bims-mideyd 2025-10-19 papers

J Transl Med. 2025 Oct 15. 23(1): 1103

Ferrostatin-1, a ferroptosis inhibitor, mitigates all-trans-retinal-induced retinal pigment epithelium degeneration in mice.

Xiaoqing Shen, Yuling Chen, Beiting He, Ruitong Xi, Jingmeng Chen, Yalin Wu.

BACKGROUND: Disruption of the retinoid (visual) cycle causes all-trans-retinal (atRAL) to accumulate in photoreceptors and retinal pigment epithelium (RPE), contributing to Stargardt disease type 1 (STGD1) and dry age-related macular degeneration (dAMD). Yet, the mechanisms underlying atRAL-induced RPE degeneration are not well understood. Here, we explored whether ferroptosis, a form of regulated cell death marked by iron-dependent lipid peroxidation, mediated RPE damage by atRAL.
METHODS: Cell and animal models of STGD1 and dAMD were established using ARPE-19 cells loaded with atRAL and Abca4-/-Rdh8-/- mice subjected to light exposure. Cell viability and morphology, mitochondrial morphology, ferrous iron (Fe2+) levels, reactive oxygen species (ROS) production, lipid peroxidation, and ferroptosis-related gene and protein expression were assessed using MTS assay, inverted and confocal microscopy, fluorescence staining, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting, respectively. The conditions of mouse retina were evaluated by electroretinography (ERG), optical coherence tomography (OCT), fundus imaging, and immunofluorescence labeling.
RESULTS: atRAL triggered ferroptosis of ARPE-19 cells through Fe2+ accumulation, ROS generation, lipid peroxidation, mitochondrial damage, and abnormal expression of typical ferroptosis-related genes and proteins. These effects were capable of being alleviated by treatment with ferrostatin-1 (Fer-1), a potent ferroptosis inhibitor. Moreover, ferroptosis was clearly observed in the RPE of light-exposed Abca4-/-Rdh8-/- mice that showed rapid and excessive accumulation of atRAL in the retina. Notably, intraperitoneal administration of Fer-1 effectively mitigated the degeneration of the RPE and photoreceptors and significantly ameliorated retinal function in Abca4-/-Rdh8-/- mice following light exposure.
CONCLUSIONS: Ferroptosis plays a critical role in RPE damage by atRAL. Inhibition of ferroptosis by Fer-1 may enhance RPE cell survival and prevent subsequent photoreceptor degeneration in STGD1 and dAMD.

Keywords: Age-related macular degeneration; Ferroptosis; Lipid peroxidation; Retinal pigment epithelium; Stargardt disease

DOI: https://doi.org/10.1186/s12967-025-07195-7

Folia Histochem Cytobiol. 2025 Oct 14.

Tectochrysin alleviates high-glucose-induced retinal pigment epithelial cell injury through Nrf2/HO-1 activation.

Yuan Sui, Chengsen Zhang, Bingbing Jiang, Wei Li, Shuang Wang.

INTRODUCTION: Diabetic retinopathy involves retinal pigment epithelium (RPE) dysfunction. Tectochrysin is a natural flavonoid and antioxidant. However, its effects on retinal pigment epithelial cells remain unveiled. In this study, the investigation undertook the question of whether tectochrysin could protect human adult RPE cells ARPE-19 from high-glucose (HG) damage. Also the potential regulatory mechanism was explored.
MATERIAL AND: METHODS: Cell counting assay 8(CCK8) was used to measure cell viability in ARPE-19 cells with tectochrysin treatment for 72 h to confirm the potential cytotoxicity. Furthermore, cells were treated by HG (40 mM glucose) for 48 h with or without tectochrysin treatment (5 or 10 μg/mL). Then cell viability, apoptosis and Reactive Oxygen Species (ROS) levels were evaluated using CCK8, flow cytometry and DCFH-DA fluorescence methods. Migration capacity was evaluated using wound healing and Transwel assays. In addition, malondialdehyde (MDA) content, glutathione (GSH), and Fe²⁺ levels were also examined with kits. Protein expression of ferroptosis markers (ACSL4, GPX4), EMT-related proteins (E-cadherin, vimentin, Snail), and Nrf2/HO-1 were determined using western blotting.
RESULTS: In ARPE-19 cells tectochrysin (5 or 10 μg/mL) significantly reversed HG-induced cytotoxicity, reducing apoptosis, ROS, MDA and Fe²⁺ levels, and increasing GSH. Tectochrysin reversed HG-induced ferroptosis-related protein ACSL4 and restored HG-inhibited GPX4 expression. In addition, tectochrysin inhibited HG-induced cell migration and vimentin and Snail levels and restored expression of HG-inhibited mesenchymal marker E-cadherin. Moreover, tectochrysin activated the Nrf2/HO-1 pathway.
CONCLUSIONS: The findings demonstrate that tectochrysin protects ARPE-19 cells from HG-induced injury by inhibiting apoptosis, ferroptosis and EMT while activating Nrf2/HO-1 signaling, suggesting its potential as a therapeutic agent for diabetic retinopathy.

