Epidemiologic association and shared genetic architecture between cataract and hearing difficulties among middle-aged and older adults.

Age-related cataract and hearing difficulties are major sensory disorders that often co-exist in the global-wide elderly and have a tangible influence on the quality of life. However, the epidemiologic association between cataract and hearing difficulties remains unexplored, while little is known about whether the two share their genetic etiology. We first investigated the clinical association between cataract and hearing difficulties using the UK Biobank covering 502,543 individuals. Both unmatched analysis (adjusted for confounders) and a matched analysis (one control matched for each patient with cataract according to confounding factors) were undertaken and confirmed that cataract was associated with hearing difficulties (OR, 2.12; 95% CI, 1.98-2.27; OR, 2.03; 95% CI, 1.86-2.23, respectively). Furthermore, we explored and quantified the shared genetic architecture of these two complex sensory disorders at the common variant level using the bivariate causal mixture model (MiXeR) and conditional/conjunctional false discovery rate method based on the largest available genome-wide association studies of cataract (N = 585,243) and hearing difficulties (N = 323,978). Despite detecting only a negligible genetic correlation, we observe polygenic overlap between cataract and hearing difficulties and identify 6 shared loci with mixed directions of effects. Follow-up analysis of the shared loci implicates candidate genes QKI, STK17A, TYR, NSF, and TCF4 likely contribute to the pathophysiology of cataracts and hearing difficulties. In conclusion, this study demonstrates the presence of epidemiologic association between cataract and hearing difficulties and provides new insights into the shared genetic architecture of these two disorders at the common variant level.

A role for YAP/FOXM1/Nrf2 axis in oxidative stress and apoptosis of cataract induced by UVB irradiation.

This study aims to investigate the hypothesis that Yes-associated protein (YAP) significantly regulates antioxidant potential and anti-apoptosis in UVB-induced cataract by exploring the underlying molecular mechanisms. To investigate the association between YAP and cataract, various experimental techniques were employed, including cell viability assessment, Annexin V FITC/PI assay, measurement of ROS production, RT-PCR, Western blot assay, and Immunoprecipitation. UVB exposure on human lens epithelium cells (HLECs) reduced total and nuclear YAP protein expression, increased cleaved/pro-caspase 3 ratios, decreased cell viability, and elevated ROS levels compared to controls. Similar Western blot results were observed in in vivo experiments involving UVB-treated mice. YAP knockdown in vitro demonstrated a decrease in the protein expression of FOXM1, Nrf2, and HO-1, which correlated with the mRNA expression, accompanied by an increase in cell apoptosis, caspase 3 activation, and the release of ROS. Conversely, YAP overexpression mitigated these effects induced by UVB irradiation. Immunoprecipitation revealed a FOXM1-YAP interaction. Notably, inhibiting FOXM1 decreased Nrf2 and HO-1, activating caspase 3. Additionally, administering the ROS inhibitor N-acetyl-L-cysteine (NAC) effectively mitigated the apoptotic effects induced by oxidative stress from UVB irradiation, rescuing the protein expression levels of YAP, FOXM1, Nrf2, and HO-1. The initial findings of our study demonstrate the existence of a feedback loop involving YAP, FOXM1, Nrf2, and ROS that significantly influences the cell apoptosis in HLECs under UVB-induced oxidative stress.

High glucose promotes osteogenic differentiation of human lens epithelial cells through hypoxia-inducible factor (HIF) activation.

Cataract, a leading cause of blindness, is characterised by lens opacification. Type 2 diabetes is associated with a two- to fivefold higher prevalence of cataracts. The risk of cataract formation increases with the duration of diabetes and the severity of hyperglycaemia. Hydroxyapatite deposition is present in cataractous lenses that could be the consequence of osteogenic differentiation and calcification of lens epithelial cells (LECs). We hypothesised that hyperglycaemia might promote the osteogenic differentiation of human LECs (HuLECs). Osteogenic medium (OM) containing excess phosphate and calcium with normal (1 g/L) or high (4.5 g/L) glucose was used to induce HuLEC calcification. High glucose accelerated and intensified OM-induced calcification of HuLECs, which was accompanied by hyperglycaemia-induced upregulation of the osteogenic markers Runx2, Sox9, alkaline phosphatase and osteocalcin, as well as nuclear translocation of Runx2. High glucose-induced calcification was abolished in Runx2-deficient HuLECs. Additionally, high glucose stabilised the regulatory alpha subunits of hypoxia-inducible factor 1 (HIF-1), triggered nuclear translocation of HIF-1α and increased the expression of HIF-1 target genes. Gene silencing of HIF-1α or HIF-2α attenuated hyperglycaemia-induced calcification of HuLECs, while hypoxia mimetics (desferrioxamine, CoCl2) enhanced calcification of HuLECs under normal glucose conditions. Overall, this study suggests that high glucose promotes HuLEC calcification via Runx2 and the activation of the HIF-1 signalling pathway. These findings may provide new insights into the pathogenesis of diabetic cataracts, shedding light on potential factors for intervention to treat this sight-threatening condition.

