Novel prevention of development of life style-related liver diseases and liver carcinogenesis through an activation of transcription factor induced by functional foods

• Project/Area Number: 21300275
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Eating habits, studies on eating habits
• Research Institution: Wakayama Medical University (2010-2011); University of Tsukuba (2009)
• Principal Investigator: UTSUNOMIYA Hirotoshi (2010-2011) 和歌山県立医科大学, 医学部, 准教授 (60264876); 中原 朗 (2009) University of Tsukuba, 大学院・人間総合科学研究科, 准教授 (90114107)
• Co-Investigator(Kenkyū-buntansha): ISHII Tetsuro 筑波大学, 大学院, 教授 (20111370) ; SHODA Junichi 筑波大学, 医学医療系, 教授 (90241827) ; TAKAHASHI Hiroshi 筑波大学, 医学医療系, 准教授 (70236313) ; 宇都宮 洋才 和歌山県立医科大学, 医学部, 講師 (60264876)
• Co-Investigator(Renkei-kenkyūsha): YAMAMOTO Masayuki 東北大学, 医学研究科, 教授 (50166823)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥18,980,000 (Direct Cost: ¥14,600,000、Indirect Cost: ¥4,380,000); Fiscal Year 2011: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2010: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2009: ¥9,490,000 (Direct Cost: ¥7,300,000、Indirect Cost: ¥2,190,000)
• Keywords: 生活習慣病 / 脂肪性肝炎 / 肝発癌 / 機能性食品 / 転写因子 / Nrf2 / 分子標的治療

Research Abstract

Nrf2 is a transcription factor that exerts an in vivo defense mechanism against oxidative stress. Therefore, we studied whether Nrf2 inhibits onset and progression of NASH in the animal model of NASH induced by a mechionine-and choline-deficient(MCD) diet. Nrf2 has an inhibitory effect against the onset and progression of MCD-induced NASH through the induction of detoxifying and antioxidative stress gene molecules. It is suggested that Nrf2 is an important target for the treatment of NASH.

Research Products

• [Journal Article] Novel function of Niemann-Pick C1-Like 1 as a negative regulator of Niemann-Pick C2 protein (2012)
  • Author(s): Yamanashi Y, Takada T, Shoda J, Suzuki H
  • Journal Title: Hepatology Volume: (In press)
  • Peer Reviewed
• [Journal Article] Nrf2 inhibits hepatic iron accumulation and counteracts oxidative stress-induced liver injury in nutritional steatohepatitis (2012)
  • Author(s): Okada K, Warabi E, Sugimoto H, Horie M, Tokushige K, Ueda T, Harada N, Taguchi K, Hashimoto E, Itoh K, Ishii T, Utsunomiya H, Yamamoto M, Shoda J
  • Journal Title: J Gastroenterol Volume: (In press)
  • NAID: 10031051379
  • Peer Reviewed
• [Journal Article] Orexin 2 receptioor as a potential target for the immunotoxin and antibody-drug conjugate cancer tgherapy (2012)
  • Author(s): Kishida M, Ishige, K., Horibe, T., Tada, N., Koibuchi, N., Shoda J, Kita, K., Kawakami, K
  • Journal Title: Oncology Letters Volume: 3 Pages: 525-529
  • Peer Reviewed
• [Journal Article] Nrf2 inhibits hepatic iron accumulation and counteracts oxidative stress-induced (2012)
  • Author(s): Okada K, Shoda J, et al
  • Journal Title: J Gastroenterol Volume: (In press)
  • Peer Reviewed
• [Journal Article] Novel function of Niemann-Pick C1-Like 1 as a negative regulator (2012)
  • Author(s): Yamanashi Y, Shoda J, et al
  • Journal Title: Hepatology Volume: (In press)
  • Peer Reviewed
