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AimsTo compare the change in iris–trabecular contact (ITC) area using swept-source optical coherence tomography (SS-OCT) in eyes with primary angle closure glaucoma (PACG) and cataract that underwent phacoemulsification (PE) with intraocular lens implantation alone compared with PE with goniosynechialysis (GSL).MethodsOne eye of 22 patients with PACG with peripheral anterior synechiae (PAS) detected by indentation gonioscopy was randomised into two groups (PE alone (n=11) and PE+GSL (n=11)). The anterior chamber angles were evaluated by SS-OCT under dark conditions before and 12 months after surgery using the three-dimensional angle analysis scan protocol that simultaneously obtains 128 cross-sectional radial scans across the anterior chamber at equal intervals (every 1.4°). The ITC area, defined as the area of extent of the circumferential contact of peripheral iris to the angle wall, was computed automatically by SS-OCT after an observer marked the scleral spurs of all 128 scans of each eye.ResultsThe majority of the 22 subjects were women (77.3%) and the mean±SD age was 67.3±5.8 years. The ITC area was significantly reduced in the PE+GSL group compared with the PE alone group (10.2 mm2 vs 4.6 mm2, β=0.54, p=0.03) after adjusting for age, gender, intraocular pressure, extent of PAS and pupil diameter before surgery. Smaller iris volume at baseline was associated with greater ITC area reduction by PE+GSL (β=−0.728, p=0.03).ConclusionsEyes that undergo PE+GSL surgery have a greater reduction in circumferential ITC area than eyes that undergo PE alone.

The underlying pathological mechanisms of glaucomatous trabecular meshwork (TM) damage and elevation of intraocular pressure (IOP) are poorly understood. Here, we report that the chronic endoplasmic reticulum (ER) stress-induced ATF4-CHOP-GADD34 pathway is activated in TM of human and mouse glaucoma. Expression of ATF4 in TM promotes aberrant protein synthesis and ER client protein load, leading to TM dysfunction and cell death. These events lead to IOP elevation and glaucomatous neurodegeneration. ATF4 interacts with CHOP and this interaction is essential for IOP elevation. Notably, genetic depletion or pharmacological inhibition of ATF4-CHOP-GADD34 pathway prevents TM cell death and rescues mouse models of glaucoma by reducing protein synthesis and ER client protein load in TM cells. Importantly, glaucomatous TM cells exhibit significantly increased protein synthesis along with induction of ATF4-CHOP-GADD34 pathway. These studies indicate a pathological role of ATF4-CHOP-GADD34 pathway in glaucoma and provide a possible treatment for glaucoma by targeting this pathway. Glaucoma is the leading cause of irreversible blindness affecting over 70 million people worldwide. Here, the authors show that inhibition of chronic ER stress-induced ATF4-CHOP-GADD34 signaling pathway rescues pathology in mouse models of glaucoma, thus suggesting a possible treatment strategy.

The oxidative stress‐induced premature senescence of trabecular meshwork (TM) represents a pivotal risk factor for the development of glucocorticoid‐induced glaucoma (GIG). This study aimed to elucidate the pathogenesis of TM senescence in GIG. MethodsIntraocular pressure (IOP), transmission electron microscopy and senescence‐associated protein expression in TM were evaluated in GIG mice. Protein expression of phosphoinositide‐3‐kinase regulatory subunit 1 (PIK3R1) and monoamine oxidase A (MAOA), phosphorylation of AKT were quantified. ROS and mitochondrial superoxide levels were measured to evaluate cellular oxidative stress. Cell cycle analysis, β‐galactosidase staining, senescence‐associated protein expression were employed to assess the aging status of primary human trabecular meshwork cells (pHTMs). ResultsmRNA‐seq and KEGG analysis indicating PI3K/AKT pathway as a key regulator in TM of GIG. PI3K inhibitor significantly prevented IOP elevation and abnormal mitochondrial morphology of TM in the GIG mouse model. PI3K inhibitor or selective silencing of PIK3R1 alleviated dexamethasone (DEX)‐induced oxidative stress, also mitochondrial dysfunction, inhibiting MAOA expression in pHTMs. The same phenomenon was observed in the GIG models with inhibition of MAOA. Further KEGG analysis indicates that cellular senescence is the key factor in the pathogenesis of GIG. TM senescence was observed in both GIG mouse and cell models. Inhibition of the PI3K/AKT/MAOA pathway significantly alleviated DEX‐induced premature cellular senescence of TM in GIG models. Glucocorticoids activated the PI3K/AKT/MAOA pathway, leading to mitochondrial dysfunction, oxidative stress, and premature aging in TM, elevating IOP. This mechanism could be associated with the onset and progression of GIG, providing a potential approach for its treatment. Glucocorticoids activated the PI3K/AKT/MAOA pathway, leading to mitochondrial dysfunction, oxidative stress, and premature aging in TM, elevating IOP.

