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64 results on '"MESH : Liver"'

1. Chitosan nanoparticles plus quercetin suppress the oxidative stress, modulate DNA fragmentation and gene expression in the kidney of rats fed ochratoxin A-contaminated diet

Author

Abdulhadi Aljawish, Mosaad A. Abdel-Wahhab, Nabila S. Hassan, Sekena H. Abdel-Aziem, Aziza A. El-Nekeety, National Research Center ( NRC ), National Research Center, Equipe NuTox (LNC - U1231) ( NUTOX ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), and Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM )

Subjects
0301 basic medicine, Ochratoxin A, Male, MESH : Oxidative Stress, MESH : Carcinogens, Antioxidant, medicine.medical_treatment, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, [ SDV.TOX ] Life Sciences [q-bio]/Toxicology, Pharmacology, Toxicology, medicine.disease_cause, Kidney, Antioxidants, Rats, Sprague-Dawley, chemistry.chemical_compound, 0302 clinical medicine, Malondialdehyde, MESH : Ochratoxins, MESH : Protective Agents, MESH : DNA Fragmentation, Nephrotoxicity, Chemistry, MESH : Rats, General Medicine, Ochratoxins, MESH : Kidney, Drug Combinations, medicine.anatomical_structure, MESH : Drug Combinations, Biochemistry, Liver, 030220 oncology & carcinogenesis, MESH : Quercetin, DNA fragmentation, MESH : Antioxidants, Quercetin, MESH : Chitosan, MESH : Male, Food Contamination, DNA Fragmentation, Protective Agents, MESH : Diet, 03 medical and health sciences, medicine, Animals, MESH : Malondialdehyde, Chitosan, technology, industry, and agriculture, MESH : Liver, Mycotoxins, Chitosan nanoparticles, MESH : Rats, Sprague-Dawley, Diet, Rats, MESH : Food Contamination, 030104 developmental biology, Oxidative stress, MESH : Nanoparticles, Carcinogens, Nanoparticles, MESH : Animals, Genotoxicity, Food Science
Abstract

IF 3.778; International audience; This study aimed to evaluate the protective role of chitosan nanoparticles (COS-NPs) singly or plus quercetin (Q) against OTA-induced oxidative stress and renal genotoxicity. Twelve groups of male Sprague-Dawley rats were treated orally for 3 weeks included the control group, animals fed OTA-contaminated diet (3 mg/kg diet); COS-NPs-treated groups at low (140 mg/kg b.w.) or high (280 mg/kg b.w.) dose, Q-treated group (50 mg/kg b.w.), Q plus low or high dose of COS-NPs-treated groups and OTA plus Q and/or COS-NPs at the two tested doses-treated groups. The results indicated that COS-NPs were roughly rod in shape with average particle size of 200 nm and zeta potential 31.4 ± 2.8 mV. Animals fed OTA-contaminated diet showed significant changes in serum biochemical parameters, increase kidney MDA and DNA fragmentation and decreased GPx and SOD gene expression accompanied with severe histological changes. Q and/or COS-NPs at the two tested doses induced significant improvements in all tested parameters and succeeded to overcome these effects especially in the animals treated with Q plus the high dose of COS-NPs. It could be concluded that COS-NPs are promise candidate to enhance the antioxidant effect of Q and protect against the nephrotoxicity of OTA in high endemic areas.

Published
2017

2. GCKR polymorphism influences liver fat content in patients with type 2 diabetes

Author

Jean-Michel Petit, Marie-Claude Brindisi, Laurence Duvillard, Patrick Hillon, Boris Guiu, Fabien Rollot, David Masson, Benjamin Bouillet, Perrine Buffier, Bruno Vergès, Jean-Pierre Cercueil, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Service d'Endocrinologie, Diabétologie et Maladies Métaboliques (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Service de radiologie et d'Imagerie médicale diagnostique et thérapeutique (CHU de Dijon), Service d'Hépato-Gastro-Entérologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon, and Conseil Regional de Bourgogne (AOI)

Subjects
Male, 0301 basic medicine, Magnetic Resonance Spectroscopy, Steatosis, MESH : Polymorphism, Genetic, Endocrinology, Diabetes and Metabolism, MESH : Aged, Type 2 diabetes, Body Mass Index, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, MESH : Diabetes Mellitus, Type 2, MESH : Lipid Metabolism, MESH : Female, MESH : Adaptor Proteins, Signal Transducing, education.field_of_study, Glucokinase regulatory protein, 1H-MR spectroscopy, General Medicine, Middle Aged, MESH : Adult, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH : Non-alcoholic Fatty Liver Disease, Metformin, Liver, Female, medicine.drug, GCKR, Adult, Heterozygote, medicine.medical_specialty, MESH : Heterozygote, MESH : Male, Population, 030209 endocrinology & metabolism, Biology, 03 medical and health sciences, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Humans, MESH : Middle Aged, education, Alleles, Adaptor Proteins, Signal Transducing, Aged, Polymorphism, Genetic, Triglyceride, MESH : Humans, MESH : Liver, Lipid Metabolism, medicine.disease, MESH : Body Mass Index, 030104 developmental biology, Diabetes Mellitus, Type 2, chemistry, biology.protein, MESH : Magnetic Resonance Spectroscopy, MESH : Alleles, Body mass index, Non-alcoholic fatty liver disease
Abstract

IF 3.074; International audience; It has recently been shown that an allele in the glucokinase regulatory protein (GCKR) gene was associated with increased liver fat content in obese children. In this study, we set out to determine whether GCKR rs1260326 polymorphism was associated with liver fat content in patients with type 2 diabetes.Three hundred and eight patients with type 2 diabetes were included in this study. Liver fat content was evaluated using 1H-MR spectroscopy.In our population, carriers of the rs1260326 minor T allele had a higher liver fat content than did carriers of the C allele homozygote (12.4 +/- A 9.6 vs. 10.3 +/- A 9.1 %, p = 0.03). The number of patients with steatosis was significantly higher in minor T allele carriers than in C allele homozygote carriers (70.7 vs. 55.4 %; p = 0.008). In multivariate analysis, the predictive variables for steatosis were BMI [odds ratio (OR) 1.08; 95 % confidence interval (CI) 1.03-1.13; p = 0.002], statin therapy (yes) [OR 0.54; 95 % CI 0.31-0.94; p = 0.03], metformin therapy (yes) [OR 2.67; 95 % CI 1.50-4.75; p < 0.001], and rs1260326 GCKR polymorphism (TT+CT) [OR 1.99; 95 % CI 1.14-3.47; p = 0.01].This study shows that in patients with type 2 diabetes who were not selected for liver abnormalities, liver fat content was related to GCKR rs1260326 polymorphism independent of BMI, triglyceride levels, and age.

Published
2016

3. Insulin Dissociates the Effects of Liver X Receptor on Lipogenesis, Endoplasmic Reticulum Stress, and Inflammation

Author

Rosanne M. Crooke, Jianguo Wang, Xiaowei Sun, Jean-Paul Pais de Barros, Abhiruchi J Mehta, David Masson, Ji Miao, Mary E. Haas, Sudha B. Biddinger, Mark J. Graham, Masanori Aikawa, Division of Endocrinology, Children's Hospital Boston, Harvard Medical School, Harvard Medical School [Boston] (HMS), Isis Pharmaceuticals, IBIS THERAPEUTICS-ISIS Therapeutics, Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Center for Interdisciplinary Cardiovascular Sciences, Harvard Medical School [Boston] (HMS)-Brigham and Women's Hospital [Boston], ANR-11-LABX-0021,Lipstic,Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du(2011), Harvard Medical School [Boston] ( HMS ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Harvard Medical School [Boston] ( HMS ) -Brigham and Women's Hospital [Boston], and ANR-11-LABX-0021/11-LABX-0021,Lipstic,Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du ( 2011 )

Subjects
0301 basic medicine, medicine.medical_treatment, Lipid-metabolism, Resistance, Biochemistry, Hepatitis, MESH: Hepatitis, MESH: Endoplasmic Reticulum Stress, polycyclic compounds, Insulin, Gene-expression, Phospholipids, Liver X Receptors, Mice, Knockout, biology, MESH : Gene Expression Regulation, Fatty-acid synthesis, food and beverages, Endoplasmic Reticulum Stress, Orphan Nuclear Receptors, Cultured-cells, Lipids, MESH: Gene Expression Regulation, MESH : Endoplasmic Reticulum Stress, Messenger-rna, Liver, MESH: Orphan Nuclear Receptors, Gene Knockdown Techniques, Lipogenesis, Female, lipids (amino acids, peptides, and proteins), Signal Transduction, liver X receptor, medicine.medical_specialty, Lxr-alpha, Mice, Transgenic, digestive system, Phospholipid transfer protein, Gene Expression Regulation, Enzymologic, 03 medical and health sciences, Insulin resistance, MESH : Hepatitis, Lysophosphatidylcholine acyltransferase, Internal medicine, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Liver X receptor, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Crosses, Genetic, Endoplasmic reticulum, Element-binding protein-1c, MESH : Liver, Cell Biology, medicine.disease, MESH : Orphan Nuclear Receptors, Receptor, Insulin, Mice, Inbred C57BL, Insulin receptor, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, Gene Expression Regulation, Nuclear receptor, biology.protein, Unfolded protein response, Insulin Resistance, MESH: Liver
Abstract

IF 4.258; International audience; Diabetes is characterized by increased lipogenesis as well as increased endoplasmic reticulum (ER) stress and inflammation. The nuclear hormone receptor liver X receptor (LXR) is induced by insulin and is a key regulator of lipid metabolism. It promotes lipogenesis and cholesterol efflux, but suppresses endoplasmic reticulum stress and inflammation. The goal of these studies was to dissect the effects of insulin on LXR action. We used antisense oligonucleotides to knock down Lxr alpha in mice with hepatocytespecific deletion of the insulin receptor and their controls. We found, surprisingly, that knock-out of the insulin receptor and knockdown of Lxr alpha produced equivalent, non-additive effects on the lipogenic genes. Thus, insulin was unable to induce the lipogenic genes in the absence of Lxr alpha, and LXR alpha was unable to induce the lipogenic genes in the absence of insulin. However, insulin was not required for LXR alpha to modulate the phospholipid profile, or to suppress genes in the ER stress or inflammation pathways. These data show that insulin is required specifically for the lipogenic effects of LXR alpha and that manipulation of the insulin signaling pathway could dissociate the beneficial effects of LXR on cholesterol efflux, inflammation, and ER stress from the negative effects on lipogenesis.

Published
2016

4. Decreasing dietary linoleic acid promotes long chain omega-3 fatty acid incorporation into rat retina and modifies gene expression

Author

Stéphane Grégoire, Lionel Bretillon, Catherine Creuzot-Garcher, Niyazi Acar, Bertrand Bardet, Emilie Simon, Alain M. Bron, Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Service d'Ophtalmologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre National de la Recherche Scientifique (CNRS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB), INRA (Human Nutrition Department, France), Laboratoires Horus Pharma (Saint Laurent du Var, France) 29000305, and Regional Council of Burgundy (France) 29000362

Subjects
CD36 Antigens, Male, MESH : RNA, Messenger, MESH: 5-Lipoxygenase-Activating Proteins, MESH : Receptors, LDL, MESH: Electroretinography, 0302 clinical medicine, MESH: Fatty Acids, Omega-3, MESH: Animals, MESH : Retinal Ganglion Cells, chemistry.chemical_classification, 0303 health sciences, MESH : Gene Expression Regulation, MESH : Electroretinography, MESH: Retina, MESH: Chromatography, Gas, MESH: Dietary Fats, Unsaturated, docosahexaenoic acid, polyunsaturated fatty acid, Sensory Systems, 3. Good health, nutrition, MESH: Photic Stimulation, Adipose Tissue, MESH: Adipose Tissue, medicine.medical_specialty, Chromatography, Gas, macular degeneration, Linoleic acid, MESH : Arachidonate 12-Lipoxygenase, Arachidonate 12-Lipoxygenase, MESH : Adipose Tissue, MESH: Arachidonate 12-Lipoxygenase, pufa, 03 medical and health sciences, MESH : Dietary Fats, Unsaturated, lipid, Electroretinography, Rats, Long-Evans, RNA, Messenger, MESH: Linoleic Acid, MESH: Antigens, CD36, MESH : Retina, Fatty acid, MESH: Retinal Ganglion Cells, eye diseases, Ophthalmology, Endocrinology, chemistry, MESH: Receptors, LDL, 030221 ophthalmology & optometry, ATP-Binding Cassette Transporters, n 3, MESH: Female, Photic Stimulation, MESH: Liver, Retinal Ganglion Cells, retina, MESH : 5-Lipoxygenase-Activating Proteins, genetic structures, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, retinal pigment epithelium, electroretinogram, MESH : Photic Stimulation, Adipose tissue, angiogenesis, chemistry.chemical_compound, MESH : Female, MESH : Rats, Long-Evans, 2. Zero hunger, medicine.diagnostic_test, MESH : Rats, MESH: Real-Time Polymerase Chain Reaction, MESH: Gene Expression Regulation, MESH : Antigens, CD36, medicine.anatomical_structure, Liver, ALOX12, Biochemistry, MESH: ATP-Binding Cassette Transporters, Female, ATP Binding Cassette Transporter 1, Polyunsaturated fatty acid, MESH : Fatty Acids, Omega-3, MESH: Rats, brain, MESH : Male, 5-Lipoxygenase-Activating Proteins, MESH : Real-Time Polymerase Chain Reaction, rhesus monkey, Biology, Real-Time Polymerase Chain Reaction, MESH : Chromatography, Gas, Linoleic Acid, Cellular and Molecular Neuroscience, Dietary Fats, Unsaturated, MESH : Linoleic Acid, MESH: Rats, Long-Evans, Internal medicine, Fatty Acids, Omega-3, medicine, Animals, MESH : ATP-Binding Cassette Transporters, Omega 3 fatty acid, MESH: RNA, Messenger, 030304 developmental biology, deficient diet, Retinal pigment epithelium, MESH : Liver, MESH: Male, Rats, Gene Expression Regulation, Receptors, LDL, gene expression, MESH : Animals, sense organs, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

International audience; Age-related macular degeneration (AMD) may be partially prevented by dietary habits privileging the consumption of ω3 long chain polyunsaturated fatty acids (ω3s) while lowering linoleic acid (LA) intake. The present study aimed to document whether following these epidemiological guidelines would enrich the neurosensory retina and RPE with ω3s and modulate gene expression in the neurosensory retina. Rat progenitors and pups were fed with diets containing low or high LA, and low or high ω3s. After scotopic single flash and 8-Hz-Flicker electroretinography, rat pups were euthanized at adulthood. The fatty acid profile of the neurosensory retina, RPE, liver, adipose tissue and plasma was analyzed using gas chromatography. Gene expression was analyzed with real-time PCR in the neurosensory retina. Diets rich in ω3s efficiently improved the incorporation of ω3s into the organs and tissues. This raising effect was magnified by lowering LA intake. Compared to a diet with high LA and low ω3s, low LA diets significantly upregulated LDL-receptor gene expression. Similar but not significant upregulation of CD36, ABCA1, ALOX5 and ALOX12 gene expression was observed in rats fed with low LA. No effect was observed on retinal function. Increasing the intake in ω3s and lowering LA improved the enrichment with ω3s of the tissues, including the neurosensory retina and RPE, and upregulated genes involved in lipid trafficking in the neurosensory retina. Those results consistently reinforced the beneficial role of ω3s in the prevention of AMD, especially when the diet contained low levels of LA, as suggested from epidemiological data.

Published
2011

5. Liver methylene fraction by dual- and triple-echo gradient-echo imaging at 3.0T: Correlation with proton MR spectroscopy and estimation of robustness after SPIO administration

Author

David Masson, Patrick Hillon, Isabelle Robin, Romaric Loffroy, Boris Guiu, Serge Aho, Jean-Michel Petit, Bruno Vergès, Jean-Pierre Cercueil, Douraied Ben Salem, Denis Krausé, Service de radiologie et d'Imagerie médicale diagnostique et thérapeutique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Unité de Génétique Moléculaire Animale (UGMA), Université de Limoges (UNILIM)-Institut National de la Recherche Agronomique (INRA), Service d'Ophtalmologie (CHU de Dijon), Laboratoire Electronique, Informatique et Image [UMR6306] (Le2i), Université de Bourgogne (UB)-École Nationale Supérieure d'Arts et Métiers (ENSAM), Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Service de Diabétologie, Service d'Hépato-Gastroentérologie, Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Unité de Génétique Moléculaire Animale (UMR GMA), Université de Brest (UBO)-Université de Brest (UBO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Service d'Endocrinologie, Diabétologie et Maladies Métaboliques (CHU de Dijon), Service d'hépato-gastroentérologie et cancérologie digestive (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Unité de Génétique Moléculaire Animale ( UGMA ), Université de Limoges ( UNILIM ) -Institut National de la Recherche Agronomique ( INRA ), Laboratoire Electronique, Informatique et Image ( Le2i ), Université de Bourgogne ( UB ) -Centre National de la Recherche Scientifique ( CNRS ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Groupe d'Etude de la Thrombose de Bretagne Occidentale ( GETBO ), Université de Brest ( UBO ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), and Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon )

Subjects
Male, Magnetic Resonance Spectroscopy, MESH : Fatty Liver, MESH: Echo-Planar Imaging, [SDV]Life Sciences [q-bio], Carbon Compounds, Inorganic, MESH : Statistics as Topic, Statistics as Topic, MESH : Aged, Contrast Media, MESH : Carbon Compounds, Inorganic, MESH : Tissue Distribution, 030218 nuclear medicine & medical imaging, Correlation, chemistry.chemical_compound, 0302 clinical medicine, MESH : Dextrans, Non-alcoholic Fatty Liver Disease, MESH : Female, Tissue Distribution, MESH: Dextrans, Methylene, Magnetite Nanoparticles, MESH: Fatty Liver, MESH: Aged, MESH: Middle Aged, medicine.diagnostic_test, Echo-Planar Imaging, Dextrans, Nuclear magnetic resonance spectroscopy, MESH : Adult, Middle Aged, MESH: Reproducibility of Results, Adipose Tissue, Liver, Female, 030211 gastroenterology & hepatology, MESH : Sensitivity and Specificity, Protons, MESH: Adipose Tissue, Adult, Iron Overload, MESH : Male, MESH: Magnetite Nanoparticles, MESH : Adipose Tissue, Sensitivity and Specificity, MESH: Iron Overload, 03 medical and health sciences, Flip angle, Robustness (computer science), MESH: Contrast Media, Linear regression, medicine, MESH : Protons, Humans, MESH : Middle Aged, Radiology, Nuclear Medicine and imaging, MESH: Tissue Distribution, MESH: Statistics as Topic, Aged, MESH : Contrast Media, MESH : Iron Overload, MESH: Humans, MESH : Echo-Planar Imaging, [ SDV ] Life Sciences [q-bio], MESH: Magnetic Resonance Spectroscopy, business.industry, MESH : Reproducibility of Results, MESH : Humans, MESH: Biological Markers, MESH: Carbon Compounds, Inorganic, MESH : Liver, MESH : Magnetite Nanoparticles, Reproducibility of Results, MESH: Adult, Magnetic resonance imaging, MESH: Male, MESH: Sensitivity and Specificity, Proton mr spectroscopy, MESH : Biological Markers, Fatty Liver, chemistry, MESH : Magnetic Resonance Spectroscopy, MESH: Protons, Nuclear medicine, business, MESH: Female, Biomarkers, MESH: Liver
Abstract

Purpose To assess the systematic errors in liver methylene fraction (LMF) resulting from fat–fat interference effects with dual- and triple-echo gradient-recalled-echo Dual/Triple GRE) sequences and to test the robustness of these sequences after iron overloading. Materials and Methods Forty type-2 diabetic patients underwent LMF measurement by 3.0T 1H magnetic resonance spectroscopy (corrected for T1 and T2 decays) as the reference standard and liver fat fraction (%Fat) measurement by four Dual/Triple GRE sequences with 20° and 60° flip angle (α), corrected for T1 recovery. The same four sequences were repeated in eight patients after ferumoxide injection. Corrections for systematic errors were determined from the linear regressions (spectroscopy LMF values over Dual/Triple GRE %Fat values). Robustness was tested using Wilcoxon's signed-rank test. Results Fat–fat interference effects produced a ∼10% relative systematic error and T2* decay produced a 1.9%–4.2% absolute systematic error in LMF. When comparing before and after ferumoxide, dual-echo imaging with α = 20° and α = 60°, even when corrected, showed absolute differences of 7.23% [2.81%–10.25%] (P = 0.0117) and 5.65% [1.89%–8.216.8%] (P = 0.0117), respectively; compared to only 1.17% [0.08%–2.83%] (P = 0.0251) and 1.15% [0.37%–2.73%] (P = 0.2626) with triple-echo imaging and α = 20° and α = 60°, respectively. Conclusion Triple-echo imaging with α = 60° corrected for both T1 recovery and fat–fat interference effects is robust after superparamagnetic iron oxide (SPIO) administration and can reliably quantify LMF. J. Magn. Reson. Imaging 2011;33:119–127. © 2010 Wiley-Liss, Inc.

Published
2010

6. Differential Regulation of Peroxisome Proliferator-Activated Receptor (PPAR)-α1 and Truncated PPARα2 as an Adaptive Response to Fasting in the Control of Hepatic Peroxisomal Fatty Acid β-Oxidation in the Hibernating Mammal

Author

Mustapha Cherkaoui-Malki, Norbert Latruffe, Mostafa Kabine, Zakaria El Kebbaj, Michel Dauça, M'Hammed Saïd El Kebbaj, Pierre Andreoletti, Driss Mountassif, Hervé Schohn, Laboratoire Biochimie et Biologie Moléculaire ( LBBM ), Université Hassan II, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Proliférateurs de Peroxysomes - EA3446, Université Henri Poincaré - Nancy 1 ( UHP ), Laboratoire de Biochimie Moléculaire et Cellulaire ( LBMC ), Université de Bourgogne ( UB ), Bancod, Nathalie, Laboratoire Biochimie et Biologie Moléculaire (LBBM), Université Hassan II [Casablanca] (UH2MC), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Université Henri Poincaré - Nancy 1 (UHP), Laboratoire de Biochimie Moléculaire et Cellulaire (LBMC), and Université de Bourgogne (UB)

Subjects
MESH: Oxidation-Reduction, Hibernation, MESH : Transcription Factors, MESH : Hibernation, MESH : Rodentia, MESH: Rodentia, Peroxisome proliferator-activated receptor, MESH: Protein Isoforms, MESH : Fasting, Clofibric Acid, Endocrinology, MESH : Lipid Metabolism, MESH : Mammals, Protein Isoforms, MESH: Animals, MESH: PPAR alpha, Receptor, MESH : Fatty Acids, Beta oxidation, MESH : Adaptation, Physiological, MESH: Lipid Metabolism, Hypolipidemic Agents, Mammals, chemistry.chemical_classification, MESH : Gene Expression Regulation, Fatty Acids, Fibric Acids, MESH: Transcription Factors, Fasting, MESH : Clofibric Acid, Peroxisome, MESH: Gene Expression Regulation, Adaptation, Physiological, MESH: Fatty Acids, Liver, lipids (amino acids, peptides, and proteins), MESH: Hibernation, Oxidation-Reduction, medicine.medical_specialty, MESH : PPAR alpha, MESH: Fasting, Rodentia, Biology, MESH: Mammals, MESH: Clofibric Acid, Internal medicine, Coactivator, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Peroxisomes, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, PPAR alpha, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Oxidation-Reduction, MESH : Liver, MESH : Protein Isoforms, Lipid metabolism, Lipid Metabolism, MESH: Adaptation, Physiological, MESH: Peroxisomes, Gene Expression Regulation, chemistry, Nuclear receptor, MESH : Animals, MESH: Antilipemic Agents, MESH : Peroxisomes, MESH: Liver, MESH : Antilipemic Agents, Transcription Factors
Abstract

Seasonal obesity and fasting-associated hibernation are the two major metabolic events governing hepatic lipid metabolism in hibernating mammals. In this process, however, the role of the nuclear receptor known as peroxisome proliferator-activated receptor (PPAR)-α has not been elucidated yet. Here we show, as in human, that jerboa (Jaculus orientalis) liver expresses both active wild-type PPARα (PPARα1wt) and truncated PPARα forms and that the PPARα1wt to truncated PPARα2 ratio, which indicates the availability of active PPARα1wt, is differentially regulated during fasting-associated hibernation. Functional activation of hepatic jerboa PPARα, during prehibernating and hibernating states, was demonstrated by the induction of its target genes, which encode peroxisomal proteins such as acyl-CoA oxidase 1, peroxisomal membrane protein 70, and catalase, accompanied by a concomitant induction of PPARα thermogenic coactivator PPARγ coactivator-1α. Interestingly, sustained activation of PPARα by its hypolipidemic ligand, ciprofibrate, abrogates the adaptive fasting response of PPARα during prehibernation and overinduces its target genes, disrupting the prehibernation fattening process. In striking contrast, during fasting-associated hibernation, jerboas exhibit preferential up-regulation of hepatic peroxisomal fatty acid oxidation instead of the mitochondrial pathway, which is down-regulated. Taken together, our results strongly suggest that PPARα is subject to a hibernation-dependent splicing regulation in response to feeding-fasting conditions, which defines the activity of PPARα and the activation of its target genes during hibernation bouts of jerboas.Jerboa PPARα is subject to a hibernation-dependent splicing regulation in response to feeding-fasting conditions, which define activation of PPARα and its target genes.

Published
2008

7. Exposure of fathead minnows to municipal wastewater effluent affects intracellular signaling pathways in the liver

Author

François Gagné, Daniel G. Cyr, Jennifer Arstikaitis, Institut Armand Frappier ( INRS-IAF ), Institut National de la Recherche Scientifique [Québec] ( INRS ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut Armand Frappier, Environment and Climate Change Canada, and This work was supported by grants from NSERC (155065-06), the Canadian Water Network, Fonds de Recherches Santé du Québec-Réseau de recherches en santé environnementale to DGC and from Environment Canada to FG.

