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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.


Hishimura Y.,Hiroshima International University
Behavioural Processes | Year: 2015

The present study examines the effect of interaction with a conspecific on conditioned taste aversion in 32 male mice. Subjects were injected with lithium chloride immediately after drinking saccharin solution for 30. min. They were then exposed to a male conspecific for 3. h following the poisoning. In the subsequent three consecutive days of two-bottle tests involving a choice between saccharin solution and water, they showed attenuated conditioned taste aversion compared with controls exposed to no conspecific after poisoning. These results confirm social interaction with a conspecific reduces conditioned taste aversion in mice. The implications of these findings are discussed with regard to social buffering effect and stress-induced analgesia. © 2014 Elsevier B.V.


Abe T.,Health Sciences University of Hokkaido | Ikeda T.,Health Sciences University of Hokkaido | Yanada R.,Hiroshima International University | Ishikura M.,Health Sciences University of Hokkaido
Organic Letters | Year: 2011

The concise total synthesis of calothrixins A and B has been accomplished by utilizing the one-pot formation of hexatriene as a key intermediate via the palladium-catalyzed tandem cyclization/cross-coupling reaction of triethyl(indol-2-yl)borate. In another key transformation, the indolo[3,2-j]phenanthridine core was prepared in high yield via Cu(I)-mediated 6π-electrocyclization. © 2011 American Chemical Society.


Sueda T.,Hiroshima International University | Oshima A.,Hiroshima International University | Teno N.,Hiroshima International University
Organic Letters | Year: 2011

This study describes the first reliable synthesis of N-alkynyl imides (ynimides). This was accomplished with a copper-catalyzed coupling reaction between alkynyl(triaryl)bismuthonium salts and five-membered imides. We also found that it was possible to utilize N-ethynyl phthalimide as a variant of the highly labile ethynamine. 4-Amino-1,2,3-triazole was successfully obtained via the CuAAC reaction of N-ethynyl phthalimide with azide followed by hydrazinolysis of the phthaloyl protecting group. © 2011 American Chemical Society.


Takeda S.,Hiroshima International University
Biological and Pharmaceutical Bulletin | Year: 2014

Δ9-Tetrahydrocannabinol (Δ9-THC), a biologically active constituent of marijuana, possesses a wide variety of pharmacological and toxicological effects (e.g., analgesia, hypotension, reduction of inflammation, and anti-cancer effects). Among Δ9-THC's biological activities, its recognized anti-estrogenic activity has been the subject of investigations. Since Δ9-THC is used as both a drug of abuse (marijuana) and as a preventive therapeutic to treat pain and nausea in cancer patients undergoing chemotherapy in the United States and other countries (synthesized Δ9-THC; dronabinol), it is important to investigate the mechanistic basis underlying the anti-estrogenic activity of Δ9-THC. Since Δ9-THC has "no" binding potential for estrogen receptor α (ERα) which can be activated by estrogen (E2), the question of how Δ9-THC exerts its inhibitory effect on ERα is not resolved. We have recently reported that ERβ, a second type of ER, is involved in the Δ9-THC abrogation of E2/ERα-mediated transcriptional activity. Here we discuss the possible mechanism(s) of the Δ9-THC-mediated disruption of E2/ERα signaling by presenting our recent findings as well. © 2014 The Pharmaceutical Society of Japan.


Shimizu R.,Hiroshima International University
Biological and Pharmaceutical Bulletin | Year: 2014

Many synthetic chemicals have been identified as environmental contaminants with activity to disrupt normal function of the thyroid hormone system. Thyroid hormones play important roles in growth, development, differentiation, and basal metabolic homeostasis, as well as in brain development in human fetus and children, and thyroid dysfunction can have very serious consequences, including mental retardation. Environmental chemicals may affect thyroid hormone action in multiple ways, including reduced thyroid hormone synthesis owing to direct toxicity at the thyroid gland, interaction with thyroid hormone receptors and transporters such as transthyretin, and disturbance of thyroid hormone metabolism (e.g., glucuronidation, sulfation and deiodination). In addition, iodotyrosine deiodinase, which is involved in iodide salvage by catalyzing deiodination of iodinated by-products of thyroid hormone production, was recently identified as a possible new target for disruption of thyroid hormone homeostasis by environmental halogenated chemicals. This topic, after briefly summarizing findings on the thyroid hormone-disrupting action of environmental chemicals in mammals, focuses on the effects of environmental halogenated chemicals on iodotyrosine deio-dinase activity. © 2014 The Pharmaceutical Society of Japan.


