Macrophage specific delivery of TNF-a inhibits NASH liver injury.

• Project/Area Number: 26460992
• 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, 大学院医学薬学研究部(医学), 准教授 (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): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 非アルコール性脂肪肝炎 / マクロファージ / ドラッグデリバリー / NASH / クッパー細胞 / siRNA / 核酸医薬 / 拡散医薬

Outline of Final Research Achievements

Macrophages play important roles in liver injury and fibrosis during the progression of non-alcoholic steatohepatitis (NASH). In this study we try to establish effective delivery system into macrophages, and elucidate whether TNF-α siRNA complexed with schizophyllan (TNFα-SPG) inhibit liver inflammation and fibrosis in murine NASH models. We confirmed siRNA complexed with SPG can be specifically delivered into macrophage. In addition, TNFα-SPG successfully ameliorate inflammation, fibrosis, apoptosis, and ROS production in murine NASH model. Our result demonstrated a possible new therapeutic approach on macrophages by administration of siRNA-SPG for treatment of NASH.

Research Products

• [Journal Article] High-pressure carbon monoxide preserves rat kidney grafts from apoptosis and inflammation. (2017)
  • Author(s): Abe T, Yazawa K, Fujino M, Imamura R, Hatayama N, Kakuta Y, Tsutahara K, Okumi M, Ichimaru, Kaimori J, Isaka Y, Seki K, Takahara S, Li Xiao K*, Nonomura. N
  • Journal Title: Lab Invest Volume: 97 Pages: 468-477
  • Peer Reviewed
• [Journal Article] 5-Aminolevulinic acid combined with ferrous iron ameliorate ischemia-reperfusion injury in the mouse fatty liver model. (2016)
  • Author(s): Li S, Takahara T, Li XK, Fujino M, Sugiyama T, Tsukada K, Liu C, Kakuta Y, Nonomura N, Ito H, Takahashi K, Nakajima M, Tanaka T, Takahara S.
  • Journal Title: Biochem Biophys Res Commun Volume: 470 Issue: 4 Pages: 900-6
  • DOI: 10.1016/j.bbrc.2016.01.136
  • Peer Reviewed / Open Access
• [Journal Article] Neutrophil-to-lymphocyte ratio predicts recurrence after radiofrequency ablation in hepatitis B virus infection. (2016)
  • Author(s): Tajiri K, Baba H, Kawai K, Minemura M, Yasumura S, Takahara T, Sugiyama T.
  • Journal Title: J Gastroenterol Hepatol Volume: 31 Issue: 7 Pages: 1291-1299
  • DOI: 10.1111/jgh.13287
  • Peer Reviewed
• [Journal Article] 5-Aminolevulinic acid with sodium ferrous citrate induces autophagy and protects cardiomyocytes from hypoxia-induced cellular injury through MAPK-Nrf-2-HO-1 signaling cascade. (2016)
  • Author(s): Zhao M, Zhu P, Fujino M, Nishio Y, Chen J, Ito H, Takahashi K, Nakajima M, Tanaka T, Zhao L, Zhuang J, Li Xiao K
  • Journal Title: Biochem Biophys Res Commun Volume: 479 Issue: 4 Pages: 663-669
  • DOI: 10.1016/j.bbrc.2016.09.156
  • Peer Reviewed
• [Journal Article] Functional evaluation of rat hearts transplanted after preservation in a high-pressure gaseous mixture of carbon monoxide and oxygen. (2016)
  • Author(s): Hatayama N, Inubushi M, Naito M, Hirai S, Jin YN, Tsuji AB, Seki K, Itoh M, Saga T, Li XK.．
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 32120-32120
  • DOI: 10.1038/srep32120
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] MicroRNAs involved in acute rejection and tolerance in murine cardiac allografts. (2016)
  • Author(s): Fujino M, Zhu P, Cai S, Nishio Y, Zhuang J, Li Xiao K
  • Journal Title: Exp Clin Transplant Volume: 14 Pages: 424-30
