Department of Pharmacy Practice, University of Illinois-Chicago, 833 South Wood Street, Chicago, IL, 60612, USA.
Department of Food Science, University of Wisconsin-Madison, Babcock Hall, 1605 Linden Drive, Madison, WI, 53706, USA.
Free Radic Biol Med. 2021 Feb 1;163:102-115. doi: 10.1016/j.freeradbiomed.2020.11.018. Epub 2020 Dec 9.
Xanthones from the tropical fruit mangosteen (Garcinia mangostana) display anti-inflammatory and anti-oxidative activities. Here, we isolate and identify potential inducers of the aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways from mangosteen using a bioassay-guided strategy. Mangosteen fruit pericarp extracts were subjected to sequential solvent extractions, followed by chromatography coupled with NMR spectroscopy and mass spectrometric analyses for identification and isolation of pure compounds. Isolation of active fractions led to seven prenylated xanthones that were identified and subsequently evaluated for bioactivity. In vitro luciferase reporter cellular assays using H1L6.1c3 (AhR induction) and HepG2-ARE (Nrf2 induction) were used to identify AhR and Nrf2 activators. All seven prenylated xanthones displayed AhR inducing activity, whereas only five xanthones activated Nrf2. Garcinone D (GarD) significantly upregulated AhR/Cyp1a1 and Nrf2/HO-1 protein expression and enhanced zonula occludens-1 and occludin protein levels in HT-29 cells. In addition, GarD inhibited oxidative stress-induced intestinal epithelial barrier dysfunction by enhancing tight junction (TJ) proteins and inhibition of reactive oxygen species production. Inhibition of AhR by pretreating cells with an AhR antagonist revealed that the AhR pathway is required for the improved epithelial barrier functions of GarD. These results highlight a dual mechanism by GarD that confers protection against intestinal epithelial barrier dysfunction.
热带水果山竹（ Garcinia mangostana ）中的紫檀芪具有抗炎和抗氧化活性。在这里，我们采用基于生物测定的策略，从山竹中分离和鉴定芳基烃受体（ AhR ）和核因子红细胞 2 相关因子 2 （ Nrf2 ）信号通路的潜在诱导剂。山竹果皮提取物经过连续溶剂萃取，然后进行色谱分离，结合 NMR 光谱和质谱分析，用于鉴定和分离纯化合物。活性馏分的分离导致了七种被酰基化的紫檀芪，这些化合物被鉴定并随后进行了生物活性评价。使用 H1L6.1c3 （ AhR 诱导）和 HepG2-ARE （ Nrf2 诱导）的体外荧光素酶报告细胞测定用于鉴定 AhR 和 Nrf2 激活剂。七种被酰基化的紫檀芪均显示出 AhR 诱导活性，而只有五种紫檀芪激活了 Nrf2 。紫檀酮 D （ GarD ）显著上调 AhR/Cyp1a1 和 Nrf2/HO-1 蛋白表达，并增强 HT-29 细胞中的紧密连接蛋白-1 和紧密连接蛋白的水平。此外， GarD 通过增强紧密连接蛋白和抑制活性氧产生来抑制氧化应激诱导的肠上皮屏障功能障碍。用 AhR 拮抗剂预处理细胞可抑制 AhR ，表明 AhR 通路是 GarD 改善上皮屏障功能所必需的。这些结果突出了 GarD 赋予肠上皮屏障功能障碍保护的双重机制。
