Treatment Diabetic Retinopathy Research Articles

Genipin ameliorates diabetic retinopathy via the HIF-1α and AGEs-RAGE pathways

BackgroundTraditional Chinese medicine (TCM) is useful in disease treatment and prevention. Genipin is an active TCM compound used to treat diabetic retinopathy (DR). In this study, a network pharmacology (NP)-based approach was employed to investigate the therapeutic mechanisms underlying genipin administration in DR. MethodsThe potential targets of DR were identified using the gene expression omnibus (GEO) database. TCM database screening and NP were used to predict the potential active targets and pathways of genipin in DR. Cell viability was tested in vitro to determine the effects of different doses of glucose and genipin on Human Retinal Microvascular Endothelial Cells (hRMECs). CCK-8, CCK-F, colony formation, CellTiter-Lum, Annexin V-FITC, wound healing, Transwell, tube-forming, reactive oxygen species (ROS), and other assay kits were used to detect the effects of genipin on hRMECs during high levels of glucose. In vivo, a streptozotocin (STZ)-mouse intraocular genipin injection (IOI.) model was used to explore the effects of genipin on diabetes-induced retinal dysfunction. Western blotting was performed to identify the cytokines involved in proliferation, apoptosis, angiogenesis, ROS, and inflammation. The protein expression of the AKT/ PI3K/ HIF-1α and AGEs/ RAGE pathways was also examined. ResultsApproximately 14 types of TCM, and nearly 300 active ingredients, including genipin, were identified. The NP approach successfully identified the HIF-1α and AGEs-RAGE pathways, with the EGR1 and UCP2 genes, as key targets of genipin in DR. In the in vitro and in vivo models, we discovered that high glucose increased cell proliferation, apoptosis, angiogenesis, ROS, and inflammation. However, genipin application regulated cell proliferation and apoptosis, inhibited angiogenesis, and reduced ROS and inflammation in the HRMECs exposed to high glucose. Furthermore, the retinal thickness in the genipin-treated group was lower than that in the untreated group. AKT/ PI3K/ HIF-1α and AGEs/ RAGE signaling was increased by high glucose levels; however, genipin treatment decreased AKT/ PI3K and AGEs/ RAGE pathway expressions. Genipin also increased HIF-1α phosphorylation, oxidative phosphorylation of ATP synthesis, lipid peroxidation, and the upregulation of oxidoreductase. Genipin was found to protect HG-induced hRMECs and the retina of STZ-mice, based on; 1 the inhibition of UCP2 and Glut1 decreased intracellular glucose, and glycosylation; 2 the increased presence of HIF-1α, which increased oxidative phosphorylation and decreased substrate phosphorylation; 3 the increase in oxidative phosphorylation from ATP synthesis increased lipid peroxidation and oxidoreductase activity, and; 4 the parallel effect of phosphorylation and glycosylation on vascular endothelial growth factor (VEGF), MMP9, and Scg3. ConclusionBased on NP, we demonstrated the potential targets and pathways of genipin in the treatment of DR and confirmed its effective molecular mechanism in vitro and in vivo. Genipin protects cells and tissues from high glucose levels by regulating phosphorylation and glycosylation. The activation of the HIF-1α pathway can also be used to treat DR. Our study provides new insights into the key genes and pathways associated with the prognosis and pathogenesis of DR.

Risk factors for erectile dysfunction in diabetes mellitus: a systematic review and meta-analysis.

