Low-Dose Trans-Resveratrol Ameliorates Diabetes-Induced Retinal Ganglion Cell Degeneration via TyrRS/c-Jun Pathway.
Low-Dose Trans-Resveratrol Ameliorates Diabetes-Induced Retinal Ganglion Cell Degeneration via TyrRS/c-Jun Pathway.
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DOI：
10.1167/iovs.64.7.2
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发表时间：
2023-06-01
影响因子：
4.4
通讯作者：
中科院分区：
文献类型：
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本研究的目的是探讨低剂量反式白藜芦醇（trans-RSV）对糖尿病引起的视网膜神经节细胞（RGC）变性的保护作用及其可能机制。建立链脲佐菌素诱导的糖尿病小鼠模型，并用或不用反式RSV灌胃（10 mg/kg体重/天）治疗12周。记录暗适应视网膜电图（ERG）的振荡电位（Ops）。通过Tuj1和TUNEL染色检测RGC的数量。通过蛋白质印迹分析视网膜中的凋亡标记物。通过透射电子显微镜观察视神经的横截面。此外，小鼠神经母细胞瘤 N2a 细胞因高葡萄糖 (HG) 治疗而受损。在有或没有低剂量反式RSV处理的情况下测量细胞活力和细胞凋亡。在小鼠视网膜和 N2a 细胞中均观察到酪氨酰转移 RNA 合成酶 (TyrRS) 的细胞内定位。在 HEK 293 细胞中通过 co-IP 和 ChIP 测定分析低剂量 trans-RSV 对 TyrRS 与转录因子 c-Jun 结合以及 c-Jun 与促凋亡基因结合的影响。 Trans-RSV 可减轻糖尿病小鼠视网膜电生理损伤并抑制 RGC 凋亡。它还保护 N2a 细胞免受 HG 诱导的细胞凋亡。此外，它还能促进糖尿病小鼠视网膜和 HG 处理的 N2a 细胞中的 TyrRS 核转位。 Trans-RSV促进TyrRS与c-Jun结合，抑制c-Jun的Ser-63磷酸化，并下调促凋亡基因转录。低剂量反式 RSV 可通过 TyrRS/c-Jun 途径改善糖尿病引起的 RGC 变性。它可以促进 TyrRS 核转位并与 c-Jun 结合，下调 c-Jun 磷酸化和下游促凋亡基因。
The purpose of this study was to investigate the protective effect of low-dose trans-resveratrol (trans-RSV) on diabetes-induced retinal ganglion cell (RGC) degeneration and its possible mechanism. A streptozotocin-induced diabetic mouse model was established and treated with or without trans-RSV intragastric administration (10 mg/kg body weight/day) for 12 weeks. Oscillatory potentials (Ops) of the dark-adapted electroretinogram (ERG) were recorded. The number of RGCs was detected by Tuj1 and TUNEL staining. The apoptosis markers in the retina were analyzed by Western blot. The cross sections of optic nerves were observed by transmission electron microscopy. In addition, mouse neuroblastoma N2a cells were injured by high-glucose (HG) treatment. Cell viability and apoptosis were measured with or without low-dose trans-RSV treatment. The intracellular localization of tyrosyl transfer-RNA synthetase (TyrRS) was observed in both mouse retinas and N2a cells. The effects of low-dose trans-RSV on the binding of TyrRS to the transcription factor c-Jun and the binding of c-Jun to pro-apoptotic genes were analyzed by co-IP and ChIP assays in HEK 293 cells. Trans-RSV relieved electrophysiological injury of retinas and inhibited RGC apoptosis in diabetic mice. It also protected N2a cells from HG-induced apoptosis. Additionally, it promoted TyrRS nuclear translocation in both diabetic mouse retinas and HG-treated N2a cells. Trans-RSV promoted TyrRS binding to c-Jun, inhibited the phosphorylation of Ser-63 of c-Jun, and downregulated pro-apoptotic gene transcription. Low-dose trans-RSV can ameliorate diabetes-induced RGC degeneration via the TyrRS/c-Jun pathway. It can promote TyrRS nuclear translocation and bind to c-Jun, downregulating c-Jun phosphorylation and downstream pro-apoptotic genes.
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