bims-mideyd 2026-10-04 papers

Phytomedicine. 2026 Jul 31. pii: S0944-7113(26)00894-9. [Epub ahead of print]162 158663

Yingmu San ameliorates pathological myopia by protecting retinal pigment epithelium and enhancing mitophagy-associated responses.

Yang Cao, Jianxin Liu, Qian Feng, Biao Li, Fei Gao, Kaimin Xiao, Jiexin Bai, Hua Zhou, Hudan Pan, Junguo Duan, Juyi Wan, Anguo Wu, Jing Wei.

BACKGROUND: Pathological myopia is associated with progressive axial elongation and retinal pigment epithelium (RPE) injury, in which oxidative stress, inflammation, and mitochondrial dysfunction are important pathological contributors. Yingmu San (YMS) is a defined multi-component formulation composed of peony seed oil (PSO), lutein, and zeaxanthin at fixed proportions. However, whether YMS protects the RPE during myopia progression and whether mitophagy-associated responses are involved in this effect remain unclear.
PURPOSE: This study aimed to determine whether YMS protects RPE cells and alleviates myopia-associated retinal injury and to clarify whether mitochondrial quality control, particularly AMPK/mTOR/ULK1- and PINK1/Parkin-associated mitophagy responses, contributes to this protection.
STUDY DESIGN: This mechanism-oriented study integrated form-deprivation myopia (FDM) mouse and hypoxia (Hx)-induced adult retinal pigment epithelial cell line-19 (ARPE-19) cell models to evaluate YMS-mediated retinal protection and investigate mitophagy-associated mechanisms using transcriptomic, pharmacological, and genetic approaches.
METHODS: An FDM mouse model and Hx-injured ARPE-19 cells were used to evaluate myopia-associated retinal injury and RPE damage. The chemical profile and batch consistency of YMS were assessed by UHPLC-APCI-MS, and the contribution of representative components was evaluated in Hx-injured cells. Retinal outcomes, mitochondrial function, oxidative stress, apoptosis, and NLRP3 inflammasome activation were examined. RNA sequencing, pathway enrichment analysis, autophagic/mitophagic flux assays, intracellular ATP measurement, pharmacological modulation, AKT overexpression, siAMPK, and siPINK1 interventions were used to investigate the mechanism of YMS.
RESULTS: YMS reduced axial elongation and refractive shifts, preserved retinal and RPE architecture, and improved retinal and choroidal blood flow in FDM mice. YMS displayed consistent chromatographic profiles across five independently prepared batches, and the complete formulation protected Hx-injured ARPE-19 cells more effectively than individual formulation-matched components. In Hx-injured cells, YMS restored mitochondrial membrane potential and ATP levels, reduced ROS accumulation, and suppressed apoptosis and NLRP3 inflammasome-associated responses. Transcriptomic analyses identified autophagy-, lysosome-, AMPK-, mTOR-, and mitophagy-related pathways associated with YMS treatment. Mechanistically, YMS increased AMPK and activation-associated ULK1 signaling, suppressed PI3K/AKT-mTOR signaling, and enhanced PINK1/Parkin-associated mitophagy responses. Genetic analyses suggested that YMS-induced AMPK activation and PI3K/AKT suppression are not fully explained by a simple one-direction linear hierarchy, although complete pathway independence was not established. Importantly, PINK1 knockdown attenuated YMS-induced autophagic responses and weakened its mitochondrial protective, anti-apoptotic, and anti-inflammatory effects in Hx-injured ARPE-19 cells. In FDM mice, YMS preserved RPE mitochondrial morphology and was associated with increased mitophagy-related signals and reduced apoptosis- and inflammasome-associated injury.
CONCLUSION: YMS protects RPE cells and alleviates myopia-associated retinal injury by preserving mitochondrial function and reducing oxidative and inflammatory damage, accompanied by enhanced PINK1/Parkin-associated mitophagy responses. These findings support the further evaluation of YMS as a potential intervention for myopia-associated retinal degeneration, while the in vivo requirement of mitophagy remains to be defined.

Keywords: Mitophagy; NLRP3 inflammasome; Retinal pigment epithelium cells

DOI: https://doi.org/10.1016/j.phymed.2026.158663

Acta Biomater. 2026 Oct 01. pii: S1742-7061(26)00667-7. [Epub ahead of print]

Spatio-temporal Mechanosensitive Phagocytic Response of Retinal Pigment Epithelial Cells to Reversible Changes in Substrate Stiffness.