Previous studies have established that diabetes mellitus (DM) markedly raises the risk of developing erectile dysfunction (ED). Despite extensive investigations, the risk factors associated with ED in diabetic men have yet to be unequivocally determined, owing to incongruent and inconclusive results reported in various studies. The objective of this systematic review and meta-analysis was to assess the risk factors for ED in men with DM. A comprehensive systematic review was conducted, encompassing studies published in the PubMed, Scopus and Embase databases up to August 24th, 2023. All studies examining the risk factors of ED in patients with DM were included in the analysis. To identify significant variations among the risk factors, odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were employed. The risk of bias was evaluated using the Newcastle-Ottawa Scale(NOS) for longitudinal studies and the Agency for Healthcare Research and Quality Scale(AHRQ) for cross-sectional studies. A total of 58 studies, including a substantial participant pool of 66,925 individuals diagnosed with DM, both with or without ED, were included in the meta-analysis. Mean age (OR: 1.31, 95% CI=1.24-1.37), smoking status (OR: 1.32, 95% CI=1.18-1.47), HbA1C (OR: 1.44, 95% CI=1.28-1.62), duration of DM (OR: 1.39, 95% CI=1.29-1.50), diabetic neuropathy (OR: 3.47, 95% CI=2.16-5.56), diabetic retinopathy (OR: 3.01, 95% CI=2.02-4.48), diabetic foot (OR: 3.96, 95% CI=2.87-5.47), cardiovascular disease (OR: 1.92, 95% CI=1.71-2.16), hypertension (OR: 1.74, 95% CI=1.52-2.00), microvascular disease (OR: 2.14, 95% CI=1.61-2.85), vascular disease (OR: 2.75, 95% CI=2.35-3.21), nephropathy (OR: 2.67, 95% CI=2.06-3.46), depression (OR: 1.82, 95% CI=1.04-3.20), metabolic syndrome (OR: 2.22, 95% CI=1.98-2.49), and diuretic treatment (OR: 2.42, 95% CI=1.38-4.22) were associated with increased risk factors of ED in men with DM. Our study indicates that in men with DM, several risk factors for ED have been identified, including mean age, HbA1C, duration of DM, diabetic neuropathy, diabetic retinopathy, diabetic foot, cardiovascular disease, hypertension, microvascular disease, vascular disease, nephropathy, depression, metabolic syndrome, and diuretic treatment. By clarifying the connection between these risk factors and ED, clinicians and scientific experts can intervene and address these risk factors, ultimately reducing the occurrence of ED and improving patient management.

Diabetic Retinopathy: Diverse Perspectives of Available Herbal Resolutions

Abstract: Uncontrolled blood sugar levels bring on an eye condition known as diabetic retinopathy. If untreated, the damage to the blood vessels in the retina can result in blindness. Early symptoms include impaired vision, difficulties distinguishing colours, and dark patches of vision. Since ancient times, people all around the world have utilized herbs to manage diabetes and the various additional problems it might cause. Numerous herbs, including Salvia, Ginseng, Gingko, and Scrophularia ningpoensis, have unique qualities that make them capable of lowering the various pathological incidences of hyperglycemia-related retinal disease. Biomolecules, known as carotenoids, such as lutein, beta carotene, and zeaxanthin, have a significant anti-oxidant capability that aids in visual recovery. In addition to acting as a natural and safe treatment for diabetic retinopathy, herbal remedies in the form of herbs, concentrated extracts, and isolated phytoactives can also operate as a viable alternative to prevent the destruction brought on by laser-based photocoagulation and vitrectomy. The goal of the current study is to analyze the natural herb-based alternatives for diabetic retinopathy that are now available.

SIRT1/P53 in retinal pigment epithelial cells in diabetic retinopathy: a gene co-expression analysis and He-Ying-Qing-Re formula treatment.

Diabetic retinopathy (DR) is a severe diabetic complication that leads to severe visual impairment or blindness. He-Ying-Qing-Re formula (HF), a traditional Chinese medicinal concoction, has been identified as an efficient therapy for DR with retinal vascular dysfunction for decades and has been experimentally reported to ameliorate retinal conditions in diabetic mice. This study endeavors to explore the therapeutic potential of HF with key ingredients in DR and its underlying novel mechanisms. Co-expression gene modules and hub genes were calculated by weighted gene co-expression network analysis (WGCNA) based on transcriptome sequencing data from high-glucose-treated adult retinal pigment epithelial cell line-19 (ARPE-19). The chromatographic fingerprint of HF was established by ultra-performance liquid chromatography coupled with high-resolution mass spectrometry (UPLC-Q-TOF-MS). The molecular affinity of the herbal compound was measured by molecular docking. Reactive oxygen species (ROS) was measured by a DCFDA/H2DCFDA assay. Apoptosis was detected using the TUNEL Assay Kit, while ELISA, Western blot, and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used for detecting the cytokine, protein, and mRNA expressions, respectively. Key compounds in HF were identified as luteolin, paeoniflorin, and nobiletin. For WGCNA, ME-salmon ("protein deacetylation") was negatively correlated with ME-purple ("oxidative impairment") in high-glucose-treated ARPE-19. Luteolin has a high affinity for SIRT1 and P53, as indicated by molecular docking. Luteolin has a hypoglycemic effect on type I diabetic mice. Moreover, HF and luteolin suppress oxidative stress production (ROS and MDA), inflammatory factor expression (IL-6, TNF-α, IL1-β, and MCP-1), and apoptosis, as shown in the in vivo and in vitro experiments. Concurrently, treatment with HF and luteolin led to an upregulation of SIRT1 and a corresponding downregulation of P53. Using HF and its active compound luteolin as therapeutic agents offers a promising approach to diabetic retinopathy treatment. It primarily suppressed protein acetylation and oxidative stress via the SIRT1/P53 pathway in retinal pigment epithelial cells.

