Vision Loss In Diabetic Retinopathy Research Articles

Investigation of the recurrent vitreous hemorrhage risk factors after early 25G vitrectomy in diabetic vitreous hemorrhage.

Vitreous hemorrhage (VH) is one of the main causes of vision loss in diabetic retinopathy (DRP). Early surgery increases the visibility of the retina, allowing early recognition of DRP complications and additional treatments. One of the most important reasons affecting success after surgery is recurrent vitreous hemorrhage (RVH). We aimed to investigate the risk factors for RVH after early 25G vitrectomy in diabetic VH. Eighty eyes of eighty patients who underwent early 25G PPV surgery with a diagnosis of VH due to proliferative diabetic retinopathy (PDR) were included in this retrospective study. Vision acuity changes and intraocular pressure (IOP) changes were compared. The effect of arterial hypertension (HT), coronary artery disease (CAD), preoperative antiglaucomatous usage, and anticoagulant usage on RVH was investigated. A value of P < .05 was accepted as statistically significant. Postoperative RVH was observed in 18 (22.5%) patients. There was no correlation between the age of the patients and the development of postoperative RVH (r = -0.197, P = .08). The rate of HT and the mean HbA1C levels were found to be higher in the patients who developed RVH than in those who did not (P = .04 and < 0.001, respectively). The presence of CAD, preoperative glaucoma disease, and the use of anticoagulants did not have any effect on RVH (P = .229, 0.843, 0.932, respectively). HT and increased HbA1c were found to be risk factors for RVH in VH patients who underwent 25G vitrectomy in the early period in our study.

Semi-supervised Blindness Detection with Neural Network Ensemble

Diabetic retinopathy (DR), a common complication of diabetes mellitus, is a major cause of visual loss among the working-age population. Since DR vision loss is irreversible, early detection of DR is crucial for preventing vision loss in patients. However, manual detection of DR remains time costly and inefficient. In this paper, an ensemble of 6 pre-trained neural networks (including EfficientNets, ResNet, and Inception) are combined. The compatibility of different networks is tested by creating different combinations of networks and evaluating their relative performance. Pseudo-labelling is used to further increase accuracy. With a limited training data set of only 5592 images, the final neural network ensemble achieved an accuracy of 0.864.

44-OR: NFAT Inhibition Reduces Retinal Vascular Leakage and Inflammation in Diabetic Retinopathy

Purpose: Macular edema resulting from retinal vascular leakage is the leading cause of vision loss in diabetic retinopathy (DR) . The nuclear factor of activated T-cells (NFAT) family of transcription factors is known to upregulate inflammatory cytokines in response to high glucose. This study explored the effect of NFAT inhibition on retinal vascular leakage and inflammation in DR in vivo and in vitro. Methods: The streptozocin-induced (STZ) model was used as the mouse model of diabetic retinopathy. Hyperglycemia was induced at 4 weeks in C57BL/6J mice and confirmed when fasting plasma glucose became persistently elevated (&amp;gt;300 mg/dL) . Experiments were performed at weeks of hyperglycemia. STZ mice were injected intravitreally with the NFAT signaling inhibitor INCA-6 (25 uM) or vehicle (0.1% DMSO in PBS) . Uninjected eyes of both STZ and control mice served as additional controls. Evans blue dye (EBD) was used to measure retinal vascular leakage. Primary mouse retinal microvascular endothelial cells (MRMECs) were used for in vitro experiments. MRMEC monolayers were treated with INCA-6 (2.5 uM) or with vehicle and cell permeability was induced with mouse VEGF165. The transendothelial electrical resistance (TEER) was measured with the electrical cell-substrate impedance sensing method. MRMEC IL-6 production was investigated by ELISA. Results: In the STZ model of diabetic retinopathy, EBD vascular leakage was significantly reduced in INCA-6-treated eyes (INCA-6: 0.85 ± 0.57, n=5; vehicle: 1.78 ± 0.38, n= 7; P=0.007) , and in INCA-6 treated eyes compared to untreated eyes (untreated: 2.83 ± 1.63, n=4, P=0.04) . In the VEGF-induced MRMEC monolayer permeability model, INCA-6 significantly preserved TEER compared to vehicle (n=12, P&amp;lt;0.05) and decreased the VEGF-induced production of IL-6 (n=5, P&amp;lt;0.05) . Conclusions: NFAT inhibition has therapeutic potential to prevent and treat retinal vascular leakage and inflammation in DR. Disclosure I.De la huerta: None. J.L.Nunez: None. J.M.Poloway: None. V.Reddy: None. J.Penn: None. Funding National Institutes of Health (EY032620) International Retinal Research Foundation Grant Knights Templar Foundation Career Starter Grant