LncRNA MEG3 regulates ferroptosis of lens epithelial cells via PTBP1/GPX4 axis to participate in age-related cataract.

Age-related cataract (ARC) is regarded as the principal cause of vision impairment among the aged. The regulatory role of long noncoding RNAs (LncRNAs) in ARC remains unclear. The lncRNA maternally expressed gene 3 (MEG3) has been reported to promote ARC progression, and the underlying mechanism was further investigated in this study. Lens epithelium samples were collected to verify the expression of MEG3. Lens epithelial cells (LECs) were treated with H2O2 to mimic microenvironment of ARC in vitro. Cell viability, reactive oxygen species, and ferroptosis were evaluated during the in viro experiments. In the present work, lncRNA MEG3 was highly expressed in ARC group, compared with normal group. MEG3 was induced, cell viability and glutathione peroxidase 4 (GPX4) level were inhibited, and ferroptosis was promoted in H2O2 treated LECs. LncRNA MEG3 silence reversed the effects of H2O2 on viability and ferroptosis in LECs. Thereafter, lncRNA MEG3 was found to bind to PTBP1 for GPX4 degradation. Silencing of GPX4 reversed the regulation of lncRNA MEG3 inhibition in H2O2-treated LECs. To sum up, lncRNA MEG3 exhibited high expression in ARC. In H2O2-induced LECs, inhibition of lncRNA MEG3 accelerated cell viability and repressed ferroptosis by interaction with PTBP1 for GPX4 messenger RNA decay. Targeting lncRNA MEG3 may be a novel treatment of ARC.

Cataract Surgery and Cognitive Benefits in the Older Person: A Systematic Review and Meta-analysis.

TOPIC: This systematic review and meta-analysis aims to clarify the association of cataract surgery with cognitive impairment and dementia. CLINICAL RELEVANCE: The association between vision impairment and cognitive decline is well-established. However, the cognitive benefits of cataract surgery are less clear. Given the lack of cure for dementia, identifying modifiable risk factors is key in caring for patients with cognitive deficits. METHODS: The study was conducted following Preferred Reporting Items for Systematic Review and Meta-analyses guidelines. PubMed, Embase, and Cochrane Library were searched from inception through October 11, 2022, for studies reporting the effect of cataract surgery on cognitive impairment and dementia. We pooled maximally adjusted hazard ratios (HRs) for dichotomous outcomes and ratio of means (RoM) for continuous outcomes using a random-effects model. Heterogeneity was examined using sensitivity and subgroup analyses. The quality of evidence was evaluated using the Newcastle-Ottawa scale, Cochrane risk-of-bias tool for randomized trials, and Grading of Recommendations, Assessment, Development and Evaluations (GRADE) guidelines. RESULTS: This review included 24 articles comprising 558 276 participants, of which 19 articles were analyzed qualitatively. The bias of studies ranged from low to moderate, and GRADE extended from very low to low. Cataract surgery was associated with a 25% reduced risk of long-term cognitive decline compared with those with uncorrected cataracts (HR, 0.75; 95% confidence interval [CI], 0.72-0.78). This cognitive benefit was seen across various cognitive outcomes and remained robust to sensitivity analyses. Participants who underwent cataract surgery showed a similar risk of long-term cognitive decline as healthy controls without cataracts (HR, 0.84; 95% CI, 0.66-1.06). Additionally, cataract surgery was associated with a 4% improvement in short-term cognitive test scores among participants with normal cognition (RoM, 0.96; 95% CI, 0.94-0.99), but no significant association was observed among participants with preexisting cognitive impairment. DISCUSSION: Cataract surgery may be associated with a lower risk of cognitive impairment and dementia, and cataract-associated vision impairment may be a modifiable risk factor for cognitive decline. Physicians should be aware of the cognitive sequelae of cataracts and the possible benefits of surgery. The cognitive benefits of cataract surgery should be investigated further in randomized trials. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Complications, Visual Acuity, and Refractive Error 3 Years after Secondary Intraocular Lens Implantation for Pediatric Aphakia.

