Treatment Diabetic Retinopathy Research Articles

Development and characterization of dexamethasone nanodispersion for the effective treatment of diabetic retinopathy

Diabetic retinopathy is the most common complication of diabetes and remains the leading cause of vision loss worldwide. The potent glucocorticoid based anti-inflammatory drug dexamethasone (DEX) chosen for the present work is long-acting with half-life of 37–72 h extensively metabolized in to 6-hydroxy-dexamethasone (6-OH-DEX). The present work aimed to develop dexamethasone loaded nanodispersion (DEX-ND) by improving its solubility, half-life, and bioavailability in biological system thereby this formulation may be afforded economically. With the concept that polymeric surfactant improves the solubility of challenging water insoluble drug the present work has been hypothesized to improve its solubility using polyvinyl pyrrolidone (PVP-K30) polymer and polysorbate 80 (Tween 80) hydrophilic non-ionic surfactant, thereby the bioavailability is expected to get enhanced. By varying the PVP K30 and Tween 80 concentrations three different formulations were developed. The developed DEX-ND was further characterized for its compatibility, particle size, zeta potential, morphology, and in vitro release behavior. The results of Fourier transform infrared spectrometric analysis indicate the compatibility nature of DEX-ND along with other excipients/drug used in the formulation. The developed formulations showed spherical morphology, particle size ranging from 550.46 ± 107.82 to 3560 ± 284.29 nm, zeta potential ranging from −29.23 ± 1.09 to −7.793 ± 1.01 mV. The amount of DEX present in the DEX-NDs was found to be 0.95–3.93 mg. The in vitro release studies as performed by dialysis bag method showed a sustained release pattern. The results of ex vivo corneal permeation studies indicates that the developed DEX- NDs has some exposure to the posterior segment of the eye.

Cellular communication network factor 1 promotes retinal leakage in diabetic retinopathy via inducing neutrophil stasis and neutrophil extracellular traps extrusion

BackgroundDiabetic retinopathy (DR) is a major cause of blindness and is characterized by dysfunction of the retinal microvasculature. Neutrophil stasis, resulting in retinal inflammation and the occlusion of retinal microvessels, is a key mechanism driving DR. These plugging neutrophils subsequently release neutrophil extracellular traps (NETs), which further disrupts the retinal vasculature. Nevertheless, the primary catalyst for NETs extrusion in the retinal microenvironment under diabetic conditions remains unidentified. In recent studies, cellular communication network factor 1 (CCN1) has emerged as a central molecule modulating inflammation in pathological settings. Additionally, our previous research has shed light on the pathogenic role of CCN1 in maintaining endothelial integrity. However, the precise role of CCN1 in microvascular occlusion and its potential interaction with neutrophils in diabetic retinopathy have not yet been investigated.MethodsWe first examined the circulating level of CCN1 and NETs in our study cohort and analyzed related clinical parameters. To further evaluate the effects of CCN1 in vivo, we used recombinant CCN1 protein and CCN1 overexpression for gain-of-function, and CCN1 knockdown for loss-of-function by intravitreal injection in diabetic mice. The underlying mechanisms were further validated on human and mouse primary neutrophils and dHL60 cells.ResultsWe detected increases in CCN1 and neutrophil elastase in the plasma of DR patients and the retinas of diabetic mice. CCN1 gain-of-function in the retina resulted in neutrophil stasis, NETs extrusion, capillary degeneration, and retinal leakage. Pre-treatment with DNase I to reduce NETs effectively eliminated CCN1-induced retinal leakage. Notably, both CCN1 knockdown and DNase I treatment rescued the retinal leakage in the context of diabetes. In vitro, CCN1 promoted adherence, migration, and NETs extrusion of neutrophils.ConclusionIn this study, we uncover that CCN1 contributed to retinal inflammation, vessel occlusion and leakage by recruiting neutrophils and triggering NETs extrusion under diabetic conditions. Notably, manipulating CCN1 was able to hold therapeutic promise for the treatment of diabetic retinopathy.

