Development of therapeutic method to suppress liver disease progression by drug repositioning

• Project/Area Number: 17K09438
• 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, 教授 (40336855)
• Co-Investigator(Kenkyū-buntansha): 鍛治 孝祐 奈良県立医科大学, 医学部, 学内講師 (20623490) ; 北出 光輝 奈良県立医科大学, 医学部, 研究員 (40526795)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 肝硬変 / 肝線維化 / エンドトキシン / 腸内細菌 / 肝癌 / 新規マーカー / ヒアルロン酸ミセル / アンジオテンシン受容体阻害薬 / 肝臓学

Outline of Final Research Achievements

In this research, we were able to obtain results close to the original goals for each application item. A drug delivery system using hyaluronan micelles is established in this study. Significant results have also been obtained in the subject of studies on intestinal bacteria and liver fibrosis. In patients with liver cirrhosis, changes in permeability-related markers were parallel to changes in endogenous endotoxin, and it was possible to clarify the involvement of endogenous endotoxin due to increased intestinal permeability. Furthermore, we have obtained great results from a new perspective regarding the search for new biomarkers. In this study, we found that VWF and ADAMTS13 in patients with chronic liver disease could be useful biomarkers for various diagnosis.

Academic Significance and Societal Importance of the Research Achievements

本研究は未だ治療法が確率されていない慢性肝疾患の終末像である肝硬変にたいして多面的アプローチによる病態の解明、新規治療法への基礎的知見、特に腸肝相関に注目した内因性エンドトキシンの役割について明らかにすると共に各種血清マーカーが肝疾患における様々な病態に有用であることを明らかにしており、慢性肝疾患患者の予後改善に大きく寄与し得る成果を獲得できた。

