Somatostatin, a naturally produced neuroprotective peptide, depresses excitatory neurotransmission and exerts anti-proliferative and anti-inflammatory effects on the retina. In this review, we summarize the progress of somatostatin treatment of diabetic retinopathy through analysis of relevant studies published from February 2019 to February 2023 extracted from the PubMed and Google Scholar databases. Insufficient neuroprotection, which occurs as a consequence of declined expression or dysregulation of retinal somatostatin in the very early stages of diabetic retinopathy, triggers retinal neurovascular unit impairment and microvascular damage. Somatostatin replacement is a promising treatment for retinal neurodegeneration in diabetic retinopathy. Numerous pre-clinical and clinical trials of somatostatin analog treatment for early diabetic retinopathy have been initiated. In one such trial (EUROCONDOR), topical administration of somatostatin was found to exert neuroprotective effects in patients with pre-existing retinal neurodysfunction, but had no impact on the onset of diabetic retinopathy. Overall, we concluded that somatostatin restoration may be especially beneficial for the growing population of patients with early-stage retinopathy. In order to achieve early prevention of diabetic retinopathy initiation, and thereby salvage visual function before the appearance of moderate non-proliferative diabetic retinopathy, several issues need to be addressed. These include the needs to: a) update and standardize the retinal screening scheme to incorporate the detection of early neurodegeneration, b) identify patient subgroups who would benefit from somatostatin analog supplementation, c) elucidate the interactions of somatostatin, particularly exogenously-delivered somatostatin analogs, with other retinal peptides in the context of hyperglycemia, and d) design safe, feasible, low cost, and effective administration routes.

Hyperglycemia triggers metabolic and inflammatory responses, which lead to vascular inflammation and consequently induce microvascular and/or macrovascular diabetic complications. 5-bromo-3,4-dihydroxybenzaldehyde (BDB), a marine red algae-derived bromophenol compound, is found to have diverse bioactivities, including the effect of anti-inflammation and anti-diabetes, though the mechanism of which is still unclear. To evaluate the anti-vasculopathy of BDB and explore the possible mechanism involved. Firstly, MTT assay was used to optimize the treatment concentration of glucose and BDB with HUVECs. Subsequently, we adopted two concentrations of BDB (50 µM and 100 µM) to verify the protective effect of BDB on vascular model, which was established by HUVECs from high glucose (30 mM)-induced damage. The cell migration and tube formation were used to evaluate the function of HUVECS. Moreover, the related mechanisms were analyzed by assays for flow cytometry, ELISA, qPCR, intracellular ROS and western blot. The present study demonstrated that BDB could protect endothelial cells from apoptosis caused by high glucose treatment. BDB also significantly reduced the secretion of inflammatory cytokines, such as TNF-α, IL-1β and IL-6, induced by high glucose, which was also in agreement to the decrease of p65 protein expression and activities of NF-ĸB regulated by BDB. The reactive oxygen species (ROS) production and phosphorylation of 38 protein expression were also down-regulated by BDB compared to high glucose alone treatment. Furthermore, BDB reserved the endothelial cells functions of migration and tube formation under high glucose condition, which suggested that BDB could be a potential candidate in treating vascular inflammation induced by hyperglycemia.

