2022/02/25 更新

写真a

ナカツカ アツコ
中司 敦子
NAKATSUKA Atsuko
所属
岡山大学病院 講師
職名
講師
外部リンク

学位

  • 医学博士 ( 岡山大学 )

研究キーワード

  • 糖尿病

  • 肥満症

  • 腎臓病

  • 脂質異常症

研究分野

  • ライフサイエンス / 代謝、内分泌学

  • ライフサイエンス / 腎臓内科学

学歴

  • 岡山大学   Medical School   Faculty of Medicine

    1992年4月 - 1998年3月

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経歴

  • 岡山大学   腎臓・糖尿病・内分泌内科   講師

    2019年7月 - 現在

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  • 岡山大学   腎臓・糖尿病・内分泌内科   助教

    2014年4月 - 2019年6月

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  • 岡山大学   糖尿病性腎症治療学講座   助教

    2012年7月 - 2014年3月

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所属学協会

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委員歴

  • 日本腎臓学会   腎臓学会 症例評価委員  

    2021年1月 - 2022年3月   

  • 日本肥満学会   専門医認定試験委員  

    2020年5月 - 2021年12月   

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    団体区分:学協会

  • 日本肥満学会   教育委員会委員  

    2020年5月 - 2021年12月   

  • 日本腎臓学会   評議員  

    2020年4月 - 現在   

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  • 日本肥満学会   評議員  

    2019年11月 - 現在   

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    団体区分:学協会

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  • 日本糖尿病学会   中国・四国支部評議員  

    2019年5月 - 現在   

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    団体区分:学協会

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  • 日本内科学会   中国支部評議員  

    2013年6月 - 現在   

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    団体区分:学協会

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  • JSN Next Frontier 2028委員会  

    2000年9月 - 2022年3月   

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論文

  • Lgals9 deficiency ameliorates obesity by modulating redox state of PRDX2

    Tomokazu Nunoue, Satoshi Yamaguchi, Sanae Teshigawara, Akihiro Katayama, Atsuko Nakatsuka, Jun Eguchi, Toshiro Niki, Jun Wada

    Scientific Reports   11 ( 1 )   2021年12月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    <title>Abstract</title>The adipose tissue is regarded as an endocrine organ and secretes bioactive adipokines modulating chronic inflammation and oxidative stress in obesity. Gal-9 is secreted out upon cell injuries, interacts with T-cell immunoglobulin-3 (Tim-3) and induces apoptosis in activated Th1 cells. Gal-9 also binds to protein disulfide isomerase (PDI), maintains PDI on surface of T cells, and increases free thiols in the disulfide/thiol cycles. To explore the molecular mechanism of obesity, we investigated Gal-9−/− and Gal-9wt/wt C57BL/6J mice fed with high fat-high sucrose (HFHS) chow. Gal-9−/− mice were resistant to diet-induced obesity associated with reduction of epididymal and mesenteric fat tissues and improved glucose tolerance compared with Gal-9wt/wt mice. However, the number of M1, M2 macrophages, and M1/M2 ratio in epididymal fat were unaltered. Under HFHS chow, Gal-9−/− mice receiving Gal-9−/− or Gal-9wt/wt bone marrow-derived cells (BMCs) demonstrated significantly lower body weight compared with Gal-9wt/wt mice receiving Gal-9−/− BMCs. We identified the binding between Gal-9 and peroxiredoxin-2 (PRDX2) in sugar chain-independent manner by nanoLC-MS/MS, immunoprecipitation, and pull-down assay. In 3T3L1 adipocytes, Gal-9 knockdown shifts PRDX2 monomer (reduced form) dominant from PRDX2 dimer (oxidized form) under oxidative stress with H2O2. The inhibition of Gal-9 in adipocytes may be a new therapeutic approach targeting the oxidative stress and subsequent glucose intolerance in obesity.

    DOI: 10.1038/s41598-021-85080-1

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    その他リンク: http://www.nature.com/articles/s41598-021-85080-1

  • A Vaspin–HSPA1L complex protects proximal tubular cells from organelle stress in diabetic kidney disease 国際誌

    Atsuko Nakatsuka, Satoshi Yamaguchi, Jun Eguchi, Shigeru Kakuta, Yoichiro Iwakura, Hitoshi Sugiyama, Jun Wada

    Communications Biology   4 ( 1 )   373 - 373   2021年12月

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    担当区分:筆頭著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    <title>Abstract</title>Proximal tubular cells (PTCs) are crucial for maintaining renal homeostasis, and tubular injuries contribute to progression of diabetic kidney disease (DKD). However, the roles of visceral adipose tissue-derived serine protease inhibitor (vaspin) in the development of DKD is not known. We found vaspin maintains PTCs through ameliorating ER stress, autophagy impairment, and lysosome dysfunction in DKD. <italic>Vaspin</italic>−/− obese mice showed enlarged and leaky lysosomes in PTCs associated with increased apoptosis, and these abnormalities were also observed in the patients with DKD. During internalization into PTCs, vaspin formed a complex with heat shock protein family A (Hsp70) member 1 like (HSPA1L) as well as 78 kDa glucose-regulated protein (GRP78). Both vaspin-partners bind to clathrin heavy chain and involve in the endocytosis. Notably, albumin-overload enhanced extracellular release of HSPA1L and overexpression of HSPA1L dissolved organelle stresses, especially autophagy impairment. Thus, vapsin/HSPA1L-mediated pathways play critical roles in maintaining organellar function of PTCs in DKD.

    DOI: 10.1038/s42003-021-01902-y

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    その他リンク: http://www.nature.com/articles/s42003-021-01902-y

  • Upregulation of Mir342 in Diet-Induced Obesity Mouse and the Hypothalamic Appetite Control

    Dongxiao Zhang, Satoshi Yamaguchi, Xinhao Zhang, Boxuan Yang, Naoko Kurooka, Ryosuke Sugawara, Haya Hamed H. Albuayjan, Atsuko Nakatsuka, Jun Eguchi, Takeshi Y. Hiyama, Atsunori Kamiya, Jun Wada

    Frontiers in Endocrinology   12   2021年8月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Frontiers Media SA  

    In obesity and type 2 diabetes, numerous genes are differentially expressed, and microRNAs are involved in transcriptional regulation of target mRNAs, but miRNAs critically involved in the appetite control are not known. Here, we identified upregulation of miR-342-3p and its host gene <italic>Evl</italic> in brain and adipose tissues in C57BL/6 mice fed with high fat-high sucrose (HFHS) chow by RNA sequencing. <italic>Mir342</italic> (-/-) mice fed with HFHS chow were protected from obesity and diabetes. The hypothalamic arcuate nucleus neurons co-express <italic>Mir342</italic> and EVL. The percentage of activated NPY+pSTAT3+ neurons were reduced, while POMC+pSTAT3+ neurons increased in <italic>Mir342</italic> (-/-) mice, and they demonstrated the reduction of food intake and amelioration of metabolic phenotypes. <italic>Snap25</italic> was identified as a major target gene of miR-342-3p and the reduced expression of <italic>Snap25</italic> may link to functional impairment hypothalamic neurons and excess of food intake. The inhibition of miR-342-3p may be a potential candidate for miRNA-based therapy.

    DOI: 10.3389/fendo.2021.727915

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  • Current Status of Familial LCAT Deficiency in Japan

    Masayuki Kuroda, Hideaki Bujo, Koutaro Yokote, Takeyoshi Murano, Takashi Yamaguchi, Masatsune Ogura, Katsunori Ikewaki, Masahiro Koseki, Yasuo Takeuchi, Atsuko Nakatsuka, Mika Hori, Kota Matsuki, Takashi Miida, Shinji Yokoyama, Jun Wada, Mariko Harada-Shiba

    Journal of Atherosclerosis and Thrombosis   28 ( 7 )   679 - 691   2021年7月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Japan Atherosclerosis Society  

    DOI: 10.5551/jat.rv17051

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  • Novel Urinary Glycan Biomarkers Predict Cardiovascular Events in Patients With Type 2 Diabetes: A Multicenter Prospective Study With 5-Year Follow Up (U-CARE Study 2)

    Koki Mise, Mariko Imamura, Satoshi Yamaguchi, Mayu Watanabe, Chigusa Higuchi, Akihiro Katayama, Satoshi Miyamoto, Haruhito A. Uchida, Atsuko Nakatsuka, Jun Eguchi, Kazuyuki Hida, Tatsuaki Nakato, Atsuhito Tone, Sanae Teshigawara, Takashi Matsuoka, Shinji Kamei, Kazutoshi Murakami, Ikki Shimizu, Katsuhiro Miyashita, Shinichiro Ando, Tomokazu Nunoue, Michihiro Yoshida, Masao Yamada, Kenichi Shikata, Jun Wada

    Frontiers in Cardiovascular Medicine   8   2021年5月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Frontiers Media SA  

    <bold>Background:</bold> Although various biomarkers predict cardiovascular event (CVE) in patients with diabetes, the relationship of urinary glycan profile with CVE in patients with diabetes remains unclear.

    <bold>Methods:</bold> Among 680 patients with type 2 diabetes, we examined the baseline urinary glycan signals binding to 45 lectins with different specificities. Primary outcome was defined as CVE including cardiovascular disease, stroke, and peripheral arterial disease.

    <bold>Results:</bold> During approximately a 5-year follow-up period, 62 patients reached the endpoint. Cox proportional hazards analysis revealed that urinary glycan signals binding to two lectins were significantly associated with the outcome after adjustment for known indicators of CVE and for false discovery rate, as well as increased model fitness. Hazard ratios for these lectins (+1 SD for the glycan index) were UDA (recognizing glycan: mixture of Man5 to Man9): 1.78 (95% CI: 1.24–2.55, <italic>P</italic> = 0.002) and Calsepa [High-Man (Man2–6)]: 1.56 (1.19–2.04, <italic>P</italic> = 0.001). Common glycan binding to these lectins was high-mannose type of <italic>N</italic>-glycans. Moreover, adding glycan index for UDA to a model including known confounders improved the outcome prediction [Difference of Harrel's C-index: 0.028 (95% CI: 0.001–0.055, <italic>P</italic> = 0.044), net reclassification improvement at 5-year risk increased by 0.368 (0.045–0.692, <italic>P</italic> = 0.026), and the Akaike information criterion and Bayesian information criterion decreased from 725.7 to 716.5, and 761.8 to 757.2, respectively].

    <bold>Conclusion:</bold> The urinary excretion of high-mannose glycan may be a valuable biomarker for improving prediction of CVE in patients with type 2 diabetes, and provides the rationale to explore the mechanism underlying abnormal <italic>N</italic>-glycosylation occurring in patients with diabetes at higher risk of CVE.

    <bold>Trial Registration:</bold> This study was registered with the University Hospital Medical Information Network on June 26, 2012 (Clinical trial number: UMIN000011525, URL: <ext-link>https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000013482</ext-link>).

    DOI: 10.3389/fcvm.2021.668059

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  • Dysfunction of CD8 + PD-1 + T cells in type 2 diabetes caused by the impairment of metabolism-immune axis

    Ichiro Nojima, Shingo Eikawa, Nahoko Tomonobu, Yoshiko Hada, Nobuo Kajitani, Sanae Teshigawara, Satoshi Miyamoto, Atsuhito Tone, Haruhito A. Uchida, Atsuko Nakatsuka, Jun Eguchi, Kenichi Shikata, Heiichiro Udono, Jun Wada

    Scientific Reports   10 ( 1 )   2020年12月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    <title>Abstract</title>
    The metabolic changes and dysfunction in CD8 + T cells may be involved in tumor progression and susceptibility to virus infection in type 2 diabetes (T2D). In C57BL/6JJcl mice fed with high fat-high sucrose chow (HFS), multifunctionality of CD8 + splenic and tumor-infiltrating lymphocytes (TILs) was impaired and associated with enhanced tumor growth, which were inhibited by metformin. In CD8 + splenic T cells from the HFS mice, glycolysis/basal respiration ratio was significantly reduced and reversed by metformin. In the patients with T2D (DM), multifunctionality of circulating CD8 + PD-1 + T cells stimulated with PMA/ionomycin as well as with HLA-A*24:02 CMV peptide was dampened, while metformin recovered multifunctionality. Both glycolysis and basal respiration were reduced in DM, and glycolysis was increased by metformin. The disturbance of the link between metabolism and immune function in CD8 + PD-1 + T cells in T2D was proved by recovery of antigen-specific and non-specific cytokine production via metformin-mediated increase in glycolytic activity.

