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Neuroprotective effects of G9a inhibition through modulation of peroxisome-proliferator activator receptor gamma-dependent pathways by miR-128

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Neural Regeneration Research 2024年第11期19卷 2532-2542页

作者： Aina Bellver-sanchis Pedro AAvila-López Iva Tic David Valle-García Marta Ribalta-Vilella Luis Labrador Deb Ranjan Banerjee Ana Guerrero Gemma Casadesus Coralie Poulard Mercè Pallàs Christian Grinán-Ferré Department of Pharmacology and Therapeutic Chemistry Institut de Neurociències-Universitat de BarcelonaBarcelonaSpain Department of Biochemistry and Molecular Genetics Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Institute of Biotechnology National Autonomous University of MexicoCuernavacaMexico Department of Pharmacology and Therapeutics Health Science Center-University of FloridaGainesvilleFLUSA Department of Chemistry National Institute of Technology DurgapurM G AvenueDurgapurWest BengalIndia Cancer Research Cancer Lyon Universitéde LyonLyonFrance inserm U1052 Centre de Recherche en Cancérologie de LyonLyonFrance CNRs umr5286 Centre de Recherche en Cancérlogie de LyonLyonFrance Centro de Investigación en Red Enfermedades Neurodegenerativas(CIBERNED)Instituto de Salud Carlos IIIMadridSpain Neuroimmunology Department National Institute of Neurology and Neurosurgery“Manuel Velasco Suárez”Mexico CityMexico

Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative ***,microRNAs are involved in many biological processes and diseases playing a key role in pathogenesis,especially in multifactorial diseases such as Alzheimer’s ***,our aim has been to provide partial insights into the interconnection between G9a,microRNAs,oxidative stress,and *** better understand the biology of G9a,we compared the global microRNA expression between senescence-accelerated mouse-prone 8(sAMP8)control mice and sAMP8 treated with G9a inhibitor *** found a downregulation of miR-128 after a G9a inhibition treatment,which interestingly binds to the 3′untranslated region(3′-UTR)of peroxisome-proliferator activator receptor γ(PPARG)***,Pparg gene expression levels were higher in the sAMP8 group treated with G9a inhibitor than in the sAMP8 control *** also observed modulation of oxidative stress responses might be mainly driven Pparg after G9a *** confirm these antioxidant effects,we treated primary neuron cell cultures with hydrogen peroxide as an oxidative *** this setting,treatment with G9a inhibitor increases both cell survival and antioxidant ***,up-regulation of PPARγby G9a inhibitor could also increase the expression of genes involved in DNA damage responses and *** addition,we also described that the PPARγ/AMPK axis partially explains the regulation of autophagy markers ***,PPARγ/GADD45αpotentially contributes to enhancing synaptic plasticity and neurogenesis after G9a ***,we propose that pharmacological inhibition of G9a leads to a neuroprotective effect that could be due,at least in part,by the modulation of PPARγ-dependent pathways by miR-128.

关键词： aging cognitive decline epigenetics G9a inhibition microRNAs miR-128 peroxisome-proliferator activator receptorγ(PPARγ) PPARG sAMP8

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stochastic simulation of saline Intrusion in the Coastal Aquifer of saloum, senegal

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Journal of Environmental Protection 2024年第8期15卷 863-873页

作者： seyni Ndoye Amadou sarr Mathieu Le Coz Cheikh Becaye Gaye Moumtaz Razack Philippe Le Coustumer Laboratoire Eau-Energie-Environnement-Procds industriels (LE3PI) Ecole Suprieure Polytechnique Universit Cheikh Anta DIOP Dakar Sngal Dpartement de Gologie Facult des Sciences et Techniques Universit Cheikh Anta Diop Dakar Sngal CNRs UMR 7285 IC2MP Universit de Poitiers Poitiers France Bordeaux Imaging Center CNRS UAR3420-INSERM US4 Université de Bordeaux Bordeaux France

