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Age-related macular degeneration (AMD) leads to gradual central vision loss and is the third leading cause of irreversible blindness worldwide. The underlying mechanisms for this progressive neurodegenerative disease remain unclear and there is currently no preventive treatment for dry AMD. Sodium iodate (NaIO3) has been reported to induce AMD-like retinal pathology in mice. We established a mouse model for AMD to evaluate the effects of quercetin on NaIO3-induced retinal apoptosis, and to investigate the pertinent underlying mechanisms. Our in vitro results indicated that quercetin protected human retinal pigment epithelium (ARPE-19) cells from NaIO3-induced apoptosis by inhibiting reactive oxygen species production and loss of mitochondrial membrane potential as detected by Annexin V-FITC/PI flow cytometry. We also evaluated the relative expression of proteins in the apoptosis pathway. Quercetin downregulated the protein expressions of Bax, cleaved caspase-3, and cleaved PARP and upregulated the expression of Bcl-2 through reduced PI3K and pAKT expressions. Furthermore, our in vivo results indicated that quercetin improved retinal deformation and increased the thickness of both the outer nuclear layer and inner nuclear layer, whereas the expression of caspase-3 was inhibited. Taken together, these results demonstrate that quercetin could protect retinal pigment epithelium and the retina from NaIO3-induced cell apoptosis via reactive oxygen species-mediated mitochondrial dysfunction, involving the PI3K/AKT signaling pathway. This suggests that quercetin has the potential to prevent and delay AMD and other retinal diseases involving NaIO3-mediated apoptosis.

Retinal vascular diseases encompass several retinal disorders, including diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, and retinal vascular occlusion; these disorders are classified as similar groups of disorders due to impaired retinal vascularization. The aim of this review is to address the main signaling pathways involved in the pathogenesis of retinal vascular diseases and to identify crucial molecules and the importance of their interactions. Vascular endothelial growth factor (VEGF) is recognized as a crucial and central molecule in abnormal neovascularization and a key phenomenon in retinal vascular occlusion; thus, anti-VEGF therapy is now the most successful form of treatment for these disorders. Interaction between angiopoietin 2 and the Tie2 receptor results in aberrant Tie2 signaling, resulting in loss of pericytes, neovascularization, and inflammation. Notch signaling and hypoxia-inducible factors in ischemic conditions induce pathological neovascularization and disruption of the blood–retina barrier. An increase in the pro-inflammatory cytokines—TNF-α, IL-1β, and IL-6—and activation of microglia create a persistent inflammatory milieu that promotes breakage of the blood–retinal barrier and neovascularization. Toll-like receptor signaling and nuclear factor-kappa B are important factors in the dysregulation of the immune response in retinal vascular diseases. Increased production of reactive oxygen species and oxidative damage follow inflammation and together create a vicious cycle because each factor amplifies the other. Understanding the complex interplay among various signaling pathways, signaling cascades, and molecules enables the development of new and more successful therapeutic options.

Precision medicine seeks to treat disease with molecular specificity. Advances in genome sequence analysis, gene delivery, and genome surgery have allowed clinician-scientists to treat genetic conditions at the level of their pathology. As a result, progress in treating retinal disease using genetic tools has advanced tremendously over the past several decades. Breakthroughs in gene delivery vectors, both viral and nonviral, have allowed the delivery of genetic payloads in preclinical models of retinal disorders and have paved the way for numerous successful clinical trials. Moreover, the adaptation of CRISPR-Cas systems for genome engineering have enabled the correction of both recessive and dominant pathogenic alleles, expanding the disease-modifying power of gene therapies. Here, we highlight the translational progress of gene therapy and genome editing of several retinal disorders, including RPE65-, CEP290-, and GUY2D-associated Leber congenital amaurosis, as well as choroideremia, achromatopsia, Mer tyrosine kinase- (MERTK-) and RPGR X-linked retinitis pigmentosa, Usher syndrome, neovascular age-related macular degeneration, X-linked retinoschisis, Stargardt disease, and Leber hereditary optic neuropathy.

