The Potential Role of Small-Molecule PERK Inhibitor LDN-0060609 in Primary Open-Angle Glaucoma Treatment

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.

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Reduction of ER stress via a chemical chaperone prevents disease phenotypes in a mouse model of primary open angle glaucoma

Journal of Clinical Investigation ◽

10.1172/jci58183 ◽

2011 ◽

Vol 121 (9) ◽

pp. 3542-3553 ◽

Cited By ~ 149

Author(s):

Gulab S. Zode ◽

Markus H. Kuehn ◽

Darryl Y. Nishimura ◽

Charles C. Searby ◽

Kabhilan Mohan ◽

...

Keyword(s):

Mouse Model ◽

Er Stress ◽

Primary Open Angle Glaucoma ◽

Open Angle Glaucoma ◽

Open Angle ◽

Chemical Chaperone ◽

Disease Phenotypes

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Faculty Opinions recommendation of Reduction of ER stress via a chemical chaperone prevents disease phenotypes in a mouse model of primary open angle glaucoma.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717960189.793463376 ◽

2012 ◽

Author(s):

Ernst Tamm ◽

Rudolf Fuchshofer

Keyword(s):

Mouse Model ◽

Er Stress ◽

Primary Open Angle Glaucoma ◽

Open Angle Glaucoma ◽

Open Angle ◽

Chemical Chaperone ◽

Disease Phenotypes

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The Genetic and Endoplasmic Reticulum-Mediated Molecular Mechanisms of Primary Open-Angle Glaucoma

International Journal of Molecular Sciences ◽

10.3390/ijms21114171 ◽

2020 ◽

Vol 21 (11) ◽

pp. 4171

Author(s):

Wioletta Rozpędek-Kamińska ◽

Radosław Wojtczak ◽

Jacek P. Szaflik ◽

Jerzy Szaflik ◽

Ireneusz Majsterek

Keyword(s):

Endoplasmic Reticulum ◽

Molecular Mechanisms ◽

Primary Open Angle Glaucoma ◽

Open Angle Glaucoma ◽

Detailed Knowledge ◽

Open Angle ◽

Unfolded Protein ◽

Progressive Group ◽

Subsequent Activation ◽

Protein Response

Glaucoma is a heterogenous, chronic, progressive group of eye diseases, which results in irreversible loss of vision. There are several types of glaucoma, whereas the primary open-angle glaucoma (POAG) constitutes the most common type of glaucoma, accounting for three-quarters of all glaucoma cases. The pathological mechanisms leading to POAG pathogenesis are multifactorial and still poorly understood, but it is commonly known that significantly elevated intraocular pressure (IOP) plays a crucial role in POAG pathogenesis. Besides, genetic predisposition and aggregation of abrogated proteins within the endoplasmic reticulum (ER) lumen and subsequent activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dependent unfolded protein response (UPR) signaling pathway may also constitute important factors for POAG pathogenesis at the molecular level. Glaucoma is commonly known as a ‘silent thief of sight’, as it remains asymptomatic until later stages, and thus its diagnosis is frequently delayed. Thereby, detailed knowledge about the glaucoma pathophysiology is necessary to develop both biochemical and genetic tests to improve its early diagnosis as well as develop a novel, ground-breaking treatment strategy, as currently used medical therapies against glaucoma are limited and may evoke numerous adverse side-effects in patients.

