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1. Circumsporozoite Protein of Plasmodium berghei- and George Baker Virus A-Derived Peptides Trigger Efficient Cell Internalization of Bioconjugates and Functionalized Poly(ethylene glycol)-b-poly(benzyl malate)-Based Nanoparticles in Human Hepatoma Cells

Author: Elise Vène, Kathleen Jarnouen, Catherine Ribault, Manuel Vlach, Yann Verres, Mickaël Bourgeois, Nicolas Lepareur, Sandrine Cammas-Marion, and Pascal Loyer
Subjects: hepatoma cells, macrophages, George Baker (GB) virus A10-9, circumsporozoite protein of Plasmodium berghei, polymeric nanoparticles, bioconjugates, Pharmacy and materia medica, RS1-441
Abstract: In order to identify the peptides, selected from the literature, that exhibit the strongest tropism towards human hepatoma cells, cell uptake assays were performed using biotinylated synthetic peptides bound to fluorescent streptavidin or engrafted onto nanoparticles (NPs), prepared from biotin-poly(ethylene glycol)-block-poly(benzyl malate) (Biot-PEG-b-PMLABe) via streptavidin bridging. Two peptides, derived from the circumsporozoite protein of Plasmodium berghei- (CPB) and George Baker (GB) Virus A (GBVA10-9), strongly enhanced the endocytosis of both streptavidin conjugates and NPs in hepatoma cells, compared to primary human hepatocytes and non-hepatic cells. Unexpectedly, the uptake of CPB- and GBVA10-9 functionalized PEG-b-PMLABe-based NPs by hepatoma cells involved, at least in part, the peptide binding to apolipoproteins, which would promote NP’s interactions with cell membrane receptors of HDL particles. In addition, CPB and GBVA10-9 peptide–streptavidin conjugates favored the uptake by hepatoma cells over that of the human macrophages, known to strongly internalize nanoparticles by phagocytosis. These two peptides are promising candidate ligands for targeting hepatocellular carcinomas.
Published: 2022
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2. Synthesis of Poly(Malic Acid) Derivatives End-Functionalized with Peptides and Preparation of Biocompatible Nanoparticles to Target Hepatoma Cells

Author: Clarisse Brossard, Manuel Vlach, Elise Vène, Catherine Ribault, Vincent Dorcet, Nicolas Noiret, Pascal Loyer, Nicolas Lepareur, and Sandrine Cammas-Marion
Subjects: poly(malic acid) derivatives, GB virus A, circumsporozoite protein of Plasmodium berghei, (Co)polymers end-functionalized with peptide, multifunctional nanoparticles, human hepatoma cells, Chemistry, QD1-999
Abstract: Recently, short synthetic peptides have gained interest as targeting agents in the design of site-specific nanomedicines. In this context, our work aimed at developing new tools for the diagnosis and/or therapy of hepatocellular carcinoma (HCC) by grafting the hepatotropic George Baker (GB) virus A (GBVA10-9) and Plasmodium circumsporozoite protein (CPB)-derived peptides to the biocompatible poly(benzyl malate), PMLABe. We successfully synthesized PMLABe derivatives end-functionalized with peptides GBVA10-9, CPB, and their corresponding scrambled peptides through a thiol/maleimide reaction. The corresponding nanoparticles (NPs), varying by the nature of the peptide (GBVA10-9, CPB, and their scrambled peptides) and the absence or presence of poly(ethylene glycol) were also successfully formulated using nanoprecipitation technique. NPs were further characterized by dynamic light scattering (DLS), electrophoretic light scattering (ELS) and transmission electron microscopy (TEM), highlighting a diameter lower than 150 nm, a negative surface charge, and a more or less spherical shape. Moreover, a fluorescent probe (DiD Oil) has been encapsulated during the nanoprecipitation process. Finally, preliminary in vitro internalisation assays using HepaRG hepatoma cells demonstrated that CPB peptide-functionalized PMLABe NPs were efficiently internalized by endocytosis, and that such nanoobjects may be promising drug delivery systems for the theranostics of HCC.
Published: 2021
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3. Cytochrome P450 1A1/2, 2B6 and 3A4 HepaRG Cell-Based Biosensors to Monitor Hepatocyte Differentiation, Drug Metabolism and Toxicity

Author: Manuel Vlach, Nicolas Quesnot, Hélène Dubois-Pot-Schneider, Catherine Ribault, Yann Verres, Kilian Petitjean, Claudine Rauch, Fabrice Morel, Marie-Anne Robin, Anne Corlu, and Pascal Loyer
Subjects: HepaRG cells, cell-based biosensors, cytochromes P450, drug screening, hepatotoxicity, Chemical technology, TP1-1185
Abstract: Human hepatoma HepaRG cells express most drug metabolizing enzymes and constitute a pertinent in vitro alternative cell system to primary cultures of human hepatocytes in order to determine drug metabolism and evaluate the toxicity of xenobiotics. In this work, we established novel transgenic HepaRG cells transduced with lentiviruses encoding the reporter green fluorescent protein (GFP) transcriptionally regulated by promoter sequences of cytochromes P450 (CYP) 1A1/2, 2B6 and 3A4 genes. Here, we demonstrated that GFP-biosensor transgenes shared similar expression patterns with the corresponding endogenous CYP genes during proliferation and differentiation in HepaRG cells. Interestingly, differentiated hepatocyte-like HepaRG cells expressed GFP at higher levels than cholangiocyte-like cells. Despite weaker inductions of GFP expression compared to the strong increases in mRNA levels of endogenous genes, we also demonstrated that the biosensor transgenes were induced by prototypical drug inducers benzo(a)pyrene and phenobarbital. In addition, we used the differentiated biosensor HepaRG cells to evidence that pesticide mancozeb triggered selective cytotoxicity of hepatocyte-like cells. Our data demonstrate that these new biosensor HepaRG cells have potential applications in the field of chemicals safety evaluation and the assessment of drug hepatotoxicity.
Published: 2019
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4. Pretreatment with mangafodipir improves liver graft tolerance to ischemia/reperfusion injury in rat.

Author: Ismail Ben Mosbah, Yann Mouchel, Julie Pajaud, Catherine Ribault, Catherine Lucas, Alexis Laurent, Karim Boudjema, Fabrice Morel, Anne Corlu, and Philippe Compagnon
Subjects: Medicine, Science
Abstract: Ischemia/reperfusion injury occurring during liver transplantation is mainly due to the generation of reactive oxygen species (ROS) upon revascularization. Thus, delivery of antioxidant enzymes might reduce the deleterious effects of ROS and improve liver graft initial function. Mangafodipir trisodium (MnDPDP), a contrast agent currently used in magnetic resonance imaging of the liver, has been shown to be endowed with powerful antioxidant properties. We hypothesized that MnDPDP could have a protective effect against liver ischemia reperfusion injury when administrated to the donor prior to harvesting. Livers from Sprague Dawley rats pretreated or not with MnDPDP were harvested and subsequently preserved for 24 h in Celsior® solution at 4°C. Organs were then perfused ex vivo for 120 min at 37°C with Krebs Henseleit solution. In MnDPDP (5 µmol/kg) group, we observed that ATP content was significantly higher at the end of the cold preservation period relative to untreated group. After reperfusion, livers from MnDPDP-treated rats showed better tissue integrity, less hepatocellular and endothelial cell injury. This was accompanied by larger amounts of bile production and higher ATP recovery as compared to untreated livers. The protective effect of MnDPDP was associated with a significant decrease of lipid peroxidation, mitochondrial damage, and apoptosis. Interestingly, MnDPDP-pretreated livers exhibited activation of Nfr2 and HIF-1α pathways resulting in a higher catalase and HO-1 activities. MnDPDP also increased total nitric oxide (NO) production which derived from higher expression of constitutive NO synthase and lower expression of inducible NO synthase. In conclusion, our results show that donor pretreatment with MnDPDP protects the rat liver graft from cold ischemia/reperfusion injury and demonstrate for the first time the potential interest of this molecule in the field of organ preservation. Since MnDPDP is safely used in liver imaging, this preservation strategy holds great promise for translation to clinical liver transplantation.
Published: 2012
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5. Combined Stimulation with the Tumor Necrosis Factor α and the Epidermal Growth Factor Promotes the Proliferation of Hepatocytes in Rat Liver Cultured Slices

