Vitamin C alleviates hyperglycemic stress in retinal pigment epithelial cells.

BACKGROUND: Retinal pigment epithelial cells (RPECs) are a type of retinal cells that structurally and physiologically support photoreceptors. However, hyperglycemia has been shown to play a critical role in the progression of diabetic retinopathy (DR), which is one of the leading causes of vision impairment. In the diabetic eye, the high glucose environment damages RPECs via the induction of oxidative stress, leading to the release of excess reactive oxygen species (ROS) and triggering apoptosis. In this study, we aim to investigate the antioxidant mechanism of Vitamin C in reducing hyperglycemia-induced stress and whether this mechanism can preserve the function of RPECs. METHODS AND RESULTS: ARPE-19 cells were treated with high glucose in the presence or absence of Vitamin C. Cell viability was measured by MTT assay. Cleaved poly ADP-ribose polymerase (PARP) was used to identify apoptosis in the cells. ROS were detected by the DCFH-DA reaction. The accumulation of sorbitol in the aldose reductase (AR) polyol pathway was determined using the sorbitol detection assay. Primary mouse RPECs were isolated from adult mice and identified by Rpe65 expression. The mitochondrial damage was measured by mitochondrial membrane depolarization. Our results showed that high glucose conditions reduce cell viability in RPECs while Vitamin C can restore cell viability, compared to the vehicle treatment. We also demonstrated that Vitamin C reduces hyperglycemia-induced ROS production and prevents cell apoptosis in RPECs in an AR-independent pathway. CONCLUSIONS: These results suggest that Vitamin C is not only a nutritional necessity but also an adjuvant that can be combined with AR inhibitors for alleviating hyperglycemic stress in RPECs.

[Pharmacoeconomic analysis of anti-angiogenic drugs for diabetic macular edema]. / Farmakoekonomicheskii analiz primeneniya antiangiogennykh preparatov pri diabeticheskom makulyarnom oteke.

Diabetic macular edema (DME) is a degenerative disease of the macular area in diabetes mellitus and can lead to vision loss, disability, and significantly reduced quality of life. Faricimab is the only bispecific antibody for DME therapy that targets two pathogenic pathways (Ang-2 and VEGF-A). PURPOSE: This study comparatively evaluates the clinical and economic feasibility of faricimab and other angiogenesis inhibitors in patients with DME. MATERIAL AND METHODS: This article analyzed literature on the efficacy and safety of intravitreal injections (IVI) of ranibizumab 0.5 mg, aflibercept 2 mg, and faricimab 6 mg. A model of medical care was developed for patients with DME receiving anti-angiogenic therapy. Pharmacoeconomic analysis was performed using cost minimization and budget impact analysis (BIA) methods. Modeling time horizon was 2 years. The research was performed from the perspective of the healthcare system of the Russian Federation. RESULTS: The efficacy and safety of faricimab in a personalized regimen (up to one IVI in 16 weeks) are comparable to those of aflibercept and ranibizumab, administered in various regimens. The use of faricimab is associated with the lowest number of IVIs. Over 2 years, the maximum costs of drug therapy were associated with the use of ranibizumab (about 914 thousand rubles), while the minimum costs were associated with the use of faricimab (614 thousand rubles). The reduction in inpatient care costs with faricimab therapy was 36% compared to aflibercept (216 and 201 thousand rubles in inpatient and day hospitals, respectively) and 82% compared to ranibizumab (486 and 451 thousand rubles in inpatient and day hospitals, respectively). BIA demonstrated that the use of faricimab will reduce the economic burden on the healthcare system by 11.3 billion rubles (9.8%) over 2 years. CONCLUSION: The use of faricimab is a cost-effective approach to treatment of adult patients with DME in Russia.

Topical insulin in neurotrophic keratopathy after diabetic vitrectomy.

