bims-mideyd 2025-08-24 papers

Biochem Biophys Rep. 2025 Sep;43 102195

Reduction of Heterogeneous nuclear ribonucleoprotein A1 levels in retinal pigment epithelial cells induces inflammation and inhibits autophagy flux: pathology of age-related macular degeneration.

Tomofumi Yatsu, Ayaka Nagata, Takuya Chiba, Yoshiki Miyata.

Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) regulates RNA metabolism and inhibits various aging processes. It has also been reported as an inhibitor of inflammation; however, its role in the retina, particularly in retinal pigment epithelial (RPE) cells-a major source of inflammatory cytokines in the retina-remains unclear. Retinal inflammation is a key factor in the development of dry age-related macular degeneration (AMD), an age-related disease that can lead to blindness and currently lacks an established treatment. Therapeutic strategies are focused on preventing the suppression of autophagy, a precursor to inflammation. However, the factors regulating autophagy in RPE cells are not yet fully understood. In this study, we investigated the role of HNRNPA1 in RPE cells to evaluate its potential as a therapeutic target for dry AMD. HNRNPA1 knockdown experiments were conducted, followed by RNA sequencing (RNA-seq) and Gene Ontology term analyses to elucidate the impact of HNRNPA1 reduction. The results revealed that reduced HNRNPA1 levels induced the increased expression of CXCL8 and IL1B, decreased autolysosome formation, and increased autophagosome formation, showing that HNRNPA1 reduction induces inflammation and suppressed autophagy, demonstrating its essential role in maintaining autophagy and mitigating inflammation under normal conditions. Furthermore, in an NaIO3-induced dryAMD model, RPE degeneration was accompanied by a reduction in HNRNPA1. These findings raise the possibility that decreased HNRNPA1 levels play a role in the onset and progression of dry AMD, and support the rationale for further exploring HNRNPA1 as a potential therapeutic target for this currently untreatable condition.

Keywords: Age-related macular degeneration; Autophagy; Heterogeneous nuclear ribonucleoprotein A1; Inflammation

DOI: https://doi.org/10.1016/j.bbrep.2025.102195

Transl Vis Sci Technol. 2025 Aug 01. 14(8): 21

OBM1701 Alleviates Choroidal Neovascularization in Experimental Animals Via Suppressing the Expression of HIF-1α in Retinal Pigment Epithelial Cells.

Shu-I Yeh, Tsung-Chuan Ho, Ting-Wen Chu, Show-Li Chen, Ruchong Ou, Yeou-Ping Tsao.

Purpose: OBM1701, a pigment epithelium-derived factor-derived short peptide, can eliminate corneal neovascularization by blocking endothelial cell angiogenesis. Activation of hypoxia-inducible factor (HIF)-1α in the retinal pigment epithelium (RPE) is critical for the pathogenesis of choroidal neovascularization (CNV), the hallmark of neovascular age-related macular degeneration (nAMD). Here, the potential inhibitory effect of OBM1701 on laser-induced CNV in animals was investigated.
Methods: Two days after the laser injury, topical OBM1701 eye drops were applied once daily for 12 days. Subsequently, CNV vascular leakage and CNV area were measured by fluorescein angiography and isolectin GS-IB4 staining on choroidal/RPE flatmounts, respectively. Immunostaining was used to detect the expression of HIF-1α and vascular endothelial growth factor A (VEGFA) in CNV lesions. In vitro, ARPE-19 cells and primary porcine RPE were exposed to hypoxia mimetic condition by adding dimethyloxalylglycine and oxygen deprivation in cultures, respectively. Then the gene and protein expression of HIF-1α and VEGFA were evaluated by real-time PCR and Western blotting.
Results: OBM1701 effectively reduced vascular leakage and CNV formation. Meanwhile, OBM1701 treatment blocked the overexpression of HIF-1α and VEGFA in RPE cells located within CNV lesions. In culture, OBM1701 pretreatment suppressed hypoxia-induced HIF-1α and VEGFA expressions.
Conclusions: Through animal studies, we demonstrate that OBM1701 has the potential to treat CNV. We also suggest RPE as a drug target for OBM1701 to treat CNV, by attenuating the hypoxia-induced HIF-1α/VEGFA signaling.
Translational Relevance: OBM1701 in ophthalmic drop shows the potential to be developed into a novel therapy for the treatment of nAMD.

DOI: https://doi.org/10.1167/tvst.14.8.21

Sci Rep. 2025 Aug 17. 15(1): 30153

Modulation of retinal inflammation delays degeneration in a mouse model of geographic atrophy.

Raela B Ridley, Brianna M Tischner, Jieun Lee, Erin Walsh, Michael T Massengill, Alfred S Lewin, Cristhian J Ildefonso.

