Trabeculotomy Using the Kahook Dual Blade for Exfoliation Glaucoma and Primary Open Angle Glaucoma: Comparison of Outcomes According to Incision Range.

PRCIS: Large amount of trabeculotomy with Kahook Dual Blade (KDB) confers better intraocular pressure (IOP) lowering. PURPOSE: We compared the postoperative outcomes of trabeculotomy using the KDB in patients with exfoliation glaucoma (EXG) and primary open angle glaucoma between the 120-degree incision and the 210- to 240-degree incision groups. PATIENTS AND METHODS: We retrospectively analyzed the postoperative outcomes of trabeculotomy performed using the KDB in 101 eyes with EXG and primary open angle glaucoma, who received 120- and 210- to 240-degree incisions at Kumamoto University Hospital between April 25, 2018, and August 11, 2021. Kaplan-Meyer survival curves were used to assess the outcomes. Surgical failure was defined as IOP ≥21 mm Hg (criterion A) and ≥19 mm Hg (criterion B), or an IOP ≤4 mm Hg in either criterion and the need for additional glaucoma surgery. RESULTS: In total, 64 and 37 eyes were included in the 120 and 210- to 240-degree groups, respectively. The 210- to 240-degree group had a higher 1-year success rate compared with the 120-degree group, both when considering all eyes and when considering only those with EXG (P<0.05). CONCLUSIONS: In trabeculotomy with KDB, a 210- to 240-degree incision was more effective than a 120-degree incision in lowering IOP in EXG cases.

Silencing of ocular transthyretin, a gene responsible for hereditary transthyretin amyloidosis, by intravitreal injection of an siRNA conjugate into rabbit eyes.

The first small interfering RNA (siRNA) therapeutic received approval for hereditary transthyretin (ATTRv) amyloidosis, and the patients' lifespan extension by specific inhibition of hepatic synthesis of transthyretin (TTR) is expected. However, ocular amyloidosis in these patients has been a crucial issue. This study aims to evaluate the efficacy and safety of intravitreal TTR siRNA conjugate injection into rabbit eyes. Rabbit (r) TTR siRNA is a screened TTR siRNA conjugate from 53 candidates. The intraocular pressure (IOP) immediately after injection was high despite the 65.9 % decrease of aqueous humor TTR protein levels in the rTTR siRNA group compared with those in the Control siRNA group 2 weeks after the 50 µL siRNA injection. The IOP spike was milder after the 30 µL siRNA injection, and aqueous humor TTR levels decreased by ∼50 % in the rTTR siRNA group, which is consistent with the mRNA levels in the retina. The parameters of dark-adapted, light-adapted, and light-adapted 30 Hz electroretinogram and the thickness of each retinal layer in histological analysis demonstrated no significant differences between the groups. In conclusion, we developed TTR siRNA conjugates for rabbit eyes, and the results indicate that intravitreal TTR siRNA conjugate injection could be a therapeutic option for ocular amyloidosis caused by ATTRv amyloidosis.

A ROCK inhibitor suppresses the transforming growth factor-beta-2-induced endothelial-mesenchymal transition in Schlemm's canal endothelial cells.

In the normal eye, most of the aqueous humor drains through the trabecular meshwork (TM) and Schlemm's canal (SC). The concentration of transforming growth factor beta 2 (TGF-ß2) is increased in the aqueous humor of primary open angle glaucoma patients. TGF-ß2 increases outflow resistance by affecting the TM and SC, and endothelial-mesenchymal transition (EndMT) of SC cells is involved in these changes. Here, we investigated the effect of a ROCK inhibitor on TGF-ß2-induced EndMT in SC cells. The ROCK inhibitor Y-27632 suppressed the TGF-ß2-induced increase in the trans-endothelial electrical resistance (TER) and proliferation of SC cells. Y-27632 suppressed the expression of α-SMA, N-cadherin, and Snail, which are upregulated by TGF-ß2. Moreover, TGF-ß2 decreased mRNA levels of bone morphogenetic protein (BMP) 4 and increased those of the BMP antagonist gremlin (GREM1), but Y-27632 significantly suppressed these changes. Y-27632 also inhibited TGF-ß2-induced phosphorylation of p-38 mitogen-activated protein kinase (MAPK). BMP4 and the p-38 MAPK inhibitor SB203580 suppressed the TGF-ß2-induced TER elevation in SC cells. Moreover, SB203580 suppressed TGF-ß2-induced upregulation of fibronectin, Snail, and GREM1. These results indicate that a ROCK inhibitor inhibited the TGF-ß2-induced EndMT in SC cells, implying the involvement of p38 MAPK and BMP4 signaling.