Objective: Choroidal neovascularization (CNV) represents the predominant form of advanced wet Age-related Macular Degeneration (wAMD). Macrophages play a pivotal role in the pathological progression of CNV. Meteorin-like (Metrnl), a novel cytokine known for its anti-inflammatory properties in macrophages, is the focus of our investigation into its mechanism of action and its potential to impede CNV progression.Methods: Cell viability was evaluated through CCK-8 and EdU assays following Metrnl treatment. Expression levels of inflammatory cytokines and proteins were assessed using quantitative reverse‐transcription polymerase chain reaction(qRT‐PCR), enzyme-linked immunosorbent assay (ELISA), and western blot techniques. Protein-protein interactions were identified through protein mass spectrometry and co-immunoprecipitation (Co‐IP). Additionally, in vivo and in vitro neovascularization models were employed to evaluate angiogenesis.Results: Our results revealed downregulated Metrnl levels in the choroid-sclera complex of CNV mice, the aqueous humor of wAMD patients, and activated macrophages. Metrnl overexpression demonstrated a reduction in pro-inflammatory cytokine production, influenced endothelial cell function, and suppressed angiogenesis in choroid explants and CNV models. Through protein mass spectrometry and Co‐IP, we confirmed Metrnl binds to UCHL-1 to modulate the NF-κB signaling pathway. This interaction inhibited the transcription and expression of pro-inflammatory cytokines, ultimately suppressing angiogenesis.Conclusion: In summary, our findings indicate that Metrnl down-regulates macrophage pro-inflammatory cytokine secretion via the UCHL-1/NF-κB signaling pathway. This mechanism alleviates the inflammatory microenvironment and effectively inhibits choroidal neovascularization.

Diabetic retinopathy (DR) is a leading cause of blindness characterized by damage to the retinal neurovascular unit, which is caused by hyperglycemia-induced metabolic and inflammatory responses. 5-Bromo-3,4-dihydroxybenzaldehyde (BDB) is a compound derived from marine red algae and known for its anti-inflammatory effects. This study aimed to investigate the potential protective effects of BDB on DR using primary human retinal vascular endothelial cells and retinal tissue explants. The analysis involved assessing vascular integrity, expression of tight junction protein, hyperglycemia-induced permeability, and retinal ganglion cell (RGC) apoptosis. The protective effect of BDB in maintaining the diabetic retinal neurovascular units was verified using type 1 diabetic mouse models. Additionally, the inhibitory effect of BDB on the levels of inflammatory cytokines TNF-α, IL-1β, and IL-6 were examined. In vitro experiments revealed that BDB promoted vascular integrity, inhibited the transcription of pro-inflammatory factors, and alleviated hyperglycemia-induced permeability. BDB also protected RGC from hyperglycemia-induced apoptosis. In diabetic mice models, BDB treatment maintained the integrity of diabetic retinal neurovascular units and inhibited the secretion of TNF-α, IL-1β, and IL-6. BDB demonstrated a protective effect on DR by inhibiting the secretion of inflammatory factors, suggesting its potential as a therapeutic agent for the treatment of DR. Further research is warranted to validate its safety and efficacy for clinical application.

With rising life expectancy, age-related diseases such as age-related macular degeneration (AMD) increasingly threaten the quality of life in older adults. This chapter contributes to the discourse on longevity and geriatrics by focusing on strategies to preserve vision, a key determinant of independence in aging populations. AMD, a progressive neurodegenerative retinal disease, is a leading cause of vision loss in the elderly. The dry form (dAMD), which accounts for 85–90% of cases, is marked by drusen accumulation beneath the retinal pigment epithelium (RPE), leading to RPE and photoreceptor degeneration. Its pathogenesis involves a multifactorial interplay of aging, genetic predisposition, oxidative stress, and immune dysregulation. Currently, there are no effective treatments for dAMD; anti-complement therapies for geographic atrophy (GA), the late stage of dAMD, have shown limited functional benefit in patients. Topical therapies offer promising advantages, including non-invasiveness, localized action, reduced systemic toxicity, and potential for cost-effective, patient-friendly interventions. However, developing effective eye drop formulations for dAMD remains a significant challenge, largely due to limited drug penetration to the posterior segment of the eye. Advances in understanding dAMD pathophysiology, coupled with novel delivery platforms, are essential to circumventing these barriers. A growing pipeline of small molecules and peptides targeting inflammation, autophagy, mitochondrial dysfunction, amyloid-beta toxicity, and choroidal circulation is currently under preclinical and clinical investigation. This chapter reviews the evolving therapeutic landscape for dAMD, emphasizing the potential of topical treatments to enhance patient care and support healthy aging.