    DOI: 10.1038/s41598-020-71946-3

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    その他リンク: http://www.nature.com/articles/s41598-020-71946-3

  • High expression of a vascular stricture‐related marker is predictive of an early response to tolvaptan, and a low fractional excretion of sodium is predictive of a poor long‐term survival after tolvaptan administration for liver cirrhosis

    Takuya Adachi, Akinobu Takaki, Shuichi Sato, Hiroshi Tobita, Haruhiko Kobashi, Masaru Kinomura, Atsuko Nakatsuka, Atsushi Oyama, Nozomu Wada, Masahiro Sakata, Yasuto Takeuchi, Tetsuya Yasunaka, Hideki Onishi, Hidenori Shiraha, Hiroyuki Okada

    Hepatology Research   50 ( 12 )   1347 - 1354   2020年12月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    DOI: 10.1111/hepr.13573

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1111/hepr.13573

  • The hypoglycemia-prevention effect of sensor-augmented pump therapy with predictive low glucose management in Japanese patients with type 1 diabetes mellitus: a short-term study

    Akihiro Katayama, Atsuhito Tone, Mayu Watanabe, Sanae Teshigawara, Satoshi Miyamoto, Jun Eguchi, Atsuko Nakatsuka, Kenichi Shikata, Jun Wada

    Diabetology International   11 ( 2 )   97 - 104   2020年4月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    DOI: 10.1007/s13340-019-00408-7

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    その他リンク: http://link.springer.com/article/10.1007/s13340-019-00408-7/fulltext.html

  • GPIHBP1 autoantibody syndrome during interferon β1a treatment. 査読

    Eguchi J, Miyashita K, Fukamachi I, Nakajima K, Murakami M, Kawahara Y, Yamashita T, Ohta Y, Abe K, Nakatsuka A, Mino M, Takase S, Okazaki H, Hegele RA, Ploug M, Hu X, Wada J, Young SG, Beigneux AP

    Journal of clinical lipidology   13 ( 1 )   62 - 69   2019年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.jacl.2018.10.004

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  • Acquired partial lipoatrophy as graft-versus-host disease and treatment with metreleptin: two case reports. 査読 国際誌

    Shibata Y, Nakatsuka A, Eguchi J, Miyamoto S, Masuda Y, Awazawa M, Takaki A, Yoshida R, Yagi T, Wada J

    Journal of medical case reports   12 ( 1 )   368 - 368   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1186/s13256-018-1901-y

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  • Identification of Novel Urinary Biomarkers for Predicting Renal Prognosis in Patients With Type 2 Diabetes by Glycan Profiling in a Multicenter Prospective Cohort Study: U-CARE Study 1. 査読 国際誌

    Mise K, Imamura M, Yamaguchi S, Teshigawara S, Tone A, Uchida HA, Eguchi J, Nakatsuka A, Ogawa D, Yoshida M, Yamada M, Shikata K, Wada J

    Diabetes care   41 ( 8 )   1765 - 1775   2018年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.2337/dc18-0030

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  • Serum-inducible protein (IP)-10 is a disease progression-related marker for non-alcoholic fatty liver disease 査読

    Nozomu Wada, Akinobu Takaki, Fusao Ikeda, Tetsuya Yasunaka, Masahiro Onji, Kazuhiro Nouso, Atsuko Nakatsuka, Jun Wada, Kazuko Koike, Koji Miyahara, Hidenori Shiraha, Kazuhide Yamamoto, Hiroyuki Okada

    HEPATOLOGY INTERNATIONAL   11 ( 1 )   115 - 124   2017年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    The molecular pathogenesis of non-alcoholic steatohepatitis (NASH) is not well defined. The objective of the present study was to identify disease progression-related cytokines and investigate the molecular pathogenesis of such changes in NASH.
    A study population of 20 non-alcoholic fatty liver (NAFL) and 59 NASH patients diagnosed by liver biopsy and 15 healthy volunteers was recruited. The serum pro- and anti-inflammatory cytokines were measured by a multiple enzyme-linked immunosorbent assay. The hepatic mRNA expressions of cytokines were measured by real-time PCR. A monocyte cell line was stimulated with Toll-like receptor (TLR) ligand under a high glucose and insulin condition, and cellular cytokine mRNA expression was quantified.
    One group of cytokines was higher in NAFL and NASH than in controls, while another group was higher in NASH than in NAFL and controls. The NASH-specific second group included interleukin (IL)-15 and interferon-gamma-inducible protein (IP)-10. In particular, IP-10 was higher in NAFL than in controls and higher in NASH than in NAFL and controls. The sensitivity to diagnose NASH was 90%, with specificity of 50%. Insulin resistance reflecting a high glucose and insulin condition resulted in higher IP-10 mRNA expression in the monocyte cell line only with concomitant TLR-2 stimulation.
    IP-10 is a sensitive marker of the need for liver biopsy. Insulin resistance with bacteria-related TLR-2 stimulation might induce IP-10 production from monocytes. Insulin resistance and intestinal barrier function should be intensively controlled to prevent progression from NAFL to NASH.

    DOI: 10.1007/s12072-016-9773-y

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  • Microinflammation and organelle dysfunctions in diabetic nephropathy. 査読

    Nakatsuka A, Wada J

    Nihon Jinzo Gakkai shi   59 ( 2 )   58 - 64   2017年

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  • Mitochondrial Dynamics and Mitochondrial Dysfunction in Diabetes 査読

    Jun Wada, Atsuko Nakatsuka

    ACTA MEDICA OKAYAMA   70 ( 3 )   151 - 158   2016年6月

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    記述言語:英語   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    The mitochondria are involved in active and dynamic processes, such as mitochondrial biogenesis, fission, fusion and mitophagy to maintain mitochondrial and cellular functions. In obesity and type 2 diabetes, impaired oxidation, reduced mitochondrial contents, lowered rates of oxidative phosphorylation and excessive reactive oxygen species (ROS) production have been reported. Mitochondrial biogenesis is regulated by various transcription factors such as peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha), peroxisome proliferator-activated receptors (PPARs), estrogen-related receptors (ERRs), and nuclear respiratory factors (NRFs). Mitochondrial fusion is promoted by mitofusin 1 (MFN1), mitofusin 2 (MFN2) and optic atrophy 1 (OPA1), while fission is governed by the recruitment of dynamin-related protein 1 (DRP1) by adaptor proteins such as mitochondrial fission factor (MFF), mitochondrial dynamics proteins of 49 and 51 kDa (MiD49 and MiD51), and fission 1 (FIS1). Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and PARKIN promote DRP1-dependent mitochondrial fission, and the outer mitochondrial adaptor MiD51 is required in DRP1 recruitment and PARKIN-dependent mitophagy. This review describes the molecular mechanism of mitochondrial dynamics, its abnormality in diabetes and obesity, and pharmaceuticals targeting mitochondrial biogenesis, fission, fusion and mitophagy.

    DOI: 10.18926/AMO/54413

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  • Antiobesity Action of ACAM by Modulating the Dynamics of Cell Adhesion and Actin Polymerization in Adipocytes 査読

    Kazutoshi Murakami, Jun Eguchi, Kazuyuki Hida, Atsuko Nakatsuka, Akihiro Katayama, Miwa Sakurai, Haruki Choshi, Masumi Furutani, Daisuke Ogawa, Kohji Takei, Fumio Otsuka, Jun Wada

    DIABETES   65 ( 5 )   1255 - 1267   2016年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER DIABETES ASSOC  

    Coxsackie virus and adenovirus receptor-like membrane protein (CLMP) was identified as the tight junction-associated transmembrane protein of epithelial cells with homophilic binding activities. CLMP is also recognized as adipocyte adhesion molecule (ACAM), and it is upregulated in mature adipocytes in rodents and humans with obesity. Here, we present that aP2 promoter-driven ACAM transgenic mice are protected from obesity and diabetes with the prominent reduction of adipose tissue mass and smaller size of adipocytes. ACAM is abundantly expressed on plasma membrane of mature adipocytes and associated with formation of phalloidin-positive polymerized form of cortical actin (F-actin). By electron microscopy, the structure of zonula adherens with an intercellular space of approximate to 10-20 nm was observed with strict parallelism of the adjoining cell membranes over distances of 1-20 m, where ACAM and -actin are abundantly expressed. The formation of zonula adherens may increase the mechanical strength, inhibit the adipocyte hypertrophy, and improve the insulin sensitivity.

    DOI: 10.2337/db15-1304

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  • Insufficiency of phosphatidylethanolamine N-methyltransferase is risk for lean non-alcoholic steatohepatitis 査読

    Atsuko Nakatsuka, Makoto Matsuyama, Satoshi Yamaguchi, Akihiro Katayama, Jun Eguchi, Kazutoshi Murakami, Sanae Teshigawara, Daisuke Ogawa, Nozomu Wada, Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Eijiro Watanabe, Jun Wada

    SCIENTIFIC REPORTS   6   21721   2016年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Although obesity is undoubtedly major risk for non-alcoholic steatohepatitis (NASH), the presence of lean NASH patients with normal body mass index has been recognized. Here, we report that the insufficiency of phosphatidylethanolamine N-methyltransferase (PEMT) is a risk for the lean NASH. The Pemt-/-mice fed high fat-high sucrose (HFHS) diet were protected from diet-induced obesity and diabetes, while they demonstrated prominent steatohepatitis and developed multiple liver tumors. Pemt exerted inhibitory effects on p53-driven transcription by forming the complex with clathrin heavy chain and p53, and Pemt-/-mice fed HFHS diet demonstrated prominent apoptosis of hepatocytes. Furthermore, hypermethylation and suppressed mRNA expression of F-box protein 31 and hepatocyte nuclear factor 4 alpha resulted in the prominent activation of cyclin D1. PEMT mRNA expression in liver tissues of NASH patients was significantly lower than those with simple steatosis and we postulated the distinct clinical entity of lean NASH with insufficiency of PEMT activities.

    DOI: 10.1038/srep21721

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  • Beneficial impact of Gpnmb and its significance as a biomarker in nonalcoholic steatohepatitis 査読

    Akihiro Katayama, Atsuko Nakatsuka, Jun Eguchi, Kazutoshi Murakami, Sanae Teshigawara, Motoko Kanzaki, Tomokazu Nunoue, Kazuyuki Hida, Nozomu Wada, Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Kazuhide Yamamoto, Hiroshi Kiyonari, Hirofumi Makino, Jun Wada

    SCIENTIFIC REPORTS   5   16920   2015年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Gpnmb is classified as a type 1 membrane protein and its soluble form is secreted by ADAM10-mediated cleavage. Gpnmb mRNA was found in the Kupffer cells and white adipose tissues (WATs) and its upregulation in obesity was recently found. Here, we generated aP2 promoter-driven Gpnmb transgenic (Tg) mice and the overexpression of Gpnmb ameliorated the fat accumulation and fibrosis of the liver in diet-induced obesity model. Soluble form of Gpnmb in sera was elevated in Gpnmb Tg mice and Gpnmb concentrated in hepatic macrophages and stellate cells interacted with calnexin, which resulted in the reduction of oxidative stress. In the patients with non-alcoholic steatohepatitis, serum soluble GPNMB concentrations were higher compared with the patients with simple steatosis. The GPNMB is a promising biomarker and therapeutic target for the development and progression of NAFLD in obesity.

    DOI: 10.1038/srep16920

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  • Translocase of inner mitochondrial membrane 44 alters the mitochondrial fusion and fission dynamics and protects from type 2 diabetes 査読

    Yu Wang, Akihiro Katayama, Takahiro Terami, Xiaoying Han, Tomokazu Nunoue, Dongxiao Zhang, Sanae Teshigawara, Jun Eguchi, Atsuko Nakatsuka, Kazutoshi Murakami, Daisuke Ogawa, Yasuhide Furuta, Hirofumi Makino, Jun Wada

    METABOLISM-CLINICAL AND EXPERIMENTAL   64 ( 6 )   677 - 688   2015年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:W B SAUNDERS CO-ELSEVIER INC  

    Objective. In obesity and type 2 diabetes, the impairment of mitochondrial function in white adipose tissue (WAT) is linked to a reduction in whole body insulin sensitivity. Timm44 is upregulated in the kidneys of streptozotocin-induced diabetic mice. In the inner mitochondrial membrane, Timm44 anchors mitochondrial heat-shock protein 70 (mtHsp70) to the translocase of inner mitochondrial membrane 23 (TIM23) complex and facilitates the import of mitochondria-targeted preproteins into the mitochondrial matrix dependent on the inner membrane potential and ATP hydrolysis on ATPase domain of mtHsp70.
    Methods. We generated the aP2-promoter driven Timm44 transgenic (Tg) mouse model and investigated whether Timm44 Tg mice fed high-fat/high-sucrose (HFHS) chow are protected from type 2 diabetes and obesity.
    Results. The body weight of aP2-promoter driven Timm44 Tg mice was lower than that of wild type mice, and insulin sensitivity was greater in Timm44 Tg mice than in wild type mice. Although WAT weight was not altered in Timm44 Tg mice fed HFHS chow, adipocyte size was reduced, and mitochondrial fusion associated with decreased expression of fission genes, such as Dnm11 and Fis1, was observed. In addition, when fed standard (STD) chow, the expressions of the fusion genes Opal, Mfn1 and Mfn2, and Mfn1 were significantly increased in Timm44 Tg mice compared to wild type mice, and fused mitochondria were also observed in Timm44 Tg mice fed STD chow.
    Conclusions. The Timm44 gene may be a new target for the treatment of type 2 diabetes. (C) 2015 Elsevier Inc. All rights reserved.

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  • Identification of Circulating miR-101, miR-375 and miR-802 as Biomarkers for Type 2 Diabetes 査読

    Chigusa Higuchi, Atsuko Nakatsuka, Jun Eguchi, Sanae Teshigawara, Motoko Kanzaki, Akihiro Katayama, Satoshi Yamaguchi, Naoto Takahashi, Kazutoshi Murakami, Daisuke Ogawa, Sakiko Sasaki, Hirofumi Makino, Jun Wada

    METABOLISM-CLINICAL AND EXPERIMENTAL   64 ( 4 )   489 - 497   2015年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:W B SAUNDERS CO-ELSEVIER INC  

    Purpose. The unique circulating microRNAs (miRNAs) observed in patients with type 2 diabetes (T2D) are candidates as new biomarkers and therapeutic targets. In order to identify circulating miRNAs relevant to the disease process in case of type 2 diabetes, we performed the Illumina sequencing of miRNAs derived from the serum, liver and epididymal white adipose tissue (WAT) of diet-induced obese male C57BL/6J mice.
    Basic Procedures. We selected four miRNAs, miR-101, miR-335, miR-375, and miR-802, which are increased in the sera and tissues of obese mice, and measured the serum levels of miRNAs in T2D and subjects with normal glucose tolerance (NGT).
    Main Findings. The serum concentrations of miRNAs, log10miR-101, log(10)miR-375, and log(10)miR-802, were significantly increased in the T2D patients compared with NGT subjects (1.41 +/- 2.01 u.s. -0.57 +/- 1.05 (P = 1.36 x 10(-5)), 0.20 +/- 0.58 v.s. 0.038 +/- 1.00 (P = 3.06 x 10(-6)), and 2.45 +/- 1.27 u.s. 0.97 +/- 0.98 (P = 0.014), respectively). The log(10)miR-335 values did not demonstrate any significant differences between the T2D and NGT groups (-1.08 +/- 1.35 v.s. 0.38 +/- 1.21 (P = 0.25)). According to the stepwise regression analysis, the HbA1c was an independent predictor of miR-101. Regarding the serum miR-802 levels, eGFR, HbA1c and HDL-C values were identified as significant determinants.
    Principal Conclusions. The present findings demonstrated that the circulating miR-101, miR-375 and miR-802 levels are significantly increased in T2D patients versus NGT subjects and they may become the new biomarkers for type 2 diabetes. (C) 2015 Elsevier Inc. All rights reserved.

