Fibrovascular Membranes Research Articles

Effect of Intravitreal Conbercept Injection on Complications of Pars Plana Vitrectomy in Patients with Proliferative Diabetic Retinopathy.

The effect of intravitreal conbercept (IVC) before pars plana vitrectomy (PPV) on surgical complications in patients with proliferative diabetic retinopathy (PDR) was observed. A total of 152 patients with PDR operated on in Jiangsu Provincial People's Hospital from November 2019 to November 2020 were divided into two groups: 124 patients in the preoperative intravitreal conbercept injection + PPV group (IVC group) and 28 patients in the PPV only group (No-IVC group). Vitreous samples were collected in all eyes of patients who underwent vitrectomy, and the content of VEGF-A was measured by Luminex. The effect of conbercept on intraoperative and postoperative complications of PDR was assessed. The content of VEGF in the vitreous of the IVC group was significantly lower than that in the No-IVC group (64.50 ± 58.40 pg/mL vs. 805.17 ± 417.60 pg/mL, p < 0.001). During postoperative follow-up, early postoperative vitreous hemorrhage (VH) occurred in 13 of 142 eyes (9.15%). Compared with the No-IVC group, PDR patients with VH and fibrovascular membrane (FVM) or high complexity in the IVC group had lower intraoperative bleeding rates (p < 0.05). The early postoperative hemorrhage rate in the IVC group was lower than in the No-IVC group (6.03% vs. 23.08%, p < 0.05). The number of intraoperative electrocoagulation and iatrogenic retinal holes in the IVC group was significantly lower than in the No-IVC group (p < 0.05). There were no significant differences in intraocular hypertension and NVG numbers between the two groups. Visual acuity in both groups improved after PPV surgery, reaching the highest level in the 3rd month after the operation. IVC before PPV can reduce the level of VEGF-A in the vitreous body and reduce surgical complications.

N-cadherin cleavage: A critical function that induces diabetic retinopathy fibrosis via regulation of β-catenin translocation.

Retinal fibrosis is a severe pathological change in the late stage of diabetic retinopathy and is also the leading cause of blindness. We have previously revealed that N-cadherin was significantly increased in type 1 and type 2 diabetic mice retinas and the fibrovascular membranes from proliferative diabetic retinopathy (PDR) patients. However, whether N-cadherin directly induces retinal fibrosis in DR and the related mechanism is unknown. Here, we investigated the pathogenic role of N-cadherin in mediating retinal fibrosis and further explored the relevant therapeutic targets. We found that the level of N-cadherin was significantly increased in PDR patients and STZ-induced diabetic mice and positively correlated with the fibrotic molecules Connective Tissue Growth Factor (CTGF) and fibronectin (FN). Moreover, intravitreal injection of N-cadherin adenovirus significantly increased the expression of FN and CTGF in normal mice retinas. Mechanistically, overexpression of N-cadherin promotes N-cadherin cleavage, and N-cadherin cleavage can further induce translocation of non-p-β-catenin in the nucleus and upregulation of fibrotic molecules. Furthermore, we found a novel N-cadherin cleavage inhibitor, pigment epithelial-derived factor (PEDF), which ameliorated the N-cadherin cleavage and subsequent retinal fibrosis in diabetic mice. Thus, our findings provide novel evidence that elevated N-cadherin level not only acts as a classic EMT maker but also plays a causative role in diabetic retinal fibrosis, and targeting N-cadherin cleavage may provide a strategy to inhibit retinal fibrosis in DR patients.

