Jahan Sadaf, Ansari Uzair Ahmad, Srivastava Ankur Kumar, Aldosari Sahar, Alabdallat Nessrin Ghazi, Siddiqui Arif Jamal, Khan Andleeb, Albadrani Hind Muteb, Sarkar Sana, Khan Bushra, Adnan Mohd, Pant Aditya Bhushan
Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah, 11952, Saudi Arabia.
Health and Basic Sciences Research Center, Majmaah University, 11952 Majmaah, Saudi Arabia.
Front Pharmacol. 2024 Jan 25;15:1343569. doi: 10.3389/fphar.2024.1343569. eCollection 2024.
Chemical-induced neurotoxicity is increasingly recognized to accelerate the development of neurodegenerative disorders (NDs), which pose an increasing health burden to society. Attempts are being made to develop drugs that can cross the blood-brain barrier and have minimal or no side effects. Nobiletin (NOB), a polymethoxylated flavonoid with anti-oxidative and anti-inflammatory effects, has been demonstrated to be a promising compound to treat a variety of NDs. Here, we investigated the potential role of NOB in sodium arsenate (NA)-induced deregulated miRNAs and target proteins in human neural progenitor cells (hNPCs). The proteomics and microRNA (miRNA) profiling was done for different groups, namely, unexposed control, NA-exposed, NA + NOB, and NOB groups. Following the correlation analysis between deregulated miRNAs and target proteins, RT-PCR analysis was used to validate the selected genes. The proteomic analysis showed that significantly deregulated proteins were associated with neurodegeneration pathways, response to oxidative stress, RNA processing, DNA repair, and apoptotic process following exposure to NA. The OpenArray analysis confirmed that NA exposure significantly altered miRNAs that regulate P53 signaling, Wnt signaling, cell death, and cell cycle pathways. The RT-PCR validation studies concur with proteomic data as marker genes associated with autophagy and apoptosis (HO-1, SQSTM1, LC-3, Cas3, Apaf1, HSP70, and SNCA1) were altered following NA exposure. It was observed that the treatment of NOB significantly restored the deregulated miRNAs and proteins to their basal levels. Hence, it may be considered one of its neuroprotective mechanisms. Together, the findings are promising to demonstrate the potential applicability of NOB as a neuroprotectant against chemical-induced neurotoxicity.
化学诱导的神经毒性越来越被认为会加速神经退行性疾病（NDs）的发展，而神经退行性疾病给社会带来的健康负担日益加重。人们正在尝试开发能够穿越血脑屏障且副作用最小或无副作用的药物。川陈皮素（NOB）是一种具有抗氧化和抗炎作用的多甲氧基黄酮，已被证明是一种治疗多种神经退行性疾病的有前景的化合物。在此，我们研究了川陈皮素在人神经祖细胞（hNPCs）中对砷酸钠（NA）诱导的miRNA失调和靶蛋白的潜在作用。对不同组进行了蛋白质组学和微小RNA（miRNA）分析，即未暴露对照组、NA暴露组、NA + NOB组和NOB组。在对失调的miRNA和靶蛋白进行相关性分析之后，使用逆转录聚合酶链反应（RT-PCR）分析来验证所选基因。蛋白质组学分析表明，暴露于NA后，显著失调的蛋白质与神经退行性变途径、对氧化应激的反应、RNA加工、DNA修复和凋亡过程相关。开放式芯片分析证实，NA暴露显著改变了调节P53信号、Wnt信号、细胞死亡和细胞周期途径的miRNA。RT-PCR验证研究与蛋白质组学数据一致，因为与自噬和凋亡相关的标记基因（血红素加氧酶-1、 sequestosome 1、微管相关蛋白1轻链3、半胱天冬酶3、凋亡蛋白酶激活因子1、热休克蛋白70和α-突触核蛋白）在NA暴露后发生了改变。据观察，川陈皮素治疗显著将失调的miRNA和蛋白质恢复到其基础水平。因此，这可能被认为是其神经保护机制之一。总之，这些发现有望证明川陈皮素作为一种抗化学诱导神经毒性的神经保护剂的潜在适用性。
