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Age‑related macular degeneration (AMD) is an ocular disease that threatens the visual function of older adults worldwide. Key pathological processes involved in AMD include oxidative stress, inflammation and choroidal vascular dysfunction. Retinal pigment epithelial cells and Müller cells are most susceptible to oxidative stress. Traditional herbal medicines are increasingly being investigated in the field of personalized medicine in ophthalmology. Triptonide (Tn) is a diterpene tricyclic oxide, the main active ingredient in the extract from the Chinese herbal medicinal plant Tripterygium wilfordii , and is considered an effective immunosuppressant and anti‑inflammatory drug. The present study investigated the potential beneficial role of Tn in retinal oxidative damage in order to achieve personalized treatment for early AMD. An oxidative stress model of retinal cells induced by H 2 O 2 and a retinal injury model of mice induced by light and N‑Methyl‑D‑aspartic acid were constructed. In vitro , JC‑1 staining, flow cytometry and apoptosis assay confirmed that low concentrations of Tn effectively protected retinal cells from oxidative damage, and reverse transcription‑quantitative PCR and western blotting analyses revealed that Tn reduced the expression of retinal oxidative stress‑related genes and inflammatory factors, which may depend on the PI3K/AKT/mTOR‑induced Nrf2 signaling pathway. In vivo , by retinal immunohistochemistry, hematoxylin and eosin staining and electroretinogram assay, it was found that retinal function and structure improved and choroidal neovascularization was significantly inhibited after Tn pretreatment. These results suggested that Tn is an efficient Nrf2 activator, which can be expected to become a new intervention for diseases such as AMD, to inhibit retinal oxidative stress damage and pathological neovascularization.

Several microRNAs (miRNAs) expressed in the retina were confirmed to involve in retinal cell apoptosis, which was closely linked with the development of retinal diseases. Our previous studies have confirmed a vital role of miR-187 in retinal cells apoptosis. The aim of this study was to further elucidate the precise role of miR-187 and its probable mechanisms in RGC-5 cells apoptosis. The cellular oxidative stress status was assessed by reactive oxygen species (ROS) production and malondialdehyde (MDA) level. Our results showed that the elevated pressure, glutamate and H 2 O 2 -induced oxidative stress in RGC-5 cells was accompanied by a decrease in miR-187 expression and an increase in P2X7R expression. However, overexpression of miR-187 reversed this activation of oxidative stress in RGC-5 cells. Moreover, we also revealed that miR-187 inhibited the oxidative stress-induced apoptosis of RGC-5 cells through negative regulating P2X7R, probably through interacting with the 3'UTR of P2X7R. Finally, we confirmed that the forced miR-187 expression alleviated oxidative stress injury in retina tissues of rat models with chronic ocular hypertension. Our data demonstrated that miR-187/P2X7R signaling was involved in retinal cell apoptosis, at least in part, through activating oxidative stress., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Intensified oxidative stress can cause severe damage to human retinal pigment epithelium (RPE) cells and retinal ganglion cells (RGCs). The potential effect of neuroligin-3 (NLGN3) against the process is studied here. Our results show that NLGN3 efficiently inhibited hydrogen peroxide (H 2 O 2 )-induced death and apoptosis in human RPE cells and RGCs. H 2 O 2 -induced reactive oxygen species (ROS) production, lipid peroxidation and DNA damage in retinal cells were alleviated by NLGN3. NLGN3 activated nuclear-factor-E2-related factor 2 (Nrf2) signaling, enabling Nrf2 protein stabilization, nuclear translocation and expression of key anti-oxidant enzymes (HO1, NOQ1 and GCLC) in RPE cells and RGCs. Further results demonstrate that NLGN3 activated Akt-mTORC1 signaling in retinal cells. Conversely, Akt-mTORC1 inhibitors (RAD001 and LY294002) reduced NLGN3-induced HO1, NOQ1 and GCLC mRNA expression. Significantly, Nrf2 silencing by targeted shRNAs reversed NLGN3-induced retinal cytoprotection against H 2 O 2 . We conclude that NLGN3 activates Nrf2 signaling to protect human retinal cells from H 2 O 2 . NLGN3 could be further tested as a valuable retinal protection agent., (Copyright © 2018 Elsevier Inc. All rights reserved.)

During COVID‐19, there was increased use of handheld displays in educational settings. There is growing concern that eye health may be affected by prolonged exposure to the light‐emitting diodes used as frontlights or backlights in handheld displays. The potential impact of light exposure from tablet‐sized devices with different display technologies and various spectral outputs was assessed in an in vitro model using human retinal epithelial (ARPE‐19) cells. Cellular response was quantified by measuring reactive oxidative species (ROS) and by analyzing mitochondrial morphology. Control experiments established a baseline ROS response to hazardous blue light exposure and also that red light resulted in no detectable ROS response. Under identical conditions, ROS response increased with time for all devices. However, different device spectra caused ROS to accumulate at different rates. When operating the devices in the same mode (day or night), cells accumulated ROS two to three times more slowly on exposure to frontlit electronic paper displays compared to backlit liquid crystal displays. With increasing ROS accumulation, mitochondrial morphology shifted from elongate interconnected features typically observed under normal conditions to rounded disconnected features associated with oxidative stress response. [ABSTRACT FROM AUTHOR]

