研究者詳細 - 寺井　崇二

多発性肝転移に対し, Degradable starch microspheres (DSM) とリピオドールによる肝動脈化学塞栓療法を施行後, オクトレオチド酢酸塩を継続投与した回腸原発神経内分泌腫瘍肝転移の一例

大野高嗣, 瀬川誠, 橋本真一, 内田耕一, 寺井崇二, 山崎隆弘, 星井嘉信, 坂井田功

山口医学 60 ( 6 ) 255 - 261 2011年12月

記述言語：日本語出版者・発行元：山口大学医学会

症例は50歳代女性．健診の腹部超音波検査で多発肝腫瘤を指摘され当院を受診．ダブルバルーン小腸内視鏡で回腸に多発する腫瘤性病変を認め，生検により，回腸原発神経内分泌腫瘍の多発肝転移と診断された．肝転移病巣に対し，微小デンプン球（degradable starch microspheres：DSM）とリピオドールを用いた肝動脈化学塞栓療法を施行し，良好な腫瘍縮小効果を認めた．さらに，術後に持続性ソマトスタチンアナログマイクロスフェア型徐放性製剤（オクトレオチド酢酸塩徐放性製剤：商品名：サンドスタチンLAR筋注用）を継続投与し，長期間にわたる腫瘍の増殖抑制効果を維持し得た．切除不能の消化管神経内分泌腫瘍の肝転移症例に対する治療法として有用であると考えられた．

DOI： 10.2342/ymj.60.255

CiNii Article

Melanocortin 4 Receptor-Deficient Mice as a Novel Mouse Model of Nonalcoholic Steatohepatitis 査読

Michiko Itoh, Takayoshi Suganami, Nobutaka Nakagawa, Miyako Tanaka, Yukio Yamamoto, Yasutomi Kamei, Shuji Terai, Isao Sakaida, Yoshihiro Ogawa

AMERICAN JOURNAL OF PATHOLOGY 179 ( 5 ) 2454 - 2463 2011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：ELSEVIER SCIENCE INC

Obesity may be viewed as a state of chronic low-grade inflammation that participates in the development of the metabolic syndrome. Nonalcoholic steatohepatitis (NASH) is considered a hepatic phenotype of the metabolic syndrome and a high risk for progression to cirrhosis and hepatocellular carcinoma. Although the "two hit" hypothesis suggests involvement of excessive hepatic lipid accumulation and chronic inflammation, the molecular mechanisms underlying the development of NASH remain unclear, in part because of lack of appropriate animal models. Herein we report that melanocortin 4 receptor deficient mice (MC4R-KO) develop steatohepatitis when fed a high-fat diet, which is associated with obesity, insulin resistance, and dyslipidemia. Histologic analysis reveals inflammatory cell infiltration, hepatocyte ballooning, and pericellular fibrosis in the liver in MC4R-KO mice. Of note, all of the MC4R-KO mice examined developed well-differentiated hepatocellular carcinoma after being fed a high-fat diet for 1 year. They also demonstrated enhanced adipose tissue inflammation, ie, increased macrophage infiltration and fibrotic changes, which may contribute to excessive lipid accumulation and enhanced fibrosis in the liver. Thus, MC4R-KO mice provide a novel mouse model of NASH with which to investigate the sequence of events that make up diet-induced hepatic steatosis, liver fibrosis, and hepatocellular carcinoma and to aid in understanding the pathogenesis of NASH, pursuing specific biomarkers, and evaluating potential therapeutic strategies. (Am J Pathol 2011, 179:2454-2463; DOI: 10.1016/j.ajpath.2011.07.014)

DOI： 10.1016/j.ajpath.2011.07.014

肝細胞癌・慢性関節リウマチの加療中に悪性リンパ腫を発症した一例

播磨博文, 石川剛, 土屋昌子, 内田耕一, 星井嘉信, 寺井崇二, 山崎隆弘, 坂井田功

肝臓 52 ( Suppl.3 ) A954 - A954 2011年11月

TNFR1-mediated signaling is important to induce the improvement of liver fibrosis by bone marrow cell infusion 査読

Takuro Hisanaga, Shuji Terai, Takuya Iwamoto, Taro Takami, Naoki Yamamoto, Tomoaki Murata, Toshifumi Matsuyama, Hiroshi Nishina, Isao Sakaida

