bims-mideyd 2022-10-23 papers

Issue of 2022‒10‒23
four papers selected by
Raji Shyam
Indiana University Bloomington

FASEB J. 2022 Nov;36(11): e22619

Endothelial CYP2J2 overexpression restores the BRB via METTL3-mediated ANXA1 upregulation.

Bowen Zhao, Jingqiu Huang, Xiaotong Lou, Ke Yao, Meng Ye, Qianxue Mou, Zheng Wen, Qiming Duan, Hong Zhang, Yin Zhao.

Blood-retinal barrier (BRB) breakdown is responsible for multiple ocular diseases, such as diabetic retinopathy, age-related macular degeneration, and retinal vascular occlusive diseases. Increased vascular permeability contributes to vasogenic edema and tissue damage, with consequent adverse effects on vision. Herein, we found that endothelial CYP2J2 overexpression maintained BRB integrity after ischemia-reperfusion injury and consequently protected against retinal ganglion cell loss. Oxidative stress repressed endothelial ANXA1 expression in vivo and in vitro. CYP2J2 upregulated methyltransferase-like 3 (METTL3) expression and hence promoted ANXA1 translation via ANXA1 m6 A modification in endothelium under oxidative stress. CYP2J2 maintained the distribution of endothelial tight junctions and adherens junctions in an ANXA1-dependent manner. Endothelial ANXA1 plays an indispensable role in vascular homeostasis and stabilization during development. Endothelial ANXA1 deletion disrupted retinal vascular perfusion as well as BRB integrity. CYP2J2 metabolites restored BRB integrity in the presence of ANXA1. Our findings identified the CYP2J2-METTL3-ANXA1 pathway as a potential therapeutic target for relieving BRB impairments.

Keywords: ANXA1; BRB; CYP2J2; endothelial junctions; vascular development; vascular integrity

DOI: https://doi.org/10.1096/fj.202201061RR

ACS Nano. 2022 Oct 21.

Melanin-like Nanoparticles as an Alternative to Natural Melanin in Retinal Pigment Epithelium Cells and Their Therapeutic Effects against Age-Related Macular Degeneration.

Yong-Su Kwon, Min Zheng, Alice Yang Zhang, Zongchao Han.

Melanin is a natural pigment that is widely distributed in many parts of the human body, such as the skin and retinal pigment epithelium (RPE) in eyes. In contrast to skin melanin, which is being constantly synthesized by the epidermal melanocytes, melanin in the RPE does not regenerate. Melanin is known to function as a potential radical scavenger and photoprotective agent. However, the protective effects of melanin against oxidative stress decline with increasing age. This phenomenon has been correlated with the pathogenesis of age-related macular degeneration (AMD). To increase the potential antioxidant and photoprotective characteristics of melanin, we designed a therapeutic strategy for replenishment of melanin using PEGylated synthetic melanin-like nanoparticles (MNPs) in the RPE for the treatment of AMD. We performed experiments using AMD-like cellular and mouse models and demonstrated that MNPs are biocompatible and selectively target reactive oxygen species (ROS) with powerful antioxidant properties. MNPs can traffic and accumulate in the RPE and are exclusively located in cytosol, but not the nucleus and mitochondria of the cells, for at least 3 months after a single-dose intravitreal injection. Our findings demonstrate that MNPs are able to substitute for natural melanin in the RPE and suggest the potential efficacy of MNPs as a natural radical scavenger against oxidative stress in ROS-related diseases, such as AMD.

Keywords: age-related macular degeneration; intracellular trafficking; melanin-like nanoparticles; natural antioxidant; reactive oxygen species

DOI: https://doi.org/10.1021/acsnano.2c09087

BMC Ophthalmol. 2022 Oct 20. 22(1): 406

Differential distribution of steroid hormone signaling networks in the human choroid-retinal pigment epithelial complex.

Sydney M Galindez, Andrew Keightley, Peter Koulen.

BACKGROUND: The retinal pigment epithelium (RPE), a layer of pigmented cells that lies between the neurosensory retina and the underlying choroid, plays a critical role in maintaining the functional integrity of photoreceptor cells and in mediating communication between the neurosensory retina and choroid. Prior studies have demonstrated neurotrophic effects of select steroids that mitigate the development and progression of retinal degenerative diseases via an array of distinct mechanisms of action.METHODS: Here, we identified major steroid hormone signaling pathways and their key functional protein constituents controlling steroid hormone signaling, which are potentially involved in the mitigation or propagation of retinal degenerative processes, from human proteome datasets with respect to their relative abundances in the retinal periphery, macula, and fovea.
RESULTS: Androgen, glucocorticoid, and progesterone signaling networks were identified and displayed differential distribution patterns within these three anatomically distinct regions of the choroid-retinal pigment epithelial complex. Classical and non-classical estrogen and mineralocorticoid receptors were not identified.
CONCLUSION: Identified differential distribution patterns suggest both selective susceptibility to chronic neurodegenerative disease processes, as well as potential substrates for drug target discovery and novel drug development focused on steroid signaling pathways in the choroid-RPE.

Keywords: Androgen; Choroid; Estrogen; Glucocorticoids; Mineralocorticoid; RPE; Retina; Retinal pigment epithelium; Steroid receptor

DOI: https://doi.org/10.1186/s12886-022-02585-7

Front Aging Neurosci. 2022 ;14 965943

Proteomic analysis of s-acylated proteins in human retinal pigment epithelial cells and the role of palmitoylation of Niemann-Pick type C1 protein in cholesterol transport.

Jia Kai Li, Yu Qing Rao, Siew Kwan Koh, Peiquan Zhao, Lei Zhou, Jing Li.

Palmitoylation is a dynamic process that regulates the activity of the modified proteins. Retinal pigment epithelial (RPE) cells play pivotal roles in the visual cycle and maintaining healthy photoreceptor cells. Dysfunctional RPE cells are often associated with degenerative retinal diseases. The aim of the study was to identify potentially palmitoylated proteins in human RPE cells. By using the detergent-resistant membrane, we found 312 potentially palmitoylated peptides which corresponded to 192 proteins in RPE cells, including 55 new candidate proteins which were not reported before. Gene enrichment analysis highlighted significant enrichment of palmitoylated proteins in cell-matrix adhesion, cell-cell recognition, protein cellular localization, and translation, among others. We further studied the effect of 3 potential palmitoylation sites (Cys 799, 900, and 816) of Niemann-Pick type C1 protein (NPC1) on cholesterol accumulation. We found that mutation of any single Cys alone had no significant effect on intracellular cholesterol accumulation while simultaneous mutation of Cys799 and 800 caused significant cholesterol accumulation in the late endosome. No further cholesterol accumulation was observed by adding another mutation at Cys 816. However, the mutation did not alter the cellular localization of the protein. Conclusion: PRE cells have an abundant number of palmitoylated proteins which are involved in cellular processes critical to visual function. The palmitoylation at Cys799 and 800 was needed for cholesterol export, but not the intracellular localization of NPC1.

Keywords: Niemann-Pick type C1 protein; acyl-biotin exchange (ABE); cholesterol transport; palmitoylation; protein post-translational modification; retinal pigment epithelial cells

DOI: https://doi.org/10.3389/fnagi.2022.965943