Expression of X-chromosome linked inhibitor of apoptosis protein in mature purkinje cells and in retinal bipolar cells in transgenic mice induces neurodegeneration

Transgenic mice with overexpression of the caspase-inhibitor, X-chromosome-linked inhibitor of apoptosis protein (XIAP) in Purkinje cell (PC) and in retinal bipolar cells (RBCs) were produced to study the regulation of cell death. Unexpectedly, an increased neurodegeneration was observed in the PCs in these L7-XIAP mice after the third postnatal week with the mice exhibiting severe ataxia. The loss of PCs was independent of Bax as shown by crossing the L7-XIAP mice with Bax gene–deleted mice. Electron microscopy revealed intact organelles in PCs but with the stacking of ER cisterns indicative of cell stress. Immunostaining for cell death proteins showed an increased phosphorylation of c-Jun in the PCs, suggesting an involvement in cell degeneration. Apart from PCs, the number of RBCs was decreased in adult retina in line with the expression pattern for the L7 promoter. The data show that overexpression of the anti-apoptotic protein XIAP in vulnerable neurons leads to enhanced cell death. The mechanisms underlying this neurodegeneration can be related to the effects of XIAP on cell stress and altered cell signaling.Supported by Sigrid Juselius Foundation, Academy of Finland, EU Biotech Grant, Liv och Hälsa, Maud Kuistila, Ylppö Foundation, Uppsala University and Minerva Foundation. We thank Dr. Urmas Arumäe for discussions, and Dr. Patrik Ernfors for the Bax KO mice, and Eeva Lehto for technical assistance. L7AUG was a kind gift from Dr. J. Oberdick, Ohio State University, USA.Peer reviewe

Possible effects of counterions on biological activities of anionic surfactants

The aggressiveness in terms of apogenic and necrotic activities of lysine-derived anionic surfactants towards a mammalian cell line (U937) were studied. We used N(alpha)N(epsilon)-dioctanoyl lysine as the model surfactant with lysine, tris, Na(+) or Li(+) as counterions. The aggressiveness of the different surfactants was assessed as the concentrations leading to apoptosis or necrosis after the cells were incubated in the presence of surfactants and then cultivated in their absence. Used in the same conditions, acetates associated with the same cations, had no effects on the cells. Our results show that the aggressiveness of the surfactants depended on the nature of the counterions: it was high when surfactants were associated with small counterions, and low with large counterions.Peer reviewe

Interactions of surfactants with living cells. Induction of apoptosis by detergents containing a β-lactam moiety

The toxicity of new surfactants containing a beta-lactam ring has been established by studying their interaction with a hybridoma cell line. An hour of contact is sufficient to generate an apoptotic signal after two days of culture. Under the experimental conditions chosen for the experiments, surfactants have been divided into three categories: i) biocompatible and non-apogenic; ii) surfactants triggering an apoptotic signal without inducing cell necrosis; iii) surfactants triggering an apoptotic signal at low concentrations and destroying the cells by necrosis at higher concentrations. The necrosis inducing surfactants also had haemolytic properties. These properties were related to the values of the hydrophilic-lipophilic balance of the molecules.This work was generously supported by CNRS and CSIC “Cooperation project n° 1940”.Peer reviewe

Tensiobioactifs trimodulaires non ioniques comportant un cycle β-lactame et un sucre

A synthetic methodology for surfactant molecules containing a beta-lac tame ring and a glycosamine has been developed. From 3-hydroxy-2-hydro xymethyl-2-methyl-propionic acid we prepared a hydrophobic 1,3-diol mo dule A by selective amidation using a fatty amine. One of the primary alcohol functions of this product A is selectively activated in the fo rm of the ATDP sit B. The cyclization of B into the beta-lactame C is then effected by reaction in a basic medium (K2CO3). These derivatives C: constitute an interesting bimodular surfactant. By esterification of C with succinic anhydride we obtained products D. The carboxy[ic fu nction introduced by the succinyl group was activated by BOP and coupl ed to the glucosamine giving the trimodular biotensides E. These deriv atives display air-water interface activity as shown by the surface te nsion; the values of which have been lowered to 32 mN/m. The Critical Micellar Concentration (CMC) is of the order of 10(-4) mol dm(-3), com parable in magnitude to what has been observed for surfactants with su gar-type polar heads. Binary phase diagrams with water for these produ cts C, as a function of temperature and concentration, show the behavi or of hydrophilic surfactants with a large direct micellar phase L-1. Products E show little toxicity in cell culture, however they induce a poptosis at concentrations larger than 3x10(-4) g/L. They also show an tibiotic properties with respect to gram(+) or gram(-) bacterial strai ns with Minimal Inhibition Concentrations (MIG) on the order of 32 mu g/mL in the cases where they appear to be the most efficient. These va lues remain, however, below those of commercial monobactames.Peer reviewe