CELL AND TISSUE RESEARCH 346 ( 1 ) 79 - 88 2011年10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

The importance of TNF-alpha signals mediated by tumor necrosis factor receptor type 1 (TNFR1) in inflammation and fibrosis induced by carbon tetrachloride (CCl(4)), and in post-injury liver regeneration including a GFP/CCl(4) model developed as a liver repair model by bone marrow cell (BMC) infusion, was investigated. In mice in which TNFR1 was suppressed by antagonist administration or by knockout, liver fibrosis induced by CCl(4) was significantly decreased. In these mice, intrahepatic macrophage infiltration and TGF-beta 1 expression were reduced and stellate cell activity was decreased; however, expression of MMP-9 was also decreased. With GFP-positive BMC (TNFR1 wildtype, WT) infusion in these mice, fibrosis proliferation, including host endogenous intrahepatic macrophage infiltration, TGF-beta 1 expression and stellate cell activity, increased significantly. There was no significant increase of MMP-9 expression. In this study, TNFR1 in hosts had a promoting effect on CCl(4)-induced hepatotoxicity and fibrosis, whereas BMC infusion in TNFR1 knockout mice enhanced host-derived intrahepatic inflammation and fibrosis proliferation. These findings differed from those in WT recipient mice, in which improvement in inflammation and fibrosis with BMC infusion had previously been reported. TNFR1-mediated signaling might be important to induce the improvement of liver fibrosis by bone marrow cell infusion.

DOI： 10.1007/s00441-011-1236-0

Senescence marker protein 30 (SMP30)/regucalcin (RGN) expression decreases with aging, acute liver injuries and tumors in zebrafish 査読

Koichi Fujisawa, Shuji Terai, Yoshikazu Hirose, Taro Takami, Naoki Yamamoto, Isao Sakaida

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 414 ( 2 ) 331 - 336 2011年10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

Senescence marker protein 30 (SMP30)/regucalcin (RGN) is known to be related to aging, hepatocyte proliferation and tumorigenesis. However, expression and function of non-mammalian SMP30/RGN is poorly understood. We found that zebrafish SMP30/RGN mRNA expression decreases with aging, partial hepatectomy and thioacetamide-induced acute liver injury. SMP30/RGN expression was also greatly decreased in a zebrafish liver cell line. In addition, we induced liver tumors in adult zebrafish by administering diethylnitrosamine. Decreased expression was observed in foci, hepatocellular carcinomas, cholangiocellular carcinomas and mixed tumors as compared to the surrounding area. We thus showed the importance of SMP30/RGN in liver proliferation and tumorigenesis. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2011.09.067

Potential Therapeutic Application of Intravenous Autologous Bone Marrow Infusion in Patients with Alcoholic Liver Cirrhosis 査読

Takafumi Saito, Kazuo Okumoto, Hiroaki Haga, Yuko Nishise, Rika Ishii, Chikako Sato, Hisayoshi Watanabe, Akio Okada, Motoki Ikeda, Hitoshi Togashi, Tsuyoshi Ishikawa, Shuji Terai, Isao Sakaida, Sumio Kawata

STEM CELLS AND DEVELOPMENT 20 ( 9 ) 1504 - 1511 2011年9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：MARY ANN LIEBERT INC

The present study was conducted to evaluate the application and efficacy of autologous bone marrow infusion (ABMi) for improvement of liver function in patients with alcoholic liver cirrhosis (ALC). Five subjects and 5 control patients with ALC who had abstained from alcohol intake for 24 weeks before the study were enrolled. Autologous bone marrow cells were washed and injected intravenously, and the changes in serum liver function parameters, and the level of the type IV collagen 7S domain as a marker of fibrosis, were monitored for 24 weeks. The distribution of activated bone marrow was assessed by indium-111-chloride bone marrow scintigraphy. The number of cells infused was 8.0 +/- 7.3x10(9) (mean +/- standard error). The serum levels of albumin and total protein and the prothrombin time were significantly higher during the follow-up period after ABMi than during the observation period in treated patients, whereas no such changes were observed in the controls. In the patients who received ABMi, the Child-Pugh score decreased in all 3 who were classified as class B; the serum levels of type IV collagen 7S domain improved in 4 of the 5 patients; and bone marrow scintigraphy demonstrated an increase of indium-111-chloride uptake in 3 of the 4 patients tested. ABMi for patients with ALC helps improve liver function parameters in comparison with observation during abstinence and ameliorates the degree of fibrosis in terms of serum markers and bone marrow activation in most cases.

