلحات موضوعية: MESH: Cell Death, Cancer Research, [SDV]Life Sciences [q-bio], Intracellular Space, Cystic Fibrosis Transmembrane Conductance Regulator, Pharmacology, Kidney, medicine.disease_cause, Benzoates, Kidney Tubules, Proximal, DNA Adducts, Mice, 0302 clinical medicine, MESH: Caspase 3, MESH: Animals, NGAL, chemistry.chemical_classification, MESH: Glutathione, MESH: Cystic Fibrosis Transmembrane Conductance Regulator, 0303 health sciences, MESH: Oxidative Stress, Cell Death, biology, Caspase 3, apoptosis, MESH: Reactive Oxygen Species, respiratory system, Glutathione, Cystic fibrosis transmembrane conductance regulator, 3. Good health, medicine.anatomical_structure, Biochemistry, MESH: Cell Survival, 030220 oncology & carcinogenesis, kidney injury, Thiazolidines, MESH: Intracellular Space, Original Article, Female, Kidney Diseases, MESH: Thiazolidines, Intracellular, MESH: DNA Adducts, medicine.drug, MESH: Enzyme Activation, MESH: Cell Line, Tumor, MESH: Rats, Cell Survival, Immunology, Nephrotoxicity, 03 medical and health sciences, Cellular and Molecular Neuroscience, CFTRinh-172, MESH: Kidney Tubules, Proximal, Cell Line, Tumor, GSH, medicine, cancer, Animals, Humans, Rats, Wistar, MESH: Mice, Platinum, 030304 developmental biology, Cisplatin, Reactive oxygen species, MESH: Kidney Diseases, MESH: Humans, Body Weight, MESH: Platinum, Cell Biology, MESH: Kidney, MESH: Rats, Wistar, MESH: Benzoates, Rats, respiratory tract diseases, MESH: Body Weight, Enzyme Activation, Oxidative Stress, chemistry, MESH: Cisplatin, Apoptosis, biology.protein, MESH: Biomarkers, Reactive Oxygen Species, MESH: Female, Biomarkers, Oxidative stress

الوصف: International audience; The clinical use of the antineoplastic drug cisplatin is limited by its deleterious nephrotoxic side effect. Cisplatin-induced nephrotoxicity is associated with an increase in oxidative stress, leading ultimately to renal cell death and irreversible kidney dysfunction. Oxidative stress could be modified by the cystic fibrosis transmembrane conductance regulator protein (CFTR), a Cl(-) channel not only involved in chloride secretion but as well in glutathione (GSH) transport. Thus, we tested whether the inhibition of CFTR could protect against cisplatin-induced nephrotoxicity. Using a renal proximal cell line, we show that the specific inhibitor of CFTR, CFTR(inh)-172, prevents cisplatin-induced cell death and apoptosis by modulating the intracellular reactive oxygen species balance and the intracellular GSH concentration. This CFTR(inh)-172-mediated protective effect occurs without affecting cellular cisplatin uptake or the formation of platinum-DNA adducts. The protective effect of CFTR(inh)-172 in cisplatin-induced nephrotoxicity was also investigated in a rat model. Five days after receiving a single cisplatin injection (5 mg/kg), rats exhibited renal failure, as evidenced by the alteration of biochemical and functional parameters. Pretreatment of rats with CFTR(inh)-172 (1 mg/kg) prior to cisplatin injection significantly prevented these deleterious cisplatin-induced nephrotoxic effects. Finally, we demonstrate that CFTR(inh)-172 does not impair cisplatin-induced cell death in the cisplatin-sensitive A549 cancer cell line. In conclusion, the use of a specific inhibitor of CFTR may represent a novel therapeutic approach in the prevention of nephrotoxic side effects during cisplatin treatment without affecting its antitumor efficacy.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1aad302b8e24e30a35968a54b7baed2fTest
https://hal.archives-ouvertes.fr/hal-02466033Test

المؤلفون: Marc Cougnon, Nicolas Melis, Christophe Duranton, Baharia Mograbi, Isabelle Rubera, Abderrahman Chargui, Michel Tauc

المساهمون: Transport Ionique Aspects Normaux et Pathologiques (TIANP), CNRS, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Physiologie cellulaire et moléculaire des systèmes intégrés (PCMSI), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)

المصدر: American Journal of Pathology
American Journal of Pathology, American Society for Investigative Pathology, 2012, 181 (4), pp.1367-1377. ⟨10.1016/j.ajpath.2012.06.017⟩