• [Journal Article] Proton beam therapy for hepatocellular carcinoma located adjacent to the alimentary tarct (2011)
  • Author(s): Nakayama, H., Sugahara, S., Fukuda, K., Abei, M., Shoda, J., Tokita, M., Sakurai H., Tsuboi, K., Matsuzaki, Y., Tokuue, K
  • Journal Title: Int J Radiat Oncol Biol Phys Volume: 80 Pages: 992-995
  • Peer Reviewed
• [Journal Article] Potent in vitro and in vivo antitumor activity of sorafenib against human intrahepatic cholangiocarcinoma cells (2011)
  • Author(s): Sugiyama, H., Onuki, K., Ishige, K., Baba, N., Ueda, T., Matsuda, S., Takeuchi, K., Onodera, M., Nakanuma, Y., Yamato, M., Yamamoto, M., Hyodo, I., Shoda, J
  • Journal Title: J Gastroenterol Volume: 46 Pages: 779-789
  • NAID: 10029029679
  • Peer Reviewed
• [Journal Article] NPC2 regulates biliary cholesterol secretion via stimulation of ABCG5/G8-mediated cholesterol transport (2011)
  • Author(s): Yamanashi, Y., Takada, T., Yoshikado, T., Shoda, J., Suzuki, H
  • Journal Title: Gastroenterology Volume: 140 Pages: 1664-1674
  • Peer Reviewed
• [Journal Article] 梅肉エキスとがん予防 (2011)
  • Author(s): 宇都宮洋才、稲田健一
  • Journal Title: Functional food Volume: 14 Pages: 368-373
  • Peer Reviewed
• [Journal Article] NPC2 regulates biliary cholesterol secretion via stimulation of ABCG5/G8- (2011)
  • Author(s): Yamanashi Y, Shoda J, et al
  • Journal Title: Gastroenterology Volume: 140 Pages: 1644-74
  • Peer Reviewed
• [Journal Article] Biliary NPC2 regulates biliary cholesterol secretion via stimulation of (2011)
  • Author(s): Yamanashi, Y., et al.
  • Journal Title: Gastroenterology Volume: (In press)
  • Peer Reviewed
• [Journal Article] Proton beam therapy for large hepatocellular carcinoma (2010)
  • Author(s): Sugahara, S., Oshiro, Y., Nakayama, H., Fukuda, K., Mizumoto, M., Abei, M., Shoda, J., Matsuzaki, Y., Tohno, E., Tokita, M., Tsuboi, K., Tokuue, K
  • Journal Title: Int J Radiat Oncol Biol Phys Volume: 76 Pages: 460-466
  • NAID: 120007138229
  • Peer Reviewed
• [Journal Article] Deletion of nuclear factor-E2-related factor-2 leads to rapid onset and progression of nutritional steatohepatitis in mice (2010)
  • Author(s): Sugimoto, H., Okada, K., Shoda, J., Warabi, E., Ishige, K., Ueda, T., Taguchi, K., Yanagawa, T., Nakahara, A., Hyodo, I., Ishii, T., Yamamoto, M
  • Journal Title: Am J Physiol Volume: 298 Pages: 283-294
  • Peer Reviewed
• [Journal Article] S-1化学療法が奏効し根治手術が可能となったStage IVb進行胆嚢癌の1例 (2010)
  • Author(s): 長谷川直之, 安倍井誠人, 佐々木亮孝, 朴秀吉, 森脇俊和, 南優子, 福田邦明, 平井祥子, 正田純一, 大河内信弘, 兵頭一之介
  • Journal Title: 胆道学会誌 Volume: 24 Pages: 723-728
  • NAID: 10030361628
  • Peer Reviewed
• [Journal Article] WFA-positive sialylated MUC1 is a high-sensitivity biliary marker for intrahepatic cholangiocarcinoma (2010)
  • Author(s): Matsuda, A., Kuno, A., Kawamoto, K., Matsuzaki, H., Irimura, T., Ikehara, Y., Zen, Y., Nakanuma, Y., Yamamoto, M., Ohkohchi, N., Shoda, J., Hirabayashi, J., Narimatsu, H
  • Journal Title: Hepatology Volume: 52 Pages: 174-182
  • Peer Reviewed
• [Journal Article] Deletion of Nuclear Factor-E2-Related Factor-2 Leads to Rapid Onset (2010)
  • Author(s): Sugimoto, H., et al.
