Hamamatsu, Japan
Hamamatsu, Japan

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Kadonosono T.,Tokyo Institute of Technology | Kuchimaru T.,Tokyo Institute of Technology | Yamada S.,Akita University | Murakami A.,Kobe Biomedical Laboratory | And 17 more authors.
PLoS ONE | Year: 2011

An animal model for the early detection of common fatal diseases such as ischemic diseases and cancer is desirable for the development of new drugs and treatment strategies. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that regulates oxygen homeostasis and plays key roles in a number of diseases, including cancer. Here, we established transgenic (Tg) mice that carry HRE/ODD-luciferase (HOL) gene, which generates bioluminescence in an HIF-1-dependent manner and was successfully used in this study to monitor HIF-1 activity in ischemic tissues. To monitor carcinogenesis in vivo, we mated HOL mice with rasH2 Tg mice, which are highly sensitive to carcinogens and are used for short-term carcinogenicity assessments. After rasH2-HOL Tg mice were treated with N-methyl-N-nitrosourea, bioluminescence was detected noninvasively as early as 9 weeks in tissues that contained papillomas and malignant lesions. These results suggest that the Tg mouse lines we established hold significant potential for monitoring the early onset of both ischemia and carcinogenesis and that these lines will be useful for screening chemicals for carcinogenic potential. © 2011 Kadonosono et al.


Ueno S.,Kyorin University | Kimura T.,Kyorin University | Yamaga T.,Kyorin University | Kawada A.,Japan SLC Inc. | And 4 more authors.
Journal of Pharmacological Sciences | Year: 2016

Background: In many cancer cells, L-type amino acid transporter 1 (LAT1) transports neutral amino acids with bulky side chain, which activate mammalian target of rapamycin (mTOR) to cause cell proliferation. An anti-diabetic drug, metformin, has been shown to activate AMP-activated protein kinase (AMPK), which leads to inhibition of mTOR. LAT1 inhibition in combination with metformin could result in more prominent suppression of mTOR activity. Purpose: Anti-proliferative effect of a newly developed LAT1 specific inhibitor JPH203 in combination with metformin is evaluated in 2 head and neck cancer cell lines, Ca9-22 and HEp-2 cells and in nude mice inoculated with Ca9-22 cells. Results and Discussion: By MTT assay, 0.5 mM metformin inhibited proliferation of Ca9-22 cells to 70% of control. In the presence of 100 μM JPH203, proliferation of Ca9-22 cells was inhibited to 60% of control. By combining these 2 drugs, proliferation of Ca9-22 was significantly inhibited to 40% of control. However, this regimen was not very effective against HEp-2 cells. This combination also suppressed in vivo growth of Ca9-22 cells in a xenotransplant model. A combination of anti-LAT1 drug with metformin may be an effective anti-proliferative therapy for certain subsets of cancers. © 2016 The Authors.


Yamanaka H.,Nagasaki University | Nakanishi T.,Nagasaki University | Takagi T.,Nagasaki University | Takagi T.,Japan SLC Inc. | And 5 more authors.
Experimental Animals | Year: 2015

Helicobacter sp. MIT 01-6451 has been detected in SPF mice kept in Japan. To characterize strain MIT 01-6451, its infection route during fetal and neonatal life and effects on pregnancy were investigated using immunocompetent and immunodeficient mouse strains (BALB/c, C57BL/6, and SCID). MIT 01-6451 was detected in the uterus, vagina, and mammary glands of 50% of infected SCID mice, whereas these tissues were all negative in immunocompetent mice. No fetal infections with MIT 01-6451 were detected at 16–18 days after pregnancy in any mouse strain. In newborn mice, MIT 01-6451 was detected in intestinal tissue of C57BL/6 and SCID mice at 9–11 days after birth, but not in BALB/c mice. The IgA and IgG titers to MIT 01-6451 in sera of C57BL/6 female mice were significantly lower than those of BALB/c mice. Although no significant differences in the number of newborns per litter were observed between MIT 01-6451-infected and MIT 01-6451-free dams, the birth rate was lower in infected SCID mice than in control SCID mice. The present results indicated that MIT 01-6451 infects newborn mice after birth rather than by vertical transmission to the fetus via the placenta and that MIT 01-6451 infection shows opportunistically negative effects on the birth rate. In addition, the maternal immune response may affect infection of newborn mice with MIT 01-6451 through breast milk. ©2015 Japanese Association for Laboratory Animal Science.


Yokoi N.,Kobe University | Hidaka S.,Kobe University | Tanabe S.,Kobe University | Ohya M.,Kobe University | And 4 more authors.
Genes and Immunity | Year: 2012

Although the MHC class II u haplotype is strongly associated with type 1 diabetes (T1D) in rats, the role of MHC class II in the development of tissue-specific autoimmune diseases including T1D and autoimmune thyroiditis remains unclear. To clarify this, we produced a congenic strain carrying MHC class II a and u haplotypes on the Komeda diabetes-prone (KDP) genetic background. The u/u homozygous animals developed T1D similar to the original KDP rat; a/u heterozygous animals did develop T1D but with delayed onset and low frequency. In contrast, none of the a/a homozygous animals developed T1D; about half of the animals with a/u heterozygous or a/a homozygous genotypes showed autoimmune thyroiditis. To investigate the role of genetic background in the development of thyroiditis, we also produced a congenic strain carrying Cblb mutation of the KDP rat on the PVG.R23 genetic background (MHC class II a haplotype). The congenic rats with homozygous Cblb mutation showed autoimmune thyroiditis without T1D and slight to severe alopecia, a clinical symptom of hypothyroidism such as Hashimoto's thyroiditis. These data indicate that MHC class II is involved in the tissue-specific development of autoimmune diseases, including T1D and thyroiditis. © 2012 Macmillan Publishers Limited All rights reserved.


