Withaferin a Attenuates Retinal Ischemia-Reperfusion Injury via Akt-Dependent Inhibition of Oxidative Stress.
Withaferin a Attenuates Retinal Ischemia-Reperfusion Injury via Akt-Dependent Inhibition of Oxidative Stress.
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Withaferin a 通过 Akt 依赖性氧化应激抑制减轻视网膜缺血再灌注损伤
作者：
背景：视网膜缺血再灌注（I/R）损伤常导致顽固性视力损害。视网膜毛细血管内皮细胞的存活对于视网膜I/R损伤的治疗至关重要。如何保护视网膜内皮细胞免受损伤是一项具有挑战性的工作。Withaferin A是一种来自植物的小分子，具有抗菌和抗炎作用，已在传统医学中使用了大约数千年。本研究旨在探讨醉茄素A对视网膜I/R损伤的保护作用。方法：采用SwissADME网络工具评价醉茄素A的药物相似性。采用多种方法研究了醉茄素A对I/R诱导的人视网膜微血管内皮细胞（HRMEC）损伤的潜在保护作用。进行RNA测序，并基于京都基因和基因组百科全书数据分析相关的机制信号通路。通过体外和体内实验进一步验证了RNA测序数据的分析结果。结果：Withaferin A具有较好的类药物作用，可减少体外培养的HRMECs I/R损伤诱导的凋亡。RNA测序和实验验证结果表明，醉茄素A在I/R期间增加了关键的抗氧化分子血红素加氧酶1（HO-1）和过氧化物氧还蛋白1（Prdx-1）的产生。此外，醉茄素A激活Akt信号通路，增加HO-1和Prdx-1的表达，从而发挥抗氧化作用，减轻视网膜I/R损伤，减少HRMECs凋亡。Akt的阻断完全消除了醉茄素A的作用。结论：该研究首次发现，醉茄素A可以通过增加抗氧化剂Prdx-1和HO-1的产生来防止I/R诱导的人微血管视网膜内皮细胞凋亡。结果表明，醉茄素A是一个有前途的药物候选治疗视网膜I/R损伤。
Background: Retinal ischemia-reperfusion (I/R) injury often results in intractable visual impairments. The survival of retinal capillary endothelial cells is crucial for the treatment of retinal I/R injury. How to protect retinal endothelia from damage is a challenging work. Withaferin A, a small molecule derived from plants, has antibacterial and anti-inflammatory effects and has been used for about millennia in traditional medicine. The present study aimed to investigate the potential protective effect of withaferin A on retinal I/R injury. Methods: The drug-likeness of withaferin A was evaluated by the SwissADME web tool. The potential protective effect of withaferin A on the I/R-induced injury of human retinal microvascular endothelial cells (HRMECs) was investigated using multiple approaches. RNA sequencing was performed and associated mechanistic signaling pathways were analyzed based on the Kyoto Encyclopedia of Genes and Genomes data. The analytical results of RNA sequencing data were further validated by in vitro and in vivo experiments. Results: Withaferin A reduced the I/R injury-induced apoptotic death of HRMECs in vitro with a good drug-like property. RNA sequencing and experimental validation results indicated that withaferin A increased the production of the crucial antioxidant molecules heme oxygenase 1 (HO-1) and peroxiredoxin 1 (Prdx-1) during I/R. In addition, withaferin A activated the Akt signaling pathway and increased the expression of HO-1 and Prdx-1, thereby exerting an antioxidant effect, attenuated the retinal I/R injury, and decreased the apoptosis of HRMECs. The blockade of Akt completely abolished the effects of withaferin A. Conclusions: The study identified for the first time that withaferin A can protect against the I/R-induced apoptosis of human microvascular retinal endothelial cells via increasing the production of the antioxidants Prdx-1 and HO-1. Results suggest that withaferin A is a promising drug candidate for the treatment of retinal I/R injury.
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影响因子：
5.1
作者：
Roy RV;Suman S;Das TP;Luevano JE;Damodaran C
通讯作者：
Damodaran C
DOI：
10.1016/j.bbamcr.2019.01.011
发表时间：
2019-04-01
影响因子：
5.1
作者：
Fao, Ligia;Mota, Sandra I.;Cristina Rego, A.
通讯作者：
Cristina Rego, A.
影响因子：
4.5
作者：
Hiramatsu, Kei;Tsuneyoshi, Tadamitsu;Morihara, Naoaki
通讯作者：
Morihara, Naoaki
影响因子：
4.6
作者：
Daina A;Michielin O;Zoete V
通讯作者：
Zoete V
DOI：
10.3390/molecules14072373
发表时间：
2009-07-03
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Mirjalili MH;Moyano E;Bonfill M;Cusido RM;Palazón J
通讯作者：
Palazón J