  • Journal Title: Am J Physiol Volume: 298 Pages: 283-294
  • Peer Reviewed
• [Journal Article] WFA-Positive Sialylated MUCI is a High-Sensitivity Biliary Marker for (2010)
  • Author(s): Matsuda, A., et al.
  • Journal Title: Hepatology Volume: 52 Pages: 174-182
  • Peer Reviewed
• [Journal Article] Deletion of nuclear factor-E2-related factor-2 leads to rapid onset and progression of nutritional steatohepatitis in mice (2010)
  • Author(s): Sugimoto H, et al.
  • Journal Title: American Journal of Physiology 298 Pages: 283-294
  • Peer Reviewed
• [Journal Article] Acarbose, an α-glucosidase inhibitor, prevents obesity and hepatic steatosis in SQSTM1/A170/p62-deficient mice (2009)
  • Author(s): Okada, K., Yanagawa, T., Warabi, E., Yamastu, K., Uwayama, J., Takeda, K., Utsunomiya, H., Yoshida, H., Shoda, J., Ishii, T
  • Journal Title: Hepatology Res Volume: 39 Pages: 490-500
  • Peer Reviewed
• [Journal Article] Strategy for glycoproteomics : identification of glyco-alteration using multiple glycan profiling tools (2009)
  • Author(s): Ito, H., Kuno, A., Sawaki, H., Sogabe, M., Ozaki, H., Tanaka, Y., Mizogami, M., Shoda, J., Angata, T., Sato, T., Hirabayashi, J., Ikehara, Y., Narimatsu, H
  • Journal Title: J Proteome Res Volume: 8 Pages: 1358-67
  • Peer Reviewed
• [Journal Article] Proton beam therapy for hepatocellular carcinoma : the University of Tsukuba Experience (2009)
  • Author(s): Nakayama, H., Sugahara, S., Tokita, M., Fukuda, K., Mizumoto, M., Abei, M., Shoda, J., Sakurai, H., Tsuboi, K., Tokuuye, K
  • Journal Title: Cancer Volume: 115 Pages: 5499-5506
  • Peer Reviewed
• [Journal Article] 重症肝炎における劇症化予知式に基づいた早期抗ウイルス・抗免疫療法の有効性の検証.特集:急性肝不全における内科治療と肝移植の進歩 (2009)
  • Author(s): 安倍井誠人, 福田邦明, 正田純一, 兵頭一之介
  • Journal Title: 日本腹部救急医学会雑誌 Volume: 29 Pages: 597-600
  • Peer Reviewed
• [Journal Article] Proton beam therapy for hepatocellular carcinoma associated with portal vein tumor thrombosis (2009)
  • Author(s): Sugahara, S., Nakayama, H., Fukuda, K., Mizumoto, M., Tokita, M., Abei, M., Shoda, J., Matsuzaki, Y., Thono, E., Tsuboi, K., Tokuuye, K
  • Journal Title: Strahlenther Onkol Volume: 185 Pages: 782-788
  • Peer Reviewed
• [Journal Article] Co-operative thermal inactivation of herpes simplex virus and influenza virus by arginine and NaCl (2009)
  • Author(s): Utsunomiya H, Ichinose M, Tsujimoto K, Katsuyama Y, Yamasaki H, Koyama AH, Ejima D, Arakawa T
  • Journal Title: Int J Pharm Volume: 21(366) Pages: 99-102
  • Peer Reviewed