Risk factors for Baerveldt glaucoma drainage implantation for uveitic glaucoma.

Uveitic glaucoma (UG) is sometimes intractable, including intricate interaction between intraocular pressure (IOP) elevation associated with inflammation and side effects of steroids. Based on the Tube Versus Trabeculectomy study in refractory glaucoma results in 2012, tube shunt surgeries have been performed for UG, but few reports have focused on UG. We retrospectively examined the surgical efficacy, complications, and risk factors in 62 eyes with UG that underwent Baerveldt glaucoma drainage device (BGD) implantation at Kumamoto University. The IOPs significantly dropped, and the mean number of glaucoma medications was reduced by more than two. Kaplan‒Meier survival curves were presented under 2 conditions: an IOP reduction of 20% and 6 ≤ IOP ≤ 18 mmHg (criterion A) or 6 ≤ IOP ≤ 15 mmHg (criterion B). In criterion A, the median survival times (MST) were 124 days (complete) and 997 days (qualified). In criterion B, the MST was 129 days (complete) and 867 days (qualified). The Cox hazard proportional model found that the hazard ratio was 0.170 for a history of cataract surgery (95% CI 0.0303-0.950) and 8.669 for systemic immunosuppressive therapy (95% CI 1.810-41.51). BGD implantation is effective for treating UG, but the presence of systemic treatment and the lens status should be considered.

The Japan Glaucoma Society guidelines for glaucoma 5th edition.

We are pleased to bring you the 5th edition of the Glaucoma Clinical Practice Guidelines. Clinical practice guidelines are based on evidence (scientific grounds). It is a document that presents the treatment that is the most appropriate for the patient. "Glaucoma Clinical Guidelines" was first published in 2003. This was the first guideline for glaucoma treatment in Japan. The principle of glaucoma treatment is to lower intraocular pressure. Means for lowering intraocular pressure includes drugs, lasers, and surgery; Glaucoma is a disease that should be considered as a complex syndrome rather than a single condition. Therefore, the actual medical treatment is not as simple as one word. This time we set the Clinical Questionnaire with a focus on glaucoma treatment. We hope that you will take advantage of the 5th edition.

Ipilimumab-related uveitis and refractory hypotony with a flat chamber in a trabeculectomized eye with exfoliation glaucoma: A case report.

Purpose: Ipilimumab is an immune checkpoint inhibitor that occasionally causes ophthalmic immune-related adverse events (irAEs) such as dry eye, uveitis, and episcleritis. We report a case of ipilimumab-related uveitis and refractory hypotony with a flat anterior chamber (AC) in a trabeculectomized eye with exfoliation glaucoma. Observation: A 69-year-old man with a history of cataract surgery and trabeculectomy for exfoliation glaucoma in the right eye presented with blurred vision at 2 months after initiation of ipilimumab for metastatic malignant melanoma (day 0). Although no ophthalmic irAEs were observed at the first visit, he developed iritis, vitreous opacity, and choroidal detachment by day 18.As a result of the irAEs, the scheduled course of ipilimumab was canceled and he was instead treated with corticosteroids (eye drops and systemic). The symptoms progressed, and on day 32 visual acuity was light perception, with a flat AC, hypotony maculopathy, and severe choroidal detachment in the right eye. The patient received two AC formations with a viscoelastic substance, but the flat AC and hypotony recurred. Because the effects of the surgeries were temporary, high doses of corticosteroids were administered. AC depth, anterior uveitis, intraocular pressure, and choroidal detachment resolved by day 91. Conclusions: Ophthalmologists and oncologists should be aware of the rare but severe irAEs, and careful follow-up is required for ophthalmic irAEs caused by ipilimumab, especially in cases with a history of glaucoma surgery.

