bims-mideyd 2025-04-20 papers

Biomol Ther (Seoul). 2025 Apr 17.

Paeoniflorin Protects Retinal Pigment Epithelial Cells from High Glucose-Induced Oxidative Damage by Activating Nrf2-Mediated HO-1 Signaling.

Cheol Park, Hee-Jae Cha, Su Hyun Hong, Jeong Sook Noh, Sang Hoon Hong, Gi Young Kim, Jung-Hyun Shim, Jin Won Hyun, Yung Hyun Choi.

Oxidative stress due to hyperglycemia damages the functions of retinal pigment epithelial (RPE) cells and is a major risk factor for diabetic retinopathy (DR). Paeoniflorin is a monoterpenoid glycoside found in the roots of Paeonia lactiflora Pall and has been reported to have a variety of health benefits. However, the mechanisms underlying its therapeutic effects on high glucose (HG)-induced oxidative damage in RPE cells are not fully understood. In this study, we investigated the protective effect of paeoniflorin against HG-induced oxidative damage in cultured human RPE ARPE-19 cells, an in vitro model of hyperglycemia. Pretreatment with paeoniflorin markedly reduced HG-induced cytotoxicity and DNA damage. Paeoniflorin inhibited HG-induced apoptosis by suppressing activation of the caspase cascade, and this suppression was associated with the blockade of cytochrome c release to cytoplasm by maintaining mitochondrial membrane stability. In addition, paeoniflorin suppressed the HG-induced production of reactive oxygen species (ROS), increased the phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf2), a key redox regulator, and the expression of its downstream factor heme oxygenase-1 (HO-1). On the other hand, zinc protoporphyrin (ZnPP), an inhibitor of HO-1, abolished the protective effect of paeoniflorin against ROS production in HG-treated cells. Furthermore, ZnPP reversed the protective effects of paeoniflorin against HG-induced cellular damage and induced mitochondrial damage, DNA injury, and apoptosis in paeoniflorin-treated cells. These results suggest that paeoniflorin protects RPE cells from HG-mediated oxidative stress-induced cytotoxicity by activating Nrf2/HO-1 signaling and highlight the potential therapeutic use of paeoniflorin to improve the symptoms of DR.

Keywords: High glucose; Nrf2/HO-1; Oxidative stress; Paeoniflorin; Retinal pigment epithelial cells

DOI: https://doi.org/10.4062/biomolther.2025.025

BMC Biol. 2025 Apr 12. 23(1): 96

Dysregulated lipid metabolism in a retinal pigment epithelial cell model and serum of patients with age-related macular degeneration.

Ana Álvarez-Barrios, Lydia Álvarez, Pilar Sáenz de Santa María, Montserrat García, Jorge R Álvarez-Buylla, Rosario Pereiro, Héctor González-Iglesias.

BACKGROUND: Age-related macular degeneration (AMD) is a leading cause of blindness, characterized by retinal pigment epithelium (RPE) dysfunction, extracellular deposit formation, and disrupted lipid metabolism. Understanding the molecular changes underlying AMD is essential for identifying diagnostic markers and therapeutic targets.
RESULTS: This multiomic study employed a primary RPE culture model to investigate age-related changes associated with AMD. Over 25 weeks, RPE cells exhibited phenotypic deterioration, including depigmentation, cell shape deformation, and barrier integrity loss, accompanied by extracellular deposit formation. Transcriptomic analysis revealed dysregulation of genes involved in lipid metabolism, including pathways for cholesterol transport, glycerophospholipids, and ceramide biosynthesis. Metabolomic profiling further identified significant changes in glycerophospholipid and sphingolipid metabolism, highlighting a decline in phospholipid species and ceramide accumulation. Serum analysis of AMD patients revealed altered levels of 18 lipids identified in RPE cultures. Four lipids showed significant differences compared to controls: GlcCer(d16:1/18:0) (1.23-fold increase, adj. p value < 0.001), PE(19:1(9Z)/22:2(13Z,16Z)) (0.34-fold decrease, adj. p value < 0.001), PE(15:0/20:3(5Z,8Z,11Z)) (0.66-fold decrease, adj. p value < 0.05), and PC(22:2(13Z,16Z)/13:0) (0.71-fold decrease, adj. p value < 0.05). These findings underscore the systemic nature of lipid dysregulation in AMD and the translational relevance of the RPE model.
CONCLUSIONS: This study highlights the significant role of lipid metabolism dysregulation in AMD pathogenesis. The consistent lipidomic alterations observed in RPE cultures and AMD patient serum reinforce their potential as biomarkers for disease progression and therapeutic targets. These findings provide a robust framework for understanding AMD-associated lipid metabolism changes and their systemic impact.

