Thioredoxin glutathione reductase from Schistosoma mansoni: an essential parasite enzyme and a key drug target.

Background: Schistosomiasis--infection with helminth parasites in the genus Schistosoma, including S. mansoni--is a widespread, devastating tropical disease affecting more than 200 million people. No vaccine is available, and praziquantel, the only drug extensively utilized, is currently administered more than 100 million people yearly.

Profiling Schistosoma mansoni development using serial analysis of gene expression (SAGE).

Despite the widespread use of chemotherapy and other control strategies over the past 50years, transmission rates for schistosomiasis have changed little. Regardless of the approach used, future control efforts will require a more complete understanding of fundamental parasite biology. Schistosomes undergo complex development involving an alteration of parasite generations within a mammalian and freshwater molluscan host in the completion of its lifecycle.

Protection against myocardial ischemia/reperfusion injury in TLR4-deficient mice is mediated through a phosphoinositide 3-kinase-dependent mechanism.

TLRs play a critical role in the induction of innate and adaptive immunity. However, TLRs have also been reported to mediate the pathophysiology of organ damage following ischemia/reperfusion (I/R) injury. We have reported that TLR4(-/-) mice show decreased myocardial injury following I/R; however, the protective mechanisms have not been elucidated.

Differential regulation of lipopolysaccharide and Gram-positive bacteria induced cytokine and chemokine production in macrophages by Galpha(i) proteins.

Heterotrimeric G(i) proteins play a role in signalling activated by lipopolysaccharide (LPS), Staphylococcus aureus (SA) and group B streptococci (GBS), leading to production of inflammatory mediators. We hypothesized that genetic deletion of G(i) proteins would alter cytokine and chemokine production induced by LPS, SA and GBS stimulation. LPS-induced, heat-killed SA-induced and heat-killed GBS-induced cytokine and chemokine production in peritoneal macrophages from wild-type (WT), Galpha(i2) (-/-) or Galpha(i1/3) (-/-) mice were investigated.

Syk-dependent ERK activation regulates IL-2 and IL-10 production by DC stimulated with zymosan.

Zymosan is a particulate yeast preparation that elicits high levels of IL-2 and IL-10 from dendritic cells (DC) and engages multiple innate receptors, including the Syk-coupled receptor dectin-1 and the MyD88-coupled receptor TLR2. Here, we show that induction of IL-2 and IL-10 by zymosan requires activation of ERK MAP kinase in murine DC. Surprisingly, ERK activation in response to zymosan is completely blocked in Syk-deficient DC and unaffected by MyD88 deficiency.

Effects of amino acid substitutions at glycine 420 on SR-BI cholesterol transport function.

Scavenger receptor class B type I (SR-BI) facilitates the uptake of HDL cholesteryl esters (CEs) in a two-step process involving binding of HDL to its extracellular domain and transfer of HDL core CEs to a metabolically active membrane pool, where they are subsequently hydrolyzed by a neutral CE hydrolase. Recently, we characterized a mutant, G420H, which replaced glycine 420 in the extracellular domain of SR-BI with a histidine residue and had a profound effect on SR-BI function. The G420H mutant receptor exhibited a reduced ability to mediate selective HDL CE uptake and was unable to deliver HDL CE for hydrolysis, despite the fact that it retained the ability to bind HDL.

Dectin-1 promotes fungicidal activity of human neutrophils.

Human polymorphonuclear leukocytes (PMN) are a first line of defense against fungal infections. PMN express numerous pattern recognition receptors (PRR) that facilitate identification of invading microorganisms and ultimately promote resolution of disease. Dectin-1 (beta-glucan receptor) is a PRR expressed on several cell types and has been studied on monocytes and macrophages.

Challenges in the development of mGluR5 positive allosteric modulators: the discovery of CPPHA.

This Letter describes, for the first time, the synthesis and SAR, developed through an iterative analog library approach, that led to the discovery of the positive allosteric modulator (PAM) of the metabotropic glutamate receptor mGluR5 CPPHA. Binding to a unique allosteric binding site distinct from other mGluR5 PAMs, CPPHA has been the focus of numerous pharmacology studies by several laboratories.

Optical molecular imaging in drug discovery and clinical development.

Recently, the drug discovery process has greatly benefited from a wealth of novel druggable targets following the sequencing of the human genome and the parallel development of combinatorial chemistry and high-throughput screening technologies. The large number of drug candidates generated by this combined approach requires an evolution and refinement of in vivo measurement methodologies and animal models to cope with this flux of novel compounds. At the same time, drug developers are looking for translational biomarkers that can facilitate the clinical evaluation of the most promising molecules.

Synthesis and SAR of GlyT1 inhibitors derived from a series of N-((4-(morpholine-4-carbonyl)-1-(propylsulfonyl)piperidin-4-yl)methyl)benzamides.

This Letter describes the synthesis and SAR, developed through an iterative analog library approach, of potent and selective non-sarcosine-derived GlyT1 inhibitors.

Differential regulation of lipopolysaccharide and Gram-positive bacteria induced cytokine and chemokine production in splenocytes by Galphai proteins.

Heterotrimeric Gi proteins play a role in lipopolysaccharide (LPS) and Staphylococcus aureus (SA) activated signaling leading to inflammatory mediator production. We hypothesized that genetic deletion of Gi proteins would alter cytokine and chemokine production induced by LPS and SA. LPS- and heat killed SA-induced cytokine and chemokine production in splenocytes from wild type (WT), Galpha(i2) (-/-) or Galpha(i1/3) (-/-) mice were investigated.

