IntroductionDiabetic retinopathy (DR) is a blindness-causing disease which belongs to the group of neurodegenerative diseases. Neurodegeneration of the retina is a process, in which retinal neurons suffer irreversible damage. This study aimed to assess the involvement of neurotrophins (brain-derived neurotrophic factor [BDNF] and nerve growth factor [NGF]) in the pathogenesis of DR.MethodsThe study was performed using male Lewis rats with type 1 diabetes mellitus induced by streptozotocin, and the control group included rats without drug administration. In vivo examinations performed over four weeks included eye fundus imaging, measurement of intraocular pressure, and glycemia. After sacrifice, serum and eyeballs were harvested. Post-mortem analyses included a histopathological analysis of the retina and the measurement of BDNF and NGF levels in the serum and eyeball homogenate.ResultsIn the experimental group, early-stage DR was confirmed, and changes in the retina were observed: diabetic rats had relatively thicker outer nuclear layers and relatively thinner inner plexiform layers. A lower level of BDNF was observed in the serum of rats with DR, while the level of NGF in the eyeball homogenate positively correlated with vascular changes.ConclusionsThe observed changes in the levels of neurotrophins in early-stage DR may indicate their involvement in the disease pathogenesis.

VEGF is not only the most potent angiogenic factor, but also an important neurotrophic factor. In this study, vitreous expression of six neurotrophic factors were examined in proliferative diabetic retinopathy (PDR) patients with prior anti-VEGF therapy (n = 48) or without anti-VEGF treatment (n = 41) via ELISA. Potential source, variation and impact of these factors were further investigated in a mouse model of oxygen-induced retinopathy (OIR), as well as primary Müller cells and 661W photoreceptor cell line under hypoxic condition. Results showed that vitreous levels of NGF, NT-3, NT-4, BDNF, GDNF and CNTF were significantly higher in eyes undergoing anti-VEGF therapy compared with PDR controls. Statistical correlation between vitreous VEGF and each trophic factor was found. Hypoxia significantly induced the expressions of these neurotrophic factors, whereas application of anti-VEGF agent in OIR model could further upregulate retinal NGF, NT-3, NT-4, together with downregulation of BDNF, GDNF, CNTF, especially in Müller glia. Inhibition of Müller cell-derived VEGF would result in similar neurotrophic changes under hypoxia. With changes of corresponding neurotrophic receptors in the cocultured photoreceptor cells, their synergic effect could protect hypoxic photoreceptor from apoptosis when VEGF inhibition was present. These findings demonstrated that regulation of Müller cell-derived neurotrophic factors might be one of the possible mechanisms by which anti-VEGF therapy produced neuroprotective effects on PDR. These results provided new evidence for the therapeutic strategy of PDR.

Metabolomic profiling of aqueous humor from primary open-angle glaucoma (POAG) patients using targeted metabolomics analysis and assessment of the potential anti-neuroinflammatory and neuroprotective roles of key dysregulated metabolites in a mouse model of retinal neuroinflammation.

A targeted metabolomics was performed on aqueous humor from POAG patients (n = 19) and healthy subjects (n = 10) via LC-MS/MS. In vitro neuroprotection studies were performed using a mouse cone photoreceptor cell line (661W) exposed to oxidative stress. For in vivo therapeutic studies, a few key dysregulated metabolites were delivered either topically via extracellular vesicle (EV)-mediated delivery or intravitreally into a C57BL/6 mouse model of retinal neuroinflammation. The neuroprotective and anti-neuroinflammatory properties were determined in the presence and absence of metabolites through pattern electroretinography, TUNEL, and quantitative PCR analyses.

Among the 135 endogenous metabolites identified, 31 metabolites showed significant dysregulation in POAG. Metabolite set enrichment analysis revealed that these altered metabolites were associated with dysregulation of multiple key cellular pathways, including glycolysis, pentose phosphate pathway, short-/long-chain fatty acid metabolism, mitochondrial β-oxidation, and electron transport chain under glaucomatous conditions. Among these differentially expressed metabolites, a putative neuromodulator (agmatine) and a vitamin (thiamine) significantly decreased in POAG patients. Intravitreal or EV-mediated topical delivery of agmatine and thiamine significantly reduced the inflammatory response and protected retinal ganglion cell function against neuroinflammatory damage in the mouse retina. Agmatine and thiamine treatment also significantly protected photoreceptor cells from oxidative stress-induced cell death and attenuated the inflammatory cytokine response.

Our results revealed significant metabolic alterations in POAG that affect key cellular functions. Agmatine and thiamine could be potential immunomodulatory or neuroprotective drugs to treat or prevent neuroinflammatory damage to the retina during glaucoma.

Purpose: The Spontaneously Diabetic Torii (SDT) fatty rat is an animal model of obese Type 2 diabetes. We previously reported that the SDT fatty rats develop diabetic cataracts. This study aimed to elucidate early diabetic changes in the retina of the SDT fatty rats. Materials and Methods: The retinal thickness, capillary diameter, and pericyte/endothelial cell (P/E) ratio were assessed in the male SDT fatty rats and Sprague-Dawley (SD) rats at 24 weeks of age. Immunostaining was performed to assess the intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) levels in the retinal capillaries. DNA microarray analysis was performed to detect inflammation-associated molecules in the retina of the SDT fatty rats. Real-time PCR and Magnetic Luminex Assay were performed to validate the results. Results: The retinal thickness in the SDT fatty rats was significantly greater than that in SD rats. The capillary diameter in the retina of the SDT fatty rats was significantly higher than that of SD rats. The P/E ratio in the SDT fatty rats was significantly lower than that in SD rats. ICAM-1 and VCAM-1 were observed in the retinal vessels of the SDT fatty rats. The levels of mRNA and protein of Mcp1, Il1b, Icam1, and Tnf were upregulated in the retinal tissues of the 24-week-old SDT fatty rats. Conclusions: Our study demonstrated that the SDT fatty rats exhibited early diabetic retinal changes, suggesting that the SDT fatty rats may be useful in research on the pathogenesis of early human diabetic retinopathy.