  • DOI: 10.2147/ott.s99401
  • Peer Reviewed / Open Access
• [Journal Article] Impaired CD98 signaling protects against graft-versus-host disease by increasing regulatory T cells. (2016)
  • Author(s): Nishio Y, Fujino M, Cai S, Kitajima Y, Saito T, Tsumura H, Ito M, Ito Y, Nagahara Y, Li Xiao K
  • Journal Title: Transpl Immunol Volume: 35 Pages: 34-9
  • DOI: 10.1016/j.trim.2016.01.005
  • Peer Reviewed
• [Journal Article] Prolonged Mouse Cardiac Graft Cold Storage via Attenuating Ischemia-Reperfusion Injury Using a New Antioxidant-Based Preservation Solution. (2016)
  • Author(s): Cai S, Ichimaru N, Zhao M, Fujino M, Ito H, Ota U, Nakajima M, Tanaka T, Nonomura N, Li XK, Takahara S.
  • Journal Title: Transplantation Volume: 100 Issue: 5 Pages: 1032-40
  • DOI: 10.1097/tp.0000000000001079
  • Peer Reviewed / Open Access
• [Journal Article] Luminal injection of hydrogen-rich solution attenuates intestine ischemia-reperfusion injury in rats (2015)
  • Author(s): Shigeta T, Sakamoto S, Li Xiao K, Cai SJ, Liu C, Kurokawa R, Nakazawa A, Kasahara M, Uemoto S.
  • Journal Title: Transplantation Volume: 99(3) Issue: 3 Pages: 500-7
  • DOI: 10.1097/tp.0000000000000510
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Permanent acceptance of mouse cardiac allografts with CD40 siRNA to induce regulatory myeloid cells by use of a novel polysaccharide siRNA delivery system (2015)
  • Author(s): Zhang Q, Ichimaru N, Higuchi S, Cai SJ, Hou JG, Fujino M, Nonomura N, Kobayashi M, Ando H, Uno A, Sakurai K, Mochizuki S, Adachi Y, Ohno N, Zou HJ, Xu JH, Li Xiao K*. Takahara S
  • Journal Title: Gene Ther Volume: 22(3) Issue: 3 Pages: 1-10
  • DOI: 10.1038/gt.2014.119
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 5-aminolevulinic acid combined with sodium ferrous citrate ameliorates H2O2-induced cardiomyocyte hypertrophy via activation of the MAPK/Nrf2/HO-1 pathway. (2015)
  • Author(s): Zhao M, Guo H, Chen J, Fujino M, Ito H, Takahashi K, Abe F, Nakajima M, Tanaka T, Wang J, Huang H, Zheng S, Hei M, Li J, Huang S, Li J, Ma X, Chen Y, Zhao L, Zhuang J, Zhu P, Li XK.
  • Journal Title: Am J Physiol Cell Physiol. Volume: 308 Issue: 8 Pages: C665-C672
  • DOI: 10.1152/ajpcell.00369.2014
  • Peer Reviewed / Open Access
• [Journal Article] Dihydroquercetin (DHQ) ameliorated concanavalin A-induced mouse experimental fulminant hepatitis and enhanced HO-1 expression through MAPK/Nrf2 antioxidant pathway in RAW cells. (2015)
  • Author(s): Zhao M, Guo H, Chen J, Fujino M, Ito H, Takahashi K, Abe F, Nakajima M, Tanaka T, Wang J, Huang H, Zheng S, Hei M, Li J, Huang S, Li J, Ma X, Chen Y, Zhao L, Zhuang J, Zhu P, Li XK
  • Journal Title: Int Immunopharmacol. Volume: Oct;28(2) Issue: 2 Pages: 938-44
  • DOI: 10.1016/j.intimp.2015.04.032
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Noninvasive monitoring of mouse renal allograft rejection using micro-CT. (2015)
  • Author(s): Hou J, Fujino M, Cai S, Ding Q, Li XK
  • Journal Title: Int Surg Volume: 88 Issue: 5 Pages: 276-80
  • DOI: 10.4174/astr.2015.88.5.276
  • Peer Reviewed / Open Access
• [Journal Article] Noninvasive Monitoring and Evaluation of the Renal Structure and Function in a Mouse Model of Unilateral Ureteral Occlusion Using Microcomputed Tomography. (2015)
  • Author(s): Hou J, Fujino M, Cai S, Ding Q, Li XK.
  • Journal Title: Int Surg. Volume: 100 Issue: 7-8 Pages: 1237-43