To assess the efficacy and safety of topical insulin (TI) for treating neurotrophic keratopathy (NK) within one-month post-diabetic vitrectomy (DV) compared to conventional non-invasive measures, we conducted this retrospective case-control study including all eyes that developed acute NK (stages 2 and 3) following DV between October 2020 and June 2023. The control group included NK cases managed with preservative-free lubricant eye drops and prophylactic topical antibiotics. In contrast, the study group included NK cases treated with TI [1 unit per drop] four times daily, in addition to the previously mentioned treatment. The primary outcome measure was time to epithelial healing. Secondary outcome measures included any adverse effect of TI or the need for amniotic membrane transplantation (AMT). During the study period, 19 patients with a mean age of 49.3 ± 8.6 years received TI versus 18 controls with a mean age of 52.5 ± 10.7 years. Corneal epithelial healing was significantly faster in the TI-treated group compared to controls, with a mean difference of 12.16 days (95% CI 6.1-18.3, P = 0.001). Survival analysis indicated that the insulin-treated group had 0% and 20% of NK stages 2 and 3, respectively, that failed to achieve corneal epithelial healing, compared to 20% and 66.7% for the control group (P < 0.001). In the control group, two eyes required AMT due to progressive thinning. Additionally, three patients in the control group, progressing to stage 3 NK, were switched to TI, achieving healing after a mean of 14 days. No adverse effects were reported in the TI-treated group. Our study suggests that TI can effectively and safely promote the healing of NK after DV.

Apigenin suppresses epithelial-mesenchymal transition in high glucose-induced retinal pigment epithelial cell by inhibiting CBP/p300-mediated histone acetylation.

Epithelial mesenchymal transition (EMT) is a critical process implicated in the pathogenesis of retinal fibrosis and the exacerbation of diabetic retinopathy (DR) within retinal pigment epithelium (RPE) cells. Apigenin (AP), a potential dietary supplement for managing diabetes and its associated complications, has demonstrated inhibitory effects on EMT in various diseases. However, the specific impact and underlying mechanisms of AP on EMT in RPE cells remain poorly understood. In this study, we have successfully validated the inhibitory effects of AP on high glucose-induced EMT in ARPE-19 cells and diabetic db/db mice. Notably, our findings have identified CBP/p300 as a potential therapeutic target for EMT in RPE cells and have further substantiated that AP effectively downregulates the expression of EMT-related genes by attenuating the activity of CBP/p300, consequently reducing histone acetylation alterations within the promoter region of these genes. Taken together, our results provide novel evidence supporting the inhibitory effect of AP on EMT in RPE cells, and highlight the potential of specifically targeting CBP/p300 as a strategy for inhibiting retinal fibrosis in the context of DR.

Clinical features, management, and outcomes of patients with sterile endophthalmitis associated with intravitreal bevacizumab injection: retrospective case series.

PURPOSE: To evaluate clinical features, treatment protocol, outcomes, and complications that developed in this case series of 24 patients who had consecutive sterile endophthalmitis after intravitreal bevacizumab (IVB) injection. METHODS: In this retrospective case series, IVB was repackaged in individual aliquots from the three batches that were used on the same day. IVB was injected into 26 eyes of 26 patients due to diabetic macular edema, age-related macular degeneration, and branch retinal vein occlusion. All patients had intraocular inflammation. Patients were divided into two groups severe and moderate inflammation according to the intraocular inflammation. The medical records of all patients were reviewed. At each follow-up visit, the complete ophthalmologic examination was performed, including best corrected visual acuity (BCVA), intraocular pressure, biomicroscopy, and posterior fundus examination. RESULTS: Twenty-four of 26 patients were included in the study. Two patients were excluded from this study since they didn't come to follow-up visits. The mean BCVA was 1.00 ± 0.52 Log MAR units before IVB. At the final visit, the BCVA was 1.04 ± 0.47 Log MAR units. These differences were not significant (p = 0.58). Of the 24 eyes, 16 eyes had severe, and 8 eyes had moderate intraocular inflammation. Eleven eyes in the severe inflammation group underwent pars plana vitrectomy due to intense vitreous opacity. Smear, culture results, and polymerase chain reaction results were negative. CONCLUSION: Sterile endophthalmitis may occur after IVB injection. Differential diagnosis of sterile endophthalmitis from infective endophthalmitis is crucial to adjust the appropriate treatment and prevent long-term complications due to unnecessary treatment.