PURPOSE: To report the cumulative incidence of complications and to describe refractive error and visual acuity (VA) outcomes in children undergoing secondary intraocular lens (IOL) implantation after previous surgery for nontraumatic cataract. DESIGN: Pediatric cataract registry. PARTICIPANTS: Eighty children (108 eyes: 60 bilateral, 48 unilateral) undergoing lensectomy at younger than 13 years of age. METHODS: Annual data collection from medical record review through 5 years after lensectomy. MAIN OUTCOME MEASURES: Cumulative incidence of newly emergent complications after secondary IOL implantation; refractive error and VA by 5 years after lensectomy. RESULTS: Median follow-up after secondary IOL implantation was 2.7 years (interquartile range [IQR], 0.8-3.3 years; range, 0.6-5.0 years) for bilateral and 2.1 years (range, 0.5-6.4 years) for unilateral cases. A common complication after secondary IOL implantation was a glaucoma-related adverse event (GRAE; glaucoma or glaucoma suspect); the cumulative incidence was 17% (95% confidence interval [CI], 3%-29%) in bilateral cases and 12% (95% CI, 0%-23%) in unilateral cases. The cumulative incidence of surgery for visual axis opacification was 2% (95% CI, 0%-7%) for bilateral cases and 4% (95% CI, 0%-10%) for unilateral cases. The median prediction error within 90 days of implantation was 0.88 diopter (D; IQR, -0.50 to +3.00 D) less hyperopic than intended among 21 eyes for bilateral cases and 1.50 D (IQR, -0.25 to +2.38 D) less among 19 unilateral cases. The median spherical equivalent refractive error at 5 years (at a median of 5.1 years of age) in eyes receiving a secondary IOL was +0.50 D (IQR, -2.38 to +2.94 D) for 48 bilateral cases and +0.06 D (IQR, -2.25 to +0.75 D) for 22 unilateral cases. Median monocular VA at 5 years was 20/63 (IQR, 20/50-20/100) for bilateral cases (n = 42) and 20/400 (IQR, 20/160-20/800) for unilateral cases (n = 33). CONCLUSIONS: Eyes with secondary IOL implantation have a risk of developing new GRAEs. Five years after lensectomy (approximately 2.5 years after secondary IOL implantation), the average refractive error was less hyperopic than desired given the anticipated further myopic shift before refraction stabilizes. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Retinal Tear and Retinal Detachment Following Cataract Surgery in Eyes with a Previous History of Treated Phakic Retinal Tears.

OBJECTIVE: To investigate the incidence and outcomes of retinal tear (RT) and retinal detachment (RD) after cataract extraction in patients with a history of previous phakic RT. DESIGN: Retrospective case series. SUBJECTS: Phakic eyes with RT that were successfully treated with laser photocoagulation or cryotherapy and subsequently underwent cataract surgery. METHOD: A retrospective review of phakic eyes treated for RTs between April 1, 2012 and May 31, 2023 was performed. Exclusions included prior vitreoretinal surgery before cataract removal and follow-up of less than 6 months post-cataract surgery. MAIN OUTCOME MEASURES: The incidence of RTs and RDs after cataract surgery, along with visual and anatomic outcomes. RESULTS: Of 12,109 phakic eyes treated for RTs, 1039 (8.6%) eyes underwent cataract surgery. After exclusions, 713 eyes of 660 patients were studied. The mean (standard deviation, SD) follow-up period post-cataract surgery was 34.8 (24.6) months with a median of 239 and 246 days to a new RT or RD development. The overall incidence for diagnosis of post-cataract surgery RT and RD was 7.3% (52/713) (2.9% and 4.3%, respectively), with a one-year incidence of 5.6% (2.2% and 3.4%, respectively). Multivariable regression analysis identified a higher risk of RT/RD among younger individuals (odds ratio [OR] 1.034; 95% confidence interval [CI] 1.004-1.065, P=0.028), males (OR 2.058; 95% CI 1.110-3.816, P=0.022), and those with shorter interval between laser treatment and cataract surgery (OR 1.001; 95% CI 1.001-1.001, P=0.011). Single surgery anatomic success for the RD repair was achieved in 25 eyes (80.6%) at 3 months, with a 100% final reattachment rate. The median final logMAR visual acuity was 0.10 (20/25) for RT, showing no significant change from post-cataract surgery, and 0.18 (20/30) for RD, a significant worsening from after cataract surgery. CONCLUSION: One year post-cataract surgery, the rate of diagnosed RT and RD in patients with previously treated RTs was relatively high, occurring in nearly 1 in 18 eyes. Higher risk was noted among younger individuals, males, and patients with a shorter interval between initial treatment for RT and cataract surgery. RD repair achieved good anatomical results, but vision declined.

Triamcinolone Acetonide Subconjunctival Injection as Stand-alone Inflammation Prophylaxis after Phacoemulsification Cataract Surgery.