Outcomes and risk factors for ab interno trabeculotomy with a Kahook Dual Blade.

PURPOSE: To verify the surgical results and risk factors for ab interno trabeculotomy using a Kahook Dual Blade (KDB-LOT) in patients with various glaucoma types. METHODS: This study was a retrospective case series of 205 eyes that underwent KDB-LOT. For Kaplan-Meier survival analysis, criterion A was defined as a ≤ 20% reduction in intraocular pressure (IOP) from baseline. Criteria B, C, and D were IOPs of ≤ 21, 18, and 15 mmHg, respectively. The Cox proportional hazard (CPH) model investigated prognostic factors. RESULTS: The mean (SD) IOP decreased from 24.7 (7.98) to 17.6 (4.80) mmHg in all cases, from 21.3 (6.88) to 17.8 (3.52) mmHg in primary open-angle glaucoma (POAG), from 25.4 (7.32) to 17.1 (4.65) mmHg in exfoliation glaucoma, from 30.6 (8.88) to 17.8 (8.29) mmHg in uveitic glaucoma, and from 30.8 (7.29) to 17.3 (0.83) mmHg in steroid-induced glaucoma at 1 year after KDB-LOT. The Kaplan-Meier survival analysis showed that patients with POAG had the best prognosis under criteria B and C, and the 1-year survival rate in patients under criterion D was less than 35% for any disease type. CPH analysis revealed that age and KDB-LOT with phacoemulsification were good prognostic factors. Risk factors for surgical failure were previous cataract surgery, selective laser trabeculoplasty, and postoperative peripheral anterior synechiae. CONCLUSION: KDB-LOT was effective in treating patients with several glaucoma types but showed difficulty in pushing IOP below 15 mmHg. Prognostic factors should be considered when making decisions regarding surgical indications.

Elevated soluble vascular endothelial growth factor receptor levels in aqueous humor from patients with different types of glaucoma.

We investigated the aqueous humor levels of vascular endothelial growth factor (VEGF), soluble VEGF receptor (sVEGFR)1, and sVEGFR2 in glaucoma patients and the correlations among them. Aqueous humor was collected from the anterior chamber at the start of glaucoma or cataract surgery. The levels of VEGF and its receptors, sVEGFR1 and sVEGFR2, were measured using multiplex bead-based immunoassays. Aqueous humor samples were obtained from 79 participants: 21 with primary open angle glaucoma (POAG), 22 with uveitic glaucoma (UG), 19 with neovascular glaucoma (NVG), and 17 with cataracts as controls. sVEGFR1 levels were significantly higher in NVG than in the other cases (NVG, 2839.8 pg/mL, P < 0.001). The sVEGFR2 levels of glaucoma patients were significantly higher than those of the controls (POAG, 699.0 pg/mL; UG, 866.2 pg/mL; NVG, 1198.1 pg/mL; P < 0.001). In the aqueous humor of glaucoma patients, sVEGFR1 and sVEGFR2 levels were positively correlated (POAG, P = 0.0196; UG, P = 0.0047; NVG, P = 0.0050). VEGF levels were negatively correlated with both sVEGFR1 (P = 0.0197) and sVEGFR2 (P = 0.0015) in POAG patients. In UG patients, the correlation between VEGF and sVEGFR1 levels was negative (P = 0.0144). sVEGFR2 levels were increased in various glaucomatous eyes. sVEGFR levels were negatively correlated with VEGF levels in some glaucoma types, implying that sVEGFRs may modulate the effects of aqueous VEGF in glaucoma pathogenesis.

Bone marrow imaging reveals the migration dynamics of neonatal hematopoietic stem cells.

Hematopoietic stem cells (HSCs) are produced from the blood vessel walls and circulate in the blood during the perinatal period. However, the migration dynamics of how HSCs enter the bone marrow remain elusive. To observe the dynamics of HSCs over time, the present study develops an intravital imaging method to visualize bone marrow in neonatal long bones formed by endochondral ossification which is essential for HSC niche formation. Endogenous HSCs are labeled with tdTomato under the control of an HSC marker gene Hlf, and a customized imaging system with a bone penetrating laser is developed for intravital imaging of tdTomato-labeled neonatal HSCs in undrilled tibia, which is essential to avoid bleeding from fragile neonatal tibia by bone drilling. The migration speed of neonatal HSCs is higher than that of adult HSCs. Neonatal HSCs migrate from outside to inside the tibia via the blood vessels that penetrate the bone, which is a transient structure during the neonatal period, and settle on the blood vessel wall in the bone marrow. The results obtained from direct observations in vivo reveal the motile dynamics and colonization process of neonatal HSCs during bone marrow formation.

