The relationship between <i>HDAC6, CXCR3</i>, and <i>SIRT1</i> genes expression levels with progression of primary open-angle glaucoma

Siwak, Mateusz; Maślankiewicz, Marcin; Nowak-Zduńczyk, Alicja; Rozpędek, Wioletta; Wojtczak, Radosław; Szymanek, K.; Szaflik, Marta; Szaflik, Jerzy; Szaflik, Jacek P.; Majsterek, Ireneusz

doi:10.1080/13816810.2018.1432061

Cited by 7 publications

(3 citation statements)

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“…The results of our studies show that HDAC6 inhibition by TS decreased the appearance of the senescence marker γH2AX and significantly augmented the expression of the redox homeostatic histone deacetylase SIRT1, of which expression levels are inversely correlated with the induction of endothelial cell senescence [4,7]. A contrasting balance between HDAC6 and SIRT1 could significantly impact the redox status of a number of cells including endothelial and other retinal cells [28].…”

Section: Discussionmentioning

confidence: 72%

Inhibition of HDAC6 Attenuates Diabetes-Induced Retinal Redox Imbalance and Microangiopathy

et al. 2020

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We investigated the contributing role of the histone deacetylase 6 (HDAC6) to the early stages of diabetic retinopathy (DR). Furthermore, we examined the mechanism of action of HDAC6 in human retinal endothelial cells (HuREC) exposed to glucidic stress. Streptozotocin-induced diabetic rats (STZ-rats), a rat model of type 1 diabetes, were used as model of DR. HDAC6 expression and activity were increased in human diabetic postmortem donors and STZ-rat retinas and were augmented in HuREC exposed to glucidic stress (25 mM glucose). Administration of the HDAC6 specific inhibitor Tubastatin A (TS) (10 mg/kg) prevented retinal microvascular hyperpermeability and up-regulation of inflammatory markers. Furthermore, in STZ-rats, TS decreased the levels of senescence markers and rescued the expression and activity of the histone deacetylase sirtuin 1 (SIRT1), while downregulating the levels of free radicals and of the redox stress markers 4-hydroxynonenal (4-HNE) and nitrotyrosine (NT). The antioxidant effects of TS, consequent to HDAC6 inhibition, were associated with preservation of Nrf2-dependent gene expression and up-regulation of thioredoxin-1 activity. In vitro data, obtained from HuREC, exposed to glucidic stress, largely replicated the in vivo results further confirming the antioxidant effects of HDAC6 inhibition by TS in the diabetic rat retina. In summary, our data implicate HDAC6 activation in mediating hyperglycemia-induced retinal oxidative/nitrative stress leading to retinal microangiopathy and, potentially, DR.

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Section: Discussionmentioning

confidence: 72%

Inhibition of HDAC6 Attenuates Diabetes-Induced Retinal Redox Imbalance and Microangiopathy

et al. 2020

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“…Consequently, it has been observed that there is an increase in cell-adhesion molecules on the endothelial cells in inflamed retinas. Moreover, RGCs have been reported to express many chemokines that are responsible for chemokine recruitment [60][61][62]. However, many aspects of immune infiltration and BRB integrity and their role in glaucoma pathogenesis remain elusive (Fig.…”

Section: Glial Cells Responses In Glaucoma: a Systematic Reviewmentioning

confidence: 99%

Glial Cell Activation and Immune Responses in Glaucoma: A Systematic Review of Human Postmortem Studies of the Retina and Optic Nerve

