The role of retinal glial cells and related factors in macular edema.

Macular edema (ME) has emerged as a leading cause of visual impairment, representing a critical clinical manifestation and complication associated with many eye diseases. In the occurrence and development of ME, retinal glial cells like Müller cells and microglial cells play vital roles. Moreover, growth factor and cytokines associated with them, such as vascular endothelial growth factor (VEGF), pigment epithelium-derived factor (PEDF), hypoxia-inducible factor-1α (HIF-1α), angiopoietin-like protein 4 (ANGPTL4), interleukin-6(IL-6), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), prostaglandin, etc., also take part in the pathogenesis of ME. Changes in these cytokines can lead to retinal angiogenesis, increased vascular permeability, blood-retinal barrier (BRB) breakdown, and fluid leakage, further causing ME to occur or deteriorate. Research on the role of retinal glial cells and related cytokines in ME will provide new therapeutic directions and effective remedies. This article is a literature review on the role of Müller cells, microglial cells and related factors in ME pathogenesis.

Acute acquired concomitant esotropia with congenital paralytic strabismus: A case report.

BACKGROUND: An unusual case of acute acquired concomitant esotropia (AACE) with congenital paralytic strabismus in the right eye is reported. CASE SUMMARY: A 23-year-old woman presented with complaints of binocular diplopia and esotropia of the right eye lasting 4 years and head tilt to the left since 1 year after birth. The Bielschowsky head tilt test showed right hypertropia on a right head tilt. She did not report any other intracranial pathology. A diagnosis of AACE and right congenital paralytic strabismus was made. Then, she underwent medial rectus muscle recession and lateral rectus muscle resection combined with inferior oblique muscle myectomy in the right eye. One day after surgery, the patient reported that she had no diplopia at either distance or near fixation and was found to be orthophoric in the primary position; furthermore, her head posture immediately and markedly improved. CONCLUSION: In future clinical work, in cases of AACE combined with other types of strabismus, we can perform conventional single surgery for both at the same time, and the two types of strabismus can be solved simultaneously.

The role of retinal Müller cells in diabetic retinopathy and related therapeutic advances.

Diabetic retinopathy (DR) is a significant complication of diabetes. During the pathogenesis of retinal microangiopathy and neuronopathy, activated retinal Müller cells (RMCs) undergo morphological and structural changes such as increased expression of glial fibrillary acidic protein, disturbance of potassium and water transport regulation, and onset of production of a large number of inflammatory and vascular growth factors as well as chemokines. Evidently, activated RMCs are necessary for the pathogenesis of DR; therefore, exploring the role of RMCs in DR may provide a new target for the treatment thereof. This article reviews the mechanism of RMCs involvement in DR and the progress in related treatments.

Pars plana vitrectomy with air tamponade for the treatment of medium-large macular holes.

BACKGROUND: To evaluate the surgical outcomes of pars plana vitrectomy (PPV) with air tamponade in medium-large macular holes (MHs). METHODS: Data for 26 eyes of 26 consecutive patients with medium-large full-thickness MHs (> 400 µm) who underwent PPV, internal limiting membrane (ILM) peeling, and sterile air tamponade were studied retrospectively. Best-corrected visual acuity and the closure rate were noted. The follow-up period was one to 20 months (median, four months). RESULTS: The age range of the patients was 53-73 years (median, 65 years). The mean minimum diameter of the MHs was 550 ± 99 µm. Prior to surgery, 10 eyes (38 per cent) were stage three, and 16 eyes (62 per cent) were stage four. The pre-operative symptom duration ranged from one month to 24 months (median, four months). Twenty-four MHs (92.3 per cent) were successfully closed after a single operation. Two (7.7 per cent) patients had a persistent MH. The average visual acuity, calculated as the logarithm of the minimal angle of resolution, improved from 1.44 ± 0.45 pre-operatively to 0.54 ± 0.29 at the end of the follow-up period (p < 0.001, paired t-test). CONCLUSION: Vitrectomy with ILM peeling and sterile air tamponade is an effective and safe surgical technique for managing medium-large MHs with a shorter history and does not require intravitreal long-acting gas tamponade while maintaining a long-term, face-down position.