Ayurvedic management of retinopathy combined with central serous macular edema: A case report

Dealing with intemperate diabetes and hypertension, one of the main challenge to deal with is retinopathy. Early management and preventive treatments through Ayurveda can make a great impact as it helps in preventing vision loss. The major cause of vision loss in diabetic retinopathy is macular edema, which is the thickening of macula due to fluid accumulation. This will result in significant deterioration of vision and if untreated will result in permanent loss of vision. The pathophysiology of hypertension and diabetes can cause altered immune functions and vascular endothelial dysfunction. In Ayurveda, retinopathy can be considered as Timira (~errors of refraction/partial blindness). A 61-year-old male patient complaining of defective distant and near vision for one year sought Ayurvedic treatment. Clinical findings include Central Serous Macular Edema (CSME), Non-proliferative Diabetic Retinopathy (NPDR) with maculopathy, and Grade 2 hypertensive retinopathy in both eyes. The selected treatment protocol includes Rakta sangrahi (~medicine that helps in blood coagulation), Stambhana (~procedure or action of drug causing arrest of secretion or control of bleeding), and Ama pachana (~the action of a drug or medicine which helps in digesting toxins in body), Sirovirechana (~medication through nose for cleansing or errhine), Talapotichil (~patching the scalp with herbal paste), Sirodhara (~pouring medicated oil over the scalp), Takradhara (~therapeutic butter milk-streaming over body), and Akshi tarpanam (~filling the eyes with medicated Ghee). Significant improvement in Visual Acuity (VA) and changes in CSME were observed at the end of the treatment. During follow-up period of three months, VA was further improved. The observations reveal that Ayurvedic management of the mixed retinopathy is significantly effective in reducing the subjective and objective symptoms and improve VA.

Therapeutic Effects of Fenofibrate Nano-Emulsion Eye Drops on Retinal Vascular Leakage and Neovascularization.

Simple SummaryAge-related macular degeneration (AMD) and diabetic retinopathy (DR) are the leading causes of blindness and lack non-invasive drug treatments. Macular edema and neovascularization are the key pathogenic features responsible for vision loss in AMD and DR. Clinical studies showed that fenofibrate, a PPARα agonist, has robust therapeutic effects on macular edema and retinal neovascularization after oral administration. However, the efficacy of oral fenofibrate remains to be improved, due to limited amounts of the drug delivered to the retina after systemic administration. To increase the drug availability in the retina, this study developed a novel nano-emulsion fenofibrate eye drop. Topical administration of the fenofibrate eye drop delivered significantly higher drug concentrations to the retina/vitreous, relative to the systemic administration. The fenofibrate eye drop alleviated retinal inflammation and vascular leakage in both DR and AMD models. Further, the fenofibrate eye drop also alleviated laser-induced choroidal neovascularization. These findings suggest that topical administration of the nano-emulsion-based eye drop of a PPARα agonist has potential to become a non-invasive therapeutic strategy for long-term treatment of DR and AMD.Macular edema caused by retinal vascular leakage and ocular neovascularization are the leading causes of severe vision loss in diabetic retinopathy (DR) and age-related macular degeneration (AMD) patients. Oral administration of fenofibrate, a PPARα agonist, has shown therapeutic effects on macular edema and retinal neovascularization in diabetic patients. To improve the drug delivery to the retina and its efficacy, we have developed a nano-emulsion-based fenofibrate eye drop formulation that delivered significantly higher amounts of the drug to the retina compared to the systemic administration, as measured by liquid chromatography–mass spectrometer (LC-MS). The fenofibrate eye drop decreased leukocytes adherent to retinal vasculature and attenuated overexpression of multiple inflammatory factors in the retina of very low-density lipoprotein receptor knockout (Vldlr−/−) mice, a model manifesting AMD phenotypes, and streptozotocin-induced diabetic rats. The fenofibrate eye drop also reduced retinal vascular leakage in these models. The laser-induced choroidal neovascularization was also alleviated by the fenofibrate eye drop. There were no detectable ocular toxicities associated with the fenofibrate eye drop treatment. These findings suggest that fenofibrate can be delivered efficiently to the retina through topical administration of the nano-emulsion eye drop, which has therapeutic potential for macular edema and neovascularization.