Comparing the efficacy of glucocorticoids and anti-VEGF in treating diabetic macular edema: systematic review and comprehensive analysis.

Introduction: The aim of this study was to better understand the efficacy of various drugs, such as glucocorticoids and anti-vascular endothelial growth factors (VEGF), in the treatment of diabetic macular edema (DME), and to evaluate various clinical treatment regimens consisting of different therapeutic measures. Methods: This study included randomized controlled trials up to February 2023 comparing the efficacy of corticosteroid-related therapy and anti-VEGF therapy. PubMed, the Cochrane Library, and Embase were searched, and the quality of the studies was carefully assessed. Finally, 39 studies were included. Results: Results at 3-month followup showed that intravitreal injection of bevacizumab (IVB) + triamcinolone acetonide (TA) was the most beneficial in improving best-corrected visual acuity and reducing the thickness of macular edema in the center of the retina in patients with DME. Results at 6-month follow-up showed that intravitreal dexamethasone (DEX) was the most effective in improving patients' bestcorrected visual acuity and reducing the thickness of central macular edema. Discussion: Overall, IVB+TA was beneficial in improving best-corrected visual acuity and reducing central macular edema thickness over a 3-month follow-up period, while DEX implants had a better therapeutic effect than anti-VEGF agents at 6 months, especially the patients with severe macular edema and visual acuity impaired. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=397100, identifier CRD42023397100.

Management after cataract surgery for patients with diabetic retinopathy: a systematic review and meta-analysis.

PURPOSE: To evaluate the safety and effectiveness of various treatment modalities in patients with diabetic retinopathy (DR) who underwent cataract surgery. METHODS: A comprehensive search for randomized controlled trials (RCTs) was conducted using the PubMed, Embase, Cochrane Library, and CNKI databases up to December 22, 2021. The safety and efficacy of treatment modalities were assessed using the risk ratio (RR) to compare the progression of DR and the mean difference to evaluate the best corrected visual acuity (BCVA) and macular thickness (MT). RESULTS: The meta-analysis of the RCTs revealed that anti-VEGF (anti-vascular endothelial growth factor) drugs significantly reduced the progression of DR [RR: 0.37 (95%CI 0.19, 0.70), P = 0.002] and improved BCVA [mean difference = - 0.06 (- 0.12, - 0.01), P = 0.03] in patients with pre-existing DR who underwent cataract surgery. Steroid drugs also showed a significant reduction in macular thickness [mean difference = - 55.63 (- 90.73, - 20.53), I2 = 56%, P = 0.002] in DR patients two weeks after cataract surgery compared to the control group. The safety profiles of different management options did not differ significantly. CONCLUSION: The present meta-analysis suggests that anti-VEGF drugs can effectively slow down the progression of diabetic retinopathy, improve BCVA, and reduce MT in DR patients who underwent cataract surgery. Steroid drugs also show promise in reducing MT. However, further studies with larger sample sizes are required to compare the efficacy and safety of different management options in a multi-center clinical setting.

Sustained release gel based on CT image inspection for treatment of diabetes fundus macular lesions.

Currently, slow-release gel therapy is considered to be an effective treatment for fundus macular disease, but the lack of effective evaluation methods limits its clinical application. Therefore, the purpose of this study was to investigate the application and clinical effect of slow-release gel based on CT image examination in the treatment of diabetic fundus macular disease. CT images of fundus macular lesions were collected in a group of diabetic patients. Then the professional image processing software is used to process and analyze the image and extract the key parameters. A slow-release gel was designed and prepared, and applied to the treatment of diabetic fundus macular disease. CT images before and after treatment were compared and analyzed, and the effect of slow-release gel was evaluated. In a certain period of time after treatment, the lesion size and lesion degree of diabetic fundus macular disease were significantly improved by using slow-release gel therapy with CT image examination. No significant adverse reactions or complications were observed during the treatment. This indicates that the slow-release gel based on CT image examination is a safe, effective and feasible treatment method for diabetic fundus macular disease. This method can help improve the vision and quality of life of patients, and provide a new idea and plan for clinical treatment.

