Temporary alleviation of MAPK by arbutin alleviates oxidative damage in the retina and ARPE-19 cells

Age-related macular degeneration (AMD) is the most common cause of irreversible loss of central vision in elderly subjects, affecting men and women equally. It is a degenerative pathology that causes progressive damage to the macula, the central and most vital part of the retina. There are two forms of AMD depending on how the macula is damaged, dry AMD and wet or neovascular AMD. Dry AMD is the most common form; waste materials accumulate under the retina as old cells die, not being replaced. Wet AMD is less common, but can lead to vision loss much more quickly. Wet AMD is characterized by new abnormal blood vessels developing under the macula, where they do not normally grow. This frequently occurs in patients who already have dry AMD, as new blood vessels are developed to try to solve the problem. It is not known what causes AMD to develop; however, certain risk factors (i.e., age, smoking, genetic factors) can increase the risk of developing AMD. There are currently no treatments for dry AMD. There is evidence that not smoking, exercising regularly, eating nutritious food, and taking certain supplements can reduce the risk of acquiring AMD or slow its development. The main treatment for wet AMD is inhibitors of VEGF (vascular endothelial growth factor), a protein that stimulates the growth of new blood vessels. VEGF inhibitors can stop the growth of new blood vessels, preventing further damage to the macula and vision loss. In most patients, VEGF inhibitors can improve vision if macular degeneration is diagnosed early and treated accordingly. However, VEGF inhibitors cannot repair damage that has already occurred. Current AMD research is trying to find treatments for dry AMD and other options for wet AMD. This review provides a summary of the current evidence regarding the different treatments aimed at both forms of AMD with particular and greater attention to the dry form.

Age related macular degeneration (AMD) is the leading cause of blindness and visual disability among old patients in Europe and North America. AMD has been divided into two broad clinical categories depending on whether there is a presence of abnormal neovascularization: neovascular (exudative or wet) AMD and dry (or geographic atrophic) AMD. VEGF has been understood as a pathogenesis of wet AMD which allows us to get breakthroughs in treatment. While the progression of dry AMD treatment is very slow because the lack of pathogenesis, no acute loss of vision, and without appropriate standards for treatment. This review tries to introduce about the recent researches and progressions for dry AMD treatment.

Oxidative stress to retinal pigment epithelial (RPE) cells is thought to play a critical role in the pathogenesis of age-related macular degeneration (AMD). This study was conducted to investigate whether clusterin protects human RPE cells from ROS-induced apoptosis through a PI3K/Akt survival pathway. The preventive effect of clusterin on reactive oxygen species (ROS) production and RPE cell death induced by hydrogen peroxide was determined in ARPE-19 cells. The ability of clusterin to protect RPE cells against ROS-mediated apoptosis was assessed by caspase-3 activity and DAPI staining. Furthermore, the protective effect of clusterin via the PI3K/Akt pathway was determined by Western blot analysis. Clusterin prevented ARPE-19 cells from H(2)O(2)-induced cell death and ROS production. H(2)O(2)-induced oxidative stress increased caspase-3 activity, which was significantly inhibited by clusterin, as determined by the abrogation of apoptotic bodies. Interestingly, clusterin induced Akt phosphorylation in human RPE cells under oxidative stress, which contributed to cell viability in ARPE-19 cells. This cell survival by clusterin was blocked by a PI3K inhibitor. Clusterin may play a protective role in responding to the local redox environment of human RPE cells, which contributes to the cell survival via the PI3K/Akt pathway. Therefore, clusterin could be considered for the preventive approach to AMD.

PARP1 Impedes SIRT1-Mediated Autophagy during Degeneration of the Retinal Pigment Epithelium under Oxidative Stress.