• [Journal Article] Nrf2 counteracts cholestatic liver injury via stimulation of hepatic defense systems (2009)
  • Author(s): Okada, K., Shoda, J., Taguchi, K., Maher, J. M., Ishizaki, K., Inoue, Y., Ohtsuki, M., Goto, N., Sugimoto, H., Utsunomiya, H., Oda, K., Warabi, E., Ishii, T., Yamamoto, M
  • Journal Title: Biochem Biophys Res Commun Volume: 389 Pages: 431-436
  • Peer Reviewed
• [Journal Article] Choleretic effect of Inchikoto on the cholestatic livers of patients with biliary obstruction due to biliary tract carcinoma : A randomized controlled study (2009)
  • Author(s): Watanabe, S., Yokoyama, Y., Oda, K., Kokuryo, T., Shoda, J., Okada, K., Utsunomiya, H., Nagino, M
  • Journal Title: Hepatology Res Volume: 39 Pages: 247-255
  • Peer Reviewed
• [Journal Article] A prospective study of hypofractionated proton beam therapy for patients with hepatocellular carcinoma (2009)
  • Author(s): Fukumitsu, N., Sugahara, S., Nakayama, H., Fukuda, K., Mizumoto, M., Abei, M., Shoda, J., Thono, E., Tsuboi, K., Tokuuye, K
  • Journal Title: Int J Radiat Oncol Biol Phys Volume: 74 Pages: 831-836
  • Peer Reviewed
• [Presentation] 転写因子Nrf2は動脈硬化+高脂肪食誘発脂肪性肝炎の脂肪酸代謝修飾による (2011)
  • Author(s): 岡田浩介, 蕨栄治, 正田純一
  • Organizer: 第15回日本肝臓学会大会
  • Place of Presentation: 福岡
  • Year and Date: 2011-10-12
• [Presentation] インチンコウ湯は転写因子Nrf2を活性化し,生体の抗酸化ストレス応答機構を賦活化する (2011)
  • Author(s): 岡田浩介, 正田純一, 山本雅浩
  • Organizer: 第97回日本消化器病学会総会
  • Place of Presentation: 東京
• [Presentation] 糖鎖プロファイリング解析による肝内胆管癌の新規糖蛋白質マーカーの開発 (2011)
  • Author(s): 正田純一, 川本徹, 中沼安二, 山本雅一, 大河内信弘, 松田厚志, 久野敦, 池原譲, 平林淳, 成松久
  • Organizer: 第47回日本肝臓総会
  • Place of Presentation: 東京
• [Presentation] 動脈硬化+高脂肪食誘発肝炎における転写因子Nrf2の役割 (2011)
  • Author(s): 岡田浩介, 杉本浩一, 正田純一, 堀江正樹, 蕨栄治, 後藤直宏, 石井哲郎, 山本雅之
  • Organizer: 第47回日本肝臓学会総会
  • Place of Presentation: 東京
• [Presentation] Sulforaphen(SFN)による転写因子Nrf2賦活化はメチオニンコリン欠乏食(MCD)誘発脂肪性肝炎の炎症と線維化を抑止する (2011)
  • Author(s): 岡田浩介, 正田純一, 徳重克年
  • Organizer: 第15回日本肝臓学会大会
  • Place of Presentation: 福岡
• [Presentation] 転写因子Nrf2は動脈硬化+高脂肪食誘発脂肪性肝炎の脂肪酸代謝修飾による肝脂肪蓄積を抑止し,肝病変の発症と進展を防御する (2011)
  • Author(s): 岡田浩介, 蕨栄治, 正田純一
  • Organizer: 第15回日本肝臓学会大会
  • Place of Presentation: 福岡
• [Presentation] 胆管がん診断へ向けた新たなコンビネーション診断系の確立 (2011)
  • Author(s): 松田厚志、久野敦、松崎英樹、川本徹、鹿内俊秀、中沼安二、山本雅一、大河内信弘、池原譲、正田純一、平林淳、成松久
  • Organizer: 第31回日本分子腫瘍マーカー研究会
• [Presentation] 動脈硬化+高脂肪食誘発脂肪性肝炎における転写因子Nrf2の役割 (2010)
  • Author(s): 杉本浩一, 他
  • Organizer: 日本肝臓学会大会
  • Place of Presentation: 横浜
  • Year and Date: 2010-10-13
