bims-mideyd 2025-01-05 papers

Eur J Pharmacol. 2024 Dec 28. pii: S0014-2999(24)00917-8. [Epub ahead of print]989 177227

FADS1 inhibition protects retinal pigment epithelium cells from ferroptosis in age related macular degeneration.

Ao Zhang, Ting-Ting Wei, Xin Tan, Cheng-Ye Tan, Miao Zhuang, Tian-Hua Xie, Jiping Cai, Yong Yao, Lingpeng Zhu.

PURPOSE: Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly individuals. Retinal pigment epithelium (RPE) ferroptosis is a significant pathogenetic component in AMD. This study aims to elucidate the role and mechanisms of fatty acid desaturase 1 (FADS1) in ferroptosis as well as AMD progression.
METHODS: An integrated bioinformatics analysis based on the array of data from the GEO database was conducted to identify candidates involved in ferroptosis during AMD. Subsequently, cellular and mouse models of AMD were developed using sodium iodate (NaIO3) to confirm the altered expression of FADS1. After treatment with a FADS1 inhibitor, cell survival, lipid peroxidation, and indicators of AMD were assessed in vitro and in vivo models. Further, immunofluorescence, immunohistochemistry, and swept-source OCT imaging were performed to assess the impacts of pharmacological inhibition of transcription factor specificity protein 1 (Sp1) on FADS1 and ferroptosis.
RESULTS: FADS1 expression was upregulated in AMD patients and in vitro and in vivo models of AMD. Its pharmacological inhibition had decreased mitochondrial ROS formation, lipid peroxidation, and ferroptosis as well as increased RPE cell function in ARPE-19 cells and C57BL/6J mouse models of AMD. Mechanistically, Sp1 was identified as a key transcription factor of FADS1. Moreover, Sp1 inhibition downregulated FADS1 expression consequently attenuating FADS1-mediated ferroptosis as well as AMD phenotypes.
CONCLUSION: For the first time, we demonstrated that Sp1 regulates FADS1-mediated ferroptosis in RPE cells. Our findings provide novel insights into the progression and treatment of AMD.

Keywords: Age-related macular degeneration; FADS1; Ferroptosis; Sp1

DOI: https://doi.org/10.1016/j.ejphar.2024.177227

Fundam Res. 2024 Nov;4(6): 1710-1718

The retinal pigment epithelium: Functions and roles in ocular diseases.

Shasha Wang, Wanhong Li, Min Chen, Yihai Cao, Weisi Lu, Xuri Li.

The retinal pigment epithelium (RPE) between retinal photoreceptors and choroidal capillaries is a single layer of cells that are of critical importance to the eye. RPE cells are derived from the anterior neural plate of neuroectodermal origin. Instructed by specific molecules and signaling pathways, the RPE undergoes formation and maturation to form a functional unit together with photoreceptors. The RPE plays crucial roles in maintaining normal retinal structure and functions, such as phagocytosis; barrier function; transportation of nutrients, ions, and water; resistance to oxidative damage; maintenance of visual cycle; and production of various important factors. RPE cells have an efficient metabolic machinery to provide sufficient energy to the retina. RPE dysfunction or atrophy can lead to many retinopathies, such as age-related macular degeneration and proliferative vitreoretinopathy. Here, we discuss RPE development, functions, and roles in various ocular diseases, and the mechanisms involved. A better understanding of the functions of the RPE and related regulatory pathways may help identify novel or better therapies for the treatment of many blinding diseases.

Keywords: Blood–retinal barrier; Choroid; Ocular disease; Photoreceptor; Retina; Retinal pigment epithelium

DOI: https://doi.org/10.1016/j.fmre.2023.08.011

Front Aging Neurosci. 2024 ;16 1509434

Blue light-induced phototoxicity in retinal cells: implications in age-related macular degeneration.

Harshini Chakravarthy, Vasil Georgyev, Cole Wagen, Amir Hosseini, Joanne Matsubara.

