bims-mideyd 2024-12-15 papers

Free Radic Res. 2024 Dec 08. 1-13

Urban aerosol particulate matter promotes cellular senescence through mitochondrial ROS-mediated Akt/Nrf2 downregulation in human retinal pigment epithelial cells.

Beom Su Park, EunJin Bang, Hyun Hwangbo, Gi-Young Kim, JaeHun Cheong, Yung Hyun Choi.

Urban aerosol particulate matter (UPM) is widespread in the environment, and its concentration continues to increase. Several recent studies have reported that UPM results in premature cellular senescence, but few studies have investigated the molecular basis of UPM-induced senescence in retinal pigment epithelial (RPE) cells. In this study, we primarily evaluated UPM-induced premature senescence and the protective function of nuclear factor erythroid 2-related factor 2 (Nrf2) in human RPE ARPE-19 cells. The findings indicated that UPM exposure substantially induced premature cellular senescence in ARPE-19 cells, as observed by increased β-galactosidase activity, expression levels of senescence-associated marker proteins, and senescence-associated phenotypes. Such UPM-induced senescence is associated with mitochondrial oxidative stress-mediated phosphatidylinositol 3'-kinase/Akt/Nrf2 downregulation. Sulforaphane-mediated Nrf2 activation Sulforaphane-mediated upregulation of phosphorylated Nrf2 suppressed the decrease in its target antioxidant gene, NAD(P)H quinone oxidoreductase 1, under UPM, which notably prevented ARPE-19 cells from UPM-induced cellular senescence. By contrast, Nrf2 knockdown exacerbated cellular senescence and promoted oxidative stress. Collectively, our results demonstrate the regulatory role of Nrf2 in UPM-induced senescence of RPE cells and suggest that Nrf2 is a potential molecular target.

Keywords: Urban aerosol particulate matter; cellular senescence; nuclear factor erythroid-related factor 2; oxidative stress; retinal pigment epithelial cells

DOI: https://doi.org/10.1080/10715762.2024.2438919

J Biol Chem. 2024 Dec 07. pii: S0021-9258(24)02556-0. [Epub ahead of print] 108054

Transferrin ameliorates retinal degeneration by mediating the dimerization of all-trans-retinal.

Lei Tao, Danxue He, Yuling Chen, Kunhuan Yang, Beiting He, Peixin Cai, Binxiang Cai, Chunyan Liao, Zuguo Liu, Shiying Li, Jingmeng Chen, Yalin Wu.

High levels of all-trans-retinal (atRAL) in the retina is considered to be responsible for the development of autosomal recessive Stargardt's disease (STGD1) and dry age-related macular degeneration (dAMD). Two bisretinoids, all-trans-retinal dimer (atRAL-dimer) and N-retinyl-N-retinylidene ethanolamine (A2E), form from the dimerization of atRAL in the retina but they possess much lower toxicity and phototoxicity toward retinal pigment epithelium (RPE) cells than atRAL. Here, we introduced a novel function of transferrin (TRF) in mediating the conversion of atRAL into atRAL-dimer and A2E, which effectively protected the retina from damage by atRAL and prevented retinal function decline in mice, and rescued atRAL-loaded RPE cells. Moreover, TRF-mediated conversion of atRAL to atRAL-dimer and A2E required the help of bicarbonate ions (HCO3─). atRAL had the capacity to stimulate the expression of TRF in RPE and photoreceptor cells as well as RPE/choroid and neural retina of mice, reflecting that the elevation of TRF levels by atRAL is most likely to help defy level increase and cytotoxicity of atRAL through facilitating its dimerization and thereby serves as a mechanism of retinal self-protection. Our findings offer a promising avenue for the treatment of retinopathies characterized by disrupted clearance of atRAL.

Keywords: all-trans-retinal; dimerization; macular degeneration; transferrin

DOI: https://doi.org/10.1016/j.jbc.2024.108054

Int Immunopharmacol. 2024 Dec 05. pii: S1567-5769(24)02257-4. [Epub ahead of print]145 113735

Neutrophils promote laser-induced choroidal neovascularization by increasing pro-inflammatory cytokines secretion and cell cycle arrest in retinal pigment epithelium.

Qian Fan, Xian Song, Mengyao Li, Qian Xu, Chenfei Yan, Haiming Li, Yi Qu.

Inflammation is hypothesized to have essential functions in the development of wet age-related macular degeneration (AMD). Polymorphonuclear neutrophils (PMNs), recognized as major players in inflammation, are typically the first leukocytes to be recruited to an inflammatory site. Previous studies have identified neutrophil aggregates in the lesion site of the choroidal neovascularization model, and systemic depletion of neutrophils in adult mice is associated with reduced choroidal neovascularization (CNV) area, suggesting a pivotal role of PMNs in CNV pathogenesis. Here, we investigate the role of neutrophils in promoting CNV, a key feature of wet AMD. The malfunction and demise of retinal pigment epithelium cells are essential elements in CNV pathogenesis. Our hypothesis posits that neutrophils exacerbate CNV by influencing pro-inflammatory cytokines secreted by retinal pigment epithelium (RPE) cells. Using in vivo laser-induced CNV models with mice and in vitro experiments with the human ARPE-19 cell line, we demonstrated that co-culturing neutrophils with ARPE-19 cells induces an increase in pro-inflammatory cytokines and leads to S-phase cell cycle arrest, potentially through the induction of double-strand breaks (DSBs). Further exploration of this interaction revealed a potential pathway involving reactive oxygen species (ROS) and microRNA-23a, wherein PMNs induce DSBs by initiating the downregulation of LB1 via microRNA-23a. Additionally, we found that dHL-60 cell line could serve as a substitute for primary PMNs, highlighting its potential as a valuable tool in experimental models involving interactions with retinal cells. Our findings underscore the significant role of neutrophils in CNV pathogenesis, providing insights into potential therapeutic targets for wet AMD.

