bims-mideyd 2026-02-15 papers

J Biochem Mol Toxicol. 2026 Feb;40(2): e70738

Selenium Nanoparticles Protect Retinal Pigment Epithelial Cells Against Experimental Age-Related Macular Degeneration-Induced Mitochondrial Oxidative Toxicity and Apoptosis Through the Modulation of the TRPM2 Channel.

Mehmet Argun, Mustafa Nazıroğlu.

Excessive Ca2+ influx leads to mitochondrial oxidative injury and cell death, contributing to the development of age-related macular degeneration (AMD). The protective role of selenium nanoparticle (SeNPs), through inhibition of ADP-ribose- and hydrogen peroxide (H2O2)-induced TRPM2 cation channel stimulation, was recently reported in human retinal pigment epithelial 19 (ARPE-19) cells for hypoxia-induced oxidative cytotoxicity and cell death, but not for AMD. We aimed to investigate the protective effects of SeNPs through inhibition of TRPM2 on AMD (sodium iodate [NaI])-induced oxidative injury, cell death, and apoptosis in ARPE-19 cells. The ARPE-19 cells were divided into four main groups: control (CNT), SeNPs (2.5 μg/mL for 24 h), AMD (10 mM NaI for 24 h) and AMD + SeNPs. The AMD treatment increased TRPM2 current density and cytosolic Ca2+ and Zn2+ fluorescence intensities, as well as the percentage of cell death. It also elevated apoptotic markers (caspases 3, 8, and 9) and oxidative stress markers (mitochondrial membrane dysfunction, oxygen free radicals, and lipid peroxidation), while decreasing antioxidants (glutathione and glutathione peroxidase), cell viability and the number of live cells. TRPM2 stimulation further increased these markers. When SeNPs and TRPM2 antagonists were used to treat the AMD-induced increase in TRPM2 activation, they increased antioxidants and cell viability while decreasing oxidative stress and cell death markers. In conclusion, SeNP treatment reduced AMD-induced mitochondrial oxidative cytotoxicity and cell death by inhibiting TRPM2-mediated Ca2+ signaling. SeNP represents a potential therapeutic option for AMD-induced retinal disorders linked to abnormal oxygen free radical production and Ca2+ influx.

Keywords: TRPM2 channel; age‐related macular degeneration; apoptosis; oxidative cytotoxicity; selenium nanoparticles

DOI: https://doi.org/10.1002/jbt.70738

Indian J Ophthalmol. 2026 Feb 11.

Ferroptosis in retinal pigment epithelial cells: Current status and future developments.

Wen Liu, Wenwen Li, Dan Wang, Peijuan Wu, Jieyu Jiang, Zhiming Liu, Xiangdong Chen.

ABSTRACT: Retinal pigment epithelial (RPE) cells play a crucial role in maintaining the normal function of the retina. In recent years, research on ferroptosis-a novel iron-dependent form of cell death-in RPE cells has gradually attracted attention. This article reviews the mechanisms of ferroptosis in RPE cells, including iron metabolism imbalance, lipid peroxidation, and functional impairment of the glutathione-glutathione peroxidase 4 (GSH-GPX4) system. It explores the association between ferroptosis in RPE cells and retinal diseases such as age-related macular degeneration and Stargardt disease. Additionally, it analyzes the future challenges in current research on ferroptosis in RPE cells, such as gaining in-depth understanding of complex regulatory networks and developing precise intervention strategies, so as to provide new insights and directions for the prevention and treatment of retinal diseases.

Keywords: Age-related macular degeneration; ferroptosis; iron metabolism imbalance; retina; retinal pigment epithelial cells

DOI: https://doi.org/10.4103/IJO.IJO_2875_25

Mol Ther. 2026 Feb 06. pii: S1525-0016(26)00091-2. [Epub ahead of print]

AAV NRF2 Gene Therapy Preserves Retinal Structure and Function in Rodent Models of Oxidative Damage.