Subjects
Physiology, Health, Toxicology and Mutagenesis, [ SDV.TOX ] Life Sciences [q-bio]/Toxicology, 010501 environmental sciences, Microarray, Wastewater, Toxicology, 01 natural sciences, Biochemistry, WNT4, Oligonucleotide Array Sequence Analysis, 0303 health sciences, biology, MESH : Gene Expression Regulation, Kinase, Wnt signaling pathway, Quebec, LRP6, General Medicine, 6. Clean water, Cell biology, MESH : Oligonucleotide Array Sequence Analysis, Liver, Intracellular signaling, Toxicity, Signal transduction, Signal Transduction, medicine.medical_specialty, Cell signaling, MESH : Water Pollutants, Chemical, MESH : Quebec, Cyprinidae, Fathead minnow, 03 medical and health sciences, Vitellogenin, Internal medicine, MESH : Cyprinidae, medicine, Animals, 14. Life underwater, 030304 developmental biology, 0105 earth and related environmental sciences, MESH : Signal Transduction, MESH : Liver, Cell Biology, Environmental Exposure, Endocrinology, Gene Expression Regulation, biology.protein, MESH : Animals, MESH : Waste Water, MESH : Environmental Exposure, Water Pollutants, Chemical
Abstract

International audience; Municipal wastewater effluent can impact its receiving environment. In the St. Lawrence River, male fish living downstream from Montreal exhibit increased hepatic vitellogenin, intersex, delayed spermatogenesis and altered immune function. Few studies have examined genome-wide effects associated with municipal effluent exposure in fish to decipher the mechanisms of toxicity. The present objective was to identify hepatic cellular signaling pathways in fathead minnows following exposure to municipal wastewater effluent. Immature minnows were exposed for 21 days to either 0% (Control) or 20% municipal effluent, the highest concentration in the St. Lawrence River. Hepatic RNA was extracted and used to hybridize a fathead minnow oligonucleotide microarray containing approximately 15 k gene sequences. A total of 1300 genes were differentially expressed, of which 309 genes had more than 2-fold change in expression level between control and MWWE-exposed fish. Of those, 118 were up-regulated and 191 were down-regulated. Altered genes grouped according to function, indicated effects on various signaling pathways, apoptosis, immune responses, and cellular metabolism. Pathway analysis software predicted at least 5 signaling pathways that were altered by treatment: cell adhesion, inflammation, various kinases, estrogen receptor signaling and WNT signaling. Various components of the canonical Wnt pathway were dramatically down-regulated, while several other genes involved in the non-canonical Wnt pathway, such as Wnt4, LRP6, and PPP2R5E, which are known to inhibit the canonical Wnt pathway, were increased. These results indicate that municipal wastewater effluent from Montreal can target and inhibit various signaling including those implicated in hepatic Wnt signaling pathway in fathead minnows.

Published
2014

8. Molecular diagnosis of polycystic echinococcosis due to Echinococcus vogeli in a Paraguayan immigrant in Argentina

Author

Laurence Millon, Arnault Cazorla, Marcelo Amante, M. L. Pestalardo, Solange Bresson-Hadni, J. Alvarez Rodriguez, Frédéric Grenouillet, Bernardo Frider, Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service de parasitologie et mycologie [CHRU de Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Laboratoire Chrono-environnement ( LCE ), Université Bourgogne Franche-Comté ( UBFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), Parasitologie-Mycologie CHU Besançon, and Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon )

Subjects
Male, MESH: Histocytochemistry, Pathology, MESH : Pathology, Molecular, MESH : Argentina, MESH : Aged, MESH: Echinococcus, Case Reports, MESH : Blotting, Western, MESH: Molecular Diagnostic Techniques, MESH : Echinococcosis, 0302 clinical medicine, Liver tissue, MESH : Tomography, X-Ray Computed, Molecular diagnostic techniques, MESH : Echinococcus, MESH: Animals, Pathology, Molecular, MESH: Paraguay, [ SDV.MP.MYC ] Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, MESH: Aged, MESH: Immunoglobulin G, 0303 health sciences, biology, Histocytochemistry, MESH: Argentina, MESH : Paraguay, Echinococcosis, MESH: Emigrants and Immigrants, 3. Good health, Liver, Molecular Diagnostic Techniques, MESH: Tomography, X-Ray Computed, Microbiology (medical), Radiography, Abdominal, medicine.medical_specialty, MESH : Immunoglobulin G, MESH : Male, 030231 tropical medicine, Blotting, Western, Antibodies, Helminth, Argentina, Emigrants and Immigrants, Parasitic infection, Echinococcus vogeli, 03 medical and health sciences, MESH: Echinococcosis, MESH: Antibodies, Helminth, parasitic diseases, medicine, Animals, Humans, MESH: Blotting, Western, Molecular identification, Aged, MESH : Antibodies, Helminth, MESH: Pathology, Molecular, MESH: Humans, 030306 microbiology, business.industry, MESH : Humans, MESH : Liver, MESH : Radiography, Abdominal, biology.organism_classification, medicine.disease, Virology, MESH: Male, Echinococcus, Tomography x ray computed, Paraguay, Immunoglobulin G, MESH : Emigrants and Immigrants, MESH: Radiography, Abdominal, MESH : Animals, MESH : Histocytochemistry, business, Tomography, X-Ray Computed, MESH : Molecular Diagnostic Techniques, MESH: Liver
Abstract

Polycystic echinococcosis due to Echinococcus vogeli is a rare parasitic infection that occurs in rural areas of Central and South America. Only molecular identification performed on formalin-fixed paraffin-embedded liver tissue samples gave an unequivocal diagnosis of this disease in a Paraguayan immigrant in Argentina.

Published
2013

9. Populations at risk for alveolar echinococcosis, France

Author

Piarroux, Martine, Piarroux, Renaud, Knapp, Jenny, Bardonnet, Karine, Dumortier, Jérôme, Watelet, Jérôme, Gerard, Alain, Beytout, Jean, Abergel, Armand, Bresson-Hadni, Solange, Gaudart, Jean, Surveillance Network, Francechino, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), service d'Hépato-gastro-entérologie, Hospices Civiles de Lyon-Hôpital Edouard Heriault, Service d'Hépato-gastro-entérologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut de Mécanique et d'Ingénierie de Bordeaux (I2M), Institut National de la Recherche Agronomique (INRA)-Université de Bordeaux (UB)-École Nationale Supérieure d'Arts et Métiers (ENSAM), Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS), Service des Maladies Infectieuses et Tropicales [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Service d'hépatologie, CHU Etaing, Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), Laboratoire Chrono-environnement - UFC (UMR 6249) (LCE), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Hôpital Jean Minjoz, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Service des Maladies Infectieuses et Tropicales, Hôpital Gabriel Montpied, Clermont-Ferrand, France, Service des Maladies Infectieuses et Tropicales, Hopital Gabriel Montpied, Clermont-Ferrand, France, Laboratoire Chrono-environnement (UMR 6249) (LCE), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Arts et Métiers Sciences et Technologies, HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale ( SESSTIM ), Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -ORS PACA-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques ( IP-TPT ), Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Service de Santé des Armées-Université de Montpellier ( UM ), Laboratoire Chrono-environnement ( LCE ), Université Bourgogne Franche-Comté ( UBFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Institut de Mécanique et d'Ingénierie de Bordeaux ( I2M ), Institut National de la Recherche Agronomique ( INRA ) -Université de Bordeaux ( UB ) -Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique ( CNRS ), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM), Aix Marseille Université (AMU) - ORS PACA - Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Chrono-environnement (LCE), Centre National de la Recherche Scientifique (CNRS) - Université de Franche-Comté (UFC), Hospices Civiles de Lyon - Hôpital Edouard Heriault, Service d'Hépatogastroentérologie, CHU de Nancy-Brabois, Université Sciences et Technologies - Bordeaux 1 - Arts et Métiers ParisTech - Institut Polytechnique de Bordeaux - Centre National de la Recherche Scientifique (CNRS), Service d'Hépato-Gastro-Entérologie, CHU de Clermont-Ferrand - Hôpital d'Estaing, and Aix Marseille Université (AMU)

Subjects
Male, Rural Population, [MATH.MATH-PR] Mathematics [math]/Probability [math.PR], Veterinary medicine, communicable disease prevention and control, MESH : Retrospective Studies, MESH : Anthelmintics, Alveolar echinococcosis, 0302 clinical medicine, [STAT.AP] Statistics [stat]/Applications [stat.AP], MESH: Rural Population, [SDV.SPEE] Life Sciences [q-bio]/Public Health and Epidemiology, Medicine, MESH: Animals, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Anthelmintics, 0303 health sciences, MESH: Middle Aged, MESH: Echinococcosis, Hepatic, 3. Good health, MESH: Anthelmintics, agricultural workers diseases, alveolar echinococcosis, MESH : Endemic Diseases, Microbiology (medical), MESH : Albendazole, medicine.medical_specialty, Echinococcus multilocularis. epidemiology, Echinococcus multilocularis, Albendazole, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, [SDV.EE.SANT] Life Sciences [q-bio]/Ecology, environment/Health, Humans, MESH : Middle Aged, Risk factor, MESH : Mebendazole, Retrospective Studies, MESH : Foxes, MESH: Echinococcus multilocularis, MESH: Humans, 030306 microbiology, MESH : Humans, lcsh:R, MESH: Adult, MESH: Retrospective Studies, Odds ratio, zoonoses, Relative risk, [SDE.ES] Environmental Sciences/Environmental and Society, MESH: Female, Demography, MESH: Liver, Endemic Diseases, MESH: Registries, Foxes, lcsh:Medicine, MESH : Echinococcus multilocularis, Risk Factors, MESH: Risk Factors, Epidemiology, MESH : Socioeconomic Factors, MESH : Female, Registries, rural health, [MATH.MATH-ST] Mathematics [math]/Statistics [math.ST], [STAT.ME] Statistics [stat]/Methodology [stat.ME], biology, Rural health, MESH : Adult, Middle Aged, MESH : Risk Factors, Mebendazole, Infectious Diseases, Liver, MESH: Endemic Diseases, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, epidemiology, France, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Adult, [ SDV.MP.PAR ] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Echinococcosis, Hepatic, MESH: Socioeconomic Factors, MESH : Male, 030231 tropical medicine, [MATH.MATH-DS] Mathematics [math]/Dynamical Systems [math.DS], parasites, MESH: Mebendazole, Echinococcosis, MESH: Albendazole, Animals, lcsh:RC109-216, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, MESH : France, MESH: Foxes, business.industry, Research, MESH : Liver, Retrospective cohort study, biology.organism_classification, MESH: Male, MESH : Rural Population, MESH: France, Socioeconomic Factors, MESH : Animals, business, MESH : Echinococcosis, Hepatic, MESH : Registries
Abstract

International audience; During 1982-2007, alveolar echinococcosis (AE) was diagnosed in 407 patients in France, a country previously known to register half of all European patients. To better define high-risk groups in France, we conducted a national registry-based study to identify areas where persons were at risk and spatial clusters of cases. We interviewed 180 AE patients about their way of life and compared responses to those of 517 controls. We found that almost all AE patients lived in 22 départements in eastern and central France (relative risk 78.63, 95% CI 52.84-117.02). Classification and regression tree analysis showed that the main risk factor was living in AE-endemic areas. There, most at-risk populations lived in rural settings (odds ratio [OR] 66.67, 95% CI 6.21-464.51 for farmers and OR 6.98, 95% CI 2.88-18.25 for other persons) or gardened in nonrural settings (OR 4.30, 95% CI 1.82-10.91). These findings can help sensitization campaigns focus on specific groups.

Published
2013

10. In vivo germination of Bacillus anthracis spores during murine cutaneous infection

Author

Marie Moya-Nilges, Jean-Philippe Corre, Michèle Mock, Jean-Claude Sirard, Agnès Fouet, Ian J. Glomski, Pierre L. Goossens, Alejandro Piris-Gimenez, Grégory Jouvion, Toxines et Pathogénie Bactérienne, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Histopathologie humaine et Modèles animaux, Institut Pasteur [Paris], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Microbiology, Immunology and Cancer Biology, University of Virginia [Charlottesville], Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 ( CIIL ), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR142-Université de Lille-Centre National de la Recherche Scientifique ( CNRS ), Sirard, Jean-Claude, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and University of Virginia

Subjects
MESH: Skin Diseases, Bacterial, MESH: Spleen, Colony Count, Microbial, Bacterial growth, Mice, MESH: Spores, Bacterial, MESH : Skin Diseases, Bacterial, Spore germination, Immunology and Allergy, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH : Female, MESH: Animals, MESH : Host-Pathogen Interactions, MESH : Lymphoid Tissue, Spores, Bacterial, 0303 health sciences, biology, MESH : Spores, Bacterial, MESH : Bacillus anthracis, MESH : Anthrax, Bacillus anthracis, MESH: Bacillus anthracis, Infectious Diseases, medicine.anatomical_structure, Liver, Germination, Host-Pathogen Interactions, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH : Guinea Pigs, MESH : Spleen, [SDV.IMM] Life Sciences [q-bio]/Immunology, Lymphoid Tissue, MESH : Colony Count, Microbial, Guinea Pigs, Spleen, Microbiology, MESH: Guinea Pigs, Anthrax, 03 medical and health sciences, In vivo, MESH : Mice, medicine, MESH: Anthrax, Animals, MESH: Mice, MESH: Colony Count, Microbial, 030304 developmental biology, 030306 microbiology, Inoculation, fungi, MESH: Host-Pathogen Interactions, MESH : Liver, Skin Diseases, Bacterial, biology.organism_classification, MESH : Disease Models, Animal, Spore, Disease Models, Animal, MESH: Lymphoid Tissue, MESH : Animals, MESH: Disease Models, Animal, MESH: Female, MESH: Liver
Abstract

International audience; BACKGROUND: Germination is a key step for successful Bacillus anthracis colonization and systemic dissemination. Few data are available on spore germination in vivo, and the necessity of spore and host cell interactions to initiate germination is unclear. METHODS: To investigate the early interactions between B. anthracis spores and cutaneous tissue, spores were inoculated in an intraperitoneal cell-free device in guinea pigs or into the pinna of mice. Germination and bacterial growth were analyzed through colony-forming unit enumeration and electron microscopy. RESULTS: In the guinea pig model, germination occurred in vivo in the absence of cell contact. Similarly, in the mouse ear, germination started within 15 minutes after inoculation, and germinating spores were found in the absence of surrounding cells. Germination was not observed in macrophage-rich draining lymph nodes, liver, and spleen. Edema and lethal toxin production were not required for germination, as a toxin-deficient strain was as effective as a Sterne-like strain. B. anthracis growth was locally controlled for 6 hours. CONCLUSIONS: Spore germination involving no cell interactions can occur in vivo, suggesting that diffusible germinants or other signals appear sufficient. Different host tissues display drastic differences in germination-triggering capacity. Initial control of bacterial growth suggests a therapeutic means to exploit host innate defenses to hinder B. anthracis colonization.

Published
2013

11. General oxidative stress during doxorubicin-induced cardiotoxicity in rats: Absence of cardioprotection and low antioxidant efficiency of alpha-lipoic acid

Author

Luc Rochette, Ségolène Gambert, Laurent Martin, Stéphanie Delemasure, Catherine Vergely, Carole Richard, Steliana Ghibu, Jean-Claude Guilland, Laboratoire de Physiopathologie et Pharmacologie Cardio-Métaboliques (U866, Lipides et nutrition, équipe 5) (LPPCM), Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Physiopathologie et épidémiologie cérébro-cardiovasculaire [Dijon] (PEC2), Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Vergely, Catherine, and Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)

Subjects
Male, MESH : Oxidative Stress, Antioxidant, medicine.medical_treatment, MESH : Hematocrit, MESH : Thioctic Acid, Biochemistry, Antioxidants, 0302 clinical medicine, Superoxides, Ascitic Fluid, MESH: Animals, MESH : Body Weight, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Thioctic Acid, Cumulative dose, MESH: Heart Diseases, Heart, General Medicine, 3. Good health, MESH: Ascitic Fluid, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, MESH : Ascitic Fluid, MESH: Hydrogen Peroxide, MESH : Antioxidants, MESH: Thioctic Acid, medicine.medical_specialty, Cardiotonic Agents, Cardiotoxins, MESH: Hematocrit, 03 medical and health sciences, MESH: Doxorubicin, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, In vivo, Rats, Wistar, [ SDV ] Life Sciences [q-bio], Myocardium, MESH: Antioxidants, Hydrogen Peroxide, MESH: Cardiotonic Agents, MESH : Organ Size, MESH: Body Weight, MESH: Heart, carbohydrates (lipids), Endocrinology, MESH: Liver, MESH : Superoxides, MESH: Organ Size, [SDV]Life Sciences [q-bio], MESH : Cardiotonic Agents, Ascorbic Acid, MESH: Superoxides, medicine.disease_cause, MESH: Eating, Eating, polycyclic compounds, MESH : Myocardium, MESH: Thiobarbituric Acid Reactive Substances, MESH: Ascorbic Acid, Antibiotics, Antineoplastic, MESH: Oxidative Stress, Chemistry, MESH : Rats, Organ Size, MESH : Antibiotics, Antineoplastic, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Hematocrit, Liver, MESH : Cardiotoxins, medicine.drug, MESH : Eating, MESH: Myocardium, Heart Diseases, MESH: Rats, MESH : Male, MESH : Thiobarbituric Acid Reactive Substances, MESH : Rats, Wistar, Thiobarbituric Acid Reactive Substances, Contractility, MESH : Heart, Internal medicine, medicine, TBARS, Animals, MESH : Doxorubicin, Doxorubicin, MESH: Antibiotics, Antineoplastic, MESH : Ascorbic Acid, 030304 developmental biology, Cardiotoxicity, Body Weight, MESH : Liver, MESH : Heart Diseases, MESH: Rats, Wistar, MESH: Male, Rats, Oxidative Stress, MESH: Cardiotoxins, MESH : Animals, MESH : Hydrogen Peroxide, Oxidative stress
Abstract

International audience; To evaluate the effects of alpha-lipoic acid (AL) in a model of doxorubicin (DOX)-induced cardiotoxicity, male Wistar rats were treated with DOX (1 mg/kg/d; 10 d) in combination or not with AL (50 mg/kg/d; 15 d). Plasma oxidative stress was determined by hydroperoxides (ROOH) and the ascorbyl radical/ascorbate ratio. One and two months later, the functional parameters of the hearts were determined in vivo by catheterization and cardiac oxidative stress was assessed by malonedialdehyde (MDA) and O₂*⁻ (dihydroethidium fluorescence) content in tissue. After two months, body weight was higher in the DOX-AL group than in DOX (+16%), but this was due to ascites. Histological liver alterations were observed in both the DOX and DOX-AL groups. Plasma ROOH concentrations decreased after 10 days of AL treatment, but were greater in both the DOX and DOX-AL groups. After two months, a decrease in the cardiac contractility index (-27% and -29%, respectively) and cardiac hypertrophy were observed in DOX and DOX-AL. These dysfunctions were associated with 1) a reduction in plasma ascorbate levels and an increase in the ascorbyl/ascorbate ratio and 2) an increase MDA and O₂*⁻ content in cardiac tissue. In conclusion, a cumulative dose of 10 mg/kg doxorubicin induced functional alterations in the heart associated with plasma and cardiac oxidative stress. The co-administration of the antioxidant compound AL had no beneficial effects in this situation.

Published
2012

12. Functionalized single-walled carbon nanotubes containing traces of iron as new negative MRI contrast agents for in vivo imaging

Author

Doan , Bich-Thuy, Seguin , Johanne, Breton , Marie, Le Beherec , Ronan, Bessodes , Michel, Rodríguez-Manzo , Julio A, Banhart , Florian, Beloeil , Jean-Claude, Scherman , Daniel, Richard , Cyrille, Unité de pharmacologie chimique et génétique et d'imagerie (UPCGI - UMR 8151 / UMR_S 1022 ), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC), Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Institut de Physique et Chimie des Matériaux de Strasbourg (IPCMS), Université de Strasbourg (UNISTRA)-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de physique et de chimie des matériaux (IPCM), Unité de pharmacologie chimique et génétique et d'imagerie ( UPCGI - UMR 8151 / UMR_S 1022 ), Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de biophysique moléculaire ( CBM ), Université d'Orléans ( UO ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Institut de physique et de chimie des matériaux ( IPCM )

Subjects
MESH: Cell Death, Contrast Media, MESH : Iron, TOXICITY, MESH: Magnetic Resonance Imaging, X-Ray Diffraction, BIODISTRIBUTION, MAGNETIC-RESONANCE, MRI contrast agents, NANOPARTICLES, MESH: Animals, Lung, MESH: Iron, Cell Death, MESH : Hep G2 Cells, MESH: X-Ray Diffraction, Hep G2 Cells, Magnetic Resonance Imaging, CANCER, in vivo, Liver, MESH: Nanotubes, Carbon, MESH : Imaging, Three-Dimensional, functionalization, TOXICOLOGY, MESH : Lung, Iron, MESH: Hep G2 Cells, MESH: Imaging, Three-Dimensional, MESH : X-Ray Diffraction, Imaging, Three-Dimensional, MESH : Magnetic Resonance Imaging, MESH: Contrast Media, MESH : Mice, Animals, Humans, MESH: Lung, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, MESH : Contrast Media, MESH: Humans, carbon nanotubes, Nanotubes, Carbon, MESH : Humans, MESH : Liver, TRANSPORTERS, GADONANOTUBES, MICE, MESH : Cell Death, traces of iron, ENHANCED MRI, MESH : Nanotubes, Carbon, MESH : Animals, MESH: Liver
Abstract

International audience; Single-walled carbon nanotubes (SWCNTs) containing traces of iron oxide were functionalized by noncovalent lipid-PEG or covalent carboxylic acid function to supply new efficient MRI contrast agents for in vitro and in vivo applications. Longitudinal (r(1)) and transversal (r(2)) water proton relaxivities were measured at 300 MHz, showing a stronger T(2) feature as an MRI contrast agent (r(2)/r(1) = 190 for CO(2) H functionalisation). The r(2) relaxivity was demonstrated to be correlated to the presence of iron oxide in the SWNT-carboxylic function COOH, in comparison to iron-free ones. Biodistribution studies on mice after a systemic injection showed a negative MRI contrast in liver, suggesting the presence of the nanotubes in this organ until 48 h after i.v. injection. The presence of carbon nanotubes in liver was confirmed after ex vivo carbon extraction. Finally, cytotoxicity studies showed no apparent effect owing to the presence of the carbon nanotubes. The functionalized carbon nanotubes were well tolerated by the animals at the dose of 10 µg g(-1) body weight.

Published
2012

13. Hepatocyte proliferation/growth arrest balance in the liver of mice during E. multilocularis infection: a coordinated 3-stage course

Author

Junhua Wang, Jing Li, Dominique A. Vuitton, Guodong Lü, Georges Mantion, Xiaomei Lu, Renyong Lin, Chuanshan Zhang, Hao Wen, Institut de Recherche en Communications et en Cybernétique de Nantes ( IRCCyN ), Mines Nantes ( Mines Nantes ) -École Centrale de Nantes ( ECN ) -Ecole Polytechnique de l'Université de Nantes ( Polytech Nantes ), Université de Nantes ( UN ) -Université de Nantes ( UN ) -PRES Université Nantes Angers Le Mans ( UNAM ) -Centre National de la Recherche Scientifique ( CNRS ), WHO Collaborating Center on Prevention and Treatment of Human Echinococcosis, Université de Franche-Comté ( UFC ), WHO Collaborating Center on Prevention and Treatment of Human Echinococcosis, SERF Unit, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Xinjiang Medical University, Chinese Government, Institut de Recherche en Communications et en Cybernétique de Nantes (IRCCyN), Mines Nantes (Mines Nantes)-École Centrale de Nantes (ECN)-Ecole Polytechnique de l'Université de Nantes (EPUN), Université de Nantes (UN)-Université de Nantes (UN)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)

Subjects
Proteomics, MESH : Hepatocytes, MESH : Echinococcosis, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Hepatocytes, Mice, 0302 clinical medicine, Gene expression, MESH : Cell Proliferation, MESH: Animals, MESH : Antigens, Differentiation, MESH: In Situ Nick-End Labeling, lcsh:Science, MESH: Tumor Suppressor Protein p53, Regulation of gene expression, 0303 health sciences, MESH : Gene Expression Regulation, Intracellular Signaling Peptides and Proteins, 3. Good health, 030220 oncology & carcinogenesis, Disease Progression, Medicine, MESH: Disease Progression, MESH : Carrier Proteins, Cyclin-Dependent Kinase Inhibitor p21, MESH : Cyclin-Dependent Kinase Inhibitor p21, MESH: Enzyme Activation, MESH : Cyclins, Caspase 3, MESH: Carrier Proteins, Gastroenterology and Hepatology, Echinococcus multilocularis, Microbiology, MESH: Cyclin-Dependent Kinase Inhibitor p21, 03 medical and health sciences, MESH: Echinococcosis, Cyclins, In Situ Nick-End Labeling, Biology, MESH: Echinococcus multilocularis, lcsh:R, MESH : Mitogen-Activated Protein Kinases, MESH : Disease Progression, Enzyme Activation, Apoptosis, Immunology, lcsh:Q, Parasitology, Carrier Proteins, MESH: Female, MESH: Liver, Necrosis, lcsh:Medicine, MESH : Models, Biological, MESH : Echinococcus multilocularis, Molecular Cell Biology, MESH: Caspase 3, MESH : Female, MESH : Caspase 3, Mice, Inbred BALB C, Multidisciplinary, biology, Animal Models, MESH: Gene Expression Regulation, medicine.anatomical_structure, Infectious Diseases, Liver, Hepatocyte, MESH: Antigens, Differentiation, MESH : In Situ Nick-End Labeling, Female, medicine.symptom, Mitogen-Activated Protein Kinases, Research Article, Neglected Tropical Diseases, MESH: Mice, Inbred BALB C, [SDV.CAN]Life Sciences [q-bio]/Cancer, Models, Biological, Andrology, Immune system, Model Organisms, Echinococcosis, Proliferating Cell Nuclear Antigen, MESH: Cell Proliferation, MESH : Mice, medicine, Animals, MESH: Mice, MESH : Mice, Inbred BALB C, 030304 developmental biology, Cell Proliferation, MESH: Models, Biological, MESH : Liver, biology.organism_classification, MESH: Cyclins, Antigens, Differentiation, MESH: Mitogen-Activated Protein Kinases, MESH : Tumor Suppressor Protein p53, MESH: Proliferating Cell Nuclear Antigen, Gene Expression Regulation, MESH : Proliferating Cell Nuclear Antigen, Hepatocytes, MESH : Animals, Tumor Suppressor Protein p53, MESH : Enzyme Activation
Abstract

International audience; BACKGROUND: Alveolar echinococcosis (AE) is characterized by the tumor-like growth of Echinococcus (E.) multilocularis. Very little is known on the influence of helminth parasites which develop in the liver on the proliferation/growth arrest metabolic pathways in the hepatocytes of the infected liver over the various stages of infection. METHODOLOGY/PRINCIPAL FINDINGS: Using Western blot analysis, qPCR and immunohistochemistry, we measured the levels of MAPKs activation, Cyclins, PCNA, Gadd45β, Gadd45γ, p53 and p21 expression in the murine AE model, from day 2 to 360 post-infection. Within the early (day 2-60) and middle (day60-180) stages, CyclinB1 and CyclinD1 gene expression increased up to day30 and then returned to control level after day60; Gadd45β, CyclinA and PCNA increased all over the period; ERK1/2 was permanently activated. Meanwhile, p53, p21 and Gadd45γ gene expression, and caspase 3 activation, gradually increased in a time-dependent manner. In the late stage (day180-360), p53, p21 and Gadd45γ gene expression were significantly higher in infected mice; JNK and caspase 3 were activated. TUNEL analysis showed apoptosis of hepatocytes. No significant change in CyclinE, p53 mRNA and p-p38 expression were observed at any time. CONCLUSIONS: Our data support the concept of a sequential activation of metabolic pathways which 1) would first favor parasitic, liver and immune cell proliferation and survival, and thus promote metacestode fertility and tolerance by the host, and 2) would then favor liver damage/apoptosis, impairment in protein synthesis and xenobiotic metabolism, as well as promote immune deficiency, and thus contribute to the dissemination of the protoscoleces after metacestode fertility has been acquired. These findings give a rational explanation to the clinical observations of hepatomegaly and of unexpected survival of AE patients after major hepatic resections, and of chronic liver injury, necrosis and of hepatic failure at an advanced stage and in experimental animals.