DOI： 10.1089/scd.2011.0074

肝疾患と幹細胞炎症、再生、発癌まで骨髄細胞頻回投与による肝細胞がん合併肝硬変症に対する修復再生・抗腫瘍療法開発のための基礎研究

高見太郎, 寺井崇二, 坂井田功

日本消化器病学会雑誌 108 ( 臨増大会 ) A687 - A687 2011年9月

肝疾患動物モデルとtranslational research 肝硬変症に対する骨髄由来培養細胞を用いた修復再生療法開発のために橋渡し研究

寺井崇二, 高見太郎, 坂井田功

日本消化器病学会雑誌 108 ( 臨増大会 ) A566 - A566 2011年9月

Deferoxamine for Advanced Hepatocellular Carcinoma 査読

Takahiro Yamasaki, Shuji Terai, Isao Sakaida

NEW ENGLAND JOURNAL OF MEDICINE 365 ( 6 ) 576 - 578 2011年8月

内視鏡的静脈瘤硬化結紮療法後におけるAT3製剤投与による門脈血栓予防効果

浜辺功一, 石川剛, 岩本拓也, 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 17 ( 3 ) 111 - 111 2011年8月

肝細胞癌との鑑別に苦慮した脈絡膜悪性黒色腫肝転移の1例

在津潤一, 石川剛, 播磨陽平, 土屋昌子, 高見太郎, 山口裕樹, 内田耕一, 寺井崇二, 山崎隆弘, 坂井田功

肝臓 52 ( 7 ) 468 - 476 2011年7月

記述言語：日本語出版者・発行元：一般社団法人日本肝臓学会

左脈絡膜悪性黒色腫に対する手術歴（2004年4月，左眼球摘出術）を有する79歳の男性患者が2009年10月に右季肋部痛を主訴に当院外来を受診した．血液検査にて軽度の肝機能障害と高度の凝固系異常が認められたため精査加療目的で同日当科に緊急入院となった．HBs抗原・抗HBs抗体・抗HBc-IgG抗体・抗HCV抗体はいずれも陰性であり，腹部超音波検査・CT検査・MRI検査・血管造影検査で肝両葉に多血性腫瘤が多数認められた．悪性黒色腫に特異的な腫瘍マーカーである5-S-cysteinyldopaが異常高値を呈したがPIVKA IIも著明に上昇していたため画像・血液検査所見からは悪性黒色腫肝転移と肝細胞癌の鑑別には至らなかった．超音波下肝腫瘍生検にて悪性黒色腫の確定診断を得た上で同病変に対してシスプラチンを用いた肝動脈化学塞栓療法を施行した．今回我々は「脈絡膜悪性黒色腫肝転移」という非常に稀な一例を経験したので報告する．<br>

DOI： 10.2957/kanzo.52.468

CiNii Article

An abdominal aorta wall extraction for liver cirrhosis classification using ultrasonic images

Takaya Hayashi, Yusuke Fujita, Yoshihiro Mitani, Yoshihiko Hamamoto, Makoto Segawa, Shuji Terai, Isao Sakaida

AIP Conference Proceedings 1371 343 - 344 2011年7月

Splenectomy reduces fibrosis and preneoplastic lesions with increased triglycerides and essential fatty acids in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet 査読

Toshiyuki Oishi, Shuji Terai, Takuya Iwamoto, Taro Takami, Naoki Yamamoto, Isao Sakaida

HEPATOLOGY RESEARCH 41 ( 5 ) 463 - 474 2011年5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：WILEY-BLACKWELL