Tumor necrosis factor alpha (TNF-α) is a key cytokine in inflammation and immune responses, making its rapid and accurate detection essential for disease diagnosis and management. In this study, we developed a highly sensitive chemiluminescence immunoassay (CLIA) using antibody-coated magnetic particles (Ab-MPs-CLIA) for TNF-α detection. From nine candidate antibodies, we identified an optimal pair through epitope competition and affinity assessments, significantly improving assay performance. The Ab-MPs-CLIA achieved a detection limit of 0.25 pg/mL, 6.8 times more sensitive than Siemens commercial kits, with a broad linear range of 9.2-1077 pg/mL. The method demonstrated excellent stability, both under accelerated conditions at 37 °C for 7 days and long-term storage at 4 °C for 12 months. It showed no cross-reactivity with common interfering substances in human serum, ensuring high specificity. Notably, the entire process, from sample preparation to result, takes just 25 min, compared to 3-4 h for both ELISA and RIA, and CLIA typically offers 10-100 times higher sensitivity than these methods. These advantages make the Ab-MPs-CLIA an ideal option for clinical laboratories, providing superior sensitivity, specificity, broader dynamic range, and greater operational efficiency than existing TNF-α detection technologies.

This study aimed to compare the expression of midkine (MK) in the vitreous of patients with proliferative diabetic retinopathy (PDR) and non-diabetic individuals, elucidating its potential role in the pathogenesis of the disease.

This prospective cross-sectional study included three groups of patients who underwent pars plana vitrectomy (PPV) surgery. The first group (control) consisted of patients who underwent PPV for epiretinal membrane and macular hole and did not have diabetes mellitus (DM). The second group included patients who underwent PPV for vitreous hemorrhage (VH) and tractional retinal detachment (TRD) secondary to PDR without prior anti-VEGF treatment (No preoperative anti-VEGF application: NPa-VEGF). The third group comprised patients who underwent PPV for VH and TRD secondary to PDR and received a preoperative anti-VEGF injection one week before surgery (preoperative anti-VEGF application: Pa-VEGF). Vitreous samples were collected intraoperatively, and the concentrations of MK, interleukin (IL)-6, and IL-8 were measured using specific Enzyme-Linked Immunosorbent Assay (ELISA) kits.

The study included a total of 49 eyes from 49 patients undergoing PPV. The concentrations of IL-6 and IL-8 in vitreous samples from the NPa-VEGF group (n=15) and the Pa-VEGF group (n=14) were not significantly different compared to the control group (n=20) (p>0.05). However, the vitreous fluid of patients in the NPa-VEGF group exhibited significantly higher MK concentrations compared to the control group (p<0.007). Similarly, MK concentrations were significantly elevated in the Pa-VEGF group compared to the control group (p<0.046). No significant difference in MK levels was detected between the NPa-VEGF and Pa-VEGF groups (p>0.05).

These findings suggest that increased MK expression in the vitreous may be associated with the pathogenesis of PDR. Further studies are warranted to elucidate the precise mechanisms underlying this association and to explore the potential of MK as a therapeutic target for PDR management.

Pre-diabetes is the preceding condition of diabetes, and in some cases, fundus changes have been seen in pre-diabetes. The inflammatory response is widely recognized as being involved in the pathophysiologic process of diabetic eye disease. Therefore, we aimed to acquire understanding of the role of early altered blood glucose levels in the development and etiology of diabetic ocular disorders from the perspective of inflammation. In this study, serum, tear, aqueous humor and vitreous fluid samples were collected from patients undergoing cataract surgery. VEGF, IL-6, TNF-a, MCP-1, APOA-1, ICAM-1, VCAM-1, PEDF, TSP-1 were measured by ELISA. The quantity of hyperreflective retinal spots (HRS) was counted by optical coherence tomography OCT images. We found that the levels of inflammatory cytokines are already altered in pre-diabetes. Levels of pro-inflammatory cytokine expression and quantity of HRS can reflect the disease process to some extent.

This study aimed to elucidate whether machine learning algorithms applied to vitreous levels of immune mediators predict the diagnosis of 12 representative intraocular diseases, and identify immune mediators driving the predictive power of machine learning model.

Vitreous samples in 522 eyes diagnosed with 12 intraocular diseases were collected, and 28 immune mediators were measured using a cytometric bead array. The significance of each immune mediator was determined by employing five machine learning algorithms. Stratified k-fold cross-validation was performed to divide the dataset into training and test sets. The algorithms were assessed by analyzing precision, recall, accuracy, F-score, area under the receiver operating characteristics curve, area under the precision-recall curve, and feature importance.

Of the five machine learning models, random forest attained the maximum accuracy in the classification of 12 intraocular diseases in a multi-class setting. The random forest prediction models for vitreoretinal lymphoma, endophthalmitis, uveal melanoma, rhegmatogenous retinal detachment, and acute retinal necrosis demonstrated superior classification accuracy, precision, and recall. The top three important immune mediators for predicting vitreoretinal lymphoma were IL-10, granzyme A, and IL-6; those for endophthalmitis were IL-6, G-CSF, and IL-8; and those for uveal melanoma were RANTES, IL-8 and bFGF.

The random forest algorithm effectively classified 28 immune mediators in the vitreous to accurately predict the diagnosis of vitreoretinal lymphoma, endophthalmitis, and uveal melanoma among 12 representative intraocular diseases. In summary, the results of this study enhance our understanding of potential new biomarkers that may contribute to elucidating the pathophysiology of intraocular diseases in the future.

