Sunplanet Co.

Ōgaki, Japan

Sunplanet Co.

Ōgaki, Japan

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Hata K.,Gifu University | Hata K.,Sunplanet Co. | Kubota M.,Gifu University | Shimizu M.,Gifu University | And 7 more authors.
Carcinogenesis | Year: 2012

Obese people and diabetic patients are known to be high risk of colorectal cancer (CRC), suggesting need of a new preclinical animal model, by which to extensively study the diverse mechanisms, therapy and prevention. The present study aimed to determine whether experimental obese and diabetic mice produced by monosodium glutamate (MSG) treatment are susceptible to azoxymethane (AOM)-induced colon tumorigenesis using early biomarkers, aberrant crypts foci (ACF) and β-catenin-accumulated crypts (BCACs), of colorectal carcinogenesis. Male Crj:CD-1 (ICR) newborns were daily given four subcutaneous injections of MSG (2 mg/g body wt) to induce diabetes and obesity. They were then given four intraperitoneal injections of AOM (15 mg/kg body wt) or saline (0.1 ml saline/10 g body wt). Ten weeks after the last injection of AOM, the MSG-AOM mice had a significant increase in the multiplicity of BCAC (13.83 ± 7.44, P < 0.002), but not ACF (78.00 ± 11.20), when compare to the Saline-AOM mice (5.45 ± 1.86 of BCAC and 69.27 ± 8.06 of ACF). Serum biochemical profile of the MSG-treated mice with or without AOM showed hyperinsulinemia, hypercholesteremia and hyperglycemia. The mRNA expression of insulin-like growth factor-1 receptor (IGF-1R, P<0.01) was increased in the MSG-AOM mice, when compared with the mice given AOM alone. IGF-1R was immunohistochemically expressed in the BCAC, but not ACF, in the AOM-treated mice. Our findings suggest that the MSG mice are highly susceptible to AOM-induced colorectal carcinogenesis, suggesting potential utility of our MSG-AOM mice for further investigation of the possible underlying events that affect the positive association between obese/diabetes and CRC. © The Author 2012. Published by Oxford University Press. All rights reserved.


Yasuda Y.,Gifu University | Shimizu M.,Gifu University | Shirakami Y.,Gifu University | Sakai H.,Gifu University | And 6 more authors.
Cancer Science | Year: 2010

Obesity and related metabolic abnormalities are risk factors for colorectal cancer. A state of chronic inflammation and adipocytokine imbalance may play a role in colorectal carcinogenesis. Statins, which are commonly used for the treatment of hyperlipidemia, are known to possess anti-inflammatory effects. Statins also exert chemopreventive properties against various cancers. The present study examined the effects of pitavastatin, a recently developed lipophilic statin, on the development of azoxymethane (AOM)-initiated colonic premalignant lesions in C57BL/KsJ-db/db (db/db) obese mice. Male db/db mice were administrated weekly subcutaneous injections of AOM (15 mg/kg body weight) for 4 weeks and then were subsequently fed a diet containing 1 ppm or 10 ppm pitavastatin for 8 weeks. Feeding with either dose of pitavastatin significantly reduced the number of colonic premalignant lesions, β-catenin accumulated crypts, by inhibiting proliferation and the surrounding inflammation. Pitavastatin increased the serum levels of adiponectin while conversely decreasing the serum levels of total cholesterol, tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-18, and leptin. Pitavastatin also caused a significant increase in the expression of phosphorylated form of the AMP-activated kinase (AMPK) protein on the colonic mucosa of AOM-treated mice. In addition, the expression levels of TNF-α, IL-6, IL-18, and COX-2 mRNAs on the colonic mucosa of AOM-treated mice were decreased by treatment with this agent. These findings suggest that pitavastatin attenuates chronic inflammation and improves the imbalance of adipocytokines, both of which are caused by the presence of excess adipose tissues, thereby preventing the development of colonic premalignancies in an obesity-related colon cancer model. Therefore, some types of statins, including pitavastatin, may be a useful chemoprevention modality for colon cancer in obese individuals. © 2010 Japanese Cancer Association.


Mano Y.,Eisai Co. | Kita K.,Sunplanet Co. | Kusano K.,Eisai Co.
Bioanalysis | Year: 2015

Background: A novel microsampling device, MitraTM, was evaluated for bioanalysis of E6005 and its O-desmethylated metabolite in human whole blood using an UPLC-MS. Results: A constant volume of blood samples was absorbed onto the tip of Mitra, the analytes were extracted by various solvents and then detected by UPLC-MS. Recovery of the analytes was high in acetonitrile-water (1:1, v/v) but was dependent on hematocrit (Hct) without sonication process, which led to biased accuracy at low and high Hcts. Inclusion of sonication process in extraction improved recovery at high Hct to yield acceptable accuracy across Hcts. Conclusion: Optimization of extraction process to achieve high recovery regardless of Hct is critical in accurate bioanalysis via Mitra. © 2015 Future Science Ltd.