Author: Francis Finot, Régis Masson, Fabienne Desmots, Catherine Ribault, Nicole Bichet, Joan A. Vericat, Patricia Lafouge, Christiane Guguen-Guillouzo, and Pascal Loyer
Subjects: Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: The culture liver slices are mainly used to investigate drug metabolism and xenobiotic-mediated liver injuries while apoptosis and proliferation remain unexplored in this culture model. Here, we show a transient increase in LDH release and caspase activities indicating an ischemic injury during the slicing procedure. Then, caspase activities decrease and remain low in cultured slices demonstrating a low level of apoptosis. The slicing procedure is also associated with the G0/G1 transition of hepatocytes demonstrated by the activation of stress and proliferation signalling pathways including the ERK1/2 and JNK1/2/3 MAPKinases and the transient upregulation of c-fos. The cells further progress up to mid-G1 phase as indicated by the sequential induction of c-myc and p53 mRNA levels after the slicing procedure and at 24 h of culture, respectively. The stimulation by epidermal growth factor induces the ERK1/2 phosphorylation but fails to activate expression of late G1 and S phase markers such as cyclin D1 and Cdk1 indicating that hepatocytes are arrested in mid-G1 phase of the cell cycle. However, we found that combined stimulation by the proinflammatory cytokine tumor necrosis factor α and the epidermal growth factor promotes the commitment to DNA replication as observed in vivo during the liver regeneration.
Published: 2012
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6. Circumsporozoite Protein of

Author: Elise, Vène, Kathleen, Jarnouen, Catherine, Ribault, Manuel, Vlach, Yann, Verres, Mickaël, Bourgeois, Nicolas, Lepareur, Sandrine, Cammas-Marion, and Pascal, Loyer
Abstract: In order to identify the peptides, selected from the literature, that exhibit the strongest tropism towards human hepatoma cells, cell uptake assays were performed using biotinylated synthetic peptides bound to fluorescent streptavidin or engrafted onto nanoparticles (NPs), prepared from biotin-poly(ethylene glycol)
Published: 2022

7. A therapeutic oxygen carrier isolated from Arenicola marina decreases amanitin-induced hepatotoxicity

Author: Franck Zal, Catherine Ribault, Brendan Le Daré, Vincent Lagente, Eric Delpy, Thomas Gicquel, Pierre-Jean Ferron, Nessrine Bellamri, Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Pontchaillou [Rennes], HEMARINA SA, This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Jonchère, Laurent
Subjects: endocrine system, Amanitins, animal structures, [SDV]Life Sciences [q-bio], chemistry.chemical_element, Toxicology, Oxygen, Marine worm, 03 medical and health sciences, Hemoglobins, Extracellular, medicine, polycyclic compounds, Humans, Hepatocyte, Oxygen carrier, 030304 developmental biology, Amanitin, 0303 health sciences, biology, Bicyclic molecule, 030302 biochemistry & molecular biology, Hepatotoxicity, biology.organism_classification, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, chemistry, Biochemistry, Arenicola, Hemoglobin, Chemical and Drug Induced Liver Injury, M101
Abstract: International audience; The amanitins (namely α- and β-amanitin) contained in certain mushrooms are bicyclic octapeptides that, when ingested, are responsible for potentially lethal hepatotoxicity. M101 is an extracellular hemoglobin extracted from the marine worm Arenicola marina. It has intrinsic Cu/Zn-SOD-like activity and is currently used as an oxygen carrier in organ preservation solutions. Our present results suggest that M101 might be effective in reducing amanitin-induced hepatotoxicity and may have potential for therapeutic development.
Published: 2021
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8. Synthesis of Poly(Malic Acid) Derivatives End-Functionalized with Peptides and Preparation of Biocompatible Nanoparticles to Target Hepatoma Cells

Author: Catherine Ribault, Elise Vene, Clarisse Brossard, Nicolas Lepareur, Pascal Loyer, Manuel Vlach, Nicolas Noiret, Sandrine Cammas-Marion, Vincent Dorcet, Synthèse Caractérisation Analyse de la Matière (ScanMAT), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut de Chimie du CNRS (INC), Institut des Sciences Chimiques de Rennes (ISCR), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Pontchaillou [Rennes], This work was funded by the Fondation pour la Recherche Médicale (FRM N°DCM20181039540), Cancéropôle Grand Ouest (CGO n° 17/028), Labex IRON (n° ANR-11-LABX-0018), Institut National de la Santé et de la Recherche Médicale (Inserm), l’Ecole Nationale Supérieure de Chimie de Rennes (ENSCR, France), the Centre National de la Recherche Scientifique (CNRS). Clarisse Brossard was recipient of a PhD fellowship from the Fondation pour la Recherche Médicale (FRM N°DCM20181039540)., ANR-11-LABX-0018,IRON,Radiopharmaceutiques Innovants en Oncologie et Neurologie(2011), Université de Rennes (UR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), HAL UR1, Admin, and Radiopharmaceutiques Innovants en Oncologie et Neurologie - - IRON2011 - ANR-11-LABX-0018 - LABX - VALID
Subjects: human hepatoma cells, General Chemical Engineering, Nanoparticle, Context (language use), Peptide, circumsporozoite protein of Plasmodium berghei, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, Article, GB virus A, lcsh:Chemistry, chemistry.chemical_compound, Dynamic light scattering, [CHIM] Chemical Sciences, [CHIM]Chemical Sciences, General Materials Science, Maleimide, chemistry.chemical_classification, poly(malic acid) derivatives, (Co)polymers end-functionalized with peptide, 021001 nanoscience & nanotechnology, Combinatorial chemistry, 0104 chemical sciences, multifunctional nanoparticles, chemistry, lcsh:QD1-999, Drug delivery, Electrophoretic light scattering, 0210 nano-technology, Ethylene glycol
Abstract: International audience; Recently, short synthetic peptides have gained interest as targeting agents in the design of site-specific nanomedicines. In this context, our work aimed at developing new tools for the diagnosis and/or therapy of hepatocellular carcinoma (HCC) by grafting the hepatotropic George Baker (GB) virus A (GBVA10-9) and Plasmodium circumsporozoite protein (CPB)-derived peptides to the biocompatible poly(benzyl malate), PMLABe. We successfully synthesized PMLABe derivatives end-functionalized with peptides GBVA10-9, CPB, and their corresponding scrambled peptides through a thiol/maleimide reaction. The corresponding nanoparticles (NPs), varying by the nature of the peptide (GBVA10-9, CPB, and their scrambled peptides) and the absence or presence of poly(ethylene glycol) were also successfully formulated using nanoprecipitation technique. NPs were further characterized by dynamic light scattering (DLS), electrophoretic light scattering (ELS) and transmission electron microscopy (TEM), highlighting a diameter lower than 150 nm, a negative surface charge, and a more or less spherical shape. Moreover, a fluorescent probe (DiD Oil) has been encapsulated during the nanoprecipitation process. Finally, preliminary in vitro internalisation assays using HepaRG hepatoma cells demonstrated that CPB peptide-functionalized PMLABe NPs were efficiently internalized by endocytosis, and that such nanoobjects may be promising drug delivery systems for the theranostics of HCC.
Published: 2021
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9. In vivo and in vitro α-amanitin metabolism studies using molecular networking

Author: Pierre-Jean Ferron, Thomas Gicquel, Catherine Ribault, Brendan Le Daré, Isabelle Morel, Aurélien Couette, Jonchère, Laurent, CHU Pontchaillou [Rennes], Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), None, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
Subjects: 0301 basic medicine, Amanita, endocrine system, animal structures, Cell Survival, [SDV]Life Sciences [q-bio], Mushroom Poisoning, Toxicology, Tandem mass spectrometry, Cell Line, 03 medical and health sciences, 0302 clinical medicine, In vivo, polycyclic compounds, Amatoxin, Animals, Humans, Amanitin, Alpha-Amanitin, biology, Molecular Structure, Chemistry, General Medicine, Metabolism, biology.organism_classification, In vitro, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, α-amanitin, Biochemistry, Toxicity, HepaRG cells, Molecular network, 030217 neurology & neurosurgery
Abstract: International audience; Amanitin poisonings are among the most life-threatening mushroom poisonings, and are mainly caused by the genus Amanita. Hepatotoxicity is the hallmark of amanitins, powerful toxins contained in these mushrooms, and can require liver transplant. Among amatoxins, α-amanitin is the most studied. However, the hypothesis of a possible metabolism of amanitins is still controversial in this pathophysiology. Therefore, there is a need of clarification using cutting-edge tools allowing metabolism study. Molecular network has emerged as powerful tool allowing metabolism study through organization and representation of untargeted tandem mass spectrometry (MS/MS) data in a graphical form. The aim of this study is to investigate amanitin metabolism using molecular networking. In vivo (four positive amanitin urine samples) and in vitro (differentiated HepaRG cells supernatant incubated with α-amanitin 2 μM for 24 h) samples were extracted and analyzed by LC-HRMS/MS using a Q Exactive™ Orbitrap mass spectrometer. Using molecular networking on both in vitro and in vivo, we have demonstrated that α-amanitin does not undergo metabolism in human. Thus, we provide solid evidence that a possible production of amanitin metabolites cannot be involved in its toxicity pathways. These findings can help to settle the debate on amanitin metabolism and toxicity.
Published: 2020
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10. Synthesis of Poly(Dimethylmalic Acid) Homo- and Copolymers to Produce Biodegradable Nanoparticles for Drug Delivery: Cell Uptake and Biocompatibility Evaluation in Human Heparg Hepatoma Cells

