bims-mideyd 2025-02-09 papers

Eur J Pharmacol. 2025 Jan 29. pii: S0014-2999(25)00069-X. [Epub ahead of print]991 177316

Tyrosol protects RPE cells from H2O2-induced oxidative damage in vitro and in vivo through activation of the Nrf2/HO-1 pathway.

Longtai You, Wenwen Zhao, Xiao Li, Chunjing Yang, Peng Guo.

Oxidative stress-induced damage to the retinal pigment epithelium (RPE) is a critical factor in the pathogenesis of age-related macular degeneration (AMD). Tyrosol is a phenolic compound with antioxidant properties, but its protective effect against oxidative stress-induced AMD and its underlying mechanisms are unknown. The aim of this study was to investigate the protective effects of tyrosol on hydrogen peroxide (H2O2)-induced retinal damage and demonstrate its underlying mechanisms in ARPE-19 cells and C57BL/6J mice retinas. We found that tyrosol significantly enhanced the survival of ARPE-19 cells under H2O2-induced oxidative stress in a concentration-dependent manner. It effectively attenuated the production of reactive oxygen species (ROS) and lipid peroxides, while also counteracting the associated reduction in glutathione (GSH) concentration and superoxide dismutase (SOD) activity. Furthermore, pretreatment with tyrosol ameliorated apoptosis-related damage in ARPE-19 cells induced by H2O2 and normalized the levels of apoptosis-related proteins. Notably, tyrosol significantly upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant enzymes heme oxygenase-1 (HO-1) and NADPH dehydrogenase quinone 1 (NQO1). Interestingly, in vivo study demonstrated that tyrosol administration effectively improved retinal function and morphology in H2O2-exposed mice, restored the thickness of the outer nuclear layer and inner core layer, and normalized the expression of proteins Bax, cleaved caspase-3, and Nrf2, which was consistent with the results of in vitro experiments. Overall, our findings suggest that tyrosol can protect RPE cells from oxidative stress damage by activating the Nrf2/HO-1 pathway, which may be a promising new strategy for the treatment of AMD.

Keywords: ARPE-19 cells; Age-related macular degeneration; Mice; Oxidative stress; Retinal pigment epithelium; Tyrosol

DOI: https://doi.org/10.1016/j.ejphar.2025.177316

Invest Ophthalmol Vis Sci. 2025 Feb 03. 66(2): 2

Lamp2 Deficiency Enhances Susceptibility to Oxidative Stress-Induced RPE Degeneration.

Guannan Wu, Shoji Notomi, Ziming Xu, Yosuke Fukuda, Yusuke Maehara, Yan Tao, Huanyu Zhao, Keijiro Ishikawa, Yusuke Murakami, Toshio Hisatomi, Koh-Hei Sonoda.

Purpose: Autophagy and lysosomal degradation are vital processes that protect cells from oxidative stress. This study investigated the role of lysosome-associated membrane protein 2 (Lamp2), a lysosomal protein essential for autophagosome maturation and lysosome biogenesis, in maintaining retinal health under oxidative stress.
Methods: To induce oxidative stress, young Lamp2 knockout (KO) and wild-type mice received an intravenous injection of a low dose (10 mg/kg) of sodium iodate (NaIO3). We examined retinal histopathology and morphological changes in the RPE. The involvement of resident microglia or infiltrating macrophages was assessed using immunostaining, flow cytometry, and real-time PCR for chemokines and cytokines.
Results: After administering a low-dose NaIO3, Lamp2 KO mice showed significant RPE degeneration, whereas wild-type mice had minimal damage. Histological analysis and electron microscopy revealed significant thinning of the outer nuclear layer and loss of RPE epithelial polarity in Lamp2 KO mice. Additionally, there was a significant increase in ionized calcium-binding adaptor molecule 1-positive microglia and macrophages in the outer retina. Early proliferation of CD45lowMHC-IIlow resident microglia was followed by the infiltration of CD45highLy6Chigh monocytes and the engraftment of CD11b+CD45high monocyte-derived macrophages. Transcript levels of monocyte chemoattractant protein 1, macrophage inflammatory protein 1β, Il- 1β, and Il-6 also increased in the retinas of Lamp2 KO mice. Furthermore, pretreatment with the macrophage-depleting agent clodronate prevented NaIO3-induced RPE degeneration and macrophage infiltration in Lamp2 KO mice.
Conclusions: Lamp2 deficiency, when combined with oxidative stress, leads to RPE degeneration in vivo. Lysosomal dysfunction also promotes macrophage engraftment and triggers neurotoxic inflammation.

DOI: https://doi.org/10.1167/iovs.66.2.2

Biochim Biophys Acta Mol Basis Dis. 2025 Feb 04. pii: S0925-4439(25)00050-X. [Epub ahead of print]1871(3): 167705

Exogenous hydrogen sulfide and NOX2 inhibition mitigate ferroptosis in pressure-induced retinal ganglion cell damage.

Yuan Feng, Xiaosha Wang, Panpan Li, Xin Shi, Verena Prokosch, Hanhan Liu.

Glaucoma, a leading cause of irreversible blindness worldwide, is characterized by the progressive degeneration of retinal ganglion cells (RGCs). While elevated intraocular pressure (IOP) significantly contributes to disease progression, managing IOP alone does not completely halt it. The mechanisms underlying RGCs loss in glaucoma remain unclear, but ferroptosis-an iron-dependent form of oxidative cell death-has been implicated, particularly in IOP-induced RGCs loss. There is an urgent need for neuroprotective treatments. Our previous research showed that hydrogen sulfide (H2S) protects RGCs against glaucomatous injury. This study aims to investigate the interplay between elevated pressure, mitochondrial dysfunction, iron homeostasis, and ferroptosis in RGCs death, focusing on how H2S may mitigate pressure-induced ferroptosis and protect RGCs. We demonstrate alterations in iron metabolism and mitochondrial function in a subacute IOP elevation model in vivo. In vitro, we confirm that elevated pressure, iron overload, and mitochondrial dysfunction lead to RGCs loss, increased retinal ferrous iron and total iron content, and heightened reactive oxygen species (ROS). Notably, pressure increases NADPH oxidase 2 (NOX2) and decreases glutathione peroxidase 4 (GPX4), a key regulator of ferroptosis. NOX2 deletion or inhibition by H2S prevents pressure-induced RGCs loss and ferroptosis. Our findings reveal that H2S chelates iron, regulates iron metabolism, reduces oxidative stress, and mitigates ferroptosis, positioning slow-releasing H2S donors are positioning as a promising multi-target therapy for glaucoma, with NOX2 emerging as a key regulator of ferroptosis.

Keywords: Ferroptosis; Hydrogen sulfide; Mitochondrial function; Retinal ganglion cells; glaucoma therapy; iron metabolism

DOI: https://doi.org/10.1016/j.bbadis.2025.167705