硫化水素は脂質過酸化を阻害し,細胞をフェロプトーシスから保護する
Zijun Wu1, Vinayak S Khodade2, Jean-Philippe R Chauvin1
1Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ONK1N 6N5, Canada.
Journal of the American Chemical Society
|August 17, 2022
まとめ
水素硫化物 (RSSH) は,有害なラジカルを取り除き,強力な阻害剤に匹敵してフェロプトーシスを効果的に阻害します. 細胞の防御システムにおける重要な役割を示唆しています.
科学分野:
- 生物化学
- 細胞生物学
- 酸化ストレスに関する研究
背景:
- 硫化水素 (RSSH) は,有害な酸化物質と電化物質の除去に関与する重要な内生性分子です.
- α効果は,RSSHの核好性およびH原子移転 (HAT) 能力を強化し,チオール (RSH) に比べて改善する.
- HATは,フォスフォリピド過酸化とフェロプトーシスの強力な小分子阻害剤の確立されたメカニズムです.
研究 の 目的:
- フォスフォリピド過酸化およびフェロプトーシスの抑制剤としての水素硫化物 (RSSH) の反応性を調査する.
- 放射性物質を捕まえる効率を高めるために,RSSHの"in situ"生成戦略を探求する.
- 生理学的フェロプトーシス抑制システムとしてのRSSHの可能性を評価する.
主な方法:
- RSSHの反応性を定量化するために,光活性化抑制自己酸化 (FENIX) のアプローチを使用した.
- 生理学的条件下でRSSHと関連する (ポリ) 硫化物の反応性を調査した.
- 設計された前駆体を使用してRSSHの*in situ*生成を用い,細胞培養におけるその有効性を評価した.
主要な成果:
- RSSHは,主要なフェロプトーシス阻害剤に匹敵する,フォスフォリピド由来ペロキシルラジカル (kinh = 2 × 105 M-1 s-1) に対する高い反応性を示した.
- 特に分子内置または水解のために設計された前駆体からRSSHの"in situ"生成は,自己反応を最小限に抑えることで,過激な捕獲効率を向上させました.
- RSSHおよびその前駆体は,GPX4が不活性化またはその遺伝子が削除されたとき,マウスの胚性線維細胞におけるフェロプトーシスを効果的に抑制しました.
結論:
- RSSHはフェロプトーシスの強力な阻害剤であり,H原子移転によって有害なラジカルを中和する.
- RSHの"in situ"生成を可能にする設計された前駆体は,自己反応の限界を克服し,治療の可能性を高める戦略を提供します.
- これらの発見は,FSP1/ウビキノンおよびGCH1/BH4/DHFRのような既知の経路と共に,RSSHとその生合成経路をフェロプトーシス抑制のための重要な内生システムとして強調しています.
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