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1. Machine learning approach to assess the association between anthropometric, metabolic, and nutritional status and semen parameters

Author: Guillaume Bachelot, Antonin Lamaziere, Sebastien Czernichow, Celine Faure, Chrystelle Racine, Rachel Levy, Charlotte Dupont, and Nutrition and Fertility (ALIFERT) Group
Subjects: lifestyle, machine learning, metabolism, nutrition, sperm dna fragmentation, Diseases of the genitourinary system. Urology, RC870-923
Abstract: Many lifestyle factors, such as nutritional imbalance leading to obesity, metabolic disorders, and nutritional deficiency, have been identified as potential risk factors for male infertility. The aim of this study was to evaluate the relationship between semen parameters and anthropometric, metabolic and nutritional parameters. Relationship was first assessed individually, then after the application of a previously constructed and validated machine learning score that allows their combination. Anthropometric, metabolic, antioxidant, micronutrient, and sperm parameters from 75 men suffering from idiopathic infertility from four infertility centers in France (Jean-Verdier ART Center Hospital, Bondy; North Hospital ART Center, Saint-Étienne; Navarre Polyclinic ART Center, Pau; and Cochin Hospital ART Center, Paris) between September 2009 and December 2013 were collected. After assessing standard correlation analysis, a previously built machine learning model, providing a score ranging from 0 (the poorest) to 1 (the most favorable), was calculated for each man in the study cohort. This machine learning model, which separates infertile/fertile men with unexplained infertility on the basis of their bioclinical signature, provides a more holistic evaluation of the influence of the considered markers (anthropometric, metabolic, and oxidative status). We observed a significant correlation of some anthropometric, metabolic, and nutritional disorders with some sperm characteristics. Moreover, an unfavorable machine learning score was associated with a high level of sperm DNA fragmentation. Favorable anthropometric, metabolic, and oxidative patterns, which may reflect an appropriate lifestyle, appear to positively impact overall health, in particular reproductive function. This study, consistent with previous publications, suggests that beyond semen quality parameters, in an essential assessment of male fertility, other key factors should be taken into account. In this regard, the application of emerging artificial intelligence techniques may provide a unique opportunity to integrate all these parameters and deliver personalized care.
Published: 2024
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2. Dose-response evaluation of intravenous gene therapy in a symptomatic mouse model of metachromatic leukodystrophy

Author: Emilie Audouard, Nicolas Khefif, Charlotte Mansat, Océane Nelcha, Elena-Gaia Banchi, Camille Lupiet, Dominique Farabos, Antonin Lamaziere, Caroline Sevin, and Françoise Piguet
Subjects: metachromatic leukodystrophy, gene therapy, intravenous, AAV, Genetics, QH426-470, Cytology, QH573-671
Abstract: Metachromatic leukodystrophy (MLD) is a rare, autosomal recessive neurodegenerative disease caused by deficient activity of the lysosomal enzyme arylsulfatase A (ARSA), resulting in sulfatide accumulation and subsequent demyelination and neuronal damage within the central and peripheral nervous systems. Three clinical forms of MLD have been described, based on age at symptom onset. The most frequent and severe forms have an early onset, with the disease progressing rapidly toward severe motor and cognitive regression and ultimately premature death. There are currently no approved therapies for most of these early-onset patients once symptoms are present. Thus, it is crucial to develop new approaches to treat symptomatic patients. Here, we proposed a gene therapy approach based on the intravenous delivery of AAVPHP.eB encoding ARSA. MLD mice were treated at 6 months for a dose-response study and at 9 months to assess late-treatment efficacy. Therapeutic efficacy was evaluated 3 or 6 months after injection. We demonstrated a broad transduction in the central nervous system, a complete correction of sulfatide storage, and a significant improvement in neuroinflammation at low dose and late treatment. Taken together, this work establishes a strong rationale for proposing a phase I/II clinical trial in MLD patients.
Published: 2024
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3. Fecal microbiota and bile acids in IBD patients undergoing screening for colorectal cancer

Author: Aonghus Lavelle, Stéphane Nancey, Jean-Marie Reimund, David Laharie, Philippe Marteau, Xavier Treton, Matthieu Allez, Xavier Roblin, Georgia Malamut, Cyriane Oeuvray, Nathalie Rolhion, Xavier Dray, Dominique Rainteau, Antonin Lamaziere, Emilie Gauliard, Julien Kirchgesner, Laurent Beaugerie, Philippe Seksik, Laurent Peyrin-Biroulet, and Harry Sokol
Subjects: Gut microbiota, inflammatory bowel disease, dysplasia, colitis-associated colorectal cancer, crohn’s disease, ulcerative colitis, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: Due to the potential role of the gut microbiota and bile acids in the pathogenesis of both inflammatory bowel disease (IBD) and sporadic colorectal cancer, we aimed to determine whether these factors were associated with colorectal cancer in IBD patients. 215 IBD patients and 51 non-IBD control subjects were enrolled from 10 French IBD centers between September 2011 and July 2018. Fecal samples were processed for bacterial 16S rRNA gene sequencing and bile acid profiling. Demographic, clinical, endoscopic, and histological outcomes were recorded. Characteristics of IBD patients included: median age: 41.6 (IQR 22); disease duration 13.2 (13.1); 47% female; 21.9% primary sclerosing cholangitis; 109 patients with Crohn’s disease (CD); 106 patients with ulcerative colitis (UC). The prevalence of cancer was 2.8% (6/215: 1 CD; 5 UC), high-grade dysplasia 3.7% (8/215) and low-grade dysplasia 7.9% (17/215). Lachnospira was decreased in IBD patients with cancer, while Agathobacter was decreased and Escherichia-Shigella increased in UC patients with any neoplasia. Bile acids were not associated with cancer or neoplasia. Unsupervised clustering identified three gut microbiota clusters in IBD patients associated with bile acid composition and clinical features, including a higher risk of neoplasia in UC in two clusters when compared to the third (relative risk (RR) 4.07 (95% CI 1.6–10.3, P
Published: 2022
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4. SARS-CoV-2 infection in nonhuman primates alters the composition and functional activity of the gut microbiota

Author: Harry Sokol, Vanessa Contreras, Pauline Maisonnasse, Aurore Desmons, Benoit Delache, Valentin Sencio, Arnaud Machelart, Angela Brisebarre, Lydie Humbert, Lucie Deryuter, Emilie Gauliard, Severine Heumel, Dominique Rainteau, Nathalie Dereuddre-Bosquet, Elisabeth Menu, Raphael Ho Tsong Fang, Antonin Lamaziere, Loic Brot, Celine Wahl, Cyriane Oeuvray, Nathalie Rolhion, Sylvie Van Der Werf, Stéphanie Ferreira, Roger Le Grand, and François Trottein
Subjects: gut microbiota, sars-cov-2, nonhuman primates, gut dysbiosis, metabolic output, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: The current pandemic of coronavirus disease (COVID) 2019 constitutes a global public health issue. Regarding the emerging importance of the gut-lung axis in viral respiratory infections, analysis of the gut microbiota’s composition and functional activity during a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection might be instrumental in understanding and controling COVID 19. We used a nonhuman primate model (the macaque), that recapitulates mild COVID-19 symptoms, to analyze the effects of a SARS-CoV-2 infection on dynamic changes of the gut microbiota. 16S rRNA gene profiling and analysis of β diversity indicated significant changes in the composition of the gut microbiota with a peak at 10–13 days post-infection (dpi). Analysis of bacterial abundance correlation networks confirmed disruption of the bacterial community at 10–13 dpi. Some alterations in microbiota persisted after the resolution of the infection until day 26. Some changes in the relative bacterial taxon abundance associated with infectious parameters. Interestingly, the relative abundance of Acinetobacter (Proteobacteria) and some genera of the Ruminococcaceae family (Firmicutes) was positively correlated with the presence of SARS-CoV-2 in the upper respiratory tract. Targeted quantitative metabolomics indicated a drop in short-chain fatty acids (SCFAs) and changes in several bile acids and tryptophan metabolites in infected animals. The relative abundance of several taxa known to be SCFA producers (mostly from the Ruminococcaceae family) was negatively correlated with systemic inflammatory markers while the opposite correlation was seen with several members of the genus Streptococcus. Collectively, SARS-CoV-2 infection in a nonhuman primate is associated with changes in the gut microbiota’s composition and functional activity.
Published: 2021
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5. Diurnal Interplay between Epithelium Physiology and Gut Microbiota as a Metronome for Orchestrating Immune and Metabolic Homeostasis

Author: Juan Jose Martínez-García, Dominique Rainteau, Lydie Humbert, Antonin Lamaziere, Philippe Lesnik, and Mathias Chamaillard
Subjects: aging, antimicrobial peptides, bile acids, circadian rhythms, diurnal oscillations in gut microbiota composition, intestinal epithelial cells, Microbiology, QR1-502
Abstract: The behavior and physiology of most organisms are temporally coordinated and aligned with geophysical time by a complex interplay between the master and peripheral clocks. Disruption of such rhythmic physiological activities that are hierarchically organized has been linked to a greater risk of developing diseases ranging from cancer to metabolic syndrome. Herein, we summarize the molecular clockwork that is employed by intestinal epithelial cells to anticipate environmental changes such as rhythmic food intake and potentially dangerous environmental stress. We also discuss recent discoveries contributing to our understanding of how a proper rhythm of intestinal stem cells may achieve coherence for the maintenance of tissue integrity. Emerging evidence indicates that the circadian oscillations in the composition of the microbiota may operate as an important metronome for the proper preservation of intestinal physiology and more. Furthermore, in this review, we outline how epigenetic clocks that are based on DNA methylation levels may extensively rewire the clock-controlled functions of the intestinal epithelium that are believed to become arrhythmic during aging.
Published: 2022
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6. Dendrogenin A drives LXR to trigger lethal autophagy in cancers

Author: Gregory Segala, Marion David, Philippe de Medina, Mathias C. Poirot, Nizar Serhan, François Vergez, Aurelie Mougel, Estelle Saland, Kevin Carayon, Julie Leignadier, Nicolas Caron, Maud Voisin, Julia Cherier, Laetitia Ligat, Frederic Lopez, Emmanuel Noguer, Arnaud Rives, Bruno Payré, Talal al Saati, Antonin Lamaziere, Gaëtan Despres, Jean-Marc Lobaccaro, Silvere Baron, Cecile Demur, Fabienne de Toni, Clément Larrue, Helena Boutzen, Fabienne Thomas, Jean-Emmanuel Sarry, Marie Tosolini, Didier Picard, Michel Record, Christian Récher, Marc Poirot, and Sandrine Silvente-Poirot
Subjects: Science
Abstract: Dendrogenin A, cholesterol metabolite, has tumor suppressive properties but the mechanisms are unknown. Here the authors show that Dendrogenin A can induce autophagy-mediated cell death in both melanoma and acute myeloid leukaemia.
Published: 2017
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7. Comparing Transgenic Production to Supplementation of ω-3 PUFA Reveals Distinct But Overlapping Mechanisms Underlying Protection Against Metabolic and Hepatic Disorders

Author: Noëmie Daniel, Mélanie Le Barz, Patricia L Mitchell, Thibault V Varin, Isabelle Bourdeau Julien, Dominique Farabos, Geneviève Pilon, Josée Gauthier, Carole Garofalo, Jing X Kang, Jocelyn Trottier, Olivier Barbier, Denis Roy, Benoit Chassaing, Emile Levy, Frédéric Raymond, Antonin Lamaziere, Nicolas Flamand, Cristoforo Silvestri, Christian Jobin, Vincenzo Di Marzo, and André Marette
Abstract: We compared endogenous ω-3 PUFA production to supplementation for improving obesity-related metabolic dysfunction. Fat-1 transgenic mice, who endogenously convert exogenous ω-6 to ω-3 PUFA, and wild-type littermates were fed a high-fat diet and a daily dose of either ω-3 or ω-6 PUFA-rich oil for 12 wk. The endogenous ω-3 PUFA production improved glucose intolerance and insulin resistance but not hepatic steatosis. Conversely, ω-3 PUFA supplementation fully prevented hepatic steatosis but failed to improve insulin resistance. Both models increased hepatic levels of ω-3 PUFA-containing 2-monoacylglycerol and N-acylethanolamine congeners, and reduced levels of ω-6 PUFA-derived endocannabinoids with ω-3 PUFA supplementation being more efficacious. Reduced hepatic lipid accumulation associated with the endocannabinoidome metabolites EPEA and DHEA, which was causally demonstrated by lower lipid accumulation in oleic acid-treated hepatic cells treated with these metabolites. While both models induced a significant fecal enrichment of the beneficial Allobaculum genus, mice supplemented with ω-3 PUFA displayed additional changes in the gut microbiota functions with a significant reduction of fecal levels of the proinflammatory molecules lipopolysaccharide and flagellin. Multiple-factor analysis identify that the metabolic improvements induced by ω-3 PUFAs were accompanied by a reduced production of the proinflammatory cytokine TNFα, and that ω-3 PUFA supplementation had a stronger effect on improving the hepatic fatty acid profile than endogenous ω-3 PUFA. While endogenous ω-3 PUFA production preferably improves glucose tolerance and insulin resistance, ω-3 PUFA intake appears to be required to elicit selective changes in hepatic endocannabinoidome signaling that are essential to alleviate high-fat diet-induced hepatic steatosis.
Published: 2022
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8. Découverte du premier modèle pré-clinique développant spontanément un syndrome des ovaires polykystiques

Author: Dominique Farabos, Marthe Moldes, Nathalie di Clemente, Emmanuelle Mathieu d'Argent, Natacha Roblot, Camille Bourgneuf, Danielle Bailbe, Charlotte Dupont, Camille Gauthier, Chrystèle Racine, Danielle Monniaux, Joëlle Cohen-Tannoudji, Bruno Fève, Jamileh Movassat, and Antonin Lamaziere
Subjects: Nutrition and Dietetics, business.industry, Endocrinology, Diabetes and Metabolism, Internal Medicine, Medicine, Cardiology and Cardiovascular Medicine, business
Published: 2021
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9. Fat gain differs by sex and hormonal status in persons living with suppressed HIV switched to raltegravir/etravirine

Author: Chrystèle Racine, Jacqueline Capeau, Bruno Fève, Lydie Beniguel, Lambert Assoumou, Antonin Lamaziere, Jean-Philippe Bastard, Soraya Fellahi, Christine Katlama, Dominique Costagliola, Séverine Gibowski, and Dominique Farabos
Subjects: Male, 0301 basic medicine, Anti-HIV Agents, Immunology, Human immunodeficiency virus (HIV), Etravirine, Physiology, HIV Infections, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Raltegravir Potassium, Nitriles, medicine, Humans, Immunology and Allergy, HIV Integrase Inhibitors, 030212 general & internal medicine, Ovarian reserve, biology, business.industry, Raltegravir, medicine.disease, Integrase, Pyrimidines, 030104 developmental biology, Infectious Diseases, biology.protein, Female, medicine.symptom, business, Weight gain, medicine.drug, Hormone
Abstract: Fat gain is reported in integrase strand transfer inhibitors exposed persons living with HIV. We investigated in 165 persons living with HIV (117 men/48 women), included in the 96-week ANRS-163-ETRAL trial and switched to raltegravir/etravirine, the impact of sex, menopausal status and ovarian reserve (detectable anti-Müllerian hormone). From baseline to 48/96 weeks, women with ovarian reserve were protected from raltegravir/etravirine-induced weight/fat gain and associated insulin-resistance while peri/postmenopausal women increased weight, fat and insulin resistance as did men. The functional ovarian status could protect against raltegravir/etravirine-induced weight gain.
Published: 2020
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10. Membrane lipids in schizophrenia and early phases of psychosis: Potential biomarkers and therapeutic targets?

