Emodin Attenuates The Neurotoxicity Induced by Nitric Oxide Through Inhibiting FOXO1 Transcriptional Activity
- 公共卫生－已发表论文 
氧化应激所产生的活性氧和一氧化氮(nitric oxide,NO)自由基在心脑血管疾病、神经退行性疾病中发挥着重要作用,过量的NO可以导致自由基损伤,并诱导神经元的凋亡.大黄作为中医传统药物具有重要的药用价值,临床应用非常广泛.近年研究表明,大黄素具有抗氧化、免疫调节、抗菌、抗炎等功能,被广泛应用于肠道疾病、肾病、心血管疾病、胰腺炎等病症的治疗.Forkhead转录因子1(FOXO1)是Forkhead转录因子家族的一个重要成员,FOXO1对于胰岛素信号通路、DNA修复、清除活性氧损伤、细胞周期和凋亡的调控非常重要.而NO自由基对FOXO1的调控作用还不清楚,我们研究发现,NO的供体GSNO(亚硝基谷胱甘肽)或者L-Arg(L-精氨酸)可显著提高FOXO1的转录活性并促进其下游促凋亡基因Fas L、Bim的转录表达,进而诱导神经元死亡.我们进一步研究发现,大黄素可以通过降低FOXO1的转录水平以及蛋白质水平,缓解NO所诱导的神经元凋亡.该研究揭示了NO自由基诱导神经元损伤的新机制,同时也为了解大黄素的抗氧化作用提供了新的实验依据,对大黄素等中药有效成分的临床应用提供了重要参考.Reactive oxygen species(ROS) and NO free radicals generated from oxidative stress play an important role in the pathogenesis of neurodegenerative disease and cardiovascular and cerebrovascular diseases. Excessive NO production can cause free radical damage and induce neuron death. As one of the traditional Chinese medicine,Emodin have valuable and widely clinical applications. Recently, Emodin has been reported to have antioxidant,immunomodulatory, antibacterial, anti-inflamatory functions etc. FOXO1 is a vital member of the Forkhead family of transcription factors known to regulate the transcription of genes involved in cell cycle arrest, DNA repair in response to oxidative stress or apoptosis. However, it is unclear how the NO effect on FOXO1. In this study, we observed vital role of FOXO1 dependent transcriptional activation on neuronal death in response to Nitric oxide over-production. We found that NO donor GSNO or L-Arginine significantly increased the FOXO1 transcriptional activity, which induce the FOXO1 downstream proapoptotic genes(Fas L, Bim) expression and finally induce neuronal death. In addition, we screen natural Chinese herb extracts targets to regulating FOXO1 activity. Emodin shows dramatically effect in suppression of FOXO1 transcription activity and protein levels. What's more, Emodin can attenuate neuronal death induced by L-Arg. The current study first demonstrate that Nitric Oxide could regulate FOXO1 transcriptional activity to damage neuronal cell, which will benefit to deep understanding the neurotoxicity of NO free radical. Secondly, by Chinese herb extracts and antioxidants screen, we identified Emodin as one FOXO1 activity modulator which can attenuate neurotoxicity induced by NO. The current study will also provide a new insight for explaining the mechanisms of pathology of neurodegenerative disease and neuroprotective effects of Emodin.