Author: Saad Saba, Sandrine Cammas-Marion, Pascal Loyer, Manuel Vlach, Ali Khalil, Olivier Coulembier, Catherine Ribault, Jonchère, Laurent, University of Mons [Belgium] (UMONS), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire [Rennes], Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), 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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: [CHIM.POLY] Chemical Sciences/Polymers, Polymers and Plastics, Biocompatibility, Dispersity, Nanoparticle, 02 engineering and technology, [SDV.SP.PG] Life Sciences [q-bio]/Pharmaceutical sciences/Galenic pharmacology, 010402 general chemistry, 01 natural sciences, Article, poly(dimethylmalic acid) derivatives, lcsh:QD241-441, lcsh:Organic chemistry, Dynamic light scattering, Amphiphile, Copolymer, chemistry.chemical_classification, Chemistry, technology, industry, and agriculture, In vitro cytotoxicity, cellular uptake, General Chemistry, Polymer, 021001 nanoscience & nanotechnology, 0104 chemical sciences, [CHIM.POLY]Chemical Sciences/Polymers, [SDV.SP.PG]Life Sciences [q-bio]/Pharmaceutical sciences/Galenic pharmacology, polymeric nanoparticles, Polymerization, Chemical engineering, HepaRG cells, 0210 nano-technology
Abstract: Hydrophobic and amphiphilic derivatives of the biocompatible and biodegradable poly(dimethylmalic acid) (PdiMeMLA), varying by the nature of the lateral chains and the length of each block, respectively, have been synthesized by anionic ring-opening polymerization (aROP) of the corresponding monomers using an initiator/base system, which allowed for very good control over the (co)polymers&rsquo, characteristics (molar masses, dispersity, nature of end-chains). Hydrophobic and core-shell nanoparticles (NPs) were then prepared by nanoprecipitation of hydrophobic homopolymers and amphiphilic block copolymers, respectively. Negatively charged NPs, showing hydrodynamic diameters (Dh) between 50 and 130 nm and narrow size distributions (0.08 &lt, PDI &lt, 0.22) depending on the (co)polymers nature, were obtained and characterized by dynamic light scattering (DLS), zetametry, and transmission electron microscopy (TEM). Finally, the cytotoxicity and cellular uptake of the obtained NPs were evaluated in vitro using the hepatoma HepaRG cell line. Our results showed that both cytotoxicity and cellular uptake were influenced by the nature of the (co)polymer constituting the NPs.
Published: 2020
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11. Thymoquinone protects rat liver after partial hepatectomy under ischemia/reperfusion through oxidative stress and endoplasmic reticulum stress prevention

Author: Najet Hadj Abdallah, Anne Corlu, Mohamed Bejaoui, Hassen Ben Abdennebi, Catherine Ribault, Ahlem Bouhlel, Hassen Hentati, Ismail Ben Mosbah, Roselyne Viel, Université de Monastir ( UM ), Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Bioprédic International, Nutrition, Métabolismes et Cancer ( NuMeCan ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), H2P2 - Histo Pathologie Hight Precision ( H2P2 ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ), Université de Monastir - University of Monastir (UM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), H2P2 - Histo Pathologie Hight Precision (H2P2), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Tunisian Ministry of Higher Education and Scientific Research, Jonchère, Laurent, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1)
Subjects: 0301 basic medicine, Physiology, medicine.medical_treatment, thymoquinone, Pharmacology, medicine.disease_cause, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, hepatectomy, Physiology (medical), medicine, oxidative stress, Thymoquinone, Liver injury, [ SDV ] Life Sciences [q-bio], Chemistry, Endoplasmic reticulum, apoptosis, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Liver regeneration, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 030104 developmental biology, Apoptosis, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Unfolded protein response, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, endoplasmic reticulum stress, Hepatectomy, Oxidative stress, Ischemia reperfusion injury
Abstract: International audience; Ischemia reperfusion (I/R) is associated with liver injury and impaired regeneration during partial hepatectomy (PH). The aim of this study was to investigate the effect of thymoquinone (TQ), the active compound of essential oil obtained from Nigella sativa seeds, on rat liver after PH. Male Wistar rats were equally divided into four groups (n=6) receiving an oral administration of either vehicle solution (Sham and PH groups) or TQ at 30 mg/kg (TQ and TQ+PH groups) for ten consecutive days. Then, rats underwent PH (70%) with 60 min of ischemia followed by 24h of reperfusion (PH and TQ+PH groups). Alanine aminotransferase (ALT) activity and histopathological damage were determined. Also, antioxidant parameters, liver regeneration index, hepatic adenosine triphosphate (ATP) content, endoplasmic reticulum (ER) stress and apoptosis were assessed. In response to PH under I/R, liver damage was significantly alleviated by TQ treatment as evidenced by the decrease in ALT activity (P < 0.01) and histological findings (P < 0.001). In parallel, TQ preconditioning increased hepatic antioxidant capacities. Moreover, TQ improved mitochondrial function (ATP, P < 0.05), attenuated ER stress parameters and repressed the expression of apoptotic effectors. Taken together, our results suggest that TQ preconditioning could be an effective strategy to reduce liver injury after PH under I/R. The protective effects were mediated by the increase of antioxidant capacities and the decrease of ER stress and apoptosis. This article is protected by copyright. All rights reserved.
Published: 2018
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12. Thymoquinone prevents endoplasmic reticulum stress and mitochondria-induced apoptosis in a rat model of partial hepatic warm ischemia reperfusion

Author: Ahlem Bouhlel, Hassen Ben Abdennebi, Anne Corlu, Roselyne Viel, Catherine Ribault, Saber Mannai, Ismail Ben Mosbah, Najet Hadj Abdallah, Bioprédic International, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), H2P2 - Histo Pathologie Hight Precision (H2P2), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), UR12ES11, Tunisian Ministry of Higher Education and Scientific Research, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: 0301 basic medicine, MAPK/ERK pathway, Male, MAP Kinase Signaling System, p38 mitogen-activated protein kinases, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mitochondrion, Pharmacology, medicine.disease_cause, Protective Agents, p38 Mitogen-Activated Protein Kinases, Antioxidants, 03 medical and health sciences, chemistry.chemical_compound, Ischemia, Benzoquinones, Medicine, Animals, Warm Ischemia, Phosphorylation, Rats, Wistar, Thymoquinone, business.industry, Tumor Necrosis Factor-alpha, Endoplasmic reticulum, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Endoplasmic Reticulum Stress, Mitochondria, Rats, Oxidative Stress, 030104 developmental biology, chemistry, Liver, Reperfusion Injury, Immunology, Reperfusion, Unfolded protein response, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Oxidative stress, Ischemia reperfusion injury
Abstract: International audience; This study was undertaken to evaluate the protective effect of thymoquinone (TQ), the bioactive compound of Nigella sativa seeds, against warm ischemia-reperfusion (I/R) injury in liver. Rats were given an oral administration of a vehicle solution (sham group) or TQ at the appropriate dose (10, 20, 30 and 40mg/kg) for ten days consecutively. Following, they were subjected to 60min of partial hepatic ischemia followed by 24h of reperfusion. .Transaminase activities, histopathological changes, TNFα and antioxidant parameters were evaluated. Also, endoplasmic reticulum (ER) stress, mitochondrial damage and apoptosis were studied. In addition, ERK and P38 phosphorylation was determined by Western blot technique. We found that TQ at 30mg/kg is the effective dose to protect rat liver against I/R injury. Moreover, 30mg/kg of TQ prevented histological damages, inflammation and oxidative stress. Interestingly, it decreased the expression of ER stress parameters including GRP78, CHOP and caspase-12. In parallel, it improved mitochondrial function and attenuated the expression of apoptotic parameters. Furthermore, TQ significantly enhanced ERK and P38 phosphorylation. In conclusion, we demonstrated the potential of TQ to protect the rat liver against I/R injury through the prevention of ER stress and mitochondrial dysfunction. These effects implicate the prevention of oxidative stress.
Published: 2017
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13. Opsonisation of nanoparticles prepared from poly(β-hydroxybutyrate) and poly(trimethylene carbonate)-b-poly(malic acid) amphiphilic diblock copolymers: Impact on the in vitro cell uptake by primary human macrophages and HepaRG hepatoma cells

