Differential Immunomodulatory Effect of Graphene Oxide and Vanillin-Functionalized Graphene Oxide Nanoparticles in Human Acute Monocytic Leukemia Cell Line (THP-1)
Differential Immunomodulatory Effect of Graphene Oxide and Vanillin-Functionalized Graphene Oxide Nanoparticles in Human Acute Monocytic Leukemia Cell Line (THP-1)
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DOI：
10.3390/ijms20020247
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发表时间：
2019-01-02
影响因子：
5.6
通讯作者：
Kim, Jin-Hoi
中科院分区：
文献类型：
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作者：
Gurunathan, Sangiliyandi;Kang, Min-Hee;Kim, Jin-Hoi
石墨烯及其衍生物正在成为具有吸引力的生物医学应用材料，包括抗菌、基因传递、对比成像和抗癌治疗应用。研究这些材料的细胞毒性和生物相容性及其与免疫系统的相互作用具有重要意义。本研究旨在评估氧化石墨烯（GO）和香草素功能化氧化石墨烯（V-rGO）对THP-1细胞（一种人类急性单核细胞白血病细胞系）的免疫毒性。利用各种分析技术对合成的氧化石墨烯和V-rGO进行了表征。不同浓度的氧化石墨烯和V-rGO对THP-1细胞表现出毒性作用，如细胞活力和增殖的丧失，并呈剂量依赖性。细胞毒性进一步表现为乳酸脱氢酶（LDH）水平升高、线粒体膜电位（MMP）丧失、ATP含量水平降低和细胞死亡。活性氧（ROS）和脂质过氧化水平升高导致THP-1细胞氧化还原失衡，导致丙二醛（MDA）水平升高，抗氧化剂如谷胱甘肽（GSH）、谷胱甘肽过氧化物酶（GPX）、超氧化物歧化酶（SOD）和过氧化氢酶（CAT）水平降低。ROS生成增加，MMP减少，促凋亡基因表达增加，抗凋亡基因表达下调，提示氧化石墨烯和v - rgo诱导的细胞凋亡有线粒体介导途径参与。凋亡的诱导与THP-1细胞中8-oxo-dG水平升高和各种关键DNA调控基因上调引起的显著DNA损伤一致，表明GO和V-rGO通过氧化应激诱导细胞死亡。由于这些事件，氧化石墨烯和V-rGO刺激了各种细胞因子和趋化因子的分泌，表明石墨烯材料诱导了对THP-1细胞的强烈炎症反应。在所有测试中，v -还原氧化石墨烯的强度都是因为更好的电荷转移、不同的碳氧比和还原氧化石墨烯中的化学成分。总的来说，这些发现表明，有必要更好地了解氧化石墨烯和功能化氧化石墨烯在免疫毒性和炎症中的控制参数。合理设计用于各种应用（包括纳米医学）的安全氧化石墨烯配方，可能会导致开发针对接触石墨烯及其家族材料的人的风险管理方法，因为这些纳米颗粒可用于各种生物医学应用中的递送剂。
Graphene and its derivatives are emerging as attractive materials for biomedical applications, including antibacterial, gene delivery, contrast imaging, and anticancer therapy applications. It is of fundamental importance to study the cytotoxicity and biocompatibility of these materials as well as how they interact with the immune system. The present study was conducted to assess the immunotoxicity of graphene oxide (GO) and vanillin-functionalized GO (V-rGO) on THP-1 cells, a human acute monocytic leukemia cell line. The synthesized GO and V-rGO were characterized by using various analytical techniques. Various concentrations of GO and V-rGO showed toxic effects on THP-1 cells such as the loss of cell viability and proliferation in a dose-dependent manner. Cytotoxicity was further demonstrated as an increased level of lactate dehydrogenase (LDH), loss of mitochondrial membrane potential (MMP), decreased level of ATP content, and cell death. Increased levels of reactive oxygen species (ROS) and lipid peroxidation caused redox imbalance in THP-1 cells, leading to increased levels of malondialdehyde (MDA) and decreased levels of anti-oxidants such as glutathione (GSH), glutathione peroxidase (GPX), super oxide dismutase (SOD), and catalase (CAT). Increased generation of ROS and reduced MMP with simultaneous increases in the expression of pro-apoptotic genes and downregulation of anti-apoptotic genes suggest that the mitochondria-mediated pathway is involved in GO and V-rGO-induced apoptosis. Apoptosis was induced consistently with the significant DNA damage caused by increased levels of 8-oxo-dG and upregulation of various key DNA-regulating genes in THP-1 cells, indicating that GO and V-rGO induce cell death through oxidative stress. As a result of these events, GO and V-rGO stimulated the secretion of various cytokines and chemokines, indicating that the graphene materials induced potent inflammatory responses to THP-1 cells. The harshness of V-rGO in all assays tested occurred because of better charge transfer, various carbon to oxygen ratios, and chemical compositions in the rGO. Overall, these findings suggest that it is essential to better understand the parameters governing GO and functionalized GO in immunotoxicity and inflammation. Rational design of safe GO-based formulations for various applications, including nanomedicine, may result in the development of risk management methods for people exposed to graphene and graphene family materials, as these nanoparticles can be used as delivery agents in various biomedical applications.