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Targeting γ-secretase triggers the selective enrichment of oligomeric APP-CTFs in brain extracellular vesicles from Alzheimer cell and mouse models

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Translational Neurodegeneration 2019年第1期8卷 433-449页

作者： Inger Lauritzen Anaïs Bécot Alexandre Bourgeois Raphaëlle Pardossi-Piquard Maria-Grazia Biferi Martine Barkats Fréderic Checler institut de pharmacologie moléculaire et cellulaire CNRS-UMR7275team labeled«Fondation pour la Recherche Médicale»et«Laboratoire d’excellence Distalz»Universitéde Nice-Sophia-AntipolisSophia-AntipolisFrance institut-Myologie ParisFrance

Background:We recently demonstrated an endolysosomal accumulation of theβ-secretase-derived APP C-terminal fragment(CTF)C99 in brains of Alzheimer disease(AD)mouse ***,we showed that the treatment with theγ-secretase inhibitor(D6)led to further increased endolysosomal APP-CTF levels,but also revealed extracellular APP-CTF-associated *** here hypothesized that this latter staining could reflect extracellular vesicle(EV)-associated APP-CTFs and aimed to characterize theseγ-secretase inhibitor-induced ***:EVs were purified from cell media or mouse brains from vehicle-or D6-treated C99 or APPswedish expressing cells/mice and analyzed for APP-CTFs by *** pharmacological,immunological and genetic approaches(presenilin invalidation and C99 dimerization mutants(GXXXG))were used to characterize vesicle-containing *** APP-CTF localization was determined by ***:Purified EVs from both AD cell or mouse models were enriched in APP-CTFs as compared to EVs from control cells/***,EVs from D6-treated cells not only displayed increased C99 and C99-derived C83 levels but also higher molecular weight(HMW)APP-CTF-immunoreactivities that were hardly detectable in whole cell ***,the intracellular levels of HMW APP-CTFs were amplified by the exosomal inhibitor *** combined pharmacological,immunological and genetic approaches,we established that these HMW APP-CTFs correspond to oligomeric APP-CTFs composed of C99 and/or *** analysis showed that monomers were localized mainly to the trans-Golgi network,whereas oligomers were confined to endosomes and lysosomes,thus providing an anatomical support for the selective recovery of HMW APP-CTFs in *** D6-induced APP-CTF oligomerization and subcellular mislocalization was indeed due toγ-secretase blockade,since it similarly occurred in presenilin-deficient ***,our data proposed t

关键词： Extracellular vesicles C99 APP-CTFs Homo-and hetero-oligomerization Endosomes Lysosomes trans-Golgi network SorLA γ-Secretase inhibition Presenilin knockout Alzheimer’s disease

BABA-induced pathogen resistance: a multi-omics analysis of the tomato response reveals a hyper-receptive status involving ethylene

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Horticulture Research 2023年第6期10卷 16-29页

作者： Martina Zapletalova Corinne Rancurel Benoit Industri Marc Bardin Kevin Le Brigand Philippe Nicot Virginie Magnone Aurelie Seassau Pascal Barbry David Potesil Zbynek Zdrahal Michel Ponchet Jan Lochman umr institut Sophia Agrobiotech INRAE 1355 CNRS 6254UniversitéCôte d’Azur400Route des Chappes06903 Sophia AntipolisFrance department of Biochemistry Faculty of ScienceMasaryk UniversityKotlarska261137 BrnoCzech Republic Unité407 Pathologie végétale INRAEDomaine Saint-Maurice84143 Montfavet cedexFrance umr institut de pharmacologie moléculaire et cellulaire UniversitéCôte d’AzurCNRS 7275660 Route des Lucioles 06560 ValbonneFrance Central European institute of Technology Masaryk UniversityKamenice 562500 BrnoCzech Republic