Author: Ghislaine Barouti, Kathleen Jarnouen, Claudine Rauch, Sophie M. Guillaume, Thomas Gicquel, Sandrine Cammas-Marion, Pascal Loyer, Elise Vene, Catherine Ribault, Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut des Sciences Chimiques de Rennes (ISCR), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), CHU Pontchaillou [Rennes], CNRS, Centre National de la Recherche Scientifique, FRM, Fondation pour la Recherche Médicale, Inserm, Institut National de la Santé et de la Recherche Médicale, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Jonchère, Laurent
Subjects: Carcinoma, Hepatocellular, Biocompatibility, Polymers, media_common.quotation_subject, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Polyesters, Cell, Malates, Pharmaceutical Science, Poly(hydroxy alkanoate), Hydroxybutyrates, 02 engineering and technology, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 010402 general chemistry, Endocytosis, Poly(malic acid), 01 natural sciences, Dioxanes, chemistry.chemical_compound, Nanoparticle, Cell Line, Tumor, Amphiphile, Poly(trimethylene carbonate), Prohibitins, medicine, Humans, Secretion, Internalization, media_common, L-Lactate Dehydrogenase, Chemistry, Macrophages, Liver Neoplasms, technology, industry, and agriculture, Biological Transport, Blood Proteins, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 021001 nanoscience & nanotechnology, In vitro, 0104 chemical sciences, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, medicine.anatomical_structure, Biochemistry, HepaRG cells, Cytokines, Nanoparticles, Trimethylene carbonate, 0210 nano-technology
Abstract: International audience; The present work reports the investigation of the biocompatibility, opsonisation and cell uptake by human primary macrophages and HepaRG cells of nanoparticles (NPs) formulated from poly(β-malic acid)-b-poly(β-hydroxybutyrate) (PMLA-b-PHB) and poly(β-malic acid)-b-poly(trimethylene carbonate) (PMLA-b-PTMC) diblock copolymers, namely PMLA800-b-PHB7300, PMLA4500-b-PHB4400, PMLA2500-b-PTMC2800 and PMLA4300-b-PTMC1400. NPs derived from PMLA-b-PHB and PMLA-b-PTMC do not trigger lactate dehydrogenase release and do not activate the secretion of pro-inflammatory cytokines demonstrating the excellent biocompatibility of these copolymers derived nano-objects. Using a protein adsorption assay, we demonstrate that the binding of plasma proteins is very low for PMLA-b-PHB-based nano-objects, and higher for those prepared from PMLA-b-PTMC copolymers. Moreover, a more efficient uptake by macrophages and HepaRG cells is observed for NPs formulated from PMLA-b-PHB copolymers compared to that of PMLA-b-PTMC-based NPs. Interestingly, the uptake in HepaRG cells of NPs formulated from PMLA800-b-PHB7300 is much higher than that of NPs based on PMLA4500-b-PHB4400. In addition, the cell internalization of PMLA800-b-PHB7300 based-NPs, probably through endocytosis, is strongly increased by serum pre-coating in HepaRG cells but not in macrophages. Together, these data strongly suggest that the binding of a specific subset of plasmatic proteins onto the PMLA800-b-PHB7300-based NPs favors the HepaRG cell uptake while reducing that of macrophages.
Published: 2016
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14. Cell Uptake and Biocompatibility of Nanoparticles Prepared from Poly(benzyl malate) (Co)polymers Obtained through Chemical and Enzymatic Polymerization in Human HepaRG Cells and Primary Macrophages

Author: Elise Vene, Hubert Casajus, Caroline Nugier-Chauvin, Manuel Vlach, Pascal Loyer, Nicolas Lepareur, Catherine Ribault, Eric Dubreucq, Sylvain Tranchimand, Sandrine Cammas-Marion, Saad Saba, Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ingénierie des Agro-polymères et Technologies Émergentes (UMR IATE), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université de Montpellier (UM)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut National de la Sante et de la Recherche Medicale (Inserm), Ecole Nationale Superieure de Chimie de Rennes (ENSCR, France), Centre National de la Recherche Scientifique (CNRS), comites departementaux de la Ligue contre le Cancer du Grand Ouest (comites 17 et 35), Ministere de l'Enseignement Superieur et de la Recherche (France), Islamic Center Association for Guidance and Higher Education (Lebanon), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA), Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Rennes-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)
Subjects: inorganic chemicals, biocompatibilité, Polymers and Plastics, Biocompatibility, Cytotoxicity, polymérisation enzymatique, education, Ingénierie des aliments, Nanoparticle, 02 engineering and technology, 010402 general chemistry, nanoparticule, 01 natural sciences, Article, macrophage humain, lcsh:QD241-441, biocompatibility, Poly(benzyl malate), lcsh:Organic chemistry, In vivo, [SDV.IDA]Life Sciences [q-bio]/Food engineering, Food engineering, Enzymatic polymerization, Chemical polymerization, Biocompatible nanoparticles, Cell uptake, HepaRG cells, Human macrophages, Viability assay, ComputingMilieux_MISCELLANEOUS, health care economics and organizations, chemistry.chemical_classification, nanoparticle, technology, industry, and agriculture, cytotoxicité, General Chemistry, Polymer, respiratory system, 021001 nanoscience & nanotechnology, Combinatorial chemistry, 0104 chemical sciences, Polymerization, chemistry, Drug delivery, 0210 nano-technology
Abstract: International audience; The design of drug-loaded nanoparticles (NPs) appears to be a suitable strategy for the prolonged plasma concentration of therapeutic payloads, higher bioavailability, and the reduction of side effects compared with classical chemotherapies. Inmost cases, NPs are prepared from(co)polymers obtained through chemical polymerization. However, procedures have been developed to synthesize some polymers via enzymatic polymerization in the absence of chemical initiators. The aim of this work was to compare the acute in vitro cytotoxicities and cell uptake of NPs prepared from poly(benzyl malate) (PMLABe) synthesized by chemical and enzymatic polymerization. Herein, we report the synthesis and characterization of eight PMLABe-based polymers. Corresponding NPs were produced, their cytotoxicity was studied in hepatoma HepaRG cells, and their uptake by primary macrophages and HepaRG cells was measured. In vitro cell viability evidenced a mild toxicity of the NPs only at high concentrations/densities of NPs in culture media. These data did not evidence a higher biocompatibility of the NPs prepared from enzymatic polymerization, and further demonstrated that chemical polymerization and the nanoprecipitation procedure led to biocompatible PMLABe-based NPs. In contrast, NPs produced from enzymatically synthesized polymers were more efficiently internalized than NPs produced from chemically synthesized polymers. The efficient uptake, combined with low cytotoxicity, indicate that PMLABe-based NPs are suitable nanovectors for drug delivery, deserving further evaluation in vivo to target either hepatocytes or resident liver macrophages.
Published: 2018
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15. Reperfusion stress induced during intermittent selective clamping accelerates rat liver regeneration through JNK pathway

Author: Stéphane Grandadam, Catherine Ribault, Claire Piquet-Pellorce, Hélène Duval, Claire Legendre, Sasse-Fanie Mbatchi, Pascal Loyer, Karim Boudjema, Christiane Guguen-Guillouzo, Anne Corlu, Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], Régulations des équilibres fonctionnels du foie normal et pathologique, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Chirurgie Hépatobiliaire et Digestive [Rennes] = Hepatobiliary and Digestive Surgery [Rennes], Foie, métabolismes et cancer, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UR)
Subjects: Male, MESH: Signal Transduction, MESH: Cyclin D1, medicine.medical_treatment, Gene Expression, Nitric Oxide Synthase Type II, MESH: Rats, Sprague-Dawley, medicine.disease_cause, S Phase, Rats, Sprague-Dawley, MESH: Hepatocytes, 0302 clinical medicine, Cyclin D1, MESH: Animals, MESH: Stress, Physiological, MESH: Superoxide Dismutase, 0303 health sciences, MESH: Heme Oxygenase-1, MESH: Proto-Oncogene Proteins c-fos, MESH: G0 Phase, MESH: S Phase, MESH: STAT3 Transcription Factor, MESH: Hepatectomy, Surgical Instruments, Liver regeneration, Nitric oxide synthase, Reperfusion Injury, MESH: Cell Division, MESH: Liver Regeneration, MESH: Nitric Oxide Synthase Type II, 030211 gastroenterology & hepatology, Proto-Oncogene Proteins c-fos, Signal Transduction, STAT3 Transcription Factor, medicine.medical_specialty, MESH: Gene Expression, Cell division, MESH: Rats, MESH: Surgical Instruments, JUNB, Reperfusion stress, Intermittent clamping, SOD2, Ischemia, Biology, Resting Phase, Cell Cycle, MESH: G1 Phase, 03 medical and health sciences, Stress, Physiological, Internal medicine, medicine, Animals, Hepatectomy, 030304 developmental biology, Hepatology, Interleukin-6, Superoxide Dismutase, G1 Phase, JNK Mitogen-Activated Protein Kinases, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: JNK Mitogen-Activated Protein Kinases, medicine.disease, MESH: Interleukin-6, MESH: Male, Rats, Surgery, Endocrinology, Hepatocytes, biology.protein, MESH: Reperfusion Injury, Selective clamping, Reperfusion injury, Heme Oxygenase-1, Oxidative stress
Abstract: International audience; BACKGROUND & AIMS: Liver resection includes temporal vascular inflow occlusion resulting in ischemia/reperfusion injury in the remnant liver. Here, we developed a rat model of selective lobe occlusion to isolate reperfusion stress from ischemia and to analyze its effect on liver regeneration. METHODS: Left lateral and median lobes of liver were either mobilized or subjected twice for 10min to ischemia followed by 5min reperfusion prior to resection while the regenerative lobes were only subjected to reperfusion. RESULTS: Although intermittent reperfusion stress induced higher levels of serum transaminases, analysis of cell cycle regulators revealed accelerated regenerative response compared to standard partial hepatectomy. The G0/G1 transition occurred before tissue resection, as evidenced by c-fos, junB, and IL-6 induction. Following hepatectomy, Cyclin D1 up-regulation, G1/S transition, and cell division occurred earlier than normal. Unexpectedly, liver mobilization, a component of the clamping procedure, also resulted in earlier G1/S transition. The shortened G1-phase was driven by the c-Jun N-terminal Kinase pathway and was associated with an oxidative stress response as evidenced by the expression of inducible nitric oxide synthase. CONCLUSION: Intermittent selective clamping of lobes to be resected induced reperfusion stress on remnant liver that was beneficial for liver regeneration, suggesting this procedure could be applied in clinical practice.
Published: 2010
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16. IL-1β production is dependent of the activation of purinergic receptors and NLRP3 pathway in human macrophages

