A multifactorial screening model based on the Graves ophthalmopathy quality of life scores in dysthyroid optic neuropathy.

PURPOSE: To validate the Graves ophthalmopathy quality of life (GO-QOL) questionnaire in screening DON and to construct an effective model. METHODS: A total of 194 GO patients were recruited and divided into DON and non-DON (mild and moderate-to-severe) groups. Eye examinations were performed, and quality of life was assessed by the GO-QOL questionnaire. The random forest, decision tree model, receiver operator characteristic (ROC) curve, accuracy and Brier score were determined by R software. RESULTS: In GO-QOL, age, best corrected visual acuity (BCVA), exophthalmos, CAS, severity, and Gorman score were found to be factors related to visual function scores. On the appearance scale, gender, duration of GO, BCVA, exophthalmos, CAS and severity of GO were relevant. Both the visual function scores and appearance scores were significantly lower in DON groups than in non-DON groups (33.18 ± 24.54 versus 81.26 ± 17.39, 60.08 ± 24.82 versus 76.14 ± 27.56). The sensitivity, specificity, and AUC of the visual function scores were 91.1%, 81.7% and 0.939, respectively Visual function scores were used to construct a decision tree model. The sensitivity, specificity, and AUC of the model were 92.9%, 88.0% and 0.941, respectively, with an accuracy of 89.7% and a Brier score of 0.024. CONCLUSIONS: Visual function scores were qualified as a screening method for DON, with a cutoff point of 58. A multifactorial screening model based on visual function scores was constructed.

Anterior segment optical coherence tomography for superficial keratectomy.

PURPOSE: To report the use of anterior segment optical coherence tomography (AS-OCT) for superficial keratectomy (SK) in anterior corneal opacity. METHODS: The characteristics of 43 eyes (39 patients) with various lesions responsible for anterior corneal opacity were included in this retrospective non-comparative study. AS-OCT was performed on all eyes before surgery. The thickness of corneal opacity and the underlying healthy stroma were measured. SK was performed on each individual. RESULTS: Four types of anterior corneal opacity were evaluated, including corneal degeneration (26/43), Reis-Bücklers corneal dystrophy (8/43), alkali burn (1/43) and corneal tumors (8/43). Based on AS-OCT images, all eyes showed abnormal hyper-reflective signals in the superficial cornea to less than one-third of the normal corneal thickness in the deepest corneal opacity. All 43 eyes underwent an SK procedure. In addition, 1 eye with alkali burns and 7 eyes with corneal tumors were combined with amniotic membrane transplantation. All eyes restored transparency without significant complications. CONCLUSION: AS-OCT is a valuable method for objective preoperative and noninvasive assessments of anterior corneal opacities and is useful for guiding SK.

A Rabbit Dry Eye Model Induced by Subcutaneous Scopolamine.

PURPOSE: To establish and characterize a dry eye model in New Zealand rabbits by subcutaneous injections of scopolamine hydrobromide (SCOP). METHODS: Twenty New Zealand male rabbits were injected subcutaneously SCOP for 14 consecutive days; subcutaneous saline was used as a negative control. The correlated clinical parameters of ocular surface dryness were detected in vivo using tear secretion and corneal fluorescein staining. The expression of IL-1ß and TNF-α on the ocular surface and in lacrimal glands were analyzed by real-time PCR and western blot on the 14th day. The expression of Mucin-5 subtype AC (MUC5AC) was detected by Immunofluorescence staining in conjunctival tissue. RESULTS: The SCOP-treated rabbits exhibited significantly decreased aqueous tear secretion and increased corneal fluorescein staining scores over time. Both the mRNA expression levels and the protein expression levels of IL-1ß and TNF-α were significantly increased after SCOP treatment compared with those after saline treatment. The loss of conjunctival MUC5AC was found in the SCOP-injected rabbits. Some infiltrated inflammatory cells and atrophic acinar cells were observed in the lacrimal gland after SCOP treatment. The disordered structures of the ocular surface and lacrimal glands were also observed. CONCLUSIONS: This study showed that repeated subcutaneous SCOP injections successfully elicited some of the typical dry eye symptoms commonly seen in humans.

Corrigendum: Involvement of endoplasmic reticulum stress in trigeminal ganglion corneal neuron injury in dry eye disease.