Malfunction of outer retinal barrier and choroid in the occurrence and progression of diabetic macular edema.

Diabetic macular edema (DME) is the most common cause of vision loss in diabetic retinopathy, affecting 1 in 15 patients with diabetes mellitus (DM). The disruption of the inner blood-retina barrier (BRB) has been largely investigated and attributed the primary role in the pathogenesis and progression in DME, but there is increasing evidence regarding the role of outer BRB, separating the RPE from the underlying choriocapillaris, in the occurrence and evolution of DME. The development of novel imaging technologies has led to major improvement in the field of in vivo structural analysis of the macula allowing us to delve deeper into the pathogenesis of DME and expanding our vision regarding this condition. In this review we gathered the results of studies that investigated specific outer BRB optical coherence tomography parameters in patients with DM with the aim to outline the current status of its role in the pathogenesis and progression of DME and identify new research pathways contributing to the advancement of knowledge in the understanding of this condition.

N-Methyl-D-aspartate receptor activation, novel mechanism of homocysteine-induced blood-retinal barrier dysfunction.

Elevated levels of amino acid homocysteine (Hcy) recognized as hyperhomocysteinemia (HHcy) was reported in several human visual disorders, such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). Breakdown of blood-retinal barrier (BRB) is concomitant with vision loss in DR and AMD. We previously reported that HHcy alters BRB. Here, we tested the hypothesis that HHcy alters BRB via activation of N-methyl-D-aspartate receptor (NMDAR). Human retinal endothelial cells subjected to high level of Hcy and mouse model of HHcy were used. We injected Hcy intravitreal and used a mouse model of HHcy that lacks cystathionine-β-synthase (CBS). RT-PCR, western blot, and immunofluorescence showed that retinal endothelial cells (RECs) express NMDAR at the gene and protein levels both in vitro and in vivo and this was increased by HHcy. We assessed BRB function and retinal morphology using fluorescein angiogram and optical coherence tomography (OCT) under HHcy with and without pharmacological inhibition of NMDAR by (MK801) or in mice lacking endothelial NMDAR (NMDARE-/- mouse). Additionally, retinal albumin leakage and tight junction proteins ZO-1 and occludin were assessed by western blotting analysis. Inhibition or elimination of NMDAR was able to improve the altered retinal hyperpermeability and morphology under HHcy as indicated by significant decrease in retinal albumin leakage and restoration of tight junction proteins ZO-1 and occludin. Our findings underscore a potential role for endothelial NMDAR in mediating Hcy-induced breakdown of BRB and subsequently as a potential therapeutic target in retinal diseases associated with HHcy such as DR and AMD. KEY MESSAGES: • Elevated levels of homocysteine (Hcy) are defined as hyperhomocysteinemia (HHcy). • HHcy is implicated in diabetic retinopathy and age-related macular degeneration. • HHcy alters BRB via activation of N-methyl-D-aspartate receptor.

Implication of Hyperhomocysteinemia in Blood Retinal Barrier (BRB) Dysfunction.

Elevated plasma homocysteine (Hcy) level, known as hyperhomocysteinemia (HHcy) has been linked to different systemic and neurological diseases, well-known as a risk factor for systemic atherosclerosis and cardiovascular disease (CVD) and has been identified as a risk factor for several ocular disorders, such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). Different mechanisms have been proposed to explain HHcy-induced visual dysfunction, including oxidative stress, upregulation of inflammatory mediators, retinal ganglion cell apoptosis, and extracellular matrix remodeling. Our previous studies using in vivo and in vitro models of HHcy have demonstrated that Hcy impairs the function of both inner and outer blood retinal barrier (BRB). Dysfunction of BRB is a hallmark of vision loss in DR and AMD. Our findings highlighted oxidative stress, ER stress, inflammation, and epigenetic modifications as possible mechanisms of HHcy-induced BRB dysfunction. In addition, we recently reported HHcy-induced brain inflammation as a mechanism of blood–brain barrier (BBB) dysfunction and pathogenesis of Alzheimer’s disease (AD). Moreover, we are currently investigating the activation of glutamate receptor N-methyl-d-aspartate receptor (NMDAR) as the molecular mechanism for HHcy-induced BRB dysfunction. This review focuses on the studied effects of HHcy on BRB and the controversial role of HHcy in the pathogenesis of aging neurological diseases such as DR, AMD, and AD. We also highlight the possible mechanisms for such deleterious effects of HHcy.

