Ferulic Acid Regulates the Nrf2/Heme Oxygenase-1 System and Counteracts Trimethyltin-Induced Neuronal Damage in the Human Neuroblastoma Cell Line SH-SY5Y.
Ferulic Acid Regulates the Nrf2/Heme Oxygenase-1 System and Counteracts Trimethyltin-Induced Neuronal Damage in the Human Neuroblastoma Cell Line SH-SY5Y.
复制标题
DOI：
10.3389/fphar.2015.00305
复制
发表时间：
2015
影响因子：
5.6
通讯作者：
Mancuso C
中科院分区：
文献类型：
--
作者：
Catino S;Paciello F;Miceli F;Rolesi R;Troiani D;Calabrese V;Santangelo R;Mancuso C
在过去的几年中，几条证据已经指出了阿魏酸（FA）在抵消由β-淀粉样蛋白或自由基引发剂引起的氧化应激方面的功效，这是基于这种天然抗氧化剂上调血红素加氧酶-1（HO-1）和胆绿素还原酶（BVR）系统的能力。然而，很少的结果可以在文献中找到关于FA的细胞保护作用的情况下，神经毒物造成的损害。本研究的目的是探讨FA对神经毒素三甲基锡（TMT）诱导的SH-SY 5 Y神经母细胞瘤细胞的神经保护作用。FA（1-10 μM，6 h）通过促进转录激活因子Nrf 2的核转位，剂量依赖性地增加SH-SY 5 Y细胞中基础和TMT（10 μM，24 h）诱导的HO-1表达。特别是，FA（10 μM）与TMT的共同处理也导致HO-1的核转位，试图进一步增加SH-SY 5 Y细胞的细胞应激反应。除HO-1外，FA（1-10 μM，6 h）剂量依赖性地增加BVR的基础表达。FA通过增加HO活性的抗氧化和神经保护特性得到以下证据的支持：FA抑制TMT（10 μM）诱导的SH-SY 5 Y细胞中的脂质过氧化（通过检测4-羟基-壬烯醛进行评价）和DNA片段化，并且这种抗氧化作用可被HO抑制剂锌-原卟啉-IX（5 μM）逆转。在HO/BVR系统的副产物中，一氧化碳（CORM-2，50 nM）和胆红素（BR，50 nM）显著抑制TMT诱导的SH-SY 5 Y细胞中超氧阴离子的形成。总之，这些结果证实了FA通过一氧化碳和BR形成上调HO-1/BVR系统的神经保护作用，并提供了关于HO-1/Nrf 2轴在FA相关的增强人类神经元细胞应激反应中的作用的第一个证据。
Over the past years, several lines of evidence have pointed out the efficacy of ferulic acid (FA) in counteracting oxidative stress elicited by β-amyloid or free radical initiators, based on the ability of this natural antioxidant to up-regulate the heme oxygenase-1 (HO-1) and biliverdin reductase (BVR) system. However, scarce results can be found in literature regarding the cytoprotective effects of FA in case of damage caused by neurotoxicants. The aim of this work is to investigate the mechanisms through which FA exerts neuroprotection in SH-SY5Y neuroblastoma cells exposed to the neurotoxin trimethyltin (TMT). FA (1–10 μM for 6 h) dose-dependently increased both basal and TMT (10 μM for 24 h)-induced HO-1 expression in SH-SY5Y cells by fostering the nuclear translocation of the transcriptional activator Nrf2. In particular, the co-treatment of FA (10 μM) with TMT was also responsible for the nuclear translocation of HO-1 in an attempt to further increase cell stress response in SH-SY5Y cells. In addition to HO-1, FA (1–10 μM for 6 h) dose-dependently increased the basal expression of BVR. The antioxidant and neuroprotective features of FA, through the increase of HO activity, were supported by the evidence that FA inhibited TMT (10 μM)-induced lipid peroxidation (evaluated by detecting 4-hydroxy-nonenal) and DNA fragmentation in SH-SY5Y cells and that this antioxidant effect was reversed by the HO inhibitor Zinc-protoporphyrin-IX (5 μM). Among the by-products of the HO/BVR system, carbon monoxide (CORM-2, 50 nM) and bilirubin (BR, 50 nM) significantly inhibited TMT-induced superoxide anion formation in SH-SY5Y cells. All together, these results corroborate the neuroprotective effect of FA through the up-regulation of the HO-1/BVR system, via carbon monoxide and BR formation, and provide the first evidence on the role of HO-1/Nrf2 axis in FA-related enhancement of cell stress response in human neurons.