Improvement of visual acuity in non-proliferative diabetic retinopathy with Nimi Nirdishta Yoga- A case report

Ayurveda can serve in many disease conditions, whereas conventional systems face several limitations. Diabetic Retinopathy (DR) is among such conditions, where effective management is becoming a challenge. Diabetic Retinopathy leads to visual disability and is one of the major complications of Diabetes Mellitus (DM). Currently available conventional treatments for DR have certain limitations; considering this fact, options from alternative resources are being searched. In Ayurveda, retinal diseases can be included in Drishtigata roga (~eye sight disorder) and DR can be correlated with Timir (~a class of morbid affections of the coats of the eye), as pathology of Timir is secondary to systemic Dosha Dushti (~vitiation of body humor) and DR can be considered as Pramehajanya Timir. A male patient of 61 years visited the Netra (ophthalmic) OPD complaining of defective distant and near vision for two months. Based upon the history of diabetes and clinical signs and symptoms, he was diagnosed with Non-Proliferative Diabetic Retinopathy (NPDR) in both eyes. The indirect ophthalmoscopy investigation was used to confirm the diagnosis. Nimi Nirdishta yoga which contains Triphala, Yashtimadhu (Glycyrrhiza glabra Linn.), and Ghrita was administered for one month daily at night with honey. At the end of one month, there was improvement noted in distant vision without glasses from 6/18 to 6/12 in the right eye and 6/9 to 6/6p in the left eye while near vision from N/8 to N/6 in both eyes with glasses. Indirect ophthalmoscopy revealed a reduction in exudates and hemorrhages. The observations reveal that Ayurvedic approaches are helpful in managing Diabetic Retinopathy.

Microaneurysms and Exudates Detection in Retinal Images using Deep Neural Network

One frequent diabetes consequence that affects the eyes is diabetic retinopathy(DR). The most frequent reasonfor blindness in working-age adults in the world is diabetic retinopathy. One in three diabetics has diabetic retinopathy to some extent. DR affects nearly all persons having type 1 diabetes and more than 60% of people having type 2 diabetes to some extent after 20 years of diabetes. In the US, approximately 4.2 million persons, 40 and older have diabetic retinopathy. In the United States, 12% of all new occurrences of blindness are caused by diabetic retinopathy.A 95% reduction in the risk of blindness is possible with a diabetic retinopathy early detection and treatment. The retina's appearance, the presence or absence of Microaneurysm and Exudates, and the degree of participation are all taken into account in the grading process. It has been demonstrated that deep neural networks (DNNs) work well for automatically grading diabetic retinopathy. The features like Microaneurysm and Exudates that are diagnostic of various stages of diabetic retinopathy are taught to these DNNs utilizing vast datasets of retinal pictures and accompanying grading information.It has been demonstrated that deep neural networks (DNNs) are efficient in automatically detecting diabetic retinopathy from retinal pictures. Sensitivity, specificity, precision, accuracy, and Kappa value are used to measure how well DNNs work in detecting diabetic retinopathy; these values are 95.74%, 92.31%, 96.77%, 94.74%, and 0.87, respectively.

Redox Regulation of Immunometabolism in Microglia Underpinning Diabetic Retinopathy.

Diabetic retinopathy (DR) is the leading cause of visual impairment and blindness among the working-age population. Microglia, resident immune cells in the retina, are recognized as crucial drivers in the DR process. Microglia activation is a tightly regulated immunometabolic process. In the early stages of DR, the M1 phenotype commonly shifts from oxidative phosphorylation to aerobic glycolysis for energy production. Emerging evidence suggests that microglia in DR not only engage specific metabolic pathways but also rearrange their oxidation-reduction (redox) system. This redox adaptation supports metabolic reprogramming and offers potential therapeutic strategies using antioxidants. Here, we provide an overview of recent insights into the involvement of reactive oxygen species and the distinct roles played by key cellular antioxidant pathways, including the NADPH oxidase 2 system, which promotes glycolysis via enhanced glucose transporter 4 translocation to the cell membrane through the AKT/mTOR pathway, as well as the involvement of the thioredoxin and nuclear factor E2-related factor 2 antioxidant systems, which maintain microglia in an anti-inflammatory state. Therefore, we highlight the potential for targeting the modulation of microglial redox metabolism to offer new concepts for DR treatment.

Aldose Reductase as a Key Target in the Prevention and Treatment of Diabetic Retinopathy: A Comprehensive Review.

