Establishment of new therapy for chronic liver diseases progression

• Project/Area Number: 23590986
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Nara Medical University
• Principal Investigator: YOSHIJI Hitoshi 奈良県立医科大学, 医学部, 准教授 (40336855)
• Co-Investigator(Kenkyū-buntansha): NOGUCHI Ryuuichi 奈良県立医科大学, 医学部, 助教 (30423908)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 肝硬変 / 肝癌 / 血管新生 / 慢性肝疾患 / カクテル療法

Research Abstract

During the period of this grant, we revealed many new findings about the usefulness of the combined cocktail therapy of clinical available agents in patients with chronic liver diseases. Even at clinical comparable low doses of these agents, we observed significant inhibitory effects on the liver fibrosis development, hepatocarcinogenesis, and the growth of hepatocellular carcinoma (HCC). We mainly focused on renin-angiotensin system (RAS) in the chronic liver diseases, and found that angiotensin-II (AT-II), aldosterone (Ald), and renin play important roles in the respective processes. Several different combination cocktail treatments also exerted marked inhibitory effects even at clinically comparable low doses. Furthermore, not only in the animal studies, but also we revealed clinical usefulness with these agents.
Collectively, our studies with this grant could contribute to the improvement of prognosis in patients with chronic liver diseases.

Research Products

• [Journal Article] Cross talk between toll-like receptor-4 signaling and angiotensin-IIin liver fibrosis development in the rat model of non-alcoholic steatohepatitis (2013)
  • Author(s): Shirai Y, Yoshiji H, Noguchi R, Kaji K, Aihara Y, Douhara A, Moriya K, Namisaki T, Kawaratani H, Fukui H
  • Journal Title: J Gastroenterol Hepatol Volume: 28(4) Pages: 723-30
• [Journal Article] Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2(VEGFR2) induces synergistic anti-tumour effect in vivo (2013)
  • Author(s): Yasuda S, Sho M, Yamato H, Yoshiji H, Wakatsuki K, Nishiwada S, Yagita H, Nakajima Y
  • Journal Title: Clnical and Exprtimental Immunology Volume: 172 Pages: 500-506
• [Journal Article] Direct renin inhibitor, aliskiren, attenuates the progression of non-alcoholic steatohepatitis in the rat model. (2013)
  • Author(s): Aihara Y, Yoshiji H et al
  • Journal Title: Hepatol Res. Volume: 43 Issue: 11 Pages: 1241-1250
  • DOI: 10.1111/hepr.12081
  • Peer Reviewed
• [Journal Article] Branched-chain amino acids suppress the cumulative recurrence of hepatocellular carcinoma under conditions of insulin-resistance (2013)
  • Author(s): Yoshiji H, Noguchi R, Namisaki T, Moriya K, Kitade M, Aihara Y, Douhara A, Yamao J, Fujimoto M, Toyohara M, Mitoro A, Sawai M, Yoshida M, Morioka C, Uejima M, Uemura M, Fukui H
  • Journal Title: Oncology Reports Volume: 30 Pages: 545-552
• [Journal Article] Dual blockade of angiotensin-IIand aldosterone suppresses the progression of a non-diabetic rat model of steatohepatitis (2013)
  • Author(s): Noguchi R, Yoshiji H, Ikenaka Y, Kaji K, Aihara Y, Shirai Y, Namisaki T, Kitade M, Douhara A, Moriya K, Fukui H
  • Journal Title: Hepatology Research Volume: 43(7) Pages: 765-774
• [Journal Article] High hemoglobin level predicts non-alcoholic fatty liver disease in japanese women (2013)
  • Author(s): Akahane T, Fukui K, Shirai Y, Yoshiji H, Uemura M, Fukui H
  • Journal Title: Journal of Gastroenterology and Hepatology Research Volume: 2(6 Pages: 623-627
• [Journal Article] Dual blockade of angiotensin-IIand aldosterone suppresses the progression of a non-diabetic rat model of steatohepatitis (2013)
  • Author(s): Noguchi R, Yoshiji H et al
  • Journal Title: Hepatology Research Volume: 43 Issue: 7 Pages: 765-774
  • DOI: 10.1111/hepr.12008
  • Peer Reviewed
• [Journal Article] Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats (2013)
  • Author(s): Kaji K, Yoshiji H et al
  • Journal Title: J Gastroenterol. Volume: 49 Issue: 3 Pages: 481-491
  • DOI: 10.1007/s00535-013-0783-4
  • Peer Reviewed
• [Journal Article] Direct renin inhibitor, aliskiren, attenuates the progression of non-alcoholic steatohepatitis in the rat model. (2013)
  • Author(s): Aihara Y, Yoshiji H, et al.