Ischemia-reperfusion (I/R) is a common pathology when the blood supply to an organ was disrupted and then restored. During the reperfusion process, inflammation and tissue injury were triggered, which were mediated by immunocytes and cytokines. However, the mechanisms initiating I/R-induced inflammation and driving immunocytes activation remained largely unknown. In this study, we identified long non-coding RNA (lncRNA)-H19 as the key onset of I/R-induced inflammation. We found that I/R increased lncRNA-H19 expression to significantly promote NLRP3/6 inflammasome imbalance and resulted in microglial pyroptosis, cytokines overproduction, and neuronal death. These damages were effectively inhibited by lncRNA-H19 knockout. Specifically, lncRNA-H19 functioned via sponging miR-21 to facilitate PDCD4 expression and formed a competing endogenous RNA network (ceRNET) in ischemic cascade. LncRNA H19/miR-21/PDCD4 ceRNET can directly regulate I/R-induced sterile inflammation and neuronal lesion in vivo. We thus propose that lncRNA-H19 is a previously unknown danger signals in the molecular and immunological pathways of I/R injury, and pharmacological approaches to inhibit H19 seem likely to become treatment modalities for patients in the near future based on these mechanistic findings.

Retinal diseases continue to command the attention of clinicians and scientists alike because they compress complex biology into the span of a single, fragile tissue and translate molecular perturbations into life-altering vision loss [...]

Background/Objective Adolescents with type 1 diabetes have early macrovascular changes (increased intima‐media thickness [IMT]) and early retinal changes that predict clinical disease in adulthood. We hypothesized that early changes in the macrovascular and retinal microvascular beds develop in parallel before retinopathy develops. We therefore aimed to investigate the relationship between changes in atherosclerosis (carotid and aortic IMT) and retinal vascular geometry cross‐sectionally and longitudinally in adolescents with type 1 diabetes. Methods Ninety adolescents with type 1 diabetes (41 boys, aged 13.6 ± 3.5 years) who were enrolled in a randomized controlled trial had evaluations at baseline; 41 randomized to placebo were also investigated at 12 months for carotid and aortic IMT using ultrasound and retinal vascular geometry was measured from retinal photographs. Results There were significant associations between thicker mean/maximum carotid IMT and wider retinal arteriolar and venular calibers; for every 0.1 mm increase in mean carotid IMT, retinal arteriolar caliber increased by 7.90 μm (95% confidence interval [CI] 4.50, 11.30, P < 0.0001) and venular caliber by 9.61 μm (95% CI 4.16, 15.06, P = 0.0008). Increased mean aortic IMT was associated with increased arteriolar tortuosity (2.61, 95% CI 0.50, 4.71, P = 0.02). Conclusions The early changes of atherosclerosis are associated with retinal microvascular changes in adolescents with type 1 diabetes. This supports parallel adverse changes in the macro and microvascular circulations from early adolescence in type 1 diabetes, and highlights the importance of early intervention.

The aim of the study was to find out whether participation in earlier intervention had an effect on the occurrence of retinopathy in study participants. We also examined risk factors (age, sex, weight, fasting and 2 h glucose, fasting insulin, blood pressure, serum lipids) for early retinal changes. The study included 522 individuals (mean 55 years old, range 40–64 years) with impaired glucose tolerance who were randomized into intervention (weight loss, healthy diet, and physical activity, N = 265) and control groups (N = 257). Intervention lasted for median of four years in 1993–2000, after which annual follow-up visits at study clinics were conducted. In the years 2002–2006 (at least five years after stopping intervention), fundus photography was offered for all study participants in four of five study clinics. Photographs were assessed by two experienced ophthalmologists (A.A. and K.K.), masked for the group assignment. After exclusion of poor quality photographs, the data of 211 individuals (N = 113 for intervention and N = 98 for control group) were included in the present study. The occurrence of microaneurysms was significantly higher in the control (37/98, 38%) than in the intervention group (27/113, 24%; p = 0.029). In the model, including age, sex, diabetes diagnosis before the retinal assessment, body mass index (BMI), and treatment group, the odds ratio for microaneurysms was markedly lower in intervention group (OR 0.52; 0.28–0.97, p = 0.039). The only risk factor that predicted the occurrence of microaneurysms was serum triglycerides at baseline (mean ± SD 1.9 ± 0.9 vs. 1.6 ± 0.7, mmol/L, with and without microaneurysms, respectively, p = 0.003). Triglycerides associated with decreased microaneurysms in regression analysis for age, sex, fasting glucose, and intervention group (OR 1.92, p = 0.018). Lifestyle intervention in overweight and obese individuals with impaired glucose tolerance showed decreased occurrence of retinal microaneurysms. Elevated serum triglycerides were associated to the development of early diabetic microangiopathy.

