Triclorosilane-mediated stereoselective synthesis of beta-amino esters and their conversion to highly enantiomerically enriched beta-lactams

A highly stereoselective trichlorosilane-mediated reduction of N-benzyl enamines was developed; the combination of a low cost, easy to make metal-free catalyst and an inexpensive chiral auxiliary allowed to perform the reaction on substrates with different structural features often with total control of the stereoselectivity. By easy deprotection through hydrogenolysis followed by conversion of \u3b2-aminoester to 2-azetidinones, the synthesis of enantiomerically pure \u3b2-lactams (>98% e.e.) was successfully accomplished

Mechanistic investigations of the asymmetric hydrosilylation of ketimines with trichlorosilane reveals a dual activation model and an organocatalyst with enhanced efficiency.

Structural probes used to help elucidate mechanistic information of the organocatalyzed asymmetric ketimine hydrosilylation have revealed a new catalyst with unprecedented catalytic activity, maintaining adequate performance at 0.01 mol% loading. A new 'dual activation' model has been proposed that relies on the presence of both a Lewis basic and Brønsted acidic site within the catalyst architecture

Portable instrument for in-vivo infrared oxymetry using spread-spectrum modulation

Near Infrared Spectroscopy (NIRS) can be employed to monitor noninvasively and continuously local changes in hemodynamics and oxygenation of human tissues. A portable NIRS research-grade acquisition system, dedicated to measurements during muscular exercise, is presented. The instrument is able to control up to eight LED sources and two detectors. A digital correlation technique, implemented on a single-chip RISC microcontroller, performs source-to-detector multiplexing. Such algorithm is highly optimized for computational efficiency and ambient noise rejection. Software-configurable input stages allow for flexibility in instrument setup. As a result of the specific correlation technique employed, the instrument is compact, lightweight and efficient. Clinical tests on oxygen consumption show excellent performance

Portable instrument for in-vivo infrared oxymetry using spread-spectrum modulation

Near Infrared Spectroscopy (NIRS) can be employed to monitor noninvasively and continuously local changes in hemodynamics and oxygenation of human tissues. A portable NIRS research-grade acquisition system, dedicated to measurements during muscular exercise, is presented. The instrument is able to control up to eight LED sources and two detectors. A digital correlation technique, implemented on a single-chip RISC microcontroller, performs source-to-detector multiplexing. Such algorithm is highly optimized for computational efficiency and ambient noise rejection. Software-configurable input stages allow for flexibility in instrument setup. As a result of the specific correlation technique employed, the instrument is compact, lightweight and efficient. Clinical tests on oxygen consumption show excellent performance

Monitoring the Fate of Orally Administered PLGA Nanoformulation for Local Delivery of Therapeutic Drugs

One of the goals of the pharmaceutical sciences is the amelioration of targeted drug delivery. In this context, nanocarrier-dependent transportation represents an ideal method for confronting a broad range of human disorders. In this study, we investigated the possibility of improving the selective release of the anti-cancer drug paclitaxel (PTX) in the gastro-intestinal tract by encapsulating it into the biodegradable nanoparticles made by FDA-approved poly(lactic-co-glycolic acid) (PLGA) and coated with polyethylene glycol to improve their stability (PLGA-PEG-NPs). Our study was performed by combining the synthesis and characterization of the nanodrug with in vivo studies of pharmacokinetics after oral administration in mice. Moreover, fluorescent PLGA-nanoparticles (NPs), were tested both in vitro and in vivo to observe their fate and biodistribution. Our study demonstrated that PLGA-NPs: (1) are stable in the gastric tract; (2) can easily penetrate inside carcinoma colon 2 (CaCo2) cells; (3) reduce the PTX absorption from the gastrointestinal tract, further limiting systemic exposure; (4) enable PTX local targeting. At present, the oral administration of biodegradable nanocarriers is limited because of stomach degradation and the sink effect played by the duodenum. Our findings, however, exhibit promising evidence towards our overcoming these limitations for a more specific and safer strategy against gastrointestinal disorders

