bims-mideyd 2026-08-23 papers

Front Physiol. 2026 ;17 1866784

ADORA2A activation restores lysosomal function and photoreceptor outer segment degradation in stressed retinal pigment epithelium.

Daodian Tao, Daiying Zhou, Mingjuan Wu, Peiling Xie, Yunhao Zhang, Jing Bao.

Background: Age-related macular degeneration (AMD) involves early retinal pigment epithelium (RPE) dysfunction and impaired processing of photoreceptor outer segments (POS). We investigated whether ADORA2A regulates post-ingestive POS handling and lysosomal recovery under AMD-relevant stress.
Methods: A2E-stressed ARPE-19 cells, primary porcine RPE cells, and a sodium iodate-induced mouse model were studied. ADORA2A was activated with CGS21680 and inhibited with ZM241385. POS handling, LC3B/Rubicon association with POS, lysosomal function, Rubicon depletion, chronic stress phenotypes, and retinal protection were assessed.
Results: A2E increased ADORA2A expression while preserving receptor-dependent cAMP responsiveness. CGS21680 had modest effects on early POS binding and uptake but enhanced post-ingestive POS clearance and rhodopsin degradation; these effects were attenuated by ZM241385 and ADORA2A knockdown. CGS21680 increased LC3B and Rubicon association with POS-containing structures, improved lysosomal acidification, and restored DQ Green BSA processing, Cathepsin D activity, and V-ATPase-associated assembly. Bafilomycin A1 increased LC3-II and p62 accumulation and impaired CGS21680-associated POS clearance, supporting lysosome-dependent turnover. Rubicon depletion attenuated CGS21680-associated improvements in POS clearance and lysosomal acidification. CGS21680 also reduced chronic stress-associated autofluorescence, oxidative stress, apoptosis, and junctional disruption. These protective effects were reproduced in primary RPE cells. In sodium iodate-injured mice, CGS21680 preserved outer retinal structure, reduced FITC-BSA leakage, improved electroretinographic responses, and was accompanied by increased CREB phosphorylation and recovery of Cathepsin D proteolytic competence.
Conclusion: ADORA2A activation promotes Rubicon-associated, lysosome-dependent LC3 processing of internalized POS and restores lysosomal degradative competence, supporting ADORA2A as a potential therapeutic target for early AMD.

Keywords: ADORA2A; age-related macular degeneration; lysosomal acidification; post-ingestive degradation; retinal pigment epithelium

DOI: https://doi.org/10.3389/fphys.2026.1866784

Biochem Biophys Res Commun. 2026 Aug 17. pii: S0006-291X(26)01213-1. [Epub ahead of print]834 154449

Aryl hydrocarbon receptor modulates dysregulatory inflammatory responses in human retinal pigment epithelial cells.

Shih-Tsung Fu, George Hsiao, Ching-Hao Li, Yen-Ju Chan, Tai-Ju Hsu, Yueh-Chen Kung, Yu-Wen Cheng, Chen-Chen Lee.

Blue light-induced retinopathy is a sight-threatening condition which leads to chronic parainflammation, in which retinal pigment epithelium (RPE) dysfunction plays a critical role. While the complement system and the inflammatory cytokine IL-17A are implicated in its pathogenesis, their precise interplay within the RPE, along with the role of the immunomodulatory aryl hydrocarbon receptor (AhR), remains unclear. To address this gap, we investigated the interaction between AhR, the complement system, and IL-17A in RPE inflammation using an in vivo mouse model involving chronic low-intensity blue light exposure (300 Lux, 12 h/day for 35 days) and an in vitro system with human ARPE-19 cells (wild-type and AhR-knockout). We found that blue light exposure increased retinal C3, C5, and IL-17A while downregulating AhR. In cell cultures, treatment with C3a, C5a, or IL-17A triggered the expression of inflammatory and angiogenic factors, an effect that was significantly amplified in AhR-knockout cells through increased C3a and IL-8 expression. This heightened inflammatory response was mediated by enhanced NF-κB signaling, associated with defective p65 dephosphorylation by WIP1. These findings reveal a novel regulatory axis where AhR suppresses complement- and IL-17A-driven inflammation, highlighting it as a key hub for regulating blue light-induced retinopathy.

Keywords: Aryl hydrocarbon receptor (AhR); Blue light-induced retinopathy; Complement system; IL-17A; NF-κB signaling; Retinal pigment epithelium (RPE); Wild-type p53-induced phosphatase (WIP1)

DOI: https://doi.org/10.1016/j.bbrc.2026.154449

PLoS One. 2026 ;21(8): e0356284

Generation of dual mouse models of retinal degeneration with slow and rapid progression driven by ectopic RIP3 expression.

Young Do Song, Jiyeong Kim, Jun-Ho Jang, Youngjin Kim, Hye-Kyoung Oh, Min Jeong Ji, Minji Choi, Minsun Park, Dae-Won Kim.

