NADPH and NAC synergistically inhibits chronic ocular hypertension-induced neurodegeneration and neuroinflammation through regulating p38/MAPK pathway and peroxidation.

Glaucoma, the leading cause of irreversible blindness worldwide, is characterized by neurodegeneration and neuroinflammation with retinal NAD/NADP and GSH decline. Nicotinamide adenine dinucleotide (NAD)/NAD phosphate (NADP) and glutathione (GSH) are two redox reducers in neuronal and glial metabolism. However, therapeutic strategies targeting NAD/NADP or GSH do not exert ideal effects, and the underlying mechanisms are still poorly understood. We assessed morphological changes in retinal ganglion cells (RGCs), the affected neurons in glaucoma, and Müller cells, the major glial cells in the retina, as well as the levels of phosphorylated p38 (p-p38) and Caspase-3 in glaucoma patients. We constructed a modified chronic ocular hypertensive rat model and an oxygen-glucose deprivation (OGD) cell model. After applying NADPH and N-acetylcysteine (NAC), a precursor to cysteine, the rate-limiting substrate in GSH biosynthesis, to cells, apoptosis, axonal damage and peroxidation were reduced in the RGCs of the NAC group and p-p38 levels were decreased in the RGCs of the NADPH group, while in stimulated Müller cells cultured individually or cocultured with RGCs, gliosis and p38/MAPK, rather than JNK/MAPK, activation were inhibited. The results were more synergistic in the rat model, where either NADPH or NAC showed crossover effects on inhibiting peroxidation and p38/MAPK pathway activation. Moreover, the combination of NADPH and NAC ameliorated RGC electrophysiological function and prevented Müller cell gliosis to the greatest extent. These data illustrated conjoined mechanisms in glaucomatous RGC injury and Müller cell gliosis and suggested that NADPH and NAC collaborate as a neuroprotective and anti-inflammatory combination treatment for glaucoma and other underlying human neurodegenerative diseases.

The efficacy of bandage contact lens in relieving the aggravation of dry eye disease after complicated cataract or/and IOL surgery.

PURPOSE: In the present study, we aimed to evaluate the efficacy of the bandage contact lens (BCLs) in the treatment of dry eye disease (DED) after complicated cataract or/and intraocular lens (IOL) surgery. METHODS: In this retrospective, single-centered, observational study, we collected data from 69 patients who underwent complicated cataract or/and IOL surgery. Of these, 35 cases wore their own BCLs immediately after the operation, while the other 34 cases did not have their own BCLs and were instead covered with gauze. The Ocular Surface Disease Index (OSDI) questionnaire, slit-lamp microscope examination, keratograph analysis, and Schirmer I test were measured at baseline, 1 week and 1 month postoperatively. RESULTS: In the BCL group, the score of the OSDI questionnaire was significantly decreased at 1 week and 1 month postoperatively compared with baseline levels (P = 0.000, collectively). Moreover, the fluorescein staining score of the BCL group was remarkably decreased 1-week and 1-month postoperatively compared with the non-BCL group (P = 0.000 and P = 0.000, respectively). Furthermore, the redness score of the BCL group was also better compared with the non-BCL group at 1 week and 1 month postoperatively (P = 0.014 and P = 0.004, respectively). CONCLUSIONS: Complicated cataract or/and IOL surgery would intensify the DED. Early application of BCLs postoperatively improved patients' comfort and alleviated dry eye-related symptoms and signs. Furthermore, this mechanism might involve the acceleration of corneal epithelial healing, the alleviation of ocular stress response and the stabilization of the tear film. TRIAL REGISTRATION: Trial registration ClinicalTrials, NCT04120389. Registered 10 October 2019-retrospectively registered.

Inhibition of cGAS-STING pathway alleviates neuroinflammation-induced retinal ganglion cell death after ischemia/reperfusion injury.