The prognostic value of peripheral retinal nonperfusion in diabetic retinopathy using ultra-widefield fluorescein angiography.

To investigate the prognostic value of peripheral retinal nonperfusion in patients with diabetic retinopathy using ultra-widefield fluorescein angiography (UWFA). A cross-sectional study included 78 treatment-naïve eyes with nonproliferative and proliferative diabetic retinopathy (NPDR and PDR). Eyes were divided into three groups: mild/moderate NPDR (n = 31), severe NPDR (n = 31), and PDR (n = 16). Three nonperfusion variables were calculated reflecting the proportion of nonperfused to visible retina based on initial UWFA: central nonperfusion (CNP) index, peripheral nonperfusion (PNP) index, and PNP ratio. The relationships between these indices and central subfield thickness (CST) and spectacle-corrected visual acuity (SCVA) were evaluated. CNP and PNP indices were significantly higher in the PDR group vs. mild/moderate NPDR group (p = 0.007 and 0.008, respectively) but not in the PDR group vs. severe NPDR group (p = 0.149 and p = 0.535, respectively). A significant linear correlation was found between the CNP and PNP indices in both severe NPDR and PDR groups (R2 = 0.141, p = 0.041, and R2 = 0.311, p = 0.025, respectively). Nonperfusion predominance was not statistically correlated with the presence of macular edema (p = 0.058) or disorganization of retinal inner layers (p = 1). In the severe NPDR group, there was a moderately positive correlation between CNP index and CST (rs = 0.496, p = 0.019) and no correlation between CNP index and SCVA when controlling for CST (p = 0.160). In the PDR group, a strong negative correlation between PNP ratio and CST was found (rs = -0.659, p = 0.014), but no correlation was observed between CNP index, CST, and SCVA. In the PDR group, a positive correlation was found between PNP index, PNP ratio, and SCVA (rs = 0.549, p = 0.027, and rs = 0.626, p = 0.010, respectively), even after controlling for CST (rs = 0.599, p = 0.040). Higher amounts of retinal nonperfusion are seen in patients with more severe retinopathy. Increased CNP is associated with macular thickening and subsequent vision loss. Having predominantly PNP was independently associated with worse VA, regardless of macular thickness. Further studies are needed to investigate the role of PNP in vision loss in diabetic retinopathy.

Novel imaging biomarkers in diabetic retinopathy and diabetic macular edema.

Diabetic retinopathy is one of the major microvascular complications of diabetes mellitus. The most common causes of vision loss in diabetic retinopathy are diabetic macular edema and proliferative diabetic retinopathy. Recent developments in ocular imaging have played a significant role in early diagnosis and management of these complications. Color fundus photography is an imaging modality, which is helpful for screening patients with diabetic eye disease and monitoring its progression as well as response to treatment. Fundus fluorescein angiography (FFA) is a dye-based invasive test to detect subtle neovascularization, look for areas of capillary non-perfusion, diagnose macular ischemia, and differentiate between focal and diffuse capillary bed leak in cases of macular edema. Recent advances in retinal imaging like the introduction of spectral-domain and swept source-based optical coherence tomography (OCT), fundus autofluorescence (FAF), OCT angiography, and ultrawide field imaging and FFA have helped clinicians in the detection of certain biomarkers that can identify disease at an early stage and predict response to treatment in diabetic macular edema. This article will summarize the role of different imaging biomarkers in characterizing diabetic retinopathy and their potential contribution in its management.

Elucidation of Pathophysiology and Novel Treatment for Diabetic Macular Edema Derived from the Concept of Neurovascular Unit.

The retina transmits light signals to the brain via a complex structure composed of photoreceptor cells, neurons including ganglion cells, glial cells such as astrocytes and Mueller cells, as well as retinal blood vessels that feed the retina. The retina performs such high-level physiological function and maintains homeostasis effectively through interactions among the cells that form the neurovascular units (NVUs). Furthermore, as a component of the blood‒retinal barrier (BRB), the vascular structure of the retina is functionally based on the NVUs, in which the nervous system and the vascular tissues collaborate in a mutually supportive relationship. Retinal neurons such as ganglion cells and amacrine cells are traditionally considered to be involved only in visual function, but multiple functionality of neurons attracted attention lately, and retinal neurons play an important role in the formation and function of retinal blood vessels. In other words, damage to neurons indirectly affects retinal blood vessels. Diabetic macular edema is the leading cause of vision loss in diabetic retinopathy, and this type of edema results in neurological and vascular disorders. In this article, the regulatory mechanism of retinal capillaries in diabetic macular edema is reviewed from the viewpoint of NVU.