Sunlight exposure is recognized as a risk factor for the development of age-related macular degeneration (AMD), a common neurodegenerative retinal disease in the elderly. Specifically, the blue light wavelengths within sunlight can negatively impact the physiology of light-sensitive retinal cells, including retinal pigmented epithelium (RPE) and photoreceptors. This review explores blue light-induced retinal degeneration, emphasizing the structural and functional impairments in RPE. The initial section provides a brief overview of blue light's effects on photoreceptors, followed by a comprehensive analysis of its detrimental impact on RPE. In vitro studies reveal that blue light exposure induces morphological alterations and functional impairments in RPE, including reduced phagocytic activity, disrupted secretion of neurotrophic factors, and compromised barrier function. Mechanisms of retinal damage, including oxidative stress, inflammation, lipofuscin accumulation, mitochondrial dysfunction and ER stress in RPE, are also explored. The strengths and limitations of in vitro, animal and ex vivo models for studying blue light exposure are discussed, with recommendations for improving reproducibility in future studies.

Keywords: LED; age-related macular degeneration (AMD); blue light; blue light exposure; photoreceptors; phototoxicity; retinal inflammation; retinal pigmented epithelial (RPE) cells

DOI: https://doi.org/10.3389/fnagi.2024.1509434

Mol Med. 2024 Dec 30. 30(1): 283

Thioredoxin-interacting protein (TXNIP) inhibition promotes retinal ganglion cell survival and facilitates M1-like microglial transformation via the PI3K/Akt pathway in glaucoma.

Junjue Chen, Huimin Zhong, Bingqiao Shen, Huan Yu, Yang Zhang, Ruiqi Han, Ping Huang, Shouyue Huang, Yisheng Zhong.

BACKGROUND: Glaucoma is a group of heterogeneous neurodegenerative diseases with abnormal energy metabolism and imbalanced neuroinflammation in the retina. Thioredoxin-interacting protein (TXNIP) is involved in glucose and lipid metabolism, and associated with oxidative stress and inflammation, however, not known whether to be involved in glaucoma neuropathy and its underlying mechanisms.
METHODS: To establish the chronic ocular hypertension (COH) mice model. Western blot, RT-PCR, immunofluorescence and F-VEP were used to detect neuroinflammation level, glial activation and RGCs survival in retina of wild type, TXNIP knockout and MCC950 treatment COH mice. Microglia high-pressure cultured model was constructed. Western blot, RT-PCR and immunofluorescence were used to investigate the proinflammatory cytokines secretion, glucose uptake and phenotype transformation in wild type, TXNIP knockout and overexpressed microglia combined with IL-17A treatment. Finally, we explored the possible underlying mechanisms using relevant pathway inhibitor interventions.
RESULTS: In this study, for the first time we reported that TXNIP expression was remarkably increased in experimental glaucomatous retina of chronic ocular hypertension (COH) mice, and it was mainly expressed in the ganglion cells layer (GCL). In addition, we found that ablation of TXNIP promoted retinal ganglion cells (RGCs) survival and alleviated visual function impairment in experimental glaucoma. Then, we explored the spatiotemporal consistency between glial activation and retinal inflammation levels in COH mice respectively with TXNIP-deficiency and under treatment of a thermo-containing protein domain 3 (NLRP3) inhibitor MCC950, and the results indicated that TXNIP probably mediated neuroinflammation in glaucomatous retina by activating microglia. Furthermore, upregulation of TXNIP was found in pressure-stimulated microglia, whereas silencing TXNIP facilitated microglial polarization trending towards M1 type and reduced glucose transporter-1 (Glut-1) expression on microglia under high pressure in vitro. Moreover, IL-17A was found to play a role in acting synergistically with TXNIP upon the regulation of microglia polarity transformation. Finally, knockout of TXNIP was revealed to promote PI3K phosphorylation, whereas inhibition of PI3K by LY294002 effectively suppressed Glut-1 expression, glucose uptake, and M1-like transformation tendency in microglia obtained from TXNIP-deficiency mice under high pressure stimulation.
CONCLUSIONS: TXNIP is significantly involved in the inflammation-related neuropathy of experimental glaucoma and probably facilitates M1-like microglial transformation via PI3K/Akt pathway.

Keywords: Energy metabolism; Experimental glaucoma; Microglia; Neuroinflammation; PI3K/AKT; TXNIP

DOI: https://doi.org/10.1186/s10020-024-01058-5