Glycosylation defects underlying fetal alcohol spectrum disorder: a novel pathogenetic model: “When the wine goes in, strange things come out” – S.T. Coleridge, The Piccolomini

Fetal alcohol spectrum disorder (FASD) is an umbrella term used to describe the craniofacial dysmorphic features, malformations, and disturbances in growth, neurodevelopment and behavior occurring in individuals prenatally exposed to alcohol. Fetal alcohol syndrome (FAS) represents the severe end of this spectrum. Many pathophysiological mechanisms have hitherto been proposed to account for the disrupted growth and morphogenesis seen in FAS. These include impaired cholesterol-modification of the Sonic hedgehog morphogen, retinoic acid deficiency, lipoperoxidative damage due to alcohol-induced reactive oxygen species combined with reduced antioxidant defences, and malfunctioning cell adhesion molecules. In this report, we propose a completely novel concept regarding the pathogenesis of FAS. Based on our observation that transferrin isoelectric focusing (TIEF) – the most widely used screening tool for congenital disorders of glycosylation (CDG) – was transiently abnormal in a newborn with FAS and a confirmed maternal history of gestational alcohol abuse, we came to believe that FAS exemplifies a congenital disorder of glycosylation secondary to alcohol-inflicted disruption of (N-linked) protein glycosylation. Various pieces of evidence were found in the literature to substantiate this hypothesis. This observation implies, among others, that one might need to consider the possibility of maternal alcohol consumption in newborns with transient glycosylation abnormalities. We also present an integrated pathophysiological model of FAS, which incorporates all existing theories mentioned above as well as our novel concept. This model highlights the pivotal role of disrupted isoprenoid metabolism in the origination of FAS

Two common nonsynonymous paraoxonase 1 (PON1) gene polymorphisms and brain astrocytoma and meningioma

<p>Abstract</p> <p>Background</p> <p>Human serum paraoxonase 1 (PON1) plays a major role in the metabolism of several organophosphorus compounds. The enzyme is encoded by the polymorphic gene <it>PON1</it>, located on chromosome 7q21.3. Aiming to identify genetic variations related to the risk of developing brain tumors, we investigated the putative association between common nonsynonymous <it>PON1 </it>polymorphisms and the risk of developing astrocytoma and meningioma.</p> <p>Methods</p> <p>Seventy one consecutive patients with brain tumors (43 with astrocytoma grade II/III and 28 with meningioma) with ages ranging 21 to 76 years, and 220 healthy controls subjects were analyzed for the frequency of the nonsynonymous <it>PON1 </it>genotypes L55M rs854560 and Q192R rs662. All participants were adult Caucasian individuals recruited in the central area of Spain.</p> <p>Results</p> <p>The frequencies of the <it>PON1 </it>genotypes and allelic variants of the polymorphisms <it>PON1 </it>L55M and <it>PON1 </it>Q192R did not differ significantly between patients with astrocytoma and meningioma and controls. The minor allele frequencies were as follows: <it>PON1 </it>55L, 0.398, 0.328 and 0.286 for patients with astrocytoma, meningioma and control individuals, respectively; <it>PON1 </it>192R, 0.341, 0.362 and 0.302 for patients with astrocytoma, meningioma and control individuals, respectively. Correction for age, gender, or education, made no difference in odds ratios and the <it>p </it>values remained non-significant. Haplotype association analyses did not identify any significant association with the risk of developing astrocytoma or meningioma.</p> <p>Conclusions</p> <p>Common nonsynonymous <it>PON1 </it>polymorphisms are not related with the risk of developing astrocytoma and meningioma.</p

Signal transduction underlying the control of urinary bladder smooth muscle tone by muscarinic receptors and β-adrenoceptors