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  • Long-Term Treatment with the Sodium Glucose Cotransporter 2 Inhibitor, Dapagliflozin, Ameliorates Glucose Homeostasis and Diabetic Nephropathy in db/db Mice 査読

    Naoto Terami, Daisuke Ogawa, Hiromi Tachibana, Takashi Hatanaka, Jun Wada, Atsuko Nakatsuka, Jun Eguchi, Chikage Sato Horiguchi, Naoko Nishii, Hiroshi Yamada, Kohji Takei, Hirofumi Makino

    PLOS ONE   9 ( 6 )   e100777   2014年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Inhibition of sodium glucose cotransporter 2 (SGLT2) has been reported as a new therapeutic strategy for treating diabetes. However, the effect of SGLT2 inhibitors on the kidney is unknown. In addition, whether SGLT2 inhibitors have an anti-inflammatory or antioxidative stress effect is still unclear. In this study, to resolve these issues, we evaluated the effects of the SGLT2 inhibitor, dapagliflozin, using a mouse model of type 2 diabetes and cultured proximal tubular epithelial (mProx24) cells. Male db/db mice were administered 0.1 or 1.0 mg/kg of dapagliflozin for 12 weeks. Body weight, blood pressure, blood glucose, hemoglobin A1c, albuminuria and creatinine clearance were measured. Mesangial matrix accumulation and interstitial fibrosis in the kidney and pancreatic beta-cell mass were evaluated by histological analysis. Furthermore, gene expression of inflammatory mediators, such as osteopontin, monocyte chemoattractant protein-1 and transforming growth factor-beta, was evaluated by quantitative reverse transcriptase-PCR. In addition, oxidative stress was evaluated by dihydroethidium and NADPH oxidase 4 staining. Administration of 0.1 or 1.0 mg/kg of dapagliflozin ameliorated hyperglycemia, beta-cell damage and albuminuria in db/db mice. Serum creatinine, creatinine clearance and blood pressure were not affected by administration of dapagliflozin, but glomerular mesangial expansion and interstitial fibrosis were suppressed in a dose-dependent manner. Dapagliflozin treatment markedly decreased macrophage infiltration and the gene expression of inflammation and oxidative stress in the kidney of db/db mice. Moreover, dapagliflozin suppressed the high-glucose-induced gene expression of inflammatory cytokines and oxidative stress in cultured mProx24 cells. These data suggest that dapagliflozin ameliorates diabetic nephropathy by improving hyperglycemia along with inhibiting inflammation and oxidative stress.

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  • Serum vaspin levels are associated with physical activity or physical fitness in Japanese: a pilot study 査読

    Nobuyuki Miyatake, Jun Wada, Atsuko Nakatsuka, Noriko Sakano, Sanae Teshigawara, Motohiko Miyachi, Izumi Tabata, Takeyuki Numata

    ENVIRONMENTAL HEALTH AND PREVENTIVE MEDICINE   19 ( 3 )   200 - 206   2014年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    To investigate the link between serum vaspin levels and physical activity and/or physical fitness in Japanese.
    A total of 156 subjects (81 men and 75 women) was enrolled in this cross-sectional study. Serum vaspin levels, physical activity by uniaxial accelerometers, peak oxygen uptake, and metabolic risk parameters were evaluated. We also assessed anthropometric and body composition parameters.
    Serum vaspin levels were over the level of 10 ng/mL in 15 subjects (9.6 %: Vaspin High group). In Vaspin Low group (&lt; 5 ng/mL: 74 men and 67 women), serum vaspin levels were 0.12 +/- A 0.18 ng/mL in men and 0.39 +/- A 0.70 ng/mL in women. Peak oxygen uptake was significantly and positively correlated with serum vaspin levels even after adjusting for age, physical activity evaluated by I [metabolic pound equivalents x h per week (METsa &lt;...h/w)], BMI, and other confounding factors in men. In turn, physical activity was significantly and positively correlated with serum vaspin levels even after adjusting for confounding factors in women.
    Serum vaspin levels were closely associated with physical fitness in men and physical activity in women independent of body composition in this Japanese cohort.

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  • Pemt Deficiency Ameliorates Endoplasmic Reticulum Stress in Diabetic Nephropathy 査読

    Mayu Watanabe, Atsuko Nakatsuka, Kazutoshi Murakami, Kentaro Inoue, Takahiro Terami, Chigusa Higuchi, Akihiro Katayama, Sanae Teshigawara, Jun Eguchi, Daisuke Ogawa, Eijiro Watanabe, Jun Wada, Hirofumi Makino

    PLOS ONE   9 ( 3 )   e92647   2014年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Phosphatidylethanolamine N-methyltransferase (Pemt) catalyzes the methylation of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) mainly in the liver. Under an obese state, the upregulation of Pemt induces endoplasmic reticulum (ER) stress by increasing the PC/PE ratio in the liver. We targeted the Pemt gene in mice to explore the therapeutic impact of Pemt on the progression of diabetic nephropathy and diabetes, which was induced by the injection of streptozotocin (STZ). Although the blood glucose levels were similar in STZ-induced diabetic Pemt+/+ and Pemt-/-mice, the glomerular hypertrophy and albuminuria in Pemt-/- mice were significantly reduced. Pemt deficiency reduced the intraglomerular F4/80-positive macrophages, hydroethidine fluorescence, tubulointerstitial fibrosis and tubular atrophy. The expression of glucose-regulated protein-78 (GRP78) was enriched in the renal tubular cells in STZ-induced diabetic mice, and this was ameliorated by Pemt deficiency. In mProx24 renal proximal tubular cells, the treatment with ER-stress inducers, tunicamycin and thapsigargin, increased the expression of GRP78, which was reduced by transfection of a shRNA lentivirus for Pemt (shRNA-Pemt). The number of apoptotic cells in the renal tubules was significantly reduced in Pemt-/- diabetic mice, and shRNA-Pemt upregulated the phosphorylation of Akt and decreased the cleavage of caspase 3 and 7 in mProx24 cells. Taken together, these findings indicate that the inhibition of Pemt activity ameliorates the ER stress associated with diabetic nephropathy in a model of type 1 diabetes and corrects the functions of the three major pathways downstream of ER stress, i.e. oxidative stress, inflammation and apoptosis.

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  • Metallothionein deficiency exacerbates diabetic nephropathy in streptozotocin-induced diabetic mice 査読

    Hiromi Tachibana, Daisuke Ogawa, Norio Sogawa, Masato Asanuma, Ikuko Miyazaki, Naoto Terami, Takashi Hatanaka, Chikage Sato Horiguchi, Atsuko Nakatsuka, Jun Eguchi, Jun Wada, Hiroshi Yamada, Kohji Takei, Hirofumi Makino

    American Journal of Physiology - Renal Physiology   306 ( 1 )   F105 - F115   2014年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Oxidative stress and inflammation play important roles in diabetic complications, including diabetic nephropathy. Metallothionein (MT) is induced in proximal tubular epithelial cells as an antioxidant in the diabetic kidney
    however, the role of MT in renal function remains unclear. We therefore investigated whether MT deficiency accelerates diabetic nephropathy through oxidative stress and inflammation. Diabetes was induced by streptozotocin injection in MT-deficient (MT-/-) and MT+/+ mice. Urinary albumin excretion, histological changes, markers for reactive oxygen species (ROS), and kidney inflammation were measured. Murine proximal tubular epithelial (mProx24) cells were used to further elucidate the role of MT under high-glucose conditions. Parameters of diabetic nephropathy and markers of ROS and inflammation were accelerated in diabetic MT-/- mice compared with diabetic MT+/+ mice, despite equivalent levels of hyperglycemia. MT deficiency accelerated interstitial fibrosis and macrophage infiltration into the interstitium in the diabetic kidney. Electron microscopy revealed abnormal mitochondrial morphology in proximal tubular epithelial cells in diabetic MT-/- mice. In vitro studies demonstrated that knockdown of MT by small interfering RNA enhanced mitochondrial ROS generation and inflammation-related gene expression in mProx24 cells cultured under high-glucose conditions. The results of this study suggest that MT may play a key role in protecting the kidney against high glucose-induced ROS and subsequent inflammation in diabetic nephropathy. © 2014 the American Physiological Society.

    DOI: 10.1152/ajprenal.00034.2013

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  • Nuclear Hormone Receptor Expression in Mouse Kidney and Renal Cell Lines 査読

    Daisuke Ogawa, Jun Eguchi, Jun Wada, Naoto Terami, Takashi Hatanaka, Hiromi Tachibana, Atsuko Nakatsuka, Chikage Sato Horiguchi, Naoko Nishii, Hirofumi Makino

    PLOS ONE   9 ( 1 )   e85594   2014年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Nuclear hormone receptors (NHRs) are transcription factors that regulate carbohydrate and lipid metabolism, immune responses, and inflammation. Although several NHRs, including peroxisome proliferator-activated receptor-gamma (PPAR gamma) and PPAR alpha, demonstrate a renoprotective effect in the context of diabetic nephropathy (DN), the expression and role of other NHRs in the kidney are still unrecognized. To investigate potential roles of NHRs in the biology of the kidney, we used quantitative real-time polymerase chain reaction to profile the expression of all 49 members of the mouse NHR superfamily in mouse kidney tissue (C57BL/6 and db/m), and cell lines of mesangial (MES13), podocyte (MPC), proximal tubular epithelial (mProx24) and collecting duct (mIMCD3) origins in both normal and high-glucose conditions. In C57BL/6 mouse kidney cells, hepatocyte nuclear factor 4 alpha, chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) and COUP-TFIII were highly expressed. During hyperglycemia, the expression of the NHR 4A subgroup including neuron-derived clone 77 (Nur77), nuclear receptor-related factor 1, and neuron-derived orphan receptor 1 significantly increased in diabetic C57BL/6 and db/db mice. In renal cell lines, PPAR delta was highly expressed in mesangial and proximal tubular epithelial cells, while COUP-TFs were highly expressed in podocytes, proximal tubular epithelial cells, and collecting duct cells. High-glucose conditions increased the expression of Nur77 in mesangial and collecting duct cells, and liver x receptor alpha in podocytes. These data demonstrate NHR expression in mouse kidney cells and cultured renal cell lines and suggest potential therapeutic targets in the kidney for the treatment of DN.

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  • Metallothionein deficiency exacerbates diabetic nephropathy in streptozotocin-induced diabetic mice 査読

    Hiromi Tachibana, Daisuke Ogawa, Norio Sogawa, Masato Asanuma, Ikuko Miyazaki, Naoto Terami, Takashi Hatanaka, Chikage Sato Horiguchi, Atsuko Nakatsuka, Jun Eguchi, Jun Wada, Hiroshi Yamada, Kohji Takei, Hirofumi Makino

    AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY   306 ( 1 )   F105 - F115   2014年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER PHYSIOLOGICAL SOC  

    Oxidative stress and inflammation play important roles in diabetic complications, including diabetic nephropathy. Metallothionein (MT) is induced in proximal tubular epithelial cells as an antioxidant in the diabetic kidney; however, the role of MT in renal function remains unclear. We therefore investigated whether MT deficiency accelerates diabetic nephropathy through oxidative stress and inflammation. Diabetes was induced by streptozotocin injection in MT-deficient (MT-/-) and MT+/+ mice. Urinary albumin excretion, histological changes, markers for reactive oxygen species (ROS), and kidney inflammation were measured. Murine proximal tubular epithelial (mProx24) cells were used to further elucidate the role of MT under high-glucose conditions. Parameters of diabetic nephropathy and markers of ROS and inflammation were accelerated in diabetic MT-/- mice compared with diabetic MT+/+ mice, despite equivalent levels of hyperglycemia. MT deficiency accelerated interstitial fibrosis and macrophage infiltration into the interstitium in the diabetic kidney. Electron microscopy revealed abnormal mitochondrial morphology in proximal tubular epithelial cells in diabetic MT-/- mice. In vitro studies demonstrated that knockdown of MT by small interfering RNA enhanced mitochondrial ROS generation and inflammation-related gene expression in mProx24 cells cultured under high-glucose conditions. The results of this study suggest that MT may play a key role in protecting the kidney against high glucose-induced ROS and subsequent inflammation in diabetic nephropathy.

