研究者詳細 - 寺井　崇二

論文 - 寺井　崇二

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非アルコール性脂肪性肝疾患の病態と治療メダカモデルから人へ NASH治療剤の開発の新ストラテジー

寺井崇二, 松本俊彦, 坂井田功

肝臓 49 ( Suppl.1 ) A36 - A36 2008年4月

Increased expression of heat shock protein-binding protein 1 and heat shock protein 70 in human hepatocellular carcinoma tissues 査読

Yuichiro Yokoyama, Yasuhiro Kuramitsu, Motonari Takashima, Masanori Fujimoto, Norio Iizuka, Shuji Terai, Kiwamu Okita, Isao Sakaida, Masaaki Oka, Deborah A. Raynes, Vince Guerriero, Kazuyuki Nakamura

MOLECULAR MEDICINE REPORTS 1 ( 2 ) 197 - 201 2008年3月

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

Heat shock protein-binding protein 1 (HspBP1) is a co-chaperone that inhibits heat shock 70-kDa protein (Hsp70) activity. In mouse neuroblastomas and lung tumors, the protein levels of HspBP1 and Hsp70 are elevated by a similar amount compared to non-tumor tissues. However, no studies have been reported regarding the levels of HspBP1 in human cancer tissues. Our previous proteomic study demonstrated that the expression of Hsp70 was increased in human hepatitis C virus-related hepatocellular carcinoma (HCV-HCC) tissues. Here, we investigated the expression of HspBP1 in human HCV-HCC. Immunoblotting analysis of HspBP1 and Hsp70 was performed in human HCV-HCC tissues from 20 patients. In 80% of the patients, Hsp70 increased an average of 3.55-fold, and in 50% of the patients, HspBP1 increased an average of 2.02-fold. Comparison and analysis of expression and clinical data revealed a significant difference between moderately-differentiated HCC and non-tumor tissues. In addition, there was a significant difference between the ratio of HspBP1 to Hsp70 levels and tumor size (<3 cm vs. >= 3cm) with larger tumors having a lower ratio. This ratio was significantly lower in moderately-differentiated HCC tissues than in non-tumor HCC tissues. In conclusion, HspBP1 was up-regulated in human HCV-HCC, an increase which correlated with the increase of Hsp70 levels. The ratio of HspBP1 to Hsp70 in HCC may provide novel information concerning the characterization of tumors, tumor progression and resistance to treatment.

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Continuous high expression of XBP1 and GRP78 is important for the survival of bone marrow cells in CCl4-treated cirrhotic liver 査読

Yoshio Marumoto, Shuji Tera, Yohei Urata, Toshihiko Matsumoto, Yuko Mizunaga, Naoki Yamamoto, Haiyan Jina, Koichi Fujisawa, Tomoaki Murata, Koh Shinoda, Hiroshi Nishina, Isao Sakaida

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 367 ( 3 ) 546 - 552 2008年3月

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

We have previously shown that infusion of bone marrow cells (BMC) improves CCl4-induced cirrhosis. However, it is unclear why the injected BMC are resistant to CCl4 damage and subsequently improve the local microenvironment in damaged liver. To analyze the cellular phenomena involved in this process, we studied the damaged liver using electron microscopy. We found that CCl4 caused rough endoplasmic reticula to swell in hepatocytes. To analyze the gene expression patterns associated with this process, we conducted PCR-selected suppressive subtractive hybridization. We found that expression levels of HSP84, HSP40, and XBP1 differed markedly between control liver and liver infused with BMC. Immunohistochemical staining revealed that expression levels of HSP84 and HSP40 were markedly higher in the early phase of differentiation immediately after BMC infusion, but decreased over time. XBP1 expression remained high during the late phase, and GRP78 expression increased with XBP1 activation. We also found that GFP-positive BMC expressed XBP1 and GRP78. XBP1 and GRP78 are associated with ER stress. Thus, continuous high XBP1 and GRP78 expression might be essential for the survival and proliferation of BMC in a CCl4-induced persistent liver damage environment. (C) 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2007.12.171

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A new hepatic encephalopathy model to monitor the change of neural amino acids and astrocytes with behaviour disorder 査読

Yumiko Isobe-Harima, Shuji Terai, Izumi Miura, Makoto Segawa, Tomoaki Murata, Kazuhito Itamoto, Yasuho Taura, Koh Shinoda, Isao Sakaida

