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2019 Fiscal Year Final Research Report

Molecular mechanism of autophagy inhibition and cytotoxicity by silver nanoparticles

Research Project

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Project/Area Number 17K15856
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Hygiene and public health
Research InstitutionTokyo Women's Medical University

Principal Investigator

MIYAYAMA TAKAMITSU  東京女子医科大学, 医学部, 助教 (20620397)

Project Period (FY) 2017-04-01 – 2020-03-31
Keywords銀ナノ粒子 / オートファジー / リソソーム / 肺がん細胞 / 初代培養細胞 / 肺気道上皮細胞 / 肺胞上皮細胞
Outline of Final Research Achievements

Although silver nanoparticles (AgNPs) are widely expected in nano medicine, the mechanism by which AgNPs cause pulmonary damage is unclear. In cells exposed to citrate-coated 60-nm AgNPs, confocal laser microscopic examination showed a decrease in the LysoTracker fluorescence signal and an increase in that of Cyto-ID, indicating lysosomal pH alkalization and autophagosome formation, respectively. The proteins p62 and microtubule-associated protein light chain 3B-II (LC3B-II) are both degraded by autophagy, and their levels increased depending on AgNP dose. Furthermore, AgNP-induced increase in LC3B-II was not enhanced by treatment with the autophagic inhibitor bafilomycin A1. TFEB mRNA levels, and protein levels in cytosolic and nuclear fractions, were suppressed by exposure to AgNPs, suggesting transcriptional inhibition of TFEB expression. The present study suggests that AgNP-induced lysosomal dysfunction plays a principal role in the autophagic flux defect.

Free Research Field

分子細胞毒性学

Academic Significance and Societal Importance of the Research Achievements

肺を構成するあらゆる細胞種において、銀ナノ粒子の応答は共通に保存されていたことから、確かな学術的証明を得た。一方で、銀ナノ粒子の毒性はTFEBの遺伝子発現調節のみでは解決できない新しい学術的問いを見出すこととなった。このことは、銀ナノ粒子の科学的エビデンスに基づいた創薬開発が、より一層波及すると期待される。また、他の金属ナノ粒子の創薬開発にも応用できるので、将来的に抗がん剤や抗病原微生物薬などの治療を受ける患者が恩恵を受けるのみならず、開発製造に関わる研究者や技術者へのナノ粒子曝露に対する健康リスクを確保することにもつながり、衛生学分野において学術的なインパクトが期待される。

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Published: 2021-02-19  

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