New highly sensitive rodent and human tests for soluble amyloid precursor protein alpha quantification: preclinical and clinical applications in Alzheimer’s disease

Background

Exposure to ethanol during early development triggers severe neuronal death by activating multiple stress pathways and causes neurological disorders, such as fetal alcohol effects or fetal alcohol syndrome. This study investigated the effect of ethanol on intracellular events that predispose developing neurons for apoptosis via calcium-mediated signaling. Although the underlying molecular mechanisms of ethanol neurotoxicity are not completely determined, mitochondrial dysfunction, altered calcium homeostasis and apoptosis-related proteins have been implicated in ethanol neurotoxicity. The present study was designed to evaluate the neuroprotective mechanisms of metformin (Met) and thymoquinone (TQ) during ethanol toxicity in rat prenatal cortical neurons at gestational day (GD) 17.5.

Results

We found that Met and TQ, separately and synergistically, increased cell viability after ethanol (100 mM) exposure for 12 hours and attenuated the elevation of cytosolic free calcium [Ca²⁺]_c. Furthermore, Met and TQ maintained normal physiological mitochondrial transmembrane potential (????_M), which is typically lowered by ethanol exposure. Increased cytosolic free [Ca²⁺]_c and lowered mitochondrial transmembrane potential after ethanol exposure significantly decreased the expression of a key anti-apoptotic protein (Bcl-2), increased expression of Bax, and stimulated the release of cytochrome-c from mitochondria. Met and TQ treatment inhibited the apoptotic cascade by increasing Bcl-2 expression. These compounds also repressed the activation of caspase-9 and caspase-3 and reduced the cleavage of PARP-1. Morphological conformation of cell death was assessed by TUNEL, Fluoro-Jade-B, and PI staining. These staining methods demonstrated more cell death after ethanol treatment, while Met, TQ or Met plus TQ prevented ethanol-induced apoptotic cell death.

Conclusion

These findings suggested that Met and TQ are strong protective agents against ethanol-induced neuronal apoptosis in primary rat cortical neurons. The collective data demonstrated that Met and TQ have the potential to ameliorate ethanol neurotoxicity and revealed a possible protective target mechanism for the damaging effects of ethanol during early brain development.     

Pyrazolidine-3,5-dione angiotensin-II receptor antagonists

The crystal structures of three angiotensin-II receptor antagonists involving different spacer groups (CO, CONH and NHCO) between the aryl rings are presented, namely 2-{4-[(3-butyl-1,4-dioxo-2,3-di­aza­spiro­[4.4]­non-2-yl)­methyl]­benzoyl}benzoic acid, C₂₆H₂₈N₂O₅, (I), 2-{4-[(3-butyl-1,4-dioxo-2,3-di­aza­spiro­[4.4]­non-2-yl)­methyl]­benz­amido}benzoic acid, C₂₆H₂₉N₃O₅, (II), and 2-{4-[(3-butyl-1,4-dioxo-2,3-di­azaspiro­[4.4]­non-2-yl)­methyl]­anilino­carbonyl}benzoic acid monohydrate, C₂₆H₂₉N₃O₅·H₂O, (III). The aryl rings of (II) are almost coplanar, in contrast with compounds (I) and (III). The conformation of (II) is induced by an intramolecular N—H⋯O hydrogen bond between the amide and carboxyl­ic acid groups.     

Studies on pyrrolidinones. Synthesis and cyclization of N‐[α‐naphthyl‐(3,4,5‐trimethoxyphenyl)‐methyl]pyroglutamic acid

Condensation of trimethoxyphenyl naphthylcarbinol trimethylsilyl ether with methyl N‐trimethylsilyl‐pyroglutamate yields two separable esters. The Friedel‐Crafts cyclization of the acids obtained after saponification gives analogs of azapodophylloxin. Reduction and treatment of the obtained products with hydrobromic acid yields analogs of azatoxin.     

Pentacarbonyl(di‐2‐pyridyl­amine)tungsten(0)

In the title molecular complex, (I), the W atom is in an octahedral environment with four equatorial carbonyl ligands and a fifth in an axial position trans to the monodentate dipyridyl­amine ligand. The long dimension of this last bisects the angle between two of the equatorial carbonyl groups and while the non‐bonded pyridyl N atom is directed away from the W atom, the bridging amine group is directed towards it. Thus, in addition to the N atom to which it is attached, the amino H has two nearest neighbour C atoms of equatorial carbonyl groups but does not participate in hydrogen bonding in any real or usual sense. The W—C bond distance for the axial carbonyl group is notably less than those of the equatorial groups.     

