Sesamin Enhances Nrf2-Mediated Protective Defense against Oxidative Stress and Inflammation in Colitis via AKT and ERK Activation
Sesamin Enhances Nrf2-Mediated Protective Defense against Oxidative Stress and Inflammation in Colitis via AKT and ERK Activation
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DOI：
10.1155/2019/2432416
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发表时间：
2019-08-26
影响因子：
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通讯作者：
Jin, Jing
中科院分区：
文献类型：
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作者：
Bai, Xupeng;Gou, Xiaoli;Jin, Jing
溃疡性结肠炎(UC)是炎症性肠病(IBD)的一种主要形式，在许多国家有较高的发病率和流行率。UC患者通常会遭受终生虚弱的身体症状。因此，迫切需要制定有效的治疗策略，更好地管理本病，提高患者的生活质量。芝麻素(SSM)是一种从芝麻中提取的木脂素。本研究通过体外和体内实验，探讨SSM对UC的保护作用及其机制。我们的数据表明，SSM通过清除GSH介导的ROS来保护Caco-2细胞免受H_2O_2诱导的氧化应激损伤。双荧光素酶报告基因分析显示，SSM显著增强了核因子红系相关因子2(Nrf2)的转录活性，并通过Western印迹和实时定量聚合酶链式反应(qRT-PCR)进一步证实了SSM激活Nrf2靶基因的能力。相反，Nrf2基因敲除取消了SSM的保护作用。此外，我们还发现SSM还激活了Caco-2细胞中的高级蛋白激酶B(AKT)和细胞外信号调节激酶(ERK)，而抑制AKT或ERK都可以阻止SSM介导的Nrf2核转位。此外，与5-氨基水杨酸(5-ASA)相比，SSM对葡聚糖硫酸钠(DSS)诱导的C57BL/6小鼠UC有更好的保护作用。给药后小鼠结肠组织中Nrf2信号转导增强，AKT/ERK激活。这些结果首次证实了SSM对UC的保护作用，并表明该作用与AKT/ERK激活和随后的Nrf2信号增强有关。本研究对SSM的药用价值提供了新的认识，并建议将其作为一种新的天然营养，以更好地管理UC的症状。
Ulcerative colitis (UC) is a major form of inflammatory bowel disease (IBD) with high incidence and prevalence in many countries. Patients with UC usually suffer from a lifetime of debilitating physical symptoms. Therefore, developing effective therapeutic strategy that can manage this disease better and improve patients' life quality is in urgent need. Sesamin (SSM) is a lignan derived from sesame seeds. In this study, the protective effect of SSM against UC and the underlying mechanism were investigated in vitro and in vivo. Our data showed that SSM protected Caco-2 cells from H2O2-induced oxidative stress injury via GSH-mediated scavenging of reactive oxygen species (ROS). Dual luciferase reporter assay showed that the transcriptional activity of nuclear factor erythroid-related factor 2 (Nrf2) was significantly increased by SSM, and the ability of SSM to activate Nrf2-targeted genes was further confirmed in Caco-2 cells using western blot and quantitative real-time PCR (qRT-PCR). In contrast, Nrf2 knockdown abolished the protective effect of SSM. Additionally, we found that SSM also activated advanced protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) in Caco-2 cells, while either AKT or ERK inhibition can prevent SSM-mediated nuclear translocation of Nrf2. Furthermore, SSM displayed a better protective effect against dextran sulfate sodium- (DSS-) induced UC compared with 5-aminosalicylic acid (5-ASA) in C57BL/6 mice. The enhanced Nrf2 signaling and activated AKT/ERK were also observed in the colon of mice after SSM administration. These results first demonstrate the protective effect of SSM against UC and indicate that the effect is associated with AKT/ERK activation and subsequent Nrf2 signaling enhancement. This study provides a new insight into the medicinal value of SSM and proposes it as a new natural nutrition for better managing the symptoms of UC.