Diabetic retinopathy (DR) is a leading cause of vision loss and a common microvascular complication of diabetes mellitus. Although diagnosis and management are typically guided by retinal findings, systemic metabolic factors—including glycemic control, diabetes duration, blood pressure, renal function, lipid status, and overall complication burden—play a central role in disease development and progression. Clinical decision-making often remains fragmented across endocrinology, primary care, and ophthalmology, contributing to variability in screening, referral, treatment selection, and patient education. This review proposes an integrated framework that applies endocrinology as a lens through which to better understand and manage diabetic retinopathy. The approach begins with a classification of systemic diabetes and metabolic disorders, then aligns these metabolically defined patient profiles with retinal diagnosis, monitoring, and stage-appropriate treatment strategies. Evidence is drawn from landmark endocrinology studies defining epidemiologic cohorts, diagnostic validation studies, and major randomized clinical trials as the basis for best practices in ophthalmological care. The goal is not only to synthesize evidence for clinicians, but also to support development of a concise patient-facing educational roadmap, presented as supplementary material, that summarizes disease progression, screening, treatment options, and anticipated next steps for patients. By integrating longitudinal endocrinology data with findings in ophthalmology, this framework may provide a strong rationale for interdisciplinary care, improve treatment outcomes, and promote more effective engagement of patients and their ophthalmologists in prevention and treatment of diabetic retinopathy.

Background: Initial manifestations of neurodegenerative ocular conditions, including age-related macular degeneration (AMD) and glaucoma, often remain undetected in the early stages and can begin after the age of 50 years with the likelihood gradually increasing each year thereafter. This study aimed to explore variances in visual and retinal function and anatomy among C57BL/6J mice, aiming to pinpoint differences between biological age and sex factors that potentially lead to the onset of vision impairment. Methods: A longitudinal study evaluated visual acuity (VA) and contrast sensitivity (CS) using optomotor reflex (OMR), and retinal function, encompassing scotopic and photopic measurements, was recorded by electroretinogram (ERG) at 12 months of age. Tissue was subsequently harvested for histological analysis, complementing the in vivo findings. Disparities in visual function were observed between individual male and female mice, necessitating categorization of visual impairment levels to investigate further sex-specific differences in the study’s aging population. Comparisons between sex and the degree of visual impairment were conducted using ANOVA followed by Tukey’s or Bonferroni’s post-hoc corrections and unpaired t-tests. Pearson correlation analysis determined the association between biological factors. Results: Sex-related disparities were found in the visual function of male (n = 13) and female (n = 18) mice aged 5–12 months. Eyes were categorized by vision impairment: normal vision, or low, moderate, or severe vision loss at the end of the study. Male and female mice differed in mean contrast sensitivity, indicating less sensitivity to fine detail and moving stimuli in female mice (11–12 months old, p < 0.001). Spectral-domain optical coherence tomography (SD-OCT) revealed a thinner retinal outer nuclear layer in male mice (p < 0.0001), although this did not vary across different levels of vision impairment. ERG indicated slower retinal responses in male mice (p < 0.05), while histology showed a significant reduction in the inner plexiform layer thickness in male mice with severe vision loss (p < 0.0001). Conversely, female mice exhibited greater thinning in the photoreceptor layer when vision was unimpaired (p < 0.01). Conclusions: The study shows that sex and extent of vision impairment influence visual and retinal health, with individual retinal layers differentially changing in thickness over time.

Cannabinoids are lipophilic substances derived from Cannabis sativa that can exert a variety of effects in the human body. They have been studied in cellular and animal models as well as in human clinical trials for their therapeutic benefits in several human diseases. Some of these include central nervous system (CNS) diseases and dysfunctions such as forms of epilepsy, multiple sclerosis, Parkinson’s disease, pain and neuropsychiatric disorders. In addition, the endogenously produced cannabinoid lipids, endocannabinoids, are critical for normal CNS function, and if controlled or modified, may represent an additional therapeutic avenue for CNS diseases. This review discusses in vitro cellular, ex vivo tissue and in vivo animal model studies on cannabinoids and their utility as therapeutics in multiple CNS pathologies. In addition, the review provides an overview on the use of cannabinoids in human clinical trials for a variety of CNS diseases. Cannabinoids and endocannabinoids hold promise for use as disease modifiers and therapeutic agents for the prevention or treatment of neurodegenerative diseases and neurological disorders.