AUROLAB AQUEOUS DRAINAGE IMPLANT IN YOUNG ADULT WITH NEOVASCULAR GLAUCOMA AND TUBERCULOSIS HISTORY: A CASE REPORT

Introduction: Neovascular glaucoma (NVG) is historically known as rubeotic glaucoma, from “rubeosis iridis” that refers to the iris neovascularization. One of several causes that lead to rubeosis iridis is changes in Pigment Epithelium-Derived Growth Factor (PEDF) that may be caused by Mycobacterium tuberculosis. The influence of NVG may cause intraocular pressure (IOP) to rise rapidly. It can be decreased by Aurolab Aqueous Drainage Implant (AADI). Case Report: A 34-year-old male complained of left eye pain and sudden decreased vision for the past 2 months. He had been diagnosed with tuberculosis since 8 months ago. The patient’s blood pressure, blood sugar, cholesterol, and triglycerides were within normal limit. Diabetes Mellitus (-). Human Immunodeficiency Virus (-). Visual acuity of left eye was hand movement. The pupil was dilated and non-reactive, anterior chamber depth is shallow, and rubeosis iridis (+). IOP is 60 mmHg. Medical management was failed to decrease the IOP. Funduscopy image showed cup-disc ratio was 0,7. Ganglion cell complex parameters showed 80,91. On the next day after AADI implantation surgery, the patient’s left eye IOP was reduced to 10 mmHg. On the 14th day post operative visual acuity was 2 meter counting finger. The anterior segment of the conjunctiva bulbi was hyperemic and conjunctival injection was reduced. The camera oculi anterior showed remainder of the implant. In the iris, rubeosis iridis disappeared, pupil was dilated, IOP was increased to 12 mmHg Discussion: Neovascular glaucoma was caused by the growth of the fibrovascular membrane on the surface of the iris and the anterior chamber angle. The three most common causes of neovascular glaucoma were diabetes mellitus, central retinal vein occlusion, and carotid artery occlusion. Conclusion:AADI is a safe and effective option for patients with neovascular glaucoma following tuberculosis.

Intravitreal Anti-Vascular Endothelial Growth Factor (VEGF) as an Adjuvant Before Vitrectomy for Proliferative Diabetic Retinopathy (PDR)

Introduction: The primary treatment in proliferative diabetic retinopathy (PDR) is vitrectomy; however, direct intervention to the dense proliferative fibrovascular membrane may lead to massive hemorrhage obscuring the surgery process. Purpose: to review the use of anti-vascular endothelial growth factor (VEGF) as an adjuvant therapy before pars plana vitrectomy in PDR cases. Review: Anti-VEGF has been proposed as an adjuvant preceding the vitrectomy to lower intraoperative and post-operative complications. On the other hand, it could increase fibrosis which triggers tractional retinal detachment (TRD) in PDR cases. Conclusion: Intervals of five to ten days are considered the most ideal between anti-VEGF injection and pars plana vitrectomy (PPV) surgery in which the adjuvant therapy has made neovascularization regression and before the occurrence of fibrovascular contractions.

MiR-92a and integrin expression in fibrovascular membranes in proliferative diabetic retinopathy.

Diabetic retinopathy (DR) is a leading cause of vision impairment. The proliferative form of DR (PDR) involves fibrovascular membrane (FVM) formation at the vitreoretinal interface. MicroRNAs (miRNAs) are a class of non-coding RNA molecules that play an important role in gene regulation; a single miRNA could regulate multiple genes. We previously reported that miR-92a, a suppressor of integrins α5 and αv, was downregulated in DR. Considering the integrin's role in FVM pathology and the potential involvement of miR-92a in DR, we asked a question whether miR-92a could play a critical role in FVM pathology. We collected the FVM and epiretinal membranes of individuals with PDR and macular pucker (control) undergoing pars plana vitrectomy. The frozen sections of membranes were stained for α5 and αvβ3 integrins. The miR-92a levels were assessed using real-time quantitative PCR. The FVMs of individuals with PDR stained brighter for integrin subunits α5 and αvβ3 compared to the epiretinal membranes of subjects with macular pucker. miR-92a levels were decreased in FVM subjects. In conclusion, our studies demonstrate that miR-92a decrease is associated with an increase in integrins α5 and αvβ3, thus contributing to the inflammatory milieu in PDR.

Prognostic factors for the development and progression of proliferative diabetic retinopathy in people with diabetic retinopathy.

