20(R)-人参皂苷 Rg3 通过激活 Nrf2/HO-1 轴减轻 ROS 介导的 ER 应激缓解 T2DM 小鼠糖尿病视网膜损伤。
20(R)-ginsenoside Rg3 alleviates diabetic retinal injury in T2DM mice by attenuating ROS-mediated ER stress through the activation of the Nrf2/HO-1 axis.
机构信息
College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China; College of Life Sciences, Engineering Research Center of the Chinese Ministry of Education for Bioreactor and Pharmaceutical Development, Jilin Agricultural University, Changchun, 130118, China; Jilin Provincial International Joint Research Center for the Development and Utilization of Authentic Medicinal Materials, Changchun, 130118, China.
Institute for Translational Medicine, The Affiliated Hospital, Qingdao University, Qingdao, China.
出版信息
Phytomedicine. 2024 Dec;135:156202. doi: 10.1016/j.phymed.2024.156202. Epub 2024 Nov 7.
BACKGROUND
Although our previous work confirmed 20(R)-ginsenoside Rg3 (R-Rg3), which is an active ingredient in the Panax Ginseng C.A. Meyer, to have good anti-diabetic activity, its beneficial effect on diabetic retinal injury was found to be limited.
PURPOSE
This study aims to investigate the protective effects of R-Rg3 on diabetes-induced retinal injury and the associated molecular mechanisms of action.
METHODS
Diabetic retinal injury was induced in mice using a combination of a high-fat diet (HFD) and intraperitoneal injection of streptozotocin (STZ). R-Rg3 (10 and 20 mg/kg) was subsequently administered for 6 weeks. The human retinal endothelial cells (HRECs) were subjected to high glucose (HG)-induced injury for the in vitro analysis and treated with R-Rg3 (4, 8, 16 μM), antioxidant N-Acetylcysteine (NAC, 1 mM) and Nrf2 inhibitor ML385 (5 μM). The mice retinas then underwent functional and histopathological analysis. Expression levels of proteins related to the Nrf2/HO-1 axis, tight junction proteins, endoplasmic reticulum (ER) stress and the apoptosis in retinal tissue and HRECs were determined by western blot. Expressions of ZO-1 and Nrf2 in the retina and HRECs were assessed by immunofluorescence. Additional evaluations included measuring body weights, fasting blood glucose (FBG), lipid levels and oxidative markers.
RESULTS
The results showed 6 weeks of R-Rg3 treatment significantly restored the functional changes and redox system imbalance that was induced by HFD/STZ in mice. R-Rg3 was also found to significantly reduce retinal barrier damage and thickness changes resulting from hyperglycaemia exposure. At the same time, R-Rg3 also protected HRECs from HG-induced damage. R-Rg3 could also activate Nrf2/HO-1 axis and inhibit endoplasmic reticulum stress as a means of alleviating retinal endothelial cells apoptosis. The molecular docking results also demonstrated that R-Rg3 had a good binding ability with Nrf2.
CONCLUSION
Our study suggested Nrf2/HO-1 axis might be crucial for the ability of R-Rg3 to prevent diabetic retinal injury.
背景
虽然我们之前的工作证实了人参中的 20(R)-人参皂苷 Rg3（R-Rg3）具有良好的抗糖尿病活性，但它对糖尿病性视网膜损伤的有益作用被发现是有限的。
目的
本研究旨在探讨 R-Rg3 对糖尿病诱导的视网膜损伤的保护作用及其相关作用机制。
方法
通过高脂肪饮食（HFD）和腹腔注射链脲佐菌素（STZ）联合诱导小鼠糖尿病视网膜损伤模型，随后给予 R-Rg3（10 和 20mg/kg）治疗 6 周。体外分析采用高糖（HG）诱导人视网膜内皮细胞（HRECs）损伤，并给予 R-Rg3（4、8、16μM）、抗氧化剂 N-乙酰半胱氨酸（NAC，1mM）和 Nrf2 抑制剂 ML385（5μM）处理。对小鼠视网膜进行功能和组织病理学分析。通过 Western blot 测定视网膜组织和 HRECs 中与 Nrf2/HO-1 轴、紧密连接蛋白、内质网（ER）应激和细胞凋亡相关的蛋白表达水平。免疫荧光法检测视网膜和 HRECs 中 ZO-1 和 Nrf2 的表达。进一步评估包括测量体重、空腹血糖（FBG）、血脂水平和氧化标志物。
结果
结果表明，6 周的 R-Rg3 治疗显著恢复了 HFD/STZ 诱导的小鼠功能变化和氧化还原系统失衡。R-Rg3 还显著减轻了高血糖暴露引起的视网膜屏障损伤和厚度变化。同时，R-Rg3 还保护 HRECs 免受 HG 诱导的损伤。R-Rg3 还可以通过激活 Nrf2/HO-1 轴和抑制内质网应激来减轻视网膜内皮细胞凋亡。分子对接结果还表明，R-Rg3 与 Nrf2 具有良好的结合能力。
结论
本研究表明，Nrf2/HO-1 轴可能是 R-Rg3 预防糖尿病性视网膜损伤的关键。
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