Neurotoxicity Of Channel Mutations In Heterologously Expressed α7-Nicotinic Acetylcholine Receptors

Nicotinic acetylcholine receptors (nAChR) composed of chick α7 subunits mutated to threonine at amino acid valine-251 in the putative channel-lining M2 domain were expressed heterologously in several neuron-like and non-neuronal mammalian cell lines. Expression of mutant α7-nAChR is toxic to neuron-like cells of the human neuroblastoma cell lines SH-SY5Y and IMR-32, but not to several other cell types. Growth in the presence of the α7-nAChR antagonist methyllycaconitine (MLA) protects against neurotoxicity, as does gradual downregulation of functional, mutant α7-nAChR in surviving transfected SH-SY5Y cells. Relative to wild-type α7-nAChR, functional α7-nAChR mutants show a higher affinity for agonists, slower rates of desensitization, and sensitivity to dihydro-β-erythroidine (DHβE) as an agonist, but they retain sensitivity to MLA as a competitive antagonist. These findings demonstrate that expression of hyperfunctional, mutant forms of Ca2+-permeable α7-nAChR is toxic to neuron-like cells

Composition contenant au moins un inhibiteur de certaines chimiokines, son procédé d’obtention et son utilisation en dermocosmétique pharmaceutique

La présente invention concerne l'obtention de dérivés de l'acide salicylique OU nicotinique inhibant les chimiokines, leurs préparations et leurs utilisations dans des compositions cosmétiques ou pharmaceutiques destinées à prévenir ou traiter les affections inflammatoires chroniques internes et/ou topiques

Pyrimidinone derivatives and uses thereof to neutralize the biological activity of chemokines

A subject of the present invention is a compound having the general formula (I) a pharmaceutically acceptable salt thereof or a tautomeric form thereof, wherein A, B3, B4, B5, Y, X, B1 and B2 are as defined in any one of claims 1 to 10. Another subject of the invention is the compound as defined above for use as a medicament, in particular for preventing and/or treating inflammation and inflammatory diseases, immune and auto-immune diseases, pain related diseases, genetic diseases and/or cancer. L'objet de la présente invention est un composé de la formule générale (I), son sel pharmaceutiquement accepté ou un tautomère de celui-ci, où A, B3, B4, B5, Y, X, B1 et B2 sont tels que définis dans les déclarations 1 à 10. Un autre objet de l'invention est le composé tel que défini ci-dessus pour une utilisation en tant que médicament, en particulier pour prévenir et/ou traiter une inflammation et des maladies inflammatoires, de maladies immunitaires et auto-immunes, de maladies liées à la douleur, de maladies génétiques et/ou du cancer

A Selective Neutraligand for CXCL12/SDF-1α With Beneficial Regulatory Functions in MRL/Lpr Lupus Prone Mice

Dysregulation of CXCL12/SDF-1-CXCR4/CD184 signaling is associated with inflammatory diseases and notably with systemic lupus erythematosus. Issued from the lead molecule chalcone-4, the first neutraligand of the CXCL12 chemokine, LIT- 927 was recently described as a potent analogue with improved solubility and stability. We aimed to investigate the capacity of LIT-927 to correct immune alterations in lupus-prone MRL/lpr mice and to explore the mechanism of action implemented by this small molecule in this model. We found that in contrast to AMD3100, an antagonist of CXCR4 and agonist of CXCR7, LIT-927 reduces the excessive number of several B/T lymphocyte subsets occurring in the blood of sick MRL/lpr mice (including CD3+/CD4-/CD8-/B220+ double negative T cells). In vitro, LIT-927 downregulated the overexpression of several activation markers on splenic MRL/lpr lymphocytes. It exerted effects on the CXCR4 pathway in MRL/lpr CD4+ T spleen cells. The results underline the importance of the CXCL12/CXCR4 axis in lupus pathophysiology. They indicate that neutralizing CXCL12 by the neutraligand LIT-927 can attenuate hyperactive lymphocytes in lupus. This mode of intervention might represent a novel strategy to control a common pathophysiological mechanism occurring in inflammatory diseases

Analytical chemistry

Swiftness, reliability, and sensitivity of live bacteria detection in drinking water are key issues for human safety. The most widespread used indicator of live bacteria is a caged form of carboxyfluorescein in which 3' and 6' hydroxyl groups are masked as acetate esters (CFDA). This derivatization altogether abolishes fluorescein fluorescence and renders the molecule prone to passive diffusion through bacterial membranes. Once in the cytoplasm, acetate groups from CFDA are removed by bacterial hydrolases and fluorescence develops, rendering live but not dead cells detectable. Yet the reagent, carboxyfluorescein diacetate, still possesses a free carboxyl group whose ionization constant is such that the majority of the probe is charged at physiological pH. This unfavors probe permeation through membranes. Here, we prepare several chemical modifications of the carboxyl moiety of CFDA, in order to neutralize its charge and improve its passive diffusion through membranes. We show that the ethylamido derivative of the 5-carboxyl group from 5-carboxy-fluorescein diacetate or from Oregon green diacetate or from Oregon green diacetoxymethylester are stable molecules in biological media, penetrate into bacterial cells and are metabolized into fluorescent species. Only live bacteria are revealed since bleached samples are not labeled. Other derivatives with modification of the 5-carboxyl group with an ester group or with a thiourea-based moiety were almost inefficient probes. The most interesting probe, triembarine (5-ethylaminocarboxy-oregon green, 3',6'diacetoxymethyl ester) leads to 6-10 times more sensitive detection of bacteria as compared to CFDA. Addition of contrast agents (trypan blue or brilliant blue R) improve the signal-to-noise ratio by quenching extracellular fluorescence while bromophenol blue quenches both intracellular and extracellular fluorescence, allowing standardization of detections

ACS Med Chem Lett

Chalcone 4 (compound 1) is a small molecule that neutralizes the CXC chemokine CXCL12 and prevents it from acting on the CXCR4 and CXCR7 receptors. To overcome its poor solubility in aqueous buffers, we designed highly soluble analogues of compound 1, phosphate, l-seryl, and sulfate, all inactive by themselves on CXCL12 but when cleaved in vivo into 1, highly active locally at a low dose in a mouse airway hypereosinophilia model