Prognostic factors for the development and progression of proliferative diabetic retinopathy in people with diabetic retinopathy.

Autophagy and senescence of rat retinal precursor cells under high glucose.

Diabetic retinopathy (DR) is a common diabetic ocular disease characterized by retinal ganglion cell (RGC) changes. An abnormal environment, hyperglycemia, may progressively alter the structure and function of RGCs, which is a primary pathological feature of retinal neurodegeneration in DR. Accumulated studies confirmed autophagy and senescence play a vital role in DR; however, the underlying mechanisms need to be clarified. This study included the microarray expression profiling dataset GSE60436 from Gene Expression Omnibus (GEO) to conduct the bioinformatics analysis. The R software was used to identify autophagy-related genes (ARGs) that were differentially expressed in fibrovascular membranes (FVMs) and normal retinas. Co-expression and tissue-specific expression were elicited for the filtered genes. The genes were then analyzed by ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and Gene Set Enrichment Analysis (GSEA). R28 cells were cultured with high glucose, detected by reverse transcription-quantitative (RT-qPCR) and stained by apoptosis kit. In the retina, 31 differentially expressed ARGs (24 up-regulated genes) were discovered and enriched. The enrichment results revealed that differentially expressed ARGs were significantly enriched in autophagy, apoptosis, aging, and neural function. Four hub genes (i.e., TP53, CASP1, CCL2, and CASP1) were significantly up-regulated. Upregulation of cellular autophagy and apoptosis level was detected in the hyperglycemia model in vitro. Our results provide evidence for the autophagy and cellular senescence mechanisms involved in retinal hyperglycemia injury, and the protective function of autophagy is limited. Further study may favour understanding the disease progression and neuroprotection of DR.

The G-Protein-Coupled Formyl Peptide Receptor 2 Promotes Endothelial-Mesenchymal Transition in Diabetic Retinopathy

Introduction: In proliferative diabetic retinopathy (PDR), retinal neovascularization is the essential pathogenic process that is linked to endothelial-to-mesenchymal transition (EndoMT) induced by high glucose (HG). This pathophysiological process may be regulated by a G-protein-coupled chemoattractant receptor FPR2 (mouse Fpr2), involved in inflammatory cell migration and proliferation. In the current study, we investigated the role of Fpr2 in regulating EndoMT and the underlying mechanisms during diabetic retinopathy progression. Methods: FPR2 agonist or inhibitor was added to human microvascular endothelial cells (HMECs) exposed to normal glucose or HG. Morphologic, phenotypic, and functional changes of HMECs as well as the formation of microvasculature related to EndoMT were assessed. EndoMT biomarkers were detected in the retinal tissues of diabetic mice and fibrovascular epiretinal membranes (FVMs) from patients with PDR. Results: HG upregulated FPR2 in HMECs, which triggered morphological changes, and the cells acquired mesenchymal phenotype, with enhanced cell migration, viability, and angiogenic process shown by tube formation and aortic ring sprouting. Inhibition of FPR2 attenuated HG-induced EndoMT and endothelial cell migration to form vessel-like tube structures. RNA sequence and protein analysis further revealed that inhibition of FPR2 decreased the expression of genes associated with EndoMT. ERK1/2 and P38 signaling pathway was activated in HMECs, promoting neovascularization in HG-induced EndoMT of HMECs. In vivo, increased expression of mesenchymal markers was detected in the retina of diabetic mice and FVMs from patients with PDR. FPR2 deficiency was associated with diminished EndoMT-related phenotypic changes in the retina of diabetic mice. Conclusions: FPR2 is actively involved in the progression of EndoMT that may contribute to the pathogenesis of PDR. Thus, FPR2 may be a potential therapeutic target for PDR.

Genome Editing of Pik3cd Impedes Abnormal Retinal Angiogenesis.