  • Journal Title: Hepatol Res. Volume: Jan 29
  • Peer Reviewed
• [Journal Article] Possible involvement of angiogenesis in chronic liver diseases : Interaction among renin-angiotensin-aldosterone system, Insulin resistance and oxidative stress (2012)
  • Author(s): Yoshiji H, Ikenaka Y, Noguchi R, Aihara Y, Shirai Y, Douhara A, Fukui H, Kaji K
  • Journal Title: Current Medicinal Chemistry Volume: 19(12) Pages: 1889-1898
• [Journal Article] Combination of branched-chain amino acid and angiotensin-converting enzyme inhibitor improves liver fibrosis progression in patients with cirrhosis (2012)
  • Author(s): Yoshiji H, Noguchi R, Ikenaka Y, Kaji K, Aihara Y, Douhara A, Yamao J, Toyohara M, Mitoro A, Sawai M, Yoshida M, Morioka C, Fujimoto M, Uemura M, Fukui H
  • Journal Title: Molecular Medicine Reports Volume: 5 Pages: 539-544
• [Journal Article] Combination of branched-chain amino acid and angiotensin-converting enzyme inhibitor improves liver fibrosis progression in patients with cirrhosis. (2012)
  • Author(s): Yoshiji H, et al.
  • Journal Title: Molecular Medicine Reports Volume: 5 Pages: 539-544
  • Peer Reviewed
• [Journal Article] Dual blockade of angiotensin-II and aldosterone suppresses the progression of a non-diabetic rat model of steatohepatitis. (2012)
  • Author(s): Noguchi R, Yoshiji H, et al.
  • Journal Title: Hepatol Res. Volume: Nov 20
  • Peer Reviewed
• [Journal Article] Combination of branched-chain amino acid and angiotensin-converting enzyme inhibitor improves liver fibrosis progression in patients with cirrhosis. (2012)
  • Author(s): Yoshiji H, et al
  • Journal Title: Mol Med Report Volume: 5 Pages: 539-544
  • DOI: 10.3892/mmr.2011.676
  • Peer Reviewed
• [Journal Article] Impact of Renin-angiotensin system in hepatocellular carcinoma (2011)
  • Author(s): Yoshiji H, Noguchi R, Ikenaka Y, Kaji K, Aihara Y, Fukui H
  • Journal Title: Current Cancer Drug Targets Volume: 11(4) Pages: 431-441
• [Journal Article] Cocktail therapy with a combination of interferon, ribavirin and angiotensin-IItype 1 receptor blocker attenuates murine liver fibrosis development (2011)
  • Author(s): Yoshiji H, Noguchi R, Ikenaka Y, Kaji K, Aihara Y, Shirai Y, Yoshiji H, Yanase K, Fukui H
  • Journal Title: International Journal of Molecular Medicine Volume: 28 Pages: 81-88
• [Journal Article] Combination treatment of angiotensinIItypeIreceptor blocker and new oral iron chelator attenuates progression of nonalcoholic steatohepatitis in rats (2011)
  • Author(s): Kaji K, Yoshiji H, Kitade M, Ikenaka Y, Noguchi R, Shirai Y, Aihara Y, Namisaki T, Yoshii J, Yanase K, Tsujimoto T, Kawaratani H, Fukui H
  • Journal Title: Am J Physiol Gastrointest Liver Physiol Volume: 300 Pages: 1094-1104
• [Journal Article] Therapeutic effects of cytokine modulator Y-40138 in the rat alcoholic liver disease model (2011)
  • Author(s): Kawaratani H, Tsujimoto T, Kitazawa T, Yoshiji H, Uemura M, Fukui H
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: 26 Pages: 775-783
• [Journal Article] Rapid detection of spotaneous bacterial peritonitis by granulocyte elastase latex immunoassay and reagent strip (2011)
  • Author(s): Yamazaki M, Sano R, Kuramoto C, Yoshiji H, Uemura M, Fukui H, Kamiya M, Okamoto Y
  • Journal Title: Rinsho Byori Volume: 59(6) Pages: 549-558
• [Journal Article] Combination of branched-chain amino acids and angiotensin-converting enzyme inhibitor suppresses the cumulative recurrence of hepatocellular carcinoma : A randomized control trial (2011)