LIVER INTERNATIONAL 28 ( 1 ) 117 - 125 2008年1月

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

Background/Aims: To elucidate the pathogenesis of hepatic encephalopathy (HE), we developed a new HE model with behaviour disorder. Methods: Male Wistar rats were divided into four treatment groups: a HE model: acetaminophen (APAP)+3-methylcholanthrene (3-MC) group (APAP+MC group); control group: acetaminophen group; 3-methylcholanthrene group; and a no-treatment group. We monitored the changes of neural amino acids in the synaptic cleft and astrocytes in the brain during behaviour disorder. Results: In the APAP+MC group, alanine amino transferase, blood ammonia and glucose increased from 3 h and total bilirubin increased at 6 h. Prothrombin time was prolonged from 3 h in the APAP+MC group. The APAP+MC group exhibited centrilobular necrosis in the liver after 8 h. In the APAP+MC group, rats jumped vertically and this vertical activity increased significantly from 4 to 7 h. During the behaviour disorder, we found that glutamate and aspartate increased in the synaptic cleft from 4 h after treatment with APAP+3-MC, glutamate increased 23.9-fold at 7 h and aspartate increased 16.1-fold at 4 h, whereas glutamine did not change. At that time, we observed morphological changes of the astrocytes by immunostaining for the glial fibrillary acidic protein. Conclusion: Our new HE model demonstrated that increased excitatory neural amino acids and morphological change in astrocytes were involved in the behaviour disorder that occurs with HE.

DOI： 10.1111/j.1478-3231.2007.01589.x

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Serum S100b (astrocyte-specific protein) is a useful marker of hepatic encephalopathy in patients with fulminant hepatitis 査読

Yumiko Isobe-Harima, Shuji Terai, Makoto Segawa, Koichi Uchida, Takahiro Yamasaki, Isao Sakaida

LIVER INTERNATIONAL 28 ( 1 ) 146 - 147 2008年1月

FibroScanを用いた食道静脈瘤の存在診断の現状

瀬川誠, 寺井崇二, 山崎隆弘, 坂井田功

日本門脈圧亢進症学会雑誌 14 ( 4 ) 313 - 316 2008年

記述言語：日本語出版者・発行元：日本門脈圧亢進症学会

肝硬変の診断方法として, 肝臓の硬さの診断は, 主として触診によってなされてきたが, 最近の技術の進歩により, 超音波を用いて非侵襲的に肝臓の硬さ (肝硬度, 肝弾性値) を測定する機器 (FibroScan) が臨床応用され, 肝線維化の進行と肝弾性値が相関することが明らかとなり, 肝線維化の非侵襲的な評価方法として確立しつつある.一方で, 肝弾性値は, 肝線維化などの静的因子に加え, 血流, 炎症, 胆汁鬱滞などの動的因子も関与していることが明らかになってきた.肝弾性値と門脈圧との関連性が検討されつつあり, 肝弾性値測定による門脈圧亢進症診断への応用が試みられている.肝弾性値測定により, 門脈圧亢進症の合併症である食道静脈瘤の存在診断が可能となれば, 現在肝硬変患者に対しての非侵襲的な定期検査の実施も期待できる.本総説では, 肝弾性値測定による門脈圧亢進症診断に関する現状を述べる.

DOI： 10.11423/jsph1999.14.4_313

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その他リンク： http://search.jamas.or.jp/link/ui/2009287768

Telmisartan prevents hepatic fibrosis and enzyme-altered lesions in liver cirrhosis rat induced by a choline-deficient L-amino acid-defined diet 査読

Haiyan Jin, Naoki Yamamoto, Koichi Uchida, Shuji Terai, Isao Sakaida

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 364 ( 4 ) 801 - 807 2007年12月

