通过NRF2/探索NRF2过表达的神经外囊泡针对顺铂诱导的神经毒性的保护潜力

神经毒性的特征在于有害化学物质（例如重金属和药物）在神经组织中的积累，导致随后的神经元死亡。在化学物质基于铂的癌症药物中，由于其抗肿瘤作用而经常使用，但已知该药物也会引起广泛的毒性，例如神经毒性。核因子 - 刺激性2相关因子2（NRF2）对于打击氧化应激和维持细胞稳态至关重要。这项研究彻底探讨了源自NRF2基因过表达的神经祖细胞（NEV）对顺铂诱导的神经毒性的保护作用。因此，分离并表征了源自神经祖细胞的细胞外囊泡。成熟的有丝分裂后神经元中的顺铂神经毒性剂量为75µm。诱导NRF2/途径的1.25µm的TERT叔丁基羟基喹酮用作阳性对照。使用功能和分子测定（例如PCR和基于蛋白质的测定法）研究了细胞外囊泡（EV）的作用。在这里，我们观察到NEVS剂量依赖性地受保护后有丝裂蛋白的响应于顺铂。该研究还检查了该作用是否是通过限制EV生物发生引起的。建立了预防性治疗的分子基础。预先管理时，1×108颗粒/ml NEV保持抗氧化剂和排毒基因和蛋白质表达水平，类似于对照细胞水平。此外，NEV降低了细胞和线粒体ROS水平，并保留了线粒体膜电位。另外，与顺铂对照相比，在NEV处理的细胞中发现过氧化氢酶和SOD水平更高。基于NRF2对顺铂诱导的神经毒性的保护中的发现可能为通过NRF2/通过NRF2/抑制神经元压力之间的关系提供进一步的证据，从而增加了对神经保护反应的理解，以及对基因工程性EV疗法的理解，用于基因工程性EV疗法的外围神经性神经性神经性神经疗法或其他神经疾病。这是文献中首次研究NRF2过表达神经电动汽车的中和效力的研究。

Neurotoxicity is characterized by the accumulation of harmful chemicals such as heavy metals and drugs in neural tissue, resulting in subsequent neuronal death. Among chemicals platinum-based cancer drugs are frequently used due to their antineoplastic effects, but this drug is also known to cause a wide range of toxicities, such as neurotoxicity. The nuclear-factor-erythroid 2-related factor-2 (NRF2) is crucial in combating oxidative stress and maintaining cellular homeostasis. This study thoroughly explores the protective effects of extracellular vesicles derived from NRF2 gene overexpressed neural progenitor cells (NEVs) on cisplatin-induced neurotoxicity. Therefore, extracellular vesicles derived from neural progenitor cells were isolated and characterized. The Cisplatin neurotoxicity dose was 75 µM in mature, post-mitotic neurons. 1.25 µM of tert-butyl hydroquinone that induces NRF2/ARE pathway was used as the positive control. The effects of extracellular vesicles (EVs) were investigated using functional and molecular assays such as PCR and protein-based assays. Here, we observed that NEVs dose-dependently protected post-mitotic neuron cells in response to cisplatin. The study also examined whether the effect was EV-induced by limiting EV biogenesis. The molecular basis of preventive treatment was established. When pre-administered, 1×108 particles/ml of NEVs maintained antioxidant and detoxifying gene and protein expression levels similar to control cell levels. Furthermore, NEVs reduced both cellular and mitochondrial ROS levels and preserved mitochondrial membrane potential. In addition, Catalase and SOD levels were found higher in NEV-treated cells compared to cisplatin control. The findings in NRF2-based protection of cisplatin-induced neurotoxicity may provide further evidence for the relationship between EVs and inhibition of neuronal stress through the NRF2/ARE pathway, increasing the understanding of neuroprotective responses and the development of gene-engineered EV therapy options for peripheral neuropathy or other neurodegenerative diseases. This is the first study in the literature to investigate the neutralizing potency of NRF2 overexpressed neural EVs against cisplatin-induced neurotoxicity.