Age-related macular degeneration (AMD) is the most prevalent ocular disease in the elderly, resulting in blindness. Oxidative stress plays a role in retinal pigment epithelium (RPE) pathology observed in AMD. Tocopherols are potent antioxidants that prevent cellular oxidative damage and have been shown to upregulate the expression of cellular antioxidant proteins. Here, we determined whether oxidative stress and tocopherols, using either normal cellular conditions or conditions of sublethal cellular oxidative stress, alter the expression of proteins mediating sterol uptake, transport, and metabolism. Human telomerase transcriptase-overexpressing RPE cells (hTERT-RPE) were used to identify differential expression of proteins resulting from treatments. We utilized a proteomics strategy to identify protein expression changes in treated cells. After the identification and organization of data, we divided the identified proteins into groups related to biological function: cellular sterol uptake, sterol transport and sterol metabolism. Exposure of cells to conditions of oxidative stress and exposure to tocopherols led to similar protein expression changes within these three groups, suggesting that α-tocopherol (αT) and γ-tocopherol (γT) can regulate the expression of sterol uptake, transport and metabolic proteins in RPE cells. These data suggest that proteins involved in sterol transport and metabolism may be important for RPE adaptation to oxidative stress, and these proteins represent potential therapeutic targets.

The retina is composed of neuronal layers that include several types of interneurons and photoreceptor cells, and separate underlying retinal pigment epithelium (RPE), Bruch’s membrane, and choroid. Different regions of the human retina include the fovea, macula, and periphery, which have unique physiological functions and anatomical features. These regions are also unique in their protein expression, and corresponding cellular and molecular responses to physiological and pathophysiological stimuli. Skeie and Mahajan analyzed regional protein expression in the human choroid–RPE complex. Mitogen-Activated Protein Kinase (MAPK) signaling pathways have been implicated in responses to stimuli such as oxidative stress and inflammation, which are critical factors in retina diseases including age-related macular degeneration. We, therefore, analyzed the Skeie and Mahajan, 2014, dataset for regional differences in the expression of MAPK-related proteins and discussed the potential implications in retinal diseases presenting with regional signs and symptoms. Regional protein expression data from the Skeie and Mahajan, 2014, study were analyzed for members of signaling networks involving MAPK and MAPK-related proteins, categorized by specific MAPK cascades, such as p38, ERK1/2, and JNK1/2, both upstream or downstream of the respective MAPK and MAPK-related proteins. We were able to identify 207 MAPK and MAPK-related proteins, 187 of which belonging to specific MAPK cascades. A total of 31 of these had been identified in the retina with two proteins, DLG2 and FLG downstream, and the other 29 upstream, of MAPK proteins. Our findings provide evidence for potential molecular substrates of retina region-specific disease manifestation and potential new targets for therapeutics development.

Age related macular degeneration (AMD) is the most common cause of blindness in the elderly. Oxidative stress contributes to retinal pigment epithelium (RPE) dysfunction and cell death thereby leading to AMD. Using improved RPE cell model systems, such as human telomerase transcriptase-overexpressing (hTERT) RPE cells (hTERT-RPE), pathophysiological changes in RPE during oxidative stress can be better understood. Using this model system, we identified changes in the expression of proteins involved in the cellular antioxidant responses after induction of oxidative stress. Some antioxidants such as vitamin E (tocopherols and tocotrienols) are powerful antioxidants that can reduce oxidative damage in cells. Alpha-tocopherol (α-Toc or αT) and gamma-tocopherol (γ-Toc or γT) are well-studied tocopherols, but signaling mechanisms underlying their respective cytoprotective properties may be distinct. Here, we determined what effect oxidative stress, induced by extracellularly applied tBHP in the presence and absence of αT and/or γT, has on the expression of antioxidant proteins and related signaling networks. Using proteomics approaches, we identified differential protein expression in cellular antioxidant response pathways during oxidative stress and after tocopherol treatment. We identified three groups of proteins based on biochemical function: glutathione metabolism/transfer, peroxidases and redox-sensitive proteins involved in cytoprotective signaling. We found that oxidative stress and tocopherol treatment resulted in unique changes in these three groups of antioxidant proteins indicate that αT and γT independently and by themselves can induce the expression of antioxidant proteins in RPE cells. These results provide novel rationales for potential therapeutic strategies to protect RPE cells from oxidative stress.