Research Products

• [Journal Article] Gut dysbiosis associated with clinical prognosis of patients with primary biliary cholangitis. (2020)
  • Author(s): Furukawa M, Moriya K, Nakayama J, Inoue T, Momoda R, Kawaratani H, Namisaki T, Sato S, Douhara A, Kaji K, Kitade M, Shimozato N, Sawada Y, Saikawa S, Takaya H, Kitagawa K, Akahane T, Mitoro A, Yamao J, Tanaka Y, Yoshiji H.
  • Journal Title: Hepatol Res. Volume: 4 Issue: 7 Pages: 840-852
  • DOI: 10.1111/hepr.13509
  • Peer Reviewed
• [Journal Article] Rifaximin Alleviates Endotoxemia with Decreased Serum Levels of Soluble CD163 and Mannose Receptor and Partial Modification of Gut Microbiota in Cirrhotic Patients. (2020)
  • Author(s): Kaji K, Saikawa S, Takaya H, Fujinaga Y, Furukawa M, Kitagawa K, Ozutsumi T, Kaya D, Tsuji Y, Sawada Y, Kawaratani H, Moriya K, Namisaki T, Akahane T, Mitoro A, Yoshiji H.
  • Journal Title: Antibiotics (Basel) Volume: 9 Issue: 4 Pages: 145-145
  • DOI: 10.3390/antibiotics9040145
  • Peer Reviewed
• [Journal Article] Combining probiotics and an angiotensin-II type 1 receptor blocker has beneficial effects on hepatic fibrogenesis in a rat model of non-alcoholic steatohepatitis. (2019)
  • Author(s): Sawada Y, Kawaratani H, Kubo T, Fujinaga Y, Furukawa M, Saikawa S, Sato S, Seki K, Takaya H, Okura Y, Kaji K, Shimozato N, Mashitani T, Kitade M, Moriya K, Namisaki T, Akahane T, Mitoro A, Yamao J, Yoshiji H.
  • Journal Title: Hepatol Res. Volume: 49 Issue: 3 Pages: 404-418
  • DOI: 10.1111/hepr.13281
  • Peer Reviewed
• [Journal Article] TGR5 Activation Modulates an Inhibitory Effect on Liver Fibrosis Development Mediated by Anagliptin in Diabetic Rats (2019)
  • Author(s): Kaya Daisuke、Kaji Kosuke、Tsuji Yuki、Yamashita Satoko、Kitagawa Koh、Ozutsumi Takahiro、Fujinaga Yukihisa、Takaya Hiroaki、Kawaratani Hideto、Moriya Kei、Namisaki Tadashi、Akahane Takemi、Yoshiji Hitoshi
  • Journal Title: Cells Volume: 8 Issue: 10 Pages: 1153-1153
  • DOI: 10.3390/cells8101153
  • Peer Reviewed
• [Journal Article] Late-Evening Snack with Branched-Chain Amino Acid-Enriched Nutrients Does Not Always Inhibit Overt Diabetes in Patients with Cirrhosis: A Pilot Study. (2019)
  • Author(s): Nakanishi K, Namisaki T, Mashitani T, Kaji K, Ozaki K, Saikawa S, Sato S, Inoue T, Sawada Y, Kitagawa K, Takaya H, Shimozato N, Kawaratani H, Moriya K, Akahane T, Mitoro A, Yoshiji H.
  • Journal Title: Nutrients. Volume: 7 Issue: 9 Pages: 2140-2140
  • DOI: 10.3390/nu11092140
• [Journal Article] Oral administration of fructose exacerbates liver fibrosis and hepatocarcinogenesis via increased intestinal permeability in a rat steatohepatitis model (2018)
  • Author(s): Seki K, Kitade M, Nishimura N, Kaji K, Asada K, Namisaki T, Moriya K, Kawaratani H, Okura Y, Takaya H, Sawada Y, Sato S, Nakanishi K, Yoshiji H.
  • Journal Title: Oncotarget. Volume: 9 Issue: 47 Pages: 28638-51
  • DOI: 10.18632/oncotarget.25587
  • Peer Reviewed
• [Journal Article] Angiotensin receptor blockade attenuates cholangiocarcinoma cell growth by inhibiting the oncogenic activity of Yes-associated protein. (2018)
  • Author(s): Saikawa S, Kaji K, Nishimura N, Seki K, Sato S, Nakanishi K, Kitagawa K, Kawaratani H, Kitade M, Moriya K, Namisaki T, Mitoro A, Yoshiji H.
  • Journal Title: Cancer Letters Volume: 434 Pages: 120-129
  • DOI: 10.1016/j.canlet.2018.07.021
  • Peer Reviewed
• [Journal Article] Acyclic retinoid and angiotensin-II receptor blocker exert a combined protective effect against diethylnitrosamine-induced hepatocarcinogenesis in diabetic OLETF rats. (2018)