مصطلحات موضوعية: MESH: Oxidation-Reduction, [SDV]Life Sciences [q-bio], Cell, MESH: Cell Hypoxia, Regulator, Cystic fibrosis, chemistry.chemical_compound, MESH: Protein Structure, Tertiary, 0302 clinical medicine, MESH: Osmolar Concentration, MESH: Animals, MESH: Cystic Fibrosis Transmembrane Conductance Regulator, MESH: Glutathione, 0303 health sciences, Kidney, MESH: Reactive Oxygen Species, 3. Good health, Cell biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, MESH: Intracellular Space, medicine.symptom, Intracellular, medicine.medical_specialty, MESH: Mutation, MESH: Carbonic Anhydrases, MESH: Cystic Fibrosis, Biology, MESH: Hypoxia-Inducible Factor 1, alpha Subunit, Pathology and Forensic Medicine, 03 medical and health sciences, MESH: Acetylcysteine, MESH: Green Fluorescent Proteins, MESH: Kidney Tubules, Proximal, MESH: Mice, Inbred C57BL, Internal medicine, MESH: Protein Stability, medicine, MESH: Mice, 030304 developmental biology, MESH: Humans, MESH: Chloride Channels, MESH: Models, Biological, Glutathione, Hypoxia (medical), medicine.disease, MESH: Male, MESH: Cell Line, Endocrinology, chemistry, Cell culture, MESH: Disease Models, Animal

الوصف: International audience; Adaptation to hypoxia is an essential physiological response to decrease in tissue oxygenation. This process is primarily under the control of transcriptional activator hypoxia-inducible factor (HIF1). A better understanding of the intracellular HIF1 stabilization pathway would help in management of various diseases characterized by anemia. Among human pathologies, cystic fibrosis disease is characterized by a chronic anemia that is inadequately compensated by the classical erythroid response mediated by the HIF pathway. Because the kidney expresses CFTR and is a master organ involved in the adaptation to hypoxia, we used renal cells to explore the relationship between CFTR and the HIF1-mediated pathway. To monitor the adaptive response to hypoxia, we engineered a hypoxia-induced fluorescent reporter system to determine whether CFTR modulates hypoxia-induced HIF1 stabilization. We show that CFTR is a regulator of HIF stabilization by controlling the intracellular reactive oxygen species (ROS) level through its ability to transport glutathione (a ROS scavenger) out of the cell. Moreover, we demonstrated in a mouse model that both the pharmacological inhibition and the ΔF508 mutation of CFTR lead to an impairment of the adaptive erythroid response to oxygen deprivation. We conclude that CFTR controls HIF stabilization through control of the level of intracellular ROS that act as signaling agents in the HIF-1 pathway.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d08af3c77280c5f2d0cd3caa3fc7ae66Test
https://hal.archives-ouvertes.fr/hal-02466034Test

المؤلفون: Christophe, Duranton, Isabelle, Rubera, Marc, Cougnon, Nicolas, Melis, Abderrahman, Chargui, Baharia, Mograbi, Michel, Tauc

المصدر: The American journal of pathology. 181(4)

مصطلحات موضوعية: Male, Cystic Fibrosis, Protein Stability, Green Fluorescent Proteins, Osmolar Concentration, Intracellular Space, Cystic Fibrosis Transmembrane Conductance Regulator, Hypoxia-Inducible Factor 1, alpha Subunit, Glutathione, Models, Biological, Cell Hypoxia, Acetylcysteine, Cell Line, Protein Structure, Tertiary, Kidney Tubules, Proximal, Mice, Inbred C57BL, Disease Models, Animal, Mice, Chloride Channels, Mutation, Animals, Humans, Reactive Oxygen Species, Oxidation-Reduction, Carbonic Anhydrases

الوصف: Adaptation to hypoxia is an essential physiological response to decrease in tissue oxygenation. This process is primarily under the control of transcriptional activator hypoxia-inducible factor (HIF1). A better understanding of the intracellular HIF1 stabilization pathway would help in management of various diseases characterized by anemia. Among human pathologies, cystic fibrosis disease is characterized by a chronic anemia that is inadequately compensated by the classical erythroid response mediated by the HIF pathway. Because the kidney expresses CFTR and is a master organ involved in the adaptation to hypoxia, we used renal cells to explore the relationship between CFTR and the HIF1-mediated pathway. To monitor the adaptive response to hypoxia, we engineered a hypoxia-induced fluorescent reporter system to determine whether CFTR modulates hypoxia-induced HIF1 stabilization. We show that CFTR is a regulator of HIF stabilization by controlling the intracellular reactive oxygen species (ROS) level through its ability to transport glutathione (a ROS scavenger) out of the cell. Moreover, we demonstrated in a mouse model that both the pharmacological inhibition and the ΔF508 mutation of CFTR lead to an impairment of the adaptive erythroid response to oxygen deprivation. We conclude that CFTR controls HIF stabilization through control of the level of intracellular ROS that act as signaling agents in the HIF-1 pathway.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=pmid________::566f282cee94c06c514034ae7952f149Test
https://pubmed.ncbi.nlm.nih.gov/22846720Test

المؤلفون: Nicolas Melis

المصدر: Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1837:e29

مصطلحات موضوعية: 0106 biological sciences, 0303 health sciences, Programmed cell death, Chemistry, Biophysics, Cell Biology, Mitochondrion, 01 natural sciences, Biochemistry, Cell biology, 03 medical and health sciences, Modulation, EIF5A, 030304 developmental biology, 010606 plant biology & botany

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::621990e9b4e0a8d2a2c5e6228f10c17dTest
https://doi.org/10.1016/j.bbabio.2014.05.302Test