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

2011 ◽  
Vol 121 (9) ◽  
pp. 3542-3553 ◽  
Author(s):  
Gulab S. Zode ◽  
Markus H. Kuehn ◽  
Darryl Y. Nishimura ◽  
Charles C. Searby ◽  
Kabhilan Mohan ◽  
...  
2015 ◽  
Vol 125 (8) ◽  
pp. 3303-3303 ◽  
Author(s):  
Gulab S. Zode ◽  
Markus H. Kuehn ◽  
Darryl Y. Nishimura ◽  
Charles C. Searby ◽  
Kabhilan Mohan ◽  
...  

2012 ◽  
Vol 53 (3) ◽  
pp. 1557 ◽  
Author(s):  
Gulab S. Zode ◽  
Kevin E. Bugge ◽  
Kabhilan Mohan ◽  
Sinisa D. Grozdanic ◽  
Joseph C. Peters ◽  
...  

2021 ◽  
Vol 22 (9) ◽  
pp. 4494
Author(s):  
Wioletta Rozpędek-Kamińska ◽  
Grzegorz Galita ◽  
Natalia Siwecka ◽  
Steven L. Carroll ◽  
John Alan Diehl ◽  
...  

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.


2015 ◽  
Vol 36 (6) ◽  
pp. 2201-2212 ◽  
Author(s):  
Henry C. Tseng ◽  
Thorfinn T. Riday ◽  
Celia McKee ◽  
Catherine E. Braine ◽  
Howard Bomze ◽  
...  

2021 ◽  
Vol 22 (22) ◽  
pp. 12508
Author(s):  
Ramesh B. Kasetti ◽  
Prabhavathi Maddineni ◽  
Bindu Kodati ◽  
Bhavani Nagarajan ◽  
Sam Yacoub

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.


2019 ◽  
Vol 23 (8) ◽  
pp. 5497-5507 ◽  
Author(s):  
Sabrina Reinehr ◽  
Dennis Koch ◽  
Maximilian Weiss ◽  
Franziska Froemel ◽  
Christina Voss ◽  
...  

Author(s):  
E. N. Simakova ◽  
O. V. Stenkova

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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