  • Author(s): Nishimura N, Kaji K, Kitade M, Aihara Y, Sato S, Seki K, Sawada Y, Takaya H, Okura Y, Kawaratani H, Moriya K, Namisaki T, Mitoro A, Yoshiji H
  • Journal Title: BMC Cancer. Volume: 18 Issue: 1 Pages: 164-171
  • DOI: 10.1186/s12885-018-5099-6
  • Peer Reviewed
• [Journal Article] von Willebrand factor is a useful biomarker for liver fibrosis and prediction of hepatocellular carcinoma development in patients with hepatitis B and C. (2018)
  • Author(s): Takaya H, Kawaratani H, Tsuji Y, Nakanishi K, Saikawa S, Sato S, Sawada Y, Kaji K, Okura Y, Shimozato N, Kitade M, Akahane T, Moriya K, Namisaki T, Mitoro A, Matsumoto M, Fukui H, Yoshiji H
  • Journal Title: United European Gastroenterol J. Volume: 6 Issue: 9 Pages: 1401-1409
  • DOI: 10.1177/2050640618779660
  • Peer Reviewed
• [Journal Article] Sodium glucose cotransporter 2 inhibitor canagliflozin attenuates liver cancer cell growth and angiogenic activity by inhibiting glucose uptake. (2018)
  • Author(s): Kaji K, Nishimura N, Seki K, Sato S, Saikawa S, Nakanishi K, Furukawa M, Kawaratani H, Kitade M, Moriya K, Namisaki T, Yoshiji H.
  • Journal Title: International Journal of Cancer Volume: 142 Issue: 8 Pages: 17121722-17121722
  • DOI: 10.1002/ijc.31193
  • Peer Reviewed
• [Journal Article] Rifaximin ameliorates hepatic encephalopathy and endotoxemia without affecting the gut microbiome diversity. (2017)
  • Author(s): Kaji K, Takaya H, Saikawa S, Furukawa M, Sato S, Kawaratani H, Kitade M, Moriya K, Namisaki T, Akahane T, Mitoro A, Yoshiji H.
  • Journal Title: World J Gastroenterol. Volume: 23 Issue: 47 Pages: 83358366-83358366
  • DOI: 10.3748/wjg.v23.i47.8355
  • Peer Reviewed
• [Journal Article] Effect of combined farnesoid X receptor agonist and angiotensin Ⅱtipe 1 receptor blocker on hepatic fibrosis. (2017)
  • Author(s): Namisaki T. Moriya K, Kitade M, Takeda K, Kaji K, Okura Y, Shimozato N. Sato S, Nishimura N, Seki K, Kawaratani H, Takaya H, Sawada Y, Akahane T, Saikawa S, Nakanishi K, Kubo T, Furukawa M, Noguchi R, Asada K, Kitagawa K, Ozutsumi T, Tsuji Y, Kaya H Yoshiji
  • Journal Title: Hepatol commun. Volume: 1 Issue: 9 Pages: 928945-928945
  • DOI: 10.1002/hep4.1104
  • Peer Reviewed / Open Access
• [Presentation] Rifaximin ameliorates hepatic encephalopathy and endotoxemia without affecting the gut microbiome diversity (2019)
  • Author(s): Takaya H, Kaji K, Saikawa S, Furukawa M, Sato S, Sawada Y, Kawaratani H, Kitade M, Moriya K, Namisaki T, Akahane T, Mitoro A, Yoshiji H
  • Organizer: EASL
  • Int'l Joint Research
• [Presentation] Exogenous administration of low-dose lipopolysaccharide potentiates the development of liver fibrosis in a choline-deficient L-amino-acide-defined diet-induced murine steatohepatitis model (2019)
  • Author(s): Nakanishi K, Kaya D, Tsuji Y, Saikawa S, Kaji K, Akahane T, Namisaki T, Yoshiji H
  • Organizer: AASLD
  • Int'l Joint Research
• [Presentation] Effect of ARB and Rifaximin combination therapy on hepatic fibrosis in nonalcoholic steatohepatitis model rats (2019)
  • Author(s): Fujinaga Y, Kawaratani H, Namisaki T, Moriya K, kaji K, Takaya H, Sawada Y, Akahane T, Sato S, Shimozato N, Saikawa S, Nakanishi K, Kubo T, Furukawa M, Yoshiji H
  • Organizer: AASLD
  • Int'l Joint Research