• [Presentation] 胆嚢発癌とその癌進展に果たすアラキドン酸代謝活性化の役割: Cyclooxygenase-2(COX-2),プロスタグランジンE合成酵素(PGES),プロスタグランジンE受容体(EP)の発現に着目して (2010)
  • Author(s): 川本徹, 山本雅一, 正田純一
  • Organizer: 第14回日本肝臓学会大会
  • Place of Presentation: 横浜
• [Presentation] 動脈硬化+高脂肪食誘発脂肪性肝炎における転写因子Nrf2の役割 (2010)
  • Author(s): 杉本浩一, 岡田浩介, 正田純一, 蕨栄治, 石井哲郎, 山本雅之
  • Organizer: 第14回肝臓学会大会
  • Place of Presentation: 横浜
• [Presentation] 糖鎖プロファイリング解析による肝内胆管癌の新規糖蛋白質マーカーの開発 (2010)
  • Author(s): 正田純一, 平林淳, 成松久
  • Organizer: 第96回日本消化器病学会総会
  • Place of Presentation: 新潟
• [Presentation] Deletion of nuclear factor-E2-related factor-2 leads to rapid onset and progression of nutritional steatohepatitis in mice (2010)
  • Author(s): Okada K, Sugimoto H, Shoda J, Warabi E, Ishige K, Ueda T, Taguchi K, Yanagawa T, Nakahara A, Hyodo I, Ishii T, Yamamoto M
  • Organizer: The 2nd International Forum
  • Place of Presentation: Niigata, Japan
• [Presentation] Deletion of nuclear factor-E2-related factor-2 leads to rapid onset and progression of nutritional steatohepatitis in mice fed atherogenic plus high-fat diet (2010)
  • Author(s): Okada K, Sugimoto H, Warabi E, Gotoh N, Takahashi H, Utsunomiya H, Ishii T, Yamamoto M, Shoda J
  • Organizer: The 8th JSH Single Topic Conference
• [Presentation] インチンコウ湯は肝Mrp2/MRP2の発現増加と毛細胆管膜への集積により胆汁酸非依存性の胆汁分泌を誘発する (2009)
  • Author(s): 岡田浩介, 正田純一, 山本雅浩
  • Organizer: 第95回消化器病学会総会
  • Place of Presentation: 札幌
• [Presentation] 転写因子Nrf2はコリンメチオニン欠乏食(MCDD)誘発非アルコール性脂肪性肝炎(NASH)を防御する (2009)
  • Author(s): 杉本浩一, 岡田浩介, 正田純一, 蕨栄治, 石井哲郎, 山本雅之
  • Organizer: 第13回肝臓学会大会
  • Place of Presentation: 京都
• [Book] Gallbladder Cancer-Pathogenesis and Molecular Targeting Strategies for Therapeutic Options.(Gallbladder Cancer, Christopher V Aiello) (2012)
  • Author(s): Shoda, J, Kawamoto T, Yamamoto, M
  • Publisher: NOVA Science Publishers(In press)
• [Book] 胆石症・胆道炎・胆道がん胆石症概念・定義と疫学 (2011)
  • Author(s): 正田純一
  • Publisher: 最新医学社(大阪)
• [Book] 胆石症・胆道炎・胆道がん (2011)
  • Author(s): 正田純一
  • Publisher: 最新医学社
• [Book] 胆道癌発生の分子機序 Annual Review消化器2011 (2011)
  • Author(s): 正田純一
  • Publisher: 中外医学社(東京)
• [Book] 胆道癌発生の分子機序Annual Review(消化器2011) (2010)
  • Author(s): 正田純一
  • Publisher: 中外医学社(東京)
• [Book] 胆道感染症 (2010)
  • Author(s): 正田純一
  • Publisher: 南江堂(東京)
• [Book] 原発性硬化性胆管炎内科学書第7版Vol.4肝・胆道・膵疾患 (2009)
  • Author(s): 正田純一
  • Publisher: 中山書店(東京)
• [Book] 胆道の炎症内科学書第7版Vol.4肝・胆道・膵疾患疾患 (2009)
  • Author(s): 正田純一
  • Publisher: 中山書店(東京)
• [Book] 胆石症診療ガイドライン(疫学・病態) (2009)
  • Author(s): 正田純一
  • Publisher: 南江堂(東京)