Pathological corneal neovascularization remains a major therapeutic challenge due to the limited efficacy and safety of currently available antiangiogenic treatments. Although C-type lectins from snake venom possess various biological activities, their potential to modulate pathological ocular angiogenesis has not been explored. This study investigated the antiangiogenic effects of Leuculectin, a C-type lectin isolated from Bothrops leucurus venom using an experimental model of corneal neovascularization (CNV), a HUVEC (human umbilical vein endothelial cell) tube formation assay, and the chick embryo chorioallantoic membrane (CAM) assay. In the HUVEC tube formation assay, Leuculectin demonstrated strong antiangiogenic activity. In the CAM assay, Leuculectin applied at concentrations of 1.5, 2.5 and 3.5 μg/mL significantly decreased new vessel formation, with effects comparable to those achieved with 250 μg/mL bevacizumab, a widely used clinical antiangiogenic agent. In the HET-CAM assay Leuculectin was classified as non-irritant and supporting its potential safety for topical ocular use. In the suture-induced CNV model, topical Leuculectin resulted in a significant reduction in neovascularized areas, achieving results similar to bevacizumab administered at considerably higher doses. These findings indicate that Leuculectin has potent antiangiogenic properties and significant therapeutic promise for ocular angiogenic disorders. Histological analyses and optical coherence tomography (OCT) further revealed improved organization of corneal epithelial and stromal layers, accompanied by fewer blood vessels in treated regions. Overall, the results suggest that Leuculectin may serve as a safe and effective alternative for managing ocular angiogenic diseases. Further studies are required to elucidate its mechanisms of action and assess its potential clinical applications.

Diabetic retinopathy (DR) has traditionally been viewed as a consequence of cumulative oxidative damage. However, the clinical phenomenon of metabolic memory, whereby prior hyperglycemia continues to exert adverse effects despite subsequent glucose normalization, indicates a more complex redox biology. This review advances a paradigm shift from considering reactive species merely as markers of injury to interpreting oxidative signatures as a dynamic, compartment-specific code that records glycemic history, predicts disease trajectory, and enables therapeutic subtyping. We synthesize evidence across multiple redox layers, including protein oxidative post-translational modifications such as S-glutathionylation and tyrosine nitration, lipid peroxidation products, mitochondrial DNA damage, and epigenetic rewriting mediated by SET domain-containing lysine methyltransferase 7 (SETD7, also known as SET7/9)-dependent monomethylation of histone H3 lysine 4 (H3K4me1). Persistent failure of mitochondrial quality control and maladaptive chromatin remodeling may stabilize hyperglycemia-induced redox programs after glucose normalization, whereas exosomal signaling may contribute to their intercellular propagation. In this context, metabolic memory refers to the durable yet potentially modifiable maintenance of these molecular programs rather than absolute biological irreversibility. Moving beyond the failure of generic antioxidant approaches, we introduce a clinical taxonomy of redox subphenotypes, glutathione-deficient, lipid-peroxidation-dominant, mitochondrial reactive oxygen species (ROS)-driven, and epigenetic redox-lock, each linked to candidate, predominantly preclinical, mechanism-matched interventions, including thiol-repleting agents, ferroptosis inhibitors, mitophagy-enhancing or mitochondrial-protective agents, and epigenetic modulators. Finally, we outline an integrated roadmap combining single-cell redox profiling, liquid-biopsy multi-omics, and biomarker-enriched clinical trial designs to translate redox signatures into precision management. Decoding the redox code may extend the traditional oxidative stress paradigm by revealing biologically heterogeneous molecular states with distinct therapeutic implications.

Visual impairment resulting from accidental chemical exposure is commonly encountered in emergency medicine, yet effective clinical interventions remain lacking. Given the critical roles of both resident microglia and peripheral macrophages in retinal degenerative diseases, this study systematically evaluated the protective effects of minocycline, PLX3397, and clodronate liposomes in sodium iodate (NaIO3)- and N-methyl-N-nitrosourea (MNU)-induced retinal degeneration models. Suppression of microglial activation with minocycline or depletion of resident microglia with PLX3397 failed to ameliorate retinal damage in either model, as evidenced by persistent fundus atrophy, diminished electroretinogram responses, and robust photoreceptor apoptosis. In contrast, systemic depletion of peripheral macrophages using clodronate liposomes significantly alleviated fundus atrophy, partially preserved visual function, and increased photoreceptor and retinal pigment epithelium (RPE) survival in the NaIO3 model, but conferred no protection in the MNU model. These findings suggest that clodronate liposomes exert model-dependent protection, likely through modulation of peripheral macrophage-mediated RPE toxicity following chemical exposure.

