hsa_circ_0087100/hsa-miR-6743-5p affects Th1 cell differentiation by regulating STAT1 in diabetic retinopathy.

Objective: To elucidate the role of the competitive endogenous RNA (ceRNA) network in immune infiltration of diabetic retinopathy (DR). Methods: We obtained differentially expressed (DE) circRNAs, miRNAs and mRNAs from the Gene Expression Omnibus database. Then, we identified immune infiltration by CIBERSORT and single-sample gene set enrichment analysis and discovered co-expression genes by weighted gene co-expression network analysis. Furthermore, STAT1-mediated Th1 differentiation was determined in DR cell models, DR patients and DR mouse models. Results: hsa_circ_0087100/hsa-miR-6743-5p/STAT1 was involved in immune infiltration of Th1 cells. Aberrant expression of the ceRNA network and STAT1-mediated Th1 differentiation was thus verified in vitro and in vivo. Conclusion: hsa_circ_0087100/hsa-miR-6743-5p/STAT1 may affect Th1 cell differentiation in DR.

TET2-mediated ECM1 hypomethylation promotes the neovascularization in active proliferative diabetic retinopathy.

BACKGROUND: Studies have shown that tet methylcytosine dioxygenase 2 (TET2) is highly expressed in diabetic retinopathy (DR), which reduces the DNA methylation of downstream gene promoters and activates the transcription. Abnormally expressed TET2 and downstream genes in a high-glucose environment are associated with retinal capillary leakage and neovascularization. Here, we investigated the downstream genes of TET2 and its potential association with neovascularization in proliferative diabetic retinopathy (PDR). METHODS: GSE60436, GSE57362, and GSE158333 datasets were analyzed to identify TET2-related hypomethylated and upregulated genes in PDR. Gene expression and promoter methylation of these genes under high glucose treatment were verified. Moreover, TET2 knockdown was used to assess its impact on tube formation and migration in human retinal microvascular endothelial cells (HRMECs), as well as its influence on downstream genes. RESULTS: Our analysis identified three key genes (PARVB, PTPRE, ECM1) that were closely associated with TET2 regulation. High glucose-treated HRMECs exhibited increased expression of TET2 and ECM1 while decreasing the promoter methylation level of ECM1. Subsequently, TET2 knockdown led to decreased migration ability and tube formation function of HRMECs. We further found a decreased expression of PARVB, PTPRE, and ECM1, accompanied by an increase in the promoter methylation of ECM1. CONCLUSIONS: Our findings indicate the involvement of dysregulated TET2 expression in neovascularization by regulating the promoter methylation and transcription of downstream genes (notably ECM1), eventually leading to PDR. The TET2-induced hypomethylation of downstream gene promoters represents a potential therapeutic target and offers a novel perspective on the mechanism underlying neovascularization in PDR.

COMPARISON OF THE EFFICACY AND SAFETY OF RANIBIZUMAB 0.5 MG VERSUS 1.0 MG WITH PARS PLANA VITRECTOMY FOR THE TREATMENT OF PROLIFERATIVE DIABETIC RETINOPATHY: A Randomized Controlled Trial.

PURPOSE: To investigate the effectiveness of two regimens of ranibizumab-assisted pars plana vitrectomy in the treatment of patients with proliferative diabetic retinopathy. METHODS: This is a prospective, 6-month, randomized controlled trial. Eighty patients with 87 eyes requiring pars plana vitrectomy treatment for proliferative diabetic retinopathy were included and randomly divided into a 1.0-mg injection group and a 0.5-mg injection group. The ranibizumab was delivered intraoperatively, at the close of surgery. The vitreous hemorrhage grade, best-corrected visual acuity, central macular thickness, and safety data were assessed to Month 6. RESULTS: The 1.0-mg injection group had a milder grade and a lower reoccurrence rate of early postoperatively vitreous hemorrhage than the 0.5-mg injection group (35.0% and 63.4%, respectively, P = 0.0195). The mean best-corrected visual acuity of two groups was significantly improved from baseline to 6 months after surgery, 1.60 ± 0.72 Logarithm of the Minimum Angle of Resolution (LogMAR) (<20/200) to 0.47 ± 0.49 LogMAR (20/59) for the 1.0-mg injection group and 1.51 ± 0.69 LogMAR (<20/200) to 0.50 ± 0.31 LogMAR (20/63) for the 0.5-mg injection group, but there was no significant difference between the two groups ( P = 0.74). There was no significant difference in the mean decrease in central macular thickness and probability of postoperative adverse events between the two groups. CONCLUSION: Intravitreal injection of 1.0 mg of ranibizumab after pars plana vitrectomy compared with the recommended dose of 0.5 mg significantly reduced the recurrence and severity of early postoperative vitreous hemorrhage in patients with proliferative diabetic retinopathy. It also contributed to the early recovery of visual acuity after surgery and did not increase postoperative adverse events.