Haneda K.,Hiroshima International University
Progress in Biomedical Optics and Imaging - Proceedings of SPIE | Year: 2016

The purpose of this study was to estimate an impact on radical effect in the proton beams using a combined approach with physical data and gel data. The study used two dosimeters: ionization chambers and polymer gel dosimeters. Polymer gel dosimeters have specific advantages when compared to other dosimeters. They can measure chemical reaction and they are at the same time a phantom that can map in three dimensions continuously and easily. First, a depth-dose curve for a 210 MeV proton beam measured using an ionization chamber and a gel dosimeter. Second, the spatial distribution of the physical dose was calculated by Monte Carlo code system PHITS: To verify of the accuracy of Monte Carlo calculation, and the calculation results were compared with experimental data of the ionization chamber. Last, to evaluate of the rate of the radical effect against the physical dose. The simulation results were compared with the measured depth-dose distribution and showed good agreement. The spatial distribution of a gel dose with threshold LET value of proton beam was calculated by the same simulation code. Then, the relative distribution of the radical effect was calculated from the physical dose and gel dose. The relative distribution of the radical effect was calculated at each depth as the quotient of relative dose obtained using physical and gel dose. The agreement between the relative distributions of the gel dosimeter and Radical effect was good at the proton beams. © 2016 SPIE.


Okamoto N.,Hiroshima International University | Ishikura M.,Health Sciences University of Hokkaido | Yanada R.,Hiroshima International University
Organic Letters | Year: 2013

A new cleavage reaction of carbon-carbon triple bonds proceeds efficiently with NIS and TMSN3, giving the corresponding nitriles in moderate to good yields. © 2013 American Chemical Society.


Ehara A.,Hiroshima International University
Pediatrics International | Year: 2013

Background According to the Japan Pediatric Society, the mean extra work hours of hospital pediatricians in 2010 was approximately 80 h per month, which is the certification criterion for Karoshi (death from overwork), but there is no precise picture of personnel management at hospitals because the labor authorities do not disclose detailed statistics concerning labor law violations to the public. Methods Most local governments have a disclosure system, and the local governments that operate public hospitals were requested to disclose warning documents issued by the labor authorities from March 2002 to March 2011. Results A total of 208/369 public hospitals (56.4%) with ≥200 beds in Japan were warned of labor law violations. Offenses included exceeding the limit of working hours (177 hospitals) and non-payment of increased wages for night and holiday work (98 hospitals). Conclusions Many public hospitals in Japan did not always pay workers including physicians for increased workload because they do not regard night and holiday duties as work hours. © 2012 The Authors.


Takino J.,Hiroshima International University | Yamagishi S.,Kurume University | Takeuchi M.,Kanazawa Medical University
World Journal of Gastroenterology | Year: 2012

AIM: To investigate the effect of glyceraldehyde-derived advanced glycation end-products (Glycer-AGEs) on hepatocellular carcinoma (HCC) cells. METHODS: Two HCC cell lines (Hep3B and HepG2 cells) and human umbilical vein endothelial cells (HUVEC) were used. Cell viability was determined using the WST-8 assay. Western blotting, enzyme linked immunosorbent assay, and real-time reverse transcription polymerase chain reactions were used to detect protein and mRNA. Angiogenesis was evaluated by assessing the proliferation, migration, and tube formation of HU-VEC. RESULTS: The receptor for AGEs (RAGE) protein was detected in Hep3B and HepG2 cells. HepG2 cells were not affected by the addition of Glycer-AGEs. Glycer-AGEs markedly increased vascular endothelial growth factor (VEGF) mRNA and protein expression, which is one of the most potent angiogenic factors. Compared with the control unglycated bovine serum albumin (BSA) treatment, VEGF mRNA expression levels induced by the Glycer-AGEs treatment were 1.00 ± 0.10 vs 1.92 ± 0.09 (P < 0.01). Similarly, protein expression levels induced by the Glycer-AGEs treatment were 1.63 ± 0.04 ng/mL vs 2.28 ± 0.17 ng/mL for the 24 h treatment and 3.36 ± 0.10 ng/mL vs 4.79 ± 0.31 ng/mL for the 48 h treatment, respectively (P < 0.01). Furthermore, compared with the effect of the control unglycated BSA-treated conditioned medium, the Glycer-AGEs-treated conditioned medium significantly increased the proliferation, migration, and tube formation of HUVEC, with values of 122.4% ± 9.0% vs 144.5% ± 11.3% for cell viability, 4.29 ± 1.53 vs 6.78 ± 1.84 for migration indices, and 71.0 ± 7.5 vs 112.4 ± 8.0 for the number of branching points, respectively (P < 0.01). CONCLUSION: These results suggest that Glycer-AG-Es-RAGE signaling enhances the angiogenic potential of HCC cells by upregulating VEGF expression. © 2012 Baishideng. All rights reserved.

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