In the saloum region of central-western senegal, water needs are essentially met by tapping an underground aquifer associated with the sandy-clay formations of the Continental Terminal, in contact with both the ocean to the west and the highly saline waters of the saloum River to the north. In this estuarine and deltaic zone with its very low relief, the hydraulic loads in the water tables are generally close to zero or even negative, creating a reversal of the natural flow and encouraging saline intrusion into this system, which makes it very vulnerable. This study concerns the implementation of a numerical model of saline intrusion to provide a better understanding of the vulnerability of the water table by analyzing the variability of the freshwater/saltwater interface. The Modflow-2005 code is used to simulate saline intrusion using the sWI2 module, coupled with the GRAss (Geographic Resources Analysis support system) software under the Linux operating system with the steep interface approach. The probable expansion of the wedge is studied in three scenarios, taking into account its position relative to the bedrock at 1 m, 5 m and 10 m. simulations carried out under imposed potential and river conditions, based on variations in groundwater reserves using two effective porosity values, 10−1 and 10−2, show that the water table is highly vulnerable in the northwest sector. The probable expansion of the wedge increases as the storage coefficient decreases and is more marked with river conditions in the areas surrounding the saloum River, reaching 6 km with a probability of 1. The probability of the wedge reaching a certain degree of expansion decreases from 1 to 0.5, and then cancels out as it moves inland. The probable position of the wedge is limited to 500 m or even 1 km depending on the corner around the coast to the southwest and in the southern zone. This modelling, carried out under natural conditions, will be developed further, taking into account climatic p

关键词： saline Intrusion stochastic Modelling Modflow sWI2 Grass GIs Aquifer saloum senegal

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Recombination-Independent Mechanisms and Pairing of Homologous Chromosomes during Meiosis in Plants

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Molecular Plant 2014年第3期7卷 492-501页

作者： Olivier Da Ines Maria E. Gallego Charles I. White Genetique Reproduction et Developpement UMR CNRS 6293 Clermont UniversitY INSERM U1103 63171 Aubiere France

Meiosis is the specialized eukaryotic cell division that permits the halving of ploidy necessary for game- togenesis in sexually reproducing organisms, This involves a single round of DNA replication followed by two successive divisions. To ensure balanced segregation, homologous chromosome pairs must migrate to opposite poles at the first meiotic division and this means that they must recognize and pair with each other beforehand. Although understanding of the mechanisms by which meiotic chromosomes find and pair with their homologs has greatly advanced, it remains far from being fully understood. With some notable exceptions such as male Drosophila, the recognition and physical link- age of homologs at the first meiotic division involves homologous recombination. However, in addition to this, it is clear that many organisms, including plants, have also evolved a series of recombination-independent mechanisms to facili- tate homolog recognition and pairing. These implicate chromosome structure and dynamics, telomeres, centromeres, and, most recently, small RNAs. With a particular focus on plants, we present here an overview of understanding of these early, recombination-independent events that act in the pairing of homologous chromosomes during the first meiotic division,

关键词： meiosis homolog pairing chromatin centromeres telomeres.

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Autophagy in dendritic cells

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Cellular & Molecular Immunology 2018年第11期15卷 944-952页

作者： Ghita Ghislat Toby Lawrence Centre d‘Immunologie de Marseille-Luminy InsermU1104CNRS UMR7280MarseilleFrance

Autophagy and immunity share the property of being auto-protective for the *** is an important degradation pathway that buffers nutrient deprivation by recycling macromolecules in organisms from yeast to *** in autophagy are associated with inflammation and cancer *** studies have characterized the molecular details regarding how autophagy is controlled by immune *** these,dendritic cells(DCs)are one of the most potent professional antigen-presenting cells critical for the activation of naïve T cells to maintain immune tolerance and drive protective immunity to infection and *** undergo functional maturation that can either lead to an immunostimulatory phenotype,as in the context of infection,or to a tolerogenic phenotype associated with immunosuppression to self-antigens,as well as to *** increasing number of recent studies has characterized the involvement of autophagy in DC functions in various physiological and pathological ***,we provide a comprehensive review of these outcomes and discuss the limitation of the models used and the forefront of the knowledge concerning the crosstalk between autophagy and DC biology.