[This corrects the article DOI: 10.3389/fnmol.2023.1083850.].

Comparison of photodynamic therapy with two different parameters combined with subconjunctival injection of bevacizumab for corneal neovascularization.

BACKGROUND: To the best of our knowledge, no studies have been performed to determine the optimal parameters of photodynamic therapy (PDT) combined with subconjunctival injection of bevacizumab for corneal neovascularization. This study aimed to compare the effect of photodynamic therapy with two different sets of parameters combined with subconjunctival injection of bevacizumab for corneal neovascularization. METHODS: Patients with stable corneal neovascularization (CNV) unresponsive to conventional treatment (topical steroid) were included in this study. Patients were divided into two groups, receiving PDT with two different sets of parameters (group 1 receiving fluence of 50 J/cm2 at 15 min after intravenous injection of verteporfin with, group 2 receiving fluence of 150 J/cm2 at 60 min after intravenous injection of verteporfin with). Subconjunctival injection of bevacizumab was performed immediately after PDT. All patients were followed for 6 months. Best-corrected visual acuity and intraocular pressure were evaluated, and slit-lamp biomicroscopy as well as digital photography were performed. Average diameter and cumulative length of corneal neovascular were measured to evaluate the corneal neovascularization. RESULTS: Seventeen patients (20 eyes) were included in this study. At the last visit, the vision was improved in 12 eyes (60 %), steady in 4 eyes (20 %) and worsen in 4 eyes (20 %). The intraocular pressure (IOP) of all patients remained in normal range. A significant decrease in corneal neovascularization was showed in all the eyes after treatment. At 6 months after the combined treatment, the average diameter and cumulative length of vessels significantly decreased to 0.041 ± 0.023 mm (P < 0.05) and 18.78 ± 17.73 mm (P < 0.05), respectively, compared with the pretreatment data (0.062 ± 0.015 mm, 31.48 ± 18.21 mm). The reduction was more remarkable in group 2 compared to group 1.In group 1, the average diameter was 0.062 ± 0.013mm before and 0.056 ± 0.017mm after, the cumulative length of vessels was 38.66 ± 22.55mm before and 31.21 ± 17.30 after. In group 2, the date were 0.061 ± 0.016mm before and 0.029 ± 0.020mm after, 25.60 ± 8.95 mm before and 8.61 ± 8.26 mm. The reported complications included epithelial defect in four eyes, small white filaments in two eyes and corneal epithelial erosion in two eyes. CONCLUSION: The PDT combined with subconjunctival injection of bevacizumab was effective for the chronic corneal neovascularization. A more promising treatment outcome was observed when PDT was performed at 60 min after intravenous injection of verteporfin with fluence of 150 J/cm2. No serious complications or systemic events were observed throughout the follow-up period.

Macular blood flow changes in dysthyroid optic neuropathy after high-dose intravenous pulse methylprednisolone (IVMP).

OBJECTIVE: To investigate the changes in macular vessel density (VD) of the superficial layer of retina (SLR) and deep layer of retina (DLR) in dysthyroid optic neuropathy (DON) after high-dose intravenous pulse methylprednisolone (IVMP). MATERIALS AND METHODS: Eighteen DON patients (29 eyes) who completed high-dose IVMP and 16 healthy individuals (32 eyes) were enrolled in this study. Optical coherence tomography angiography (OCTA) image analysis and comprehensive ophthalmic examinations were performed, including the SLR macular whole-image VD (SLR-mwiVD) and DLR-mwiVD, best-corrected visual acuity (BCVA), the mean deviation of visual field (VF-MD), pattern standard deviation of visual field (VF-PSD) and the other parameters. RESULTS: The SLR-mwiVD (41.39 ± 4.71 vs. 48.13 ± 3.68, p < 0.001) and DLR-mwiVD (40.77 ± 5.85 vs. 49.14 ± 7.02, p < 0.001) were decreased in DON compared to control eyes. After IVMP, visual function parameters were improved, and SLR-mwiVD (49.41 ± 3.18, p < 0.001) and DLR-mwiVD (50.41 ± 4.04, p < 0.001) were increased in the DON group compared to pretreatment. The increased SLR-mwiVD and DLR-mwiVD were significantly correlated with improvements in BCVA (Log MAR: from 0.62 ± 0.49 to -0.01 ± 0.03, p < 0.001), VF-MD (from - 6.89 ± 2.89 dB to - 1.75 ± 1.29 dB, p < 0.001) and VF-PSD (from 4.38 ± 2.52 dB to 2.32 ± 1.64 dB, p < 0.001). CONCLUSION: The increase in macular VD was significantly correlated with the improvement in visual function in DON after IVMP. Macular VD changes on OCTA may be a useful indicator for the response in DON after IVMP.

