Silica-coated magnetic-nanoparticle-induced cytotoxicity is reduced in microglia by glutathione and citrate identified using integrated omics.
Silica-coated magnetic-nanoparticle-induced cytotoxicity is reduced in microglia by glutathione and citrate identified using integrated omics.
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DOI：
10.1186/s12989-021-00433-y
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发表时间：
2021-11-25
影响因子：
10
通讯作者：
Lee G
中科院分区：
文献类型：
--
作者：
Shin TH;Manavalan B;Lee DY;Basith S;Seo C;Paik MJ;Kim SW;Seo H;Lee JY;Kim JY;Kim AY;Chung JM;Baik EJ;Kang SH;Choi DK;Kang Y;Mouradian MM;Lee G
纳米颗粒由于其与块状材料相比的多功能特性，已被用于脑研究和治疗，包括成像、诊断和药物递送。然而，暴露于纳米颗粒会导致它们在大脑中积累，但是对抗这种纳米毒性的药物开发仍然具有挑战性。到目前为止，人们已经开始关注与纳米颗粒通过穿透脑血屏障暴露相关的脑潜在毒性，以解决这一问题。在这里，通过毒理学研究，包括生物学分析和转录组学，蛋白质组学和代谢组学的整合，评估了含有罗丹明B异硫氰酸盐染料[MNPs@SiO2（RITC）]的二氧化硅涂层磁性纳米颗粒对小胶质细胞的影响。在BV 2小鼠小胶质细胞中分析了MNPs@SiO2（RITC）诱导的生物学变化，如形态学、活性氧物质的产生、使用透射电子显微镜观察的MNPs@SiO2（RITC）的细胞内积累和葡萄糖摄取效率。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收集每个组学数据。使用机器学习算法将三个组学数据集集成并生成为单个网络。19种化合物进行了筛选，并预测其对纳米毒性的三重组学网络内的影响。细胞内活性氧的产生，炎症反应，和细胞的形态激活更大，但葡萄糖摄取较低的MNPs@SiO2（RITC）处理的BV 2小胶质细胞和原代大鼠小胶质细胞的剂量依赖性方式。在MNPs@SiO2（RITC）处理的小胶质细胞中，与上述现象相关的121个基因（来自41，214个已识别基因）的表达以及45种蛋白质（来自5918个已识别蛋白质）和17种代谢物（来自47个已识别代谢物）的水平发生了变化。谷胱甘肽和柠檬酸盐的组合减弱了MNPs@SiO2（RITC）和其他十种纳米颗粒在体外和小鼠大脑中诱导的纳米毒性，主要保护海马和丘脑。谷胱甘肽和柠檬酸盐的组合可以是针对MNPs@SiO2（RITC）诱导的有害作用的纳米毒性缓解药物的候选物之一，所述有害作用包括细胞内活性氧水平升高、小胶质细胞活化和葡萄糖摄取效率降低。此外，我们的研究结果表明，一个集成的三重组学方法提供了有用的和敏感的毒理学评估的纳米颗粒和筛选药物的纳米毒性。在线版本包含补充材料，可通过10.1186/s12989-021-00433-y获得。
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@SiO2(RITC)] were assessed on microglia through toxicological investigation, including biological analysis and integration of transcriptomics, proteomics, and metabolomics. MNPs@SiO2(RITC)-induced biological changes, such as morphology, generation of reactive oxygen species, intracellular accumulation of MNPs@SiO2(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@SiO2(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@SiO2(RITC)-treated microglia. A combination of glutathione and citrate attenuated nanotoxicity induced by MNPs@SiO2(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@SiO2(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. The online version contains supplementary material available at 10.1186/s12989-021-00433-y.
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影响因子：
46.2
作者：
Behzadi S;Serpooshan V;Tao W;Hamaly MA;Alkawareek MY;Dreaden EC;Brown D;Alkilany AM;Farokhzad OC;Mahmoudi M
通讯作者：
Mahmoudi M
影响因子：
9.3
作者：
Das A;Kim SH;Arifuzzaman S;Yoon T;Chai JC;Lee YS;Park KS;Jung KH;Chai YG
通讯作者：
Chai YG
影响因子：
5.3
作者：
Fernández-Arjona MDM;Grondona JM;Granados-Durán P;Fernández-Llebrez P;López-Ávalos MD
通讯作者：
López-Ávalos MD
影响因子：
--
作者：
Foroozandeh P;Aziz AA
通讯作者：
Aziz AA
氧化锌纳米颗粒诱导的内质网应激是纳米毒理学评估的早期生物标志物
影响因子：
17.1
作者：
Chen, Rui;Huo, Lingling;Chen, Chunying
通讯作者：
Chen, Chunying