Author: Isabelle Couillin, Aude Bodin, Thomas Gicquel, Florence Gleonnec, Catherine Ribault, Sacha Robert, Vincent Lagente, Elisabeth Boichot, Pascal Loyer, Tatiana Victoni, Hépatotoxicité et xénobiotiques, Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Laboratoire de Toxicologie Biologique et Médico-légale, Hôpital Pontchaillou-Hôpital Pontchaillou, Université européenne de Bretagne - European University of Brittany (UEB), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Laboratoire de Toxicologie Biologique et Médico-légale, and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Lipopolysaccharides, [SDV]Life Sciences [q-bio], Immunoblotting, Interleukin-1beta, Gene Expression, Stimulation, Biochemistry, Cathepsin B, Amino Acid Chloromethyl Ketones, 03 medical and health sciences, 0302 clinical medicine, uric acid, Cell Line, Tumor, Interleukin-1alpha, Acetamides, NLR Family, Pyrin Domain-Containing 3 Protein, Genetics, medicine, Humans, Secretion, Receptor, Molecular Biology, Cells, Cultured, 030304 developmental biology, 0303 health sciences, Messenger RNA, Dose-Response Relationship, Drug, Chemistry, Interleukin-6, Reverse Transcriptase Polymerase Chain Reaction, Macrophages, Purinergic receptor, Antagonist, Inflammasome, Dipeptides, Flow Cytometry, Molecular biology, cytokines, NLRP3 inflammasome, 3. Good health, P2X7 receptor, Quinolines, Receptors, Purinergic P2X7, Carrier Proteins, 030217 neurology & neurosurgery, Biotechnology, medicine.drug, Signal Transduction
Abstract: International audience; The Nod-like receptor family protein 3 (NLRP3)-inflammasome pathway is known to be activated by danger signals such as monosodium urate (MSU). We investigated the role of P2 purinergic receptors in the activation of NLRP3-inflammasome pathway after MSU treatment of primary human monocyte-derived macrophages (MDMs). After initial stimulation with a low concentration of LPS (0.1 µg/ml), a 6 h treatment with MSU crystals (250, 500, and 1000 µg/ml) induced the MDMs to release IL-1β, IL-1α, and IL-6 in a dose-dependent manner. Moreover, the caspase 1 inhibitor Z-YVAD-FMK and the cathepsin B inhibitor CA-074Me reduced production of IL-1β in a dose-dependent manner after LPS + MSU treatment. We used real-time reverse transcription-quantitative PCR to show that treatment with LPS and MSU (500 µg/ml) induced significantly greater expression of NLRP3 and IL-1β than after treatment with LPS. We also found that MSU treatment induced P2X purinergic receptor 7 (P2X7R) mRNA and protein expression. Furthermore, addition of the P2X7 purinergic receptor antagonist A-740003 significantly impeded IL-1β production and pro-IL-1β cleavage after treatment with LPS + MSU. Remarkably, RNA silencing of P2X7R (but not P2X4R) inhibited the release of IL-1β and other M1 macrophage cytokines (such as IL-1α, IL-6, and TNF-α) from MDMs stimulated with LPS + MSU. Taken as a whole, our results show that P2 purinergic receptors and the NLRP3 inflammasome pathway are involved in the secretion of IL-1β from MSU-stimulated human macrophages. This pathway may constitute a novel therapeutic target for controlling the inflammatory process in several associated pathologies.-Gicquel, T., Robert, S., Loyer, P., Victoni, T., Bodin, A., Ribault, C., Gleonnec, F., Couillin, I., Boichot, E., Lagente, V. IL-1β production is dependent of the activation of purinergic receptors and NLRP3 pathway in human macrophages
Published: 2015
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17. Glutathione transferases P1/P2 regulate the timing of signaling pathway activations and cell cycle progression during mouse liver regeneration

Author: Pascale Bellaud, I. Ben Mosbah, Colin J. Henderson, Pascal Loyer, Caroline Aninat, Frédéric Morel, Anne Corlu, Julie Pajaud, Catherine Ribault, Claudine Rauch, Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Plate-forme d'histopathologie, Université de Rennes (UR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
Subjects: Cancer Research, Time Factors, Cell Survival, Liver cytology, [SDV]Life Sciences [q-bio], Immunology, Biology, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Stress, Physiological, medicine, Animals, Hepatectomy, RNA, Messenger, Extracellular Signal-Regulated MAP Kinases, Cell Proliferation, Glutathione Transferase, 030304 developmental biology, 0303 health sciences, Cell Death, Cell growth, Gene Expression Profiling, Cell Cycle, JNK Mitogen-Activated Protein Kinases, Cell Biology, Cell cycle, Liver regeneration, Liver Regeneration, Cell biology, Mice, Inbred C57BL, Protein Transport, medicine.anatomical_structure, Gene Expression Regulation, Glutathione S-Transferase pi, Liver, 030220 oncology & carcinogenesis, Hepatocyte, Knockout mouse, Hepatocytes, Phosphorylation, Original Article, Signal transduction, Signal Transduction
Abstract: Glutathione transferases (GST) are phase II enzymes catalyzing the detoxification of endogenous noxious compounds and xenobiotics. They also regulate phosphorylation activities of MAPKinases in a catalytic-independent manner. Previous studies have demonstrated the regulation of JNK-dependent pathway by GSTP1/2. Considering the crucial role of JNK in the early steps of the hepatocyte cell cycle, we sought to determine whether GSTP1/2 were essential for hepatocyte proliferation following partial hepatectomy (PH). Using a conventional double knockout mouse model for the Gstp1 and Gstp2 genes, we found that the lack of GSTP1/P2 reduced the rate of DNA replication and mitotic index during the first wave of hepatocyte proliferation. The lowered proliferation was associated with the decrease in TNFalpha and IL-6 plasma concentrations, reduced hepatic HGF expression and delayed and/or altered activation of STAT3, JNK and ERK1/2 signaling pathways. In addition, the expression and/or activation of cell cycle regulators such as Cyclin D1, CDK4, E2F1 and MCM7 was postponed demonstrating that the absence of GSTP1/2 delayed the entry into and progression through the G1 phase of the cell cycle and impaired the synchrony of proliferation in hepatocytes following PH. Furthermore, while JNK and its downstream targets c-Jun and ATF2 were activated during the early steps of the liver regeneration in wild-type animals, the constitutively active JNK found in the quiescent liver of Gstp1/2 knockout mice underwent a decrease in its activity after PH. Transient induction of antioxidant enzymes and nitric oxide synthase were also delayed or repressed during the regenerative response. Altogether our results demonstrate that GSTP1/2 are a critical regulators of hepatocyte proliferation in the initial phases of liver regeneration.
Published: 2015
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18. Intermittent selective clamping improves rat liver regeneration by attenuating oxidative and endoplasmic reticulum stress