Charge doping and electric field tunable ferromagnetism and Curie temperature of the MnS2 monolayer.

Two-dimensional ferromagnets with a long-range ferromagnetic ordering at finite temperature present a bright prospect for their potential applications in nanoscale spintronic devices. The tuning of their intrinsic ferromagnetism and Curie temperature is essential for the development of next-generation data storage and spintronic devices. In this work, the electronic structures, ferromagnetism and Curie temperature of two-dimensional MnS2 monolayer are controlled by charge doping and electric field using first principles calculations. The results show that the dynamic and thermal stability of monolayer MnS2 for all of the cases can be still maintained. Moreover, there is no existence of phase transition and all MnS2 monolayers at any charge doping concentrations and electric field intensities favor ferromagnetic coupling. For the manipulation of electron doping, the calculated total magnetic moment Mtot of the MnS2 monolayer exhibits an increase from 3.112 to 3.491µB per unit cell. Further analysis indicates that a transition from half-metal to metal occurs by introducing the charge doping and vertical electric field, and the Mn 3d electronic states are the major determinants of ferromagnetism. Additionally, the charge doping enables the magnetic anisotropy energy to transform from an in-plane easy axis to the magnetization direction out of the plane. The Curie temperature Tc of the MnS2 monolayer can be moderately enhanced above room temperature by hole doping and application of a vertical electric field. Remarkably, Tc reaches its peak at 767 K at a hole doping concentration of -0.8e. This work enriches the microscopic understanding of the tuning mechanism of ferromagnetism and supplies a sound theoretical basis for subsequent experimental studies.

Discovery of Ingenane Diterpenoids from Euphorbia hylonoma as Antiadipogenic Agents.

Thirteen new Euphorbia diterpenoids, euphylonanes A-M (1-13), and eight known ones were isolated from the whole plants of Euphorbia hylonoma. Compounds 1 and 2 are two rearranged ingenanes bearing a rare 6/6/7/3-fused ring system. Compound 3 represents the first example of a 9,10-epoxy tigliane, while 4-21 are typical ingenanes varying with substituents. Structures were elucidated using a combination of spectroscopic, computational, and chemical methods. Most ingenanes exerted a significant antiadipogenic effect in 3T3-L1 adipocytes, among which 4 was the most active with an EC50 value of 0.60 ± 0.27 µM. Mechanistic study revealed that 4 inhibited the adipogenesis and lipogenesis in adipocytes via activation of the AMPK signaling pathway.

Acrolein Induces Retinal Abnormalities of Alzheimer's Disease in Mice.

It is reported that retinal abnormities are related to Alzheimer's disease (AD) in patients and animal models. However, it is unclear whether the retinal abnormities appear in the mouse model of sporadic Alzheimer's disease (sAD) induced by acrolein. We investigated the alterations of retinal function and structure, the levels of ß-amyloid (Aß) and phosphorylated Tau (p-Tau) in the retina, and the changes in the retinal vascular system in this mouse model. We demonstrated that the levels of Aß and p-Tau were increased in the retinas of mice from the acrolein groups. Subsequently, a decreased amplitudes of b-waves in the scotopic and photopic electroretinogram (ERG), decreased thicknesses of the retinal nerve fiber layer (RNFL) in the retina, and slight retinal venous beading were found in the mice induced by acrolein. We propose that sAD mice induced by acrolein showed abnormalities in the retina, which may provide a valuable reference for the study of the retina in sAD.

Evaluation of Mooren's corneal ulcer by anterior segment optical coherence tomography.

