Rikkunshito increased hypothalamic SIRT1 activity

• Project/Area Number: 25460922
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Hokkaido University
• Principal Investigator: TAKEDA Hiroshi 北海道大学, 薬学研究科(研究院), 教授 (60261294)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 六君子湯 / 食欲

Outline of Final Research Achievements

To examine the roles of SIRT1 and AMPK in the orexigenic effect of rikkunshito, a ghrelin signaling potentiator, in vitro experiments using gherkin receptor(GHSR1a)-expressing HEK293 cells and human umbilical vein endothelial cells (HUVEC) were done. The elevated SIRT1 activity and protein expression through cAMP-CREB pathway was observed after ghrelin and rikkunshito treatment in these cells. Rikkunshito increased hypothalamic SIRT1 activity and SIRT1 protein expression of the heart in ICR mouse. Furthermore, rikkunshito prolonged survival in aged ICR mice. The potentiation of ghrelin signaling by rikkunshito not only acts as appetite stimulator but may provide a novel approach for the improvement of both health- and life-span in aging societies.

Research Products

• [Journal Article] Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1. (2016)
  • Author(s): Fujitsuka N, Asakawa A, Morinaga A, Amitani MS, Amitani H, Katsuura G, Sawada Y, Sudo Y, Uezono Y, Mochiki E, Sakata I, Sakai T, Hanazaki K, Yada T, Yakabi K, Sakuma E, Ueki T, Niijima A, Nakagawa K, Okubo N, Takeda H, Asaka M, Inui A.
  • Journal Title: Mol Psychiatry Volume: 21 Issue: 11 Pages: 1-11
  • DOI: 10.1038/mp.2015.220
  • Peer Reviewed / Open Access
• [Journal Article] Serotonin 2C receptor contributes to gender differences in stress-induced hypophagia in aged mice. (2015)
  • Author(s): Yamada C, Sadakane C, Nahata C, Saegusa Y, Nakagawa K, Okubo N, Ohnishi S, Hattori T, Takeda H
  • Journal Title: Psychoneuroendocrinology Volume: 55 Pages: 81-93
  • DOI: 10.1016/j.psyneuen.2015.02.006
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Gender Differences on Feeding Behavior and Ghrelin-Related Factors during Social Isolation in Mice. (2015)
  • Author(s): Yamada C, Saegusa Y, Nahata M, Sadakane C, Hattori T, Takeda H.
  • Journal Title: PLoS One Volume: 10 Issue: 10 Pages: e0140094-e0140094
  • DOI: 10.1371/journal.pone.0140094
  • Peer Reviewed / Open Access
• [Journal Article] Herbal medicines for the treatment of cancer chemotherapy-induced side effects. (2015)
  • Author(s): Ohnishi S, Takeda H.
  • Journal Title: Front Pharmacol Volume: 6 Pages: 14-14
  • DOI: 10.3389/fphar.2015.00014
  • NAID: 120005773990
  • Peer Reviewed / Open Access
• [Journal Article] A New Strategy Using Rikkunshito to Treat Anorexia and Gastrointestinal Dysfunction. (2015)
  • Author(s): Saegusa Y, Hattori T, Nahata M, Yamada C, Takeda H.
  • Journal Title: Evid Based Complement Alternat Med. Volume: 2015 Pages: 364260-364260
  • DOI: 10.1155/2015/364260
  • Peer Reviewed / Open Access
• [Journal Article] Administration of exogenous acylated ghrelin or rikkunshito, an endogenous ghrelin enhancer, improves the decrease in postprandial gastric motility in an acute restraint stress mouse model. (2014)
  • Author(s): Nahata M, Saegusa Y, Sadakane C, Yamada C, Nakagawa K, Okubo N, Ohnishi S, Hattori T, Sakamoto N, Takeda H.