关键词： autophagy dendritic cells maturation

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Inhibition of mitochondrial fatty acid oxidation in drug-induced hepatic steatosis

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Liver Research 2019年第3期3卷 157-169页

作者： Bernard Fromenty inserm UMR 1241Universitéde Rennes 1RennesFrance

Mitochondrial fatty acid oxidation(mtFAO)is a key metabolic pathway required for energy production in the liver,in particular during periods of *** major consequence of drug-induced impairment of mtFAO is hepatic steatosis,which is characterized by an accumulation of triglycerides and other lipid species,such as ***,the severity of this liver lesion is dependent on the residual mitochondrial b-oxidation ***,a severe inhibition of mtFAO leads to microvesicular steatosis,hypoglycemia and liver *** contrast,moderate impairment of mtFAO can cause macrovacuolar steatosis,which is a benign lesion in the short *** some drugs can induce both microvesicular and macrovacuolar steatosis,it is surmised that severe mitochondrial dysfunction could be favored in some patients by non-genetic factors(e.g.,high doses and polymedication),or genetic predispositions involving genes that encode proteins playing directly or indirectly a role in the mtFAO *** of drugs inducing steatosis include acetaminophen(APAP),amiodarone,ibuprofen,linezolid,nucleoside reverse transcriptase inhibitors,such as stavudine and didanosine,perhexiline,tamoxifen,tetracyclines,troglitazone and valproic *** several previous articles reviewed in depth the mechanism(s)whereby most of these drugs are able to inhibit mtFAO and induce steatosis,the present review is rather focused on APAP,linezolid and *** steatogenic drugs are indeed rarely discussed in the literature as regards their ability to impair mtFAO.

关键词： Drug-induced liver injury(DILI) steatosis Mitochondria b-Oxidation Acetaminophen(APAP) Troglitazone

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Therapeutic potential of α7 nicotinic receptor agonists to regulate neuroinflammation in neurodegenerative diseases

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Neural Regeneration Research 2017年第9期12卷 1418-1421页

作者： Laura Foucault-Fruchard Daniel Antier umr inserm U930 Université Fran?ois Rabelais CHRU de Tours H?pital Bretonneau

Neurodegenerative diseases, such as Alzheimer＇s, Parkinson＇s and Huntington＇s diseases, are all character- ized by a component of innate immunity called neuroinflammation. Neuronal loss and neuroinflammation are two phenomena closely linked. Hence, the neuroinflammation is a relevant target for the management of the neurodegenerative diseases given that, to date, there is no treatment to stop neuronal loss. several studies have investigated the potential effects of activators of alpha 7 nicotinic acetylcholine receptors in animal models of neurodegenerative diseases. These receptors are widely distributed in the central nervous system. After activation, they seem to mediate the cholinergic anti-inflammatory pathway in the brain. This anti-inflammatory pathway, first described in periphery, regulates activation of microglial cells considered as the resident macrophage population of the central nervous system. In this article, we shortly review the agonists of the alpha 7 nicotinic acetylcholine receptors that have been evaluated in vivo and we focused on the selective positive allosteric modulators of these receptors. These compounds represent a key element to enhance receptor activity only in the presence of the endogenous agonist.

关键词： α7 nicotinic receptors cholinergic anti-inflammatory pathway Alzheimer's disease Huntington's disease Parkinson's disease neuroinflammation neurodegeneration positive allosteric modulators

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Mediator contributes to IgH locus VDJ rearrangements by promoting usage of most distal V segments

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Cellular & Molecular Immunology 2020年第4期17卷 407-409页

作者： Iman Dalloul Zeinab Dalloul sandrine Le Noir François Boyer Bernardo Reina-san-Martin Jeanne Cook-Moreau Michel Cogné umr CNRs 7276 INSERM U1262Universite de LimogesLimoges 87025France inserm U1258 UMR CNRS 7104Institut de Genetique et de Biologie Moleculaire et CellulaireUniversitéde StrasbourgIllkirch 67400France

INTRODUCTION The immunoglobulin heavy(IgH)chain locus includes a large cluster of V,D and J segments spanning thousands of kilobases in mammals and its expression implies long-range 3D-regulation of various gene modifications.1 V(D)J recombination occurs during early B-cell ontogeny.2 It is regulated by multiple transcription factors and cis-regulatory elements,and most notably by the intronic 5′Eμelement located in the JH to Cμintron.3 The intergenic control region 1(IGCR1)located between the VH and D gene clusters inhibits rearrangement of the most DH-proximal VH gene segments,while promoting usage of distal VH gene segments.4 Other downstream elements of the locus,flanking its 3′end might have more subtle roles:while the large 3′regulatory region(3′RR)shows strong internal synergies2 and behaves as a superenhancer in mature B *** deletion showed no influence on the VDJ repertoire and rather increased transcription of unrearranged V segments.3–5 Insulators binding CTCF farther downstream of the 3′RR were shown,however,to promote usage of distal VH segments.6 Altogether,there are strong indications that elements involved in long-distance regulation of transcription might also influence VDJ ***-frame splicing of VDJ exons is also needed for full Ig expression.7 Given the functional importance of gene architecture and long-range interactions for the IgH locus physiology,we explored the dependence of the VDJ repertoire on Med1,a known actor of long-range enhancer interactions.

