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University of ShizuokaShizuoka

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Takahashi T.,University of ShizuokaShizuoka | Suzuki T.,University of ShizuokaShizuoka
Biological and Pharmaceutical Bulletin | Year: 2015

The spike glycoprotein neuraminidase (NA) of influenza A virus (IAV) has sialidase activity that cleaves the terminal sialic acids (viral receptors) from oligosaccharide chains of glycoconjugates. A new antigenicity of viral surface glycoproteins for humans has pandemic potential. We found "low-pH stability of sialidase activity" in NA. The low-pH stability can maintain sialidase activity under acidic conditions of pH 4-5. For human IAVs, NAs of all pandemic viruses were low-pH-stable, whereas those of almost all human seasonal viruses were not. The low-pH stability was dependent on amino acid residues near the active site, the calcium ion-binding site, and the subunit interfaces of the NA homotetramer, suggesting effects of the active site and the homotetramer on structural stability. IAVs with the low-pH-stable NA showed much higher virus replication rates than those of IAVs with low-pH-unstable NA, which was correlated with maintenance of sialidase activity under an endocytic pathway of the viral cell entry mechanism, indicating contribution of low-pH stability to high replication rates of pandemic viruses. The low-pH-stable NA of the 1968 H3N2 pandemic virus was derived from the low-pH-stable NA of H2N2 human seasonal virus, one of two types classified by both low-pH stability in N2 NA and a phylogenetic tree of N2 NA genes. The 2009 H1N1 pandemic virus acquired low-pH-stable NA by two amino acid substitutions at the early stage of the 2009 pandemic. It is thought that low-pH stability contributes to infection spread in a pandemic through enhancement of virus replication. © 2015 The Pharmaceutical Society of Japan.

Hiramatsu M.,Hamamatsu Photonics K K | Chida K.,Hamamatsu University School of Medicine | Chida K.,Hamamatsu Toyooka Hospital | Hashimoto D.,Hamamatsu University School of Medicine | And 7 more authors.
Luminescence | Year: 2016

The aim of this study was to assess whether a particular value of noninvasive salivary ultra-weak chemiluminescence (UCL) could be used as a biomarker of psychological stress. Our study covered two groups. Group 1 comprised six healthy volunteers who stayed in a hospital for one night and group 2 comprised 15 patients with lung cancer and 24 patients with respiratory diseases other than lung cancer who were in hospital for an extended stay. First, we evaluated the UCL of saliva from six healthy volunteers before and after one night in hospital. Immunoglobulin A (IgA) concentrations were also measured. The integrated intensity value of UCL was correlated with the IgA concentration (correlation coefficient 0.90). Second, in the case of a long hospital stay, we found that the maximum salivary UCL intensities were higher in patients with lung cancer than in those with respiratory diseases other than lung cancer or in 28 healthy controls. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Inamochi Y.,University of ShizuokaShizuoka | Dey A.,U.S. National Institutes of Health | Nishiyama A.,U.S. National Institutes of Health | Kubota T.,Yamanashi University | And 4 more authors.
Biochemistry and Biophysics Reports | Year: 2016

Background Expression of the fructose transporter gene SLC2A5 and histone acetylation in the transcribed region are induced by differentiation associated-signals such as glucocorticoids and p44/42 mitogen-activated protein kinase (MAPK) inhibition in small intestinal Caco-2 cells. Methods We co-treated with glucocorticoid receptor agonist dexamethasone (Dex) and p44/42 MAPK inhibitor PD98059 (PD) in Caco-2 cells with or without Brd4 small hairpin (sh) RNA expression vector, and the cells were analyzed by qRT-PCR and chromatin immunoprecipitation assays. The small intestine of wild-type mice and Brd4+/− mice during weaning period were analyzed by qRT-PCR. Results Co-treatment with Dex and PD increased binding of the bromodomain-containing protein-4 (Brd4)–positive transcriptional elongation factor-b (P-TEFb)–RNA polymerase II complex to acetylated histones in the transcribed region of SLC2A5. Brd4-protein depletion by shRNA revealed that the association of these proteins on the transcribed region of SLC2A5 promoted gene expression in a Brd4-dependent manner. Expression of small-intestine Slc2a5, but not another intestinal gene sucrase-isomaltase, during weaning period, was significantly lower in Brd4+/− mice compared with wild-type mice. Conclusions Brd4-P-TEFb plays a crucial role in differentiation-associated transcription of SLC2A5 gene in intestinal Caco-2 cells and in the small intestine of mice during weaning period. General significance Histone acetylation and the transcription elongation factor Brd4 are important for SLC2A5 expression in the small intestine. © 2016 The Authors