Author: Hélène Duval, Julie Pajaud, S-F Mbatchi, Frédéric Morel, Stéphane Grandadam, Karim Boudjema, I. Ben Mosbah, Philippe Compagnon, Catherine Ribault, Anne Corlu, Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Régulations des équilibres fonctionnels du foie normal et pathologique, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Chirurgie Hépatobiliaire et Digestive [Rennes] = Hepatobiliary and Digestive Surgery [Rennes], CHU Pontchaillou [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Cancer Research, Time Factors, mitochondrial damage, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Apoptosis, Pharmacology, Endoplasmic Reticulum, Antioxidants, Rats, Sprague-Dawley, chemistry.chemical_compound, Adenosine Triphosphate, 0302 clinical medicine, ischemia reperfusion injury, unfolded protein response, Endoplasmic Reticulum Stress, Constriction, Liver regeneration, oxidative and endoplasmic reticulum stress, medicine.anatomical_structure, Liver, Biochemistry, Reperfusion Injury, 030220 oncology & carcinogenesis, Hepatocyte, Original Article, 030211 gastroenterology & hepatology, Mitogen-Activated Protein Kinases, Liver Circulation, Signal Transduction, Immunology, Ischemia, Biology, Nitric Oxide, Nitric oxide, 03 medical and health sciences, Cellular and Molecular Neuroscience, medicine, Animals, Hepatectomy, Cell Proliferation, Endoplasmic reticulum, Cell Biology, medicine.disease, Liver Regeneration, Rats, Oxidative Stress, chemistry, Unfolded protein response, Lipid Peroxidation, Reactive Oxygen Species, Reperfusion injury
Abstract: International audience; Intermittent clamping of the portal trial is an effective method to avoid excessive blood loss during hepatic resection, but this procedure may cause ischemic damage to liver. Intermittent selective clamping of the lobes to be resected may represent a good alternative as it exposes the remnant liver only to the reperfusion stress. We compared the effect of intermittent total or selective clamping on hepatocellular injury and liver regeneration. Entire hepatic lobes or only lobes to be resected were subjected twice to 10 min of ischemia followed by 5 min of reperfusion before hepatectomy. We provided evidence that the effect of intermittent clamping can be damaging or beneficial depending to its mode of application. Although transaminase levels were similar in all groups, intermittent total clamping impaired liver regeneration and increased apoptosis. In contrast, intermittent selective clamping improved liver protein secretion and hepatocyte proliferation when compared with standard hepatectomy. This beneficial effect was linked to better adenosine-5'-triphosphate (ATP) recovery, nitric oxide production, antioxidant activities and endoplasmic reticulum adaptation leading to limit mitochondrial damage and apoptosis. Interestingly, transient and early chaperone inductions resulted in a controlled activation of the unfolded protein response concomitantly to endothelial nitric oxide synthase, extracellular signal-regulated kinase-1/2 (ERK1/2) and p38 MAPK activation that favors liver regeneration. Endoplasmic reticulum stress is a central target through which intermittent selective clamping exerts its cytoprotective effect and improves liver regeneration. This procedure could be applied as a powerful protective modality in the field of living donor liver transplantation and liver surgery.
Published: 2014
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19. Differences in early acetaminophen hepatotoxicity between obese ob/ob and db/db mice

Author: Julie Pajaud, Bruno Turlin, Jacinthe Aubert, Karima Begriche, Marie-Anne Robin, Matthieu Delannoy, Mitchell R. McGill, Sylvie Lepage, Catherine Lucas-Clerc, Catherine Ribault, Isabelle Morel, Bernard Fromenty, Hartmut Jaeschke, Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Hépatotoxicité et xénobiotiques, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Laboratoire de Toxicologie Biologique et Médico-Légale, Hôpital Pontchaillou-CHU Pontchaillou [Rennes]-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Laboratoire de Toxicologie Biologique et Médico-Légale, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Department of pharmacology, toxicology, and therapeutics, University of Kansas Medical Center [Kansas City, KS, USA], Laboratoire de biochimie générale, H2P2 - Histo Pathologie Hight Precision (H2P2), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Laboratoire de Toxicologie Biologique et Médico-Légale, University of Kansas Medical Center [Lawrence], Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Le Corre, Morgane
Subjects: Male, MESH: Mice, Inbred NOD, Basal (phylogenetics), Mice, 0302 clinical medicine, MESH: Glucuronides, Mice, Inbred NOD, Nonalcoholic fatty liver disease, MESH: 3-Hydroxybutyric Acid, MESH: Obesity, MESH: Animals, MESH: Fatty Liver, Liver injury, MESH: Glutathione, 0303 health sciences, 3-Hydroxybutyric Acid, Kinase, Chemistry, Sulfates, Fatty liver, digestive, oral, and skin physiology, Cytochrome P-450 CYP2E1, CYP2E1, Glutathione, 3. Good health, Liver, Molecular Medicine, 030211 gastroenterology & hepatology, Female, Chemical and Drug Induced Liver Injury, medicine.drug, MESH: Triglycerides, medicine.medical_specialty, MESH: Drug-Induced Liver Injury, MESH: Acetaminophen, Context (language use), DNA, Mitochondrial, 03 medical and health sciences, Glucuronides, MESH: Mice, Inbred C57BL, Internal medicine, medicine, Animals, Lactic Acid, Obesity, MESH: Mice, Triglycerides, 030304 developmental biology, Acetaminophen, Pharmacology, JNK Mitogen-Activated Protein Kinases, MESH: DNA, Mitochondrial, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: JNK Mitogen-Activated Protein Kinases, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Male, Fatty Liver, Mice, Inbred C57BL, Endocrinology, MESH: Cytochrome P-450 CYP2E1, MESH: Lactic Acid, MESH: Female, MESH: Liver, MESH: Sulfates
Abstract: International audience; Clinical investigations suggest that hepatotoxicity after acetaminophen (APAP) overdose could be more severe in the context of obesity and nonalcoholic fatty liver disease. The pre-existence of fat accumulation and CYP2E1 induction could be major mechanisms accounting for such hepatic susceptibility. To explore this issue, experiments were performed in obese diabetic ob/ob and db/db mice. Preliminary investigations performed in male and female wild-type, ob/ob, and db/db mice showed a selective increase in hepatic CYP2E1 activity in female db/db mice. However, liver triglycerides in these animals were significantly lower compared with ob/ob mice. Next, APAP (500 mg/kg) was administered in female wild-type, ob/ob, and db/db mice, and investigations were carried out 0.5, 2, 4, and 8 h after APAP intoxication. Liver injury 8 h after APAP intoxication was higher in db/db mice, as assessed by plasma transaminases, liver histology, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. In db/db mice, however, the extent of hepatic glutathione depletion, levels of APAP-protein adducts, c-Jun N-terminal kinase activation, changes in gene expression, and mitochondrial DNA levels were not greater compared with the other genotypes. Furthermore, in the db/db genotype plasma lactate and β-hydroxybutyrate were not specifically altered, whereas the plasma levels of APAP-glucuronide were intermediary between wild-type and ob/ob mice. Thus, early APAP-induced hepatotoxicity was greater in db/db than ob/ob mice, despite less severe fatty liver and similar basal levels of transaminases. Hepatic CYP2E1 induction could have an important pathogenic role when APAP-induced liver injury occurs in the context of obesity and related metabolic disorders.
Published: 2012
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20. Pretreatment with mangafodipir improves liver graft tolerance to ischemia/reperfusion injury in rat