Mangiferin is a kind of natural xanthone glycosides and is known to have various pharmacological activities. However, since the beneficial efficacy of this compound has not been reported in retinal pigment epithelial (RPE) cells, this study aimed to evaluate whether mangiferin could protect human RPE ARPE-19 cells from oxidative injury mimicked by hydrogen peroxide (H2O2). The results showed that mangiferin attenuated H2O2-induced cell viability reduction and DNA damage, while inhibiting reactive oxygen species (ROS) production and preserving diminished glutathione (GSH). Mangiferin also antagonized H2O2-induced inhibition of the expression and activity of antioxidant enzymes such as manganese superoxide dismutase and GSH peroxidase, which was associated with inhibition of mitochondrial ROS production. In addition, mangiferin protected ARPE-19 cells from H2O2-induced apoptosis by increasing the Bcl-2/Bax ratio, decreasing caspase-3 activation, and blocking poly(ADP-ribose) polymerase cleavage. Moreover, mangiferin suppressed the release of cytochrome c into the cytosol, which was achieved by interfering with mitochondrial membrane disruption. Furthermore, mangiferin increased the expression and activity of heme oxygenase-1 (HO-1) and nuclear factor-erythroid-2 related factor 2 (Nrf2). However, the inhibition of ROS production, cytoprotective and anti-apoptotic effects of mangiferin were significantly attenuated by the HO-1 inhibitor, indicating that mangiferin promoted Nrf2-mediated HO-1 activity to prevent ARPE-19 cells from oxidative injury. The results of this study suggest that mangiferin, as an Nrf2 activator, has potent ROS scavenging activity and may have the potential to protect oxidative stress-mediated ocular diseases.

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly population, and Dry AMD is the most common clinical subtype. However, effective measures for the early diagnosis and treatment of dry AMD have not been proposed. In recent years, NOD-like receptors (NLRs) have received attention in the study of AMD as an important class of pattern recognition receptors. We attempted to elucidate the pathogenesis of NLRs in dry AMD from the perspective of chronic inflammation. This study involved 13 patients with dry AMD, 10 age- and sex-matched normal population without any history of disease and 8 patients with wet AMD as controls. Using RT-qPCR, the mRNA expression levels of NLRs in peripheral blood peripheral blood mononuclear cells (PBMCs) were compared to analyze the statistical differences in the expression contents among the three populations. The relative RNA expression of nucleotide-binding oligomerization-like receptor protein 12 (NLRP12) with negative regulation of inflammation was significantly lower in dry AMD patients than in normal people and wet AMD patients. And NLRX1, which also has an anti-inflammatory effect, was lower in dry AMD patients than in wet AMD patients. However, NLRP3 with proinflammatory effect was significantly expressed in wet AMD. The significant decrease in NLRP12 in dry AMD may become a breakthrough in the study of dry AMD and systemic chronic inflammatory response. However, NLRP3 may have a more important role in wet AMD.