Mano Y.,Eisai Co. | Ishii T.,Sunplanet Co. | Hotta K.,Eisai Co. | Kusano K.,Eisai Co.
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2015

E6005, a novel phosphodiesterase 4 inhibitor, is currently under clinical development for the treatment of atopic dermatitis. As ER-392710 (M11), a hydrolyzed metabolite, is a main metabolite, a simultaneous assay method for quantification of E6005 and M11 in human plasma has been developed and validated using ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS). E6005, M11, and each deuterium-labeled compound used as internal standard were extracted from 100. μL human plasma by solid phase extraction then chromatographed on an Acquity UPLC BEH C18 column (100. mm. ×. 2.1. mm i.d., 1.7. μm) under gradient elution. The analytes were detected by selected reaction monitoring in the positive ion mode with the mass transition of m/. z 473.1/163.0 and m/. z 459.1/149.0 for E6005 and M11, respectively. E6005 and M11 were quantifiable ranging from 1 to 200. ng/mL with no carryover. Accuracy and precision in intra- and inter-batch reproducibility assays were within the acceptance criteria recommended by the regulatory bioanalytical guidelines. Various stability assessments including possible conversion of E6005 to M11 were thoroughly performed to demonstrate the stability of E6005 and M11 in human blood and plasma. The method was successfully applied to support clinical trials. © 2015 Elsevier B.V.


Asakawa Y.,Sunplanet Co. | Yamamoto E.,Pharmaceutical Scientific and Technology Core Function Unit | Asakawa N.,Eisai Co.
Journal of Separation Science | Year: 2014

A novel metal aquo-ion affinity chromatography has been developed for the analysis of basic compounds using heat-treated silica gel containing hydratedmetal cations (metal aquo-ions) as the packingmaterial. The packing materials of the metal aquo-ion affinity chromatography were prepared by the immobilization of a single metal component such as Fe(III), Al(III), Ag(I), and Ni(II) on silica gel followed by extensive heat treatment. The immobilizedmetals form aquo-ions to present cation-exchange ability for basic analytes and the cation-exchange ability for basic analytes depends on pKa of the immobilized metal species. In the present study, to evaluate the retention characteristics of metal aquo-ion affinity chromatography, the on-line solid-phase extraction of drugs was investigated. Obtained data clearly evidence the selective retention capability of metal aquo-ion affinity chromatography for basic analytes with sufficient capacity. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


PubMed | Sunplanet Co. and Eisai Co.
Type: Journal Article | Journal: Journal of toxicologic pathology | Year: 2016

Carcinosarcoma is a rare neoplasm composed of malignant epithelial and stromal elements, and, for rats, carcinosarcomas in the kidney have not been reported. In a long-term study to gather background data, we encountered a spontaneous carcinosarcoma originating from the renal pelvis with metastasis to the lung. At necropsy, a mass was observed in the abdominal cavity, and white nodules were scattered in lung lobes. Microscopically, there was polypoid hyperplasia of the urothelium accompanied by hyperplasia of spindle stromal cells in the pelvis. The intra-abdominal tumor was composed of epithelial and stromal elements; in the lung, the tumor cells invaded along alveoli/bronchi and occasionally invaded the parenchyma from the blood vessels. Immunohistochemical and electron microscopic examinations revealed that the epithelial element consisted of transitional epithelial cells and that the stromal element consisted of lipoblasts. The tumor was diagnosed as a carcinosarcoma originating from the renal pelvis, and this is the first report of a carcinosarcoma originating from the renal pelvis in a rat.


PubMed | Sunplanet Co. and Eisai Co.
Type: Journal Article | Journal: Bioanalysis | Year: 2015

A novel microsampling device, Mitra(TM), was evaluated for bioanalysis of E6005 and its O-desmethylated metabolite in human whole blood using an UPLC-MS.A constant volume of blood samples was absorbed onto the tip of Mitra, the analytes were extracted by various solvents and then detected by UPLC-MS. Recovery of the analytes was high in acetonitrile-water (1:1, v/v) but was dependent on hematocrit (Hct) without sonication process, which led to biased accuracy at low and high Hcts. Inclusion of sonication process in extraction improved recovery at high Hct to yield acceptable accuracy across Hcts.Optimization of extraction process to achieve high recovery regardless of Hct is critical in accurate bioanalysis via Mitra.


