Department of Periodontics, School of Stomatology, Wenzhou Medical University, Wenzhou, China.
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
J Periodontal Res. 2021 Aug;56(4):656-666. doi: 10.1111/jre.12862. Epub 2021 Feb 18.
The application of curcumin is limited by its instability. Mono-carbonyl analogues of curcumin (MCACs) are structurally stable, yet the intermediate bridging ketones in their skeletons account for increased toxicity. This study aimed to synthesize and screen MCACs that exhibit low cytotoxicity and high antioxidant ability, and the effects of MCACs on experimental periodontitis were also investigated.
The cytotoxicity of MCACs on MC3 T3-E1 was determined by MTT assay. The antioxidant capacity was investigated by the cell viability against H O -induced damage and the level of reactive oxygen species (ROS) and malondialdehyde (MDA). The localization and protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) was detected by immunofluorescence and western blot, respectively. In addition, MCAC was intragastrically administrated in rats with ligature-induced experimental periodontitis. The effects were assessed by bone resorption, as well as the immunohistology staining of inflammatory and oxidative stress markers.
MCACs with cyclopentanone and containing pyrone showed lower toxicity than natural curcumin were synthesized (1A-10A, 1H-10H), among which, 1A exhibited the most potent cytoprotective effect against H O -induced damage. Such effects could be explained by the reduced MDA and ROS level, possibly through the nucleus translocation of Nrf2 and the induction of HO-1. Micro-CT results further indicated that 1A significantly reduced bone loss, along with an increased level of Nrf2 and HO-1, and decreased TNF-α and IL-1β.
The present study has synthesized a novel antioxidant MCAC 1A with good biosafety and stability. MCAC 1A could serve as a host response modulator with preventive and protective effects on periodontitis.
姜黄素的应用受到其不稳定性的限制。姜黄素的单羰基类似物（MCACs）结构稳定，但骨架中的中间桥接酮导致毒性增加。本研究旨在合成和筛选具有低细胞毒性和高抗氧化能力的 MCACs，并研究 MCACs 对实验性牙周炎的影响。
通过 MTT 法测定 MCACs 对 MC3T3-E1 的细胞毒性。通过细胞活力对抗 H2O2 诱导的损伤以及活性氧（ROS）和丙二醛（MDA）水平来研究抗氧化能力。通过免疫荧光和 Western blot 分别检测核因子红细胞 2 相关因子 2（Nrf2）和血红素加氧酶-1（HO-1）的定位和蛋白表达。此外，将 MCAC 灌胃给予结扎诱导的实验性牙周炎大鼠。通过骨吸收以及炎症和氧化应激标志物的免疫组织化学染色评估效果。
合成了具有环戊酮和吡喃酮的毒性低于天然姜黄素的 MCAC（1A-10A，1H-10H），其中 1A 对 H2O2 诱导的损伤具有最强的细胞保护作用。这种作用可以通过降低 MDA 和 ROS 水平来解释，可能是通过 Nrf2 的核转位和 HO-1 的诱导。Micro-CT 结果进一步表明，1A 显著减少了骨丢失，同时增加了 Nrf2 和 HO-1 的水平，降低了 TNF-α和 IL-1β的水平。
本研究合成了一种新型抗氧化 MCAC 1A，具有良好的生物安全性和稳定性。MCAC 1A 可以作为一种宿主反应调节剂，对牙周炎具有预防和保护作用。