The escalating global prevalence of diabetes mellitus (DM) over the past two decades has led to a persistent high incidence of diabetic retinopathy (DR), necessitating screening for early symptoms and proper treatment. Effective management of DR aims to decrease vision impairment by controlling modifiable risk factors including hypertension, obesity, and dyslipidemia. Moreover, systemic medications and plant-based therapy show promise in advancing DR treatment. One of the key mechanisms related to DR pathogenesis is the polyol pathway, through which aldose reductase (AR) catalyzes the conversion of glucose to sorbitol within various tissues, including the retina, lens, ciliary body and iris. Elevated glucose levels activate AR, leading to osmotic stress, advanced glycation end-product formation, and oxidative damage. This further implies chronic inflammation, vascular permeability, and angiogenesis. Our comprehensive narrative review describes the therapeutic potential of aldose reductase inhibitors in treating DR, where both synthetic and natural inhibitors have been studied in recent decades. Our synthesis aims to guide future research and clinical interventions in DR management.

Anti–Vascular Endothelial Growth Factor Drugs Compared With Panretinal Photocoagulation for the Treatment of Proliferative Diabetic Retinopathy: A Cost-Effectiveness Analysis

ObjectivesThis study aimed to evaluate the cost-effectiveness of anti–vascular endothelial growth factor drugs (anti-VEGFs) compared with panretinal photocoagulation (PRP) for treating proliferative diabetic retinopathy (PDR) in the United Kingdom. MethodsA discrete event simulation model was developed, informed by individual participant data meta-analysis. The model captures treatment effects on best corrected visual acuity in both eyes, and the occurrence of diabetic macular edema and vitreous hemorrhage. The model also estimates the value of undertaking further research to resolve decision uncertainty. ResultsAnti-VEGFs are unlikely to generate clinically meaningful benefits over PRP. The model predicted anti-VEGFs be more costly and similarly effective as PRP, generating 0.029 fewer quality-adjusted life-years at an additional cost of £3688, with a net health benefit of −0.214 at a £20 000 willingness-to-pay threshold. Scenario analysis results suggest that only under very select conditions may anti-VEGFs offer potential for cost-effective treatment of PDR. The consequences of loss to follow-up were an important driver of model outcomes. ConclusionsAnti-VEGFs are unlikely to be a cost-effective treatment for early PDR compared with PRP. Anti-VEGFs are generally associated with higher costs and similar health outcomes across various scenarios. Although anti-VEGFs were associated with lower diabetic macular edema rates, the number of cases avoided is insufficient to offset the additional treatment costs. Key uncertainties relate to the long-term comparative effectiveness of anti-VEGFs, particularly considering the real-world rates and consequences of treatment nonadherence. Further research on long-term visual acuity and rates of vision-threatening complications may be beneficial in resolving uncertainties.

Sirt3 Protects Retinal Pigment Epithelial Cells From High Glucose-Induced Injury by Promoting Mitophagy Through the AMPK/mTOR/ULK1 Pathway.

The regulation of mitophagy by Sirt3 has rarely been studied in ocular diseases. In the present study, we determined the effects of Sirt3 on AMPK/mTOR/ULK1 signaling pathway-mediated mitophagy in retinal pigment epithelial (RPE) cells in a high glucose environment. The mRNA expression levels of Sirt3, AMPK, mTOR, ULK1, and LC3B in RPE cells under varying glucose conditions were measured by real-time polymerase chain reaction (RT-PCR). The expressions of Sirt3, mitophagy protein, and AMPK/mTOR/ULK1 signaling pathway-related proteins were detected by Western blotting. Lentivirus (LV) transfection mediated the stable overexpression of Sirt3 in cell lines. The experimental groups were NG (5.5mM glucose), hypertonic, HG (30mM glucose), HG + LV-GFP, and HG + LV-Sirt3. Western blotting was performed to detect the expressions of mitophagy proteins and AMPK/mTOR/ULK1-related proteins in a high glucose environment during the overexpression of Sirt3. Reactive oxygen species (ROS) production in a high glucose environment was measured by DCFH-DA staining. Mitophagy was detected by labeling mitochondria and lysosomes with MitoTracker and LysoTracker probes, respectively. Apoptosis was detected by flow cytometry. Sirt3 expression was reduced in the high glucose group, inhibiting the AMPK/mTOR/ULK1 pathway, with diminished mitophagy and increased intracellular ROS production. The overexpression of Sirt3, increased expression of p-AMPK/AMPK and p-ULK1/ULK1, and decreased expression of p-mTOR/mTOR inhibited cell apoptosis and enhanced mitophagy. Sirt3 protected RPE cells from high glucose-induced injury by activating the AMPK/mTOR/ULK1 signaling pathway. By identifying new targets of action, we aimed to establish effective therapeutic targets for diabetic retinopathy treatment.

