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61.
Akihiro Honda Shotaro Kamata Makoto Akahane Yui Machida Kie Uchii Yui Shiiyama Yuki Habu Saeka Miyawaki Chihiro Kaneko Takuji Oyama Isao Ishii 《International journal of molecular sciences》2022,23(9)
Among the agonists against three peroxisome proliferator-activated receptor (PPAR) subtypes, those against PPARα (fibrates) and PPARγ (glitazones) are currently used to treat dyslipidemia and type 2 diabetes, respectively, whereas PPARδ agonists are expected to be the next-generation metabolic disease drug. In addition, some dual/pan PPAR agonists are currently being investigated via clinical trials as one of the first curative drugs against nonalcoholic fatty liver disease (NAFLD). Because PPARα/δ/γ share considerable amino acid identity and three-dimensional structures, especially in ligand-binding domains (LBDs), clinically approved fibrates, such as bezafibrate, fenofibric acid, and pemafibrate, could also act on PPARδ/γ when used as anti-NAFLD drugs. Therefore, this study examined their PPARα/δ/γ selectivity using three independent assays—a dual luciferase-based GAL4 transactivation assay for COS-7 cells, time-resolved fluorescence resonance energy transfer-based coactivator recruitment assay, and circular dichroism spectroscopy-based thermostability assay. Although the efficacy and efficiency highly varied between agonists, assay types, and PPAR subtypes, the three fibrates, except fenofibric acid that did not affect PPARδ-mediated transactivation and coactivator recruitment, activated all PPAR subtypes in those assays. Furthermore, we aimed to obtain cocrystal structures of PPARδ/γ-LBD and the three fibrates via X-ray diffraction and versatile crystallization methods, which we recently used to obtain 34 structures of PPARα-LBD cocrystallized with 17 ligands, including the fibrates. We herein reveal five novel high-resolution structures of PPARδ/γ–bezafibrate, PPARγ–fenofibric acid, and PPARδ/γ–pemafibrate, thereby providing the molecular basis for their application beyond dyslipidemia treatment. 相似文献
62.
Atsushi Kanamori Fumio Tanaka Masaki Ominami Yuji Nadatani Shusei Fukunaga Koji Otani Shuhei Hosomi Noriko Kamata Yasuaki Nagami Koichi Taira Yasuhiro Fujiwara 《International journal of molecular sciences》2022,23(15)
The effects of psychological stress on eosinophilic gastrointestinal disorders have not been elucidated. This study investigated the effects of psychological stress in a mouse model of eosinophilic enteritis (EoN). BALB/c mice were treated with ovalbumin (OVA) to create an EoN model and subjected to either water avoidance stress (WAS) or sham stress (SS). Microscopic inflammation, eosinophil and mast cell counts, mRNA expression, and protein levels of type 2 helper T cell (Th2) cytokines in the ileum were compared between groups. We evaluated ex vivo intestinal permeability using an Ussing chamber. A corticotropin-releasing hormone type 1 receptor (CRH-R1) antagonist was administered before WAS, and its effects were analyzed. WAS significantly increased diarrhea occurrence and, eosinophil and mast cell counts, and decreased the villus/crypt ratio compared to those in the SS group. The mRNA expression of CRH, interleukin IL-4, IL-5, IL-13, eotaxin-1, and mast cell tryptase β2 significantly increased, and the protein levels of IL-5, IL-13, and OVA-specific immunoglobulin E (IgE) also significantly increased in the WAS group. Moreover, WAS significantly increased the intestinal permeability. The CRH-R1 antagonist significantly inhibited all changes induced by WAS. Psychological stress exacerbated ileal inflammation via the CRH-mast cell axis in an EoN mouse model. 相似文献
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66.
Tetsuo Fukuchi Takuya Nayuki Koshichi Nemoto Kiichiro Uchino 《Electrical Engineering in Japan》2004,148(2):76-83
An acousto‐optic laser deflector was used as a shutter for high‐speed imaging of laser interference fringes using an ordinary CCD camera. The exposure duration was set by the pulse width of the high‐frequency signal applied to the acousto‐optic deflector. Changes in laser interference fringes due to an impulse discharge in air were obtained at an exposure duration of 4 µs. By applying a sequence of high‐frequency signals with different frequency, the beam was deflected to four different angles at different times, allowing four interference images to be captured on a single video frame. This was used for time‐resolved imaging of the interference fringe pattern. © 2004 Wiley Periodicals, Inc. Electr Eng Jpn, 148(2): 76–83, 2004; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/eej.20011 相似文献
67.
