bims-mideyd 2023-02-12 papers

Int J Mol Sci. 2023 Jan 27. pii: 2462. [Epub ahead of print]24(3):

Anti-Inflammatory Activity and Mechanism of Sweet Corn Extract on Il-1β-Induced Inflammation in a Human Retinal Pigment Epithelial Cell Line (ARPE-19).

Inthra Koraneeyakijkulchai, Rianthong Phumsuay, Parunya Thiyajai, Siriporn Tuntipopipat, Chawanphat Muangnoi.

Age-related macular degeneration (AMD) is an eye disease associated with aging. Development of AMD is related to degeneration and dysfunction of the retinal pigment epithelium (RPE) caused by low-grade chronic inflammation in aged RPE cells leading to visual loss and blindness. Sweet corn is a good source of lutein and zeaxanthin, which were reported to exert various biological activities, including anti-inflammatory activity. The present study aims to investigate the anti-inflammatory activity and mechanisms of SCE to inhibit the production of inflammatory biomarkers related to AMD development. Cells were pretreated with SCE for 1 h followed by stimulation with IL-1β for another 24 h. The results demonstrated that SCE attenuated IL-1β-induced production of IL-6, IL-8, and MCP-1 and the expression of ICAM-1 and iNOS in a dose-dependent manner. In addition, SCE suppressed the phosphorylation of ERK1/2, SAPK/JNK, p38, and NF-κB (p65) in IL-1β-stimulated ARPE-19 cells. These results proved that SCE protected ARPE-19 cells from IL-1β-induced inflammation by inhibiting inflammatory markers partly via suppressing the activation of MAPK and NF-κB signaling pathways. Overall, SCE is a potential agent for the prevention of AMD development, which should be further evaluated in animals.

Keywords: age-related macular degeneration; anti-inflammatory activity; carotenoids; human retinal pigment epithelial cell line; sweet corn

DOI: https://doi.org/10.3390/ijms24032462

Int J Mol Sci. 2023 Jan 30. pii: 2636. [Epub ahead of print]24(3):

Non-Coding RNAs Regulating Mitochondrial Functions and the Oxidative Stress Response as Putative Targets against Age-Related Macular Degeneration (AMD).

Juha M T Hyttinen, Janusz Blasiak, Kai Kaarniranta.

Age-related macular degeneration (AMD) is an ever-increasing, insidious disease which reduces the quality of life of millions of elderly people around the world. AMD is characterised by damage to the retinal pigment epithelium (RPE) in the macula region of the retina. The origins of this multi-factorial disease are complex and still not fully understood. Oxidative stress and mitochondrial imbalance in the RPE are believed to be important factors in the development of AMD. In this review, the regulation of the mitochondrial function and antioxidant stress response by non-coding RNAs (ncRNAs), newly emerged epigenetic factors, is discussed. These molecules include microRNAs, long non-coding RNAs, and circular non-coding RNAs. They act mainly as mRNA suppressors, controllers of other ncRNAs, or by interacting with proteins. We include here examples of these RNA molecules which affect various mitochondrial processes and antioxidant signaling of the cell. As a future prospect, the possibility to manipulate these ncRNAs to strengthen mitochondrial and antioxidant response functions is discussed. Non-coding RNAs could be used as potential diagnostic markers for AMD, and in the future, also as therapeutic targets, either by suppressing or increasing their expression. In addition to AMD, it is possible that non-coding RNAs could be regulators in other oxidative stress-related degenerative diseases.

Keywords: age-related macular degeneration; epigenetic therapy; mitochondria; non-coding RNA; oxidative stress

DOI: https://doi.org/10.3390/ijms24032636

Eur J Pharm Biopharm. 2023 Feb 03. pii: S0939-6411(23)00031-0. [Epub ahead of print]

Comparison of barrier properties of outer blood-retinal barrier models - human stem cell-based models as a novel tool for ocular drug discovery.

Laura Hellinen, Heidi Hongisto, Eva Ramsay, Kai Kaarniranta, Kati-Sisko Vellonen, Heli Skottman, Marika Ruponen.

The retinal pigment epithelial (RPE) cell monolayer forms the outer blood-retinal barrier and has a crucial role in ocular pharmacokinetics. Although several RPE cell models are available, there have been no systematic comparisons of their barrier properties with respect to drug permeability. We compared the barrier properties of RPE secondary cell lines (ARPE19, and ARPE19mel) and both primary (hfRPE) and stem-cell derived RPE (hESC-RPE) cells by investigating the permeability of nine drugs (aztreonam, ciprofloxacin, dexamethasone, fluconazole, ganciclovir, ketorolac, methotrexate, voriconazole, and quinidine) across cell monolayers. ARPE19, ARPE19mel, and hfRPE cells displayed a narrow Papp value range, with relatively high permeation rates (5.2-26 × 10-6 cm/s). In contrast, hESC-RPE cells efficiently restricted the drug flux, and displayed even lower Papp values than those reported for bovine RPE-choroid, with the range of 0.4-32 cm-6/s. Therefore, ARPE19, ARPE19mel, and hfRPE cells failed to form a tight barrier, whereas hESC-RPE cells restricted the drug flux to a similar extent as bovine RPE-choroid. Therefore, hESC-RPE cells are valuable tools in ocular drug discovery.