Multiple Bioinformatics Analyses of Integrated Gene Expression Profiling Data and Verification of Hub Genes Associated with Diabetic Retinopathy.

BACKGROUND Diabetic retinopathy (DR) is a serious complication of diabetes that can lead to blindness. This study aimed to identify the core genes and molecular functions involved in DR through multiple bioinformatics analyses. MATERIAL AND METHODS The mRNA gene profiles of human DR tissues from the GSE60436 and GSE53257 datasets were assessed with R software and integrated to identify the co-expressed differentially expressed genes (DEGs). Multiple bioinformatics analyses were used: Gene Ontology (GO) analysis, signaling pathway analysis, and hub gene prediction. Quantitative reverse transcription-PCR (qRT-PCR) was used to verify the hub genes. RESULTS The Database for Annotation, Visualization and Integrated Discovery (DAVID) online tool suggested that the biological processes of the DEGs focused on mitochondrial transport, the cellular components focused on mitochondria, and molecular functions focused on catalytic activity. The results provided by DAVID were consistent with those provided by STRING and the GeneMANIA online database. All the DEGs function in metabolic pathways, consistent with the g: Profiler online analysis results. The protein-protein interaction (PPI) networks forecasted by STRING and GeneMANIA were entered into Cytoscape for cytoHubba degree analysis. The hub genes predicted by cytoHubba suggested that fumarate hydratase (FH) might be relevant to DR. qRT-PCR suggested that the expression of FH was higher in DR retinal tissues than in normal control tissues. CONCLUSIONS Multiple bioinformatics analyses verified that FH could be used as a potential diagnostic marker and new therapeutic target of DR.

Interaction between XRCC 1 gene polymorphisms and diabetes on susceptibility to primary open-angle glaucoma.

IMPACT STATEMENT: Some studies have suggested that diabetes and XRCC gene may be risk factors for glaucoma; however, no studies have focused on the interaction between the XRCC gene and T2DM with respect to POAG risk. Therefore, the present study evaluated the initiative gene-environment interactions in POAG.

3,5-Dimethoxy-4-hydroxy myricanol ameliorates photoreceptor cell degeneration in Pde6brd10 mouse model.

INTRODUCTION: Retinitis pigmentosa (RP) caused by the photoreceptor cell degeneration is currently incurable and leads to partial or complete blindness eventually. 3,5-dimethoxy-4-hydroxy myricanol (DM) is a novel compound isolated from the leaves of Micromelum integerrimum, with proliferative activities on NIH3T3 cells. This study was to investigate whether DM could mitigate retinal degeneration of rd10 mice, a well-characterized mouse model of RP. MATERIALS AND METHOD: Rd10 mice were treated with DM daily by intraperitoneal injection from postnatal day 12 (P12) to P26. Electroretinography (ERG) reflects the mass response of photoreceptor cells and was used to test the outer retinal function after DM treatment. Haematoxylin and Eosin staining was used to show the retinal morphology and evaluate the rod photoreceptor cell loss. TUNEL assay was used to detect the apoptosis-positive cells. Inflammatory factors were measured by ELISA to show the inflammatory response. Real-time PCR and western blot were applied to measure the gene and protein change to explore the underlying mechanisms. RESULTS: Results showed that DM significantly improved the retinal function by increasing the ERG amplitude, preserving the retinal morphology, reducing photoreceptor cell apoptosis, decreasing inflammatory response, and inhibiting endoplasmic reticulum stress in rd10 mice. CONCLUSION: This is the first time when the protective effects of DM against photoreceptor cell degeneration of rd10 mice have been demonstrated, providing scientific rationale to develop DM as a potential agent to treat RP.

