bims-mideyd 2024-09-29 papers

J Photochem Photobiol B. 2024 Sep 24. pii: S1011-1344(24)00197-0. [Epub ahead of print]260 113037

Maintaining KEAP1 levels in retinal pigment epithelial cells preserves their viability during prolonged exposure to artificial blue light.

Ching-Hao Li, Tsung-Min Yang, Ida Fitriana, Te-Chao Fang, Liang-Huan Wu, George Hsiao, Yu-Wen Cheng.

Exposure to artificial blue light, one of the most energetic forms of visible light, can increase oxidative stress in retinal cells, potentially enhancing the risk of macular degeneration. Retinal pigment epithelial (RPE) cells play a crucial role in this process; the loss of RPE cells is the primary pathway through which retinal degeneration occurs. In RPE cells, Kelch-like ECH-associated protein 1 (KEAP1) is located in both the nucleus and cytosol, where it binds to nuclear factor erythroid 2-related factor 2 (NRF2) and p62 (sequestosome-1), respectively. Blue light exposure activates the NRF2-heme oxygenase 1 (HMOX1) axis through both canonical and noncanonical p62 pathways thereby reducing oxidative damage, and initiates autophagy, which helps remove damaged proteins. These protective responses may support the survival of RPE cells. However, extended exposure to blue light drastically decreases the viability of RPE cells. This exposure diminishes the ability of KEAP1 to bind to p62 and reduces the level of KEAP1. Inhibition of autophagy does not prevent KEAP1 degradation, the NRF2-HMOX1 axis, or blue-light-induced cytotoxicity. However, proteasome inhibitor along with a transient increase in the amount of KEAP1 in RPE cells, partially restores the p62-KEAP1 complex and reduces blue-light-induced cytotoxicity. In vivo studies confirmed the downregulation of KEAP1 in damaged RPE cells. Mice subjected to periodic blue light exposure exhibited significant atrophy in the outer retina, particularly in the peripheral areas. Additionally, there was a significant decrease in c-wave electroretinography and pupillary light reflex, indicating functional impairments in both visual and nonvisual physiological processes. These data underscore the essential role of KEAP1 in managing oxidative defense and autophagy pathways triggered by blue light exposure in RPE cells.

Keywords: Autophagy; Blue light; KEAP1; Retinal pigment epithelial cell; p62/sequestosome-1

DOI: https://doi.org/10.1016/j.jphotobiol.2024.113037

Int Immunopharmacol. 2024 Sep 19. pii: S1567-5769(24)01689-8. [Epub ahead of print]142(Pt B): 113167

Small molecule SIRT1 activators counteract oxidative stress-induced inflammasome activation and nucleolar stress in retinal degeneration.

Mengyao Li, Qian Xu, Qian Fan, Haiming Li, Yu Zhang, Fan Jiang, Yi Qu.

BACKGROUND: The nicotinamide adenosine dinucleotide-dependent deacetylase Sirtuin 1 (SIRT1) has been identified as a protective factor that inhibits the activation of nucleotide-binding and oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome. However, whether pharmacological SIRT1 activators can protect retinal pigment epithelial (RPE) cells against oxidative and inflammatory injuries related to age-related macular degeneration remains to be explored.
METHODS: Two small molecule specific SIRT1 activators (SRT2104 and CAY10602) were tested, with resveratrol being used as a positive control. Mouse models with sodium iodate-induced retinal degeneration were constructed. ARPE-19 cells in culture were used for in vitro experiments. The effects of SIRT1 activators on H2O2-induced ARPE-19 cell injury were determined by reactive oxygen species quantification, western blotting, flow cytometry and immunofluorescence staining. In vivo, the severity of retinal damage was assessed using flash electroretinography and histopathological analysis.
RESULTS: In vitro, SRT2104, CAY10602 and resveratrol significantly attenuated H2O2-induced cell death, nucleolar stress response, and reactive oxygen species accumulation. In H2O2-stimulated cells, SIRT1 activators reduced the level of NLRP3, inhibited the activation of caspase-1, and decreased the production of interleukin (IL)-1β and IL-18. The inhibitory effects of SIRT1 activators on caspase-1 activation and IL-1β production were blunted by SIRT1 gene silencing. In vivo, treatment with SRT2104 or CAY10602 in mice with sodium iodate-induced retinal degeneration markedly improved the retinal functions and reduced the loss of RPE cells.
CONCLUSION: Our study suggests that small molecule SIRT1 activators are effective for protection of RPE cells against oxidative stress-induced NLRP3 inflammasome activation, highlighting potential applications in the treatment of macular degeneration associated RPE dysfunctions.