Development of a Resveratrol Nanoformulation for the Treatment of Diabetic Retinopathy.

Diabetic retinopathy (RD) is a microvascular disease that can cause the formation of fragile neovessels, increasing the risk of hemorrhages and leading to vision loss. Current therapies are based on the intravitreal injection of anti-VEGF (vascular endothelial growth factor), which is invasive and can cause secondary effects. The development of new treatments that complement the current therapies is necessary to improve the patient's outcomes. Nanostructured formulations offer several advantages regarding drug delivery and penetration. In this research, a resveratrol nanosuspension (RSV-NS) was prepared and characterized using dynamic light scattering, field emission scanning electron microscopy, and infrared spectroscopy. The RSV-NS had an average particle size of 304.0 ± 81.21 nm with a PDI of 0.225 ± 0.036, and a spherical-like morphology and uniform particle distribution. Cell viability, proliferation, and migration were tested on endothelial cells (HMRECs). RSV-NS in a concentration of less than 18.75 µM did not have a cytotoxic effect on HMRECs. Likewise, proliferation and migration were significantly reduced compared to the unstimulated control at 37.5 µM. The RSV-NS did not present cytotoxic effects but decreased cell proliferation and migration, indicating that it could provide an important contribution to future medical implementations and could have a high potential to treat this disease.

Telemedicine Screening for Diabetic Retinopathy Using Digital Technology: Foreign Experience

Background. Timely detection and treatment of diabetic retinopathy (DR) could prevent the development of blindness. However, large number of patients are diagnosed at late stages when effective treatment becomes impossible. In this context, active screening for DR plays an important role. Various screening programs have been developed, including programs using digital technologies.Objective. To analyze and summarize the literature data on digitalization of DR screening.Materials and methods. The study was carried out based on the results of a search in the PubMed / Medline bibliographic database and the Google system. The used keywords were “diabetes”, “retinopathy”, “telemedi-cine”, “digital technologies”, “artificial intelligence” and others. Relevant publications were selected by exam-ining the titles and abstracts of articles.Results. The study addressed the approaches to organizing the telemedicine programs of DR screening. The examples of innovative digital technologies for performing diagnostic studies as well as the characteristics of various electronic systems and devices are presented. It was noted that the DR screening could be performed in a local center with data transfer to a regional specialized diagnostic (analytical) center where telemedicine analysis is done. All diagnostic information is available to the diabetologist who prescribes and adjusts ther-apy. This operating principle facilitates the interaction between various specialists and thus increases the efficiency of screening.Discussion. Although the telemedicine screening for diabetic retinopathy has already been introduced in a number of countries, it is still at its early stages of development. Many modern technologies such as portable mobile devices could be adapted and used in the implementation of telemedicine programs. Deep machine learning algorithms and other artificial intelligence-based approaches demonstrate excellent results. Some systems have already received regulatory approval. Conclusions. The early diagnostics of diabetic retinopathy could be improved by integrating innovative screening technologies in a unified digital platform implemented in routine clinical practice.

Network Pharmacology and Molecular Docking to Explore the Mechanism of Compound Qilian Tablets in Treating Diabetic Retinopathy

Background: Diabetic Retinopathy (DR) is one of the common chronic complications of diabetes mellitus, which has developed into the leading cause of irreversible visual impairment in adults worldwide. The Compound Qilian Tablets (CQLT) were developed in China for the treatment and prevention of DR, but their mechanism of action is still unclear. Objective: In the present study, network pharmacology, molecular docking, and in vivo validation experiments were used to investigate the active components and molecular mechanisms of CQLT against DR. Methods: The active components and targets of CQLT were collected through the TCSMP database, and the targets of DR were obtained from GeneCards, OMIM, and Drugbank databases. We established a protein-protein interaction network using the STRING database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted using the Metascape database. Molecular docking using AutoDock Vina was performed to investigate the interactions between components of CQLT and core targets. Moreover, we selected ZDF rats to establish a DR model for the experimental studies. Results: 39 active components and 448 targets in CQLT were screened, among which 90 targets were shared with DR. KEGG pathway enrichment analysis identified 181 pathways. The molecular docking results demonstrated that the main active components had strong binding ability to the core targets. The results from animal experiments indicate that the mechanism of CQLT against DR is associated with inhibiting the retinal mTOR/HIF-1α/VEGF signaling pathway, alleviating the inflammatory response, suppressing retinal neovascularization, and protecting the function and morphology of the retina. Conclusion: The present study preliminarily explored the mechanism of CQLT in treating DR and demonstrated that CQLT exerts anti-DR effects through multiple components, multiple targets, and multiple pathways. These findings suggest that CQLT shows promise as a potential therapeutic agent for DR and could contribute to developing novel treatments.