Aflibercept Off-Target Effects in Diabetic Macular Edema: An In Silico Modeling Approach.

Intravitreal aflibercept injection (IAI) is a treatment for diabetic macular edema (DME), but its mechanism of action (MoA) has not been completely elucidated. Here, we aimed to explore IAI's MoA and its multi-target nature in DME pathophysiology with an in silico (computer simulation) disease model. We used the Therapeutic Performance Mapping System (Anaxomics Biotech property) to generate mathematical models based on the available scientific knowledge at the time of the study, describing the relationship between the modulation of vascular endothelial growth factor receptors (VEGFRs) by IAI and DME pathophysiological processes. We also undertook an enrichment analysis to explore the processes modulated by IAI, visualized the effectors' predicted protein activity, and specifically evaluated the role of VEGFR1 pathway inhibition on DME treatment. The models simulated the potential pathophysiology of DME and the likely IAI's MoA by inhibiting VEGFR1 and VEGFR2 signaling. The action of IAI through both signaling pathways modulated the identified pathophysiological processes associated with DME, with the strongest effects in angiogenesis, blood-retinal barrier alteration and permeability, and inflammation. VEGFR1 inhibition was essential to modulate inflammatory protein effectors. Given the role of VEGFR1 signaling on the modulation of inflammatory-related pathways, IAI may offer therapeutic advantages for DME through sustained VEGFR1 pathway inhibition.

Machine learning and optical coherence tomography-derived radiomics analysis to predict persistent diabetic macular edema in patients undergoing anti-VEGF intravitreal therapy.

BACKGROUND: Diabetic macular edema (DME) is a leading cause of vision loss in patients with diabetes. This study aimed to develop and evaluate an OCT-omics prediction model for assessing anti-vascular endothelial growth factor (VEGF) treatment response in patients with DME. METHODS: A retrospective analysis of 113 eyes from 82 patients with DME was conducted. Comprehensive feature engineering was applied to clinical and optical coherence tomography (OCT) data. Logistic regression, support vector machine (SVM), and backpropagation neural network (BPNN) classifiers were trained using a training set of 79 eyes, and evaluated on a test set of 34 eyes. Clinical implications of the OCT-omics prediction model were assessed by decision curve analysis. Performance metrics (sensitivity, specificity, F1 score, and AUC) were calculated. RESULTS: The logistic, SVM, and BPNN classifiers demonstrated robust discriminative abilities in both the training and test sets. In the training set, the logistic classifier achieved a sensitivity of 0.904, specificity of 0.741, F1 score of 0.887, and AUC of 0.910. The SVM classifier showed a sensitivity of 0.923, specificity of 0.667, F1 score of 0.881, and AUC of 0.897. The BPNN classifier exhibited a sensitivity of 0.962, specificity of 0.926, F1 score of 0.962, and AUC of 0.982. Similar discriminative capabilities were maintained in the test set. The OCT-omics scores were significantly higher in the non-persistent DME group than in the persistent DME group (p < 0.001). OCT-omics scores were also positively correlated with the rate of decline in central subfield thickness after treatment (Pearson's R = 0.44, p < 0.001). CONCLUSION: The developed OCT-omics model accurately assesses anti-VEGF treatment response in DME patients. The model's robust performance and clinical implications highlight its utility as a non-invasive tool for personalized treatment prediction and retinal pathology assessment.

Optical coherence tomography biomarkers DROL, PROS, SND, hyperreflective walls of foveal cystoid spaces as predictors of central macular thickness and visual acuity in diabetic macular edema treated with intravitreal ranibizumab.