Geographic atrophy, the advanced form of age-related macular degeneration (AMD), is associated with increased oxidative stress and chronic inflammation. Pro-inflammatory genes, like TNF-α and IL-1β, are under the regulation of the transcription factor p65/RelA. We have previously shown that adeno-associated virus (AAV) delivery of the RelA inhibitory gene M013 blocks retinal inflammation in uveitis models. In this study, we evaluated the effects of RelA inhibition in an oxidative stress-driven geographic atrophy mouse model. We injected Sod2RPEcKO mice with rAAV, delivering either secreted GFP (sGFP control) or sGFP fused to a cell-penetrating version of the tagged M013 (sGFP-TatM013v5). Over nine months, we measured retinal function, structure, and morphological changes using electroretinography, optical coherence tomography, and fundoscopy. We quantified changes in inflammatory markers using multiplex ELISA, RT-qPCR, and immunofluorescence staining of the retinal tissue. Finally, we generated an NF-kB-luciferase reporter microglia cell line to study the impact of immune signaling changes on microglia. Mice injected with the rAAV delivering M013 had transient protection of their retinal function at 3 months. Based on ERG evaluations, the intravitreal injection of rAAV delivering sGFP-TatM013v5 significantly delayed the loss of retinal function. Furthermore, the rAAV-mediated expression of the sGFP-TatM013v5 protected photoreceptors' outer and inner segments based on OCT and immunofluorescence analysis. Analysis of postmortem tissues showed decreased migration of immune cells towards the RPE. Retinas injected with the sGFP-M013v5 vector showed increased levels of IL-9, IL10 and LIF. Finally, adding LIF to our NF-kB reporter cell line showed decreased TNF-induced reporter expression and modulation of microglia-specific genes. Our results indicate that modulating retinal inflammation could significantly slow the degeneration associated with geographic atrophy. Specifically, inhibiting the RelA protein in the retina may offer protective effects against retinal degeneration. Additionally, we demonstrated that LIF can counteract the influence of TNF on microglial gene expression. Future research will explore the dynamic interactions between RelA and other transcription factors and the NF-kB signaling pathway in the retina as they relate to retinal diseases.

Keywords: Age-related macular degeneration; Myxoma virus; NF-kB; Retinal inflammation

DOI: https://doi.org/10.1038/s41598-025-15891-z

Eur J Med Res. 2025 Aug 20. 30(1): 777

Jinquan Chen, Zhao Long, Dandan Shi, Qian Zhang, H Peng.

BACKGROUND: Age-related Macular Degeneration (AMD) is widely acknowledged as a principal cause of vision loss in the elderly. Currently, the therapeutic interventions available in clinical practice fail to achieve satisfactory outcomes. Therefore, it is imperative that we approach the progress of AMD from novel perspectives in order to explore new therapeutic strategies.
METHOD: We obtained transcriptomic data from the macular and the peripheral retina from patients with AMD and a control group from the Gene Expression Omnibus (GEO) database. Through Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, we identified differentially expressed genes (DEGs) that were significantly enriched in functions associated with ferroptosis. Subsequent application of machine learning techniques enabled the identification of key hub genes, whose diagnostic potential was further validated. Additionally, the expression of these hub genes was corroborated in both animal and cellular models. Finally, we performed a functional enrichment analysis of these hub genes.
RESULTS: In the macula of patients with AMD, 452 DEGs were identified, while in the peripheral retina, 222 DEGs were discovered. Within the macula, 19 genes were associated with ferroptosis, compared to 3 in the peripheral retina. Consequently, the macular was selected as the primary focus of the study. Subsequent screening of these 19 genes using LASSO regression, Support Vector Machine (SVM), and Random Forest algorithms identified four hub genes: FADS1, TFAP2A, AKR1C3, and TTPA. Consequently, we utilized cigarette smoke extract (CSE) to either stimulate retinal pigment epithelial (RPE) cells in vitro or administer it via intravitreal injection, thereby establishing in vitro and in vivo models of AMD. Results from RT-PCR and Western blot analyses revealed an upregulation of FADS1, AKR1C3, and TTPA, while TFAP2A exhibited decreased expression. Finally, we investigated the infiltration of immune cells within the macular and performed a functional enrichment analysis of the hub genes.
CONCLUSION: We identified four key ferroptosis-related genes (FRGs)-FADS1, AKR1C3, TFAP2A, and TTPA-that possess diagnostic relevance for AMD and correlate with immune cell infiltration. Moreover, significant changes in both mRNA and protein expression levels of these genes have been observed in in vitro experiments and mice models.

Keywords: Age-related macular degeneration; Ferroptosis-related genes; Immune cells; Machine learning

DOI: https://doi.org/10.1186/s40001-025-03044-x