Published
2012

14. Acute lung, heart, liver, and pancreatic involvements with hyponatremia and retinochoroiditis in a 33-year-old French Guianan patient

Author

Matthieu Groh, Patrick Yeni, Daniel Ajzenberg, Magalie Demar, Véronique Joly, Dominique Aubert, Isabelle Villena, Sandrine Houze, Bernard Carme, Cécile Charlois-Ou, Alexandra Faussart, Stéphane Simon, Service des maladies infectieuses et tropicales, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Centre National de Référence (CNR) Toxoplasmose/Toxoplasma Biological Resource Center (BRC) (CNR Toxoplasmose-Toxoplasma BRC), CHU Limoges, Université de Limoges (UNILIM), Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Centre d'investigation clinique Antilles-Guyane (CIC - Antilles Guyane), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU de la Martinique [Fort de France]-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Epidémiologie des parasitoses et mycoses tropicales, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles et de la Guyane (UAG), Unité des Maladies Infectieuses et Tropicales (UMIT), Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Service de maladies infectieuses et tropicales, AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Mère et enfant face aux infections tropicales (MERIT - UMR_D 216), Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5), Laboratoire de Recherche en Pathologie Infectieuse, Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Centre National de Référence (CNR) Toxoplasmose/Toxoplasma Biological Resource Center (BRC) ( CNR Toxoplasmose-Toxoplasma BRC ), Université de Limoges ( UNILIM ), Neuroépidémiologie Tropicale ( NET ), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST ), Université de Limoges ( UNILIM ) -Université de Limoges ( UNILIM ), Centre d'investigation clinique Antilles-Guyane ( CIC - Antilles Guyane ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU de la Martinique-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Université des Antilles et de la Guyane ( UAG ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Unité des Maladies Infectieuses et Tropicales ( UMIT ), AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Mère et enfant face aux infections tropicales ( MERIT - UMR_D 216 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut de Recherche pour le Développement ( IRD ), Université Paris Diderot - Paris 7 ( UPD7 ), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université des Antilles et de la Guyane (UAG)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), and Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Travel-Associated Diseases, Pathology, Choroiditis, RC955-962, Lung pathology, MESH: Choroiditis, 0302 clinical medicine, Arctic medicine. Tropical medicine, MESH : Myocardium, Neuroepidemiology, MESH : Pancreas, Lung, ComputingMilieux_MISCELLANEOUS, MESH: Guinea, 0303 health sciences, MESH : Guinea, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, MESH : Adult, MESH : Hyponatremia, MESH: Pancreas, 3. Good health, Infectious Diseases, Liver, MESH: Toxoplasmosis, language, Medicine, Public aspects of medicine, RA1-1270, Liver pathology, Toxoplasmosis, Hyponatremia, Neglected Tropical Diseases, Adult, medicine.medical_specialty, MESH: Myocardium, Infectious Disease Control, MESH : Lung, MESH : Male, 030231 tropical medicine, Old French, MESH : Toxoplasmosis, 03 medical and health sciences, Parasitic Diseases, Lung heart, medicine, Humans, MESH: Lung, Pancreas, 030304 developmental biology, Symposium, MESH: Humans, business.industry, Myocardium, General surgery, MESH : Humans, Public Health, Environmental and Occupational Health, MESH : Liver, MESH: Adult, MESH: Male, language.human_language, MESH: Hyponatremia, Guinea, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH : Choroiditis, MESH: Liver
Abstract

1 Department of Infectious Diseases, Hopital Bichat, Paris Diderot University, Paris, France, 2 Department of Parasitology and Mycology, Hopital Bichat, Paris Diderot University, Paris, France, 3 National Reference Centre on Toxoplasmosis and Biological Resource Centre Toxoplasma, EA3800, Department of Parasitology and Mycology, CHU Maison Blanche, University of Reims Champagne-Ardenne, Reims, France, 4 INSERM UMR 1094, Tropical Neuroepidemiology, Department of Parasitology and Mycology, University of Limoges, Limoges, France, 5 EA 3593, Department of Parasitology and Mycology, Cayenne Hospital, University of the Antilles and Guyana, Cayenne, French Guiana

Published
2012

15. Expression and differential localization of xenobiotic transporters in the rat olfactory neuro-epithelium

Author

Yves Artur, Christine Belloir, Nicolas Thiebaud, Anne-Marie Le Bon, Jean-Marie Heydel, Franck Ménétrier, Anne-Laure Minn, Fabrice Neiers, Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB), Agence Nationale de la Recherche (ANR-05-PNRA-1.E7), Aromalim Burgundy Regional Council (IFR92), French Ministry of Research, Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), and Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS )

Subjects
Male, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, MESH : Multidrug Resistance-Associated Proteins, p glycoprotein, ATP-binding cassette transporter, MESH : Hepatocytes, Receptors, Odorant, MESH : P-Glycoprotein, MESH: Hepatocytes, MESH : Lymphatic Vessels, 0302 clinical medicine, MESH : Protein Transport, ugt2a1, MESH: Smell, MESH: Receptors, Odorant, MESH: Animals, Receptor, xenobiotic metabolizing, mucosa, 0303 health sciences, MESH : Gene Expression Regulation, MESH : Rats, General Neuroscience, MESH : Odors, MESH: Gene Expression Regulation, Smell, Protein Transport, medicine.anatomical_structure, Biochemistry, Liver, transporter, barrier, Efflux, Multidrug Resistance-Associated Proteins, MESH: Multidrug Resistance-Associated Proteins, MESH: Xenobiotics, MESH: Protein Transport, MESH: P-Glycoprotein, MESH: Rats, MESH: Lymphatic Vessels, MESH : Male, odorant clearance, brain, MESH : Xenobiotics, xenobiotic, Biology, system, MESH : Rats, Wistar, Olfactory Receptor Neurons, Xenobiotics, 03 medical and health sciences, bulb, Olfactory Mucosa, multidrug resistance, MESH : Receptors, Odorant, medicine, Animals, ATP Binding Cassette Transporter, Subfamily B, Member 1, Rats, Wistar, detoxification, MESH: Olfactory Mucosa, 030304 developmental biology, Lymphatic Vessels, MESH : Olfactory Mucosa, MESH: Odors, MESH : Liver, Transporter, MESH: Rats, Wistar, MESH: Olfactory Receptor Neurons, Epithelium, MESH: Male, Olfactory bulb, Rats, enzyme, Gene Expression Regulation, Odorants, Hepatocytes, MESH : Smell, MESH : Olfactory Receptor Neurons, MESH : Animals, olfactory epithelium, Olfactory epithelium, perireceptor event, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery, Drug metabolism, MESH: Liver
Abstract

International audience; Transporters, such as multidrug resistance P-glycoproteins (MDR), multidrug resistance-related proteins (MRP) and organic anion transporters (OATs), are involved in xenobiotic metabolism, particularly the cellular uptake or efflux of xenobiotics (and endobiotics) or their metabolites. The olfactory epithelium is exposed to both inhaled xenobiotics and those coming from systemic circulation. This tissue has been described as a pathway for xenobiotics to the brain via olfactory perineural space. Thereby, olfactory transporters and xenobiotic metabolizing enzymes, dedicated to the inactivation and the elimination of xenobiotics, have been involved in the toxicological protection of the brain, the olfactory epithelium itself and the whole body. These proteins could also have a role in the preservation of the olfactory sensitivity by inactivation and clearance of the excess of odorant molecules from the perireceptor space. The goal of the present study was to increase our understanding of the expression and the localization of transporters in this tissue. For most of the studied transporters, we observed an opposite mRNA expression pattern (RT-PCR) in the olfactory epithelium compared to the liver, which is considered to be the main metabolic organ. Olfactory epithelium mainly expressed efflux transporters (MRP, MDR). However, a similar pattern was observed between the olfactory epithelium and the olfactory bulb. We also demonstrate distinct cellular immunolocalization of the transporters in the olfactory epithelium. As previously reported, Mrp1 was mainly found in the supranuclear portions of supporting cells. In addition, Mrp3 and Mrp5 proteins, which were detected for the first time in olfactory epithelium, were localized to the olfactory neuron layer, while Mdr1 was localized to the capillary endothelium of lymphatic vessels in the subepithelial region. The pattern of expression and the distinct localization of the olfactory transporters showed in this work may highlight on their specific function in the whole olfactory epithelium.

Published
2011

16. NKT cells are required to induce high IL-33 expression in hepatocytes during ConA-induced acute hepatitis

Author

Michel Rauch, Muhammad Imran Arshad, Michel Samson, Maria Leite-de-Moraes, Valérie Julia, Catherine Lucas-Clerc, Claire Piquet-Pellorce, Annie L'Helgoualc'h, Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes (UR), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biochimie générale, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], INSERM, Ministère de l'Education Nationale de la Recherche et de la Technologie, University de Rennes 1, Région Bretagne, National French Society of Gastro-Enterology (SNFGE), Ligue contre le cancer, IFR 140, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140, Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA), Signalisation et Réponses aux Agents Infectieux et Chimiques ( SeRAIC ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140, Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ), Cytokines, hématopoïèse et réponse immune ( CHRI ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)

Subjects
Male, medicine.medical_treatment, Fluorescent Antibody Technique, MESH : Carbon Tetrachloride, MESH: Flow Cytometry, MESH : Hepatocytes, MESH: Hepatocytes, Mice, 0302 clinical medicine, MESH: Interleukin-1beta, Concanavalin A, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH: Animals, MESH: Fluorescent Antibody Technique, 0303 health sciences, MESH : Acute Disease, MESH : Reverse Transcriptase Polymerase Chain Reaction, MESH: Hepatitis, Animal, Flow Cytometry, Natural killer T cell, Adoptive Transfer, 3. Good health, NKT cells, Alarmin, CD1D, Acute Disease, MESH: Acute Disease, Tumor necrosis factor alpha, MESH : Antigens, CD1d, MESH: Interleukins, MESH: Gene Expression, Immunology, MESH: Concanavalin A, MESH : Interleukin-1beta, 03 medical and health sciences, Tumor Necrosis Factor-alpha, Interleukins, MESH: Carbon Tetrachloride, Interleukin-33, medicine.disease, MESH: Interleukin-6, MESH : Gene Expression, MESH : Fluorescent Antibody Technique, MESH: Adoptive Transfer, MESH: Antigens, CD1d, MESH: Tumor Necrosis Factor-alpha, Natural Killer T-Cells, MESH : Hepatitis, Animal, MESH: Female, MESH: Liver, Adoptive cell transfer, Interleukin-1beta, Gene Expression, Hepatitis, Animal, MESH: Mice, Knockout, Hepatitis, MESH: Reverse Transcriptase Polymerase Chain Reaction, Immunology and Allergy, MESH : Female, Carbon Tetrachloride, MESH : Concanavalin A, Mice, Knockout, MESH : Tumor Necrosis Factor-alpha, Mice, Inbred BALB C, biology, Reverse Transcriptase Polymerase Chain Reaction, MESH : Adoptive Transfer, Cytokine, Liver, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH : Interleukin-6, MESH : Flow Cytometry, MESH : Male, MESH: Mice, Inbred BALB C, chemical and pharmacologic phenomena, MESH : Mice, medicine, Animals, MESH: Mice, MESH : Mice, Inbred BALB C, 030304 developmental biology, Interleukin-6, MESH : Liver, MESH : Natural Killer T-Cells, Molecular biology, MESH: Male, Interleukin 33, MESH: Natural Killer T-Cells, Hepatocytes, biology.protein, IL-33, MESH : Mice, Knockout, MESH : Animals, Antigens, CD1d, MESH : Interleukins, 030215 immunology
Abstract

International audience; Interleukin-33 (IL-33) is thought to be released during cellular death as an alarming cytokine during the acute phase of disease, but its regulation in vivo is poorly understood. We investigated the expression of IL-33 in two mouse models of acute hepatitis by administering either carbon tetrachloride (CCl(4) ) or concanavalin A (ConA). IL-33 was overexpressed in both models but with a stronger induction in ConA-induced hepatitis. IL-33 was weakly expressed in vascular and sinusoidal endothelial cells from normal liver and was clearly induced in CCl(4) -treated mice. Surprisingly, we found that hepatocytes strongly expressed IL-33 exclusively in the ConA model. CD1d knock-out mice, which are deficient in NKT cells and resistant to ConA-induced hepatitis, no longer expressed IL-33 in hepatocytes following ConA administration. Interestingly, invariant NKT (iNKT) cells adoptively transferred into ConA-treated CD1d KO mouse restored IL-33 expression in hepatocytes. This strongly suggests that NKT cells are responsible for the induction of IL-33 in hepatocytes.

Published
2011

17. Coagulation factor X mediates adenovirus type 5 liver gene transfer in non-human primates (Microcebus murinus)

Author

Nadine Mestre-Francés, Angela C. Bradshaw, Daniel Henaff, Andrew H. Baker, Raul Alba, Jean-Michel Verdier, British Heart Foundation Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow-NHS Greater Glasgow and Clyde, Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Université Montpellier 2 - Sciences et Techniques (UM2)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the European Commission FP7 BRAINCAV programme., European Project: 222992,EC:FP7:HEALTH,FP7-HEALTH-2007-B,BRAINCAV(2008), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Mécanismes moléculaires dans les démences neurodégénératives ( MMDN ), École pratique des hautes études ( EPHE ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Université de Montpellier ( UM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Montpellier ( UM ), European Project : 222992,EC:FP7:HEALTH,FP7-HEALTH-2007-B,BRAINCAV ( 2008 ), Université Montpellier 2 - Sciences et Techniques (UM2)-École pratique des hautes études (EPHE), Verdier, Jean-Michel, and NONHUMAN ADENOVIRUS VECTORS FOR GENE TRANSFER TO THE BRAIN - BRAINCAV - - EC:FP7:HEALTH2008-10-01 - 2013-03-31 - 222992 - VALID

Subjects
Liver cytology, MESH: Spleen, MESH : Immunohistochemistry, viruses, MESH: Factor X, MESH : Hepatocytes, MESH: Gene Targeting, medicine.disease_cause, MESH: Hepatocytes, chemistry.chemical_compound, Transduction (genetics), 0302 clinical medicine, MESH: Genetic Vectors, MESH: Animals, 0303 health sciences, biology, Factor X, Gene Transfer Techniques, Gene targeting, MESH : Protein Binding, MESH: Adenoviridae, Immunohistochemistry, MESH : Genetic Vectors, 3. Good health, MESH : Factor X, medicine.anatomical_structure, Liver, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], 030220 oncology & carcinogenesis, Hepatocyte, Gene Targeting, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Molecular Medicine, MESH: Cheirogaleidae, MESH: Genome, Viral, Cheirogaleidae, MESH : Gene Therapy, MESH : Genome, Viral, MESH : Heparan Sulfate Proteoglycans, Protein Binding, MESH : Spleen, Microcebus murinus, MESH : Cell Membrane, Genetic Vectors, Spleen, MESH: Gene Transfer Techniques, Genome, Viral, Article, Adenoviridae, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, medicine, MESH: Protein Binding, Animals, MESH : Adenoviridae, MESH : Gene Transfer Techniques, Molecular Biology, 030304 developmental biology, MESH : Cheirogaleidae, Cell Membrane, MESH : Liver, MESH: Immunohistochemistry, Genetic Therapy, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, Molecular biology, chemistry, MESH: Heparan Sulfate Proteoglycans, Hepatocytes, MESH : Animals, MESH: Gene Therapy, MESH : Gene Targeting, Heparan Sulfate Proteoglycans, MESH: Liver, MESH: Cell Membrane
Abstract

International audience; Coagulation factor X (FX)-binding ablated adenovirus type 5 (Ad5) vectors have been genetically engineered to ablate the interaction with FX, resulting in substantially reduced hepatocyte transduction following intravenous administration in rodents. Here, we quantify viral genomes and gene transfer mediated by Ad5 and FX-binding-ablated Ad5 vectors in non-human primates. Ad5 vectors accumulated in and mediated gene transfer predominantly to the liver, whereas FX-binding-ablated vectors primarily targeted the spleen but showed negligible liver gene transfer. In addition, we show that Ad5 binding to hepatocytes may be due to the presence of heparan sulfate proteoglycans (HSPGs) on the cell membrane. Therefore, the Ad5-FX-HSPG pathway mediating liver gene transfer in rodents is also the mechanism underlying Ad5 hepatocyte transduction in Microcebus murinus.

Published
2011

18. Invariant natural killer T-cell-deficient mice display increased CCl₄ -induced hepatitis associated with CXCL1 over-expression and neutrophil infiltration

Author

Lisbonne, Mariette, L'Helgoualc'H, Annie, Nauwelaers, Gwendoline, Turlin, Bruno, Lucas, Catherine, Herbelin, André, Piquet-Pellorce, Claire, Samson, Michel, Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), departement de pathologie, Laboratoire de biochimie générale, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140, Signalisation et Réponses aux Agents Infectieux et Chimiques ( SeRAIC ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140, Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ), Cytokines, hématopoïèse et réponse immune ( CHRI ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Rennes (UR), and CHU Pontchaillou [Rennes]

Subjects
CXCL1/KC, Neutrophils, Chemokine CXCL1, Receptors, Antigen, T-Cell, alpha-beta, MESH : Carbon Tetrachloride, Apoptosis, MESH : Hepatocytes, Hepatitis, Animal, MESH: Neutrophils, MESH: Mice, Knockout, Hepatitis, MESH : Neutrophils, MESH: Hepatocytes, Mice, Cell Movement, MESH : Cell Movement, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH: Animals, MESH : Matrix Metalloproteinase 8, Carbon Tetrachloride, MESH: Cell Movement, Cells, Cultured, Mice, Knockout, Alanine, MESH: Receptors, Antigen, T-Cell, alpha-beta, MESH : Acute Disease, Neutrophil, MESH: Hepatitis, Animal, MESH : Chemokine CXCL1, Matrix Metalloproteinase 8, MESH : Receptors, Antigen, T-Cell, alpha-beta, Liver, Acute Disease, MESH: Acute Disease, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Cells, Cultured, MESH: Alanine, MESH : Aspartate Aminotransferases, MESH: Aspartate Aminotransferases, MESH : Mice, MESH : Cells, Cultured, Animals, MESH: Chemokine CXCL1, Aspartate Aminotransferases, MESH: Mice, MESH: Apoptosis, MESH: Carbon Tetrachloride, MESH : Liver, MESH : Natural Killer T-Cells, MESH: Natural Killer T-Cells, MESH: Matrix Metalloproteinase 8, Hepatocytes, Invariant NKT cells, MESH : Mice, Knockout, Natural Killer T-Cells, MESH : Animals, MESH : Alanine, MESH : Hepatitis, Animal, MESH : Apoptosis, MESH: Liver
Abstract

International audience; Invariant natural killer T (iNKT) cells are involved in the intrahepatic immune response and in hepatitis. In particular, iNKT lymphocytes are responsible for hepatocyte death in concanavalin A-induced hepatitis in mice. We examined the role of iNKT cells in acute hepatitis induced by a hepatotoxic agent, carbon tetrachloride (CCl(4) ). WT and iNKT cell-deficient (Jα18(-/-) ) mice were challenged with a single dose of 2.4 g/kg CCl(4) and both hepatic physiopathology and immune responses were studied. Plasma alanine and aspartate amino-transferase levels were significantly higher in Jα18(-/-) mice than in WT mice two days after CCl(4) administration. Chemokine CXCL1/keratinocyte-derived chemokine (KC) and MMP-8 were significantly higher in iNKT cell-deficient mice than in control mice. The more severe liver injury in Jα18(-/-) mice was associated with greater leukocyte infiltrate, which was enriched in neutrophils (CD11b(+) CD11c(-) Gr-1(+) cells), in agreement with CXCL1/KC and MMP-8 levels. Complementary experiments with NK-depleted animals indicate a minor role for NK cells in the liver damage found in iNKT-deficient mice. Thus, unlike for ConA-induced hepatitis, we report that iNKT cells protect the liver against acute hepatitis induced by CCl(4) and limit neutrophil infiltration.

Published
2011

19. A role for the peroxisomal 3-ketoacyl-CoA thiolase B enzyme in the control of PPARα-mediated upregulation of SREBP-2 target genes in the liver.: ThB and cholesterol biosynthesis in the liver

Author

Marc Espeel, Norbert Latruffe, Marie Charlotte Royer, Grégory Chevillard, Ronald J.A. Wanders, Melina De Bruycker, Valérie Nicolas-Francès, Sander Kersten, Ségolène Arnauld, Anne Athias, Pierre Clouet, Marie Claude Clémencet, Stéphane Mandard, Joseph Gresti, Pascal Degrace, Marco Fidaleo, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Department of Human Anatomy, Embryology, Histology and Medical Physics, Universiteit Gent = Ghent University [Belgium] (UGENT), Laboratory Genetic Metabolic Diseases, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA)-Universiteit van Amsterdam (UvA), Plateforme Lipidomique [Dijon] (LAP), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-IFR100 - Structure fédérative de recherche Santé-STIC-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Nutrition, Metabolism and Genomics Group, Wageningen University and Research [Wageningen] (WUR), This work was supported by grants from the European Union project 'Peroxisomes' LSHG-CT-2004-512018, the Regional Council of Burgundy and the INSERM U866 center (Dijon). G.C. was supported by a French Ministry of Research and Technology Ph.D. fellowship and M.F. by the Italian 'Ministero della Ricerca Scientifica e Tecnologica'., AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Ghent University [Belgium] ( UGENT ), Universiteit van Amsterdam ( UvA ) -Academic Medical Center [Amsterdam] ( AMC ), University of Amsterdam [Amsterdam] ( UvA ) -University of Amsterdam [Amsterdam] ( UvA ), Plateforme Lipidomique [Dijon] ( LAP ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -IFR100 - Structure fédérative de recherche Santé-STIC-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Wageningen University and Research Centre [Wageningen] ( WUR ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Universiteit van Amsterdam (UvA)-Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-IFR100 - Structure fédérative de recherche Santé-STIC-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)

Subjects
Male, MESH: Hepatomegaly, Palmitates, MESH : Pyrimidines, MESH : Gene Deletion, Biochemistry, element-binding proteins, MESH : Acetyl-CoA C-Acyltransferase, Mice, MESH: Up-Regulation, MESH: Animals, MESH : Up-Regulation, MESH: Lipid Metabolism, 0303 health sciences, MESH : Gene Expression Regulation, Thiolase, 030302 biochemistry & molecular biology, General Medicine, MESH : Hepatomegaly, Up-Regulation, zellweger-syndrome, Peroxisome Proliferators, MESH: Peroxisome Proliferators, Hepatomegaly, Sterol Regulatory Element Binding Protein 2, peroxisomal 3-ketoacyl-CoA thiolase B, MESH: Mitochondria, 3-oxoacyl-coa thiolase, Lathosterol, fatty-acid oxidation, rat-liver, MESH: Sterol Regulatory Element Binding Protein 2, 03 medical and health sciences, MESH : Sterol Regulatory Element Binding Protein 2, Humans, PPAR alpha, MESH : Peroxisome Proliferators, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, PPARa, VLAG, MESH : Oxidation-Reduction, Fatty Acid Oxidation, MESH: Humans, Cholesterol, MESH : Humans, cholesterol, Lipid Metabolism, MESH: Peroxisomes, Sterol regulatory element-binding protein, chemistry, MESH: Pyrimidines, Micro-array analysis, Peroxisomal 3-ketoacyl-CoA thiolase B, PPARα and SREBP-2, Wy14,643, Gene Deletion, MESH: Liver, MESH: Oxidation-Reduction, MESH: Signal Transduction, MESH: Mice, Knockout, Voeding, Metabolisme en Genomica, chemistry.chemical_compound, MESH: Cholesterol, MESH : Lipid Metabolism, Wy14, MESH : Palmitates, MESH: PPAR alpha, MESH : Cholesterol, Mice, Knockout, neuronal migration, Peroxisome, Acetyl-CoA C-Acyltransferase, MESH: Gene Expression Regulation, Metabolism and Genomics, Mitochondria, Liver, Metabolisme en Genomica, ACOX1, Nutrition, Metabolism and Genomics, MESH : Mitochondria, Oxidation-Reduction, Signal Transduction, acyl-coa oxidase, cholesterol-synthesis, MESH : Male, MESH : PPAR alpha, Peroxisome Proliferation, Biology, beta-oxidation, Voeding, proliferator-activated receptors, MESH : Mice, Peroxisomes, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, 030304 developmental biology, SCP2, Nutrition, MESH : Signal Transduction, MESH : Liver, MESH: Palmitates, MESH: Male, Pyrimidines, MESH: Acetyl-CoA C-Acyltransferase, Gene Expression Regulation, MESH: Gene Deletion, MESH : Mice, Knockout, MESH : Animals, MESH : Peroxisomes
Abstract

International audience; Peroxisomal 3-ketoacyl-CoA thiolase B (Thb) catalyzes the final step in the peroxisomal β-oxidation of straight-chain acyl-CoAs and is under the transcription control of the nuclear hormone receptor PPARα. PPARα binds to and is activated by the synthetic compound Wy14,643 (Wy). Here, we show that the magnitude of Wy-mediated induction of peroxisomal β-oxidation of radiolabeled (1-(14)C) palmitate was significantly reduced in mice deficient for Thb. In contrast, mitochondrial β-oxidation was unaltered in Thb(-/-) mice. Given that Wy-treatment induced Acox1 and MFP-1/-2 activity at a similar level in both genotypes, we concluded that the thiolase step alone was responsible for the reduced peroxisomal β-oxidation of fatty acids. Electron microscopic analysis and cytochemical localization of catalase indicated that peroxisome proliferation in the liver after Wy-treatment was normal in Thb(-/-) mice. Intriguingly, micro-array analysis revealed that mRNA levels of genes encoding cholesterol biosynthesis enzymes were upregulated by Wy in Wild-Type (WT) mice but not in Thb(-/-) mice, which was confirmed at the protein level for the selected genes. The non-induction of genes encoding cholesterol biosynthesis enzymes by Wy in Thb(-/-) mice appeared to be unrelated to defective SREBP-2 or PPARα signaling. No difference was observed in the plasma lathosterol/cholesterol ratio (a marker for de novo cholesterol biosynthesis) between Wy-treated WT and Thb(-/-) mice, suggesting functional compensation. Overall, we conclude that ThA and SCPx/SCP2 thiolases cannot fully compensate for the absence of ThB. In addition, our data indicate that ThB is involved in the regulation of genes encoding cholesterol biosynthesis enzymes in the liver, suggesting that the peroxisome could be a promising candidate for the correction of cholesterol imbalance in dyslipidemia.

