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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.
The reactive oxygen species (ROS) and nitric oxide (NO) generated by oxidative stress play an important role in cardiovascular and cerebrovascular diseases and neurodegenerative diseases. Excess NO can induce free radical damage and induce neuronal Apoptosis.Rhutang as traditional Chinese medicine has important medicinal value, clinical application is very wide.Recent studies have shown that emodin has antioxidant, immunomodulatory, anti-bacterial, anti-inflammatory and other functions, is widely used in intestinal diseases, kidney disease, Cardiovascular disease, pancreatitis, etc. Forkhead transcription factor 1 (FOXO1) is an important member of the Forkhead family of transcription factors. Regulation of FOXO1 on insulin signaling, DNA repair, reactive oxygen species scavenging, cell cycle arrest, and apoptosis is very poor Importantly, the regulatory role of NO on FOXO1 remains unclear. Our study found that NO donor GSNO (nitrosoglutathione) or L-Arg (L-arginine) significantly increased FOXO1 transcription Activity and promote the transcriptional expression of its downstream pro-apoptotic genes Fas L, Bim, thereby inducing neuronal death.We further study found that emodin can reduce FOXO1 transcription level and egg Which can relieve the neuronal apoptosis induced by nitric oxide (NO) .This study reveals a new mechanism of NO-induced neuronal damage and provides a new experimental basis for understanding the antioxidant effect of emodin, The clinical application of active ingredients provides an important reference.