关键词： B cells mediator VDJ repertoire

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self-assembly of peptide-based nanostructures： synthesis and biological activity

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Nano Research 2018年第5期11卷 2315-2335页

作者： Lena Guyon Elise Lepeltier Catherine Passirani Micro & Nanomedecines Translationnelles-MINT UNIV Angers INSERM U 1066 CNRS UMR 6021 UBL Universite Bretagne Loire Angers F-49933 France

Peptide-based nanostructures have received much attention in the field of drug targeting. In fact, peptides have many advantages such as simplicity of the structure, biocompatibility, and chemical diversity. Moreover, some peptides, which are called cell-penetrating peptides, can cross cellular membranes and carry small molecules, small interfering RNA, or viruses inside live cells. These molecules are often covalently or noncovalently linked to cargoes, thus forming amphiphilic conjugates that can self-assemble. supramolecular nanostructures formed from peptides are used in nanomedicine as a carrier to protect a drug and to target cancer cells. This review explores aliphatic-chain-conjugated peptides and drug-conjugated peptides that can self-assemble. special emphasis is placed on the synthesis procedure, nanostructure formation, and biological activity.

关键词： self-assembly cell penetrating peptide nanoparticle peptide

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Recent advances in cytokines:Therapeutic implications for inflammatory bowel diseases

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World Journal of Gastroenterology 2011年第5期17卷 547-556页

作者： Guillaume Bouguen Jean-Baptiste Chevaux Laurent Peyrin-Biroulet inserm umr991 Department of HepatoGastroenterologyUniversity Hospital of RennesPontchaillou35000 RennesFrance inserm U954 Department of Hepato-GastroenterologyUniversity Hospital of Nancy54511 Vandoeuvre-les-NancyFrance

Inflammatory bowel diseases （IBDs） are complex and chronic disabling conditions resulting from a dysregulated dialogue between intestinal microbiota and components of both the innate and adaptive immune systems. Cytokines are essential mediators between activated immune and non-immune cells, including epithelial and mes- enchymal cells. They are immunomodulatory peptides released by numerous cells and these have significant effects on immune function leading to the differentiation and survival of T cells. The physiology of IBD is becom- ing a very attractive field of research for development of new therapeutic agents. These include cytokines involved in intestinal immune inflammation. This review will focus on mechanisms of action of oytokines involved in IBD and new therapeutic opportunities for these diseases.

关键词： Inflammatory bowel disease Ulcerative coli-tis Crohn's disease Cytokine Pathophysiology Biologi-cal therapy

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The RNA binding proteins TIA1 and TIAL1 promote Mcl1 mRNA translation to protect germinal center responses from apoptosis

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Cellular & Molecular Immunology 2023年第9期20卷 1063-1076页

作者： Ines COsma-Garcia Mailys Mouysset Dunja Capitan-sobrino Yann Aubert Martin Turner Manuel D.Diaz-Muñoz Institute for Infectious and Inflammatory Diseases(INFINITy) Inserm UMR1291CNRS UMR5051University Paul SabatierCHU PurpanToulouse 31024France Immunology Program The Babraham InstituteCambridgeUK

Germinal centers(GCs)are essential for the establishment of long-lasting antibody *** B cells rely on post-transcriptional RNA mechanisms to translate activation-associated transcriptional programs into functional changes in the cell ***,the critical proteins driving these key mechanisms are still ***,we show that the RNA binding proteins TIA1 and TIAL1 are required for the generation of long-lasting GC ***1-and TIAL1-deficient GC B cells fail to undergo antigen-mediated positive selection,expansion and differentiation into B-cell clones producing high-affinity ***,TIA1 and TIAL1 control the transcriptional identity of dark-and light-zone GC B cells and enable timely expression of the prosurvival molecule ***,we demonstrate here that TIA1 and TIAL1 are key players in the post-transcriptional program that selects high-affinity antigen-specific GC B cells.

关键词： Adaptive immunity Germinal centers Post-transcriptional gene regulation RNA binding proteins Cell identity Apoptosis/10.1038/s41423-023-01063-4

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