AimTo compare the efficacy of macular buckling (MB) and pars plana vitrectomy (PPV) for full-thickness macular holes (FTMH) and associated macular detachment (MD) in highly myopic eyes.MethodsProspective interventional case series of eyes undergoing PPV or MB for FTMH and MD.Main outcome measuresBest-corrected visual acuity (BCVA) at postoperative month 24. Other measured outcomes include the initial surgical success rate, macular hole closure rate and the progression of myopic maculopathy.ResultsA total of 53 eyes from 53 participants were included in this study (26 participants receiving MB and 27 participants receiving PPV), and finally 49 eyes from 49 participants (25 participants in the MB group and 24 participants in the PPV group) were analysed. At postoperative month 24, the BCVA had improved significantly in those that underwent either MB (p<0.001) or PPV (p=0.04). The difference between the groups was not significant (p=0.653). The surgical failure rate after the primary treatment was significantly higher in the PPV group than the MB group (25.00% vs 4.00%, respectively; p=0.04). The macular closure rate was higher in the MB group compared with the PPV group, but the difference was not statistically significant (64.00% vs 58.33%, respectively; p=0.45). Myopic maculopathy development may be more severe following PPV than following MB surgery.ConclusionPatients with high myopia obtained anatomical and functional improvements from either MB or PPV. However, MB achieved a significantly higher success rate in retinal reattachment compared with PPV.Trial registration number NCT03433547.

The volume and complexity of diagnostic imaging is increasing at a pace faster than the availability of human expertise to interpret it. Artificial intelligence has shown great promise in classifying two-dimensional photographs of some common diseases and typically relies on databases of millions of annotated images. Until now, the challenge of reaching the performance of expert clinicians in a real-world clinical pathway with three-dimensional diagnostic scans has remained unsolved. Here, we apply a novel deep learning architecture to a clinically heterogeneous set of three-dimensional optical coherence tomography scans from patients referred to a major eye hospital. We demonstrate performance in making a referral recommendation that reaches or exceeds that of experts on a range of sight-threatening retinal diseases after training on only 14,884 scans. Moreover, we demonstrate that the tissue segmentations produced by our architecture act as a device-independent representation; referral accuracy is maintained when using tissue segmentations from a different type of device. Our work removes previous barriers to wider clinical use without prohibitive training data requirements across multiple pathologies in a real-world setting. A novel deep learning architecture performs device-independent tissue segmentation of clinical 3D retinal images followed by separate diagnostic classification that meets or exceeds human expert clinical diagnoses of retinal disease.

Background and Objective: Our objective was to monitor variables via spectral-domain optical coherence tomography (SD-OCT) and identify the most relevant biomarkers related to best-corrected visual acuity (BCVA) in radiation retinopathy (RR). Patients and Methods: A post-hoc analysis of the two-year Ranibizumab for Radiation Retinopathy (RRR) trial analyzed vision and OCT parameters including intraretinal fluid, ellipsoid zone (EZ) disruption, retinal pigment epithelium atrophy, hard exudates, retinal hemorrhage, retinal neovascularization, and subfoveal fluid. BCVA and SD-OCT parameters were evaluated by univariate analysis and a mixed-effects model. Results: Forty eyes from the RRR trial were included. Intraretinal cyst vertical size (week 24: P = 0.032; week 48: P = 0.021), neovascularization (week 48: P = 0.028; week 72: P = 0.025), and EZ disruption (week 72: P = 0.029; week 104: P = 0.019) were the clinical parameters most relevant to BCVA by univariate analysis in at least two time points. The mixed-effects model confirmed the relevance of intraretinal cyst vertical size (P = 0.001) and neovascularization (P = 0.001) but not EZ disruption (P = 0.119) over the course of the study. Conclusions: This study characterizes the course of visual loss in RR by identifying intraretinal cyst vertical size, neovascularization, and EZ disruption as biomarkers of poor BCVA over a span of two years. Larger multicenter studies are needed to confirm these findings. [Ophthalmic Surg Lasers Imaging Retina 2024;55:255–262.]