Abstract:
In the search for novel potent immunomodulatory nuclear factor-erythroid 2 related factor 2 (Nrf2) activators, a derivative of cholic bile acid, SB140, was synthesized. The synthesis of SB140 aimed to increase the electrophilic functionality of the compound, enhancing its ability to activate Nrf2. Effects of SB140 on microglial cells, myeloid-derived cells (MDC), and T cells were explored in the context of (central nervous system) CNS autoimmunity. SB140 potently activated Nrf2 signaling in MDC and microglia. It was efficient in reducing the ability of microglial cells to produce inflammatory nitric oxide, interleukin (IL)-6, and tumor necrosis factor (TNF). Also, SB140 reduced the proliferation of encephalitogenic T cells and the production of their effector cytokines: IL-17 and interferon (IFN)-γ. On the contrary, the effects of SB140 on anti-inflammatory IL-10 production in microglial and encephalitogenic T cells were limited or absent. These results show that SB140 is a potent Nrf2 activator, as well as an immunomodulatory compound. Thus, further research on the application of SB140 in the treatment of neuroinflammatory diseases is warranted. Animal models of multiple sclerosis and other inflammatory neurological disorders will be a suitable choice for such studies.
摘要:
在寻找新型有效的免疫调节核因子-红细胞2相关因子2(Nrf2)激活剂时,胆酸胆汁酸的衍生物,SB140,进行了合成。SB140的合成旨在增加化合物的亲电子官能度,增强其激活Nrf2的能力。SB140对小胶质细胞的影响,骨髓衍生细胞(MDC),在(中枢神经系统)CNS自身免疫的背景下探索T细胞。SB140有效激活MDC和小胶质细胞中的Nrf2信号。它能有效降低小胶质细胞产生炎性一氧化氮的能力,白细胞介素(IL)-6和肿瘤坏死因子(TNF)。此外,SB140减少了致脑炎性T细胞的增殖及其效应细胞因子IL-17和干扰素(IFN)-γ的产生。相反,SB140对小胶质细胞和致脑病T细胞中抗炎IL-10产生的影响有限或不存在.这些结果表明,SB140是一种有效的Nrf2活化剂,以及免疫调节化合物。因此,有必要进一步研究SB140在治疗神经炎症性疾病中的应用。多发性硬化和其它炎性神经病症的动物模型将是此类研究的合适选择。