Éditeur(s) : CRPLC : Centre de Recherche sur les Pouvoirs Locaux dans la Caraïbe CCEE : Conseil de la Culture, de l'Education et de l'Environnement
Extrait de : "La collectivité territoriale de Martinique : enjeux, débats et perspectives" : séminaire, le 24 octobre 2015. Université des Antilles
Description : La mise en place de la CTM nécessite une nouvelle approche des politiques publiques territoriales. En effet, en procédant à la fusion des compétences de la région et de celles du département, elle impose de penser globalement et de manière transversale l'action publique locale. Un exemple mérite d'être signalé : là où, dans l'Hexagone, les départements sont en charge des collèges, les régions des lycées et des transports scolaires, à la Martinique, une seule entité, la CTM, exerce l'ensemble de ces compétences. D'où la possibilité de dégager désormais une vision globale du système éducatif.
Siècle(s) traité(s) : 21
Droits : CC-BY-NC-ND - Attribution - Pas d'utilisation commerciale - Pas de modification
Permalien : http://www.manioc.org/fichiers/V15421
V15421

Éditeur(s) : CRILLASH : Centre de Recherches Interdisciplinaires en Lettres, Langues, Arts et Sciences Humaines
Extrait de : "Patrimonialisation et développement dans la Caraïbe et les Amériques" : colloque international, du 2 au 4 mars 2011. Université des Antilles et de la Guyane
Description : Dans cet atelier, il sera abordé les enjeux et questions liés à la numérisation. Pour cela, un panorama des collections numériques tant des bibliothèques que des musées sera présenté. Ensuite, il sera traité la préparation des documents à la numérisation c'est à dire la sélection, l'envoi et le signalement puis la mise en ligne des contenus et l'archivage numérique. Enfin, ils échangeront autour de l'exploitation et la réutilisation des contenus de ses bibliothèques numériques.
Siècle(s) traité(s) : 21
Droits : CC-BY-NC-ND - Attribution - Pas d'utilisation commerciale - Pas de modification
Permalien : http://www.manioc.org/fichiers/V12085
V12085

Éditeur(s) : CRILLASH : Centre de Recherches Interdisciplinaires en Lettres, Langues, Arts et Sciences Humaines
Extrait de : "Patrimonialisation et développement dans la Caraïbe et les Amériques" : colloque international, du 2 au 4 mars 2011. Université des Antilles et de la Guyane
Description : Dans cet atelier, il sera abordé les enjeux et questions liés à la numérisation. Pour cela, un panorama des collections numériques tant des bibliothèques que des musées sera présenté. Ensuite, il sera traité la préparation des documents à la numérisation c'est à dire la sélection, l'envoi et le signalement puis la mise en ligne des contenus et l'archivage numérique. Enfin, ils échangeront autour de l'exploitation et la réutilisation des contenus de ses bibliothèques numériques.
Siècle(s) traité(s) : 21
Droits : CC-BY-NC-ND - Attribution - Pas d'utilisation commerciale - Pas de modification
Permalien : http://www.manioc.org/fichiers/V12083
V12083

Éditeur(s) : CRILLASH : Centre de Recherches Interdisciplinaires en Lettres, Langues, Arts et Sciences Humaines
Extrait de : "Patrimonialisation et développement dans la Caraïbe et les Amériques" : colloque international, du 2 au 4 mars 2011. Université des Antilles et de la Guyane
Description : Dans cet atelier, il sera abordé les enjeux et questions liés à la numérisation. Pour cela, un panorama des collections numériques tant des bibliothèques que des musées sera présenté. Ensuite, il sera traité la préparation des documents à la numérisation c'est à dire la sélection, l'envoi et le signalement puis la mise en ligne des contenus et l'archivage numérique. Enfin, ils échangeront autour de l'exploitation et la réutilisation des contenus de ses bibliothèques numériques.
Siècle(s) traité(s) : 21
Droits : CC-BY-NC-ND - Attribution - Pas d'utilisation commerciale - Pas de modification
Permalien : http://www.manioc.org/fichiers/V12082
V12082

Éditeur(s) : CRILLASH : Centre de Recherches Interdisciplinaires en Lettres, Langues, Arts et Sciences Humaines
Extrait de : "Patrimonialisation et développement dans la Caraïbe et les Amériques" : colloque international, du 2 au 4 mars 2011. Université des Antilles et de la Guyane
Description : Dans cet atelier, il sera abordé les enjeux et questions liés à la numérisation. Pour cela, un panorama des collections numériques tant des bibliothèques que des musées sera présenté. Ensuite, il sera traité la préparation des documents à la numérisation c'est à dire la sélection, l'envoi et le signalement puis la mise en ligne des contenus et l'archivage numérique. Enfin, ils échangeront autour de l'exploitation et la réutilisation des contenus de ses bibliothèques numériques.
Siècle(s) traité(s) : 21
Droits : CC-BY-NC-ND - Attribution - Pas d'utilisation commerciale - Pas de modification
Permalien : http://www.manioc.org/fichiers/V12081
V12081

