Establishment of antibody drug on non-alcoholic steatohepatitis through Met signaling.

• Project/Area Number: 17K09411
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: University of Toyama
• Principal Investigator: Takahara Terumi 富山大学, 医学部, 教授 (60240777)
• Co-Investigator(Kenkyū-buntansha): 梨井 康 国立研究開発法人国立成育医療研究センター, 移植免疫研究室, 室長 (60321890)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: HGF / Met / 抗体医薬 / NASH / 再生医療 / 肝再生

Outline of Final Research Achievements

HGF receptor Met makes a hybrid with insulin receptor and acts as a regulator for insulin sensitivity in the liver. The present study tried to establish new antibody drug therapy for NASH using Met-activating antibody. Treatment with Met-activating antibody on STAM mice (NASH model) did not show the significant decreased blood sugar or fatty liver, compared with control. However, treatment with Met-activating antibody on hepatectomized cirrhotic liver showed significant recovery of fibrosis, inflammation and regeneration and this effects continuedfor long period. Met-activating antibody can be used as an antibody drug for organ regeneration.

Academic Significance and Societal Importance of the Research Achievements

dbdbマウスではMet作動性抗体を投与したところ血糖値、脂肪肝の改善を認めることからMet 作動性抗体はNASH治療に有効と考えられる。一方で肝硬変の肝切除モデルでは抗体投与群で著明な線維化・炎症の改善、肝再生の促進を認め、その効果は長く持続した。Met作動性抗体は抗体医薬としての安定性を示し、HGFが持つ多彩な作用を考えると、NASHのみならず幅広い組織修復・再生療法に有効である。