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  • Comparison of Incubation Solutions Prior to the Purification of Porcine Islet Cells. 査読

    Kawai T, Noguchi H, Kuise T, Nakatsuka A, Katayama A, Imagawa N, Kataoka HU, Saitoh I, Noguchi Y, Watanabe M, Fujiwara T

    Cell medicine   6 ( 1-2 )   9 - 14   2013年12月

  • Comparison of New Preservation Solutions, HN-1 and University of Wisconsin Solution, in Pancreas Preservation for Porcine Islet Isolation. 査読

    Katayama A, Noguchi H, Kuise T, Nakatsuka A, Hirota D, Kataoka HU, Kawai T, Inoue K, Imagawa N, Saitoh I, Noguchi Y, Watanabe M, Wada J, Fujiwara T

    Cell medicine   6 ( 1-2 )   3 - 8   2013年12月

  • Urinary angiotensinogen is a marker for tubular injuries in patients with type 2 diabetes 査読

    Takahiro Terami, Jun Wada, Kentaro Inoue, Atsuko Nakatsuka, Daisuke Ogawa, Sanae Teshigawara, Kazutoshi Murakami, Akihiro Katayama, Jun Eguchi, Hirofumi Makino

    International Journal of Nephrology and Renovascular Disease   6   233 - 240   2013年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Purpose: Urinary angiotensinogen has been reported as a marker for the activation of intrarenal renin-angiotensin system (RAS) in various kidney diseases. To investigate the importance of urinary angiotensinogen in diabetic nephropathy, we compared the urinary levels of angiotensinogen, albumin, and α1-microglobulin. Materials and methods: Japanese patients with type 2 diabetes at various stages of nephropathy (n=85) were enrolled, and we measured albumin/creatinine ratio (ACR) and urinary excretion of angiotensinogen and α1-microglobulin. We also compared the clinical data of the patients treated with or without angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors (RAS inhibitors [+], n=51
    RAS inhibitors [-], n=34). Results: Urinary angiotensinogen levels positively correlated with ACR (r =0.367, P=3.84×10-4) and urinary α1-microglobulin (r=0.734, P=1.32 × 10-15), while they negatively correlated with estimated glomerular filtration ratio (eGFR) (r=-0.350, P=1.02 × 10-3) and high-density lipoprotein cholesterol (r=-0.216, P=0.049). Multiple regression analysis was carried out to predict urinary angiotensinogen levels by employing eGFR, ACR, and urinary α1-microglobulin as independent variables
    only urinary α1-microglobulin entered the regression equation at a significant level. Although ACR was higher in the RAS inhibitors (+) group, urinary α1-microglobulin and angiotensinogen did not show significant increase in the RAS inhibitors (+) group. Conclusion: Urinary angiotensinogen is well correlated with urinary α1-microglobulin and reflected the tubular injuries which may be associated with the intrarenal RAS activation in patients with type 2 diabetes. © 2013 Terami et al.

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  • Urinary Fetuin-A Is a Novel Marker for Diabetic Nephropathy in Type 2 Diabetes Identified by Lectin Microarray 査読

    Kentaro Inoue, Jun Wada, Jun Eguchi, Atsuko Nakatsuka, Sanae Teshigawara, Kazutoshi Murakami, Daisuke Ogawa, Takahiro Terami, Akihiro Katayama, Atsuhito Tone, Izumi Iseda, Kazuyuki Hida, Masao Yamada, Tomohisa Ogawa, Hirofumi Makino

    PLoS ONE   8 ( 10 )   e77118   2013年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We analyzed the urine samples of patients with type 2 diabetes at various stages of diabetic nephropathy by lectin microarray to identify a biomarker to predict the progression of diabetic nephropathy. Japanese patients with type 2 diabetes at various stages of nephropathy were enrolled and we performed lectin microarray analyses (n = 17) and measured urinary excretion of fetuin-A (n = 85). The increased signals of urine samples were observed in Siaα2-6Gal/GalNAc-binding lectins (SNA, SSA, TJA-I) during the progression of diabetic nephropathy. We next isolated sialylated glycoproteins by using SSA-lectin affinity chromatography and identified fetuin-A by liquid chromatography-tandem mass spectrometer. Urinary excretion of fetuin-A significantly increased during the progression of albuminuria (A1, 0.40±0.43
    A2, 0.60±0.53
    A3 1.57±1.13 ng/gCr
    p = 7.29×10-8) and of GFR stages (G1, 0.39±0.39
    G2, 0.49±0.45
    G3, 1.25±1.18
    G4, 1.34±0.80 ng/gCr
    p = 3.89×10-4). Multivariate logistic regression analysis was employed to assess fetuin-A as a risk for diabetic nephropathy with microalbuminuria or GFR&lt
    60 mL/min. Fetuin-A is demonstrated as a risk factor for both microalbuminuria and reduction of GFR in diabetic nephropathy with the odds ratio of 4.721 (1.881-11.844) and 3.739 (1.785-7.841), respectively. Collectively, the glycan profiling analysis is useful method to identify the urine biomarkers and fetuin-A is a candidate to predict the progression of diabetic nephropathy. © 2013 Inoue et al.

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  • Nuclear Hormone Receptor Expression in Mouse Kidney and Renal Cell Lines

    Naoto Terami, Daisuke Ogawa, Jun Eguchi, Hiromi Tachibana, Chikage Sato-Horiguchi, Takashi Hatanaka, Atsuko Nakatsuka, Jun Wada, Hirofumi Makino

    DIABETES   62   A134 - A134   2013年7月

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    記述言語:英語   出版者・発行元:AMER DIABETES ASSOC  

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  • Phosphatidylethanolamine N-Methyltransferase (PEMT) Deficiency Protects from Obesity and Insulin Resistance but Promote Steatoheptitis With Tumorigenesis

    Atsuko Nakatsuka, Jun Wada, Kazutoshi Murakami, Takahiro Terami, Jun Eguchi, Daisuke Ogawa, Hirofumi Makino

    DIABETES   62   A529 - A529   2013年7月

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    記述言語:英語   出版者・発行元:AMER DIABETES ASSOC  

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  • Cell Cycle Abnormality in Metabolic Syndrome and Nuclear Receptors as an Emerging Therapeutic Target 査読

    Atsuko Nakatsuka, Jun Wada, Hirofumi Makino

    ACTA MEDICA OKAYAMA   67 ( 3 )   129 - 134   2013年6月

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    記述言語:英語   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    In recent years, many researchers have emphasized the importance of metabolic syndrome based on its increasing prevalence and its adverse prognosis due to associated chronic vascular complications. Upstream of a cluster of metabolic and vascular disorders is the accumulation of visceral adipose tissue, which plays a central role in the pathophysiology. In the accumulation of adipose tissues, cell cycle regulation is tightly linked to cellular processes such as proliferation, hypertrophy and apoptosis. In addition, various cell cycle abnormalities have also been observed in other tissues, such as kidneys and the cardiovascular system, and they are critically involved in the progression of disease. Here, we discuss cell cycle abnormalities in metabolic syndrome in various tissues. Furthermore, we describe the role of nuclear receptors in cell growth and survival, and glucose and lipid metabolism in the whole body. Therapeutic strategies for modulating various cell cycles in metabolic disorders by targeting nuclear receptors may overcome obesity and its chronic vascular complications in the future.

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  • Visceral adipose tissue-derived serine proteinase inhibitor inhibits apoptosis of endothelial cells as a ligand for the cell-surface GRP78/voltage-dependent anion channel complex (vol 112, pg 771, 2013)

    A. Nakatsuka, J. Wada, I. Iseda

    CIRCULATION RESEARCH   112 ( 9 )   E98 - E98   2013年4月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Visceral Adipose Tissue-derived Serine Proteinase Inhibitor Inhibits Apoptosis of Endothelial Cells as a Ligand for the Cell-Surface GRP78/Voltage-dependent Anion Channel Complex 査読

    Atsuko Nakatsuka, Jun Wada, Izumi Iseda, Sanae Teshigawara, Kanji Higashio, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Kazuyuki Hida, Jun Eguchi, Daisuke Ogawa, Yasushi Matsuki, Ryuji Hiramatsu, Hideo Yagita, Shigeru Kakuta, Yoichiro Iwakura, Hirofumi Makino

    CIRCULATION RESEARCH   112 ( 5 )   771 - +   2013年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Rationale: Visceral adipose tissue-derived serine proteinase inhibitor (vaspin) is an adipokine identified from visceral adipose tissues of genetically obese rats.
    Objective: The role of vaspin in the diabetic vascular complications remains elusive, and we investigated the effects of vaspin on the vascular function under the diabetic milieu.
    Methods and Results: Adenovirus carrying the full length of the vaspin gene (Vaspin-Ad) ameliorated intimal proliferation of balloon-injured carotid arteries in diabetic Wistar rats. The expression of Ccl2, Pdgfb, and Pdgfrb genes was significantly reduced by the treatment of Vaspin-Ad. In cuff-injured femoral arteries, the intimal proliferation was ameliorated in vaspin transgenic (Vaspin Tg) mice. The application of recombinant vaspin and Vaspin-Ad promoted the proliferation and inhibited the apoptosis of human aortic endothelial cells. Adenovirus expressing vaspin with calmodulin and streptavidin-binding peptides was applied to human aortic endothelial cells, subjected to tandem tag purification and liquid chromatography-tandem mass spectrometry, and we identified GRP78 (78-kDa glucose-regulated protein) as an interacting molecule. The complex formation of vaspin, GRP78, and voltage-dependent anion channel on the plasma membrane was confirmed by the immunoprecipitation studies using aortas of Vaspin Tg mice. The binding assay using 125I-vaspin in human aortic endothelial cells revealed high-affinity binding (dissociation constant = 0.565x10(-9) m) by the treatment of 5 mu M thapsigargin, which recruited GRP78 from the endoplasmic reticulum to plasma membrane by inducing endoplasmic reticulum stress. In human aortic endothelial cells, vaspin induced phosphorylation of Akt and inhibited the kringle 5-induced Ca2+ influx and subsequent apoptosis.
    Conclusions: Vaspin is a novel ligand for the cell-surface GRP78/voltage-dependent anion channel complex in endothelial cells and promotes proliferation, inhibits apoptosis, and protects vascular injuries in diabetes mellitus. (Circ Res. 2013;112:771-780.)

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  • Serum galectin-9 levels are elevated in the patients with type 2 diabetes and chronic kidney disease 査読

    Yuko Kurose, Jun Wada, Motoko Kanzaki, Sanae Teshigawara, Atsuko Nakatsuka, Kazutoshi Murakami, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Mayu Watanabe, Chigusa Higuchi, Jun Eguchi, Nobuyuki Miyatake, Hirofumi Makino

    BMC NEPHROLOGY   14   23   2013年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    Background: Galectin-9 (Gal-9) induces apoptosis in activated T helper 1 (T(H)1) cells as a ligand for T cell immunoglobulin mucin-3 (Tim-3). Gal-9 also inhibits the G1 phase cell cycle arrest and hypertrophy in db/db mice, the hallmark of early diabetic nephropathy, by reversing the high glucose-induced up-regulation of cyclin dependent kinase inhibitors such as p27(Kip1) and p21(Cip1).
    Methods: We investigated the serum levels of Gal-9 in the patients with type 2 diabetes and various stages of chronic kidney disease (CKD) (n = 182).
    Results: Serum Gal-9 levels in the patients with type 2 diabetes were 131.9 +/- 105.4 pg/ml and Log(10)Gal-9 levels significantly and positively correlated with age (r = 0.227, p = 0.002), creatinine (r = 0.175, p = 0.018), urea nitrogen (r = 0.162, p = 0.028) and osmotic pressure (r = 0.187, p = 0.014) and negatively correlated with estimated glomerular filtration rate (eGFR) (r = -0.188, p = 0.011). Log(10)Gal-9 levels increased along with the progression of GFR categories of G1 to G4, and they were statistically significant by Jonckheere-Terpstra test (p = 0.012). Log(10)Gal-9 levels remained similar levels in albuminuria stages of A1 to A3.
    Conclusion: The elevation of serum Gal-9 in the patients with type 2 diabetes is closely linked to GFR and they may be related to the alteration of the immune response and inflammation of the patients with type 2 diabetes and CKD.

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  • The serum vaspin levels are reduced in Japanese chronic hemodialysis patients 査読

    Junko Inoue, Jun Wada, Sanae Teshigawara, Kazuyuki Hida, Atsuko Nakatsuka, Yuji Takatori, Shoichirou Kojo, Shigeru Akagi, Kazushi Nakao, Nobuyuki Miyatake, John F. McDonald, Hirofumi Makino

    BMC NEPHROLOGY   13   163   2012年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    Background: Visceral adipose tissue-derived serine proteinase inhibitor (vaspin) is an adipokine identified in genetically obese rats that correlates with insulin resistance and obesity in humans. Recently, we found that 7% of the Japanese population with the minor allele sequence (A) of rs77060950 exhibit higher levels of serum vaspin. We therefore evaluated the serum vaspin levels in Japanese chronic hemodialysis patients.
    Methods: Healthy Japanese control volunteers (control; n = 95, 49.9 +/- 6.91 years) and Japanese patients undergoing hemodialysis therapy (HD; n = 138, 51.4 +/- 10.5 years) were enrolled in this study, and serum samples were subjected to the human vaspin RIA system.
    Results: The measurement of the serum vaspin levels demonstrated that a fraction of control subjects (n = 5) and HD patients (n = 11) exhibited much higher levels (&gt; 10 ng/ml; Vaspin(High) group), while the rest of the population exhibited lower levels (&lt; 3 ng/ml; Vaspin(Low) group). By comparing the patients in the Vaspin(Low) group, the serum vaspin levels were found to be significantly higher in the control subjects (0.87 +/- 0.24 ng/ml) than in the HD patients (0.32 +/- 0.15 ng/ml) (p &lt; 0.0001). In the stepwise regression analyses, the serum creatinine and triglyceride levels were found to be independently and significantly associated with the vaspin concentrations in all subjects.
    Conclusions: The creatinine levels are negatively correlated with the serum vaspin levels and were significantly reduced in the Japanese HD patients in the Vaspin(Low) group.