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

Rennin-angiotensin system is involved in liver fibrogenesis through activating hepatic stellate cells (HSCs). Telmisartan (Tel) is an angiotensin II type 1 receptor antagonist, could function as a selective peroxisome proliferator-activated receptor gamma activator. Here we studied the effect of Tel on liver fibrosis, pre-neoplastic lesions in vivo and primary HSCs in vitro. In vivo study, we used the choline-deficient L-amino acid-defined (CDAA)-diet induced rat NASH model. The rats were fed the CDAA diet for 8 weeks to induce liver fibrosis and pre-neoplastic lesions, and then co-administrated with Tel for another 10 weeks. Tel prevented liver fibrogenesis and pre-neoplastic lesions by down-regulating TGF beta 1 and TIMP-1, 2 and increasing MMP-13 expression. Tel inhibited HSCs activation and proliferation. These results suggested that Tel could be a promising drug for NASH related liver fibrosis. (C) 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2007.10.083

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強皮症に肝細胞癌と乳癌を合併した一例

佐伯一成, 是永匡紹, 岩本拓也, 松本俊彦, 瀬川誠, 山口裕樹, 是永圭子, 内田耕一, 寺井崇二, 山崎隆弘, 為佐卓夫, 岡正朗, 坂井田功

肝臓 48 ( Suppl3 ) A622 - A622 2007年11月

NASHにおける肝線維化と発癌をめぐって耐糖能異常は脂肪肝症例における肝線維化・発癌のリスクファクターの可能性がある

松本俊彦, 寺井崇二, 坂井田功

肝臓 48 ( Suppl3 ) A514 - A514 2007年11月

The development of new drug screening system using steatohepatitis medaka fish model induced by high-fat diet 査読

Matsumoto Toshihiko, Terai Shuji, Kuwashiro Shinya, Fujisawa Koichi, Yamamoto Naoki, Hamamoto Yoshihiko, Sakaida Isao

HEPATOLOGY 46 ( 4 ) 756A 2007年10月

Is an arterial infusion chemotherapy with pegylated interferon-alpha-2b effective for advanced hepatocellular carcinoma? 査読

Yamasaki Takahiro, Saeki Issei, Okita Kousuke, Yamaguchi Yuhki, Uchida Koichi, Terai Shuji, Sakaida Isao

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 22 A193 2007年10月

肝の再生医学・医療/人工肝臓の現状と展望肝硬変症に対する自己骨髄細胞投与療法(ABMI療法)の現状および今後の工夫について

寺井崇二, 丸本芳雄, 坂井田功

肝臓 48 ( Suppl.2 ) A357 - A357 2007年9月

メダカNASHモデルにおける病態解析

松本俊彦, 寺井崇二, 坂井田功

肝臓 48 ( Suppl.2 ) A474 - A474 2007年9月

Importance of inhibitor of DNA binding/differentiation 2 in hepatic stellate cell differentiation and proliferation 査読

Kunihiko Tajima, Shuji Terai, Taro Takami, Kotaro Kawaguchi, Kiwamu Okita, Isao Sakaida

HEPATOLOGY RESEARCH 37 ( 8 ) 647 - 655 2007年8月

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

Background/Aim: in liver fibrosis, activated hepatic stellate cells (HSC) are transformed into myofibroblasts. Helix-loop-helix (HLH) transcriptional factors such as MyoD regulate the differentiation of myocytes, and the inhibitor of DNA binding/ differentiation (Id) family comprises dominant negative HLH transcriptional regulators that inhibit differentiation and promote cell proliferation. In the present study, we investigated how the Id family proteins regulate HSC.
Methods: in primary rat HSC, inhibitor of DNA binding/ differentiation (ld)2 and alpha-smooth muscle actin (alpha-SIVIA) mRNA expression increased 4 days after isolation. Next we established ld2 expressing HSC (HSC-T6-Id2-green fluorescent protein (GFP)) using HSC-T6 cells with retrovirus that expressed GFP-tagged ld2.
Results: HSC-T6-Id2-GFP increased cell proliferation with cyclin D1 expression. In contrast, alpha-SMA expression was suppressed. Real-time reverse transcri ption-polym erase chain reaction analysis showed ld2 induction significantly suppressed alpha-SMA, collagen-1, matrix metalloproteinase (MMP)-2, and MMP-9 mRNA (P < 0.05) but had no effect on tissue inhibitor of metalloproteinase or transforming growth factor-beta 1 levels.
Conclusion: These findings suggest ld2, an HLH transcriptional regulator, plays an important regulatory role in the proliferation and differentiation of HSC.