Objective: To investigate any relationships between exfoliation syndrome or exfoliation glaucoma and age-related macular degeneration utilizing the Utah population database. Design: This was a retrospective, case–control cohort study. Subjects, Participants, and/or Controls: We identified 3405 patients diagnosed with exfoliation syndrome (XFS) or exfoliation glaucoma (XFG) during a dilated eye exam within the UHealth system from 1996 to 2021, whose dry or wet age-related macular degeneration (AMD) status was assessed. A population-based control pool of 257,714 UHealth patients with no XFS/XFG diagnosis and a dilated eye exam history from 1996 to 2021 was compiled, with its patients randomly selected and individually matched 3:1 to cases based on sex and age at index diagnosis of their respective case. Methods: A covariate analysis was performed of characteristics and risk factors associated with XFS/XFG, which included race/ethnicity, residence location, partner/marital status, and family history of XFS/XFG, obesity, tobacco use, alcohol use, osteoporosis/vitamin D deficiency, primary/essential hypertension, ocular hypertension, and cataract surgery. Main Outcome Measure: We studied the trends of non-exudative (dry) or exudative (wet) AMD in a large Utah population study of XFS/XFG patients and controls. Results: Of 3396 XFS/XFG patients, as well as 10,179 individually matched 3:1 control patients, 64% were female and the average age of XFS onset was 74.3 yrs. In a univariate model, we observed a very modest increased risk of wet AMD in XFS/XFG patients (odds ratio, OR = 1.14, 95% confidence interval (CI) 0.99–1.32), which did not achieve statistical significance (p = 0.07). After adjusting for the main effects of potential confounders, there was no greater presentation of AMD in XFS/XFG patients when compared with controls (dry AMD: OR = 0.94, 95% CI 0.85–1.05, p = 031; wet AMD: OR = 0.98, 95% CI 0.83–1.14, p = 0.76). In XFS/XFG patients compared to controls, the risk of having cataract surgery was elevated (OR = 2.39, 95% CI 2.18–2.62). However, after accounting for an interaction with AMD, XFS/XFG patients who underwent cataract surgery did not exhibit an increased risk of either dry or wet AMD (dry AMD: OR = 0.91, 95% CI 0.80–1.03; wet AMD: OR = 0.89, 95% CI 0.75–1.07). The risk of AMD in XFS/XFG patients vs. controls showed no association with osteoporosis/vitamin D deficiency for dry (OR 0.78 95% CI 0.66–0.92 p = 0.004) or wet AMD (OR = 0.72 95% CI 0.56–0.92 p = 0.01), while we found a borderline positive association with both dry and wet AMD if they had osteoporosis/vitamin D deficiency. Conclusion: Using the Utah Population Database, we found that a cataract surgery history significantly impacts the association between AMD and XFS, and that vitamin D deficiency/osteoporosis is a significant confounder of the association. However, no direct association between XFS and AMD was found in this study.

Purpose This study aims to evaluate the association between age-related macular degeneration (AMD) and cardiovascular disease by using the noninvasive flow-mediated dilation (FMD) test to show endothelial dysfunction as an indicator of subclinical atherosclerosis. Method Participants in this study included 30 dry AMD patients, 30 wet AMD patients, and 30 healthy controls without any systemic disease, including AMD. FMD and the intima media thickness (IMT) of the carotid artery were compared between the groups. Results Comparison of FMD between the groups showed a 10.96% brachial artery dilation in the healthy controls, 3.99% in the dry AMD group, and 5.03% in the wet AMD group. While a significant difference was not observed between the wet and dry AMD groups, comparison of the control group to the wet and dry AMD groups yielded a significant difference. When brachial artery dilation below 7% was accepted as an abnormal FMD, 26.7% of the healthy controls, 66.7% of the dry AMD patients and 76.7% of the wet AMD patients were found to be abnormal. Similarly, while no significant difference was observed between the wet and dry AMD groups, comparison of the control group with the wet and dry AMD patients yielded a significant difference. When an IMT below 0.7 mm was accepted as abnormal, 26.7% of the healthy controls, 33.3% of the dry AMD, and 43.3% of the wet AMD were found to have an abnormal IMT. However, differences between the groups did not reach statistical significance. Conclusions In this study, use of the FMD test showed endothelial dysfunction among AMD patients. No significant differences were found between the dry and wet AMD patient groups.

Oxya chinensis sinuosa (OC) is a well-known edible insect. Several researches on the health benefits of OC consumption have been performed to date; however, their effect on eye health remains largely unknown. This study aimed to assess the protective effects of OC extracts on the oxidative stress on the retinal pigment epithelium (RPE) cells. Oxidative damage has been identified as one of the key regulatory factors in age-related macular degeneration. H2O2-induced reactive oxygen species (ROS) production, a well-known oxidative stress factor, can cause cell death in retinal pigment epithelia cells. In this study, we found that three OC extracts effectively prevented H2O2-induced ROS production and subsequent death of ARPE-19 cells in a dose-dependent manner. In addition, the OC extracts inhibited the phosphorylation of mitogen-activated protein kinases including p38, JNK, and ERK. The OC extracts restored IκBα degradation induced by H2O2, indicating that OC extracts suppressed the activation of nuclear factor-κB. Furthermore, the three OC extracts were shown to have antioxidant effects by up-regulating the intracellular expression of key antioxidant proteins such as SOD, NQO, and HO-1. Here we demonstrated the antioxidant and anti-apoptotic effects of the OC extracts on ARPE-19, indicating their potential role in improving eye health. These results suggest that three OC extracts plays a critical role in oxidative stress-induced cell death protects in ARPE-19 cells.