Colleen M Simmerly, Mohammad Aminul Islam, Adam P Williamson, Elise A Corbin.

In aging and diseased retina, Bruch's membrane (BrM) stiffens heterogeneously, impairing phagocytic clearance of photoreceptor outer segments by the overlying retinal pigment epithelial (RPE) monolayer and contributing to retinal degeneration. While substrate stiffness is known to influence RPE phagocytosis, conventional assays lack the spatial resolution to capture how mechanical cues coordinate behavior across the monolayer over time. Here, dynamic magnetorheological elastomer (MRE) substrates are combined with an automated machine-learning image-analysis pipeline to simultaneously quantify particle engagement kinetics, cell morphology, and spatial organization at single-cell resolution. This combination enables spatiotemporal observation of RPE mechanosensitivity inaccessible to population-level assays. Substrate stiffness shaped particle engagement kinetics, modulating engagement rate and maximum particle capacity. Soft substrates additionally increased cell area and eccentricity, suggesting stiffness-dependent cytoskeletal remodeling. Strikingly, cells with increased levels of particle engagement form spatially localized clusters whose organization was sensitive to substrate stiffness, revealing that mechanical cues coordinate engagement behavior at the tissue level rather than acting on cells independently. This work reveals how dynamic BrM stiffening drives coupled changes in particle engagement kinetics, cell morphology, and spatial coordination, highlighting the tissue-level complexity of RPE mechanosensitivity. Together, these findings reframe RPE particle engagement as a spatially coordinated, mechanosensitive process, providing new insight into how dynamic alterations in extracellular mechanical environments regulate cellular function. STATEMENT OF SIGNIFICANCE: The retinal pigment epithelium (RPE) clears cellular debris daily to maintain vision, a process that falters as the underlying tissue stiffens with age, a hallmark of macular degeneration. Existing tools capture only population averages on static surfaces, obscuring both the timing and spatial organization of the response. This study combines dynamically tunable substrates with automated machine-learning image analysis to quantify receptor-mediated particle engagement at single-cell resolution across time and space. Mechanical transitions, not stiffness magnitude alone, accelerate engagement rate while reducing total capacity. Cell shape predicts particle engagement activity in a stiffness-dependent manner, and highly active cells cluster spatially in patterns governed by the mechanical environment. These findings reframe RPE dysfunction as a spatially coordinated, mechanosensitive process with direct implications for early AMD.

Keywords: Mathematical Modeling; Mechanosensitivity; Phagocytosis; Retinal Pigment Epithelial; mechanobiology

DOI: https://doi.org/10.1016/j.actbio.2026.09.053

Genes Genomics. 2026 Sep 30.

Cisplatin-induced oxidative stress and ferroptosis-associated injury in retinal pigment epithelial cells attenuated by Toxoplasma gondii infection.

Xin-Cheng Wang, Yu-Sun Yun, In-Wook Choi, Wei Zhou, Jaemin Yuk, Guang-Ho Cha.

BACKGROUND: Cisplatin causes oxidative and iron-dependent injury, but whether it induces ferroptosis-associated damage in retinal pigment epithelial cells and how Toxoplasma gondii (T. gondii) can modify this response remain unclear.
OBJECTIVE: This study investigated cisplatin-induced oxidative stress, apoptosis, ferroptosis-associated changes, and iron dysregulation in ARPE-19 cells and evaluated the effects of acute T. gondii infection.
METHODS: ARPE-19 cells were exposed to increasing concentrations of cisplatin for 24 h. Cell viability, oxidative stress, antioxidant capacity, apoptosis-related proteins, ferroptosis-defense molecules, and intracellular iron were assessed using biochemical assays, fluorescence staining, reverse-transcription polymerase chain reaction, and western blotting. Cells treated with 20 μM cisplatin were additionally infected with T. gondii at a multiplicity of infection of 5 or treated with ferrostatin-1, deferoxamine, or Z-VAD-FMK.
RESULTS: Cisplatin reduced cell viability in a concentration-dependent manner, with a half-maximal inhibitory concentration of 20.37 μM, and increased reactive oxygen species, malondialdehyde, cleaved caspase-3, and Bax while decreasing superoxide dismutase, glutathione, and Bcl-xL. It also reduced GPX4 and SLC7A11 protein expression and FSP1 mRNA levels, while increasing FTH1 and SLC11A2 protein expression and intracellular Fe2+ and total iron. T. gondii infection improved viability, reduced oxidative stress and cleaved caspase-3, restored antioxidant capacity and GPX4/SLC7A11 expression, and limited iron accumulation. Ferrostatin-1 and deferoxamine did not markedly suppress apoptotic proteins, whereas Z-VAD-FMK inhibited apoptotic signaling without restoring GPX4 or SLC7A11.
CONCLUSIONS: Cisplatin induces concurrent oxidative stress, apoptosis, impairment of ferroptotic defense, and iron accumulation in ARPE-19 cells. Acute T. gondii infection attenuates these alterations by preserving redox balance, ferroptosis-defense pathways, and iron homeostasis.