Risk factors for intraocular pressure elevation in a six-month period after ab interno trabeculotomy using a Kahook Dual Blade.

BACKGROUND: To examine the risk factors for an early postoperative intraocular pressure (IOP) increase after ab interno trabeculotomy using a Kahook Dual Blade (KDB trabeculotomy). METHODS: A retrospective study was performed in 76 exfoliation glaucoma (EXG) eyes and 56 primary open angle glaucoma (POAG) eyes that underwent KDB trabeculotomy, with or without cataract surgery at Kumamoto University Hospital. Postoperative high IOP was classified as IOP≥20 mmHg (within three months after surgery, whether persistent or temporary), transient IOP≥20 mmHg (IOP≥20 mmHg after surgery, then dropped below 20 mmHg), and the presence of IOP spikes (≥ 10 mmHg from baseline). Risk factors were examined using logistic regression analysis. RESULTS: The preoperative mean IOP (SD) was 24.98 (7.23) mmHg in patients with EXG and 21.28 (6.58) mmHg in patients with POAG. IOP was reduced by 32.1% in patients with EXG and by 17.7% in patients with POAG at 6 months after surgery. Postoperative IOP≥20 mmHg was observed in 56.6% of EXG patients and in 51.8% of POAG patients. IOP spikes occurred in 15.8% of EXG patients and in 14.3% of POAG patients. Logistic regression analysis showed that factors with significant odds ratios (ORs) were age (OR = 0.866, 95% CI = 0.793-0.945), preoperative medication use (OR = 2.02, 95% CI = 1.17-3.49), trabeculotomy in combination with cataract surgery (OR = 0.0674, 95% CI = 0.015-0.303), and IOP at day 1 (OR = 1.41, 95% CI = 1.18-1.68) for postoperative IOP≥20 mmHg, the IOP at day 1 (OR = 1.1, 95% CI = 1.03-1.17) for transient IOP≥20 mmHg, and age (OR = 0.948, 95% CI = 0.901-0.997) and preoperative IOP (OR = 0.83, 95% CI = 0.736-0.936) for IOP spikes. CONCLUSION: Although KDB trabeculotomy is an effective treatment for patients with EXG and POAG, patients who take multiple preoperative medications and have a high IOP on day 1 require careful follow-up to prevent postoperative IOP elevation.

Comparing Surgical Outcomes in Neovascular Glaucoma between Tube and Trabeculectomy: A Multicenter Study.

OBJECTIVE: To compare the surgical outcomes between Baerveldt glaucoma implant (BGI) surgery and trabeculectomy with mitomycin C for patients with neovascular glaucoma (NVG). DESIGN: Retrospective clinical cohort study at 5 clinical centers in Japan. PARTICIPANTS: Patients treated with trabeculectomy or BGI for NVG between April 1, 2012, and December 31, 2019, at 5 clinical centers were recruited. METHODS: The inclusion criteria were age ≥ 20 years and having NVG. The exclusion criteria were eyes with no light perception vision and with previous tube-shunt surgery. If both eyes in the same patient satisfied the inclusion criteria, the eye that was treated first was investigated. We included 100 eyes undergoing BGI surgery and 204 eyes undergoing trabeculectomy. MAIN OUTCOME MEASURES: The primary outcome was surgical success or failure, with failure being defined according to 3 criteria: < 20% reduction of the preoperative intraocular pressure (IOP) or criterion A (IOP > 21 mmHg), criterion B (IOP > 17 mmHg), or criterion C (IOP > 14 mmHg). Cases of reoperation, a loss of light perception vision, or hypotony were also considered failures. RESULTS: The probability of success was significantly higher in patients undergoing BGI surgery than in those receiving trabeculectomy for criteria A (P < 0.01) and B (P = 0.01). Trabeculectomy was significantly associated with surgical failure in the multivariable analysis for criterion A (hazard ratio, 1.70) and criterion B (hazard ratio, 1.50). The overall incidence of postoperative complications was similar between the 2 groups. Reoperations for glaucoma were required significantly more frequently in the trabeculectomy group than in the BGI surgery group (20.1 % vs. 5.0%; P < 0.01). CONCLUSIONS: Baerveldt glaucoma implant surgery had a higher success rate compared with trabeculectomy in patients with NVG for a target IOP < 21 mmHg or < 17 mmHg. The rates of postoperative complications were similar between both surgical procedures. Additional glaucoma surgery was required more frequently after trabeculectomy than after BGI surgery.