Keywords: Age-related macular degeneration; NLRP3 inflammasome; Oxidative stress; Retinal pigment epithelial cell; SIRT1; SIRT1 activators

DOI: https://doi.org/10.1016/j.intimp.2024.113167

Front Pharmacol. 2024 ;15 1455439

DJ-1 regulates mitochondrial function and promotes retinal ganglion cell survival under high glucose-induced oxidative stress.

Hanhan Peng, Haoyu Li, Benteng Ma, Xinyue Sun, Baihua Chen.

Purpose: This study aimed to investigate the antioxidative and neuroprotective effects of DJ-1 in mitigating retinal ganglion cell (RGC) damage induced by high glucose (HG).
Methods: A diabetic mouse model and an HG-induced R28 cell model were employed for loss- and gain-of-function experiments. The expression levels of apoptosis and oxidative stress-related factors, including Bax, Bcl-2, caspase3, Catalase, MnSOD, GCLC, Cyto c, and GPx-1/2, were assessed in both animal and cell models using Western blotting. Retinal structure and function were evaluated through HE staining, electroretinogram, and RGC counting. Mitochondrial function and apoptosis were determined using JC-1 and TUNEL staining, and reactive oxygen species (ROS) measurement.
Results: In the mouse model, hyperglycemia resulted in reduced retinal DJ-1 expression, retinal structural and functional damage, disrupted redox protein profiles, and mitochondrial dysfunction. Elevated glucose levels induced mitochondrial impairment, ROS generation, abnormal protein expression, and apoptosis in R28 cells. Augmenting DJ-1 expression demonstrated a restoration of mitochondrial homeostasis and alleviated diabetes-induced morphological and functional impairments both in vivo and in vitro.
Conclusion: This study provides novel insights into the regulatory role of DJ-1 in mitochondrial dynamics, suggesting a potential avenue for enhancing RGC survival in diabetic retinopathy.

Keywords: DJ-1; diabetic retinopathy; mitochondria; oxidative stress; retinal ganglion cells

DOI: https://doi.org/10.3389/fphar.2024.1455439

Invest Ophthalmol Vis Sci. 2024 Sep 03. 65(11): 31

Blue Light-Induced Accelerated Formation of Melanolipofuscin-Like Organelles in Japanese Quail RPE Cells: An Electron Microscopic Study.

Natalia B Serejnikova, Natalia N Trofimova, Marina A Yakovleva, Alexander E Dontsov, Pavel P Zak, Mikhail A Ostrovsky.

Purpose: The retinal pigment epithelium (RPE) is a monolayer of epithelial cells essential for photoreceptor function and viability. Quail Coturnix japonica is a convenient experimental animal model for the study of age and pathological retina processes to an accelerated time regime. The three main types of pigment granules present in the RPE are melanin-containing melanosomes, lipofuscin-containing lipofuscin granules, and mixed melanolipofuscin granules containing both melanin and lipofuscin. The purpose of this work was to study the process of melanolipofuscinogenesis during aging and under light exposure.
Methods: We examined melanolipofuscin granules in "macular" areas, the area of the retina containing oxycarotenoids, as a function of the macula in humans, of the quail retina by transmission electron microscopy in young, middle-aged, and old birds, and in middle-aged birds irradiated with blue LED light (450 nm, 4 J/cm2).
Results: It has been shown that during photo-oxidative stress caused by the action of blue light on the quail eye, active fusion of melanosomes and lipofuscin granules occurs with formation of various types, including giant, mixed melanolipofuscin-like granules. Increased accumulation of melanolipofuscin-like granules was also observed in non-irradiated old birds.
Conclusions: It is assumed that the decrease in the number of melanosomes in the RPE during aging and photo-oxidative stress is associated with their fusion with lipofuscin granules and subsequent degradation of melanin by reactive oxygen species formed in melanolipofuscin-like granules. The disappearance of melanin deprives the RPE cells of light-filtering and antioxidant protection, and significantly increases the risk of their oxidative stress.

DOI: https://doi.org/10.1167/iovs.65.11.31