Solanum melongena L. Extract Protects Retinal Pigment Epithelial Cells from Blue Light-Induced Phototoxicity in In Vitro and In Vivo Models

Pham, Thu Nguyen Minh; Shin, Chaeyoung; Park, Seo Hyun; Lee, Taek Hwan; Ryu, Hyeon Yeol; Kim, Sung‐Bae; Auh, Kwang; Jeong, Kwang Won

doi:10.3390/nu13020359

Cited by 16 publications

(13 citation statements)

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“…These results are similar to those in patients with AMD. Specifically, the genes corresponding to TNFα signaling through NF-κB were upregulated during the late stage, which differed from previous findings of TNFα signaling, being a major pathway that is rapidly affected by a single exposure of high-dose A2E and BL ( Pham et al ., 2021 ). Notably, the changes in late gene (e.g., CHN2 , DUSP5 , and SLC6A15 ) expression in our model correlated with the changes in expression that are characteristic of patients with advanced dry AMD dry AMD ( Radeke et al ., 2007 ).…”

Section: Discussioncontrasting

confidence: 99%

Transcriptome Analysis of Long-Term Exposure to Blue Light in Retinal Pigment Epithelial Cells

Jin

Jeong

2022

Biomol Ther (Seoul)

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Dry age-related macular degeneration (AMD) is a type of progressive blindness that is primarily due to dysfunction and the loss of retinal pigment epithelium (RPE). The accumulation of N-retinylidene-N-retinylethanolamine (A2E), a by-product of the visual cycle, causes RPE and photoreceptor degeneration that impairs vision. Genes associated with dry AMD have been identified using a blue light model of A2E accumulation in the retinal pigment epithelium and transcriptomic studies of retinal tissue from patients with AMD. However, dry macular degeneration progresses slowly, and current approaches cannot reveal changes in gene transcription according to stages of AMD progression. Thus, they are limited in terms of identifying genes responsible for pathogenesis. Here, we created a model of long-term exposure to identify temporally-dependent changes in gene expression induced in human retinal pigment epithelial cells (ARPE-19) exposed to blue light and a non-cytotoxic dose of A2E for 120 days. We identified stage-specific genes at 40, 100, and 120 days, respectively. The expression of genes corresponding to epithelial-mesenchymal transition (EMT) during the early stage, glycolysis and angiogenesis during the middle stage, and apoptosis and inflammation pathways during the late stage was significantly altered by A2E and blue light. Changes in the expression of genes at the late stages of the EMT were similar to those found in human eyes with late-stage AMD. Our results provide further insight into the pathogenesis of dry AMD induced by blue light and a novel model in vitro with which relevant genes can be identified in the future.

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Section: Discussioncontrasting

confidence: 99%

Transcriptome Analysis of Long-Term Exposure to Blue Light in Retinal Pigment Epithelial Cells

Jin

Jeong

2022

Biomol Ther (Seoul)

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“…Attempts to inhibit A2E accumulation in retinal cells by using natural extracts have been reported [21,46,47]. However, since these extracts contain multiple physiologically active substances, it is difficult to ascertain the exact mechanism of A2E elimination.…”

Section: Discussionmentioning

confidence: 99%

NMDA Receptor Antagonists Degrade Lipofuscin via Autophagy in Human Retinal Pigment Epithelial Cells

