ホルムアルデヒド反復経気道暴露のモルモット喘息モデルに及ぼす影響に関する研究

取得学位 : 博士（医学）, 学位授与番号 : 医博乙第1496号, 学位授与年月日：平成11年5月19日,学位授与年：199

Crystal Structure of the Complex between Calyculin A and the Catalytic Subunit of Protein Phosphatase 1

AbstractThe crystal structure of the catalytic subunit of the protein phosphatase 1 (PP1), PP1γ, in complex with a marine toxin, calyculin A, was determined at 2.0 Å resolution. The metal binding site contains the phosphate group of calyculin A and forms a tight network via the hydrophilic interactions between PP1 and calyculin A. Calyculin A is located in two of the three grooves, namely, in the hydrophobic groove and the acidic groove on the molecular surface. This is the first observation to note that the inhibitor adopts not a pseudocyclic conformation but an extended conformation in order to form a complex with the protein. The amino acid terminus of calyculin A contributes, in a limited manner, to the binding to PP1γ, which is consistent with findings from the studies of dose-inhibition analysis

Western North Pacific Integrated Physical-Biogeochemical Ocean Observation Experiment (INBOX): Part 1.Specifications and chronology of the S1-INBOX floats

An interdisciplinary project called the Western North Pacific Integrated Physical-Biogeochemical Ocean Observation Experiment (INBOX) has been conducted since 2011. In the oligotrophic subtropics south of the Kuroshio Extension near biogeochemical mooring S1 (30° N, 145° E), 18 floats, each with a dissolved oxygen sensor, have been deployed in a 150 × 150 km square area. With the horizontal (30 km) and temporal (2 days) resolution of the data, we observed an upper ocean structure associated with mesoscale eddies and ocean responses to atmospheric forcing. The data set obtained from the S1-INBOX study was used to elucidate the impacts of physical processes on biogeochemical phenomena. This article is the first in a series of articles: specific information about the floats and a chronology of events are provided

Airway wall structure assessed by endobronchial ultrasonography and bronchial hyperresponsiveness in patients with asthma

金沢大学医薬保健研究域医学系Background and Objective: The purpose of this study was to evaluate the relationship between the wall structure assessed by using endobronchial ultrasonography (EBUS) and bronchial hyperresponsiveness in patients with asthma. Methods: Twenty-four patients with stable asthma and 11 individuals without asthma were studied. EBUS was performed with a radial 20-MHz ultrasonic probe inserted into the intermediate bronchus undergoing flexible bronchoscopy to assess the airway wall structure. The percentage of airway wall thickness {WT%; defined as [(ideal outer diameter-ideal luminal diameter)/ideal outer diameter] × 100} was determined by EBUS. We measured bronchial hyperresponsiveness to methacholine [the provocative concentration of methacholine causing a decrease of 20% or more in forced expiratory volume in 1 s (PC20)]. Results: Percentage wall thickness measured by EBUS was significantly greater in patients with asthma than that in subjects without asthma (P < 0.01). The evaluation of the laminar structure using EBUS indicated that the thickness of the second layer in patients with asthma was greater than that in subjects without asthma (P < 0.05). PC20 was negatively correlated with the thickness of the second layer (r=0.52, P < 0.01) but was not significantly correlated with other layers in patients with asthma. Conclusions: The evaluation of the bronchial mural structure using EBUS might be advantageous for assessing the relationship between airway wall remodeling and bronchial hyperresponsiveness. © 2010 Lippincott Williams & Wilkins

Purification, crystallization and preliminary X-ray diffraction studies of N-acetylglucosamine-phosphate mutase from Candida albicans

Preliminary X-ray diffraction studies on N-acetylglucosamine-phosphate mutase from C. albicans are reported

Acute eosinophilic pneumonia following cigarette smoking: A case report including cigarette-smoking challenge test

金沢大学医薬保健研究域医学系A 21-year-old woman presented with acute progressive dyspnea. Chest computed tomography (CT) revealed diffuse bilateral infiltrates. Based on the results of transbronchial lung biopsy (TBLB) and bronchoalveolar lavage fluid (BALF) and her clinical course, she was diagnosed as having acute eosinophilic pneumonia. We suspected that the disease was related to smoking because she had started smoking ten days before the onset of symptoms. Therefore, a cigarette-smoking challenge test was done with the patient\u27s informed consent. After the challenge, eosinophilic pneumonia was documented by BALF and TBLB findings, which were similar to those detected on admission, without significant radiographic findings

Neuropeptide signaling through neurokinin-1 and neurokinin-2 receptors augments antigen presentation by human dendritic cells

