Qiao Lei, Yan Shuqi, Dou Xina, Song Xiaofan, Chang Jiajing, Pi Shanyao, Zhang Xinyi, Xu Chunlan
The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China.
Oxid Med Cell Longev. 2022 Aug 5;2022:3982613. doi: 10.1155/2022/3982613. eCollection 2022.
The intestinal barrier plays a fundamental role in body health. Intracellular redox imbalance can trigger endoplasmic reticulum stress (ERS) and mitophagy, leading to intestinal barrier damage. Our previous studies demonstrated that mitophagy is closely associated with the protective effects of biogenic selenium nanoparticles (SeNPs) on intestinal epithelial barrier function. Thus, we hypothesize that ERS and mitophagy are likely involved in the regulatory effects of SeNPs on oxidative stress-induced intestinal epithelial barrier dysfunction. The results showed that oxidative stress or ERS caused the increase of intestinal epithelial permeability. SeNPs effectively alleviated hydrogen peroxide (HO-)-induced structural damage of endoplasmic reticulum (ER) and mitochondria of porcine jejunal epithelial cells (IPEC-J2). SeNPs significantly decreased intracellular inositol triphosphate (IP3) and Ca concentration, down-regulated inositol trisphosphate receptor (IP3R) expression level, and up-regulated ER-resident selenoproteins mRNA levels in IPEC-J2 cells exposed to HO. In addition, SeNPs pretreatment significantly decreased the intracellular Ca, IP3, IP3R, and reactive oxygen species (ROS) levels; protected the structure and function of ER and mitochondria; and effectively alleviated the increase of intestinal epithelial permeability of IPEC-J2 cells exposed to tunicamycin (TM). Moreover, SeNPs significantly inhibited the colocalization of mitochondria and lysosomes. Furthermore, compared with TM model group, SeNPs significantly inhibited the activation of PERK/eIF2/ATF4 and AMPK/mTOR/PINK1 signaling pathway. The PERK agonist (CCT020312) and the AMPK agonist (AICAR) could reverse the protective effects of SeNPs on IPEC-J2 cells. The PERK inhibitor (GSK2656157) and the AMPK inhibitor (compound C) had a similar effect on IPEC-J2 cells as that of SeNPs. In summary, the protective effects of SeNPs on intestinal barrier dysfunction are closely associated with ERS-related PERK and mitophagy-related AMPK signaling pathway.
肠道屏障在身体健康中起着至关重要的作用。细胞内氧化还原失衡可引发内质网应激（ERS）和线粒体自噬，导致肠道屏障损伤。我们之前的研究表明，线粒体自噬与生物源硒纳米颗粒（SeNPs）对肠道上皮屏障功能的保护作用密切相关。因此，我们推测ERS和线粒体自噬可能参与了SeNPs对氧化应激诱导的肠道上皮屏障功能障碍的调节作用。结果表明，氧化应激或ERS导致肠道上皮通透性增加。SeNPs有效减轻了过氧化氢（HO-）诱导的猪空肠上皮细胞（IPEC-J2）内质网（ER）和线粒体的结构损伤。SeNPs显著降低了IPEC-J2细胞内肌醇三磷酸（IP3）和Ca浓度，下调了肌醇三磷酸受体（IP3R）表达水平，并上调了暴露于HO的IPEC-J2细胞中内质网驻留硒蛋白的mRNA水平。此外，SeNPs预处理显著降低了细胞内Ca、IP3、IP3R和活性氧（ROS）水平；保护了ER和线粒体的结构和功能；并有效减轻了暴露于衣霉素（TM）的IPEC-J2细胞肠道上皮通透性的增加。此外，SeNPs显著抑制了线粒体与溶酶体的共定位。此外，与TM模型组相比，SeNPs显著抑制了PERK/eIF2/ATF4和AMPK/mTOR/PINK1信号通路的激活。PERK激动剂（CCT020312）和AMPK激动剂（AICAR）可逆转SeNPs对IPEC-J2细胞的保护作用。PERK抑制剂（GSK2656157）和AMPK抑制剂（化合物C）对IPEC-J2细胞的作用与SeNPs相似。综上所述，SeNPs对肠道屏障功能障碍的保护作用与ERS相关的PERK和线粒体自噬相关的AMPK信号通路密切相关。