To evaluate structural alterations and healing responses in the trabecular meshwork region with optical coherence tomography (AS-OCT) following after gonioscopy assisted transluminal trabeculotomy (GATT) and microincisional trabeculectomy (MIT). 73 eyes of 67 patients (M:F = 45:22) with ≥6 months of follow-up after MIT (n = 41) or GATT (n = 32) with or without combined cataract surgery were included for this prospective study. The angle as seen on AS-OCT at 1, 3, 6 months after surgery were evaluated for structural alterations like peripheral anterior synechiae (PAS), hyphema, and hyperreflective scarring responses. The scarring was graded according to the linear extent measured from the centre of the trabecular meshwork (TM) gutter to the sclera/cornea as mild (<250μ), moderate (250-500μ), and severe(˃500μ), while the pattern of scarring was graded as open saucer/gutter, closed gutter, and trench pattern. The association of the need for medication or surgical outcome and clinical variables and AS-OCT parameters including the pattern and severity of scarring were analysed using multivariate regression. All eyes achieved significant reduction of IOP and number of medications with a final IOP of 15±3.2mm Hg at a mean follow-up of 8±32. months. While mild scarring was seen more common in MIT, severe scarring was seen in >65% of GATT eyes compared to 31% of MIT eye, p<0.001. An open saucer was equally seen in MIT and GATT while the trench pattern was more commonly seen in GATT eyes (>50%). Severe scarring in a trench pattern seemed to predict the need for medications for IOP control, though they independently did not seem to influence the final IOP or surgical outcome. A severe form of scarring in a trench pattern on AS-OCT predicted the need for glaucoma medications after MIGS surgery. Regular monitoring of the scarring responses by AS-OCT and clinical examination are necessary to identify those at need for medications after MIGS.

Glaucoma is a common cause of vision loss or blindness and reduction of intraocular pressure (IOP) has been proven beneficial in a large fraction of glaucoma patients. The IOP is maintained by the trabecular meshwork (TM) and the elevation of IOP in open-angle glaucoma is associated with dysfunction and loss of the postmitotic cells residing within this tissue. To determine if IOP control can be maintained by replacing lost TM cells, we transplanted TM-like cells derived from induced pluripotent stem cells into the anterior chamber of a transgenic mouse model of glaucoma. Transplantation led to significantly reduced IOP and improved aqueous humor outflow facility, which was sustained for at least 9 wk. The ability to maintain normal IOP engendered survival of retinal ganglion cells, whose loss is ultimately the cause for reduced vision in glaucoma. In vivo and in vitro analyses demonstrated higher TM cellularity in treated mice compared with littermate controls and indicated that this increase is primarily because of a proliferative response of endogenous TM cells. Thus, our study provides in vivo demonstration that regeneration of the glaucomatous TM is possible and points toward novel approaches in the treatment of this disease.