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Astragaloside IV Attenuates Ocular Hypertension in a Mouse Model of TGFβ2 Induced Primary Open Angle Glaucoma

International Journal of Molecular Sciences ◽

10.3390/ijms222212508 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12508

Author(s):

Ramesh B. Kasetti ◽

Prabhavathi Maddineni ◽

Bindu Kodati ◽

Bhavani Nagarajan ◽

Sam Yacoub

Keyword(s):

Er Stress ◽

Ocular Hypertension ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Primary Open Angle Glaucoma ◽

Open Angle Glaucoma ◽

Matrix Metalloproteases ◽

Eye Drops ◽

Open Angle ◽

Astragaloside Iv

Elevated intraocular pressure (IOP) is a major risk factor in developing primary open angle glaucoma (POAG), which is the most common form of glaucoma. Transforming growth factor-beta 2 (TGFβ2) is a pro-fibrotic cytokine that plays an important role in POAG pathogenesis. TGFβ2 induced extracellular matrix (ECM) production, deposition and endoplasmic reticulum (ER) stress in the trabecular meshwork (TM) contribute to increased aqueous humor (AH) outflow resistance and IOP elevation. Drugs which alter the glaucomatous fibrotic changes and ER stress in the TM may be effective in reducing ocular hypertension. Astragaloside IV (AS.IV), a novel saponin isolated from the roots of Astragalus membranaceus, has demonstrated antifibrotic and ER stress lowering effects in various tissues during disease conditions. However, the effect of AS.IV on glaucomatous TM fibrosis, ER stress and ocular hypertension has not been studied. Primary human TM cells treated with AS.IV decreased TGFβ2 induced ECM (FN, Col-I) deposition and ER stress (KDEL, ATF4 and CHOP). Moreover, AS.IV treatment reduced TGFβ2 induced NF-κB activation and αSMA expression in TM cells. We found that AS.IV treatment significantly increased levels of matrix metalloproteases (MMP9 and MMP2) and MMP2 enzymatic activity, indicating that the antifibrotic effects of AS.IV are mediated via inhibition of NF-κB and activation of MMPs. AS.IV treatment also reduced ER stress in TM3 cells stably expressing mutant myocilin. Interestingly, the topical ocular AS.IV eye drops (1 mM) significantly decreased TGFβ2 induced ocular hypertension in mice, and this was associated with a decrease in FN, Col-1 (ECM), KDEL (ER stress) and αSMA in mouse TM tissues. Taken together, the results suggest that AS.IV prevents TGFβ2 induced ocular hypertension by modulating ECM deposition and ER stress in the TM.

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Reduction of ER stress via a chemical chaperone prevents disease phenotypes in a mouse model of primary open angle glaucoma

Journal of Clinical Investigation ◽

10.1172/jci82799 ◽

2015 ◽

Vol 125 (8) ◽

pp. 3303-3303 ◽

Cited By ~ 13

Author(s):

Gulab S. Zode ◽

Markus H. Kuehn ◽

Darryl Y. Nishimura ◽

Charles C. Searby ◽

Kabhilan Mohan ◽

...

Keyword(s):

Mouse Model ◽

Er Stress ◽

Primary Open Angle Glaucoma ◽

Open Angle Glaucoma ◽

Open Angle ◽

Chemical Chaperone ◽

Disease Phenotypes

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Titanium dioxide nanoparticles induce endoplasmic reticulum stress-mediated apoptotic cell death in liver cancer cells

Journal of International Medical Research ◽

10.1177/0300060520903652 ◽

2020 ◽

Vol 48 (4) ◽

pp. 030006052090365

Author(s):

Zhiwang Li ◽

Jingliang He ◽

Bowei Li ◽

Jinqian Zhang ◽

Ke He ◽

...

Keyword(s):