Keywords: cell models; drug permeation; ocular drug delivery; outer blood–retinal barrier; retinal pigment epithelium; tight junctions

DOI: https://doi.org/10.1016/j.ejpb.2023.01.026

PLoS One. 2023 ;18(2): e0281404

Denuded Descemet's membrane supports human embryonic stem cell-derived retinal pigment epithelial cell culture.

Elena Daniele, Lorenzo Bosio, Noor Ahmed Hussain, Barbara Ferrari, Stefano Ferrari, Vanessa Barbaro, Brian McArdle, Nicolò Rassu, Marco Mura, Francesco Parmeggiani, Diego Ponzin.

Recent clinical studies suggest that retinal pigment epithelial (RPE) cell replacement therapy may preserve vision in retinal degenerative diseases. Scaffold-based methods are being tested in ongoing clinical trials for delivering pluripotent-derived RPE cells to the back of the eye. The aim of this study was to investigate human embryonic stem cell-derived retinal pigment epithelial (hESC-RPE) cells survival and behaviour on a decellularized Descemet's Membrane (DM), which may be of clinical relevance in retinal transplantation. DMs were isolated from human donor corneas and treated with thermolysin. The DM surface topology and the efficiency of the denudation method were evaluated by atomic force microscope, scanning electron microscopy and histology. hESC-RPE cells were seeded onto the endothelial-side surface of decellularized DM in order to determine the potential of the membrane to support hESC-RPE cell culture, alongside maintaining their viability. Integrity of the hESC-RPE monolayer was assessed by measuring transepithelial resistance. RPE-specific gene expression and growth factors secretion were assessed to confirm maturation and functionality of the cells over the new substrate. Thermolysin treatment did not affect the integrity of the tissue, thus ensuring a reliable method to standardize the preparation of decellularized DM. 24 hours post-seeding, hESC-RPE cell attachment and initial proliferation rate over the denuded DM were higher than hESC-RPE cells cultured on tissue culture inserts. On the new matrix, hESC-RPE cells succeeded in forming an intact monolayer with mature tight junctions. The resulting cell culture showed characteristic RPE cell morphology and proper protein localization. Gene expression analysis and VEGF secretion demonstrate DM provides supportive scaffolding and inductive properties to enhance hESC-RPE cells maturation. Decellularized DM was shown to be capable of sustaining hESC-RPE cells culture, thus confirming to be potentially a suitable candidate for retinal cell therapy.

DOI: https://doi.org/10.1371/journal.pone.0281404

Int J Mol Sci. 2023 Feb 03. pii: 2985. [Epub ahead of print]24(3):

Erythropoietin in Glaucoma: From Mechanism to Therapy.

Yi-Fen Lai, Ting-Yi Lin, Yi-Hao Chen, Da-Wen Lu.

Glaucoma can cause irreversible vision loss and is the second leading cause of blindness worldwide. The disease mechanism is complex and various factors have been implicated in its pathogenesis, including ischemia, excessive oxidative stress, neurotropic factor deprivation, and neuron excitotoxicity. Erythropoietin (EPO) is a hormone that induces erythropoiesis in response to hypoxia. However, studies have shown that EPO also has neuroprotective effects and may be useful for rescuing apoptotic retinal ganglion cells in glaucoma. This article explores the relationship between EPO and glaucoma and summarizes preclinical experiments that have used EPO to treat glaucoma, with an aim to provide a different perspective from the current view that glaucoma is incurable.

Keywords: erythropoietin; glaucoma; neuroprotection; retinal ganglion cell

DOI: https://doi.org/10.3390/ijms24032985

Int J Mol Sci. 2023 Jan 29. pii: 2573. [Epub ahead of print]24(3):

Aging Effects on Optic Nerve Neurodegeneration.

Janet Coleman-Belin, Alon Harris, Bo Chen, Jing Zhou, Thomas Ciulla, Alice Verticchio, Gal Antman, Michael Chang, Brent Siesky.

Common risk factors for many ocular pathologies involve non-pathologic, age-related damage to the optic nerve. Understanding the mechanisms of age-related changes can facilitate targeted treatments for ocular pathologies that arise at any point in life. In this review, we examine these age-related, neurodegenerative changes in the optic nerve, contextualize these changes from the anatomic to the molecular level, and appreciate their relationship with ocular pathophysiology. From simple structural and mechanical changes at the optic nerve head (ONH), to epigenetic and biochemical alterations of tissue and the environment, multiple age-dependent mechanisms drive extracellular matrix (ECM) remodeling, retinal ganglion cell (RGC) loss, and lowered regenerative ability of respective axons. In conjunction, aging decreases the ability of myelin to preserve maximal conductivity, even with "successfully" regenerated axons. Glial cells, however, regeneratively overcompensate and result in a microenvironment that promotes RGC axonal death. Better elucidating optic nerve neurodegeneration remains of interest, specifically investigating human ECM, RGCs, axons, oligodendrocytes, and astrocytes; clarifying the exact processes of aged ocular connective tissue alterations and their ultrastructural impacts; and developing novel technologies and pharmacotherapies that target known genetic, biochemical, matrisome, and neuroinflammatory markers. Management models should account for age-related changes when addressing glaucoma, diabetic retinopathy, and other blinding diseases.

Keywords: active aging; diabetic retinopathy; embryology; glaucoma; inflammation; neurodegeneration; neuroregeneration; optic nerve; oxidative stress; senescence

DOI: https://doi.org/10.3390/ijms24032573