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Poly(lactic-co-glycolic acid) Nanoparticles Encapsulating the Prenylated Flavonoid, Xanthohumol, Protect Corneal Epithelial Cells from Dry Eye Disease-Associated Oxidative Stress.

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.

SUBMITTER: Ghosh AK

PROVIDER: S-EPMC8471707 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:To investigate corneal sensitivity to selective mechanical, chemical, and thermal stimulation and to evaluate their relation to dry eye symptoms in patients with keratoconus.Corneal sensitivity to mechanical, chemical, and thermal thresholds were determined using a gas esthesiometer in 19 patients with keratoconus (KC group) and in 20 age-matched healthy subjects (control group). Tear film dynamics was assessed by Schirmer I test and by the non-invasive tear film breakup time (NI-BUT). All eyes were examined with a rotating Scheimpflug camera to assess keratoconus severity.KC patients had significatly decreased tear secretion and significantly higher ocular surface disease index (OSDI) scores compared to controls (5.3±2.2 vs. 13.2±2.0 mm and 26.8±15.8 vs. 8.1±2.3; p<0.001). There was no significant difference in NI-BUT between the two groups (KC: 9.8±4.8 vs. control: 10.7±3.8; p>0.05). The mean threshold for selective mechanical (KC: 139.2±25.8 vs. control: 109.1±24.0 ml/min), chemical (KC: 39.4±3.9 vs. control: 35.2±1.9%CO2), heat (KC: 0.91±0.32 vs. control: 0.54±0.26 ?°C) and cold (KC: 1.28±0.27 vs. control: 0.98±0.25 ?°C) stimulation in the KC patients were significantly higher than in the control subjects (p<0.001, for all parameters). No correlation was found between age and mechanical, chemical, heat or cold thresholds in the patients with KC (p>0.05), whereas in the control subjects both mechanical (r = 0.52, p = 0.02), chemical (r = 0.47, p = 0.04), heat (r = 0.26, p = 0.04) and cold threshold (r = 0.40, p = 0.03) increased with age. In the KC group, neither corneal thickness nor tear flow, NI-BUT or OSDI correlated significantly with mechanical, chemical, heat or cold thresholds (p>0.05 for all variables).Corneal sensitivity to different types of stimuli is decreased in patients with keratoconus independently of age and disease severity. The reduction of the sensory input from corneal nerves may contribute to the onset of unpleasant sensations in these patients and might lead to the impaired tear film dynamics.

Project description:PurposeTo evaluate the association between symptoms and signs of dry eye diseases (DED) with corneal biomechanical parameters.MethodsThis cross-sectional study enrolled 81 participants without history of ocular hypertension, glaucoma, keratoconus, corneal edema, contact lens use, diabetes, and ocular surgery. All participants were evaluated for symptoms and signs of DED using OSDI questionnaire, tear film break-up time (TBUT), conjunctival and corneal staining (NEI grading) and Schirmer test. Corneal biomechanical parameters were obtained using Corvis ST. Mixed-effects linear regression analysis was used to determine the association between symptoms and signs of DED with corneal biomechanical parameters. Difference in corneal biomechanical parameter between participants with low (Schirmer value ≤10 mm; LT group) and normal (Schirmer value >10mm; NT group) tear production was analyzed using ANCOVA test.ResultsThe median OSDI scores, TBUT, conjunctival and corneal staining scores as well as Schirmer test were 13±16.5 (range; 0-77), 5.3±4.2 seconds (range; 1.3-11), 0±1 (range; 0-4), 0±2 (ranges; 0-9) and 16±14 mm (range; 0-45) respectively. Regression analysis adjusted with participants' refraction, intraocular pressure, and central corneal thickness showed that OSDI had a negative association with highest concavity radius (P = 0.02). The association between DED signs and corneal biomechanical parameters were found between conjunctival staining scores with second applanation velocity (A2V, P = 0.04), corneal staining scores with second applanation length (A2L, P = 0.01), Schirmer test with first applanation time (A1T, P = 0.04) and first applanation velocity (P = 0.01). In subgroup analysis, there was no difference in corneal biomechanical parameters between participants with low and normal tear production (P>0.05). The associations were found between OSDI with time to highest concavity (P<0.01) and highest displacement of corneal apex (HC-DA, P = 0.04), conjunctival staining scores with A2L (P = 0.01) and A2V (P<0.01) in LT group, and Schirmer test with A1T (P = 0.02) and HC-DA (P = 0.03), corneal staining scores with A2L (P<0.01) in NT group.ConclusionsAccording to in vivo observation with Corvis ST, patients with DED showed more compliant corneas. The increase in dry eye severity was associated with the worsening of corneal biomechanics in both patients with low and normal tear production.

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Poly(lactic-co-glycolic acid) Nanoparticles Encapsulating the Prenylated Flavonoid, Xanthohumol, Protect Corneal Epithelial Cells from Dry Eye Disease-Associated Oxidative Stress.

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