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| 1.
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論文
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Yokota, Shinichi ; Higashi, Eriko ; Fukami, Tatsuki ; Yokoi, Tsuyoshi ; Nakajima, Miki
概要:
金沢大学医薬保健研究域薬学系<br />Human CYP2A6 is responsible for the metabolism of nicotine and coumarin as well as the metabolic act
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ivation of tobacco-related nitrosamines. Earlier studies revealed that CYP2A6 activity was increased by dietary cadmium or cruciferous vegetables, but the underlying mechanisms remain to be clarified. In the present study, we investigated the possibility that Nrf2 might be involved in the regulation of CYP2A6. Real-time RT-PCR analysis revealed that the CYP2A6 mRNA level in human hepatocytes was significantly (P < 0.01, 1.4-fold) induced by 10 μM sulforaphane (SFN), a typical activator of Nrf2. A computer-based search identified three putative antioxidant response elements (AREs) in the 5′-flanking region of the CYP2A6 gene at positions -1212, -2444, and -3441, termed ARE1, ARE2, and ARE3, respectively. Electrophoretic mobility shift assays demonstrated that Nrf2 bound only to ARE1. Luciferase assays using HepG2 cells revealed that the overexpression of Nrf2 significantly increased the reporter activities of the constructs containing a 30-bp fragment that included ARE1. However, the activity of the construct containing the intact 5′-flanking region (-1 to -1395) including ARE1 was not increased by the overexpression of Nrf2. In contrast, when the reporter construct was injected into mice via the tail vein, the reporter activity in the liver was significantly (P < 0.05, 1.9-fold) increased by SFN (1 mg/head) administration. In conclusion, we found that human CYP2A6 is regulated via Nrf2, suggesting that CYP2A6 is induced under oxidative stress. © 2010 Elsevier Inc. All rights reserved.
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| 2.
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Nakata, Shunji ; Maeda, Ryoji ; Kawae, Takeshi ; Morimoto, Akiharu ; Shimizu, Tatsuo
概要:
A thin-film structure comprising Al2O3/Al-rich Al2O3/SiO2 was fabricated on Si substrate. We used radio-frequency magnet
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ron co-sputtering with Al metal plates set on an Al2O3 target to fabricate the Al-rich Al2O 3 thin film, which is used as a charge storage layer for nonvolatile Al2O3 memory. We investigated the charge trapping characteristics of the film. When the applied voltage between the gate and the substrate is increased, the hysteresis window of capacitance-voltage (C-V) characteristics becomes larger, which is caused by the charge trapping in the film. For a fabricated Al-O capacitor structure, we clarified experimentally that the maximum capacitance in the C-V hysteresis agrees well with the series capacitance of insulators and that the minimum capacitance agrees well with the series capacitance of the semiconductor depletion layer and stacked insulator. When the Al content in the Al-rich Al2O3 is increased, a large charge trap density is obtained. When the Al content in the Al-O is changed from 40 to 58%, the charge trap density increases from 0 to 18 × 1018 cm-3, which is 2.6 times larger than that of the trap memory using SiN as the charge storage layer. The device structure would be promising for low-cost nonvolatile memory. © 2011 Elsevier B.V. All rights reserved.
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| 4.
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Takeichi, Toshiaki ; Takarada-Iemata, Mika ; Hashida, Koji ; Sudo, Hirofumi ; Okuda, Tomohiko ; Kokame, Koichi ; Hatano, Taku ; Takanashi, Masashi ; Funabe, Sayaka ; Hattori, Nobutaka ; Kitamura, Osamu ; Kitao, Yasuko ; Hori, Osamu
概要:
N-myc downstream-regulated gene 2 (Ndrg2) is a differentiation- and stress-associated molecule predominantly expressed i
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n astrocytes in the central nervous system (CNS). To study the expression and possible role of Ndrg2 in quiescent and activated astrocytes, mice were administrated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine (MPTP), a Parkinson disease (PD)-related neurotoxin which causes both neurodegeneration and glial activation. Immunohistological analysis revealed that Ndrg2 was highly expressed in both types of astrocytes, but less so in astrocytes during the early process of activation. Ndrg2 was also expressed in astrocyte-like cells, but not in neurons, in human brains from PD and Cortico-basal degeneration (CBD) patients. In cultured astrocytes, gene silencing of Ndrg2 significantly enhanced the numbers of 5-bromo-2′-deoxy-uridine (BrdU)-incorporated and proliferating cell nuclear antigen (PCNA)-positive cells, and reduced the length of cell processes and the amount of F-actin. In contrast, adenovirus-mediated overexpression of Ndrg2 significantly reduced the numbers of BrdU-incorporated and PCNA-positive cells, and enhanced the amount of F-actin. Fractionation and immunocytochemical analysis further revealed that Ndrg2 was located in different cellular fractions including the cytosol and cell surface membranes. These results suggest that Ndrg2 may regulate astroglial activation through the suppression of cell proliferation and stabilization of cell morphology. © 2011 Elsevier Ltd. All rights reserved.
