Citrate-modified silver nanoparticles (AgNP-cit) have received extensive attention due to their excellent antimicrobial properties. However, these particles tend to migrate in vivo, thereby entering the blood circulatory system in granular form and accumulating in the liver, causing toxic reactions. However, the mechanism underlying AgNP-cit toxicity is not yet clear. Thus, we adopted a tandem mass tag (TMT)-labeled quantitative proteomics and metabolomics approach to identify proteins and small molecule metabolites associated with AgNP-cit-induced liver damage and constructed interaction networks between the differentially expressed proteins and metabolites to explain the AgNP-cit toxicity mechanism. AgNP-cit resulted in abnormal purine metabolism mainly by affecting xanthine and other key metabolites along with pyruvate kinase and other bodily proteins, leading to oxidative stress. AgNP-cit regulated the metabolism of amino acids and glycerol phospholipids through glycerol phospholipids, CYP450 enzymes and other key proteins, causing liver inflammation. Via alanine, isoleucine, L-serine dehydratase/L-threonine deaminase and other proteins, AgNP-cit altered the metabolism of glycine, serine and threonine, cysteine and methionine, affecting oxidation and deamination, and ultimately leading to liver damage. This work clearly explains toxic reactions induced by AgNP-cit from three perspectives, oxidative stress, inflammatory response, and oxidation and deamination, thus providing an experimental basis for the safe application of nanomaterials.

中文翻译：

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基于代谢组学和蛋白质组学的柠檬酸盐修饰的银纳米颗粒的肝毒性机理研究

柠檬酸盐修饰的银纳米颗粒（AgNP-cit）由于其优异的抗菌性能而受到广泛关注。但是，这些颗粒倾向于在体内迁移从而以颗粒形式进入血液循环系统并在肝脏中蓄积，引起毒性反应。但是，AgNP-cit毒性的潜在机制尚不清楚。因此，我们采用了串联质谱标签（TMT）标记的定量蛋白质组学和代谢组学方法来鉴定与AgNP-cit引起的肝损害相关的蛋白质和小分子代谢物，并在差异表达的蛋白质和代谢物之间构建了相互作用网络来解释AgNP- cit毒性机制。AgNP-cit主要通过影响黄嘌呤和其他主要代谢产物以及丙酮酸激酶和其他身体蛋白质，导致嘌呤代谢异常，从而导致氧化应激。AgNP-cit通过甘油磷脂调节氨基酸和甘油磷脂的代谢，CYP450酶和其他关键蛋白，引起肝脏炎症。AgNP-cit通过丙氨酸，异亮氨酸，L-丝氨酸脱水酶/ L-苏氨酸脱氨酶和其他蛋白质，改变了甘氨酸，丝氨酸和苏氨酸，半胱氨酸和蛋氨酸的代谢，影响了氧化和脱氨基作用，最终导致肝损伤。这项工作从三个方面（氧化应激，炎症反应以及氧化和脱氨基）清楚地解释了AgNP-cit引起的毒性反应，从而为纳米材料的安全应用提供了实验基础。