BACKGROUND: This study evaluates the use of anterior segment optical coherence tomography (AS-OCT) to identify focal changes and inform surgical plans in eyes with Mooren's ulcer. METHODS: A total of 18 eyes of 17 patients with Mooren's ulcer were examined prospectively using the AS-OCT system. RESULTS: Optical hyperreflectivity noted on AS-OCT images was in accordance with corneal ulceration, neovascularization, fibrovascular membranes, the junction of the native stromal bed, and the overlying lamellar corneal grafts. Focal corneal ectasia was observed in 13 eyes with a decrease in corneal thickness to ≤0.39 mm. There was a cut-off value of 0.39 mm in corneal thickness between the eyes with and without focal corneal ectasia in the thinned corneal area (Fisher = 0.383, χ2 = 14.873, P = 0.000). Based on the AS-OCT findings, six eyes were subjected to an individualized lamellar corneal graft. The thickness of the residual cornea after surgery was 47 ± 34 µm less than the presumed healthy corneal thickness before surgery (t = 3.376, P = 0.02). A small corneal perforation covered by a pseudopterygium in Mooren's ulcer was found through AS-OCT but undetectable by slit-lamp biomicroscopy. CONCLUSIONS: AS-OCT is a valuable non-contact technique for monitoring corneal thinning in Mooren's ulcer, and assisting surgical design. A decrease in peripheral corneal thickness to ≤0.39 mm may cause focal corneal ectasia.

Successful regression of newly formed corneal neovascularization by subconjunctival injection of bevacizumab in patients with chemical burns.

Purpose: To investigate the effect and timing of subconjunctival bevacizumab injection on inhibiting corneal neovascularization (CorNV) in patients after chemical burns. Methods: Patients with CorNV secondary to chemical burns were involved. Two subconjunctival injections of bevacizumab (2.5 mg/0.1 mL per involved quadrant) with an interval of 4 weeks were administered, and followed up a year. The area occupied by neovascular vessels (NA), accumulative neovascular length (NL), mean neovascular diameter (ND), best-corrected visual acuity (BCVA) and intraocular pressure (IOP) were evaluated. Complication was also recorded. Results: Eleven patients with CorNV were involved. Eight patients had a history of surgery (four had amniotic grafts, one had keratoplasty, and three had amniotic grafts and keratoplasty). Decreasing in NA, NL, and ND were statistically significant at each time point compared to the baseline (p < 0.01). CorNV that developed within 1 month was considerably regressed, and vessels with fibrovascular membranes were found to be narrower and shorter than pretreatment. BCVA improved in five patients (from one to five lines), remained unchanged in five patients, and decreased in one patient compared to pretreatment. Conclusion: Subconjunctival bevacizumab injection has a particular potential for the regression of CorNV, especially newly formed within 1 month in patients after chemical burns.

Decreased macular choriocapillaris in thyroid-associated ophthalmopathy: focusing on chorioretinal folds with and without optic disc edema.

Purpose: The aim of this study was to evaluate the vessel density (VD) of the macular choriocapillaris (CC) and retina in thyroid-associated ophthalmopathy (TAO) patients with chorioretinal folds (CRFs) with and without optic disc edema (ODE) and the correlations of these characteristics with visual function. Method: This was a cross-sectional study. Twenty TAO patients with CRFs (35 eyes) and 20 normal subjects (normal group, 40 eyes) were recruited at the Ophthalmology Department of the Sun Yat-sen Memorial Hospital from March 2018 to October 2022. Then, CRF patients were divided into two groups, the ODE and non-ODE groups (NODE), based on the presence or absence of ODE. All the patients underwent optical coherence tomography angiography (OCTA) and the VD of the macular CC and retina was computed. The correlation of VD and visual function was analyzed. Results: Compared with the normal group, the macular whole-image VD in the retinal superficial layer (SLR-mwiVD: 49.82 ± 3.38 in the normal group, 42.44 ± 5.40 in the NODE group, and 42.51 ± 5.37 in the ODE group), deep layer (DLR-mwiVD: 51.05 ± 6.23 in the normal group, 45.71 ± 6.66 in the NODE group, and 46.31 ± 5.48 in the ODE group), and CC (CC-mwiVD: 70.23 ± 2.47 in the normal group, 68.04 ± 3.73 in the NODE group, and 63.09 ± 6.51 in the ODE group) was decreased in the NODE (all p < 0.05) and ODE group (all p < 0.01). There was no difference in these parameters except CC-mwiVD between the ODE and NODE groups. The CC-mwiVD in the ODE group (63.09 ± 6.51) was significantly reduced compared with that in the NODE group (68.04 ± 3.73, p = 0.004). All these VD parameters were negatively correlated with BCVA, VF-PSD, and P100 latency and positively associated with VF-MD, P100 amplitude, and HRR scores (all p < 0.05). Conclusions: There was a significant decrease in the VD of the macular CC and retina of patients with CRFs with or without ODE, which was correlated with visual dysfunction. The VD of the macular CC in CRF patients with ODE was significantly reduced compared with that in the NODE group, but similar results were not observed in the retina.

