Background: Increasing evidence shows that systemic inflammation is an embedded mechanism of proliferative diabetic retinopathy (PDR). However, the specific systemic inflammatory factors involved in this process remained obscure. The study aimed to identify the upstream and downstream systemic regulators of PDR by using Mendelian randomization (MR) analyses.Methods: We performed a bidirectional two-sample MR analysis implementing the results from genome-wide association studies for 41 serum cytokines from 8,293 Finnish individuals, and PDR from FinnGen consortium (2,025 cases vs. 284,826 controls) and eight cohorts of European ancestry (398 cases vs. 2,848 controls), respectively. The inverse-variance-weighted method was adopted as the main MR method, and four additional MR methods (MR-Egger, weighted-median, MR-pleiotropy residual sum and outlier (MR-PRESSO), and MR-Steiger filtering methods) were used for the sensitivity analyses. Results from FinnGen and eight cohorts were pooled into a meta-analysis.Results: Our results showed that genetically predicted higher stem cell growth factor-β (SCGFb) and interleukin-8 were positively associated with an elevated risk of PDR, with a combined effect of one standard deviation (SD) increase in SCGFb and interleukin-8 causing 11.8% [95% confidence interval (CI): 0.6%, 24.2%]) and 21.4% [95% CI: 3.8%, 41.9%]) higher risk of PDR, respectively. In contrast, genetically predisposition to PDR showed a positive association with the increased levels of growth-regulated oncogene-α (GROa), stromal cell-derived factor-1 alpha (SDF1a), monocyte chemotactic protein-3 (MCP3), granulocyte colony-stimulating factor (GCSF), interleukin-12p70, and interleukin-2 receptor subunit alpha (IL-2ra).Conclusions: Our MR study identified two upstream regulators and six downstream effectors of PDR, providing opportunities for new therapeutic exploitation of PDR onset. Nonetheless, these nominal associations of systemic inflammatory regulators and PDR require validation in larger cohorts.

Purpose: Diabetic retinopathy (DR) is characterized by increased oxidative and nitrosative stress, both of which lead to neurotoxicity and vascular permeability. Previous studies on a variety of organs indicate that hydrogen-rich saline not only has considerable antioxidant and anti-inflammatory properties, but also suppresses oxidative stress-induced injury. In the present study, we assessed the effects of hydrogen-rich saline on neurovascular dysfunction and oxidative stress in an animal model (rat) of DR. Materials and Methods: Male Sprague-Dawley rats with streptozotocin (STZ)-induced diabetes mellitus (DM) were injected intraperitoneally with 5 ml/kg hydrogen-saturated (experimental) or plain (control) saline daily for one month. Visual function and blood–retinal barrier (BRB) integrity were evaluated by electroretinography (ERG) and bovine serum albumin (BSA)-fluorescence, respectively. Histological changes in the inner retina were assessed by light microscopy. Biomarkers of oxidative stress, including 4-hydroxynonenal (4-HNE) and 8-hydroxy-2-deoxyguanosine (8-OH-dG), and antioxidant enzymes, including superoxide dismutase, glutathione peroxidase, glutathione reductase and glutathione transferase, were evaluated by ELISA. Synaptophysin and brain-derived neurotrophic factor (BDNF) levels were measured by immunoblotting. Results: STZ-diabetic rats were marked by clearly reduced b-wave amplitudes and oscillatory potentials, DM-related BRB breakdown and histological changes in the inner retina, all of which were suppressed following treatment with hydrogen-rich saline. Furthermore, hydrogen-rich saline reduced oxidative stress, increased antioxidant enzyme activities and preserved synaptophysin and BDNF levels in the diabetic rat retina. Conclusions: Based on its inhibition of oxidative stress and up-regulation of anti-oxidative enzymes, we conclude that hydrogen-rich saline is a potentially valuable therapeutic modality for the treatment of DR.

To explore the association between retinal microvascular parameters and glaucoma. Prospective study. The UK Biobank subjects with fundus images and without a history of glaucoma. We employed the Retina-based Microvascular Health Assessment System to utilize the noninvasive nature of fundus photography and quantify retinal microvascular parameters including retinal vascular skeleton density (VSD) and fractal dimension (FD). We also utilized propensity score matching (PSM) to pair individuals with glaucoma and healthy controls. Propensity score matching was implemented via a logistic regression model with a caliper of 0.1 and a matching ratio of 1:4 no replacements. We conducted univariable Cox regression analyses to study the association between retinal microvascular parameters and incident glaucoma, in both continuous and quartile forms. Vascular skeleton density, FD, and glaucoma. In a study of 41 632 participants without prior glaucoma, 482 cases of glaucoma were recorded during a median follow-up of 11.0 years. In the Cox proportional hazards regression model post-PSM, we found that incident glaucoma has significant negative associations with arteriolar VSD (hazard ratio [HR] = 0.24, 95% confidence interval [CI] 0.11–0.52, P < 0.001), venular VSD (HR = 0.34, 95% CI 0.15–0.74, P = 0.007), arteriolar FD (HR = 0.24, 95% CI 0.10–0.60, P = 0.002), and venular FD (HR = 0.31, 95% CI 0.12–0.85, P = 0.022). Subgroup analysis using covariates revealed that individuals aged ≥60 years, nonsmokers, moderate alcohol consumers, and those with hypertension and myopia exhibited P values <0.05 consistently prematching and postmatching, differing from other subgroups within this covariate. Our study found that reduced retinal VSD and lower FD are linked to elevated glaucoma risk. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Optic neurodegeneration, in addition to central nervous trauma, initiates impairments to neurons resulting in retinal ganglion cell (RGC) damage. Carbon monoxide (CO) has been observed to elicit neuroprotection in various experimental models. The present study investigated the potential retinal neuroprotection of preconditioning with CO inhalation in a rat model of optic nerve crush (ONC). Adult male Sprague‑Dawley rats were preconditioned with inhaled CO (250 ppm) or air for 1 h prior to ONC. Animals were euthanized at 1 or 2 weeks following surgery. RGC densities were quantified by hematoxylin and eosin (H&E) staining and FluoroGold labeling. Visual function was measured via flash visual evoked potentials (FVEP). Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and caspase‑9 and caspase‑3 activity in the retinas, were assessed at 2 weeks post‑ONC. The RGC density of CO + crush rats was significantly increased compared with that of the corresponding crush‑only rats at 2 weeks (survival rate, 66.2 vs. 48.2% as demonstrated by H&E staining, P<0.01; and 67.6 vs. 37.6% as demonstrated by FluoroGold labeling, P<0.05). FVEP measures indicated a significantly better‑preserved latency and amplitude of the P1 wave in the CO + crush rats compared with the crush‑only rats. The TUNEL assays demonstrated fewer apoptotic cells in the CO + crush group compared with the crush‑only group, accompanied by the suppression of caspase‑9 and caspase‑3 activity. The results of the present study suggested that inhaled CO preconditioning may be neuroprotective against ONC insult via inhibition of neuronal apoptosis.