PURPOSE: This study aims to establish DROL (disruption of retinal outer layers), PROS (photoreceptor outer segment length), SND (subfoveal neuroretinal detachment), and hyperreflective walls of foveal cystoid spaces (HRW) as optical coherence tomography (OCT) biomarkers and predictors of central macular thickness (CMT) and visual acuity in diabetic macular edema (DME) treated with intravitreal ranibizumab (IVR). METHODS: In this prospective, interventional study performed at a tertiary care center over a span of 1 year from December 2021 to December 2022, 50 eyes of 46 patients of DME were included. Visual acuity and spectral domain OCT imaging were performed at baseline. Using inbuilt calipers on SD-OCT, the horizontal extent of DROL and the vertical extent of PROS were measured manually. SND and HRW were assessed qualitatively. IVR was administered and patients were followed up at 4, 8, and 12 weeks. RESULTS: The eyes without DROL had statistically significant (P < 0.05) lesser CMT and better BCVA (best-corrected visual acuity) (P < 0.05) after pro re nata injection of IVR. There was a positive correlation between the extent of baseline DROL with final CMT (P < 0.05) and final logMAR BCVA (P > 0.05), whereas negative correlation with the extent of baseline PROS with final CMT (P < 0.05) and final logMAR BCVA (P > 0.05). The presence of HRW and SND predicted non-resolution of CMT and worse visual acuity after treatment with IVR in DME. CONCLUSION: DROL, PROS, SND, and hyperreflective walls of foveal cystoid spaces may be utilized as qualitative as well as quantitative biomarkers to predict the post-treatment CMT and visual acuity in DME.

Comparison of ranibizumab, aflibercept, and dexamethasone implant monotherapy in treatment-naive eyes with diabetic macular edema: A 12-month real-life experience.

PURPOSE: To compare the functional and anatomical outcomes of ranibizumab, aflibercept, and dexamethasone implant monotherapy in treatment-naive eyes with diabetic macular edema (DME) in real-life conditions. METHODS: In this retrospective cohort study, data were obtained from the hospital database of treatment-naive patients diagnosed with DME with at least 12 months of follow-up. Best corrected visual acuity (BCVA) and central retinal thickness (CRT) at baseline, third month, sixth month, ninth month, and 12th month were recorded. In addition, a subgroup analysis was performed based on having good (below 0.4 log of minimum angle of resolution [logMAR]) or poor (0.4 logMAR and above) vision. RESULTS: A total of 219 eyes of 142 patients were included in the study. The change in the mean BCVA from baseline to 12th month was from 0.62 logMAR to 0.42 logMAR (P < 0.001) in the ranibizumab group, from 0.56 logMAR to 0.39 logMAR (P < 0.001) in the aflibercept group, and from 0.46 logMAR to 0.5 logMAR (P = 0.653) in the dexamethasone group. There was no significant difference between the treatment groups at any time point (P > 0.05). The mean amount of CRT change was statistically significant at 12 months in all groups (ranibizumab: -175.4 µm, aflibercept: -153.3 µm, dexamethasone: -71.4 µm) (P < 0.05). In eyes with initially good vision, the final BCVA at 12 months was significantly better in the ranibizumab group compared to the dexamethasone group (P = 0.008). The aflibercept group had better visual acuity than the dexamethasone group, but there was no statistically significant difference (P = 0.059). There was no significant difference in final BCVA in eyes with initially poor vision. No serious ocular/systemic complications were noted. CONCLUSION: At the 12th month, a significant decrease in CRT was achieved in all treatment groups, whereas only ranibizumab and aflibercept groups had a significant BCVA increase. In eyes with initially good vision, the final BCVA at 12 months was better in the ranibizumab group compared to the dexamethasone group, whereas it was similar in all groups having initially poor vision.

RAAS in diabetic retinopathy: mechanisms and therapies.