PURPOSE: To compare the effectiveness and safety of a single injection of subconjunctival triamcinolone acetonide (TA) with that of postoperative topical prednisolone acetate (PA) with and without nonsteroidal anti-inflammatory drugs (NSAIDs) for cataract surgery prophylaxis. DESIGN: Retrospective, comparative effectiveness cohort study. PARTICIPANTS: Patients at Kaiser Permanente Northern California from 2018 through 2021. INTERVENTION: Exposure groups included topical PA with or without NSAID and subconjunctival injection of TA (Kenalog; Bristol-Myers-Squibb) 10 mg/ml or 40 mg/ml in a low dose (1.0-3.0 mg) or high dose (3.1-5.0 mg). MAIN OUTCOME MEASURES: The adjusted odds ratio (OR) and 95% confidence interval (CI) for the association of postoperative macular edema (ME) and iritis diagnoses 15 to 120 days after surgery (effectiveness measures) and a glaucoma-related event (safety measure) between 15 days and 1 year after surgery. RESULTS: Of 69 832 eligible patient-eyes, postoperative ME, iritis, and a glaucoma-related event occurred on average in 1.3%, 0.8%, and 3.4% of eyes in the topical groups and 0.8%, 0.5%, and 2.8% of eyes in the injection groups, respectively. In multivariable analysis, compared with the PA reference group, the PA plus NSAID group had a lower OR of ME (OR, 0.88; 95% CI, 0.74-1.04; P = 0.135). and all injection groups had even lower odds, with the high-dose TA 10-mg/ml group reaching statistical significance (OR, 0.64; 95% CI, 0.43-0.97; P = 0.033). A trend of lower odds of a postoperative iritis diagnosis was noted in the high-strength (40 mg/ml) groups. For postoperative glaucoma-related events, compared with PA, the TA 10-mg/ml low-dose group showed lower odds (OR, 0.69; 95% CI, 0.55-0.86; P = 0.001), the TA 10-mg/ml high-dose group showed similar odds (OR, 0.90; 95% CI, 0.70-1.15; P = 0.40), and the TA 40-mg/ml low-dose and high-dose groups showed higher odds of an event occurring (OR, 1.46 [95% CI, 0.98-2.18; P = 0.062] and OR, 2.14 [95% CI, 1.36-3.37; P = 0.001], respectively). CONCLUSIONS: The TA 10-mg/ml high-dose (4 mg) group was associated with a lower risk of postoperative ME and a similar risk of glaucoma-related events compared with the topical groups. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

The Effect of Racial/Ethnic and Socioeconomic Differences on Visual Impairment Prior to Cataract Surgery.

PURPOSE: To compare the associations of race/ethnicity and socioeconomic status (SES) with visual impairment (VI) prior to surgical removal of cataracts across two large health systems in the U.S. Mid-Atlantic region. DESIGN: Multi-institutional cross-sectional data study. PARTICIPANTS: Patients aged 65 and older who underwent cataract surgery at Johns Hopkins Hospital (JHH) and Kaiser Permanente (KP) between January 1, 2017 and December 31, 2019. METHODS: Covariates included patient age, sex, smoking status, surgery laterality, Charlson Comorbidity Index (CCI), and ocular comorbidities. Multivariable generalized estimating equation models were used to examine the association of race/ethnicity and area deprivation index (ADI) with visual acuity. MAIN OUTCOME MEASURES: Visual acuity prior to cataract surgery was assessed using Log of Minimum Angle of Resolution (logMAR). Race/ethnicity and ADI were the main exposures of interest. RESULTS: At JHH, 11,509 patients (17,731 eyes) were included, while KP had 7,143 patients (10,542 eyes). After adjusting for covariates, Black (ß, 0.49), Asian (ß, 0.83), and Hispanic patients (ß, 0.95) were more likely to have worse visual acuity secondary to cataracts at JHH (P < 0.001 for all) compared to White patients. Similarly, at KP, Black (ß, 0.56), Asian (ß, 0.70), and Hispanic patients (ß, 0.89) were more likely to have worse visual acuity (P < 0.001 for all) compared to White patients. Compared to those living in the least disadvantaged neighborhoods (Quartile [Q]1 ADI) at JHH, higher ADI quartiles (more deprived) were more likely to have worse visual acuity (ß, 0.27; P = 0.001 for Q2, ß, 0.40; P = 0.001 for Q3, ß, 0.95; P < 0.001 for Q4). There was no significant association found between ADI and VI secondary to cataracts at KP. CONCLUSIONS: Among older adults, non-White race/ethnicity was independently associated with VI secondary to cataracts in two large health systems in the U.S. Mid-Atlantic region, after adjustment for ADI. Area deprivation was also associated with VI but only in the JHH system. Our study suggests that non-White patients and those with lower SES are at greater risk of VI secondary to cataracts possibly due to social, structural and institutional barriers.

Intraocular Pressure Spike Following Stand-Alone Phacoemulsification in the IRIS® Registry (Intelligent Research in Sight).