Cell Cycle ◽

Endoplasmic Reticulum ◽

Cell Growth ◽

Liver Cancer ◽

Er Stress ◽

Cancer Cells ◽

Cell Cycle Distribution ◽

Expression Levels ◽

Liver Cancer Cells

Objective Titanium oxide (TiO2) acts as a photosensitizer in photodynamic therapy by mediating reactive oxygen species (ROS)-induced endoplasmic reticulum (ER) stress. This study aimed to investigate the effect of TiO2 on ER stress in liver cancer cells. Methods Normal human liver and human hepatocarcinoma cell lines were incubated with various concentrations of TiO2 nanotubes for 48 hours. Cell growth, apoptosis, cell cycle, and cellular ROS were detected. Expression levels of ER stress sensors (PERK and ATF6) and Bax were evaluated by western blot. The effect of TiO2 on liver cancer growth was also investigated in mice in vivo. Results TiO2 inhibited cell growth, increased apoptosis and cellular ROS levels, and arrested the cell cycle in G1 stage in liver cancer cells. TiO2 also increased PERK, ATF6, and Bax expression levels in liver cancer cells in dose-dependent manners. TiO2 had no significant effect on cell growth, apoptosis, ROS level, cell cycle distribution, or PERK, ATF6, or Bax expression in normal liver cells. TiO2 administration reduced tumor volume and increased PERK, Bax, and ATF6 expression levels in tumor tissues in vivo. Conclusions TiO2 nanoparticles increased ROS-induced ER stress and activated the PERK/ATF6/Bax axis in liver cancer cells in vitro and in vivo.

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Clinical efficacy of osteopathic correction in the complex treatment of patients with unoperated open-angle glaucoma

Russian Osteopathic Journal ◽

10.32885/2220-0975-2019-3-4-97-105 ◽

2020 ◽

pp. 97-105

Author(s):

E. N. Simakova ◽

O. V. Stenkova

Keyword(s):

Intraocular Pressure ◽

Drug Therapy ◽

Primary Open Angle Glaucoma ◽

Open Angle Glaucoma ◽

Randomized Study ◽

Main Group ◽

Control Group ◽

Open Angle ◽

Complex Treatment ◽

Hypotensive Drug

Introduction. Glaucoma is one of the most significant eye diseases. It is often diagnosed, not always amenable to therapy, and can lead to a complete loss of visual functions. In recent years, the method of osteopathic correction has become widespread as one of the effective methods of treatment and rehabilitation of patients with pathologies of various body systems. In the pathogenesis of glaucoma, it is customary to distinguish a dystrophic concept, which considers primary open-angle glaucoma as a result of dystrophic changes in the connective tissue, as well as in the endothelial lining of the trabeculae and Schlemm′s canal, especially destructive changes in mitochondria and the alteration of their functional activity. A vascular concept is also distinguished. According to this concept, the central link in the pathogenesis of glaucoma is circulatory disorder in the ciliary vessels, ocular artery, and major vessels of the head and neck, it can be assumed that osteopathic correction in the treatment of patients with open-angle glaucoma will be pathogenetically substantiated and will have a positive effect on intraocular pressure and trophicity of the optic nerve. The goal of research — to study the influence of in osteopathic correction on the nature of unoperated glaucoma (stage IIA) and to substantiate the possibility of using osteopathic correction in the complex treatment of patients with this pathology.Materials and methods. A prospective controlled randomized study was conducted at 52 city polyclinics, branch 3, Moscow, from January 2018 to January 2019. 40 patients (70 eyes) aged 50 to 75 years with primary open-angle glaucoma IIA stage were examined. At this stage of the disease, patients most often seek medical care and the issue of conservative management is primarily considered. All patients were divided into two groups of 20 people: the main group and the control group. The treatment in the main group included hypotensive drug therapy and osteopathic correction. Patients of the control group received only drug therapy. All patients underwent ophthalmic (visometry, tonometry, perimetry) and osteopathic examination twice: before the treatment and after 3 months.Results. For patients with primary open-angle IIA non-operated glaucoma, regional (most often regions of the head, neck, dura mater) and local (abdominal diaphragm, iliac bones, hip and knee joints) somatic dysfunctions were the most typical. In the main group a statistically significant decrease in the frequency and severity of dysfunctions at all levels was stated. Also, in patients receiving osteopathic correction, a significant decrease in the level of intraocular pressure and perimetric indices was noted. In patients of the control group, no reliable changes in these indicators were obtained.Conclusion. The results obtained indicate that osteopathic correction is clinically effective in the complex treatment of patients with primary open-angle II A glaucoma.

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