Author: A. Frajerman, C. Tessier, Philippe Nuss, Oussama Kebir, M.-O. Krebs, Boris Chaumette, Antonin Lamaziere, Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), GHU Paris Psychiatrie et Neurosciences, Microorganismes et physiopathologie intestinale (ERL INSERM U1157 - CNRS UMR 7203), Laboratoire des biomolécules (LBM UMR 7203), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Psychosis, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Membrane lipids, Population, Acide arachidonique, 03 medical and health sciences, 0302 clinical medicine, Arts and Humanities (miscellaneous), Phospholipase A2, Internal medicine, medicine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, education, Lipid raft, education.field_of_study, business.industry, Lipidomic, Lipid metabolism, Lipidomique, medicine.disease, Sphingolipid, 3. Good health, 030227 psychiatry, Endophenotype, Prodromes, Psychiatry and Mental health, Endocrinology, Arachidonic acid, Schizophrenia, Patient à haut risque de transition psychotique, lipids (amino acids, peptides, and proteins), Sphingomyelin, business, Clinical High risk, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Endophénotype
Abstract: International audience; The various roles of membrane lipids in human health has urged researchers to study their impact in neuropsychiatric diseases, especially in schizophrenia spectrum disorders and more recently in early stages of psychosis. The progress in mass spectrometry technologies now allows a more comprehensive analysis of phospholipids (PL) and their fatty acid (FA) molecular species. FA are defined by a carbon chain of variable length and are said to be unsaturated when their chain has one or more carbon-carbon double bonds. The PL are composed of a hydrophilic polar head with a phosphoric acid group and an hydrophobic part with FAs; they encompass glycerophospholipids and sphingolipids. The plasma membrane is a complex and dynamic structure consisting of a lipid bilayer composed of an outer layer and an inner layer of specific lipid composition. The permanent remodeling of membrane lipids involves phospholipases especially the phospholipase A2. Seventy percent of the brain consists of lipids from different classes and molecular species. Most of the brain lipids are composed of polyunsaturated fatty acid (PUFA)-enriched diacyl classes where omega-3 and omega-6 molecular species predominate. The balance between omega-3 and omega-6 is important for the neurodevelopment. PUFA are also involved in neurogenesis and neurotransmission. Sphingomyelin (SM) is a sphingolipid that influences inflammation, cell proliferation and lipid rafts formation. It is an important component of myelin sheaths of white matter and therefore is involved in cerebral connectivity. In rat models, deficiency in omega-3 causes abnormalities in dopaminergic neurotransmission, impacts on the functioning of some receptors (including cannabinoids CB1, glutamatergic N-methyl-D-aspartate receptor, NMDA), and increases sensitivity to hallucinogens. In contrast, omega-3 supplementation improves cognitive function and prevents psychotic-like behavior in some animal models for schizophrenia. It also reduces oxidative stress and prevents demyelination. The historical membrane hypothesis of schizophrenia has led to explore the lipids abnormality in this disorder. This hypothesis was initially based on the observation of an abnormal membrane prostaglandin production in schizophrenia caused by a membrane arachidonic acid deficiency. It has evolved emphasizing the various PUFA membrane's roles in particular regarding oxidative stress, inflammation and regulation of the NMDA receptors. In patients with mental disorders, low omega-3 index is more frequent than in the general population. This lipid abnormality could lead to myelination abnormalities and cognitive deficits observed in patients. It could also participate in oxidative stress abnormalities and inflammation reported in schizophrenia. On the other hand, low omega-3 index deficit was reported to be associated with an increased cardiovascular risk, and omega-3 supplementation may also have a positive cardiovascular impact in psychiatric patients, even more than in the general population. The presence of membrane lipid abnormalities is also found in patients during the first psychotic episode (FEP). The omega-3 supplementation improved the recovery rate and prevented the loss of gray matter in FEP. In patients at ultra-high risk to develop a psychotic disorder (UHR), omega-3 supplementation has been associated with a reduction of the rate of conversion to psychosis and with metabolic changes, such as decreased activity of phospholipase A2. However, this study has not as yet been replicated. Not all patients exhibit lipid abnormalities. Several studies, including studies from our team, have found a bimodal distribution of lipids in patients with schizophrenia. But some studies have found differences (in PUFA) in the acute phase whereas our studies (on phospholipids) are in chronic phases. It will be interesting to study in more depth the links between these two parameters. Furthermore, we identified a subgroup which was identified with a deficit in sphingomyelin and PUFA whereas others have found an increase of sphingomyelin. Individuals with this abnormal lipid cluster had more cognitive impairments and more severe clinical symptoms. Because the niacin test is an indirect reflection of arachidonic acid levels, it has been proposed to identify a subset of patients with membrane lipids anomalies. Niacin test response is influenced by several factors related to lipid metabolism, including cannabis use and phospholipase A2 activity. Despite progress, the function and impact of membrane lipids are still poorly understood in schizophrenia. They could serve as biomarkers for identifying biological subgroups among patients with schizophrenia. In UHR patients, their predictive value on the conversion to psychosis should be tested. Omega-3 supplementation could be a promising treatment thanks to its good tolerance and acceptability. It could be more appropriate for patients with PUFA anomalies in a more personalized medical approach.; Les lipides membranaires jouent un rôle important dans le fonctionnement cérébral et peuvent désormais être étudiés de manière précise. Cette revue vise à familiariser le lecteur avec les lipides membranaires et les conséquences de leurs anomalies dans les troubles du spectre schizophrénique. Nous nous intéresserons aux données concernant les acides gras poly-insaturés (AGPI), les phospholipides et les sphingolipides membranaires, dans la schizophrénie, notamment dans ses phases débutantes et dans les modèles animaux correspondants. Chez l’animal, une carence en oméga-3 entraîne des anomalies neuro-développementales, tandis qu’une supplémentation en oméga-3 a un effet protecteur dans certains modèles. Chez l’homme, une altération dans la concentration membranaire en oméga-3 est observée chez certains patients. Le déficit en AGPI a été décrit comme associé à des anomalies de myélinisation et des troubles cognitifs. Des anomalies similaires peuvent également être retrouvées chez certains sujets lors du premier épisode psychotique (PEP) ou à ultra-haut risque (UHR) et certaines études suggèrent un effet bénéfique d’une supplémentation en oméga-3. Ainsi, l’identification d’une anomalie de la composition des lipides membranaires pourrait servir de biomarqueur chez certains patients, qui pourraient bénéficier d’une supplémentation en oméga-3. Dans ce contexte, l’étude de la composition des anomalies lipidiques membranaires pourrait permettre de prédire la transition psychotique ou le pronostic fonctionnel et cognitif et d’optimiser leur prise en charge. De nouvelles études sur les lipides membranaires sont nécessaires pour mieux comprendre leur implication en psychiatrie et se diriger vers une médecine personnalisée.
Published: 2020
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11. DYRK1A Overexpression in Mice Downregulates the Gonadotropic Axis and Disturbs Early Stages of Spermatogenesis

Author: Nathalie Janel, Antonin Lamaziere, Chrystèle Racine, François Vialard, Rodolphe Dard, Valérie Serazin, Nadim Kassis, Estelle Parizot, Farah Ghieh, Nathalie di Clemente, Manon Moreau, Leslie Brehier, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Biologie de la Reproduction, Environnement, Epigénétique & Développement (BREED), Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), CHI Poissy-Saint-Germain, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), École nationale vétérinaire - Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Gestionnaire, HAL Sorbonne Université 5
Subjects: Male, Genetically modified mouse, Infertility, Down syndrome, medicine.medical_specialty, DYRK1A, Transgene, [SDV.GEN] Life Sciences [q-bio]/Genetics, Protein Serine-Threonine Kinases, QH426-470, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, Hypogonadotropic hypogonadism, Internal medicine, Testis, Genetics, medicine, Animals, Spermatogenesis, Zebrafish, Infertility, Male, Genetics (clinical), 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, biology, Hypogonadism, Protein-Tyrosine Kinases, biology.organism_classification, medicine.disease, Up-Regulation, Mice, Inbred C57BL, Endocrinology, infertility, 030217 neurology & neurosurgery
Abstract: International audience; Down syndrome (DS) is the most common chromosomal disorder. It is responsible for intellectual disability (ID) and several medical conditions. Although men with DS are thought to be infertile, some spontaneous paternities have been reported. The few studies of the mechanism of infertility in men with DS are now dated. Recent research in zebrafish has indicated that overexpression of DYRK1A (the protein primarily responsible for ID in DS) impairs gonadogenesis at the embryonic stage. To better ascertain DYRK1A’s role in infertility in DS, we investigated the effect of DYRK1A overexpression in a transgenic mouse model. We found that overexpression of DYRK1A impairs fertility in transgenic male mice. Interestingly, the mechanism in mice differs slightly from that observed in zebrafish but, with disruption of the early stages of spermatogenesis, is similar to that seen in humans. Unexpectedly, we observed hypogonadotropic hypogonadism in the transgenic mice.
Published: 2021
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12. CYP46A1 gene therapy deciphers the role of brain cholesterol metabolism in Huntington’s disease

Author: Antonin Lamaziere, Coline Mounier, Wilhelm Christaller, Sandrine Betuing, Peter Vanhoutte, Satish Sasidharan Nair, Jocelyne Caboche, Nicolas Heck, Radhia Kacher, Vincent Kappes, Nathalie Cartier, Valérie Messent, Gaëtan Despres, Elodie Perrin, Laurent Venance, Frédéric Saudou, Yulia Dembitskaya, Christian Neri, Université Pierre et Marie Curie - Paris 6 (UPMC), Signalisation Neuronale et Régulations Géniques = Neuronal Signaling and Gene Regulation (NPS-02), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Team Dynamic and Pathophysiology of Neuronal Networks, Center for Interdisciplinary Research in Biology (CIRB), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745), 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)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Chaire Neuropharmacologie (INSERM U114), Collège de France (CdF (institution)), Régulations cellulaires et oncogenèse (RCO), Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des biomolécules (LBM UMR 7203), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Chimie Moléculaire de Paris Centre (FR 2769), Institut de Chimie du CNRS (INC)-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)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL), Centre Hospitalier Universitaire [Grenoble] (CHU), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Collège de France (CdF)-PSL Research University (PSL), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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)-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)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurobiologie pharmacologique, Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), 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)-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)-Centre National de la Recherche Scientifique (CNRS), Thérapie génique, Génomique et Epigénomique (U 1169), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Dynamics and Pathophysiology of neuronal networks, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Vanhoutte, Peter, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Chimie Moléculaire de Paris Centre (FR 2769), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Huntingtin, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Tropomyosin receptor kinase B, Disease, Axonal Transport, Mice, 0302 clinical medicine, Neural Pathways, Medicine, Gene Knock-In Techniques, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Cerebral Cortex, Huntingtin Protein, Membrane Glycoproteins, Brain, Oxysterols, Dependovirus, Protein-Tyrosine Kinases, 3. Good health, Huntington Disease, Neuroprotective Agents, neuroprotection, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Proteasome Endopeptidase Complex, autophagy, Genetic Vectors, Mice, Transgenic, Endosomes, Protein Aggregation, Pathological, Neuroprotection, 03 medical and health sciences, Huntington's disease, mental disorders, Cholesterol 24-Hydroxylase, Animals, Humans, synaptic transmission, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Brain-derived neurotrophic factor, business.industry, Brain-Derived Neurotrophic Factor, Autophagy, cholesterol, Genetic Therapy, medicine.disease, Corpus Striatum, Mice, Inbred C57BL, 030104 developmental biology, Proteasome, Rotarod Performance Test, Neurology (clinical), business, transcriptome, Neuroscience, 030217 neurology & neurosurgery
Abstract: Dysfunctions in brain cholesterol homeostasis have been extensively related to brain disorders. The main pathway for brain cholesterol elimination is its hydroxylation into 24S-hydroxycholesterol by the cholesterol 24-hydrolase, CYP46A1. Increasing evidence suggests that CYP46A1 has a role in the pathogenesis and progression of neurodegenerative disorders, and that increasing its levels in the brain is neuroprotective. However, the mechanisms underlying this neuroprotection remain to be fully understood. Huntington’s disease is a fatal autosomal dominant neurodegenerative disease caused by an abnormal CAG expansion in huntingtin’s gene. Among the multiple cellular and molecular dysfunctions caused by this mutation, altered brain cholesterol homeostasis has been described in patients and animal models as a critical event in Huntington’s disease. Here, we demonstrate that a gene therapy approach based on the delivery of CYP46A1, the rate-limiting enzyme for cholesterol degradation in the brain, has a long-lasting neuroprotective effect in Huntington’s disease and counteracts multiple detrimental effects of the mutated huntingtin. In zQ175 Huntington’s disease knock-in mice, CYP46A1 prevented neuronal dysfunctions and restored cholesterol homeostasis. These events were associated to a specific striatal transcriptomic signature that compensates for multiple mHTT-induced dysfunctions. We thus explored the mechanisms for these compensations and showed an improvement of synaptic activity and connectivity along with the stimulation of the proteasome and autophagy machineries, which participate to the clearance of mutant huntingtin (mHTT) aggregates. Furthermore, BDNF vesicle axonal transport and TrkB endosome trafficking were restored in a cellular model of Huntington’s disease. These results highlight the large-scale beneficial effect of restoring cholesterol homeostasis in neurodegenerative diseases and give new opportunities for developing innovative disease-modifying strategies in Huntington’s disease.
Published: 2019
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13. Intrications organo-psychiatriques : le concept de troubles psychiatriques complexes, quels examens complémentaires ?