PURPOSE: To evaluate risk factors for intraocular pressure (IOP) spike after cataract surgery using the IRIS® Registry (Intelligent Research in Sight). DESIGN: Retrospective clinical cohort study. PARTICIPANTS: Adults with IRIS Registry data who underwent stand-alone phacoemulsification from January 1, 2013, through September 30, 2019. METHODS: Intraocular pressure spike was defined as postoperative IOP of > 30 mmHg and > 10 mmHg from the baseline within the first postoperative week. Odds ratios (ORs) for demographic and clinical characteristics were calculated with univariable and multivariable logistic regression analyses. MAIN OUTCOME MEASURES: Incidence and OR of IOP spike. RESULTS: We analyzed data from 1 191 034 eyes (patient mean age, 71.3 years; 61.2% female sex; and 24.8% with glaucoma). An IOP spike occurred in 3.7% of all eyes, 5.2% of eyes with glaucoma, and 3.2% of eyes without glaucoma (P < 0.0001). Multivariable analyses of all eyes indicated a greater risk of IOP spike with higher baseline IOP (OR, 1.57 per 3 mmHg), male sex (OR, 1.79), glaucoma (OR, 1.20), Black race (OR, 1.39 vs. Asian and 1.21 vs. Hispanic), older age (OR, 1.07 per 10 years), and complex surgery coding (OR, 1.22; all P < 0.0001). Diabetes (OR, 0.90) and aphakia after surgery (OR, 0.60) seemed to be protective against IOP spike (both P < 0.0001). Compared with glaucoma suspects, ocular hypertension (OR, 1.55), pigmentary glaucoma (OR, 1.56), and pseudoexfoliative glaucoma (OR, 1.52) showed a greater risk of IOP spike and normal-tension glaucoma (OR, 0.55), suspected primary angle closure (PAC; OR, 0.67), and PAC glaucoma (OR, 0.81) showed less risk (all P < 0.0001). Using more baseline glaucoma medications was associated with IOP spike (OR, 1.18 per medication), whereas topical ß-blocker use (OR, 0.68) was protective (both P < 0.0001). CONCLUSIONS: Higher baseline IOP, male sex, glaucoma, Black race, older age, and complex cataract coding were associated with early postoperative IOP spike, whereas diabetes and postoperative aphakia were protective against a spike after stand-alone phacoemulsification. Glaucomatous eyes demonstrated different risk profiles dependent on glaucoma subtype. The findings may help surgeons to stratify and mitigate the risk of IOP spike after cataract surgery. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Novel molecular, structural and clinical findings in an Italian cohort of congenital cataract.

The current genetic diagnostic workup of congenital cataract (CC) is mainly based on NGS panels, whereas exome sequencing (ES) has occasionally been employed. In this multicentre study, we investigated by ES the detection yield, mutational spectrum and genotype-phenotype correlations in a CC cohort recruited between 2020 and mid-2022. The cohort consisted of 67 affected individuals from 51 unrelated families and included both non-syndromic (75%) and syndromic (25%) phenotypes, with extra-CC ocular/visual features present in both groups (48% and 76%, respectively). The functional effect of variants was predicted by 3D modelling and hydropathy properties changes. Variant clustering was used for the in-depth assessment of genotype-phenotype correlations. A diagnostic (pathogenic or likely pathogenic) variant was identified in 19 out of 51 probands/families (~37%). In a further 14 probands/families a candidate variant was identified: in 12 families a VUS was detected, of which 9 were considered plausibly pathogenic (i.e., 4 or 5 points according to ACMG criteria), while in 2 probands ES identified a single variant in an autosomal recessive gene associated with CC. Eighteen probands/families, manifesting primarily non-syndromic CC (15/18, 83%), remained unsolved. The identified variants (8 P, 12 LP, 10 VUS-PP, and 5 VUS), half of which were unreported in the literature, affected five functional categories of genes involved in transcription/splicing, lens formation/homeostasis (i.e., crystallin genes), membrane signalling, cell-cell interaction, and immune response. A phenotype-specific variant clustering was observed in four genes (KIF1A, MAF, PAX6, SPTAN1), whereas variable expressivity and potential phenotypic expansion in two (BCOR, NHS) and five genes (CWC27, KIF1A, IFIH1, PAX6, SPTAN1), respectively. Finally, ES allowed to detect variants in six genes not commonly included in commercial CC panels. These findings broaden the genotype-phenotype correlations in one of the largest CC cohorts tested by ES, providing novel insights into the underlying pathogenetic mechanisms and emphasising the power of ES as first-tier test.

Intake of Blueberries, Anthocyanins, and Risk of Eye Disease in Women.

