Search for the target molecule of the licorice component inhibiting NLRP3 inflammasome and development into drug discovery research

• Project/Area Number: 15K07960
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Toyama Prefectural Institute. for Pharmaceutical Research.
• Principal Investigator: HONDA Hiroe 富山県薬事研究所, 主任研究員 (10463134)
• Co-Investigator(Renkei-kenkyūsha): NAGAI Yoshinori 富山大学, 大学院医学薬学研究部(医学), 客員教授 (30431761)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: NLRP3 / IL-1β / 糖尿病 / イソリクイリチゲニン / NLRP3インフラマソーム / 慢性炎症 / インフラマソーム

Outline of Final Research Achievements

Isoliquiritigenin(ILG) , one of the licorice components, suppressed visceral adipose tissue inflammation and fibrosis in high-fat diet (HFD)-fed model mice of type 2 diabetes. As a result of in-vitro analysis, ILG suppressed the expression of fibrosis-related genes induced by Mincle and TLR4 in macrophages.
We also demonstrated that the administration of ILG to db/db mice improves insulin resistance and glucose tolerance test. In db/db mice, ILG did not suppress the chronic inflammation of visceral adipose tissue unlike HFD-fed mice, and improved the pancreatic damage state.
In addition, we identified several candidate target proteins of ILG inhibiting the NLRP3 inflammasome activation by the DARTS method.

Research Products

• [Journal Article] Funiculosin variants and phosphorylated derivatives promote innate immune responses via the Toll-like receptor 4/myeloid differentiation factor-2 complex (2017)
  • Author(s): Okamoto N, Mizote K, Honda H, Saeki A, Watanabe Y, Yamaguchi-Miyamoto T, Fukui R, Tanimura N, Motoi Y, Akashi-Takamura S, Kato T, Fujishita S, Kimura T, Ohto U, Shimizu T, Hirokawa T, Miyake K, Fukase K, Fujimoto Y, Nagai Y, Takatsu K
  • Journal Title: Journal of Biological Chemistry Volume: 292 Issue: 37 Pages: 15378-15394
  • DOI: 10.1074/jbc.m117.791780
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Eplerenone prevented obesity-induced inflammasome activation and glucose intolerance (2017)
  • Author(s): Wada T, Ishikawa A, Watanabe E, Nakamura Y, Aruga Y, Hasegawa H, Onogi Y, Honda H, Nagai Y, Takatsu K, Ishii Y, Sasahara M, Koya D, Tsuneki H, Sasaoka T
  • Journal Title: J Endocrinol. Volume: 235 Issue: 3 Pages: 179-191
  • DOI: 10.1530/joe-17-0351
  • Peer Reviewed
• [Journal Article] Isoliquiritigenin attenuates adipose tissue inflammation in vitro and adipose tissue fibrosis through inhibition of innate immune responses in mice. (2016)
  • Author(s): Watanabe Y, Nagai Y, Honda H, Okamoto N, Yamamoto S, Hamashima T, Ishii Y, Tanaka M, Suganami T, Sasahara M, Miyake, K, Takatsu K.
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 23097-23097
  • DOI: 10.1038/srep23097
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 糖尿病モデルマウスの内臓脂肪組織に対するイソリクイリチゲニンの抗炎症・抗線維化作用の解析 (2018)
  • Author(s): 本田裕恵, 渡邉康春, 長井良憲, 松永孝之, 岡本直樹, 平井嘉勝, 高津聖志
  • Organizer: 日本薬学会 第138年会
• [Presentation] 甘草成分イソリクイリチゲニンはNLRP3インフラマソーム活性化を阻害し、2型糖尿病の慢性炎症を改善する (2016)
  • Author(s): 本田裕恵, 長井良憲, 松永孝之, 岡本直樹, 渡邉康春, 常山幸一, 林宏明, 藤井勲, 平井嘉勝, 高津聖志
  • Organizer: 日本薬学会 第136年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-03-29
• [Presentation] 甘草成分イソリクイリチゲニンは内臓脂肪組織の炎症・線維化を抑制する (2016)
  • Author(s): 本田裕恵, 渡邉康春, 長井良憲, 松永孝之, 岡本直樹, 平井嘉勝, 高津聖志
  • Organizer: 日本生薬学会第63回年会
  • Place of Presentation: 富山国際会議場（富山県・富山市）
• [Presentation] 天然薬物イソリクイリチゲニンは自然免疫系に作用し、内臓脂肪組織の線維化を抑制する (2016)
  • Author(s): 渡邉康春, 長井良憲, 本田裕恵, 高津聖志
  • Organizer: 第37回日本肥満学会
  • Place of Presentation: 東京ファッションタウン(東京都・江東区）
• [Presentation] Agonistic effects of synthetic derivatives of funiculosin on mouse/human TLR4/MD-2 (2016)
  • Author(s): Okamoto N, Honda H, Akashi-Takamura S, Nagai Y, Takatsu K
  • Organizer: 第45回日本免疫学会学術集会
  • Place of Presentation: 沖縄コンベンションセンター（沖縄県・宜野湾市）
• [Book] Chapter 8 Isoliquiritigenin: A unique licorice component that attenuates adipose tissue inflammation and fibrosis by targeting the innate immune sensors. In “Biological activities and action mechanisms of licorice ingredients” (ed. H. Sakagami) (2017)
  • Author(s): Nagai Y, Watanabe Y, Honda H, Takatsu K
  • Total Pages: 14
  • Publisher: InTech
• [Book] Chapter 30 Potential therapeutic natural products for the treatment of obesity-associated inflammation by targeting TLRs and inflammasomes. In “Chronic Inflammation-Mechanisms and Regulation-” (M. Miyasaka and K. Takatsu), pp. 379-397 (2016)
  • Author(s): Nagai Y, Honda H, Watanabe Y, Takatsu K.
  • Total Pages: 19
  • Publisher: Springer Japan
• [Remarks] 富山県薬事研究所
  • URL: http://www.pref.toyama.jp/branches/1285/
• [Remarks] 富山大学大学院医学薬学研究部免疫バイオ・創薬探索研究講座
  • URL: http://www.med.u-toyama.ac.jp/immbio/index.html
• [Remarks] 富山県薬事研究所
  • URL: http://www.toyama-yakuji.com/