Éditeur(s) : CRILLASH : Centre de Recherches Interdisciplinaires en Lettres, Langues, Arts et Sciences Humaines
Extrait de : "Patrimonialisation et développement dans la Caraïbe et les Amériques" : colloque international, du 2 au 4 mars 2011. Université des Antilles et de la Guyane
Description : Dans cet atelier, il sera abordé les enjeux et questions liés à la numérisation. Pour cela, un panorama des collections numériques tant des bibliothèques que des musées sera présenté. Ensuite, il sera traité la préparation des documents à la numérisation c'est à dire la sélection, l'envoi et le signalement puis la mise en ligne des contenus et l'archivage numérique. Enfin, ils échangeront autour de l'exploitation et la réutilisation des contenus de ses bibliothèques numériques.
Siècle(s) traité(s) : 21
Droits : CC-BY-NC-ND - Attribution - Pas d'utilisation commerciale - Pas de modification
Permalien : http://www.manioc.org/fichiers/V12084
V12084

Éditeur(s) : HAL CCSD American Society of Hematology
Résumé : International audience
Polycythemia vera (PV) is characterized by an increased RBC mass, spontaneous erythroid colony formation, and the JAK2V617F mutation. PV is associated with a high risk of mesenteric and cerebral thrombosis. PV RBC adhesion to endothelial laminin is increased and mediated by phosphorylated erythroid Lu/BCAM. In the present work, we investigated the mechanism responsible for Lu/BCAM phosphorylation in the presence of JAK2V617F using HEL and BaF3 cell lines as well as RBCs from patients with PV. High levels of Rap1-GTP were found in HEL and BaF3 cells expressing JAK2V617F compared with BaF3 cells with wild-type JAK2. This finding was associated with increased Akt activity, Lu/BCAM phosphorylation, and cell adhesion to laminin that were inhibited by the dominant-negative Rap1S17N or by the specific Rap1 inhibitor GGTI-298. Surprisingly, knocking-down EpoR in HEL cells did not alter Akt activity or cell adhesion to laminin. Our findings reveal a novel EpoR-independent Rap1/Akt signaling pathway that is activated by JAK2V617F in circulating PV RBCs and responsible for Lu/BCAM activation. This new characteristic of JAK2V617F could play a critical role in initiating abnormal interactions among circulating and endothelial cells in patients with PV.
ISSN: 0006-4971

inserm-00821109
http://www.hal.inserm.fr/inserm-00821109
http://www.hal.inserm.fr/inserm-00821109/document
http://www.hal.inserm.fr/inserm-00821109/file/De_Grandis_Blood_2013.pdf
DOI : 10.1182/blood-2012-07-440487

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Recently it has become clear that exposure to xenobiotics may result in various forms of cell death; not only passive cell deaths like necrosis, or programmed cell deaths such as apoptosis, but also regulated necrosis, autophagy, senescence, or mitotic catastrophe. Complex cell signaling networks influence the processing of cell death. Furthermore, recent research has revealed early complex molecular interactions between organelles prior to the final triggering of cell death. The plasma membrane may play an important role in the early cell death signaling events. Regarding this latter aspect, drugs and environmental pollutants have been reported to affect plasma membrane characteristics which may further affect cell fate. Changes in membrane fluidity or in composition and function of specialized membrane microdomains (plasma membrane remodeling) have been proven to be involved in the regulation of many important physiological signaling pathways, including cell death. Furthermore, it has been suggested that a crosstalk between chemical-induced cellular membrane effects and other organelles may be of vital importance to explain the final outcome of chemical exposure. Here, we review the effects of plasma membrane remodeling on cell survival and cell death; we describe how the cell signaling pathways activated by changes in plasma membrane characteristics may influence cell fate. Since plasma membrane function plays an important role in the regulation of a number of cellular responses, it has been implicated in the development or progress of several diseases. A better knowledge of the effects of various chemicals on plasma membrane remodeling may be important for understanding the pathogenesis of major diseases, and may assist in developing new therapeutic strategies.
ISSN: 0300-483X

inserm-00818916
http://www.hal.inserm.fr/inserm-00818916
DOI : 10.1016/j.tox.2012.12.014
PUBMED : 23287390