Author: Antonin Lamaziere, Jérôme Guéchot, Jean Capron, Julien Rossignol, Alaina Borden, Florian Ferreri, Bluenn Quillerou, Arsène Mekinian, Philippe Nuss, Alexis Bourla, Stéphane Mouchabac, Sorbonne Université (SU), Service de psychiatrie adulte [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Neurologie [CHU Saint-Antoine], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Ressources Biologiques HUEP-UPMC (CRB HUEP-UPMC), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Laboratoire des biomolécules (LBM UMR 7203), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Chimie Moléculaire de Paris Centre (FR 2769), Institut de Chimie du CNRS (INC)-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)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Microorganismes et physiopathologie intestinale (ERL INSERM U1157 - CNRS UMR 7203), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Médecine Interne [CHU Saint-Antoine], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: medicine.medical_specialty, Recall, Heart disease, business.industry, MEDLINE, General Medicine, Depressive Syndrome, medicine.disease, 3. Good health, 030227 psychiatry, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Psychiatric diagnosis, Medicine, business, Psychiatry, 030217 neurology & neurosurgery, Anxiety disorder
Abstract: International audience; The purpose of this article is to describe complex psychiatric disorders, to recall “minimal classical” explorations in psychiatry, to describe the concept of “complex psychiatric disorders” and to propose a systematized method of exploration.Some organic diseases are well known for their links with psychiatric disorders (manic syndrome and hyperthyroidism, depressive syndrome and corticotropic insufficiency, anxiety disorder and heart disease, etc.).Many other neurological, autoimmune, metabolic, paraneoplastic or endocrine pathologies can have essentially psycho-behavioral manifestations before being neurological or systemic.A large number of factors (nutritional, toxic, immunological, etc.), often ignored, influence the links between organicity and psychiatric pathologies.It is necessary to optimize the medical management of these patients in whom the psychiatric diagnosis masks a curable organo-psychiatric cause.; Cet article a pour objectifs de décrire des troubles psychiatriques complexes, de rappeler les explorations « classiques minimales » en psychiatrie, de décrire le concept de « troubles psychiatriques complexes » et de proposer une méthode d’exploration systématisée.Certaines pathologies organiques sont bien connues pour leurs liens avec les troubles psychiatriques (syndrome maniaque et hyperthyroïdie, syndrome dépressif et insuffisance corticotrope, trouble anxieux et maladie cardiaque, etc.).De nombreuses autres pathologies neurologiques, auto-immunes, métaboliques, paranéoplasiques ou endocriniennes peuvent avoir des manifestations essentiellement psycho-comportementales avant d’être neurologiques ou systémiques.Un grand nombre de facteurs (nutritionnels, toxiques, immunologiques, etc.), souvent ignorés, exercent une influence sur les liens existants entre organicité et pathologies psychiatriques.Il est nécessaire d’optimiser la prise en charge médicale de ces patients chez qui le diagnostic psychiatrique masque une cause organo-psychiatrique curable.
Published: 2019
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14. Erythrocyte fatty acid membrane composition in children on long-term parenteral nutrition enriched with ω-3 fatty acids

Author: Cécile Lambe, Olivier Goulet, Antonin Lamaziere, Elie Nader, Claude Wolf, and Cécile Talbotec
Subjects: Male, Fat Emulsions, Intravenous, food.ingredient, Bilirubin, Medicine (miscellaneous), Soybean oil, Intestinal Failure, chemistry.chemical_compound, Animal science, food, Fish Oils, Fatty Acids, Omega-3, Citrulline, Humans, Child, Olive Oil, Triglycerides, chemistry.chemical_classification, Nutrition and Dietetics, Erythrocyte Membrane, Fatty Acids, Fatty acid, Fish oil, Soybean Oil, Parenteral nutrition, Cross-Sectional Studies, Treatment Outcome, Editorial, chemistry, Child, Preschool, Food, Fortified, Arachidonic acid, Female, Parenteral Nutrition, Home, Polyunsaturated fatty acid
Abstract: BACKGROUND Composite lipid emulsions containing soybean oil (30%), medium-chain triglycerides (30%), olive oil (25%), and fish oil (15%) (SMOF) are now widely used. OBJECTIVES We aimed to evaluate the tolerance, the efficiency, and the erythrocyte fatty acid (FA) profile for children on long-term home parenteral nutrition (HPN) receiving a composite fish oil-based emulsion (FOLE). METHODS At baseline, children (n = 46) with severe intestinal failure highly dependent on parenteral nutrition (PN) for ≥1 y were included in the study when they had received the composite FOLE for >6 mo. Out of this baseline group, only 25 children remained highly PN-dependent (SMOF1, n = 25) and could be assessed a second time, 2.4 y later (SMOF2, n = 25). An independent control group ("weaned off PN" group; n = 24) included children who had been weaned off PN for >2 y (median: 4 y). RBC-FA composition was established by GC-MS. Growth parameters, plasma citrulline, conjugated bilirubin, FA profiles, and the Holman ratio (20:3ω-9/20:4ω-6) were compared between groups. RESULTS No difference for growth parameters, citrulline, and bilirubin was observed between the SMOF groups after 2.4 y (0.2
Published: 2021

15. Perturbation and resilience of the gut microbiome up to 3 months after β-lactams exposure in healthy volunteers suggest an important role of microbial β-lactamases

Author: Camille d’Humières, Margot Delavy, Laurie Alla, Farid Ichou, Emilie Gauliard, Amine Ghozlane, Florence Levenez, Nathalie Galleron, Benoit Quinquis, Nicolas Pons, Jimmy Mullaert, Antoine Bridier-Nahmias, Bénédicte Condamine, Marie Touchon, Dominique Rainteau, Antonin Lamazière, Philippe Lesnik, Maharajah Ponnaiah, Marie Lhomme, Natacha Sertour, Savannah Devente, Jean-Denis Docquier, Marie-Elisabeth Bougnoux, Olivier Tenaillon, Mélanie Magnan, Etienne Ruppé, Nathalie Grall, Xavier Duval, Dusko Ehrlich, France Mentré, Erick Denamur, Eduardo P. C. Rocha, Emmanuelle Le Chatelier, Charles Burdet, and for the PrediRes study group
Subjects: Antibiotics, Human gut microbiota, Metagenomics, Metabolomics, Resilience, β-lactamase, Microbial ecology, QR100-130
Abstract: Abstract Background Antibiotics notoriously perturb the gut microbiota. We treated healthy volunteers either with cefotaxime or ceftriaxone for 3 days, and collected in each subject 12 faecal samples up to day 90. Using untargeted and targeted phenotypic and genotypic approaches, we studied the changes in the bacterial, phage and fungal components of the microbiota as well as the metabolome and the β-lactamase activity of the stools. This allowed assessing their degrees of perturbation and resilience. Results While only two subjects had detectable concentrations of antibiotics in their faeces, suggesting important antibiotic degradation in the gut, the intravenous treatment perturbed very significantly the bacterial and phage microbiota, as well as the composition of the metabolome. In contrast, treatment impact was relatively low on the fungal microbiota. At the end of the surveillance period, we found evidence of resilience across the gut system since most components returned to a state like the initial one, even if the structure of the bacterial microbiota changed and the dynamics of the different components over time were rarely correlated. The observed richness of the antibiotic resistance genes repertoire was significantly reduced up to day 30, while a significant increase in the relative abundance of β-lactamase encoding genes was observed up to day 10, consistent with a concomitant increase in the β-lactamase activity of the microbiota. The level of β-lactamase activity at baseline was positively associated with the resilience of the metabolome content of the stools. Conclusions In healthy adults, antibiotics perturb many components of the microbiota, which return close to the baseline state within 30 days. These data suggest an important role of endogenous β-lactamase-producing anaerobes in protecting the functions of the microbiota by de-activating the antibiotics reaching the colon. Video Abstract
Published: 2024
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16. Lysosomal Acid Lipase Drives Adipocyte Cholesterol Homeostasis and Modulates Lipid Storage in Obesity, Independent of Autophagy

Author: Emmanuel L. Gautier, Amélie Lacombe, Dominique Farabos, Christine Rouault, Camille Gamblin, Antonin Lamaziere, Laurent Yvan-Charvet, Francina Langa-Vives, Karine Clément, Isabelle Dugail, Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), 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)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre d'Ingénierie génétique murine - Mouse Genetics Engineering Center (CIGM), Institut Pasteur [Paris] (IP), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Centre méditerranéen de médecine moléculaire (C3M), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases [IHU ICAN], Institut Pasteur [Paris]-Université Paris Cité (UPCité), Gestionnaire, Hal Sorbonne Université, Nutrition et obésités: approches systémiques (nutriomics) (UMR-S 1269 INSERM - Sorbonne Université), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pasteur [Paris], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [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), Université Nice Sophia Antipolis (... - 2019) (UNS), and 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)
Subjects: 0301 basic medicine, MESH: 3T3 Cells, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Adipose tissue, Endoplasmic Reticulum, Mice, chemistry.chemical_compound, 0302 clinical medicine, MESH: Cholesterol, Adipocyte, Adipocytes, MESH: Obesity, MESH: Thermogenesis, MESH: Animals, MESH: Lipid Metabolism, MESH: Sterol Esterase, MESH: Middle Aged, Chemistry, Thermogenesis, 3T3 Cells, Middle Aged, [SDV] Life Sciences [q-bio], Cholesterol, medicine.anatomical_structure, Adult, MESH: Triglycerides, medicine.medical_specialty, Lipolysis, 030209 endocrinology & metabolism, 03 medical and health sciences, MESH: Endoplasmic Reticulum, Lysosome, Internal medicine, Autophagy, Internal Medicine, medicine, Animals, Humans, MESH: Autophagy, MESH: Lipolysis, Obesity, MESH: Mice, Triglycerides, MESH: Adipocytes, MESH: Humans, MESH: Adult, Sterol Esterase, Lipid Metabolism, Sterol regulatory element-binding protein, 030104 developmental biology, Endocrinology, Homeostasis
Abstract: International audience; Besides cytoplasmic lipase-dependent adipocyte fat mobilization, the metabolic role of lysosomal acid lipase (LAL), highly expressed in adipocytes, is unclear. We show that the isolated adipocyte fraction, but not the total undigested adipose tissue (ATs), from obese patients has decreased LAL expression compared with that from nonobese people. Lentiviral-mediated LAL knockdown in the 3T3L1 mouse cell line to mimic the obese adipocytes condition did not affect lysosome density or autophagic flux, but it did increase triglyceride storage and disrupt endoplasmic reticulum cholesterol, as indicated by activated SREBP. Conversely, mice with adipose-specific LAL overexpression (Adpn-rtTA x TetO-hLAL) gained less weight and body fat than did control mice fed a high-fat diet, resulting in ameliorated glucose tolerance. Blood cholesterol level in the former was lower than that of control mice, although triglyceridemia in the two groups of mice was similar. The adipose-specific LAL-overexpressing mouse phenotype depends on the housing temperature and develops only under mild hypothermic stress (e.g., room temperature) but not at thermoneutrality (30°C), demonstrating the prominent contribution of brown AT (BAT) thermogenesis. LAL overexpression increased levels of BAT free cholesterol, decreased SREBP targets, and induced the expression of genes involved in initial steps of mitochondrial steroidogenesis, suggesting conversion of lysosome-derived cholesterol to pregnenolone. In conclusion, our study demonstrates that adipose LAL drives tissue-cholesterol homeostasis and affects BAT metabolism, suggesting beneficial LAL activation in anti-obesity approaches aimed at reactivating thermogenic energy expenditure.
Published: 2020
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17. Lysosomal acid lipase drives adipocyte cholesterol homeostasis and modulates lipid storage in obesity, independent of autophagy

Author: Isabelle Dugail, Laurent Yvan-Charvet, Emmanuel L. Gautier, Karine Clément, Antonin Lamaziere, Dominique Farabos, Francina Langa-Vives, Amélie Lacombe, Christine Rouault, Camille Gamblin, and Ada Admin
Abstract: Besides cytoplasmic lipase-dependent adipocyte fat mobilization, the metabolic role of lysosomal acid lipase (LAL), highly expressed in adipocytes is unclear. We show that the isolated adipocyte fraction but not the total undigested adipose tissue from obese patients has decreased LAL expression compared to non-obese. Lentiviral-mediated LAL knockdown in 3T3L1 to mimic obese adipocytes condition did not affect lysosome density or autophagic flux, but increased triglyceride storage and disrupted ER cholesterol as indicated by activated SREBP. Conversely, mice with adipose-specific LAL overexpression (Adpn-rtTA x TetO-hLAL) gained less weight and body fat than controls on a high fat diet, resulting in ameliorated glucose tolerance. Blood cholesterol was lower than controls albeit similar triglyceridemia. Adipose-LAL overexpressing mice phenotype is dependent on the housing temperature, and develops only under mild hypothermic stress (room temperature) but not at thermoneutrality (30°C), demonstrating prominent contribution of BAT thermogenesis. LAL overexpression increased BAT free cholesterol, decreased SREBP targets, and induced the expression of genes involved in initial steps of mitochondrial steroidogenesis, suggesting conversion of lysosome-derived cholesterol to pregnenolone. In conclusion, our study demonstrates that adipose LAL drives tissue cholesterol homeostasis and impacts BAT metabolism, suggesting beneficial LAL activation in anti-obesity approaches aimed at reactivating thermogenic energy expenditure.
Published: 2020
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18. Dendrogenin A Synergizes with Cytarabine to Kill Acute Myeloid Leukemia Cells In Vitro and In Vivo

Author: Nizar, Serhan, Pierre-Luc, Mouchel, Philippe de, Medina, Gregory, Segala, Aurélie, Mougel, Estelle, Saland, Arnaud, Rives, Antonin, Lamaziere, Gaëtan, Despres, Jean-Emmanuel, Sarry, Clément, Larrue, François, Vergez, Laetitia, Largeaud, Michel, Record, Christian, Récher, Sandrine, Silvente-Poirot, Marc, Poirot, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches en Cancérologie de Toulouse (CRCT), 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), Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Affichem, Dendrogenix [Liège, Belgium], Microorganismes et physiopathologie intestinale (ERL INSERM U1157 - CNRS UMR 7203), Laboratoire des biomolécules (LBM UMR 7203), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC), Poirot, Marc, 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), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), 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 Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, 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 Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and This work was supported by an internal grant from the 'Institut National de la Recherche Médicale',the university of Toulouse III, Onco San Tech (projet DEMODA RMN13001BBA).
Subjects: Acute myeloid leukemia, tumor suppressor, primary cancer cells, [SDV]Life Sciences [q-bio], synergy, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, Article, [SDV] Life Sciences [q-bio], hemic and lymphatic diseases, Dendrogenin A, cholesterol metabolism, lipids (amino acids, peptides, and proteins)
Abstract: International audience; Dendrogenin A (DDA) is a mammalian cholesterol metabolite that displays potent antitumor properties on acute myeloid leukemia (AML). DDA triggers lethal autophagy in cancer cells through a biased activation of the oxysterol receptor LXRβ, and the inhibition of a sterol isomerase. We hypothesize that DDA could potentiate the activity of an anticancer drug acting through a different molecular mechanism, and conducted in vitro and in vivo combination tests on AML cell lines and patient primary tumors. We report here results from tests combining DDA with antimetabolite cytarabine (Ara-C), one of the main drugs used for AML treatment worldwide. We demonstrated that DDA potentiated and sensitized AML cells, including primary patient samples, to Ara-C in vitro and in vivo. Mechanistic studies revealed that this sensitization was LXRβ-dependent and was due to the activation of lethal autophagy. This study demonstrates a positive in vitro and in vivo interaction between DDA and Ara-C, and supports the clinical evaluation of DDA in combination with Ara-C for the treatment of AML.
Published: 2020
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19. New splicing pathogenic variant in EBP causing extreme familial variability of Conradi–Hünermann–Happle Syndrome

Author: Stéphane Bézieau, Sandra Mercier, Thomas Besnard, Mathilde Nizon, Mathilde Pacault, Norbert Winer, Smail Hadj-Rabia, Stéphanie Leclerc-Mercier, Madeleine Joubert, Sébastien Barbarot, Khaldia Belabbas, Claire Beneteau, Marie Vincent, Caroline Kannengiesser, Antonin Lamaziere, Fabienne Dufernez, Xenia Latypova, Bertrand Isidor, Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Hopital Xavier Bichat, Partenaires INRAE, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Anatomo-pathologie, Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique, and Centre hospitalier universitaire de Poitiers (CHU Poitiers)
Subjects: Adult, Male, 0301 basic medicine, Chondrodysplasia Punctata, RNA Splicing, Steroid Isomerases, medicine.disease_cause, Short stature, Article, X-inactivation, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, Chondrodysplasia punctata, Genetics (clinical), Mutation, Ichthyosis, business.industry, Alternative splicing, Intron, syndrome, medicine.disease, Pedigree, Phenotype, 030104 developmental biology, Aborted Fetus, Female, medicine.symptom, Klinefelter syndrome, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; X-linked dominant chondrodysplasia punctata (CDPX2 or Conradi-Hünermann-Happle syndrome, MIM #302960) is caused by mutations in the EBP gene. Affected female patients present with Blaschkolinear ichthyosis, coarse hair or alopecia, short stature, and normal psychomotor development. The disease is usually lethal in boys. Nevertheless, few male patients have been reported; they carry a somatic mosaicism in EBP or present with Klinefelter syndrome. Here, we report CDPX2 patients belonging to a three-generation family, carrying the splice variant c.301 + 5 G > C in intron 2 of EBP. The grandfather carries the variant as mosaic state and presents with short stature and mild ichthyosis. The mother also presents with short stature and mild ichthyosis and the female fetus with severe limb and vertebrae abnormalities and no skin lesions, with random X inactivation in both. This further characterizes the phenotypical spectrum of CDPX2, as well as intrafamilial variability, and raises the question of differential EBP mRNA splicing between the different target tissues.
Published: 2018
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20. Infertility revealing a classical form of congenital adrenal hyperplasia in a 39 years old man

Author: Alassane, Ilboudo, primary, Yempabou, Sagnan, additional, Mathilde, Guigui, additional, Sophie, Dubreuil, additional, Antonin, Lamaziere, additional, Bachelot, Anne, additional, Touraine, Philippe, additional, and Carine, Courtillot, additional
Published: 2021
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21. P.115 Membrane lipids in early phases of psychosis: potential biomarkers for a personalised medicine?