Keywords: apoptosis; ferroptosis; flavonoid; oxidative stress

DOI: https://doi.org/10.5603/fhc.107923

J Agric Food Chem. 2025 Oct 13.

Hesperidin and Hesperetin from Orange Peel Water Extract Protect against NaIO3-Induced Oxidative Damage in Retinal Pigment Epithelial Cells by Modulating PI3K/Akt/HIF-1α/BNIP3 Signaling.

Jui-Hsuan Yeh, Yuan-Yen Chang, Chen-Ju Chuang, Tzu-Chun Chen, Shang-Chun Tsou, Chieh-Jung Huang, Yi-Hsien Hsieh, Inga Wang, Ming-Chung Lee, Hui-Wen Lin.

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly, with oxidative stress a major causative factor. Orange peel, rich in polyphenols and flavonoids, possesses potent antioxidant and anti-inflammatory activities. This study evaluated the protective effects of an ultrasound-assisted aqueous extract (OPWE) of orange peel and its major components, hesperidin and hesperetin, against sodium iodate (NaIO3)-induced retinal damage. Component identification was performed using 3D-HPLC and LC/MS, and the antioxidant capacity was determined using the DPPH and ABTS assays. In vitro, OPWE reduced oxidative stress, mitochondrial dysfunction, and apoptosis in NaIO3-treated ARPE-19 cells through the PI3K/Akt and HIF-1α/BNIP3 pathways. Notably, hesperetin exhibited comparable protective effects to OPWE, restoring cell viability and inhibiting ROS production. In vivo, oral administration of OPWE maintained retinal morphology and function in mice induced by NaIO3. These findings suggest that OPWE, especially hesperetin, is a promising natural candidate for preventing oxidative stress-related retinal degeneration and maintaining retinal health.

Keywords: age-related macular degeneration (AMD); apoptosis; orange peel water extract (OPWE); reactive oxygen species (ROS); sodium iodate (NaIO3)

DOI: https://doi.org/10.1021/acs.jafc.5c03766

J Physiol Sci. 2025 Oct 01. pii: S1880-6546(25)00109-X. [Epub ahead of print]75(3): 100045

LAMC1 aggravates diabetic retinopathy through PI3K/AKT signaling-regulated epithelial-mesenchymal transition in retinal pigment epithelial cells.

Lei Liu, Yanlin Gao, Shiqi Yao.

Diabetic retinopathy (DR), a leading cause of adult blindness, with LAMC1-mediated epithelial-mesenchymal transition (EMT) playing a key role. By analyzing DR-related microarray datasets (GSE60436/GSE102485) from GEO, we identified 685 differentially expressed genes (570 downregulated, 115 upregulated). Functional and WGCNA analyses linked these to PI3K/Akt signaling, revealing 11 diagnostic hub genes, including LAMC1. Western blot analysis confirmed that LAMC1 significantly upregulated in high glucose (HG)-treated ARPE-19 cells and diabetic mouse retinas. In vitro and in vivo experiments confirmed that LAMC1 promotes EMT in retinal pigment epithelial (RPE) cells via PI3K/Akt activation, enhancing migration and invasion. Conversely, LAMC1 knockdown alleviated retinal damage in diabetic mice. Our studies uncovered that LAMC1's role in DR progression through PI3K/Akt-driven EMT, suggesting its potential as a therapeutic target.

