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Articles by S Kato
Total Records ( 9 ) for S Kato
  M Ishizawa , K. i Iwasaki , S Kato and M. Makishima

The possibility of pathological calcium metabolism is a critical health concern introduced by long-term space travel. Because vitamin D plays an important role in calcium homeostasis, we evaluated the effects of hypergravity on the expression of genes involved in vitamin D and calcium metabolism in ICR mice. When exposed to 2G hypergravity for 2 days, the mRNA expression of renal 25-hydroxyvitamin D 24-hydroxylase (Cyp24a1) was increased and that of 25-hydroxyvitamin D 1-hydroxylase (Cyp27b1) was decreased. Although hypergravity decreased food intake and increased the expression of starvation-induced genes, the changes in Cyp24a1 and Cyp27b1 expression were not due to starvation, suggesting that hypergravity affects these genes directly. Hypergravity decreased plasma 1,25-dihydroxyvitamin D3 levels in ICR mice, suggesting a consequence of decreased Cyp27b1 and increased Cyp24a1 expression. Although 1-hydroxyvitamin D3 [1(OH)D3] treatment induced the expression of vitamin D receptor (VDR) target genes in the kidney of 2G-exposed ICR mice to similar levels as controls, 1(OH)D3 increased the intestinal expression of Cyp24a1 in ICR mice. Hypergravity-dependent changes of Cyp24a1 and Cyp27b1 expression were diminished in mice exposed to hypergravity for 14 days, which may represent an adaptation to hypergravity stress. Hypergravity exposure also increased Cyp24a1 expression in the kidney of C57BL/6J mice. We examined the effects of hypergravity on VDR-null mice and found that renal Cyp27b1 expression in VDR-null mice was decreased by hypergravity while renal Cyp24a1 expression was not detected in VDR-null mice. Thus hypergravity modifies the expression of genes involved in vitamin D metabolism.

  Y Ikeda , K. i Aihara , S Yoshida , T Sato , S Yagi , T Iwase , Y Sumitomo , T Ise , K Ishikawa , H Azuma , M Akaike , S Kato and T. Matsumoto

Age-related andropause promotes cardiovascular disease in males. Although we had previously reported that the androgen-androgen receptor (AR) system plays important roles in cardiac growth and remodeling, the system’s involvement in vascular remodeling remains unclear. To clarify this role, 25-wk-old male AR knockout (ARKO) mice and littermate male wild-type (WT) mice were divided into two groups with and without angiotensin II (Ang II) administration (2.0 mg/kg · d) for 14 d, respectively. No morphological differences in the coronary artery and thoracic aorta were observed between the groups without Ang II. Ang II stimulation markedly increased medial thickness and perivascular fibrosis in ARKO mice, with enhanced TGF-β1, collagen type I, and collagen type III gene expression in the aorta. Ang II stimulation also prominently increased superoxide production, lipid peroxidation, and gene expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase components in ARKO mice compared with WT mice. In addition, phosphorylation of c-Jun N-terminal kinase (JNK) and phosphorylated (Smad2/3) was remarkably enhanced in Ang II-treated ARKO mice compared with Ang II-treated WT mice. Notably, daily urinary nitric oxide (NO) metabolites excretion as a marker of NO bioavailability, aortic endothelial NO synthase expression and phosphorylation, and Akt phosphorylation were significantly reduced in ARKO mice compared with WT mice, regardless of Ang II stimulation. In conclusion, the androgen-AR system is required for the preservation of NO bioavailability through Akt-endothelial NO synthase system activation and exerts protective effects against Ang II-induced vascular remodeling by regulating oxidative stress, c-Jun N-terminal kinase (JNK) signaling, and the TGF-β-phosphorylated Smad pathway.

  T Toita , M Oguchi , T Ohno , S Kato , Y Niibe , T Kodaira , T Kazumoto , M Kataoka , N Shikama , M Kenjo , T Teshima and Y. Kagami

To assess compliance with the radiotherapy protocol of a multi-institutional prospective study (JAROG0401/JROSG04-2), which investigated the efficacy and toxicity of definitive radiotherapy using high-dose-rate intracavitary brachytherapy (HDR-ICBT) for early-stage uterine cervical cancer patients.


Individual case reviews (ICRs) were performed on all 60 study participants. Radiotherapy data were submitted to the quality assurance (QA) committee, which performed ICRs on 16 QA items according to previously selected criteria. The items focused on quality of external beam radiotherapy (EBRT), HDR-ICBT and both. Each item was determined to be either acceptable or a deviation. The QA committee performed ICR three times as planned, two during the patient accrual and the final one just after the final patient accrued. The QA results of the first and second reviews were reported back to the investigators after each ICR.