Author: Oussama Kebir, Marie-Odile Krebs, Boris Chaumette, A. Frajerman, Philippe Nuss, C. Tessier, and Antonin Lamaziere
Subjects: Pharmacology, Psychosis, business.industry, Membrane lipids, medicine.disease, Psychiatry and Mental health, Neurology, Potential biomarkers, medicine, Pharmacology (medical), Neurology (clinical), business, Biological Psychiatry
Published: 2021
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22. M10. SERUM AND CLINICAL MARKERS ASSOCIATED WITH MEMBRANE PUFA CONTENT IN A POPULATION OF STABILISED AND TREATED SCHIZOPHRENIA OUTPATIENTS

Author: Antonin Lamaziere, Vladimir Adrien, David Tareste, Hugo Fumat, Stéphane Mouchabac, Nicolas Bosc, Florian Ferreri, Philippe Nuss, and Cedric Tessier
Subjects: chemistry.chemical_classification, education.field_of_study, medicine.medical_specialty, Poster Session II, AcademicSubjects/MED00810, business.industry, Population, medicine.disease, Psychiatry and Mental health, Endocrinology, chemistry, Schizophrenia, Internal medicine, Medicine, lipids (amino acids, peptides, and proteins), business, education, Polyunsaturated fatty acid
Abstract: Background Various candidate biomarkers have been proposed in schizophrenia to better characterise the several forms of the disorder. Among these candidates, peripheral (e.g. immunological, inflammatory, microbial) and brain (structural and functional) factors have been suggested and could help subtyping schizophrenia. One other potential biomarker, the membrane polyunsaturated fatty acid (PUFA) content, has been described both in peripheral cells and brain membranes of patients. Increased symptom severity along with more severe cognitive impairment were shown to be associated with decrease in the red blood cell (RBC) membrane sphingomyelin and PUFA content. However, little is known regarding the association between this membrane biomarker and serum related ones. The results presented here are preliminary and come from a study examining clinical and cognitive symptoms, RBC total membrane fatty-acid (FA) content, and serum biomarkers in a population of schizophrenia patients. We hypothesised that the sub-group of patients with decreased membrane PUFA content will also exhibit a higher incidence of abnormalities in some other serum biomarkers in comparison with patients with normal membrane PUFA content. Methods A population of 33 chronic, medicated, and clinically stable patients with schizophrenia gave their informed consent for a study examining in particular their medical, psychiatric, and treatment history. The other measures assessed psychopathology (PANSS, CGI, Calgary scale), functioning and quality of life (GAF, SF36), and cognition (MOCA, MCST). Various biological biomarkers - in particular those related to inflammation, immunity, energy and hormone metabolism - were also examined. The total RBC membrane FA content was also measured using GC-FID (Gas Chromatography–Flame-Ionization Detection). Results Based on the standard values of the docosohexaenoic acid (DHA) (expressed as percentage of total fatty acids) in the RBC lipid membrane, a subgroup of 18 patients exhibited an abnormal decrease in DHA content (DHA-), while the remaining 15 individuals had DHA value within the normal range (DHAn). DHA- and DHAn groups were compared using univariate analysis in terms of other clinical and biological associated characteristics. We could also demonstrate a decrease in total membrane PUFAs in the DHA- group (p=0.004). Of interest, serum IL-6 was significantly (p=0.02) increased in the DHA- population. There was also a trend in favour of an increase in serum TNF-alpha in DHA- (mean value 30.5 vs 21 in DHA- and DHAn, respectively). In addition, the DHA- group have had significantly (p=0.03) more hospitalisations since the beginning of the disorder. The duration of untreated psychosis was 4 years vs 1 year in the DHA- vs DHAn groups, respectively. The same applied for the mean duration of hospitalisations (45 vs 34 days in DHA- vs DHAn). These values could not be explained by a longer duration in disease treatment in the 2 subpopulations. Discussion The presented data are in accordance with repeated findings showing decreased RBC membrane DHA and total PUFA content in a subgroup of individuals meeting criteria for schizophrenia. The splitting of the studied population into 2 groups numerically comparable as a function of their RBC membrane DHA content was thus justified. Interestingly, patients with lower membrane DHA content also exhibited abnormalities in other known biomarkers described in schizophrenia such as increased inflammation and disease severity. The presented data also show for the first time a biomarker associated with the duration of untreated psychosis. Altogether, these results, despite preliminary, are paving the way towards the identification of schizophrenia subtypes.
Published: 2020
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23. Cortisol and Aldosterone Responses to Hypoglycemia and Na Depletion in Women With Non-Classic 21-Hydroxylase Deficiency

Author: Laurence Pietri, Jean-François Gautier, H. Bry, Michel Azizi, Anne Blanchard, Julien Thomas, Antonin Lamaziere, Yves Le Bouc, Sylvie Salenave, Sylvie Brailly-Tabard, Sophie Christin-Maitre, Lise Duranteau, Bruno Donadille, Céline Piedvache, Aurélien Lorthioir, Peter Kamenický, Jacques Young, Philippe Chanson, Seray Genc, Marie-Laure Raffin-Sanson, CIC - HEGP (CIC 1418), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)
Subjects: Hydrocortisone, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Biochemistry, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Prospective Studies, Aldosterone, 030219 obstetrics & reproductive medicine, biology, Incidence, 21-Hydroxylase, Middle Aged, Prognosis, Female, France, Pseudogenes, Cortisol secretion, Adult, medicine.medical_specialty, Adolescent, food.diet, 030209 endocrinology & metabolism, Equivalence Trials as Topic, Low sodium diet, Hypoglycemia, 03 medical and health sciences, Young Adult, food, Internal medicine, Renin–angiotensin system, medicine, Adrenal insufficiency, Humans, Adrenal Hyperplasia, Congenital, business.industry, Biochemistry (medical), Insulin tolerance test, Sodium, medicine.disease, chemistry, Case-Control Studies, biology.protein, business, Biomarkers, Follow-Up Studies
Abstract: Background Non-classic 21-hydroxylase deficiency is usually diagnosed in post-pubertal women because of androgen excess. Indication of systematic steroid replacement therapy is controversial because the risk of acute adrenal insufficiency is unknown. In order to specify this risk we evaluated the cortisol and aldosterone secretions in response to appropriate pharmacologic challenges. Methods In this prospective case–control non-inferiority study we investigated 20 women with non-classic 21-hydroxylase deficiency carrying biallelic CYP21A2 mutations and with serum 17-hydroxyprogesterone (17OHP) >10 ng/mL after stimulation with Synacthen® (tetracosactrin) and 20 age- and body mass index-matched healthy women with 17OHP after Synacthen® Findings The peak serum cortisol concentration after insulin hypoglycemia was lower in patients than in controls (mean difference –47 ng/mL, 90% CI, –66, P = 0.0026). A peak serum cortisol above a cutoff value of 170 ng/mL was obtained in all controls but only in 55% of patients (P = 0.0039). Twenty-four hours after sodium depletion, blood pressure, plasma sodium, potassium, and serum aldosterone concentrations were comparable between the two groups, but patients had higher stimulated renin concentrations than controls (P = 0.0044). Interpretation Patients with non-classic 21-hydroxylase deficiency frequently display partial cortisol insufficiency and compensated defect in aldosterone secretion. Their clinical management should systematically include assessment of adrenal functions.
Published: 2020
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24. Direct liquid chromatography tandem mass spectrometry analysis of amino acids in human plasma

Author: Jean-Yves Hautem, Bruno Baudin, Aurore Desmons, Antonin Lamaziere, Elizabeth Thioulouse, Anne Saintier, Fathi Moussa, Claude Netter, Institut de Chimie Physique (ICP), and Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)
Subjects: 01 natural sciences, Biochemistry, High-performance liquid chromatography, Analytical Chemistry, 03 medical and health sciences, chemistry.chemical_compound, Liquid chromatography–mass spectrometry, Tandem Mass Spectrometry, Protein precipitation, [CHIM]Chemical Sciences, Humans, Sample preparation, Amino Acids, Derivatization, Chromatography, High Pressure Liquid, 030304 developmental biology, Detection limit, 0303 health sciences, Sulfosalicylic acid, Chromatography, Chemistry, Elution, 010401 analytical chemistry, Organic Chemistry, Infant, Newborn, Reproducibility of Results, General Medicine, Reference Standards, 0104 chemical sciences, Calibration, Female, Chromatography, Liquid
Abstract: Here we describe a new HPLC–MS/MS method using a mixed mode stationary phase and a binary gradient of elution for the rapid separation and quantification of AAs in human plasma without derivatization or ion pairing reagent addition. The sample preparation procedure consists in a single dilution step after protein precipitation with sulfosalicylic acid. The proposed method allows for the unambiguous identification and analysis of 52 AAs and related compounds including the separation of isomers and isobars in an 18 min chromatographic run including the conditioning and the equilibration times. AAs were detected by selective reaction monitoring. Internal calibration was used for the quantification of 37 AAs, including 25 using the corresponding isotopically labeled internal standards. External calibration (no internal standard) was used for five additional analytes. Qualitative detection was achieved for the remaining compounds. Validation studies evaluated accuracy, linearity, within- and between-run precision, lower limits of detection and quantification for 37 amino acids present in commonly used quality control samples. For within-run precision CVs averaged 3.8 % (n = 30) for all compounds. For between-run precision, CVs averaged 8.6 % for all compounds (n = 20). Correlation with the common standard ion-exchange chromatography with post-column derivatization method was also performed for 32 plasma samples. While the proposed method is at least 50 times more sensitive, the data showed good correlation with slopes equal or higher than 0.9 and correlation coefficients mostly higher than 0.90. The method was successfully applied for analysis of plasma samples for detection of inherited disorders of amino acid metabolism.
Published: 2019
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25. Adrenal adaptation in potassium-depleted men: role of progesterone?

Author: Valentina Zhygalina, Antoine Jacques, Damien Bergerot, Antonin Lamaziere, Michel Azizi, Gilles Crambert, Delphine Hourton, Sylvie Brailly Tabard, Anne Blanchard, Aurélien Lorthioir, Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), CIC - HEGP (CIC 1418), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de Génétique Moléculaire Pharmacogénétique et Hormonologie [CHU Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Université Paris-Saclay, Signalisation Hormonale, Physiopathologie Endocrinienne et Métabolique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Microorganismes et physiopathologie intestinale (ERL INSERM U1157 - CNRS UMR 7203), Laboratoire des biomolécules (LBM UMR 7203), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC), 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), Métabolisme et physiologie rénales (ERL 8228), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), 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)-Sorbonne Université (SU)-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)-Sorbonne Université (SU), Crambert, Gilles, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-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), Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), 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 Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, 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 Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138))
Subjects: 0301 basic medicine, Male, Potassium, 030232 urology & nephrology, Stimulation, Plasma renin activity, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, chemistry.chemical_compound, Mice, 0302 clinical medicine, Tandem Mass Spectrometry, Adrenal Glands, Renin, Aldosterone, 2. Zero hunger, adrenal steroids, Middle Aged, Hypokalemia, Nephrology, Pregnenolone, Gitelman syndrome, Female, Steroids, medicine.symptom, potassium depletion, medicine.drug, Adult, medicine.medical_specialty, Adolescent, chemistry.chemical_element, progesterone, 03 medical and health sciences, Young Adult, Tubulopathy, Internal medicine, Renin–angiotensin system, medicine, Animals, Humans, Aged, Transplantation, business.industry, hypokalaemia, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 030104 developmental biology, Endocrinology, chemistry, Case-Control Studies, business, Chromatography, Liquid
Abstract: BackgroundIn rodents, the stimulation of adrenal progesterone is necessary for renal adaptation under potassium depletion. Here, we sought to determine the role of progesterone in adrenal adaptation in potassium-depleted healthy human volunteers and compared our findings with data collected in patients with Gitelman syndrome (GS), a salt-losing tubulopathy.MethodsTwelve healthy young men were given a potassium-depleted diet for 7 days at a tertiary referral medical centre (NCT02297048). We measured by liquid chromatography coupled to tandem mass spectroscopy plasma steroid concentrations at Days 0 and 7 before and 30 min after treatment with tetracosactide. We compared these data with data collected in 10 GS patients submitted to tetracosactide test.ResultsThe potassium-depleted diet decreased plasma potassium in healthy subjects by 0.3 ± 0.1 mmol/L, decreased plasma aldosterone concentration by 50% (P = 0.0332) and increased plasma 17-hydroxypregnenolone concentration by 45% (P = 0.0232) without affecting other steroids. CYP17 activity, as assessed by 17-hydroxypregnenolone/pregnenolone ratio, increased by 60% (P = 0.0389). As compared with healthy subjects, GS patients had 3-fold higher plasma concentrations of aldosterone, 11-deoxycortisol (+30%) and delta 4-androstenedione (+14%). Their post-tetracosactide progesterone concentration was 2-fold higher than that of healthy subjects and better correlated to plasma potassium than to plasma renin.ConclusionThe increase in 17-hydroxypregnenolone concentration after mild potassium depletion in otherwise healthy human subjects suggests that 17 hydroxylation of pregnenolone prevents the increase in progesterone observed in potassium-depleted mice. The unexpected over-response of non-mineralocorticoid steroids to tetracosactide in GS subjects suggests that the adrenal system not only adapts to sodium depletion but may also respond to hypokalaemia.
Published: 2019
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26. Distinct Postprandial Bile Acids Responses to a High-Calorie Diet in Men Volunteers Underscore Metabolically Healthy and Unhealthy Phenotypes

