bims-mideyd 2023-12-24 papers

Issue of 2023‒12‒24
five papers selected by
Raji Shyam, Indiana University Bloomington

Antioxidants (Basel). 2023 Dec 17. pii: 2129. [Epub ahead of print]12(12):

Buspirone Enhances Cell Survival and Preserves Structural Integrity during Oxidative Injury to the Retinal Pigment Epithelium.

Manas R Biswal, Ryan J Paulson, Riddhi Vichare, Alfred S Lewin.

Chronic oxidative stress impairs the normal functioning of the retinal pigment epithelium (RPE), leading to atrophy of this cell layer in cases of advance age-related macular degeneration (AMD). The purpose of our study was to determine if buspirone, a partial serotonin 1A (5-HT1A) receptor agonist, protected against oxidative stress-induced changes in the RPE. We exposed differentiated human ARPE-19 cells to paraquat to induce oxidative damage in culture, and utilized a mouse model with sodium iodate (NaIO3)-induced oxidative injury to evaluate the effect of buspirone. To investigate buspirone's effect on protective gene expression, we performed RT-PCR. Cellular toxicities and junctional abnormalities due to paraquat induction in ARPE-19 cells and buspirone's impact were assessed via WST-1 assays and ZO-1 immunostaining. We used spectral-domain optical coherence tomography (SD-OCT) and ZO-1 immunostaining of RPE/choroid for structural analysis. WST-1 assays showed dose-dependent protection of viability in buspirone-treated ARPE-19 cells in culture and preservation of RPE junctional integrity under oxidative stress conditions. In the NaIO3 model, daily intraperitoneal injection (i.p.) of buspirone (30 mg/kg) for 12 days improved the survival of photoreceptors compared to those of vehicle-treated eyes. ZO-1-stained RPE flat-mounts revealed the structural preservation of RPE from oxidative damage in buspirone-treated mice, as well as in buspirone-induced Nqo1, Cat, Sqstm1, Gstm1, and Sod2 genes in the RPE/choroid compared to untreated eyes. Since oxidative stress is implicated in the pathogenesis AMD, repurposing buspirone, which is currently approved for the treatment of anxiety, might be useful in treating or preventing dry AMD.

Keywords: ARPE-19; NaIO3; ZO-1; antioxidants; buspirone; oxidative stress; retina; retinal pigment epithelium

DOI: https://doi.org/10.3390/antiox12122129

Cells. 2023 Dec 08. pii: 2797. [Epub ahead of print]12(24):

The Role of Retinal Ganglion Cell Structure and Function in Glaucoma.

Kathy Ming Feng, Ta-Hsin Tsung, Yi-Hao Chen, Da-Wen Lu.

Glaucoma, a leading cause of irreversible blindness globally, primarily affects retinal ganglion cells (RGCs). This review dives into the anatomy of RGC subtypes, covering the different underlying theoretical mechanisms that lead to RGC susceptibility in glaucoma, including mechanical, vascular, excitotoxicity, and neurotrophic factor deficiency, as well as oxidative stress and inflammation. Furthermore, we examined numerous imaging methods and functional assessments to gain insight into RGC health. Finally, we investigated the current possible neuroprotective targets for RGCs that could help with future glaucoma research and management.

Keywords: glaucoma; imaging; neurodegeneration; neuroprotection; optical coherence tomography; retinal ganglion cells

DOI: https://doi.org/10.3390/cells12242797

Int J Mol Sci. 2023 Dec 12. pii: 17385. [Epub ahead of print]24(24):

Indenopyrene and Blue-Light Co-Exposure Impairs the Tightly Controlled Activation of Xenobiotic Metabolism in Retinal Pigment Epithelial Cells: A Mechanism for Synergistic Toxicity.

Corinne Zinflou, Patrick J Rochette.

High energy visible (HEV) blue light is an increasing source of concern for visual health. Polycyclic aromatic hydrocarbons (PAH), a group of compounds found in high concentrations in smokers and polluted environments, accumulate in the retinal pigment epithelium (RPE). HEV absorption by indeno [1,2,3-cd]pyrene (IcdP), a common PAH, synergizes their toxicities and promotes degenerative changes in RPE cells comparable to the ones observed in age-related macular degeneration. In this study, we decipher the processes underlying IcdP and HEV synergic toxicity in human RPE cells. We found that IcdP-HEV toxicity is caused by the loss of the tight coupling between the two metabolic phases ensuring IcdP efficient detoxification. Indeed, IcdP/HEV co-exposure induces an overactivation of key actors in phase I metabolism. IcdP/HEV interaction is also associated with a downregulation of proteins involved in phase II. Our data thus indicate that phase II is hindered in response to co-exposure and that it is insufficient to sustain the enhanced phase I induction. This is reflected by an accelerated production of endogenous reactive oxygen species (ROS) and an increased accumulation of IcdP-related bulky DNA damage. Our work raises the prospect that lifestyle and environmental pollution may be significant modulators of HEV toxicity in the retina.