Tissue Reactivity to, and Stability of, Glaucoma Drainage Device Materials Placed Under Rabbit Conjunctiva.

Purpose: To evaluate tissue reactivity to, and the stability of, glaucoma drainage device materials placed under rabbit conjunctiva in vivo. Methods: Disks (diameter, 3 mm; thickness, ∼0.3 mm) fabricated from poly(styrene-block-isobutylene-block-styrene) (SIBS), silicone, stainless-steel, or glutaraldehyde cross-linked collagen (GACLC) were inserted under rabbit conjunctiva. Conjunctival and scleral sections obtained at 4, 8, and 12 weeks after surgery were immunostained for α-smooth muscle actin (SMA). The ratio of the maximum thickness of the α-SMA-positive conjunctiva to the scleral thickness (α-SMA/S ratio) was calculated. The in vivo stability of the drainage devices at 12 weeks after insertion was evaluated. Results: The mean α-SMA/S ratios of the SIBS and silicone groups were lower than that of the stainless-steel group at 4 weeks after surgery (P < 0.05), and that of the SIBS group was lower than that of the GACLC group (P < 0.05). The ratios at 8 weeks after surgery were lower in the SIBS and silicone groups than in the GACLC group (P < 0.01). The ratios at 12 weeks after surgery were lower in the SIBS and silicone groups than in the GACLC group (P < 0.05). The surface areas of GACLC disks explanted from conjunctivae were significantly lower than that of intact disks (P < 0.01). Conclusions: SIBS and silicon were highly biostable and exhibited less tissue reactivity than GACLC in vivo. Translational Relevance: Comparisons of materials using animal models can predict the clinical stability and safety of such materials in humans.

Factors associated with the surgical outcomes of Baerveldt glaucoma implant for open-angle glaucoma, an age-related eye disease.

To identify the factors associated with the surgical outcomes of Baerveldt glaucoma implant (BGI) for open-angle glaucoma (OAG), the medical records of 51 consecutive OAG patients (age, 43-91 years) who underwent BGI were retrospectively reviewed (median follow-up, 21.7 months). Surgical success was defined as the following postoperative intraocular pressures (IOPs, mmHg): (A) 6 ≤ IOP ≤ 21; (B) 6 ≤ IOP ≤ 18; and (C) 6 ≤ IOP ≤ 15 without loss of light perception or additional glaucoma surgery. Univariate analysis showed that age (all criteria), glaucoma type (criterion C), and preoperative IOP (criteria A and B) were the candidate factors (P < 0.20). When the patients were divided into two groups according to median age (72 years), the success probability was higher in the older group for criteria B (P = 0.047) and C (P = 0.02), and the postoperative IOP was lower in the older group 1-year post-surgery (P = 0.002). Furthermore, the multivariate Cox proportional hazards model revealed that older age was independently associated with surgical success for criteria B (relative risk [RR], 0.94; P = 0.02) and C (RR, 0.94; P = 0.01). In conclusion, older age is a factor associated with the surgical success of BGI for OAG.

Elevated Cytokine Levels in Aqueous Humor Are Associated with Peripheral Anterior Synechiae after Penetrating Keratoplasty.