Apolonia Gardner, Shuai Wang, Adam Daniels, Dan Li, Christine Wu, Lucas Lin, Christin Hong, Sophia R Zhao, Kamil Kruczek, Genevieve Weist, Laura Barrio Real, Joan Wicks, Mohamad Nayal, Ashley Carter, Christine Ott, Virginia Haurigot, Richard T Born, Constance L Cepko.

Dry age-related macular degeneration is the most frequent cause of visual impairment in individuals over age 50 in developed countries. It is characterized by deposits of oxidized proteins and lipids and results in progressive loss of high acuity vision. One major risk factor is smoking, which causes oxidative stress in many tissues, including the eye. We previously showed that an adeno-associated viral vector expressing human NRF2 (AAV8/Best1-NRF2), a transcription factor that regulates responses to oxidative damage, slowed degeneration in mouse models of another blinding disorder, retinitis pigmentosa, which also includes oxidative stress. Here, our AAV8/Best1-NRF2 vector was tested in a model of oxidative stress wherein sodium iodate was injected systemically, as this is often used to model dry age-related macular degeneration. Sodium iodate causes acute oxidative damage to the retinal pigment epithelial cells, which provide support to the photoreceptor cells. In addition, this toxin ultimately leads to photoreceptor death. Subretinal injection of AAV8/Best1-NRF2 led to protection of the retinal pigment epithelium and photoreceptors, as well as preservation of visual function, in rat and mouse sodium iodate models. AAV8/Best1-NRF2 may serve as an effective gene-agnostic therapy for diseases with oxidative stress, including dry age-related macular degeneration.

DOI: https://doi.org/10.1016/j.ymthe.2026.02.005

Biomed Pharmacother. 2026 Feb 06. pii: S0753-3322(26)00138-1. [Epub ahead of print]196 119106

Redox, inflammatory, and ferroptosis pathway modulation by methotrexate and dexamethasone in primary human RPE cells under basal and acute H₂O₂-induced oxidative stress: An in vitro study.

Zahra Souri, Mohammad Malekahmadi.

PURPOSE: Oxidative stress, inflammation, and ferroptosis drive retinal disease. Methotrexate (MTX) and dexamethasone (DEX) are clinically used to counter these insults, but their effects on retinal pigment epithelium (RPE) homeostasis remain unclear. This study investigates how MTX, DEX, and their combination affect cell viability, redox balance, inflammatory signaling, and ferroptosis-related gene expression in human RPE cells under basal and oxidative stress conditions.
METHODS: Human RPE cells were exposed to 100 µM H2O2 for 24 h and treated with MTX (100 µg/ml), DEX (50 µg/ml), or their combination. Cell viability was assessed using MTT assay. Total oxidant status (TOS), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD) were measured from cell lysates. IL-6, IL-8, IL-10, and TGF-β levels were quantified by ELISA, and GPX4, ACSL4, and SLC7A11 mRNA expression was measured by qPCR.
RESULTS: Under basal conditions, treatments did not affect viability. DEX and combination increased TOS, with MDA elevated by combination only. CAT activity increased with DEX. MTX reduced IL-8, DEX reduced IL-6, and combination reduced IL-6, IL-8, and TGF-β. GPX4, ACSL4, and SLC7A11 decreased with all treatments. Under oxidative stress, viability declined. DEX restored CAT activity; IL-6 and IL-8 were reduced by both drugs, while combination additionally reduced TGF-β and IL-10. GPX4 increased with MTX and combination, ACSL4 with combination, and SLC7A11 with MTX.
CONCLUSIONS: MTX and DEX exert context-dependent effects in RPE cells. Basally, they induce adaptive preconditioning; under oxidative stress, combination therapy triggers a coordinated protective response. These findings support strategies integrating redox modulation, immune regulation, and ferroptosis control to preserve RPE function.

Keywords: Ferroptosis; Inflammation; Oxidative stress; Retinal pigment epithelium (RPE)

DOI: https://doi.org/10.1016/j.biopha.2026.119106