  • DOI: 10.9738/intsurg-d-14-00273.1
  • Peer Reviewed / Open Access
• [Journal Article] Influence of sirolimus-induced TGF-β secretion on mouse Treg cell proliferation. (2015)
  • Author(s): Li JN, Li JX, Huang HL, Zhu XL, Ding H, Huang CF, Lin J, Huang JG, Wu ZC, Ashraf M, Wang YG, Li XK, Zheng SY, Chen JM, Guo HM, Zhuang J, Zhu P.
  • Journal Title: Genet Mol Res Volume: 14 Issue: 4 Pages: 18569-79
  • DOI: 10.4238/2015.december.28.4
  • Peer Reviewed / Open Access
• [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NASH 治療の試み (2017)
  • Author(s): 高原照美、李少偉、李小康
  • Organizer: 第53回日本肝臓学会総会
  • Place of Presentation: 広島
  • Year and Date: 2017-06-08
• [Presentation] Macrophage specific delivery of TNF-a siRNA complexed with schizophyllan inhibits fatty-induced inflammation and fibrosis in a murine NASH model. (2016)
  • Author(s): Li S, Takahara T, Fujino M, Higuchi S, Ando H, Li XL
  • Organizer: 第 30 回肝類洞壁細胞研究会
  • Place of Presentation: 富山
  • Year and Date: 2016-11-25
• [Presentation] Efficacies of Astaxanthin treatment on Ischemia-Reperfusion Injury in Fatty Liver Model of Mice. (2016)
  • Author(s): Li S, Takahara T, Fujino M, Liu C, Li XL
  • Organizer: 第 48 回日本臨床分子形態学会総会
  • Place of Presentation: 熊本
  • Year and Date: 2016-09-23
• [Presentation] Efficacies of Astaxanthin treatment on Ischemia-Reperfusion Injury in Fatty Liver Model of Mice. (2016)
  • Author(s): Li S, Takahara T, Fujino M, Tsukada K, Liu C, Li XL
  • Organizer: 第 52 回日本肝臓学会総会
  • Place of Presentation: 千葉
  • Year and Date: 2016-05-19
• [Presentation] Effects of astaxanthin pretreatment on ischemia-reperfusion injury in fatty liver model of mice. (2015)
  • Author(s): 5．SW Li, T Takahara, M Fujino, K Tsukada, C Liu, XK Li
  • Organizer: 第29回肝類洞壁細胞研究会
  • Place of Presentation: 秋田
  • Year and Date: 2015-10-31
• [Presentation] 水素水はNASH肝障害を軽減する (2015)
  • Author(s): 高原照美、李 少偉、河合健吾、杉山敏郎、塚田一博
  • Organizer: 第47回日本臨床分子形態学会総会
  • Place of Presentation: 長崎
  • Year and Date: 2015-09-18
• [Presentation] NASH肝障害における水素水投与の有効性とその機序 (2015)
  • Author(s): 高原照美、李 少偉、河合健吾、杉山敏郎、塚田一博、李 小康
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: 熊本
  • Year and Date: 2015-05-21 – 2015-05-22
• [Presentation] 5-アミノレブリン酸は一酸化炭素を誘導してNASHモデルの虚血再潅流障害を軽減する (2015)
  • Author(s): 李 少偉、高原照美、河合健吾、杉山敏郎、塚田一博、田中徹、李 小康
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: 熊本
  • Year and Date: 2015-05-21
• [Presentation] NASH肝障害における水素水の有効性とその作用機序 (2015)
  • Author(s): 3．高原照美、李 少偉、河合健吾、杉山敏郎、塚田一博、李小康
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: 熊本
  • Year and Date: 2015-05-21
• [Presentation] 5-アミノレブリン酸は一酸化炭素を誘導してNASH モデルの虚血再潅流障害を軽減する (2014)
  • Author(s): 李 少偉、高原照美、杉山敏郎、塚田一博、田中 徹、李 小康
  • Organizer: 第２８回肝類洞壁細胞研究会
  • Place of Presentation: 岡山
  • Year and Date: 2014-12-13 – 2014-12-14
• [Presentation] 5-aminolevulinic acid combined with ferrous iron protects from ischemia-reperfusion injury in mouse steatotic liver model by inducing carbon monoxide generation. (2014)
  • Author(s): S. Li, T. Takahara, T. Sugiyama, K. Tsukada, T. Tanaka, XK Li.
  • Organizer: American Association for the Study of Liver Disease 2014
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-09 – 2014-11-11
• [Presentation] Metron factor-1 トランスジェニックマウスにおける肝組織修復作用の検討 (2014)
  • Author(s): 高原照美、河合健吾、羅 小雨、李 少偉、杉山敏郎、塚田一博、李 小康
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 2014-05-29 – 2014-05-30