Involvement of endoplasmic reticulum stress in trigeminal ganglion corneal neuron injury in dry eye disease.

Dry eye disease (DED) is a multifactorial disease with a high prevalence worldwide. Uncomfortable corneal sensations severely affect daily life in DED patients. Hence, corneal neuron injury is a vital pathogenesis in DED. Notably, endoplasmic reticulum stress (ERS) plays a role in peripheral neuron injury. However, the role of ERS in DED corneal neuron injury is still far from being clear. In this study, we established an environmental DED (eDED) model in vivo and a hyperosmotic DED model in vitro. Subsequently, trigeminal ganglion (TG) corneal neurons were retrograde labeled by WGA-Alexa Fluor 555, and fluorescence-activated cell sorting was used to collect targeted corneal neurons for RNA sequencing in mice. Our results revealed that TG corneal neuron injury but not apoptosis in DED. ERS-related genes and proteins were upregulated in TG corneal neurons of the eDED mice. ERS inhibition alleviated TG corneal neuron's ERS-related injury. Therefore, ERS-induced TG corneal neuron injury may be an important pathomechanism and provide a promising therapeutic approach to DED.

The Outcomes of Balanced Orbital Decompression for Dysthyroid Optic Neuropathy: Focusing on Choroiretinal Folds with and without Optic Disc Edema.

Purpose: To assess the outcomes of balanced orbital decompression for chorioretinal folds (CRFs) with and without optic disc edema (ODE) in dysthyroid optic neuropathy (DON). Method: A retrospective, interventional study was performed at Sun Yat-sen Memorial Hospital from April 2018 to November 2021. We collected the medical records of 13 patients (24 eyes) with DON and CRFs. Then, we divided them into the ODE group (15 eyes, 62.5%) and the non-ODE group (NODE group, 9 eyes, 37.5%). The valid ophthalmic examination parameters of 8 eyes in each group after balanced orbital decompression were compared at the 6-month follow-up. Results: The mean best corrected visual acuity (BCVA, 0.29 ± 0.27) and visual field-mean deviation (VF-MD, -6.55 ± 3.71 dB) in the ODE group were significantly worse than those in the NODE group (0.06 ± 0.15 and -3.49 ± 1.56 dB; all p < 0.01). Six months after orbital decompression, all parameters were found to have significantly improved in both groups, including BCVA and VF-MD (all p < 0.05). Moreover, the improvement amplitude of BCVA (p = 0.020) in the ODE group was significantly greater than that in the NODE group. There was no difference in BCVA between the ODE group (0.13 ± 0.19) and the NODE group (0.10 ± 0.13). The disc edema of all eyes (8/8 eyes, 100%) in the ODE group was completely mitigated after orbital decompression. The CRF resolution of 2 eyes (2/8 eyes, 25%) in the ODE group and no eyes in the NODE group was mitigated. Conclusions: Balanced orbital decompression can significantly improve visual functions and eliminate optic disc edema in DON patients, whether CRF relieves or not.

Macular and peripapillary optical coherence tomography angiography metrics in thyroid-associated ophthalmopathy with chorioretinal folds.

