Nihon Pharmaceutical University
Ina, Japan

Nihon Pharmaceutical University is a private university in Ina, Saitama, Japan, established in 2004. Wikipedia.

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Kitamura S.,Nihon Pharmaceutical University | Sugihara K.,Hiroshima International University
Xenobiotica | Year: 2014

1. Human-chimeric mice with humanized liver have been constructed by transplantation of human hepatocytes into several types of mice having genetic modifications that injure endogenous liver cells. Here, we focus on liver urokinase-type plasminogen activator-transgenic severe combined immunodeficiency (uPA/SCID) mice, which are the most widely used human-chimeric mice. Studies so far indicate that drug metabolism, drug transport, pharmacological effects and toxicological action in these mice are broadly similar to those in humans. 2. Expression of various drug-metabolizing enzymes is known to be different between humans and rodents. However, the expression pattern of cytochrome P450, aldehyde oxidase and phase II enzymes in the liver of human-chimeric mice resembles that in humans, not that in the host mice. 3. Metabolism of various drugs, including S-warfarin, zaleplon, ibuprofen, naproxen, coumarin, troglitazone and midazolam, in human-chimeric mice is mediated by human drug-metabolizing enzymes, not by host mouse enzymes, and thus resembles that in humans. 4. Pharmacological and toxicological effects of various drugs in human-chimeric mice are also similar to those in humans. 5. The current consensus is that chimeric mice with humanized liver are useful to predict drug metabolism catalyzed by cytochrome P450, aldehyde oxidase and phase II enzymes in humans in vivo and in vitro. Some remaining issues are discussed in this review. © 2014 Informa UK Ltd. All rights reserved: reproduction in whole or part not permitted.

Sanoh S.,Hiroshima University | Tayama Y.,Hiroshima International University | Sugihara K.,Hiroshima International University | Kitamura S.,Nihon Pharmaceutical University | Ohta S.,Hiroshima University
Drug Metabolism and Pharmacokinetics | Year: 2015

Aldehyde oxidase contributes to drug metabolism and pharmacokinetics (PK), and a few clinical studies were discontinued because of aldehyde oxidase metabolism. Its AOX1, AOX3, AOX3L1, and AOX4 isoforms are expressed in mammals, and species differences in expression profiles reflect differences in drug metabolism and PK between animals and humans. Individual differences in aldehyde oxidase activity also influence drug metabolism in humans. Moreover, the reduced solubility of the aldehyde oxidase metabolites may induce drug toxicity. Because various drugs inhibit aldehyde oxidase, assessments of ensuing drug-drug interactions (DDI) are critical for drug optimization. Although drug metabolism, PK, safety, and DDI are important, drugs such as famciclovir and O6-benzylguanine that affect aldehyde oxidase activity in humans have been reported. Recently, various in vitro approaches have been developed to predict PK in humans. However, in vitro studies on aldehyde oxidase may be hampered because of its instability. In contrast, in vivo studies on chimeric mice with humanized livers have also been focused on to predict aldehyde oxidase-mediated metabolism. Additionally, the ratios of N1-methylnicotinamide to metabolites in urinary excretions may represent useful biomarkers of aldehyde oxidase activity in humans. Thus, assessing the contributions of aldehyde oxidase to drug metabolism in humans is necessary. © 2014, The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Yasuhara S.,Toho University | Sasa M.,Toho University | Kusakabe T.,Toho University | Takayama H.,Nihon Pharmaceutical University | And 3 more authors.
Angewandte Chemie - International Edition | Year: 2011

Clever boxing: A cyclization-carbonylation-cyclization-coupling reaction of propargyl acetates 1 or amides 2 in the presence of a palladium(II)- bisoxazoline (box) catalyst afforded symmetrical ketones of types 3 and 4, respectively, containing two heterocyclic groups in moderate to excellent yields (see scheme; tfa=trifluoroacetate). Compounds 3 were converted into ketones containing two 3(2H)-furanone rings. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Nakagawa K.,Fukushima Medical University | Anzai K.,Nihon Pharmaceutical University
Applied Magnetic Resonance | Year: 2010