Aim:
This study investigated whether splenectomy is of significance in non-alcoholic steatohepatitis (NASH).
Methods:
Five-week-old Wistar rats were fed a choline-deficient diet for 8 weeks to create a NASH model. A sham-operation or splenectomy was then performed, and rats were killed 4 weeks later.
Results:
Liver fibrosis and liver preneoplastic lesions were significantly reduced in the splenectomy group compared to the sham-operation group, and alpha-smooth muscle actin (SMA) expression was significantly inhibited (liver fibrosis area: sham 8.63 +/- 4.09%, splenectomy 5.45 +/- 3.69%, P < 0.01; preneoplastic lesion size: sham 6.56 +/- 3.68 x106 mu m2/cm2, splenectomy 4.63 +/- 3.27 x106 mu m2/cm2, P < 0.05; the number of preneoplastic lesions: sham 8.33 +/- 3.96/cm2, splenectomy 5.17 +/- 1.80/cm2, P < 0.01; alpha-smooth muscle actin-positive area: sham 4.41 +/- 2.48%, splenectomy 2.75 +/- 1.66%, P < 0.01) On the other hand, liver triglycerides and essential fatty acids were significantly increased in the splenectomy group (liver triglycerides: sham 182 +/- 35.0 mg/g, splenectomy 230 +/- 35.0 mg/g, P < 0.05; liver linoleic acid: sham 17.2 +/- 4.9 mg/g, splenectomy 23.3 +/- 6.9 mg/g, P < 0.05; liver alpha-linolenic acid: sham 118 +/- 36.6 mu g/g, splenectomy 162 +/- 51.4 mu g/g, P < 0.05). In addition, expressions of hepatic fatty acid metabolism-related genes (e.g. acyl-CoA oxidase, liver carnitine palmitoyl-CoA transferase I, cytochrome P450 4A, long-chain acyl-CoA dehydrogenase and medium-chain acyl-CoA dehydrogenase) were significantly inhibited in the splenectomy group.
Conclusion:
These findings suggest that spleen plays an important regulatory role in the fibrosis, preneoplastic lesion and lipid metabolism of liver in a rat choline-deficient L-amino acid model.

DOI： 10.1111/j.1872-034X.2011.00784.x

Telmisartan improves nonalcoholic steatohepatitis in medaka (Oryzias latipes) by reducing macrophage infiltration and fat accumulation 査読

Shinya Kuwashiro, Shuji Terai, Toshiyuki Oishi, Koichi Fujisawa, Toshihiko Matsumoto, Hiroshi Nishina, Isao Sakaida

CELL AND TISSUE RESEARCH 344 ( 1 ) 125 - 134 2011年4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 investigated the efficacy of the antihypertensive drug telmisartan (Tel) and the mechanisms underlying the progression from simple steatosis to nonalcoholic steatohepatitis (NASH) in a medaka (Oryzias latipes) NASH model. We used the NASH activity score (NAS) developed in humans to assess the histology of the medaka NASH model and found that NAS increased with time. Further, TUNEL-positive apoptosis hepatocytes were found in the medaka NASH model. Tel administration resulted in the increased expression of liver peroxisome proliferator-activated receptor-gamma, carnitine palmitoyltransferase 1 and acyl-CoA oxidase 1 and decreased the number of 8-hydroxydeoxyguanosine-positive hepatocytes and the migration of macrophages positive for diastase-periodic-acid-Schiff. Medaka NAS was improved by Tel administration but fatty acid content was not affected. Tel reduced the infiltration of macrophages into the liver and ameliorated NASH pathology.

DOI： 10.1007/s00441-011-1132-7

Imaging mass spectrometry reveals characteristic changes in triglyceride and phospholipid species in regenerating mouse liver 査読

Norio Miyamura, Takashi Nakamura, Naoko Goto-Inoue, Nobuhiro Zaima, Takahiro Hayasaka, Tokiwa Yamasaki, Shuji Terai, Isao Sakaida, Mitsutoshi Setou, Hiroshi Nishina

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 408 ( 1 ) 120 - 125 2011年4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

After partial hepatectomy (PH), regenerating liver accumulates unknown lipid species. Here, we analyzed lipids in murine liver and adipose tissues following PH by thin-layer chromatography (TLC), imaging mass spectrometry (IMS), and real-time RT-PCR. In liver, IMS revealed that a single TLC band comprised major 19 TG species. Similarly, IMS showed a single phospholipid TLC band to be major 13 species. In adipose tissues, PH induced changes to expression of genes regulating lipid metabolism. Finally, IMS of phosphatidylcholine species demonstrated distribution gradients in lobules that resembled hepatic zonation. IMS is thus a novel and power tool for analyzing lipid species with high resolution. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2011.03.133