Excessive Ultra-violet (UV) radiation shall induce damages to resident retinal pigment epithelium (RPE) cells (RPEs) and retinal ganglion cells (RGCs). Here we tested the potential activity of Ginsenoside Rh3 (“Rh3”) against the process. In cultured human RPEs and RGCs, pretreatment with Rh3 inhibited UV-induced reactive oxygen species (ROS) production and following apoptotic/non-apoptotic cell death. Rh3 treatment in retinal cells induced nuclear-factor-E2-related factor 2 (Nrf2) activation, which was evidenced by Nrf2 protein stabilization and its nuclear translocation, along with transcription of antioxidant responsive element (ARE)-dependent genes ( HO1 , NOQ1 and GCLC ). Nrf2 knockdown by targeted-shRNA almost abolished Rh3-induced retinal cell protection against UV. Further studies found that Rh3 induced microRNA-141 (“miR-141”) expression, causing downregulation of its targeted gene Keap1 in RPEs and RGCs. On the other hand, Rh3-induced Nrf2 activation and retinal cell protection were largely attenuated by the miR-141's inhibitor, antagomiR-141. In vivo , intravitreal injection of Rh3 inhibited retinal dysfunction by light damage in mice. Rh3 intravitreal injection also induced miR-141 expression, Keap1 downregulation and Nrf2 activation in mouse retinas. We conclude that Rh3 protects retinal cells from UV via activating Nrf2 signaling. [ABSTRACT FROM AUTHOR]

Diabetic patients are at risk of increased morbidity and mortality from macrovascular and microvascular complications. The increased risk of the vascular complications includes genetic factors, hyperglycaemia, hypertension, hyperlipidaemiaand oxidative stress. The mechanisms by which hyperglycaemia causes vision loss and blindness and other diabetic complications include the polyol pathway, accumulation of AGEs, activation of PKC, increased oxidative stress, increased flux through the hexosamine pathway and vascular inflammation. All these pathways play critical roles in the development and progression of diabetic retinopathy and other diabetic complications. There is an individual variation in the presentation and course of diabetic retinopathy, and other diabetes-induced complications. Some patients, after many years with diabetes, never develop sight-threatening retinal changes, thus maintaining good visual acuity. However, there are patients who after only a few years of diabetes show diabetic retinopathy that progresses rapidly and may not respond to available treatment. Some patients do not lose their vision even with poor metabolic control; others develop vision loss despite good metabolic control. The threat of vision loss requires a lot of patient education and psychological support, not only after a loss but also before any loss is recognized by the patient. Care for patients with diabetes requires an understanding that the diabetic eye is an end-organ response to a general metabolic disease. [ABSTRACT FROM AUTHOR]

Abstract: αB-crystallin is a small heat shock protein that exhibits chaperone activity and can protect multiple cell types against oxidative stress damage. Altered levels and specific mutations of αB-crystallin are associated with multiple degenerative diseases. We previously found that αB-crystallin translocates to lens and retinal cell mitochondria upon oxidative stress exposure where it provides protection against oxidative stress damage. To date, the role of the chaperone function of αB-crystallin in mitochondrial translocation and protection has not been established. Here, we sought to determine the relationship between the chaperone activity of αB-crystallin and its ability to translocate to and protect retinal cell mitochondria against oxidative stress damage. Our data provide evidence that three forms of αB-crystallin exhibiting different chaperone activity levels including wild-type, R120G (decreased chaperone activity) and M68A (increased chaperone activity) provide comparable levels of mitochondrial translocation and protection to retinal cells exposed to oxidative stress. The results provide evidence that mitochondrial translocation and protection by αB-crystallin is independent of its chaperone activity and that other functions of αB-crystallin may also be independent of its chaperone activity. [Copyright &y& Elsevier]

Purpose: The purpose of this study was to investigate the role played by platelet-derived growth factor-αα (PDGFRαα) in oxidative stress-induced retinal cell death. A previous proteomic study from our laboratory showed that expression of PDGFRαα is elevated considerably in the retinas of an animal model of glaucoma--the excitatory amino acid carrier (EAAC) 1-deficient (EAAC1-/-) mouse. Methods: Retinal sites and expression patterns of PDGFRαα were determined by immunohistochemistry in the retinas of EAAC1-/- and control CRL:CD1(ICR) mice. A retinal cell line was exposed to hydrogen peroxide, and expression PDGFRαα determined by Western blot analysis. Effects of PDGF-AA and PDGFRαα-siRNA on hydrogen peroxide-induced retinal cell death were examined. Results: PDGFRαα was detected in the retinal ganglion cell layer (RGL) of both EAAC1-/- and ICR mice, and was also localized in the internal nuclear layer (INL) of EAAC1-/- mice. While treatment with excess PDGF-AA had no additional effect on retinal cell death, expression of PDGFRαα increased with exposure to hydrogen peroxide. Hydrogen peroxide-induced retinal cell death was inhibited by exposure to PDGF-AA via phosphatidylinositol 3 kinase (PI3K); cell death was promoted by PDGFRαα-siRNA. Conclusions: PDGFRαα is expressed in mouse retina, where it is essential for retinal cell survival under conditions of oxidative stress. [ABSTRACT FROM AUTHOR]