Diabetic retinopathy (DR) is a leading cause of vision loss globally, with early detection and intervention critical to preventing severe outcomes. This narrative review examines the role of retinal biomarkers-molecular and imaging-in improving early diagnosis, tracking disease progression, and advancing personalized treatment for DR. Key biomarkers, such as inflammatory and metabolic markers, imaging findings from optical coherence tomography and fluorescence angiography and genetic markers, provide insights into disease mechanisms, help predict progression, and monitor responses to treatments, like anti-VEGF and corticosteroids. While challenges in standardization and clinical integration remain, these biomarkers hold promise for a precision medicine approach that could transform DR management through early, individualized care.

Since inflammation plays an important role in the pathogenesis of diabetic retinopathy, serum biomarkers and retinal imaging aimed at evaluating the presence of inflammation have emerged as useful tools to monitor the appearance and progression of diabetic retinopathy.

This study aims to investigate the value of YKL-40 levels in patients with diabetes mellitus with different stages of diabetic retinopathy and without diabetic retinopathy, and to compare those findings with results from healthy individuals without diabetes mellitus.

This prospective cross-sectional study included 67 diabetic patients with or without diabetic retinopathy who underwent cataract surgery and 23 patients (control group) having no ocular and systemic disease other than senile cataract. Participants with diabetes mellitus were separated into three subgroups: the first group consisted of 26 patients without diabetic retinopathy, the second group included 21 patients with non-proliferative diabetic retinopathy and the third group included 20 patients with proliferative diabetic retinopathy. Serum and aqueous humour YKL-40 levels were analysed and compared between the groups.

The mean serum (p < 0.001) and aqueous humour (p < 0.001) YKL-40 levels were statistically significantly lower in control subjects compared to patients with diabetes mellitus. The aqueous humour YKL-40 levels showed statistically significant elevations with the progression of diabetic retinopathy. Duration of diabetes mellitus was significantly correlated with aqueous humour YKL-40 levels (p = 0.001, r = 0.384).

Both serum and aqueous humour YKL-40 levels are higher in patients with diabetes mellitus compared to healthy subjects. Levels of YKL-40 in aqueous humour increase with the progression of diabetic retinopathy.

Parkinson's disease (PD) is a multifaceted neurodegenerative disorder characterized by predominantly motor symptoms. However, recent research has broadened our understanding of PD by revealing its impact on non-motor functions, including ocular manifestations. This review explored the intricate relationship between PD and ocular health, shedding light on the mechanisms underlying common ocular diseases such as dry eye disease, cataract, glaucoma, age-related macular degeneration, and diabetic retinopathy. It also underscores the importance of recognizing ocular manifestations as potential early markers of PD, as well as their impact on patients' daily activities, necessitating prompt identification and intervention to prevent complications and enhance the overall quality of life. Furthermore, future research should prioritize unraveling the potential association between PD and other prevalent ocular diseases, such as myopia, to formulate effective treatment strategies.

Retinal pericytes are mural cells surrounding capillaries to maintain the integrity of blood-retina barrier and regulate vascular behaviors. Pericyte loss has been considered as the hallmark of diabetic retinopathy (DR), which is a major complication of diabetes and the leading cause of blindness in adults. However, the precise function of pericytes in regulating the retinal microenvironment and the underlying mechanism remains largely unknown. In this study, we observed a secretory phenotype of pericytes with elevated inflammatory cytokines in response to Interleukin-1β (IL-1β), a canonical inflammatory cytokine which significantly increases during the initial stages of diabetic retinopathy. This phenotype is also accompanied by reduced expression of adherent junction proteins and contractile proteins. Paracrine cytokines derived from pericytes further induce the chemotaxis of microglia cells and trigger detrimental changes in endothelial cells, including reduced expression of tight junction protein Occludin and increased apoptosis. Mechanically, the secretion potential in pericytes is partially mediated by Hes1/STAT3 signaling pathway. Moreover, co-injection of stattic, an inhibitor targeting STAT3 activation, could effectively attenuate IL-1β-induced retinal inflammation and microglial activation in retina tissues. Collectively, these findings demonstrate the potential of retinal pericytes as an initial inflammatory sensor prior to their anatomical pathological loss, via undergoing phenotypic changes and secreting paracrine factors to amplify local inflammation and damage endothelial cells in vitro. Furthermore, inhibition of STAT3 activation by inhibitors significantly ameliorates IL-1β-induced retinal inflammation, suggesting STAT3 in retinal pericytes as a promising target for alleviating DR and other IL-1β-induced ocular diseases.

Diabetic retinopathy (DR) is a microvascular disease affecting the eyes of diabetic patients, and is the most prevalent complication of diabetes mellitus. Vision improvement is not possible in the majority of DR patients. Several studies have indicated that microvascular changes, inflammation, oxidative stress, and retinal neurodegeneration are involved in the pathogenesis of DR. Therefore, there is an urgent need for the development of new and effective treatment for DR. Understanding the molecular mechanisms involved in the pathogenesis of disease will pave a way for better treatment and management of DR. This article has emphasized the molecular pathogenesis and treatment of DR.

Determining the levels of molecular biomarkers detected in the vitreous body in various pathological conditions (including diabetic retinopathy), allows for a better understanding of their pathogenesis and optimization of treatment approaches. The multiplex assay is a modern alternative to enzyme-linked immunosorbent assay (ELISA), enabling the simultaneous analysis of a large number of biomarkers.

This study was performed to identify changes in the levels of vitreous biomarkers in patients with proliferative diabetic retinopathy (PDR) in the early postoperative period following 25-gauge vitrectomy.

The study included 24 patients (24 eyes) with type 2 diabetes mellitus complicated by PDR requiring surgical intervention for tractional retinal detachment, subtotal or total vitreous hemorrhage, or tractional diabetic macular edema (DME). Vitreous samples were collected from all patients at the first stage of vitrectomy and one month after surgery.