Published
2011

20. Differential liver proteome mapping of control and cadmium-fed rats

Author

Pierre-Marie Badot, C. Schaeffer, F. Hispard, Hélène Martin, A. de Vaufleury, Renaud Scheifler, Lysiane Richert, Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire de Spectrométrie de Masse BioOrganique [Strasbourg] (LSMBO), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biophotonique et Pharmacologie - UMR 7213 (LBP), Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA)), Conseil Regional of Franche-Comte, ADEME (Agence De l'Environnement et de la Maitrise de l'Energie) [0572 C0058], ANR (Agence Nationale de la Recherche) [ANR-05-ECC0-004], Laboratoire Chrono-environnement ( LCE ), Université Bourgogne Franche-Comté ( UBFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), Laboratoire de spectrométrie de masse bioorganique, institut pluridisciplinaire hubert curien ( UMRCNRS-ULP7178 ), Laboratoire de Biophotonique et Pharmacologie - UMR 7213 ( LBP ), Centre National de la Recherche Scientifique ( CNRS ) -Réseau nanophotonique et optique, Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire Magmas et Volcans ( LMV ), and Université Blaise Pascal - Clermont-Ferrand 2 ( UBP ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Université Jean Monnet [Saint-Étienne] ( UJM ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
Proteome, Health, Toxicology and Mutagenesis, [ SDV.TOX.ECO ] Life Sciences [q-bio]/Toxicology/Ecotoxicology, Phosphatidylethanolamine Binding Protein, GUIDELINES, 01 natural sciences, TOXICITY, MESH : Protein Interaction Mapping, Protein Interaction Mapping, PF-2D, Metallothionein, MESH: Thiobarbituric Acid Reactive Substances, Electrophoresis, Gel, Two-Dimensional, MESH : Female, MESH: Animals, MESH : Cadmium, MESH : Environmental Pollutants, MESH: Superoxide Dismutase, 0303 health sciences, Cadmium, GEL, MESH : Rats, General Medicine, Repeatability, Pollution, 3. Good health, TIME, MESH: Proteome, Biochemistry, Liver, MESH: Environmental Pollutants, Toxicity, Environmental Pollutants, Female, [SDV.TOX.ECO]Life Sciences [q-bio]/Toxicology/Ecotoxicology, LIQUID-CHROMATOGRAPHY, Rat liver, TISSUES, MESH: Rats, MESH: Cadmium, chemistry.chemical_element, MESH : Proteome, MESH : Thiobarbituric Acid Reactive Substances, Biology, BINDING PROTEIN, MESH : Rats, Wistar, Thiobarbituric Acid Reactive Substances, 03 medical and health sciences, Digestive exposure, Ecotoxicology, Animals, MESH : Superoxide Dismutase, Rats, Wistar, 030304 developmental biology, FLIGHT-MASS-SPECTROMETRY, IDENTIFICATION, Superoxide Dismutase, METALLOTHIONEIN, Binding protein, 010401 analytical chemistry, MESH: Protein Interaction Mapping, Public Health, Environmental and Occupational Health, MESH : Liver, MESH : Electrophoresis, Gel, Two-Dimensional, MESH: Rats, Wistar, MESH: Electrophoresis, Gel, Two-Dimensional, 0104 chemical sciences, Rats, MESH: Phosphatidylethanolamine Binding Protein, chemistry, MESH : Phosphatidylethanolamine Binding Protein, MESH : Animals, MESH: Female, MESH: Liver
Abstract

International audience; A comparative study of proteome maps from control and Cd-exposed rat liver was performed using a new technology of two-dimensional liquid chromatography separation method (PF-2D system, Beckman Coulter). Rats were fed for one month 0 or 100 μg Cd g(-1). The between-replicate and between-sample variations showed good repeatability and suitable reproducibility for the two dimensions of separation of proteins. In this complex mixture, PF-2D led to the separation of two major peaks which differed between control and Cd-exposed rat livers, one being identified by mass spectrometry as Cu/Zn superoxide dismutase (SOD), a well-known biomarker of Cd exposure, the other as phosphatidylethanolamine binding protein (PEBP). SOD content was decreased in Cd-exposed rat liver, compared to the control group which was corroborated by a significant decrease of SOD activity. PEBP content also tended to be decreased after Cd exposure. Present results demonstrate interest but also limitations of proteomic approach using PF-2D system to analyze effects of chemicals on organisms.

Published
2011

21. Effects of a high-fat diet on energy metabolism and ROS production in rat liver

Author

Anne Galinier, Hervé Dubouchaud, Nellie Taleux, Karine Couturier, Cécile Cottet-Rousselle, Louis Casteilla, Anne Athias, Xavier Leverve, Guillaume Vial, Bioenergétique fondamentale et appliquée ( LBFA ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Métabolisme, plasticité et mitochondrie, Université Paul Sabatier - Toulouse 3 ( UPS ) -IFR31-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Métabolisme Plasticité et Mitochondrie [lié à l'ex IFR 31] (LMPM), IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Hamant, Sarah

Subjects
Mitochondrial ROS, Male, Transcription, Genetic, MESH : Reactive Oxygen Species, Mitochondria, Liver, MESH : Hepatocytes, Mitochondrion, Oxidative Phosphorylation, MESH: Hepatocytes, 0302 clinical medicine, MESH: Membrane Potential, Mitochondrial, Citrate synthase, MESH: Animals, Beta oxidation, MESH : Electron Transport, 2. Zero hunger, Membrane Potential, Mitochondrial, 0303 health sciences, MESH : Rats, Adenine nucleotide translocator, MESH: Energy Metabolism, MESH: Reactive Oxygen Species, Lipids, Biochemistry, Liver, MESH: Dietary Fats, Mitochondrial matrix, 030220 oncology & carcinogenesis, Body Composition, MESH : Oxidative Phosphorylation, ATP–ADP translocase, MESH: Mitochondria, Liver, MESH: Rats, MESH : Body Composition, MESH : Male, Oxidative phosphorylation, Biology, MESH : Rats, Wistar, Electron Transport, 03 medical and health sciences, MESH: Oxidative Phosphorylation, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Rats, Wistar, MESH: Electron Transport, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Hepatology, MESH: Transcription, Genetic, MESH : Transcription, Genetic, MESH : Liver, MESH : Lipids, MESH: Body Composition, MESH: Rats, Wistar, MESH: Lipids, Dietary Fats, MESH: Male, Rats, MESH : Energy Metabolism, MESH : Membrane Potential, Mitochondrial, MESH : Mitochondria, Liver, biology.protein, Hepatocytes, MESH : Animals, Energy Metabolism, Reactive Oxygen Species, MESH : Dietary Fats, MESH: Liver
Abstract

International audience; BACKGROUND & AIMS: A high-fat diet affects liver metabolism, leading to steatosis, a complex disorder related to insulin resistance and mitochondrial alterations. Steatosis is still poorly understood since diverse effects have been reported, depending on the different experimental models used. METHODS: We hereby report the effects of an 8 week high-fat diet on liver energy metabolism in a rat model, investigated in both isolated mitochondria and hepatocytes. RESULTS: Liver mass was unchanged but lipid content and composition were markedly affected. State-3 mitochondrial oxidative phosphorylation was inhibited, contrasting with unaffected cytochrome content. Oxidative phosphorylation stoichiometry was unaffected, as were ATPase and adenine nucleotide translocator proteins and mRNAs. Mitochondrial acylcarnitine-related H(2)O(2) production was substantially higher and the mitochondrial quinone pool was smaller and more reduced. Cellular consequences of these mitochondrial alterations were investigated in perifused, freshly isolated hepatocytes. Ketogenesis and fatty acid-dependent respiration were lower, indicating a lower β-oxidation rate contrasting with higher RNA contents of CD36, FABP, CPT-1, and AcylCoA dehydrogenases. Concomitantly, the cellular redox state was more reduced in the mitochondrial matrix but more oxidized in the cytosol: these opposing changes are in agreement with a significantly higher in situ mitochondrial proton motive force. CONCLUSIONS: A high-fat diet results in both a decrease in mitochondrial quinone pool and a profound modification in mitochondrial lipid composition. These changes appear to play a key role in the resulting inhibition of fatty acid oxidation and of mitochondrial oxidative-phosphorylation associated with an increased mitochondrial ROS production. Mitochondrial quinone pool could have prospects as a crucial event, potentially leading to interesting therapeutic perspectives.

Published
2011

22. Iron-deficiency anemia from matriptase-2 inactivation is dependent on the presence of functional Bmp6.: Matriptase-2 and Bmp6 deficiency in mice

Author

Lenoir, Anne, Deschemin, Jean-Christophe, Kautz, Léon, Ramsay, Andrew, Roth, Marie-Paule, Lopez-Otin, Carlos, Vaulont, Sophie, Nicolas, Gaël, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo-Instituto Universitario de Oncología, Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Physiopathologie Toulouse Purpan (ex IFR 30 et IFR 150), Université Toulouse III - Paul Sabatier ( UPS ), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR30-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM )

Subjects
inorganic chemicals, MESH: Signal Transduction, congenital, hereditary, and neonatal diseases and abnormalities, matriptase2, MESH: Anemia, Iron-Deficiency, MESH: Bone Morphogenetic Protein 6, digestive system, MESH: Mice, Knockout, MESH : Iron, MESH : Iron, Dietary, MESH : Serine Endopeptidases, hemic and lymphatic diseases, MESH : Mice, tmprss6, MESH : Female, MESH: Animals, bmp6, MESH: Serine Endopeptidases, MESH: Mice, MESH : Signal Transduction, MESH : Anemia, Iron-Deficiency, MESH: Iron, hemojuvelin, MESH: Antimicrobial Cationic Peptides, MESH : Liver, nutritional and metabolic diseases, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH : Antimicrobial Cationic Peptides, MESH: Iron, Dietary, MESH : Membrane Proteins, MESH : Mice, Knockout, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH : Animals, hepcidin, MESH: Membrane Proteins, MESH: Female, MESH : Bone Morphogenetic Protein 6, MESH: Liver
Abstract

International audience; Hepcidin is the master regulator of iron homeostasis. In the liver, iron-dependent hepcidin activation is regulated through Bmp6 and its membrane receptor hemojuvelin (Hjv), whereas, in response to iron deficiency, hepcidin repression seems to be controlled by a pathway involving the serine protease matriptase-2 (encoded by Tmprss6). To determine the relationship between Bmp6 and matriptase-2 pathways, Tmprss6(-/-) mice (characterized by increased hepcidin levels and anemia) and Bmp6(-/-) mice (exhibiting severe iron overload because of hepcidin deficiency) were intercrossed. We showed that loss of Bmp6 decreased hepcidin levels; increased hepatic iron; and, importantly, corrected hematologic abnormalities in Tmprss6(-/-) mice. This finding suggests that elevated hepcidin levels in patients with familial iron-refractory, iron-deficiency anemia are the result of excess signaling through the Bmp6/Hjv pathway.

Published
2011

23. PPARα activation differently affects microparticle content in atherosclerotic lesions and liver of a mouse model of atherosclerosis and NASH

Author

Aurélie S. Leroyer, Anne Tailleux, Philippe Delerive, Emmanuelle Vallez, Morgane Baron, Fanny Lalloyer, Kadiombo Bantubungi, Chantal M. Boulanger, Bart Staels, Zouher Majd, Giulia Chinetti-Gbaguidi, Derudas, Marie-Hélène, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Genfit, Entreprise biopharmaceutique GENFIT Loos, This work was supported by grants of EU grant Hepadip 018734, the Foundation Coeur et Artères and Région Nord-Pas de Calais / FEDER, Récepteurs nucléaires, maladies cardiovasculaires et diabète ( EGID ), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)

Subjects
Pathology, MESH : Fatty Liver, MESH : Atherosclerosis, MESH : Cell-Derived Microparticles, MESH: Flow Cytometry, 030204 cardiovascular system & hematology, MESH: Mice, Knockout, murine model, MESH: Atherosclerosis, Mice, 0302 clinical medicine, Fenofibrate, Cell-Derived Microparticles, Non-alcoholic Fatty Liver Disease, MESH: Cell-Derived Microparticles, MESH : Female, MESH: Animals, MESH: PPAR alpha, MESH: Fatty Liver, Mice, Knockout, microparticles, 0303 health sciences, medicine.diagnostic_test, Fatty liver, Flow Cytometry, MESH : Mice, Transgenic, Liver, Female, medicine.symptom, Cardiology and Cardiovascular Medicine, medicine.drug, medicine.medical_specialty, MESH : Flow Cytometry, MESH: Mice, Transgenic, Transgene, MESH : PPAR alpha, Inflammation, Mice, Transgenic, MESH : Mice, Inbred C57BL, Biology, Flow cytometry, 03 medical and health sciences, MESH: Mice, Inbred C57BL, Internal medicine, MESH : Mice, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, PPAR alpha, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: Humans, MESH : Humans, MESH: Biological Markers, MESH : Liver, nutritional and metabolic diseases, medicine.disease, MESH: Fenofibrate, MESH : Disease Models, Animal, Fatty Liver, Mice, Inbred C57BL, MESH : Biological Markers, Disease Models, Animal, Endocrinology, Nuclear receptor, Apoptosis, MESH : Mice, Knockout, fatty liver disease, MESH : Animals, Steatohepatitis, atherosclerosis, pharmacology, MESH: Disease Models, Animal, MESH : Fenofibrate, MESH: Female, Biomarkers, MESH: Liver
Abstract

International audience; BACKGROUND: Atherosclerosis and non-alcoholic fatty liver disease (NAFLD) are complex pathologies characterized by lipid accumulation, chronic inflammation and extensive tissue remodelling. Microparticles (MPs), small membrane vesicles produced by activated and apoptotic cells, might not only be biomarkers, but also functional actors in these pathologies. The apoE2-KI mouse is a model of atherosclerosis and NAFLD. Activation of the nuclear receptor PPARα decreases atherosclerosis and components of non-alcoholic steatohepatitis (NASH) in the apoE2-KI mouse. OBJECTIVES: (1) To determine whether MPs are present in atherosclerotic lesions, liver and plasma during atherosclerosis and NASH progression in apoE2-KI mice, and (2) to study whether PPARα activation modulates MP concentrations. METHODS: ApoE2-KI mice were fed a Western diet to induce atherosclerosis and NASH. MPs were isolated from atherosclerotic lesions, liver and blood and quantified by flow cytometry. RESULTS: An increase of MPs was observed in the atherosclerotic lesions and in the liver of apoE2-KI mice upon Western diet feeding. PPARα activation with fenofibrate decreased MP levels in the atherosclerotic lesions in a PPARα-dependent manner, but did not influence MP concentrations in the liver. CONCLUSION: Here we report that MPs are present in atherosclerotic lesions and in the liver of apoE2-KI mice. Their concentration increased during atherosclerosis and NASH development. PPARα activation differentially modulates MP levels in a tissue-specific manner.

Published
2011

24. Antiviral activity of Bay 41-4109 on hepatitis B virus in humanized Alb-uPA/SCID mice

Author

Eric Giang, Jacques Belghiti, Serban Morosan, Sophie Berissi, Céline Lamant, Johan Neyts, Eva Wimmer, Gherard Puerstinger, Patrick Soussan, Lucie DaSilva, Olivier Hantz, Marie-Noëlle Brunelle, Laurent Hannoun, Dina Kremsdorf, Hélène Massinet, Nicolas Brezillon, IFR Laennec (IL), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), neuroscience and barin technology, Service de chirurgie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Chirurgie Digestive, Hépato-Bilio-pancréatique et Transplantation Hépatique [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Microbiology and Immunology, Rega Institute for Medical Research, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), equipe 16, Physiopathologie moléculaire et nouveaux traitements des hépatites virales, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-IFR62-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-IFR62-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Carcinogenèse Hépatique et Virologie Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM), Pathogénèse des Hépatites Virales B et Immunothérapie (UMR_S 812), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), IFR Laennec ( IL ), Institut National de la Recherche Agronomique ( INRA ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Beaujon, Service de chirurgie digestive et hépato-bilio-pancréatique [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Catholic University of Leuven ( KU Leuven ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-IFR62-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-IFR62-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Pathogénèse des Hépatites Virales B et Immunothérapie ( UMR_S 812 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Beaujon, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université de Lyon-Université de Lyon-IFR62-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Cancérologie de Lyon (CRCL), and Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Mouse, Pyridines, Gastroenterology and hepatology, Biopsy, medicine.medical_treatment, MESH : Immunohistochemistry, MESH : Pyrimidines, MESH : Hepatitis B virus, MESH : Viral Load, Mice, SCID, MESH : Hepatocytes, Liver transplantation, medicine.disease_cause, Hepatitis, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Hepatocytes, Mice, MESH: Biopsy, 0302 clinical medicine, MESH : Albumins, MESH: Animals, MESH : DNA, Viral, MESH: Mice, SCID, 0303 health sciences, Multidisciplinary, MESH: Kinetics, virus diseases, Animal Models, Viral Load, Hepatitis B, Antivirals, Immunohistochemistry, 3. Good health, MESH : Antiviral Agents, Infectious hepatitis, MESH: Hepatitis B virus, Real-time polymerase chain reaction, Liver, Capsid, 030220 oncology & carcinogenesis, Infectious diseases, Medicine, MESH : Kinetics, MESH: Viral Load, Viral load, Research Article, MESH: Antiviral Agents, Hepatitis B virus, MESH : Pyridines, Science, Alpha interferon, Viremia, [SDV.CAN]Life Sciences [q-bio]/Cancer, Viral diseases, Biology, Antiviral Agents, Microbiology, 03 medical and health sciences, Model Organisms, Albumins, Virology, MESH : Mice, medicine, Animals, Humans, MESH: Mice, Liver diseases, 030304 developmental biology, MESH: Humans, MESH: Hepatitis B, MESH : Humans, MESH: Pyridines, MESH : Liver, MESH : Hepatitis B, MESH: Immunohistochemistry, medicine.disease, MESH : Mice, SCID, digestive system diseases, MESH: DNA, Viral, Kinetics, Animal Models of Infection, Pyrimidines, Viral replication, MESH : Biopsy, MESH: Pyrimidines, DNA, Viral, Immunology, Hepatocytes, MESH : Animals, MESH: Albumins, MESH: Liver
Abstract

International audience; Current treatments for HBV chronic carriers using interferon alpha or nucleoside analogues are not effective in all patients and may induce the emergence of HBV resistant strains. Bay 41-4109, a member of the heteroaryldihydropyrimidine family, inhibits HBV replication by destabilizing capsid assembly. The aim of this study was to determine the antiviral effect of Bay 41-4109 in a mouse model with humanized liver and the spread of active HBV. Antiviral assays of Bay 41-4109 on HepG2.2.15 cells constitutively expressing HBV, displayed an IC(50) of about 202 nM with no cell toxicity. Alb-uPA/SCID mice were transplanted with human hepatocytes and infected with HBV. Ten days post-infection, the mice were treated with Bay 41-4109 for five days. During the 30 days of follow-up, the HBV load was evaluated by quantitative PCR. At the end of treatment, decreased HBV viremia of about 1 log(10) copies/ml was observed. By contrast, increased HBV viremia of about 0.5 log(10) copies/ml was measured in the control group. Five days after the end of treatment, a rebound of HBV viremia occurred in the treated group. Furthermore, 15 days after treatment discontinuation, a similar expression of the viral capsid was evidenced in liver biopsies. Our findings demonstrate that Bay 41-4109 displayed antiviral properties against HBV in humanized Alb-uPA/SCID mice and confirm the usefulness of Alb-uPA/SCID mice for the evaluation of pharmaceutical compounds. The administration of Bay 41-4109 may constitute a new strategy for the treatment of patients in escape from standard antiviral therapy.

Published
2011

25. Comparison of liver fibrosis blood tests developed for HCV with new specific tests in HIV/HCV co-infection

Author

Dominique Salmon, Philippe Halfon, P. Perré, Guillaume Penaranda, Isabelle Fouchard-Hubert, Pascal Veillon, Laurence Weiss, Christian Michelet, Paul Calès, Patrice Cacoub, Dominique Guyader, Dominique Batisse, Jérôme Lambert, Fabrice Carrat, Louis d’Alteroche, Département d'hépato-gastroentérologie, Centre Hospitalier Universitaire d'Angers ( CHU Angers ), PRES Université Nantes Angers Le Mans ( UNAM ) -PRES Université Nantes Angers Le Mans ( UNAM ), Laboratoire HIFIH, PRES Université Nantes Angers Le Mans ( UNAM ) -IFR132-UPRES 3859, Laboratoire Alphabio, Laboratoire alphabio, Service d'immunologie, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Epidémiologie des maladies infectieuses et modélisation ( ESIM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Internal Medicine Department, CHG, CHG, Microenvironnement et remodelage, Centre Hospitalier Universitaire [Rennes]-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 ), Département d'hépatologie, CHRU Tours, Service des maladies infectieuses et réanimation médicale, Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou, Service de médecine interne et centre de référence des maladies rares [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Service de médecine interne [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Biologie et thérapeutique des pathologies immunitaires ( BTPI ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Service d'immunologie [HEGP, Paris], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Epidémiologie des maladies infectieuses et modélisation (ESIM), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-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 ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service des maladies infectieuses et réanimation médicale [Rennes] = Infectious Disease and Intensive Care [Rennes], CHU Pontchaillou [Rennes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biologie et thérapeutique des pathologies immunitaires (BTPI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), 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 ), CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Liver Cirrhosis, Male, FIBROMETER, Biopsy, MESH : Prospective Studies, HIV Infections, MESH: Comorbidity, Comorbidity, Chronic liver disease, Gastroenterology, MESH: Biopsy, 0302 clinical medicine, MESH : Female, Prospective Studies, 030212 general & internal medicine, Prospective cohort study, MESH: Prothrombin, education.field_of_study, Hematologic Tests, MESH: Middle Aged, medicine.diagnostic_test, Hepatitis C virus, Human immunodeficiency virus, MESH : Hematologic Tests, Hepatitis C, MESH: HIV Infections, Middle Aged, Diagnostic test, MESH : Adult, 3. Good health, MESH: Reproducibility of Results, Liver, Liver biopsy, MESH : Comorbidity, Female, Prothrombin, 030211 gastroenterology & hepatology, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Liver Cirrhosis, MESH : Sensitivity and Specificity, Blood test, Adult, medicine.medical_specialty, MESH : Male, Population, Liver fibrosis, Sensitivity and Specificity, MESH : Aspartate Aminotransferases, MESH: Hematologic Tests, 03 medical and health sciences, MESH: Aspartate Aminotransferases, MESH : alpha-Macroglobulins, Internal medicine, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, medicine, MESH : HIV Infections, Humans, MESH : Liver Cirrhosis, alpha-Macroglobulins, MESH : Middle Aged, Aspartate Aminotransferases, education, MESH: Hepatitis C, Metavir staging, MESH: Humans, Hepatology, business.industry, FibroTest, MESH: alpha-Macroglobulins, MESH : Reproducibility of Results, MESH : Humans, MESH: Biological Markers, Reproducibility of Results, MESH : Liver, MESH: Adult, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: ROC Curve, MESH : Prothrombin, MESH : Hepatitis C, medicine.disease, MESH: Male, MESH: Prospective Studies, MESH: Sensitivity and Specificity, MESH : Biological Markers, ROC Curve, MESH : Biopsy, Immunology, business, MESH: Female, Biomarkers, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, MESH : ROC Curve, MESH: Liver
Abstract

International audience; BACKGROUND & AIMS: We compared 5 non-specific and 2 specific blood tests for liver fibrosis in HCV/HIV co-infection. METHODS: Four hundred and sixty-seven patients were included into derivation (n=183) or validation (n=284) populations. Within these populations, the diagnostic target, significant fibrosis (Metavir F > or = 2), was found in 66% and 72% of the patients, respectively. Two new fibrosis tests, FibroMeter HICV and HICV test, were constructed in the derivation population. RESULTS: Unadjusted AUROCs in the derivation population were: APRI: 0.716, Fib-4: 0.722, Fibrotest: 0.778, Hepascore: 0.779, FibroMeter: 0.783, HICV test: 0.822, FibroMeter HICV: 0.828. AUROCs adjusted on classification and distribution of fibrosis stages in a reference population showed similar values in both populations. FibroMeter, FibroMeter HICV and HICV test had the highest correct classification rates in F0/1 and F3/4 (which account for high predictive values): 77-79% vs. 70-72% in the other tests (p=0.002). Reliable individual diagnosis based on predictive values > or = 90% distinguished three test categories: poorly reliable: Fib-4 (2.4% of patients), APRI (8.9%); moderately reliable: Fibrotest (25.4%), FibroMeter (26.6%), Hepascore (30.2%); acceptably reliable: HICV test (40.2%), FibroMeter HICV (45.6%) (p or =F1, > or =F2) with an overall accuracy of 93% vs. 79% (p

Published
2010

26. CB1 antagonism exerts specific molecular effects on visceral and subcutaneous fat and reverses liver steatosis in diet-induced obese mice

Author

Louiza Djaouti, Pascal Degrace, Joseph Gresti, Laurent Demizieux, Tony Jourdan, Bruno Vergès, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), This work was supported by grants from sanofi-aventisand the Re´gion Bourgogne., Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), and DEGRACE, Pascal

Subjects
Sucrose, MESH : Fatty Liver, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, MESH: Organ Size, MESH : Piperidines, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, Adipose tissue, Mice, Obese, MESH: Receptor, Cannabinoid, CB1, MESH : Pyrazoles, chemistry.chemical_compound, Mice, Piperidines, Receptor, Cannabinoid, CB1, Adipocyte, MESH: Obesity, MESH: Animals, MESH: Animal Feed, MESH: Fatty Liver, MESH: Mice, Obese, MESH : Body Weight, MESH : Gene Expression Regulation, Fatty liver, MESH: Apolipoproteins A, Organ Size, MESH: Adiponectin, MESH: Apolipoproteins B, MESH : Mice, Obese, MESH: Gene Expression Regulation, MESH: Piperidines, MESH : Animal Feed, Adipose Tissue, Liver, Original Article, lipids (amino acids, peptides, and proteins), MESH : Obesity, Adiponectin, Rimonabant, Obesity Studies, MESH: Adipose Tissue, MESH : Cannabinoid Receptor Antagonists, medicine.medical_specialty, Biology, MESH : Receptor, Cannabinoid, CB1, MESH : Adipose Tissue, MESH : Diet, MESH: Diet, Internal medicine, MESH : Mice, Internal Medicine, medicine, Animals, Obesity, MESH: Cannabinoid Receptor Antagonists, Cannabinoid Receptor Antagonists, MESH: Mice, Apolipoproteins A, Apolipoproteins B, MESH : Adiponectin, Insulin, Body Weight, MESH: Sucrose, MESH : Liver, Lipid metabolism, MESH : Apolipoproteins B, MESH : Organ Size, MESH : Apolipoproteins A, medicine.disease, Animal Feed, MESH : Sucrose, Diet, MESH: Body Weight, Fatty Liver, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Endocrinology, chemistry, Gene Expression Regulation, Pyrazoles, Hepatic lipase, MESH : Animals, Diet-induced obese, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, MESH: Pyrazoles, MESH: Liver
Abstract

OBJECTIVE The beneficial effects of the inactivation of endocannabinoid system (ECS) by administration of antagonists of the cannabinoid receptor (CB) 1 on several pathological features associated with obesity is well demonstrated, but the relative contribution of central versus peripheral mechanisms is unclear. We examined the impact of CB1 antagonism on liver and adipose tissue lipid metabolism in a mouse model of diet-induced obesity. RESEARCH DESIGN AND METHODS Mice were fed either with a standard diet or a high-sucrose high-fat (HSHF) diet for 19 weeks and then treated with the CB1-specific antagonist SR141716 (10 mg · kg−1 · day−1) for 6 weeks. RESULTS Treatment with SR141716 reduced fat mass, insulin levels, and liver triglycerides primarily increased by HSHF feeding. Serum adiponectin levels were restored after being reduced in HSHF mice. Gene expression of scavenger receptor class B type I and hepatic lipase was induced by CB1 blockade and associated with an increase in HDL-cholesteryl ether uptake. Concomitantly, the expression of CB1, which was strongly increased in the liver and adipose tissue of HSHF mice, was totally normalized by the treatment. Interestingly, in visceral but not subcutaneous fat, genes involved in transport, synthesis, oxidation, and release of fatty acids were upregulated by HSHF feeding, while this effect was counteracted by CB1 antagonism. CONCLUSIONS A reduction in the CB1-mediated ECS activity in visceral fat is associated with a normalization of adipocyte metabolism, which may be a determining factor in the reversion of liver steatosis induced by treatment with SR141716.