PubMed | Sunplanet Co. and Eisai Co.
Type: Journal Article | Journal: Journal of toxicologic pathology | Year: 2014

Malakoplakia is a rare form of chronic granulomatous inflammation in mammals, and usually affects the urinary tract in humans. In this report, we present a case of granulomatous nephritis consistent with malakoplakia in a 4-year-old male cynomolgus monkey. Gross examination showed that the kidney was markedly enlarged and adhered to the surrounding organs. Histology showed that there was diffuse interstitial infiltration of histiocytes with abundant foamy eosinophilic cytoplasm resembling von Hansemann cells, PAS-positive granular cytoplasm and occasional PAS- and iron-positive intracellular small inclusion bodies. Electron microscopy showed that these histiocytes contained abundant lysosomes and phagolysosomes but no obvious Michaelis-Gutmann bodies. Based on these findings, a diagnosis of granulomatous nephritis consistent with early malakoplakia was made. This is the first report in a monkey of a renal lesion consistent with malakoplakia.


Matsui T.,Tokyo Medical and Dental University | Matsui T.,Kyoto University | Miyamoto K.,Keio University | Kubo A.,Keio University | And 10 more authors.
EMBO Molecular Medicine | Year: 2011

The stratum corneum (SC), the outermost layer of the epidermis, acts as a barrier against the external environment. It is hydrated by endogenous humectants to avoid desiccation. However, the molecular mechanisms of SC hydration remain unclear. We report that skin-specific retroviral-like aspartic protease (SASPase) deficiency in hairless mice resulted in dry skin and a thicker and less hydrated SC with an accumulation of aberrantly processed profilaggrin, a marked decrease of filaggrin, but no alteration in free amino acid composition, compared with control hairless mice. We demonstrated that recombinant SASPase directly cleaved a linker peptide of recombinant profilaggrin. Furthermore, missense mutations were detected in 5 of 196 atopic dermatitis (AD) patients and 2 of 28 normal individuals. Among these, the V243A mutation induced complete absence of protease activity in vitro, while the V187I mutation induced a marked decrease in its activity. These findings indicate that SASPase activity is indispensable for processing profilaggrin and maintaining the texture and hydration of the SC. This provides a novel approach for elucidating the complex pathophysiology of atopic dry skin. © 2011 EMBO Molecular Medicine.


Yoshimi K.,Kyoto University | Hashimoto T.,Sunplanet Co. | Niwa Y.,Sunplanet Co. | Hata K.,Sunplanet Co. | And 3 more authors.
BMC Cancer | Year: 2012

Background: Chemotherapeutic bioassay for colorectal cancer (CRC) with a rat model bearing chemically-induced CRCs plays an important role in the development of new anti-tumor drugs and regimens. Although several protocols to induce CRCs have been developed, the incidence and number of CRCs are not much enough for the efficient bioassay. Recently, we established the very efficient system to induce CRCs with a chemically induced-colon carcinogenesis-prone Apc-mutant rat, Kyoto Apc Delta (KAD) rat. Here, we applied the KAD rat to the chemotherapeutic bioassay for CRC and showed the utility of the KAD rat.Methods: The KAD rat has been developed by the ENU mutagenesis and carries a homozygous nonsense mutation in the Apc gene (S2523X). Male KAD rats were given a single subcutaneous injection of AOM (20 mg/kg body weight) at 5 weeks of age. Starting at 1 week after the AOM injection, they were given 2% DSS in drinking water for 7 days. Tumor-bearing KAD rats were divided into experimental and control groups on the basis of the number of tumors observed by endoscopy at week 8. The 5-fluorouracil (5-FU) was administrated intravenously a dose of 50 or 75 mg/kg weekly at week 9, 10, and 11. After one-week interval, the 5-FU was given again at week 13, 14, and 15. At week 16, animals were sacrificed and tumor number and volume were measured macroscopically and microscopically.Results: In total 48 tumors were observed in 27 KAD rats with a 100% incidence at week 8. The maximum tolerated dose for the KAD rat was 50 mg/kg of 5-FU. Macroscopically, the number or volume of tumors in the 5-FU treated rats was not significantly different from the control. Microscopically, the number of adenocarcinoma in the 5-FU treated rats was not significantly different (p < 0.02) from that of the control. However, the volume of adenocarcinomas was significantly lower than in the control. Anticancer effect of the 5-FU could be obtained only after the 16 weeks of experimental period.Conclusion: The use of the AOM/DSS-treated tumor-bearing KAD rats could shorten the experimental period and reduce the number of animals examined in the chemotherapeutic bioassay. The efficient bioassay with the AOM/DSS-treated tumor-bearing KAD rats would promote the development of new anti-tumor drugs and regimens. © 2012 Yoshimi et al.; licensee BioMed Central Ltd.

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