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  • Vaspin Is an Adipokine Ameliorating ER Stress in Obesity as a Ligand for Cell-Surface GRP78/MTJ-1 Complex 査読

    Atsuko Nakatsuka, Jun Wada, Izumi Iseda, Sanae Teshigawara, Kanji Higashio, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Kazuyuki Hida, Jun Eguchi, Chikage Sato Horiguchi, Daisuke Ogawa, Yasushi Matsuki, Ryuji Hiramatsu, Hideo Yagita, Shigeru Kakuta, Yoichiro Iwakura, Hirofumi Makino

    DIABETES   61 ( 11 )   2823 - 2832   2012年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER DIABETES ASSOC  

    It is unknown whether adipokines derived from adipose tissues modulate endoplasmic reticulum (ER) stress induced in obesity. Here, we show that visceral adipose tissue-derived serine protease inhibitor (vaspin) binds to cell-surface 78-kDa glucose-regulated protein (GRP78), which is recruited from ER to plasma membrane under ER stress. Vaspin transgenic mice were protected from diet-induced obesity, glucose intolerance, and hepatic steatosis, while vaspin-deficient mice developed glucose intolerance associated with upregulation of ER stress markers. With tandem affinity tag purification using HepG2 cells, we identified GRP78 as an interacting molecule. The complex formation of vaspin, GRP78, and murine tumor cell DnaJ-like protein 1 (MTJ-1) (DnaJ homolog, subfamily C, member 1) on plasma membrane was confirmed by cell-surface labeling with biotin and immunoprecipitation in liver tissues and H-4-II-E-C3 cells. The addition of recombinant human vaspin in the cultured H-4-II-E-C3 cells also increased the phosphorylation of Akt and AMP-activated protein kinase (AMPK) in a dose-dependent manner, and anti-GRP78 antibodies completely abrogated the vaspin-induced upregulation of pAkt and pAMPK Vaspin is a novel ligand for cell-surface GRP78/MTJ-1 complex, and its subsequent signals exert beneficial effects on ER stress-induced metabolic dysfunctions. Diabetes 61:2823-2832, 2012

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  • Hydrogen-rich water prevents progression of nonalcoholic steatohepatitis and accompanying hepatocarcinogenesis in mice 査読

    Daisuke Kawai, Akinobu Takaki, Atsuko Nakatsuka, Jun Wada, Naofumi Tamaki, Tetsuya Yasunaka, Kazuko Koike, Ryuichiro Tsuzaki, Kazuyuki Matsumoto, Yasuhiro Miyake, Hidenori Shiraha, Manabu Morita, Hirofumi Makino, Kazuhide Yamamoto

    HEPATOLOGY   56 ( 3 )   912 - 921   2012年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Oxidative stress is a strong contributor to the progression from simple fatty liver to nonalcoholic steatohepatitis (NASH). Molecular hydrogen is an effective antioxidant that reduces cytotoxic reactive oxygen species. In this study, we investigated the effects of hydrogen-rich water and the drug pioglitazone on the progression of NASH in mouse models. A methionine-cholinedeficient (MCD) diet mouse model was prepared. Mice were divided into three experimental groups and fed for 8 weeks as follows: (1) MCD diet + control water (CW group); (2) MCD diet + hydrogen-rich water (HW group); and (3) MCD diet mixed with pioglitazone (PGZ group). Plasma alanine aminotransferase levels, hepatic expression of tumor necrosis factor-a, interleukin-6, fatty acid synthesisrelated genes, oxidative stress biomarker 8-hydroxydeoxyguanosine (8-OHdG), and apoptosis marker terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate nick-end labeling (TUNEL)positive cells in the liver were decreased in the HW and PGZ groups. The HW group showed a smaller decrease in hepatic cholesterol; however, stronger antioxidative effects in serum and lower peroxisome proliferator-activated receptor-a expression in the liver were seen in comparison with the PGZ group. We then investigated the effects of hydrogen in the prevention of hepatocarcinogenesis in STAM mice, known as the NASH-related hepatocarcinogenesis model. Eight-week-old male STAM mice were divided into three experimental groups as follows: (1) control water (CW-STAM); (2) hydrogen-rich water (HW-STAM); and (3) pioglitazone (PGZ-STAM). After 8 weeks, hepatic tumors were evaluated. The number of tumors was significantly lower in the HW-STAM and PGZ-STAM groups than in the CW-STAM group. The maximum tumor size was smaller in the HW-STAM group than in the other groups. Conclusion: Consumption of hydrogen-rich water may be an effective treatment for NASH by reducing hepatic oxidative stress, apoptosis, inflammation, and hepatocarcinogenesis. (HEPATOLOGY 2012;56:912921)

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  • Serum Vaspin Concentrations Are Closely Related to Insulin Resistance, and rs77060950 at SERPINA12 Genetically Defines Distinct Group with Higher Serum Levels in Japanese Population 査読

    Sanae Teshigawara, Jun Wada, Kazuyuki Hida, Atsuko Nakatsuka, Jun Eguchi, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Izumi Iseda, Yuichi Matsushita, Nobuyuki Miyatake, John F. McDonald, Kikuko Hotta, Hirofumi Makino

    JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM   97 ( 7 )   E1202 - E1207   2012年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ENDOCRINE SOC  

    Context: Vaspin is an adipokine with insulin-sensitizing effects identified from visceral adipose tissues of genetically obese rats.
    Objective: We investigated genetic and nongenetic factors that define serum concentrations of vaspin.
    Design, Setting and Participants: Vaspin levels were measured with RIA in Japanese subjects with normal fasting plasma glucose (NFG; n = 259) and type 2 diabetes patients (T2D; n = 275). Single nucleotide polymorphisms (SNP) at SERPINA12 (vaspin) gene locus were discovered, and five SNP were genotyped in the subjects with varied body mass index (n = 1138).
    Results: The level of serum vaspin in 93% of the samples was found to vary from 0.2 to nearly 2 ng/ml in NFG subjects (n = 259) and from 0.2 to nearly 3 ng/ml in T2D patients (n = 275) (Vaspin(Low) group), whereas a significant subpopulation (7%) in both groups displayed much higher levels of 10-40 ng/ml (Vaspin(High) group). In the Vaspin(Low) group, serum vaspin levels in T2D were significantly higher than healthy subjects (0.99 +/- 0.04 vs. 0.86 +/- 0.02 ng/ml; P &lt; 0.01). Both in T2D and genotyped Japanese population, serum vaspin levels closely correlated with homeostasis model of assessment for insulin resistance rather than anthropometric parameters. By genotyping, rs77060950 tightly linked to serum vaspin levels, i.e. CC (0.6 +/- 0.4 ng/ml), CA (18.4 +/- 9.6 ng/ml), and AA (30.5 +/- 5.1 ng/ml) (P &lt; 2 x 10(-16)). Putative GATA-2 and GATA-3 binding consensus site was found at rs77060950.
    Conclusions: Serum vaspin levels were related to insulin resistance, and higher levels of serum vaspin in 7% of the Japanese population are closely linked to minor allele sequence (A) of rs77060950. (J Clin Endocrinol Metab 97: E1202-E1207, 2012)

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  • RXR antagonism induces G0/G1 cell cycle arrest and ameliorates obesity by up-regulating the p53-p21(Cip1) pathway in adipocytes 査読

    Atsuko Nakatsuka, Jun Wada, Kazuyuki Hida, Aya Hida, Jun Eguchi, Sanae Teshigawara, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Daisuke Ogawa, Hiroyuki Kagechika, Hirofumi Makino

    JOURNAL OF PATHOLOGY   226 ( 5 )   784 - 795   2012年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    The peroxisome proliferator activated receptor-gamma (PPAR gamma) agonist, pioglitazone (PIO), exerts anti-diabetic properties associated with increased fat mass, whereas the retinoid X receptor (RXR) antagonist HX531 demonstrates anti-obesity and anti-diabetic effects with reduced body weight and fat pad mass. The cell cycle abnormality in adipocytes has not been well-investigated in obesity or during treatment with modulators of nuclear receptors. We therefore investigated cell size and cell cycle distributions of adipocytes in vivo and examined the expression of cell cycle regulators in cultured human visceral preadipocytes. The cell size distribution and cell cycle analyses of in vivo adipocytes derived from OLETF rats demonstrated that HX531 brought about G(0)/G(1) cell cycle arrest associated with the inhibition of cellular hypertrophy, which resulted in the reduction of fat pad mass. In contrast, PIO promoted proliferation activities associated with the increase in M + late M:G(0) + G(1) ratio and the appearance of both small and hypertrophied adipocytes. In cultured human visceral preadipocytes HX531 up-regulated cell cycle regulators, p53, p21(Cip1), cyclin D1, Fbxw7 and Skp2, which are known contributors towards G(0)/G(1) cell cycle arrest. The knockdown of p53 with a shRNA lentivirus reversed the HX531-induced up-regulation of p21(Cip1), which is one of the major p53-effector molecules. We conclude that HX531 exerts anti-obesity and anti-diabetes properties by up-regulating the p53-p21(Cip1) pathway, resulting in G(0)/G(1) cell cycle arrest and the inhibition of cellular hypertrophy of adipocytes. Copyright (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    DOI: 10.1002/path.3001

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  • Galectin-9 and T Cell Immunoglobulin Mucin-3 Pathway Is a Therapeutic Target for Type 1 Diabetes 査読

    Motoko Kanzaki, Jun Wada, Koichi Sugiyama, Atsuko Nakatsuka, Sanae Teshigawara, Kazutoshi Murakami, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Jun Eguchi, Hisaya Akiba, Hideo Yagita, Hirofumi Makino

    ENDOCRINOLOGY   153 ( 2 )   612 - 620   2012年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ENDOCRINE SOC  

    Galectin-9 (Gal-9), a ligand for T cell Ig mucin-3 (Tim-3), induces apoptosis in cluster of differentiation 4 (CD4)(+) Tim-3(+) T helper 1 (T(H)1) cells via the Gal-9-Tim-3 pathway and negatively regulates T(H)1 immunity. In turn, Gal-9 activates dendritic cells (DC) to produce TNF-alpha, which promotes the T(H)1 response. We investigated the efficacy of Gal-9 against T(H)1-mediated autoimmune diabetes in NOD mice and compared with anti-Tim-3 monoclonal antibody (RMT3-23), which inhibited the binding between Tim-3-Ig and Gal-9 in a solid-phase binding assay. mRNA expression of Gal-9 was prominently induced by the treatment of interferon-gamma in MIN6 cells, and Gal-9 was also expressed in the pancreatic beta-cells in NOD mice, suggesting Gal-9 may be released from pancreatic beta-cells to terminate T(H)1-mediated inflammation. Long-term injection of Gal-9 exhibits preventive efficacy for development of diabetes in NOD mice, but RMT3-23 demonstrated further prominent therapeutic potential compared with Gal-9. Gal-9 induced apoptosis of CD4(+)Tim-3(+) T(H)1 cells at the concentration of 0.2 mu M, whereas RMT3-23 failed to enhance the apoptosis of CD4(+)Tim-3(+) T(H)1 cells. In contrast, Gal-9 induced TNF-alpha production in cultured DC in a dose-dependent manner; however, RMT3-23 inhibited Gal-9-induced TNF-alpha production in a dose-dependent manner. Although Gal-9 exhibited certain therapeutic potential against autoimmune diabetes by enhancing apoptosis of CD4(+)Tim-3(+) T(H)1 cells, RMT3-23 exhibited prominent therapeutic efficacy by suppressing the TNF-alpha production and activation of DC. Taken together, the inhibition of the Gal-9-Tim-3 pathway on DC, upstream of T(H)1 response, may be a new target for the treatment of type 1 diabetes. (Endocrinology 153: 612-620, 2012)

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  • Telmisartan attenuates diabetic nephropathy by suppressing oxidative stress in db/db mice. 査読

    Sato-Horiguchi C, Ogawa D, Wada J, Tachibana H, Kodera R, Eguchi J, Nakatsuka A, Terami N, Shikata K, Makino H

    Nephron. Experimental nephrology   121 ( 3-4 )   e97 - e108   2012年

  • A Case of Type 2 Diabetes and Metastatic Liver Cancer Exhibiting Hypercholesterolemia with Abnormal Lipoproteins 査読

    Motoko Kanzaki, Jun Wada, Atsuko Nakatsuka, Sanae Teshigawara, Kazutoshi Murakami, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Junichiro Nasu, Kazuhide Yamamoto, Hirofumi Makino

    INTERNAL MEDICINE   51 ( 6 )   619 - 623   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JAPAN SOC INTERNAL MEDICINE  

    Although the appearance of abnormal lipoproteins in liver diseases is well known, the precise analyses of abnormal lipoproteins remain elusive. Here, we report a 71-year-old woman with type 2 diabetes whose serum cholesterol levels were elevated to 560 mg/dL over a 4-month period. High-performance liquid chromatography demonstrated the presence of lipoprotein-X and lipoprotein-Y and sigmoid colon cancer and multiple liver metastases were found by colonoscopy and computed tomography. Remission of the primary colon cancer and liver lesions was achieved by chemotherapy with oxaliplatin and fluorouracil and her serum cholesterol went back to basal levels associated with the disappearance of abnormal lipoproteins.