In 40 cases (67%), all 16 QA items were classified as acceptable. One deviation was found in 16 cases, two deviations were identified in 3 cases and three deviations were noted in 1 case. The most frequently observed deviation was missing the rules for determining point A (10 cases). The items described by quantitative values, such as prescribed doses, certain time intervals and overall treatment time, were well followed. The proportion of deviations gradually decreased during the ICR process.


The present ICR demonstrated the favorable radiotherapy compliance with the JAROG0401/JROSG04-2 protocol. The QA process using ICRs can potentially be used to improve the quality of radiotherapy, including HDR-ICBT in the multi-institutional prospective studies for cervical cancer.

  N Ohoka , S Kato , Y Takahashi , H Hayashi and R. Sato

The nuclear receptor-type transcription factor retinoic acid receptor-related orphan receptor (ROR) is a multifunctional molecule involved in tissue development and cellular function, such as inflammation, metabolism, and differentiation; however, the role of ROR during adipocyte differentiation has not yet been fully understood. Here we show that ROR inhibits the transcriptional activity of CCAAT/enhancer-binding protein β (C/EBPβ) without affecting its expression, thereby blocking the induction of both PPAR and C/EBP, resulting in the suppression of C/EBPβ-dependent adipogenesis. ROR interacted with C/EBPβ so as to repress both the C/EBPβ-p300 association and the C/EBPβ-dependent recruitment of p300 to chromatin. In addition to the inhibitory effect on C/EBPβ function, ROR also prevents the expression of the lipid droplet coating protein gene perilipin by peroxisome proliferators-activated receptor (PPAR), acting through the specific mechanism of its promoter. We identified a suppressive ROR-responsive element overlapping the PPAR-responsive element in the perilipin promoter and verified that ROR competitively antagonizes the binding of PPAR. ROR inhibits PPAR-dependent adipogenesis along with the repression of perilipin induction. These findings suggest that ROR is a novel negative regulator of adipocyte differentiation that acts through dual mechanisms.

  S Miyagawa , Y Satoh , R Haraguchi , K Suzuki , T Iguchi , M. M Taketo , N Nakagata , T Matsumoto , K. i Takeyama , S Kato and G. Yamada

In most mammals, the sexually dimorphic development of embryos is typically achieved by the differentiation of the external genitalia. Hence, the sexual distinction of mammalian newborns is based on the external genital structure. Although it was shown in the 1940s and 1950s that androgen from the testes establishes the male sexual characteristics, the involvement of nongonadal and locally produced masculine effectors remains totally unknown. It is noteworthy that the disorders of fetal masculinization, including hypospadias, one of the most frequent birth defects, occur at a high frequency. Furthermore, their causative factors remain unclear. In this study, the involvement of the coordinated actions of androgen and the growth factor systems was genetically analyzed for the first time on mammalian reproductive organ formation. The results demonstrated that the Wnt/β-catenin pathway is indispensable masculine factor for the external genital development. The bilateral mesenchymal region adjacent to the urethral plate epithelium displayed a sexually dimorphic activity of Wnt/β-catenin signaling. Loss- and gain-of-function β-catenin mutants displayed altered sexual development of the external genitalia. These results indicate the novel functions of the Wnt/β-catenin pathway as a locally expressed masculine effector. This could be the first genetic study analyzing the roles of the genetic interactions between androgen and locally expressed growth factor signaling during the development of reproductive organs. These results also shed new insight on the reproductive genetics and the causative factors of genital disorders.

  Y Ikeda , K. i Aihara , M Akaike , T Sato , K Ishikawa , T Ise , S Yagi , T Iwase , Y Ueda , S Yoshida , H Azuma , K Walsh , T Tamaki , S Kato and T. Matsumoto

Doxorubicin (Dox) has been used as a potent anticancer agent, but serious cardiotoxicity precludes its use in a wide range of patients. We have reported that the androgen-androgen receptor (AR) system plays important roles in cardiac growth and protection from angiotensin II-induced cardiac remodeling. The present study was undertaken to clarify whether the androgen-AR system exerts a cardioprotective effect against Dox-induced cardiotoxicity. Male AR knockout (ARKO) and age-matched littermate male wild-type (WT) mice at 25 wk of age were given ip injections of Dox (20 mg/kg) or a vehicle. The survival rate and left ventricular function in Dox-treated male ARKO mice were reduced compared with those in Dox-treated male WT mice. Electron microscopic study showed prominent vacuole formation of myocardial mitochondria in Dox-treated male ARKO mice. Cardiac oxidative stress and apoptosis of cardiomyocytes were increased more prominently by Dox treatment in male ARKO mice than in male WT mice. In addition, Dox-induced reduction in the expression of cardiac mitochondria transcription factor A (Tfam) and phosphorylation of serine-threonine kinase (Akt) was more pronounced in male ARKO mice than in male WT mice. In cardiac myoblast cells, testosterone up-regulated Akt phosphorylation and Tfam expression and exerted an antiapoptotic effect against Dox-induced cardiotoxicity. Collectively, the results demonstrate that Dox-induced cardiotoxicity is aggravated in male ARKO mice via exacerbation of mitochondrial damage and superoxide generation, leading to enhanced apoptosis of cardiomyocytes. Thus, the androgen-AR system is thought to counteract Dox-induced cardiotoxicity partly through activation of the Akt pathway and up-regulation of Tfam to protect cardiomyocytes from mitochondrial damage and apoptosis.