Author: Lydie Humbert, Pukar Kc, Farid Ichou, Joe-Elie Salem, Antonin Lamaziere, Nadine Bouby, Maharajah Ponnaiah, Dominique Rainteau, Maryse Guerin, Jean-Maurice Mallet, Emilie Gauliard, Philippe Lesnik, Mallet, Jean-Maurice, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Microorganismes, Molécules Bioactives et Physiopathologie Intestinale (LBM-E4), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), 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)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Center for Computational Imaging and Simulation Technologies in Biomedicine (CISTIB), Universitat Pompeu Fabra [Barcelona] (UPF), ICANalytics [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Métabolisme et physiologie rénale (CRC - UMR_S 1138), Centre National de la Recherche Scientifique (CNRS)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), 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)-Sorbonne Université (SU)-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)-Sorbonne Université (SU), Laboratoire des biomolécules (LBM UMR 7203), Chimie Moléculaire de Paris Centre (FR 2769), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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)-Sorbonne Université (SU)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Chimie Moléculaire de Paris Centre (FR 2769), Institut de Chimie du CNRS (INC)-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)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [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), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138))
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Waist, Calorie, HDL, Adolescent, education, Dietary lipid, lcsh:TX341-641, postprandial, health status, Biology, Article, LDL, Bile Acids and Salts, Pathogenesis, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, microbiota, medicine, Humans, triglycerides, ComputingMilieux_MISCELLANEOUS, bile acids, 2. Zero hunger, Meal, Nutrition and Dietetics, Triglyceride, Metabolism, Middle Aged, Postprandial Period, lipoproteins, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Phenotype, 030104 developmental biology, Postprandial, Endocrinology, chemistry, Diet, Western, profiling, lcsh:Nutrition. Foods and food supply, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery, Food Science
Abstract: Bile acids (BAs) regulate dietary lipid hydrolysis and absorption in the proximal intestine. Several studies have highlighted a determinant role of circulating levels and/or metabolism of BAs in the pathogenesis of major cardiometabolic diseases. Whether changes in BA profiles are causative or are consequence of these diseases remains to be determined. Healthy male volunteers (n = 71) underwent a postprandial exploration following consumption of a hypercaloric high fat typical Western meal providing 1200 kcal. We investigated variations of circulating levels of 28 BA species, together with BA synthesis marker 7&alpha, hydroxy-4-cholesten-3-one (C4) over an approximately diurnal 12 h period. Analysis of BA variations during the postprandial time course revealed two major phenotypes with opposite fluctuations, i.e., circulating levels of each individual species of unconjugated BAs were reduced after meal consumption whereas those of tauro- and glyco-conjugated BAs were increased. By an unbiased classification strategy based on absolute postprandial changes in BA species levels, we classified subjects into three distinct clusters, the two extreme clusters being characterized by the smallest absolute changes in either unconjugated-BAs or conjugated-BAs. Finally, we demonstrated that our clustering based on postprandial changes in BA profiles was associated with specific clinical and biochemical features, including postprandial triglyceride levels, BMI or waist circumference. Altogether, our study reveals that postprandial profiles/patterns of BAs in response to a hypercaloric high fat challenge is associated with healthy or unhealthy metabolic phenotypes that may help in the early identification of subjects at risk of developing metabolic disorders.
Published: 2020
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27. Intelligence artificielle en métabolomique clinique : exemple de l’exploration des HCS

Author: Antonin Lamaziere
Subjects: Endocrinology, Metabolomics, medicine.diagnostic_test, business.industry, Endocrinology, Diabetes and Metabolism, Immunoassay, ACTH stimulation test, Medicine, General Medicine, Computational biology, Steroid biosynthesis, business, Acth stimulation
Abstract: The development of liquid chromatography tandem mass spectrometry (LC-MS/MS) allows clinical laboratory to propose targeted and quantitative steroidomics analysis for diagnostic and follow-up explorations. Quantitative profiles of circulating steroids are now available in one single run. However, the screening and diagnostic thresholds for LC-MS/MS are yet to be completely defined in both basal and post synacthen states. These thresholds are likely to differ from those established with immunoassays due to the enhanced specificity and sensitivity of LC-MS/MS, a method less prone to cross-reactivity and interferences (Fiet et al., 2017). The concept of profiling or multiplexing the circulating steroidome is a paradigm shift as it appears to be way more accurate than single specie immunoassay quantitation to stratify patients. In subnormal or atypical cases, we showed that an exhaustive profile in a basal state (i.e. without ACTH stimulation test) could differentiate 21-hydroxylase deficiency from other enzyme defects and establish a more accurate diagnosis (Fiet et al., 2017). In parallel to these analytical progresses, machine learning (ML) approaches are emerging as essential tools in diagnosis thank to its classification strength compare to classical univariate statistics. Our main hypothesis is that these statistical models can be all the more powerful as, when combined with the metabolic profiling of the steroid biosynthesis pathway, it will be possible to avoid, or at least, limit the use of ACTH stimulation tests. In our experience, ML is indeed, particularly adapted to convert these metabolomic signatures, potentially concatenated with other bio-clinical parameters, into straightforward diagnostic outputs for clinicians.
Published: 2020
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28. Lipidome variations of deep-sea vent shrimps according to acclimation pressure: A homeoviscous response?

Author: Bruce Shillito, Juliette Ravaux, Magali Zbinden, D. Farabos, G. Després, D. Barthelemy, C. Desurmont, Antonin Lamaziere, Biologie des Organismes et Ecosystèmes Aquatiques (BOREA), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Muséum national d'Histoire naturelle (MNHN)-Institut de Recherche pour le Développement (IRD)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles (UA), Sorbonne Université (SU), Océanopolis [Brest], Centre de Recherche Saint-Antoine (CRSA), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: 0106 biological sciences, chemistry.chemical_classification, 0303 health sciences, Atmospheric pressure, [SDV]Life Sciences [q-bio], 010604 marine biology & hydrobiology, Membrane lipids, Hydrostatic pressure, Vaccenic acid, Fatty acid, Aquatic Science, Lipidome, Oceanography, 01 natural sciences, Acclimatization, Shrimp, 03 medical and health sciences, chemistry.chemical_compound, chemistry, 14. Life underwater, Food science, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: The present study questions the ability of marine fauna to modulate the molecular composition of their membrane lipids, as a function of environmental hydrostatic pressure conditions. Specific variations in the cell lipidome composition are presented for the deep-sea hydrothermal vent shrimp Mirocaris fortunata, acclimated at the laboratory for several months at both natural (18 MPa) and atmospheric pressures, but fed with the same diet. These animals display physiological capabilities of acclimation to pressure variations, possibly driven by a particular composition of their lipid species. In particular, it is shown that shrimps exposed to atmospheric pressure exhibit a significantly lower level of the mono-unsaturated fatty acid, vaccenic acid (C18:1n-7), compared to those maintained at natural pressure. The observed fatty acid variations are consistent with a homeoviscous response, i.e. a modulation of the lipidome composition, in response to physical constraints, in order to balance the effects of pressure on membrane order. Additionally, supervised multivariate data analysis was performed for complex lipids and revealed an increase in levels of sterols, sphingomyelin, and ether-phosphatidylethanolamine lipids for animals exposed to atmospheric pressure, with respect to natural pressure. These observations strongly suggest that lipidic domains are involved in the shrimp's response to experimental conditions, and their consistency with a homeoviscous response to pressure is discussed.
Published: 2020
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29. Adipocyte Glucocorticoid Receptor Deficiency Promotes Adipose Tissue Expandability and Improves the Metabolic Profile Under Corticosterone Exposure

Author: Marie Garcia, M. Buyse, Marthe Moldes, Raphaël George Denis, Héloïse Dalle, Bénédicte Antoine, V. Boehm, Christophe Magnan, Thi Thu Huong Do, Antonin Lamaziere, Serge Luquet, Tatiana Ledent, Catherine Postic, Bruno Fève, Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de Pharmacie [CHU Saint Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire de physiopathologie de la nutrition (LPN), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), 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), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Endocrinologie, Diabétologie et d'Endocrinologie de la Reproduction [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire des biomolécules (LBM UMR 7203), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Chimie Moléculaire de Paris Centre (FR 2769), Institut de Chimie du CNRS (INC)-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)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Endocrinologie, diabétologie et endocrinologie de la reproduction [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Chimie Moléculaire de Paris Centre (FR 2769), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Luquet, Serge
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, [SDV.BA] Life Sciences [q-bio]/Animal biology, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, Macrophage polarization, Adipose tissue, 030209 endocrinology & metabolism, Mice, 03 medical and health sciences, chemistry.chemical_compound, Receptors, Glucocorticoid, 0302 clinical medicine, Glucocorticoid receptor, Corticosterone, Internal medicine, Adipocyte, Adipocytes, Internal Medicine, medicine, Animals, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Mice, Knockout, Glucose tolerance test, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, medicine.diagnostic_test, [SDV.BA]Life Sciences [q-bio]/Animal biology, Lipid metabolism, Glucose Tolerance Test, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Flow Cytometry, medicine.disease, [SDV] Life Sciences [q-bio], Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Adipose Tissue, chemistry, Lipodystrophy, Metabolism, Inborn Errors, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Widely used for their anti-inflammatory and immunosuppressive properties, glucocorticoids are nonetheless responsible for the development of diabetes and lipodystrophy. Despite an increasing number of studies focused on the adipocyte glucocorticoid receptor (GR), its precise role in the molecular mechanisms of these complications has not been elucidated. In keeping with this goal, we generated a conditional adipocyte-specific murine model of GR invalidation (AdipoGR knockout [KO] mice). Interestingly, when administered a corticosterone treatment to mimic hypercorticism conditions, AdipoGR-KO mice exhibited an improved glucose tolerance and insulin sensitivity. This was related to the adipose-specific activation of the insulin-signaling pathway, which contributed to fat mass expansion, as well as a shift toward an anti-inflammatory macrophage polarization in adipose tissue of AdipoGR-KO animals. Moreover, these mice were protected against ectopic lipid accumulation in the liver and displayed an improved lipid profile, contributing to their overall healthier phenotype. Altogether, our results indicate that adipocyte GR is a key factor of adipose tissue expansion and glucose and lipid metabolism control, which should be taken into account in the further design of adipocyte GR-selective modulators.
Published: 2019
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30. Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome

Author: Wallid Deb, Bertrand Cariou, Arnaud Wiedemann, Julien Thevenon, Rhonda E. Schnur, Vincent Ramaekers, Alexandre N. Datta, Richard Redon, Solène Conrad, Natacha Sloboda, Benjamin Cogné, François Feillet, Geneviève Baujat, Bertrand Isidor, Pierre Vabres, Tawfeg Ben-Omran, Marie Vincent, Flora Breheret, Dorothea Wand, Aline Delignières, Laurence Faivre, Betty Gardie, Xavier Balguerie, Anne-Claire Bursztejn, Marion Lenglet, Lionel Van Maldergem, Sébastien Küry, Antonin Lamaziere, Virginie Carmignac, Eva Trochu, Sébastien Barbarot, Marie-Cécile Nassogne, Erin Torti, Yue Si, Paul Kuentz, Thomas Besnard, Jean-Louis Guéant, Alice Goldenberg, Stéphane Bézieau, UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie pédiatrique, Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHU Rouen, Hamad medical corporation, Centre Hospitalier Universitaire de Nancy (CHU Nancy), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université Bourgogne Franche-Comté [COMUE] (UBFC), University of Basel (Unibas), Hôpital Bretagne Atlantique, Partenaires INRAE, École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Université Catholique de Louvain = Catholic University of Louvain (UCL), Centre Hospitalier Universitaire de Liège (CHU-Liège), Gene Dx, Centre de Génétique, and Hôpital St-Antoine
Subjects: Male, Developmental Disabilities, Intellectual disability, cholesterol pathway, Whole Exome Sequencing, chemistry.chemical_compound, Missense mutation, Age of Onset, Child, Intramolecular Transferases, Genetics (clinical), Exome sequencing, Genetics, Sanger sequencing, 0303 health sciences, biology, Lanosterol, 030305 genetics & heredity, LSS, 3. Good health, Pedigree, Cholesterol, Phenotype, intellectual disability, Child, Preschool, Allelic Imbalance, Congenital cataracts, symbols, Female, Squalene, early-onset epileptic encephalopathy, 03 medical and health sciences, symbols.namesake, Cholesterol pathway, Exome Sequencing, medicine, Humans, 030304 developmental biology, Epilepsy, Infant, Alopecia, alopecia, medicine.disease, Early-onset epileptic encephalopathy, chemistry, Mutation, biology.protein, Hypotrichosis, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, Lanosterol synthase
Abstract: International audience; Purpose Lanosterol synthase (LSS) gene was initially described in families with extensive congenital cataracts. Recently, a study has highlighted LSS associated with hypotrichosis simplex. We expanded the phenotypic spectrum of LSS to a recessive neuroectodermal syndrome formerly named alopecia with mental retardation (APMR) syndrome. It is a rare autosomal recessive condition characterized by hypotrichosis and intellectual disability (ID) or developmental delay (DD), frequently associated with early-onset epilepsy and other dermatological features. Methods Through a multicenter international collaborative study, we identified LSS pathogenic variants in APMR individuals either by exome sequencing or LSS Sanger sequencing. Splicing defects were assessed by transcript analysis and minigene assay. Results We reported ten APMR individuals from six unrelated families with biallelic variants in LSS. We additionally identified one affected individual with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. Quantification of cholesterol and its precursors did not reveal noticeable imbalance. Conclusion In the cholesterol biosynthesis pathway, lanosterol synthase leads to the cyclization of (S)-2,3-oxidosqualene into lanosterol. Our data suggest LSS as a major gene causing a rare recessive neuroectodermal syndrome.
Published: 2019
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31. Cortisol and Aldosterone Responses to Insulin-Induced Hypoglycemia and Sodium Depletion in Women with Non-Classic 21-Hydroxylase Deficiency

Author: Sylvie Salenave, Sylvie Brailly-Tabard, Bruno Donadille, H. Bry, Céline Piedvache, Jean-François Gautier, Lise Duranteau, Julien Thomas, Yves Le Bouc, Anne Blanchard, Laurence Pietri, M. Azizi, Sophie Christin-Maitre, Marie-Laure Raffin-Sanson, Peter Kamenicky, Aurelien Lorthioir, Jacques Young, Antonin Lamaziere, Philippe Chanson, and Seray Genc
Subjects: Cortisol secretion, medicine.medical_specialty, Aldosterone, biology, business.industry, food.diet, Insulin tolerance test, 21-Hydroxylase, Furosemide, Low sodium diet, medicine.disease, chemistry.chemical_compound, Endocrinology, food, chemistry, Internal medicine, Renin–angiotensin system, medicine, Adrenal insufficiency, biology.protein, business, medicine.drug
Abstract: Background: Non-classic 21-hydroxylase deficiency is usually diagnosed in post-pubertal women because of androgen excess. Indication of systematic steroid replacement therapy is controversial because the risk of acute adrenal insufficiency is unknown. In order to specify this risk we evaluated the cortisol and aldosterone secretions in response to appropriate pharmacological challenges. Methods: In this prospective case-control non-inferiority study we investigated 20 women with non-classic 21-hydroxylase deficiency carrying biallelic CYP21A2 mutations and with serum 17-hydroxyprogesterone (17OHP) >10ng/mL after stimulation with Synacthen® (tetracosactrin) and 20 ageand BMI-matched healthy women with 17OHP after Synacthen®
Published: 2019
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32. Intrications organo-psychiatriques : le concept de troubles psychiatriques complexes, quels examens complémentaires ?