Yamanaka H.,Nagasaki University | Arita M.,Nagasaki University | Oi R.,Nagasaki University | Ohsawa M.,Nagasaki University | And 7 more authors.
Experimental Animals | Year: 2013

An unidentified Helicobacter species, strain MIT 01-6451, was frequently detected in mice obtained from domestic commercial and academic institutions in Japan. To partially characterize this strain, its distributions in the gastrointestinal tract and hepatobiliary system of mice were investigated. In gastrointestinal tissues, this strain was detected in all cecum, colon, and feces samples tested, whereas fewer mice were positive in the ileum, jejunum, and duodenum. Interestingly, strain MIT 01-6451 was also detected in most stomach samples and in 33% of gallbladder samples. One mouse was found to be infected with multiple Helicobacter species. Fourteen copies of 16S rRNA genes were cloned from the tissues of this mouse. One had the highest level of sequence homology with H. canadensis, while 13 had the highest level of homology with the H. ganmani type strain or strain MIT 01-6451. Twelve of these 13 16S rRNA genes were mosaic sequences, being partially derived from H. ganmani and strain MIT 01-6451. These results suggest that H. ganmani and Helicobacter sp. MIT 01-6451 are prevalent in specific-pathogen-free mouse colonies in Japan and that lateral gene transfer probably occurs among Helicobacter species during coinfection. © 2013 Japanese Association for Laboratory Animal Science.


Yokoi N.,Kobe University | Hoshino M.,Hoshino Laboratory Animals Inc. | Hidaka S.,Kobe University | Yoshida E.,Kobe University | And 6 more authors.
Journal of Diabetes Research | Year: 2013

The Zucker fatty (ZF) rat harboring a missense mutation (fatty, fa) in the leptin receptor gene (Lepr) develops obesity without diabetes; Zucker diabetic fatty (ZDF) rats derived from the ZF strain exhibit obesity with diabetes and are widely used for research on type 2 diabetes (T2D). Here we establish a novel diabetic strain derived from normoglycemic ZF rats. In our ZF rat colony, we incidentally found fa/fa homozygous male rats having reproductive ability, which is generally absent in these animals. During maintenance of this strain by mating fa/fa males and fa/+ heterozygous females, we further identified fa/fa male rats exhibiting diabetes. We then performed selective breeding using the fa/fa male rats that exhibited relatively high blood glucose levels at 10 weeks of age, resulting in establishment of a diabetic strain that we designated Hos:ZFDM-Leprfa (ZFDM). These fa/fa male rats developed diabetes as early as 10 weeks of age, reaching 100% incidence by 21 weeks of age, while none of the fa/+ male rats developed diabetes. The phenotypic characteristics of this diabetic strain are distinct from those of normoglycemic ZF rats. ZFDM rat strain having high reproductive efficiency should serve as a more useful animal model of T2D. © 2013 Norihide Yokoi et al.


PubMed | Japan SLC Inc., U.S. National Institutes of Health and Baylor College of Medicine
Type: | Journal: Gut microbes | Year: 2017

Recent discoveries on the role of commensal microbiota have significantly changed our understanding of human physiology. The host-microbiota interplay is now an important aspect to take into account to understand immune responses and immunological diseases. Autoimmune uveitis is a sight-threatening disease that arises without a known infectious etiology. It is unknown where and how autoreactive T cells become primed to trigger disease in the eye, which is an immune privileged site. We recently reported data supporting the notion that retina-specific T cells receive a signal in the gut from commensal microbiota-derived cross-reactive antigen(s) and trigger autoimmune uveitis in the R161H mouse model. Here we discuss our published findings, as well as our recent attempts to identify the responsible microbe(s) by using different antibiotic treatments, 16S rDNA sequencing and homology searches for candidate antigenic mimic(s) of the retinal antigen.


PubMed | Japan SLC Inc. and Kyorin University
Type: Journal Article | Journal: Journal of pharmacological sciences | Year: 2016

In many cancer cells, L-type amino acid transporter 1 (LAT1) transports neutral amino acids with bulky side chain, which activate mammalian target of rapamycin (mTOR) to cause cell proliferation. An anti-diabetic drug, metformin, has been shown to activate AMP-activated protein kinase (AMPK), which leads to inhibition of mTOR. LAT1 inhibition in combination with metformin could result in more prominent suppression of mTOR activity.Anti-proliferative effect of a newly developed LAT1 specific inhibitor JPH203 in combination with metformin is evaluated in 2 head and neck cancer cell lines, Ca9-22 and HEp-2 cells and in nude mice inoculated with Ca9-22 cells.By MTT assay, 0.5mM metformin inhibited proliferation of Ca9-22 cells to 70%of control. In the presence of 100M JPH203, proliferation of Ca9-22 cells was inhibited to 60%of control. By combining these 2 drugs, proliferation of Ca9-22 was significantly inhibited to 40%of control. However, this regimen was not very effective against HEp-2 cells. This combination also suppressed invivo growth of Ca9-22 cells in a xenotransplant model. A combination of anti-LAT1 drug with metformin may be an effective anti-proliferative therapy for certain subsets of cancers.

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