Diabetic Retinopathy (DR) is a leading cause of vision loss in diabetic patients, driven by oxidative stress, inflammation, and vascular abnormalities. Recent studies highlight amino acid metabolism abnormalities, particularly in glutamate, arginine, and tryptophan, as critical factors in DR pathogenesis. Preclinical evidence suggests that these metabolic disturbances may contribute to retinal neurodegeneration and vascular damage, offering potential new targets for therapy. Natural plant-derived compounds, such as flavonoids, catechins, and alkaloids, have been shown in animal and cell culture studies to regulate amino acid metabolism and may offer therapeutic potential for DR, although clinical validation remains limited. These compounds exhibit antioxidant, anti-inflammatory, and neuroprotective properties. Flavonoids improve amino acid accumulation, reduce oxidative stress, and protect retinal cells, while catechins enhance amino acid synthesis and redox balance. Alkaloids like berberine regulate nitric oxide synthesis, improving retinal microcirculation and endothelial function. In DR, glutamate excess activates NMDA receptors, leading to retinal neuronal toxicity, while arginine and tryptophan metabolism abnormalities further disrupt vascular and immune function. Natural drugs targeting these pathways could alleviate oxidative stress, inflammation, and retinal damage. However, challenges remain in clinical application, including low bioavailability and variability in product quality. Future research should focus on multi-omics integration, personalized medicine, and clinical trials to establish robust evidence for the use of natural drugs in DR treatment, ultimately improving long-term visual outcomes and quality of life.
BackgroundWe developed and validated RetinalVNG-Net, a multimodal deep learning framework for simultaneous risk stratification of hypertensive retinopathy, diabetic retinopathy, and neurodegenerative-associated retinal changes from integrated fundus photography, optical coherence tomography, and clinical metadata.MethodsThis retrospective multi-center study included 2,740 subjects from three independent ophthalmology centers (January 2019–December 2023). Centers A and B (n = 2,220) constituted the development set, with a stratified 15% subset (n = 333) reserved for hyperparameter tuning and the remainder (n = 1,887) used for five-fold cross-validation. Center C (n = 520) served as a geographically distinct, device-heterogeneous external test set. RetinalVNG-Net employs a RETFound ViT-Large fundus encoder, a dual-stream Optical Coherence Tomography (OCT) branch (ResNet-3D-18 for volumetric B-scans and 2D-CNN for layer thickness maps), and a tabular transformer for metadata, fused via cross-modal attention. An auxiliary regression head outputs a continuous Retinal Biological Age Gap (RBAG) score as an interpretable severity biomarker.ResultsInternal cross-validation yielded macro-averaged AUC-ROC 0.957 (±0.008), sensitivity 0.913, specificity 0.941, and F1 0.908 across four classes. On the external test set, macro-averaged AUC-ROC reached 0.944 (95% CI 0.922–0.958), with per-class AUCs of 0.963 (hypertensive retinopathy), 0.951 (diabetic retinopathy), 0.924 (neurodegenerative changes), and 0.938 (controls). RetinalVNG-Net significantly outperformed the best single-modality fundus model (macro-AUC 0.944 vs. 0.901; p < 0.001).ConclusionRetinalVNG-Net demonstrates promising robustness and generalizability for simultaneous multimodal risk stratification of vascular and neurodegenerative retinal changes across diverse devices and settings, supporting further evaluation as a tool for risk stratification of retinal manifestations associated with systemic vascular and neurodegenerative disease. Prospective longitudinal studies would be required to establish value for early or predictive detection.
Age-related macular degeneration (AMD) is a major cause of visual impairment in the elderly, with oxidative stress as its core pathogenesis. Herein, a prokaryotic expression system in Escherichia coli (E. coli) BL21 was developed to yield recombinant human vascular endothelial growth factor B 167(VEGFB167), after systematic optimization of expression and purification parameters, the antioxidant capacity of the target protein was experimentally verified. VEGFB167 was efficiently expressed as inclusion bodies. Following chromatographic purification, the protein purity attained 97% with a concentration of 1.4 mg/mL. Cellular functional assays revealed that VEGFB167 significantly reduced reactive oxygen species, malondialdehyde, and lactate dehydrogenase release, enhanced both superoxide dismutase activity and SOD1/SOD2 gene expression level, inhibited apoptosis, and promoted cell proliferation. These results support further development of VEGFB167 as a biotherapeutic candidate for oxidative injury-triggered illnesses exemplified by AMD.
The causal link between the aging microenvironment and T cell aging remains elusive. Here, we demonstrate that adenosine within aging tissues actively reprograms CD8+ T cells into a pro-aging Granzyme K+ (Gzmk+) population. Mechanistically, senescent cells create an adenosine-rich niche via p16-dependent CD39 upregulation, triggering A2aR signaling to induce Gzmk+ T cell differentiation. Once released, Gzmk promotes systemic inflammaging through PAR1 and complement activation. Crucially, targeting this axis—either via genetic Gzmk ablation or pharmacological A2aR blockade—reverses multi-organ aging phenotypes and significantly extends healthy lifespan in mice. Human analysis reveals age-dependent Gzmk+ T cell accumulation in multi organs, while coffee intake (an A2aR antagonist) inversely correlates with plasma Gzmk levels. Our findings uncover how metabolic niche changes drive T cell aging and establish the adenosine-Gzmk axis as a pivotal therapeutic target for combating age-related diseases. ### Competing Interest Statement The authors have declared no competing interest. the National Key Research and Development Program of China, 2023YFC3606600 the National Natural Science Foundation of China, 82571797, 32270938 the Public Hospital Research Collaboration Fund of Inner Mongolia, 2023GLLH0336
AIM Diabetic retinopathy (DR) is a leading cause of vision loss in type 2 diabetes, and concerns remain regarding semaglutide's potential association with DR progression. This study aimed to evaluate semaglutide-related DR risk using real-world pharmacovigilance data and explore its direct effects on retinal microvascular cells under high glucose conditions. METHODS Data from the FDA Adverse Event Reporting System (FAERS, 2004 Q1–2024 Q2) were analyzed, including 287,470 semaglutide users with 82,931 adverse events. Four disproportionality algorithms [reported odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), empirical Bayesian geometric mean (EBGM)] were used to detect DR-related signals. In vitro experiments were performed on human retinal microvascular endothelial cells (HRMECs) cultured in normal glucose (5 mM) or high glucose (30 mM). Semaglutide (5–1000 nM) cytotoxicity was assessed via MTT assay. Cell proliferation (EdU labeling), angiogenesis (Matrigel assay), migration (Transwell), and GLP-1 receptor (GLP-1R) expression (Western blotting) were evaluated. RESULTS FAERS analysis identified 2004 ocular adverse events in semaglutide users, with 88 cases of DR (ROR = 19.57, PRR = 19.55, IC025 = 3.67, EBGM05 = 15.37) that did not rank among top 30 adverse event terms. Gastrointestinal (n = 22,801) and metabolic disorders (n = 5,230) were the most frequently reported. High glucose significantly downregulated GLP-1R in HRMECs (P < 0.05). Semaglutide at non-cytotoxic concentrations (50, 100 nM) inhibited high glucose-induced hyperproliferation, excessive angiogenesis, and enhanced migration (all P < 0.01 vs. high glucose group). CONCLUSION Real-world FAERS data indicate a low clinical association between semaglutide and DR. Preclinically, semaglutide protects HRMECs from high glucose-induced dysfunction via GLP-1R modulation, supporting its safety profile in DR-prone individuals. These findings contribute to understanding GLP-1RA effects on diabetic microvascular complications.
