Novel Carbon Nanodots against Vascular Inflammation

项目摘要/摘要 这项研究的长期目标是开发新型的碳纳米点作为一种新的 治疗血管疾病的“纳米药剂学”。血管炎症及其后遗症 内皮功能障碍在动脉粥样硬化性血管病变的发生和发展中起重要作用 疾病。肿瘤坏死因子-α被认为在肿瘤的发病机制中起重要作用。 动脉硬化。碳纳米点(C-dots)是纳米世界中令人着迷的新来者，具有 尺寸小于10纳米。碳纳米点已引起人们的广泛关注，成为纳米碳领域的一颗冉冉升起的新星。 由于其毒性较低、表面改性用途广泛、绿色合成方法、光学稳定性和 良好的生物相容性。我们最近的初步数据首次显示，C-点显著减少 肿瘤坏死因子-α诱导单核细胞与人原代脐静脉内皮细胞的黏附 提示C-DOTS对血管功能障碍有潜在的抗炎作用。生产过剩 已知活性氧簇(ROS)可导致内皮功能障碍。我们的初步数据进一步 结果表明，C-DOTS减少了ROS的产生，治疗是无毒的。这些结果表明了一种新的 为更有效地治疗炎症性疾病开辟“纳米药理学”之路 动脉硬化。广泛的研究表明，核因子-κB的激活在 IL-8和MCP-1的转录调控。我们的初步数据进一步表明，TNF-α 显著提高了核因子-κB的结合活性，表明转录因子核因子-κB的激活 可能在肿瘤坏死因子-α诱导的炎症反应中起关键作用。基于这些数据，我们因此 假设C-点在抗氧化性质方面抑制了肿瘤坏死因子-α诱导的血管内皮细胞黏附 单核细胞通过抑制NF-κB信号转导内皮细胞，进而调节趋化因子和 黏附分子的表达。因此，该R15提案的具体目标是：1)：确定是否 碳纳米点抑制肿瘤坏死因子-α诱导的血管标志物黏附分子的表达 核因子-κB的炎症和核移位及其机制是否通过核因子-κB信号转导 HUVECs；2)开展碳纳米点的生物分布、安全性研究以及 碳纳米点对载脂蛋白E-/-小鼠血管氧化应激、炎症和动脉粥样硬化的影响。基于 我们的初步研究，我们相信，C-DOTS可能会为更多的 对动脉粥样硬化等炎症性疾病的有效治疗和拟议的研究也将 为对基础科学感兴趣的本科生和研究生提供宝贵的培训机会 研究。这一研究项目的实施有望提供有关该潜力的新信息。 新型碳纳米点在血管疾病治疗中的应用。

PROJECT SUMMARY/ABSTRACT The long-range goal of this research is to development novel carbon nanodots as a new avenue of "nanopharmacology" for treatment of vascular diseases. Vascular inflammation and its subsequent endothelial dysfunction play a fundamental role in the initiation and progression of atherosclerotic vascular disease. It is believed that tumor necrosis factor (TNF)-alpha is critically involved in the pathogenesis of atherosclerosis. Carbon nanodots (C-dots) are fascinating newcomers to the world of nanoparticles with sizes below 10 nm. C-dots have drawn considerable attentions and become a rising star in the nanocarbon family due to their lower toxicity, versatile surface modification, green synthetic method, optical stability, and good bio-compatibility. Our recent preliminary data for the first time showed that C-dots significantly reduced TNF-alpha-induced adhesion of monocytes to human primary umbilical vein endothelial cells (HUVECs) suggesting a potential anti-inflammatory action of C-dots against vascular dysfunction. Overproduction of reactive oxygen species (ROS) is known to cause endothelial dysfunction. Our preliminary data further showed that C-dots decreased ROS production and the treatment is nontoxic. These results suggest a new avenue of "nanopharmacology" for more effective treatment of inflammatory disorders such as atherosclerosis. Extensive studies demonstrated that the activation of NF-κB is essential for the transcriptional regulation of IL-8 and MCP-1. Our preliminary data further showed that TNF-alpha significantly increased NF-κB binding activity indicating that activation of the transcription factor NF-κB might be critical for the TNF-alpha-induced inflammatory response. Based on these data, we therefore hypothesize that C-dots with respect to antioxidant properties suppress TNF-alpha-induced adhesion of monocytes to endothelial cells via inhibition of NF-κB signaling that subsequently regulates chemokine and adhesion molecular expression. Thus, the specific aims of this R15 proposal are: 1): to determine whether carbon nanodots inhibit TNF-alpha-induced expression of adhesion molecules, markers of vascular inflammation and nuclear translocation of NF-κB, and whether the mechanism is through NF-κB signaling in HUVECs; 2) to carry out the Bio-distribution, safe studies of carbon nanodots and the protective effects of carbon nanodots on vascular oxidative stress, inflammation and atherosclerosis in Apo E-/- mice. Based on our pilot studies, we believe that C-dots may provide a new avenue of "nanopharmacology" for more effective treatment of inflammatory disorders such as atherosclerosis and the proposed studies will also provide valuable training opportunities to undergraduate and graduate students interested in basic science research. Fulfillment of this research project is expected to provide new information on the potential application of novel carbon nanodots to the treatment of vascular diseases.