Abstract
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 tert-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.
Highlights
Dry eye disease is an umbrella term describing various subtypes of the disease
The objectives of this study were to determine the cytoprotective effects of xanthohumol in human corneal epithelial cells in vitro, and in the mouse desiccating stress/scopolamine model for dry eye disease in vivo, using both non-formulated and poly(lactic-co-glycolic acid) nanoparticle (PLGA NP)-encapsulating xanthohumol
In order to determine the cytotoxicity of xanthohumol, human corneal epithelial (HCE-T) cells were exposed to a concentration range of xanthohumol (10 nM–100 μM) and incubated for 48 h
Summary
Existing pharmacologic management for dry eye disease targets T cell-mediated inflammatory pathways and in the United States consists of ophthalmic formulations of cyclosporine (Restasis® or CequaTM) or the lymphocyte function-associated antigen 1 inhibitor, lifitegrast (Xiidra® ). Both agents are associated with limited efficacy and adverse effects in up to. Elevated levels of oxidative stress have been identified in patients with dry eye disease [5,6], while hyperosmolar conditions cause oxidative stress in cultured corneal epithelial cells [7]. Lacrimal gland dysfunction as a result of mitochondrial oxidative stress produces an ocular phenotype reminiscent of dry eye disease in mice [9,10]
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