The study was designed to quantify retina function in a spontaneous mutation mouse model of diabetes, in which sustained dyslipidemia was induced chemically. The goal of the study was to identify if dyslipidemia in the presence of hyperglycemia resulted in either a synergistic, or a merely additive, exacerbation of retinal and visual dysfunctions in diabetes. Two cohorts of mice, male C57BL/6 and C57BL/KsJ- db/db mice were divided into two groups each. One group of each strain received the triblock copolymer, poloxamer 407 (P-407), administered by intraperitoneal injection (“WT P-407” and “ db/db P-407” groups) with saline as a control in the remaining two groups (“WT” and “ db/db ” groups). Blood glucose, total cholesterol (TC) and total triglyceride (TG) levels were quantified using enzyme-based colorimetric assays. Retina function was measured using electroretinography (ERG) and visual acuity was determined by behaviorally assessing parameters of the optomotor reflex. TC and TG levels were normal in both saline controls (WT) and db/db mice but were significantly elevated in the WT P-407 group ( p < 0.01 for TC; p < 0.001 for TG), while levels of the same lipids were further elevated in the db/db P-407 group when compared to the WT P-407 group levels ( p < 0.001 for both TC and TG). Behavioral assessment of the optomotor reflex indicated reduced visual acuity for the db/db P-407 group when compared to either the WT P-407 or the db/db groups ( p < 0.001, p < 0.0001). ERG measurements of scotopic retina function showed a significant decline in the scotopic b-wave amplitude of the WT P-407 animals ( p < 0.01) and a further reduction for the db/db P-407 group when compared to controls ( p < 0.0001). Very significant, strong correlations between scotopic b-wave amplitude and implicit time to TC (r = − 0.8376, p = < 0.0001 and r = 0.7069, p = 0.0022, respectively) and TG levels (r = − 0.8554, p = < 0.0001 and r = 0.7150, p = 0.0019, respectively) were found. Dyslipidemia in the presence of hyperglycemia synergistically exacerbated the severity of retinal dysfunction in diabetes. P-407 administration significantly elevated plasma TC and TG levels in male wild-type (WT) and diabetic mice ( db/db ), but the resulting hyperlipidemia was more significantly pronounced in the diabetic mice. While elevated plasma lipid and blood glucose levels were individually correlated with a decline in retinal function, the combination of both exacerbated retinal dysfunction. This model of combined hyperglycemia and dyslipidemia can be used to dissect individual contributions of features of the metabolic syndrome to the pathogenesis of retinal dysfunction in diabetes.

The eyes are relatively immune privileged organs, making them ideal targets for stem cell therapy. Researchers have recently developed and described straightforward protocols for differentiating embryonic and induced pluripotent stem cells into retinal pigment epithelium (RPE), making diseases affecting the RPE, such as age-related macular degeneration (AMD), viable targets for stem cell therapy. With the advent of optical coherence tomography, microperimetry, and various other diagnostic technologies, the ability to document disease progression and monitor response to treatments such as stem cell therapy has been significantly enhanced in recent years. Previous phase I/II clinical trials have employed various cell origins, transplant methods, and surgical techniques to identify safe and efficacious methods of RPE transplantation, and many more are currently underway. Indeed, findings from these studies have been promising and future carefully devised clinical trials will continue to enhance our understanding of the most effective methods of RPE-based stem cell therapy, with the hope to eventually identify treatments for disabling and currently incurable retinal diseases. The purpose of this review is to briefly outline existing outcomes from initial clinical trials, review recent developments, and discuss future directions of clinical research involving stem-cell derived RPE cell transplantation for retinal disease.

