Redox stress and brain functions

抗氧化剂是所有有氧生物控制活性氧（ROS）水平和氧化应激诱导毒性的基础。然而，抗氧化剂的作用不仅限于它们的氧化还原活性，因为它们还可以调节应激反应途径(Nrf2, NF-？B)和蛋白质磷酸化。脂质氧化的副产物也可以调节信号转导途径。我的研究项目的长期目标是了解氧化应激和抗氧化剂系统在大脑功能和体内平衡中的基本作用。***抗氧化剂不稳定，易氧化，生物利用度和吸收度低，导致其生物效应降低。为了克服这个缺点，我们在纳米科学或自然科学领域开发了一个新的研究项目，通过工程设计生物相容性和可生物降解的纳米颗粒（NPs）来保护和提高它们的生物利用度和功效。因此，该项目是一项持续进行的项目，具有长期愿景，旨在增强抗氧化剂与靶向NPs的血液到脑输送。为此，我们设计了含有或不含有聚乙二醇（PEG）的聚乳酸（PLA） NPs或聚乳酸（PLGA） NPs来封装抗氧化剂，并研究了它们对神经元功能的影响。我们发现姜黄素加载到PLGA-NPs中增加了其神经元摄取，抗氧化和神经保护活性。姜黄素是一种食物成分，也是一种强大的抗氧化剂。我们的初步数据加强了聚合物组成和涂层性质对抗氧化剂负载的nps的神经元效应至关重要的概念。这些结果引起了人们的极大兴趣，因为PLGA-NPs和PLA-NPs是脑靶向和药物递送的有前途的纳米载体。这一最新进展为本提案中概述的研究目标提供了基础。然而，脑与血流被血脑屏障隔开，血脑屏障由非常特化的内皮细胞代表。这些细胞与NPs之间的相互作用仍有待考证。***我们假设NPs与血脑屏障（BBB）相互作用的每一步（内吞作用、胞吞作用、细胞效应）及其生物分布都需要NPs不同且最佳的物理化学性质。因此，对于本提案，我们的具体目标是：(1)合成和表征生物相容性和可生物降解的NPs库；(2)分析血脑屏障内皮细胞对这些NPs的内吞、胞吞作用及其对细胞氧化还原电位的影响和载脂蛋白的影响；(3)研究这些NPs在斑马鱼和小鼠模型中的生物分布。我们相信，这样一个全面的研究计划将为我们的长期目标提供肥沃的土壤，即开发用于大脑靶向的NPs

Antioxidants are fundamental for all aerobic organisms to control the levels of reactive oxygen species (ROS) and of oxidative stress induced-toxicity. However, the role of antioxidants is not only limited to their redox activity because they can also regulate stress response pathways (Nrf2, NF-?B) and protein phosphorylation. It is also well recognized that by-product of lipids oxidation can modulate signal transduction pathways. The long-term goal of my research program aims to understand the fundamental role of oxidative stress and antioxidants systems on brain functions and homeostasis.***Antioxidants are unstable, easily oxidized with low bioavailability and absorption, causing a reduction of their biological effect. To overcome this drawback, we have developed a new research program, in nanoscience or natural sciences, to preserve and increase their bioavailability and efficacy by engineering biocompatible and biodegradable nanoparticles (NPs). Thus, the program presents here is an ongoing program with long term vision to enhance the blood-to-brain delivery of antioxidants with targeted NPs. For this, we have engineered ***poly(lactic-co-glycolide acid) (PLGA) or polylactic acid (PLA) NPs with or without poly(ethylene glycol) (PEG) to encapsulate antioxidants and studied their effects on neuronal functions. We found that curcumin-loaded into PLGA-NPs increase its neuronal uptake, antioxidant and neuroprotective activity. Curcumin is a food ingredient and a powerful antioxidant. Our preliminary data strengthened the concept that the polymer composition and the nature of the coating is crucial for the neuronal effect of antioxidant loaded-NPs. These results are of great interest since PLGA-NPs and PLA-NPs are promising nanocarriers for brain targeting and drug delivery. This recent progress provides the foundation for the research objectives outlined in the current proposal. However, the brain is separated from the blood stream by the BBB which is represented by very specialized endothelial cells. The interaction between these cells and the NPs remain to be documented. ***We hypothesize that each step of interaction between NPs and the blood brain barrier (BBB) (endocystosis, transcytosis, cellular effects) and their biodistribution require different and optimal physico-chemical properties of NPs. Therefore, for this current proposal, our specific aims are: (1) To synthesize and characterize of a library of biocompatible and biodegradable NPs; (2) To analyze the endocytosis, transcytosis of these NPs by the endothelial cells of the BBB, their effects on the cellular redox potential and the impact of apolipoproteins; (3) To study the biodistribution of these NPs in zebrafish and in mouse models.***We are confident that such a comprehensive research program will provide a fertile ground for our long term goals for the development of NPs for brain targeting.**