Salkar,

Wall,

Basavarajappa

et al. 2024

Aging and disease

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Although researched extensively the understanding regarding mechanisms underlying glaucoma pathogenesis remains limited. Further, the exact mechanism behind neuronal death remains elusive. The role of neuroinflammation in retinal ganglion cell (RGC) death has been prominently theorised. This review provides a comprehensive summary of neuroinflammatory responses in glaucoma. A systematic search of Medline and Embase for articles published up to 8th March 2023 yielded 32 studies using post-mortem tissues from glaucoma patients. The raw data were extracted from tables and text to calculate the standardized mean differences (SMDs). These studies utilized post-mortem tissues from glaucoma patients, totalling 490 samples, compared with 380 control samples. Among the included studies, 27 reported glial cell activation based on changes to cellular morphology and molecular staining. Molecular changes were predominantly attributed to astrocytes (62.5%) and microglia (15.6%), with some involvement of Muller cells. These glial cell changes included amoeboid microglial cells with increased CD45 or HLA-DR intensity and hypertrophied astrocytes with increased glial fibrillary acidic protein labelling. Further, changes to extracellular matrix proteins like collagen, galectin, and tenascin-C suggested glial cells' influence on structural changes in the optic nerve head. The activation of DAMPs-driven immune response and the classical complement cascade was reported and found to be associated with activated glial cells in glaucomatous tissue. Increased pro-inflammatory markers such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were also linked to glial cells. Glial cell activation was also associated with mitochondrial, vascular, metabolic and antioxidant component disruptions. Association of the activated glial cells with pro-inflammatory responses, dysregulation of homeostatic components and antigen presentation indicates that glial cell responses influence glaucoma progression. However, the exact mechanism triggering these responses and underlying interactions remains unexplored. This necessitates further research using human samples for an increased understanding of the precise role of neuroinflammation in glaucoma progression.

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“…Another pair of chemokines (C-X-C motif) ligand 10/(C-X-C motif) receptor 3 (CXCL10/CXCR3) are found to be induced by acute IOP elevation and subsequently contribute to the release of proinflammatory cytokines, elevated expression of E-selectin, and infiltration of inflammatory cells ( 91 ). In patients with glaucoma, the levels of chemokines of macrophage chemoattractant protein-1 (MCP-1), CXCR3, CCL2, and CCL7 show prognostic value and are correlated with disease progression ( 92 – 94 ). On the other hand, the induced expression of corresponding chemokines and receptors on the T cell surface under inflamed conditions favors their interplay with the vascular endothelium ( 90 , 95 ).…”

Section: Compromised Brb Is Essential For T Cell Infiltration In Glaucoma Eyesmentioning

confidence: 99%

T Cell-Mediated Autoimmunity in Glaucoma Neurodegeneration

Wang

Wei

2021

Front. Immunol.

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Glaucoma as the leading neurodegenerative disease leads to blindness in 3.6 million people aged 50 years and older worldwide. For many decades, glaucoma therapy has primarily focused on controlling intraocular pressure (IOP) and sound evidence supports its role in delaying the progress of retinal ganglial cell (RGC) damage and protecting patients from vision loss. Meanwhile, accumulating data point to the immune-mediated attack of the neural retina as the underlying pathological process behind glaucoma that may come independent of raised IOP. Recently, some scholars have suggested autoimmune aspects in glaucoma, with autoreactive T cells mediating the chief pathogenic process. This autoimmune process, as well as the pathological features of glaucoma, largely overlaps with other neurodegenerative diseases in the central nervous system (CNS), including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. In addition, immune modulation therapy, which is regarded as a potential solution for glaucoma, has been boosted in trials in some CNS neurodegenerative diseases. Thus, novel insights into the T cell-mediated immunity and treatment in CNS neurodegenerative diseases may serve as valuable inspirations for ophthalmologists. This review focuses on the role of T cell-mediated immunity in the pathogenesis of glaucoma and discusses potential applications of relevant findings of CNS neurodegenerative diseases in future glaucoma research.

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The relationship between HDAC6, CXCR3, and SIRT1 genes expression levels with progression of primary open-angle glaucoma

Abstract: The expression level of HDAC6, CXCR3, and SIRT1 genes may be involved in the progression of POAG.

Cited by 7 publications

References 51 publications

Inhibition of HDAC6 Attenuates Diabetes-Induced Retinal Redox Imbalance and Microangiopathy

Inhibition of HDAC6 Attenuates Diabetes-Induced Retinal Redox Imbalance and Microangiopathy

Glial Cell Activation and Immune Responses in Glaucoma: A Systematic Review of Human Postmortem Studies of the Retina and Optic Nerve

T Cell-Mediated Autoimmunity in Glaucoma Neurodegeneration

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