  • Journal Title: Neurogastroenterol Motil Volume: 26 Issue: 6 Pages: 821-831
  • DOI: 10.1111/nmo.12336
  • Peer Reviewed
• [Journal Article] Clinical characteristics of elderly patients with proton pump inhibitor-refractory non-erosive reflux disease from the G-PRIDE study who responded to rikkunshito. (2014)
  • Author(s): Sakata Y, Tominaga K, Kato M, Takeda H, Shimoyama Y, Takeuchi T, Iwakiri R, Furuta K, Sakurai K, Odaka T, Kusunoki H, Nagahara A, Iwakiri K, Furuta T, Murakami K, Miwa H, Kinoshita Y, Haruma K, Takahashi S, Watanabe S, Higuchi K, Fujimoto K, Kusano M, Arakawa T; G-PRIDE study group.
  • Journal Title: BMC Gastroenterol Volume: 14 Issue: 1 Pages: 116-116
  • DOI: 10.1186/1471-230x-14-116
  • Peer Reviewed
• [Journal Article] Effects of Rikkunshito (traditional Japanese medicine) on enteral feeding and the plasma ghrelin level in critically ill patients: a pilot study. (2014)
  • Author(s): Hayakawa M, 他6名
  • Journal Title: Journal of Intensive Care Volume: 2 Issue: 1 Pages: 53-53
  • DOI: 10.1186/s40560-014-0053-4
  • NAID: 120005595707
  • Peer Reviewed / Open Access
• [Journal Article] Serotonin 2C receptor antagonism ameliorates novelty-induced hypophagia in aged mice. (2013)
  • Author(s): Nahata M, Muto S, Nakagawa K, Ohnishi S, Sadakane C, Saegusa Y, Iizuka S, Hattori T, Asaka M, Takeda H.
  • Journal Title: Psychoneuroendocrinology. Volume: 38 Issue: 10 Pages: 2051-2064
  • DOI: 10.1016/j.psyneuen.2013.03.014
  • Peer Reviewed
• [Journal Article] Pathophysiological basis of anorexia. (2013)
  • Author(s): Takeda H, Muto S, Nakagawa K, Ohnishi S, Sadakane C, Saegusa Y, Nahata M, Hattori T, Asaka M.
  • Journal Title: Biol. Pharm. Bull. Volume: 36 Pages: 1401-1405
  • Peer Reviewed
• [Journal Article] Cisplatin-induced anorexia and ghrelin. (2013)
  • Author(s): Hattori T, Yakabi K, Takeda H.
  • Journal Title: Vitam Horm. Volume: 92 Pages: 301-317
  • DOI: 10.1016/b978-0-12-410473-0.00012-x
  • Peer Reviewed
• [Presentation] Different response to chronic isolation stress between young and aged mice. (2015)
  • Author(s): Takeda H, Ohnishi S, Nakagawa K, Okudo N, Yamada C, Saegusa Y, Nahata M, Hattori T, Sakamoto, N
  • Organizer: Digestive Disease Week 2015
  • Place of Presentation: ワシントンDC（米国）
  • Year and Date: 2015-05-16
  • Int'l Joint Research
• [Presentation] The hypophagia after psychological stress in aged male mice is mediated by an interaction of activation of estrogen receptor α with serotonin 2C receptor. (2015)
  • Author(s): Ohnishi S, Nakagawa K, Okudo N, Yamada C, Saegusa Y, Nahata M, Sadakane C, Hattori T, Sakamoto, N, Takeda H
  • Organizer: Digestive Disease Week 2015
  • Place of Presentation: ワシントンDC（米国）
  • Year and Date: 2015-05-16
  • Int'l Joint Research
• [Presentation] セロトニンによるグレリン分泌の調節機構 (2015)
  • Author(s): 武藤修一、大西俊介、武田宏司
  • Organizer: 第101回日本消化器病学会総会
  • Place of Presentation: 仙台国際センター （宮城県仙台市）
  • Year and Date: 2015-04-23
• [Presentation] ストレスによる老齢動物の摂食低下には性差が存在する (2015)
  • Author(s): 大西俊介、武藤修一、武田宏司
  • Organizer: 第101回日本消化器病学会総会
  • Place of Presentation: 仙台国際センター （宮城県仙台市）
  • Year and Date: 2015-04-23
• [Presentation] グレリンシグナルからみた六君子湯の作用メカニズム（漢方セミナー） (2014)
  • Author(s): 武田 宏司
  • Organizer: 第56回日本平滑筋学会総会
  • Place of Presentation: 新横浜プリンスホテル（横浜）
  • Year and Date: 2014-08-08
  • Invited