Terbogrel,a dual‐acting agent for thromboxane receptor antagonism and thromboxane synthase inhibition

Terbogrel, (E)‐6‐[4‐(3‐tert‐butyl‐2‐cyano­guanidino)­phenyl]‐6‐(3‐pyridyl)­hex‐5‐enoic acid, C₂₃H₂₇N₅O₂, a mixed thromboxane A₂ receptor antagonist and thromboxane A₂ synthase inhibitor, shows a hairpin‐like conformation stabilized by an intramolecular hydrogen bond. A structural feature characteristic of the thromboxane A₂ synthase inhibitor mode is observed: a distance of 8.4257 (19) Å between the pyridine N atom and the carboxyl group.     

Differential Complexing by Cyclodextrin Twin-cavity Hosts

The twin-cavity cyclodextrin (1) in which the link is a dithiotrehalosyl unit, and the flexibly-linked dimer (2) were shown to distinguish between the heterocyclic guests 3 and 4 (clofazimine drug) in spite of the guests' small structural difference. Both cyclodextrin dimer hosts form 1:1 complexes with methyl orange and with 3, as shown by double reciprocal plots of UV-absorbance change and host concentration. However with 4, both host molecules formed a 2 : 1 (host : guest) complex . Since both dimer cavities are used to create this effect, it is a new type of selectivity for macrocyclic hosts.     

Synthesis of amphiphilic polyelectrolyte block copolymers using “living” radical polymerization. Application as stabilizers in emulsion polymerization

This paper describes the synthesis of amphiphilic block copolymers composed of an ionic poly(styrenesulfonate) first segment and a hydrophobic polystyrene second one, using TEMPO-mediated “living” radical polymerization. These copolymers proved to be efficient stabilizers in the emulsion polymerization of styrene.     

Nitroxide-mediated miniemulsion polymerization of n-butyl acrylate: synthesis of controlled homopolymers and gradient copolymers with styrene

Controlled free-radical homopolymerization of n-butyl acrylate and its copolymerization with styrene have been studied in aqueous miniemulsion, using an acyclic β-phosphonylated nitroxide as a mediator, the N-tert-butyl-N-(1-diethylphosphono-2,2-dimethylpropyl) nitroxide, also called SG1. Polymerization kinetics have been studied and characterization of the (co)polymers has been performed, demonstrating the successful synthesis of well-defined poly(n-butyl acrylate) homopolymers and poly(n-butyl acrylate-co-styrene) gradient copolymers.     

Pulsed‐laser radical polymerization and propagation kinetic parameters of some alkyl acrylates

Pulsed‐laser photoinitiated polymerization was used to determine, in toluene solution, the propagation kinetic parameters of a series of acrylates with increasing size of the alkyl side group. Transfer to monomer and to toluene did not occur significantly in our PLP conditions and our temperature range since no broadening of the MMD was observed, allowing generally to work with two inflection points. In contrast, depending on the nature of the acrylate and on the PLP conditions, transfer to polymer, and thus long chain branching, can critically interfere. Indeed, the Mark‐Houwink‐Sakurada parameters, which are used to calculate the absolute molar mass at the inflection point, strongly depend on the polymer structure and thus, should be carefully measured for each PLP sample. Although still preliminary, the results show that the k_ps measured in toluene solution present a tendency to continuously decrease when increasing the size of the side group. This observation is conflicting with the reported behaviour for PLP experiments in bulk, revealing a possible solvent effect.     

Functionalized latexes as substrates for atom transfer radical polymerization

The application of atom transfer radical polymerization (ATRP) to the homopolymerization of 2‐hydroxyethyl acrylate and 2‐(methacryloyloxy) ethyl trimethylammonium chloride at the surface of a crosslinked polystyrene latex functionalized with alkyl bromide groups is reported. Polymerization was carried out using the surface groups of the dialyzed latex as initiators. The resulting hydrophobic core, hydrophilic shell latexes, were analyzed by FTIR, ¹³C‐NMR spectroscopy, and dynamic light scattering.