Research Products

• [Int'l Joint Research] University of Turin(イタリア)
• [Journal Article] Anatomy of the coronary arteries in fetal pigs: comparison with human anatomy. (2020)
  • Author(s): Dai Y, Yi K, Shimada K, Ren K, Wang Z, Terayama H, Li Xiao K, Yi SQ.
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  • DOI: 10.1007/s12565-019-00516-z
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Hydrogen Gas Attenuates Hypoxic-Ischemic Brain Injury via Regulation of the MAPK/HO-1/PGC-1a Pathway in Neonatal Rats (2020)
  • Author(s): Wang Peipei、Zhao Mingyi、Chen Zhiheng、Wu Guojiao、Fujino Masayuki、Zhang Chen、Zhou Wenjuan、Zhao Mengwen、Hirano Shin-ichi、Li Xiao-Kang、Zhao Lingling
  • Journal Title: Oxidative Medicine and Cellular Longevity Volume: 2020 Pages: 1-16
  • DOI: 10.1155/2020/6978784
  • Peer Reviewed
• [Journal Article] Immunomodulatory effects of Salvianolic acid B in a spontaneous abortion mouse model (2020)
  • Author(s): Wang Jing、Liu Chi、Que Weitao、Fujino Masayuki、Tong Guoqing、Yan Hua、Li Xiao-Kang
  • Journal Title: Journal of Reproductive Immunology Volume: 137 Pages: 103075-103075
  • DOI: 10.1016/j.jri.2019.103075
  • Peer Reviewed
• [Journal Article] Efficacy of on-demand intrahepatic arterial therapy in combination with sorafenib for advanced hepatocellular carcinoma. (2019)
  • Author(s): Tajiri K, Futsukaichi Y, Kobayashi S, Nagata K, Yasumura S, Takahara T, Minemura M, Yasuda I.
  • Journal Title: Onco Targets Ther. Volume: 12 Pages: 2205-2214
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• [Journal Article] Combined hepatocellular-cholangiocarcinoma successfully treated with sorafenib: case report and review of the literature. (2019)
  • Author(s): Futsukaichi Y, Tajiri K, Kobayashi S, Nagata K, Yasumura S, Takahara T, Minemura M, Yasuda I.
  • Journal Title: Clin J Gastroenterol. Volume: 12 Issue: 2 Pages: 128-134
  • DOI: 10.1007/s12328-018-0918-5
  • Peer Reviewed
• [Journal Article] Protective role of heme oxygenase-1 in fatty liver ischemia-reperfusion injury. (2019)
  • Author(s): Li S, Fujino M, Takahara T, Li XK
  • Journal Title: Med Mol Morphol Volume: 印刷中 Issue: 2 Pages: 61-72
  • DOI: 10.1007/s00795-018-0205-z
  • Peer Reviewed / Open Access
• [Journal Article] 5‐ALA/SFC enhances HO‐1 expression through the MAPK/Nrf2 antioxidant pathway and attenuates murine tubular epithelial cell apoptosis (2019)
  • Author(s): Liu Chi、Fujino Masayuki、Zhu Shuoji、Isaka Yoshitaka、Ito Hidenori、Takahashi Kiwamu、Nakajima Motowo、Tanaka Tohru、Zhu Ping、Li Xiao‐Kang
  • Journal Title: FEBS Open Bio Volume: 9 Issue: 11 Pages: 1928-1938
  • DOI: 10.1002/2211-5463.12729
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 5‐ALA/SFC Attenuated Binge Alcohol-Induced Gut Leakiness and Inflammatory Liver Disease in HIV Transgenic Rats (2019)
  • Author(s): Liu Chi、Zhu Ping、Fujino Masayuki、Zhu Shuoji、Ito Hidenori、Takahashi Kiwamu、Nakajima Motowo、Tanaka Tohru、Zhuang Jian、Li Xiao‐Kang
  • Journal Title: Alcoholism: Clinical and Experimental Research Volume: 43 Issue: 8 Pages: 1651-1661
  • DOI: 10.1111/acer.14117
  • Peer Reviewed
• [Journal Article] Novel Molecular Targets Participating in Myocardial Ischemia-Reperfusion Injury and Cardioprotection (2019)
  • Author(s): Liu Nan-Bo、Wu Min、Chen Chen、Fujino Masayuki、Huang Jing-Song、Zhu Ping、Li Xiao-Kang
  • Journal Title: Cardiology Research and Practice Volume: 2019 Pages: 1-16
  • DOI: 10.1155/2019/6935147
  • Peer Reviewed
• [Journal Article] Stem Cells as a Resource for Treatment of Infertility-related Diseases (2019)
  • Author(s): Wang Jing、Liu Chi、Fujino Masayuki、Tong Guoqing、Zhang Qinxiu、Li Xiao-Kang、Yan Hua
  • Journal Title: Current Molecular Medicine Volume: 19 Issue: 8 Pages: 539-546
  • DOI: 10.2174/1566524019666190709172636
  • Peer Reviewed
• [Journal Article] Hydrogen inhalation protects hypoxic-ischemic brain damage by attenuating inflammation and apoptosis in neonatal rats (2019)
  • Author(s): Wu Guojiao、Chen Zhiheng、Wang Peipei、Zhao Mingyi、Fujino Masayuki、Zhang Chen、Zhou Wenjuan、Hirano Shin-Ichi、Li Xiao-Kang、Zhao Lingling
  • Journal Title: Experimental Biology and Medicine Volume: 244 Issue: 12 Pages: 1017-1027
  • DOI: 10.1177/1535370219855399
• [Journal Article] Salvianolic acid B ameliorates liver injury in a murine aGvHD model by decreasing inflammatory responses via upregulation of HO-1 (2019)
  • Author(s): Zhao Jing、Yang Xing-Chen、Fujino Masayuki、Ichimaru Naotsugu、Que Weitao、Li Xiao-Kang、Takahara Shiro
  • Journal Title: Transplant Immunology Volume: 55 Pages: 101203-101203
  • DOI: 10.1016/j.trim.2019.03.002
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Liver transplantation: New treatment for mucopolysaccharidosis type VI in rats. (2019)
  • Author(s): Toyama S, Migita O, Fujino M, Kunieda T, Kosuga M, Fukuhara Y, Nagahara Y, Li XK, Okuyama T.
  • Journal Title: Pediatr Int Volume: 261 Issue: 2 Pages: 180-189
  • DOI: 10.1111/ped.13751
  • Peer Reviewed / Open Access
• [Journal Article] Hydrogen-rich solution attenuates cold ischemia-reperfusion injury in rat liver transplantation. (2019)
  • Author(s): Uto K, Sakamoto S, Que W, Shimata K, Hashimoto S, Sakisaka M, Narita Y, Yoshii D, Zhong L, Komohara Y, Li XK, Inomata Y, Hibi T
  • Journal Title: BMC Gastroenterol Volume: 19 Issue: 1 Pages: 25-25
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  • Peer Reviewed / Open Access