Keywords: aryl hydrocarbon receptor (AhR); blue light); high-energy visible light (HEV; indenopyrene (IcdP) phototoxicity; nuclear factor erythroid-2 related factor-2 (Nrf2); oxidative stress; polycyclic aromatic hydrocarbons metabolism; retinal pigment epithelial (RPE) cells

DOI: https://doi.org/10.3390/ijms242417385

Front Med (Lausanne). 2023 ;10 1310050

Adeno-associated virus vectors for retinal gene therapy in basic research and clinical studies.

Xue Xia, Xinzheng Guo.

Retinal degenerative diseases, including glaucoma, age-related macular degeneration, diabetic retinopathy, and a broad range of inherited retinal diseases, are leading causes of irreversible vision loss and blindness. Gene therapy is a promising and fast-growing strategy to treat both monogenic and multifactorial retinal disorders. Vectors for gene delivery are crucial for efficient and specific transfer of therapeutic gene(s) into target cells. AAV vectors are ideal for retinal gene therapy due to their inherent advantages in safety, gene expression stability, and amenability for directional engineering. The eye is a highly compartmentalized organ composed of multiple disease-related cell types. To determine a suitable AAV vector for a specific cell type, the route of administration and choice of AAV variant must be considered together. Here, we provide a brief overview of AAV vectors for gene transfer into important ocular cell types, including retinal pigment epithelium cells, photoreceptors, retinal ganglion cells, Müller glial cells, ciliary epithelial cells, trabecular meshwork cells, vascular endothelial cells, and pericytes, via distinct injection methods. By listing suitable AAV vectors in basic research and (pre)clinical studies, we aim to highlight the progress and unmet needs of AAV vectors in retinal gene therapy.

Keywords: adeno-associated virus; age-related macular degeneration; diabetic retinopathy; gene therapy; glaucoma; inherited retinal diseases; retina; vector

DOI: https://doi.org/10.3389/fmed.2023.1310050

J Extracell Biol. 2023 Oct;pii: e116. [Epub ahead of print]2(10):

Polarized Desmosome and Hemidesmosome Shedding via Small Extracellular Vesicles is an Early Indicator of Outer Blood-Retina Barrier Dysfunction.

Belinda J Hernandez, Nikolai P Skiba, Karolina Plössl, Madison Strain, Yutao Liu, Daniel Grigsby, Una Kelly, Martha A Cady, Vikram Manocha, Arvydas Maminishkis, TeddiJo Watkins, Sheldon S Miller, Allison Ashley-Koch, W Daniel Stamer, Bernhard H F Weber, Catherine Bowes Rickman, Mikael Klingeborn.

The retinal pigmented epithelium (RPE) constitutes the outer blood-retinal barrier, enables photoreceptor function of the eye, and is constantly exposed to oxidative stress. As such, dysfunction of the RPE underlies pathology leading to development of age-related macular degeneration (AMD), the leading cause of vision loss among the elderly in industrialized nations. A major responsibility of the RPE is to process photoreceptor outer segments, which relies on the proper functioning of its endocytic pathways and endosomal trafficking. Exosomes and other extracellular vesicles (EVs) from RPE are an essential part of these pathways and may be early indicators of cellular stress. To test the role of small EVs (sEVs) including exosomes, that may underlie the early stages of AMD, we used a polarized primary RPE cell culture model under chronic subtoxic oxidative stress. Unbiased proteomic analyses of highly purified basolateral sEVs from oxidatively stressed RPE cultures revealed changes in proteins involved in epithelial barrier integrity. There were also significant changes in proteins accumulating in the basal-side sub-RPE extracellular matrix during oxidative stress, that could be prevented with an inhibitor of sEV release. Thus, chronic subtoxic oxidative stress in primary RPE cultures induces changes in sEV content, including basal-side specific desmosome and hemidesmosome shedding via sEVs. These findings provide novel biomarkers of early cellular dysfunction and opportunity for therapeutic intervention in age-related retinal diseases (e.g., AMD).

Keywords: age-related macular degeneration (AMD); exosome; oxidative stress; polarized; proteomics; retinal pigmented epithelium (RPE); small extracellular vesicle (sEV)

DOI: https://doi.org/10.1002/jex2.116