BACKGROUND: Blueberries and anthocyanins, their key bioactive component, may improve eye health. However, few long-term studies have examined blueberries and anthocyanins with cataract and age-related macular degeneration (AMD). OBJECTIVES: To investigate the prospective association between blueberry and anthocyanin intake with incident cataract, total AMD, and visually significant AMD among middle-aged and older women. METHODS: A total of 36,653 and 35,402 women initially free of AMD and cataract, respectively, aged ≥45 y from the Women's Health Study provided semiquantitative food frequency questionnaire data on blueberry intake categorized as none, 1-3 servings/mo, 1 serving/wk, or ≥2 servings/wk, plus a combined category of ≥1 serving/wk. Total anthocyanin intake and major subclasses were energy-adjusted and categorized into quintiles. Self-reported risk factors of eye disease were adjusted in multivariable hazard ratios (HRs) (95% confidence intervals [CIs]) of confirmed cataract, AMD, and visually significant AMD with mean follow-up of 11 y. RESULTS: Among the participants, 10.5% consumed ≥1 serving/wk of blueberries, with mean total anthocyanin intake of 11.2 mg/d. Compared to no blueberry intake, women consuming 1-3 servings/mo, 1 serving/wk, and ≥2 servings/wk had corresponding multivariable HRs of total AMD of 0.90 (95% CI: 0.73, 1.11), 0.71 (95% CI: 0.50, 1.00), and 0.36 (95% CI: 0.14, 0.93) (Ptrend = 0.011); those consuming ≥1 servings/wk had an HR of 0.68 (95% CI: 0.47, 0.98). A similar magnitude of HRs were found for visually significant AMD (Ptrend = 0.012) but not for cataract. There were no significant associations between increasing total anthocyanin quintiles and total and visually significant AMD, but there was a modest inverse association with cataract (Ptrend = 0.022), driven by a 10% reduction in cataract in the upper 2 quintiles. CONCLUSIONS: Greater blueberry intake significantly reduced total AMD, but not visually significant AMD or cataract. However, the magnitude of effect for visually significant AMD was similar to total AMD. There was a modest but significant inverse association between dietary anthocyanin intake with cataract but not AMD.

Metabolomic profiling of the aqueous humor in patients with pediatric cataract.

Pediatric cataract, including congenital and developmental cataract, is a kind of pediatric vision-threatening disease with extensive phenotypic heterogeneity and multiple mechanisms. We aimed to investigate the metabolite profile of aqueous humor (AH) in patients with pediatric cataracts, and identify underlying mutual correlations between differential metabolites. Metabolomic profiles of AH were analyzed and compared between pediatric cataract patients (n = 33) and age-related cataract patients without metabolic diseases (n = 29), using global untargeted metabolomics with ultra-high-performance liquid chromatography tandem mass spectrometry. Principal component analysis, partial least squares discriminant analysis and heat map were applied. Enriched pathway analysis was conducted using Kyoto Encyclopedia of Genes and Genomes. Receiver-operating characteristic (ROC) analyses were employed to select potential biomarkers. A total of 318 metabolites were identified, of which 54 differential metabolites (25 upregulated and 29 downregulated) were detected in pediatric cataract group compared with controls (variable importance of projection >1.0, fold change ≥1.5 or ≤ 0.667 and P < 0.05). A significant accumulation of N-Acetyl-Dl-glutamic acid was observed in pediatric cataract group. The differential metabolites were mainly enriched in histidine metabolism (increased L-Histidine and decreased 1-Methylhistamine) and the tryptophan metabolism (increased N-Formylkynurenine and L-Kynurenine). 5-Aminosalicylic acid showed strong positive mutual inter-correlation with L-Tyrosinemethylester and N,N-Diethylethanolamine, both of which were down-regulated in pediatric cataract group. The ROC analysis implied 11 metabolites served as potential biomarkers for pediatric cataract patients (all area under the ROC curve ≥0.900). These results illustrated novel potential metabolites and metabolic pathways in pediatric cataract, which provides new insights into the pathophysiology of pediatric cataract.

Comparison of baseline cataract rates in AB and TL wildtype zebrafish strains.

Zebrafish are an outstanding model for assessing the involvement of genes in paediatric cataracts. Gene discovery for cataracts is enhanced by manipulation of the genome of zebrafish embryos and comparing the phenotypes of mutant progeny with the wildtype embryos. However, wildtype laboratory fish can also develop cataracts, potentially confounding the results. In this study, we compared the baseline cataract rate between two commonly used wildtype laboratory strains, AB and TL, and also an outbred transgenic line with mCherry reporter. We assessed a total of 805 lens images of fish at 4 days post-fertilisation for cataracts and scored each cataract observed as mild, moderate or severe. We found that the AB strain had a cataract rate of 16.2%, TL had 8.9%, and mCherry had 0.7% and these rates were significantly different. We found that TL strain had a lower rate of mild cataracts than AB fish, however, the rate of moderate and severe phenotypes in the AB and the TL strain was similar. Overall, we showed that the baseline cataract rate varies significantly between the strains housed in a single facility and conclude that baseline rates of cataracts should be assessed when planning experiments to assess the genetic causes of cataracts.

Comprehensive analysis of the miRNA-mRNA regulatory network involved in spontaneous recovery of an H2O2-induced zebrafish cataract model.