  • Author(s): Yoshiji H, Noguchi R, Ikenaka Y, Kaji K, Aihara Y, Shirai Y, Yoshiji H, Yanase K, Fukui H
  • Journal Title: Oncology Reports Volume: 26 Pages: 1547-1553
• [Journal Article] Soluble VEGF receptor-2 may be a predictive marker of anti-angiogenic therapy with clinically available safe agents (2011)
  • Author(s): Yoshiji H, Noguchi R, Ikenaka Y, Kaji K, Shirai Y, Aihara Y, Yamao J, Toyohara M, Mitoro A, Sawai M, Yoshida M, Morioka C, Fujimoto M, Uemura M, Kawaratani H, Tsujimoto T, Fukui H
  • Journal Title: Oncology Letters Volume: 2 Pages: 69-73
• [Journal Article] Cocktail therapy with a combination of interferon, ribavirin and angiotensin-II type 1 receptor blocker attenuates murine liver fibrosis development. (2011)
  • Author(s): Yoshiji H, et al
  • Journal Title: Int J Mol Med Volume: 28 Pages: 81-88
  • DOI: 10.3892/ijmm.2011.658
  • Peer Reviewed
• [Journal Article] Combination of branched-chain amino acids and angiotensin-converting enzyme inhibitor suppresses the cumulative recurrence of hepatocellular carcinoma: a randomized control trial. (2011)
  • Author(s): Yoshiji H, et al
  • Journal Title: Oncol Rep Volume: 26 Pages: 1547-1553
  • DOI: 10.3892/or.2011.1433
• [Presentation] Distinct role of EGFR and Met on adult hepatic progenitor cell differentiation in mice (2013)
  • Author(s): Kitade M, Yoshiji H, Snorri Thorgeirsson, Fukui H
  • Organizer: Annual Meeting of the Japanese Society for the Research of Hepatic Cells
  • Place of Presentation: Osaka
  • Year and Date: 2013-09-26
• [Presentation] Beneficial effects of combined treatment with ursodoxycholic acid (UDCA) and Angiotensin-IItype1 receptor blocker(ARB) on liver fibrosis development in the rat model of nonalcoholic steatohepatitis (2013)
  • Author(s): Namisaki T, Yoshiji H, Noguchi R, Moriya K, Kitade M, Aihara Y, Douhara A, Kawaratani H, Nishimura N, Fukui H
  • Organizer: Annual Meeting of the Japanese Society for the Research of Hepatic Cells
  • Place of Presentation: Osaka
  • Year and Date: 2013-09-26
• [Presentation] Combination of angiotensin-converting enzyme inhibitor and selective aldosterone blocker, suppresses the liver fibrosis carcinogenesis of nonalcoholic steatohepatitis in the rat (2013)
  • Author(s): Noguchi R, Yoshiji H, Namisaki T, Moriya K, Kitade M, Aihara Y, Douhara A, Kawaratani H, Nishimura N, Fukui H
  • Organizer: International Society for Hepatic Sinusoidal Research
  • Place of Presentation: Osaka
  • Year and Date: 2013-09-24
• [Presentation] Combined treatment of sorafenib and angiotensin-IIreceptor blocker attenuates preneoplastic lesion development of non-alcoholic steatohepatitis in rats (2013)
  • Author(s): Yoshiji H, Noguchi,R, Namisaki T. Moriya K, Kitade M, Aihara Y, Douhara A, Kawaratani H, Nishimura N, Fukui H
  • Organizer: International Society for Hepatic Sinusoidal Research
  • Place of Presentation: Osaka
  • Year and Date: 2013-09-24
• [Presentation] Inhibition of endotoxin cascade with antibiotics attenuates the liver fibrosis development in rat model of nonalcoholic steatohepatitis (2013)
  • Author(s): Douhara A, Moriya K, Yoshiji H, Noguchi R, Namisaki T, Kitade M, Aihara Y, Kawaratani H, Nishimura N, Fukui H
  • Organizer: International Society for Hepatic Sinusoidal Research
  • Place of Presentation: Osaka
  • Year and Date: 2013-09-24
• [Presentation] VEGF-targeted cancer therapy : Friends of Foes (2013)
  • Author(s): Yoshiji H
  • Organizer: National Cancer Institute Special Seminar 2013
  • Place of Presentation: Washington, DC.