Acute glaucoma is a vision-threatening disease characterized by a sudden elevation in intraocular pressure (IOP), followed by retinal ganglion cell (RGC) death. Cytosolic double-stranded DNA (dsDNA)-a damage-associated molecular pattern (DAMP) that triggers inflammation and immune responses-has been implicated in the pathogenesis of IOP-induced RGC death, but the underlying mechanism is not entirely clear. In this study, we investigated the effect of the inflammatory cascade on dsDNA recognition and examined the neuroprotective effect of the cyclic GMP-AMP (cGAMP) synthase (cGAS) antagonist A151 on a retinal ischemia/reperfusion (RIR) mouse model. Our findings reveal a novel mechanism of microglia-induced neuroinflammation-mediated RGC death associated with glaucomatous vision loss. We found that RIR injury facilitated the release of dsDNA, which initiated inflammatory responses by activating cGAS-stimulator of interferon genes (STING) pathway. Correspondingly, elevated expressions of cGAS and STING were found in retinal samples from human glaucoma donors. Furthermore, we found that deletion or inhibition of cGAS or STING in microglia transfected with poly(dA:dT) specifically decreased microglia activation and inflammation response. We also observed that A151 treatment promoted poly(dA:dT)--stimulated changes in polarization from the M1 to the M2 phenotype in microglia. Subsequently, A151 administered to mice effectively inhibited the cGAS-STING pathway, absent in melanoma 2 (AIM2) inflammasome and pyroptosis-related molecules. Furthermore, A151 administration significantly reduced neuroinflammation, ameliorated RGC death and RGC-related reductions in visual function. These findings provide a unique perspective on glaucomatous neuropathogenesis and suggest cGAS as an underlying target of retinal inflammation to provide a potential therapeutic for acute glaucoma.

Keratin8 Deficiency Aggravates Retinal Ganglion Cell Damage Under Acute Ocular Hypertension.

Purpose: Keratin 8/18 (KRT8/18), paired members of the intermediate filament family, have shown vital functions in regulating physiological activities more than supporting the mechanic strength for cells and organelles. However, the KRT8/18 presence in retinal ganglion cells (RGCs) and functions on neuroprotection in a mouse model of acute ocular hypertension (AOH) are unknown and worthy of exploration. Methods: We identified the existence of KRT8/18 in normal human and mouse retinas and primary RGCs. KRT8/18 levels were detected after AOH modeling. The adeno-associated virus (AAV) system was intravitreally used for selective KRT8 knockdown in RGCs. The histological changes, the loss and dysfunction of RGCs, and the gliosis in retinas were detected. The markers of cell apoptosis and MAPK pathways were investigated. Results: KRT8/18 existed in all retinal layers and was highly expressed in RGCs, and they increased after AOH induction. The KRT8 knockdown in RGCs caused no histopathological changes and RGC loss in retinas without AOH modeling. However, after the KRT8 deficiency, AOH significantly promoted the loss of whole retina and inner retina thickness, the reduction, apoptosis, and dysfunction of RGCs, and the glial activation. Besides, downregulated Bcl-2 and upregulated cleaved-Caspase 3 were found in the AOH retinas with KRT8 knockdown, which may be caused by the increased phosphorylation level of MAPK pathways (JNK, p38, and ERK). Conclusions: The KRT8 deficiency promoted RGC apoptosis and neurodegeneration by abnormal activation of MAPK pathways in AOH retinas. Targeting KRT8 may serve as a novel treatment for saving RCGs from glaucomatous injuries.

Prediction of postoperative visual acuity in patients with age-related cataracts using macular optical coherence tomography-based deep learning method.