Diabetic retinopathy (DR) is a complication of diabetes with a complex pathophysiology and multiple factors involved. Recently, it has been found that the upregulation of the renin-angiotensin-aldosterone system (RAAS) leads to overexpression of angiotensin II (Ang II), which induces oxidative stress, inflammation, and angiogenesis in the retina. Therefore, RAAS may be a promising therapeutic target in DR. Notably, RAAS inhibitors are often used in the treatment of hypertension. Still, the potential role and mechanism of DR must be further studied. In this review, we discuss and summarize the pathology and potential therapeutic goals of RAAS in DR.

Immunomodulatory effects of Kaempferol on microglial and Macrophage cells during the progression of diabetic retinopathy.

BACKGROUND: Diabetic retinopathy (DR) stands as a prevalent secondary complication of diabetes, notably Type 1 Diabetes Mellitus (T1D), characterized by immune system involvement potentially impacting the retinal immune response mediated by microglia. Early stages of DR witness blood-retinal barrier permeabilization, facilitating peripheral immune cell interaction with the retinal immune system. Kaempferol (Kae), known for its potent anti-inflammatory activity, presents a promising avenue in DR treatment by targeting the immune mechanisms underlying its onset and progression. Our investigation delves into the molecular intricacies of innate immune cell interaction during DR progression and the attenuation of inflammatory processes pivotal to its pathology. METHODS: Employing in vitro studies, we exposed HAPI microglial and J774.A1 macrophage cells to pro-inflammatory stimuli in the presence or absence of Kae. Ex vivo and in vivo experiments utilized BB rats, a T1D animal model. Retinal explants from BB rats were cultured with Kae, while intraperitoneal Kae injections were administered to BB rats for 15 days. Quantitative PCR, Western blotting, immunofluorescence, and Spectral Domain - Optical Coherence Tomography (SD-OCT) facilitated survival assessment, cellular signaling analysis, and inflammatory marker determination. RESULTS: Results demonstrate Kae significantly mitigates inflammatory processes across in vitro, ex vivo, and in vivo DR models, primarily targeting immune cell responses. Kae administration notably inhibits proinflammatory responses during DR progression while promoting an anti-inflammatory milieu, chiefly through microglia-mediated synthesis of Arginase-1 and Hemeoxygenase-1(HO-1). In vivo, Kae administration effectively preserves retinal integrity amid DR progression. CONCLUSIONS: Our findings elucidate the interplay between retinal and systemic immune cells in DR progression, underscoring a differential treatment response predominantly orchestrated by microglia's anti-inflammatory action. Kae treatment induces a phenotypic and functional shift in immune cells, delaying DR progression, thereby spotlighting microglial cells as a promising therapeutic target in DR management.

Association between the response of intravitreal antivascular endothelial growth factor injection and systemic factors of diabetic macular edema.

BACKGROUND: This study investigated the effects of systemic factors in response to intravitreal injections in patients with macular edema due to non-proliferative diabetic retinopathy (NPDR). METHODS: We retrospectively reviewed the medical records of patients treated with intravitreal injections for macular edema secondary to NPDR between January 2018 and January 2021. The patients were divided into three groups according to the injection response. When patients with diabetic macular edema showed 20µ or more reduction in central retinal thickness compared to baseline, they were classified as responsive group, and if not, they were classified as refractory group. The responsive group was further divided into the complete and incomplete response groups. Patients with complete disappearance of edema at seven months were classified as the complete response group, whereas those in which edema did not disappear were classified as the incomplete response group. The clinical characteristics of each group, including medical history, ophthalmic examination results, and laboratory examination results at the time of diagnosis, were analyzed. RESULTS: Of the 112 eyes (91 patients) that satisfied the inclusion criteria, 89 (77 patients) in the responsive group and 23 (14 patients) in the refractory group were included in the analysis. The responsive group was further divided into the complete (51 eyes) and incomplete (38 eyes) response groups. The refractory group had significantly higher glycated hemoglobin levels and significantly lower estimated glomerular filtration rates than the responsive group (p = 0.026 and p = 0.012, respectively). In the multivariate logistic regression analysis, both factors were found to be significant in predicting the degree of response (all p < 0.05). No factor showed a significant difference between the incomplete and complete response groups(all p > 0.05). CONCLUSIONS: In macular edema caused by NPDR, low glomerular filtration rates and high glycated hemoglobin levels may be used as predictors of poor response to intravitreal injection therapy. In addition to blood glucose control, education should be provided regarding the need for the continuous monitoring of renal function.