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
Cell proliferation is a hallmark of cancer and depends on complex signaling networks that are chiefly supported by protein kinase activities. Therapeutic strategies have been used to target specific kinases but new methods are required to identify combined targets and improve treatment. Here, we propose a small interfering RNA genetic screen and an integrative approach to identify kinase networks involved in the proliferation of cancer cells. The functional siRNA screen of 714 kinases in HeLa cells identified 91 kinases implicated in the regulation of cell growth, most of them never being reported in previous whole-genome siRNA screens. Based on gene ontology annotations, we have further discriminated between two classes of kinases that, when suppressed, result in alterations of the mitotic index and provoke cell-cycle arrest. Extinguished kinases that lead to a low mitotic index mostly include kinases implicated in cytosolic signaling. In contrast, extinguished kinases that result in a high mitotic index mostly include kinases implicated in cell division. By mapping hit kinases in the PhosphPOINT phosphoprotein database, we generated scale-free networks consisting of 449 and 661 protein-protein interactions for kinases from low MI and high MI groups, respectively. Further analyses of the kinase interactomes revealed specific modules such as FER- and CRKL-containing modules that connect three members of the epidermal growth factor receptor (EGFR) family, suggesting a tight control of the mitogenic EGF-dependent pathway. Based on experimental studies, we confirm the involvement of these two kinases in the regulation of tumor cell growth. Based on a combined approach of large kinome-wide siRNA screens and ontology annotations, our study identifies for the first time two kinase groups differentially implicated in the control of cell proliferation. We further demonstrate that integrative analysis of the kinase interactome provides key information which can be used to facilitate or optimize target design for new therapeutic strategies. The complete list of protein-protein interactions from the two functional kinase groups will provide a useful database for future investigations.
ISSN: 1471-2164

hal-01118475
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01118475
DOI : 10.1186/1471-2164-15-1169
PUBMED : 25540073

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
The mycotoxin alternariol (AOH), a frequent contaminant in fruit and grain, is known to induce cellular stress responses such as reactive oxygen production, DNA damage and cell cycle arrest. Cellular stress is often connected to autophagy, and we employed the RAW264.7 macrophage model to test the hypothesis that AOH induces autophagy. Indeed, AOH treatment led to a massive increase in acidic vacuoles often observed upon autophagy induction. Moreover, expression of the autophagy marker LC3 was markedly increased and there was a strong accumulation of LC3-positive puncta. Increased autophagic activity was verified biochemically by measuring the degradation rate of long-lived proteins. Furthermore, AOH induced expression of Sestrin2 and phosphorylation of AMPK as well as reduced phosphorylation of mTOR and S6 kinase, common mediators of signaling pathways involved in autophagy. Transmission electron microscopy analyzes of AOH treated cells not only clearly displayed structures associated with autophagy such as autophagosomes and autolysosomes, but also the appearance of lamellar bodies. Prolonged AOH treatment resulted in changed cell morphology from round into more star-shaped as well as increased β-galactosidase activity. This suggests that the cells eventually entered senescence. In conclusion, our data identify here AOH as an inducer of both autophagy and senescence. These effects are suggested to be to be linked to AOH-induced DSB (via a reported effect on topoisomerase activity), resulting in an activation of p53 and the Sestrin2-AMPK-mTOR-S6K signaling pathway.
ISSN: 0300-483X

hal-01117627
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01117627
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01117627/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01117627/file/Autophagy%20and%20senescence_accepted.pdf
PUBMED : 25456271

Éditeur(s) : HAL CCSD
Résumé : Cell signaling contains the whole biological mecanisms allowing the response of a cell to its microenvironnement in an adapted way. Many extremely intertwinned biological reactions are involved in a network that behaves as a complex system. The understanding of cell response requires the development of data acquisition technics and methods to formalize data into models. This point is the main drive of this thesis. We present here two approaches in order to analyse different granularities of cell signaling. In the first one, we used differential model to study the role of a new component of TGF-β canonical pathway. In the second one, we explored the combinatorial complexity of cell signaling, developing a discrete formalism based on guarded transitions. In this approach, we interpreted the whole database Pathway Interaction Database into a single unified model of signal transduction. Simulation and analysis methods, such as reachability and invariance research, have been developed. The interests are presented through an application on cell cycle regulation by cell signaling, and a global analysis on the regulation of genes compared to experimental data.
La signalisation cellulaire regroupe l'ensemble des mécanismes biologiques permettant à une cellule de répondre de façon adaptée à son microenvironnement. Pour ce faire, de nombreuses réactions biologiques entrent en jeux avec un important enchevêtrement, créant ainsi un réseau dont le comportement s'apparente à un système complexe. Le compréhension de la réponse cellulaire à une stimulation passe par le développement conjoint des techniques d'acquisition de données, et des méthodes permettant de formaliser ces données dans un modèle. C'est sur ce dernier point que s'inscrivent les travaux exposés dans cette thèse. Nous présentons ici deux approches visant à répondre à des questions de natures différentes sur la signalisation cellulaire. Dans la première nous utilisons un modèle différentiel pour étudier le rôle d'un nouvel interactant dans la voie canonique du TGF-beta. Dans la seconde nous avons exploré la combinatoire de la signalisation cellulaire en développant un formalisme discret basé sur les transitions gardées. Cette approche regroupe l'interprétation de la base de données Pathway Interaction Database dans un unique modèle dynamique de propagation du signal. Des méthodes de simulations et d'analyses inspirées des techniques de vérification de modèles telles que l'atteignabilité et l'invariance ont été développées. En outre, nous avons étudié la régulation du cycle cellulaire en réponse à la signalisation, ainsi que la régulation des gènes de notre modèle en comparaison avec des données d'expressions.
https://tel.archives-ouvertes.fr/tel-00926487