A long-term ‘memory’ of hyperglycaemic stress, even when glycaemia is normalised, has been previously reported in endothelial cells. In this report we sought to duplicate and extend this finding. HUVECs and ARPE-19 retinal cells were incubated in 5 or in 30 mmol/l glucose for 3 weeks or subjected to 1 week of normal glucose after being exposed for 2 weeks to continuous high glucose. HUVECs were also treated in this last condition with several antioxidants. Similarly, four groups of rats were studied for 3 weeks: (1) normal rats; (2) diabetic rats not treated with insulin; (3) diabetic rats treated with insulin during the last week; and (4) diabetic rats treated with insulin plus α-lipoic acid in the last week. In human endothelial cells and ARPE-19 retinal cells in culture, as well as in the retina of diabetic rats, levels of the following markers of high glucose stress remained induced for 1 week after levels of glucose had normalised: protein kinase C-β, NAD(P)H oxidase subunit p47phox, BCL-2-associated X protein, 3-nitrotyrosine, fibronectin, poly(ADP-ribose) Blockade of reactive species using different approaches, i.e. the mitochondrial antioxidant α-lipoic acid, overexpression of uncoupling protein 2, oxypurinol, apocynin and the poly(ADP-ribose) polymerase inhibitor PJ34, interrupted the induction both of high glucose stress markers and of the fluorescent reactive oxygen species (ROS) probe CM-H2DCFDA in human endothelial cells. Similar results were obtained in the retina of diabetic rats with α-lipoic acid added to the last week of normalised glucose. These results provide proof-of-principle of a ROS-mediated cellular persistence of vascular stress after glucose normalisation. [ABSTRACT FROM AUTHOR]

Oxidative stress is believed to play a significant role in the development of diabetic retinopathy. In this study, we have investigated the effects of elevated glucose concentration on the production of superoxide anion by retina and retinal cells, the cellular source of the superoxide, the effect of therapies that are known to inhibit diabetic retinopathy on the superoxide production, and the role of the superoxide in cell death in elevated glucose concentration. Superoxide release was measured from retinas collected from streptozotocin-diabetic rats (2 months) treated with or without aminoguanidine, aspirin, or vitamin E, and from transformed retinal Mu¨ller cells (rMC-1) and bovine retinal endothelial cells (BREC) incubated in normal (5 mM) and high (25 mM) glucose. Diabetes (retina) or incubation in elevated glucose concentration (rMC-1 and BREC cells) significantly increased superoxide production, primarily from mitochondria, because an inhibitor of mitochondrial electron transport chain complex II normalized superoxide production. Inhibition of reduced nicotinamine adenine dinucleotide phosphate (NADPH) oxidase or nitric oxide synthase had little or no effect on the glucose-induced increase in superoxide. Treatment of diabetic animals with aminoguanidine, aspirin, or vitamin E for 2 months significantly inhibited the diabetes-induced increase in production of superoxide in the retinas. Despite the increased production of superoxide, no increase in protein carbonyls was detected in retinal proteins from animals diabetic for 2–6 months or rMC-1 cells incubated in 25 mM glucose for 5 d unless the activities of calpain or the proteosome were inhibited. Addition of copper/zinc-containing superoxide dismutase to the media of rMC-1 and BREC cells inhibited the apoptotic death caused by elevated glucose. Diabetes-like glucose concentration increases superoxide production in retinal cells, and the superoxide contributes to impaired viability and increased cell death under those circumstances. Three therapies that inhibit the development of diabetic retinopathy all inhibit superoxide production, raising a possibility that these therapies inhibit retinopathy in part by inhibiting a hyperglycemia-induced increase in superoxide production. [Copyright &y& Elsevier]

Acetylcholinesterase (AChE) activity is increased within and around amyloid plaques, which are present in Alzheimer''s disease (AD) patient''s brain. In this study, using cultured retinal cells as a neuronal model, we analyzed the effect of the synthetic peptide Aβ25–35 on the activity of AChE, the degradation enzyme of acetylcholine, as well as the involvement of oxidative stress in this process. The activity of AChE was increased when retinal cells were incubated with Aβ25–35 (25 μM, 24 h) and antioxidants such as α-tocopherol acetate and nitric oxide synthase (NOS) inhibitors were capable of preventing this effect. Despite Aβ25–35 did not affect cell membrane integrity, the redox capacity of cells decreased. The incubation with this amyloidogenic peptide led to an increment of reactive oxygen species formation (20%), of lipid peroxidation (65%), and basal intracellular calcium levels (40%). The data obtained show that the enhancement of AChE activity induced by Aβ25–35 is mediated by oxidative stress, and that vitamin E and NOS inhibitors, by preventing the compromise of the enzyme activity, can have an important role in the maintenance of acetylcholine synaptic levels, thus preventing or improving cognitive and memory functions of AD patients. [Copyright &y& Elsevier]