Müller glial cells (MGCs), non-neuronal retinal cells, have a role in supporting retinal ganglion cells (RGCs) and are a potential therapeutic target for retinal nerve diseases such as glaucoma. Here we analyzed the characteristics of induced MGCs (iMGCs) differentiated from human induced pluripotent stem cells (hiPSCs) and investigated the therapeutic potential of proteins secreted by iMGCs. Early developmental iMGCs were generated from hiPSCs. RNA-sequencing was performed on iMGCs, and the gene expressions were compared with those of human primary MGCs (pMGCs). Chemerin and NPC2, proteins identified from the conditioned medium of iPSC-derived retinal organoid, were added to iPSC-derived optic vesicles to evaluate their effects on RGC axon elongation. Chemerin and NPC2 produced from iMGCs were quantified using ELISA. Each protein was added to rat RGC transplantation to retinal explants, and the number of RGC with neurite was counted. Finally, chemerin and NPC2 were added to rat primary retinal cells under hypoxia/reoxygenation conditions, and the number of survived RGCs was counted. Transcriptome analysis of early-stage iMGCs showed common characteristics with pMGCs. Chemerin and NPC2 were found to promote RGC axon elongation and confirmed to be secreted from iMGCs. Futhermore, the addition of these proteins increased the number of RGCs with neurites in ex vivo transplantation and inhibited RGC death under hypoxia/reoxygenation conditions. This study demonstrated that chemerin and NPC2 were secreted from iMGCs and promoted RGC survival and axon elongation. These proteins may be future drug candidates for retinal regeneration.

This study compared short-term epithelial and stromal responses associated with human umbilical cord mesenchymal stem cell (hucMSC)-derived exosome-enriched extracellular vesicle treatment and serum therapy in a rabbit corneal epithelial defect model. Three groups were evaluated: exosome-enriched extracellular vesicles, 20% pooled human serum, and preservative-free artificial tears as a supportive-care control. Exosome-enriched extracellular vesicle characterization included nanoparticle tracking analysis and CD9-based flow cytometry, while parental hucMSCs were characterized by phase-contrast morphology and flow cytometric expression of CD90, CD44, CD73, and CD105. Fifteen animals were analysed (exosome-enriched extracellular vesicle group n = 6, serum group n = 5, artificial tear control group n = 4). Mean epithelial closure time was 3.50 ± 0.54 days in the exosome-enriched extracellular vesicle group, 4.00 ± 0.70 days in the serum group, and 4.75 ± 0.96 days in the artificial tear control group; however, this difference did not reach statistical significance (p = 0.081). Post-hoc power for the primary endpoint was low, approximately 22%, indicating that the study was underpowered for efficacy or superiority conclusions. Stromal thickness was higher in the exosome-enriched extracellular vesicle group (p = 0.001), but this finding was not accompanied by significant differences in stromal oedema, fibrosis, or cellularity scores. Therefore, the increased stromal thickness remains mechanistically unexplained within the limits of the present dataset. These findings should be interpreted as exploratory observations from a small preclinical study. Larger, adequately powered studies incorporating expanded extracellular vesicle characterization, longer follow-up, and mechanistic endpoints are required before therapeutic efficacy can be inferred.

Diabetic retinopathy (DR), a primary cause of working-age vision loss, is characterized by neuroinflammation, in which microglial polarization toward the proinflammatory M1 phenotype serves as a pivotal driver. Reprogramming microglia toward an anti-inflammatory and reparative phenotype may therefore represent a promising therapeutic strategy. This study investigated the effects of tetrandrine (Tet) on hypoxia-induced microglial activation and explored the underlying mechanisms. We established a chemical hypoxia model using CoCl2 and evaluated inflammatory mediators and associated molecules by qRT-PCR, western blotting, and immunofluorescence. Microglial migratory and phagocytic functions were assessed by scratch wound and phagocytosis assays, respectively. Potential drug targets were identified through an integrative approach combining network pharmacology, molecular docking, and cellular thermal shift assay (CETSA). Tet suppressed CoCl2-induced M1-associated inflammatory gene expression in BV2 cells and attenuated p65 activation and cytotoxic responses in HMC3 cells. Functionally, Tet restored impaired phagocytic capacity, attenuated aberrant migration, and mitigated microglia-mediated injury to 661W photoreceptor-derived cells. Mechanistic analyses showed that Tet reduced p65 phosphorylation and apparent nuclear accumulation, thereby limiting activation of the HIF-1α/NF-κB signaling axis; docking and CETSA findings further supported a potential interaction between Tet and p65. In summary, Tet alleviates hypoxia-induced microglial M1 polarization and microglia-mediated photoreceptor cell injury, at least partly through modulation of NF-κB/p65 signaling. These findings identify Tet as a candidate compound for further preclinical investigation in retinal neuroinflammation associated with DR.