  • Year and Date: 2013-04-10
• [Presentation] Response-guided anti-angiogenic therapy for hepatocellular carcinoma recurrence with clinically available safety agent (2013)
  • Author(s): Yoshiji H, Noguchi R, Kaji K, Aihara Y, Namisaki T, Moriya K, Douhara A, Kitade M, Fukui H
  • Organizer: AACR Annual Meeting 2013
  • Place of Presentation: Washington, DC.
  • Year and Date: 2013-04-10
• [Presentation] Direct renin inhibitor attenuates rat hepatocarcinogenesisi via anti-angiogenic activity (2013)
  • Author(s): Aihara Y, Yoshiji H, Noguchi R, Kaji K, Namisaki T, Moriya K, Kitade M, Fukui H
  • Organizer: AACR Annual Meeting 2013
  • Place of Presentation: Washington, DC.
  • Year and Date: 2013-04-10
• [Presentation] Response-guided anti-angiogenic therapy for hepatocellular carcinoma recurrence with clinically available safety agent (2013)
  • Author(s): Yoshiji H et al
  • Organizer: AACR Annual Meeting 2013
  • Place of Presentation: Washington, DC, USA
• [Presentation] インターフェロン，リバビリン，Angiotensin-II受容体阻害薬（ARB)の３剤併用による肝線維化抑制効果：抗血管新生作用との関連 (2013)
  • Author(s): 吉治仁志他
  • Organizer: 日本消化器病学会総会
  • Place of Presentation: 鹿児島
• [Presentation] NASH肝発癌に対するソラフェニブとangiotensin-II受容体阻害薬（ARB)の併用効果 (2013)
  • Author(s): 吉治仁志他
  • Organizer: 日本肝臓学会総会
  • Place of Presentation: 東京
• [Presentation] Chemoprevention of HCV-associated HCC by BCAA and ACE-inhibitor (2012)
  • Author(s): Yoshiji H
  • Organizer: JSH Single Topic Conference
  • Place of Presentation: Tokyo
  • Year and Date: 2012-11-22
• [Presentation] Douhara A, Aihara Y, Yamao J, Mitoro A, Fukui H. Efficacy of combination therapy with peg-interferon alpha and ribavirin in elderly chronic hepatitis C (2012)
  • Author(s): Moriya K, Yoshiji H, Noguchi R, Namisaki T, Kaji K
  • Organizer: JSH Single Topic Conference
  • Place of Presentation: Tokyo
  • Year and Date: 2012-11-21
• [Presentation] Crosstalk between glucose intolerance and liver fibrosis development in patients with chronic hepatitis C (2012)
  • Author(s): Aihara Y, Yoshiji H, Noguchi R, Namisaki T, Moriya K, Kaji K, Douhara A, Fukui H
  • Organizer: JSH Single Topic Conference
  • Place of Presentation: Tokyo
  • Year and Date: 2012-11-21
• [Presentation] Effect of sorafenib on HCV-related hepatocellular carcinoma (HCC) (2012)
  • Author(s): Douhara A, Moriya K, Yoshiji H, Noguchi R, Namisaki T, Kaji K, Aihara Y, Yamao J, Mitoro A, Fukui H
  • Organizer: JSH Single Topic Conference
  • Place of Presentation: Tokyo
  • Year and Date: 2012-11-21
• [Presentation] Sorafenibとangiotensin-II受容体阻害薬 (ARB)併用による肝発癌抑制 (2012)
  • Author(s): 吉治仁志
  • Organizer: 日本肝臓学会
  • Place of Presentation: 神戸国際会議場
• [Presentation] Inhibitory effect of selective aldosterone blocker on hepatocellular carcinoma development via angiogenesis suppression (2011)
  • Author(s): Kaji K, Yoshiji H, Ikenaka Y, Noguchi R, Fukui H
  • Organizer: ILCA