OBJECTIVE: To identify the hub miRNAs and mRNAs contributing to the spontaneous recovery of an H2O2-induced zebrafish cataract model. METHODS: Zebrafishes were divided into three groups, i.e., Group A, which included normal control fish (day 0), and Groups B and C, where fish were injected with 2.5% hydrogen peroxide into the anterior chamber and reared for 14 and 30 days, respectively. Fish eyes were examined by stereomicroscope photography and optical coherence tomography (OCT). RNA profiles of fish lenses were detected by RNA sequencing. Differentially expressed genes (DEGs) and differentially expressed miRNAs (DEmiRs) were identified among three groups. The DEGs and DEmiRs, which changed in opposite positions between "B vs. A" and "C vs. B" were defined as ODGs (opposite positions changed DEGs) and ODmiRs (opposite positions changed DEmiRs). Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) analysis were carried out by R language. The protein-protein interaction network (PPI) was constructed using STRING. Potential targets of miRNAs were obtained using miRanda. miRNA-mRNA networks were constructed by Cytoscape. RESULTS: The fish lens opacity formed on day 14 and recovered to transparent on day 30 after injection. Compared to group B, 1366 DEGs and 54 DEmiRs were identified in group C. "C vs. B" DEGs were enriched in gene clusters related to development and oxidative phosphorylation. Target genes of DEmiRs were enriched in clusters such as development and cysteine metabolism. Among three groups, 786 ODGs and 27 ODmiRs were identified, and 480 ODGs were predicted as targets of ODmiRs. Target ODGs were enriched in pathways related to methionine metabolism, ubiquitin, sensory system development, and structural constituents of the eye lens. In addition, we established an ODmiRs-ODGs regulation network. CONCLUSION: We identified several hub mRNAs and altered miRNAs in the formation and reversal of zebrafish cataracts. These hub miRNAs/mRNAs could be potential targets for the non-surgical treatment of ARC.

Loss of αBa-crystallin, but not αA-crystallin, increases age-related cataract in the zebrafish lens.

The vertebrate eye lens is an unusual organ in that most of its cells lack nuclei and the ability to replace aging protein. The small heat shock protein α-crystallins evolved to become key components of this lens, possibly because of their ability to prevent aggregation of aging protein that would otherwise lead to lens opacity. Most vertebrates express two α-crystallins, αA- and αB-crystallin, and mutations in each are linked to human cataract. In a mouse knockout model only the loss of αA-crystallin led to early-stage lens cataract. We have used the zebrafish as a model system to investigate the role of α-crystallins during lens development. Interestingly, while zebrafish express one lens-specific αA-crystallin gene (cryaa), they express two αB-crystallin genes, with one evolving lens specificity (cryaba) and the other retaining the broad expression of its mammalian ortholog (cryabb). In this study we used individual mutant zebrafish lines for all three α-crystallin genes to determine the impact of their loss on age-related cataract. Surprisingly, unlike mouse knockout models, we found that the loss of the αBa-crystallin gene cryaba led to an increase in lens opacity compared to cryaa null fish at 24 months of age. Loss of αA-crystallin did not increase the prevalence of cataract. We also used single cell RNA-Seq and RT-qPCR data to show a shift in the lens expression of zebrafish α-crystallins between 5 and 10 days post fertilization (dpf), with 5 and 6 dpf lenses expressing cryaa almost exclusively, and expression of cryaba and cryabb becoming more prominent after 10 dpf. These data show that cryaa is the primary α-crystallin during early lens development, while the protective role for cryaba becomes more important during lens aging. This study is the first to quantify cataract prevalence in wild-type aging zebrafish, showing that lens opacities develop in approximately 25% of fish by 18 months of age. None of the three α-crystallin mutants showed a compensatory increase in the expression of the remaining two crystallins, or in the abundant ßB1-crystallin. Overall, these findings indicate an ontogenetic shift in the functional importance of individual α-crystallins during zebrafish lens development. Our finding that the lens-specific zebrafish αBa-crystallin plays the leading role in preventing age-related cataract adds a new twist to our understanding of vertebrate lens evolution.

The role of the SIRT1/NF-κB/NLRP3 pathway in the pyroptosis of lens epithelial cells under shortwave blue light radiation.

Cataracts are the world's number one blinding eye disease. Cataracts can only be effectively treated surgically, although there is a chance of surgical complications. One of the pathogenic processes of cataracts is oxidative stress, which closely correlated with pyroptosis. SIRT1 is essential for the regulation of pyroptosis. Nevertheless, the role of SIRT1 in formation of cataracts is unclear. In this work, we developed an in vitro model of shortwave blue light (SWBL)-induced scotomization in human lens epithelial cells (HLECs) and an in vivo model of SWBL-induced cataracts in rats. The study aimed to understand how the SIRT1/NF-κB/NLRP3 pathway functions. Additionally, the evaluation included cell death and the release of lactate dehydrogenase (LDH), a cytotoxicity marker, from injured cells. First, we discovered that SWBL exposure resulted in lens clouding in Sprague- Dawley (SD) rats and that the degree of clouding was positively linked to the duration of irradiation. Second, we discovered that SIRT1 exhibited antioxidant properties and was connected to the NF-κB/NLRP3 pathway. SWBL irradiation inhibited SIRT1 expression, exacerbated oxidative stress, and promoted nuclear translocation of NF-κB and the activation of the NLRP3 inflammasome, which caused LEC pyroptosis and ultimately led to cataract formation. Transient transfection to increase the expression of SIRT1 decreased the protein expression levels of NF-κB, NLRP3, caspase-1, and GSDMD, inhibited HLEC pyroptosis, and reduced the release of LDH, providing a potential method for cataract prevention and treatment.

