Molecular mechanism of steroids for the suppression of histamine H1 receptor signaling.

• Project/Area Number: 15K07933
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Osaka Ohtani University (2017); The University of Tokushima (2015-2016)
• Principal Investigator: Mizuguchi Hiroyuki 大阪大谷大学, 薬学部, 教授 (40247838)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ヒスタミンH１受容体遺伝子発現シグナル / ステロイドシグナル / PKCδ / Hsp90 / マーキアイン / ステロイド受容体 / GRE / ヒスタミンH1受容体遺伝子発現シグナル / AP-1 / (-)マーキアイン

Outline of Final Research Achievements

The expression level of an allergic disease-sensitive gene is correlated with the symptoms severity. We demonstrated that histamine H1 receptor (H1R) gene is a pollinosis-sensitive gene. Maackiain was isolated as an anti-allergic compound that suppresses H1R signaling, and Hsp90 was identified as its intracellular target molecule that was common to the steroid signaling. We examined the effect of steroids on the H1R signaling. We also investigated the effect of maackiain on the steroid signaling. Suppression of H1R signaling by steroids was ambiguous compared to the results from the animal experiments. Maackain increased steroid-stimulated up-regulation of anti-inflammatory gene expression. These data suggest that steroids might suppress H1R signaling indirectly through the histamine-cytokine network. Data also suggest that maackiain show the anti-allergic effect through not only the suppression of H1R signaling but also reinforcement the anti-inflammatory effect of steroids.