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  • Telmisartan Attenuates Diabetic Nephropathy by Suppressing Oxidative Stress in db/db Mice 査読

    Chikage Sato-Horiguchi, Daisuke Ogawa, Jun Wada, Hiromi Tachibana, Ryo Kodera, Jun Eguchi, Atsuko Nakatsuka, Naoto Terami, Kenichi Shikata, Hirofumi Makino

    NEPHRON EXPERIMENTAL NEPHROLOGY   121 ( 3-4 )   E97 - E108   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:KARGER  

    Background/Aims: Telmisartan, an angiotensin II type 1 receptor blocker, is widely used to treat hypertension and kidney diseases, including diabetic nephropathy, because of its renoprotective effects. However, the mechanism by which telmisartan prevents proteinuria and renal dysfunction in diabetic nephropathy is still unclear. In this study, we examined the effects of telmisartan against diabetic nephropathy in db/db mice. Methods: Telmisartan was administered at a dose of 5 mg/kg/day for 3 weeks to db/db (diabetic) and db/m (control) mice. Urinary albumin excretion, renal histology, and the gene expression of oxidative stress and inflammatory markers in renal tissue were determined. To evaluate the effects of telmisartan on reactive oxygen species (ROS) production, superoxide was detected by dihydroethidium (DHE) staining in vivo and in vitro. Results: Telmisartan reduced albuminuria, mesangial matrix expansion, macrophage infiltration, and the expression of ROS markers (NADPH oxidase 4- and 8-hydroxydeoxyguanosine) and inflammatory cytokines (monocyte chemoattractant protein-1, osteopontin, and transforming growth factor-beta) in the kidney. DHE staining showed that telmisartan decreased ROS generation in the kidney and in cultured mesangial and proximal tubular epithelial cells. Conclusions: Taken together, these findings indicate that telmisartan protects against diabetic nephropathy by reducing diabetes-induced oxidative stress. Copyright (c) 2013 S. Karger AG, Basel

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  • Two novel mutations of lecithin:cholesterol acyltransferase (LCAT) gene and the influence of APOE genotypes on clinical manifestations 査読

    Akihiro Katayama, Jun Wada, Hitomi Usui Kataoka, Hiroko Yamasaki, Sanae Teshigawara, Takahiro Terami, Kentaro Inoue, Motoko Kanzaki, Kazutoshi Murakami, Atsuko Nakatsuka, Hitoshi Sugiyama, Norio Koide, Hideaki Bujo, Hirofumi Makino

    NDT Plus   4 ( 5 )   299 - 302   2011年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Familial lecithin:cholesterol acyltransferase deficiency (FLD) is an autosomal recessive disorder characterized by corneal opacity, hemolytic anemia, low high-density lipoprotein cholesterol (HDL-C) and proteinuria. Two novel lecithin:cholesterol acyltransferase (LCAT) mutations[c.278 C&gt
    T (p.Pro69Leu)
    c.950 T&gt
    C (p.Met293Thr)] were identified in a 27-year-old man and in a 30-year-old woman, respectively. Both patients manifested corneal opacity, hemolytic anemia, low low-density lipoprotein cholesterol and HDL-C and proteinuria. Lipid deposits with vacuolar lucent appearance in glomerular basement membranes were observed in both cases. APOE genotype was also investigated: the first case results ε4/ε3, the second ε2/ε2
    however, they shared a similar phenotype characterized by the presence of intermediate-density lipoproteins (IDL) remnant and the absence of lipoprotein-X. In conclusion, our findings suggest that APOE ε2/ε2 may not be the major determinant gene for the appearance of IDL in FLD patients. © 2011 The Author.

    DOI: 10.1093/ndtplus/sfr091

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  • [Obesity: Progress in diagnosis and treatment; Topics, IV. Recent topics: 3. Obesity and new secretory factors; 1) Vaspin]. 査読

    Wada J, Teshigawara S, Nakatsuka A, Makino H

    Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine   100 ( 4 )   996 - 1001   2011年4月

  • [Chemerin, RBP4 and vaspin]. 査読

    Wada J, Teshigawara S, Nakatsuka A

    Nihon rinsho. Japanese journal of clinical medicine   69 Suppl 1   231 - 236   2011年1月

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  • Collectrin Is Involved in the Development of Salt-Sensitive Hypertension by Facilitating the Membrane Trafficking of Apical Membrane Proteins via Interaction With Soluble N-Ethylmaleiamide-Sensitive Factor Attachment Protein Receptor Complex 査読

    Akihiro Yasuhara, Jun Wada, Sandra M. Malakauskas, Yanling Zhang, Jun Eguchi, Atsuko Nakatsuka, Kazutoshi Murakami, Motoko Kanzaki, Sanae Teshigawara, Kazuya Yamagata, Thu H. Le, Hirofumi Makino

    CIRCULATION   118 ( 21 )   2146 - 2155   2008年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Background-Collectrin, a homologue of angiotensin converting enzyme 2, is expressed in pancreatic beta cells and renal proximal tubular and collecting duct cells under the control of hepatocyte nuclear factors-1 alpha and-1 beta. Because collectrin interacts with the soluble N-ethylmaleiamide-sensitive factor attachment protein receptor (SNARE) complexes, we investigated whether collectrin is involved in sodium handling in hypertension by vesicle trafficking of apical membrane proteins.
    Methods and Results-Collectrin physically interacts with the SNARE complex: snapin, synaptosomal-associated protein 23 kDa, syntaxin-4, and vesicle-associated membrane protein-2 in mIMCD-3 cells. siRNA knockdown of collectrin resulted in a reduction in membrane-associated aquaporin-2, alpha-epithelial Na(+) channel, and H(+)-ATPase. Collectrin and SNARE proteins were abundantly expressed in collecting ducts of Wistar-Kyoto rats. Wistar-Kyoto rats and spontaneously hypertensive rats 7 weeks of age were subjected to normal-salt (1% NaCl) and high-salt (8% NaCl) chow for 10 weeks. High-salt chow prominently elevated blood pressure, oral intake, and urinary excretion of NaCl and water in both groups. Although urinary excretion of aldosterone was significantly suppressed in both groups, collectrin expression was upregulated and associated with the maintenance of aquaporin-2, alpha-epithelial Na(+) channel, and H(+)-ATPase in membrane fractions. Collectrin promoter activities and mRNA and protein expressions were upregulated and ubiquitinated collectrin was reduced by high NaCl (175 to 225 mmol/L) and not altered by 1 mu mol/L aldosterone in mIMCD-3 cells.
    Conclusions-Upregulation of collectrin by high NaCl independent of aldosterone functionally links to the trafficking of apical membrane proteins via the SNARE complex, and collectrin may be responsible for the sodium retention in salt-sensitive hypertension. (Circulation. 2008; 118: 2146-2155.)

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  • Adipocyte adhesion molecule (ACAM) inhibits adipocyte hypertrophy in obesity

    Kazutoshi Murakami, Jun Wada, Atsuko Nakatsuka, Motoko Kanzaki, Sanae Teshigawara, Takahiro Terami, Kentaro Inoue, Hirofumi Makino

    DIABETES   57   A110 - A111   2008年6月

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    記述言語:英語   出版者・発行元:AMER DIABETES ASSOC  

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  • Vaspin (visceral adipose tissue-derived serpin), improves insulin sensitivity in metabolic syndrome

    Atsuko Nakatsuka, Jun Wada, Kazutoshi Murakami, Sanae Teshigawara, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Hirofumi Makino

    DIABETES   57   A396 - A396   2008年6月

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    記述言語:英語   出版者・発行元:AMER DIABETES ASSOC  

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  • Galectin-9 inhibits the development of type 1 diabetes in female NOD mice

    Motoko Kanzaki, Jun Wada, Atsuko Nakatsuka, Kazutoshi Murakami, Sanae Teshigawara, Takahiro Terami, Kentaro Inoue, Hirofumi Makino

    DIABETES   57   A78 - A78   2008年6月

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    記述言語:英語   出版者・発行元:AMER DIABETES ASSOC  

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  • Serum vaspin levels correlate with the accumulation of visceral adipose tissues in type 2 diabetes patients

    Sanae Teshigawara, Jun Wada, John Mcdonald, Jehangir Mistry, Atsuko Nakatsuka, Kazutoshi Murakami, Motoko Kanzaki, Takahiro Terami, Kentaro Inoue, Hirofumi Makino

    DIABETES   57   A394 - A395   2008年6月

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    記述言語:英語   出版者・発行元:AMER DIABETES ASSOC  

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  • Procollagen C-proteinase enhancer-1 (POPE-1) interacts with beta 2-microglobulin (beta 2-m) and may help initiate beta 2-m amyloid fibril formation in connective tissues 査読

    Hisanori Morimoto, Jun Wada, Bernard Font, Joni D. Mott, David J. S. Hulmes, Tadakazu Ookoshi, Hironobu Naiki, Akihiro Yasuhara, Atsuko Nakatsuka, Kousuke Fukuoka, Yuji Takatori, Haruo Ichikawa, Shigeru Akagi, Kazushi Nakao, Hirofumi Makino

    MATRIX BIOLOGY   27 ( 3 )   211 - 219   2008年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Dialysis related amyloidosis (DRA) is a progressive and serious complication in patients under long-term hemodialysis and mainly leads to osteo-articular diseases. Although beta 2-microglobulin (beta 2-m) is the major structural component of beta 2-m amyloid fibrils, the initiation of amyloid formation is not clearly understood. Here, we have identified procollagen C-proteinase enhance-1 (POPE-1) as a new interacting protein with beta 2-m by screening a human synovium cDNA library. The interaction of beta 2-m with full-length POPE-1 was confirmed by immunoprecipitation, solid-phase binding and pull-down assays. By yeast two-hybrid analysis and pull-down assay, beta 2-m appeared to interact with POPE-1 via the NTR (netrin-like) domain and not via the CUB (C1r/C1s, Uegf and BMP-1) domain region. In synovial tissues derived from hemodialysis patients with DRA, beta 2-m co-localized and formed a complex with POPE-1. beta 2-m did not alter the basal activity of bone morphogenetic protein-1/procollagen C-proteinase (BMP-1/PCP) nor BMP-1/PCP activity enhanced by PCPE-1. PCPE-1 did not stimulate beta 2-m amyloid fibril formation from monomeric beta 2-m in vitro under acidic and neutral conditions as revealed by thioflavin T fluorescence spectroscopy and electron microscopy. Since PCPE-1 is abundantly expressed in connective tissues rich in type I collagen, it may be involved in the initial accumulation of beta 2-m in selected tissues such as tendon, synovium and bone. Furthermore, since such preferential deposition of beta 2-m may be linked to subsequent beta 2-m amyloid fibril formation, the disruption of the interaction between beta 2-m and POPE-1 may prevent beta 2-m amyloid fibril formation and therefore POPE-1 could be a new target for the treatment of DRA. (C) 2007 Elsevier B.V./International Society of Matrix Biology. All rights reserved.

    DOI: 10.1016/j.matbio.2007.11.005

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  • Adipocyte adhesion molecule (ACAM) inhibits adipocyte hypertrophy in obesity

    K. Murakami, J. Wada, A. Nakatsuka, S. Teshigawara, R. Yoshikawa, M. Kanzaki, A. Yasuhara, K. Shikata, H. Makino

    DIABETOLOGIA   50   S57 - S57   2007年9月

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    記述言語:英語   出版者・発行元:SPRINGER  

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  • Vaspin improves insulin sensitivity in obesity

    A. Nakatsuka, J. Wada, K. Murakami, S. Teshigawara, R. Yoshikawa, M. Kanzaki, A. Yasuhara, K. Shikata, H. Makino

    DIABETOLOGIA   50   S56 - S56   2007年9月

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    記述言語:英語   出版者・発行元:SPRINGER  

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  • Hemophagocytic syndrome associated with fatal veno-occlusive disease in the liver 査読

    Atsuko Nakatsuka, Jun Wada, Ryo Nagase, Masaya Takeda, Tadashi Yoshino, Hirofumi Makino

    INTERNAL MEDICINE   46 ( 8 )   495 - 499   2007年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JAPAN SOC INTERNAL MEDICINE  

    A 47-year-old man presented with hemophagocytic syndrome (HPS) without any obvious underlying diseases. On computed tomography, his liver was occupied by multiple ill-defined low intensity lesions. Liver biopsy revealed diffuse infiltration of numerous histiocytes without cytologic atypism and prominent fibrotic changes. These histiocyes showed S100(+), CD68(+), CD1a(-), and lysozyme(+) and Langerhans cell granules were not observed by electron microscopic examination. He failed to respond to immunosuppressive and chemotherapeutic treatments and progressed to severe liver failure. At autopsy, his liver exhibited veno-occulusive disease (VOD). Since VOD is regarded as a rare complication of HPS, the presence of VOD associated with HPS may be easily overlooked.

    DOI: 10.2169/internalmedicine.46.6294

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  • [Molecular biology of regulation in renal functions; biosynthesis, metabolism, and action of insulin and glucagon]. 査読

    Nakatsuka A, Wada J, Makino H

    Nihon rinsho. Japanese journal of clinical medicine   64 Suppl 2   222 - 226   2006年2月

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  • Visceral adipose tissue-derived serine protease inhibitor: A unique insulin-sensitizing adipocytokine in obesity 査読

    K Hida, J Wada, J Eguchi, H Zhang, M Baba, A Seida, L Hashimoto, T Okada, A Yasuhara, A Nakatsuka, K Shikata, S Hourai, J Futami, E Watanabe, Y Matsuki, R Hiramatsu, S Akagi, H Makino, YS Kanwar

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   102 ( 30 )   10610 - 10615   2005年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATL ACAD SCIENCES  

    There is a rapid global rise in obesity, and the link between obesity and diabetes remains somewhat obscure. We identified an adipocytokine, designated as visceral adipose tissue-derived serpin (vaspin), which is a member of serine protease inhibitor family. Vaspin cDNA was isolated by from visceral white adipose tissues (WATs) of Otsuka Long-Evans Tokushima fatty (OLETIF) rat, an animal model of abdominal obesity with type 2 diabetes. Rat, mouse, and human vaspins are made up of 392,394, and 395 amino acids, respectively; exhibit approximate to 40% homology with alpha(1)-antitrypsin; and are related to serine protease inhibitor family. Vaspin was barely detectable in rats at 6 wk and was highly expressed in adipocytes of visceral WATs at 30 wk, the age when obesity, body weight, and insulin levels peak in OLETF rats. The tissue expression of vaspin and its serum levels decrease with worsening of diabetes and body weight loss at 50 wk. The expression and serum levels were normalized with the treatment of insulin or insulin-sensitizing agent, pioglitazone, in OLETF rats. Administration of vaspin to obese CRL:CD-1 (ICR) (ICR) mice fed with high-fat high-sucrose chow improved glucose tolerance and insulin sensitivity reflected by normalized serum glucose levels. It also led to the reversal of altered expression of genes relevant to insulin resistance, e.g., leptin, resistin, TNF alpha, glucose transporter-4, and adiponectin. In DNA chip analyses, vaspin treatment resulted in the reversal of expression in approximate to 50% of the high-fat high-sucrose-induced genes in WATs. These findings indicate that vaspin exerts an insulin-sensitizing effect targeted toward WATs in states of obesity.

