从蛋白质组学分析推断小鼠巨噬细胞对铜和氧化铜纳米颗粒的分子反应
Molecular responses of mouse macrophages to copper and copper oxide nanoparticles inferred from proteomic analyses
摘要：
巨噬细胞对铜基纳米颗粒的分子反应已经通过蛋白质组学和生物化学方法的组合进行了研究，使用RAW 264.7细胞系作为模型。已经测试了金属铜和氧化铜纳米颗粒，使用铜离子和氧化锆纳米颗粒作为对照。蛋白质组学分析突出了氧化应激反应（超氧化物歧化酶和过氧化物酶），谷胱甘肽生物合成，肌动球蛋白细胞骨架和线粒体蛋白（特别是氧化磷酸化复合物亚基）中涉及的蛋白质的变化。采用功能分析的验证研究表明，在蛋白质组学筛选中观察到的谷胱甘肽生物合成和线粒体复合物的增加对铜基纳米颗粒应激后的细胞存活至关重要;这两种途径的药理学抑制增强了细胞对铜基纳米颗粒的脆弱性，但对铜离子没有影响。此外，使用来自骨髓的原代巨噬细胞的功能分析显示还原型谷胱甘肽水平降低，线粒体跨膜电位降低，以及吞噬作用和脂多糖诱导的一氧化氮产生的抑制。然而，只有一小部分的这些效果可以获得与铜离子。总之，这项研究表明，巨噬细胞的功能显着改变铜基纳米粒子。还强调的是由细胞调节的细胞通路的生存和示例性的交叉毒性，可以发生在铜基纳米粒子和药理学试剂之间。
英文摘要：
The molecular responses of macrophages to copper-based nanoparticles have been investigated via a combination of proteomic and biochemical approaches, using the RAW264.7 cell line as a model. Both metallic copper and copper oxide nanoparticles have been tested, with copper ion and zirconium oxide nanoparticles used as controls. Proteomic analysis highlighted changes in proteins implicated in oxidative stress responses (superoxide dismutases and peroxiredoxins), glutathione biosynthesis, the actomyosin cytoskeleton, and mitochondrial proteins (especially oxidative phosphorylation complex subunits). Validation studies employing functional analyses showed that the increases in glutathione biosynthesis and in mitochondrial complexes observed in the proteomic screen were critical to cell survival upon stress with copper-based nanoparticles; pharmacological inhibition of these two pathways enhanced cell vulnerability to copper-based nanoparticles, but not to copper ions. Furthermore, functional analyses using primary macrophages derived from bone marrow showed a decrease in reduced glutathione levels, a decrease in the mitochondrial transmembrane potential, and inhibition of phagocytosis and of lipopolysaccharide-induced nitric oxide production. However, only a fraction of these effects could be obtained with copper ions. In conclusion, this study showed that macrophage functions are significantly altered by copper-based nanoparticles. Also highlighted are the cellular pathways modulated by cells for survival and the exemplified cross-toxicities that can occur between copper-based nanoparticles and pharmacological agents.
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