Retinal organotypic culture - A candidate for research on retinas.

Reliable disease models are essential for investigations on mechanisms and therapies. The Retinal organotypic culture can maintain the architecture and cellular connections within the tissue in vitro. The system is a refined retinal experiment platform. It narrows the gap between cell line studies and in vivo models and is flexible enough for sophisticated experimental procedures. It greatly reduces the consumption of time or resources. Retinas of many species in various development stages have been used for diverse explorations based on their morphologies and physical characteristics. But the culture time course and the viability of the cultured tissue restrict the utility of the system. Recently, researchers have made increasing attempts to improve the culture conditions and applications of this systems for retina experiments in vitro. Accordingly, there is a great need for a comprehensive summary of these systems for researchers seeking proper in vitro models. In this review, we clarify several key points for the culture procedure and summarize its utility in retinal research.

Intraperitoneal injection of (-)-Epigallocatechin-3-gallate protects against light-induced photoreceptor degeneration in the mouse retina.

PURPOSE: (-)-epigallocatechin-3-gallate (EGCG), a major catechin component of green tea, is reported to delay or prevent certain forms of cancer, arthritis, cardiovascular disease, and neurodegenerative disorders. In this study, we determined if systemically administered EGCG could protect the retina against light damage (LD) in mice. METHODS: BALB/cJ mice were treated with either EGCG or saline via intraperitoneal (IP) injection, and then placed under constant cool white light-emitting diode (LED) light (10,000 lux) for 5 h. Retinal structure and function were evaluated using optical coherence tomography (OCT), histology, and electroretinography (ERG) 7 days after LD. In addition, the mRNAs of several oxidative stress genes were quantified by qPCR before LD and 24 h after LD. RESULTS: OCT and photomicrographs of mouse retinas showed morphologic protection of photoreceptors. Mice in the EGCG group had significantly higher ERG amplitudes for all three wave types compared with mice in the saline control group, which indicated that EGCG protected retinal function. Furthermore, qPCR results showed that EGCG administration can increase the mRNA level of the antioxidant gene Sod2 before LD and 24 h after LD. CONCLUSIONS: The IP injection of EGCG attenuated the detrimental effects of bright light on the retinas of BALB/cJ mice by protecting the structure and function of the retina.

The association of peroxisome proliferator-activated receptor α with diabetic retinopathy, and additional gene-obesity interaction in Chinese type 2 diabetes mellitus patients.

AIMS: To investigate the impact of peroxisome proliferator-activated receptor α (PPAR α) SNPs and gene-obesity interaction on diabetic retinopathy (DR) susceptibility in a Chinese Han population. METHODS: A total of 812 patients (373men, 439 women) with type 2 diabetes mellitus (T2DM), with a mean age of 53.3±14.0 years old, were selected, including 402 diabetic retinopathy patients and 410 controls. Three single nucleotide polymorphisms (SNPs) were selected for genotyping in the case-control study: rs4253778, rs135539 and rs1800206. Generalised multifactor dimensionality reduction (GMDR) and logistic regression model was used to examine the association and interaction between SNP and obesity on DR, odds ratio (OR) and 95% confident interval (95%CI) were calculated. RESULTS: The carriers of homozygous mutant of rs1800206 SNP revealed decreased DR risk than those with wild-type homozygotes, OR (95%CI) was 0.78 (0.66-0.94). GMDR analysis indicated a significant two-locus model (p=0.0107) involving rs1800206 and abdominal obesity, indicating a potential interaction among rs1800206 and abdominal obesity. Overall, the two-locus models had a cross-validation consistency of 10 of 10, and had the testing accuracy of 60.72%. We also found that subjects with abdominal obesity and LV or VV genotype have lowest DR risk, compared to subjects with normal WC and LL genotype, OR (95%CI) was 0.39 (0.30-0.74), after covariates adjustment. CONCLUSIONS: Our results support an important association between rs1800206 minor allele of PPAR α and DR, and the interaction analysis also shown a combined effect of Leu162 allele-abdominal obesity interaction on DR.