Prior exposure to microbial-associated molecular patterns or specific chemical compounds can promote plants into a primed state with stronger defence responses.β-aminobutyric acid(BABA)is an endogenous stress metabolite that induces resistance protecting various plants towards diverse *** this study,by integrating BABA-induced changes in selected metabolites with transcriptome and proteome data,we generated a global map of the molecular processes operating in BABA-induced resistance(BABA-IR)in *** significantly restricts the growth of the pathogens Oidium neolycopersici and Phytophthora parasitica but not Botrytis cinerea.A cluster analysis of the upregulated processes showed that BABA acts mainly as a stress factor in *** main factor distinguishing BABA-IR from other stress conditions was the extensive induction of signaling and perception machinery playing a key role in effective resistance against ***,the signalling processes and immune response activated during BABA-IR in tomato differed from those in Arabidopsis with substantial enrichment of genes associated with jasmonic acid(JA)and ethylene(et)signalling and no change in Asp *** results revealed key differences between the effect of BABA on tomato and other model plants studied until ***,salicylic acid(SA)is not involved in BABA downstream signalization whereas et and JA play a crucial role.

关键词： BABA resistance analysis

A novel regulatory region controls IgH locus transcription and switch recombination to a subset of isotypes

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Cellular & molecular Immunology 2019年第11期16卷 887-889页

作者： Rocío Amoretti-Villa Mélanie Rogier Isabelle Robert Vincent Heyer Bernardo Reina-San-Martin institut de Génétique et de Biologie moléculaire et cellulaire(IGBMC) IllkirchFrance institut National de la Santéet de la Recherche Médicale(INSERM) U1258IllkirchFrance Centre National de la Recherche Scientifique(CNRS) UMR7104IllkirchFrance Universitéde Strasbourg IllkirchFrance

Class switch recombination(CSR)occurs at the IgH locus and replaces the immunoglobulin(Ig)isotype expressed from IgM to IgG,IgE or IgA,endowing the B cell receptor with novel effector *** is triggered by activation-induced cytidine deaminase(AID),1 an enzyme that deaminates cytosines to uracils in single-stranded DNA exposed by *** distinct antibody isotypes are encoded in the IgH locus in individual transcription units composed of a cytokine-inducible promoter,an intronic exon,and a switch region(Sx),followed by the exons encoding the constant region(Cx)(Fig.S1a).During CSR,the choice of recombination to a particular isotype is determined by the stimulation-dependent activation of specific promoters,triggering the generation of noncoding germline transcripts(GLTs).2 Thus far,the transcriptional regulation of the IgH locus is known to be controlled by the Eμenhancer,located downstream of the variable region and upstream of the donor switch region(Sμ),and the 3′regulatory region(3′RR)super-enhancer located downstream of Cα.

关键词： IgH stimulation replace

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

Tumor cells educate mesenchymal stromal cells to release chemoprotective and immunomodulatory factors

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Journal of molecular Cell Biology 2020年第3期12卷 202-215页

作者： Augustin Le Naour Melissa Prat Benolt Thibault Renaud Mével Léa Lemaitre Helene Leray Marie-Veronique Joubert Kimberley Coulson Muriel Golzio Lise Lefevre Eliane Mery Alejandra Martinez Gwénael Ferron Jean-Pierre delord Agnès Coste Bettina Couderc institut Claudius Regaud-IUCT Oncopole Universite de ToulouseToulouseFrance INSERM umr 1037 Cancer Research Center of Toulouse(CRCT)ToulouseFrance umr 152 Pharma dev Universite de ToulouseIRDUPSToulouseFrance umr CNRS 5089 Institut de Pharmacologie et de Biologie Structurale(IPBS)ToulouseFrance

Factors released by surrounding cells such as cancer-associated mesenchymal stromal cells(CA-MSCs)are involved in tumor progression and *** this study,we characterize the mechanisms by which naYve mesenchymal stromal cells(MSCs)can acquire a CA-MSCs *** tumor cells trigger the transformation of MSCs to CA-MSCs by expressing pro-tumoral genes implicated in the chemoresistance of cancer cells,resulting in the secretion of high levels of CXC chemokine receptors 1 and 2(CXCR1/2)ligands such as chemokine(C-X-C motif)ligand 1(CXCL1),CXCL2,and interleukin 8(IL-8).CXCR1/2 ligands can also inhibit the immune response against ovarian tumor ***,through their released factors,CA-MSCs promote the differentiation of monocytes towards M2 macrophages,which favors tumor *** CXCR1/2 receptors are inhibited,these CA-MSC-activated macrophages lose their M2 properties and acquire an anti-tumoral *** ex vivo and in vivo,we used a CXCR1/2 inhibitor to sensitize ovarian tumor cells to carboplatin and circumvent the pro-tumoral effects of *** high concentrations of CXCR1/2 ligands in patients*blood are associated with chemoresistance,CXCR1/2 inhibition could be a potential therapeutic strategy to revert carboplatin resistance.