Purpose:Early-stage glaucoma diagnosis has been a challenging problem in ophthalmology. The current state-of-the-art glaucoma diagnosis techniques do not completely leverage the functional measures' such as electroretinogram's immense potential; instead, focus is on structural measures like optical coherence tomography. The current study aims to take a foundational step toward the development of a novel and reliable predictive framework for early detection of glaucoma using machine-learning-based algorithm capable of leveraging medically relevant information that ERG signals contain.Methods:ERG signals from 60 eyes of DBA/2 mice were grouped for binary classification based on age. The signals were also grouped based on intraocular pressure (IOP) for multiclass classification. Statistical and wavelet-based features were engineered and extracted. Important predictors (ERG tests and features) were determined, and the performance of five machine learning-based methods were evaluated.Results:Random forest (bagged trees) ensemble classifier provided the best performance in both binary and multiclass classification of ERG signals. An accuracy of 91.7 and 80% was achieved for binary and multiclass classification, respectively, suggesting that machine-learning-based models can detect subtle changes in ERG signals if trained using advanced features such as those based on wavelet analyses.Conclusions:The present study describes a novel, machine-learning-based method to analyze ERG signals providing additional information that may be used to detect early-stage glaucoma. Based on promising performance metrics obtained using the proposed machine-learning-based framework leveraging an established ERG data set, we conclude that the novel framework allows for detection of functional deficits of early/various stages of glaucoma in mice.

The purpose of this study was to determine if different vitamin E components exhibit similar efficacy and mechanism of action in protecting Retinal pigment epithelium (RPE) cells from oxidative damage. We hypothesized that α-tocopherol (αT) is unique among vitamin E components in its cytoprotective mechanism of action against oxidative stress in RPE cells and that it requires protein synthesis for optimal antioxidant effect. We used cell viability assays, fluorescent chemical labeling of DNA and actin and immuno-labeling of the antioxidant proteins Nrf2 and Sod2 and of the tight junction protein, ZO-1, and confocal microscopy to determine the effects of αT and γT against oxidative stress in immortalized human RPE cells (hTERT-RPE). Using the four main vitamin E components, αT, γT, δ-tocopherol (δT) and α-tocotrienol (αTr), we ascertained that they exhibit similar, but not identical, antioxidant activity as αT when used at equimolar concentrations. In addition, we determined that the exposure time of RPE cells to α-tocopherol is critical for its ability to protect against oxidative damage. Lastly, we determined that αT, but not γT, partially requires the synthesis of new proteins within a 24-h period and prior to exposure to tBHP for optimal cytoprotection. We conclude that, unlike γT and δT, αT appears to be unique in its requirement for transport and/or signaling for it to be an effective antioxidant. As a result, more focus should be paid to which vitamin E components are used for antioxidant interventions.

Introduction: Glaucoma is the second leading cause of blindness worldwide and despite its prevalence, there are still many unanswered questions related to its pathogenesis. There is evidence that oxidative stress and inflammation play a major role in disease progression. Glaucoma patients from several studies showed altered gene expression in leukocytes, revealing the possibility of using peripheral biomarkers to diagnose or stage glaucoma. The fact that glaucoma is associated with gene expression changes in tissues distant from the retina underscores the possible involvement of systemic oxidative stress and inflammation as potential contributing or compounding factors in glaucoma. Methods: We assembled a list of oxidative stress and inflammatory markers related to glaucoma based on a review of the literature. In addition, we utilized publicly available data sets of gene expression values collected from peripheral blood mononuclear cells and macrophages from two patient groups: those chronically infected by the hepatitis C virus and those who have cleared it. Activation of the innate immune response can render cells or tissues more responsive to a second delayed proinflammatory stimulus. Additional gene expression data from these cells after subsequent polyinosinic:polycytidylic acid treatment, used to elicit an acute inflammatory response, allowed for the investigation of the acute inflammatory response in these groups. We used fold-change comparison values between the two patient groups to identify genes of interest. Results: A comparison analysis identified 17 glaucoma biomarkers that were differentially expressed in response to HCV-mediated inflammation. Of these 17, six had significant p-values in the baseline vs treated values. Expression data of these genes were compared between patients who had cleared the Hepatitis C virus versus those who had not and identified three genes of interest for further study. Discussion: These results support our hypothesis that inflammation secondary to Hepatitis C virus infection affects the expression of glaucoma biomarker genes related to the antioxidant response and inflammation. In addition, they provide several potential targets for further research into understanding the relationship between innate responses to viral infection and inflammatory aspects of glaucoma and for potential use as a predictive biomarker or pharmacological intervention in glaucoma.