    DOI: 10.1073/pnas.0504703102

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  • A case of monoclonal immunoglobulin light- and heavy-chain deposition disease exhibiting atypical deposition with fibrillary structures, successfully treated with chemotherapy. 査読

    Nakatsuka A, Maeshima Y, Sarai A, Yanai H, Sugiyama H, Yamasaki Y, Makino H

    Clin Nephrol   2005年

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  • A case of focal segmental glomerulosclerosis (FSGS) complicated with chronic hepatitis B and treated with steroid and LDL apheresis 査読

    Akinobu Takaki, Atsuko Nakatsuka, Chikage Satou, Yasuyoshi Iwata, Hiroshi Ikeda, Masaki Fukushima

    Japanese Journal of Nephrology   44 ( 8 )   806 - 812   2002年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    A 52-year-old man was admitted to our hospital because of nephrotic syndrome. He had been monitored at our outpatient clinic for chronic hepatitis B, and had experienced histologically proven minimal change nephrotic syndrome at the ages of 40 and 51 years. Because of HBsAg positivity in his serum, steroid therapy was withheld in his earlier episodes and he recovered from nephrotic syndrome spontaneously. However, in the most recent episode the nephrotic syndrome was found difficult to control and the findings of renal biopsy showed FSGS, which is not expected in HBV-associated nephropathy. Finally, prednisolone was administered at the dose of 40 mg/day for four weeks, after which the dose was tapered. LDL apheresis was also administered three times because of the patient's incomplete response to prednisolone. His proteinuria was reduced from&gt
    10 g/day to&lt
    1 g/day, but the ALT levels and HBsAg titer increased. With stronger neominophagen C induction and very careful tapering of glucocorticoid, ALT levels and the HBsAg titer decreased. During the two-year period since the induction of glucocorticoid therapy, urinary protein excretion has been maintained at less than 1 g/gcr, and ALT levels and HBsAg titer have not increased. We conclude that attention must be paid to dose modification of steroid therapy and strategies without immunosuppressive agents such as LDL apheresis should be considered in the case of treatment of nephrotic syndrome with HB virus.

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MISC

  • 糖尿病と心腎連関

    中司敦子, 和田淳

    循環器内科   90 ( 6 )   601 - 609   2021年12月

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    担当区分:筆頭著者   記述言語:日本語   掲載種別:記事・総説・解説・論説等(商業誌、新聞、ウェブメディア)  

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  • DKDの基礎 小胞体ストレス(特集 糖尿病性腎臓病DKD)

    中司敦子, 和田淳

    腎と透析   91 ( 4 )   568 - 574   2021年10月

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  • 薬物療法 : 経口血糖降下薬による治療 : BG薬,SU薬・グリニド薬からピオグリタゾン,αGI,DPP-4阻害薬,SGLT2阻害薬まで (特集 糖尿病) -- (治療)

    片岡 仁美, 和田 淳, 江口 潤, 柴田, 佑助, 高橋, 寛子, 中司, 敦子, 山口 哲志

    Hospitalist = ホスピタリスト   6 ( 2 )   343 - 360   2018年6月

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  • 糖尿病性腎症の基礎研究(特集 糖尿病性腎症)

    中司敦子, 和田淳

    日本腎臓学会誌   59 ( 2 )   58 - 64   2017年2月

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    担当区分:筆頭著者  

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  • 糖尿病と心腎連関(特集 心腎連関を理解する)

    中司敦子, 和田淳

    臨床検査   62   72 - 77   2017年1月

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  • 血糖制御に関わる臓器・関連因子-脂肪細胞

    中司敦子, 和田淳

    日本臨牀.   増刊号 ( 1 )   258 - 262   2016年1月

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  • 肥満と腎障害 (特集 肥満に伴う臓器障害) -- (肥満に伴う臓器障害の成因と病態)

    中司 敦子, 和田淳

    ホルモンと臨床   63 ( 2 )   103 - 107   2015年2月

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  • Vaspinのメタボリックシンドロームにおける意義

    和田淳, 中司敦子, 槇野博史

    腎と透析   78   267 - 271   2015年2月

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  • 慢性腎臓病(CKD) (特集 肥満症診療最前線) -- (肥満に起因する疾患の検査,治療のポイントは? : 体重減少の効果を主に)

    中司敦子, 和田淳

    Modern Physician.   35 ( 2 )   216 - 218   2015年2月

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  • バスピン

    中司敦子, 和田淳

    循環器内科   77 ( 6 )   569 - 574   2015年

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  • Vaspinとインスリン抵抗性 (特集 インスリン感受性,エネルギー代謝の新規モディファイヤー)

    中司 敦子, 勅使川原 早苗, 和田 淳

    内分泌・糖尿病・代謝内科   37 ( 6 )   633 - 639   2013年12月

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    記述言語:日本語   出版者・発行元:科学評論社  

    CiNii Article

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    その他リンク: http://search.jamas.or.jp/link/ui/2014078091

  • Streptozotocin投与NASH発癌モデルマウスにおける病態進行と水素水投与の有効性の検討

    河合 大介, 高木 章乃夫, 山本 和秀, 中司 敦子, 和田 淳, 玉木 直文, 安中 哲也, 小池 和子, 津崎 龍一郎, 松本 和幸, 三宅 康広, 白羽 英則, 森田 学, 槇野 博史

    日本消化器病学会雑誌   109 ( 臨増大会 )   A708 - A708   2012年9月

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    記述言語:日本語   出版者・発行元:(一財)日本消化器病学会  

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  • 平成23年度岡山医学会賞(結城賞) RXR阻害によるp53-p21[Cip]¹経路の活性化およびG0/G1細胞周期停止を介した抗肥満作用

    中司 敦子, 和田 淳, 槇野 博史

    岡山医学会雑誌   124 ( 2 )   97 - 100   2012年8月

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    記述言語:日本語   出版者・発行元:岡山医学会  

    DOI: 10.4044/joma.124.97

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    その他リンク: http://ousar.lib.okayama-u.ac.jp/48587

  • Streptozotocin投与NASHモデルマウスにおける病態進行と水素水投与の有効性の検討

    河合 大介, 高木 章乃夫, 山本 和秀, 松本 和幸, 石川 久, 津崎 龍一郎, 安中 哲也, 中司 敦子, 小池 和子, 三宅 康広, 白羽 英則, 和田 淳

    日本消化器病学会雑誌   109 ( 臨増総会 )   A325 - A325   2012年3月

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    記述言語:日本語   出版者・発行元:(一財)日本消化器病学会  

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  • ヒト血中Vaspin濃度の検討とメタボリックシンドロームにおける意義

    勅使川原, 早苗, 和田 淳, 中司 敦子, 堀田 紀久子, 肥田 和之, 村上 和敏, 神崎 資子, 井上 謙太郎, 寺見 隆宏, 松下 裕一, 片山 晶博, 江口 潤, 槇野 博史

    肥満研究   17 ( Suppl. )   160 - 160   2011年9月

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    記述言語:日本語   出版者・発行元:(一社)日本肥満学会  

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  • 新規アディポカイン--バスピン(Vaspin) (脂肪細胞)

    中司敦子, 和田淳

    臨床検査   66 ( 6 )   599 - 604   2011年6月

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  • 非アルコール性脂肪性肝炎(NASH)モデルマウスの病態進行に対する水素水の効果の検討

    河合 大介, 高木 章乃夫, 松本 和幸, 津崎 龍一郎, 安中 哲也, 中司 敦子, 小池 和子, 三宅 康広, 白羽 英則, 和田 淳, 山本 和秀

    肝臓   52 ( Suppl.1 )   A259 - A259   2011年4月

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    記述言語:日本語   出版者・発行元:(一社)日本肝臓学会  

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  • Galectin-9-Tim-3経路を介した1型糖尿病制御

    神崎 資子, 和田 淳, 中司 敦子, 村上 和敏, 勅使川原 早苗, 寺見 隆宏, 井上 謙太郎, 片山 晶博, 四方 賢一, 秋葉 久弥, 八木田 秀雄, 槇野 博史

    糖尿病   54 ( Suppl.1 )   S - 105   2011年4月

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    記述言語:日本語  

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  • ヒト血中Vaspin濃度の検討とメタボリックシンドロームにおける意義

    勅使川原, 早苗, 和田 淳, 中司 敦子, 村上 和敏, 神崎 資子, 井上 謙太郎, 寺見 隆宏, 松下 裕一, 利根 淳仁, 伊勢田 泉, 肥田 和之, 宮武 伸行, 堀田 紀久子, 四方 賢一, 槇野 博史

    糖尿病   53 ( Suppl.1 )   S - 164   2010年4月

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    記述言語:日本語   出版者・発行元:(一社)日本糖尿病学会  

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  • Galectin-9-Tim-3経路を介した1型糖尿病制御

    神崎 資子, 和田 淳, 中司 敦子, 村上 和敏, 勅使川原, 早苗, 寺見 隆宏, 井上 謙太郎, 四方 賢一, 秋葉 久弥, 八木田 秀雄, 槇野 博史

    糖尿病   53 ( Suppl.1 )   S - 236   2010年4月

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    記述言語:日本語  

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  • Vaspinによる炎症制御とインスリン抵抗性

    中司敦子、和田淳

    医学のあゆみ   229 ( 7 )   526 - 530   2009年5月

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  • Galectin-9-Tim-3経路による1型糖尿病制御

    神崎 資子, 和田 淳, 中司 敦子, 村上 和敏, 勅使川原 早苗, 寺見 隆宏, 井上 謙太郎, 黒瀬 祐子, 四方 賢一, 秋葉 久弥, 八木田 秀雄, 槇野 博史

    糖尿病   52 ( Suppl.1 )   S - 300   2009年4月

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    記述言語:日本語  

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  • 高マグネシウム血症により意識障害を来たした慢性腎不全の2例

    中司敦子, 神崎資子, 高木章乃夫, 岩田康義, 福島正樹, 池田弘

    日本透析医学会雑誌   2004年

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  • 糖尿病性腎症に合併したANCA関連急速進行性糸球体腎炎の1例

    中司敦子, 佐藤千景, 岩田康義, 高木章乃夫, 福島正樹, 津嘉山朝達, 西崎哲一

    腎と透析   2002年

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  • アンギオテンシン変換酵素阻害剤(ACE-I)投与中に発生した急性腎不全症例の検討

    高木章乃夫, 岩田康義, 佐藤千景, 江口潤, 中司敦子, 福島正樹

    ICUとCCU   2002年

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  • 慢性B型肝炎に巣状分節性糸球体硬化症(FSGS)によるネフローゼ症候群を合併し,ステロイド,LDL吸着療法にて緩解した1例

    高木章乃夫, 央病院, 腎臓内科, 中司敦子, 佐藤千景, 岩田康義, 池田弘, 福島正樹

    日本腎臓学会誌   2002年

  • ANCA関連腎炎の治療と予後に関する検討

    中司敦子, 高木章乃夫, 岩田康義, 福島正樹

    倉敷中央病院年報   2002年

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  • 深部静脈血栓症(DVT)を合併した糖尿病性腎症透析患者の一例

    山崎浩子, 長宅芳男, 平櫛恵太, 肥田和之, 中司敦子, 西下伸吾, 大石和弘, 福田真治, 槇野博史, 万波智彦, 吉野 正, 赤木忠厚

    中国腎不全研究会誌   1999年

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▼全件表示

講演・口頭発表等

  • 糖尿病における近位尿細管障害とVaspin/HSP70sの意義

    中司敦子

    第32回日本糖尿病性腎症研究会(ワークショップ)  2021年12月5日 

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    開催年月日: 2021年12月4日 - 2021年12月5日

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  • 基礎研究と臨床の間で考える糖尿病合併症(女性医師ワークショップ) 招待

    中司敦子

    日本糖尿病学会中国四国地方会第59回総会  2021年10月22日 

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    開催年月日: 2021年10月22日 - 2021年10月23日

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  • 糖尿病合併症におけるバスピンの作用と新たな病態解明 (女性研究者賞受賞講演) 招待

    中司敦子

    第64回日本糖尿病学会年次学術集会  2021年5月21日 

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    開催年月日: 2021年5月20日 - 2021年5月22日

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  • 臨床医・研究者として継続してきたVaspinの機能解析 (会長企画ー研究者のサークルを作ろうー3 女性、連携、新しい糖尿病学を切り拓く)

    中司敦子

    第64回日本糖尿病学会年次学術集会  2021年5月20日 

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    開催年月日: 2021年5月20日 - 2021年5月22日

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  • 肥満糖尿病の近位尿細管障害におけるHSPsの新規機能の解明

    中司敦子,山口哲志,江口潤,和田淳

    第40回日本肥満学会  2019年11月2日 

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    開催年月日: 2019年11月2日 - 2019年11月3日

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  • 糖尿病における近位尿細管細胞のGRP78局在変化とバスピンの受容体としての意義

    中司敦子、江口潤、和田淳

    第62回日本腎臓学会総会  2019年6月21日 

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    開催年月日: 2019年6月21日 - 2019年6月23日

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  • 脂肪肝における脂肪酸20:3(n6),20:3(n9)の意義

    中司敦子, 山口哲志, 江口潤, 和田淳

    第62回日本糖尿病学会年次学術集会  2019年5月24日 

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    開催年月日: 2019年5月23日 - 2019年6月25日

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  • Vaspin regulates lysosome function and protects from tubulopathy in metabolic syndrome

    Keystone Symposia, Immunometabolism, Metaflammation and Metabolic Disorders (D6), Workshop  2019年4月 

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    記述言語:英語   会議種別:シンポジウム・ワークショップ パネル(公募)  

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  • Vaspin and proximal tubular cell injury in metabolic syndrome