DOI： 10.1111/j.1872-034X.2007.00089.x

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The iron chelator deferoxamine causes activated hepatic stellate cells to become quiescent and to undergo apoptosis 査読

Haiyan Jin, Shuii Terai, Isao Sakaida

JOURNAL OF GASTROENTEROLOGY 42 ( 6 ) 475 - 484 2007年6月

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 TOKYO

Background. Hepatic stellate cells (HSCs) play a pivotal role in liver fibrogenesis. Here, we studied whether the iron chelator deferoxamine (DFO) affected cultured HSC activation and apoptosis. Methods. The effect of DFO on HSCs was investigated using quiescent and activated stellate cells. Results. Treatment with DFO inhibited HSC activation, resulting in the reduced expression of a-smooth muscle actin protein and type I procollagen, matrix metalloproteinase-2 and -9, and tissue inhibitors of metalloproteinase-1 and -2 mRNAs. DFO induced apoptosis of activated HSCs, which was associated with decreasing Bcl-2 expression and the release of cytochrome c from the mitochondria to the cytosol with enhanced caspase-3 activity. DFO also induced activated HSCs to express peroxisome proliferator-activated receptor gamma with the reaccumulation of intracellular lipids. Conclusions. The iron chelation of stellate cells inhibits their activation, causing them to become deactivated as well as to undergo apoptosis. These data suggest a potential role for an iron chelation treatment of liver fibrosis.

DOI： 10.1007/s00535-007-2020-5

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[Candidate drugs for non-alcoholic steatohepatitis (NASH)]. 査読

Terai S, Matsumoto T, Sakaida I

Nihon yakurigaku zasshi. Folia pharmacologica Japonica 129 ( 4 ) 271 - 275 2007年4月

記述言語：日本語出版者・発行元：公益社団法人日本薬理学会

非アルコール性脂肪性肝炎（NASH）は肝硬変症に進行する病態であり，その病態としてFree fatty acid（FFA），Tumor necrosis factor-α（TNF-α），レプチン，レジスチンの上昇とアディポネクチンの低下が報告されている．これらの変化は体重の減量によって可逆的で，NASHの改善につながることが知られているが，実際には生活習慣の改善が難しい症例が多く，NASHの病態から考えた薬物療法が必要とされている．薬物療法は4つの方向性が考えられる．(1)インスリン抵抗性の改善（インスリン抵抗性改善薬），(2)脂肪酸生合成の抑制と肝内に蓄積した脂肪酸の燃焼（高脂血症薬），(3)脂肪酸の代謝過程で生じた酸化ストレスからの保護（抗酸化剤や肝庇護剤）である．(4)さらに抗NASH作用を持つアディポネクチンのレセプターに対するアゴニストや抗TNF-α剤なども，今後，検討すべきだろう．また，肝線維化抑制の側面より，アンジオテンシンIIレセプター拮抗薬が，NASHにおける肝線維化抑制薬として作用する可能性が期待される．<br>

DOI： 10.1254/fpj.129.271

その他リンク： https://jlc.jst.go.jp/DN/JALC/00291948050?from=CiNii

治療薬シリーズ高脂血症非アルコール性脂肪性肝疾患、肝炎に対する薬物療法について

寺井崇二, 松本俊彦, 坂井田功

日本薬理学雑誌 129 ( 4 ) 271 - 275 2007年4月

記述言語：日本語出版者・発行元：(公社)日本薬理学会

非アルコール性脂肪性肝炎(NASH)は肝硬変症に進行する病態であり、その病態としてFree fatty acid(FFA),Tumor necrosis factor-α(TNF-α)、レプチン、レジスチンの上昇とアディポネクチンの低下が報告されている。これらの変化は体重の減量によって可逆的で、NASHの改善につながることが知られているが、実際には生活習慣の改善が難しい症例が多く、NASHの病態から考えた薬物療法が必要とされている。薬物療法は4つの方向性が考えられる。(1)インスリン抵抗性の改善(インスリン抵抗性改善薬)、(2)脂肪酸生合成の抑制と肝内に蓄積した脂肪酸の燃焼(高脂血症薬)、(3)脂肪酸の代謝過程で生じた酸化ストレスからの保護(抗酸化剤や肝庇護剤)である。(4)さらに抗NASH作用を持つアディポネクチンのレセプターに対するアゴニストや抗TNF-α剤なども、今後、検討すべきだろう。また、肝線維化抑制の側面より、アンジオテンシンIIレセプター拮抗薬が、NASHにおける肝線維化抑制薬として作用する可能性が期待される。(著者抄録)