Keywords: Toxoplasma gondii ; ARPE-19 cells; Cisplatin; Ferroptosis; Iron homeostasis; Oxidative stress

DOI: https://doi.org/10.1007/s13258-026-01806-3

PLoS One. 2026 ;21(9): e0359423

Dioscin attenuates D‑galactose‑induced retinal pigment epithelium senescence and epithelial-mesenchymal transition via the TGF‑β2/PI3K/Akt/β‑catenin pathway.

Qi Ouyang, Huiqin Zhou, Chenhao Ji, Hong Jiang, Linhui Zhao, Yiwei Pan, Shuanglin Xiang, Xiang Hu.

PURPOSE: This study aimed to evaluate the protective effects of Dioscin in an age-related macular degeneration (AMD) -like model and to explore its potential therapeutic mechanisms.
METHODS: The therapeutic potential of Dioscin for AMD was investigated using D-galactose-induced senescence models in ARPE-19 cells (an in vitro preliminary screening model) and C57BL/6J mice using RT-qPCR, western blotting, immunofluorescence, and SA-β-gal staining. Bioinformatic analysis and molecular docking identified TGF-β2 as a computationally predicted potential target of Dioscin in AMD. Key mechanisms involving TGF-β2 and the PI3K/Akt/β-catenin signaling pathway were assessed in vitro using RT-qPCR, western blotting.
RESULTS: In D-galactose-induced senescence models, Dioscin significantly alleviated RPE senescence and EMT. Single-cell transcriptome analysis revealed that TGF-β2 is highly expressed in choroidal vascular endothelial cells of AMD patients. Mechanistically, computational predictions (molecular docking and dynamics simulations) identified TGF-β2 as a computationally predicted potential target of Dioscin, and experimental data showed that Dioscin suppressed D-galactose-induced activation of the TGF-β2/PI3K/Akt/β-catenin pathway in RPE cells, suggesting a potential paracrine regulatory mechanism.
CONCLUSION: Dioscin alleviates RPE senescence and EMT through suppression of the TGF-β2/PI3K/Akt/β-catenin pathway. Single-cell transcriptomics reveals that TGF-β2 is specifically upregulated in choroidal vascular endothelial cells in AMD, suggesting a paracrine mechanism linking vascular pathology to RPE dysfunction. These findings suggest that Dioscin may have potential value in mitigating RPE senescence and EMT in an AMD‑like model, although further validation in more clinically relevant AMD models is required.

DOI: https://doi.org/10.1371/journal.pone.0359423

J Mol Med (Berl). 2026 Sep 28. pii: 114. [Epub ahead of print]104(1):

CTCF-FXN regulatory axis plays critical roles in clinical assessments and disease progression of primary open-angle glaucoma.

Danrui Cai, Yao Yu, Junze Ma, Ting Li, Ziyao Liu.

Primary open-angle glaucoma (POAG) is an irreversible ophthalmic disease that is the leading cause of blindness. Oxidative stress (OS) is considered an important contributor to POAG pathogenesis. However, its mechanism of action in POAG remains vague. FXN was identified as a candidate OS-related gene associated with POAG through WGCNA and two machine learning methods (LASSO regression and SVM-RFE). Through multiple bioinformatic analyses, FXN exhibited potential diagnostic value and was associated with immune-related signatures in POAG samples. GSEA revealed that high FXN expression was associated with enrichment of glycolysis- and pyruvate metabolism-related gene sets. FXN expression was significantly decreased in an H2O2 in vitro model (R28 cells). CCK8, EdU, TUNEL, ROS detection and flow cytometry assays indicated that FXN overexpression improved retinal ganglion cells (RGCs) viability and inhibited cell apoptosis and ROS accumulation. Mechanistically, CTCF was demonstrated to transcriptionally regulate FXN by binding to its promoter region, as confirmed by ChIP assay. FXN deletion partially abolished the protective effects of CTCF overexpression on RGC viability, apoptosis, and oxidative stress responses. In conclusions, FXN may represent a potential biomarker associated with POAG. The identification of the CTCF-FXN regulatory axis provides new insights into the molecular mechanisms underlying POAG.