Possible retinotoxicity of long-term vardenafil treatment.

Phosphodiesterase (PDE) inhibitors - such as vardenafil - are used primarily for treating erectile dysfunction via increasing cyclic guanosine monophosphate (cGMP) levels. Recent studies have also demonstrated their significant cardioprotective effects in several diseases, including diabetes, upon long-term, continuous application. However, PDE inhibitors are not specific for PDE5 and also inhibit the retinal isoform. A sustained rise in cGMP in photoreceptors is known to be toxic; therefore, we hypothesized that long-term vardenafil treatment might result in retinotoxicity. The hypothesis was tested in a clinically relevant animal model of type 2 diabetes mellitus. Histological experiments were performed on lean and diabetic Zucker Diabetic Fatty rats. Half of the animals were treated with vardenafil for six months, and the retinal effects were evaluated. Vardenafil treatment alleviated rod outer segment degeneration but decreased rod numbers in some positions and induced changes in the interphotoreceptor matrix, even in control animals. Vardenafil treatment decreased total retinal thickness in the control and diabetic groups and reduced the number of nuclei in the outer nuclear layer. Müller cell activation was detectable even in the vardenafil-treated control animals, and vardenafil did not improve gliosis in the diabetic group. Vardenafil-treated animals showed complex retinal alterations with improvements in some parameters while deterioration in others. Our results point towards the retinotoxicity of vardenafil, even without diabetes, which raises doubts about the retinal safety of long-term continuous vardenafil administration. This effect needs to be considered when approving PDE inhibitors for alternative indications.

Short Term Effect of Pre-Operative Anti-VEGF on Angiogenic and Fibrotic Profile of Fibrovascular Membranes of Proliferative Diabetic Retinopathy.

Purpose: Adjuvant, pre-operative intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections have been used to reduce peri-operative bleeding in eyes undergoing pars-plana vitrectomy for complications of proliferative diabetic retinopathy (PDR). To address the concern over their potential off-target effects of progressive fibrous contraction, we sought to dissect the transcriptional changes in the surgically extracted fibrovascular membranes (FVMs). Methods: We analyzed surgically extracted FVMs from 10 eyes: 4 eyes pretreated with intravitreal bevacizumab (IVB) and 6 untreated eyes. FVMs were digested into single cells, mRNA was extracted from endothelial cell-enriched (microbead selection with CD31) and non-endothelial cell compartments, followed by RT-qPCR quantification. We then compared the relative expression of genes involved in angiogenesis, endothelial cell integrity, and myofibroblastic processes between treated and untreated FVMs. Results: Endothelial cells from IVB pretreated FVMs showed significant reduction of VEGFA, VEGF receptors (FLT1 and KDR), and angiopoietin 2 expression as well as increased vascular endothelial cadherin and endothelin, suggesting reduced angiogenesis and enhanced vascular integrity. The non-endothelial cell fraction showed decreased expression of VEGFA and fibronectin, without significant difference in the expression of other profibrotic factors. Conclusions: Our findings confirm that adjuvant pre-operative IVB decreased fibronectin and increase endothelin-1 expression without affecting other profibrotic gene expression, uncovering an important interaction between IVB and endothelin-1 that deserves further study.

Photocoagulation or sham laser in addition to conventional anti-VEGF therapy in macular edema associated with TelCaps due to diabetic macular edema or retinal vein occlusion (TalaDME): a study protocol for a multicentric, French, two-group, non-commercial, active-control, observer-masked, non-inferiority, randomized controlled clinical trial.