Abnormal angiogenesis is associated with myriad human diseases, including proliferative diabetic retinopathy (PDR). Signaling transduction through phosphoinositide 3-kinases (PI3Ks) plays a critical role in angiogenesis. Herein, we showed that p110δ, the catalytic subunit of PI3Kδ, was highly expressed in pathological retinal vascular endothelial cells (ECs) in a mouse model of oxygen-induced retinopathy (OIR) and in fibrovascular membranes from patients with PDR. To explore novel intervention with PI3Kδ expression, we developed a recombinant dual adeno-associated viral (rAAV) system for delivering CRISPR/Cas9 in which Streptococcus pyogenes (Sp) Cas9 expression was driven by an endothelial specific promoter of the intercellular adhesion molecule 2 (pICAM2) to edit genomic Pik3cd, the gene encoding p110δ. We then demonstrated that infection of cultured mouse vascular ECs with the dual rAAV1s of rAAV1-pICAM2-SpCas9 and rAAV1-SpGuide targeting genomic Pik3cd resulted in 80% DNA insertion/deletion in the locus of genomic Pik3cd and 70% depletion of p110δ expression. Furthermore, we showed that in the mouse model of OIR editing retinal Pik3cd with the dual rAAV1s resulted in not only a significant decrease in p110δ expression, and Akt activation, but also a dramatic reduction in pathological retinal angiogenesis. These findings reveal that Pik3cd editing is a novel approach to treating abnormal retinal angiogenesis.

The integrated transcriptome bioinformatics analysis identifies key genes and cellular components for proliferative diabetic retinopathy.

Proliferative Diabetic Retinopathy (PDR) is a chronic complication of Diabetes and the main cause of blindness among the world's working population at present. While there have been many studies on the pathogenesis of PDR, its intrinsic molecular mechanisms have not yet been fully elucidated. In recent years, several studies have employed bulk RNA-sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) to profile differentially expressed genes (DEGs) and cellular components associated with PDR. This study adds to this expanding body of work by identifying PDR's target genes and cellular components by conducting an integrated transcriptome bioinformatics analysis. This study integrately examined two public bulk RNA-seq datasets(including 11 PDR patients and 7 controls) and one single-cell RNA-seq datasets(including 5 PDR patients) of Fibro (Vascular) Membranes (FVMs) from PDR patients and control. A total of 176 genes were identified as DEGs between PDR patients and control among both bulk RNA-seq datasets. Based on these DEGs, 14 proteins were identified in the protein overlap within the significant ligand-receptor interactions of retinal FVMs and Protein-Protein Interaction (PPI) network, three of which were associated with PDR (CD44, ICAM1, POSTN), and POSTN might act as key ligand. This finding may provide novel gene signatures and therapeutic targets for PDR.

Decreased expression of Glucagon-like peptide-1 receptor and Sodium-glucose co-transporter 2 in patients with proliferative diabetic retinopathy.

To investigate the expression of Glucagon-like peptide-1 receptor (GLP-1R), sodium-glucose co-transporter (SGLT) 1, SGLT2, Glucose transporter type 1 (GLUT1) and GLUT2 in patients with diabetic retinopathy (DR). We obtained peripheral blood mononuclear cells (PBMCs) and vitreous samples from 26 proliferative DR (PDR) patients, 25 non-proliferative DR (NPDR) patients, 25 non-DR (NDR) patients, and 26 nondiabetic patients with idiopathic epiretinal membranes (ERMs, control). The protein level and mRNA expression level of GLP-1R were quantified by immunoblot and qRT-PCR and the levels of SGLT1, SGLT2, GLUT1, and GLUT2 expression were determined by PCR. Their association with clinical parameters and PBMCs/vitreous cytokine was analyzed. Furthermore, immunofluorescence staining of GLP-1R and SGLT2 was carried out on samples of fibrovascular membranes (FVMs) retrieved from 26 patients with PDR and 26 patients with ERMs. The transcriptional levels of GLP-1R and SGLT2 in PBMCs were significantly more decreased in PDR patients than in patients without DR and controls, which was simultaneously associated with an increased level of expression of tumor necrosis factor (TNF)-α and interferon (IFN)-γ. The expression levels of GLUT1 and GLUT2 were tightly correlated with their SGLT partners, respectively. Further, Immunofluorescence staining showed no positive staining of GLP-1R and SGLT2 was detected in the FVMs from PDR. GLP-1R and SGLT2 were significantly decreased in PDR patients which was associated with an increased level of expression of TNF-α and IFN-γ. These findings implicate that defective GLP-1R and SGLT2 signaling may potentially correlate with immune response cytokines in patients with PDR.