Keywords: CTCF; FXN; Oxidative stress; Primary open-angle glaucoma

DOI: https://doi.org/10.1007/s00109-026-02717-2

Eur J Med Chem. 2026 Sep 23. pii: S0223-5234(26)00806-8. [Epub ahead of print]320 119361

The oxidative and carbonyl stress axis in anti-vascular endothelial growth factor-refractory neovascular age-related macular degeneration: Implications for therapeutic repurposing.

BACKGROUND AND PURPOSE: Neovascular age-related macular degeneration is a leading cause of irreversible blindness, and approximately 25% of patients respond inadequately to intravitreal anti-VEGF therapy, representing a major unmet clinical need. We aimed to identify repurposable therapeutic alternatives by anchoring a phenotypic screen in the molecular signature of inadequate responders.
EXPERIMENTAL APPROACH: The molecular phenotype of the disease was characterised by data-independent acquisition proteomic profiling of peripheral blood mononuclear cells from patients with an inadequate anti-VEGF response and from controls. Guided by this signature, the Prestwick Chemical Library (1160 approved compounds) was screened in ARPE-19 retinal pigment epithelial cells exposed to cigarette smoke extract. Cytoprotection was assessed by a primary viability assay and examined further by orthogonal high-content imaging of intracellular reactive oxygen species and by concentration-range evaluation.
KEY RESULTS: Baseline profiling showed increased thiol-reductase, lipid-peroxidation, platelet and immune-redox pathways, together with reduced high-density-lipoprotein-associated antioxidant components. Dual angiopoietin-2/VEGF inhibition partially reversed these changes, with oxidative and carbonyl stress emerging as a prominent axis. The single-replicate primary screen performed robustly and recovered 29 primary hits, including established antioxidants, which attenuated intracellular reactive oxygen species in the orthogonal assay. Of six candidates advanced to concentration-range evaluation, todralazine produced the most consistent and pronounced protective effect.
CONCLUSION AND IMPLICATIONS: These preliminary findings nominate todralazine, a hydrazinophthalazine structurally related to known carbonyl-scavenging agents, as a repurposable candidate requiring mechanistic and translational validation, and illustrate the value of anchoring phenotypic screens in disease-relevant molecular signatures.

Keywords: Age-related macular degeneration; Anti-VEGF; Drug repurposing; Oxidative stress; Proteomics; Retinal pigment epithelium; Todralazine

DOI: https://doi.org/10.1016/j.ejmech.2026.119361

Ann Agric Environ Med. 2026 Sep 21. pii: 219307. [Epub ahead of print]33(3): 425-430

Expression of miR-802 in glaucoma and its diagnostic significance.

Tingting Zhang, Yufei Wang.

INTRODUCTION AND OBJECTIVE: Glaucoma ranks as the second leading cause of blindness globally. The key factors leading to glaucoma are increased intraocular pressure and retinal ganglion cell apoptosis. Glaucoma is an irreversible disease that causes blindness in the eye, characterized by progressive optic nerve damage and visual field defects. The expression of miR-802 is abnormal in the plasma of glaucoma patients, but its function and mechanism remain unclear. The aim of the study is to investigate the expression of miR-802 in glaucoma and retinal ganglion cells, and the effect of miR-802 on 661W cells under oxidative stress.
MATERIAL AND METHODS: The study used RT-qPCR to detect the expression level of miR-802 in 661W cells and glaucoma patients. Receiver operating characteristic curve (ROC) was used to assess the diagnostic value of miR-802 in glaucoma. Cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay, while cell apoptosis was detected via flow cytometry.
RESULTS: In glaucoma patients, miR-802 expression was significantly downregulated and correlated with elevated IOP, reduced RNFL, and increased eGFR. MiR-802 demonstrated exceptional diagnostic value for the onset of glaucoma. In addition, decreased miR-802 expression was a risk factor associated with glaucoma. MiR-802 accelerated the proliferation of 661W cells and slowed down the apoptosis rate. Moreover, miR-802 mimic inhibited H2O2-induced 661W cell apoptosis.
CONCLUSIONS: Upregulation of miR-802 alleviated oxidative stress-induced damage in 661W cells. miR-802 might be used as a marker for detecting glaucoma.

Keywords: 661W cells; MiR-802; apoptosis rate; glaucoma; oxidative stress

DOI: https://doi.org/10.26444/aaem/219307