Diabetic Macular Edema: State of Art and Intraocular Pharmacological Approaches.

Diabetic macular edema (DME) is the main cause of vision loss in diabetic retinopathy (DR). Although it is one of the main complications of diabetes, the pathogenesis of DME is not completely understood. The hyperglycemic state promotes the activation of multiple interlinked pathways leading to DME. Different classifications have been proposed: based on clinical features, on pathogenesis or on diagnostic tests (optical coherence tomography - OCT and fluorescin angiography - FA). The multimodal imaging allows a better analysis of the morphological features of the DME. Indeed, new inflammatory biomarkers have been identified on OCT. Also, several studies are evaluating the role of the morphological features, identified on multimodal imaging, to find new prognostic factors. Over the past decade, great progresses have been made in the management of DME. Therapeutic alternatives include intraocular injection of anti-vascular endothelial grow factor agents (anti-VEGF) and steroid molecules, focal/grid laser photocoagulation and vitreo-retinal surgery. This review is focused on the description and analysis of the current intravitreal therapeutic pharmacological strategies. Current guidelines recommend anti-VEGF as first line therapy in DME. Corticosteroids are becoming increasingly relevant blocking the inflammatory cascade and indirectly reducing VEGF synthesis.

Pathophysiology of Diabetic Retinopathy: The Old and the New.

Vision loss in diabetic retinopathy (DR) is ascribed primarily to retinal vascular abnormalities—including hyperpermeability, hypoperfusion, and neoangiogenesis—that eventually lead to anatomical and functional alterations in retinal neurons and glial cells. Recent advances in retinal imaging systems using optical coherence tomography technologies and pharmacological treatments using anti-vascular endothelial growth factor drugs and corticosteroids have revolutionized the clinical management of DR. However, the cellular and molecular mechanisms underlying the pathophysiology of DR are not fully determined, largely because hyperglycemic animal models only reproduce limited aspects of subclinical and early DR. Conversely, non-diabetic mouse models that represent the hallmark vascular disorders in DR, such as pericyte deficiency and retinal ischemia, have provided clues toward an understanding of the sequential events that are responsible for vision-impairing conditions. In this review, we summarize the clinical manifestations and treatment modalities of DR, discuss current and emerging concepts with regard to the pathophysiology of DR, and introduce perspectives on the development of new drugs, emphasizing the breakdown of the blood-retina barrier and retinal neovascularization.

Hyperhomocysteinemia Alters Retinal Endothelial Cells Barrier Function and Angiogenic Potential via Activation of Oxidative Stress

Hyperhomocysteinemia (HHcy) is associated with several human visual disorders, such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). Breakdown of the blood-retinal barrier (BRB) is linked to vision loss in DR and AMD. Our previous work revealed that HHcy altered BRB in retinal endothelial cells in vivo. Here we hypothesize that homocysteine (Hcy) alters retinal endothelial cell barrier function and angiogenic potential via activation of oxidative stress. Human retinal endothelial cells (HRECs) treated with and without different concentrations of Hcy showed a reduction of tight junction protein expression, increased FITC dextran leakage, decreased transcellular electrical resistance and increased angiogenic potential. In addition, HRECs treated with Hcy showed increased production of reactive oxygen species (ROS). The anti-oxidant N-acetyl-cysteine (NAC) reduced ROS formation and decreased FITC-dextran leakage in Hcy treated HRECs. A mouse model of HHcy, in which cystathionine-β-synthase is deficient (cbs−/−), was evaluated for oxidative stress by dichlolorofluorescein (DCF), dihydroethidium (DHE) staining. There was a marked increase in ROS production and augmented GSH reductase and antioxidant regulator NRF2 activity, but decreased antioxidant gene expression in retinas of hyperhomocysteinemic mice. Our results suggest activation of oxidative stress as a possible mechanism of HHcy induced retinal endothelial cell dysfunction.