Dry age-related macular degeneration (AMD) is a leading cause of blindness, characterized by progressive loss of retinal pigment epithelium (RPE) and subsequent photoreceptor degeneration. Current experimental models, including sodium iodate-induced injury, fail to fully recapitulate the chronic, age-related progression of the human disease. Although RIP3-mediated necroptosis has been strongly implicated in RPE cell death, its direct contribution to retinal degeneration in vivo remains unclear. To address this limitation, we generated two RIP3 transgenic mouse lines with distinct patterns of RIP3 overexpression. While RIP3-Tg mice exhibit systemic RIP3 overexpression, RIP3-Tg-RPE mice display additional RPE-specific overexpression beyond the levels observed in RIP3-Tg mice. We then evaluated these transgenic lines, along with wild-type controls, for age-driven retinal degeneration by using optical coherence tomography (OCT), behavior-based visual function assays, and molecular profiling of inflammation and cell death. First, RIP3-Tg mice exhibited gradual retinal thinning, progressive visual decline, and sustained upregulation of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6) over 6-15 months, recapitulating the slow progression of dry-AMD. Second, RIP3-Tg-RPE mice, which exhibit further RPE-specific increases in RIP3 expression, showed markedly accelerated retinal degeneration, with significant structural and functional deficits evident as early as 2 months of age. These findings indicate that ectopic RIP3 expression in the RPE contributes to inflammatory responses and subsequent retinal degeneration. Collectively, our results highlight RIP3 as a potential contributing factor in the progression of retinal degeneration and introduce biologically relevant transgenic models that capture both slow and accelerated disease progression. These models provide a valuable platform for investigating disease mechanisms and developing therapeutic strategies targeting necroptosis in dry-AMD.

DOI: https://doi.org/10.1371/journal.pone.0356284

J Ophthalmol. 2026 ;2026 3194421

CircMETTL3 Inhibits H2O2-Induced Senescence, Oxidative Stress, and DNA Damage in ARPE-19 Cells via miR-100/BMPR2 Axis.

Xiangyang Xin, Xin Zhao, Feng Ling, Liru Qin, Xinyue Liu, Changhe Liu.

Background: Age-related macular degeneration (AMD) is a common degenerative eye disease that eventually leads to irreversible vision loss. CircRNAs have received increasing attention for their regulatory role in AMD. In this study, whole transcriptome sequencing identified differentially expressed circRNA (circMETTL3) in AMD. Previous studies have unlocked the potential mechanism of circMETTL3 in cancer, but its role in AMD has not been studied.
Methods: ARPE-19 cells treated with H2O2 were used as the AMD cell model. The senescence, oxidative stress, and DNA damage of ARPE-19 cells were determined by SA-β-gal staining, DCFH-DA staining, and IF assay. The levels of RPE-specific markers or mRNA levels were assessed using western blot assay. The potential mechanism of circMETTL3 was investigated by luciferase reporting assay and RIP assay.
Results: CircMETTL3 was revealed to decrease in AMD cell models. The addition of circMETTL3 decreased SA-β-gal staining and ROS production and facilitated cell viability in H2O2-treated ARPE-19 cells. Moreover, γH2AX and KRT18 levels were suppressed, and TJP1, BEST1, and CTNNB1 protein levels were increased by circMETTL3 addition. In addition, circMETTL3 could bind to and negatively regulate miR-100. Overexpression of miR-100 exacerbated senescence, oxidative stress, and DNA damage in H2O2-treated ARPE-19 cells, which reversed the effects of circMETTL3. Furthermore, BMPR2 was targeted by miR-100. Overexpression of BMPR2 inhibited H2O2-induced cell damage in ARPE-19 cells, which reversed the effects of miR-100.
Conclusions: In sum, these findings demonstrated that the circMETTL3/miR-100/BMPR2 axis plays a vital regulatory role in AMD development.

Keywords: ARPE-19 cells; BMPR2; H2O2; circMETTL3; miR-100

DOI: https://doi.org/10.1155/joph/3194421

J Ocul Pharmacol Ther. 2026 Aug 21. 10807683261480480

Cytoprotective Potential of N-Acetylcysteine in an In Vitro Model of Retinal Oxidative Injury.

Kainat Ahmed, Rabbia Muneer, Haroon Tayyab, Abdul Sami Memon, Karim F Damji, Irfan Khan.

PURPOSE: Sodium iodate (NaIO3) is a well-established oxidizing agent that induces oxidative stress (OS) in ARPE-19 cells, while antioxidants such as N-acetylcysteine (NAC) have demonstrated cytoprotective effects in retinal degeneration models. This study establishes an in vitro NaIO3-induced OS disease model to investigate pathways involved in RPE damage and restoration, providing a platform for preclinical screening of antioxidant molecules.
METHODS: The cytoprotective effect of NAC on NaIO3-induced OS in RPE cells was evaluated using CMFDA cell viability assay (2',7'-dichlorofluorescin diacetate), JC-1 staining, colony-forming unit assay, scratch assay, PI/Annexin V staining, and gene expression analysis related to OS, inflammation, the cell cycle, and autophagy.
RESULTS: NAC treatment significantly decreased ROS levels and stabilized mitochondrial potential, increased cell viability and colony-forming ability, cell adhesion and migration potential. Furthermore, NAC prevented NaIO3-induced cell death and modulated the expression of genes associated with OS, inflammation, cell cycle, and autophagy.
CONCLUSION: The results showed successful establishment of a reproducible OS-based retinal degeneration model in ARPE-19 cells. Additionally, NAC exhibited significant cytoprotective activity against OS in RPE cells, highlighting its therapeutic potential as an antioxidant agent against retinal degeneration by reducing ROS levels, restoring mitochondrial membrane potential, and attenuating cell cycle dysregulation and inflammation.

Keywords: autophagy; cell viability; oxidative stress; reactive oxygen species; retinal pigment epithelium; sodium iodate

DOI: https://doi.org/10.1177/10807683261480480