The normal physiological contraction of the urinary bladder, which is required for voiding, is predominantly mediated by muscarinic receptors, primarily the M3 subtype, with the M2 subtype providing a secondary backup role. Bladder relaxation, which is required for urine storage, is mediated by β-adrenoceptors, in most species involving a strong β3-component. An excessive stimulation of contraction or a reduced relaxation of the detrusor smooth muscle during the storage phase of the micturition cycle may contribute to bladder dysfunction known as the overactive bladder. Therefore, interference with the signal transduction of these receptors may be a viable approach to develop drugs for the treatment of overactive bladder. The prototypical signaling pathway of M3 receptors is activation of phospholipase C (PLC), and this pathway is also activated in the bladder. Nevertheless, PLC apparently contributes only in a very minor way to bladder contraction. Rather, muscarinic-receptor-mediated bladder contraction involves voltage-operated Ca2+ channels and Rho kinase. The prototypical signaling pathway of β-adrenoceptors is an activation of adenylyl cyclase with the subsequent formation of cAMP. Nevertheless, cAMP apparently contributes in a minor way only to β-adrenoceptor-mediated bladder relaxation. BKCa channels may play a greater role in β-adrenoceptor-mediated bladder relaxation. We conclude that apart from muscarinic receptor antagonists and β-adrenoceptor agonists, inhibitors of Rho kinase and activators of BKCa channels may have potential to treat an overactive bladder

A Role for Thrombospondin-1 Deficits in Astrocyte-Mediated Spine and Synaptic Pathology in Down's Syndrome

Down's syndrome (DS) is the most common genetic cause of mental retardation. Reduced number and aberrant architecture of dendritic spines are common features of DS neuropathology. However, the mechanisms involved in DS spine alterations are not known. In addition to a relevant role in synapse formation and maintenance, astrocytes can regulate spine dynamics by releasing soluble factors or by physical contact with neurons. We have previously shown impaired mitochondrial function in DS astrocytes leading to metabolic alterations in protein processing and secretion. In this study, we investigated whether deficits in astrocyte function contribute to DS spine pathology.Using a human astrocyte/rat hippocampal neuron coculture, we found that DS astrocytes are directly involved in the development of spine malformations and reduced synaptic density. We also show that thrombospondin 1 (TSP-1), an astrocyte-secreted protein, possesses a potent modulatory effect on spine number and morphology, and that both DS brains and DS astrocytes exhibit marked deficits in TSP-1 protein expression. Depletion of TSP-1 from normal astrocytes resulted in dramatic changes in spine morphology, while restoration of TSP-1 levels prevented DS astrocyte-mediated spine and synaptic alterations. Astrocyte cultures derived from TSP-1 KO mice exhibited similar deficits to support spine formation and structure than DS astrocytes.These results indicate that human astrocytes promote spine and synapse formation, identify astrocyte dysfunction as a significant factor of spine and synaptic pathology in the DS brain, and provide a mechanistic rationale for the exploration of TSP-1-based therapies to treat spine and synaptic pathology in DS and other neurological conditions

Cholinergic receptor pathways involved in apoptosis, cell proliferation and neuronal differentiation

Acetylcholine (ACh) has been shown to modulate neuronal differentiation during early development. Both muscarinic and nicotinic acetylcholine receptors (AChRs) regulate a wide variety of physiological responses, including apoptosis, cellular proliferation and neuronal differentiation. However, the intracellular mechanisms underlying these effects of AChR signaling are not fully understood. It is known that activation of AChRs increase cellular proliferation and neurogenesis and that regulation of intracellular calcium through AChRs may underlie the many functions of ACh. Intriguingly, activation of diverse signaling molecules such as Ras-mitogen-activated protein kinase, phosphatidylinositol 3-kinase-Akt, protein kinase C and c-Src is modulated by AChRs. Here we discuss the roles of ACh in neuronal differentiation, cell proliferation and apoptosis. We also discuss the pathways involved in these processes, as well as the effects of novel endogenous AChRs agonists and strategies to enhance neuronal-differentiation of stem and neural progenitor cells. Further understanding of the intracellular mechanisms underlying AChR signaling may provide insights for novel therapeutic strategies, as abnormal AChR activity is present in many diseases