Although reactive oxygen species (ROS) basically play beneficial roles to maintain host homeostasis against external disturbance/stress including infection, excessive ROS generation by activated neutrophils can sometimes cause organ damage. We investigated the role of burn-induced ROS generation in the injured hosts, focusing on postburn infection. C57BL/6 mice received a 20% full-thickness burn injury. In these mice, the burn-induced ROS generation was inhibited during and immediately after injury by pretreatment with superoxide dismutase (at 1 h before and immediately before injury), or the subsequent ROS production was inhibited posttreatment with superoxide dismutase (at 1 and 2 h after injury), which could not scavenge the ROS produced immediately after injury. As expected, inhibition of ROS production during/immediately after injury reduced the burn-induced pulmonary damage at 6 h, whereas inhibition of the subsequent ROS production did not lead to any improvements. Burn injury rendered the mice susceptible to bacterial infection at 5 days after injury and impaired bactericidal activity of neutrophils. Nevertheless, inhibition of the ROS production during/immediately after injury did not improve the burn-induced susceptibility to infection or the neutrophil dysfunction. Interestingly, inhibition of the subsequent ROS production potently restored the neutrophil functions and hematopoietic function of the bone marrow myelocytes, thereby improving the postburn infection. Thus, although the inhibition of burn-evoked ROS generation is effective against burn-induced organ injury, it may be ineffective against postburn infection. Preservation of the immediate burn-evoked ROS production, but the inhibition of subsequent ROS production, may be crucial to protect against postburn infection.

Age-related macular degeneration (AMD) is a significant visual impairment in older people, and there is no treatment for dry AMD. Spirulina maxima (S. maxima), a cyanobacterium, has inhibitory effects against oxidative stress. However, the protective effects of S. maxima and its underlying mechanisms on blue light (BL)-caused macular degeneration are unknown. We aimed to investigate the protective effects of S. maxima on blue light-caused retinal damage and demonstrate its underlying mechanisms in human retinal pigment epithelial (ARPE-19) cells and Balb/c retinas. Additionally, the active component of S. maxima was examined in the RPE cells. In vitro, S. maxima decreased BL-induced RPE cell death by inhibiting reactive oxygen species (ROS) production. S. maxima inhibited BL-induced inflammation via regulating the NF-κB pathway, inflammatory-related gene expression, and the apoptosis pathway in RPE cells. In vivo, administration of S. maxima inhibited BL-induced retinal degeneration by restoring the thicknesses of whole retina, ONL (outer nuclear layer), INL (inner nuclear layer), and PL (photoreceptor layer) by BL exposure. Phycocyanin exerted protective effects in the pre-and post-treatment system. Therefore, S. maxima could be a potential nutraceutical approach to intercept the patho-physiological processes leading to dry AMD and advancement to wet AMD. Moreover, phycocyanin was a major active compound of S. maxima. These findings need to be investigated in human studies, particularly through a clinical trial.