Droits : info:eu-repo/semantics/OpenAccess
tel-00926487
https://tel.archives-ouvertes.fr/tel-00926487
https://tel.archives-ouvertes.fr/tel-00926487/document
https://tel.archives-ouvertes.fr/tel-00926487/file/AndrieuxThese.pdf

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Estrogen receptor alpha (ERα) is generally considered to be a good prognostic marker because almost 70% of ERα-positive tumors respond to anti-hormone therapies. Unfortunately, during cancer progression, mammary tumors can escape from estrogen control, resulting in resistance to treatment. In this study, we demonstrate that activation of the actin/megakaryoblastic leukemia 1 (MKL1) signaling pathway promotes the hormonal escape of estrogen-sensitive breast cancer cell lines. The actin/MKL1 signaling pathway is silenced in differentiated ERα-positive breast cancer MCF-7 and T47D cell lines and active in ERα-negative HMT-3522 T4-2 and MDA-MB-231 breast cancer cells, which have undergone epithelial-mesenchymal transition. We showed that MKL1 activation in MCF-7 cells, either by modulating actin dynamics or using MKL1 mutants, down-regulates ERα expression and abolishes E2-dependent cell growth. Interestingly, the constitutively active form of MKL1 represses PR and HER2 expression in these cells and increases the expression of HB-EGF, TGFβ, and amphiregulin growth factors in an E2-independent manner. The resulting expression profile (ER-, PR-, HER2-) typically corresponds to the triple-negative breast cancer expression profile.
ISSN: 0303-7207

hal-01061363
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01061363
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01061363/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01061363/file/Activationsur the_MKL1actin_Kerdivel_et_al._text_Figures.pdf
DOI : 10.1016/j.mce.2014.03.009

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
Transmembrane CD95L (Fas ligand) can be cleaved to release a promigratory soluble ligand, cl-CD95L, which can contribute to chronic inflammation and cancer cell dissemination. The motility signaling pathway elicited by cl-CD95L remains poorly defined. Here, we show that in the presence of cl-CD95L, CD95 activates the Akt and RhoA signaling pathways, which together orchestrate an allosteric activation of the Na+/H+ exchanger NHE1. Pharmacologic inhibition of Akt or ROCK1 independently blocks the cl-CD95L-induced migration. Confirming these pharmacologic data, disruption of the Akt and ROCK1 phosphorylation sites on NHE1 decreases cell migration in cells exposed to cl-CD95L. Together, these findings demonstrate that NHE1 is a novel molecular actor in the CD95 signaling pathway that drives the cl-CD95L-induced cell migration through both the Akt and RhoA signaling pathways.
ISSN: 2045-2322

hal-01334067
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01334067
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01334067/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01334067/file/Cleaved%20FAS%20ligand%20CC-BY.pdf
DOI : 10.1038/srep28008

Éditeur(s) : HAL CCSD
Résumé : Communication between tumoral cells and the microenvironnement plays an essential role in the developpement of tumors. In that context, the new family of metalloproteases, the ADAM proteins, are major regulators of the tumoral progression by acting on the bioavaibility of importants mediators of cellular communication as cytokines and growth factors. Among this family, ADAM12 is the most associated with cancer. It has been shown to mediate signaling pathways by a process independant of its metalloproteasis activity, in particular for TGFβ signaling. This study show for the first time a role for the membrane form of ADAM12 in the induction of epithelial to mesenchymal transition (EMT), a essential process involved in tumor invasion, whom TGFβ is a main inducer. This effect is mediated by the activation of TGFβ signaling pathways, SMAD3, AKT and ERK and require the cytoplasmic tail of ADAM12L but not its catalytic activity. Activation of these pathways could involve a relocalisation of ADAM12L in special signaling platform in lipid rafts. Moreover, we have shown that ADAM12L interact with ZO-1 and ZO-2, two proteins of tight junctions, and could facilitate their desassembling during EMT. This work underscore for the first time a new function of ADAM12L in EMT, by a mecanism invovlving a modulation of signals regulating this process. A better understanding of the dynamic of these molecular mecanisms could allow the developpement of new targeted therapies to fight against tumoral progression.
Les échanges entre les cellules tumorales et le microenvironnement jouent un rôle essentiel dans le développement des tumeurs. Dans ce contexte, la nouvelle famille de métalloprotéases, les protéines ADAM, constituent aujourd’hui des régulateurs majeurs de la progression tumorale en agissant sur la biodisponibilité des médiateurs de la communication cellulaire que sont les cytokines, chimiokines et facteurs de croissance. Au sein de cette famille, ADAM12 est la plus associée au cancer. Elle possède la particularité de jouer un rôle dans la signalisation cellulaire, de façon indépendante de son activité métalloprotéase, notamment dans les voies de signalisation du TGFβ. Notre étude montre pour la première fois un rôle pour la forme membranaire d'ADAM12 dans l'induction de la transition épithélio-mésenchymateuse (EMT), un processus essentiel à l'invasion tumorale dont le TGFβ est un inducteur majeur. Cet effet est médié par l'activation des voies de signalisation du TGFβ, impliquant les protéines SMAD3, AKT et ERK et requiert le domaine cytoplasmique d'ADAM12L mais pas son domaine catalytique. L'activation de ces voies de signalisation pourrait impliquer une relocalisation d'ADAM12L au sein de plates-formes de signalisation dans les radeaux lipidiques. Par ailleurs, nous avons montré qu'ADAM12L interagit avec les protéines ZO-1 et ZO-2, des protéines des jonctions serrées, et pourrait favoriser leur désassemblage au cours de l'EMT. Nos travaux ont permis de mettre en évidence une nouvelle fonction pour ADAM12L dans l'EMT, par un mécanisme impliquant une modulation des signaux régulant ce processus. Une meilleure compréhension de la dynamique de ces mécanismes moléculaires pourrait permettre de développer de nouvelles thérapies ciblées pour lutter contre la progression tumorale.
https://tel.archives-ouvertes.fr/tel-01267577