Background: To predict postoperative visual acuity (VA) in patients with age-related cataracts using macular optical coherence tomography-based deep learning method. Methods: A total of 2,051 eyes from 2,051 patients with age-related cataracts were included. Preoperative optical coherence tomography (OCT) images and best-corrected visual acuity (BCVA) were collected. Five novel models (I, II, III, IV, and V) were proposed to predict postoperative BCVA. The dataset was randomly divided into a training (n = 1,231), validation (n = 410), and test set (n = 410). The performance of the models in predicting exact postoperative BCVA was evaluated using mean absolute error (MAE) and root mean square error (RMSE). The performance of the models in predicting whether postoperative BCVA was improved by at least two lines in the visual chart (0.2LogMAR) was evaluated using precision, sensitivity, accuracy, F1 and area under curve (AUC). Results: Model V containing preoperative OCT images with horizontal and vertical B-scans, macular morphological feature indices, and preoperative BCVA had a better performance in predicting postoperative VA, with the lowest MAE (0.1250 and 0.1194LogMAR) and RMSE (0.2284 and 0.2362LogMAR), and the highest precision (90.7% and 91.7%), sensitivity (93.4% and 93.8%), accuracy (88% and 89%), F1 (92% and 92.7%) and AUCs (0.856 and 0.854) in the validation and test datasets, respectively. Conclusion: The model had a good performance in predicting postoperative VA, when the input information contained preoperative OCT scans, macular morphological feature indices, and preoperative BCVA. The preoperative BCVA and macular OCT indices were of great significance in predicting postoperative VA in patients with age-related cataracts.

Tacrolimus Loaded Cationic Liposomes for Dry Eye Treatment.

Eye drops are ophthalmic formulations routinely used to treat dry eye. However, the low ocular bioavailability is an obvious drawback of eye drops owing to short ocular retention time and weak permeability of the cornea. Herein, to improve the ocular bioavailability of eye drops, a cationic liposome eye drop was constructed and used to treat dry eye. Tacrolimus liposomes exhibit a diameter of around 300 nm and a surface charge of +30 mV. Cationic liposomes could interact with the anionic ocular surface, extending the ocular retention time and improving tacrolimus amount into the cornea. The cationic liposomes notably prolonged the ocular retention time of eye drops, leading to an increased tacrolimus concentration in the ocular surface. The tacrolimus liposomes were also demonstrated to reduce reactive oxygen species and dry eye-related inflammation factors. The use of drug-loaded cationic liposomes is a good formulation in the treatment of ocular disease; the improved ocular retention time and biocompatibility give tremendous scope for application in the treatment of ocular disease, with further work in the area recommended.

Role of ocular blood flow in normal tension glaucoma.

Background: Normal tension glaucoma (NTG) is a multifactorial disease in the pathogenesis of which intraocular pressure (IOP)-independent factors play a key role. Main text: There is considerable evidence that impairment of the ocular blood flow (OBF) is involved both in the onset and progression of this disease. With the development of the hypothesis of OBF in NTG, various imaging techniques have been developed to evaluate the OBF and blood vessels. Moreover, vascular dysregulation, which is a main factor in Flammer syndrome, was frequently observed in NTG patients. Disturbed OBF leads to increased oxidative stress, which plays an important role in the pathogenesis of glaucomatous optic neuropathy. These results suggested that IOP-independent management may provide alternative treatment options for NTG patients. Conclusions: In this review, we mainly focus on the mechanisms of the abnormal OBF in NTG.

Intellective and stimuli-responsive drug delivery systems in eyes.

Stimuli-responsive drug delivery systems have attracted widespread attention in recent years since they can control drug release in a spatiotemporal manner and can achieve tunable drug release according to patient's physiological or pathological condition. In this review, we briefly introduce the drug delivery barriers and drug delivery systems in the anterior and posterior segment of eyes, and collect the recent advances in stimuli-responsive drug delivery systems in eyes for controlled drug release in response to exogenous stimuli (ultrasound, magnetic stimulus, electrical stimulus, and light) or endogenous stimuli (enzyme, active oxygen species, temperature, ions, and pH). In addition, the design and mechanisms of the stimuli-responsive drug delivery systems have been summarized in this review, and the advantages and limitations are also briefly discussed.

Efficacy of bandage contact lens for the management of dry eye disease after cataract surgery.

