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核应激通过劫持DNA损伤反应途径促进小岛β细胞衰老

Yaqi Jiao^1,2, Weirong Lu¹, Xiaohua Wang³

¹Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu 226019, China.

|October 1, 2025

概括

核细胞应激,由被破坏的核糖体RNA合成引起,在糖尿病中触发胰腺β细胞衰老. 使用KU60019抑制ATM通路阻止了这种衰老,提供了一个潜在的治疗点.

科学领域:

细胞生物学细胞生物学
内分泌学在内分泌学.
分子生物学分子生物学

背景情况:

胰腺β细胞功能障碍是糖尿病进展的核心原因.
细胞衰老对这种功能障碍有很大的贡献.
贝塔细胞衰老的上游触发因素仍然不完全理解.

研究的目的:

为了研究核子应激在驱动β细胞衰老中的作用.
阐明将核子压力与衰老联系起来的分子机制.
评估针对已识别的途径的治疗潜力.

主要方法:

在培养的β细胞中使用CX-5461和actinomycin D (ActD) 诱导核应激.
对衰老标志物的评估,包括SA-β-gal活性,p53,p21,p16和SASP.
在体内核细胞形态和核胺 (NPM) 局部化的分析.
对DNA损伤标记 (γ-H2AX) 和ATM激活的评估.
使用KU60019.19进行ATM的药理抑制.

主要成果:

核细胞应激诱导β细胞衰老,其特征是核细胞形态变化和NPM再分配.
在核应力诱导时观察到SA-β-gal活性,p53,p21,p16上调和SASP.
核突应激触发了g-H2AX焦点和ATM激活,独立于DNA双链断裂.
通过KU60019的ATM抑制显著减弱核应激诱导的β细胞衰老.

结论:

核应激是胰腺β细胞衰老的关键上游驱动因素.
γ-H2AX-ATM信号轴是核应激诱导的β细胞衰老的关键调解器.
针对ATM可能通过保留β细胞功能来代表糖尿病的新疗法策略.

关键词:

生物化学生物化学细胞生物学细胞生物学

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