Peripheral anterior synechiae (PAS) after corneal transplantation leads to refractory glaucoma and permanent loss of vision. However, the exact mechanism remains elusive. This study aimed to evaluate the association between cytokine levels in the aqueous humor (AqH) and the progression of PAS after penetrating keratoplasty (PKP). We measured 20 cytokine levels in AqH and assessed the correlation with PAS progression after PKP in 85 consecutive patients who underwent PKP. We also evaluated age-dependent alterations in PAS and cytokine levels in DBA2J mice. PAS developed in 38 (44.7%) of 85 eyes after PKP. The incidence of intraocular pressure increase after PKP was significantly greater in eyes with PAS (26.3%) than in those without PAS (2%, p = 0.0009). The PAS area at 12 months after PKP was significantly positively correlated with the preoperative levels of interleukin (IL)-6, interferon (IFN)-γ and monocyte chemotactic protein (MCP)-1 (p ≤ 0.049). In the DBA2J mice, an experimental glaucoma model that developed PAS at 50 weeks, the AqH levels of IL-2, IL-6, IL-10, IFN-γ, tumor necrosis factor-α, MCP-1 and granulocyte-macrophage colony-stimulating factor (GM-CSF) significantly increased at 50 weeks compared to 8 weeks (p ≤ 0.021). In conclusion, inflammatory alterations in the AqH microenvironment, such as high preoperative specific cytokine levels, can lead to PAS formation and glaucoma.

Potential roles of the IL-6 family in conjunctival fibrosis.

Elevated intraocular pressure (IOP) is a significant risk factor for vision loss due to glaucoma, which is a major cause of blindness worldwide. Glaucoma filtration surgery (GFS) is an important method to reduce IOP by guidance of aqueous humor into a newly built filtration bleb in the conjunctiva; management of the wound healing mechanism is essential for the success of GFS. Here, we investigated the roles of interleukin (IL)-6 family members during the wound healing process after GFS. At the surgical site, the expression levels of genes encoding IL-6, oncostatin M (OSM), their receptors, and collagen I were elevated at 3 h after GFS, whereas the levels of genes encoding transforming growth factor (TGF)-ß, α-smooth muscle actin (SMA), type IV collagen, and fibronectin were elevated at 3 days after GFS. IL-6 trans-signaling and OSM signaling suppressed TGF-ß-induced expression of α-SMA and collagen IV, as well as activation of the non-canonical TGF-ß pathway, suggesting that IL-6 and OSM may aid in controlling the phase transition from inflammation to proliferation and remodeling. The suppressive effects of OSM were accompanied by STAT3 activation, such that STAT1 function was complementary to STAT3. Taken together, these observations indicated that IL-6 family members constitute early response genes after GFS, which can suppress TGF-ß-induced expression of late response genes at the surgical site after GFS.

Intraocular Pressure-Lowering Effects of Trabeculectomy Versus MicroShunt Insertion in Rabbit Eyes.

Purpose: To compare the surgical results of PRESERFLO MicroShunt (MicroShunt) insertion and trabeculectomy in rabbit eyes. Methods: Trabeculectomy or MicroShunt insertion was performed on the eyes of Japanese white rabbits. Intraocular pressure (IOP) was measured on conscious rabbits using a rebound tonometer for up to 12 weeks after surgery. Filtering bleb appearance was evaluated. Scarring in the filtering bleb was assessed by immunohistochemical analyses. The change in mRNA expression in the conjunctiva was evaluated using RNA sequence analyses. Results: The preoperative IOP of the operative eye did not differ significantly between trabeculectomy (11.6 ± 1.0 mmHg, n = 10) and MicroShunt insertion (12.6 ± 1.3 mmHg, n = 10). In both groups, the IOP of the operative eye was significantly lower than that of the contralateral eye at one day postoperatively, which continued until 12 weeks after surgery. The peak differences in IOP were -8.4 ± 3.0 (trabeculectomy) and -8.1 ± 2.1 mmHg (MicroShunt) at two weeks after surgery; no significant differences were observed in IOP reduction between the groups. Appearance and immunohistochemical analyses of the filtering bleb showed no significant difference between the groups. Moreover, RNA sequence analysis results showed no difference between the groups in mRNA expression fluctuations. Conclusions: Postoperative IOP, bleb appearance, and immunohistochemical analysis results were similar in the trabeculectomy and MicroShunt groups, indicating that MicroShunt insertion is as effective as trabeculectomy in lowering IOP. Translational Relevance: Comparison of surgical procedures using animal models has made it possible to predict clinical efficacy and safety.