Published
2010

27. A minimal model for hepatic fatty acid balance during fasting: Application to PPAR alpha-deficient mice

Author

J. van Milgen, Anne Siegel, P. Blavy, Hervé Guillou, Florence Gondret, Pascal G.P. Martin, Ovidiu Radulescu, Sandrine Lagarrigue, Biological systems and models, bioinformatics and sequences (SYMBIOSE), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria), Laboratoire de Pharmacologie et Toxicologie, UR66, INRA, Institut National de la Recherche Agronomique (INRA), Université de Rennes (UNIV-RENNES), Institut de Recherche Mathématique de Rennes (IRMAR), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-AGROCAMPUS OUEST-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)-École normale supérieure - Rennes (ENS Rennes)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), CNRS, Centre National de la Recherche Scientifique (CNRS), Systèmes d'élevage, nutrition animale et humaine (SENAH), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, 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), Génétique Animale (GARen), 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)-Ecole Nationale Supérieure Agronomique de Rennes, Génétique fonctionnelle, agronomie et santé [IFR 140] (GFAS), Centre National de la Recherche Scientifique (CNRS)-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)-Institut National de la Recherche Agronomique (INRA), AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-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), CentraleSupélec-Télécom Bretagne-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), 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)-Institut National de la Recherche Agronomique (INRA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Inria Rennes – Bretagne Atlantique, Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST-Ecole Nationale Supérieure Agronomique de Rennes, Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École normale supérieure - Rennes (ENS Rennes)-Université de Rennes 2 (UR2)-Centre National de la Recherche Scientifique (CNRS)-INSTITUT AGRO Agrocampus Ouest, Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Biological systems and models, bioinformatics and sequences ( SYMBIOSE ), Institut de Recherche en Informatique et Systèmes Aléatoires ( IRISA ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National des Sciences Appliquées - Rennes ( INSA Rennes ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National des Sciences Appliquées - Rennes ( INSA Rennes ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Centre National de la Recherche Scientifique ( CNRS ) -Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique ( Inria ), Institut National de la Recherche Agronomique ( INRA ), Université de Rennes ( UNIV-RENNES ), Institut de Recherche Mathématique de Rennes ( IRMAR ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -AGROCAMPUS OUEST-École normale supérieure - Rennes ( ENS Rennes ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National des Sciences Appliquées ( INSA ) -Université de Rennes 2 ( UR2 ), Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ), and Centre National de la Recherche Scientifique ( CNRS )

Subjects
Male, MESH: Oxidation-Reduction, obesity, Peroxisome proliferator-activated receptor, Adipose tissue, MESH : Genotype, chain, MESH : Fasting, Polymerase Chain Reaction, adipose-tissue, MESH : Knockout, MESH: Genotype, chemistry.chemical_compound, Mice, 0302 clinical medicine, MESH : Inbred C57BL, Gene expression, MESH: Models, MESH : RNA, MESH: Animals, MESH: PPAR alpha, MESH : Fatty Acids, MESH : Polymerase Chain Reaction, MESH: Knockout, chemistry.chemical_classification, Mice, Knockout, 0303 health sciences, MESH : Gene Expression Regulation, Applied Mathematics, Fatty Acids, MESH: Messenger, null mice, General Medicine, Fasting, MESH: Gene Expression Regulation, MESH: Fatty Acids, Real-time polymerase chain reaction, Liver, rat-liver peroxisomes, Modeling and Simulation, Knockout mouse, MESH : Models, General Agricultural and Biological Sciences, Systems biology, Oxidation-Reduction, Statistics and Probability, medicine.medical_specialty, MESH: Biological, Genotype, MESH : Messenger, oxidation, MESH : Male, MESH : PPAR alpha, MESH: Fasting, Biology, Linoleoyl-CoA Desaturase, Models, Biological, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, MESH: RNA, Internal medicine, MESH : Mice, medicine, Animals, PPAR alpha, mammals, RNA, Messenger, MESH: Mice, mouse, 030304 developmental biology, MESH : Oxidation-Reduction, MESH: Linoleoyl-CoA Desaturase, General Immunology and Microbiology, Fatty acid metabolism, Modeling, Fatty acid, MESH : Liver, [ SDV.GEN.GA ] Life Sciences [q-bio]/Genetics/Animal genetics, MESH: Polymerase Chain Reaction, Metabolism, MESH : Biological, MESH: Inbred C57BL, gene-expression, MESH : Linoleoyl-CoA Desaturase, MESH: Male, Mice, Inbred C57BL, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, Endocrinology, chemistry, Gene Expression Regulation, MESH : Animals, metabolism, 030217 neurology & neurosurgery, Knockout mice, MESH: Liver
Abstract

The purpose of this study is to identify the hierarchy of importance amongst pathways involved in fatty acid (FA) metabolism and their regulators in the control of hepatic FA composition. A modeling approach was applied to experimental data obtained during fasting in PPAR α knockout (KO) mice and wild-type mice. A step-by-step procedure was used in which a very simple model was completed by additional pathways until the model fitted correctly the measured quantities of FA in the liver. The resulting model included FA uptake by the liver, FA oxidation, elongation and desaturation of FA, which were found active in both genotypes during fasting. From the model analysis we concluded that PPAR α had a strong effect on FA oxidation. There were no indications that this effect changes during the fasting period, and it was thus considered to be constant. In PPAR α KO mice, FA uptake was identified as the main pathway responsible for FA variation in the liver. The models showed that FA were oxidized at a constant and small rate, whereas desaturation of FA also occurred during fasting. The latter observation was rather unexpected, but was confirmed experimentally by the measurement of delta-6-desaturase mRNA using real-time quantitative PCR (QPCR). These results confirm that mathematical models can be a useful tool in identifying new biological hypotheses and nutritional routes in metabolism.

Published
2009

28. Complications and failure of uterine artery embolisation for intractable postpartum haemorrhage

Author

Tixier, Hervé, Loffroy, Romaric, Guiu, Boris, Coulange, L., Butori, Noémie, Cercueil, Jean-Pierre, Douvier, Serge, Krausé, Denis, Sagot, Paul, Service de gynécologie obstétrique, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Service de radiologie et d'Imagerie médicale diagnostique et thérapeutique (CHU de Dijon), Centre d'épidémiologie des populations ( CEP ), Université de Bourgogne ( UB ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Guiu, Boris, and Service de Gynécologie Obstétrique, Médecine Foetale et Stérilité Conjugale - Chirurgie Gynécologie et Oncologique [CHU de Dijon]

Subjects
MESH: Humans, MESH : Fatty Liver, MESH: Uterine Artery Embolization, MESH: Magnetic Resonance Spectroscopy, MESH: Treatment Failure, MESH : Humans, MESH : Liver, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Gelatin Sponge, Absorbable, MESH : Postpartum Hemorrhage, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Postpartum Hemorrhage, MESH : Uterine Artery Embolization, MESH : Pregnancy, MESH: Pregnancy, MESH : Treatment Failure, MESH : Magnetic Resonance Spectroscopy, MESH : Female, MESH : Gelatin Sponge, Absorbable, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Fatty Liver, MESH: Female, ComputingMilieux_MISCELLANEOUS, MESH: Liver
Abstract

International audience

Published
2009

29. AMP-activated protein kinase in the regulation of hepatic energy metabolism: from physiology to therapeutic perspectives.: AMPK in the liver

Author

Benoit Viollet, Marc Foretz, Sophie Hébrard, Fabrizio Andreelli, Bruno Guigas, Rémi Mounier, Jocelyne Leclerc, Louise Lantier, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Division of cardiology, Université Catholique de Louvain (UCL), Department of Molecular Cell Biology, Leiden University Medical Center (LUMC), Déterminants génétiques du diabète de type 2 et de ses complications vasculaires, Université Paris Diderot - Paris 7 (UPD7) - Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Diabétologie-Endocrinologie-Nutrition, Assistance publique - Hôpitaux de Paris (AP-HP) - AP-HP - Hôpital Bichat - Claude Bernard [Paris] - Université Paris Diderot - Paris 7 (UPD7), FP6 EXGENESIS Integrated Project (LSHM-CT- 2004-005272), PNRD, ALFEDIAM, Institut Benjamin Delessert., Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Catholique de Louvain = Catholic University of Louvain (UCL), Déterminants génétiques du diabète de type 2 et de ses complications vasculaires ((U 695)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Liver Cirrhosis, MESH : Ribonucleotides, MESH : Fatty Liver, Physiology, Protein Conformation, MESH : Protein Subunits, MESH : Dyslipidemias, AMP-Activated Protein Kinases, 0302 clinical medicine, MESH: Protein Conformation, AMP-activated protein kinase, MESH : Lipid Metabolism, energy metabolism, Glucose homeostasis, Homeostasis, MESH: Animals, MESH: AMP-Activated Protein Kinases, Beta oxidation, MESH: Fatty Liver, MESH : Protein Conformation, MESH: Lipid Metabolism, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, biology, MESH: Energy Metabolism, MESH: Gluconeogenesis, hepatic glucose production, MESH : AMP-Activated Protein Kinases, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Protein Subunits, Mitochondria, MESH: Glucose, MP-activated protein kinase, MESH: Homeostasis, 030220 oncology & carcinogenesis, MESH : Homeostasis, Lipogenesis, MESH : Aminoimidazole Carboxamide, type 2 diabetes, MESH : Mitochondria, MESH: Liver Cirrhosis, medicine.medical_specialty, MESH: Mitochondria, MESH : Gluconeogenesis, Carbohydrate metabolism, MESH: Aminoimidazole Carboxamide, liver, Article, 03 medical and health sciences, Internal medicine, MESH: Hypoglycemic Agents, medicine, Animals, Humans, Hypoglycemic Agents, MESH : Liver Cirrhosis, 030304 developmental biology, Dyslipidemias, fatty liver, MESH: Humans, MESH : Glucose, MESH: Dyslipidemias, MESH : Humans, Gluconeogenesis, AMPK, MESH : Liver, Lipid metabolism, Ribonucleotides, Aminoimidazole Carboxamide, Lipid Metabolism, MESH : Hypoglycemic Agents, MESH : Energy Metabolism, Protein Subunits, therapeutic, Endocrinology, Glucose, MESH: Ribonucleotides, Mitochondrial biogenesis, biology.protein, MESH : Animals, MESH: Liver
Abstract

International audience; As the liver is central in the maintenance of glucose homeostasis and energy storage, knowledge of the physiology as well as physiopathology of hepatic energy metabolism is a prerequisite to our understanding of whole-body metabolism. Hepatic fuel metabolism changes considerably depending on physiological circumstances (fed vs. fasted state). In consequence, hepatic carbohydrate, lipid and protein synthesis/utilization are tightly regulated according to needs. Fatty liver and hepatic insulin resistance (both frequently associated with the metabolic syndrome) or increased hepatic glucose production (as observed in type 2 diabetes) resulted from alterations in substrates oxidation/storage balance in the liver. Because AMP-activated protein kinase (AMPK) is considered as a cellular energy sensor, it is important to gain understanding of the mechanism by which hepatic AMPK coordinates hepatic energy metabolism. AMPK has been implicated as a key regulator of physiological energy dynamics by limiting anabolic pathways (to prevent further ATP consumption) and by facilitating catabolic pathways (to increase ATP generation). Activation of hepatic AMPK leads to increased fatty acid oxidation and simultaneously inhibition of hepatic lipogenesis, cholesterol synthesis and glucose production. In addition to a short-term effect on specific enzymes, AMPK also modulates the transcription of genes involved in lipogenesis and mitochondrial biogenesis. The identification of AMPK targets in hepatic metabolism should be useful in developing treatments to reverse metabolic abnormalities of type 2 diabetes and the metabolic syndrome.

Published
2009

30. The pro-Th2 cytokine IL-33 directly interacts with invariant NKT and NK cells to induce IFN-gamma production

Author

Michel Samson, Elvire Bourgeois, Pierre Gourdy, Séverine Diem, Stéphane Roga, Elke Schneider, Michel Dy, Linh Pham Van, Jean-Philippe Girard, Anne Barra, André Herbelin, Jean-Marc Gombert, Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Détoxication et réparation tissulaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Laboratoire d'immunologie [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), CNRS, Université de Paris Descartes, Ligue Nationale contre le Cancer, la Chancellerie des Universités de Paris, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Slama, Catherine, Université de Rennes (UR), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cytokines, hématopoïèse et réponse immune ( CHRI ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Signalisation et Réponses aux Agents Infectieux et Chimiques ( SeRAIC ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140, Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre hospitalier universitaire de Poitiers ( CHU Poitiers ), Institut de pharmacologie et de biologie structurale ( IPBS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Institut des Maladies Métaboliques et Cardiovasculaires ( I2MC ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de médecine moléculaire de Rangueil ( I2MR ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Interleukin-12, MESH: Spleen, medicine.medical_treatment, MESH: Mice, Knockout, Interleukin 21, Mice, 0302 clinical medicine, Immunology and Allergy, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH : Female, MESH: Animals, IL-2 receptor, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, 0303 health sciences, Mice, Inbred BALB C, ZAP70, Natural killer T cell, Interleukin-12, Killer Cells, Natural, Cytokine, Liver, Interleukin 12, Cytokines, Natural killer cells, Natural killer T cells, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH : Killer Cells, Natural, MESH : Spleen, MESH: Killer Cells, Natural, MESH: Interleukins, MESH: Interferon-gamma, Immunology, MESH: Mice, Inbred BALB C, MESH : Mice, Inbred C57BL, Biology, MESH : Interleukin-4, 03 medical and health sciences, Interferon-gamma, Th2 Cells, MESH: Mice, Inbred C57BL, MESH: Th2 Cells, MESH : Mice, medicine, MESH : Interleukin-12, Animals, Humans, MESH: Mice, MESH : Mice, Inbred BALB C, MESH : Interferon-gamma, 030304 developmental biology, Inflammation, Lymphokine-activated killer cell, MESH: Humans, Interleukins, MESH : Humans, MESH : Liver, MESH: Interleukin-4, Interleukin-33, MESH : Natural Killer T-Cells, MESH : Th2 Cells, Interleukin 33, Mice, Inbred C57BL, MESH: Natural Killer T-Cells, Natural Killer T-Cells, MESH : Mice, Knockout, Th1/Th2 cells, Interleukin-4, MESH : Animals, MESH : Interleukins, MESH: Female, Spleen, 030215 immunology, MESH: Liver
Abstract

International audience; IL-33 has recently been identified as a cytokine endowed with pro-Th2 functions, raising the question of its effect on invariant natural killer T cell (iNKT), which are potent IL-4 producers. Here, we report a two-fold increase of iNKT-cell counts in spleen and liver after a 7-day treatment of mice with IL-33, which results from a direct effect, given that purified iNKT cells express the T1/ST2 receptor constitutively and respond to IL-33 by in vitro expansion and functional activation. Conversely to the expected pro-Th2 effect, IL-33 induced a preferential increase in IFN-gamma rather than IL-4 production upon TCR engagement that depended on endogenous IL-12. Moreover, in combination with the pro-inflammatory cytokine IL-12, IL-33 enhanced IFN-gamma production by both iNKT and NK cells. Taken together these data support the conclusion that IL-33 can contribute as a co-stimulatory factor to innate cellular immune responses.

Published
2009

31. Analysis of gene transcription in sera during chronic hepatitis C infection

Author

Matthieu Carrière, Hervé Groux, Nadira Delhem, Olivier Moralès, Véronique Pancré, Philippe Podevin, Céline Miroux, Arnaud Carpentier, Filomena Conti, Yvon Calmus, Claude Auriault, Lynda Aoudjehane, Institut de Biologie de Lille, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Cellulaire, UPRES 1833, Service de Chirurgie Digestive, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunosearch, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Service d'Hépato Gastroentérologie, Centre Hospitalier Léon Binet, Virologie de l'hépatite C (EA 4474), Université Paris Descartes - Paris 5 (UPD5), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Centre National de la Recherche Scientifique ( CNRS ), CHU Cochin [AP-HP], Institut de pharmacologie moléculaire et cellulaire ( IPMC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Virologie de l'hépatite C ( EA 4474 ), Université Paris Descartes - Paris 5 ( UPD5 ), and Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, MESH : RNA, Messenger, Hepacivirus, Statistics as Topic, MESH : Statistics as Topic, MESH : Leukocytes, [ SDV.TOX ] Life Sciences [q-bio]/Toxicology, medicine.disease_cause, MESH : Hepacivirus, Pathogenesis, Liver disease, 0302 clinical medicine, Gene expression, Leukocytes, MESH : Serum, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH : Female, MESH: Hepacivirus, [ SDV.IB ] Life Sciences [q-bio]/Bioengineering, MESH : Host-Pathogen Interactions, 0303 health sciences, MESH: Middle Aged, biology, MESH: Serum, Hepatitis C, Middle Aged, MESH : Adult, 3. Good health, MESH: Hepatitis C, Chronic, Infectious Diseases, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Host-Pathogen Interactions, HCV, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, 030211 gastroenterology & hepatology, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Adult, medicine.medical_specialty, MESH : Hepatitis C, Chronic, Hepatitis C virus, MESH : Male, mRNA, liver, MESH: Leukocytes, 03 medical and health sciences, MESH: Gene Expression Profiling, Virology, Molecular genetics, medicine, Humans, MESH : Middle Aged, RNA, Messenger, MESH: Statistics as Topic, 030304 developmental biology, MESH: RNA, Messenger, MESH: Humans, Gene Expression Profiling, MESH : Gene Expression Profiling, MESH : Humans, MESH: Host-Pathogen Interactions, MESH : Liver, MESH: Adult, Hepatitis C, Chronic, medicine.disease, biology.organism_classification, Molecular biology, MESH: Male, Gene expression profiling, Immunology, PBMCs, transcriptome, serum, MESH: Female, MESH: Liver
Abstract

International audience; Alternative, non-invasive techniques are necessary to monitor the progression of liver disease during chronic hepatitis C. Firstly, because serum is the most accessible material for studies using qPCR in microplates, gene transcription was compared in 219 selected genes involved in the pathogenesis of hepatitis C virus (HCV) infection between sera, PBMCs and liver samples collected simultaneously from five patients infected chronically. Secondly, using sera, gene profiles were compared between HCV-infected patients (n = 10) and healthy controls (n = 10). In addition, the influence of alcohol intake was examined in patients infected with HCV genotype-1. Firstly, amplifiable mRNAs were obtained in all samples. After amplification, significant correlations were observed between: liver versus serum; liver versus PBMCs; and serum versus PBMCs (r(2) = 0.37, r(2) = 0.54, r(2) = 0.49, respectively). A comparison of gene transcription by gene involved in T- and B-cell markers, adhesion molecules, apoptosis, liver matrix turnover and inflammation, revealed comparable, significant correlations between serum and liver, (r(2) = 0.30, r(2) = 0.60, r(2) = 0.51, r(2) = 0.51, r(2) = 0.26, and r(2) = 0.61 respectively). Secondly, a quantitative analysis of gene expression in sera between genotype-1b-infected patients and healthy controls revealed that 41 genes involved closely in T-cell activation and apoptosis were over-expressed significantly in patients infected with HCV. In these patients, alcohol consumption was associated with an increased expression of six genes involved in the inflammatory response, together with a decrease of genes associated with dendritic cell function. It is concluded that in patients infected with HCV, serum can be used to evaluate expression of liver genes. Further prospective studies are clearly needed to validate the initial results and to define the relevant genes.

Published
2009

32. Quantification of liver fat content: comparison of triple-echo chemical shift gradient-echo imaging and in vivo proton MR spectroscopy

Author

David Masson, Denis Krausé, Jean-Michel Petit, Romaric Loffroy, Patrick Hillon, Douraied Ben Salem, Jean-Pierre Cercueil, Boris Guiu, Serge Aho, Service de radiologie et d'Imagerie médicale diagnostique et thérapeutique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Unité de Génétique Moléculaire Animale ( UGMA ), Université de Limoges ( UNILIM ) -Institut National de la Recherche Agronomique ( INRA ), Groupe d'Etude de la Thrombose de Bretagne Occidentale ( GETBO ), Université de Brest ( UBO ), Département de radiologie [Brest] ( DR - Brest ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Service d'Ophtalmologie (CHU de Dijon), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Service d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Unité de Génétique Moléculaire Animale (UGMA), Université de Limoges (UNILIM)-Institut National de la Recherche Agronomique (INRA), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Département de radiologie [Brest] (DR - Brest), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Hôpital du Bocage, Unité de Génétique Moléculaire Animale (UMR GMA), Université de Brest (UBO)-Université de Brest (UBO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, and Service d'hépato-gastroentérologie et cancérologie digestive (CHU de Dijon)

Subjects
Male, Magnetic Resonance Spectroscopy, MESH: Echo-Planar Imaging, MESH : Fatty Liver, [SDV]Life Sciences [q-bio], MESH : Aged, MESH : Prospective Studies, MESH : Mathematical Computing, 030218 nuclear medicine & medical imaging, MESH: Magnetic Resonance Imaging, 0302 clinical medicine, Nuclear magnetic resonance, MESH: Aged, 80 and over, MESH : Diabetes Mellitus, Type 2, Image Processing, Computer-Assisted, Medicine, MESH : Female, Prospective Studies, MESH: Mathematical Computing, MESH: Fatty Liver, Mathematical Computing, MESH: Aged, Aged, 80 and over, MESH: Middle Aged, medicine.diagnostic_test, Echo-Planar Imaging, Echo (computing), Middle Aged, MESH: Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Liver, Content (measure theory), 030211 gastroenterology & hepatology, Female, MESH : Software, MESH: Image Enhancement, MESH : Sensitivity and Specificity, MESH : Image Processing, Computer-Assisted, MESH: Diabetes Mellitus, Type 2, MESH : Male, Sensitivity and Specificity, 03 medical and health sciences, MESH: Software, Flip angle, In vivo, MESH : Magnetic Resonance Imaging, Liver fat, Humans, Radiology, Nuclear Medicine and imaging, MESH : Middle Aged, Spectroscopy, MESH : Aged, 80 and over, Aged, MESH: Humans, MESH : Echo-Planar Imaging, [ SDV ] Life Sciences [q-bio], business.industry, MESH: Magnetic Resonance Spectroscopy, MESH : Humans, MESH : Liver, Magnetic resonance imaging, Image Enhancement, Proton mr spectroscopy, MESH: Male, MESH: Prospective Studies, MESH: Sensitivity and Specificity, Fatty Liver, Diabetes Mellitus, Type 2, MESH : Magnetic Resonance Spectroscopy, MESH : Image Enhancement, business, Nuclear medicine, MESH: Female, Software, MESH: Liver
Abstract

International audience; PURPOSE: To validate a triple-echo gradient-echo sequence for measuring the fat content of the liver, by using hydrogen 1((1)H) magnetic resonance (MR) spectroscopy as the reference standard. MATERIALS AND METHODS: This prospective study was approved by the appropriate ethics committee, and written informed consent was obtained from all patients. In 37 patients with type 2 diabetes (31 men, six women; mean age, 56 years), 3.0-T single-voxel point-resolved (1)H MR spectroscopy of the liver (Couinaud segment VII) was performed to calculate the liver fat fraction from the water (4.7 ppm) and methylene (1.3 ppm) peaks, corrected for T1 and T2 decay. Liver fat fraction was also computed from triple-echo (consecutive in-phase, opposed-phase, and in-phase echo times) breath-hold spoiled gradient-echo sequence (flip angle, 20 degrees), by estimating T2* and relative signal intensity loss between in- and opposed-phase values, corrected for T2* decay. Pearson correlation coefficient, Bland-Altman 95% limit of agreement, and Lin concordance coefficient were calculated. RESULTS: Mean fat fractions calculated from the triple-echo sequence and (1)H MR spectroscopy were 10% (range, 0.7%-35.6%) and 9.7% (range, 0.2%-34.1%), respectively. Mean T2* time was 14.7 msec (range, 5.4-25.4 msec). Pearson correlation coefficient was 0.989 (P < .0001) and Lin concordance coefficient was 0.988 (P < .0001). With the Bland-Altman method, all data points were within the limits of agreement. CONCLUSION: A breath-hold triple-echo gradient-echo sequence with a low flip angle and correction for T2* decay is accurate for quantifying fat in segment VII of the liver. Given its excellent correlation and concordance with (1)H MR spectroscopy, this triple-echo sequence could replace (1)H MR spectroscopy in longitudinal studies.

