Expression of a dominant negative form of Daxx in vivo rescues motoneurons from Fas (CD95)-induced cell death.

Fas-induced death of motoneurons in vitro has been shown to involve two signaling cascades that act together to execute the death program: a Fas-Daxx-ASK-1-p38 kinase-nNOS branch, which controls transcriptional and post-translational events, and the second classical Fas-FADD-caspase-8 branch. To analyze the role of Daxx in the developmental motoneuron cell death, we studied Fas-dependent cell death in motoneurons from transgenic mice that overexpress a dominant-negative form of Daxx. Motoneurons purified from these transgenic mice are resistant to Fas-induced death.

Reactivity studies of 3-alkoxy-7-amino-4-chloroisocoumarins (beta-amyloid peptide inhibitors) versus different classes of amines.

3-Alkoxy-7-amino-4-chloroisocoumarins have been shown to lower the beta-amyloid secretion (a major component of the senile plaques involved in Alzheimer's disease). This paper reports the characterization of new adducts resulting from the reaction between the isocoumarin synthon and different classes of amines. This study allows on the one hand, a better understanding of the biological molecular processes by which such isocoumarin derivatives may interact with enzyme nucleophiles and, on the other hand, brings out the chemical potential of these synthons to generate new polycyclic derivatives.

Novel synthesis of 3,4-dihydro-5-bromo[1,4]oxazin-2-one derivatives, new protease inhibitor scaffold.

We designed and synthesized a new class of serine protease inhibitors based on the oxazinone core. To this end, we first developed a short and efficient route to synthesize a new 3,4-dihydro[1,4]oxazin-2-one ring. Then we successfully synthesised the corresponding 5-bromo derivatives which have never been reported before, and demonstrated their inhibitory activities on alpha-chymotrypsin.

Synthesis of new 3-alkoxy-7-amino-4-chloro-isocoumarin derivatives as new beta-amyloid peptide production inhibitors and their activities on various classes of protease.

A series of new 7-substituted-4-chloro-3-alkoxy isocoumarin derivatives were synthesized and evaluated as inhibitors of representative classes of proteases: serine protease (alpha-chymotrypsin, trypsin), cysteine protease (Caspase-3), and aspartyl protease (HIV-protease), 20S proteasome and also as inhibitors of amyloid peptide gamma-secretase-mediated production. Protease inhibition selectivity is directly related to the structure of the substituent at the 7-position of the isocoumarin nucleus. 7-Nitro-isocoumarin derivatives (4c, 4d, 4f) are potent alpha-chymotrypsin inhibitors but slightly active or inactive on HIV-protease, as well as on cysteine protease.

Active killing of neurons during development and following stress: a role for p75(NTR) and Fas?

Evidence for active triggering of neuronal death continues to accumulate. The transmembrane receptors p75(NTR) and Fas can trigger (and in some cases are required for) programmed cell death of the neurons that express them, through signalling pathways that are regulated by a variety of cytoplasmic effectors. Neuronal death induced by trophic deprivation often requires Fas signalling, further blurring the boundaries between naturally occurring and stress-induced neuronal death.