PURPOSE: We aimed to evaluate the efficacy of bandage contact lens (BCL) for the management of dry eye disease (DED) after cataract surgery. METHODS: A total of 120 patients (140 eyes) with age-related cataract and DED were enrolled in this study. Patients underwent standard micro-incision phacoemulsification surgeries and were divided into control or BCL groups. Slit-lamp biomicroscopic examination, Ocular Surface Disease Index, keratograph analysis and Schirmer I test were executed, and the levels of tear inflammatory molecules were detected. RESULTS: In the control group, the NIAvg-BUT and Schirmer I test scores were significantly decreased at 1 week post-operation compared with baseline levels (P = 0.035 and P = 0.009, respectively). In the BCL group, the NIF-BUT and Schemer I test scores were significantly improved at 1 month after operation compared with the control group (P = 0.012 and P < 0.001, respectively). Levels of IL-6, IL-8 and ICAM-1 were significantly increased in the control group at 1 month after the operation (P = 0.005, P = 0.038 and P = 0.022, respectively), while there was no difference in the BCL group. The increase in the IL-6 level in the control group was significantly higher compared with that in the BCL group (P = 0.047). In DED patients, there were significant correlations between ocular surface parameters and inflammatory molecules. CONCLUSIONS: Cataract surgery could lead to the development or worsening of DED. The application of BCLs after cataract surgery could stabilize the ocular surface and tear film, improve the corneal healing and reduce the inflammation. Collectively, our findings suggested that proper use of BCLs after cataract surgery played an effective role in the management of DED. TRIAL REGISTRATION: ClinicalTrials, NCT04100031. Registered 18 September 2019-retrospectively registered.

Outcome, influence factor and development of CLS measurement in continuous IOP monitoring: A narrative review.

A large fluctuation in intraocular pressure (IOP) and a high peak IOP remain the risk factors for progressive visual field loss in patients with glaucoma, which is a leading cause of irreversible blindness. However, IOP measurements during working time cannot provide sufficient information on IOP to guide clinicians in setting IOP target values. Contact lenses are extensively used in ophthalmology to correct the refractive error, and recently, they are serving as platforms for detection and drug delivery. Contact lens sensor (CLS) is a feasible and promising approach to continuously monitor IOP, with superior tolerance, non-invasiveness, and without sleep disturbance. The present work reviewed the associations between progressive course and Triggerfish® CLS outputs as well as the relationship between treatments and Triggerfish® CLS outputs. Moreover, it further summarized state-of-the-art CLS devices of the past decade.

Analysis of tear inflammatory molecules and clinical correlations in evaporative dry eye disease caused by meibomian gland dysfunction.

PURPOSE: To compare the levels of inflammatory molecules in tear samples between patients with meibomian gland dysfunction (MGD)-related evaporative dry eye (EDE) and healthy subjects and to analyze the correlations between the levels of tear inflammatory molecules and ocular surface parameters. METHODS: A total of 30 MGD-related EDE patients (48 eyes) and ten healthy volunteers (15 eyes) were enrolled. Dry eye-related examinations and questionnaires were obtained from all participants. The levels of nine inflammatory molecules were determined through multiplex bead analysis. RESULTS: Inflammatory molecules including ICAM-1, IFN-γ, CXCL8/IL-8, IL-6, TNF-α and IL-12p70 were detected in 100% of the patients, while IL-1α, IL-1ß and IL-10 were detected in 56.25%, 13.60% and 45.83% of the patients, respectively. Moreover, ICAM-1, IL-8, IL-6, TNF-α, IL-12p70 and IFN-γ were detected in 86.67-100% of the healthy subjects, and the detection rates of IL-10, IL-1α and IL-1ß were below 50%. The levels of IL-8, IL-6, IFN-γ and ICAM-1 were significantly higher in the patient group compared with the control group. In addition, IL-8 and IL-6 were negatively correlated with Schirmer I test. Besides, IFN-γ was negatively correlated with tear film breakup time. Furthermore, ICAM-1 and IL-6 were positively correlated with meibography score. CONCLUSIONS: Collectively, patients with MGD-related EDE had higher levels of inflammatory molecules in their tears, and some molecules were correlated with ocular surface parameters. These findings suggested that inflammation played an important role in MGD-related EDE, and several inflammatory molecules could be used in the diagnosis and the treatment of MGD-related EDE.