Background: Neurotransmitters, including substance P (SP) and neurokinin A (NKA), are widely distributed in both the central and peripheral nervous system and their receptors, neurokinin-1 receptor (NK1R) and neurokinin-2 receptor (NK2R), are expressed on immune cells. However, the role of the NKA-NK2R axis in immune responses relative to the SP-NK1R signaling cascade has not been elucidated. Objective: We sought to examine the effect of neuropeptide signaling through NK1Rand NK2R on antigen presentation by dendritic cells (DCs) and the subsequent activation of effector Th cells. Methods: Expression levels of NK1R, NK2R, HLA-class II and costimulatory molecules of human MoDCs and cytokine production by birch pollen antigen-specific CD4+ T cells cocultured with MoDCs in the presence of NK1R and NK2R antagonists were evaluated by quantitative RT-PCR, flow cytometry or ELISA. NK1R and NK2R expression in the lung of patients with asthma and hypersensitivity pneumonitis was evaluated by immunohistochemistry. Results: Human MoDCs significantly upregulated NK2R and NK1R expression in response to poly I:C stimulation in a STAT1-dependent manner. Both NK2R and NK1R were expressed on alveolar macrophages and lung DCs from patients with asthma and pneumonitis hypersensitivity. Surface expression levels of HLA-class II and costimulatory molecules on DCs were modulated by NK1R or NK2R antagonists. Activation of birch pollen-derived antigen-specific CD4+ T cells and their production of cytokines including IL-4 and IFN-γ as well as IL-12 production by MoDCs, were suppressed by blocking NK1R or NK2R after in vitro antigen stimulation. Conclusions: NK1R- and NK2R-mediated neuropeptide signaling promotes both innate and acquired immune responses through activation of human DCs

Comparison of cough reflex sensitivity after an inhaled antigen challenge between actively and passively sensitized guinea pigs

BACKGROUND: Late asthmatic response is observed following antigen challenge in actively, but not passively, sensitized guinea pigs. Although cough reflex sensitivity is increased after antigen challenge in actively sensitized guinea pigs, it is unknown whether the antigen-induced increase in cough reflex sensitivity develops in passively sensitized animals. The aim of this study was to compare the cough reflex sensitivity to inhaled capsaicin after an inhaled antigen challenge between actively and passively sensitized guinea pigs. METHODS: Measurement of number of coughs elicited by increasing concentrations of capsaicin (10(-6 )and 10(-4 )M) and bronchial responsiveness to ascending concentrations of methacholine, and analysis of bronchoalveolar lavage fluid (BALF) were separately performed 24 h after an antigen challenge in actively and passively sensitized guinea pigs. RESULTS: Percentage of eosinophils in BALF and bronchial responsiveness to methacholine were increased 24 h after the antigen challenge in both actively and passively sensitized animals compared with saline-challenged actively and passively sensitized animals, respectively. Absolute number of eosinophils in BALF from actively sensitized and antigen-challenged guinea pigs was significantly greater than that from passively sensitized and antigen-challenged animals. Cough response to capsaicin and concentration of substance P in BALF were increased 24 h after the antigen challenge in actively sensitized guinea pigs, but not in passively sensitized guinea pigs. Bronchial responsiveness, cough reflex sensitivity and substance P concentration and total cells in BALF were increased in actively sensitized and saline challenged guinea pigs compared with passively sensitized and saline challenged animals. CONCLUSION: The results suggest that active sensitization per se increases cough reflex sensitivity accompanied by increased inflammatory cells and substance P level in BALF, and antigen challenge further increases them, while simple IgE- and/or IgG-mediated allergic reaction per se or the low intensity of eosinophil infiltration in the airway itself may not affect cough reflex sensitivity in guinea pigs

Inhibitory effects of local anesthetics on the proteasome and their biological actions

Local anesthetics (LAs) inhibit endoplasmic reticulum-associated protein degradation, however the mechanisms remain elusive. Here, we show that the clinically used LAs pilsicainide and lidocaine bind directly to the 20S proteasome and inhibit its activity. Molecular dynamic calculation indicated that these LAs were bound to the β5 subunit of the 20S proteasome, and not to the other active subunits, β1 and β2. Consistently, pilsicainide inhibited only chymotrypsin-like activity, whereas it did not inhibit the caspase-like and trypsin-like activities. In addition, we confirmed that the aromatic ring of these LAs was critical for inhibiting the proteasome. These LAs stabilized p53 and suppressed proliferation of p53-positive but not of p53-negative cancer cells