Published
2009

33. Elevated expression of osteopontin may be related to adipose tissue macrophage accumulation and liver steatosis in morbid obesity

Author

Adeline Bertola, Keith N. Frayn, Yannick Le Marchand-Brustel, Joan Tordjman, Moncef Dahman, S. McQuaid, Albert Tran, Philippe Gual, Karine Clément, Vanessa Deveaux, Jean Gugenheim, Pierre-Michel Huet, Rodolphe Anty, Déborah Rousseau, Sophie Lotersztajn, Abdelilah Wakkach, Stéphanie Bonnafous, Centre méditérannéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Signalisation moléculaire et obésité, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), Transduction du Signal : Signalisation Calcique et Phosphorylation, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, physiopathologie et ingénierie du tissu osseux (GéPITOS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford [Oxford], Environnement et Grandes Cultures (EGC), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Service de Chirurgie Digestive et Transplantation Hépatique, Hôpital Archet II, Digestive Center, Centre Hospitalier Universitaire de Nice (CHU Nice), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), AgroParisTech-Institut National de la Recherche Agronomique (INRA), Centre méditérannéen de médecine moléculaire ( C3M ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut 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 ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -IFR50-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Génétique, physiopathologie et ingénierie du tissu osseux ( GéPITOS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Oxford Centre for Diabetes, Endocrinology and Metabolism ( OCDEM ), Environnement et Grandes Cultures ( EGC ), AgroParisTech-Institut National de la Recherche Agronomique ( INRA ), Epidémiologie et écologie des maladies animales ( Epidémiologie ), Centre de Coopération Internationale en Recherche Agronomique pour le Développement ( CIRAD ), CHU Nice, Université Nice Sophia Antipolis (1965 - 2019) (UNS), University of Oxford, and Service de Chirurgie Digestive / Centre de Transplantation Hépatique [CHU Nice]

Subjects
Male, MESH : RNA, Messenger, Endocrinology, Diabetes and Metabolism, Mice, 0302 clinical medicine, MESH : Oleic Acid, MESH: Animals, Osteopontin, MESH : Immunoblotting, MESH : Macrophages, Liver injury, 0303 health sciences, Tumor, MESH: Middle Aged, MESH: Immunoblotting, MESH : Reverse Transcriptase Polymerase Chain Reaction, Obesity, Morbid, Hyaluronan Receptors, Adipose Tissue, Tumor necrosis factor alpha, MESH: Adipose Tissue, medicine.medical_specialty, MESH: Gene Expression, MESH: Antigens, CD44, MESH : Adipose Tissue, 03 medical and health sciences, MESH: Weight Loss, Humans, MESH : Middle Aged, RNA, Messenger, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Humans, Tumor Necrosis Factor-alpha, Macrophages, MESH : Humans, MESH: Oleic Acid, MESH: Adult, medicine.disease, Mice, Inbred C57BL, MESH : Gene Expression, Endocrinology, MESH: Tumor Necrosis Factor-alpha, MESH: Female, MESH: Liver, MESH : Fatty Liver, MESH: Osteopontin, Messenger, Adipose tissue, Gene Expression, Inbred C57BL, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH : Antigens, CD44, MESH : Female, MESH : Osteopontin, CD44, Morbid, Receptor, MESH: Fatty Liver, MESH : Tumor Necrosis Factor-alpha, biology, Reverse Transcriptase Polymerase Chain Reaction, Fatty liver, MESH : Adult, Middle Aged, Liver, Female, Obesity Studies, Adult, MESH : Obesity, Morbid, MESH: Cell Line, Tumor, MESH : Male, Immunoblotting, 030209 endocrinology & metabolism, MESH : Mice, Inbred C57BL, Cell Line, Insulin resistance, stomatognathic system, MESH: Mice, Inbred C57BL, Cell Line, Tumor, Internal medicine, MESH : Mice, Weight Loss, Internal Medicine, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Obesity, Antigens, MESH: Mice, 030304 developmental biology, MESH: RNA, Messenger, MESH : Cell Line, Tumor, MESH : Liver, MESH: Macrophages, MESH: Obesity, Morbid, MESH: Male, Fatty Liver, biology.protein, RNA, MESH : Animals, MESH : Weight Loss, Steatosis, Oleic Acid
Abstract

OBJECTIVE—Osteopontin (OPN) plays an important role in the development of insulin resistance and liver complications in dietary murine models. We aimed to determine the expression pattern of OPN and its receptor CD44 in obese patients and mice according to insulin resistance and liver steatosis. RESEARCH DESIGN AND METHODS—OPN and CD44 expressions were studied in 52 morbidly obese patients and in mice. Cellular studies were performed in HepG2 cells. RESULTS—Hepatic OPN and CD44 expressions were strongly correlated with liver steatosis and insulin resistance in obese patients and mice. This increased OPN expression could be due to the accumulation of triglycerides, since fat loading in HepG2 promotes OPN expression. In contrast, OPN expression in adipose tissue (AT) was enhanced independently of insulin resistance and hepatic steatosis in obese patients. The elevated OPN expression in AT was paralleled with the AT macrophage infiltration, and both phenomena were reversed after weight loss. The circulating OPN level was slightly elevated in obese patients and was not related to liver steatosis. Further, AT did not appear to secrete OPN. In contrast, bariatric surgery–induced weight loss induced a strong increase in circulating OPN. CONCLUSIONS—The modestly elevated circulating OPN levels in morbidly obese patients were not related to liver steatosis and did not appear to result from adipose tissue secretion. In subcutaneous AT, expression of OPN was directly related to macrophage accumulation independently from liver complications. In contrast, hepatic OPN and CD44 expressions were related to insulin resistance and steatosis, suggesting their local implication in the progression of liver injury.

Published
2009

34. [Role of the Regulatory T lymphocytes in hepatitis C fibrosis progression]

Author

Delhem, Nadira, Cottrez, Françoise, Carpentier, Arnaud, Miroux, Céline, Moralès, Olivier, François, Violaine, Groux, Hervé, Auriault, Claude, Pancré, Véronique, Institut de Biologie de Lille, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS), Immunosearch, [Institut Cochin] Departement Infection, immunité, inflammation, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de pharmacologie moléculaire et cellulaire ( IPMC ), Université Nice Sophia Antipolis ( UNS ), and Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
Liver Cirrhosis, MESH : Liver Neoplasms, MESH: Interleukin-10, MESH : Cytokines, Biopsy, [ SDV.TOX ] Life Sciences [q-bio]/Toxicology, MESH : Aged, MESH : T-Lymphocytes, Helper-Inducer, Hepacivirus, T-Lymphocytes, Regulatory, MESH : Hepacivirus, MESH : T-Lymphocytes, Regulatory, MESH: Biopsy, Transforming Growth Factor beta, MESH: Liver Neoplasms, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH: Hepacivirus, [ SDV.IB ] Life Sciences [q-bio]/Bioengineering, MESH: Carcinoma, Hepatocellular, MESH: Antigens, CD, MESH: Aged, MESH: Cytokines, MESH: Middle Aged, MESH : Immune Tolerance, Liver Neoplasms, T-Lymphocytes, Helper-Inducer, MESH : Adult, Middle Aged, Hepatitis C, Interleukin-10, MESH: Hepatitis C, Chronic, Liver, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Disease Progression, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH : DNA Primers, MESH: Disease Progression, [SDV.IB]Life Sciences [q-bio]/Bioengineering, MESH: Liver Cirrhosis, MESH : Carcinoma, Hepatocellular, Adult, MESH: DNA Primers, Carcinoma, Hepatocellular, MESH: Immune Tolerance, MESH : Hepatitis C, Chronic, Antigens, CD, MESH : Interleukin-10, MESH : Antigens, CD, Immune Tolerance, MESH : Liver Cirrhosis, Humans, MESH : Middle Aged, MESH: T-Lymphocytes, Helper-Inducer, MESH: Transforming Growth Factor beta, Aged, DNA Primers, MESH: Hepatitis C, MESH: Humans, MESH: T-Lymphocytes, Regulatory, MESH : Humans, MESH : Liver, MESH: Adult, MESH : Disease Progression, MESH : Hepatitis C, Hepatitis C, Chronic, MESH : Transforming Growth Factor beta, MESH : Biopsy, MESH: Liver
Abstract

International audience; Hepatitis C virus (HCV) becomes chronic in about 85 % of infected individuals, whereas only 15 % of infected people clear spontaneously the virus. The progression of hepatitis C to chronic status is associated to a profound down-regulation of CD4 and CD8 multispecific immune response. This immune defect may participate to the immune tolerance of VHC and consequently to its persistence. Recent findings indicate that T regulatory cells as Tr1 play an inhibitory role on T helper responses notably in the context of auto-immune or inflammatory disorders. The existence of immunosuppressive mechanisms supported by Tr1 lymphocytes and their IL-10 production represent an attractive hypothesis. We have previously evaluated the existence of regulatory T cells (Tr1) via high production of IL-10, in liver biopsies of three well-defined cohorts of HCV-1b infected patients. To this purpose, we compared liver biopsies of chronically infected patients including patients without liver lesions, with cirrhosis and with hepatocellular carcinoma (HCC). Using quantitative real time PCR, the results obtained demonstrate, an increased expression of interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta)_, in liver biopsies with more severe fibrosis. This observation was correlated with an increased expression during the pathogenesis progression, of the three specific markers of the Tr1 cells sub-population, recently described and confirming the Tr1 phenotype. Evidence of regulatory T cells installation in the liver of chronically infected patient and increased frequency in cirrhosis and HCC suggest a main role of these cells in the aggravation of the liver pathology. This study should bring insight of T regulatory cell implications in VHC persistence and in the pathology progression.

Published
2008

35. Impact of visceral adipose tissue on liver metabolism and insulin resistance. Part II: Visceral adipose tissue production and liver metabolism

Author

J. Girard, Max Lafontan, Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de médecine moléculaire de Rangueil ( I2MR ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Simon, Marie Francoise, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH : Fatty Liver, Endocrinology, Diabetes and Metabolism, Adipose tissue, White adipose tissue, MESH : Hepatocytes, MESH: Hepatocytes, chemistry.chemical_compound, Endocrinology, MESH : Diabetes Mellitus, Type 2, Nonalcoholic fatty liver disease, MESH : Cardiovascular Diseases, MESH: Fatty Liver, MESH : Viscera, Fatty liver, General Medicine, MESH : Triglycerides, MESH: Viscera, MESH: Glucose, MESH: Insulin Resistance, Adipose Tissue, Liver, Cardiovascular Diseases, MESH : Insulin Resistance, MESH: Adipose Tissue, MESH: Diabetes Mellitus, Type 2, MESH: Triglycerides, medicine.medical_specialty, Adipose tissue macrophages, Biology, Carbohydrate metabolism, MESH : Adipose Tissue, Insulin resistance, Internal medicine, Internal Medicine, medicine, Humans, Triglycerides, MESH: Humans, Triglyceride, MESH : Glucose, MESH : Humans, MESH: Cardiovascular Diseases, MESH : Liver, medicine.disease, Fatty Liver, Viscera, Glucose, Diabetes Mellitus, Type 2, chemistry, Hepatocytes, Insulin Resistance, MESH: Liver
Abstract

International audience; Excess visceral adipose tissue is associated with anomalies of blood glucose homoeostasis, elevation of plasma triglycerides and low levels of high-density lipoprotein cholesterol that contribute to the development of type-2 diabetes and cardiovascular syndromes. Visceral adipose tissue releases a large amount of free fatty acids and hormones/cytokines in the portal vein that are delivered to the liver. The secreted products interact with hepatocytes and various immune cells in the liver. Altered liver metabolism and determinants of insulin resistance associated with visceral adipose tissue distribution are discussed, as well as, determinants of an insulin-resistant state promoted by the increased free fatty acids and cytokines delivered by visceral adipose tissue to the liver.

Published
2008

36. Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver

Author

Léon Kautz, Annabelle Monnier, Delphine Meynard, Marie-Paule Roth, Régis Bouvet, Valérie Darnaud, Chiuxia Deng, Hélène Coppin, Jean Mosser, Sophie Vaulont, Rui-Hong Wang, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ecosystèmes, biodiversité, évolution [Rennes] (ECOBIO), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Observatoire des Sciences de l'Univers de Rennes (OSUR)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Moléculaire et Génomique, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR, programme IRONGENES, Commission européenne (LSHM-CT-2006-037296 : EUROIRON1), Association pour la Recherche sur le Cancer (ARC), ANR-05-MRAR-0031,IRONGENES,Intégration d'approches génétiques et génomiques pour l'identification des gènes modificateurs impliqués dans l'hémochromatose génétique(2005), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), ANR: IRONGENES,IRONGENES, Centre National de la Recherche Scientifique (CNRS)-Observatoire des Sciences de l'Univers de Rennes (OSUR)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Centre de Physiopathologie Toulouse Purpan (ex IFR 30 et IFR 150), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR30-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Ecosystèmes, biodiversité, évolution [Rennes] ( ECOBIO ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -INEE-Observatoire des Sciences de l'Univers de Rennes ( OSUR ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), ANR : IRONGENES,IRONGENES, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Observatoire des Sciences de l'Univers de Rennes (OSUR), Université de Rennes (UR)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Rennes 2 (UR2)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Rennes 2 (UR2)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique moléculaire et Génomique [CHU Rennes], and CHU Pontchaillou [Rennes]

Subjects
Male, MESH: Signal Transduction, Transcription, Genetic, MESH : Basic Helix-Loop-Helix Transcription Factors, Bone Morphogenetic Protein 6, MESH: Bone Morphogenetic Protein 6, MESH: Bone Morphogenetic Proteins, Smad Proteins, SMAD, Biochemistry, MESH: Mice, Knockout, MESH : Iron, Mice, MESH : Phosphorylation, MESH : Smad1 Protein, MESH : Bone Morphogenetic Proteins, 0302 clinical medicine, Transcription (biology), Gene expression, MESH: Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Transcription Factors, MESH: Smad4 Protein, MESH: Animals, Phosphorylation, Smad4 Protein, Mice, Knockout, 2. Zero hunger, 0303 health sciences, MESH: Iron, biology, MESH : Smad5 Protein, Hematology, Erythroferrone, Cell biology, Liver, 030220 oncology & carcinogenesis, Bone Morphogenetic Proteins, MESH: Smad7 Protein, Signal transduction, MESH : Smad7 Protein, Signal Transduction, Smad5 Protein, Iron Overload, Iron, MESH : Male, Immunology, Active Transport, Cell Nucleus, MESH: Active Transport, Cell Nucleus, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Smad1 Protein, Smad7 Protein, MESH : Diet, 03 medical and health sciences, MESH: Smad5 Protein, MESH: Gene Expression Profiling, MESH: Iron Overload, MESH: Diet, Hepcidin, MESH : Mice, Animals, MESH : Smad Proteins, MESH: Mice, MESH : Active Transport, Cell Nucleus, 030304 developmental biology, Hemojuvelin, MESH : Signal Transduction, MESH : Iron Overload, MESH: Phosphorylation, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Gene Expression Profiling, MESH : Gene Expression Profiling, MESH: Transcription, Genetic, MESH: Smad1 Protein, MESH : Transcription, Genetic, MESH : Liver, MESH : Smad4 Protein, MESH: Smad Proteins, Cell Biology, MESH: Male, Diet, Smad8 Protein, biology.protein, MESH : Mice, Knockout, MESH: Smad8 Protein, MESH : Animals, MESH : Smad8 Protein, MESH : Bone Morphogenetic Protein 6, MESH: Liver
Abstract

Although hepcidin expression was shown to be induced by the BMP/Smad signaling pathway, it is not yet known how iron regulates this pathway and what its exact molecular targets are. We therefore assessed genome-wide liver transcription profiles of mice of 2 genetic backgrounds fed iron-deficient, -balanced, or -enriched diets. Among 1419 transcripts significantly modulated by the dietary iron content, 4 were regulated similarly to the hepcidin genes Hamp1 and Hamp2. They are coding for Bmp6, Smad7, Id1, and Atoh8 all related to the Bmp/Smad pathway. As shown by Western blot analysis, variations in Bmp6 expression induced by the diet iron content have for functional consequence similar changes in Smad1/5/8 phosphorylation that leads to formation of heteromeric complexes with Smad4 and their translocation to the nucleus. Gene expression variations induced by secondary iron deficiency or iron overload were compared with those consecutive to Smad4 and Hamp1 deficiency. Iron overload developed by Smad4- and Hamp1-deficient mice also increased Bmp6 transcription. However, as shown by analysis of mice with liver-specific disruption of Smad4, activation of Smad7, Id1, and Atoh8 transcription by iron requires Smad4. This study points out molecules that appear to play a critical role in the control of systemic iron balance.

Published
2008

37. Effects of subchronic digestive exposure to organic or inorganic cadmium on biomarkers in rat tissues

Author

Sylvie Devaux, Alain Berthelot, R.P. Cosson, Renaud Scheifler, Lysiane Richert, Hélène Martin, F. Hispard, Pierre-Marie Badot, A. de Vaufleury, Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Unité sous contrat biologie environnementale, Institut National de la Recherche Agronomique (INRA)-Université de Franche-Comté (UFC), Optimisation Métabolique et Cellulaire, Université de Franche-Comté (UFC), Mer, molécules et santé EA 2160 (MMS), Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN)-Le Mans Université (UM)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN), Laboratoire de Biologie Marine, Université de Nantes (UN)-ISOMer, ADEME (Agence De l'Environnement et de la Maîtrise de l'Energie, contract n° 0175037 and 0572 C0058), ANR-05-ECCO-0004,STARTT,Biodisponibilité, transferts et effets des éléments trace métalliques dans des réseaux trophiques terrestres : changements d'échelle spatiale et de niveau d'organisation biologique(2005), Laboratoire Chrono-environnement ( LCE ), Université Bourgogne Franche-Comté ( UBFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), Institut National de la Recherche Agronomique ( INRA ) -Université de Franche-Comté ( UFC ), Université de Franche-Comté ( UFC ), Mer, molécules et santé ( MMS ), Université de Nantes ( UN ), Université de Nantes ( UN ) -ISOMer, programme STARTT, ANR-05-ECC0-004,programme STARTT, ANR-05-ECC0-004, Laboratoire Chrono-environnement - UFC (UMR 6249) (LCE), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), and Le Mans Université (UM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques

Subjects
MESH : Alanine Transaminase, Snails, Wistar, Small, 01 natural sciences, MESH: Lipid Peroxidation, Lipid peroxidation, MESH: gamma-Glutamyltransferase, Malondialdehyde, Metallothionein, MESH: Animals, MESH: Snails, MESH : Cadmium, MESH : Environmental Pollutants, chemistry.chemical_classification, 0303 health sciences, Cadmium, MESH : Intestine, Small, Glutathione peroxidase, General Medicine, gamma-Glutamyltransferase, Pollution, MESH : Food Chain, Intestine, MESH: Environmental Pollutants, [SDV.TOX.ECO]Life Sciences [q-bio]/Toxicology/Ecotoxicology, medicine.medical_specialty, Food Chain, MESH : Glutathione Peroxidase, MESH : Aspartate Aminotransferases, 03 medical and health sciences, MESH: Aspartate Aminotransferases, MESH: Catalase, Aspartate Aminotransferases, Rats, Wistar, Myocardium, MESH: Metallothionein, Public Health, Environmental and Occupational Health, Kidney metabolism, MESH : Metallothionein, Endocrinology, chemistry, MESH : Snails, MESH: Glutathione Peroxidase, Lipid Peroxidation, MESH: Female, Biomarkers, MESH: Liver, MESH: Intestine, Small, Health, Toxicology and Mutagenesis, [ SDV.TOX.ECO ] Life Sciences [q-bio]/Toxicology/Ecotoxicology, 010501 environmental sciences, Kidney, chemistry.chemical_compound, Intestine, Small, MESH: Caspase 3, MESH : Myocardium, MESH : Caspase 3, MESH : Female, Gamma-glutamyltransferase, biology, MESH : Lipid Peroxidation, MESH : Rats, Caspase 3, Alanine Transaminase, Catalase, MESH : Kidney, Biochemistry, Liver, Biological Markers, Environmental Pollutants, Female, MESH: Myocardium, MESH: Rats, MESH: Malondialdehyde, MESH: Cadmium, chemistry.chemical_element, MESH : Rats, Wistar, MESH : Catalase, Internal medicine, medicine, Animals, MESH: Food Chain, 030304 developmental biology, 0105 earth and related environmental sciences, MESH : Malondialdehyde, Glutathione Peroxidase, MESH: Biological Markers, MESH : Liver, MESH: Kidney, MESH: Rats, Wistar, Rats, MESH : Biological Markers, MESH: Alanine Transaminase, biology.protein, MESH : Animals, MESH : gamma-Glutamyltransferase
Abstract

International audience; In an experimental food chain, Wistar rats were fed cadmium (Cd) in an inorganic (CdCl(2)) or organic (mainly associated with metallothionein from Helix aspersa snail viscera) form. After 1 month of exposure to 100 microg inorganic Cd g(-1) in food, an induction of metallothionein was observed in all target tissues. In liver, glutathione peroxidase (GSH-Px) activity decreased and alanine aminotransferase (ALAT) activity increased, suggesting that Cd causes hepatotoxicity. However, lipid peroxidation as well as catalase and caspase 3 (a marker of apoptosis) activities were not modified. At a rather low exposure (2.5 microg Cd g(-1)), metallothionein level in the kidney was found to be the most sensitive biomarker of exposure for both Cd forms. In the small intestine of rats ingesting inorganic Cd, metallothionein expression was significantly higher than that observed for rats fed organic Cd. Present results allowed proposing a simple design to assess the effect of a chemical in a trophic transfer approach.

Published
2008

38. MicroRNA166 controls root and nodule development in Medicago truncatula

Author

Carole Laffont, Martin Crespi, Andreas Niebel, Julie Plet, Philippe Laporte, Jean-Philippe Combier, Mariana Jovanovic, Florian Frugier, Adnane Boualem, Institut des sciences du végétal (ISV), Centre National de la Recherche Scientifique (CNRS), Nouveaux Outils pour La Coopération et l'Education (NOCE), Laboratoire d'Informatique Fondamentale de Lille (LIFL), Université de Lille, Sciences et Technologies-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lille, Sciences Humaines et Sociales-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Sciences et Technologies-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lille, Sciences Humaines et Sociales-Centre National de la Recherche Scientifique (CNRS), Université de Lille, Sciences et Technologies-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lille, Sciences Humaines et Sociales-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Ecologie Microbienne - UMR 5557 (LEM), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Ecole Nationale Vétérinaire de Lyon (ENVL), Laboratoire des interactions plantes micro-organismes (LIPM), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Lyon (ENVL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Institut des sciences du végétal ( ISV ), Centre National de la Recherche Scientifique ( CNRS ), Nouveaux Outils pour La Coopération et l'Education ( NOCE ), Laboratoire d'Informatique Fondamentale de Lille ( LIFL ), Université de Lille, Sciences et Technologies-Institut National de Recherche en Informatique et en Automatique ( Inria ) -Université de Lille, Sciences Humaines et Sociales-Centre National de la Recherche Scientifique ( CNRS ) -Université de Lille, Sciences et Technologies-Institut National de Recherche en Informatique et en Automatique ( Inria ) -Université de Lille, Sciences Humaines et Sociales-Centre National de la Recherche Scientifique ( CNRS ), Université de Lille, Sciences et Technologies-Institut National de Recherche en Informatique et en Automatique ( Inria ) -Université de Lille, Sciences Humaines et Sociales-Centre National de la Recherche Scientifique ( CNRS ), Ecologie microbienne ( EM ), Centre National de la Recherche Scientifique ( CNRS ) -Ecole Nationale Vétérinaire de Lyon ( ENVL ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique ( INRA ) -VetAgro Sup ( VAS ), Laboratoire des interactions plantes micro-organismes ( LIPMO ), and Institut National de la Recherche Agronomique ( INRA ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
0106 biological sciences, MESH : Plant Roots, MESH : Brain Chemistry, MESH: Plant Roots, clustered miRNA, Plant Science, MESH: Amino Acid Sequence, MESH: Base Sequence, 01 natural sciences, MESH : Cattle, MESH: Cattle Diseases, MESH: Animals, In Situ Hybridization, 0303 health sciences, MESH : Amino Acid Sequence, MESH : Reverse Transcriptase Polymerase Chain Reaction, MESH : In Situ Hybridization, Medicago truncatula, Cell biology, MESH : Proton-Translocating ATPases, MESH : DNA Primers, MESH: Proteolipids, MESH: DNA Primers, MESH: Mitochondria, Organogenesis, MESH: Microscopy, Electron, MESH : Electrophoresis, Polyacrylamide Gel, 03 medical and health sciences, MESH: In Situ Hybridization, microRNA, Botany, Genetics, MESH: Blotting, Northern, MESH: Mass Spectrometry, MESH : Cattle Diseases, MESH: Molecular Sequence Data, MESH : Medicago truncatula, Lateral root, HD ZIP III transcription factors, MESH : Pigments, Biological, MESH: Neuronal Ceroid-Lipofuscinoses, MESH : Brain, MESH : Amino Acids, MESH : Gene Expression Regulation, Plant, MESH: MicroRNAs, MESH: Female, MESH: Liver, [ SDV.BV ] Life Sciences [q-bio]/Vegetal Biology, MESH : Molecular Sequence Data, MESH: Amino Acids, Plant Roots, lateral root, MESH: Proton-Translocating ATPases, Gene Expression Regulation, Plant, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH : Female, MESH: Brain Chemistry, MESH : Pancreas, MESH: Medicago truncatula, biology, Reverse Transcriptase Polymerase Chain Reaction, MESH : Blotting, Northern, MESH: Pancreas, MESH: Lipoproteins, MESH : Kidney, MESH: Cattle, MESH : Mitochondria, Rhizobium, MESH: Pigments, Biological, Transgene, MESH : Lipoproteins, MESH: Brain, MESH : Mass Spectrometry, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, MESH: Gene Expression Regulation, Plant, Transcription factor, Gene, 030304 developmental biology, DNA Primers, Base Sequence, polycistronic miRNA, MESH : Liver, MESH : Lipids, Cell Biology, MESH: Kidney, Meristem, biology.organism_classification, Blotting, Northern, symbiotic nodulation, MESH: Lipids, MESH : Microscopy, Electron, MESH : MicroRNAs, MicroRNAs, MESH : Proteolipids, MESH : Base Sequence, MESH : Animals, MESH : Neuronal Ceroid-Lipofuscinoses, 010606 plant biology & botany, MESH: Electrophoresis, Polyacrylamide Gel
Abstract

International audience; Legume root architecture is characterized by the development of two de novo meristems, leading to the formation of lateral roots or symbiotic nitrogen-fixing nodules. Organogenesis involves networks of transcription factors, the encoding mRNAs of which are frequently targets of microRNA (miRNA) regulation. Most plant miRNAs, in contrast with animal miRNAs, are encoded as single entities in an miRNA precursor. In the model legume Medicago truncatula, we have identified the MtMIR166a precursor containing tandem copies of MIR166 in a single transcriptional unit. These miRNAs post-transcriptionally regulate a new family of transcription factors associated with nodule development, the class-III homeodomain-leucine zipper (HD-ZIP III) genes. In situ expression analysis revealed that these target genes are spatially co-expressed with MIR166 in vascular bundles, and in apical regions of roots and nodules. Overexpression of the tandem miRNA precursor correlated with MIR166 accumulation and the downregulation of several class-III HD-ZIP genes, indicating its functionality. MIR166 overexpression reduced the number of symbiotic nodules and lateral roots, and induced ectopic development of vascular bundles in these transgenic roots. Hence, plant polycistronic miRNA precursors, although rare, can be processed, and MIR166-mediated post-transcriptional regulation is a new regulatory pathway involved in the regulation of legume root architecture.