Nerolidol Alleviates Oxidative Stress and Inflammation in Diabetic Retinopathy Mediated by High Glucose Through Ameliorating Nrf2/HO-1 Pathway

Background Diabetic retinopathy (DR) is the foremost microvascular problem that causes drastic visual impairment in diabetes patients. Hyperglycemia-triggered reaction cascade of inflammation and oxidative stress constitute the DR pathogenesis. The existing treatment options are not completely satisfactory. Materials and Methods We investigated the cell viability by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, inflammatory mediators, lactate dehydrogenase (LDH), superoxide dismutase, glutathione, and malonaldehyde (MDA) levels by ELISA and qRT-PCR assay, protein expression of Nrf2 and heme oxygenase-1 (HO-1) by western blotting assay were analyzed. Results According to our research, nerolidol (NRD) increases the proliferation and antioxidant activity of human retinal endothelial cells (HRECs) by inducing Nrf2/HO-1 signaling, while attenuating MDA, an oxidative stress marker, LDH, and inflammatory mediators. These outcomes suggest that a substantial reaction of inflammation and oxidative stress injury happened in DR, which might be correlated to the instigation of the signaling Nrf2/HO-1. Conclusion NRD effectively suppresses oxidative stress and inflammation in HG-induced HRECs. The primary mechanism of NRD on DR may be linked to the activation of the Nrf2/HO-1 pathway and may give a useful medicine for DR treatment.

Comparison of 21 artificial intelligence algorithms in automated diabetic retinopathy screening using handheld fundus camera

Background Diabetic retinopathy (DR) is a common complication of diabetes and may lead to irreversible visual loss. Efficient screening and improved treatment of both diabetes and DR have amended visual prognosis for DR. The number of patients with diabetes is increasing and telemedicine, mobile handheld devices and automated solutions may alleviate the burden for healthcare. We compared the performance of 21 artificial intelligence (AI) algorithms for referable DR screening in datasets taken by handheld Optomed Aurora fundus camera in a real-world setting. Patients and methods Prospective study of 156 patients (312 eyes) attending DR screening and follow-up. Both papilla- and macula-centred 50° fundus images were taken from each eye. DR was graded by experienced ophthalmologists and 21 AI algorithms. Results Most eyes, 183 out of 312 (58.7%), had no DR and mild NPDR was noted in 21 (6.7%) of the eyes. Moderate NPDR was detected in 66 (21.2%) of the eyes, severe NPDR in 1 (0.3%), and PDR in 41 (13.1%) composing a group of 34.6% of eyes with referable DR. The AI algorithms achieved a mean agreement of 79.4% for referable DR, but the results varied from 49.4% to 92.3%. The mean sensitivity for referable DR was 77.5% (95% CI 69.1–85.8) and specificity 80.6% (95% CI 72.1–89.2). The rate for images ungradable by AI varied from 0% to 28.2% (mean 1.9%). Nineteen out of 21 (90.5%) AI algorithms resulted in grading for DR at least in 98% of the images. Conclusions Fundus images captured with Optomed Aurora were suitable for DR screening. The performance of the AI algorithms varied considerably emphasizing the need for external validation of screening algorithms in real-world settings before their clinical application.

Diabetic Retinopathy: New Treatment Approaches Targeting Redox and Immune Mechanisms.

Diabetic retinopathy (DR) represents a severe complication of diabetes mellitus, characterized by irreversible visual impairment resulting from microvascular abnormalities. Since the global prevalence of diabetes continues to escalate, DR has emerged as a prominent area of research interest. The development and progression of DR encompass a complex interplay of pathological and physiological mechanisms, such as high glucose-induced oxidative stress, immune responses, vascular endothelial dysfunction, as well as damage to retinal neurons. Recent years have unveiled the involvement of genomic and epigenetic factors in the formation of DR mechanisms. At present, extensive research explores the potential of biomarkers such as cytokines, molecular and cell therapies, antioxidant interventions, and gene therapy for DR treatment. Notably, certain drugs, such as anti-VEGF agents, antioxidants, inhibitors of inflammatory responses, and protein kinase C (PKC)-β inhibitors, have demonstrated promising outcomes in clinical trials. Within this context, this review article aims to introduce the recent molecular research on DR and highlight the current progress in the field, with a particular focus on the emerging and experimental treatment strategies targeting the immune and redox signaling pathways.

