Astaxanthin ameliorates benzalkonium chloride–induced dry eye disease through suppressing inflammation and oxidative stress via Keap1-Nrf2/HO-1 signaling pathways

Q1 Health Professions
Ziyu Liu, Yaqiong Li, Jiayu Bao, Siyuan Li, Ya Wen, Peng Zhang, Jun Feng, Yinghui Wang, Lei Tian, Ying Jie
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引用次数: 0

Abstract

Background

Dry eye disease (DED) predominantly results from elevated tear film osmolarity, which can not only cause ocular inconvenience but may lead to visual impairments, severely compromising patient well-being and exerting substantial economic burdens as well. Astaxanthin (AST), a member of the xanthophylls and recognized for its robust abilities to combat inflammation and oxidation, is a common dietary supplement. Nonetheless, the precise molecular pathways through which AST influences DED are still poorly understood.

Methods

Therapeutic targets for AST were identified using data from the GeneCards, PharmMapper, and Swiss Target Prediction databases, and STITCH datasets. Similarly, targets for dry eye disease (DED) were delineated leveraging resources such as the Therapeutic Target Database (TTD), DisGeNET, GeneCards, and OMIM databases, and DrugBank datasets. Interactions among shared targets were charted and displayed using CytoScape 3.9.0. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were conducted to elucidate the functions of pivotal targets within the protein–protein interaction network. Molecular interactions between AST and key targets were confirmed through molecular docking using AutoDock and PyMOL. Molecular dynamics simulations were performed using GROMACS 2022.3. Viability of human corneal epithelial cells (hCEC) was assessed across varying concentrations of AST. A mouse model of experimental DED was developed using 0.1% benzalkonium chloride (BAC), and the animals were administered 100 mg/kg/day of AST orally for 7 days. The efficacy of the treatments was assessed through a series of diagnostic tests to evaluate the condition of the ocular surface after the interventions. The levels of inflammation and oxidative stress were quantitatively assessed using methods such as reverse transcription-polymerase chain reaction (RT-PCR), Western blot, and immunofluorescence staining.

Results

Network pharmacology suggests that AST may alleviate DED by influencing oxidation–reduction signaling pathways and reducing oxidative stress provoked by BAC. In vivo experiments demonstrated an improved overall condition in AST-administered mice in contrast to the control group. Immunofluorescence staining analyses indicated a decrease in Keap1 protein in the corneal tissues of AST-treated mice and a significant increase in Nrf2 and HO-1 protein. In vitro studies demonstrated that AST significantly enhanced cell viability and suppressed reactive oxygen species expression under hyperosmotic (HS) conditions, thereby protecting the human corneal epithelium.

Conclusion

AST is capable of shielding mice from BAC-induced DED, decelerating the progression of DED, and mitigating oxidative stress damage under HS conditions in hCEC cells. The protective impact of AST on DED may operate through stimulating the Keap1-Nrf2/HO-1 signaling pathway. Our research findings indicate that AST may be a promising treatment for DED, offering new insights into DED treatment.

Abstract Image

虾青素通过Keap1-Nrf2/HO-1信号通路抑制炎症和氧化应激,改善苯唑氯铵诱导的干眼病。
背景:干眼病(DED)主要是由泪膜渗透压升高引起的,这不仅会造成眼部不便,还可能导致视力障碍,严重损害患者的健康,并造成巨大的经济负担。虾青素(AST)是叶黄素的一员,因其抗炎症和氧化的强大能力而被认可,是一种常见的膳食补充剂。尽管如此,AST影响DED的确切分子途径仍然知之甚少。方法:使用来自GeneCards、PharmMapper、Swiss Target Prediction数据库和STITCH数据集的数据确定AST的治疗靶点。类似地,干眼病(DED)的靶标是利用治疗靶标数据库(TTD)、DisGeNET、GeneCards和OMIM数据库以及DrugBank数据集等资源来描述的。使用CytoScape 3.9.0绘制和显示共享靶标之间的相互作用。通过基因本体和京都基因与基因组百科全书通路分析,阐明了蛋白-蛋白相互作用网络中关键靶点的功能。通过AutoDock和PyMOL的分子对接,确认AST与关键靶点之间的分子相互作用。采用GROMACS 2022.3进行分子动力学模拟。研究了不同浓度AST对人角膜上皮细胞(hCEC)活力的影响。采用0.1%的苯扎氯铵(BAC)建立实验性DED小鼠模型,动物口服100 mg/kg/天的AST,持续7天。通过一系列的诊断测试来评估干预后眼表的状况,以评估治疗的效果。采用逆转录聚合酶链反应(RT-PCR)、免疫印迹和免疫荧光染色等方法定量评估炎症和氧化应激水平。结果:网络药理学提示AST可能通过影响氧化还原信号通路和减轻BAC引起的氧化应激来缓解DED。体内实验表明,与对照组相比,ast给药小鼠的整体状况有所改善。免疫荧光染色分析显示,ast处理小鼠角膜组织中Keap1蛋白减少,Nrf2和HO-1蛋白显著增加。体外研究表明,AST在高渗(HS)条件下显著提高细胞活力,抑制活性氧表达,从而保护人角膜上皮。结论:AST对小鼠bac诱导的DED具有保护作用,可减缓DED的进展,减轻HS条件下hCEC细胞的氧化应激损伤。AST对DED的保护作用可能通过刺激Keap1-Nrf2/HO-1信号通路发挥作用。我们的研究结果表明AST可能是一种很有前景的治疗DED的方法,为DED的治疗提供了新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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