One month after surgery, the level of the pro-inflammatory cytokine vascular endothelial growth factor (VEGF) decreased from 203.8±228.0 to 113±95 pg/ml; however, the difference was not statistically significant (p=0.307). A significant reduction was observed in the concentrations of the following pro-inflammatory biomarkers: bFGF, CTACK, Eotaxin, HGF, IL-1β, -1α, -4, -12 (p40), -16, -18, IL-2Rα, IP-10, MIG, SCF, SCGF-β, SDF-1α, MIF, and M-CSF.

The main effect of vitrectomy on pro-inflammatory cytokines is reduction of their concentration, which confirms the buffering role of the vitreous body in the accumulation of molecular biomarkers in diabetic retinopathy.

Inflammation is a critical driver of the early stages of diabetic retinopathy (DR) and offers an opportunity for therapeutic intervention before irreversible damage and vision loss associated with later stages of DR ensue. Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown mixed efficacy in slowing early DR progression, notably including severe adverse side effects likely due to their nonselective inhibition of all downstream signaling intermediates. In this study, we investigated the role of prostanoids, the downstream signaling lipids whose production is inhibited by NSAIDs, in promoting inflammation relevant to early-stage DR in two human retinal cell types: Müller glia and retinal microvascular endothelial cells. When cultured in multiple conditions modeling distinct aspects of systemic diabetes, Müller glia significantly increased production of prostaglandin E2 (PGE2), whereas retinal endothelial cells significantly increased production of prostaglandin F2α (PGF2α). Müller glia stimulated with PGE2 or PGF2α increased proinflammatory cytokine levels dose-dependently. These effects were blocked by selective antagonists to the EP2 receptor of PGE2 or the FP receptor of PGF2α, respectively. In contrast, only PGF2α stimulated adhesion molecule expression in retinal endothelial cells and leukocyte adhesion to cultured endothelial monolayers, effects that were fully prevented by FP receptor antagonist treatment. Together these results identify PGE2-EP2 and PGF2α-FP signaling as novel, selective targets for future studies and therapeutic development to mitigate or prevent retinal inflammation characteristic of early-stage DR.

Ocular levels of IL-1β, TNFα, IL-8, and IL-6 correlate with progression of diabetic retinopathy (DR). Müller cells (MC), which are crucial to maintaining retinal homeostasis, are targets and sources of these cytokines. We explored the relative capacities of these four DR-associated cytokines to amplify inflammatory signal expression both in and between human MC (hMC) and retinal microvascular endothelial cells (hRMEC) and in the mouse retina. Of the four cytokines, IL-1β was the most potent stimulus of transcriptomic alterations in hMC and hRMEC in vitro, as well as in the mouse retina after intravitreal injection in vivo. Stimulation with IL-1β significantly induced expression of all four transcripts in hMC and hRMEC. TNFα significantly induced expression of some, but not all, of the four transcripts in each cell, while neither IL-8 nor IL-6 showed significant induction in either cell. Similarly, conditioned media (CM) derived from hMC or hRMEC treated with IL-1β, but not TNFα, upregulated inflammatory cytokine transcripts in the reciprocal cell type. hRMEC responses to hMC-derived CM were dependent on IL-1R activation. In addition, we observed a correlation between cytokine expression changes following direct and CM stimulation and NFκB-p65 nuclear translocation in both hMC and hRMEC. Finally, in mice, intravitreal injections of IL-1β, but not TNFα, induced retinal expression of Il1b and CXCL8 homologues Cxcl1, Cxcl2, Cxcl3, and Cxcl5, encoding pro-angiogenic chemokines. Our results suggest that expression of IL-1β, TNFα, IL-8, and IL-6 may be initiated, propagated, and sustained by autocrine and paracrine signals in hRMEC and hMC through a process involving IL-1β and NFκB. Targeting these signals may help thwart inflammatory amplification, preventing progression to vision-threatening stages and preserving sight.

Diabetic retinopathy, a significant trigger for blindness among working age individuals with diabetes, poses a substantial global health challenge. Understanding its underlying mechanisms is pivotal for developing effective treatments. Current treatment options, such as anti-VEGF agents, corticosteroids, laser photocoagulation, and vitreous surgery, have their limitations, prompting the exploration of innovative approaches like nanocapsules based drug-delivery systems. Nanoparticles provide promising solutions to improve drug delivery in ocular medicine, overcoming the complexities of ocular anatomy and existing treatment constraints.

This review explored advanced therapeutic strategies for diabetic retinopathy, focusing on current medications with their limitations, drug delivery methods, device innovations, and overcoming associated barriers. Through comprehensive review, it aimed to contribute to the discovery of more efficient management strategies for diabetic retinopathy in the future.

In the next five to ten years, we expect a revolutionary shift in how diabetic retinopathy is treated. As we deepen our understanding of oxidative stress and metabolic dysfunction, antioxidants with specialised delivery matrices are poised to take center stage in prevention and treatment strategies. Our vision is to create a more integrated approach to diabetic retinopathy management that not only improves patient outcomes but also reduces the risks associated to traditional therapies.

To compare the differences in clinical-related factors between patients with type 2 diabetes (T2DM) and those without diabetic retinopathy (DR) and to explore the risk factors or protective factors affecting DR in T2DM patients.

We performed a retrospective analysis of 380 patients with type 2 diabetes admitted to Handan Central Hospital from June 2023 to May 2024. Clinical data collected included baseline characteristics, hematological tests, metabolic indicators, and information on diabetic complications and comorbidities.

