Browsing by Author "Dhamodaran, Kamesh"

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    GSK3β Inhibitors Inhibit TGFβ Signaling in the Human Trabecular Meshwork
    (Association for Research in Vision and Ophthalmology, 2024) Sugali, Chenna Kesavulu; Rayana, Naga Pradeep; Dai, Jiannong; Harvey, Devon H.; Dhamodaran, Kamesh; Mao, Weiming; Ophthalmology, School of Medicine
    Purpose: Primary open-angle glaucoma (POAG) is a leading cause of blindness, and its primary risk factor is elevated intraocular pressure (IOP) due to pathologic changes in the trabecular meshwork (TM). We previously showed that there is a cross-inhibition between TGFβ and Wnt signaling pathways in the TM. In this study, we determined if activation of the Wnt signaling pathway using small-molecule Wnt activators can inhibit TGFβ2-induced TM changes and ocular hypertension (OHT). Methods: Primary human TM (pHTM) cells and transduced SBE-GTM3 cells were treated with or without Wnt and/or TGFβ signaling activators and used for luciferase assays; for the extraction of whole-cell lysate, conditioned medium, cytosolic proteins, and nuclear proteins for Western immunoblotting (WB); or for immunofluorescent staining. Human donor eyes were perfusion cultured to study the effect of Wnt activators on IOP. Results: We found that the small-molecule Wnt activators (GSK3β inhibitors) (BIO, SB216763, and CHIR99021) activated canonical Wnt signaling in pHTM cells without toxicity at tested concentrations. This activation inhibited TGFβ signaling as well as TGFβ2-induced extracellular matrix deposition and formation of cross-linked actin networks in pHTM cells or SBE-GTM3 cells. We also observed nuclear translocation of both Smad4 and β-catenin in pHTM cells, which suggested that the cross-inhibition between the TGFβ and Wnt signaling pathways may occur in the nucleus. Using our ex vivo model, we found that CHIR99021 inhibited TGFβ2-induced OHT in perfusion-cultured human eyes. Conclusions: Our results showed that small-molecule Wnt activators have the potential for treating TGFβ signaling-induced OHT in patients with POAG.
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    Inhibition of pterygium cell fibrosis by the Rho kinase inhibitor
    (Springer Nature, 2024-12-28) Dai, Jiannong; Rayana, Naga Pradeep; Peng, Michael; Sugali, Chenna Kesavulu; Harvey, Devon H.; Dhamodaran, Kamesh; Yu, Eric; Dalloul, Joseph M.; Liu, Shaohui; Mao, Weiming; Ophthalmology, School of Medicine
    Pterygium is an ocular disease in which the conjunctival tissue invades the cornea. When the pterygium tissue reaches the pupillary region, the visual function of the patient is affected. Currently, surgical removal is the only effective treatment. However, the recurrence rate of pterygium after surgery can be high. Pterygium is also a health disparity issue since it is more prevalent in the Hispanic and Latino American population. In this study, we determined if the Rho kinase inhibitor can be used to prevent pterygium recurrence since its anti-fibrosis effects have been reported in other cell and tissue types. We cultured primary pterygium cells from pterygium tissues from Hispanic and Latino American, African American, Caucasian, and Asian donors, and used those cells for viability assays, scratch assays, migration assays, and immunostaining of F-actin, fibronectin, collagen I and α smooth muscle actin. We found that the Rho kinase inhibitor Y27632 decreased cell viability, wound healing, cell migration, as well as the expression of extracellular matrix and myofibroblast markers in cultured pterygium cells. We believe that Rho kinase inhibitors are a potential post-surgical treatment to prevent pterygium recurrence.