Droits : info:eu-repo/semantics/OpenAccess
NNT : 2015REN1S063
tel-01267577
https://tel.archives-ouvertes.fr/tel-01267577
https://tel.archives-ouvertes.fr/tel-01267577/document
https://tel.archives-ouvertes.fr/tel-01267577/file/RUFF_Michael.pdf

Éditeur(s) : HAL CCSD
Résumé : International audience
Studies report that foetal exposure to paracetamol by maternal consumption can interfere with male reproductive development. Moreover, recent biomonitoring data report widespread presence of paracetamol in German and Danish populations, suggesting exposure via secondary (non-pharmaceutical) sources such as metabolic conversion from the ubiquitous industrial compound aniline. In this study we investigated the extent to which paracetamol and aniline can interfere with female reproductive development. Intrauterine exposure to paracetamol by gavage of pregnant dams resulted in shortening of the anogenital distance in adult offspring, suggesting that foetal hormone signalling had been disturbed. Female offspring of paracetamol-exposed mothers had ovaries with diminished follicle reserve and reduced fertility. Foetal gonads of exposed animals had also reduced gonocyte numbers, suggesting that the reduced follicle count in adults could be due to early disruption of germ cell development. However, ex vivo cultures of ovaries from 12.5 days post coitum foetuses showed no decrease in proliferation or expression following exposure to paracetamol. This suggests that the effect of paracetamol occurs prior to this developmental stage. Accordingly, using embryonic stem cells as a proxy for primordial germ cells we show that paracetamol is an inhibitor of cellular proliferation, but without cytotoxic effects. Collectively, our data show that intrauterine exposure to paracetamol at levels commonly observed in pregnant women, as well as its precursor aniline, may block primordial germ cell proliferation, ultimately leading to reduced follicle reserves and compromised reproductive capacity later in life
Toxicological Sciences

hal-01259211
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01259211
DOI : 10.1093/toxsci/kfv332
PUBMED : 26732887

Éditeur(s) : HAL CCSD
Résumé : International audience
The present study was conducted to assess the effects of Cd exposure on estrogen signaling in the zebrafish brain, as well as the potential protective role of Zn against Cd-induced toxicity. For this purpose, the effects on transcriptional activation of the estrogen receptors (ERs), aromatase B (Aro-B) protein expression and molecular expression of related genes were examined in vivo using wild-type and transgenic zebrafish embryos. For in vitro studies, an ER-negative glial cell line (U251MG) transfected with different zebrafish ER subtypes (ERα, ERβ1 and ERβ2) was also used. Embryos were exposed either to estradiol (E2), Cd, E2+Cd or E2+Cd+Zn for 72 h and cells were exposed to the same treatments for 30 h. Our results show that E2 treatment promoted the transcriptional activation of ERs and increased Aro-B expression, at both the protein and mRNA levels. Although exposure to Cd, does not affect the studied parameters when administered alone, it significantly abolished the E2-stimulated transcriptional response of the reporter gene for the three ER subtypes in U251-MG cells, and clearly inhibited the E2 induction of Aro-B in radial glial cells of zebrafish embryos. These inhibitory effects were accompanied by a significant downregulation of the expression of esr1, esr2a, esr2b and cyp19a1b genes compared to the E2-treated group used as a positive control. Zn administration during simultaneous exposure to E2 and Cd strongly stimulated zebrafish ERs transactivation and increased Aro-B protein expression, whereas mRNA levels of the three ERs as well as the cyp19a1b remained unchanged in comparison with Cd-treated embryos. In conclusion, our results clearly demonstrate that Cd acts as a potent anti-estrogen in vivo and in vitro, and that Cd-induced E2 antagonism can be reversed, at the protein level, by Zn supplement.
Journal of Applied Toxicology