Using electron paramagnetic resonance (EPR), we investigated stable radical-production cross sections (σ) of sucrose and L-alanine radicals produced by heavy-ion irradiations with various linear energy transfers (LET). The heavy-ion irradiation results were compared with those of X-ray irradiation at the same dose. The EPR signal areas for the two compounds showed a linear relation with the absorbed dose, as well as a logarithmic correlation with the LET. Further analysis was carried out for the radical-production cross section, which showed that stable radicals of the two compounds were produced through collisions of several particles with a single molecule. The relative σ value of sucrose for C ion irradiation was (1.29 ± 0.64) × 10-12 μm2. The σ value of alanine for C ion irradiation was (6.83 ± 0.42) × 10-13 μm2. Considering the structural molecular sizes of sucrose and alanine, the σ values are similar. In addition, a comparison of the EPR results for the C ions and X-rays at 50 Gy dose was made. Sucrose spin concentrations produced by C ions at the LET value of 13.1 keV/μm and X-rays were similar unlike alanine. Thus, the noble EPR results with X-ray and heavy-ion irradiations imply that sucrose can be useful as a radiation indicator. © 2010 Springer.

Anzai K.,Nihon Pharmaceutical University | Ban N.,University of Tokyo | Ozawa T.,Yokohama College of Pharmacy | Tokonami S.,Hirosaki University
Journal of Clinical Biochemistry and Nutrition | Year: 2012

On March 11, 2011 an earthquake led to major problems at the Fukushima Daiichi Nuclear Power Plant. A 14-m high tsunami triggered by the earthquake disabled all AC power to Units 1, 2, and 3 of the Power Plant, and carried off fuel tanks for emergency diesel generators. Despite many efforts, cooling systems did not work and hydrogen explosions damaged the facilities, releasing a large amount of radioactive material into the environment. In this review, we describe the environmental impact of the nuclear accident, and the fundamental biological effects, acute and late, of the radiation. Possible medical countermeasures to radiation exposure are also discussed. ©2012 JCBN.

Tsukahara T.,Shinshu University | Haniu H.,Shinshu University | Matsuda Y.,Nihon Pharmaceutical University
Biochemical and Biophysical Research Communications | Year: 2013

Studies on the effects of lipids on skeletal muscle cells rarely examine the effects of lysophospholipids. Through our recent studies, we identified select forms of phospholipids, such as alkyl-LPA, as ligands for the intracellular receptor peroxisome proliferator-activated receptor gamma (PPARγ). PPARγ is a nuclear hormone receptor implicated in many human diseases, including diabetes and obesity. We previously showed that alkyl-LPA is a specific agonist of PPARγ. However, the mechanism by which the alkyl-LPA-PPARγ axis affects skeletal muscle cells is poorly defined. Our objective in the present study was to determine whether alkyl-LPA and PPARγ activation promotes glucose uptake in skeletal muscle cells. Our findings indicate that PPARγ1 mRNA is more abundant than PPARγ2 mRNA in C2C12 cells. We showed that alkyl-LPA (3. μM) significantly activated PPARγ and increased intracellular glucose levels in skeletal muscle cells. We also showed that incubation of C2C12 cells with alkyl-LPA led to lipid accumulation in the cells. These findings suggest that alkyl-LPA activates PPARγ and stimulates glucose uptake in the absence of insulin in C2C12 cells. This may contribute to the plasma glucose-lowering effect in the treatment of insulin resistance. © 2013 Elsevier Inc.

Tsukahara T.,Shinshu University | Haniu H.,Shinshu University | Matsuda Y.,Nihon Pharmaceutical University
PLoS ONE | Year: 2013