Shigeru Miyoshi Yoshinori Tanimoto Kiichiro Uyama Yuji Sano 《Nuclear Engineering and Design》1987,102(3)
The X-ray computed CT scanner, capable of producing sharp tomograms, was expected to become a practical and revolutional means in nondestructive inspection in the industrial field.In Japan, the development of the Linac X-ray CT scanner is under way for the inspection of SCC in welds of a nuclear power plant. For development of the Linac-CT, the preliminary experiments for the inspection of SCC artificial defects were performed using a 420 kVp industrial X-ray CT scanner (TOSCANER 4200) which had been developed by Toshiba Corporation. This paper includes the background of this program and the summary of preliminary experiments for X-ray CT. 相似文献
68.
Dopamine releasing response in rat striatum to single and repeated electroconvulsive shock treatment
K Yoshida H Higuchi M Kamata M Yoshimoto T Shimizu Y Hishikawa 《Canadian Metallurgical Quarterly》1997,21(4):707-715
1. The effect of electroconvulsive shock (ECS) on extracellular concentration of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) was examined with the use of in vivo microdialysis in rat striatum. 2. Extracellular concentration of DA was markedly increased up to 183% after single ECS, and that of DOPAC, HVA and 5-HIAA was also significantly increased. The increase after the eighth ECS was attenuated compared to their increase soon after the first ECS. After repeated ECS, baseline concentration of DOPAC, HVA and 5-HIAA was significantly increased, and baseline DA concentration tended to increase. 3. These results suggested that single and repeated ECS activated metabolism of DA and 5-hydroxytryptamine in rat striatum. Activated metabolism of DA may be responsible for the clinical effect of electroconvulsive therapy for parkinsonism. 相似文献
69.
We examined the characteristics of the non-adrenergic, non-cholinergic (NANC) inhibitory response of the circular muscle of the rat stomach fundus to transmural nerve stimulation or high K+. Treatments with isotonic high K+ (20 mM), nitric oxide (NO) and sodium nitroprusside (SNP) all elevated cyclic GMP levels in the rat stomach fundus in the presence of atropine and guanethidine. Isotonic high K+-induced formation of cyclic GMP was completely inhibited by tetrodotoxin (TTX) or NG-nitro-L-arginine (L NNA). The K+ also increased cyclic AMP levels and this response was completely inhibited by TTX. Dose-dependent relaxation of the fundus in response to SNP was shifted to the right by a prior incubation with high concentration of SNP (10(-4) M) for 2 hrs. Incubating the fundus with SNP for 2 hrs significantly inhibited NO induced cyclic GMP formation. Relaxation responses to transmural stimulation (1 Hz or 30 Hz), isotonic high K+ and NO were significantly reduced by a prior incubation with SNP. Isotonic high K+ (20 mM)-induced relaxation of circular muscle strips was not completely inhibited by combined treatment with 10(-5)M L-NNA, 5 x 10(-5)M oxyhemoglobin and anti VIP (1:200). These results suggest that NO as well as VIP is possible transmitter from NANC nerves in the circular muscle of the rat stomach fundus and there should be one or more inhibitory mediators other than VIP and NO. 相似文献
70.
M Tokuhira M Handa T Kamata A Oda M Katayama Y Tomiyama M Murata Y Kawai K Watanabe Y Ikeda 《Canadian Metallurgical Quarterly》1996,76(6):1038-1046
We characterized a murine monoclonal antibody, PT25-2 (IgG1), raised against washed human platelets. The antibody and its Fab fragments were both capable of inducing platelet aggregation in a fibrinogen-dependent manner and induced 125I-fibrinogen binding to unstimulated platelets (120,000 molecules/platelet at a 100 nM IgG concentration). The antibody immunoprecipitated the alpha IIb beta 3 complex from lysates of iodinated platelets but did not react with the respective subunits when complex formation was disrupted by treatment with 5 mM EDTA at 37 degrees C for 30 min. However, simply removing the extracellular divalent cation with EDTA had no effect on antibody binding indicating that the antibody's epitope depends upon a conformational structure maintained by alpha beta subunit association. Antibody binding to unstimulated, washed platelets yielded binding parameters (Kd = 40 nM, Bmax = 100,000 molecules/platelet), which were found to be virtually unchanged when binding was performed using thrombin or RGDS-peptide-stimulated platelets. Thus, the PT25-2 antibody defines a novel regulatory epitope expressed by the alpha IIb beta 3 integrin on unstimulated, quiescent platelets. 相似文献