  • Place of Presentation: Hong-Kong
  • Year and Date: 2011-09-03
• [Presentation] Combination of branched-amino acids and angiotensin-converting enzyme inhibitor attenuates the insulin resistance -based hepatocarcinogenesis via angiogenesis suppression (2011)
  • Author(s): Aihara Y, Yoshiji H, Ikenaka Y, Noguchi R, Kaji K, Fukui H
  • Organizer: ILCA
  • Place of Presentation: Hong-Kong
  • Year and Date: 2011-09-03
• [Presentation] Soluble VEGF receptor-2 may be a predictive marker of anti-angiogenic chemopreventive therapy with clinically available safe agents (2011)
  • Author(s): Yoshiji H, Ikenaka Y, Noguchi R, Kaji K, Aihara Y, Fukui H
  • Organizer: ILCA
  • Place of Presentation: Hong-Kong
  • Year and Date: 2011-09-03
• [Presentation] Clinically available selective aldosterone blocker attenuates hepatocarcinogenesis via angiogenesis inhibition in rats (2011)
  • Author(s): Noguchi R, Yoshiji H, Ikenaka Y, Aihara Y, Fukui H
  • Organizer: ILCA
  • Place of Presentation: Hong-Kong
  • Year and Date: 2011-09-03
• [Presentation] Combination of branched-amino acids and angiotensin-converting enzyme inhibitor attenuates the insulin resintance-based hepatocarcinogenesis via angiogenesis suppression (2011)
  • Author(s): Aihara Y, Yoshiji H, Ikenaka Y, Noguchi R, Kaji K, Fukui H
  • Organizer: ASIA-PACIFIC PRIMARY LIVER CANCER EXPERT MEETING
  • Place of Presentation: Osaka
  • Year and Date: 2011-07-03
• [Presentation] Inhibitory effect of selective aldosterone blocker on hepatocellular carcinoma development via angiogenesis suppression (2011)
  • Author(s): Kaji K, Yoshiji H, Ikenaka Y, Noguchi R, Aihara Y, Fukui H
  • Organizer: ASIA-PACIFIC PRIMARY LIVER CANCER EXPERT MEETING
  • Place of Presentation: Osaka
  • Year and Date: 2011-07-03
• [Presentation] Clinically available selective aldosterone blocker attenuates hepatocarcinogenesis via angiogenesis inhibition in rats (2011)
  • Author(s): Noguchi R, Yoshiji H, Ikenaka Y, Kaji K, Shirai Y, Fukui H
  • Organizer: ASIA-PACIFIC PRIMARY LIVER CANCER EXPERT MEETING
  • Place of Presentation: Osaka
  • Year and Date: 2011-07-03
• [Presentation] Combination of branched-chain amino acid and angiotensin-converting enzyme inhibitor suppresses the cumulative recurrence of hepatocellular carcinoma under the condition of insulin resistance (2011)
  • Author(s): Yoshiji H, Ikenaka Y, Noguchi R, Kaji K, Aihara Y, Fukui H
  • Organizer: ASIA-PACIFIC PRIMARY LIVER CANCER EXPERT MEETING
  • Place of Presentation: Osaka
  • Year and Date: 2011-07-03
• [Presentation] 肝線維化に対する血管新生因子VEGFおよびインスリンをターゲットとした分子標的治療 (2011)
  • Author(s): 吉治仁志
  • Organizer: 日本肝臓学会
  • Place of Presentation: 福岡国際センター
• [Book] 肝硬変合併症の治療 耐糖能異常の病態と治療 (2013)
  • Author(s): 吉治仁志他
  • Total Pages: 3
  • Publisher: 医学書院
• [Book] 医学のあゆみ (2013)
  • Author(s): 吉治仁志他
  • Total Pages: 6
  • Publisher: 医歯薬出版株式会社