Investigation of the Regulation of Roundabout4 by Hypoxia-Inducible Factor-1α in Microvascular Endothelial Cells.

PURPOSE: We determined if hypoxia-inducible factor-1α (HIF-1α) and Roundabout4 (Robo4) colocalized in fibrovascular membranes (FVM) from patients with proliferative diabetic retinopathy (PDR), and investigated the regulation of HIF-1α on Robo4 in microvascular endothelial cells under normoxic and hypoxic conditions in vitro. METHODS: Immunofluorescence and confocal laser scanning microscopy were done to analyze the colocalization of HIF-1α and Robo4 in the FVM. Expression of HIF-1α was knocked down by small interfering RNA (siRNA) technology to study its effects on Robo4 expression of human retinal endothelial cells (HREC) and human dermal microvascular endothelial cells (HDMEC) under normoxic and/or hypoxic conditions. Full-length human HIF-1α gene was transfected into HREC and HDMEC using GFP lentivirus vectors to overexpress HIF-1α under normoxic conditions. The HIF-1α and Robo4 mRNA and protein expressions were quantified by real-time PCR and Western blot. A cell proliferation, migration assay, and flow cytometry were used to analyze the effect of HIF-1α regulation on Robo4 in HREC under hypoxic conditions. RESULTS: Colocalization of HIF-1α and Robo4 in vessels of FVM was confirmed by immunofluorescence staining. Knockdown of HIF-1α expression by siRNA in the HREC and HDMEC inhibited Robo4 expression in mRNA and protein level, while overexpressed HIF-1α increased Robo4 mRNA and protein expression. Silencing HIF-1α in endothelial cells under hypoxic conditions inhibited cell invasion and proliferation, which showed that HIF-1α and Robo4 overexpression due to hypoxic conditions correlated with HREC migration and proliferation. CONCLUSIONS: Both HIF-1α and Robo4 may have a vital role during the formation of FVM. The increased or decreased expression of Robo4 by stimulation or knockdown of HIF-1α suggesting that Robo4 is positively regulated by HIF-1α under normoxic and hypoxic conditions in microvascular endothelial cells in vitro. The HIF-1α gene promotes HREC invasion and proliferation by transcriptionally upregulating Robo4 under hypoxic conditions.

Effect of Robo4 on retinal endothelial permeability.

PURPOSE: To examine the role of Roundabout 4 (Robo4) in retinal endothelial permeability and analyze the structural events that lead to barrier disruption. MATERIALS AND METHODS: Small interfering RNA (siRNA) technology was used to knockdown Robo4 expression to study its effects on the permeability of human retinal vascular endothelial cells (HRVECs) in vitro. The endothelial cell permeability was detected by measuring the flux of rhodamine B isothiocyanate (RITC)-dextran across the HRVEC monolayers. The impact of Robo4 siRNA on the expression of tight junction (TJ) proteins and the activation of LIM-kinase (LIMK)/cofilin pathway were measured by western blotting. The change of actin cytoskeleton was detected using indirect immunofluorescence. RESULTS: Robo4 siRNA increased the permeability of HRVEC monolayers. The expression levels of TJ-associated proteins occludin and zonula occludens (ZO)-1 were suppressed in Robo4-depleted cells. In addition, there was rearrangement of F-actin in HRVECs. These processes were induced through increased activity in the LIMK/cofilin pathway which coincided with a disruption in the barrier properties of retinal endothelial monolayers. CONCLUSIONS: Knockdown of Robo4 expression in HRVECs induced endothelial hyperpermeability associated with the downregulation of ZO-1, occludin, and the rearrangement of F-actin and that LIM-kinase 1 (LIMK1)/cofilin signal transduction system may be involved in the modulating process.