Ghosh Anita Kirti, Thapa Rubina, Hariani Harsh Nilesh, Volyanyuk Michael, Ogle Sean David, Orloff Karoline Anne, Ankireddy Samatha, Lai Karen, Žiniauskaitė Agnė, Stubbs Evan Benjamin, Kalesnykas Giedrius, Hakkarainen Jenni Johanna, Langert Kelly Ann, Kaja Simon
Graduate Program in Biochemistry and Molecular Biology, Health Sciences Campus, Loyola University Chicago, Maywood, IL 60153, USA.
Visual Neurobiology and Signal Transduction Laboratory, Department of Ophthalmology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.
Pharmaceutics. 2021 Aug 30;13(9):1362. doi: 10.3390/pharmaceutics13091362.
Oxidative stress is a known contributor to the progression of dry eye disease pathophysiology, and previous studies have shown that antioxidant intervention is a promising therapeutic approach to reduce the disease burden and slow disease progression. In this study, we evaluated the pharmacological efficacy of the naturally occurring prenylated chalconoid, xanthohumol, in preclinical models for dry eye disease. Xanthohumol acts by promoting the transcription of phase II antioxidant enzymes. In this study, xanthohumol prevented -butyl hydroperoxide-induced loss of cell viability in human corneal epithelial (HCE-T) cells in a dose-dependent manner and resulted in a significant increase in expression of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), the master regulator of phase II endogenous antioxidant enzymes. Xanthohumol-encapsulating poly(lactic-co-glycolic acid) nanoparticles (PLGA NP) were cytoprotective against oxidative stress in vitro, and significantly reduced ocular surface damage and oxidative stress-associated DNA damage in corneal epithelial cells in the mouse desiccating stress/scopolamine model for dry eye disease in vivo. PLGA NP represent a safe and efficacious drug delivery vehicle for hydrophobic small molecules to the ocular surface. Optimization of NP-based antioxidant formulations with the goal to minimize instillation frequency may represent future therapeutic options for dry eye disease and related ocular surface disease.
氧化应激是已知的干眼疾病病理生理学进展的促成因素，先前的研究表明，抗氧化剂干预是一种有前景的治疗方法，可减轻疾病负担并减缓疾病进展。在本研究中，我们评估了天然存在的异戊烯基查耳酮——黄腐酚在干眼疾病临床前模型中的药理功效。黄腐酚通过促进II期抗氧化酶的转录发挥作用。在本研究中，黄腐酚以剂量依赖性方式预防了叔丁基过氧化氢诱导的人角膜上皮（HCE-T）细胞活力丧失，并导致转录因子核因子红细胞2相关因子2（Nrf2）的表达显著增加，Nrf2是II期内源性抗氧化酶的主要调节因子。包裹黄腐酚的聚乳酸-羟基乙酸共聚物纳米颗粒（PLGA NP）在体外对氧化应激具有细胞保护作用，并且在体内小鼠干眼疾病干燥应激/东莨菪碱模型中，显著减少了角膜上皮细胞的眼表损伤和氧化应激相关的DNA损伤。PLGA NP是一种将疏水性小分子递送至眼表的安全有效的药物递送载体。以最小化滴注频率为目标优化基于纳米颗粒的抗氧化剂配方可能代表干眼疾病和相关眼表疾病的未来治疗选择。
