School of Pharmacy at Fukuoka, International University of Health and Welfare.
Faculty of Pharmaceutical Sciences, Sojo University.
J Toxicol Sci. 2022;47(9):381-387. doi: 10.2131/jts.47.381.
Dihydropyrazines (DHPs), including 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3), are glycation products generated through non-enzymatic reactions in vivo and in food. They are recognized as compounds that are toxic to organisms as they produce radicals. However, our previous study indicated that DHP-3 suppressed Toll-like receptor 4 (TLR4) expression and decreased the phosphorylation of nuclear factor-κB (NF-κB) in lipopolysaccharide (LPS)-treated HepG2 cells. TLR4 signaling is involved in the onset of various inflammatory diseases, and NF-κB and mitogen-activated protein kinase (MAPK) play important roles in TLR4 signaling. Thus, we aimed to elucidate the effects of DHP-3 on MAPK signaling and in turn on the activated TLR4 signaling pathway. In LPS-stimulated HepG2 cells, DHP-3 reduced the phosphorylation of MAPK, extracellular signal-regulated kinase, c-Jun NH-terminal kinase, and p38. The expression of c-jun, a subunit of activator protein-1, was decreased by DHP-3 treatment. Furthermore, DHP-3-induced suppression of MAPK signaling resulted in a decrease in various inflammatory regulators, such as interleukin-6, CC-chemokine ligand 2, and cyclooxygenase-2. These results suggest that DHP-3 exerts an inhibitory effect on TLR4-dependent inflammatory response by suppressing MAPK signaling.
二氢吡嗪（DHPs），包括 3-羟-2,2,5,6-四甲基吡嗪（DHP-3），是体内和食物中非酶反应产生的糖化产物。它们被认为是产生自由基的对生物体有毒的化合物。然而，我们之前的研究表明，DHP-3 抑制脂多糖（LPS）处理的 HepG2 细胞中 Toll 样受体 4（TLR4）的表达并降低核因子-κB（NF-κB）的磷酸化。TLR4 信号通路参与各种炎症性疾病的发生，NF-κB 和丝裂原活化蛋白激酶（MAPK）在 TLR4 信号通路中发挥重要作用。因此，我们旨在阐明 DHP-3 对 MAPK 信号通路的影响，进而对激活的 TLR4 信号通路的影响。在 LPS 刺激的 HepG2 细胞中，DHP-3 降低了 MAPK、细胞外信号调节激酶、c-Jun NH2-末端激酶和 p38 的磷酸化。DHP-3 处理降低了激活蛋白-1 的亚基 c-jun 的表达。此外，DHP-3 诱导的 MAPK 信号通路抑制导致各种炎症调节剂的减少，如白细胞介素-6、CC-趋化因子配体 2 和环氧化酶-2。这些结果表明，DHP-3 通过抑制 MAPK 信号通路对 TLR4 依赖性炎症反应发挥抑制作用。