Early-stage clinical outcomes and rotational stability of TECNIS toric intraocular lens implantation in cataract cases with long axial length.

BACKGROUND: A major focus of toric intraocular lens (IOL) implantation is the rotational stability, especially in the patients with long axial length (AL). In this study, we aimed to evaluate the clinical outcomes after implantation of TECNIS toric IOL in eyes with long AL and identify factors influencing their early-stage stability with preoperative corneal astigmatism. METHODS: The study population consisted of 64 eyes from 52 cataract patients, and these patients had preoperative corneal astigmatism between 1.0 and 3.7 diopters (D) and underwent phacoemulsification and TECNIS toric IOL implantation. Ophthalmic biological measurements were carried out preoperatively, including AL, anterior chamber depth (ACD), lens thickness (LT), vitreous length (VL), anterior chamber volume (ACV), sulcus-to-sulcus (STS) and keratometric value (K). Clinical examinations, including visual acuity, manifest refraction, keratometry, digital anterior segment photographs with pupillary dilation, were performed at 1 and 3 months after surgery. RESULTS: The mean best corrected distance visual acuity (BCDVA) was improved from 0.93 ± 0.35 logarithms of the minimal angle of resolution (logMAR) preoperatively to 0.07 ± 0.10 logMAR postoperatively at 3 months after surgery. The mean residual astigmatism (RAS) was 0.91 ± 0.74D at 3 months, which was significantly decreased compared with the preoperative corneal astigmatism of 1.71 ± 0.55 D. The mean absolute rotation of TECNIS toric IOL at 1 and 3 months was 7.42 ± 11.32 degree (°) (0-79°) and 7.48 ± 11.19°(0-79°), respectively. The mean area of capsulorhexis and the overlapped area between capsulorhexis and IOL optic intraoperatively was 21.04 ± 3.30 mm2 and 7.40 ± 2.87 mm2.A positive correlation was found between IOL rotation and the area of capsulorhexis (p = 0.017) at 3 months after surgery. No correlation was found between IOL rotation and AL (p = 0.876), ACD (p = 0.387), LT (p = 0.523), VL (p = 0.546), ACV (p = 0.480), STS (p = 0.884), K1 (p = 0.429), K2 (p = 0.644), average of K1 and K2 (p = 0.520), intraoperative IOL axial direction (p = 0.396), preoperative corneal astigmatism (p = 0.269) or the overlapped area between capsulorhexis and IOL optic intraoperatively (p = 0.131) . CONCLUSIONS: The large CCC was a risk factor for toric IOL rotation. An appropriately smaller sized CCC was conducive to increase the rotational stability of TECNIS toric IOL implantation in cataract cases with long AL.

The diagnosis and phacoemulsification in combination with intraocular lens implantation for an Axenfeld-Rieger syndrome patient with small cornea: a case report.

BACKGROUND: Axenfeld-Rieger syndrome (ARS) is a congenital disease with a series of developmental abnormalities, and no case of ARS with cataract and small cornea has been reported in previous studies. In the present report, we aimed to describe the diagnosis and phacoemulsification of an ARS patient with small cornea. CASE PRESENTATION: A 58-year-old Han Chinese male patient who was referred to Eye Center of the Second Affiliated Hospital of Zhejiang University Medical College was diagnosed with ARS. Systemic and ophthalmic examination and genetic testing were performed. The slit-lamp microscopic examination of anterior segment showed obvious nuclear cataract, iris lesions, and the abnormal cornea of both eyes with small transversal and longitudinal diameters. ARS with bilateral complicated cataract and small cornea was diagnosed. Microincision-phacoemulsification in combination with intraocular lens implantation was performed on his left eye. After successful surgery of his left eye, the best-corrected visual acuity (BCVA) was obviously improved from 2 to 0.5 (LogMAR). A transient elevation of intraocular pressure (IOP) was controlled with medication. CONCLUSIONS: Through genetic testing, a known pathogenic mutation NM_153427.2:c.272G > A was detected on the PITX2 gene; and an unknown mutation NM_001453.2:c.1063C > T was detected on FOXC1 gene. For the ARS patient with complicated cataract, the visual acuity was increased by phacoemulsificasion in combination with microincision.