Droits : info:eu-repo/semantics/OpenAccess
hal-01274217
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01274217
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01274217/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01274217/file/Inhibitory%20effect%20of%20Cadmium%20on%20estrogen_accepted.pdf
DOI : 10.1002/jat.3285

Éditeur(s) : HAL CCSD
Résumé : Croton urucurana Baillon (Euphorbiaceae), plant species popularly known in Brazil as “sangra-d’água”, is commonly found in Mato Grosso do Sul State (midwestern Brazil), where its latex is popularly used to treat several types of cancer. Despite the ethnopharmacological significance of the species, no phytochemical or cytotoxic studies of its latex have been published. In this context, the aim of the present study was to assess the cytotoxic activity of crude extracts, fractions and isolated compound from the latex of C. urucurana and to investigate the effects of crourorb A1 on the viability, apoptosis, cell cycle and cell migration of human hepatocarcinoma cell lines (Huh-7). Also, we have evaluated the viability of Huh-7 cells treated with crourorb A1 in 3D collagen gels. The cytotoxicity was detected using the sulforhodamine B (SRB) assay against six human cancer cells lines and one nontumor NIH/3T3 cell line (murine fibroblast). Studies on the mechanism of cell death of crourorb A1 were conducted in different test systems in vitro. The bioactive ethyl acetate phase obtained from the latex of C. urucurana afforded a novel cyclic peptide, [1−9-NαC]-crourorb A1, that proved active against NCIADR/ RES (ovary, multidrug-resistance phenotype) cells with the same potency as doxorubicin (positive control) and inactive up to the highest concentration tested against nontumor NIH/3T3 cells (GI50 = > 250 μg/mL). Crourorb A1 treatment decreases the cell viability of Huh-7 at dose and time dependent manner associated with induction of apoptosis by caspase 3/7 activation and increasing expression of pro-apoptotic proteins: Bak, Bid, Bax, Puma, Bim, and Bad and clived-caspase3 protein. The JNK/MAP pathway is involved in this induced cell death. Crourorb A1 effect is also associated with G2/M phase cell cycle arrest. In parallel, we observed that crourorb A1 treatment resulted in an increase of cyclin-dependent kinase (CDK1), cyclin B1 and cyclin D1 expressions. A significant reduction of Huh-7 cells migration by crourorb A1 can be assessed and we also show that cells grown on 3D collagen gels exhibited increased resistance to crourorb A1 when compared to 2D cell culture.
Croton urucurana Baillon (Euphorbiaceae), est une plante très connue et utilisée en médecine traditionnelle au Brésil, la «sangra-d’água» retrouvée dans l'État du Mato Grosso do Sul (région Centre-Ouest du Brésil). Son latex est abondamment utilisé en médecine traditionnelle dans le traitement de plusieurs types de cancer. En dépit de son importance ethnopharmacologique, on ne trouve aucune étude sur sa composition chimique ou sur sa potentielle activité anti-cancéreuse. L’objectif de ce travail a été d'évaluer l'activité cytotoxique des extraits totaux, fractions d’extraits et de molécules purifiées, isolées du latex de C. urucurana. Nous avons étudié plus particulièrement les effets du crourorb A1 sur la viabilité, l'apoptose, le cycle cellulaire et la migration de cellules issues de carcinome hépatocellulaire humaine (Huh-7). Nous avons également évalué l’effet du crourorb A1sur la viabilité des cellules Huh-7 cultivées dans les gels de collagène en 3D. L' activité cytotoxique ont été réalisées par le test à la sulforhodamine B sur six lignées cellulaire cancéreuses et sur une lignée cellulaire non cancéreuse de fibroblastes murins, les cellules NIH/3T3. L'étude phytochimique de la fraction ‘acétate d'éthyle’ du latex de C. urucurana bioguidé a permis d’obtenir un nouveau cyclopeptide que nous avons nommé [1-9-NαC]-crourorb A1. Le crourorb présente une cytotoxicité puissante sur la lignée cellulaire cancéreuse NCI-ADR/RES (ovaire, le phénotype de multirésistance) à un niveau équivalent à celle de la doxorubicine (témoin positif). Ce composé est de plus