Keywords: Diabetic retinopathy; EMT; LAMC1; PI3K/Akt signaling pathway

DOI: https://doi.org/10.1016/j.jphyss.2025.100045

Int J Mol Sci. 2025 Sep 26. pii: 9442. [Epub ahead of print]26(19):

Modulation of mTOR Within Retinal Pigment Epithelium Affects Cell Viability and Mitochondrial Pathology.

Gloria Lazzeri, Michela Ferrucci, Paola Lenzi, Maria Anita Giambelluca, Francesca Biagioni, Carla Letizia Busceti, Alessandro Frati, Francesco Fornai.

The relevance of well-structured mitochondria in sustaining the integrity of the retinal pigment epithelium (RPE) is increasingly evident. Conversely, altered mitochondria are a culprit of age-related macular degeneration (AMD), which is influenced by the activity of mechanistic target of rapamycin (mTOR). In the present manuscript, the mitochondrial status of RPE cells was investigated by light and electron microscopy following the administration of various doses of compounds, which modulate mTOR. The study combines MitoTracker dyes and mitochondrial immunohistochemistry with in situ mitochondrial morphometry. Various doses of 3-methyladenine (3-MA), curcumin, and rapamycin were administered alone or in combination. The activity of autophagy and mTOR was quantified following each treatment. Administration of 3-MA led to activation of mTOR, which was associated with severe cell death, altered membrane permeability, and altered ZO-1 expression. In this condition, mitochondrial mass was reduced, despite a dramatic increase in damaged mitochondria being reported. The decrease in healthy mitochondria was concomitant with alterations in key mitochondria-related antigens such as Tomm20, Pink1, and Parkin. Specific mitochondrial alterations were quantified through in situ ultrastructural morphometry. Both curcumin and rapamycin counteract mTOR activation and rescue mitochondrial status, while preventing RPE cell loss and misplacement of decreased ZO-1 expression. Mitigation of mTOR may protect mitochondria in retinal degeneration.

Keywords: MitoTracker Green; MitoTracker Red; PINK1; Parkin; Tomm20; ZO-1; autophagy; curcumin; mitochondrial morphology; mitochondrial ultrastructure; rapamycin

DOI: https://doi.org/10.3390/ijms26199442

Commun Biol. 2025 Oct 16. 8(1): 1475

OPTN protects retinal ganglion cells and ameliorates neuroinflammation in optic neuropathies.

Qinglong Wang, Yiqi Wang, Yi Da Douglas Jiang, Ryan Donahue, Gaby Cao, Weixuan Yan, Hong Guo, Zhenghui Li, Jenna Liang, Jin Hao, Yi Lu, Fengfeng Bei, Qianbin Wang, Feng Tian.

Optineurin (OPTN) is an adaptor protein that plays a crucial role in many cellular pathways, including NF-κB signaling, programmed cell death, and vesicular trafficking. OPTN dysfunction has been implicated in the pathogenesis of several diseases, such as primary open angle glaucoma (POAG), amyotrophic lateral sclerosis (ALS). While mutations of OPTN seem to be predominantly loss-of-function in ALS, only gain-of-function mechanisms have been reported in POAG. Here, we demonstrate that OPTN knockout in the retina contributes to short-term astrogliosis, retinal ganglion cell (RGC) loss and long-term microglial activation. Moreover, OPTN loss of function does not exacerbate RGC death induced by ocular hypertension. Integrated bioinformatics and immunofluorescence analyses reveal that OPTN dysfunction leads to neuropeptide Y (NPY) downregulation and CHOP upregulation. Overexpression of wild-type OPTN in a hypertension glaucoma model prevents the RGC loss and attenuates microglial activation. Together, our findings highlight a neuroprotective role for OPTN as a key neuroimmune modulator.

DOI: https://doi.org/10.1038/s42003-025-08534-6