Glycemic Control in Patients After Initiation of Treatment for Vision-Threatening Diabetic Retinopathy.

Purpose: To understand changes in glycemic control in patients being managed with vision-threatening diabetic retinopathy (DR). Methods: A retrospective cohort study was performed of patients with type 2 diabetes mellitus who were at least 18 years old. Patients who started treatment for vision-threatening DR were matched with controls based on age, sex, race/ethnicity, duration of diabetes, history of diabetes, and history of hypertension. The primary outcome was the difference in hemoglobin A1c (HbA1c) change after 12 months between cases and controls. Results: Four hundred fifty patients were included (225 cases paired with 225 controls); 58.7% of patients were men, and 33.8% were Hispanic. The mean (±SD) baseline HbA1c was 8.12% ± 1.57%. Patients receiving retinal interventions did not experience a significant change in HbA1c compared with controls 12 months after starting treatment (0.11% ± 1.51% vs -0.02% ± 1.52%; P = .31). In addition, there was not a significant difference in HbA1c change between cases and controls when considering the number of interventions: 2 or fewer interventions (+0.08% ± 1.30% vs -0.07% ± 1.15%; P = .46), 3 to 6 interventions (+0.41% ± 1.71% vs +0.01% ± 2.0%; P = .08), and 7 or more interventions (-0.17% ± 1.49% vs 0.0% ± 1.31%; P = .50). Conclusions: Patients who received treatment for vision-threatening DR did not experience a change in HbA1c. Increasing number of retinal interventions also did not appear to impact glycemic control. There appears to be a missed opportunity for improving diabetes management in patients with vision-threatening DR.

Head to head comparison of diagnostic performance of three non-mydriatic cameras for diabetic retinopathy screening with artificial intelligence

BackgroundDiabetic Retinopathy (DR) is a leading cause of blindness worldwide, affecting people with diabetes. The timely diagnosis and treatment of DR are essential in preventing vision loss. Non-mydriatic fundus cameras and artificial intelligence (AI) software have been shown to improve DR screening efficiency. However, few studies have compared the diagnostic performance of different non-mydriatic cameras and AI software.MethodsThis clinical study was conducted at the endocrinology clinic of Akdeniz University with 900 volunteer patients that were previously diagnosed with diabetes but not with diabetic retinopathy. Fundus images of each patient were taken using three non-mydriatic fundus cameras and EyeCheckup AI software was used to diagnose more than mild diabetic retinopathy, vision-threatening diabetic retinopathy, and clinically significant diabetic macular oedema using images from all three cameras. Then patients underwent dilation and 4 wide-field fundus photography. Three retina specialists graded the 4 wide-field fundus images according to the diabetic retinopathy treatment preferred practice patterns of the American Academy of Ophthalmology. The study was pre-registered on clinicaltrials.gov with the ClinicalTrials.gov Identifier: NCT04805541.ResultsThe Canon CR2 AF AF camera had a sensitivity and specificity of 95.65% / 95.92% for diagnosing more than mild DR, the Topcon TRC-NW400 had 95.19% / 96.46%, and the Optomed Aurora had 90.48% / 97.21%. For vision threatening diabetic retinopathy, the Canon CR2 AF had a sensitivity and specificity of 96.00% / 96.34%, the Topcon TRC-NW400 had 98.52% / 95.93%, and the Optomed Aurora had 95.12% / 98.82%. For clinically significant diabetic macular oedema, the Canon CR2 AF had a sensitivity and specificity of 95.83% / 96.83%, the Topcon TRC-NW400 had 98.50% / 96.52%, and the Optomed Aurora had 94.93% / 98.95%.ConclusionThe study demonstrates the potential of using non-mydriatic fundus cameras combined with artificial intelligence software in detecting diabetic retinopathy. Several cameras were tested and, notably, each camera exhibited varying but adequate levels of sensitivity and specificity. The Canon CR2 AF emerged with the highest accuracy in identifying both more than mild diabetic retinopathy and vision-threatening cases, while the Topcon TRC-NW400 excelled in detecting clinically significant diabetic macular oedema. The findings from this study emphasize the importance of considering a non mydriatic camera and artificial intelligence software for diabetic retinopathy screening. However, further research is imperative to explore additional factors influencing the efficiency of diabetic retinopathy screening using AI and non mydriatic cameras such as costs involved and effects of screening using and on an ethnically diverse population.

