Hydroxyl radicals cause fluctuation in intracellular ferrous ion levels upon light exposure during photoreceptor cell death

Imamura, Tomoyo; Hirayama, Tasuku; Tsuruma, Kazuhiro; Shimazawa, Masamitsu; Nagasawa, Hideko; Hara, Hideaki

doi:10.1016/j.exer.2014.10.019

Cited by 24 publications

(16 citation statements)

References 31 publications

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“…An earlier study from our laboratory showed that reactive oxygen species (ROS) was produced at 6 h after light irradiation (Imamura et al . ). The nuclear extracts of 661W cells with or without RS9 exposure were examined by EMSA, and the results showed there was a higher binding of the nuclear proteins isolated from 661W cells exposed to RS9 to an oligonucleotide probe than to the nuclear proteins isolated from 661W cells exposed to the vehicle (Fig.…”

Section: Resultsmentioning

confidence: 97%

RS9, a novel Nrf2 activator, attenuates light‐induced death of cells of photoreceptor cells and Müller glia cells

Inoue

Shimazawa

Noda

et al. 2017

Journal of Neurochemistry

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The retina is highly sensitive to oxidative stress because of its high consumption of oxygen associated with the phototransductional processes. Recent findings have suggested that oxidative stress is involved in the pathology of age-related macular degeneration, a progressive degeneration of the central retina. A well-known environmental risk factor is light exposure, as excessive and continuous light exposure can damage photoreceptors. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a transcriptional factor that controls antioxidative responses and phase 2 enzymes. Thus, we hypothesized that RS9, a specific activator of Nrf2, decreases light-induced retinal cell death in vivo and in vitro. Nrf2 was detected in the nucleus of the 661W cells exposed to RS9 and also after light exposure, and the Nrf2-antioxidant response element binding was increased in 661W cells after exposure to RS9. Consequentially, the expression of the phase 2 enzyme's mRNAs of Ho-1, Nqo-1, and Gclm genes was increased in 661W cells after exposure to RS9. Furthermore, RS9 decreased the light-induced death of 661W cells (2500 lux, 24 h), and also reduced the functional damages and the histological degeneration of the nuclei in the outer nuclear layer or the retina in the in vivo studies (8000 lux, 3 h). Heme oxygenase-1 was increased after light exposure, and Nrf2 was translocated into the nucleus after light exposure in vivo. Silencing of Ho-1 reduced the protective effects of RS9 against light-induced death of 661W cells. These findings indicate that RS9 has therapeutic potential for retinal diseases that are aggravated by light exposure.

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Section: Resultsmentioning

confidence: 97%

RS9, a novel Nrf2 activator, attenuates light‐induced death of cells of photoreceptor cells and Müller glia cells

Inoue

Shimazawa

Noda

et al. 2017

Journal of Neurochemistry

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“…Previously, it was reported that oxidative stress causes fluctuation of redox balance of Fe 2+ during light-induced retinal cell death in a cellular model of aged-macular degradation. 38 As stability of Fe 2+ in aqueous buffer is highly dependent on concentration of dissolved oxygen, 6 , 8 it was hypothesized that intracellular redox balance between Fe 2+ /Fe 3+ could be altered under hypoxic conditions. An imaging study was conducted to evaluate intracellular fluctuation of labile Fe 2+ under various oxygen concentrations (1%, 5%, and 20% O 2 ) at various time points (2 h, 4 h, 8 h, and 12 h) using SiRhoNox-1 as an indicator of labile Fe 2+ ( Fig.…”

Section: Resultsmentioning

confidence: 99%

A universal fluorogenic switch for Fe(ii) ion based on N-oxide chemistry permits the visualization of intracellular redox equilibrium shift towards labile iron in hypoxic tumor cells

et al. 2017

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“…Previous studies have implicated light-induced damage in the progression of retinal degeneration focusing on the consequences of light-induced damage on cell function and homeostasis in the retina, noting changes in neural morphology, photoreceptor responsiveness, along with the induction of apoptosis 14 15 16 . It is well known that a consequence of photo-oxidative stress is an increase in the production of reactive lipid aldehydes, primarily 4HNE, leading to lipid peroxidation of retinal tissues and cytotoxic protein modifications in retinal cells 17 .…”

Section: Resultsmentioning

confidence: 99%

A novel AhR ligand, 2AI, protects the retina from environmental stress

Gutierrez

Davis

Rosko

et al. 2016

Sci Rep

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Various retinal degenerative diseases including dry and neovascular age-related macular degeneration (AMD), retinitis pigmentosa, and diabetic retinopathy are associated with the degeneration of the retinal pigmented epithelial (RPE) layer of the retina. This consequently results in the death of rod and cone photoreceptors that they support, structurally and functionally leading to legal or complete blindness. Therefore, developing therapeutic strategies to preserve cellular homeostasis in the RPE would be a favorable asset in the clinic. The aryl hydrocarbon receptor (AhR) is a conserved, environmental ligand-dependent, per ARNT-sim (PAS) domain containing bHLH transcription factor that mediates adaptive response to stress via its downstream transcriptional targets. Using in silico, in vitro and in vivo assays, we identified 2,2′-aminophenyl indole (2AI) as a potent synthetic ligand of AhR that protects RPE cells in vitro from lipid peroxidation cytotoxicity mediated by 4-hydroxynonenal (4HNE) as well as the retina in vivo from light-damage. Additionally, metabolic characterization of this molecule by LC-MS suggests that 2AI alters the lipid metabolism of RPE cells, enhancing the intracellular levels of palmitoleic acid. Finally, we show that, as a downstream effector of 2AI-mediated AhR activation, palmitoleic acid protects RPE cells from 4HNE-mediated stress, and light mediated retinal degeneration in mice.

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Hydroxyl radicals cause fluctuation in intracellular ferrous ion levels upon light exposure during photoreceptor cell death

Cited by 24 publications

References 31 publications

RS9, a novel Nrf2 activator, attenuates light‐induced death of cells of photoreceptor cells and Müller glia cells

RS9, a novel Nrf2 activator, attenuates light‐induced death of cells of photoreceptor cells and Müller glia cells

A universal fluorogenic switch for Fe(ii) ion based on N-oxide chemistry permits the visualization of intracellular redox equilibrium shift towards labile iron in hypoxic tumor cells

A novel AhR ligand, 2AI, protects the retina from environmental stress

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