CircSTRBP contributes to H2O2-induced lens epithelium cell dysfunction through increasing NOX4 mRNA stability by recruiting IGF2BP1.

Previous studies have shown that the development of age-related cataract (ARC) is involved in lens epithelium dysfunction, which is associated with abnormally expressed circular RNAs (circRNAs). The current work aims to probe the role of circSTRBP (hsa_circ_0088,427) in hydrogen peroxide (H2O2)-induced lens epitheliums. Lens epithelium tissues were harvested from ARC or normal subjects (n = 23). CircSTRBP, spermatid perinuclear RNA binding protein (STRBP), and nicotinamide adenine dinucleotide phosphate oxidase subunit 4 (NOX4) levels were measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell proliferation, cycle progression, and apoptosis were assessed using 5-ethynyl-2'-deoxyuridine (EdU), Cell Counting Kit-8 (CCK-8), and flow cytometry assays. Caspase 3 activity, reactive oxygen species (ROS), malondialdehyde (MDA), and Glutathione peroxidases (GSH-PX) levels were detected using corresponding kits. NOX4 protein level was determined using Western blot. The interaction between insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) and circSTRBP or NOX4 was assessed through RNA immunoprecipitation (RIP). CircSTRBP and NOX4 abundances were increased in lens epithelium samples from ARC patients and H2O2-treated SRA01/04 cells. CircSTRBP knockdown might abolish H2O2-triggered SRA01/04 cell proliferation repression and apoptosis and oxidative stress promotion. In mechanism, circSTRBP is bound with IGF2BP1 and improves the stability and expression of NOX4 mRNA in SRA01/04 cells. CircSTRBP facilitated H2O2-induced SRA01/04 cell apoptosis and oxidative stress through by enhancing NOX4 mRNA stability via recruiting IGF2BP1, providing novel insights for ARC progression and treatment.

In vivo quasi-elastic light scattering detects molecular changes in the lenses of adolescents with Down syndrome.

Down syndrome (DS) is the most common chromosomal disorder in humans. DS is associated with increased prevalence of several ocular sequelae, including characteristic blue-dot cerulean cataract. DS is accompanied by age-dependent accumulation of Alzheimer's disease (AD) amyloid-ß (Aß) peptides and amyloid pathology in the brain and comorbid early-onset Aß amyloidopathy and colocalizing cataracts in the lens. Quasi-elastic light scattering (QLS) is an established optical technique that noninvasively measures changes in protein size distributions in the human lens in vivo. In this cross-sectional study, lenticular QLS correlation time was decreased in adolescent subjects with DS compared to age-matched control subjects. Clinical QLS was consistent with alterations in relative particle hydrodynamic radius in lenses of adolescents with DS. These correlative results suggest that noninvasive QLS can be used to evaluate molecular changes in the lenses of individuals with DS.

A novel single-base deletional mutation of MIP impairs protein distribution and cell-to-cell adhesion in autosomal dominant cataracts in a Chinese family.

Congenital cataracts are the leading cause of irreversible visual disability in children, and genetic factors play an important role in their development. In this study, targeted exome sequencing revealed a novel single-base deletional mutation of MIP (c.301delG; p.Ala101Profs*16) segregated with congenital punctate cataract in a Chinese family. The hydrophobic properties, and secondary and tertiary structures for truncated MIP were predicted to affect the function of protein by bioinformatics analysis. When MIP-WT and MIP-Ala101fs expression constructs were singly transfected into HeLa cells, it was found that the mRNA level showed no significant difference, while the protein level of the mutant was remarkably reduced compared to that of the wild-type MIP. Immunofluorescence images showed that the MIP-WT was principally localized to the plasma membrane, whereas the MIP-Ala101fs protein was aberrantly trapped in the cytoplasm. Furthermore, the cell-to-cell adhesion capability and the cell-to-cell communication property were both significantly reduced for MIP-Ala101fs compared to the MIP-WT (all *p < 0.05). This is the first report of the c.301delG mutation in the MIP gene associated with autosomal dominant congenital cataracts. We propose that the cataract is caused by the decreased protein expression and reduced cell-to-cell adhesion by the mutant MIP. The impaired trafficking or instability of the mutant protein, as well as compromised intercellular communication is probably a concurrent result of the mutation. The results expand the genetic and phenotypic spectra of MIP and help to better understand the molecular basis of congenital cataracts.