Causal association of circulating metabolites with diabetic retinopathy: a bidirectional Mendelian randomization analysis.

The retina is a highly metabolically active tissue, and there is a lack of clarity about the relationship between metabolites and diabetic retinopathy (DR). This study used two-sample bidirectional Mendelian randomization (MR) analyses to identify causal relationships between metabolites and DR. Genetic variants were selected from the open-access Genome-Wide Association Studies (GWAS) summary database as proxies for the 1400 most recently published metabolites. MR analysis was performed to examine associations between these metabolite traits and DR. Single nucleotide polymorphism (SNP) data that were significantly associated with exposure were screened through association analysis. Validated instrumental variables (IVs) were obtained by removing SNPs with linkage disequilibrium (LD) and F-statistic values below 10. MR analyses were performed using the inverse variance weighted (IVW) method as the primary approach. The robustness of the results was verified by sensitivity analyses, including assessments of heterogeneity, horizontal pleiotropy, and the leave-one-out method. In the IVW approach and in the primary analysis of several sensitivity analyses, genetically determined glycolithocholate sulfate levels, androstenediol (3 beta, 17 beta) monosulfate (1) levels, 1-stearoyl-2-arachidonoyl-GPE (18:0/20:4) levels, 1-oleoyl-2-arachidonoyl-GPE (18:1/20:4) levels, 1-oleoyl-2-linoleoyl-GPE (18:1/18:2) levels, X-26109 levels, N6-methyllysine levels, (N6,N6-dimethyllysine levels), and (N2-acetyl,N6,N6-dimethyllysine levels) were negatively associated with the risk of DR. 5-hydroxymethyl-2-furoylcarnitine levels and the glutamate-to-alanine ratio were positively associated with the risk of DR. No reverse causal association was found between DR and metabolites. This MR study suggests that nine metabolites may have a protective effect in DR, while two metabolites may be associated with an increased risk of DR. However, further research is needed to confirm these findings. Supplementation with beneficial metabolites may reduce DR risk and could potentially be a novel therapeutic approach to DR treatment.

DEC-DRR: deep ensemble of classification model for diabetic retinopathy recognition.

Most diabetes patients are liable to have diabetic retinopathy (DR); however, the majority of them might not be even aware of the ailment. Therefore, early detection and treatment of DR are necessary to prevent vision loss. But, avoiding DR is not a simple process. An ophthalmologist can typically identify DR through an optical evaluation of the fundus and through the evaluation of color pictures. However, due to the increased count of DR patients, this could not be possible as it consumes more time. To rectify this problem, a novel deep ensemble-based DR classification technique is developed in this work. Initially, a Wiener filter (WF) is applied for preprocessing the image. Then, the enhanced U-Net-based segmentation process is done. Subsequent to the segmentation process, features are extracted that include statistical features, inferior superior nasal temporal (ISNT), cup to disc ratio (CDR), and improved LGBP as well. Further, deep ensemble classifiers (DEC) like CNN, Bi-GRU, and DMN are used to recognize the disease. The outcomes from DMN, CNN, and Bi-GRU are then subjected to improved SLF. Additionally, the weights of DMN, CNN, and Bi-GRU are adjusted via pelican updated Tasmanian devil optimization (PU-TDO). Finally, outputs on DR (microaneurysms, hemorrhages, hard exudates, and soft exudates) are obtained. The performance of DEC + PU-TDO for diabetic retinopathy is computed over extant models with regard to different measures for four datasets. The results on accuracy using the DEC + PU-TDO scheme for the IDRID dataset is maximum around 0.975 at 90th LP while other models have less accuracy. The FPR of DEC + PU-TDO is less around 0.039 at the 90th LP for the SUSTech-SYSU dataset, while other extant models have maximum FPR.