  A Fukumura , H Tsujii , T Kamada , M Baba , H Tsuji , H Kato , S Kato , S Yamada , S Yasuda , T Yanagi , R Hara , N Yamamoto , J Mizoe , K Akahane , S Fukuda , Y Furusawa , Y Iwata , T Kanai , N Kanematsu , A Kitagawa , N Matsufuji , S Minohara , N Miyahara , H Mizuno , T Murakami , K Nishizawa , K Noda , E Takada and S. Yonai

The features of relativistic carbon-ion beams are attractive from the viewpoint of radiotherapy. They exhibit not only a superior physical dose distribution but also an increase in biological efficiency with depth, because energy loss of the beams increases as they penetrate the body. This paper reviews clinical aspects of carbon-beam radiotherapy using the experience at the National Institute of Radiological Sciences. The paper also outlines the dosimetry related to carbon-beam radiotherapy, including absolute dosimetry of the carbon beam, neutron measurements and radiation protection measurements.

  H Hiura , T Matsui , M Matsumoto , Y Hori , A Isonishi , S Kato , T Iwamoto , T Mori and Y. Fujimura

ADAMTS13 is a metalloproteinase that specifically cleaves unusually large von Willbrand factor multimers under high-shear stress. Deficiency of ADAMTS13 activity induces a life-threatening generalized disease, thrombotic thrombocytopenic purpura. We established a simple and efficient method to purify plasma ADAMTS13 (pADAMTS13) from cryosupernatant using an anti-ADAMTS13 monoclonal antibody (A10) that recognizes a conformational epitope within the disintegrin-like domain. Using the purified pADAMTS13, the amino acid residues involved in cleavage by thrombin, plasmin and leucocyte elastase were determined, and the carbohydrate moieties of this enzyme was analysed by lectin blots. Purified pADAMTS13 had a specific activity of 300 U/mg (25,057-fold purification) and the pI was 5.1–5.5. Cleavage sites of the purified pADAMTS13 by three proteases were identified; thrombin cleaved the four peptidyl bonds between Arg257–Ala258, Arg459–Ser460, Arg888–Thr889 and Arg1176–Arg1177, plasmin cleaved the three peptidyl bonds between Arg257–Ala258, Arg888–Thr889 and Arg1176–Arg1177, and elastase cleaved the two peptidyl bonds between Ile380–Ala381 and Thr874–Ser875. Lectin blot analysis indicated the presence of non-reducing terminal 2–6 and 2–3-linked sialic acid residues with penultimate β-galactose residues on the N- and O-linked sugar chains of pADAMTS13, suggesting that pADAMTS13 is cleared from the circulation via the hepatic asialoglycoprotein receptor like other plasma glycoproteins.

  Y Miyauchi , K Ninomiya , H Miyamoto , A Sakamoto , R Iwasaki , H Hoshi , K Miyamoto , W Hao , S Yoshida , H Morioka , K Chiba , S Kato , T Tokuhisa , M Saitou , Y Toyama , T Suda and T. Miyamoto

Controlling osteoclastogenesis is critical to maintain physiological bone homeostasis and prevent skeletal disorders. Although signaling activating nuclear factor of activated T cells 1 (NFATc1), a transcription factor essential for osteoclastogenesis, has been intensively investigated, factors antagonistic to NFATc1 in osteoclasts have not been characterized. Here, we describe a novel pathway that maintains bone homeostasis via two transcriptional repressors, B cell lymphoma 6 (Bcl6) and B lymphocyte–induced maturation protein-1 (Blimp1). We show that Bcl6 directly targets ‘osteoclastic’ molecules such as NFATc1, cathepsin K, and dendritic cell-specific transmembrane protein (DC-STAMP), all of which are targets of NFATc1. Bcl6-overexpression inhibited osteoclastogenesis in vitro, whereas Bcl6-deficient mice showed accelerated osteoclast differentiation and severe osteoporosis. We report that Bcl6 is a direct target of Blimp1 and that mice lacking Blimp1 in osteoclasts exhibit osteopetrosis caused by impaired osteoclastogenesis resulting from Bcl6 up-regulation. Indeed, mice doubly mutant in Blimp1 and Bcl6 in osteoclasts exhibited decreased bone mass with increased osteoclastogenesis relative to osteoclast-specific Blimp1-deficient mice. These results reveal a Blimp1–Bcl6–osteoclastic molecule axis, which critically regulates bone homeostasis by controlling osteoclastogenesis and may provide a molecular basis for novel therapeutic strategies.

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