Our findings identified intervention, neck vascular disease, bilateral lower limb venous thrombosis, high creatinine, high glomerular filtration rate, high chloride, high fasting C-peptide, and high lactate dehydrogenase as risk factors for DR. In contrast, High 2-hour postprandial C-peptide is a protective factor for diabetic retinopathy. A logistic regression model was constructed using stepwise regression to predict DR occurrence, achieving an accuracy of 0.80 and an AUC of 0.83.

The science of diabetes care has progressed to provide a better understanding of the oxidative and inflammatory lesions and pathophysiology of the neurovascular unit within the retina (and brain) that occur early in diabetes, even prediabetes. Screening for retinal structural abnormalities, has traditionally been performed by fundus examination or color fundus photography; however, these imaging techniques detect the disease only when there are sufficient lesions, predominantly hemorrhagic, that are recognized to occur late in the disease process after significant neuronal apoptosis and atrophy, as well as microvascular occlusion with alterations in vision. Thus, interventions have been primarily oriented toward the later-detected stages, and clinical trials, while demonstrating a slowing of the disease progression, demonstrate minimal visual improvement and modest reduction in the continued loss over prolonged periods. Similarly, vision measurement utilizing charts detects only problems of visual function late, as the process begins most often parafoveally with increasing number and progressive expansion, including into the fovea. While visual acuity has long been used to define endpoints of visual function for such trials, current methods reviewed herein are found to be imprecise. We review improved methods of testing visual function and newer imaging techniques with the recommendation that these must be utilized to discover and evaluate the injury earlier in the disease process, even in the prediabetic state. This would allow earlier therapy with ocular as well as systemic pharmacologic treatments that lower the and neuro-inflammatory processes within eye and brain. This also may include newer, micropulsed laser therapy that, if applied during the earlier cascade, should result in improved and often normalized retinal function without the adverse treatment effects of standard photocoagulation therapy.

We established S100A9 as a myeloid-derived damage-associated molecular pattern (DAMPs) protein associated with increasing severity of diabetic retinopathy (DR) in type 2 diabetic subjects. The present study investigates the retinal localization, expression, and mechanisms of action for S100A9 in the young obese Ossabaw pig retina.

Retinae from Ossabaw pigs fed a Western diet for 10 weeks were evaluated for S100 and inflammatory mediator expression using quantitative PCR and Western blot. Double immunohistochemistry was performed to identify the cellular sources of S100A9 in the pig retina. Primary pig retinal microglial cells (pMicroglia) were examined for S100A9 production. S100A9-induced responses were also investigated, and inhibitor studies elucidated the mechanism of action via the NLRP3 inflammasome. A specific inhibitor, Paquinimod (ABR-215757), was administered in vitro to assess the rescue of S100A9-induced NLRP3 inflammasome activation in pMicroglia.

The expression of the S100 family in the obese Ossabaw pig retina showed a significant elevation of S100A9, consistent with increased levels of circulating S100A9. Moreover, the retina had elevated levels of inflammatory mediators IL-6, IL-8, MCP-1, IL-1β and NLRP3. Retinal microglia in obese Ossabaw were activated and accompanied by an increased expression of intracellular S100A9. pMicroglia isolated from pig retina transformed from ramified to amoeboid state when activated with LPS and produced high S100A9 transcript and protein levels. The S100A9 protein, in turn, further activated pMicroglia by heightened production of S100A9 transcripts and secretion of pro-inflammatory IL-1β protein. Inhibition of TLR4 with TAK242 and NLRP3 with MCC950 attenuated the production of IL-1β during S100A9 stimulus. Finally, pre-treatment with Paquinimod successfully reduced S100A9-driven increases of glycosylated-TLR4, NLRP3, ASC, Caspase-1, and IL-1β production.

We demonstrated that microglial-derived S100A9 perpetuates pro-inflammatory responses via the NLRP3 inflammasome in the retina of young Western-diet-fed Ossabaw pigs exhibiting diabetic retinopathy.

Diabetic eye disease (DED) encompasses a range of ocular complications arising from diabetes mellitus, including diabetic retinopathy, diabetic macular edema, diabetic keratopathy, diabetic cataract, and glaucoma. These conditions are leading causes of visual impairments and blindness, especially among working-age adults. Despite advancements in our understanding of DED, its underlying pathophysiological mechanisms remain incompletely understood. Chronic hyperglycemia, oxidative stress, inflammation, and neurodegeneration play central roles in the development and progression of DED, with immune-mediated processes increasingly recognized as key contributors. This review provides a comprehensive examination of the complex interactions between immune cells, inflammatory mediators, and signaling pathways implicated in the pathogenesis of DED. By delving in current research, this review aims to identify potential therapeutic targets, suggesting directions of research for future studies to address the immunopathological aspects of DED.

Diabetic retinopathy (DR) is a common complication of diabetes, with its prevalence increasing globally. While previous research has linked obesity indices such as body mass index (BMI) to DR, the association with weight-adjusted-waist index (WWI) remains unclear. Additionally, the relationship between WWI and DR has not been fully elucidated. This cross-sectional study analyzed data from the National Health and Nutrition Examination Survey (2005-2008) to investigate these associations in Americans aged 40 and above. The study included 5436 participants (2705 men and 2731 women). Weighted logistic regression analysis revealed a significant increase in DR prevalence with higher WWI and BMI values. Smooth curve analysis demonstrated a linear correlation between WWI and DR. The findings suggest that both WWI and BMI are independently associated with DR risk among older US adults, highlighting the importance of considering central obesity measures in assessing diabetic complications.

Retinopathy is one of the most common microvascular complications of diabetes mellitus and is the leading cause of vision loss in the working middle-aged population.

This study aimed to investigate the value of neopterin and orexin-A levels in patients with diabetes mellitus with different stages of diabetic retinopathy and without diabetic retinopathy and to compare those findings with results from healthy individuals without diabetes mellitus.