Keywords: Choroidal neovascularization; Double-strand breaks; Inflammation; Neutrophils; Retinal pigment epithelium cells

DOI: https://doi.org/10.1016/j.intimp.2024.113735

Toxicol Appl Pharmacol. 2024 Dec 10. pii: S0041-008X(24)00323-5. [Epub ahead of print] 117124

Epigallocatechin gallate ameliorates retinal pigment epithelial cell damage via the CYFIP2 /AKT pathway.

Sijia Li, Dongmei Su, Shanshan Hu, Qiang Hu, Dawei Sun.

Age-related macular degeneration (AMD) is a representative age-related ophthalmic disease, and the pathogenesis of AMD remains unclear. This research intended to determine whether epigallocatechin gallate (EGCG) could alleviate the progression of AMD and the possible mechanism. We constructed three groups of mice (young, aged, and EGCG), and HE and TUNEL staining of retinal tissues was performed to observe the structural changes in the retinal pigment epithelial (RPE) layer and the level of apoptosis, respectively. Through RNA-Sequencing analysis of retinal tissues and by RT-qPCR, GO, KEGG, and literature analyses, we identified cytoplasmic fragile X mental retardation 1-interacting protein 2 (CYFIP2) as a possible effector gene for EGCG action and validated its role by immunofluorescent and western blotting experiments. The CCK-8 and Hoechst 33342 apoptosis assays, and western blotting and qRT-PCR assays showed that EGCG reduced hydrogen peroxide (H2O2)-induced apoptosis in adult human RPE (ARPE-19) cells, and the expression of Cyfip2 was changed accordingly. RNA interference analysis indicated that Cyfip2 knockdown alleviated H2O2-induced ARPE apoptosis, while its overexpression weakened EGCG's protective effect. Western blot analysis showed that Cyfip2 mediated the anti-apoptotic effect of EGCG by modulating the level of protein kinase B (Akt) phosphorylation in ARPE cells, and the activation level of phosphorylated AKT (p-AKT Ser473) in retinal tissue of the EGCG-fed group was higher than that of the aged group. Taken together, this study suggests that EGCG plays a protective role in the development of AMD and the apoptosis of ARPE cells through the Cyfip2/AKT pathway.

Keywords: ARPE; Apoptosis; CYFIP2; EGCG

DOI: https://doi.org/10.1016/j.taap.2024.117124

Free Radic Biol Med. 2024 Dec 04. pii: S0891-5849(24)01105-5. [Epub ahead of print]227 179-189

Inhibition of JNK signaling attenuates photoreceptor ferroptosis caused by all-trans-retinal.

Bo Yang, Kunhuan Yang, Ruitong Xi, Shiying Li, Jingmeng Chen, Yalin Wu.

The disruption of the visual cycle leads to the accumulation of all-trans-retinal (atRAL) in the retina, a hallmark of autosomal recessive Stargardt disease (STGD1) and dry age-related macular degeneration (AMD), both of which cause retinal degeneration. Although our previous studies have shown that atRAL induces ferroptosis and activates c-Jun N-terminal kinase (JNK) signaling in the retina, the relationship between JNK signaling and ferroptosis in atRAL-mediated photoreceptor damage remains unclear. Here, we reported that JNK activation by atRAL drove photoreceptor ferroptosis through ferritinophagy. In photoreceptor cells loaded with atRAL, activated JNK phosphorylated c-Jun, which facilitated its nuclear translocation and promoted the expression of the nuclear receptor coactivator 4 (NCOA4). Elevated NCOA4 induced ferritin degradation via lysosomal processing, a process known as ferritinophagy, thereby releasing a large amount of labile iron. Iron overload led to the generation of reactive oxygen species (ROS) and lipid peroxidation, ultimately culminating in ferroptosis. Treatment with the JNK inhibitor JNK-IN-8, as well as the knockout of Jnk1 and Jnk2 genes, significantly rescued atRAL-loaded photoreceptor cells from ferritinophagy-induced ferroptosis. Abca4-/-Rdh8-/- mice, which exhibit atRAL accumulation in the retina following light exposure, are commonly used to study the pathological processes of STGD1 and dry AMD. In these mice, light exposure activated the JNK/c-Jun/NCOA4 axis, resulting in ferritinophagy in the neural retina. Importantly, intraperitoneal administration of JNK-IN-8 significantly rescued retinal function and photoreceptors from ferritinophagy-induced ferroptosis and effectively mitigated retinal degeneration in light-exposed Abca4-/-Rdh8-/- mice. This study underscores the critical role of the JNK/c-Jun/NCOA4 axis in mediating atRAL-induced ferritinophagy, which drives ferroptosis and retinal atrophy, suggesting that targeting this pathway may offer a potential therapeutic approach for STGD1 and dry AMD.

Keywords: Ferritinophagy; Ferroptosis; JNK; Macular degeneration; Photoreceptor

DOI: https://doi.org/10.1016/j.freeradbiomed.2024.12.007