pratiquement inactif (GI50 = >250 μg/mL) sur la lignée non cancéreuse NIH/3T3. L'évaluation de la cytotoxicité in vitro du crourorb A1 (test wst1) sur les cellules Huh-7 a démontré que la viabilité des cellules est inhibée de manière dose et temps-dépendant. Nous avons mesuré une forte activation des caspases 3 et 7 et une nette augmentation de l’expression des protéines pro-apoptotiques (Bak, Bid, Bax, Puma, Bim et Bad) ainsi que de la caspase 3 clivée par le crourorb A1. Nous avons également déterminé que la voie de signalisation JNK-MAPkinase semble nécessaire à l’induction de la mort cellulaire des cellules Huh-7 traitées au crourorb A1. Le crourob A1 induit un arrêt du cycle cellulaire en phase G2/M. En parallèle, les expressions de la cycline-dépendante kinase CDK1, des cyclines B1 et D1 sont augmentées après traitement au crourorb A1. De plus, le crourorb A1 a un effet inhibiteur significatif de la migration des cellules Huh-7, en présence ou absence de mitomycine C. Nous avons également confirmé, l’effet inhibiteur du crourob A1 sur la viabilité des cellules Huh7 cultivées en 3D dans les gels de collagène 1 et démontré que les cellules cultivées en 3D semblent plus résistantes au crourorb A1 par rapport aux cultures en monocouche 2D.
Croton urucurana Baillon (Euphorbiaceae) é uma espécie arbórea conhecida popularmente no Brasil como “sangra d´água”, comumente encontrada no estado de Mato Grosso do Sul, onde seu látex tem sido utilizado na medicina popular no tratamento de vários tipos de câncer. Apesar de sua importância etnofarmacológica, não há relatos de estudos relacionados à sua composição química ou atividades anticâncer na literatura. Nesse contexto, o objetivo do presente estudo foi avaliar a atividade citotóxica de extratos, fases, frações e da substância isolada do látex de C. ururucurana e investigar os mecanismos celulares e moleculares in vitro responsáveis pela citotoxicidade da substância isolada considerando seu potencial apoptótico e influência sobre a progressão do ciclo celular em uma linhagem de hepatocarcinoma celular humano (Huh-7), bem como, os efeitos desta substância sobre a migração e viabilidade de células Huh-7 cultivadas em geis de colágeno em 3D. O ensaio de citotoxicidade in vitro foi realizado com o corante sulforrodamina B (SRB) em seis linhagens de células neoplásicas humanas e uma linhagem de células não neoplásicas NIH/3T3 (fibloblasto murinho). Os estudos de mecanismos de ação com crourorb A1 foram conduzidos em diferentes sistemas-teste in vitro. O estudo fitoquímico biomonitorado da fase bioativa acetato de etila do látex de C. urucurana resultou no isolamento de um novo ciclopeptídeo denominado [19-NαC]-crourorb A1, que apresentou potente atividade citotóxica frente à linhagem de células neoplásicas NCI-ADR/RES (ovário com fenótipo de resistência a múltiplos fármacos), com a mesma potência que a doxorrubicina (controle positivo), e foi inativa até a maior concentração testada (GI50 = >250 μg/mL) frente à linhagem de células não neoplásicas 3T3. A exposição de células Huh-7 ao crourorb A1 resultou em uma diminuição da viabilidade celular de maneira dose e tempo-dependentes. Nós observamos um aumento da atividade de caspases 3 e 7 e um aumento da expressão de proteínas próapoptóticas (Bak, Bid, Bax, Puma, Bim e Bad) e caspase 3 clivada após tratamento com crourorb A1. Além disso, observamos que a via de sinalização celular MAP/JNK foi necessária para induzir a morte celular em células Huh-7 tratadas com crourorb A1. Os efeitos de crourorb A1 foram também associados com o acúmulo de células na fase G2/M do ciclo celular. Em paralelo, as expressões da cinase dependente da ciclina (CDK1), ciclina B1 e ciclina D1 foram aumentadas após tratamento com crourorb A1. Foi demonstrado também o envolvimento de crourorb A1 na redução da migração de células Huh-7 cultivadas na presença e ausência de mitomicina C. A avaliação da viabilidade de células Huh-7 cultivadas em geis de colágeno em 3D apontou uma maior resistência destas células ao crourorb A1 quando comparadas com a cultura de células em 2D.
https://tel.archives-ouvertes.fr/tel-01478286