• [Presentation] 栄養応答シグナルの解明と疾患治療への応用 グレリンシグナルおよびセロトニン2C受容体の意義 (2014)
  • Author(s): 武田宏司, 武藤 修一, 大西 俊介
  • Organizer: 第14回日本抗高齢医学会総会
  • Place of Presentation: 大阪国際会議場（大阪）
  • Year and Date: 2014-06-06
  • Invited
• [Presentation] The Possibility of Rikkunshito As a Treatment for Anorexia: a Proposal From a Basic Research Perspective. (2014)
  • Author(s): Takeda H, Ohnishi S, Muto S, Nakagawa K, Yamada C, Saegusa Y, Nahata M, Sadakane C, Hattori T, Sakamoto, N.
  • Organizer: Digestive Disease Week 2014
  • Place of Presentation: シカゴ（米国イリノイ州）
  • Year and Date: 2014-05-06
• [Presentation] Rikkunshito, a Traditional Japanese Kampo Medicine, Ameliorates the Decrease in Feeding Behavior in Aged Mice Exposed to Stress via Enhancement of Endogenous Ghrelin Production. (2014)
  • Author(s): Muto S, Ohnishi S, Nakagawa K, Yamada C, Saegusa Y, Nahata M, Sadakane C, Hattori T, Sakamoto, N, Takeda H.
  • Organizer: Digestive Disease Week 2014
  • Place of Presentation: シカゴ（米国イリノイ州）
  • Year and Date: 2014-05-06
• [Presentation] Association of abnormal ghrelin dynamics with delayed gastric emptying in acute restraint-stressed mice. (2014)
  • Author(s): Takeda H, Ohnishi S, Muto S, Nakagawa K, Yamada C, Saegusa Y, Nahata M, Sadakane C, Hattori T, Sakamoto, N.
  • Organizer: Digestive Disease Week 2014
  • Place of Presentation: シカゴ（米国イリノイ州）
  • Year and Date: 2014-05-05
• [Presentation] Gender Difference Influences Food Intake Under an Emotional Stress via 5-HT2CR Activation in Aged Mice. (2014)
  • Author(s): Ohnishi S, Muto S, Nakagawa K, Yamada C, Saegusa Y, Nahata M, Sadakane C, Hattori T, Sakamoto, N Takeda H
  • Organizer: Digestive Disease Week 2014
  • Place of Presentation: シカゴ（米国イリノイ州）
  • Year and Date: 2014-05-04
• [Presentation] ストレスによる胃機能異常にはグレリンシグナルの異常が関与する（ワークショップ） (2014)
  • Author(s): 武藤 修一, 大西 俊介, 武田 宏司
  • Organizer: 第100回日本消化器病学会総会
  • Place of Presentation: 東京国際フォーラム（東京）
  • Year and Date: 2014-04-24
• [Presentation] ctivation of Corticotropin-Releasing Factor 2 and Melanocortin-4 Receptors Mediates the Persistent Loss of Appetite Induced by Stress Loading in Advanced Age Mice.
  • Author(s): Takeda H, Muto S, Ohnishi S, Nakagawa K, Sadakane C, Saegusa Y, Nahata M, Yamada C, Hattori T, Asaka M. A
  • Organizer: Digestive Disease Week 2013
  • Place of Presentation: オーランド（米国フロリダ州）
• [Presentation] Serotonin 2C Receptor Antagonism Improves Stress-Induced Anorexia in Aged Mice.
  • Author(s): 2) Muto S, Ohnishi S, Nakagawa K, Sadakane C, Saegusa Y, Nahata M, Yamada C, Hattori T, Asaka M, Takeda H.
  • Organizer: Digestive Disease Week 2013
  • Place of Presentation: オーランド（米国フロリダ州）
• [Presentation] Involvement of Ghrelin Signaling Dysfunction in Acute Restraint Stress-Induced Delayed Gastric Emptying.
  • Author(s): 3) Ohnishi S, Muto S, Nakagawa K, Sadakane C, Saegusa Y, Nahata M, Yamada C, Hattori T, Asaka M, Sakamoto, N Takeda H.
  • Organizer: Digestive Disease Week 2013
  • Place of Presentation: オーランド（米国フロリダ州）
• [Presentation] 急性拘束ストレスによる胃排出遅延にはグレリンシグナル伝達障害が関与する
  • Author(s): 武田宏司
  • Organizer: 第55回日本平滑筋学会総会
  • Place of Presentation: 旭川市大雪クリスタルホール（北海道旭川市）
  • Invited
• [Presentation] ストレスによる老齢動物の摂食低下には5-HT2C受容体の機能亢進が関与する
  • Author(s): 大西俊介、武藤修一、武田宏司
  • Organizer: JDDW2013 （シンポジウム）
  • Place of Presentation: グランドプリンスホテル新高輪他（東京都）