Prevalence of feline cataract: results of a cross-sectional study of 2000 normal animals, 50 cats with diabetes and one hundred cats following dehydrational crises.

Objective: In this study 2000 normal cats, 50 cats with diabetes and 100 cats with a history of dehydrational crises were examined ophthalmoscopically to determine presence of cataract.

Materials And Methods: The cats examined were predominantly from veterinary hospital populations but also from re-homing facilities and breeding catteries. Prevalence of cataract was determined for different age groups (year cohorts).

The effect of a topical antioxidant formulation including N-acetyl carnosine on canine cataract: a preliminary study.

Objective: To determine the efficacy of a topical antioxidant formulation including N-acetyl carnosine in the treatment of canine cataract in a preliminary nonplacebo, controlled, unmasked study.

Animals Studied: Thirty dogs of varying breeds and ages with a spectrum of lens opacities ranging from nuclear sclerosis to total mature cataract.

Methods: Dogs were treated three times daily with topical 2% N-acetyl carnosine in a buffered vehicle containing the antioxidants glutathione, cysteine ascorbate, L-taurine and riboflavin (Ocluvet, Practivet, Phoenix, AZ, USA).

Oxidation, antioxidants and cataract formation: a literature review.

Purpose: This review aims to provide a literature survey of the association between photo-oxidation of lens proteins and lipid peroxidation with the genesis of age-related cataract in laboratory studies using rodent models, in epidemiological and interventional studies in humans.

Materials And Methods: A Medline search using initial search terms lens, oxidation, antioxidant, and diet was employed to search for research papers covering the areas noted above from 1995 to 2005. Literature cited in those papers was also reviewed to provide as comprehensive a coverage of research work as possible.

Soluble Dectin-1 as a tool to detect beta-glucans.

Beta-glucans are structural components of fungal cell walls which are involved in the immune recognition of fungal pathogens and possess beneficial immunomodulatory activities in isolated form. Here we have developed a soluble chimeric form of the major mammalian beta-glucan receptor, Dectin-1, and demonstrate its application for the detection and characterisation of soluble and insoluble beta-glucans, including fungal particles, using ELISA, flow cytometric and fluorescence-based microscopy assays.

Glucan phosphate attenuates cardiac dysfunction and inhibits cardiac MIF expression and apoptosis in septic mice.

Myocardial dysfunction is a major consequence of septic shock and contributes to the high mortality of sepsis. We have previously reported that glucan phosphate (GP) significantly increased survival in a murine model of cecal ligation and puncture (CLP)-induced sepsis. In the present study, we examined the effect of GP on cardiac dysfunction in CLP-induced septic mice.

Gi proteins regulate lipopolysaccharide and Staphylococcus aureus induced cytokine production but not (1--> 3)-beta-D-glucan induced cytokine suppression.

Previous studies have demonstrated that bacterial lipopolysaccharide (LPS) and heat killed Staphylococcus aureus (SA) activation of inflammatory cells depended in part upon activation of heterotrimeric Gi proteins. It has also been shown that (1 --> 3) beta-D-glucan can suppress inflammatory cell activation by microbial products although the cellular mechanism of the glucan effect remains to be clearly defined. We hypothesized that Gi proteins function as a common convergent signaling pathway for both LPS and SA leading to monocyte mediator production.

The serotonin transporter in rhesus monkey brain: comparison of DASB and citalopram binding sites.

We have characterized the interaction of the serotonin transporter ligand [3H]-N,N-dimethyl-2-(2-amino-4-cyanophenylthio)-benzylamine (DASB) with rhesus monkey brain in vitro using tissue homogenate binding and autoradiographic mapping. [3H]-DASB, a tritiated version of the widely used [11C] positron emission tomography tracer, was found to selectively bind to a single population of sites with high affinity (K(d)=0.20+/-0.

Progress towards validating the NMDA receptor hypofunction hypothesis of schizophrenia.

This article describes recent progress towards validation of the N-methyl-D-aspartate (NMDA) receptor hypofunction hypothesis of schizophrenia in preclinical models. Schizophrenia, a complex disease characterized by positive, negative and cognitive symptoms, affects 1% of the world population and requires lifelong, daily maintenance therapy. For the last several decades, thinking in this field has been dominated by the hypothesis that hyperfunction of dopamine pathways played a key role in schizophrenia.

Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors.

The fungal pathogen Candida albicans has a multilayered cell wall composed of an outer layer of proteins glycosylated with N- or O-linked mannosyl residues and an inner skeletal layer of beta-glucans and chitin. We demonstrate that cytokine production by human mononuclear cells or murine macrophages was markedly reduced when stimulated by C. albicans mutants defective in mannosylation.

Modulation of the phosphoinositide 3-kinase signaling pathway alters host response to sepsis, inflammation, and ischemia/reperfusion injury.

The phosphoinositide 3-kinases (PI3Ks) are a conserved family of signal transduction enzymes that are involved in regulating cellular activation, inflammatory responses, chemotaxis, and apoptosis. We have discovered that a carbohydrate ligand, glucan, will stimulate the endogenous PI3K/Akt signaling pathway. This article reviews the current data on the role of the PI3K/Akt signaling pathway as a negative feedback mechanism or compensatory regulator of septic and inflammatory responses.

Prolonged reduction of leukocyte membrane-associated Dectin-1 levels following beta-glucan administration.

Dectin-1 is the primary pattern recognition receptor for fungal glucans. Dectin-1 mediates the internalization and biological response to glucans. We examined the effect of i.