Influence of high altitude on choroid thickness, retinal thickness, and myopia: A cross-sectional study comparing adolescents in Shanghai and Tibet.

PURPOSE: This study aimed to explore the influence of high altitude on myopia, macular choroidal thickness (mCT), and macular retinal thickness (mRT) in adolescents. METHODS: Two schools, one in Shanghai (at sea level) and one in Shigatse, Tibet (more than 4000 m above sea level), were selected. Refractive error was measured by an autorefractor instrument and subjective refraction, and mCT and mRT were measured at three concentric circles by optical coherence tomography. Student's t -test, Chi-square test, and multiple linear regression analyses were used to analyze the data. RESULTS: A total of 1114 participants (657 and 457 in Shanghai and Tibet, respectively) were enrolled in this cross-sectional study. The average age of the participants was 18.81 ± 1.10 years, and 44.34% were males. The spherical equivalent (SE) of adolescents in Shanghai was significantly lower than that of adolescents in Tibet (-4.14 ± 2.37 D and -2.12 ± 1.87 D, P < 0.01). The prevalence of myopia and high myopia among adolescents in Shanghai (94.52%, 19.48%) was significantly higher than those among adolescents in Tibet (44.74%, 2.41%) ( P < 0.01). The mCT of Tibetan adolescents was significantly thicker than that of Shanghai adolescents (295.80 ± 62.46 µm and 218.71 ± 61.42 µm, P < 0.01), especially the central mCT. The mRT of Tibetan adolescents was also thicker than that of Shanghai adolescents (301.42 ± 23.26 µm and 281.04 ± 12.24 µm, P < 0.01). CONCLUSIONS: Compared with Shanghai adolescents, the choroid of Tibet adolescents is thicker, and the myopia prevalence is lower. It is speculated that increased altitude is associated with the thickening of mCT and a low myopia prevalence.

Pipecolic acid mitigates ferroptosis in diabetic retinopathy by regulating GPX4-YAP signaling.

Diabetic retinopathy (DR) is currently recognized as the leading cause of end-stage eye disease. Pipecolic acid, a metabolite, has a significant regulatory effect on several pathological processes. However, the exact mechanism by which it causes damage in diabetic retinopathy is unknown. Between September 2021 and December 2022, 40 patients were retrospectively examined and divided into two groups: the healthy group (n = 20) and the DR group (n = 20). Metabolomic analysis found that pipecolic acid plays an important role in this process. Streptozotocin-induced diabetic mice and high-glucose cultured human retinal capillary endothelial cells (HRCECs) were then treated with pipecolic acid. Several oxidative stress measurements and RNA sequencing of retinal cells were tested. A gene interaction study was conducted using bioinformatics. Comparison of serological metabolites between healthy volunteers and DR patients showed that pipecolic acid was significantly lower in DR patients, and there was a negative correlation between the level of pipecolic acid with blood glucose and glycated hemoglobin. Yes-associated protein (YAP) mRNA, Malondialdehyde (MDA), and reactive oxygen species (ROS) levels were significantly higher in diabetic mice, but glutathione peroxidase (GSH-Px) levels were significantly lower. Pipecolic acid significantly alleviated oxidative stress and YAP expression. The number of vascular tubes was significantly higher in the DR group, and pipecolic acid treatment significantly reduced tube formation. RNA-Sequencing analysis revealed that YAP and glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) expression was reduced, and functional enrichment analysis revealed that ferroptosis and Hippo signaling pathways play an important role in this process. Additionally, pipecolic acid's ability to improve DR is diminished after YAP and GPX4 ablation. This study found that pipecolic acid, as a metabolite, may impede the progression of DR by inhibiting the YAP-GPX4 signaling pathway.

DNA methylation in diabetic retinopathy: pathogenetic role and potential therapeutic targets.

BACKGROUND: Diabetic retinopathy (DR), a specific neuron-vascular complication of diabetes, is a major cause of vision loss among middle-aged people worldwide, and the number of DR patients will increase with the increasing incidence of diabetes. At present, it is limited in difficult detection in the early stages, limited treatment and unsatisfactory treatment effects in the advanced stages. MAIN BODY: The pathogenesis of DR is complicated and involves epigenetic modifications, oxidative stress, inflammation and neovascularization. These factors influence each other and jointly promote the development of DR. DNA methylation is the most studied epigenetic modification, which has been a key role in the regulation of gene expression and the occurrence and development of DR. Thus, this review investigates the relationship between DNA methylation and other complex pathological processes in the development of DR. From the perspective of DNA methylation, this review provides basic insights into potential biomarkers for diagnosis, preventable risk factors, and novel targets for treatment. CONCLUSION: DNA methylation plays an indispensable role in DR and may serve as a prospective biomarker of this blinding disease in its relatively early stages. In combination with inhibitors of DNA methyltransferases can be a potential approach to delay or even prevent patients from getting advanced stages of DR.