Lee

Jeong

2022

Medicina

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Background and Objectives: Age-related macular degeneration is a slow-progressing disease in which lipofuscin accumulates in the retina, causing inflammation and apoptosis of retinal pigment epithelial (RPE) cells. This study aimed to identify N-methyl-D-aspartate (NMDA) signaling as a novel mechanism for scavenging N-retinylidene-N-retinylethanolamine (A2E), a component of ocular lipofuscin, in human RPE cells. Materials and Methods: A2E degradation assays were performed in ARPE-19 cells using fluorescently labeled A2E. The autophagic activity in ARPE-19 cells was measured upon blue light (BL) exposure, after A2E treatment. Autophagy flux was determined by measuring LC3-II formation using immunoblotting and confocal microscopy. To determine whether autophagy via the NMDA receptor is involved in A2E clearance, ATG5-deficient cells were used. Results: Ro 25-6981, an NR2B-selective NMDA receptor antagonist, effectively cleared A2E. Ro 25-6981 reduced A2E accumulation in the lysosomes of ARPE-19 cells at sub-cytotoxic concentrations, while increasing the formation of LC3-II and decreasing p62 protein levels in a concentration-dependent manner. The autophagic flux monitored by RFP-GFP-LC3 and bafilomycin A1 assays was significantly increased by Ro 25-6981. A2E clearance by Ro 25-6981 was abolished in ATG5-depleted ARPE-19 cells, suggesting that A2E degradation by Ro 25-6981 was mediated by autophagy. Furthermore, treatment with other NMDA receptor antagonists, CP-101,606 and AZD6765, showed similar effects on autophagy activation and A2E degradation in ARPE-19 cells. In contrast, glutamate, an NMDA receptor agonist, exhibited a contrasting effect, suggesting that both the activation of autophagy and the degradation of A2E by Ro 25-6981 in ARPE-19 cells occur through inhibition of the NMDA receptor pathway. Conclusions: This study demonstrates that NMDA receptor antagonists degrade lipofuscin via autophagy in human RPE cells and suggests that NMDA receptor antagonists could be promising new therapeutics for retinal degenerative diseases.

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“…Control cell groups were incubated without A2E. Confluent cultures were transferred to PBS supplemented with Mg 2+ , Ca 2+ and glucose, before exposure to blue light emitted by a tungsten-halogen source (470 ± 20 nm; 0.4 mW/mm 2 ) for 30 min to induce phototoxicity of A2E and subsequent incubation at 37 °C, as already described by confirmed protocols [ 32 , 33 , 34 ]. A2E quantity in cell cultures post blue light induction was then confirmed by HPLC.…”

Section: Methodsmentioning

confidence: 99%

Epitranscriptome Analysis of Oxidative Stressed Retinal Epithelial Cells Depicted a Possible RNA Editing Landscape of Retinal Degeneration

et al. 2022

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Oxidative stress represents one of the principal causes of inherited retinal dystrophies, with many related molecular mechanisms still unknown. We investigated the posttranscriptional RNA editing landscape of human retinal pigment epithelium cells (RPE) exposed to the oxidant agent N-retinylidene-N-retinyl ethanolamine (A2E) for 1 h, 2 h, 3 h and 6 h. Using a transcriptomic approach, refined with a specific multialgorithm pipeline, 62,880 already annotated and de novo RNA editing sites within about 3000 genes were identified among all samples. Approximately 19% of these RNA editing sites were found within 3′ UTR, including sites common to all time points that were predicted to change the binding capacity of 359 miRNAs towards 9654 target genes. A2E exposure also determined significant gene expression differences in deaminase family ADAR, APOBEC and ADAT members, involved in canonical and tRNA editing events. On GO and KEGG enrichment analyses, genes that showed different RNA editing levels are mainly involved in pathways strongly linked to a possible neovascularization of retinal tissue, with induced apoptosis mediated by the ECM and surface protein altered signaling. Collectively, this work demonstrated dynamic RNA editome profiles in RPE cells for the first time and shed more light on new mechanisms at the basis of retinal degeneration.

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Solanum melongena L. Extract Protects Retinal Pigment Epithelial Cells from Blue Light-Induced Phototoxicity in In Vitro and In Vivo Models

Cited by 16 publications

References 50 publications

Transcriptome Analysis of Long-Term Exposure to Blue Light in Retinal Pigment Epithelial Cells

Transcriptome Analysis of Long-Term Exposure to Blue Light in Retinal Pigment Epithelial Cells

NMDA Receptor Antagonists Degrade Lipofuscin via Autophagy in Human Retinal Pigment Epithelial Cells

Epitranscriptome Analysis of Oxidative Stressed Retinal Epithelial Cells Depicted a Possible RNA Editing Landscape of Retinal Degeneration

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