关键词： chemoresistance macrophages mesenchymal stromal cells ovarian adenocarcinoma chemokines

NTR/NRX define a New Thioredoxin System in the Nucleus of Arabidopsis thaliana Cells

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molecular Plant 2014年第1期7卷 30-44页

作者： Corinne Marchal Valerie delorme-Hinoux Laetitia Bariat Wafi Siala Christophe Belin Julio Saez-Vasquez Christophe Riondet Jean-Philippe Reichheld Universite Perpignan Via Domitia CNRS Laboratoire Genome et Developpement des Plantes UMR 5096 58 Avenue Paul Alduy-Bat T F-66860 Perpignan France pharmacologie cellulaire et moleculaire Louvain Drug Research Institute Universite catholique de Louvain Brussels Belgium

Thioredoxins （TRX） are key components of cellular redox balance, regulating many target proteins through thiol/disulfide exchange reactions. In higher plants, TRX constitute a complex multigenic family whose members have been found in almost all cellular compartments. Although chloroplastic and cytosolic TRX systems have been largely studied, the presence of a nuclear TRX system has been elusive for a long time. Nucleoredoxins （NRX） are potential nuclear TRX found in most eukaryotic organisms. In contrast to mammals, which harbor a unique NRX, angiosperms gen- erally possess multiple NRX organized in three subfamilies. Here, we show thatArabidopsis thaliana has two NRXgenes （AtNRX1 and AtNRX2）, respectively, belonging to subgroups I and III. While NRX1 harbors typical TRX active sites （WCG/ PPC）, NRX2 has atypical active sites （WCRPC and WCPPF）. Nevertheless, both NRXl and NRX2 have disulfide reduction capacities, although NRX1 alone can be reduced by the thioredoxin reductase NTRA. We also show that both NRX1 and NRX2 have a dual nuclear/cytosolic localization. Interestingly, we found that NTRA, previously identified as a cytosolic protein, is also partially localized in the nucleus, suggesting that a complete TRX system is functional in the nucleus. We show that NRX1 is mainly found as a dimer in vivo. nrxl and nrx2 knockout mutant plants exhibit no phenotypic perturbations under standard growth conditions. However, the nrxl mutant shows a reduced pollen fertility phenotype, suggesting a specific role of NRX1 at the haploid phase.

关键词： thioredoxin nucleoredoxin nucleus Arabidopsis.

Transient micro-elastography:A novel non-invasive approach to measure liver stiffness in mice

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World Journal of Gastroenterology 2011年第8期17卷 968-975页

作者： Cécile Bastard Matteo R Bosisio Michèle Chabert Athina D Kalopissis Meriem Mahrouf-Yorgov Hélène Gilgenkrantz Sebastian Mueller Laurent Sandrin Laurent Sandrin Echo-sens Research and Development Department INSERM U930 CNRS ERL3106 Univ Franois Rabelais UPMC Univ Paris 06 UMR 7623 LIP CNRS UMR 7623 Laboratoire d'Imagerie Paramétrique INSERM U872 Centre de Recherche des Cordeliers Equipe 4 UPMC Univ Paris 06 UMR S 872 Equipe 4 Univ Paris descartes UMR S 872 Equipe 4 EPHE Laboratoire de Pharmacologie Cellulaire Et Moléculaire INSERM U1016 Institut Cochin CNRS UMR8104 Univ Paris descartes department of Medicine and Center for Alcohol Research Liver Disease and Nutrition Salem Medical Center University of Heidelberg

AIM:To develop and validate a transient micro-elastography device to measure liver stiffness(LS) in ***:A novel transient micro-elastography(TME) device,dedicated to LS measurements in mice with a range of measurement from 1-170 kPa,was developed using an optimized vibration frequency of 300 Hz and a 2 mm *** novel probe was validated in a classical fibrosis model(CCl4) and in a transgenic murine model of systemic ***:TME could be successfully performed in control mice below the xiphoid cartilage,with a mean LS of 4.4 ± 1.3 kPa,a mean success rate of 88%,and an excellent intra-observer agreement(0.98).Treatment with CCl4 over seven weeks drastically increased LS as compared to controls(18.2 ± 3.7 kPa vs 3.6 ± 1.2 kPa).Moreover,fibrosis stage was highly correlated with LS(Spearman coefficient = 0.88,P del,much higher LS values were obtained,reaching maximum values of > 150 *** significantly correlated with the amyloidosis index(0.93,P dels of high LS.

