25 research outputs found
Caractérisation de protéines associées aux acidocalcisomes de Trypanosoma brucei (acidocalcisomes et métabolisme des polyphosphates, nouvelles cibles thérapeutiques des trypanosomatides)
PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF
Dérégulation de la signalisation non génomique du récepteur aux androgènes dans un modèle SBMA in vitro
L'atrophie musculaire bulbo-spinale (SBMA) est une dégénérescence lente et progressive des motoneurones causée par l'élongation du triplet nucléotidique (CAG) dans le gène codant pour le récepteur aux androgènes (RA) localisé sur le chromosome X. Dans la SBMA, ce récepteur à extension polyglutaminique (polyQ) pathogène s'accumule de manière ligand dépendante dans le cytoplasme sous forme d'agrégats mais également dans le noyau y créant des corps d'inclusions nucléaires considérés comme la marque identitaire histologique, dont le caractère cytotoxique est aujourd'hui remis en question. Nous avons développé un modèle SBMA in vitro basé sur l'expression inductible d'un RA51Q dans la lignée hybride NSC34, qui est comparé au modèle normal NSC34 exprimant un RA contenant 20Q. Nous avons démontré que l'expression du RA51Q entraîne une diminution de la viabilité ainsi qu'une altération de la croissance neuritique sans formation d'agrégats insolubles dans le noyau ou le cytoplasme des cellules. Le RA en tant que membre de la superfamille des récepteurs nucléaires est un facteur de transcription mais peut également induire des voies de signalisation non génomiques via sa localisation membranaire. Après avoir montré une localisation du RA20Q et du RA51Q dans les lipid rafts , nous avons corrélé la diminution de la viabilité et de la pousse neuritique induite par le RA51Q à une altération de la signalisation cellulaire non génomique. Les résultats obtenus mettent en évidence une dérégulation des voies de signalisation PI3K/Akt et JNK/c-jun induite par l'expression du RA muté dans notre modèle SBMA.Spinal Bulbar Muscular Atrophy (SBMA) is a progressive inherited motoneuron disease caused by the expansion of a trinucleotide (CAG) repeat in the gene coding for the androgen receptor (AR) located on the X chromosome. This rare disease causes muscle weaknesses, hypotonia, hyporeflexia, fasciculations of facial muscles in male patients. The androgen-dependent formation of cytoplasmic aggregates and nuclear inclusions are pathological hallmarks of this polyglutamine disease but their potential neurotoxicity is still under debate. We developed a SBMA model based on a doxycycline-inducible AR51Q expression system in the NSC34 hybrid cell line. We have shown that the expression of the mutated AR leads to a reduced viability and to an alteration of neurite outgrowth compared to cells expressing the normal AR20Q. The AR belongs to the nuclear receptor superfamily of transcription factors. However, recent data have put in evidence a membrane localization of AR initiating non-genomic signaling pathways. Because we have not observed insoluble aggregates, reduced viability and neurite outgrowth could not be correlated to AR aggregation. We hypothesized that motoneuron death is not only due to aggregate formation but also to the alteration of AR signaling pathways. We focused on a correlation between the AR localization in lipid rafts and the observed phenotypes. Our results highlight the deregulation of PI3K/Akt and JNK/c-jun signaling pathways induced by the expression of AR51Q in our SBMA model.MONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF
Synthesis and biological applications of phosphinates and derivatives
International audienceThis review first outlines general considerations on phosphinic acids and derivatives as bioisosteric groups. The next sections present key aspects of phosphinic acid-based molecules and include a brief description of the biological pathways involved for their activities. The synthetic aspects and the biological activities of such compounds reported in the literature between 2008 and 2013 are also describe
HPLC Analysis and Cytotoxicity of n-Butanol Extract from Glyphaea brevis Roots Against C6 Glioma Cells
International audienceThe n-butanol extract of the roots of Glyphaea brevis was analysed. HPLC analysis suggested the presence of phenolic compounds like protocatechuic acid (PCA). The extract showed moderate cytotoxic activity against C6 glioma cells (EC50 > 1 mg/ml)
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A Vacuolar-type H+-Pyrophosphatase Governs Maintenance of Functional Acidocalcisomes and Growth of the Insect and Mammalian Forms of Trypanosoma brucei
Vacuolar proton pyrophosphatases (V-H+-PPases) are electrogenic proton pumps found in many organisms of considerable industrial, environmental, and clinical importance. V-H+-PPases of several parasites were shown to be associated with acidic vacuoles named acidocalcisomes, which contain polyphosphate and calcium. In this work we functionally characterized a Trypanosoma brucei V-H+-PPase gene by using double-stranded RNA interference methodology to produce inducible V-H+-PPase-deficient strains of procyclic and bloodstream forms (PFiVP1 and BFiVP1). Acidocalcisomes of these mutated parasites lost acidity and contained 90% less polyphosphate. PFiVP1 did not release calcium after the addition of nigericin, and its total acidity was reduced by 70%. This mutant also failed to stabilize its intracellular pH on exposure to external basic pH >7.4 and recovered from intracellular acidification at a slower rate and to a more acidic final intracellular pH. In the absence of T. bruceiV-H+-PPase expression, PFiVP1 and BFiVP1 grew at a slower rate with doubling times of 27 h instead of 15 h, and 10 h instead of 7.5 h, respectively. Moreover, BFiVP1 could not grow over 5 Ă— 105 cells/ml corresponding to a cell density reduction of five times for bloodstream form stationary phase growth
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Nouveaux hétérocycles phosphorés analogues de sucres et compositions à activité anti-cancéreuse contenant ces composés
NEW PHOSPHORUS CONTAINING HETEROCYCLIC COMPOUNDS, SUGAR ANALOGUES, AND COMPOSITIONS HAVING ANTI-CANCER ACTIVITY CONTAINING THE SAME
The invention provides new anticancer compounds of formula (1) such as defined in the present description. The invention also provides pharmaceutical compositions to be used in human or veterinary medicine, comprising at least one compound of formula (1). The present invention further relates to a compound of formula (1) such as defined in the present description, for use as a drug. The invention further relates to the use of a compound of formula (1) for manufacturing a human or animal anticancer pharmaceutical composition