Published
2008

39. Treatment with the arginase inhibitor N(omega)-hydroxy-nor-L-arginine improves vascular function and lowers blood pressure in adult spontaneously hypertensive rat

Author

Alain Berthelot, Céline Demougeot, Pascal Laurant, Yves Claude Guillaume, Claire André, Malika Bouhaddi, Teddy Bagnost, Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( EA 3920) (PCVP / CARDIO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( PCVP / CARDIO ), and Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon )

Subjects
Blood Glucose, Male, Arginine, Physiology, MESH: Mesenteric Arteries, MESH: Rats, Inbred SHR, Aorta, Thoracic, Blood Pressure, 030204 cardiovascular system & hematology, Kidney, Rats, Inbred WKY, MESH: Hypertension, chemistry.chemical_compound, 0302 clinical medicine, Heart Rate, MESH : Arginine, Rats, Inbred SHR, Urea, MESH: Animals, MESH: Heart Rate, MESH : Mesenteric Arteries, MESH : Body Weight, MESH : Isoenzymes, 0303 health sciences, MESH : Rats, MESH: Arginine, MESH : Hypertension, MESH : Arginase, MESH: Blood Pressure, MESH : Kidney, Mesenteric Arteries, 3. Good health, Isoenzymes, Arginase, MESH: Arginase, medicine.anatomical_structure, Liver, MESH : Nitric Oxide, Hypertension, MESH: Isoenzymes, MESH: Vasoconstriction, MESH: Endothelium, Vascular, MESH : Vasoconstriction, Cardiology and Cardiovascular Medicine, Vascular function, MESH: Rats, Inbred WKY, medicine.medical_specialty, Endothelium, MESH: Rats, MESH : Male, MESH: Aorta, Thoracic, In Vitro Techniques, MESH : Rats, Inbred WKY, Nitric Oxide, Nitric oxide, 03 medical and health sciences, Spontaneously hypertensive rat, MESH : Urea, Internal medicine, medicine.artery, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Internal Medicine, medicine, MESH : Blood Pressure, Animals, MESH: Urea, 030304 developmental biology, MESH : Aorta, Thoracic, Aorta, MESH : Rats, Inbred SHR, business.industry, MESH : Heart Rate, Body Weight, MESH : Liver, MESH: Kidney, MESH : Blood Glucose, MESH: Male, Rats, MESH: Body Weight, Endocrinology, Blood pressure, chemistry, Vasoconstriction, MESH : Endothelium, Vascular, MESH: Nitric Oxide, MESH: Blood Glucose, Endothelium, Vascular, MESH : Animals, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, MESH: Liver
Abstract

International audience; OBJECTIVE: High vascular arginase activity and subsequent reduction in vascular nitric oxide production were recently reported in animal models of hypertension. The present study investigated the effects of in-vivo arginase inhibition on blood pressure and vascular function in adult spontaneously hypertensive rats. METHODS: Ten-week-old spontaneously hypertensive rats and normotensive age-matched Wistar-Kyoto rats were treated with or without the selective arginase inhibitor N-hydroxy-nor-L-arginine for 3 weeks (10 or 40 mg/kg per day, intraperitoneally). Systolic blood pressure and cardiac rate were measured before and during treatment. Flow and pressure-dependent reactivity as well as remodeling of mesenteric arteries, acetylcholine-dependent vasodilation of aortic rings, cardiac hypertrophy, arginase activity and nitric oxide production were investigated in 13-week-old spontaneously hypertensive rats. RESULTS: In spontaneously hypertensive rats, N-hydroxy-nor-L-arginine treatment decreased arginase activity (30-40%), reduced blood pressure ( approximately 35 mmHg) and improved the reactivity of mesenteric vessels. However, vascular and cardiac remodeling was not different between treated and untreated spontaneously hypertensive rats. In Wistar-Kyoto rats, N-hydroxy-nor-L-arginine did not affect blood pressure. Finally, arginase inhibition was associated with increased nitric oxide production. Consistent with this, the response of aortic rings to acetylcholine was fully restored by N-hydroxy-nor-L-arginine, and the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester significantly reduced the effect of N-hydroxy-nor-L-arginine on flow-dependent vasodilation. CONCLUSION: Pharmacological inhibition of arginase in adult spontaneously hypertensive rats decreases blood pressure and improves the reactivity of resistance vessels. These data represent in-vivo argument in favor of selective arginase inhibition as a new therapeutic strategy against hypertension.

Published
2008

40. Expression of major histocompatibility complex class I chain-related molecule A, NKG2D, and transforming growth factor-beta in the liver of humans with alveolar echinococcosis: new actors in the tolerance to parasites?

Author

Solange Bresson-Hadni, Sophie Hue, Sophie Caillat-Zucman, Shaoling Zhang, Damien Sène, Dominique A. Vuitton, Bernadette Kantelip, Alfred Penfornis, Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( EA 3920) (PCVP / CARDIO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de Diabétologie - Endocrinologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), WHO Collaborating Center on Prevention and Treatment of Human Echinococcosis, Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Service d'Anatomie pathologique [CHRU Besançon], Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), WHO Collaborating Center on Prevention and Treatment of Human Echinococcosis, SERF Unit, Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( PCVP / CARDIO ), Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Service de diabétologie - endocrinologie, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Université de Franche-Comté ( UFC ), Laboratoire Chrono-environnement ( LCE ), Université Bourgogne Franche-Comté ( UBFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), Laboratoire d'anatomie pathologique [Besancon], Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz-Université de Franche-Comté ( UFC ), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Laboratoire Chrono-environnement - CNRS - UFC (UMR 6249) (LCE), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz-Université de Franche-Comté (UFC), and Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)

Subjects
MESH : Host-Parasite Interactions, Genes, MHC Class I, MESH : Hepatocytes, MESH : Echinococcus multilocularis, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Histocompatibility Antigens Class I, MESH: Hepatocytes, 0302 clinical medicine, Transforming Growth Factor beta, MESH : Receptors, Immunologic, Immunology and Allergy, MESH: Animals, Receptors, Immunologic, [ SDV.MP.MYC ] Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, 0303 health sciences, MESH: Echinococcosis, Hepatic, MESH: Genes, MHC Class I, 3. Good health, Infectious Diseases, medicine.anatomical_structure, Liver, NK Cell Lectin-Like Receptor Subfamily K, Receptors, Natural Killer Cell, MESH: NK Cell Lectin-Like Receptor Subfamily K, MESH : Histocompatibility Antigens Class I, Echinococcosis, Hepatic, T cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Major histocompatibility complex, MESH: Host-Parasite Interactions, MESH : Genes, MHC Class I, Natural killer cell, Host-Parasite Interactions, MESH: Receptors, Natural Killer Cell, 03 medical and health sciences, MESH : Receptors, Natural Killer Cell, MHC class I, medicine, MESH : NK Cell Lectin-Like Receptor Subfamily K, Animals, Humans, MESH: Receptors, Immunologic, MESH: Transforming Growth Factor beta, 030304 developmental biology, MESH: Echinococcus multilocularis, MESH: Humans, Histocompatibility Antigens Class I, MESH : Humans, MESH : Liver, NKG2D, Molecular biology, stomatognathic diseases, MESH : Transforming Growth Factor beta, Giant cell, Immunology, biology.protein, Hepatocytes, Echinococcus multilocularis, MESH : Animals, MESH : Echinococcosis, Hepatic, CD8, 030215 immunology, Transforming growth factor, MESH: Liver
Abstract

International audience; BACKGROUND: Echinococcus multilocularis growth and persistent granuloma, which lead to the development of the severe parasitic disease alveolar echinococcosis (AE), might be caused by abnormal expression of stress-induced proteins, with subsequent abnormalities in T cell activation. Similar to its involvement in tumors, the NKG2D-major histocompatability complex class I chain-related molecules A and B (MICA/B) signaling system could be involved in host-parasite interactions; however, its involvement in helminthic diseases has never been studied. METHODS: We studied MICA/B, NKG2D, and transforming growth factor-beta (TGF-beta) expression on liver sections and measured levels of soluble MICA in serum samples obtained from patients with progressive AE. Livers from healthy and cirrhotic subjects were studied as controls. RESULTS: Expression of MICA/B proteins was strongly enhanced in the hepatocytes and endothelial and bile duct cells; in the CD68+ cells of the periparasitic infiltrate, especially epithelioid and giant cells; and, also, in the metacestode germinal layer. Strong expression of MICA/B in the liver contrasted with low numbers of NK cells and lack of expression of NKG2D on the numerous CD8+ T lymphocytes of the periparasitic infiltrate, as well as with the absence of soluble MICA in serum. TGF-beta was strongly expressed by most of the infiltrating lymphocytes. CONCLUSIONS: Sustained expression of MICA/B molecules and TGF-beta might lead to modulation of NKG2D with subsequent inhibition of NKG2D-dependent cytotoxicity. Abnormalities of this signaling system could contribute to parasitic evasion of the host's immunity.

Published
2008

41. Comparison of transfer and effects of Cd on rats exposed in a short experimental snail-rat food chain or to CdCl2 dosed food

Author

Lysiane Richert, Michaël Cœurdassier, Frédéric Gimbert, Renaud Scheifler, A. de Vaufleury, Hélène Martin, Sylvie Devaux, Alain Berthelot, Pierre-Marie Badot, Richard P. Cosson, F. Hispard, Laboratoire Chrono-environnement (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Mer, molécules et santé EA 2160 (MMS), Le Mans Université (UM)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), Laboratoire de Biologie Marine, Université de Nantes (UN)-ISOMer, Unité sous contrat biologie environnementale, Institut National de la Recherche Agronomique (INRA)-Université de Franche-Comté (UFC), Politiss, École des Hautes Études en Santé Publique [EHESP] (EHESP), Laboratoire de physique des milieux ionisés et applications (LPMIA), Université Henri Poincaré - Nancy 1 (UHP)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Pierre Aigrain (LPA), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), ANR-05-ECCO-0004,STARTT,Biodisponibilité, transferts et effets des éléments trace métalliques dans des réseaux trophiques terrestres : changements d'échelle spatiale et de niveau d'organisation biologique(2005), Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN)-Le Mans Université (UM)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Chrono-environnement - UFC (UMR 6249) (LCE), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Le Mans Université (UM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Physique des milieux ionisés et applications (LPMIA), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), ANR: STARTT,STARTT, Laboratoire Chrono-environnement ( LCE ), Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ) -Centre National de la Recherche Scientifique ( CNRS ), Mer, molécules et santé ( MMS ), Université de Nantes ( UN ), Université de Nantes ( UN ) -ISOMer, Institut National de la Recherche Agronomique ( INRA ) -Université de Franche-Comté ( UFC ), École des Hautes Études en Santé Publique [EHESP] ( EHESP ), Physique des milieux ionisés et applications ( LPMIA ), Université Henri Poincaré - Nancy 1 ( UHP ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire Pierre Aigrain ( LPA ), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris ( FRDPENS ), Centre National de la Recherche Scientifique ( CNRS ) -École normale supérieure - Paris ( ENS Paris ) -Centre National de la Recherche Scientifique ( CNRS ) -École normale supérieure - Paris ( ENS Paris ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), and ANR : STARTT,STARTT

Subjects
0106 biological sciences, MESH: Intestine, Small, MESH : Biological Availability, Snails, Wistar, [ SDV.TOX.ECO ] Life Sciences [q-bio]/Toxicology/Ecotoxicology, 010501 environmental sciences, Small, Kidney, 01 natural sciences, Toxicology, chemistry.chemical_compound, Cadmium Chloride, Intestine, Small, Metallothionein, MESH: Animals, Food science, MESH: Snails, lcsh:Environmental sciences, MESH: Cadmium Chloride, General Environmental Science, MESH: Biological Availability, lcsh:GE1-350, MESH : Intestine, Small, Cadmium, MESH : Rats, MESH : Feeding Behavior, MESH : Food Chain, MESH : Kidney, 3. Good health, Intestine, medicine.anatomical_structure, Liver, MESH: Survival Analysis, Toxicity, MESH: Feeding Behavior, [SDV.TOX.ECO]Life Sciences [q-bio]/Toxicology/Ecotoxicology, Food Chain, MESH: Rats, MESH : Cadmium Chloride, chemistry.chemical_element, Biological Availability, Biology, Cadmium chloride, MESH : Rats, Wistar, medicine, Ecotoxicology, Animals, Rats, Wistar, MESH: Food Chain, 0105 earth and related environmental sciences, 010604 marine biology & hydrobiology, MESH: Metallothionein, MESH : Liver, Feeding Behavior, MESH: Rats, Wistar, MESH: Kidney, Survival Analysis, Small intestine, MESH : Metallothionein, Bioavailability, Rats, chemistry, MESH : Snails, MESH : Animals, MESH : Survival Analysis, Toxicant, MESH: Liver
Abstract

Transfer and toxic effects of two cadmium (Cd) forms, inorganic (CdCl2 dosed rat food) or organic (contaminated snail-based rat food) were studied in Wistar rat. Cd concentrations in rat food were 0 and 2.5 μg Cd g−1 for both inorganic and organic forms and a high concentration of 100 μg Cd g−1 was also tested for the inorganic form. Rats were exposed for four weeks to contaminated food. Both forms of Cd were bioavailable to rats, with a percentage of transfer from food to rats of around 1% for all contaminated groups. Cd concentrations in rat tissues increased with increasing Cd concentrations in the food. Rats fed with organic form of Cd accumulated significantly more Cd in the main organ for Cd toxicity, the kidney, than those eating the inorganic form. Survival was not affected for any rat group but a decrease in growth and food consumption was observed for the inorganic form. As a defence system against Cd toxicity, rats increased their metallothionein (MT) synthesis at the highest Cd concentration in the target organs (kidney, liver and small intestine) and even did the same at low Cd concentrations (2.5 μg Cd g−1) in the kidney. At this low Cd concentration, MT induction was lower in the small intestine of rats ingesting organic Cd than those ingesting inorganic Cd. Bioavailability of organic and inorganic forms of Cd was similar, but subsequent Cd distribution within organs was different. This quantification of the trophic transfer of both inorganic and organic forms of a toxicant is a basis for a better assessment of the fate and effects of chemicals in food webs. Keywords: Bioavailability, Ecotoxicology, Metallothioneins

Published
2008

42. Immunoaffinity purification and characterization of mitochondrial membrane-bound D-3-hydroxybutyrate dehydrogenase from Jaculus orientalis

Author

Mustapha Cherkaoui-Malki, Pierre Andreoletti, Driss Mountassif, Adnane Moutaouakkil, Zakaria El Kebbaj, M'Hammed Saïd El Kebbaj, Norbert Latruffe, Laboratoire Biochimie et Biologie Moléculaire ( LBBM ), Université Hassan II, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Latruffe, Norbert, Laboratoire Biochimie et Biologie Moléculaire (LBBM), Université Hassan II [Casablanca] (UH2MC), Lipides - Nutrition - Cancer (U866) (LNC), and Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)

Subjects
lcsh:Animal biochemistry, MESH : Aged, MESH : Rodentia, MESH: Rodentia, MESH: Base Sequence, Biochemistry, MESH: Lipid Peroxidation, MESH : Information Services, Antigen-Antibody Reactions, MESH: Health Education, Epitopes, MESH: Organizations, MESH: Libraries, MESH: Antigen-Antibody Reactions, lcsh:QD415-436, MESH: Animals, MESH : Organizations, MESH : Physician's Role, MESH: Bacterial Proteins, Immunosorbent Techniques, chemistry.chemical_classification, MESH: Conserved Sequence, Methodology Article, MESH : Computer Communication Networks, MESH: Chromatography, Affinity, MESH : Pseudomonas aeruginosa, MESH : Chromatography, Affinity, MESH : Immunosorbent Techniques, MESH: Ethnic Groups, MESH : Ethnic Groups, MESH: Epitopes, MESH : Patient Satisfaction, MESH : United States, MESH: Mitochondria, MESH : Antigen-Antibody Reactions, Molecular Sequence Data, MESH : Hydroxybutyrate Dehydrogenase, MESH: Sequence Alignment, Rodentia, MESH: Information Services, MESH : Epitopes, lcsh:Biochemistry, MESH : Mitochondrial Membranes, Bacterial Proteins, MESH : Conserved Sequence, Complementary DNA, MESH : Libraries, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Immunosorbent Techniques, MESH: Molecular Sequence Data, MESH: Humans, MESH : Consumer Participation, MESH : Humans, MESH: Adult, MESH: Patient Satisfaction, MESH: Hydroxybutyrate Dehydrogenase, MESH: Consumer Participation, chemistry, Lipid Peroxidation, MESH: Female, MESH: Liver, MESH : Sequence Analysis, DNA, MESH: Continental Population Groups, MESH: Sequence Analysis, DNA, MESH : Molecular Sequence Data, Dehydrogenase, Chromatography, Affinity, MESH: Mitochondrial Membranes, MESH: Antibodies, Bacterial, MESH : Bacterial Proteins, MESH : Female, MESH: Computer Communication Networks, Conserved Sequence, MESH: Aged, biology, MESH : Lipid Peroxidation, MESH : Sequence Alignment, MESH: Physician's Role, MESH : Adult, Antibodies, Bacterial, Mitochondria, Amino acid, Liver, Mitochondrial Membranes, Pseudomonas aeruginosa, MESH: Pseudomonas aeruginosa, MESH : Mitochondria, MESH : Mass Media, MESH: Mass Media, MESH : Male, Hydroxybutyrate Dehydrogenase, Affinity chromatography, MESH : Health Education, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: United States, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Antibodies, Bacterial, lcsh:QP501-801, Jaculus orientalis, MESH : Continental Population Groups, Base Sequence, MESH : Liver, Sequence Analysis, DNA, biology.organism_classification, Molecular biology, MESH: Male, Enzyme, Polyclonal antibodies, biology.protein, MESH : Base Sequence, NAD+ kinase, MESH : Animals, Sequence Alignment
Abstract

Background The interconversion of two important energy metabolites, 3-hydroxybutyrate and acetoacetate (the major ketone bodies), is catalyzed by D-3-hydroxybutyrate dehydrogenase (BDH1: EC 1.1.1.30), a NAD+-dependent enzyme. The eukaryotic enzyme is bound to the mitochondrial inner membrane and harbors a unique lecithin-dependent activity. Here, we report an advanced purification method of the mammalian BDH applied to the liver enzyme from jerboa (Jaculus orientalis), a hibernating rodent adapted to extreme diet and environmental conditions. Results Purifying BDH from jerboa liver overcomes its low specific activity in mitochondria for further biochemical characterization of the enzyme. This new procedure is based on the use of polyclonal antibodies raised against BDH from bacterial Pseudomonas aeruginosa. This study improves the procedure for purification of both soluble microbial and mammalian membrane-bound BDH. Even though the Jaculus orientalis genome has not yet been sequenced, for the first time a D-3-hydroxybutyrate dehydrogenase cDNA from jerboa was cloned and sequenced. Conclusion This study applies immunoaffinity chromatography to purify BDH, the membrane-bound and lipid-dependent enzyme, as a 31 kDa single polypeptide chain. In addition, bacterial BDH isolation was achieved in a two-step purification procedure, improving the knowledge of an enzyme involved in the lipid metabolism of a unique hibernating mammal. Sequence alignment revealed conserved putative amino acids for possible NAD+ interaction.

Published
2008

43. NOD2: a potential target for regulating liver injury

Author

Jean-Pierre Hugot, Philippe Mathurin, Sylvie Hudault, Sébastien Dharancy, Laurent Dubuquoy, Mathias Chamaillard, Filomena Conti, Pierre Desreumaux, Irene Garcia, Alexandre Louvet, Dominique Berrebi, Emilie Gantier, Philippe J. Sansonetti, Dana J. Philpott, Fabrice Chareyre, Mathilde Body-Malapel, Gilles Pagès, Marco Giovannini, Stephen E. Girardin, Physiopathologie des Maladies Inflammatoires de l'Intestin, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Université de Lille, Droit et Santé, Hôpital Duriez, Service des Maladies de l'Appareil digestif et de la Nutrition, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Anatomie et de Cytologie Pathologiques, Hôpital Robert Debré, Inflammation intestinale pathologique de l'enfant, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Immunology, University of Toronto, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de signalisation, biologie du développement et cancer (ISBDC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Department of Laboratory Medicine and Pathobiology (LMP), Université de Genève = University of Geneva (UNIGE), Pathogenes et Fonctions des Cellules Epitheliales Polarisees, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biologie Cellulaire, Université Paris Descartes - Paris 5 (UPD5), Pathogénie Microbienne Moléculaire, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Collège de France - Chaire Microbiologie et Maladies infectieuses, Collège de France (CdF (institution)), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Genomique Fonctionnelle des Tumeurs Solides, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -IFR105-Université Paris Diderot - Paris 7 ( UPD7 ), Institut de signalisation, biologie du développement et cancer ( ISBDC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Laboratory Medicine and Pathobiology ( LMP ), Department of Pathology and Immunology, Univ. Geneva, University of Geneva [Switzerland], Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], and Chaire Microbiologie et Maladies infectieuses

Subjects
MESH : RNA, Messenger, MESH: Spleen, Lymphocyte, Nod2 Signaling Adaptor Protein, RNA, Messenger/metabolism, MESH: Adjuvants, Immunologic, Apoptosis, MESH : Hepatocytes, ddc:616.07, MESH : Nod2 Signaling Adaptor Protein, Interferon-gamma/analysis/pharmacology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Hepatocytes, Mice, 0302 clinical medicine, Concanavalin A, MESH: Up-Regulation, MESH: Nod2 Signaling Adaptor Protein, MESH: Animals, MESH : Up-Regulation, MESH : Acetylmuramyl-Alanyl-Isoglutamine, Cells, Cultured, Liver injury, 0303 health sciences, Leukocytes, Mononuclear/drug effects/*immunology, MESH: Hepatitis, Animal, MESH : Interferon Type II, MESH: Case-Control Studies, 3. Good health, Up-Regulation, Acetylmuramyl-Alanyl-Isoglutamine/pharmacology, 030220 oncology & carcinogenesis, Hepatocytes/drug effects/metabolism/physiology, Muramyl dipeptide, MESH: Cells, Cultured, MESH : Case-Control Studies, Liver/*injuries, [ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Concanavalin A, Nod2 Signaling Adaptor Protein/analysis/*deficiency/genetics/*metabolism, Pathology and Forensic Medicine, Interferon-gamma, 03 medical and health sciences, Adjuvants, Immunologic, Humans, RNA, Messenger, Molecular Biology, MESH: Humans, Tumor Necrosis Factor-alpha, MESH : Humans, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, digestive system diseases, Immunity, Innate, MESH : Leukocytes, Mononuclear, Mice, Inbred C57BL, chemistry, MESH: Tumor Necrosis Factor-alpha, Case-Control Studies, Immunology, Hepatitis, Animal/chemically induced/*immunology/metabolism/pathology, Leukocytes, Mononuclear, MESH : Hepatitis, Animal, MESH : Apoptosis, MESH: Liver, MESH : Immunity, Natural, Cell Separation, Hepatitis, Animal, MESH: Mice, Knockout, chemistry.chemical_compound, Adjuvants, Immunologic/pharmacology, NOD2, MESH : Concanavalin A, Tumor Necrosis Factor-alpha/analysis/pharmacology, MESH : Tumor Necrosis Factor-alpha, Mice, Knockout, MESH: Kinetics, Concanavalin A/toxicity, MESH: Leukocytes, Mononuclear, medicine.anatomical_structure, Liver, medicine.symptom, MESH : Kinetics, Acetylmuramyl-Alanyl-Isoglutamine, Cell Separation/methods, MESH : Spleen, MESH: Interferon Type II, Inflammation, [SDV.CAN]Life Sciences [q-bio]/Cancer, chemical and pharmacologic phenomena, MESH : Mice, Inbred C57BL, Biology, MESH: Cell Separation, Immune system, MESH: Mice, Inbred C57BL, MESH : Mice, MESH : Cells, Cultured, medicine, Animals, Spleen/cytology/drug effects, MESH: Mice, 030304 developmental biology, MESH: RNA, Messenger, MESH: Immunity, Natural, Hepatitis, Innate immune system, MESH: Apoptosis, MESH : Liver, Cell Biology, Kinetics, MESH: Acetylmuramyl-Alanyl-Isoglutamine, MESH : Cell Separation, Hepatocytes, MESH : Adjuvants, Immunologic, MESH : Mice, Knockout, MESH : Animals, Spleen
Abstract

The recent discovery of bacterial receptors such as NOD2 that contribute to crosstalk between innate and adaptive immune systems in the digestive tract constitutes an important challenge in our understanding of liver injury mechanisms. The present study focuses on NOD2 functions during liver injury. NOD2, TNF-alpha and IFN-gamma mRNA were quantified using real-time PCR in liver samples from patients and mice with liver injury. We evaluated the susceptibility of concanavalin A (ConA) challenge in NOD2-deficient mice (Nod2-/-) compared to wild-type littermates. We tested the effect of muramyl dipeptide (MDP), the specific activator of NOD2, on ConA-induced liver injury in C57BL/6 mice. We studied the cellular distribution and the role of NOD2 in immune cells and hepatocytes. We demonstrated that NOD2, TNF-alpha and IFN-gamma were upregulated during liver injury in mice and humans. Nod2-/- mice were resistant to ConA-induced hepatitis compared to their wild-type littermates, through reduced IFN-gamma production by immune cells. Conversely, administration of MDP exacerbated ConA-induced liver injury. MDP was a strong inducer of IFN-gamma in freshly isolated human PBMC, splenocytes and hepatocytes. Our study supports the hypothesis that NOD2 contributes to liver injury via a regulatory mechanism affecting immune cells infiltrating the liver and hepatocytes. Taken together, our results indicate that NOD2 may represent a new therapeutic target in liver diseases.