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that plays an essential role in cell proliferation, apoptosis, and inflammation. It is over-expressed in many types of cancer, including colon, stomach, breast, and lung cancer, suggesting that regulation of PPARγ might affect cancer pathogenesis. Here, using a proteomic approach, we identify PTB-associated splicing factor (PSF) as a novel PPARγ-interacting protein and demonstrate that PSF is involved in several important regulatory steps of colon cancer cell proliferation. To investigate the relationship between PSF and PPARγ in colon cancer, we evaluated the effects of PSF expression in DLD-1 and HT-29 colon cancer cell lines, which express low and high levels of PPARγ, respectively PSF affected the ability of PPARγ to bind, and expression of PSF siRNA significantly suppressed the proliferation of colon cancer cells. Furthermore, PSF knockdown induced apoptosis via activation of caspase-3. Interestingly, DLD-1 cells were more susceptible to PSF knockdown-induced cell death than HT-29 cells. Our data suggest that PSF is an important regulator of cell death that plays critical roles in the survival and growth of colon cancer cells. The PSF-PPARγ axis may play a role in the control of colorectal carcinogenesis. Taken together, this study is the first to describe the effects of PSF on cell proliferation, tumor growth, and cell signaling associated with PPARγ. © 2013 Tsukahara et al.

Tsukahara T.,Kanazawa Medical University | Matsuda Y.,Nihon Pharmaceutical University | Usui Y.,Shinshu University | Haniu H.,Shinshu University
Biochemical and Biophysical Research Communications | Year: 2013

Bronchial epithelial cells are targets of inhalation and play a critical role in the maintenance of mucosal integrity as mechanical barriers against various particles. Our previous result suggest that vapor-grown carbon fiber, HTT2800, which is one of the most highly purified multi-wall carbon nanotubes (MWCNT) showed cellular uptake of the carbon nanotube, increased cell death, enhanced DNA damage, and induced cytokine release. Increasing evidence suggests that autophagy may critically influence vital cellular processes such as apoptosis, cell proliferation and inflammation and thereby may play a critical role in pulmonary diseases. Autophagy was recently recognized as a critical cell death pathway, and autophagosome accumulation has been found to be associated with the exposure of various nanoparticles. In this study, the authors focus on the autophagic responses of HTT2800 exposure. The HTT2800-exposed cells induced LC3B expression and induced cell growth inhibition. © 2013 .

Motoo Y.,Kanazawa Medical University | Arai I.,Nihon Pharmaceutical University | Tsutani K.,University of Tokyo
PLoS ONE | Year: 2014

Background: The Committee for Evidence-based Medicine (EBM) of the Japan Society for Oriental Medicine started compiling Evidence Reports of Kampo Treatment (EKAT) in 2007. EKAT is a compilation of structured abstracts of randomized controlled trials (RCTs), along with comments by a third party reviewer. As of 31 December, 2012, there were 378 RCTs of Kampo medicines in Japan. The primary research question of this study is "How frequently is Kampo diagnosis used in RCTs of Kampo medicines?" The secondary research question is "When is Kampo diagnosis used in RCTs?" Materials and Methods: The structured abstract (SA) of each RCT article was reviewed to examine how Kampo diagnosis was used in RCTs, especially how Kampo diagnosis was used in the randomization process. Results: Kampo diagnosis was used before randomization in 27 RCTs (7.1%), after randomization in 31 RCTs (8.2%), and not used in 320 RCTs (84.7%). Before randomization, Kampo diagnosis was used as a criterion for inclusion in 10 RCTs, criterion for exclusion in 9 RCTs, and criteria for both inclusion and exclusion in 2 RCTs. Kampo formulas were determined according to Kampo diagnosis in 7 RCTs. After randomization, subgroup analyses according to Kampo diagnosis were done in 27 RCTs, and grade of disease severity at Kampo diagnosis was used for analysis as an endpoint in 4 RCTs. Conclusions: Kampo diagnosis was used before randomization only in approximately 15% of RCTs, and the number of RCT articles using Kampo diagnosis after randomization was almost the same as that before randomization. Further studies to determine the good RCTs conforming to CONSORT requirements and good systematic reviews conforming to PRISMA requirements are needed to clarify the significance of Kampo diagnosis. © 2014 Motoo et al.

Akita H.,Nihon Pharmaceutical University
Heterocycles | Year: 2013

This review summarizes the practical synthesis of both enantiomers of chiral intermediate for the syntheses of the natural products possessing the bicyclo[4.4.0]ring system with 4,4,10-trimethyl groups and their application to the total syntheses of the related natural products. Chiral induction was carried out based on enzymatic resolution or optical resolution using chiral auxiliary.

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