Author: Julie Pajaud, Anne Corlu, Fabrice Morel, Ismail Ben Mosbah, Philippe Compagnon, Cathy H. Lucas, Yann Mouchel, Catherine Ribault, Alexis Laurent, Karim Boudjema, Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire de Biochimie Générale et Enzymologie, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Service de chirurgie digestive, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de Chirurgie Hépatobiliaire et Digestive [Rennes] = Hepatobiliary and Digestive Surgery [Rennes], CHU Pontchaillou [Rennes], This work was supported by the Institut National de la Santé et de la Recherche Médicale, the Centre National de la Recherche Scientifique, the FEDER (Fonds européen de développement régional) and the 'Contrat plan état région' (axe biothérapie). Ismail Ben Mosbah was funded by the 'Contrat plan état région' (axe biothe ́rapie) and the Fondation pour la Recherche Médicale. Julie Pajaud was funded by the Conseil Regional and the Ligue Contre le Cancer- Comité d'Ille-et-Vilaine., Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Le Corre, Morgane, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10
Subjects: Male, MESH: Primary Graft Dysfunction, medicine.medical_treatment, MESH: Transplantation Tolerance, lcsh:Medicine, Gene Expression, Apoptosis, Pharmacology, Liver transplantation, Antioxidants, MESH: Lipid Peroxidation, Lipid peroxidation, chemistry.chemical_compound, Adenosine Triphosphate, 0302 clinical medicine, MESH: Organ Preservation, Molecular Cell Biology, MESH: Adenosine Triphosphate, Mangafodipir, MESH: Animals, lcsh:Science, Cellular Stress Responses, 0303 health sciences, Multidisciplinary, biology, MESH: Heme Oxygenase-1, Chemistry, Graft Survival, MESH: Reactive Oxygen Species, Animal Models, Organ Preservation, Catalase, Transplant Surgery, Liver, Biochemistry, Pyridoxal Phosphate, Medicine, Transplantation Tolerance, 030211 gastroenterology & hepatology, MESH: Nitric Oxide Synthase, MESH: Pyridoxal Phosphate, Research Article, medicine.drug, MESH: Liver Transplantation, MESH: Gene Expression, MESH: Rats, MESH: Graft Survival, MESH: Edetic Acid, Immunology, Organ Preservation Solutions, Ischemia, Gastroenterology and Hepatology, MESH: Hypoxia-Inducible Factor 1, alpha Subunit, Nitric oxide, 03 medical and health sciences, Model Organisms, Organ Culture Techniques, MESH: Catalase, medicine, Animals, Biology, Edetic Acid, 030304 developmental biology, Transplantation, MESH: Apoptosis, lcsh:R, MESH: Antioxidants, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Immunologic Subspecialties, Hypoxia-Inducible Factor 1, alpha Subunit, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Male, MESH: Organ Culture Techniques, Liver Transplantation, Rats, biology.protein, Rat, lcsh:Q, Clinical Immunology, Surgery, Lipid Peroxidation, Nitric Oxide Synthase, Primary Graft Dysfunction, MESH: Organ Preservation Solutions, Reactive Oxygen Species, Reperfusion injury, Heme Oxygenase-1, Ex vivo, MESH: Liver
Abstract: International audience; Ischemia/reperfusion injury occurring during liver transplantation is mainly due to the generation of reactive oxygen species (ROS) upon revascularization. Thus, delivery of antioxidant enzymes might reduce the deleterious effects of ROS and improve liver graft initial function. Mangafodipir trisodium (MnDPDP), a contrast agent currently used in magnetic resonance imaging of the liver, has been shown to be endowed with powerful antioxidant properties. We hypothesized that MnDPDP could have a protective effect against liver ischemia reperfusion injury when administrated to the donor prior to harvesting. Livers from Sprague Dawley rats pretreated or not with MnDPDP were harvested and subsequently preserved for 24 h in Celsior® solution at 4°C. Organs were then perfused ex vivo for 120 min at 37°C with Krebs Henseleit solution. In MnDPDP (5 µmol/kg) group, we observed that ATP content was significantly higher at the end of the cold preservation period relative to untreated group. After reperfusion, livers from MnDPDP-treated rats showed better tissue integrity, less hepatocellular and endothelial cell injury. This was accompanied by larger amounts of bile production and higher ATP recovery as compared to untreated livers. The protective effect of MnDPDP was associated with a significant decrease of lipid peroxidation, mitochondrial damage, and apoptosis. Interestingly, MnDPDP-pretreated livers exhibited activation of Nfr2 and HIF-1α pathways resulting in a higher catalase and HO-1 activities. MnDPDP also increased total nitric oxide (NO) production which derived from higher expression of constitutive NO synthase and lower expression of inducible NO synthase. In conclusion, our results show that donor pretreatment with MnDPDP protects the rat liver graft from cold ischemia/reperfusion injury and demonstrate for the first time the potential interest of this molecule in the field of organ preservation. Since MnDPDP is safely used in liver imaging, this preservation strategy holds great promise for translation to clinical liver transplantation.
Published: 2012
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21. Carbon tetrachloride-mediated lipid peroxidation induces early mitochondrial alterations in mouse liver

Author: Laetitia Knockaert, Alain Fautrel, Julie Pajaud, Catherine Ribault, Sylvie Lepage, Catherine Lucas-Clerc, Marie-Anne Robin, Alain Berson, Pierre-Emmanuel Prost, Bernard Fromenty, Jean-Marc Bégué, Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service des explorations fonctionnelles, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Laboratoire de biochimie générale, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service des explorations fonctionnelles [CHU Rennes], CHU Pontchaillou [Rennes], and Le Corre, Morgane
Subjects: Male, antioxidant, Mitochondria, Liver, Pharmacology, Mitochondrion, medicine.disease_cause, MESH: Dehydroepiandrosterone, MESH: Lipid Peroxidation, Antioxidants, Lipid peroxidation, MESH: Hepatocytes, chemistry.chemical_compound, Mice, 0302 clinical medicine, MESH: Animals, Carbon Tetrachloride, 0303 health sciences, Carbon Tetrachloride Poisoning, Mitochondrial respiratory chain complex IV, CYP2E1, MESH: Carbon Tetrachloride Poisoning, 3. Good health, mitochondria, Cytochrome P-450 CYP2E1 Inhibitors, medicine.anatomical_structure, Biochemistry, MESH: Chromans, 030220 oncology & carcinogenesis, Hepatocyte, MESH: Mitochondria, Liver, Ditiocarb, MESH: Ditiocarb, hepatotoxicity, digestive system, Pathology and Forensic Medicine, 03 medical and health sciences, medicine, Animals, Chromans, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: Carbon Tetrachloride, MESH: Antioxidants, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cell Biology, Dehydroepiandrosterone, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Male, chemistry, MESH: Cytochrome P-450 CYP2E1, Carbon tetrachloride, Hepatocytes, cytochrome P450 2E1, Trolox, Lipid Peroxidation, Oxidative stress
Abstract: International audience; Although carbon tetrachloride (CCl(4))-induced acute and chronic hepatotoxicity have been extensively studied, little is known about the very early in vivo effects of this organic solvent on oxidative stress and mitochondrial function. In this study, mice were treated with CCl(4) (1.5 ml/kg ie 2.38 g/kg) and parameters related to liver damage, lipid peroxidation, stress/defense and mitochondria were studied 3 h later. Some CCl(4)-intoxicated mice were also pretreated with the cytochrome P450 2E1 inhibitor diethyldithiocarbamate or the antioxidants Trolox C and dehydroepiandrosterone. CCl(4) induced a moderate elevation of aminotransferases, swelling of centrilobular hepatocytes, lipid peroxidation, reduction of cytochrome P4502E1 mRNA levels and a massive increase in mRNA expression of heme oxygenase-1 and heat shock protein 70. Moreover, CCl(4) intoxication induced a severe decrease of mitochondrial respiratory chain complex IV activity, mitochondrial DNA depletion and damage as well as ultrastructural alterations. Whereas DDTC totally or partially prevented all these hepatic toxic events, both antioxidants protected only against liver lipid peroxidation and mitochondrial damage. Taken together, our results suggest that lipid peroxidation is primarily implicated in CCl(4)-induced early mitochondrial injury. However, lipid peroxidation-independent mechanisms seem to be involved in CCl(4)-induced early hepatocyte swelling and changes in expression of stress/defense-related genes. Antioxidant therapy may not be an efficient strategy to block early liver damage after CCl(4) intoxication.
Published: 2011
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22. The RNA binding motif protein 15B (RBM15B/OTT3) is a functional competitor of serine-arginine (SR) proteins and antagonizes the positive effect of the CDK11p110-cyclin L2α complex on splicing