Visualization of changes in the foveal avascular zone in both observed and treated diabetic macular edema using optical coherence tomography angiography

BackgroundCentral vision loss in diabetic retinopathy is commonly related to diabetic macular edema (DME). The objective of this study was to describe changes between consecutive visits on optical coherence tomography angiography (OCTA) of the foveal avascular zone (FAZ) in eyes with DME.Methods20 eyes from 14 patients with DME were imaged on 2 successive clinic visits separated by at least 1 month. The mean interval between visits was 3.2 months. The only intervention used was intravitreal anti-VEGF in 11 eyes; the others were observed over time without treatment. Two different readers measured FAZ area using a pseudo-automated tool in comparison to a manual tracing tool. Qualitative changes in the appearance of the vasculature surrounding the FAZ were also recorded. The retinal capillary plexus was segmented into deep and superficial plexuses, and FAZ measurements were done on the superficial, deep, and summated plexuses.ResultsPseudo-automated and manual measurements of FAZ area decreased significantly (p < 0.05) between visits in the deep, superficial, and summated plexuses. Qualitative analysis of vasculature surrounding the FAZ showed that most of the vascular changes (65%) over time were visible in the deep plexus, compared to 30 and 20% in the superficial and summated plexuses, respectively.ConclusionsThe most significant differences in FAZ size over time were in the summated plexus (p < 0.001), while changes in FAZ appearance were most prominent in the deep plexus. Absolute decrease in FAZ size over visits was largest in the deep plexus. Our results demonstrate that OCTA can effectively be used to measure FAZ area in patients with DME, visualize qualitative changes in retinal vasculature, and visualize the segmentation levels at which these changes can be best appreciated. However, larger studies are needed to evaluate the reproducibility of manual and pseudo-automated measuring techniques.

Connexin channel and its role in diabetic retinopathy.

Diabetic retinopathy is the leading cause of blindness in the working age population. Unfortunately, there is no cure for this devastating ocular complication. The early stage of diabetic retinopathy is characterized by the loss of various cell types in the retina, namely endothelial cells and pericytes. As the disease progresses, vascular leakage, a clinical hallmark of diabetic retinopathy, becomes evident and may eventually lead to diabetic macular edema, the most common cause of vision loss in diabetic retinopathy. Substantial evidence indicates that the disruption of connexin-mediated cellular communication plays a critical role in the pathogenesis of diabetic retinopathy. Yet, it is unclear how altered communication via connexin channel mediated cell-to-cell and cell-to-extracellular microenvironment is linked to the development of diabetic retinopathy. Recent observations suggest the possibility that connexin hemichannels may play a role in the pathogenesis of diabetic retinopathy by allowing communication between cells and the microenvironment. Interestingly, recent studies suggest that connexin channels may be involved in regulating retinal vascular permeability. These cellular events are coordinated at least in part via connexin-mediated intercellular communication and the maintenance of retinal vascular homeostasis. This review highlights the effect of high glucose and diabetic condition on connexin channels and their impact on the development of diabetic retinopathy.

Inhibition of Stat3 by a Small Molecule Inhibitor Slows Vision Loss in a Rat Model of Diabetic Retinopathy.

PurposeDiabetic retinopathy is a leading cause of vision loss. Previous studies have shown signaling pathways mediated by Stat3 (signal transducer and activator of transcription 3) play a primary role in diabetic retinopathy progression. This study tested CLT-005, a small molecule inhibitor of Stat3, for its dose-dependent therapeutic effects on vision loss in a rat model of diabetic retinopathy.MethodsBrown Norway rats were administered streptozotocin (STZ) to induce diabetes. CLT-005 was administered daily by oral gavage for 16 weeks at concentrations of 125, 250, or 500 mg/kg, respectively, beginning 4 days post streptozotocin administration. Systemic and ocular drug concentration was quantified with mass spectrometry. Visual function was monitored at 2-week intervals from 6 to 16 weeks using optokinetic tracking to measure visual acuity and contrast sensitivity. The presence and severity of cataracts was visually monitored and correlated to visual acuity. The transcription and translation of multiple angiogenic factors and inflammatory cytokines were measured by real-time polymerase chain reaction and Multiplex immunoassay.ResultsStreptozotocin-diabetic rats sustain progressive vision loss over 16 weeks, and this loss in visual function is rescued in a dose-dependent manner by CLT-005. This positive therapeutic effect correlates to the positive effects of CLT-005 on vascular leakage and the presence of inflammatory cytokines in the retina.ConclusionsThe present study indicates that Stat3 inhibition has strong therapeutic potential for the treatment of vision loss in diabetic retinopathy.