Author: Florian, Ferreri, Alexis, Bourla, Jean, Capron, Bluenn, Quillerou, Julien, Rossignol, Alaina, Borden, Jérome, Guechot, Antonin, Lamaziere, Philippe, Nuss, Arsène, Mekinian, Stéphane, Mouchabac, Sorbonne Université (SU), Service de Psychiatrie adultes [CHU Saint-Antoine], CHU Saint-Antoine [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), Service de Neurologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Ressources Biologiques HUEP-UPMC (CRB HUEP-UPMC), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Laboratoire des biomolécules (LBM UMR 7203), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Chimie Moléculaire de Paris Centre (FR 2769), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Microorganismes et physiopathologie intestinale (ERL INSERM U1157 - CNRS UMR 7203), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Service de Médecine Interne [CHU Saint-Antoine]
Subjects: Mental Disorders, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Humans
Abstract: International audience; The purpose of this article is to describe complex psychiatric disorders, to recall “minimal classical” explorations in psychiatry, to describe the concept of “complex psychiatric disorders” and to propose a systematized method of exploration.Some organic diseases are well known for their links with psychiatric disorders (manic syndrome and hyperthyroidism, depressive syndrome and corticotropic insufficiency, anxiety disorder and heart disease, etc.).Many other neurological, autoimmune, metabolic, paraneoplastic or endocrine pathologies can have essentially psycho-behavioral manifestations before being neurological or systemic.A large number of factors (nutritional, toxic, immunological, etc.), often ignored, influence the links between organicity and psychiatric pathologies.It is necessary to optimize the medical management of these patients in whom the psychiatric diagnosis masks a curable organo-psychiatric cause.; Cet article a pour objectifs de décrire des troubles psychiatriques complexes, de rappeler les explorations « classiques minimales » en psychiatrie, de décrire le concept de « troubles psychiatriques complexes » et de proposer une méthode d’exploration systématisée.Certaines pathologies organiques sont bien connues pour leurs liens avec les troubles psychiatriques (syndrome maniaque et hyperthyroïdie, syndrome dépressif et insuffisance corticotrope, trouble anxieux et maladie cardiaque, etc.).De nombreuses autres pathologies neurologiques, auto-immunes, métaboliques, paranéoplasiques ou endocriniennes peuvent avoir des manifestations essentiellement psycho-comportementales avant d’être neurologiques ou systémiques.Un grand nombre de facteurs (nutritionnels, toxiques, immunologiques, etc.), souvent ignorés, exercent une influence sur les liens existants entre organicité et pathologies psychiatriques.Il est nécessaire d’optimiser la prise en charge médicale de ces patients chez qui le diagnostic psychiatrique masque une cause organo-psychiatrique curable.
Published: 2019
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33. Restoring brain cholesterol turnover improves autophagy and has therapeutic potential in mouse models of spinocerebellar ataxia

Author: Carlos A. Matos, Adriana Marcelo, Wilfred F. A. den Dunnen, Gaëtan Despres, Fatich Mechmet, Luís Pereira de Almeida, Liliana Mendonça, Nathalie Cartier, Sandra Tomé, Clévio Nóbrega, Sandro Alves, Dominique Langui, Antonin Lamaziere, and Molecular Neuroscience and Ageing Research (MOLAR)
Subjects: 0301 basic medicine, Male, SCA patients, Purkinje cell, Gene, DOMINANT CEREBELLAR-ATAXIA, Purkinje Cells, 0302 clinical medicine, REPEAT, RAT MODEL, Mutant ataxin-3, SCA animal models, MACHADO-JOSEPH-DISEASE, ABNORMALITIES, Neurodegeneration, 24-hydroxylase, NEURODEGENERATION, Brain, Machado-Joseph Disease, Middle Aged, 3. Good health, Cell biology, CYP46A1, medicine.anatomical_structure, Cholesterol, Spinocerebellar ataxia, Rat model, Female, medicine.symptom, Abnormalities, Adult, congenital, hereditary, and neonatal diseases and abnormalities, Ataxia, Transgene, Mice, Transgenic, Nerve Tissue Proteins, Neuropathology, Biology, Repeat, Neuroprotection, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, Cyp46A1, medicine, Autophagy, Cholesterol metabolism, Animals, Humans, Spinocerebellar Ataxias, medicine.disease, Dominant cerebellar-ataxia, GENE, 24-Cholesterol hydroxylase, MUTANT ATAXIN-3, Disease Models, Animal, 030104 developmental biology, 24-HYDROXYLASE, Neurology (clinical), 030217 neurology & neurosurgery
Abstract: Spinocerebellar ataxias (SCAs) are devastating neurodegenerative disorders for which no curative or preventive therapies are available. Deregulation of brain cholesterol metabolism and impaired brain cholesterol turnover have been associated with several neurodegenerative diseases. SCA3 or Machado-Joseph disease (MJD) is the most prevalent ataxia worldwide. We show that cholesterol 24-hydroxylase (CYP46A1), the key enzyme allowing efflux of brain cholesterol and activating brain cholesterol turnover, is decreased in cerebellar extracts from SCA3 patients and SCA3 mice. We investigated whether reinstating CYP46A1 expression would improve the disease phenotype of SCA3 mouse models. We show that administration of adeno-associated viral vectors encoding CYP46A1 to a lentiviral-based SCA3 mouse model reduces mutant ataxin-3 accumulation, which is a hallmark of SCA3, and preserves neuronal markers. In a transgenic SCA3 model with a severe motor phenotype we confirm that cerebellar delivery of AAVrh10-CYP46A1 is strongly neuroprotective in adult mice with established pathology. CYP46A1 significantly decreases ataxin-3 protein aggregation, alleviates motor impairments and improves SCA3-associated neuropathology. In particular, improvement in Purkinje cell number and reduction of cerebellar atrophy are observed in AAVrh10-CYP46A1-treated mice. Conversely, we show that knocking-down CYP46A1 in normal mouse brain impairs cholesterol metabolism, induces motor deficits and produces strong neurodegeneration with impairment of the endosomal-lysosomal pathway, a phenotype closely resembling that of SCA3. Remarkably, we demonstrate for the first time both in vitro, in a SCA3 cellular model, and in vivo, in mouse brain, that CYP46A1 activates autophagy, which is impaired in SCA3, leading to decreased mutant ataxin-3 deposition. More broadly, we show that the beneficial effect of CYP46A1 is also observed with mutant ataxin-2 aggregates. Altogether, our results confirm a pivotal role for CYP46A1 and brain cholesterol metabolism in neuronal function, pointing to a key contribution of the neuronal cholesterol pathway in mechanisms mediating clearance of aggregate-prone proteins. This study identifies CYP46A1 as a relevant therapeutic target not only for SCA3 but also for other SCAs. Neur ATRIS: A Translational Research Infrastructure for Biotherapies in Neurosciences Fondation pour la Recherche Medicale, Bioingenierie pour la SanteFondation pour la Recherche Medicale [DBS20140930765] SATT (Societe d'Acceleration de Transfert Technologique) Ile de France Innov Paris Saclay University European Regional Development Fund (ERDF)European Union (EU) [CENTRO-01-0145-FEDER-000008] Portuguese national funds via FCT-Fundacao para a Ciencia e a Tecnologia, I.P. [POCI-01-0145-FEDER-016719 (PTDC/NEU-NMC/0084/2014), POCI-01-0145-FEDER-007440 (UID/NEU/04539/2013), POCI-01-0145-FEDER-016390] FCT under EU [CENTRO-01-0145-FEDER022095, JPCOFUND/0001/2015, JPCOFUND/0005/2015] European UnionEuropean Union (EU) [643417] Richard Chin and Lily Lock Machado Joseph Disease Research Fund National Ataxia Foundation French Muscular Dystrophy Association (AFM-Telethon) Ataxia UK CENTRO 2020 FCTPortuguese Foundation for Science and Technology FCTPortuguese Foundation for Science and Technology [SFRH/BD/133192/2017] info:eu-repo/semantics/publishedVersion
Published: 2019

34. I13 Striatal regulation of cholesterol metabolism by CYP46A1 is associated with multiple benefits in huntington’s disease knock-in mice models

Author: Wilhem Christaller, Laurent Venance, Radhia Kacher, Valérie Messent, Sandrine Betuing, Christian Neri, Gaëtan Despres, Luliia Dembitskaia, Frédéric Saudou, Antonin Lamaziere, Elodie Perrin, Peter Vanhoutte, Satish Sasidharan Nair, Vincent Kappes, Jocelyne Caboche, and Nicolas Heck
Subjects: Putamen, Autophagy, Striatum, Tropomyosin receptor kinase B, Biology, medicine.disease, Cell biology, chemistry.chemical_compound, nervous system, chemistry, Huntington's disease, Gene knockin, Desmosterol, medicine, Homeostasis
Abstract: Background Recently, altered brain cholesterol homeostasis has been implicated in Huntington’s disease (HD) pathogenesis. Our team made the original observation that expression level of CYP46A1, the rate-limiting enzyme for the degradation of cholesterol in the brain, is decreased in putamen extracts of post-mortem HD patients and in the striatum of an HD knock-in (KI) mouse model, the zQ175 mice. Method We restored CYP46A1 expression into the striatum of zQ175 mice, at a pre-symptomatic stage, using an AAV-mediated approach. A battery of behavioral, neuropathological and molecular tests was performed in these mice. Results In zQ175 mice injected with CYP46A1, locomotor activity and histological landmarks were improved; aggregates number and size were decreased and striatal projection neurons soma size was increased. In these mice, cholesterol homeostasis is restored with not only an increase of cholesterol degradation but also a regulation of cholesterol synthesis, with increased cholesterol precursor’s levels, thus a regulation of the whole pathway. Complementary studies showed that CYP46A1 improves the synaptic connectivity and the glutamatergic transmission in the striatum of zQ175 mice. Additionally, we showed that CYP46A1 increases BDNF vesicle axonal transport as well as TrkB receptor endosome trafficking in HD cortico-striatal connections reconstituted in microfluidic devices. Finally, we report that CYP46A1-regulated sterols, lanosterol and desmosterol, increased the clearance of mHTT aggregates through proteasome and autophagy machineries. Conclusion In the present project, we showed that CYP46A1 restoration alleviates the pathological phenotype of zQ175 mice. Collectively, our results provide a comprehensive model for the mechanisms by which CYP46A1 striatal restoration may promote brain homeostasis and oppose HD, opening a novel therapeutic avenue based on promoting compensation of HD phenotype.
Published: 2018
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35. O5‐06‐04: AAV‐CYP46A1 BRAIN DELIVERY MITIGATES ALZHEIMER'S DISEASE: FROM MOUSE MODELS TO NON‐HUMAN PRIMATES

Author: Antonin Lamaziere, Mickael Audrain, Gaelle Dufayet-Chaffaud, Sandro Alves, Kristin Michaelsen-Preusse, Gaëtan Despres, Romain Fol, Françoise Fouquet, Martin Korte, Aurélie Berniard, Philippe Hantraye, Jérôme Braudeau, Emilie Rey, Nathalie Cartier, Patrick Aubourg, Romina Aron Badin, and Françoise Piguet
Subjects: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, business.industry, Health Policy, Non-human, Medicine, Neurology (clinical), Disease, Geriatrics and Gerontology, business, Neuroscience
Published: 2018
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36. Severe X-linked chondrodysplasia punctata in nine new female fetuses

Author: Nadège Gigot, Julie Désir, Jean-Baptiste Rivière, Marie Gonzales, N. Joye, Bernard Aral, Dominique D'Olne, Frédérique Jossic, Caroline Daelemans, Anne-Lise Delezoide, Valérie Cormier-Daire, Alice Masurel-Paulet, Annick Toutain, Claude Vibert-Guigue, Judith Saint-Onge, Julien Thevenon, Sébastien Schmitt, Jean-Marc Labaune, Laurence Faivre, Antonin Lamaziere, Fabienne Dufernez, Fanny Pelluard, Nicole Bigi, Mathilde Lefebvre, Thierry Rousseau, Raphaele Mangione, Pierre Vabres, P. Herve, Sophie Blesson, Ange-Line Bruel, Luc Rigonnot, Christel Thauvin-Robinet, Salima El Chehadeh, Nicole Laurent, and Catherine Vincent-Delorme
Subjects: Stippling (dentistry), Fetus, business.industry, Ichthyosis, Obstetrics and Gynecology, Physiology, Anatomy, medicine.disease, 3. Good health, medicine.anatomical_structure, Dysplasia, Epiphysis, Gestation, Medicine, Chondrodysplasia punctata, business, Genetics (clinical), Epiphyseal stippling
Abstract: ObjectivesConradi-Hunermann-Happle [X-linked dominant chondrodysplasia punctata 2 (CDPX2)] syndrome is a rare X-linked dominant skeletal dysplasia usually lethal in men while affected women show wide clinical heterogeneity. Different EBP mutations have been reported. Severe female cases have rarely been reported, with only six antenatal presentations. MethodsTo better characterize the phenotype in female fetuses, we included nine antenatally diagnosed cases of women with EBP mutations. All cases were de novo except for two fetuses with an affected mother and one case of germinal mosaicism. ResultsThe mean age at diagnosis was 22weeks of gestation. The ultrasound features mainly included bone abnormalities: shortening (8/9 cases) and bowing of the long bones (5/9), punctuate epiphysis (7/9) and an irregular aspect of the spine (5/9). Postnatal X-rays and examination showed ichthyosis (8/9) and epiphyseal stippling (9/9), with frequent asymmetric short and bowed long bones. The X-inactivation pattern of the familial case revealed skewed X-inactivation in the mildly symptomatic mother and random X-inactivation in the severe fetal case. Differently affected skin samples of the same fetus revealed different patterns of X-inactivation. ConclusionPrenatal detection of asymmetric shortening and bowing of the long bones and cartilage stippling should raise the possibility of CPDX2 in female fetuses, especially because the majority of such cases involve de novo mutations.
Published: 2015
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37. Modulation of Brain Cholesterol Metabolism through CYP46A1 Overexpression for Rett Syndrome

Author: Emilie Audouard, Nicolas Khefif, Béatrix Gillet-Legrand, Fanny Nobilleau, Ouafa Bouazizi, Serena Stanga, Gaëtan Despres, Sandro Alves, Antonin Lamazière, Nathalie Cartier, and Françoise Piguet
Subjects: Rett syndrome, cholesterol pathway, AAVPHP.eB, gene therapy, Pharmacy and materia medica, RS1-441
Abstract: Rett syndrome (RTT) is a rare neurodevelopmental disorder caused by mutation in the X-linked gene methyl-CpG-binding protein 2 (Mecp2), a ubiquitously expressed transcriptional regulator. RTT results in mental retardation and developmental regression that affects approximately 1 in 10,000 females. Currently, there is no curative treatment for RTT. Thus, it is crucial to develop new therapeutic approaches for children suffering from RTT. Several studies suggested that RTT is linked with defects in cholesterol homeostasis, but for the first time, therapeutic evaluation is carried out by modulating this pathway. Moreover, AAV-based CYP46A1 overexpression, the enzyme involved in cholesterol pathway, has been demonstrated to be efficient in several neurodegenerative diseases. Based on these data, we strongly believe that CYP46A1 could be a relevant therapeutic target for RTT. Herein, we evaluated the effects of intravenous AAVPHP.eB-hCYP46A1-HA delivery in male and female Mecp2-deficient mice. The applied AAVPHP.eB-hCYP46A1 transduced essential neurons of the central nervous system (CNS). CYP46A1 overexpression alleviates behavioral alterations in both male and female Mecp2 knockout mice and extends the lifespan in Mecp2-deficient males. Several parameters related to cholesterol pathway are improved and correction of mitochondrial activity is demonstrated in treated mice, which highlighted the clear therapeutic benefit of CYP46A1 through the neuroprotection effect. IV delivery of AAVPHP.eB-CYP46A1 is perfectly well tolerated with no inflammation observed in the CNS of the treated mice. Altogether, our results strongly suggest that CYP46A1 is a relevant target and overexpression could alleviate the phenotype of Rett patients.
Published: 2024
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38. CYP46A1 protects against NMDA-mediated excitotoxicity in Huntington's disease: Analysis of lipid raft content