In total, 65 patients with type 2 diabetes mellitus and 22 healthy individuals without diabetes mellitus were enrolled in this prospective study. The participants were separated into four subgroups. The first subgroup included 25 patients without diabetic retinopathy, the second subgroup included 20 patients non-proliferative diabetic retinopathy, the third subgroup included 20 patients with proliferative diabetic retinopathy, and the fourth subgroup included 22 healthy individuals without diabetes mellitus as controls. Serum neopterin and orexin-A levels were analysed and compared among the groups.

The age and gender of the participants between the four subgroups were not statistically significantly different (p > 0.05). The mean neopterin levels were significantly higher in patients included in the diabetes mellitus subgroups compared with the controls (p < 0.001). Neopterin levels significantly increased as diabetic retinopathy progressed within the diabetes mellitus subgroups. Mean orexin-A levels were significantly lower in the diabetes mellitus subgroups compared with the controls (p < 0.001); however, orexin-A levels were not significantly different within the diabetes mellitus subgroups (p > 0.05).

Patients with diabetes mellitus have higher serum neopterin and lower serum orexin-A levels compared with healthy individuals without diabetes mellitus. Moreover, serum neopterin levels increase with progression of diabetic retinopathy.

To investigate the relationship between serum brain-derived neurotrophic factor (BDNF) and changes in macular perfusion in different stages of diabetic retinopathy (DR) using optical coherence tomography angiography (OCTA).

The study was conducted on 72 eyes of people with type 2 diabetes mellitus (DM). They were divided into five groups based on their DR stage: no DR (nDR), mild and moderate nonproliferative DR, severe nonproliferative DR, active proliferative DR (aPDR), and stable PDR. The presence or absence of diabetic maculopathy was also used to categorize the cases. All patients underwent a complete history, ophthalmological examination, OCTA imaging, and evaluation of BDNF and glycated hemoglobin A1c levels.

The mean blood BDNF levels in the aPDR group were considerably lower than those in the nDR group (P = 0.023). In comparison to eyes without maculopathy, eyes with maculopathy had considerably decreased mean blood BDNF levels (P = 0.0004). Comparing NPDR and PDR groups to nDR as well as NPDR and PDR, a substantial decrease in average and parafoveal vessel density (VD) of the retina and choriocapillaries was seen (P = 0.02). The Foveal Avascular Zone (FAZ) acircularity index and VD were found to be significantly impacted by deteriorating DR (P = 0.001 and 0.017, respectively). It was discovered that there is a positive correlation between BDNF and the FAZ fractal dimension (P = 0.03). In diabetic eyes, there was a statistically favorable correlation between BDNF levels and best corrected visual acuity (P = 0.002). Furthermore, there was a negative relationship between DM duration and BDNF (P = 0.021).

Serum BDNF levels decreased with the progression of DR and in patients with maculopathy. BDNF was found to be related to macular perfusion, particularly in the fovea.

Diabetic retinopathy (DR) stands as a prevalent complication in the eye resulting from diabetes mellitus, predominantly associated with high blood sugar levels and hypertension as individuals age. DR is a severe microvascular complication of both type I and type II diabetes mellitus and the leading cause of vision impairment. The critical approach to combatting and halting the advancement of DR lies in effectively managing blood glucose and blood pressure levels in diabetic patients; however, this is seldom achieved. Both human and animal studies have revealed the intricate nature of this condition involving various cell types and molecules. Aside from photocoagulation, the sole therapy targeting VEGF molecules in the retina to prevent abnormal blood vessel growth is intravitreal anti-VEGF therapy. However, a substantial portion of cases, approximately 30-40%, do not respond to this treatment. This review explores distinctive pathophysiological phenomena of DR and identifiable cell types and molecules that could be targeted to mitigate the chronic changes occurring in the retina due to diabetes mellitus. Addressing the significant research gap in this domain is imperative to broaden the treatment options available for managing DR effectively.

To evaluate macular sensitivity using microperimetry in patients with proliferate diabetic retinopathy following vitrectomy and to investigate the relationship between the sensitivity and foveal microstructures with optical coherence tomography/angiography.

Eighty-four eyes of 84 patients with proliferative diabetic retinopathy, who were indicated for vitrectomy, had no intraocular surgery history 3 months preoperatively, and were able to ensure fundus examination after the vitrectomy, were included. A logMAR best-corrected visual acuity, macular sensitivity of microperimetry, macular retinal thickness, and macular vessel perfusion using optical coherence tomography/angiography were examined at 1 week, 1 month, and 3 months postoperatively.

The logMAR best-corrected visual acuity and mean macular sensitivity of patients with proliferative diabetic retinopathy improved postoperatively (P < 0.05). There was a significant correlation between best-corrected visual acuity and mean sensitivity (P < 0.05). Postoperative mean macular sensitivity was significantly correlated with outer retinal thickness in the 0 to 6 mm macular area (P < 0.05) and also significantly correlated with deep capillary plexus perfusion (P < 0.05). Fixation stability and mean macular sensitivity did not show any correlation with glycated hemoglobin, triglyceride, serum total cholesterol, carbamide, and creatinine and duration of diabetes mellitus (P > 0.05).

Postoperative mean macular sensitivity was significantly correlated with outer retinal thickness and deep capillary plexus perfusion for patients with proliferative diabetic retinopathy. The authors found that the visual performance of patients can be evaluated by the outer retinal thickness and deep capillary plexus perfusion, so optical coherence tomography/angiography examination can be an important prognostic factor for visual performance in patients.Clinical Trial Registration: This trial is registered with the Chinese Clinical Trial Registry (http://www.chictr.org.cn; Registration No.: ChiCTR2100043399).