Novel Small Molecule JP-153 Targets the Src-FAK-Paxillin Signaling Complex to Inhibit VEGF-Induced Retinal Angiogenesis.

Targeting vascular endothelial growth factor (VEGF) is a common treatment strategy for neovascular eye disease, a major cause of vision loss in diabetic retinopathy and age-related macular degeneration. However, the decline in clinical efficacy over time in many patients suggests that monotherapy of anti-VEGF protein therapeutics may benefit from adjunctive treatments. Our previous work has shown that through decreased activation of the cytoskeletal protein paxillin, growth factor-induced ischemic retinopathy in the murine oxygen-induced retinopathy model could be inhibited. In this study, we demonstrated that VEGF-dependent activation of the Src/FAK/paxillin signalsome is required for human retinal endothelial cell migration and proliferation. Specifically, the disruption of focal adhesion kinase (FAK) and paxillin interactions using the small molecule JP-153 inhibited Src-dependent phosphorylation of paxillin (Y118) and downstream activation of Akt (S473), resulting in reduced migration and proliferation of retinal endothelial cells stimulated with VEGF. However, this effect did not prevent the initial activation of either Src or FAK. Furthermore, topical application of a JP-153-loaded microemulsion affected the hallmark features of pathologic retinal angiogenesis, reducing neovascular tuft formation and increased avascular area, in a dose-dependent manner. In conclusion, our results suggest that using small molecules to modulate the focal adhesion protein paxillin is an effective strategy for treating pathologic retinal neovascularization. To our knowledge, this is the first paradigm validating modulation of paxillin to inhibit angiogenesis. As such, we have identified and developed a novel class of small molecules aimed at targeting focal adhesion protein interactions that are essential for pathologic neovascularization in the eye.

Current concepts regarding developmental mechanisms in diabetic retinopathy in Taiwan.

Diabetic retinopathy (DR) is one of the most feared complications of diabetes and is a leading cause of acquired blindness in working adults. The prevalence of undiagnosed diabetes in Taiwan is about 4%, and the annual incidence of T2D (Type 2 Diabetes) in Taiwan is 1.8% following the 1985 WHO criteria. Multiple mechanisms have been shown in T2DR with some signaling pathways, including the polyol pathway, PKC pathway, AGEs pathway, and MAPK pathway. However, the cause of vision loss in diabetic retinopathy is complex and remains incompletely understood. Herein, we try to fully understand the new concepts regarding hyperglycemia-induced biochemical pathways contributing to DR pathophysiology. Our work may be able to provide new strategies for the prevention and treatment of diabetic vascular complications.

Study of relation between serum lipids and loss of vision in patients with diabetic retinopathy

Objectives The aim of this study was to evaluate the association of serum lipids with vision loss in diabetic retinopathy (DR) patients and the effect of lipid-lowering agents. Background Elevated serum lipids such as total cholesterol and triglycerides lead to vision deterioration through affection of retina in diabetic patients. Patients and methods Forty type 2 diabetic patients were evaluated for serum lipids, diabetic retinopathy (DR) and macular oedema from January 2013 to September 2013 in Menoufia University Hospital, Menoufia, Egypt. Antilipid therapy was administered to hyperlipidaemic patients with DR or macular oedema for 9 months and re-evaluated. Results Of the 40 diabetic patients, 65% were male and 35% were female, and the mean age was 50.5 years (range = 20-80 years). An overall 75% of patients had DR and 25% of patients did not have DR. Various grades of clinically significant macular oedema (CSME) were detected in 42.5% of diabetic patients. Duration of diabetes ranged from 5 to 25 years. Dyslipidaemia was found in 70% of DR patients. Of the 25 dyslipidaemic patients, 12 patients (48%) had CSME. Total cholesterol, low-density lipoprotein, very-low-density lipoprotein and triglyceride level were elevated in DR and CSME. Hard exudate was present in 70% of DR patients with total cholesterol level above 230 mg/dl, and was present in 80% of DR patients with the ratio of total cholesterol level to high-density lipoprotein above 4.5. Retinal hard exudate decreased after antilipid therapy. Conclusion Dyslipidaemia is associated with an increased risk of development and progression of retinopathy and maculopathy in diabetic patients.