The contributions of anterior segment abnormalities to the development of ocular hypertension was determined in the DBA/2J mouse model of glaucoma. Intraocular pressure (IOP) was measured non-invasively. Iris pigment dispersion (IPD) and corneal calcification were measured weekly starting at 20 weeks of age in DBA/2J and DBA/2J-Gpnmb+/SjJ mice. Thickness, surface area, auto-fluorescence intensity, and perimeter length of calcified regions were measured in postmortem corneas using confocal microscopy. DBA/2J mice developed elevated IOP between 9 and 12 months of age, but DBA/2J-Gpnmb+/SjJ mice did not. Corneal calcification was found at all ages observed and at similar frequencies in both strains with 83.3% of DBA/2J eyes and 60.0% of DBA/2J-Gpnmb+/SjJ eyes affected at 12 months (P = 0.11). Calcification increased with age in both DBA/2J (P = 0.049) and DBA/2J-Gpnmb+/SjJ mice (P = 0.04) when assessed qualitatively and based on mixed-effects analysis. No differences in the four objective measures of calcification were observed between strains or ages. At 12 months of age, DBA/2J mice with corneal calcification had greater mean IOP than DBA/2J mice without corneal calcification. IOP was not correlated with the qualitatively assessed measures of calcification. For the subset of eyes with ocular hypertension, which were only found in DBA/2J mice, IOP was negatively correlated with the qualitative degree of calcification, but was not correlated with the four quantitative measures of calcification. Differences in IOP were not observed between DBA/2J-Gpnmb+/SjJ mice with and without calcification at any age. IPD increased with age and demonstrated a moderate correlation with IOP in DBA/2J mice, but was not observed in DBA/2J-Gpnmb+/SjJ mice. In the DBA/2J mouse model of glaucoma, increased IPD is positively correlated with an increase in IOP and corneal calcification is present in the majority of eyes at and after age 9 months. However, while IPD causes ocular hypertension, corneal calcification does not appear to contribute to the elevation of IOP, as the control strain DBA/2J-Gpnmb+/SjJ exhibits corneal calcification similar to DBA/2J mice, but does not develop ocular hypertension. Corneal calcification, therefore, does not appear to be a contributing factor to the development of elevated IOP in DBA/2J mice.

The eye is particularly susceptible to oxidative stress and disruption of the delicate balance between oxygen-derived free radicals and antioxidants leading to many degenerative diseases. Attention has been called to all isoforms of vitamin E, with α-tocopherol being the most common form. Though similar in structure, each is diverse in antioxidant activity. Preclinical reports highlight vitamin E’s influence on cell physiology and survival through several signaling pathways by activating kinases and transcription factors relevant for uptake, transport, metabolism, and cellular action to promote neuroprotective effects. In the clinical setting, population-based studies on vitamin E supplementation have been inconsistent at times and follow-up studies are needed. Nonetheless, vitamin E’s health benefits outweigh the controversies. The goal of this review is to recognize the importance of vitamin E’s role in guarding against gradual central vision loss observed in age-related macular degeneration (AMD). The therapeutic role and molecular mechanisms of vitamin E’s function in the retina, clinical implications, and possible toxicity are collectively described in the present review.