    International Society of Nephrology (ISN) Frontiers Meeting  2018年2月 

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    記述言語:英語   会議種別:シンポジウム・ワークショップ パネル(指名)  

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  • protective role of vaspin against proximal tubular cell injuries in diabetes mellitus

    The 59st Annual Meeting of the Japan Diabetes Society  2016年5月 

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    記述言語:英語   会議種別:シンポジウム・ワークショップ パネル(指名)  

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受賞

  • 岡山市文化奨励賞(学術部門)

    2021年11月   岡山市  

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  • 女性研究者賞

    2021年5月   日本糖尿病学会  

    中司敦子

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  • 第2回山﨑倫子賞

    2018年   日本女医会  

    中司 敦子

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  • 両備檉園記念財団 生物学研究奨励賞

    2018年  

    中司 敦子

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  • 第三内科同門会・奨励賞

    2017年12月   第三内科同門会  

    中司敦子

  • 「日本内科学会ことはじめ2017東京」指導教官賞

    2017年   第114回日本内科学会総会  

    中司 敦子

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  • H27年度研究活動奨励賞

    2016年   日本女性腎臓病医の会(JSWN  

    中司 敦子

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  • ビジョナリーアワード

    2016年   第37回日本肥満学会  

    中司 敦子

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  • 至誠会賞(旧岡本糸枝賞)

    2015年  

    中司 敦子

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  • 岡山医学会賞(砂田賞)

    2014年  

    中司 敦子

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  • Young Investigator Award

    2013年   糖尿病合併症学会  

    中司 敦子

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  • 渡辺記念特別奨励賞

    2013年   宇部興産学術振興財団  

    中司 敦子

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  • 第27回岡本研究奨励賞

    2013年   公益財団法人成人血管病研究振興財団  

    中司 敦子

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  • 岡山医学会賞(結城賞)

    2012年  

    中司 敦子

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  • 岡山県医師会学術奨励賞

    2012年  

    中司 敦子

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  • 第10回日本心臓財団・アステラス・ファイザー「動脈硬化」Update最優秀演題

    2012年  

    中司 敦子

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  • 優秀演題賞

    2010年   第54回日本腎臓学会学術大会  

    中司 敦子

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  • Barrie Hesp scholarship

    2010年   Keystone symposia  

    中司 敦子

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  • 優秀演題賞

    2009年   第52回日本糖尿病学会年次学術集会  

    中司 敦子

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  • 若手研究奨励賞

    2009年   第7回メタボリックシンドロームカンファレンス  

    中司 敦子

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  • Travel Grant Award

    2007年   第43回ヨーロッパ糖尿病学会  

    中司 敦子

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  • 第三内科同門会・奨励賞

    2005年12月   第三内科同門会  

    中司敦子

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共同研究・競争的資金等の研究

  • ミトコンドリアダイナミクスにおけるバスピンの意義と腎尿細管間質障害の制御

    研究課題/領域番号:20K08608  2020年04月 - 2023年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    中司 敦子

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    配分額:4420000円 ( 直接経費:3400000円 、 間接経費:1020000円 )

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  • SGLT2阻害薬によるGRP78を介した尿細管間質障害抑制機構の解明

    2020年01月 - 2022年01月

    特定非営利活動法人日本腎臓協会  田辺三菱製薬株式会社共同研究 

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    担当区分:研究代表者 

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  • キーストンシンポジウム(Molecular & Cellular Biology, Immunometabolism, Metaflammation & Metabolic Disorders)発表

    2019年

    公益財団法人金原一郎記念医学医療振興財団  第33回研究交流助成金 

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    担当区分:研究代表者 

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  • 近位尿細管細胞障害におけるHSPA1Lとオルガネラストレス応答

    2018年

    公益社団法人日本女医会  第38回日本女医会学術研究助成 

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    担当区分:研究代表者 

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  • 必須脂肪酸欠乏により誘導される生体反応と炎症制御・組織修復への応用

    2018年

    公益財団法人 アサヒグループ学術振興財団  2018年度学術研究助成 

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    担当区分:研究代表者 

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  • 肝脂質代謝におけるHeat shock protein 40 Member C1 の機能解析

    2018年

    公益財団法人ノバルティス科学振興財団  ノバルティス研究奨励金 

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    担当区分:研究代表者 

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  • 分子シャペロンの新規固有機能と糖尿病腎症における意義の解明

    2018年

    公益財団法人日本糖尿病協会  若手研究者助成 

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    担当区分:研究代表者 

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  • シャペロン分子の新規固有機能を介したバスピンの尿細管保護作用の解明と治療への応用

    2018年

    公益財団法人岡山医学振興財団  第18回公募助成 

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    担当区分:研究代表者 

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  • メタボリックシンドロームにおけるオルガネラ機能不全と腎尿細管間質障害機構の解明

    研究課題/領域番号:17K09861  2017年04月 - 2020年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    中司 敦子

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    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

    肥満や糖尿病を背景とした近位尿細管細胞障害の機序のひとつとして、飽和脂肪酸による脂肪毒性や小胞体ストレスの亢進がリソソーム膜を不安定化し、リソソーム膜透過性亢進によるカテプシンBの細胞質への放出により、NLRP3インフラマソームが活性化され細胞死に至ることを示した。また、我々が発見したアディポカインであるバスピンは、これらの経路を抑制して、近位尿細管細胞保護作用を示すことを明らかにした。また、バスピンは近位尿細管細胞においてGRP78, HSPA1Lと結合して細胞内に取り込まれることや、アルブミンによりHSPA1Lの細胞外分泌が増加することなど新たな知見を得た。

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  • Dnajc1の新規固有機能の解析と肝脂肪合成における意義

    2017年

    公益財団法人赤枝医学研究財団  研究助成 

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    担当区分:研究代表者 

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  • オルガネラ機能におけるvaspinの作用と糖尿病腎症の尿細管細胞保護機構の解明

    2017年

    公益財団法人日本糖尿病財団研究助成  第4回ベーリンガー/リリー糖尿病研究助成 

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    担当区分:研究代表者 

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  • 近位尿細管細胞におけるライソゾーム機能異常とvaspinによる細胞保護機構の解明

    2016年

    JSWN研究活動奨励賞 

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    担当区分:研究代表者 

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  • アディポカインによる糖尿病性腎症の進展抑制機構の解明-細胞内小器官への作用を中心として-

    2016年

    公益財団法人石橋由紀子記念基金 

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    担当区分:研究代表者 

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  • 腎尿細管細胞におけるライソゾーム機能の破綻メカニズムの解明

    2016年

    公益財団法人金原一郎記念医学医療振興財団  第31回基礎医学研究助成金 

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    担当区分:研究代表者 

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  • Vaspinによる近位尿細管細胞の恒常性維持機構の解明

    2015年 - 2017年

    公益財団法人持田記念医学薬学振興財団  第27回持田記念研究助成金 

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    担当区分:研究代表者 

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  • Vaspinによる近位尿細管細胞に対する細胞保護作用の解明

    2015年

    一般社団法人至誠会  至誠会賞学術研究助成 

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    担当区分:研究代表者 

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  • American Diabetes Association’s 75th Scientific Sessions発表

    2015年

    公益財団法人岡山医学振興会  研究交流事業(派遣)助成 

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    担当区分:研究代表者 

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  • 一次繊毛機能を介したACAM/CLMPの脂肪細胞分化と肥満症における意義

    研究課題/領域番号:26461362  2014年04月 - 2017年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    村上 和敏, 和田 淳, 江口 潤, 中司 敦子

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    配分額:4810000円 ( 直接経費:3700000円 、 間接経費:1110000円 )

    脂肪細胞は余剰エネルギーにより肥大化すると、アディポカイン分泌異常などにより代謝調節機能が障害されメタボリックシンドロームや糖尿病を発症する。我々は、肥満ラットの内臓脂肪組織からホモフィリックな細胞接着に関わる細胞接着分子ACAMを発見した。脂肪細胞でACAMを過剰発現したマウスを高脂肪高蔗糖食で飼育すると、肥満、糖尿病の発症が予防された。このマウスでは脂肪細胞同士がACAMにより接着し、その接着部位に表層アクチン(F-actin)を形成し、電子顕微鏡で同部位にzonula adherens形成を認めた。ACAMは細胞接着と表層アクチン形成により脂肪細胞肥大化を抑制し、肥満や糖尿病を予防する。

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  • Vaspinとその相互作用分子から展開するメタボリック症候群関連創薬

    研究課題/領域番号:26293218  2014年04月 - 2017年03月

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    和田 淳, 中司 敦子

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    配分額:16510000円 ( 直接経費:12700000円 、 間接経費:3810000円 )

    Vaspinは内臓脂肪組織から発見したserine protease inhibitor (serpin)ファミリーに属する新規アディポカインであり、メタボリックシンドロームにおけるインスリン抵抗性、脂肪肝、脂質代謝異常、動脈硬化を改善する代償因子であるVaspinの受容体であるGRP78/DNAJC1 (DnaJ homolog, subfamily C, member 1)複合体のうちDNAJC1(DnaJ homolog, subfamily C, member 1)のコンディショナルノックアウトマウスを作出した。DNAJC1はメタボリックシンドロームにおける創薬ターゲットと考えられる。

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  • メタボリックシンドロームにおける腎障害とVaspinの意義

    研究課題/領域番号:26461361  2014年04月 - 2017年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    中司 敦子, 和田 淳

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    配分額:4810000円 ( 直接経費:3700000円 、 間接経費:1110000円 )

    我々はこれまでにアディポカインであるvaspinを同定し、vaspinが脂肪細胞から血中へ分泌され、インスリン抵抗性や肥満・脂肪肝、動脈硬化を抑制することを明らかにした。本研究では肥満や糖尿病の病態におけるvaspinの腎臓への作用と機序について検討した。Vaspinトランスジェニック(Tg)およびノックアウト(Vaspin-/-)、野生型マウスを用いて、ストレプトゾトシンで糖尿病を誘発、また高脂肪高蔗糖食で肥満糖尿病モデルを作成し、腎病変について検討した。いずれのモデルにおいても、vapsinは尿細管細胞障害を抑制することが示唆された。

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  • Pemt欠損による肝細胞アポトーシス遷延と脂肪肝炎進展機構の解明

    2014年

    公益財団法人山陽放送学術文化財団  第52回(平成26年度)学術奨励賞 

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    担当区分:研究代表者 

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  • 脂肪肝炎における肝再生機構に寄与する脂肪酸の同定

    2014年

    公益財団法人ウイルス肝炎研究財団  平成26年度研究奨励金 

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    担当区分:研究代表者 

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  • VaspinのGLP-1を介した血糖調節機構の解明

    2014年

    公益財団法人日本糖尿病財団  第4回(平成26年度)リリー・インクレチン基礎研究助成金 

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    担当区分:研究代表者 

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  • 第73回アメリカ糖尿病学会参加・発表, PEMTのメタボリックシンドロームにおける意義の解明

    2013年

    公益財団法人ウエスコ学術振興財団  平成25年度学術研究費助成金(海外渡航費助成) 

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    担当区分:研究代表者 

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  • 糖尿病細小血管障害におけるVaspinの意義

    2013年

    公益財団法人万有生命科学振興国際交流財団  Banyu Foundation Research Grant 2013 

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    担当区分:研究代表者 

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  • Vaspinによる小胞体ストレス制御と糖尿病性腎症治療薬の開発

    2013年

    公益財団法人 宇部興産学術振興財団  第53回学術研究費援助金(渡辺記念特別奨励賞) 

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    担当区分:研究代表者 

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  • VDAC/GRP78経路を介した血管内皮細胞アポトーシスの制御

    2013年

    公益財団法人成人血管病研究振興財団  平成25年度岡本研究奨励賞 

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    担当区分:研究代表者 

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  • 小胞体ストレスを介したVaspinのメタボリックシンドローム制御機構の解明

    研究課題/領域番号:24790926  2012年04月 - 2014年03月

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    中司 敦子

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    配分額:4160000円 ( 直接経費:3200000円 、 間接経費:960000円 )

    Vaspinの遺伝子改変マウスの検討や培養実験により、vaspinが肥満やインスリン抵抗性・脂肪肝・動脈硬化を抑制することを明らかにした。Vaspinは肝臓や血管内皮細胞の細胞表面に存在するGRP78と結合する。肝臓では肝細胞表面のGRP78/MTJ-1複合体に結合してAktやAMPKリン酸化を亢進させ、糖脂質代謝を改善する。血管では、vapsinは血管内皮細胞表面のGRP78/VDAC複合体と結合し、VDACのリガンドとして知られるkringle 5がVDACを介して細胞内Ca2+濃度を上昇させアポトーシスを起こす経路を阻害し、またAktリン酸化を亢進させ、内皮細胞のアポトーシスを抑制する。

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  • Vaspinと血管内皮細胞機能

    2012年

    公益財団法人上原記念生命科学財団  研究奨励金 

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    担当区分:研究代表者 

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  • Vaspinによる動脈硬化抑制とその作用機序の解明

    2012年

    公益財団法人日本心臓財団  日本心臓財団・アステラス・ファイザー「動脈硬化」Update研究助成 

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    担当区分:研究代表者 

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▼全件表示

 

担当授業科目

  • メタボリックシンドローム特論 (2021年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学I(演習・実習) (2021年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学I(演習・実習) (2021年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学I(演習・実習) (2021年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学I(講義・演習) (2021年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学I(講義・演習) (2021年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学II(演習・実習) (2021年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学II(講義・演習) (2021年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学II(講義・演習) (2021年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学I(演習・実習) (2020年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学I(演習・実習) (2020年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学I(講義・演習) (2020年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学I(講義・演習) (2020年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学II(演習・実習) (2020年度) 特別  - その他

  • 腎・免疫・内分泌代謝内科学II(演習・実習) (2020年度) 特別  - その他

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▼全件表示