The Potential Role of Small-Molecule PERK Inhibitor LDN-0060609 in Primary Open-Angle Glaucoma Treatment
| Autor: | Steven L. Carroll, Wioletta Rozpędek-Kamińska, Natalia Siwecka, Dariusz Pytel, Ewa Kucharska, Ireneusz Majsterek, Grzegorz Galita, John Alan Diehl |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
PERK PERK inhibitor QH301-705.5 Eukaryotic Initiation Factor-2 eIF2α Catalysis Article Cell Line Inorganic Chemistry glaucoma treatment 03 medical and health sciences eIF-2 Kinase 0302 clinical medicine medicine Humans PERK inhibitors Physical and Theoretical Chemistry Biology (General) Protein kinase A Molecular Biology Protein Kinase Inhibitors QD1-999 Spectroscopy Cell Proliferation Chemistry Endoplasmic reticulum Organic Chemistry apoptosis General Medicine unfolded protein response Computer Science Applications Cell biology Comet assay 030104 developmental biology medicine.anatomical_structure glaucoma Apoptosis 030221 ophthalmology & optometry Unfolded protein response endoplasmic reticulum stress Trabecular meshwork sense organs Signal transduction Glaucoma Open-Angle DNA Damage |
| Zdroj: | International Journal of Molecular Sciences, Vol 22, Iss 4494, p 4494 (2021) International Journal of Molecular Sciences Volume 22 Issue 9 |
| ISSN: | 1661-6596 1422-0067 |
| Popis: | Primary open-angle glaucoma (POAG) constitutes the most common type of glaucoma. Emerging evidence suggests that Endoplasmic Reticulum (ER) stress and the protein kinase RNA-like endoplasmic reticulum kinase (PERK)-mediated Unfolded Protein Response (UPR) signaling pathway play a key role in POAG pathogenesis. Thus, the main aim of the study was to evaluate the effectiveness of the PERK inhibitor LDN-0060609 in cellular model of glaucoma using primary human trabecular meshwork (HTM) cells. To evaluate the level of the ER stress marker proteins, Western blotting and TaqMan gene expression assay were used. The cytotoxicity was measured by XTT, LDH assays and Giemsa staining, whereas genotoxicity via comet assay. Changes in cell morphology were assessed by phase-contrast microscopy. Analysis of apoptosis was performed by caspase-3 assay and flow cytometry (FC), whereas cell cycle progression by FC. The results obtained have demonstrated that LDN-0060609 triggered a significant decrease of ER stress marker proteins within HTM cells with induced ER stress conditions. Moreover, LDN-0060609 effectively increased viability, reduced DNA damage, increased proliferation, restored normal morphology, reduced apoptosis and restored normal cell cycle distribution of HTM cells with induced ER stress conditions. Thereby, PERK inhibitors, such as LDN-0060609, may provide an innovative, ground-breaking treatment strategy against POAG. |
| Databáze: | OpenAIRE |
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