bims-mideyd 2024-12-01 papers

Antioxidants (Basel). 2024 Nov 05. pii: 1352. [Epub ahead of print]13(11):

Protective Mechanism of Sea buckthorn Proanthocyanidins Against Hydrogen Peroxide-Introduced Oxidative Damage in Adult Retinal Pigment Epithelial-19.

Kaiyuan Ma, Michael Yuen, Tina Yuen, Hywel Yuen, Qiang Peng.

Retinal pigment epithelial (RPE) is an oxidation-resistant cell. But if it is subjected to various harmful stimuli for a prolonged period, an excessive amount of oxyradical will be generated to cause retinal dysfunction. We investigated and elucidated the protective mechanism of Sea buckthorn proanthocyanidins (SBP) against oxidative damage in RPE. In this study, we established an oxidative damage model of adult retinal pigment epithelial cell line-19 (ARPE-19) using hydrogen peroxide (H2O2), followed by different concentrations of SBP for 24 h. The finding demonstrated that SBP effectively inhibited the generation of malondialdehyde (MDA), restored the activity of superoxide dismutase (SOD) and content of glutathione (GSH), and significantly eliminated the level of reactive oxygen species (ROS) and oxidative stress. It was revealed that 100 µg/mL of SBP was more suitable for restoring oxidative damage in ARPE-19, which enhanced cell activity and migration ability and maintained normal cell morphology. In addition, SBP increased the expression of Bcl-2, decreased the expression of Bax and caspase-3, and activated the Nrf2/HO-1 signaling pathway to protect ARPE-19 from oxidative stress. Moreover, SBP could restore the morphology and quantity of mitochondria and inhibit mitochondrial permeability and swelling. The present results provide a theoretical basis for the protective and restorative effect of SBP in retinopathy caused by oxidative stress.

Keywords: Sea buckthorn proanthocyanidins; mitochondrion; oxidative stress; reactive oxygen species; retinal pigment epithelial

DOI: https://doi.org/10.3390/antiox13111352

Aging Cell. 2024 Nov 27. e14419

The Ercc1-/Δ mouse model of XFE progeroid syndrome undergoes accelerated retinal degeneration.

Akilavalli Narasimhan, Seok Hong Min, Laura L Johnson, Heidi Roehrich, William Cho, Tracy K Her, Caeden Windschitl, Ryan D O'Kelly, Luise Angelini, Matthew J Yousefzadeh, Linda K McLoon, William W Hauswirth, Paul D Robbins, Dorota Skowronska-Krawczyk, Laura J Niedernhofer.

Age-related macular degeneration (AMD) is a major cause of vision loss in older adults. AMD is caused by degeneration in the macula of the retina. The retina is the highest oxygen consuming tissue in our body and is prone to oxidative damage. DNA damage is one hallmark of aging implicated in loss of organ function. Genome instability has been associated with several disorders that result in premature vision loss. We hypothesized that endogenous DNA damage plays a causal role in age-related retinal changes. To address this, we used a genetic model of systemic depletion of expression of the DNA repair enzyme ERCC1-XPF. The neural retina and retinal pigment epithelium (RPE) from Ercc1-/Δ mice, which models a human progeroid syndrome, were compared to age-matched wild-type (WT) and old WT mice. By 3-months-of age, Ercc1-/Δ mice presented abnormal optokinetic and electroretinogram responses consistent with photoreceptor dysfunction and visual impairment. Ercc1-/Δ mice shared many ocular characteristics with old WT mice including morphological changes, elevated DNA damage markers (γ-H2AX and 53BP1), and increased cellular senescence in the neural retinal and RPE, as well as pathological angiogenesis. The RPE is essential for the metabolic health of photoreceptors. The RPE from Ercc1-/Δ mice displayed mitochondrial dysfunction causing a compensatory glycolytic shift, a characteristic feature of aging RPE. Hence, our study suggests spontaneous endogenous DNA damage promotes the hallmarks of age-related retinal degeneration.

Keywords: DNA damage; age‐related retinal degeneration; cellular senescence

DOI: https://doi.org/10.1111/acel.14419

FEBS J. 2024 Nov 24.

Antioxidant properties of the soluble carotenoprotein AstaP and its feasibility for retinal protection against oxidative stress.