PURPOSE: To evaluate macular and radial peripapillary capillary (RPC) microvascular densities and the thickness of the retinal nerve fiber layer (RNFL) in thyroid-associated ophthalmopathy (TAO) with chorioretinal folds (CRFs) and the associations of these characteristics with visual function. METHOD: A cross-sectional study was performed at the Ophthalmology Department of the Sun Yat-sen Memorial Hospital from March 2018 to August 2021. All patients underwent ocular examination, ophthalmic function tests and optical coherence tomography angiography (OCTA). The microvascular densities in the macula and optic papilla in the TAO with CRFs or without CRFs. Correlation analyses were used to examine the association of microvascular density and visual function. RESULTS: Ten TAO patients with CRFs (CRF group, 20 eyes) and 10 TAO patients without CRFs (NCRF group, 20 eyes) were recruited for the study. Visual function measurements, including best-corrected visual acuity (BCVA), were found to be worse in the CRF group (all p < 0.05). The macular whole-image vessel density in the superficial layer (SLR-mwiVD) was significantly decreased in the CRF group (p < 0.05). The RPC whole-image vessel density (RPC-wiVD) was significantly decreased in the CRF group (p < 0.05), particularly in the temporal subfields. The P100 amplitude of visual evoked potentials (VEPs) was positively associated with SLR-mwiVD and RPC-wiVD. The thickness of RNFL in the CRF group was obviously thicker than that in the NCRF group (p < 0.05). CONCLUSIONS: Our study showed decreased microvascular density of the macula and RPC and thicker RNFL in TAO patients with CRFs. CRFs with decreased microvascular density should be regard as an indicator of visually threatening conditions.

Therapeutic effects of a novel venom abstract (ZK002) solution in an alkali-burned corneal wound-healing model.

Purpose: Corneal alkali burns can progress to corneal epithelial defects, inflammation, scarring, and angiogenesis, potentially leading to blindness. Therefore, we examined the therapeutic effects of a novel ophthalmic solution (ZK002) on wound healing in alkali-burned rat corneas. Methods: In this study, we attempted to treat alkali-exposed rat corneas using topical application of either an ophthalmic solution with ZK002 or an anti-vascular endothelial growth factor agent for 14 days. We evaluated corneal edema, corneal neovascularization area, and histological changes. We also assessed the inflammatory (MMP-9, MMP-2, and interleukin-1ß) and angiogenic (vascular endothelial growth factor receptor 2, VEGFR2) markers. Levels of inflammatory (matrix metalloproteinase (MMP)-9, MMP-2, and interleukin-1ß), profibrotic (α-smooth muscle actin, α-SMA; transforming growth factor-ß2,TGF-ß2), and angiogenic (vascular endothelial growth factor-receptor 2, VEGFR2) factors, as well as peroxisome proliferator-activated receptor γ (PPARγ) mRNA expression, were measured. Results: The analyses showed that alkali exposure caused an increase in corneal edema and fibrosis with corneal neovascularization. The accumulation of α-smooth muscle actin-positive myofibroblasts and the deposition of transforming growth factor-ß2 on the alkali-exposed corneas were noted on day 14. The mRNA expression levels of interleukin-1ß, MMP-9, MMP-2, VEGFR2, and profibrotic factors were decreased in the ZK002 group compared with the control group during the early period of corneal alkali burns on day 14. However, the expression level of PPARγ mRNA was increased in the ZK002 group. Conclusions: ZK002 decreased the fibrotic reaction and prevented neovascularization in the cornea after an alkali burn. Therefore, the novel ophthalmic solution ZK002 could be a potentially promising therapeutic clinical treatment for corneal wound healing.

Conjunctival Fluid Secretion Impairment via CaCC-CFTR Dysfunction Is the Key Mechanism in Environmental Dry Eye.

Dry eye disease (DED) is a multifactorial disease with an incidence of approximately 50% worldwide. DED seriously affects quality of life and work. The prevalence of environmental DED (eDED) ranges from 35 to 48%. Conjunctival fluid secretion dysfunction may be one of the major causes of DED. Notably, the Cl- flux corresponds to the conjunctival fluid secretion and could be affected by ATP. Both the cystic fibrosis transmembrane conductance regulator (CFTR) and the Ca2+-activated Cl- channel (CaCC) are Cl- channels involved in epithelial fluid secretion. Conjunctival fluid secretion could be increased by activating P2Y2R (an ATP receptor) in DED. However, the role of the CaCC and CFTR channels regulated by P2Y2R in eDED remains unclear. In this study, we established a rabbit eDED model using a controlled drying system. A Ussing chamber was used to perform a conjunctival short-circuit current induced by ATP to evaluate the reactivity of the ion channels to the ATP. Our results revealed that eDED accompanied by conjunctival fluid secretion impairment was caused by a P2Y2R dysfunction, which is related to CaCC-CFTR signaling in the conjunctiva epithelium. Notably, the coupling effect of the ATP-induced CaCC-CFTR activation and intracellular Ca2+ may represent a promising therapeutic target for treating eDED.