Use of ultrasound biomicroscopy to predict the outcome of anterior segment reconstruction in congenital fibrovascular pupillary membrane with secondary glaucoma

AimsTo evaluate the efficacy and safety of anterior segment reconstruction (ASR) in congenital fibrovascular pupillary membrane-induced secondary glaucoma (CFPMSG) basing ultrasound biomicroscopy (UBM) classification.MethodsThis ambispective cohort study enrolled patients with...

Effectiveness of intraoperative optical coherence tomography on vitrectomy for proliferative diabetic retinopathy.

We sought to verify the effect of intraoperative optical coherence tomography (iOCT) on vitrectomy for the treatment of proliferative diabetic retinopathy (PDR). Retrospective study. We reviewed 178 eyes with PDR treated with 25-gauge vitrectomy by a single surgeon between April 2013 and December 2017. In total, 98 eyes of 77 patients with PDR (mean age, 52.5 ± 11.7 years) treated with vitrectomy using iOCT (iOCT group) and 80 eyes of 60 patients with PDR (mean age, 53.1 ± 10.9 years) treated without iOCT (non-iOCT group) were included in the study. To determine the effects of combining vitrectomy with iOCT, a comparison was made of patients treated with this combination and patients treated with vitrectomy without iOCT. The effects of these treatments were assessed on the basis of intraoperative complications, reoperation ratios, postoperative complications, operation times, and postoperative visual acuity. The operation time was significantly reduced for the iOCT group (72.9 ± 23.9min) when compared with the non-iOCT group (91.3 ± 31.2min) (P = .001). The incidences of intraoperative complications, reoperation, and postoperative complications did not differ significantly between the 2 groups (P = .542, 0.258, and 0.860 respectively). Six months after surgery, the postoperative visual acuity did not differ significantly between the 2 groups (P = .508). Multiple linear regression analysis revealed that the operation time was significantly correlated with iOCT (beta [standard partial regression coefficient] = - 0.28, P < .001), the fibrovascular proliferative membrane (beta = 0.17, P = .009), cataract surgery (beta = 0.22, P = .016), preoperative retinal photocoagulation (beta = - 0.14, P = .021), intraoperative complications (beta = 0.16, P = .023), and posterior vitreous detachment (beta = - 0.14, P = .04). Use of iOCT reduced the operation time without affecting the incidence rates of intraoperative and postoperative complications, reoperation ratios, or postoperative visual acuities in patients who underwent vitreous surgery for PDR.

INTRAOPERATIVE THREE-DIMENSIONAL FLUORESCEIN ANGIOGRAPHY-GUIDED PARS PLANA VITRECTOMY FOR BRANCH RETINAL VEIN OCCLUSION.

To show surgical results of the intraoperative 3D fluorescein angiography-guided pars plana vitrectomy for branch retinal vein occlusion with vitreous hemorrhage and neovascularization elsewhere. The NGENUITY 3D visualization system was used for the digital-assisted vitrectomy. Three-dimensional fluorescein angiography-guided pars plana vitrectomy was performed in three patients with branch retinal vein occlusion with vitreous hemorrhage and neovascularization elsewhere. In all eyes, the scatter retinal photocoagulations for a nonperfusion area, depicted as hypofluorescein, and the segmentation and delamination of the perivascular fibrovascular proliferative membrane, depicted as hyperfluorescein, could be safely performed on the same screen while implementing intraoperative 3D fluorescein angiography. Three-dimensional fluorescein angiography-guided pars plana vitrectomy, a novel approach that fully uses the advantages of digital-assisted vitrectomy, can be one of the useful techniques for the treatment of branch retinal vein occlusion with vitreous hemorrhage and neovascularization elsewhere.

