College of Food Science and Technology, Shanghai Ocean University, No. 999 Hu Cheng Huan Road, LinGang New City, Shanghai 201306, China.
Shanghai Engineering Research Center of Aquatic-Product Processing & Preservation, Shanghai 201306, China.
Molecules. 2018 Jun 14;23(6):1447. doi: 10.3390/molecules23061447.
Advanced glycation end products (AGEs) could interact with the receptor for AGE (RAGE) as a sterile danger signal to induce inflammation. 4′-methoxyresveratrol (4′MR), a polyphenol derived from Dipterocarpaceae, has not been studied for its anti-inflammation effects. In the present study, we sought to explore the protective role of 4′MR in AGEs-induced inflammatory model using RAW264.7 macrophages. 4′MR significantly inhibited gene expression of pro-inflammatory cytokines and chemokines, such as interleukin 1β (IL-1β), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1), as well as two typical pro-inflammatory enzymes, inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2). Besides, 4′MR significantly decreased oxidative stress, demonstrated by levels of ROS production, protein carbonyl and advanced oxidation protein product via down-regulation of NADPH oxidase. Further analysis showed that 4′MR attenuated the RAGE overexpression induced by MGO-BSA. It also blocked the downstream signal of AGE-RAGE, particularly, MAPKs including p38 and JNK, and subsequently reduced NF-κB activation. Additionally, 4′MR significantly abated the activation of NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome including NLRP3 and cleaved caspase-1 and reduced the secretion of mature IL-1β. Taken together, our results suggest that the anti-inflammatory effect of 4′MR is mainly through suppressing RAGE-mediated MAPK/NF-κB signaling pathway and NLRP3 inflammasome activation. 4′MR could be a novel therapeutic agent for inflammation-related diseases.
晚期糖基化终产物（AGEs）可以与 AGE 受体（RAGE）相互作用，作为一种无菌危险信号诱导炎症。4′-甲氧基白藜芦醇（4′MR）是一种从豆科植物中提取的多酚，尚未研究其抗炎作用。在本研究中，我们试图使用 RAW264.7 巨噬细胞探索 4′MR 在 AGEs 诱导的炎症模型中的保护作用。4′MR 显著抑制了促炎细胞因子和趋化因子的基因表达，如白细胞介素 1β（IL-1β）、白细胞介素 6（IL-6）、肿瘤坏死因子-α（TNF-α）和单核细胞趋化蛋白-1（MCP-1），以及两种典型的促炎酶，诱导型一氧化氮合酶（iNOS）和环氧化酶 2（COX2）。此外，4′MR 通过下调 NADPH 氧化酶显著降低了氧化应激水平，表现为 ROS 产生、蛋白羰基和高级氧化蛋白产物的水平降低。进一步分析表明，4′MR 减弱了 MGO-BSA 诱导的 RAGE 过表达。它还阻断了 AGE-RAGE 的下游信号，特别是 MAPKs，包括 p38 和 JNK，随后减少了 NF-κB 的激活。此外，4′MR 显著减轻了 NOD 样受体含吡喃结构域蛋白 3（NLRP3）炎症小体的激活，包括 NLRP3 和切割的半胱天冬酶-1，并减少了成熟的 IL-1β 的分泌。总之，我们的结果表明，4′MR 的抗炎作用主要是通过抑制 RAGE 介导的 MAPK/NF-κB 信号通路和 NLRP3 炎症小体的激活。4′MR 可能是一种治疗炎症相关疾病的新型治疗剂。