Research Products

• [Journal Article] Development of therapeutic strategy target for intracellular signaling molecules responsible for the pathogenesis of allergic diseases (2017)
  • Author(s): 水口博之
  • Journal Title: Folia Pharmacologica Japonica Volume: 150 Issue: 4 Pages: 188-194
  • DOI: 10.1254/fpj.150.188
  • NAID: 130006107981
  • ISSN: 0015-5691, 1347-8397
  • Peer Reviewed
• [Journal Article] ヒスタミンH1受容体のヒスタミン非依存的活性化による細胞内Ca2+濃度の上昇に対するエピナスチンの抑制作用 (2017)
  • Author(s): 貞方久人、水口博之、福井裕行
  • Journal Title: アレルギー・免疫 Volume: 24 Pages: 122-126
  • Peer Reviewed
• [Journal Article] Protein kinase C-δ signaling regulates glucagon secretion from pancreatic islets (2017)
  • Author(s): Yamamoto K, Mizuguchi H, Tokashiki N, Kobayashi M, Tamaki M, Sato Y, fukui H, Yamauchi A.
  • Journal Title: The Journal of Medical Investigation Volume: 64 Issue: 1.2 Pages: 122-128
  • DOI: 10.2152/jmi.64.122
  • NAID: 130005501956
  • ISSN: 1343-1420, 1349-6867
  • Peer Reviewed / Open Access
• [Journal Article] Antihistamines suppress upregulation of histidine decarboxylase gene expression with potencies different from their binding affinities for histamine H1 receptor in toluene 2,4-diisocyanate-sensitized rats. (2016)
  • Author(s): Mizuguchi H, Das AK, Maeyama K, Dev S, Shahriar M, Kitamura Y, Takeda N, Fukui H.
  • Journal Title: J Pharmacol Sci. Volume: 130 Issue: 4 Pages: 212-218
  • DOI: 10.1016/j.jphs.2016.02.002
  • NAID: 120006556303
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Irradiation with narrowband-ultraviolet B suppresses phorbol ester-induced up-regulation of H1 receptor mRNA in HeLa cells. (2016)
  • Author(s): Kitamura Y, Mizuguchi H, Okamoto K, Kitayama M, Fujii T, Fujioka A, Matsushita T, Mukai T, Kubo Y, Kubo N, Fukui H, Takeda N.
  • Journal Title: Acta Otolaryngol. Volume: 136 Issue: 4 Pages: 409-413
  • DOI: 10.3109/00016489.2015.1129555
  • Peer Reviewed / Open Access
• [Journal Article] A novel benzofuran, 4-methoxybenzofuran-5-carboxamide, from Tephrosia purpurea suppressed histamine H1 receptor gene expression through a protein kinase C-δ-dependent signaling pathway. (2016)
  • Author(s): Shill MC, Mizuguchi H, Karmakar S, Kadota T, Mukherjee PK, Kashiwada Y, Kitamura Y, Nemoto H, Takeda N, Fukui H.
  • Journal Title: Int Immunopharmacol. Volume: 30 Pages: 18-26
  • DOI: 10.1016/j.intimp.2015.11.021
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 抗アレルギー天然物医薬、苦参の有効成分、(-)マーキアインの分子薬理機構 (2016)
  • Author(s): 福井 裕行、水口 博之、柏田 良樹、根本 尚夫、北村 嘉章、武田 憲昭
  • Journal Title: 日本薬理学雑誌 Volume: 147 Pages: 148-151
  • NAID: 130005131662
• [Journal Article] Maackiain is a novel antiallergic compound that suppresses transcriptional upregulation of the histamine H1 receptor and interleukin-4 genes. (2015)
  • Author(s): Mizuguchi H, Nariai Y, Kato S, Nakano T, Kanayama T, Kashiwada Y, Nemoto H, Kawazoe K, Takaishi Y, Kitamura Y, Takeda N, Fukui H.
  • Journal Title: Pharmacol Res Perspect Volume: 3 Issue: 5 Pages: 1-13
  • DOI: 10.1002/prp2.166
  • NAID: 120007027654
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The isolation and synthesis of a novel benzofuran compound from Tephrosia purpurea, and the synthesis of several related derivatives, which suppress histamine H1 receptor gene expression (2015)
  • Author(s): Shill MC, Das AK, Itou T, Karmakar S, Mukherjee PK, Mizuguchi H, Kashiwada Y, Fukui H, Nemoto H.
  • Journal Title: Bioorg Med Chem Volume: 23 Issue: 21 Pages: 6869-6874
  • DOI: 10.1016/j.bmc.2015.09.049
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Disruption of Heat Shock Protein 90 (Hsp90)-Protein Kinase Cδ (PKCδ) Interaction by (-)-Maackiain Suppresses Histamine H1 Receptor Gene Transcription in HeLa Cells. (2015)
  • Author(s): Nariai Y, Mizuguchi H, Ogasawara T, Nagai H, Sasaki Y, Okamoto Y, Yoshimura Y, Kitamura Y, Nemoto H, Takeda N, Fukui H.
  • Journal Title: J Biol Chem. Volume: 290 Issue: 45 Pages: 27393-27402
  • DOI: 10.1074/jbc.m115.657023
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 膵α細胞からのグルカゴン分泌に関与するPKCアイソザイムの同定 (2017)
  • Author(s): 山本清威、水口博之、渡嘉敷夏海、小林誠、佐藤陽一、藤野裕道、福井裕行、山内あい子
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台国際センターほか（仙台市、宮城県）
  • Year and Date: 2017-03-24
• [Presentation] 疾患発症シグナルを標的とした花粉症治療戦略 (2017)
  • Author(s): 中野友寛、北村紀子、内田勝幸、福井裕行、神沼 修、水口博之
  • Organizer: 第19回応用薬理シンポジウム
• [Presentation] 苦参由来抗アレルギー化合物(－)マーキアインのステロイドシグナル増強作用 (2017)
  • Author(s): 小笠原健泰、水口博之、給田愛結美、河井真季子、岡島菜津希、藤野裕道、北村嘉章、武田憲昭、福井裕行
  • Organizer: 第34回和漢医薬学会
• [Presentation] Heat shock protein 90-protein kinase Cdelta; complex as a drug target for the therapy of allergic symptoms (2017)
  • Author(s): Hiroyuki Fukui, Hiroyuki Mizuguchi, Yoshiyuki Kitamura, Noriaki Takeda
  • Organizer: 第66回日本アレルギー学会学術大会
• [Presentation] 苦参由来抗アレルギー化合物（－）マーキアインのステロイドシグナルへの影響 (2017)
  • Author(s): 岡島菜津希、水口博之、給田愛結美、河井真季子、北村嘉章、武田憲昭、藤野裕道、福井裕行
  • Organizer: 第132回日本薬理学会近畿部会
• [Presentation] 小青竜湯によるアレルギー性鼻炎疾患感受性遺伝子発現抑制 (2016)
  • Author(s): 江洲貴子、水口博之、浪花志帆、小西由貴、北村嘉章、武田憲昭、藤野裕道、福井裕行
  • Organizer: 第20回日本ヒスタミン学会
  • Place of Presentation: 倉敷市立美術館（倉敷市、岡山県）
  • Year and Date: 2016-11-24
• [Presentation] Effect of narrow-band UVB on up-regulation of Histamine H1 receptor gene expression. (2016)
  • Author(s): Okamoto K, Mizuguchi H, Fujii T, Yamada T, Kitamura Y, Takeda N, Fukui H.
  • Organizer: The 45th Annual Meeting of the European Histamine Research Society
  • Place of Presentation: フィレンツェ（イタリア）
  • Year and Date: 2016-05-11
  • Int'l Joint Research
• [Presentation] アレルギー性鼻炎発症に関与する細胞内シグナルを標的とした治療戦略の開発 (2016)
  • Author(s): 水口博之
  • Organizer: 第89回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-03-10
  • Invited
• [Presentation] Treatment with antihistamines in combination with suplatast tosilate markedly alleviated nasal symptoms in toluene-2,4-diisocyanate-sensitized rats. (2016)
  • Author(s): Wakugawa T, Mizuguchi H, Kadota T, Sawada A, Kominami T, Kitamura Y, Takeda N, Fukui H.
  • Organizer: The 45th Annual Meeting of the European Histamine Research Society
  • Place of Presentation: フィレンツェ（イタリア）
  • Int'l Joint Research
• [Presentation] 苦参由来抗アレルギー化合物 (-)マーキアインのステロイドシグナルへの影響 (2016)
  • Author(s): 小笠原健泰、水口博之、給田愛結美、河井真季子、岡島菜津希、北村嘉章、武田憲昭、藤野裕道、福井裕行
  • Organizer: 第130回日本薬理学会近畿部会
  • Place of Presentation: 京都大学（京都市、京都府）
• [Presentation] Clinical significance of antihistamines and kujin, an anti-allergic kampo medicine. (2015)
  • Author(s): Fukui H, Esu T, Mizuguchi H, Kitamura Y, Takedea N
  • Organizer: 6th International Symposium on Molecular Allergology, ISMA
  • Place of Presentation: Altis Grand Hotel, Lisbon, Portugal
  • Year and Date: 2015-11-19
  • Int'l Joint Research
• [Book] The Receptors (2016)
  • Author(s): Hiroyuki Fukui, Hiroyuki Mizuguchi, Yoshiaki Kitamura and Noriaki Takeda.
  • Publisher: Springer Science, NewYork
• [Book] Handbook of Experimental Pharmacology (2016)
  • Author(s): Hiroyuki Fukui, Hiroyuki Mizuguchi, Hisao Nemoto, Yoshiaki Kitamura, Yoshiki Kashiwada and Noriaki Takeda.
  • Publisher: Springer Science, NewYork