Ocular findings, surgery details and outcomes in proliferative diabetic retinopathy patients with chronic kidney disease.

We investigated the influence of impaired renal function on fundus characteristics, pars-plana vitrectomy (PPV) details, and outcomes in patients with proliferative diabetic retinopathy (PDR). A retrospective cohort study. We investigated a consecutive series of PDR patients who underwent PPV. The diabetic complications, previous photocoagulation, intravitreal injections before PPV, ocular findings during PPV, surgical details, short-term visual outcome and post-PPV complications were recorded and compared between patients with and without impaired renal function. 149 patients had normal renal function (67.7%), and 71 (32.3%) patients had impaired renal function; 85.4% of patients were identified with chronic kidney disease (CKD) during the preoperative assessment. Impaired renal function was related to hypertension (3.40[1.58-7.29], p = 0.002), incomplete pan-retinal photocoagulation (PRP) (3.18[1.50-6.72], p = 0.002), severe fibrovascular membrane (8.19[3.43-19.54], p<0.001), and extensive retinal vascular closure (3.40[1.54-7.52], p = 0.002). There was a more frequent occurrence of severe intraoperative bleeding (56.3%, 32.2%, p = 0.001) and a higher percentage of intraocular subretinal fluid drainage (45.1%, 22.1%, p = 0.008) in patients with impaired renal function. The percentage of patients whose visual acuity (VA) increased was similar between the two groups (42.3%, 54.4%, p = 0.34). In PDR patients, screening for CKD was required before PPV. PDR patients with impaired renal function tended to have more severe ischemic retinal conditions. Comparable PPV outcomes could be obtained in patients with and without impaired renal damage.

Effect of intravitreal ranibizumab on fibrovascular membranes in patients with proliferative diabetic retinopathy.

To assess the effects of intravitreal ranibizumab (IVR) on angiogenesis and glial activity of the fibrovascular membrane (FVM) in patients with proliferative diabetic retinopathy (PDR). Forty-two eyes from 42 patients with PDR requiring vitrectomy were included and divided into two groups: control group (n=16) did not receive IVR, while IVR group (n=26) underwent IVR 5d before vitrectomy. FVM specimens were collected by the same surgeon during the interventions. Histopathological morphology was examined by hematoxylin-eosin (H-E) staining and cell densities in the FVM was assessed. Microvessels were outlined by immunohistochemical staining of CD31 and microvessel density (MVD) assessed as an index of FVM angiogenesis. Dual-color immunofluorescence staining, and confocal microscopy was used to detect co-localization and relative expression levels of glial fibrillary acidic protein (GFAP) and α-smooth muscle actin (α-SMA) as markers of glial-mesenchymal transition (GMT). The GMT index (GI; ratio of relative GFAP/α-SMA expression) was used to semi-quantify the degree of GMT or glial activity of FVMs. H-E staining showed similar vascularization in both groups, with microvessels and scattered stromal cells in the matrix. Infiltrated cell densities did not differ significantly between the two groups (P>0.05). The MVD of the IVR group (130.62±15.46/mm2) was significantly lower than that of the controls (142.25±19.16/mm2, P<0.05). In both groups, all sections were strongly immunostained for GFAP and α-SMA. The Pearson's correlation coefficients (PCC) of intensity of automated pixel count of two markers indicated GFAP and α-SMA co-stained well and GMT participated in the remolding of FVMs in PDR. The mean relative GFAP expression in the IVR group was significantly lower, whereas that of α-SMA was significantly higher than in controls (P<0.05). GI in the IVR group (1.10±0.10) was significantly lower than in the controls (1.21±0.12, P<0.05). IVR can reduce angiogenesis, glial activity of FVM and promote glial-fibrotic transformation by reducing MVD and promoting GMT but does not decrease the cell density in patients with PDR.