Funamoto M.,University of ShizuokaShizuoka | Funamoto M.,National Hospital Organization Kyoto Medical Center | Sunagawa Y.,University of ShizuokaShizuoka | Sunagawa Y.,National Hospital Organization Kyoto Medical Center | And 16 more authors.
International Journal of COPD | Year: 2016

Purpose: COPD is mainly caused by tobacco smoking and is associated with a high frequency of coronary artery disease.There is growing recognition that the inflammation in COPD is not only confined to the lungs but also involves the systemic circulation and can impact nonpulmonary organs, including blood vessels.α1-antitrypsin-low-density lipoprotein (AT-LDL) complex is an oxidatively modified LDL that accelerates atherosclerosis.Curcumin, one of the best-investigated natural products, is a powerful antioxidant.However, the effects of curcumin on AT-LDL remain unknown.We hypothesized that Theracurmin®, a highly absorptive curcumin with improved bioavailability using a drug delivery system, ameliorates the inflammatory status in subjects with mild COPD.Patients and methods: This is a randomized, double-blind, parallel-group study.Subjects with stages I-II COPD according to the Japanese Respiratory Society criteria were randomly assigned to receive 90 mg Theracurmin® or placebo twice a day for 24 weeks, and changes in inflammatory parameters were evaluated.Results: There were no differences between the Theracurmin® and placebo groups in terms of age, male/female ratio, or body mass index in 39 evaluable subjects.The percent changes in blood pressure and hemoglobin A1c and LDL-cholesterol, triglyceride, or high-density lipoprotein-cholesterol levels after treatment were similar for the two groups.However, the percent change in the AT-LDL level was significantly (P=0.020) lower in the Theracurmin® group compared with the placebo group.Conclusion: Theracurmin® reduced levels of atherosclerotic AT-LDL, which may lead to the prevention of future cardiovascular events in mild COPD subjects. © 2016 Funamoto et al.

Tamano H.,University of ShizuokaShizuoka | Shakushi Y.,University of ShizuokaShizuoka | Watanabe M.,Watanabe Oyster Laboratory Co. | Ohashi K.,University of ShizuokaShizuoka | And 4 more authors.
Biological Bulletin | Year: 2015

The effects of 3,5-dihydroxy-4-methoxybenzyl alcohol (DHMBA), and zinc-both components of the Pacific oyster Crassostrea gigas-were examined by glutamatergic neuron activity in rats in an in vivo microdialysis experiment and an in vitro brain slice experiment. The basal concentration of extracellular glutamate in the hippocampus was decreased under hippocampal perfusion with DHMBA (1 mmol l−1) or ZnCl2 (μmol l−1), indicating that DHMBA and Zn2+suppress glutamatergic neuron activity under basal (static) conditions. To assess the preventive effect of DHMBA and Zn2+ on glutamate release from neuron terminals, brain slices were pretreated with DHMBA (1 mmol l−1) or ZnCl2 (100nmol l−1) for 1 h, then stimulated with high K+. A high, K+-induced increase in extracellular Zn2+ level, an index of glutamate release, was suppressed with pretreatment with DHMBA or zinc. A high, K+-induced increase in intracellular Ca2+ level was also suppressed with pretreatment with DHMBA or Zn2+. These results suggest that DHMBA and Zn2+, previously taken up in the hippocampal cells, suppress high, K+-induced glutamate release in the hippocampus, probably via presynaptic suppression of intracellular Ca2+ signaling. It is likely that Zn2+ and DHMBA play a preventive role in suppressing excess glutamatergic neuron activity in rats and mice. © 2015 Marine Biological Laboratory.

