Search

Orai family are a calcium channel of cell membrane extracellular Ca

BACKGROUND AND PURPOSE Cytoplasmic retention of β-catenin will lead to its nuclear translocation and subsequent interaction with the transcription factor TCF/LEF that regulates target gene expression. We have previously demonstrated aberrant expression of β-catenin in a model of asthma induced by toluene diisocyanate (TDI). The aim of this study was to examine whether the receptor for advanced glycation end products (RAGE) can regulate β-catenin expression in TDI-induced asthma. EXPERIMENTAL APPROACH Male BALB/c mice were sensitized and challenged with TDI to generate a chemically-induced asthma model. Inhibitors of RAGE, FPS-ZM1 and the RAGE antagonist peptide (RAP), were injected i.p. after each challenge. Airway resistance was measured in vivo and bronchoalveolar lavage fluid was analysed. Lungs were examined by histology and immunohistochemistry. Western blotting and quantitative PCR were also used. KEY RESULTS Expression of RAGE and of its ligands HMGB1, S100A12, S100B, HSP70 was increased in TDI-exposed lungs. These increases were inhibited by FPS-ZM1 or RAP. Either antagonist blunted airway reactivity, airway inflammation and goblet cell metaplasia, and decreased release of Th2 cytokines. TDI exposure decreased level of membrane β-catenin, phosphorylated Akt (Ser(473) ), inactivated GSK3β (Ser(9) ), dephosphorylated β-catenin at Ser(33) /(37) /Thr(41) , which controls its cytoplasmic degradation, increased phosphorylated β-catenin at Ser(552) , raised cytoplasmic and nuclear levels of β-catenin and up-regulated its targeted gene expression (MMP2, MMP7, MMP9, VEGF, cyclin D1, fibronectin), all of which were reversed by RAGE inhibition. CONCLUSION AND IMPLICATIONS RAGE was required for stabilization of β-catenin in TDI-induced asthma, identifying protective effects of RAGE blockade in this model.

Introduction Fractional exhaled nitric oxide (FeNO) has been used as a marker of airway inflammation. Airway caliber is related to the level of FeNO in asthmatics. Objectives This study aimed to investigate whether airway obstruction could interfere with real FENO levels and if different FeNO changes after albuterol inhalation could assist in distinguishing asthma from chronic obstructive pulmonary disease (COPD). Methods FeNO and spirometry measurements were performed before and after albuterol inhalation in the following three patient groups: 30 steroid-naive asthmatics, 25 asthmatics inhaling corticosteroids/long-acting β(2)-adrenergic agonists for at least 1 month and 20 COPD patients. Bronchodilator test (BDT) results were positive in all patients enrolled. The correlations among FeNO levels, pulmonary function and sputum eosinophil counts were analyzed. Results FeNO increased significantly after albuterol inhalation in steroid-naive asthmatics but not in ICS-treated asthmatics or COPD patients. The FeNO levels demonstrated no significant correlation with spirometry results or sputum eosinophil counts before or after inhaling bronchodilator in all three groups. Both the levels of FeNO and changes in FENO after albuterol inhalation in steroid-naive asthma patients were higher than those in ICS-treated asthmatics and COPD patients (P

Background and objective: Invasive pulmonary aspergillosis (IPA) remains a life-threatening infection in patients with prolonged neutropenia. Few data are available on IPA in non-neutropenic patients without underlying immunocompromising conditions. Methods: All non-neutropenic patients managed at the institution for a proven and probable IPA over the last 10 years were reviewed retrospectively, and the difference between non-neutropenic patients with and without underlying disease was investigated. Results: Among 52 cases of IPA analysed here, 33 were histologically proven; 19 were probable. Forty-two (80.8%) patients had underlying diseases; 10 (19.2%) patients had no any underlying diseases. There is a significant difference in seasonal distribution among patients with underlying conditions (P = 0.026), but no seasonal difference was found in the other group (P = 0.622). The only significant difference in symptoms between the two groups was fever (P = 0.015). Radiological findings were non-specific in the two groups. Despite treatment, the overall crude mortality rate among 52 patients was 39%. The overall mortality rate in patients with underlying disease was 45%, while that in patients without underlying conditions was 11%. A Cox multivariate analysis showed that organ failure (hazard ratios: 8.739, 95% CI: 3.770–20.255; P = 0.000) was independently associated with overall mortality. Conclusions: Clinical features of IPA are not well known in non-neutropenic patients, especially in those without underlying conditions. In this study, organ failure was associated with a lower rate of survival of non-neutropenic patients with IPA.