Diabetic retinopathy (DR) is established as the primary cause of visual impairment and preventable blindness, posing significant social and economic burdens on healthcare systems worldwide. Oxidative stress has been identified as a major contributor to DR, yet the precise role of the transmembrane glycoprotein CD200R in this context remains elusive. We studied human retinal pigment epithelia ARPE-19 cells to investigate the role of CD200R in high-glucose (HG) induced oxidative stress. Under HG conditions, we found a significant increase in CD200R expression in a time-dependent pattern. Conversely, knockdown of CD200R effectively alleviated oxidative stress and restored cell viability in HG-treated ARPE-19 cells, a phenomenon corroborated by the addition of a reactive oxygen species (ROS) scavenger. Exploration of the AKT/mTOR signaling pathway confirmed its mediating role regarding CD200R knockdown suppression of the expression of key proteins induced by HG conditions. Additionally, we found that the inhibition of mTOR signaling with Rapamycin effectively countered HG-induced oxidative stress in ARPE-19 cells, suggesting a promising therapeutic target against oxidative stress in the context of DR. This study establishes the crucial role of CD200R in HG-induced oxidative stress and identifies potential therapeutic avenues for the treatment of DR.

Neurodegenerative diseases affecting the visual system encompass glaucoma, macular degeneration, retinopathies, and inherited genetic disorders such as retinitis pigmentosa. These ocular pathologies pose a serious burden of visual impairment and blindness worldwide. Current treatment modalities include small molecule drugs, biologics, or gene therapies, most of which are administered topically as eye drops or as injectables. However, the topical route of administration faces challenges in effectively reaching the posterior segment and achieving desired concentrations at the target site, while injections and implants risk severe complications, such as retinal detachment and endophthalmitis. This necessitates the development of innovative therapeutic strategies that can prolong drug release, deliver effective concentrations to the back of the eye with minimal systemic exposure, and improve patient compliance and safety. In this review, we introduce retinal degenerative diseases, followed by a discussion of the existing clinical standard of care. We then delve into detail about drug and gene delivery systems currently in preclinical and clinical development, including formulation and delivery advantages/drawbacks, with a special emphasis on potential for clinical translation.

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.

The human retina is a complex anatomical structure that has no regenerative capacity. The pathogenesis of most retinopathies can be attributed to inflammation, with the activation of the inflammasome protein platform, and to the impact of oxidative stress on the regulation of apoptosis and autophagy/mitophagy in retinal cells. In recent years, new therapeutic approaches to treat retinopathies have been investigated. Experimental data suggest that the secretome of mesenchymal cells could reduce oxidative stress, autophagy, and the apoptosis of retinal cells, and in turn, the secretome of the latter could induce changes in mesenchymal cells. Other studies have evidenced that noncoding (nc)RNAs might be new targets for retinopathy treatment and novel disease biomarkers since a correlation has been found between ncRNA levels and retinopathies. A new field to explore is the interaction observed between the ocular and intestinal microbiota; indeed, recent findings have shown that the alteration of gut microbiota seems to be linked to ocular diseases, suggesting a gut-eye axis. To explore new therapeutical strategies for retinopathies, it is important to use proper models that can mimic the complexity of the retina. In this context, retinal organoids represent a good model for the study of the pathophysiology of the retina.

Diabetic retinopathy (DR) is a vision-threatening diabetic complication that is characterized by microvasculature impairment and immune dysfunction. The present study demonstrated that M2 microglia intensively participated in retinal microangiopathy in human diabetic proliferative membranes, mice retinas, retinas of mice with oxygen-induced retinopathy (OIR) mice, and retinas of streptozotocin-induced DR mice. Further in vivo and in vitro experiments showed that exosomes derived from M2 polarized microglia (M2-exo) could reduce pericyte apoptosis and promote endothelial cell proliferation, thereby promoting vascular remodeling and reducing vascular leakage from the diabetic retina. These effects were further enhanced by M2-exo that facilitated M2 polarization of retinal microglia. Collectively, the study demonstrated the capability of M2-exo to induce retinal microvascular remodeling, which may provide a new therapeutic strategy for the treatment of DR.

Minimally invasive liquid biopsies from the eye capture locally enriched fluids that contain thousands of proteins from highly specialized ocular cell types, presenting a promising alternative to solid tissue biopsies. The advantages of liquid biopsies include sampling the eye without causing irreversible functional damage, potentially better reflecting tissue heterogeneity, collecting samples in an outpatient setting, monitoring therapeutic response with sequential sampling, and even allowing examination of disease mechanisms at the cell level in living humans, an approach that we refer to as TEMPO (Tracing Expression of Multiple Protein Origins). Liquid biopsy proteomics has the potential to transform molecular diagnostics and prognostics and to assess disease mechanisms and personalized therapeutic strategies in individual patients. This review addresses opportunities, challenges, and future directions of high-resolution liquid biopsy proteomics in ophthalmology, with particular emphasis on the large-scale collection of high-quality samples, cutting edge proteomics technology, and artificial intelligence-supported data analysis.

Diabetes mellitus is a metabolic disease characterized by elevated blood glucose due to a deficiency of insulin secretion and/or action. Long-term poor blood glucose control may lead to chronic damage and dysfunction of the heart, kidneys, eyes, and other organs. Therefore, it is important to develop treatments for diabetes and its chronic complications. Fingolimod is a structural sphingosine analogue and sphingosine-1-phosphate receptor modulator currently used for the treatment of relapsing-remitting multiple sclerosis. Several studies have shown that it has beneficial effects on the improvement of diabetes and its chronic complications. This paper reviews the therapeutic potential of Fingolimod in diabetes and its chronic complications, aiming to further guide future treatment strategies.