Published
2008

44. HNF1alpha inactivation promotes lipogenesis in human hepatocellular adenoma independently of SREBP-1 and carbohydrate-response element-binding protein (ChREBP) activation

Author

Sandrine Imbeaud, Justine Bertrand-Michel, Sandra Rebouissou, Charles Auffray, Charles Balabaud, François Tercé, Paulette Bioulac-Sage, Virginie Boulanger, Jessica Zucman-Rossi, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Labex Immuno-oncology, Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PRES Sorbonne Paris Cité-Faculté de Médecine, Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Fibrose hépatique et cancer du foie, Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateau MetaToul-LIPIDOMIQUE = MetaToul-Lipidomics, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-MetaToul-MetaboHUB, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-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 des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, This work was supported by the Inserm (Réseau de Recherche clinique et en santé des populations), ARC n°5188, SNFGE and the Fondation de France. SR is supported by a Ligue Nationale Contre le Cancer doctoral fellowship., Zucman-Rossi, Jessica, Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PRES Sorbonne Paris Cité-Faculté de Médecine, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-MetaboHUB-MetaToul, Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), MetaToul Lipidomics, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-MetaboHUB-MetaToul, MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Genomique Fonctionnelle des Tumeurs Solides, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -IFR105-Université Paris Diderot - Paris 7 ( UPD7 ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -PRES Sorbonne Paris Cité-Faculté de Médecine, Génétique moléculaire de la neurotransmission et des processus neurodégénératifs ( LGMNPN ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Plateau de lipidomique, Hôpital Purpan [Toulouse], and CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Claude de Preval

Subjects
Male, Biochemistry, 0302 clinical medicine, MESH: Liver Neoplasms, Glycolysis, MESH : Glycolysis, Oligonucleotide Array Sequence Analysis, chemistry.chemical_classification, 0303 health sciences, MESH: Middle Aged, Fatty Acids, Liver Neoplasms, MESH: SREBP-1, MESH: Transcription Factors, Gene Expression Regulation, Neoplastic, MESH : Oligonucleotide Array Sequence Analysis, MESH: Promoter Regions (Genetics), 030220 oncology & carcinogenesis, MESH : Hepatocyte Nuclear Factor 1-alpha, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Sterol Regulatory Element Binding Protein 1, MESH: Citric Acid, MESH : Gene Expression Regulation, Neoplastic, Adenoma, Liver Cell, 03 medical and health sciences, MESH: Gene Expression Profiling, MESH: Sterol Regulatory Element Binding Protein 1, MESH : steatosis, MESH : Adenoma, Liver Cell, MESH : Sterol Regulatory Element Binding Protein 1, MESH : Adolescent, Humans, MESH : Middle Aged, MESH: Hepatocyte Nuclear Factor 1-alpha, Molecular Biology, Fatty acid synthesis, MESH: Lipogenesis, MESH: Adolescent, MESH: Humans, MESH : Gene Expression Profiling, MESH : Humans, Fatty acid, MESH : HNF1α, MESH: Adult, medicine.disease, MESH : Promoter Regions (Genetics), Sterol regulatory element-binding protein, chemistry, MESH: Tumor Markers, Biological, MESH : Response Elements, MESH: Female, Transcription Factors, MESH: Liver, MESH: Signal Transduction, MESH : Liver Neoplasms, MESH : Fatty Liver, MESH : Transcription Factors, chemistry.chemical_compound, MESH: Adenoma, Liver Cell, MESH : Tumor Markers, Biological, MESH : Female, Hepatocyte Nuclear Factor 1-alpha, Promoter Regions, Genetic, MESH : Fatty Acids, MESH: Fatty Liver, MESH: Gluconeogenesis, MESH: Gene Expression Regulation, Neoplastic, Middle Aged, MESH : Adult, MESH: Fatty Acids, Liver, Lipogenesis, MESH: Glycolysis, Female, MESH: Response Elements, MESH : SREBP-1, Signal Transduction, Adult, Adolescent, MESH : Male, MESH : Gluconeogenesis, MESH : Citric Acid, Biology, Response Elements, Citric Acid, MESH: steatosis, Biomarkers, Tumor, medicine, MESH : hepatocellular adenoma, Carbohydrate-responsive element-binding protein, Transcription factor, 030304 developmental biology, MESH : Signal Transduction, Gene Expression Profiling, MESH: hepatocellular adenoma, Gluconeogenesis, MESH : Liver, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cell Biology, MESH: HNF1α, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Male, MESH : Lipogenesis, Fatty Liver, MESH: Oligonucleotide Array Sequence Analysis, Steatosis
Abstract

International audience; Biallelic inactivating mutations of the transcription factor 1 gene (TCF1), encoding hepatocyte nuclear factor 1alpha (HNF1alpha) were identified in 50% of hepatocellular adenomas (HCA) phenotypically characterized by a striking steatosis. To understand the molecular basis of this aberrant lipid storage, we performed a microarray transcriptome analysis validated by quantitative reverse transcription-PCR, Western blotting, and lipid profiling. In mutated HCA, we showed a repression of gluconeogenesis coordinated with an activation of glycolysis, citrate shuttle, and fatty acid synthesis predicting elevated rates of lipogenesis. Moreover, the strong down-regulation of liver fatty acid-binding protein suggests that impaired fatty acid trafficking may also contribute to the fatty phenotype. In addition, transcriptional profile analysis of the observed deregulated genes in non-HNF1alpha-mutated HCA as well as in non-tumor livers allowed us to define a specific signature of the HNF1alpha-mutated HCA. In these tumors, lipid composition was dramatically modified according to the transcriptional deregulations identified in the fatty acid synthetic pathway. Surprisingly, lipogenesis activation did not operate through sterol regulatory element-binding protein-1 (SREBP-1) and carbohydrate-response element-binding protein (ChREBP) that were repressed. We conclude that steatosis in HNF1alpha-mutated HCA results mainly from an aberrant promotion of lipogenesis that is linked to HNF1alpha inactivation and that is independent of both SREBP-1 and ChREBP activation. Finally, our findings have potential clinical implications since lipogenesis can be efficiently inhibited by targeted therapies.

Published
2007

45. Hybrid gadolinium oxide nanoparticles: multimodal contrast agents for in vivo imaging

Author

Stéphane Roux, Jean-Luc Bridot, Jean-Luc Coll, Bassem Hiba, Marc Janier, Claire Billotey, Sophie Laurent, Luce Vander Elst, Olivier Tillement, Pascal Perriat, Robert N. Muller, Véronique Josserand, Anne-Charlotte Faure, Charlotte Rivière, Laboratoire de Physico-Chimie des Matériaux Luminescents (LPCML), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Laboratoire de RMN, Université de Mons-Hainaut, NanoH-sas, Centre de Recherche et d'Application en Traitement de l'Image et du Signal (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École Supérieure Chimie Physique Électronique de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U823, équipe 5 (cibles diagnostiques ou thérapeutiques et vectorisation de drogues dans le cancer du poumon), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Matériaux, ingénierie et science [Villeurbanne] (MATEIS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physico-Chimie des Matériaux Luminescents ( LPCML ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche et d'Application en Traitement de l'Image et du Signal ( CREATIS ), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -École Supérieure Chimie Physique Électronique de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Matériaux, ingénierie et science [Villeurbanne] ( MATEIS ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ) -Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ), Hurbin, Amandine, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-École Supérieure de Chimie Physique Électronique de Lyon (CPE)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Fluorescence-lifetime imaging microscopy, MESH : Siloxanes, Nanoparticle, Contrast Media, Gadolinium, 02 engineering and technology, [SPI.MAT] Engineering Sciences [physics]/Materials, MESH : Gadolinium, 01 natural sciences, Biochemistry, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Polyethylene Glycols, MESH: Magnetic Resonance Imaging, [SPI.MAT]Engineering Sciences [physics]/Materials, Paramagnetism, Mice, Colloid and Surface Chemistry, Nuclear magnetic resonance, Heterocyclic Compounds, MESH: Animals, Lung, medicine.diagnostic_test, Chemistry, MESH : Rats, MESH : Polyethylene Glycols, MESH : Mice, Nude, 021001 nanoscience & nanotechnology, Magnetic Resonance Imaging, Liver, Covalent bond, MESH : Organometallic Compounds, 0210 nano-technology, Preclinical imaging, MESH : Fluorescence, Siloxanes, MESH: Rats, MESH: Heterocyclic Compounds, MESH : Lung, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, 010402 general chemistry, Catalysis, Fluorescence, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH : Magnetic Resonance Imaging, MESH: Contrast Media, PEG ratio, MESH : Mice, medicine, Organometallic Compounds, MESH: Mice, Nude, Animals, MESH: Lung, MESH: Siloxanes, MESH: Mice, MESH : Contrast Media, MESH: Fluorescence, MESH : Liver, Magnetic resonance imaging, MESH: Organometallic Compounds, General Chemistry, 0104 chemical sciences, Rats, MESH : Heterocyclic Compounds, MESH: Polyethylene Glycols, MESH : Nanoparticles, Nanoparticles, MESH : Animals, Luminescence, MESH: Gadolinium, MESH: Nanoparticles, MESH: Liver
Abstract

International audience; Luminescent hybrid nanoparticles with a paramagnetic Gd2O 3 core were applied as contrast agents for both in vivo fluorescence and magnetic resonance imaging. These hybrid particles were obtained by encapsulating Gd2O3 cores within a polysiloxane shell which carries organic fluorophores and carboxylated PEG covalently tethered to the inorganic network. Longitudinal proton relaxivities of these particles are higher than the positive contrast agents like Gd-DOTA which are commonly used for clinical magnetic resonance imaging. Moreover these particles can be followed up by fluorescence imaging. This study revealed that these particles suited for dual modality imaging freely circulate in the blood vessels without undesirable accumulation in lungs and liver.

Published
2007

46. Transdifferentiation of hepatocyte-like cells from the human hepatoma HepaRG cell line through bipotent progenitor

Author

Philippe Gripon, Bruno Turlin, Anne Corlu, Dina Kremsdorf, Serban Morosan, Bernard Drenou, Delphine Garnier, Virginie Cerec, Christiane Guguen-Guillouzo, Denise Glaise, Régulations des équilibres fonctionnels du foie normal et pathologique, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathogénèse des Hépatites Virales B et Immunothérapie (UMR_S 812), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Haematology Department, Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA)-Groupe Hospitalier de Territoire Haute Alsace (GHTHA), Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140, 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 ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Pathogénèse des Hépatites Virales B et Immunothérapie ( UMR_S 812 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Emile Muller [Mulhouse] ( CH E.Muller Mulhouse ), Groupe Hospitalier de Territoire Haute Alsace ( GHTHA ) -Groupe Hospitalier de Territoire Haute Alsace ( GHTHA ), Signalisation et Réponses aux Agents Infectieux et Chimiques ( SeRAIC ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140, 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), 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), 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
MESH: Cell Death, Pathology, MESH : Liver Neoplasms, Cell Transplantation, Cellular differentiation, Gene Expression, MESH : Hepatocytes, Mice, SCID, MESH: Hepatocytes, Mice, 0302 clinical medicine, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Liver Neoplasms, MESH : Cell Proliferation, MESH : Female, MESH: Animals, MESH: Mice, SCID, MESH: Carcinoma, Hepatocellular, 0303 health sciences, Cell Death, Transdifferentiation, Liver Neoplasms, Cell Differentiation, Cell biology, MESH: Cell Transplantation, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Liver, 030220 oncology & carcinogenesis, Neoplastic Stem Cells, Female, MESH : Cell Differentiation, MESH : Carcinoma, Hepatocellular, MESH: Cell Differentiation, medicine.medical_specialty, MESH: Gene Expression, MESH: Cell Line, Tumor, Carcinoma, Hepatocellular, MESH : Cell Lineage, Biology, Cholangiocyte, 03 medical and health sciences, MESH : Neoplastic Stem Cells, MESH: Cell Proliferation, Cell Line, Tumor, MESH : Mice, Reversible differentiation, medicine, Animals, Humans, Cell Lineage, Progenitor cell, MESH: Mice, 030304 developmental biology, Progenitor, Cell Proliferation, MESH: Humans, Hepatology, MESH : Cell Line, Tumor, MESH : Humans, MESH: Biological Markers, MESH : Liver, MESH: Cell Lineage, MESH: Neoplastic Stem Cells, MESH : Mice, SCID, MESH : Cell Transplantation, Transplantation, MESH : Biological Markers, MESH : Gene Expression, Cell culture, MESH : Cell Death, Hepatocytes, MESH : Animals, MESH: Female, Biomarkers, MESH: Liver
Abstract

International audience; Hepatic tumors, exhibiting mature hepatocytes and undifferentiated cells merging with cholangiocyte and hepatocyte phenotypes, are frequently described. The mechanisms by which they occur remain unclear. We report differentiation and transdifferentiation behaviors of human HepaRG cells isolated from a differentiated tumor developed consecutively to chronic HCV infection. We demonstrate that, in vitro, proliferating HepaRG cells differentiate toward hepatocyte-like and biliary-like cells at confluence. If hepatocyte-like cells are selectively isolated and cultured at high cell density, they proliferate and preserve their differentiation status. However, when plated at low density, they transdifferentiate into hepatocytic and biliary lineages through a bipotent progenitor. In accordance, transplantation of either undifferentiated or differentiated HepaRG cells in uPA/SCID mouse damaged liver gives rise mainly to functional human hepatocytes infiltrating mouse parenchyma. Analysis of the differentiation/transdifferentiation process reveals that: (1) the reversible differentiation fate of HepaRG cells is related to the absence of p21(CIP1) and p53 accumulation in differentiated cells; (2) HepaRG bipotent progenitors express the main markers of in vivo hepatic progenitors, and that cell differentiation process is linked to loss of their expression; (3) early and transient changes of beta-catenin localization and HNF3beta expression are correlated to Notch3 upregulation during hepatobiliary commitment of HepaRG cells. CONCLUSION: Our results demonstrate the great plasticity of transformed hepatic progenitor cells and suggest that the transdifferentiation process could supply the pool of hepatic progenitor cells. Moreover, they highlight possible mechanisms by which transdifferentiation and proliferation of unipotent hepatocytes might cooperate in the development of mixed and differentiated tumors.

Published
2007

47. NKT cell-plasmacytoid dendritic cell cooperation via OX40 controls viral infection in a tissue-specific manner

Author

André Herbelin, Céline Tomkiewicz, Agnès Lehuen, Julien Diana, Thibault Griseri, Anne-Sophie Gautron, Lucie Beaudoin, Matthias von Herrath, Robert Barouki, Marc Dalod, Sylvie Lagaye, Elodie Autrusseau, Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Slama, Catherine, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Pharmacologie, toxicologie et signalisation cellulaire (U747), La Jolla Institute for Immunology [La Jolla, CA, États-Unis], Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Cochin [AP-HP], Physiologie Cellulaire des Regulations Hormonales, Nutritionnelles et Pharmacologiques, Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), La Jolla Institute for Allergy and Immunology (LIA), La Jolla Institute for Allergy & Immunology, and Aix Marseille Université (AMU) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Signal Transduction, MESH: Spleen, Plasmacytoid dendritic cell, CD8-Positive T-Lymphocytes, Virus Replication, Mice, 0302 clinical medicine, Interferon, Immunology and Allergy, Lymphocytic choriomeningitis virus, MESH: Animals, MESH : Pancreas, MESH: Organ Specificity, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, MESH: Dendritic Cells, hemic and immune systems, MESH : CD8-Positive T-Lymphocytes, MESH: Pancreas, MESH: Receptors, OX40, Acquired immune system, MESH: CD8-Positive T-Lymphocytes, 3. Good health, MESH : Virus Replication, MESH : Diabetes Mellitus, medicine.anatomical_structure, Infectious Diseases, Liver, Organ Specificity, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Lymphocytic choriomeningitis virus, medicine.drug, Signal Transduction, MESH : Spleen, MESH : Lymphocytic Choriomeningitis, MESH: Diabetes Mellitus, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Lymphocytic Choriomeningitis, Immunology, Spleen, OX40 Ligand, Biology, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis, MESH: OX40 Ligand, MESH : Lymphocytic choriomeningitis virus, MESH : Organ Specificity, 03 medical and health sciences, Immune system, MESH : Mice, medicine, Diabetes Mellitus, Animals, MESH : OX40 Ligand, MESH: Mice, Pancreas, 030304 developmental biology, MESH : Signal Transduction, MESH: Virus Replication, MESH : Liver, Dendritic Cells, Receptors, OX40, medicine.disease, MESH : Natural Killer T-Cells, Viral replication, MESH: Natural Killer T-Cells, CELLIMMUNO, MESH : Dendritic Cells, Natural Killer T-Cells, MESH : Animals, MESH : Receptors, OX40, CD8, 030215 immunology, MESH: Liver
Abstract

International audience; Invariant natural killer T (iNKT) cells promote immune responses to various pathogens, but exactly how iNKT cells control antiviral responses is unclear. Here, we showed that iNKT cells induced tissue-specific antiviral effects in mice infected by lymphocytic choriomeningitis virus (LCMV). Indeed, iNKT cells inhibited viral replication in the pancreas and liver but not in the spleen. In the pancreas, iNKT cells expressed the OX40 molecule and promoted type I interferon (IFN) production by plasmacytoid dendritic cells (pDCs) through OX40-OX40 ligand interaction. Subsequently, this iNKT cell-pDC cooperation attenuated the antiviral adaptive immune response in the pancreas but not in the spleen. The dampening of pancreatic anti-LCMV CD8(+) T cell response prevented tissue damage in transgenic mice expressing LCMV protein in islet beta cells. Thus, this study identifies pDCs as an essential partner of iNKT cells for mounting an efficient, nondeleterious antiviral response in peripheral tissue.

Published
2007

48. Glucagon-mediated internalization of serine-phosphorylated glucagon receptor and Gsalpha in rat liver

Author

Clémence Merlen, Sylvie Fabrega, Cecilia G. Unson, Bernard Desbuquois, François Authier, Signalisation et physiopathologie des cellules épithéliales, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Rockefeller University [New York], Codogno, Patrice, Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), The rockefeller university, and The Rockefeller University

Subjects
Male, Arrestins, MESH : GTP-Binding Protein alpha Subunits, Gs, MESH: Rats, Sprague-Dawley, MESH : Adenylate Cyclase, Biochemistry, Rats, Sprague-Dawley, MESH : Receptors, Glucagon, Phosphoserine, Structural Biology, GTP-Binding Protein alpha Subunits, Gs, Receptors, Glucagon, MESH: Animals, Internalization, beta-Arrestins, media_common, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, MESH: Phosphoserine, Endosomal protease, MESH : Glucagon, MESH : Rats, MESH: Glucagon, 030302 biochemistry & molecular biology, digestive, oral, and skin physiology, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Endocytosis, beta-Arrestin 1, Liver, MESH: Endocytosis, MESH: Arrestins, Signal transduction, Glucagon receptor family, hormones, hormone substitutes, and hormone antagonists, Adenylyl Cyclases, medicine.medical_specialty, endocrine system, G-protein, MESH: Rats, G protein, MESH : Endocytosis, MESH : Male, media_common.quotation_subject, MESH : Arrestins, Biophysics, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Glucagon, 03 medical and health sciences, MESH: Receptors, Glucagon, MESH : Phosphoserine, Internal medicine, MESH: Adenylate Cyclase, Genetics, medicine, Animals, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Glucagon-like peptide 1 receptor, 030304 developmental biology, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, MESH : Liver, Cell Biology, MESH: GTP-Binding Protein alpha Subunits, Gs, MESH : Rats, Sprague-Dawley, MESH: Male, Rats, Endocrinology, MESH : Animals, Intracellular signalling, Glucagon receptor, MESH: Liver
Abstract

To assess glucagon receptor compartmentalization and signal transduction in liver parenchyma, we have studied the functional relationship between glucagon receptor endocytosis, phosphorylation and coupling to the adenylate cyclase system. Following administration of a saturating dose of glucagon to rats, a rapid internalization of glucagon receptor was observed coincident with its serine phosphorylation both at the plasma membrane and within endosomes. Co-incident with glucagon receptor endocytosis, a massive internalization of both the 45- and 47-kDa Gsalpha proteins was also observed. In contrast, no change in the subcellular distribution of adenylate cyclase or beta-arrestin 1 and 2 was observed. In response to des-His(1)-[Glu(9)]glucagon amide, a glucagon receptor antagonist, the extent and rate of glucagon receptor endocytosis and Gsalpha shift were markedly reduced compared with wild-type glucagon. However, while the glucagon analog exhibited a wild-type affinity for endosomal acidic glucagonase activity and was processed at low pH with similar kinetics and rates, its proteolysis at neutral pH was 3-fold lower. In response to tetraiodoglucagon, a glucagon receptor agonist of enhanced biological potency, glucagon receptor endocytosis and Gsalpha shift were of higher magnitude and of longer duration, and a marked and prolonged activation of adenylate cyclase both at the plasma membrane and in endosomes was observed. The subsequent post-endosomal fate of internalized Gsalpha was evaluated in a cell-free rat liver endosome-lysosome fusion system following glucagon injection. A sustained endo-lysosomal transfer of the two 45- and 47-kDa Gsalpha isoforms was observed. Therefore, these results reveal that within hepatic target cells and consequent to glucagon-mediated internalization of the serine-phosphorylated glucagon receptor and the Gsalpha protein, extended signal transduction may occur in vivo at the locus of the endo-lysosomal apparatus.

Published
2006

49. Efficient new cationic liposome formulation for systemic delivery of small interfering RNA silencing tumor necrosis factor alpha in experimental arthritis

Author

Pascale Louis-Plence, Christian Jorgensen, Florence Apparailly, Daniel Scherman, Maroun Khoury, Céline Largeau, Céline Cantos, Danièle Noël, Virginie Escriou, Génétique, Pharmacologie Chimique Et, Immunopathologie des maladies tumorales et autoimmunes, Université Montpellier 1 (UM1)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Pharmacologie Chimique et Génétique (UPCG - UMR_S 640/UMR 8151), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Hôpital Lapeyronie [Montpellier] (CHU), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC), Université Montpellier 1 ( UM1 ) -IFR76-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Unité de Pharmacologie Chimique et Génétique ( UPCG - UMR_S 640/UMR 8151 ), Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Hôpital Lapeyronie [Montpellier] ( CHU )

Subjects
Small interfering RNA, MESH: Arthritis, Experimental, MESH: Spleen, Arthritis, 02 engineering and technology, MESH : RNA, Small Interfering, Mice, MESH: RNA, Small Interfering, Immunology and Allergy, Medicine, Pharmacology (medical), Cationic liposome, MESH: Animals, RNA, Small Interfering, MESH : Macrophages, MESH : Tumor Necrosis Factor-alpha, 0303 health sciences, Liposome, Transfection, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 021001 nanoscience & nanotechnology, 3. Good health, Monocyte Chemoattractant Proteins, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Liver, Systemic administration, Tumor necrosis factor alpha, MESH : Transfection, 0210 nano-technology, MESH : Spleen, MESH : Interleukin-6, Immunology, In Vitro Techniques, 03 medical and health sciences, Rheumatology, MESH: Monocyte Chemoattractant Proteins, Cations, MESH : Mice, Gene silencing, Animals, MESH: Cations, MESH: Mice, 030304 developmental biology, MESH : Arthritis, Experimental, MESH : Cations, business.industry, Interleukin-6, Tumor Necrosis Factor-alpha, MESH: Transfection, Macrophages, MESH : Liver, MESH: Macrophages, MESH : Monocyte Chemoattractant Proteins, medicine.disease, MESH: Interleukin-6, Arthritis, Experimental, [ SDV.SP ] Life Sciences [q-bio]/Pharmaceutical sciences, MESH : Liposomes, MESH: Tumor Necrosis Factor-alpha, Liposomes, Cancer research, MESH: Liposomes, MESH : Animals, business, Spleen, MESH: Liver
Abstract

International audience; OBJECTIVE: Tumor necrosis factor alpha (TNFalpha) is among the most prominent cytokines in rheumatoid arthritis (RA) and is secreted mainly by macrophages. A direct method for restoring the immunologic balance in RA is use of small interfering RNA (siRNA) for silencing the TNFalpha transcript. The aim of this study was to determine the therapeutic effect of systemic administration of TNFalpha siRNA in an experimental model of RA, optimizing its delivery using new liposome formulations. METHODS: Murine macrophages were transfected with siRNA targeting TNFalpha, and expression was measured. The therapeutic effect in collagen-induced arthritis (CIA) was assessed after intravenous delivery of TNFalpha siRNA. Delivery was optimized using a carrier DNA for complexation with the cationic liposome RPR209120/DOPE. Levels of TNFalpha and other cytokines were measured in sera and joint tissue-conditioned media. Biodistribution was determined using a fluorescent siRNA. RESULTS: In vitro, TNFalpha siRNA efficiently and specifically modulated the expression of TNFalpha at both the messenger RNA and protein levels. In vivo, complete cure of CIA was observed when TNFalpha siRNA was administered weekly, complexed with the liposome and combined with carrier DNA. Inhibition (50-70%) of articular and systemic TNFalpha secretion was detected in the siRNA-injected groups, which correlated with a decrease in the levels of interleukin-6 and monocyte chemotactic protein 1. The main organs targeted by siRNA were the liver and spleen; the addition of liposome RPR209120 and carrier DNA significantly increased organ uptake. CONCLUSION: We demonstrated the efficiency of systemic delivery of siRNA designed to silence TNFalpha in CIA, using a liposome carrier system as a way to address the methodologic limitations in vivo.

Published
2006

50. Expression of Pitx2 in stromal cells is required for normal hematopoiesis

Author

Bernard G. Forget, Nicole Navarro, Anne Dubart-Kupperschmitt, Georges Uzan, Brigitte Izac, Philip J. Gage, Cécile Kerdudo, Aurélie Kieusseian, Philippe E. Mangeot, Jalila Chagraoui, Garcia, Marie, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Human Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Medicine/Genetics, Yale School of Medicine [New Haven, Connecticut] (YSM), Ontogenese de l'Hematopoiese, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Yale University School of Medicine, Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Yale School of Medicine, and Université Paris-Sud - Paris 11 (UP11) - Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV.BIO]Life Sciences [q-bio]/Biotechnology, MESH : Transcription Factors, MESH: Hematopoiesis, MESH : RNA, Small Interfering, Biochemistry, MESH: Mice, Knockout, Mice, 0302 clinical medicine, MESH: RNA, Small Interfering, MESH: Gene Expression Regulation, Developmental, MESH: Animals, MESH : Homeodomain Proteins, RNA, Small Interfering, [INFO.INFO-BT]Computer Science [cs]/Biotechnology, Cells, Cultured, MESH: Lentivirus, Mice, Knockout, 0303 health sciences, PITX2, Stem Cells, Homozygote, Gene Expression Regulation, Developmental, Nuclear Proteins, Hematology, MESH: Transcription Factors, MESH : Fetus, Cell biology, Haematopoiesis, medicine.anatomical_structure, MESH : Lentivirus, Liver, 030220 oncology & carcinogenesis, MESH : Stem Cells, MESH : Transfection, MESH : Colony-Forming Units Assay, MESH: Cells, Cultured, MESH: Homozygote, congenital, hereditary, and neonatal diseases and abnormalities, Stromal cell, Ratón, Immunology, MESH : Mice, Inbred C57BL, MESH: Stem Cells, Biology, Transfection, Colony-Forming Units Assay, 03 medical and health sciences, Fetus, MESH : Homozygote, stomatognathic system, MESH: Mice, Inbred C57BL, MESH : Cells, Cultured, MESH : Mice, MESH: Homeodomain Proteins, Lymph node stromal cell, medicine, Animals, MESH: Colony-Forming Units Assay, Progenitor cell, MESH: Mice, 030304 developmental biology, Homeodomain Proteins, MESH: Transfection, Lentivirus, MESH : Nuclear Proteins, MESH : Liver, MESH: Fetus, Cell Biology, Hematopoiesis, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Mice, Inbred C57BL, MESH : Hematopoiesis, stomatognathic diseases, [INFO.INFO-BT] Computer Science [cs]/Biotechnology, MESH : Stromal Cells, MESH : Mice, Knockout, Bone marrow, MESH : Animals, MESH : Gene Expression Regulation, Developmental, sense organs, Stromal Cells, MESH: Stromal Cells, MESH: Nuclear Proteins, Transcription Factors, MESH: Liver
Abstract

Although the expression of Pitx2, a bicoid family homeodomain transcription factor, is highly regulated during hematopoiesis, its function during this process was not documented; we thus studied hematopoiesis in Pitx2-null mice. We found that Pitx2–/– embryos display hypoplastic livers with reduced numbers of hematopoietic cells, but these cells had normal hematopoietic potential, as evidenced by colony-forming assays, immature progenitor cell assays, and long-term repopulation assays. Because the microenvironment is also crucial to the development of normal hematopoiesis, we established Pitx2–/– and Pitx2+/+ stromas from fetal liver and studied their hematopoietic supportive capacity. We showed that the frequency of cobblestone area-forming cells was 4-fold decreased when using Pitx2–/– stromal cells compared with Pitx2+/+ stromal cells, whatever the Pitx2 genotype of hematopoietic cells tested in this assay. This defect was rescued by expression of Pitx2 into Pitx2–/– fetal liver stromal cells, demonstrating a major and direct role of Pitx2 in the hematopoietic supportive capacity of fetal liver stroma. Finally, we showed a reduced capacity of MS5 stromal cells expressing Pitx2 RNAi to support human hematopoiesis. Altogether these data showed that Pitx2 has major functions in the hematopoietic supportive capacity of fetal liver and adult bone marrow stromal cells.

Published
2006

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