• [Presentation] Combined treatment with anti-diabetic agents:dipeptidyl peptidase-4 inhibitor(DPP4-1) and sodiumglucose co-transporter-2 inhibitor(SGLT2-1) suppresses progression in nash rat model (2019)
  • Author(s): Namisaki T, Ozutsumi T, Kaji K, Shimozato N, Saikawa S, Takaya H, Nakanishi K, Tsuji Y, Sawada Y, Furukawa M, Fujinaga Y, Kaya D, Kawaratani H, Akahane T, Yoshiji H
  • Organizer: AASLD
  • Int'l Joint Research
• [Presentation] The potential effect of combination therapies with a farnesoid X receptor(FXR)agonist on hepatic fibrogenesis in rat nash model (2019)
  • Author(s): Shimozato N, Namisaki T, Kaji K, Takaya H, Saikawa S, Sawada Y, Nakanishi K, Furukawa M, Fujinaga Y, Kaya D, Tsuji Y, Kawaratani H, Akahane T, Yoshiji H
  • Organizer: AASLD
  • Int'l Joint Research
• [Presentation] Rifaximin ameliorates hepatic encephalopathy and endotoxemia without affecting the gut microbiome diversity (2018)
  • Author(s): Takaya H, Kaji K, Saikawa S, Furukawa M, Sato S, Sawada Y, Kawaratani H, Kitade M, Moriya K, Namisaki T, Akahane T, Mitoro A, Yoshiji H
  • Organizer: EASL
  • Int'l Joint Research
• [Presentation] Moderate alcohol consumption protects against fatty liver in males (2018)
  • Author(s): Akahane T, Namisaki T, Kitade M, Kaji K, Takaya H, Shimozato N, Sato S, Yoshiji H
  • Organizer: EASL
  • Int'l Joint Research
• [Presentation] Ratio of Von Willebrand Factor to ADAMTS13 is a Novel Potential Biomarker for Early Diagnosis of HCC (2018)
  • Author(s): Takaya H, Namisaki T, Kitade M, Kaji K, Shimozato N, Akahane T, Moriya K, Kawaratani H, Sawada Y, Seki K, Sato S, Nakanishi K, Yoshiji H
  • Organizer: APASL
  • Int'l Joint Research
• [Presentation] Rifaximin alleviates endotoxemia with improvement of intestinal hyperpermeability and minor changes in fecal microbiota in cirrohotic patients with hepatic encephalopathy (2018)
  • Author(s): Kaji K, Saikawa S, Takaya H, Sato S, Kitade M, Moriya K, Namisaki T, Akahane T, Yoshiji H
  • Organizer: AASLD
  • Int'l Joint Research
• [Presentation] Identification of von willebrand factor-to-ADAMTS13 ratio as a potential biomarker for early detection of hepatocellular carcinoma in patients with liver cirrhosis (2018)
  • Author(s): Takaya H, Namisaki T, Kaji K, Kitade M, Tsuji Y, Fujinaga Y, Furukawa M, Nakanishi K, Seki K, Sato S, Sawada Y, Saikawa S, Shimozato N, Kawaratani H, Asada K, Moriya K, Akahane T, Yoshiji H
  • Organizer: AASLD
  • Int'l Joint Research
• [Presentation] Beneficial effects of combined farnesoid X receptor agonist(INT747) and dipeptidyl peptidase-4 inhibitor(sitagliptin) on hepatic fibrogenesis in a rat model of nonalcoholic steatohepatitis (2017)
  • Author(s): Shimozato N, Namisaki T, Moriya K, Kitade M, Takeda K, Kawaratani H, Kaji K, Okura Y, Takaya H, Sawada Y, Nishimura N, Sato S, Saikawa S, Seki K, Furukawa M, Nakanishi K, Kubo T, Yoshiji H
  • Organizer: AASLD
  • Int'l Joint Research
• [Presentation] ADAMTS13 deficiency exacerbates acute liver failure with enhanced VWF accumulation and hepatic inflammation in mice. (2017)
  • Author(s): Takaya H, Kaji K, Kitade M, Seki K, Saikawa S, Nishimura N, Sato S, Sawada Y, Okura Y, Kawaratani H, Akahane T, Moriya K, Namisaki T, Mitoro A, Yoshiji H
  • Organizer: AASLD
  • Int'l Joint Research
• [Book] 今日の診断指針 第８版 (2019)
  • Author(s): 吉治仁志
  • Total Pages: 11
  • Publisher: 医学書院
• [Book] The Evolving Landscape of Liver Cirrhosis Management (2019)
  • Author(s): Kawaratani H, Yoshiji H
  • Total Pages: 10
  • Publisher: Springer
  • ISBN: 9789811376634