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| 6.
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Oshima, Hiroko ; Popivanova, Boryana K. ; Oguma, Keisuke ; Kong, Dan ; Ishikawa, Tomoo ; Oshima, Masanobu
概要:
金沢大学がん進展制御研究所<br />Cyclooxygenase-2 (COX-2) plays an important role in tumorigenesis through prostaglandin E2 (PGE2) bio
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synthesis. It has been shown by in vitro studies that PGE2 signaling transactivates epidermal growth factor receptor (EGFR) through an intracellular mechanism. However, the mechanisms underlying PGE2-induced EGFR activation in in vivo tumors are still not fully understood. We previously constructed transgenic mice that develop gastric tumors caused by oncogenic activation and PGE2 pathway induction. Importantly, expression of EGFR ligands, epiregulin, amphiregulin, heparin-binding EGF-like growth factor, and betacellulin, as well as a disintegrin and metalloproteinases (ADAMs), ADAM8, ADAM9, ADAM10, and ADAM17 were significantly increased in the mouse gastric tumors in a PGE2 pathway-dependent manner. These ADAMs can activate EGFR by ectodomain shedding of EGFR ligands. Notably, the extensive induction of EGFR ligands and ADAMs was suppressed by inhibition of the PGE2 receptor EP4. Moreover, EP4 signaling induced expression of amphiregulin and epiregulin in activated macrophages, whereas EP4 pathway was required for basal expression of epiregulin in gastric epithelial cells. In contrast, ADAMs were not induced directly by PGE2 in these cells, suggesting indirect mechanism possibly through PGE2-associated inflammatory responses. These results suggest that PGE2 signaling through EP4 activates EGFR in gastric tumors through global induction of EGFR ligands and ADAMs in several cell types either by direct or indirect mechanism. Importantly, gastric tumorigenesis of the transgenic mice was significantly suppressed by combination treatment with EGFR and COX-2 inhibitors. Therefore, it is possible that inhibition of both COX-2/PGE2 and EGFR pathways represents an effective strategy for preventing gastric cancer. © 2011 Japanese Cancer Association.
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| 7.
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Oshima, Hiroko ; Hioki, Kyoji ; Popivanova, Boryana K. ; Oguma, Keisuke ; Rooijen, Nico van ; Ishikawa, Tomoo ; Oshima, Masanobu
概要:
金沢大学がん研究所<br />Background & Aims Helicobacter pylori infection induces an inflammatory response, which can contribute to
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gastric tumorigenesis. Induction of cyclooxygenase-2 (COX-2) results in production of prostaglandin E2 (PGE2), which mediates inflammation. We investigated the roles of bacterial infection and PGE2 signaling in gastric tumorigenesis in mice. Methods We generated a germfree (GF) colony of K19-Wnt1/C2mE mice (Gan mice); these mice develop gastric cancer. We examined tumor phenotypes, expression of cytokines and chemokines, and recruitment of macrophages. We also investigated PGE2 signaling through the PGE2 receptor subtype 4 (EP4) in Gan mice given specific inhibitors. Results Gan mice raised in a specific pathogen-free facility developed large gastric tumors, whereas gastric tumorigenesis was significantly suppressed in GF-Gan mice; reconstitution of commensal flora or infection with Helicobacter felis induced gastric tumor development in these mice. Macrophage infiltration was significantly suppressed in the stomachs of GF-Gan mice. Gan mice given an EP4 inhibitor had decreased expression of cytokines and chemokines. PGE2 signaling and bacterial infection or stimulation with lipopolysaccharide induced expression of the chemokine C-C motif ligand 2 (CCL2) (which attracts macrophage) in tumor stromal cells or cultured macrophages, respectively. CCL2 inhibition suppressed macrophage infiltration in tumors, and depletion of macrophages from the tumors of Gan mice led to signs of tumor regression. Wnt signaling was suppressed in the tumors of GF-Gan and Gan mice given injections of tumor necrosis factor-α neutralizing antibody. Conclusions Bacterial infection and PGE2 signaling are required for gastric tumorigenesis in mice; they cooperate to up-regulate CCL2, which recruits macrophage to gastric tumors. Macrophage-derived tumor necrosis factor-α promotes Wnt signaling in epithelial cells, which contributes to gastric tumorigenesis. © 2011 AGA Institute.