The retina is the sensory tissue responsible for the first stages of visual processing, with a conserved anatomy and functional architecture among vertebrates. To date, retinal eye diseases, such as diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, glaucoma, and others, affect nearly 170 million people worldwide, resulting in vision loss and blindness. To tackle retinal disorders, the developing retina has been explored as a versatile model to study intercellular signaling, as it presents a broad neurochemical repertoire that has been approached in the last decades in terms of signaling and diseases. Retina, dissociated and arranged as typical cultures, as mixed or neuron- and glia-enriched, and/or organized as neurospheres and/or as organoids, are valuable to understand both neuronal and glial compartments, which have contributed to revealing roles and mechanisms between transmitter systems as well as antioxidants, trophic factors, and extracellular matrix proteins. Overall, contributions in understanding neurogenesis, tissue development, differentiation, connectivity, plasticity, and cell death are widely described. A complete access to the genome of several vertebrates, as well as the recent transcriptome at the single cell level at different stages of development, also anticipates future advances in providing cues to target blinding diseases or retinal dysfunctions.

Neovascular glaucoma is a type of secondary glaucoma characterized by the most severe course, and ranking second among the causes of irreversible blindness. This review summarizes the results of numerous studies devoted to the search for prevention measures and the most effective treatment strategy. The main ways of preventing the development of neovascular glaucoma are timely diagnosis and elimination of ischemic processes in the retina, combined with adequate control of intraocular pressure and treatment of the underlying disease.

Studies on the early retinal changes in Diabetic Retinopathy (DR) have demonstrated that neurodegeneration precedes vascular abnormalities like microaneurysms or intraretinal hemorrhages. Therefore, there is a growing field of study to analyze the cellular and molecular pathways involved to allow for the development of novel therapeutics to prevent the onset or delay the progression of DR. Molecular Mechanisms: Oxidative stress and mitochondrial dysfunction contribute to neurodegeneration through pathways involving polyol, hexosamine, advanced glycation end products, and protein kinase C. Potential interventions targeting these pathways include aldose reductase inhibitors and protein kinase C inhibitors. Neurotrophic factor imbalances, notably brain-derived neurotrophic factor and nerve growth factor, also play a role in early neurodegeneration, and supplementation of these neurotrophic factors show promise in mitigating neurodegeneration. Cellular Mechanisms: Major cellular mechanisms of neurodegeneration include caspase-mediated apoptosis, glial cell reactivity, and glutamate excitotoxicity. Therefore, inhibitors of these pathways are potential therapeutic avenues. Vascular Component: The nitric oxide pathway, critical for neurovascular coupling, is disrupted in DR due to increased reactive oxygen species. Vascular Endothelial Growth Factor (VEGF), a long-known angiogenic factor, has demonstrated both damaging and neuroprotective effects, prompting a careful consideration of long-term anti-VEGF therapy.

Current DR treatments primarily address vascular symptoms but fall short of preventing or halting the disease. Insights into the mechanisms of retinal neurodegeneration in the setting of diabetes mellitus not only enhance our understanding of DR but also pave the way for future therapeutic interventions aimed at preventing disease progression and preserving vision.

Diabetic retinopathy (DR) is a prevalent complication of diabetes, significantly impacting patients' quality of life due to vision loss. No pharmacological therapies are currently approved for DR, excepted the drugs to treat diabetic macular edema such as the anti-VEGF agents or steroids administered by intraocular route. Advancements in research have highlighted the crucial role of early intervention in DR for halting or delaying disease progression. This holds immense significance in enhancing patients' quality of life and alleviating the societal burden associated with medical care costs. The non-proliferative stage represents the early phase of DR. In comparison to the proliferative stage, pathological changes primarily manifest as microangiomas and hemorrhages, while at the cellular level, there is a loss of pericytes, neuronal cell death, and disruption of components and functionality within the retinal neuronal vascular unit encompassing pericytes and neurons. Both neurodegenerative and microvascular abnormalities manifest in the early stages of DR. Therefore, our focus lies on the non-proliferative stage of DR and we have initially summarized the mechanisms involved in its development, including pathways such as polyols, that revolve around the pathological changes occurring during this early stage. We also integrate cutting-edge mechanisms, including leukocyte adhesion, neutrophil extracellular traps, multiple RNA regulation, microorganisms, cell death (ferroptosis and pyroptosis), and other related mechanisms. The current status of drug therapy for early-stage DR is also discussed to provide insights for the development of pharmaceutical interventions targeting the early treatment of DR.

Diabetic retinopathy (DR) is a major contributor to permanent vision loss and blindness. Changes in retinal neurons, glia, and microvasculature have been the focus of intensive study in the quest to better understand DR. However, the impact of diabetes on the rest of the visual system has received less attention. There are reports of associations of changes in the visual system with preclinical and clinical manifestations of diabetes. Simultaneous investigation of the retina and the brain may shed light on the mechanisms underlying neurodegeneration in diabetics. Additionally, investigating the links between DR and other neurodegenerative disorders of the brain including Alzheimer's and Parkinson's disease may reveal shared mechanisms for neurodegeneration and potential therapy options.

Adiponectin has also been associated with diabetic retinopathy, a diabetic microvascular complication. However, the mechanism of action of adiponectin in retinopathy is still under investigation. This review summarizes emerging evidence on the association with diabetic retinopathy in type 2 diabetes.

We reviwed papers from 2004 to 2022 and included studies related to retinopathy and its association with blood and intraocular adiponectin in type 2 diabetes.

Most of the studies analyzed in this review suggested an association between the diabetic retinopathy progression and intraocular, serum, or plasma adiponectin levels. Increased levels of adiponectin contributed to the development of the disease in diabetic patients. In a minority of studies, it was indicated an inversely proportional relationship between adiponectin concentration and diabetic retinopathy severity.

The high levels of adiponectin in diabetic patients may be related to the decrease in renal clearance. Under this situation, if the predominant isoform is globular adiponectin, this may explain the retinopathy progression, considering a pro-inflammatory response induced by this isoform. However, the actions of adiponectin in diabetic retinopathy pathophysiology are still controversial.