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Administration of fibroblast growth factor 2 in combination with bone marrow transplantation synergistically improves carbon-tetrachloride-induced liver fibrosis in mice 査読

Tsuyoshi Ishikawa, Shuji Terai, Yohei Urata, Yoshio Marumoto, Koji Aoyama, Tomoaki Murata, Yuko Mizunaga, Naoki Yamamoto, Hiroshi Nishina, Koh Shinoda, Isao Sakaida

CELL AND TISSUE RESEARCH 327 ( 3 ) 463 - 470 2007年3月

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

We previously reported that fibroblast growth factor 2 (FGF2) facilitated the differentiation of transplanted bone marrow cells (BMCs) into hepatocytes. Our earlier study also demonstrated that administration of FGF2 in combination with bone marrow transplantation (BMT) synergistically activated tumor necrosis factor-alpha signaling and significantly improved liver function and prognosis more than BMT alone. However, the way that it affected the extracellular matrix remained unclear. Here, we investigated the effect of FGF2 treatment together with BMT on liver fibrosis in mice treated with carbon tetrachloride (CCl4). Transplantation of BMCs and concurrent treatment with FGF2 caused a statistically significant reduction in CCl4-induced liver fibrosis that was accompanied by strong expression of matrix metalloproteinase 9 as compared with FGF2-only treatment or BMT alone. Moreover, in this process, the proliferation of bone-marrow-derived cells was accelerated without causing apoptosis. Thus, the administration of FGF2 in combination with BMT synergistically improves CCl4-induced liver fibrosis in mice. This treatment has the potential of being an effective therapy for patients with liver cirrhosis.

DOI： 10.1007/s00441-006-0334-x

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Circulating cell-free DNA as a predictive marker for distant metastasis of hepatitis C virus-related hepatocellular carcinoma 査読

Tokuhisa, Y., Iizuka, N., Sakaida, I., Moribe, T., Fujita, N., Miura, T., Tamatsukuri, S., Ishitsuka, H., Uchida, K., Terai, S., Sakamoto, K., Tamesa, T., Oka, M.

British Journal of Cancer 97 ( 10 ) 1399 - 1403 2007年

Elevated levels of circulating cell-free DNA in the blood of patients with hepatitis C virus-associated hepatocellular carcinoma 査読

Norio Iizuka, Isao Sakaida, Toyoki Moribe, Nozomi Fujita, Toshiaki Miura, Markus Stark, Shigeru Tamatsukuri, Hideo Ishitsuka, Koichi Uchida, Shuji Terai, Kazuhiko Sakamoto, Takao Tamesa, Masaaki Oka

ANTICANCER RESEARCH 26 ( 6C ) 4713 - 4719 2006年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：INT INST ANTICANCER RESEARCH

Background: Circulating cell-free DNA is present in increased amounts in the blood of patients with one of several forms of cancer. Materials and Methods: A real-time PCR assay with glutathione S-transferase pi (GSTP1) gene was used to measure cell-free DNA levels in the sera of 52 patients with hepatocellular carcinoma (HCC) associated with hepatitis C virus (HCV), which included 30 HCV carriers without known HCC and 16 HCV-negative non-cancer patients (controls). Results: Cell-free DNA levels were significantly higher in the sera from HCC patients than in the sera from HCV carriers or the control subjects. Cell-free DNA levels were associated with the degree of tumor differentiation and size but not patient age, gender, TNM stage or levels of alpha-fetoprotein (AFP) or protein induced by vitamin K absence (PIVKA-II). The cell-free DNA assay had a sensitivity of 69.2% and a specificity of 93.3% in discriminating HCC and HCV carriers at the optimal cut-off value of 73.0 ng/ml, with an area of 0.90 (95% CI 0.83-0.96) under the receiver operating characteristic curve. The discriminative power of cell-free DNA was superior to that of AFP or PIM-II. Conclusion: Our results showed that levels of circulating cell-free DNA are significantly increased in sera of patients with HCV-associated HCC, suggesting that circulating cell-free DNA may be a good biomarker specific for HCV-associated HCC.

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論文 - 寺井 崇二

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論文 - 寺井　崇二