Cyclosporine A (0.05%) Ophthalmic Gel in the Treatment of Dry Eye Disease: A Multicenter, Randomized, Double-Masked, Phase III, COSMO Trial.

Purpose: To confirm the efficacy and safety of a novel ophthalmic cyclosporine A gel (CyclAGel, 0.05% CsA) in treating patients with moderate-to-severe dry eye disease (DED). Patients and Methods: The COSMO trial was a randomized, multicenter, double-masked, vehicle-controlled, phase III trial. Patients with moderate-to-severe DED were enrolled in 37 hospitals in China between November 2020 and April 2021. Eligible patients were randomized 1:1 to receive CyclAGel 0.05% or vehicle eye drops once nightly (QD). The primary endpoint was the proportion of subjects with at least a 1-point improvement in ICSS at day 84. Treatment-emergent adverse events (TEAEs) were recorded. Results: The full analysis set (FAS) included 315 and 312 participants in the CyclAGel and vehicle groups, respectively. The primary efficacy endpoint was achieved. The proportion of subjects with at least a 1-point improvement in ICSS from baseline to day 84 was significantly higher in the CyclAGel group than in the vehicle group (73.7% [232/315] vs 53.2% [166/312], P<0.0001). Significant improvements relative to the vehicle were also observed in the ICSS and Oxford scale scoring of corneal and conjunctival fluorescein staining at day 14, 42, and 84. The Schirmer tear test results were significantly higher in the CyclAGel group than in the vehicle group on days 14 and 84 (all P<0.05). The CyclAGel 0.05% was well tolerated, and the TEAEs were mostly mild. The most frequent treatment-related TEAE was eye pain (6.9% vs 1.6% in the CyclAGel and vehicle groups, respectively). No serious treatment-related TEAEs were reported. Conclusion: Clinically and statistically significant improvements in ICSS, tear production, and symptoms were observed in participants administered CyclAGel 0.05% QD for moderate-to-severe DED. CyclAGel 0.05% QD is a new effective, safe, and well-tolerated therapeutic option that might bring additional benefits of convenience and compliance as a once-A-day treatment for DED.

Effects of PPAR-γ and RXR-α on mouse meibomian gland epithelial cells during inflammation induced by latanoprost.

The purpose of this study is to investigate the effects of latanoprost on the secretion of cytokines and chemokines from meibomian gland epithelial cells, and to evaluate the modulation of peroxisome proliferator-activated receptor γ (PPAR-γ) and retinoid X receptor α (RXR-α) during latanoprost-induced inflammation. Mouse meibomian gland epithelial cells were cultured in proliferation and differentiation medium, respectively. Cells were exposed to latanoprost, rosiglitazone (PPAR-γ agonist), or LG100268 (RXR-α agonist), respectively. The expression of IL-6, IL-1ß, TNF-α, MMP-9, MCP-1, and CCL-5 were detected by real-time PCR and ELISA. The effect of latanoprost, rosiglitazone, LG100268, and inflammatory cytokines on the differentiation of meibocyte were evaluated by related gene expression and lipid staining. The expression of Keratin-1, 6, 17 protein was detected by western immunoblotting. The results showed that the above cytokines could be induced by latanoprost in meibomian gland epithelial cells. LG100268 and rosiglitazone could inhibit the production of IL-6 and TNF-α induced by latanoprost, respectively. Latanoprost suppressed the expression of differentiation-related mRNA through a positive feedback loop by enhancement of COX-2 expression via FP receptor-activated ERK signaling. The expression of Keratin-17 was upregulated by rosiglitazone and suppressed by LG100268. The application of IL-6 and TNF-α showed negative effects on lipid accumulation in meibomian gland epithelial cells. These results demonstrated that latanoprost could induce inflammation and suppress differentiation of mouse meibomian gland epithelial cells. The activation of PPAR-γ and RXR-α showed an anti-inflammatory effect, showing a potential role to antagonize the effect of latanoprost eyedrops on meibomian gland epithelial cells.