Early Postoperative Rotational stability and its related factors of a single-piece acrylic toric intraocular lens.

PURPOSE: In the present study, we aimed to evaluate the early postoperative rotational stability of TECNIS toric intraocular lens (IOL) and analyse its correlation with preoperative and intraoperative parameters. METHODS: A total of 102 eyes from 87 cataract patients who underwent implantation of TECNIS toric IOL during July 2016 to November 2017 were enrolled in this retrospective study. Preoperative parameters including corneal astigmatism, axial length (AL), lens thickness (LT), anterior chamber depth (ACD) and sulcus-to-sulcus (STS), were determined. The area of capsulorhexis was measured with Rhinoceros 5.0 software. The follow-up examinations including the residual astigmatism (RAS) and postoperative toric IOL axis, were performed at 1 month and 3 months after surgery. RESULTS: RAS was -0.84 ± 0.88 D at 1 month and -0.81 ± 0.89 D at 3 months after surgery. The rotation of toric IOL at 3 months was 4.83 ± 3.65°. The Pearson's r of ACD, horizontal and vertical STS, and toric IOL target axis was 0.011, 0.039, 0.045 and 0.082. The toric IOL rotation was positively correlated with the area of capsulorhexis (r = 0.522, P = 0.0003), LT (r = 0.288, P = 0.003) and AL (r = 0.259, P = 0.009). As for the area of capsulorhexis, the regressive equation was: y = 0.682 × -13.105, demonstrating that the diameter of capsulorhexis should be controlled within 5.8 mm to maintain the toric IOL rotation within 5.0°. CONCLUSIONS: TECNIS toric IOLs possessed great early postoperative rotational stability. The area of capsulorhexis, AL and LT were positively correlated with postoperative rotational stability. A capsulorhexis within 5.8 mm had an important significance in improving rotational stability.

Clinical observation of a novel technique: transscleral suture fixation of a foldable 3-looped haptics one-piece posterior chamber intraocular lens implantation through scleral pockets with intact conjunctiva.

BACKGROUND: To present the follow-up outcomes of a modified technique of transscleral suture fixation of posterior chamber intraocular lens (PCIOL) in eyes with inadequate capsule support. METHODS: A retrospective chart review of 21 patients underwent transscleral suture fixation of a foldable 3-looped haptics one-piece PCIOL implantation through scleral pockets was conducted. Preoperative data and follow-up data for at least 3 months were collected for all patients. RESULTS: The mean operative duration was 36.62 ± 10.70 min. The mean pre- and post-operative LogMAR uncorrected distance visual acuity was (1.25 ± 0.50 vs. 0.41 ± 0.22, P < 0.01). The mean pre- and post-operative LogMAR best corrected visual acuity was (0.48 ± 0.25 vs. 0.33 ± 0.24, P < 0.01). The mean proportion of postoperative endothelial cell loss was 11.46 ± 4.78%. The mean postoperative anterior chamber depth was 3.05 ± 0.44 mm. The mean postoperative IOL tilt degree was 2.81 ± 1.41°, and the mean postoperative IOL decentration degree was 0.31 ± 0.13 mm. Four patients with transient corneal edema (19.0%) and three patients with transiently elevated IOP (14.3%) were observed after operation, and such complications were resolved within 1 week. No severe complications were observed. CONCLUSIONS: The modified technique was a feasible method of PCIOL implantation.