Jiang Xinhai, Li Yining, Wang Weizhi, Han Xiaowan, Han Jiangxue, Chen Mingzhu, Zhang Jing, Wang Chenyin, Li Shunwang, Luo Jinque, Wang Xiao, Xu Yang, Xu Yanni, Cheng Jingcai, Si Shuyi
NHC Key Laboratory of Biotechnology of Antibiotics, National Center for New Microbial Drug Screening, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS and PUMC), Beijing, China.
JC (Wuxi) COMPANY, Inc., Wuxi, China.
Front Pharmacol. 2020 Nov 16;11:532568. doi: 10.3389/fphar.2020.532568. eCollection 2020.
Phenethyl isothiocyanate is widely present in cruciferous vegetables with multiple biological effects. Here we reported the antiatherogenic effects and the underlying mechanisms of JC-5411 (Phenethyl isothiocyanate formulation) and . Luciferase reporter assay showed that JC-5411 increased the activity of nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant response element (ARE). JC-5411 treatment significantly increased the protein expression of Nrf2 and its downstream target gene hemeoxygenase 1 (HO-1) in liver of apolipoprotein E deficient (ApoE) mice. Importantly, JC-5411 treatment significantly reduced atherosclerotic plaque area in both en face aorta and aortic sinus when compared with model group in WD induced ApoE mice. JC-5411 obviously decreased proinflammatory factors' levels in serum of ApoE mice, LPS stimulated macrophages and TNFα induced endothelial cells, respectively. JC-5411 significantly decreased the levels of total cholesterol (TC) and triglyceride (TG) in both serum and liver of ApoE mice and hyperlipidemic golden hamsters. Mechanism studies showed that JC-5411 exerted anti-inflammatory effect through activating Nrf2 signaling and inhibiting NF-κB and NLRP3 inflammasome pathway. JC-5411 exerted regulating lipid metabolism effect through increasing cholesterol transfer proteins (ABCA1 and LDLR) expression, regulating fatty acids synthesis related genes (p-ACC, SCD1 and FAS), and increasing fatty acids β-oxidation (CPT1A) . Furthermore, JC-5411 treatment had a favorable antioxidant effect in ApoE mice by increasing the antioxidant related genes expression. Taken together, we conclude that JC-5411 as a Nrf2 activator has anti-inflammatory, rebalancing lipid metabolism, and antioxidant effects, which makes it as a potential therapeutic agent against atherosclerosis.
异硫氰酸苯乙酯广泛存在于十字花科蔬菜中，具有多种生物学效应。在此，我们报道了JC - 5411（异硫氰酸苯乙酯制剂）的抗动脉粥样硬化作用及其潜在机制。荧光素酶报告基因检测显示，JC - 5411增加了核因子红细胞2相关因子2（Nrf2）和抗氧化反应元件（ARE）的活性。JC - 5411处理显著增加了载脂蛋白E缺陷（ApoE）小鼠肝脏中Nrf2及其下游靶基因血红素加氧酶1（HO - 1）的蛋白表达。重要的是，与高脂饮食诱导的ApoE小鼠模型组相比，JC - 5411处理显著减少了其主动脉弓和主动脉窦的动脉粥样硬化斑块面积。JC - 5411分别显著降低了ApoE小鼠血清、脂多糖刺激的巨噬细胞和肿瘤坏死因子α诱导的内皮细胞中促炎因子的水平。JC - 5411显著降低了ApoE小鼠和高脂血症金黄仓鼠血清及肝脏中的总胆固醇（TC）和甘油三酯（TG）水平。机制研究表明，JC - 5411通过激活Nrf2信号通路并抑制NF - κB和NLRP3炎性小体途径发挥抗炎作用。JC - 5411通过增加胆固醇转运蛋白（ABCA1和LDLR）的表达、调节脂肪酸合成相关基因（p - ACC、SCD1和FAS）以及增加脂肪酸β氧化（CPT1A）发挥调节脂质代谢的作用。此外，JC - 5411处理通过增加抗氧化相关基因的表达，对ApoE小鼠具有良好的抗氧化作用。综上所述，我们得出结论，JC - 5411作为一种Nrf2激活剂，具有抗炎、重新平衡脂质代谢和抗氧化作用，使其成为一种潜在的抗动脉粥样硬化治疗药物。