Keywords: Age-related macular degeneration; Ageing; Lipid metabolism; Multiomics; Retinal pigment epithelium; Serum

DOI: https://doi.org/10.1186/s12915-025-02198-8

Cytotechnology. 2025 Jun;77(3): 88

Exosomes derived from human umbilical cord blood mesenchymal stem cells protect against blue light-induced damage to retinal pigment epithelial cells by inhibiting FGF2 expression.

Guang-Ming Liu, Yan Liu.

Age-related macular degeneration (AMD) is a debilitating retinal disorder that may lead to progressive vision loss. One contributing factor to AMD pathogenesis is excessive blue light (BL) exposure. In this study, we investigated the therapeutic potential of exosomes derived from human umbilical cord blood mesenchymal stem cells (hUCMSC-EXs) in addressing BL-induced damage to ARPE-19 human retinal pigment epithelial (RPE) cells and explored the underlying mechanisms. Our findings revealed that BL exposure induced morphological alterations in ARPE-19 cells, accompanied by a time-dependent decline in cell viability, increased apoptosis, heightened oxidative stress, and inflammatory responses; however, hUCMSC-EXs dose-dependently mitigated BL-induced ARPE-19 cell damage. Interestingly, hUCMSC-EXs were found to suppress the upregulation of fibroblast growth factor 2 (FGF2) in BL-exposed ARPE-19 cells. Furthermore, FGF2 overexpression partially counteracted the inhibitory effects of hUCMSC-EXs on FGF2 expression and compromised the protective benefits of hUCMSC-EXs against BL-induced ARPE-19 cell damage. In conclusion, our results suggest that hUCMSC-EXs shield ARPE-19 cells from BL-induced harm by inhibiting FGF2 expression.

Keywords: Age-related macular degeneration; Blue light; Exosomes derived from human umbilical cord blood mesenchymal stem cells; Fibroblast growth factor 2; Retinal pigment epithelial cells

DOI: https://doi.org/10.1007/s10616-025-00752-4

Sci Rep. 2025 Apr 15. 15(1): 13012

Distinct metabolome and flux responses in the retinal pigment epithelium to cytokines associated with age-related macular degeneration: comparison of ARPE-19 cells and eyecups.

David S Hansman, Kelly Lim, Daniel Thomas, Robert J Casson, Daniel J Peet.

Age-related macular degeneration (AMD) is associated with chronic inflammation of the retinal pigment epithelium (RPE) and elevated cytokines including TNFα, TGF-β, IL-6, and IL-1β. As a metabolic intermediary supporting aerobic glycolysis in the adjacent photoreceptors, the RPE's metabolic responses to inflammation and the optimal methods to study cytokine-driven metabolic programming remain unclear. We performed a rigorous comparison of ARPE-19 cells and rat eyecup metabolomes, revealing key distinctions. Rat eyecups exhibit higher levels of lactate and palmitate but depleted glutathione and high-energy nucleotides. Conversely, ARPE-19 cells are enriched with high-energy currency metabolites and the membrane phospholipid precursors phosphocholine and inositol. Both models showed contrasting responses to individual cytokines: ARPE-19 cells were more sensitive to TNFα, while eyecups responded more strongly to TGF-β2. Notably, a combined cytokine cocktail elicited stronger metabolic effects on ARPE-19 cells, more potently impacting both metabolite abundance (41 vs. 29) and glucose carbon flux (29 vs. 5), and influencing key RPE metabolites such as alanine, glycine, aspartate, proline, citrate, α-ketoglutarate, and palmitate. Overall, these findings position ARPE-19 cells as a more responsive platform for studying inflammatory cytokine effects on RPE metabolism and reveal critical RPE metabolites which may be linked with AMD pathogenesis.

Keywords: Age-related macular degeneration; Cytokines; Metabolic ecosystem; Metabolism; Retina inflammation; Retinal pigment epithelium

DOI: https://doi.org/10.1038/s41598-025-93882-w