Suberoylanilide hydroxamic acid (SAHA) inhibits transforming growth factor-beta 2-induced increases in aqueous humor outflow resistance.

Transforming growth factor-beta 2 (TGF-ß2) is highly concentrated in the aqueous humor of primary open-angle glaucoma patients. TGF-ß2 causes fibrosis of outflow tissues, such as the trabecular meshwork (TM), and increases intraocular pressure by increasing resistance to aqueous humor outflow. Recently, histone deacetylase (HDAC) activity was investigated in fibrosis in various tissues, revealing that HDAC inhibitors suppress tissue fibrosis. However, the effect of HDAC inhibitors on fibrosis in the eye was not determined. Here, we investigated the effect of suberoylanilide hydroxamic acid (SAHA), an HDAC inhibitor, on TGF-ß2-induced increased resistance to aqueous humor outflow. We found that SAHA suppressed TGF-ß2-induced outflow resistance in perfused porcine eyes. Moreover, SAHA cotreatment suppressed TGF-ß2-induced ocular hypertension in rabbits. The permeability of monkey TM (MTM) and Schlemm's canal (MSC) cell monolayers was decreased by TGF-ß2 treatment. SAHA inhibited the effects of TGF-ß2 on the permeability of these cells. TGF-ß2 also increased the expression of extracellular matrix proteins (fibronectin and collagen type I or IV) in MTM, MSC, and human TM (HTM) cells, while SAHA inhibited TGF-ß2-induced extracellular matrix protein expression in these cells. SAHA also inhibited TGF-ß2-induced phosphorylation of Akt and ERK, but did not inhibit Smad2/3 phosphorylation, the canonical pathway of TGF-ß signaling. Moreover, SAHA induced the expression of phosphatase and tensin homolog, a PI3K/Akt signaling factor, as well as bone morphogenetic protein 7, an endogenous antagonist of TGF-ß. These results imply that SAHA prevents TGF-ß2-induced increases in outflow resistance and regulates the non-Smad pathway of TGF-ß signaling in TM and MSC cells.

Correlation between intraocular pressure reduction and anterior chamber aqueous flare after micropulse transscleral cyclophotocoagulation.

BACKGROUND: Micropulse transscleral cyclophotocoagulation (MP-CPC) is a technique that has been approved in recent years to treat glaucoma. MP-CPC causes anterior chamber inflammation; a relationship with reduced intraocular pressure (IOP) has not been reported. Therefore, we analyzed the correlation between IOP and anterior chamber aqueous flare after MP-CPC. METHODS: This retrospective study included 37 eyes of 37 patients who underwent MP-CPC between November 2018 and October 2020. IOP and flare values were measured at 1, 4, and 12 weeks after MP-CPC. Correlations were assessed between the percentage IOP reduction and flare elevation by calculating Spearman's rank correlation coefficient. RESULTS: The percentage IOP reduction at 1 week after surgery was correlated with the flare elevation at 1 week after surgery (ρ = 0.47, P = 0.006). The percentage IOP reduction at 12 weeks after surgery was correlated with the flare elevation at 4 weeks after surgery (ρ = 0.53, P = 0.006). CONCLUSIONS: A short-term correlation was implied between reduced IOP and flare elevation after MP-CPC.

N6-methyladenosine (m6A) is an endogenous A3 adenosine receptor ligand.

About 150 post-transcriptional RNA modifications have been identified in all kingdoms of life. During RNA catabolism, most modified nucleosides are resistant to degradation and are released into the extracellular space. In this study, we explored the physiological role of these extracellular modified nucleosides and found that N6-methyladenosine (m6A), widely recognized as an epigenetic mark in RNA, acts as a ligand for the human adenosine A3 receptor, for which it has greater affinity than unmodified adenosine. We used structural modeling to define the amino acids required for specific binding of m6A to the human A3 receptor. We also demonstrated that m6A was dynamically released in response to cytotoxic stimuli and facilitated type I allergy in vivo. Our findings implicate m6A as a signaling molecule capable of activating G protein-coupled receptors (GPCRs) and triggering pathophysiological responses, a previously unreported property of RNA modifications.