Background TGF-β-induced fibrogenic changes in human trabecular meshwork (HTM) cells contribute to intraocular pressure elevation in glaucoma. Silibinin, a natural polyphenolic flavonoid from milk thistle seeds, has been well investigated for its function to inhibit fibrosis. The transcriptomic changes in noncoding RNAs contributing to the pro-fibrotic effect of TGF-β2 and the anti-fibrotic activity of silibinin in HTM cells remain unknown. Methods RNA sequencing was conducted to characterize the transcriptomic profiles (mRNA, lncRNA, circRNA, and miRNA) in TGF-β2-stimulated HTM cells, with or without silibinin treatment. Pathway enrichment analysis of the differentially expressed RNAs was conducted. Competing endogenous RNA networks were constructed. Results TGF-β2 upregulated 1119 mRNAs, 319 lncRNAs, 383 circRNAs, and 30 miRNAs in HTM cells, of which 545 mRNAs, 183 lncRNAs, 265 circRNAs, and 22 miRNAs were reversed by silibinin. These rescued mRNAs, including COL1A1 and α-SMA, were enriched in pathways including cell migration, cell adhesion, and extracellular matrix. Furthermore, TGF-β2 downregulated 1165 mRNAs, 212 lncRNAs, 449 circRNAs, and 15 miRNAs, of which 395 mRNAs, 54 lncRNAs, 104 circRNAs, and 7 miRNAs were reversed by silibinin. These rescued mRNAs were enriched in cytokine-mediated signaling pathway and inflammatory response. By predicting the binding of differentially expressed mRNAs, lncRNAs, and circRNAs to miRNAs via miranda (v 3.3a) software, we constructed lncRNA-miRNA-mRNA and circRNA-miRNA-mRNA networks that might be involved in the effects of TGF-β2 and silibinin in HTM cells. Conclusions Silibinin mitigated TGF-β2-induced alterations in the coding and noncoding RNA profiles of HTM cells, presumably contributing to its anti-fibrotic activity. To our knowledge, this is the first study to illustrate the lncRNA and circRNA changes induced by TGF-β2 in HTM cells, and the first study to investigate silibinin’s anti-fibrotic effects in HTM cells from the perspective of noncoding RNAs. Our work deepened the understanding of gene regulation by noncoding RNAs in the TGF-β2-induced fibrogenic changes and the anti-fibrotic activity of silibinin in HTM cells.

Mutations in myocilin (MYOC) are the most common genetic cause of primary open angle glaucoma (POAG), but the mechanisms underlying MYOC-associated glaucoma are not fully understood. Here, we report the development of a transgenic mouse model of POAG caused by the Y437H MYOC mutation; the mice are referred to herein as Tg-MYOC(Y437H) mice. Analysis of adult Tg-MYOC(Y437H) mice, which we showed express human MYOC containing the Y437H mutation within relevant eye tissues, revealed that they display glaucoma phenotypes (i.e., elevated intraocular pressure [IOP], retinal ganglion cell death, and axonal degeneration) closely resembling those seen in patients with POAG caused by the Y437H MYOC mutation. Mutant myocilin was not secreted into the aqueous humor but accumulated in the ER of the trabecular meshwork (TM), thereby inducing ER stress in the TM of Tg-MYOC(Y437H) mice. Furthermore, chronic and persistent ER stress was found to be associated with TM cell death and elevation of IOP in Tg-MYOC(Y437H) mice. Reduction of ER stress with a chemical chaperone, phenylbutyric acid (PBA), prevented glaucoma phenotypes in Tg-MYOC(Y437H) mice by promoting the secretion of mutant myocilin in the aqueous humor and by decreasing intracellular accumulation of myocilin in the ER, thus preventing TM cell death. These results demonstrate that ER stress is linked to the pathogenesis of POAG and may be a target for treatment in human patients.