4-Hydroxy-7-oxo-5-heptenoic acid (HOHA) lactone induces apoptosis in retinal pigment epithelial cells

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss among the population above 85 worldwide. There are two main types of AMD: neovascular and dry AMD. Neovascular AMD leads to macular changes resulting from abnormal choroidal neovascularization. Untreated neovascular AMD leads to scar formation and irreversible sight deterioration. Dry AMD in consequence leads to atrophic changes of the macula.The last decades brought a breakthrough in the therapy of neovascular age-related macular degeneration by introduction of, firstly, photodynamic therapy and, later, anti-VEGF agents administered intravitreally in order to stop neoangiogenesis. However, the treatment of dry AMD is still challenging. Among the directions in dry AMD treatment, the most promising are complement cascade inhibitors and complement cascade targeted gene therapy.In the article we outline the main directions in up-to-date experimental and practical approaches to wet and dry AMD therapy with the emphasis on antiangiogenic factors and gene therapy focused on the inhibition of pathological angiogenesis.

To assess the reliability and the diagnostic performance of a novel CE (European Conformity)-marked and FDA (Food and Drug Administration)-cleared dot patient self-monitoring test (Alleye, Oculocare medical Inc.) for the detection and characterization of metamorphopsia in age-related macular degeneration (AMD). Three consecutive tests were performed in 63 wet AMD, 26 dry AMD, and 19 age-matched healthy eyes. In addition, the test was performed in 34 young healthy eyes. The mean Alleye score and standard deviations (SDs) were calculated for each eye and group. We compared and tested healthy with dry and wet AMD eyes and assessed the extent to which the test discriminated between healthy subjects and patients with dry and wet AMD using the area under the receiver operating characteristic curve (AUC). The mean (SD) Alleye score was 49.5 (16.1) in wet AMD eyes, 62.1 (22.5) in dry AMD eyes, 69.8 (10.2) in age-matched healthy eyes, and 85.3 (10.0) in young healthy subjects. Compared to age-matched healthy subjects, the AUC (95% confidence interval) to detect wet AMD was 0.845 (0.759-0.932), and 0.660 (0.520-0.799) to discriminate between dry and wet AMD. Compared to young healthy subjects, the AUC to detect dry AMD was 0.799 (0.675-0.923), and 0.969 (0.940-0.997) to detect wet AMD. This is the first assessment of Alleye in clinical practice. The test is highly accurate to detect wet AMD and reasonably accurate to classify dry vs. wet AMD. Data from longitudinal monitoring and its role in the therapeutic management of AMD is warranted.

Purpose: The lack of suitable animal models for (dry) age-related macular degeneration (AMD) has hampered therapeutic research into the disease, so far. In this study, pigmented rats and mice were systematically injected with various doses of sodium iodate (SI). After injection, the retinal structure and visual function were non-invasively characterized over time to obtain in-depth data on the suitability of these models for studying experimental therapies for retinal degenerative diseases, such as dry AMD. Methods: SI was injected into the tail vein (i.v.) using a series of doses (0–70 mg/kg) in adolescent C57BL/6J mice and Brown Norway rats. The retinal structure and function were assessed non-invasively at baseline (day 1) and at several time points (1–3, 5, and 10-weeks) post-injection by scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT), and electroretinography (ERG). Results: After the SI injection, retinal degeneration in mice and rats yielded similar results. The lowest dose (10 mg/kg) resulted in non-detectable structural or functional effects. An injection with 20 mg/kg SI did not result in an evident retinal degeneration as judged from the OCT data. In contrast, the ERG responses were temporarily decreased but returned to baseline within two-weeks. Higher doses (30, 40, 50, and 70 mg/kg) resulted in moderate to severe structural RPE and retinal injury and decreased the ERG amplitudes, indicating visual impairment in both mice and rat strains. Conclusions: After the SI injections, we observed dose-dependent structural and functional pathological effects on the retinal pigment epithelium (RPE) and retina in the pigmented mouse and rat strains that were used in this study. Similar effects were observed in both species. In particular, a dose of 30 mg/kg seems to be suitable for future studies on developing experimental therapies. These relatively easily induced non-inherited models may serve as useful tools for evaluating novel therapies for RPE-related retinal degenerations, such as AMD.