白藜芦醇调节 SIRT1 和 DNMT 的功能，并在氧化应激和炎症条件下恢复 ARPE-19 细胞内 LINE-1 的甲基化水平。

Resveratrol Modulates SIRT1 and DNMT Functions and Restores LINE-1 Methylation Levels in ARPE-19 Cells under Oxidative Stress and Inflammation.

机构信息

Department of Medical and Surgical Sciences and Advanced Technologies "GF Ingrassia", University of Catania, via S. Sofia, 87, 95123 Catania, Italy.

SIFI SpA, Research and Development Department, Via Ercole Patti 36, 95025 Catania, Italy.

出版信息

Int J Mol Sci. 2018 Jul 20;19(7):2118. doi: 10.3390/ijms19072118.

The role of epigenetic alterations in the pathogenesis of retinal degenerative diseases, including age-related macular degeneration (AMD), has been pending so far. Our study investigated the effect of oxidative stress and inflammation on DNA methyltransferases (DNMTs) and Sirtuin 1 (SIRT1) functions, as well as on long interspersed nuclear element-1 (LINE-1) methylation, in human retinal pigment epithelial (ARPE-19) cells. Therefore, we evaluated whether treatment with resveratrol may modulate DNMT and SIRT1 functions and restore changes in LINE-1 methylation. Cells were treated with 25 mU/mL glucose oxidase (GOx) or 10 µg/mL lipopolysaccharide (LPS) to mimic oxidative or inflammatory conditions, respectively. Oxidative stress decreased DNMT1, DNMT3a, DNMT3b, and SIRT1 expression (-values < 0.05), as well as total DNMTs (-28.5%; < 0.0001) and SIRT1 (-29.0%; < 0.0001) activities. Similarly, inflammatory condition decreased DNMT1 and SIRT1 expression (-values < 0.05), as well as total DNMTs (-14.9%; = 0.007) and SIRT1 (-20.1%; < 0.002) activities. Interestingly, GOx- and LPS-treated cells exhibited lower LINE-1 methylation compared to controls (-values < 0.001). We also demonstrated that treatment with 10 μM resveratrol for 24 h counteracted the detrimental effect on DNMT and SIRT1 functions, and LINE-1 methylation, in cells under oxidative and inflammatory conditions. However, further studies should explore the perspectives of resveratrol as a suitable strategy for the prevention and/or treatment of retinal degenerative diseases.

表观遗传改变在视网膜退行性疾病（包括年龄相关性黄斑变性（AMD））的发病机制中的作用尚不清楚。我们的研究调查了氧化应激和炎症对 DNA 甲基转移酶（DNMTs）和 Sirtuin 1（SIRT1）功能的影响，以及对长散布核元件-1（LINE-1）甲基化的影响，在人视网膜色素上皮（ARPE-19）细胞中。因此，我们评估了白藜芦醇治疗是否可以调节 DNMT 和 SIRT1 功能并恢复 LINE-1 甲基化的变化。细胞用 25 mU/mL 葡萄糖氧化酶（GOx）或 10 µg/mL 脂多糖（LPS）处理，分别模拟氧化或炎症条件。氧化应激降低了 DNMT1、DNMT3a、DNMT3b 和 SIRT1 的表达（-值<0.05），以及总 DNMTs（-28.5%；<0.0001）和 SIRT1（-29.0%；<0.0001）活性。同样，炎症条件降低了 DNMT1 和 SIRT1 的表达（-值<0.05），以及总 DNMTs（-14.9%；=0.007）和 SIRT1（-20.1%；<0.002）活性。有趣的是，与对照组相比，GOx 和 LPS 处理的细胞的 LINE-1 甲基化水平较低（-值<0.001）。我们还表明，用 10 μM 白藜芦醇处理 24 小时可拮抗氧化和炎症条件下细胞中 DNMT 和 SIRT1 功能以及 LINE-1 甲基化的有害影响。然而，进一步的研究应该探索白藜芦醇作为预防和/或治疗视网膜退行性疾病的合适策略的前景。