Daria A Lunegova, Danil A Gvozdev, Ivan I Senin, Victoria R Gudkova, Svetlana V Sidorenko, Veronika V Tiulina, Natalia G Shebardina, Marina A Yakovleva, Tatiana B Feldman, Alla A Ramonova, Anastasia M Moysenovich, Alexey N Semenov, Evgeni Yu Zernii, Eugene G Maksimov, Nikolai N Sluchanko, Mikhail P Kirpichnikov, Mikhail A Ostrovsky.

Photodamage to the outer segments of photoreceptor cells and their impaired utilization by retinal pigment epithelium (RPE) cells contribute to the development of age-related macular degeneration (AMD) leading to blindness. Degeneration of photoreceptor cells and RPE cells is triggered by reactive oxygen species (ROS) produced by photochemical reactions involving bisretinoids, by-products of the visual cycle, which accumulate in photoreceptor discs and lipofuscin granules of RPE. Carotenoids, natural antioxidants with high potential efficacy against a wide range of ROS, may protect against the cytotoxic properties of lipofuscin. To solve the problem of high hydrophobicity of carotenoids and increase their bioaccessibility, specialized proteins can ensure their targeted delivery to the affected tissues. In this study, we present new capabilities of the recombinant water-soluble protein AstaP from Coelastrella astaxanthina Ki-4 (Scenedesmaceae) for protein-mediated carotenoid delivery and demonstrate how zeaxanthin delivery suppresses oxidative stress in a lipofuscin-enriched model of photoreceptor and pigment epithelium cells. AstaP in complex with zeaxanthin can effectively scavenge various ROS (singlet oxygen, free radical cations, hydrogen peroxide) previously reported to be generated in AMD. In addition, we explore the potential of optimizing the structure of AstaP to enhance its thermal stability and resistance to proteolytic activity in the ocular media. This optimization aims to maximize the prevention of retinal degenerative changes in AMD.

Keywords: ROS; carotenoids; lipofuscin; photoreceptors; retinal pigment epithelium

DOI: https://doi.org/10.1111/febs.17335

Invest Ophthalmol Vis Sci. 2024 Nov 04. 65(13): 57

Small Extracellular Vesicle-Associated MiRNAs in Polarized Retinal Pigmented Epithelium.

Belinda J Hernandez, Madison Strain, Maria Fernanda Suarez, W Daniel Stamer, Allison Ashley-Koch, Yutao Liu, Mikael Klingeborn, Catherine Bowes Rickman.

Purpose: Oxidative stress in the retinal pigmented epithelium (RPE) has been implicated in age-related macular degeneration by impacting endocytic trafficking, including the formation, content, and secretion of extracellular vesicles (EVs). Using our model of polarized primary porcine RPE (pRPE) cells under chronic subtoxic oxidative stress, we tested the hypothesis that RPE miRNAs packaged into EVs are secreted in a polarized manner and contribute to maintaining RPE homeostasis.
Methods: Small EVs (sEVs) enriched for exosomes were isolated from apical and basal conditioned media from pRPE cells grown for up to four weeks with or without low concentrations of hydrogen peroxide using two sEV isolation methods, leading to eight experimental groups. The sEV miRNA expression was profiled using miRNA-Seq with Illumina MiSeq, followed by quality control and bioinformatics analysis for differential expression using the R computing environment. Expression of selected miRNAs were validated using qRT-PCR.
Results: We identified miRNA content differences carried by sEVs isolated using two ultracentrifugation-based methods. Regardless of the sEV isolation method, miR-182 and miR-183 were enriched in the cargo of apically secreted sEVs, and miR-122 in the cargo of basally secreted sEVs from RPE cells during normal homeostatic conditions. After oxidative stress, miR-183 levels were significantly decreased in the cargo of apically released sEVs from stressed RPE cells.
Conclusions: We curated RPE sEV miRNA datasets based on cell polarity and oxidative stress. Unbiased miRNA analysis identified differences based on polarity, stress, and sEV isolation methods. These findings suggest that miRNAs in sEVs may contribute to RPE homeostasis and function in a polarized manner.

DOI: https://doi.org/10.1167/iovs.65.13.57