Glucagon-like peptide-1 receptor agonists rescued diabetic vascular endothelial damage through suppression of aberrant STING signaling

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) protect against diabetic cardiovascular diseases and nephropathy. However, their activity in diabetic retinopathy (DR) remains unclear. Our retrospective cohort study involving 1626 T2DM patients revealed superior efficacy of GLP-1 RAs in controlling DR compared to other glucose-lowering medications, suggesting their advantage in DR treatment. By single-cell RNA-sequencing analysis and immunostaining, we observed a high expression of GLP-1R in retinal endothelial cells, which was down-regulated under diabetic conditions. Treatment of GLP-1 RAs significantly restored the receptor expression, resulting in an improvement in retinal degeneration, vascular tortuosity, avascular vessels, and vascular integrity in diabetic mice. GO and GSEA analyses further implicated enhanced mitochondrial gene translation and mitochondrial functions by GLP-1 RAs. Additionally, the treatment attenuated STING signaling activation in retinal endothelial cells, which is typically activated by leaked mitochondrial DNA. Expression of STING mRNA was positively correlated to the levels of angiogenic and inflammatory factors in the endothelial cells of human fibrovascular membranes. Further investigation revealed that the cAMP-responsive element binding protein played a role in the GLP-1R signaling pathway on suppression of STING signaling. This study demonstrates a novel role of GLP-1 RAs in the protection of diabetic retinal vasculature by inhibiting STING-elicited inflammatory signals.

Andrographis Paniculata (Burm. F.) Flavonoid Compound and Prevention of Diabetic Retinopathy.

To explore the effect of the flavonoid compounds of Andrographis paniculata by evaluating the glycemic profile, oxidative process, and inflammatory values in rats with diabetic retinopathy (DR). An extract of A. paniculata was macerated with ethanol which yielded flavonoid compounds. Streptozotocin was utilized to induce diabetes mellitus in male Wistar rats. Vucetic's methods were used to evaluate the retinal vessel diameters. Antioxidant parameters and inflammatory cytokines were assessed in retinal tissue. A funduscopic examination revealed some alterations in the retinal veins. In comparison to the DR group with no treatment, the diameter of the retinal vessels in the DR group that was treated with the flavonoid component of the A. paniculata extract (FAP) at doses of 20 and 40 mg/kg body weight (BW) was significantly smaller (P 0.05). The DR treatment groups administered with FAP at doses of 20 and 40 mg/kg BW had a greater ability to reduce TNF-alpha and VEGF levels as compared to the DR rats without treatment (P 0.05), Glutathione, superoxide dismutase (SOD), and catalase levels were increased after receiving FAP at doses of 20 and 40 mg/kg BW (P 0.05). Administration of doses of 20 and 40 mg/kg BW of the A. paniculata's flavonoid compoundsimproved DR in rats via retinal vessel diameter reduction, TNF- and VEGF level reduction, and increasing antioxidants, SOD, catalase, and glutathione.

Two ferroptosis-specific expressed genes NOX4 and PARP14 are considered as potential biomarkers for the diagnosis and treatment of diabetic retinopathy and atherosclerosis

ObjectivesBoth Diabetic retinopathy (DR) and Atherosclerosis (AS) are common complications in patients with diabetes, and they share major pathophysiological similarities and have a common pathogenesis. Studies performed to date have demonstrated that ferroptosis plays a vital part in the occurrence and development of DR and AS, but its mechanism in the two diseases remains poorly understood.MethodsDR Chip data (GSE60436 and GSE102485) and AS chip data (GSE100927 and GSE57691) were obtained from the Gene Expression Omnibus (GEO) database. The screening of the differential expression genes (DEGs) was analyzed using the limma package, and the genes related to ferroptosis were obtained from the FerrDb V2 database. Two key genes (NOX4 and PARP14) were identified through external datasets validation and receiver operating characteristic (ROC) curve analysis. Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) were used to conduct a functional enrichment analysis, and miRNA-mRNA networks were established. The CIBERSORT algorithm was applied to identify the immune cell infiltration between the disease group and control group. Next, the correlations between key genes and infiltrating immune cells were investigated by the Spearman method. Finally, the correlation between 2 key genes and ferroptosis markers was confirmed.ResultsNine ferroptosis differentially expressed genes (DE-FRGs) between DR and AS were identified in this study. NOX4 and PARP14 were selected as key genes for further analysis by external datasets and ROC curve analysis. The key genes NOX4, PARP14 and their correlated genes (such as CYBA, NOX1, NOX3, CYBB, PARP9, PARP10, and PARP15) are mainly enriched in oxidoreductase activity, protein ADP-ribosylation, superoxide metabolic process, reactive oxygen species metabolic process, PID pathway, and VEGFA-VEGFR2 pathway. A miRNA-mRNA network was constructed, and we got 12 miRNAs correlated with the target gene NOX4, 38 miRNAs correlated with the target gene PARP14. Three common miRNAs (hsa-miR-1-3p, hsa-miR-129-2-3p, and hsa-miR-155-5p) were observed in the network. Immune infiltration analysis displayed that activated B cell, MDSC, and Type 17 T helper cell are the common immune cells involved in the immune infiltration process of DR and AS. The results revealed that there are significant correlations between two key genes and most ferroptosis marker genes no matter in DR or AS.ConclusionFerroptosis-related genes NOX4 and PARP14 may be common biomarkers of DR and AS. Both were associated with immune infiltration in patients with DR and AS. Our data provide a theoretical basis for the early diagnosis and immunotherapy of the two diseases.