Cost-Effectiveness of Diabetic Retinopathy Screening for Newly Diagnosed Type 2 Diabetic Patients: A Nationwide Population-based Propensity Score-Matched Cohort Study

AimsThis study investigated the association between the frequency of screening for diabetic retinopathy (DR) versus the development of DR and corresponding medical expenses among patients newly diagnosed with type 2 diabetes mellitus (T2DM). MethodsThis longitudinal, population-based study used the Taiwan National Health Insurance Research Database (2004 to 2020) as a data source. Propensity score matching (PSM) (sex, age, comorbidities and concurrent medication use) was employed in the grouping of T2DM patients according to different frequency of DR screening. Outcome measures included the proportion of patients who developed DR, who received DR treatment, and the associated medical expenses and hospitalizations. ResultsThe 17-year cohort included 337,046 patients. After PSM, three groups each containing 35,739 patients were assembled and analyzed. Compared to low-frequency screening, high-frequency screening was more effective in detecting patients requiring treatment; however, the net cost for treatment was significantly lower. Standard-frequency screening appears to provide the best balance in terms of DR detection, diagnosis interval, the risk of DR-related hospitalization, and DR treatment costs. ConclusionsIn this real-world cohort study covering all levels of the healthcare system, infrequent screening was associated with delayed diagnosis and elevated treatment costs, while a fundus screening interval of 1-2 years proved optimal in terms of detection and medical expenditures.

Diabetic retinopathy is a ceramidopathy reversible by anti-ceramide immunotherapy.

Diabetic retinopathy is a microvascular disease that causes blindness. Using acid sphingomyelinase knockout mice, we reported that ceramide generation is critical for diabetic retinopathy development. Here, in patients with proliferative diabetic retinopathy, we identify vitreous ceramide imbalance with pathologic long-chain C16-ceramides increasing and protective very long-chain C26-ceramides decreasing. C16-ceramides generate pro-inflammatory/pro-apoptotic ceramide-rich platforms on endothelial surfaces. To geo-localize ceramide-rich platforms, we invented a three-dimensional confocal assay and showed that retinopathy-producing cytokines TNFα and IL-1β induce ceramide-rich platform formation on retinal endothelial cells within seconds, with volumes increasing 2-logs, yielding apoptotic death. Anti-ceramide antibodies abolish these events. Furthermore, intravitreal and systemic anti-ceramide antibodies protect fromdiabetic retinopathy in standardized rodent ischemia reperfusion and streptozotocin models. These data support (1) retinal endothelial ceramide as a diabetic retinopathy treatment target, (2) early-stage therapy of non-proliferative diabetic retinopathy to prevent progression, and (3) systemic diabetic retinopathy treatment; and they characterize diabetic retinopathy as a "ceramidopathy" reversible by anti-ceramide immunotherapy.

Comparing the Implementation of Different Diabetic Retinopathy Screening Models in Primary Health Care Settings in Northern India: Pragmatic Three-Arm Observational Study

Introduction: Early screening is recommended to prevent vision impairment (VI) and blindness globally due to diabetic retinopathy (DR). We aim to analyze the factors influencing the implementation of DR screening models in primary healthcare facilities. Methods: A pragmatic three-arm observational study will be conducted in the district of Mohali in Punjab, India. The study will compare three equal-sized groups with type 2 diabetes mellitus (T2DM) at age 30 and above. The T2DM participants and healthcare providers (HCPs) will be interviewed to identify the barriers to retinal examinations in primary healthcare settings. The study includes a comprehensive economic evaluation to determine the cost-effectiveness of implementing different DR screening models in primary health settings. The present study will use the RE-AIM framework (reach, effectiveness, adoption, implementation, and maintenance), to assess the implementation of two DR screening interventions and the extent of variation in outcomes. Qualitative and quantitative data collected from participants and research team observations will be examined to report on the five RE-AIM domains. Discussion: A screening program should ensure early detection and referral for DR treatment before it results in irreversible vision loss. However, understanding the problems of accessing DR screening and estimating the cost-effectiveness of such programs in a primary health setting is important before allocating public health resources.

Cellular and Molecular Mechanisms of Neuronal Degeneration in Early-Stage Diabetic Retinopathy.

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.