Pseudoexfoliation glaucoma is a severe form of secondary open angle glaucoma and is associated with activation of the TGF-β pathway by TGF-β1. MicroRNAs (miRNAs) are small non-coding RNA species that are involved in regulation of mRNA expression and translation. To investigate what glaucomatous changes occur in the trabecular meshwork and how these changes may be regulated by miRNAs, we performed a bioinformatics analysis resulting in a miRNA-mRNA interactome. Primary human trabecular meshwork cells originating from normal donors were treated with TGF-β1 at 5 ng/mL for 24h; total RNA was extracted followed by RNA-Seq and miRNA-Seq. For both mRNA and miRNA species, differential expression was determined using a bioinformatics pipeline consisting of FastQC, STAR, FeatureCounts, edgeR (for miRNA) and DESeq2 (for mRNA). Putative mRNA-miRNA interactions between differentially expressed mRNA and miRNA species were determined using interaction databases miRWalk, miRTarBase, TarBase and TargetScan. To classify mRNA species by function and pathway, gene enrichment was performed using Enrichr. The resulting miRNA-mRNA interactome consisted of 1202 interactions. Some highly connected microRNAs were hsa-let-7e-5p, hsa-miR-20a-5p, hsa-miR-122-5p, and hsa-miR-29c-3p. Most differentially expressed genes were indicated to be regulated by miRNAs. The sub-interactomes of genes involved in specific pseudoexfoliation glaucoma related enrichment terms such as oxidative stress, unfolded protein response, signal molecules and ECM remodelling were determined. This is the first study to present a genome-wide microRNA-mRNA regulatory network for human trabecular meshwork cells treated with TGF-β1 and may serve to generate unbiased hypotheses about regulatory functions and mRNA targets of miRNAs in pseudoexfoliation glaucoma and may help to develop miRNA-based therapeutics.

Primary open‐angle glaucoma is a leading cause of irreversible blindness, often associated with increased intraocular pressure. Extracellular vesicles (EVs) carry a specific composition of proteins, lipids and nucleotides have been considered as essential mediators of cell‐cell communication. Their potential impact for crosstalk between tissues responsible for aqueous humour production and out‐flow is largely unknown. The study objective was to investigate the effects of EVs derived from non‐pigmented ciliary epithelium (NPCE) primary cells on the expression of Wnt proteins in a human primary trabecular meshwork (TM) cells and define the mechanism underlying exosome‐mediated regulation that signalling pathway. Consistent with the results in TM cell line, EVs released by both primary NPCE cells and NPCE cell line showed diminished pGSK3β phosphorylation and decreased cytosolic levels of β‐catenin in primary TM cells. At the molecular level, we showed that NPCE exosome treatment downregulated the expression of positive GSKβ regulator‐AKT protein but increased the levels of GSKβ negative regulator‐PP2A protein in TM cells. NPCE exosome protein analysis revealed 584 miRNAs and 182 proteins involved in the regulation of TM cellular processes, including WNT/β‐catenin signalling pathway, cell adhesion and extracellular matrix deposition. We found that negative modulator of Wnt signalling miR‐29b was abundant in NPCE exosomal samples and treatment of TM cells with NPCE EVs significantly decreased COL3A1 expression. Suggesting that miR‐29b can be responsible for decreased levels of WNT/β‐catenin pathway. Overall, this study highlights a potential role of EVs derived from NPCE cells in modulating ECM proteins and TM canonical Wnt signalling.

To examine ultrastructural changes in the trabecular meshwork (TM) in patients with primary and secondary glaucoma using scanning electron microscopy (SEM). This was a qualitative descriptive hospital-based study on the ultrastructure of the TM. Pure TM samples were collected after microincisional trabeculectomy from 26 patients with primary or secondary glaucoma and 10 control samples from eye bank donor corneas. SEM was used to analyze structural changes in the TM beams, corneoscleral meshwork (CSM), and juxtacanalicular (JCT) regions. Morphological features were compared between groups and correlated with histopathological findings. SEM revealed flattened and broadened TM beams in the JCT, resembling controls, often with a dumbbell configuration. Histopathological examination (HPE) and SEM showed rounded TM beams with considerable thinning, especially in primary angle-closure glaucoma (PACG), compared to primary open-angle (POAG) and pseudoexfoliation glaucoma (XFG). Maximum thinning in all primary glaucoma occurred in the CSM region, with minimal changes in the JCT region despite a reduction in cellularity in both regions. In steroid glaucoma, amorphous, glistening material was found on the TM beams in the JCT and CSM. XFG eyes displayed vesicular bodies adjacent to fibrillar material scattered diffusely over the TM beams, particularly in the CSM, differing from the platelet clumps seen in regular blood clots. TM beam thinning in primary glaucoma primarily affects the CSM region, sparing the JCT region. Amorphous deposits or vesicular bodies, seen only in steroid-induced glaucoma and XFG, suggest different mechanisms of TM damage in these glaucoma types.