Department of Physiology, Ajou University School of Medicine, 206 World cup-ro, Suwon, 16499, Republic of Korea.
College of Pharmacy, Sunchon National University, 255 Jungang-ro, Suncheon, 57922, Republic of Korea.
Part Fibre Toxicol. 2021 Nov 25;18(1):42. doi: 10.1186/s12989-021-00433-y.
Nanoparticles have been utilized in brain research and therapeutics, including imaging, diagnosis, and drug delivery, owing to their versatile properties compared to bulk materials. However, exposure to nanoparticles leads to their accumulation in the brain, but drug development to counteract this nanotoxicity remains challenging. To date, concerns have risen about the potential toxicity to the brain associated with nanoparticles exposure via penetration of the brain blood barrier to address this issue.
Here the effect of silica-coated-magnetic nanoparticles containing the rhodamine B isothiocyanate dye [MNPs@SiO(RITC)] were assessed on microglia through toxicological investigation, including biological analysis and integration of transcriptomics, proteomics, and metabolomics. MNPs@SiO(RITC)-induced biological changes, such as morphology, generation of reactive oxygen species, intracellular accumulation of MNPs@SiO(RITC) using transmission electron microscopy, and glucose uptake efficiency, were analyzed in BV2 murine microglial cells. Each omics data was collected via RNA-sequencing-based transcriptome analysis, liquid chromatography-tandem mass spectrometry-based proteome analysis, and gas chromatography- tandem mass spectrometry-based metabolome analysis. The three omics datasets were integrated and generated as a single network using a machine learning algorithm. Nineteen compounds were screened and predicted their effects on nanotoxicity within the triple-omics network.
Intracellular reactive oxygen species production, an inflammatory response, and morphological activation of cells were greater, but glucose uptake was lower in MNPs@SiO(RITC)-treated BV2 microglia and primary rat microglia in a dose-dependent manner. Expression of 121 genes (from 41,214 identified genes), and levels of 45 proteins (from 5918 identified proteins) and 17 metabolites (from 47 identified metabolites) related to the above phenomena changed in MNPs@SiO(RITC)-treated microglia. A combination of glutathione and citrate attenuated nanotoxicity induced by MNPs@SiO(RITC) and ten other nanoparticles in vitro and in the murine brain, protecting mostly the hippocampus and thalamus.
Combination of glutathione and citrate can be one of the candidates for nanotoxicity alleviating drug against MNPs@SiO(RITC) induced detrimental effect, including elevation of intracellular reactive oxygen species level, activation of microglia, and reduction in glucose uptake efficiency. In addition, our findings indicate that an integrated triple omics approach provides useful and sensitive toxicological assessment for nanoparticles and screening of drug for nanotoxicity.
与体材料相比，纳米颗粒具有多种特性，因此已被用于脑研究和治疗学，包括成像、诊断和药物传递。然而，纳米颗粒的暴露会导致其在大脑中的积累，但是开发药物来对抗这种纳米毒性仍然具有挑战性。迄今为止，人们越来越关注通过穿透血脑屏障来解决这个问题，纳米颗粒暴露对大脑潜在的毒性。
在这里，评估了含有罗丹明 B 异硫氰酸酯染料[MNPs@SiO（RITC）]的二氧化硅涂层磁性纳米颗粒（MNPs@SiO（RITC））对小胶质细胞的影响，包括毒性学研究，包括转录组学、蛋白质组学和代谢组学的整合。使用透射电子显微镜分析了 MNPs@SiO（RITC）诱导的生物变化，如形态、活性氧的产生、细胞内 MNPs@SiO（RITC）的积累以及葡萄糖摄取效率，在 BV2 鼠小胶质细胞中进行了分析。通过基于 RNA 测序的转录组分析、基于液相色谱串联质谱的蛋白质组分析和基于气相色谱串联质谱的代谢组分析分别收集了三个组学数据。使用机器学习算法将三个组学数据集整合并生成一个单一的网络。筛选了 19 种化合物，并在三重组学网络中预测了它们对纳米毒性的影响。
在剂量依赖性方式中，MNPs@SiO（RITC）处理的 BV2 小胶质细胞和原代大鼠小胶质细胞中，细胞内活性氧的产生、炎症反应和形态激活更大，但是葡萄糖摄取更低。MNPs@SiO（RITC）处理的小胶质细胞中与上述现象相关的 121 个基因（来自 41214 个鉴定的基因）、45 个蛋白质（来自 5918 个鉴定的蛋白质）和 17 个代谢物（来自 47 个鉴定的代谢物）的表达发生了变化。谷胱甘肽和柠檬酸的组合在体外和小鼠大脑中减轻了 MNPs@SiO（RITC）和其他十种纳米颗粒引起的纳米毒性，主要保护了海马体和丘脑。
谷胱甘肽和柠檬酸的组合可以是针对 MNPs@SiO（RITC）诱导的有害作用的纳米毒性缓解药物之一，包括细胞内活性氧水平升高、小胶质细胞激活和葡萄糖摄取效率降低。此外，我们的研究结果表明，综合三重组学方法为纳米颗粒提供了有用且敏感的毒理学评估，并筛选了纳米毒性的药物。
