Wang Hui, Xu You Song, Wang Miao Lin, Cheng Chao, Bian Rui, Yuan Hao, Wang Yi, Guo Ting, Zhu Lin Lin, Zhou Hang
Department of Neurosurgery, Traffic Hospital of Shandong Province, Jinan, Shandong 250031, P.R. China.
Department of Neurosurgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China.
Int J Mol Med. 2017 Apr;39(4):819-830. doi: 10.3892/ijmm.2017.2904. Epub 2017 Feb 22.
Several studies have demonstrated that increased apoptosis plays an essential role in neurodegenerative disorders. It has been demonstrated that lipopolysaccharide (LPS) induces apoptosis largely through the production of intracellular reactive oxygen species (ROS) and inflammatory mediators. In this study, we investigated the potential protective mechanisms of naringin (Nar), a pummelo peel extract, on LPS-induced PC12 cell apoptosis. Nar pre-conditioning prior to stimulation with LPS for 18 h was a prerequisite for evaluating PC12 cell viability and the protective mechanisms of Nar. Nar significantly improved cell survival in a time- and concentration-dependent manner. On the one hand, Nar downregulated cytochrome P450 2E1 (CYP2E1), inhibited the release of ROS, mitigated the stimulation of oxidative stress, and rectified the antioxidant protein contents of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), superoxide dismutase (SOD)2 and glutathione synthetase (GSS). On the other hand, Nar downregulated inflammatory gene and protein expression, including interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, HMGB1, high mobility group box 1 protein (HMGB1), cyclooxygenase-2 (COX-2), the Toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88)-TNF receptor‑associated factor 6 (TRAF6) path-way and downstream mitogen activated protein kinase (MAPK) phosphorylation, activator protein transcription factor-1 (AP-1) and nuclear factor (NF)-κB. Moroever, Nar markedly attenuated the cytochrome c shift from the mitochondria to the cytosol and regulated caspase-3-related protein expression. To the best of our knowledge, this is the first study to report the antioxidant, anti-inflammatory and anti-apoptotic effects of Nar in neuronal-like PC12 cells. These results suggest that Nar can be utilized as a potential drug for the treatment of neurodegenerative disorders.
多项研究表明，细胞凋亡增加在神经退行性疾病中起重要作用。已证实脂多糖（LPS）主要通过产生细胞内活性氧（ROS）和炎症介质诱导细胞凋亡。在本研究中，我们研究了柚皮提取物柚皮苷（Nar）对LPS诱导的PC12细胞凋亡的潜在保护机制。在LPS刺激前18小时进行Nar预处理是评估PC12细胞活力和Nar保护机制的前提条件。Nar以时间和浓度依赖性方式显著提高细胞存活率。一方面，Nar下调细胞色素P450 2E1（CYP2E1），抑制ROS释放，减轻氧化应激刺激，并纠正核因子红细胞2相关因子2（Nrf2）、血红素加氧酶-1（HO-1）、超氧化物歧化酶（SOD）2和谷胱甘肽合成酶（GSS）的抗氧化蛋白含量。另一方面，Nar下调炎症基因和蛋白表达，包括白细胞介素（IL）-1β、IL-6、肿瘤坏死因子（TNF）-α、高迁移率族蛋白B1（HMGB1）、环氧化酶-2（COX-2）、Toll样受体4（TLR4）-髓样分化因子88（MyD88）-TNF受体相关因子6（TRAF6）通路以及下游丝裂原活化蛋白激酶（MAPK）磷酸化、活化蛋白转录因子-1（AP-1）和核因子（NF）-κB。此外，Nar显著减弱细胞色素c从线粒体向细胞质的转移，并调节半胱天冬酶-3相关蛋白表达。据我们所知，这是第一项报道Nar在神经元样PC12细胞中的抗氧化、抗炎和抗凋亡作用的研究。这些结果表明，Nar可作为治疗神经退行性疾病的潜在药物。
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