Neovascular age-related macular degeneration (nAMD) and proliferative diabetic retinopathy (PDR) continue to be significant contributors to permanent visual impairment. Although anti-vascular endothelial growth factor (anti-VEGF) therapy has substantially improved disease management, recurrent neovascularization, persistent leakage, incomplete treatment response, subretinal fibrosis in nAMD, and fibrovascular membrane formation or tractional complications in PDR indicate that disease progression involves mechanisms beyond VEGF signaling alone. Cellular senescence-a stress-induced condition marked by persistent cell-cycle arrest, altered stress responses, and context-dependent senescence-associated secretory phenotype (SASP) activity-has been identified as a potential pathogenic amplifier in posterior-segment neovascular diseases. Chronic oxidative stress, hyperglycemia, hypoxia, metabolic dysfunction, and inflammation in the retina and choroid may induce senescence-associated or senescence-like remodeling in retinal pigment epithelial cells, Müller glia, endothelial cells, and pericytes. Nonetheless, conclusive evidence of bona fide cellular senescence in human ocular tissues remains scarce and varies markedly across cell types and disease contexts. This review integrates direct experimental evidence, marker-based observations, and inferred mechanistic insights to delineate a proposed, evidence-based senescence-associated feed-forward amplification model. In this model, chronic pathological stress may initiate or reinforce senescence-related programs, whereas SASP factors, extracellular vesicles, and immune microenvironment remodeling may further amplify angiogenic, inflammatory, vascular, and fibrotic dysfunction. Importantly, this model should be interpreted as a hypothesis-generating, non-exclusive framework rather than a fully established causal pathway. We also compare disease-specific features of nAMD and PDR, discuss methodological challenges in defining retinal senescence, and evaluate the translational potential and safety concerns of senolytics and SASP-modulating strategies as adjuncts to anti-VEGF therapy. Rather than presenting cellular senescence as a fully established causal driver, this review frames senescence-associated remodeling as a context-dependent, evidence-stratified amplifying component within this proposed feed-forward framework.

Research into biomarkers has transformed the identification and management of many diseases. Keratoconus (KC) is a multifactorial corneal ectasia, and due to limited understanding of disease pathophysiology, no biomarkers have been fully validated. microRNAs (miRNAs) are involved in regulating gene expression. Differentially expressed miRNAs have been reported in KC corneal tissue and as biomarkers for other ocular disorders. Salivary biomarkers mirror systemic processes and saliva contains substantial miRNAs. However, it is unknown if salivary miRNAs are differentially expressed in KC. Salivary miRNAs were collected from healthy (n = 16) and KC subjects (n = 50) and measured by qRT-PCR. Upregulated gene expression of miR-939-5p, miR-26a-5p, miR-25-3p, and miR-92a-3p; and downregulated expression of miR-320a was observed. Bioinformatic analysis using Ingenuity Pathway Analysis identified 248 experimental validated miRNA target genes and an enriched subset of 16 genes uniquely related to KC corneal functions. Gene ontology analysis demonstrated the over-representation of genes involved in protein kinase complex, protein phosphorylation, cellular senescence, apoptosis, and stress response. Our data detected previously unknown KC-dependent dysregulation of salivary miRNA expression. Future studies are warranted to determine the viability of these miRNAs as possible KC biomarkers, and to further establish their pathophysiological function.

Traumatic brain injury is a widespread health concern that annually affects millions of people worldwide, with blast-mediated TBI (bTBI) being of particular relevance to military personnel and civilians in war zones. Current treatments primarily target symptoms, rather than the underlying neuropathology, and are ultimately limited by the need for an improved etiological understanding of TBI. Here, we utilized a pre-clinical mouse model of bTBI, previously shown to evoke a high susceptibility to retinal ganglion cell (RGC) death, to investigate whether neuroinflammatory pathways associated with the complement factor 1q (C1q) complex contribute to RGC death. To test this, C57BL/6J (B6) mice with genetic knock-out of C1qa (B6.C1qa[ko]) were exposed to bTBI, or sham control, with subsequent comparisons of RGC survival at durations of 5- and 16-weeks following exposure. Survival metrics consisted of quantifying RGC somas from immunostained retinal flat-mounts and axons from histochemically stained optic nerve cross sections. Relative to sham controls, no significant differences in the abundance of RGC somas in retina or axons in the optic nerve were detected in B6.C1qa[ko] mice at either 5- or 16-weeks after bTBI exposure. These results demonstrate that loss of C1qa confers robust and persistent neuroprotection of RGCs and identify a C1q-dependent neuroinflammatory mechanism that contributes to pathways of neuronal death that are similar to other forms of neurodegeneration, particularly glaucoma.