Actis M.L.,St Jude Childrens Research Hospital | Ambaye N.D.,St Jude Childrens Research Hospital | Evison B.J.,St Jude Childrens Research Hospital | Shao Y.,St Jude Childrens Research Hospital | And 8 more authors.
Bioorganic and Medicinal Chemistry | Year: 2016

DNA interstrand crosslink (ICL) repair (ICLR) has been implicated in the resistance of cancer cells to ICL-inducing chemotherapeutic agents. Despite the clinical significance of ICL-inducing chemotherapy, few studies have focused on developing small-molecule inhibitors for ICLR. The mammalian DNA polymerase ζ, which comprises the catalytic subunit REV3L and the non-catalytic subunit REV7, is essential for ICLR. To identify small-molecule compounds that are mechanistically capable of inhibiting ICLR by targeting REV7, high-throughput screening and structure–activity relationship (SAR) analysis were performed. Compound 1 was identified as an inhibitor of the interaction of REV7 with the REV7-binding sequence of REV3L. Compound 7 (an optimized analog of compound 1) bound directly to REV7 in nuclear magnetic resonance analyses, and inhibited the reactivation of a reporter plasmid containing an ICL in between the promoter and reporter regions. The normalized clonogenic survival of HeLa cells treated with cisplatin and compound 7 was lower than that for cells treated with cisplatin only. These findings indicate that a small-molecule inhibitor of the REV7/REV3L interaction can chemosensitize cells by inhibiting ICLR. © 2016 Elsevier Ltd

Antushevich H.,Polish Academy of Sciences | Kapica M.,Lublin University of Life Sciences | Krawczynska A.,Polish Academy of Sciences | Herman A.,Polish Academy of Sciences | And 3 more authors.
Journal of Physiology and Pharmacology | Year: 2016

Apelin is considered as important gut regulatory peptide ligand of APJ receptor with a potential physiological role in gastrointestinal cytoprotection, regulation of food intake and drinking behavior. Circulating apelin inhibits secretion of pancreatic juice through vagal- cholecystokinin-dependent mechanism and reduces local blood flow. Our study was aimed to determine the effect of fundectomy and intraperitoneal or intragastric administration of apelin-13 on pancreatic and gastric enzymes activities in adult rats. Fundectomy is a surgical removal of stomach fundus - maine site apelin synthesis. Three independent experiments were carried out on Wistar rats. In the first and second experiment apelin-13 was given by intragastric or intraperitoneal way twice a day for 10 days (100 nmol/kg b.w.). Control groups received the physiological saline respectively. In the third experiment the group of rats after fundectomy were used. Fundectomized rats did not receive apelin and the rats from control group were ‘sham operated’. At the end of experiment rats were sacrificed and blood from rats was withdrawn for apelin and CCK (cholecystokinin) radioimmunoassay analysis and pancreas and stomach tissues were collected for enzyme activity analyses. Intragastric and intraperitoneal administrations of apelin-13 increased basal plasma CCK level and stimulated gastric and pancreatic enzymes activity in rats. In animals after fundectomy decreased activity of studied enzymes was observed, as well as basal plasma apelin and CCK levels. In conclusion, apelin can effects on CCK release and stimulates some gastric and pancreatic enzymes activity in adult rats while fudectomy suppresses those processes. Changes in the level of pancreatic lipase activity point out that apelin may occurs as a regulator of lipase secretion. © 2016, Polish Physiological Society. All rights reserved.

