乌罗立A通过调节PP2A/Hippo/YAP1通路来减轻六价引起的小肠损伤
Ping Guo1, Rongfang Yang2, Shiyuan Zhong2
1Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China; School of Public Health, Guangzhou Medical University, Guangzhou, China.
The Journal of biological chemistry
|August 11, 2024
概括
六价 (Cr(VI)) 通过破坏Hippo/YAP1通路,导致肠道损伤. PP2A Aα 缺乏会使这种损伤恶化,但乌罗氨酸A 显示出对Cr (VI) 诱导的肠道问题的保护潜力.
科学领域:
- 毒理学 毒理学 毒理学
- 胃肠病学 胃肠病学
- 分子生物学分子生物学
背景情况:
- 六价 (Cr(VI)) 暴露与胃肠道毒性有关,但潜在的分子机制尚不清楚.
- 计算毒理学表明蛋白质酸酶2A (PP2A) 和CrVI诱导的肠损伤之间存在联系.
研究的目的:
- 调查PP2A Aα亚单元在Cr (VI) 诱导的小肠毒性中的作用.
- 阐明参与Cr(VI) 肠道损伤的分子途径,并确定潜在的保护剂.
主要方法:
- 生成了一种小鼠模型,肠表皮特异性淘汰Ppp2r1a (编码PP2A Aα子单元).
- 给野生型 (WT) 和淘汰型 (HE) 老鼠服用不同剂量的CrVI,持续28天.
- 分析了肠道形态,细胞亡,屏障功能标记物 (Occludin),Hippo/YAP1信号传递,以及乌罗素A的影响.
主要成果:
- 在WT小鼠中,Cr(VI) 诱导了肠道损伤 (密码增生,亡,屏障功能障碍),在缺乏PP2A Aα的HE小鼠中,这种损伤加剧了PP2A Aα.
- 的暴露改变了YAP1的酸化和活性,导致Hippo/YAP1途径的毒性.
- PP2A Aα缺乏症加剧了Cr (VI) 诱导的肠道屏障功能障碍,通过损害YAP1介导的修复.
- 乌罗立A减弱的Cr (VI) 诱导的肠道屏障破坏通过调节YAP1.
结论:
- PP2A Aα 缺乏会增加对Cr (VI) 诱导的小肠损伤的易感性.
- 河马/YAP1信号通路是CrVI诱导的肠道毒性和修复的关键参与者.
- 乌罗立A显示出作为一种治疗剂的潜力,可以对抗Cr (VI) 诱导的肠道损伤和相关疾病.
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