Author: Lydie Boussicault, Marie-Claude Potier, Jocelyne Caboche, Radhia Kacher, Peter Vanhoutte, Sandrine Betuing, Antonin Lamaziere, Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Neurobiologie des processus adaptatifs (NPA), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Neurobiologie et diversité cellulaire (NDC), ESPCI ParisTech-Centre National de la Recherche Scientifique (CNRS), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), 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)-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)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, Huntingtin, N-Methylaspartate, [SDV]Life Sciences [q-bio], Excitotoxicity, medicine.disease_cause, Biochemistry, Neuroprotection, Receptors, N-Methyl-D-Aspartate, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Membrane Microdomains, Huntington's disease, medicine, Cholesterol 24-Hydroxylase, Animals, Homeostasis, Humans, Lipid raft, ComputingMilieux_MISCELLANEOUS, Neurons, Huntingtin Protein, Chemistry, Cholesterol, Wild type, General Medicine, medicine.disease, Corpus Striatum, 3. Good health, Cell biology, 030104 developmental biology, Huntington Disease, nervous system, Mutation, NMDA receptor, lipids (amino acids, peptides, and proteins), [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, 030217 neurology & neurosurgery
Abstract: Huntington's Disease (HD) is an autosomal dominant neurodegenerative disease caused by abnormal polyglutamine expansion in huntingtin (mHtt) protein leading to degeneration of striatal neurons. Excitotoxicity, consecutive to overstimulation of N-methyl d -aspartate receptors (NMDARs) has a pivotal role in many neurological disorders including HD. Mutant Htt causes enhanced NMDA sensitivity, alteration of NMDAR expression and localization in neurons. Excitotoxic events initiate neuronal death in numerous ways, including activation of apoptotic cascades. Among the NMDAR subunits involved in glutamatergic-mediated excitotoxicity, GluN2B has been extensively reported. In addition to excitotoxicity, alteration of cholesterol metabolism has been observed in HD, with a decrease of cholesterol precursor synthesis along with an increase of cholesterol accumulation, which is deleterious for neurons. Expression of Cholesterol Hydroxylase enzyme, CYP46A1, which converts cholesterol into 24 S-hydroxycholesterol is down-regulated in HD. We found that CYP46A1 overexpression is beneficial in HD neurons and mouse model, but the mechanisms involved still remain unclear. In this study we addressed the effect of CYP46A1 on NMDAR-mediated excitotoxicity in HD primary neurons and its role in modulating cholesterol and localization of GLUN2B in lipid rafts. We showed that CYP46A1 is protective against NMDAR-mediated excitotoxicity in two different HD neuronal cell models. Cholesterol as well as GluN2B level in lipid raft, are significantly increased by mHtt. Despite a clear effect of CYP46A1 in reducing cholesterol content in lipid raft extracts from wild type neurons, CYP46A1 overexpression in HD neurons could not normalize the increased cholesterol levels in lipid rafts. This study highlights the beneficial role of CYP46A1 against NMDAR-mediated excitotoxicity and gives further insights into the cellular mechanisms underlying CYP46A1-mediated neuroprotection.
Published: 2018
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39. An Evaluation of Multivariate Data Analysis Models for Lipidomic Parameters from Patients with Metabolic Syndrome Undergoing Remedial Treatment

Author: R. Chapier, Claude Wolf, Antonin Lamaziere, D. Farabos, and Peter J. Quinn
Subjects: Multivariate statistics, medicine.medical_specialty, Multivariate analysis, business.industry, Potential biomarkers, Internal medicine, Lifestyle intervention, medicine, Blood lipids, Fatty acid composition, Metabolic syndrome, medicine.disease, business
Abstract: Multivariate data methods have been applied in analysis of parameters derived from patients with metabolic syndrome undergoing a remedial regime. In an example involving parameters derived from the fatty acid composition of serum lipids multivariate modeling is challenged to identify potential biomarkers for prediction during the intervention. Multivariate methods also reveal useful applications to monitor compliance to the prescribed exercise and diet regime, a critical feature in a lifestyle intervention conducted over a long time period.
Published: 2018
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40. Cholesterol-pyrene as a probe for cholesterol distribution on ordered and disordered membranes: Determination of spectral wavelengths

Author: Claudia Almeida, Antonin Lamaziere, Anaë Lle de Wreede, Jesus Ayala-Sanmartin, Instituto Nacional de Pesquisas Espaciais (INPE), Université Pierre et Marie Curie - Paris 6 (UPMC), Analyse, Interactions Moléculaires et Cellulaires (LBM-E2), Laboratoire des biomolécules (LBM UMR 7203), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: 0301 basic medicine, Luminescence, Cell Membranes, lcsh:Medicine, Biochemistry, chemistry.chemical_compound, Mathematical and Statistical Techniques, lcsh:Science, Phospholipids, Principal Component Analysis, Pyrenes, Multidisciplinary, Chemistry, Physics, Electromagnetic Radiation, Condensed Matter Physics, Lipids, Fluorescence, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Cholesterol, Membrane, Monomer, Physical Sciences, Pyrene, lipids (amino acids, peptides, and proteins), Cellular Structures and Organelles, Statistics (Mathematics), Research Article, Ceramide, Fluorophore, Materials Science, Material Properties, Research and Analysis Methods, 03 medical and health sciences, Membrane Microdomains, Statistical Methods, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], 030102 biochemistry & molecular biology, lcsh:R, Biology and Life Sciences, Membranes, Artificial, Biological membrane, Cell Biology, 030104 developmental biology, Multivariate Analysis, Biophysics, Anisotropy, lcsh:Q, Spectrophotometry, Ultraviolet, Mathematics, Membrane Composition
Abstract: International audience; Biological membranes contain a large variety of lipids species compartmentalized in different domains heterogeneous in size, composition and dynamics. Cholesterol induces membrane ordered domains thanks to its affinity for saturated lipids. Membrane domains had been studied with fluorescent probes either linked to phospholipids and proteins or as individual fluorophore. However, no efficient formulation of a cholesterol probe has been available so far. Herein, we described a cholesterol-pyrene probe behaviour in heterogeneous membranes. We characterised the pyrene fluorescence spectra in liquid-ordered (Lo) and liquid-disordered (Ld) membranes. Using statistical multivariate analysis, we found out the most appropriate wavelengths for membrane domains studies. 373 nm and 379 nm were the most discriminant wavelengths to follow the liquid-ordered and the liquid-disordered environments. Cholesterol clustering behaviour was quantified by the modulation of the cholesterol -pyrene excimers peak (474 nm). In liquid-ordered membranes at low temperature, cholesterol-pyrene was found as multimers and as monomers. At high temperature, the liquid ordered status of the membrane decreases and cholesterol-pyrene tends to cluster. In liquid-disordered membranes, cholesterol-pyrene was present mostly as monomers and the small quantity of excimers increased with temperature. Cholesterol-pyrene was used to test the ceramide effect on membranes, and presented a behaviour in agreement with the cholesterol behaviour reported in the literature. Overall, the presented data show that cholesterol -pyrene is an efficient sensor to study liquid ordered and liquid disordered organisation in membranes.
Published: 2018
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41. Plasma cortisol and aldosterone responses to insulin tolerance test and sodium depletion in women with non classic 21-hydroxylase deficiency caused by bi-allelic CYP21A2 mutations (NC-CAH)

Author: Veronique Tardy, Sylvie Salenave, Philippe Chanson, Anne Blanchard, Sophie Christin Maitre, Sylvie Brailly-Tabard, Jacques Young, Yves Le Bouc, Lise Duranteau, Marie Laure Raffin-Sanson, Peter Kamenicky, Antonin Lamaziere, Laurence Pietri, Jean-François Gautier, and Bruno Donadille
Subjects: medicine.medical_specialty, Aldosterone, biology, Chemistry, Insulin tolerance test, 21-Hydroxylase, chemistry.chemical_compound, Plasma cortisol, Endocrinology, Internal medicine, medicine, biology.protein, Allele, SODIUM DEPLETION
Published: 2017
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42. SU2. A Paradoxical Superior Cognitive Performance in Healthy Control With a Membrane Lipid Marker of Schizophrenia: The Role of the Compensatory Lipid Composition

Author: Jonathan P. Roiser, Marc De Hert, Kim Sweers, Nathanael Lapidus, Cedric Tessier, Antonin Lamaziere, Catherine Delva, Florian Ferreri, Philippe Nuss, A. Frajerman, and Haifa Bergaoui
Subjects: medicine.medical_specialty, business.industry, Lipid composition, Membrane lipids, Tissue membrane, medicine.disease, Psychiatry and Mental health, Abstracts, Membrane, Text mining, Endocrinology, Schizophrenia, Internal medicine, Healthy control, medicine, Effects of sleep deprivation on cognitive performance, business
Abstract: Background: Lipid membrane abnormalities have been described in several neuropsychiatric disorder, in particular schizophrenia (SCZ) and autism. A sphingomyelin (SM) decrease in the red blood cell (RBC) membrane of patients with SCZ was shown to be associated with more severe PANSS scores and poorer cognitive performance (Tessier et al, Transl Psychiatry, 2016; 6(10)). The present study aimed at examining the cognitive performance of the healthy control group as a function of the identified membrane SM status.
Published: 2017

43. P1.36: Essential fatty acids profile in pediatric patients receiving an intravenous lipid emulsion containing 15% fish oil

Author: Claude Wolf, Bruno Coat, Marie-Anne Maubert, Cécile Lambe, Antonin Lamaziere, Rozenn Clement, Cécile Talbotec, Martine Postaire, and Olivier Goulet
Subjects: Transplantation, Intravenous lipid emulsion, business.industry, Medicine, Food science, Fish oil, business
Published: 2019
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44. A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia

Author: Jérôme Guéchot, Marie-Anne Maubert, Jean Fiet, Antonin Lamaziere, Nicolas Hélin, Dominique Farabos, and Yves Le Bouc
Subjects: 0301 basic medicine, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, 030209 endocrinology & metabolism, Context (language use), urologic and male genital diseases, Pubarche, Steroid, 03 medical and health sciences, 0302 clinical medicine, congenital adrenal hyperplasia, Medicine, Congenital adrenal hyperplasia, Adrenal, LC-MS/MS, Clinical Research Articles, hirsutism, Newborn screening, Chromatography, business.industry, 21-Deoxycorticosterone, Adrenarche, 21 deoxycortisol, medicine.disease, 030104 developmental biology, 21 deoxycorticosterone, business, steroids
Abstract: Context: Congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency (CAH21) is most often diagnosed by newborn screening. The classic parameter studied is 17-hydroxy-progesterone, but the positive predictive value for the diagnosis of CAH is low in full-term newborns and even lower in preterm newborns. Objective: To evaluate the diagnostic utility of simultaneously quantifying a large number of steroids by using liquid chromatography/tandem mass spectrometry (LC-MS/MS) from a small serum volume in patients with CAH, particularly during the neonatal period. Setting and participants: LC-MS/MS was applied to sera from patients with CAH who had a classic form (n = 48) and rare forms (n = 2) of 21-hydroxylase deficiency, normal preterm (n = 10) and normal full-term (n = 20) neonates, and young patients without CAH (non-CAH; n = 149) but with various other diseases (delayed or advanced puberty, hirsutism, pubarche, adrenarche, simple growth retardation). Methods: Sixteen steroids (glucocorticoids, mineralocorticoids, androgens, Δ5-steroids) were analyzed in 150 µL of serum by LC-MS/MS. Results: An LC-MS/MS serum steroid profile was developed and validated to provide a reliable etiologic diagnosis of CAH. The serum levels of 17OH-progesterone and 21 deoxycortisol in non-CAH are reported, along with the rarely assayed 21-deoxycorticorticosterone and 11β hydroxy Δ4-androstenedione, which will aid in the diagnosis of CAH21. In addition, serum levels of mineralocorticoids, androgens, and Δ5-steroids allowed investigation of other forms of CAH. Conclusion: This steroid LC-MS/MS approach on a small serum volume is well suited for pediatrics, particularly neonatal medical practice, to aid in the diagnosis and monitoring of various forms of CAH., Liquid chromatography/tandem mass spectometry performed on a low serum volume sample is well suited to pediatrics, particularly neonatal medical practice, to aid in the diagnosis and monitoring of various forms of congenital adrenal hyperplasia.
Published: 2017
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45. Effect of Stool Sampling on a Routine Clinical Method for the Quantification of Six Short Chain Fatty Acids in Stool Using Gas Chromatography–Mass Spectrometry

Author: Tarek Mahdi, Aurore Desmons, Pranvera Krasniqi, Jean-Marc Lacorte, Nathalie Kapel, Antonin Lamazière, Salma Fourati, and Thibaut Eguether
Subjects: gut microbiome, metabolomic, short chain fatty acids, GC-MS, stool sampling, Biology (General), QH301-705.5
Abstract: Short chain fatty acids (SCFAs) are primarily produced in the caecum and proximal colon via the bacterial fermentation of undigested carbohydrates that have avoided digestion in the small intestine. Increasing evidence supports the critical role that SCFAs play in health and homeostasis. Microbial SCFAs, namely butyric acid, serve as a principal energy source for colonocytes, and their production is essential for gut integrity. A direct link between SCFAs and some human pathological conditions, such as inflammatory bowel disease, irritable bowel syndrome, diarrhea, and cancer, has been proposed. The direct measurement of SCFAs in feces provides a non-invasive approach to demonstrating connections between SCFAs, microbiota, and metabolic diseases to estimate their potential applicability as meaningful biomarkers of intestinal health. This study aimed to adapt a robust analytical method (liquid–liquid extraction, followed by isobutyl chloroformate derivatization and GC–MS analysis), with comparable performances to methods from the literature, and to use this tool to tackle the question of pre-analytical conditions, namely stool processing. We focused on the methodology of managing stool samples before the analysis (fresh stool or dilution in either ethanol/methanol, lyophilized stool, or RNAlater®), as this is a significant issue to consider for standardizing results between clinical laboratories. The objective was to standardize methods for future applications as diagnostic tools. In this paper, we propose a validated GC–MS method for SCFA quantification in stool samples, including pre- and post-analytical comparison studies that could be easily used for clinical laboratory purposes. Our results show that using lyophilization as a stool-processing method would be the best method to achieve this goal.
Published: 2024
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46. Membrane re-arrangements and rippled phase stabilisation by the cell penetrating peptide penetratin

Author: Antonin Lamaziere, Angélique Filleau, Jesus Ayala-Sanmartin, Philippe Espeau, Claudia Almeida, Yohann Corvis, Analyse, Interactions Moléculaires et Cellulaires ( LBM-E2 ), Laboratoire des biomolécules ( LBM UMR 7203 ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Département de Chimie - ENS Paris, École normale supérieure - Paris ( ENS Paris ) -École normale supérieure - Paris ( ENS Paris ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Département de Chimie - ENS Paris, École normale supérieure - Paris ( ENS Paris ) -École normale supérieure - Paris ( ENS Paris ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Microorganismes, Molécules Bioactives et Physiopathologie Intestinale ( LBM-E4 ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université Paris Descartes - Paris 5 ( UPD5 ), Analyse, Interactions Moléculaires et Cellulaires (LBM-E2), Laboratoire des biomolécules (LBM UMR 7203), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC), Microorganismes, Molécules Bioactives et Physiopathologie Intestinale (LBM-E4), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris Descartes - Paris 5 (UPD5), Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), 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 Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, 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 Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and HAL-UPMC, Gestionnaire
Subjects: 0301 basic medicine, Penetratin, Endosome, Cell, Lipid Bilayers, Biophysics, Peptide, Cell-Penetrating Peptides, Biochemistry, Phase Transition, 03 medical and health sciences, chemistry.chemical_compound, Membrane Lipids, Lipids packing, 2-Naphthylamine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Membrane fluidity, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, Rippled phase, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Fluorescent Dyes, chemistry.chemical_classification, 030102 biochemistry & molecular biology, Temperature, Phosphatidylglycerols, Cell Biology, Cytosol, 030104 developmental biology, medicine.anatomical_structure, Membrane, chemistry, Membrane organisation, Cell-penetrating peptide, Laurdan, Carrier Proteins, Dimyristoylphosphatidylcholine, Laurates
Abstract: International audience; Cell penetrating peptides are promising vectors for molecular drug delivery in eukaryotic cells. Despite of their discovery 20 years ago, the mechanisms of peptide membrane crossing are still controversial. The different suggested penetration mechanisms reflect the high sequence and structural diversity of cell penetrating peptides. The fundamental step for peptide penetration into the cytosol is the crossing of the membrane lipid barrier at the level of the plasma membrane or the endosomes. Therefore, the study of the peptide-lipid interaction is the key for peptide penetration mechanisms understanding. In order to study the changes in lipid organisation induced by the cell penetrating peptide penetratin, several experiments by three different physicochemical approaches were performed. X-ray diffraction data shows that penetratin is able to induce membrane phase separation and lipid rearrangements observed by inter-lipid distances. These changes are accompanied by a temperature stable behaviour of some of the induced membrane domains. The membrane environment fluorescent probe laurdan showed that, in DMPC and DMPC/DMPG membranes, the peptide induces de-packing of lipids. Calorimetric analyses show that penetratin favours the gel phase to gel-like rippled phase transition. Overall, the data suggest both, that the rippled phase is a heterogeneous structure formed by gel-like and fluid-like coexisting components, and that the penetratin-induced membrane heterogeneity could be important for membrane destabilisation during cell penetration.
Published: 2016
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47. Membrane lipidomics in schizophrenia patients: a correlational study with clinical and cognitive manifestations