Author: Adeline Busson, Janeen H. Trembley, Jill M. Lahti, Tristan Montier, Pascal Loyer, Judith W. Hyle, Jose Grenet, Catherine Ribault, Wei Zhao, Vincent J. Kidd, Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Group 203, School of Electronics and Information Engineering, Beihang University (BUAA), Génétique moléculaire et génétique épidémiologique, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), National Institutes of Health (Grant R01GM044088), Cancer Center (Grant P30CA021765), American Lebanese Syrian Associated Charities, INSERM, and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Nucleocytoplasmic Transport Proteins, Exonic splicing enhancer, RNA-binding protein, Biochemistry, RNA Transport, MESH: Protein Structure, Tertiary, 0302 clinical medicine, MESH: Animals, Nuclear protein, 0303 health sciences, biology, Serine-Arginine Splicing Factors, MESH: Nucleocytoplasmic Transport Proteins, Cell Cycle, Nuclear Proteins, RNA-Binding Proteins, Cyclin-Dependent Kinases, Cell biology, Protein Transport, MESH: Cyclin-Dependent Kinases, 030220 oncology & carcinogenesis, MESH: HEK293 Cells, RNA splicing, MESH: Spliceosomes, MESH: Cell Nucleus, RNA Processing, MESH: Protein Transport, RNA Splicing, MESH: Binding, Competitive, Binding, Competitive, 03 medical and health sciences, SR protein, Cyclin-dependent kinase, Cyclins, Animals, Humans, RNA, Messenger, Nuclear export signal, Molecular Biology, 030304 developmental biology, MESH: RNA, Messenger, Cell Nucleus, Messenger RNA, MESH: Humans, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cell Biology, MESH: Cyclins, Molecular biology, Protein Structure, Tertiary, MESH: RNA-Binding Proteins, HEK293 Cells, biology.protein, Spliceosomes, RNA, MESH: RNA Splicing, MESH: Nuclear Proteins
Abstract: International audience; Here, we report the identification of the RNA binding motif protein RBM15B/OTT3 as a new CDK11(p110) binding partner that alters the effects of CDK11 on splicing. RBM15B was initially identified as a binding partner of the Epstein-Barr virus mRNA export factor and, more recently, as a cofactor of the nuclear export receptor NXF1. In this study, we found that RBM15B co-elutes with CDK11(p110), cyclin L2α, and serine-arginine (SR) proteins, including SF2/ASF, in a large nuclear complex of ∼1-MDa molecular mass following size exclusion chromatography. Using co-immunoprecipitation experiments and in vitro pulldown assays, we mapped two distinct domains of RBM15B that are essential for its direct interaction with the N-terminal extension of CDK11(p110), cyclin L2α, and SR proteins such as 9G8 and SF2/ASF. Finally, we established that RBM15B is a functional competitor of the SR proteins SF2/ASF and 9G8, inhibits formation of the functional spliceosomal E complex, and antagonizes the positive effect of the CDK11(p110)-cyclin L2α complex on splicing both in vitro and in vivo.
Published: 2010
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23. Highly efficient gene transfer into hepatocyte-like HepaRG cells: New means for drug metabolism and toxicity studies

Author: Pascal Loyer, Thierry Benvegnu, Paul-Alain Jaffrès, Véronique Laurent, Tristan Montier, Aurore Fraix, Catherine Ribault, Sandrine Cammas-Marion, Chimie, Electrochimie Moléculaires et Chimie Analytique (CEMCA), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Génétique moléculaire et génétique épidémiologique, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), SynNanoVect, Université européenne de Bretagne - European University of Brittany (UEB)-Plateforme Génomique Santé Biogenouest®-Plateforme IBiSA, Institut des Sciences Chimiques de Rennes (ISCR), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Université de Brest (UBO)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Peer, Hal
Subjects: Cellular differentiation, [SDV]Life Sciences [q-bio], Green Fluorescent Proteins, Organophosphonates, Gene Expression, Biology, Transfection, 01 natural sciences, Applied Microbiology and Biotechnology, Green fluorescent protein, Cell Line, 03 medical and health sciences, Toxicity Tests, medicine, Humans, CYP2E1, Progenitor cell, Cationic lipids, Electroporation, HepaRG cells, Cell Differentiation, Cytochrome P-450 CYP2E1, Hepatocytes, Pharmaceutical Preparations, Molecular Medicine, 030304 developmental biology, 0303 health sciences, Reporter gene, 010405 organic chemistry, General Medicine, 0104 chemical sciences, Cell biology, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Biochemistry, Cell culture, Hepatocyte
Abstract: HepaRG progenitor cells are capable of differentiating into hepatocyte-like cells that express a large set of liver-specific functions. These cells, however, only express small amounts of an important cytochrome P450, the CYP2E1, which limits their use for toxicological studies of drugs metabolized by this pathway. Our aim was to establish an efficient transfection protocol to increase CYP2E1 expression in HepaRG cells. Transfection protocols of the green fluorescent protein (GFP) reporter gene were evaluated using electroporation and cationic lipids belonging to the lipophosphonates, lipophosphoramidates and lipids derived from glycine betaine. Following optimization of the charge ratios, plasmid DNA and formulations with neutral co-lipids, the lipophosphoramidate compounds KLN47 and BSV10, allowed expression of the GFP in approximately 50% of adherent progenitor HepaRG cells, while electroporation targeted GFP expression in approximately 85% of both progenitor and differentiated cells in suspension. Transient enforced expression of active CYP2E1 was also achieved in progenitors and/or differentiated HepaRG cells using the electroporation and the lipophosphoramidate compound BSV10. Importantly, in electroporated cells, CYP2E1 expression level was correlated with a significant increase in CYP2E1-specific enzymatic activity, which opens new perspectives for this CYP-dependent drug metabolism and toxicity studies using HepaRG cells.
Published: 2010
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24. Comparative assessment of acetaminophen-induced hepatotoxicity in lean and obese mice

Author: Jacinthe Aubert, Caroline Aninat, Julie Pajaud, Bernard Fromenty, Marie Robin, and Catherine Ribault
Subjects: medicine.medical_specialty, Endocrinology, business.industry, Internal medicine, medicine, General Medicine, Toxicology, business, Acetaminophen, medicine.drug, Obese Mice
Published: 2011
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25. Early carbon tetrachloride-induced liver toxicity involve lipid peroxidation-dependent and independent mechanisms

Author: J. Bégué, Alain Fautrel, Catherine Ribault, S. Lepage, Marie Robin, Laetitia Knockaert, and Bernard Fromenty
Subjects: Lipid peroxidation, chemistry.chemical_compound, Biochemistry, chemistry, Liver toxicity, Carbon tetrachloride, General Medicine, Toxicology
Published: 2011
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26. A single carbon tetrachloride administration induces early alterations of mitochondrial DNA in mouse liver, through a lipid peroxidation-dependent mechanism

Author: Alain Berson, Marie Robin, Catherine Ribault, P.E. Prost, Alain Fautrel, Bernard Fromenty, and Laetitia Knockaert
Subjects: Lipid peroxidation, chemistry.chemical_compound, Mitochondrial DNA, Biochemistry, Chemistry, Mechanism (biology), Carbon tetrachloride, General Medicine, Toxicology
Published: 2010
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27. Cyclin-Dependent Kinase 1 Plays a Critical Role in DNA Replication Control During Rat Liver Regeneration

Author: Delphine Garnier, Anne Corlu, Pascal Loyer, Christiane Guguen-Guillouzo, and Catherine Ribault
Subjects: DNA Replication, Male, Cyclin A, Eukaryotic DNA replication, Biology, Rats, Sprague-Dawley, 03 medical and health sciences, 0302 clinical medicine, Replication factor C, Minichromosome maintenance, Control of chromosome duplication, CDC2 Protein Kinase, Animals, Cyclin B1, Cells, Cultured, 030304 developmental biology, 0303 health sciences, Hepatology, DNA synthesis, Cell Cycle, DNA replication, Fibroblasts, Cell cycle, Molecular biology, Liver Regeneration, Rats, 030220 oncology & carcinogenesis, Hepatocytes, biology.protein, biological phenomena, cell phenomena, and immunity
Abstract: Liver regeneration is a unique process to restore hepatic homeostasis through rapid and synchronous proliferation of differentiated hepatocytes. Previous studies have shown that hepatocyte proliferation is characterized by high expression levels of the “mitotic” cyclin-dependent kinase 1 (Cdk1) during S-phase compared to other mammalian cells. In the light of findings showing that Cdk1 compensates for the loss of Cdk2 and drives S-phase in Cdk2-deficient cells derived from Cdk2 knockout mice, we took advantage of the models of liver regeneration following partial hepatectomy and primary cultures of normal rat hepatocytes to further examine the involvement of Cdk1 during DNA replication in hepatocytes and to dissect specific cell cycle regulation in hepatocytes compared to control human foreskin fibroblasts. In hepatocytes, Cdk1 exhibited a biphasic activation pattern correlating S-phase and G2/M transition, bound to cyclin A or B1 and localized to the nucleus during DNA replication. Importantly, small interfering RNA (siRNA)-mediated silencing of Cdk1 led to a strong decrease in DNA synthesis without affecting centrosome duplication. Furthermore, in hepatocytes arrested by the iron chelator O-Trensox in early S-phase prior to DNA replication, Cdk1/cyclin complexes were active, while replication initiation components such as the minichromosome maintenance 7 (Mcm7) protein were loaded onto DNA. Moreover, Mcm7 expression and loading onto DNA were not modified by Cdk1 silencing. Conversely, in fibroblasts, Cdk1 expression and activation were low in S-phase and its silencing did not reduce DNA synthesis. Conclusion: Cdk1 is essential for DNA replication downstream formation of replication initiation complexes in hepatocytes but not in fibroblasts and, as such, our data exemplify crucial differences in the cell cycle regulation between various mammalian cell types. (HEPATOLOGY 2009.)

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27 results on '"Catherine Ribault"'

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26. A single carbon tetrachloride administration induces early alterations of mitochondrial DNA in mouse liver, through a lipid peroxidation-dependent mechanism

27. Cyclin-Dependent Kinase 1 Plays a Critical Role in DNA Replication Control During Rat Liver Regeneration

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