Dataset Information

Mechanism of Action of VP1-001 in cryAB(R120G)-Associated and Age-Related Cataracts.

ABSTRACT: Purpose:We previously identified an oxysterol, VP1-001 (also known as compound 29), that partially restores the transparency of lenses with cataracts. To understand the mechanism of VP1-001, we tested the ability of its enantiomer, ent-VP1-001, to bind and stabilize ?B-crystallin (cryAB) in vitro and to produce a similar therapeutic effect in cryAB(R120G) mutant and aged wild-type mice with cataracts. VP1-001 and ent-VP1-001 have identical physicochemical properties. These experiments are designed to critically evaluate whether stereoselective binding to cryAB is required for activity. Methods:We compared the binding of VP1-001 and ent-VP1-001 to cryAB using in silico docking, differential scanning fluorimetry (DSF), and microscale thermophoresis (MST). Compounds were delivered by six topical administrations to mouse eyes over 2 weeks, and the effects on cataracts and lens refractive measures in vivo were examined. Additionally, lens epithelial and fiber cell morphologies were assessed via transmission electron microscopy. Results:Docking studies suggested greater binding of VP1-001 into a deep groove in the cryAB dimer compared with ent-VP1-001. Consistent with this prediction, DSF and MST experiments showed that VP1-001 bound cryAB, whereas ent-VP1-001 did not. Accordingly, topical treatment of lenses with ent-VP1-001 had no effect, whereas VP1-001 produced a statistically significant improvement in lens clarity and favorable changes in lens morphology. Conclusions:The ability of VP1-001 to bind native cryAB dimers is important for its ability to reverse lens opacity in mouse models of cataracts.

SUBMITTER: Molnar KS

PROVIDER: S-EPMC6676924 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Mechanism of Action of VP1-001 in cryAB(R120G)-Associated and Age-Related Cataracts.

Molnar Kathleen S KS Dunyak Bryan M BM Su Bonnie B Izrayelit Yevgeniy Y McGlasson-Naumann Brittney B Hamilton Paul D PD Qian Mingxing M Covey Douglas F DF Gestwicki Jason E JE Makley Leah N LN Andley Usha P UP

Investigative ophthalmology & visual science 20190801 10

<h4>Purpose</h4>We previously identified an oxysterol, VP1-001 (also known as compound 29), that partially restores the transparency of lenses with cataracts. To understand the mechanism of VP1-001, we tested the ability of its enantiomer, ent-VP1-001, to bind and stabilize αB-crystallin (cryAB) in vitro and to produce a similar therapeutic effect in cryAB(R120G) mutant and aged wild-type mice with cataracts. VP1-001 and ent-VP1-001 have identical physicochemical properties. These experiments ar ...[more]

PMID: 31369034

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Project description:BackgroundWith the development of the economy, socioeconomic factors, such as inequalities in the status of regional economies and the subsequent effects on health systems, have influenced the status of health. We explored the association between age-related cataracts and socioeconomic indicators, including the regional economy, health systems, and energy industries.MethodsThis was a prospective, multicenter, Chinese population-based, cross-sectional study. A total of 830 participants from seven centers were enrolled. Data on the best-corrected visual acuity (BCVA), Lens Opacities Classification System III (LOCS III) score, Visual Function Index-14 (VF-14) score, total and subscale scores of the 25-item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25), per capita disposable income (PCDI), medical resource-related indicators, and investments in the energy industry were obtained. Associations among these parameters were analyzed.ResultsThe PCDI ranking was correlated with the VF-14 score (R = -0.426, P < 0.01), total score of NEI-VFQ-25 (r = -0.500, P < 0.01), and BCVA (r = 0.278, P < 0.01). The number of health agencies (r1 = 0.267, r2 = -0.303, r3 = -0.291,), practicing or assistant practicing doctors (r1 = -0.283, r2 = 0.427, r3 = 0.502,), registered nurses (r1 = -0.289, r2 = 0.409, r3 = 0.469, P < 0.01), and health technicians (r1 = -0.278, r2 = 0.426, r3 = 0.500, P < 0.01) per 10,000 of the population was each correlated with the BCVA, VF-14 score, and total score of NEI-VFQ-25, respectively. Health expenditure per capita was correlated with the VF-14 score (r = 0.287, P < 0.01) and total score of NEI-VFQ-25 (r = 0.459, P < 0.01). The LOCS III P score was correlated with investments in the energy industry (r = 0.485, P < 0.001).ConclusionsPatients in higher economic regions with greater medical resources show a greater demand to undergo cataract surgery at a better subjective and objective visual function. The energy industry has a significant effect on cataracts, especially the posterior subcapsular cataract, and thus more attention should be paid to people in regions with abundant energy industries.

Project description:ObjectiveTo investigate potential risk factors associated with incident nuclear, cortical, and posterior subcapsular (PSC) cataracts and cataract surgery in participants in the Age-Related Eye Disease Study (AREDS).DesignClinic-based prospective cohort study.ParticipantsPersons (n = 4425) 55 to 80 years of age enrolled in a controlled clinical trial of antioxidant vitamins and minerals, AREDS, for age-related macular degeneration and cataract.MethodsLens photographs were graded centrally for nuclear, cortical, and PSC opacities using the AREDS system for classifying cataracts. Type-specific incident cataracts were defined as an increase in cataract grade from none or mild at baseline to a grade of moderate at follow-up, also with a grade of at least moderate at the final visit, or cataract surgery. Cox regression analyses were used to assess baseline risk factors associated with type-specific opacities and cataract surgery.Main outcome measuresModerate cataract was defined as a grade of 4.0 or more for nuclear opacity, 10% or more involvement within the full visible lens for cortical opacity, and 5% or more involvement of the central 5-mm circle of the lens for PSC opacity. These were graded on baseline and annual lens photographs.ResultsA clinic-based cohort of 4425 persons 55 to 80 years of age at baseline was followed up for an average of 9.8±2.4 years. The following associations were found: increasing age with increased risk of all types of cataract and cataract surgery; males with increased risk of PSC and decreased risk of cortical cataracts; nonwhite persons with increased risk of cortical cataract; hyperopia with decreased risk of PSC, nuclear cataract, and cataract surgery; Centrum (Wyeth Consumer Healthcare, Madison, NJ) use with decreased risk of nuclear cataract; diabetes with increased risk of cortical, PSC cataract, and cataract surgery; higher educational level with decreased risk of cortical cataract; and smoking with increased risk of cortical cataract and cataract surgery. Estrogen replacement therapy in female participants increased the risk of cataract surgery.ConclusionsThese findings largely are consistent with the results of previous studies, providing further evidence for possible modifiable risk factors for age-related cataract.Financial disclosure(s)The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Dataset Information

Mechanism of Action of VP1-001 in cryAB(R120G)-Associated and Age-Related Cataracts.

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Mechanism of Action of VP1-001 in cryAB(R120G)-Associated and Age-Related Cataracts.

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