A molecular electronegativity distance vector based on 13 atomic types (MEDV-13), is a descriptor for predicting the biological activities of molecules based on the quantitative structure-activity relationship (QSAR). The MEDV-13 with 91 descriptors is employed to describe the structures of a series of selective cyclooxygenase-2 (COX-2) inhibitors including 16 indomethacin and its amide and ester derivatives (ImAE). A principal component regression (PCR) is used to derive a QSAR model relating the biological activities expressed by p/C50 values to the MEDV-13. With the number of principal components of 6, the correlation coefficient (R) and the root mean square error (RMS) are 0.9245 and 0.1682 in modeling stage, and 0.8417 and 0.2389 in leave-one-out prediction step, respectively.

The molecular holographic distance vector (MHDV) is employed to characterize the structures of 51 substituted benzenes. 29 descriptors from 91 MHDV ones have nonzero values where 3 descriptors have only one nonzero sample and 1 descriptor only two nonzero samples. A genetic algorithm is used to select an optimal combination of the variables from the remaining 25 nonzero descriptors. Then the optimal descriptors are employed to relate to the relative biodegradability using multiple linear regression method. The 6-variable linear model developed has high quality where the correlation coefficient of estimations and the root mean square error of estimations are 0.9604 and 0.280, respectively, and the correlation coefficient of predictions and the root mean square error of predictions for leave-one-out procedure are 0.9471 and 0.324, respectively.

A novel molecular holographic distance vector (MHDV) is proposed to characterize the structures of the peptide molecules and employed to relate to the biological activities of the peptides by means of principal component regression (PCR) method. For two pan els of dipeptides, the correlation coefficient (R) between the estimated and the observed activities are respectively 0.9370 and 0.9585 and the R obtained by cross-validation method are respectively 0.8676 and 0.9295, which is the best result to date for the two sets of dipeptides. The novel MHDV descriptor only depends on distance matrix and various atomic types of non-hydrogen atoms in a molecule and requires no 3D structural information, so, it is a very simple and easy to use descriptor.

Objective Obesity is involved in the pathogenesis of obstructive sleep apnea syndrome (OSAS). Irisin, a recently discovered myokine, protects the mice from obesity. This study aims to determine the association of serum irisin concentrations with the presence and severity of OSAS. Methods This cross-sectional investigation was performed in 165 male OSAS patients and 98 healthy male subjects. Serum irisin concentrations were assessed using an enzyme-linked immunosorbent assay kit. Results The serum irisin concentrations of OSAS patients significantly decreased compared with the healthy controls (P

Surflex-Dock was employed to dock 36 thiourea and thiadiazolo [2,3-alpha] pyrimidine derivatives into neuraminidase 1a4g. Molecular docking results showed that hydrogen bonding, electrostatic, and hydrophobic features were important factors affecting inhibitory activities of these neuraminidase inhibitors. Moreover, there was a significant correlation between the predicted binding affinity (total scores) and experimental pIC50 values with correlation coefficient r=0.846 and p

A molecular electronegativity distance vector based on 13 atomic types, called MEDV-13, is a descriptor for predicting the biological activities of molecules based on the quantitative structure-activity relations (QSAR). The MEDV-13 uses a modified electrotopological state (E-state) index to substitute for the relative eletronegativity (q) of non-hydrogen atoms in the molecule of interest in the MEDV and a topological distance for the relative distance (d) in the MEDV. For an organic molecule containing several chemical elements such as C, H, O, N, S, F, Cl, Br, I, and P, the MEDV-13 includes at best 91 descriptors. Then it is essential to employ a principal component regression (PCR) technique to derive a QSAR model relating the biological activities to the MEDV-13. The MEDV-13 is used to study the QSAR of the corticosteroid-binding globulin (CBG) binding affinity of the steroids and the activity inhibiting angiotensin-converting enzyme (ACE) of dipeptides, and resulting models have a comparable quality to the current three-dimensional (3D) methods such as CoMFA though the MEDV-13 is a descriptor based on two-dimensional topological information.