No abstract

Thymic stromal lymphopoietin (TSLP) triggers dendritic cell-mediated T helper (Th) 2 inflammatory responses. A single-nucleotide polymorphism (SNP), rs3806933, in the promoter region of the TSLP gene creates a binding site for the transcription factor activating protein (AP)-1. The variant enhances AP-1 binding to the regulatory element, and increases the promoter-reporter activity of TSLP in response to polyinosinic-polycytidylic acid (poly[I:C]) stimulation in normal human bronchial epithelium (NHBE). We investigated whether polymorphisms including the SNP rs3806933 could affect the susceptibility to and clinical phenotypes of bronchial asthma. We selected three representative (i.e., Tag) SNPs and conducted association studies of the TSLP gene, using two independent populations (639 patients with childhood atopic asthma and 838 control subjects, and 641 patients with adult asthma and 376 control subjects, respectively). We further examined the effects of corticosteroids and a long-acting b 2 -agonist (salmeterol) on the expression levels of the TSLP gene in response to poly(I:C) in NHBE. We found that the promoter polymorphisms rs3806933 and rs2289276 were significantly associated with disease susceptibility in both childhood atopic and adult asthma. The functional SNP rs3806933 was associated with asthma (meta-analysis, P 5 0.000056; odds ratio, 1.29; 95% confidence interval, 1.14-1.47). A genotype of rs2289278 was correlated with pulmonary function. Moreover, the induction of TSLP mRNA and protein expression induced by poly(I:C) in NHBE was synergistically impaired by a corticosteroid and salmeterol. TSLP variants are significantly associated with bronchial asthma and pulmonary function. Thus, TSLP may serve as a therapeutic target molecule for combination therapy.Keywords: asthma; TSLP; bronchial epithelial cells; combination therapy; genetic polymorphisms Thymic stromal lymphoprotein (TSLP) is an epithelial cellderived cytokine that triggers dendritic cell-mediated T helper (Th) 2 inflammatory responses, and plays an important role in the initiation and maintenance of the allergic immune response (1-6). A recent study showed that TSLP is released by human epithelial cells in response to microbes, trauma, or inflammation, and potently activates mast cells (7). In humans, TSLP is highly expressed by airway epithelial cells during allergic inflammation (2), and the expression of the TSLP gene in asthmatic airways is correlated with both the expression of Th2-attracting chemokines and disease severity (3).Large numbers of association studies on asthma and asthmarelated phenotypes using genetic polymorphisms were performed in different populations (8). Recent studies showed roles of human genetic polymorphisms of the TSLP gene. A variant in TSLP was associated with reductions in IgE in response to cockroaches and total IgE in a sex-stratified analysis (9). A functional single-nucleotide polymorphism (SNP), rs3806933, was identified in the regulatory element of TSLP (10). The variant creates a binding site for a...

E2212, a novel γ-secretase modulator, is under development for the treatment of Alzheimer's disease. The safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending oral doses (10-250 mg, double-blind, placebo-controlled, randomized) of E2212 were evaluated. In this phase I clinical trial, E2212 was found to be well tolerated in single doses. Maximum tolerated dose was not achieved up to 250 mg. Most AEs were mild to moderate in severity with no identifiable dose related pattern. There were no clinically significant findings on physical and ophthalmologic examinations as well as vital signs, laboratory, ECG and C-SSRS assessments. E2212 was rapidly absorbed, with median tmax values ranging from 0.5 to 1.0 h. E2212 exhibited biphasic disposition with the terminal t1/2 of 12.5-19.0 h. Renal excretion was the minor pathway for E2212 elimination. Increased PD response (reduction in plasma concentrations of Aβ(x-42)) was observed with increasing doses. The maximum PD response was observed in the highest dose 250 mg cohort, with ΔAUAC(0-24 h) of 44.1% and Amax of 53.6%. These results support further clinical development of E2212.

No abstract

Alpha-aminoadipate aminotransferase (AAA-AT), a homolog of mammalian kynurenine aminotransferase II (Kat II), transfers an amino group to 2-oxoadipate to yield alpha-aminoadipate in lysine biosynthesis through the alpha-aminoadipate pathway in Thermus thermophilus. AAA-AT catalyzes transamination against various substrates, including AAA, glutamate, leucine, and aromatic amino acids. To elucidate the structural change for recognition of various substrates, we determined crystal structures of AAA-AT in four forms: with pyridoxal 5'-phosphate (PLP) (PLP complex), with PLP and leucine (PLP/Leu complex), with N-phosphopyridoxyl-leucine (PPL) (PPL complex), and with N-phosphopyridoxyl-alpha-aminoadipate (PPA) at 2.67, 2.26, 1.75, and 1.67 A resolution, respectively. The PLP complex is in an open state, whereas PLP/Leu, PPL, and PPA complexes are in closed states with maximal displacement (over 7 A) of the alpha2 helix and the beta1 strand in the small domain to cover the active site, indicating that conformational change is induced by substrate binding. In PPL and PLP/Leu complexes, several hydrophobic residues on the alpha2 helix recognize the hydrophobic side chain of the bound leucine moiety whereas, in the PPA complex, the alpha2 helix rotates to place the guanidium moiety of Arg23 on the helix at the appropriate position to interact with the carboxyl side chain of the AAA moiety. These results indicate that AAA-AT can recognize various kinds of substrates using the mobile alpha2 helix. The crystal structures and site-directed mutagenesis revealed that intersubunit-electrostatic interactions contribute to the elevated thermostability of this enzyme.

Backgrounds Acotiamide is a novel acetylcholinesterase inhibitor for treatment of postprandial distress syndrome (PDS) symptoms of functional dyspepsia (FD). This European phase 3 open‐label safety trial has been conducted to evaluate the long‐term safety of acotiamide and explore the efficacy of acotiamide on PDS symptoms using the validated LPDS, quality of life using SF‐36 and SF‐NDI, and work productivity using WPAI. Methods FD‐PDS patients (defined by ROME III criteria) aged ≥18 years with active PDS symptoms and without predominant overlapping symptoms of epigastric pain syndrome and related disorders were enrolled to receive 100 mg acotiamide three times daily for 1 year. Patients' safety profile and efficacy of acotiamide were monitored. Key Results The majority of patients (81.6%) maintained exposure to acotiamide for >50 weeks, with a mean duration of 320.3 days. No specific clinically significant safety concerns have been shown, with no deaths, treatment‐related severe/serious adverse events, or any clinically significant laboratory test results. Although being an open‐label trial, acotiamide showed a change in severity larger than the minimum clinically important difference at weeks 1 and 2 for postprandial fullness and early satiation (meal‐related symptoms), and showed improvement of quality of life and work productivity from the first measurement (at week 12) up to 1 year. Conclusions & Inferences The long‐term safety of acotiamide treatment was confirmed. A clinically important change for PDS symptoms, QoL, and work productivity was suggested; however a controlled trial is required to confirm this hypothetic efficacy of acotiamide. (NCT01973790).

No abstract

A digital imaging fluorescence microscope was used to study the effect of a protein kinase inhibitor staurosporine on the antigen-dependent calcium signals in an individual rat basophilic leukemia cell (RBL-2H3). Although dose dependency of staurosporine was different from one cell to another, staurosporine inhibited, at low concentration, the calcium influx from the external medium into RBL-2H3 cells. At high concentration, however, it inhibited both the removal of calcium ion from internal stores and the calcium influx from the external medium. These results indicated that staurosporine is necessary for the inhibition of the calcium influx from the external medium and that a protein kinase (possibly protein kinase C) is involved in the calcium influx from the external medium into the cytoplasm.