NNT : 2016REN1B010
tel-01478286
https://tel.archives-ouvertes.fr/tel-01478286
https://tel.archives-ouvertes.fr/tel-01478286/document
https://tel.archives-ouvertes.fr/tel-01478286/file/DE-MATOS-CANDIDO-BACANI-Priscila.pdf

Éditeur(s) : HAL CCSD
Résumé : International audience
BACKGROUND: The aryl hydrocarbon receptor (AhR) has gradually emerged as a regulator of inflammation in the lung and other tissues. AhR may interact with the p65-subunit of the nuclear factor (NF)-κB transcription factors, but reported outcomes of AhR/NF-κB-interactions are conflicting. Some studies suggest that AhR possess pro-inflammatory activities while others suggest that AhR may be anti-inflammatory. The present study explored the impact of AhR and its binding partner AhR nuclear translocator (Arnt) on p65-activation and two differentially regulated chemokines, CXCL8 (IL-8) and CCL5 (RANTES), in human bronchial epithelial cells (BEAS-2B). RESULTS: Cells were exposed to CXCL8- and CCL5-inducing chemicals, 1-nitropyrene (1-NP) and 1-aminopyrene (1-AP) respectively, or the synthetic double-stranded RNA analogue, polyinosinic-polycytidylic acid (Poly I:C) which induced both chemokines. Only CXCL8, and not CCL5, appeared to be p65-dependent. Yet, constitutively active unligated AhR suppressed both CXCL8 and CCL5, as shown by siRNA knock-down and the AhR antagonist α-naphthoflavone. Moreover, AhR suppressed activation of p65 by TNF-α and Poly I:C as assessed by luciferase-assay and p65-phosphorylation at serine 536, without affecting basal p65-activity. In contrast, Arnt suppressed only CXCL8, but did not prevent the p65-activation directly. However, Arnt suppressed expression of the NF-κB-subunit RelB which is under transcriptional regulation by p65. Furthermore, AhR-ligands alone at high concentrations induced a moderate CXCL8-response, without affecting CCL5, but suppressed both CXCL8 and CCL5-responses by Poly I:C. CONCLUSION: AhR and Arnt may differentially and independently regulate chemokine-responses induced by both inhaled pollutants and pulmonary infections. Constitutively active, unligated AhR suppressed the activation of p65, while Arnt may possibly interfere with the action of activated p65. Moreover, ligand-activated AhR suppressed CXCL8 and CCL5 responses by other agents, but AhR ligands alone induced CXCL8 responses when given at sufficiently high concentrations, thus underscoring the duality of AhR in regulation of inflammation. We propose that AhR-signaling may be a weak activator of p65-signaling that suppresses p65-activity induced by strong activators of NF-κB, but that its anti-inflammatory properties also are due to interference with additional pathways.
Cell communication and signaling: CCS

hal-01063555
https://hal.archives-ouvertes.fr/hal-01063555
DOI : 10.1186/s12964-014-0048-8

Éditeur(s) : HAL CCSD MDPI
Résumé : International audience
In mammals, the effects of estrogen are mainly mediated by two different estrogen receptors, ERα and ERβ. These proteins are members of the nuclear receptor family, characterized by distinct structural and functional domains, and participate in the regulation of different biological processes, including cell growth, survival and differentiation. The two estrogen receptor (ER) subtypes are generated from two distinct genes and have partially distinct expression patterns. Their activities are modulated differently by a range of natural and synthetic ligands. Some of these ligands show agonistic or antagonistic effects depending on ER subtype and are described as selective ER modulators (SERMs). Accordingly, a few phytochemicals, called phytoestrogens, which are synthesized from plants and vegetables, show low estrogenic activity or anti-estrogenic activity with potentially anti-proliferative effects that offer nutraceutical or pharmacological advantages. These compounds may be used as hormonal substitutes or as complements in breast cancer treatments. In this review, we discuss and summarize the in vitro and in vivo effects of certain phytoestrogens and their potential roles in the interaction with estrogen receptors.
ISSN: 1422-0067

hal-01560283
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560283
PUBMED : 28657580
DOI : 10.3390/ijms18071381

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
The separation of the germ line from the soma is a classic concept in animal biology, and depending on species is thought to involve fate determination either by maternally localized germ plasm (''preformation'' or ``maternal inheritance'') or by inductive signaling (classically termed ``epigenesis'' or ``zygotic induction''). The latter mechanism is generally considered to operate in non-bilaterian organisms such as cnidarians and sponges, in which germ cell fate is determined at adult stages from multipotent stem cells. We have found in the hydrozoan cnidarian Clytia hemisphaerica that the multipotent ``interstitial'' cells (i-cells) in larvae and adult medusae, from which germ cells derive, express a set of conserved germ cell markers: Vasa, Nanos1, Piwi and PL10. In situ hybridization analyses unexpectedly revealed maternal mRNAs for all these genes highly concentrated in a germ plasm-like region at the egg animal pole and inherited by the i-cell lineage, strongly suggesting i-cell fate determination by inheritance of animal-localized factors. On the other hand, experimental tests showed that i-cells can form by epigenetic mechanisms in Clytia, since larvae derived from both animal and vegetal blastomeres separated during cleavage stages developed equivalent i-cell populations. Thus Clytia embryos appear to have maternal germ plasm inherited by i-cells but also the potential to form these cells by zygotic induction. Reassessment of available data indicates that maternally localized germ plasm molecular components were plausibly present in the common cnidarian/bilaterian ancestor, but that their role may not have been strictly deterministic.
ISSN: 0012-1606

hal-01544487
https://hal.archives-ouvertes.fr/hal-01544487
DOI : 10.1016/j.ydbio.2012.01.018