Shimada A.,Azabu UniversityKanagawa | Kohara Y.,Tottori University | Naota M.,Tottori University | Kobayashi Y.,Tottori University | And 3 more authors.
Folia Histochemica et Cytobiologica | Year: 2015

Introduction. Exposure to Asian sand dust (ASD) is associated with enhanced pulmonary morbidity and mortality, and the reporting of such cases has rapidly increased in East Asia since 2000. The purpose of the study was to assess chronic lung toxicity induced by ASD. Material and methods. A total of 174 ICR mice were randomly divided into 5 control and 17 exposure groups. Suspensions of low dose (0.2, 0.4 mg) and high dose (3.0 mg) of ASD particles in saline were intratracheally instilled into ICR mice, followed by sacrifice at 24 hours, 1 week, and 1, 2, 3 and 4 months after instillation. Paraffin sections of lung tissues were stained with hematoxylin and eosin and by immunohistochemistry to detect a-smooth muscle actin, collagen III, matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinases-1 (TIMP-1), CD3, CD20, immunoglobulin G, interleukin-1β and inducible nitric oxide synthase. Results. A lung histological examination revealed similar patterns in the lesions of the groups treated with high (3.0 mg) or low dose (0.4 mg) of ASD. Acute inflammation was observed 24 h after treatment and subsided after 1 week; persistent granulomatous changes were observed at 2 months, focal lymphocytic infiltration at 3 months, and granuloma formation at 4 months. An increase in the size of granulomatous lesions was observed over time and was accompanied by collagen deposition in the lesions. The cytoplasm of macrophages in inflammatory lesions showed positive immunolabeling for MMP-9 at 24 h, 1 and 2 months after instillation of 3.0 mg of ASD. Positive immunolabeling for TIMP-1 was demonstrated in the cytoplasm of macrophages at 2 and 4 months after instillation of 3.0 mg of ASD. These findings suggest association between the expression of MMP-9 and TIMP-1 with the development of lung granulomatous lesions. Conclusions. These findings suggest that collagen deposition resulting from the altered regulation of extracellular matrix is associated with granuloma formation in the lungs of mice treated with ASD. © Polish Society for Histochemistry and Cytochemistry Folia Histochem Cytobiol. 2015.

Yamagishi Y.,University of ShizuokaShizuoka | Saito K.,University of ShizuokaShizuoka | Ikeda T.,University of ShizuokaShizuoka
Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) | Year: 2016

We attempt stochastic modeling of travel behavior processes from the observed data. To this end, based on the Lévy flight behavior process combined with the popularity of each point of interest, we first propose a probability model and efficient method that estimates the model parameters from the observed user behavior data. Then, we propose two methods for POI ranking by using the probability obtained from our proposed model. In our experiments using user behavior data constructed from a review site dataset, we report our experimental results on parameter estimation and examine the properties of POI ranking methods in comparison to a naive popularity ranking method. As our experimental results, we show that our parameter estimation results are intuitively interpretable, and as a favorable property, our ranking methods naturally give high ranks to POIs located in attractive regions. © Springer International Publishing Switzerland 2016.

Saito K.,University of ShizuokaShizuoka | Kimura M.,Ryukoku University | Ohara K.,Aoyama Gakuin University | Motoda H.,Osaka UniversityIbaraki | Motoda H.,University of Tasmania
Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) | Year: 2016

We address the problem of efficiently detecting critical links in a large network. Critical links are such links that their deletion exerts substantial effects on the network performance. Here in this paper, we define the performance as being the average node reachability. This problem is computationally very expensive because the number of links is an order of magnitude larger even for a sparse network. We tackle this problem by using bottom-k sketch algorithm and further by employing two new acceleration techniques: marginal-link updating (MLU) and redundant-link skipping (RLS). We tested the effectiveness of the proposed method using two real-world large networks and two synthetic large networks and showed that the new method can compute the performance degradation by link removal about an order of magnitude faster than the baseline method in which bottom-k sketch algorithm is applied directly. Further, we confirmed that the measures easily composed by well known existing centralities, e.g. in/out-degree, betweenness, PageRank, authority/hub, are not able to detect critical links. Those links detected by these measures do not reduce the average reachability at all, i.e. not critical at all. © Springer International Publishing Switzerland 2016.

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