Faculty of Pharmaceutical Sciences, Sojo University.
J Toxicol Sci. 2020;45(7):401-409. doi: 10.2131/jts.45.401.
Dihydropyrazines (DHPs), including 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3), are glycation products that are spontaneously generated in vivo and ingested via food. DHPs generate various radicals and reactive oxygen species (ROS), which can induce the expression of several antioxidant genes in HepG2 cells. However, detailed information on DHP-response pathways remains elusive. To address this issue, we investigated the effects of DHP-3 on the nuclear factor-κB (NF-κB) pathway, a ROS-sensitive signaling pathway. In lipopolysaccharide-stimulated (LPS-stimulated) HepG2 cells, DHP-3 decreased phosphorylation levels of inhibitor of NF-κB (IκB) and NF-κB p65, and nuclear translocation of NF-κB p65. In addition, DHP-3 reduced the expression of Toll-like receptor 4 (TLR4) and the adaptor protein myeloid differentiation primary response gene 88 (MyD88). Moreover, DHP-3 suppressed the mRNA expression of tumor necrosis factor-alpha (TNFα), and interleukin-1 beta (IL-1β). Taken together, these results suggest that DHP-3 acts as a negative regulator of the TLR4-MyD88-mediated NF-κB signaling pathway.
二氢吡嗪（DHPs），包括 3-羟-2,2,5,6-四甲基吡嗪（DHP-3），是体内自发生成和通过食物摄入的糖基化产物。DHPs 会产生各种自由基和活性氧（ROS），从而诱导 HepG2 细胞中几种抗氧化基因的表达。然而，DHPs 反应途径的详细信息仍然难以捉摸。为了解决这个问题，我们研究了 DHP-3 对核因子-κB（NF-κB）途径的影响，这是一种 ROS 敏感的信号通路。在脂多糖刺激（LPS 刺激）的 HepG2 细胞中，DHP-3 降低了 NF-κB 抑制剂（IκB）和 NF-κB p65 的磷酸化水平，以及 NF-κB p65 的核转位。此外，DHP-3 降低了 Toll 样受体 4（TLR4）和衔接蛋白髓样分化初级反应基因 88（MyD88）的表达。此外，DHP-3 抑制了肿瘤坏死因子-α（TNFα）和白细胞介素-1β（IL-1β）的 mRNA 表达。总之，这些结果表明 DHP-3 作为 TLR4-MyD88 介导的 NF-κB 信号通路的负调节剂发挥作用。