• [Journal Article] 5-aminolaevulinic acid (ALA), enhances heme oxygenase (HO)-1 expression and attenuates tubulointerstitial fibrosis and renal apoptosis in chronic cyclosporine nephropathy. (2019)
  • Author(s): Liu C, Zhu P, Fujino M, Isaka Y, Ito H, Takahashi K, Nakajima M, Tanaka T, Zhuang J, Li XK
  • Journal Title: Biochem Biophys Res Commun Volume: 508 Issue: 2 Pages: 583-589
  • DOI: 10.1016/j.bbrc.2018.11.175
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] L-Carnitine for the Treatment of Overt Hepatic Encephalopathy in Patients with Advanced Liver Cirrhosis (2018)
  • Author(s): Tajiri K, Futsukaichi Y, Kobayashi S, Yasumura S, Takahara T, Minemura M, Sugiyama T.
  • Journal Title: Journal of Nutritional Science and Vitaminology Volume: 64 Issue: 5 Pages: 321-328
  • DOI: 10.3177/jnsv.64.321
  • NAID: 130007501959
  • ISSN: 0301-4800, 1881-7742
  • Year and Date: 2018-10-31
  • Peer Reviewed / Open Access
• [Journal Article] Administration of dendritic cells and anti-pd-1 antibody converts x-ray irradiated tumors into effective in situ vaccines (2018)
  • Author(s): Wang Y, Zenkoh J, Gerelchuluun A, Sun L, Cai S, Li X, Tsuboi K
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  • DOI: 10.1016/j.ijrobp.2018.11.019
  • Peer Reviewed / Open Access
• [Journal Article] Survival Benefit of Tolvaptan for Refractory Ascites in Patients with Advanced Cirrhosis. (2018)
  • Author(s): Tajiri K, Tokimitsu Y, Ito H, Atarashi Y, Kawai K, Minemura M, Yasumura S, Takahara T, Shimizu Y, Sugiyama T.
  • Journal Title: Dig Dis Volume: 36 Issue: 4 Pages: 314-321
  • DOI: 10.1159/000489258
  • Peer Reviewed / Open Access
• [Journal Article] Combination of 5-aminolevulinic acid and iron prevents skin fibrosis in murine sclerodermatous graft-versus-host disease. (2018)
  • Author(s): Liu C, Yang X, Zhu P, Fujino M, Ito H, Takahashi K, Nakajima M, Tanaka T, Wang J, Zhuang J, Zou H, Li XK.
  • Journal Title: Exp Dermatol. Volume: 10 Issue: 10 Pages: 1104-1111
  • DOI: 10.1111/exd.13730
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular hydrogen protects against ischemia-reperfusion injury in a mouse fatty liver model via regulating HO-1 and Sirt1 expression. (2018)
  • Author(s): Li S, Fujino M, Ichimaru N, Kurokawa R, Hirano S, Mou L, Takahara S, Takahara T, Li XK.
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 14019-14019
  • DOI: 10.1038/s41598-018-32411-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Oral administration of 5-aminolevulinic acid induces heme oxygenase-1 expression in peripheral blood mononuclear cells of healthy human subjects in combination with ferrous iron. (2018)
  • Author(s): Ito H, Nishio Y, Hara T, Sugihara H, Tanaka T, Li XK.
  • Journal Title: Eur J Pharmacol Volume: 833 Pages: 25-33
  • DOI: 10.1016/j.ejphar.2018.05.009
  • Peer Reviewed / Open Access
• [Journal Article] Preservation of rat limbs by hyperbaric carbon monoxide and oxygen. (2018)
  • Author(s): Hatayama N, Hirai S, Naito M, Terayama H, Araki J, Yokota H, Matsushita M, Li XK, Itoh M.
  • Journal Title: Sci Rep Volume: 8 Pages: 6627-6627
  • Peer Reviewed / Open Access
• [Journal Article] Induced pluripotent stem cells-derived myeloid-derived suppressor cells regulate the CD8 + T cell response (2018)
  • Author(s): Joyce Daniel、Fujino Masayuki、Morita Miwa、Araki Ryoko、Fung John、Qian Shiguang、Lu Lina、Li Xiao-Kang
  • Journal Title: Stem Cell Research Volume: 29 Pages: 32-41
  • DOI: 10.1016/j.scr.2018.03.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Astaxanthin prevents ischemia-reperfusion injury of the steatotic liver in mice (2017)
  • Author(s): Li Shaowei、Takahara Terumi、Fujino Masayuki、Fukuhara Yasuyuki、Sugiyama Toshiro、Li Xiao-Kang、Takahara Shiro
  • Journal Title: PLOS ONE Volume: 12 Issue: 11 Pages: 1-16
  • DOI: 10.1371/journal.pone.0187810
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] iPSC-Derived Regulatory Dendritic Cells Inhibit Allograft Rejection by?Generating Alloantigen-Specific Regulatory T Cells (2017)
  • Author(s): Cai Songjie、Hou Jiangang、Fujino Masayuki、Zhang Qi、Ichimaru Naotsugu、Takahara Shiro、Araki Ryoko、Lu Lina、Chen Ji-Mei、Zhuang Jian、Zhu Ping、Li Xiao-Kang
  • Journal Title: Stem Cell Reports Volume: 8 Issue: 5 Pages: 1174-1189
  • DOI: 10.1016/j.stemcr.2017.03.020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Macrophage specific delivery of TNF-α siRNA inhibits inflammation and fibrosis by regulating macrophage polarization in murine NASH models (2018)
  • Author(s): Takahara T, Li S, Fujino M, Higuchi S, Ando H, Li XK
  • Organizer: The 69th Annuial Meeting of the American Association for the Study of Liver Diseases
  • Int'l Joint Research
• [Presentation] マクロファージ特異的ドラッグデリバリーシステムを用いたTNF-a siRNA はNASHモデルのM1/M2比を変化させる (2018)
  • Author(s): 高原照美、李 少偉、李小康
  • Organizer: 第54回日本肝臓学会総会
• [Presentation] Macrophage specific delivery of TNF-α siRNA complexed with schizophyllan inhibits inflammation and fibrosis in a murine NASH model. (2017)
  • Author(s): Terumi Takahara, Shaowei Li, Masayuki Fujino, Sadaharu Higuchi, Hironori Ando, Xiao-Kang Li.
  • Organizer: The 68th Annuial Meeting of the American Association for thr Study of Liver Diseases
  • Int'l Joint Research
• [Book] Diagnosis of Liver Disease, (2019)
  • Author(s): Terumi Takahara, Masaki Iwai, Wilson M S Tsui
  • Total Pages: 304
  • Publisher: Ｓｐｒｉｎｇｅｒ
  • ISBN: 9789811368059