Management of retinal diseases, therapeutic association between ophthalmology and endocrinology in the treatment of diabetic retinopathy

Introduction: Effective management of retinal diseases, especially diabetic retinopathy, is crucial for preventing severe visual complications. Collaboration between ophthalmologists and endocrinologists plays a fundamental role in the effective treatment of this condition, aiming to preserve vision and improve patients' quality of life. Methods: A bibliographic review was conducted to understand the management of retinal diseases and the therapeutic association between ophthalmology and endocrinology in the treatment of diabetic retinopathy. We used databases such as MEDLINE, PubMed, and Scielo to identify relevant articles published in the last 20 years. Inclusion and exclusion criteria were defined to ensure the selection of pertinent studies. Results: After the search and selection of articles, patterns and trends in the management of diabetic retinopathy were identified. A variety of treatment options were located, including laser photocoagulation, intravitreal injections of medications, and vitreoretinal surgery. The importance of metabolic control of diabetes to prevent retinal damage was noted. The analysis of the studies also highlighted that the interaction between these specialties ensures better clinical outcomes. Conclusion: The importance of collaboration between ophthalmologists and endocrinologists in the management of diabetic retinopathy is reinforced. An integrated approach that considers both ophthalmological and endocrinological aspects of the disease is essential to provide effective care to patients. This cooperation can result in better visual outcomes and quality of life for those affected by diabetic retinopathy.

Vision Saver Deep Learning Approaches for Diabetic Retinopathy Detection

One of the main causes of adult blindness and a frequent consequence of diabetes is diabetic retinopathy. In order to preserve eyesight, diabetic retinopathy must be identified and treated early. In this study, "Vision Saver," a deep learning-based method for the automated detection and treatment of diabetic retinopathy, is introduced. Vision Saver provides a comprehensive solution for the detection of retinal problems by utilizing deep neural networks, enabling prompt patient care and intervention. Convolutional neural networks (CNNs) and recurrent neural networks (RNNs), two cutting-edge deep learning approaches, are used by the proposed system to evaluate retinal images and provide precise diagnoses. Additionally, we investigate how generative adversarial networks (GANs) might improve image quality and produce artificial data for training. The architecture of Vision Saver is built to handle both fundus photos and optical coherence tomography (OCT) images, enabling a flexible method of evaluating diabetic retinopathy. Vision Saver's management component includes not only detection but also monitoring of therapy progression. The system aids medical personnel in making educated judgments about interventions like laser therapy, injections, or surgical operations through ongoing monitoring and follow-up. The development and assessment of Vision Saver are covered in this essay, with a focus on how well it performs in terms of sensitivity, specificity, and accuracy. We also discuss concerns with model interpretability, data protection, and integration into clinical workflows. Ultimately, the objective is to improve patient outcomes and lessen the burden of blindness brought on by diabetic retinopathy by offering a comprehensive solution that improves screening and management of the illness. Deep learning in healthcare has a lot of potential, and Vision Saver is an example of how it can significantly improve the lives of people with diabetic retinopathy.

Investigating the impact of empagliflozin on the retina of diabetic mice.

Diabetic retinopathy (DR) frequently results in compromised visual function, with hyperglycemia-induced disruption of the blood-retinal barrier (BRB) through various pathways as a critical mechanism. Existing DR treatments fail to address early and potentially reversible microvascular alterations. This study examined the effects of empagliflozin (EMPA), a selective Sodium-glucose transporter 2 (SGLT2) inhibitor, on the retina of db/db mice. The objective of this study is to investigate the potential role of EMPA in the prevention and delay of DR. db/db mice were randomly assigned to either the EMPA treatment group (db/db + Emp) or the model group (db/db), while C57 mice served as the normal control group (C57). Mice in the db/db + Emp group received EMPA for eight weeks. Body weight, fasting blood glucose (FBG), and blood VEGF were subsequently measured in all mice, along with the detection of specific inflammatory factors and BRB proteins in the retina. Retinal SGLT2 protein expression was compared using immunohistochemical analysis, and BRB structural changes were observed via electron microscopy. EMPA reduced FBG, blood VEGF, and retinal inflammatory factors TNF-α, IL-6, and VEGF levels in the eye tissues of db/db mice. EMPA also increased Claudin-1, Occludin-1, and ZO-1 levels while decreasing ICAM-1 and Fibronectin, thereby preserving BRB function in db/db mice. Immunohistochemistry revealed that EMPA reduced SGLT2 expression in the retina of diabetic mice, and electron microscopy demonstrated that EMPA diminished tight junction damage between retinal vascular endothelial cells and prevented retinal vascular basement membrane thickening in diabetic mice. EMPA mitigates inflammation and preserves BRB structure and function, suggesting that it may prevent DR or serve as an effective early treatment for DR.