Differential Expression and Localization of ADAMTS Proteinases in Proliferative Diabetic Retinopathy.

We analyzed the expression of ADAMTS proteinases ADAMTS-1, -2, -4, -5 and -13; their activating enzyme MMP-15; and the degradation products of proteoglycan substrates versican and biglycan in an ocular microenvironment of proliferative diabetic retinopathy (PDR) patients. Vitreous samples from PDR and nondiabetic patients, epiretinal fibrovascular membranes from PDR patients, rat retinas, retinal Müller glial cells and human retinal microvascular endothelial cells (HRMECs) were studied. The levels of ADAMTS proteinases and MMP-15 were increased in the vitreous from PDR patients. Both full-length and cleaved activation/degradation fragments of ADAMTS proteinases were identified. The amounts of versican and biglycan cleavage products were increased in vitreous from PDR patients. ADAMTS proteinases and MMP-15 were localized in endothelial cells, monocytes/macrophages and myofibroblasts in PDR membranes, and ADAMTS-4 was expressed in the highest number of stromal cells. The angiogenic activity of PDR membranes correlated significantly with levels of ADAMTS-1 and -4 cellular expression. ADAMTS proteinases and MMP-15 were expressed in rat retinas. ADAMTS-1 and -5 and MMP-15 levels were increased in diabetic rat retinas. HRMECs and Müller cells constitutively expressed ADAMTS proteinases but not MMP-15. The inhibition of NF-κB significantly attenuated the TNF-α-and-VEGF-induced upregulation of ADAMTS-1 and -4 in a culture medium of HRMECs and Müller cells. In conclusion, ADAMTS proteinases, MMP-15 and versican and biglycan cleavage products were increased in the ocular microenvironment of patients with PDR.

The association between different hypoglycemic regimens and postoperative diabetic macular edema after vitrectomy in the Japanese patients with proliferative diabetic retinopathy.

PurposeTo study the association between different hypoglycemic regimens and postoperative diabetic macular edema (DME).MethodsA secondary analysis based on a retrospective cohort study.ResultsIn this secondary analysis, 124 eyes from patients with proliferative diabetic retinopathy (PDR) who underwent pars plana vitrectomy (PPV) between January 2008 and September 2012 were included. We found that compared with oral hypoglycemic medication, oral hypoglycemic medication plus insulin treatment revealed an insignificant relationship with postoperative DME (odds ratio [OR]=0.8, 95% confidence interval [CI]: 0.12-5.21, P=0.8167), only insulin treatment revealed a significant association with postoperative DME (OR=0.10, 95% CI: 0.01-0.84, P=0.0337) after adjusted age, sex. After adjusted age, sex, diabetes mellitus (DM) duration, glycosylated hemoglobin (HbA1c), the results did not have obvious changes (OR=0.61, 95% CI: 0.09-4.26, P=0.6187; OR=0.07, 95% CI: 0.01-0.65, P=0.0197). Furthermore, after adjusted age, sex, DM duration, HbA1c, hypertension, intraoperative retinal photocoagulation, vitreous hemorrhage, macular detachment, fibrovascular membrane, intraocular lens implantation and microincision vitrectomy surgery, the results were consistent (OR=0.66, 95% CI: 0.05-9.49, P=0.7621; OR=0.06, 95% CI: 0.00-0.81, P=0.0342). The same trend was observed in these adjusted models as well (p for trend was 0.0254, 0.0141, and 0.0311, respectively).ConclusionIn conclusion, our results of the secondary analysis should be interpreted as a significant association between insulin treatment and reduced risks of postoperative DME in Japanese PDR patients with PPV surgery, compared with oral medications. Well glycemic control with longstanding insulin therapy may be beneficial to reduce the risks of postoperative DME in PDR patients. Our investigation calls for large-scale and long-term prospective clinical studies for a full evaluation of the exact role of insulin in the progression of postoperative DME.