关键词：转基因小鼠模型成像设备侵入性弹性瞬态淀粉样变性刚度测量范围

Role of Ikaros in T-cell acute lymphoblastic leukemia

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World Journal of Biological Chemistry 2011年第6期2卷 108-114页

作者： Philippe Kastner Susan Chan institut de Génétique et de Biologie moléculaire et cellulaire Illkirch 67400France INSERM U964Illkirch 67400France CNRS umr7104 Illkirch 67400France Université de Strasbourg Strasbourg 67000France

Ikaros is a zinc finger transcriptional regulator encoded by the Ikzf1 *** displays crucial functions in the hematopoietic system and its loss of function has been linked to the development of lymphoid *** particular,Ikaros has been found in recent years to be a major tumor suppressor involved in human B-cell acute lymphoblastic *** role in T-cell leukemia,however,has been more *** Ikaros deficiency appears to be very frequent in murine T-cell leukemias,loss of Ikaros appears to be rare in human T-cell acute lymphoblastic leukemia (T-ALL).We review here the evidence linking Ikaros to T-ALL in mouse and human systems.

关键词： Ikaros Notch T-cell leukemia

Evaluation of in vitro antioxidant and apoptotic activities of Cyperus rotundus

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Asian Pacific Journal of Tropical Medicine 2014年第2期7卷 105-112页

作者： Kilani-Jaziri Soumaya Ghedira Zied Nasr Nouha Krifa Mounira Ghedira Kamel Franca Dijoux Marie Genviève Ghedira Chekir Leila Unité de Substances Naturelles Bioactives et Biotechnologies UR12ES12.Universite de Monastic Faculte de Pharmacie de Monastir Laboratoire de Biologie moleculaire et cellulaire Faculté de Medecine Dentaire de MonastirUniversite de MonastirRue Aricenne5019 MonastirTunisie Laboratoire de Botanique.Pharmacognosie et Phytothérapie UMR CNRS 5557 Ecologie Microbienne institut des Sciences Pharmaceutiques et Biologiques-Faculte de Pharmacie Université Claude Bernard Btiment Netien-8 Avenue Rockefeller-69373 Lyon cedex 08France

Objective:To evaluate in vitro antioxidant and apoptotic activities of Crperus rotundas(***).Methods:The phytochemical study and the antioxidant activities of both methanol and aqueous extracts from *** aerial part were *** addition,these extracts were also investigated for their cytotoxic and apoptotic *** major compound of the methanol extract was *** metlianol and aqueous extracts(300,150,and 50μg/mL)were evaluated for their antioxidant activity by the xanthine/xanthine oxidase assay ***,16,8,and 4 mg/mL of each extract were tested to investigate their *** scavenging *** extract(800,*** 200μg/mL)and melhunol extract(350,175,and 88μg/mL)were tested against lipid peroxidation,induced by 75μM H_2O_2,The cytotoxicity(by MTT assay)and cell DNA fragmentation of both extracts were evaluated Inwards K562 and L1210 cell *** major compound was obtained from the butanol fraction of methanol extract and its structure was determined by KMN spectroscopic ***:The methanol and aqueous extracts showed respectively,88%and 19%inhibition of xanthine oxidase *** same extracts inhibited lipid peroxidation by 61.5%and 42.0%.*** extracts inhibited *** by 27.1%and 25.3%,*** methanol cxtract induced DNA *** was determined as the major compound isolated from the butanol fraction of metlianol ***:It appears that *** extracts exhibit a potential use as a natural antioxidant and an apoptosis inducer.

关键词： Polyphenols Orientin Xanthine/Xanthine oxidase assay Lipid peroxidation assay deoxyribose assay DNA fragmentation