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| 8.
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OpenCV2プログラミングブック制作チーム著
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| 9.
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Kato, Satoshi ; Sangadala, Sreedhara ; Tomita, Katsuro ; Titus, Louisa ; Boden, Scott D.
概要:
金沢大学附属病院リハビリテーション部<br />There is an urgent need to develop methods that lower costs of using recombinant human bone morp
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hogenetic proteins (BMPs) to promote bone induction. In this study, we demonstrate the osteogenic effect of a low-molecular weight compound, SVAK-12, that potentiated the effects of BMP-2 in inducing transdifferentiation of C2C12 myoblasts into the osteoblastic phenotype. Here, we report a specific compound, SVAK-12, which was selected based on in silico screenings of small-molecule databases using the homology modeled interaction motif of Smurf1-WW2 domain. The enhancement of BMP-2 activity by SVAK-12 was characterized by evaluating a BMP-specific reporter activity and by monitoring the BMP-2-induced expression of mRNA for osteocalcin and alkaline phosphatase (ALP), which are widely accepted marker genes of osteoblast differentiation. Finally, we confirmed these results by also measuring the enhancement of BMP-2-induced activity of ALP. Smurf1 is an E3 ligase that targets osteogenic Smads for ubiquitin-mediated proteasomal degradation. Smurf1 is an interesting potential target to enhance bone formation based on the positive effects on bone of proteins that block Smurf1-binding to Smad targets or in Smurf1-/- knockout mice. Since Smads bind Smurf1 via its WW2 domain, we performed in silico screening to identify compounds that might interact with the Smurf1-WW2 domain. We recently reported the activity of a compound, SVAK-3. However, SVAK-3, while exhibiting BMP-potentiating activity, was not stable and thus warranted a new search for a more stable and efficacious compound among a selected group of candidates. In addition to being more stable, SVAK-12 exhibited a dose-dependent activity in inducing osteoblastic differentiation of myoblastic C2C12 cells even when multiple markers of the osteoblastic phenotype were parallelly monitored. © 2010 Springer Science+Business Media, LLC.
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| 10.
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論文
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Nakade, Yusuke ; Takamura, Toshinari ; Sakurai, Masaru ; Misu, Hirofumi ; Nagata, Mitsuko ; Nanbu, Yuko ; Oe, Hiroyasu ; Takamura, Toshiji ; Sakai, Yoshio ; Kaneko, Shuichi ; Wada, Takashi
概要:
The aim of the present study was to examine whether there is a relationship between autonomic function and post-challeng
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e hyperglycemia in patients with type 2 diabetes. Subjects included 122 Japanese patients newly diagnosed with type 2 diabetes. Autonomic nerve function was assessed using coefficients of variation of the R-R intervals on electrocardiograms (CVRR). Unlike anthropometry, insulin secretion and insulin resistance, age (r =)0.209, P < 0.021) and post-challenge plasma glucose at 120 min (PG120; r =)0.219, P < 0.015) were the only variables significantly correlated with CVRR. Age was not significantly correlated with PG120. In multiple regression analyses, CVRR Z-score, but not age, was significantly correlated with PG120. The present results suggest that autonomic function affects post-challenge blood glucose levels independently of age. © 2011 Asian Association for the Study of Diabetes and Blackwell Publishing Asia Pty Ltd.
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