A mechanistic review on growing multiple therapeutic applications of lutein and its global market research.

Lutein is a naturally occurring carotenoid synthesized by plants and algae that has a beneficial effect on several biological processes and associated ailments. Its immediate application is in ophthalmology, where it significantly lowers the incidences of age-related macular degeneration (AMD). It also has anti-inflammatory action, treatment of diabetic retinopathy, and cataracts, and enhancement of visual contrast. To critically assess lutein biosynthesis, therapeutic applicability, and market research literature. We have discussed its theoretical frameworks, experimental evidence, limitations, as well as clinical trial results, and future research prospects. The literature for this review article was mined and compiled by collecting and analyzing articles from several databases, including ScienceDirect, Google Scholar, PubMed, Wiley Online Library, Patentscope, and ClinicalTrials.gov published until March 30, 2022. Patent publications were identified using the search terms like IC:(C07C67/56) AND EN_AB:(lutein) OR EN_TI:(lutein) OR EN_AB:(extraction) OR EN_TI:(process). According to the literature, lutein is an essential nutrient given that it cannot be synthesized in the human body and acts as an antioxidant, affecting AMD, diabetic retinopathy, Rheumatic diseases, inflammation, and cancer. Due to inadequate production and laborious extraction, lutein is expensive despite its high demand and applicability. Market research predicts a 6.3% compound annual growth rate for lutein by 2032. Optimizing lutein extraction for high yield and purity is necessary. Lutein has proven applicability in various ailments as well as cosmetics that can be developed as a candidate drug for various diseases discussed in the review.

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.

Impact of GLP-1 Agonists and SGLT-2 Inhibitors on Diabetic Retinopathy Progression: An Aggregated Electronic Health Record Data Study

PurposeTo examine the effects of GLP-1 agonists compared to SGLT-2 inhibitors on diabetic retinopathy. DesignRetrospective clinical cohort study using TriNetX (Cambridge, MA, USA), a federated electronic health records network comprising multiple healthcare organizations. MethodsPatients with an International Classification of Diseases, Tenth Revision (ICD-10) code of non-proliferative diabetic retinopathy and monotherapy treatment, excluding insulin, with GLP-1 agonists or SGLT-2 inhibitors. Patients with history of proliferative diabetic retinopathy prior to initiation of treatment were excluded. Rate of progression to proliferative diabetic retinopathy and rate of development of diabetic macular edema were compared between patients on GLP-1 agonists compared to those on SGLT-2 inhibitors. The groups were propensity score matched for age, gender, ethnicity, race, type of diabetes, and severity of non-proliferative diabetic retinopathy. Main outcomes included rate and relative risk of progression to proliferative diabetic retinopathy and risk of diabetic macular edema in the GLP-1 agonist group versus the SGLT-2 inhibitor group. ResultsA total of 6481 patients were identified in the GLP-1 cohort and the SGLT-2 inhibitor cohort after propensity score matching. At 1 year and 3 years after initiation of therapy, a higher rate of progression of proliferative diabetic retinopathy was noted (RR: 1.26, CI 1.04-1.51, p=0.017 at 1 year, RR: 1.284, CI 1.1-1.499, p=0.002 at 3 years) in the GLP-1 agonist cohort compared to the SGLT-2 inhibitor cohort. There was a higher rate of diabetic macular edema noted at 3 months (RR: 1.192, CI 1.059-1.276, p=0.002), 6 months (RR: 1.22, CI 1.13-1.32, p<0.001), 1 year (RR: 1.24, CI 1.15-1.33, p<0.001), and at 3 years (RR: 1.29, CI 1.21-1.38, p<0.001) in the GLP-1 agonist cohort compared to the SGLT-2 inhibitor cohort. ConclusionsA higher rate of progression of proliferative diabetic retinopathy and risk of new-onset diabetic macular edema was observed in patients on monotherapy with GLP-1 agonists compared to those on SGLT-2 inhibitors. It is important for clinicians to be aware of these potential effects and to consider the current retinopathy status when initiating treatment with newer hypoglycemic agents to ensure these patients are appropriately monitored for developing potential vision threatening complications.