The study of functional mechanism of Nobiletin, which possess the therapeutic potency for development of heart failure.

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K16396
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47050:Environmental and natural pharmaceutical resources-related
• Research Institution: University of Shizuoka
• Principal Investigator: Sunagawa Yoichi 静岡県立大学, 薬学部, 講師 (30466297)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: NBP1 / ノビレチン / 心不全 / p300 / アセチル化

Outline of Final Research Achievements

Pulldown assay demonstrated that nobiletin directly interacted with recombinant NBP1. In vitro enzyme assay showed that NOB enhanced NBP1 activity. NBP1 knockdown failed to exhibit NOB-mediated anti-hypertrophic effects. NBP1-KO mice and WT mice with TAC were divided into two groups: NOB (20 mg/kg/day) and vehicle. Oral administration was repeated for 6 weeks. NOB significantly improved TAC-induced cardiac hypertrophy, systolic dysfunction and increases in HW/BW ratio, myocardial cell hypertrophy, and mRNA levels of ANF and β-MHC in WT mice but not in NBP1-KO mice. IP-WB using HEK293T cells showed that NBP1 were associated with p300 and decreased its auto-acetylation, p300/GATA4-dependent promoter activity, and p300-mediated GATA4 acetylation. NBP1 decreased the post-transcriptional modification at activation loop motif of p300. These findings suggest that NBP1 is required to exhibit therapeutic potency of nobiletin for heart failure through the inhibition of p300 activity.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

ノビレチンは生活習慣病、ガン、アレルギー疾患、認知症、アルツハイマー病といった疾患に有効な作用を有している。これらの報告ではノビレチンの標的因子としてERK1/2やAMPKが関与している。ERK1/2やAMPKは162個のノビレチン標的候補因子の中に含まれてはいた。申請者が見出したNBP1はノビレチンにより活性が制御されており、心不全の進行との関与が示唆する成果が得られた。今後、ノビレチンの心不全進行抑制作用の詳細な作用機序の解明がなされれば、ノビレチンを用いた心不全病態に対するより根本的な新たな治療法の開発に繋がることが期待される。