Author: Jonathan P. Roiser, A. Frajerman, Philippe Nuss, Kim Sweers, Nathanael Lapidus, Florian Ferreri, Catherine Delva, Haifa Bergaoui, Cedric Tessier, M. De Hert, Antonin Lamaziere, Laboratoire des biomolécules (LBM UMR 7203), Chimie Moléculaire de Paris Centre (FR 2769), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Sylia Stat Lancrenon S.A.S., Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Institute of Cognitive Neuroscience (ICN-UCL), University College of London [London] (UCL), INSERM-ERL 1157, CHU St Antoine, UPC-KU Leuven, Service de santé publique [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and HAL-UPMC, Gestionnaire
Subjects: Male, Erythrocytes, Dopamine, Statistics as Topic, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Neuropsychological Tests, Synaptic Transmission, 0302 clinical medicine, Wisconsin Card Sorting Test, Phospholipids, Positive and Negative Syndrome Scale, Fatty Acids, Middle Aged, Sphingomyelins, 3. Good health, Psychiatry and Mental health, Female, Schizophrenic Psychology, Original Article, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Psychopharmacology, Sphingomyelin, Psychology, Signal Transduction, Psychopathology, medicine.drug, Clinical psychology, Adult, medicine.medical_specialty, Psychometrics, Membrane Lipids, 03 medical and health sciences, Cellular and Molecular Neuroscience, Internal medicine, medicine, Humans, Dementia, Cognitive Dysfunction, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Biological Psychiatry, Case-control study, Lipid Metabolism, medicine.disease, 030227 psychiatry, Endocrinology, Case-Control Studies, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Chronic Disease, Schizophrenia, 030217 neurology & neurosurgery
Abstract: Schizophrenia is a severe mental condition in which several lipid abnormalities—either structural or metabolic—have been described. We tested the hypothesis that an abnormality in membrane lipid composition may contribute to aberrant dopamine signaling, and thereby symptoms and cognitive impairment, in schizophrenia (SCZ) patients. Antipsychotic-medicated and clinically stable SCZ outpatients (n=74) were compared with matched healthy subjects (HC, n=40). A lipidomic analysis was performed in red blood cell (RBC) membranes examining the major phospholipid (PL) classes and their associated fatty acids (FAs). Clinical manifestations were examined using the positive and negative syndrome scale (PANSS). Cognitive function was assessed using the Continuous Performance Test, Salience Attribution Test and Wisconsin Card Sorting Test. Sphingomyelin (SM) percentage was the lipid abnormality most robustly associated with a schizophrenia diagnosis. Two groups of patients were defined. The first group (SCZ c/SM−) is characterized by a low SM membrane content. In this group, all other PL classes, plasmalogen and key polyunsaturated FAs known to be involved in brain function, were significantly modified, identifying a very specific membrane lipid cluster. The second patient group (SCZ c/SM+) was similar to HCs in terms of RBC membrane SM composition. Compared with SCZ c/SM+, SCZ c/SM− patients were characterized by significantly more severe PANSS total, positive, disorganized/cognitive and excited psychopathology. Cognitive performance was also significantly poorer in this subgroup. These data show that a specific RBC membrane lipid cluster is associated with clinical and cognitive manifestations of dopamine dysfunction in schizophrenia patients. We speculate that this membrane lipid abnormality influences presynaptic dopamine signaling.
Published: 2016
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48. Antenatal manifestations of inborn errors of metabolism: biological diagnosis

Author: Christine Vianey-Saban, Roseline Froissart, David Cheillan, Monique Piraud, Cécile Acquaviva, Antonin Lamaziere, Cécile Pagan, Sophie Collardeau-Frachon, Laurent Guibaud, Magali Pettazzoni, Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Jeanne de Flandres-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Maladies Héréditaires du Métabolisme, Centre de Biologie Et de Pathologie Est - Bron Centre médical, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hereditary Metabolic Diseases Department, East Medical Group, Hospices Civils de Lyon (HCL), Pediatric Gastroenterology and Nutrition, Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire des Maladies Héréditaires du Métabolisme, Hospices Civils de Lyon (HCL)-CHU de Lyon-GH Est, Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire des Maladies Héréditaires du Métabolisme et Dépistage Néonatal, Métabolomique et maladies métaboliques, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupement Hospitalier Lyon-Est (GHE), and Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)
Subjects: 0301 basic medicine, medicine.medical_specialty, Mucopolysaccharidosis, Prenatal diagnosis, Lathosterol, 030105 genetics & heredity, Biology, Transaldolase deficiency, 03 medical and health sciences, chemistry.chemical_compound, Fetus, Metabolic Diseases, Pregnancy, Internal medicine, Desmosterol, Hydrops fetalis, Prenatal Diagnosis, Peroxisomal disorder, Genetics, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics (clinical), 2. Zero hunger, medicine.disease, Amniotic Fluid, 3. Good health, 030104 developmental biology, Endocrinology, chemistry, Female, Metabolic Networks and Pathways, Metabolism, Inborn Errors
Abstract: International audience; Inborn errors of metabolism (IEMs) that present with abnormal imaging findings in the second half of pregnancy are mainly lysosomal storage disorders (LSDs), cholesterol synthesis disorders (CSDs), glycogen storage disorder type IV (GSD IV), peroxisomal disorders, mitochondrial fatty acid oxidation defects (FAODs), organic acidurias, aminoacidopathies, congenital disorders of glycosylation (CDGs), and transaldolase deficiency. Their biological investigation requires fetal material. The supernatant of amniotic fluid (AF) is useful for the analysis of mucopolysaccharides, oligosaccharides, sialic acid, lysosphingolipids and some enzyme activities for LSDs, 7- and 8-dehydrocholesterol, desmosterol and lathosterol for CSDs, acylcarnitines for FAODs, organic acids for organic acidurias, and polyols for transaldolase deficiency. Cultured AF or fetal cells allow the measurement of enzyme activities for most IEMs, whole-cell assays, or metabolite measurements. The cultured cells or tissue samples taken after fetal death can be used for metabolic profiling, enzyme activities, and DNA extraction. Fetal blood can also be helpful. The identification of vacuolated cells orients toward an LSD, and plasma is useful for diagnosing peroxisomal disorders, FAODs, CSDs, some LSDs, and possibly CDGs and aminoacidopathies. We investigated AF of 1700 pregnancies after exclusion of frequent etiologies of nonimmune hydrops fetalis and identified 108 fetuses affected with LSDs (6.3 %), 29 of them with mucopolysaccharidosis type VII (MPS VII), and six with GSD IV (0.3 %). In the AF of 873 pregnancies, investigated because of intrauterine growth restriction and/or abnormal genitalia, we diagnosed 32 fetuses affected with Smith-Lemli-Opitz syndrome (3.7 %).
Published: 2016
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49. CYP46A1, the rate-limiting enzyme for cholesterol degradation, is neuroprotective in Huntington’s disease

Author: Sandrine Betuing, Anabelle Planques, Françoise Piguet, Gaëtan Despres, Jocelyne Caboche, Christiane Pagès, Nicolas Heck, Lara Moumné, Nathalie Cartier, Amelie Hu, Laurie Galvan, Antonin Lamaziere, Susanne Bolte, Lydie Boussicault, Sandro Alves, Patrick Aubourg, Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), 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)-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)-Centre National de la Recherche Scientifique (CNRS), Thérapie génique, Génomique et Epigénomique (U 1169), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Université Pierre et Marie Curie - Paris 6 (UPMC), Développement et Neuropharmacologie / Development and Neuropharmacology, Centre interdisciplinaire de recherche en biologie (CIRB), Collège de France (CdF (institution))-Université Paris sciences et lettres (2020-....) (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Collège de France (CdF (institution))-Université Paris sciences et lettres (2020-....) (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des sciences du végétal (ISV), Centre National de la Recherche Scientifique (CNRS), Laboratory of Experimental Neurology, Université libre de Bruxelles (ULB), Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Center for Neurobehavioral Genetics, Semel Institute, University of California, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Neurogénétique moléculaire, Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris-Saclay-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11), Development and Neuropharmacology, Center for Interdisciplinary Research in Biology (INSERM CNRS 7141), Collège de France (CdF), Université Libre de Bruxelles [Bruxelles] (ULB), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), 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)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of California (UC), d'Eggis, Gilles, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Institut de Biologie Paris-Seine
Subjects: 0301 basic medicine, Male, Huntingtin, striatum, Striatum, chemistry.chemical_compound, Mice, 0302 clinical medicine, Desmosterol, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, Cerebral Cortex, Putamen, Huntington's disease, Middle Aged, Neuroprotection, 3. Good health, CYP46A1, Cholesterol, medicine.anatomical_structure, Huntington Disease, Cerebral cortex, lipids (amino acids, peptides, and proteins), Female, neuroprotection, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Huntington’s disease, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Biology, 03 medical and health sciences, Neurologie, Internal medicine, mental disorders, medicine, Cholesterol 24-Hydroxylase, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cholesterol 24-hydroxylase, Aged, cholesterol, Original Articles, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, chemistry, nervous system, Steroid Hydroxylases, Mice, Inbred CBA, Neurology (clinical), 030217 neurology & neurosurgery
Abstract: Huntington's disease is an autosomal dominant neurodegenerative disease caused by abnormal polyglutamine expansion in huntingtin (Exp-HTT) leading to degeneration of striatal neurons. Altered brain cholesterol homeostasis has been implicated in Huntington's disease, with increased accumulation of cholesterol in striatal neurons yet reduced levels of cholesterol metabolic precursors. To elucidate these two seemingly opposing dysregulations, we investigated the expression of cholesterol 24-hydroxylase (CYP46A1), the neuronal-specific and rate-limiting enzyme for cholesterol conversion to 24S-hydroxycholesterol (24S-OHC). CYP46A1 protein levels were decreased in the putamen, but not cerebral cortex samples, of post-mortem Huntington's disease patients when compared to controls. Cyp46A1 mRNA and CYP46A1 protein levels were also decreased in the striatum of the R6/2 Huntington's disease mouse model and in SThdhQ111 cell lines. In vivo, in a wild-type context, knocking down CYP46A1 expression in the striatum, via an adeno-associated virus-mediated delivery of selective shCYP46A1, reproduced the Huntington's disease phenotype, with spontaneous striatal neuron degeneration and motor deficits, as assessed by rotarod. In vitro, CYP46A1 restoration protected SThdhQ111 and Exp-HTT-expressing striatal neurons in culture from cell death. In the R6/2 Huntington's disease mouse model, adeno-associated virus-mediated delivery of CYP46A1 into the striatum decreased neuronal atrophy, decreased the number, intensity level and size of Exp-HTT aggregates and improved motor deficits, as assessed by rotarod and clasping behavioural tests. Adeno-associated virus-CYP46A1 infection in R6/2 mice also restored levels of cholesterol and lanosterol and increased levels of desmosterol. In vitro, lanosterol and desmosterol were found to protect striatal neurons expressing Exp-HTT from death. We conclude that restoring CYP46A1 activity in the striatum promises a new therapeutic approach in Huntington's disease., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2016
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50. A Machine Learning Approach for the Prediction of Testicular Sperm Extraction in Nonobstructive Azoospermia: Algorithm Development and Validation Study

Author: Guillaume Bachelot, Ferdinand Dhombres, Nathalie Sermondade, Rahaf Haj Hamid, Isabelle Berthaut, Valentine Frydman, Marie Prades, Kamila Kolanska, Lise Selleret, Emmanuelle Mathieu-D’Argent, Diane Rivet-Danon, Rachel Levy, Antonin Lamazière, and Charlotte Dupont
Subjects: Computer applications to medicine. Medical informatics, R858-859.7, Public aspects of medicine, RA1-1270
Abstract: BackgroundTesticular sperm extraction (TESE) is an essential therapeutic tool for the management of male infertility. However, it is an invasive procedure with a success rate up to 50%. To date, no model based on clinical and laboratory parameters is sufficiently powerful to accurately predict the success of sperm retrieval in TESE. ObjectiveThe aim of this study is to compare a wide range of predictive models under similar conditions for TESE outcomes in patients with nonobstructive azoospermia (NOA) to identify the correct mathematical approach to apply, most appropriate study size, and relevance of the input biomarkers. MethodsWe analyzed 201 patients who underwent TESE at Tenon Hospital (Assistance Publique-Hôpitaux de Paris, Sorbonne University, Paris), distributed in a retrospective training cohort of 175 patients (January 2012 to April 2021) and a prospective testing cohort (May 2021 to December 2021) of 26 patients. Preoperative data (according to the French standard exploration of male infertility, 16 variables) including urogenital history, hormonal data, genetic data, and TESE outcomes (representing the target variable) were collected. A TESE was considered positive if we obtained sufficient spermatozoa for intracytoplasmic sperm injection. After preprocessing the raw data, 8 machine learning (ML) models were trained and optimized on the retrospective training cohort data set: The hyperparameter tuning was performed by random search. Finally, the prospective testing cohort data set was used for the model evaluation. The metrics used to evaluate and compare the models were the following: sensitivity, specificity, area under the receiver operating characteristic curve (AUC-ROC), and accuracy. The importance of each variable in the model was assessed using the permutation feature importance technique, and the optimal number of patients to include in the study was assessed using the learning curve. ResultsThe ensemble models, based on decision trees, showed the best performance, especially the random forest model, which yielded the following results: AUC=0.90, sensitivity=100%, and specificity=69.2%. Furthermore, a study size of 120 patients seemed sufficient to properly exploit the preoperative data in the modeling process, since increasing the number of patients beyond 120 during model training did not bring any performance improvement. Furthermore, inhibin B and a history of varicoceles exhibited the highest predictive capacity. ConclusionsAn ML algorithm based on an appropriate approach can predict successful sperm retrieval in men with NOA undergoing TESE, with promising performance. However, although this study is consistent with the first step of this process, a subsequent formal prospective multicentric validation study should be undertaken before any clinical applications. As future work, we consider the use of recent and clinically relevant data sets (including seminal plasma biomarkers, especially noncoding RNAs, as markers of residual spermatogenesis in NOA patients) to improve our results even more.
Published: 2023
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