Clinical-grade human embryonic stem cell–derived mesenchymal stromal cells ameliorate diabetic retinopathy in db/db mice

Background aimsMesenchymal stromal cells (MSCs) hold great promise in the treatment of diabetic retinopathy (DR), as evidenced by increasing preclinical and clinical studies. However, the absence of standardized and industrialized clinical-grade donor cells hampers the continued development and large-scale clinical application of MSCs-based therapies for DR. Previously, we have identified a unique population of MSCs generated from a clinical-grade human embryonic stem cell (hESC) line under Good Manufacturing Practice conditions that could be a potential source to address the issues. Here, we investigated the therapeutic potential of the clinical-grade hESC line–derived MSCs (hESC-MSCs) on db/db mice with DR. MethodshESC-MSCs were initially characterized by morphological assessment, flow cytometry analysis and trilineage differentiation assays. These cells (5 × 106 cells) were then transplanted intravenously into 12-week-old db/db mice via tail vein, with phosphate-buffered saline transplantation and untreated groups used as controls. The retinal alterations in neural functions and microvascular perfusions, and inflammatory responses in peripheral blood and retina were evaluated at 4 and 6 weeks after transplantation using electroretinography, optical coherence tomography angiography and flow cytometry, respectively. Body weight and fasting blood glucose (FBG) levels were also measured to investigate their systemic implications. ResultsCompared with controls, intravenous transplantation of hESC-MSCs could significantly: (i) enhance impaired retinal electroretinography functions (including amplitudes of a-, b-wave and oscillatory potentials) at 4 weeks after transplantation; (ii) alleviate microvascular dysfunctions, especially in the inner retina with significance (including reducing non-perfusion area and increasing vascular area density) at 4 weeks after transplantation; (iii) decrease FBG levels at 4 weeks after transplantation and induce weight loss up to 6 weeks after transplantation and (iv) increase both peripheral blood and retinal interleukin-10 levels at 4 weeks after transplantation and modulate peripheral blood inflammatory cytokines and chemokines levels, such as monocyte chemotactic protein-1, up to 6 weeks after transplantation. ConclusionsThe findings of our study indicated that intravenous transplantation of hESC-MSCs ameliorated retinal neural and microvascular dysfunctions, regulated body weight and FBG and modulated peripheral blood and retinal inflammation responses in a mouse model of DR. These results suggest that hESC-MSCs could be a potentially effective clinical-grade cell source for the treatment of DR.

The potential of therapeutic strategies targeting mitochondrial biogenesis for the treatment of insulin resistance and type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is a persistent metabolic disorder marked by deficiencies in insulin secretion and/or function, affecting various tissues and organs and leading to numerous complications. Mitochondrial biogenesis, the process by which cells generate new mitochondria utilizing existing ones plays a crucial role in energy homeostasis, glucose metabolism, and lipid handling. Recent evidence suggests that promoting mitochondrial biogenesis can alleviate insulin resistance in the liver, adipose tissue, and skeletal muscle while improving pancreatic β-cell function. Moreover, enhanced mitochondrial biogenesis has been shown to ameliorate T2DM symptoms and may contribute to therapeutic effects for the treatment of diabetic nephropathy, cardiomyopathy, retinopathy, and neuropathy. This review summarizes the intricate connection between mitochondrial biogenesis and T2DM, highlighting the potential of novel therapeutic strategies targeting mitochondrial biogenesis for T2DM treatment and its associated complications. It also discusses several natural products that exhibit beneficial effects on T2DM by promoting mitochondrial biogenesis.