BACKGROUND: Macular edema (ME) results from hyperpermeability of retinal vessels, leading to chronic extravasation of plasma components into the retina and hence potentially severe visual acuity loss. Current standard of care consists in using intravitreal injections (IVI), which results in a significant medical and economic burden. During diabetic retinopathy (DR) or retinal vein occlusion (RVO), it has recently been shown that focal vascular anomalies (capillary macro-aneurysms, also termed TelCaps) for telangiectatic capillaries may play a central role in the onset, early recurrence, and/or persistence of ME. Since targeted photocoagulation of TelCaps may improve vision, identification, and photocoagulation of TelCaps, it may represent a way to improve management of ME. OBJECTIVE: The Targeted Laser in (Diabetic) Macular Edema (TalaDME) study aims to evaluate whether ICG-guided targeted laser (IGTL), in association with standard of care by IVI, allows reducing the number of injections during the first year of treatment compared with IVI only, while remaining non-inferior for visual acuity. METHODS: TalaDME is a French, multicentric, two-arms, randomized, sham laser-controlled, double-masked trial evaluating the effect of photocoagulation of TelCaps combined to IVI in patients with ME associated with TelCaps. Patients with vision loss related to center involved ME secondary to RVO or DR and presenting TelCaps are eligible. Two hundred and seventy eyes of 270 patients are randomized in a 1:1 ratio to standard care, i.e., IVI of anti-VEGF solely (control group) or combined with IGTL therapy (experimental group). Stratification is done on the cause of ME (i.e., RVO versus diabetes). Anti-VEGF IVI are administered to both groups monthly for 3 months (loading dose) and then with a pro re nata regimen with a monthly follow-up for 12 months. The primary endpoint will be the number of IVI and the change in visual acuity from baseline to 12 months. Secondary endpoints will be the changes in central macular thickness, impact on quality of life, cost of treatment, and incremental cost-utility ratio in each groups. KEY SAFETY: Rare but severe AE linked to the use of IVI and laser, and previously described, are expected. In the sham group, rescue laser photocoagulation may be administered by the unmasked investigator if deemed necessary at month 3. DISCUSSION: The best management of ME associated with TelCaps is debated, and there have been no randomized study designed to answer this question. Given the fact that TelCaps may affect 30 to 60% of patients with chronic ME due to DR or RVO, a large number of patients could benefit from a specific management of TelCaps. TalaDME aims to establish the clinical and medico-economic benefits of additional targeted laser. The results of TalaDME may raise new recommendations for managing ME and impact healthcare costs. TRIAL REGISTRATION: EudraCT: 2018-A00800-55/ NCT03751501. Registration date: Nov. 23, 2018.

Recent advances in the treatment and delivery system of diabetic retinopathy.

Diabetic retinopathy (DR) is a highly tissue-specific neurovascular complication of type 1 and type 2 diabetes mellitus and is among the leading causes of blindness worldwide. Pathophysiological changes in DR encompass neurodegeneration, inflammation, and oxidative stress. Current treatments for DR, including anti-vascular endothelial growth factor, steroids, laser photocoagulation, and vitrectomy have limitations and adverse reactions, necessitating the exploration of novel treatment strategies. This review aims to summarize the current pathophysiology, therapeutic approaches, and available drug-delivery methods for treating DR, and discuss their respective development potentials. Recent research indicates the efficacy of novel receptor inhibitors and agonists, such as aldose reductase inhibitors, angiotensin-converting enzyme inhibitors, peroxisome proliferator-activated receptor alpha agonists, and novel drugs in delaying DR. Furthermore, with continuous advancements in nanotechnology, a new form of drug delivery has been developed that can address certain limitations of clinical drug therapy, such as low solubility and poor penetration. This review serves as a theoretical foundation for future research on DR treatment. While highlighting promising therapeutic targets, it underscores the need for continuous exploration to enhance our understanding of DR pathogenesis. The limitations of current treatments and the potential for future advancements emphasize the importance of ongoing research in this field.