Integrative study of gene expression datasets in retinal samples of Diabetic Retinopathy

Diabetic Retinopathy is prevalent among patients with uncontrolled hyperglycemia resulting in vision loss. Despite numerous challenges to create a link among these conditions, the characterization of pathological neovascularization causing retinal damage due to the prognosis of early non-proliferative diabetic retinopathy to late proliferative diabetic retinopathy needs deep understanding. In this study, meta-analysis-based integration of gene expression datasets for the fibrovascular membrane of PDR and neural retina of NPDR were compared, to investigate the differentially expressed genes involved in retinal angiogenesis. Human samples with gene expression profiling of the same experiment type and platform with sufficient information for analysis were included in the study. The studies from cell lines and non-human studies, human samples that include serum, cornea, lens, and/or other ocular tissues or fluids, and studies that lack basic information for analysis were excluded. The microarray datasets available in the Gene Expression Omnibus database of the early and late stages in DR were screened to find common gene expression profiles. Using the INMEX bioinformatics tool, significantly upregulated and downregulated genes in the neural retina of Non-Proliferative Diabetic Retinopathy and fibrovascular membrane of Proliferative Diabetic Retinopathy were compared and studied by the combine effect size method. Using the STRING database PPI network, 50 upregulated and 50 downregulated genes were used to find the key candidate genes involved in retinal disease/degeneration in eye/retinal tissues. In the extensive gene expression meta-analysis performed using INMEX bioinformatics tool, overall, 7935 differentially expressed genes were identified and the respective heatmap was created by using the visualization tools of INVEX. STRING database PPI network identified Retinol Binding Protein 3, Neural Retina Leucine Zipper, S-Antigen Visual Arrestin, Peripherin 2, and Aryl Hydrocarbon Receptor Interacting Protein Like-1 to be the most highly ranked hub genes. The newly discovered potential genes related to retinal angiogenesis causing FVM formation in DR may provide insight into the cellular pathogenesis of NPDR to PDR.

CircFAT1 regulates retinal pigment epithelial cell pyroptosis and autophagy via mediating m6A reader protein YTHDF2 expression in diabetic retinopathy

Diabetic retinopathy (DR) is a serious blinding complication of diabetes. At present, the therapeutic intervention effect is limited. We aimed to investigate the circRNA expression profiles in retinal proliferative fibrovascular membranes of patients with DR and explore the effect of circFAT1 on pyroptosis and autophagy of high glucose (HG)-induced retinal pigment epithelial (RPE) cells and its molecualr mechanism. In this study, circRNA sequencing was performed to determine the expression profiles of circRNAs in DR patients. The expression of circFAT1 was measured by qRT-PCR. Cell counting kit-8, transmission electron microscope, western blot, immunofluorescence and enzyme-linked immunosorbent assay were conducted to explore the roles of HG and circFAT1 in RPE cell pyroptosis and autophagy. RNA pull down was used to determine the binding protein of circFAT1. Our data showed that HG significantly reduced the viability of RPE cells, inhibited cell autophagy and contributed to cell pyroptosis. In addition, a total of 189 differentially expressed circRNAs (DEcircRNAs) were identified between DR patients and non-DR patients, including 93 upregulated and 96 downregulated DEcircRNAs in the retinal proliferative fibrovascular membranes of DR patients. Pathway analysis showed that DEcircRNAs were mainly involved in MAPK signaling pathway, TGF-beta signaling pathway and adherens junction. Moreover, circFAT1 was significantly downregulated in retinal proliferative fibrovascular membranes of DR patients and HG-induced RPE cells. CircFAT1 overexpression remarkably enhanced the expression of LC3B, while reduced the expression of GSDMD in HG-induced RPE cells. RNA pull down combined with western blot analysis indicated that circFAT1 bound to m6A reader YTHDF2. YTHDF2 overexpression significantly increased the protein expression of LC3B in HG-induced RPE cells. In summary, circFAT1 promoted autophagy and inhibited pyroptosis of RPE cells induced by HG, and could combine with YTHDF2. This study provides new ideas for DR prevention and treatment.