Inhibiting the SARM1-NAD+ axis reduces oxidative stress-induced damage to retinal and nerve cells.

Retinal neurodegenerative diseases are a category of refractory blinding eye conditions closely associated with oxidative stress induced by mitochondrial dysfunction in retinal cells. SARM1, a core driver molecule leading to axonal degeneration, possesses NAD+ enzyme (NADase) activity. However, the role of the SARM1-NAD+ axis in oxidative stress-induced retinal cell death remains unclear. Here, we employed the SARM1 NADase inhibitor DSRM-3716 and established a glucose oxidase (GOx)-induced oxidative stress cell model. We found that compared to the GOx group, the DSRM-3716 pre-treated group reduced the hydrolysis of NAD+, inhibited the elevation of oxidative stress markers induced by GOx, decreased mitochondrial dysfunction, lowered the phosphorylation level of JNK, and attenuated the occurrence of pyroptosis in retinal and nerve cells, thereby providing protection for neurite growth. Further utilization of the JNK activator Anisomycin activated JNK, revealed that the JNK/c-Jun pathway down-regulated NMNAT2 expression. Consequently, it reduced cellular NAD+ synthesis, exacerbated mitochondrial dysfunction and cell pyroptosis, and reversed the protective effect of DSRM-3716 on cells. In summary, the inhibition of SARM1 NADase activity substantially mitigates oxidative damage to retinal cells and mitochondrial damage. Additionally, JNK simultaneously serves as both an upstream and downstream regulator in the SARM1-NAD+ axis, regulating retinal cell pyroptosis and neurite injury. Thus, this study provides new insights into the pathological processes of retinal cell oxidative stress and identifies potential therapeutic targets for retinal neurodegenerative diseases.

Extended depth of focus IOL in eyes with different axial myopia and targeted refraction.

AIM: To evaluate the objective visual outcomes following implantation of extended depth of focus intraocular lens (EDOF IOL) in individuals with varying axial lengths (AL) and targeted refraction. METHODS: This retrospective study comprised age-matched eyes that underwent implantation of the EDOF IOL. Eyes were categorized based on AL into groups: control group with AL < 26 mm; high myopia group with AL ≥ 26 mm. Each group was then subdivided based on postoperative spherical equivalent (SE). Follow-up at three months included assessment of uncorrected visual acuity at different distances, contrast sensitivity (CS), refractive outcomes, and spectacle independence. RESULTS: Overall, this study included 100 eyes from 100 patients, comprising 50 males (50.00%) and 50 females (50.00%), with 20 eyes in each group. In the control group, the uncorrected distance visual acuity (UDVA) at 5 and 3 m (m) in the - 1.50 to -0.75 group was inferior to that of the - 0.75 to 0.00 group (P = 0.004). Conversely, the uncorrected near visual acuity (UNVA) at 33 cm in the - 1.50 to -0.75 group was superior to that of the - 0.75 to 0.00 group (P = 0.005). Within the high myopia group, the UDVA at 5 and 3 m in the - 2.25 to -1.50 group was worse than in the - 0.75 to 0.00 group (P = 0.009 and 0.008, respectively). However, the UNVA at 33 cm in the - 2.25 to -1.50 group was better than in the - 0.75 to 0.00 group (P = 0.020). No significant differences were observed among the groups for corrected distance visual acuity (CDVA) (P > 0.05). Additionally, in the high myopia group, the CS of the - 2.25 to -1.50 group was lower compared to that of the - 0.75 to 0.00 group (P = 0.017). Among high myopia patients, 90.00% with refraction ranging from - 1.50 to -0.75 reported achieving overall spectacle independence. CONCLUSIONS: Implantation of extended depth of focus intraocular lenses (IOLs) yields satisfactory visual and refractive outcomes in eyes with axial myopia. Among high myopia patients, a refraction ranging from - 1.50 to -0.75 diopters achieves superior visual quality compared to other postoperative myopic diopters.

Interaction between visual impairment and subjective cognitive complaints on physical activity impairment in U.S. older adults: NHANES 2005-2008.

BACKGROUND/AIM: To investigate the independent relationships of visual impairment (VI) and Subjective cognitive complaints (SCC) with physical function impairment (PFI) and the interaction effect between VI and SCC on PFI in American older adults. METHODS: The data of this cross-sectional study was obtained from the 2005-2008 National Health and Examination Survey (NHANES) conducted in the United States. The VI criterion included both subjective self-reported eyesight conditions and objective visual acuity test results. The self-reported questionnaires were utilized to determine PFI and SCC. According to the survey design of NHANS, original data were weighted to produce nationally representative estimates. Both the unweighted original data and weighted estimates underwent analysis. Crude and adjusted logistic models were employed to assess the pairwise associations among VI, SCC, and PFI. To assess the interactive effect, measures such as the relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (S) were calculated. RESULTS: A total of 2,710 subjects (weighted n = 38,966,687) aged 60 years or older were included. Compared with subjects without subjective visual impairment (SVI), those with SVI had a significant positive association with PFI [weighted OR (95%CI): 3.11 (2.25, 4.31)]. After multi-variable adjusting, the relationship remained significant [weighted OR (95%CI): 1.90 (1.32, 2.72)]. Similarly, those with objective visual impairment (OVI) were positively associated with the risk of PFI in the crude model [weighted OR (95%CI): 2.35 (1.53, 3.61)] and adjusted model [weighted OR (95%CI): 1.84 (1.07, 3.17)]. Moreover, we found the association of SCC with an increased risk of FPI [crude weighted OR (95%CI): 5.02 (3.40, 7.40); adjusted weighted OR (95%CI): 3.29 (2.01, 5.38)]. Ultimately, the additive interaction showed there was a significant positive interaction term between SVI and SCC on PFI, while OVI and SCC did not. CONCLUSION: Both VI and SCC were significantly associated with PFI in elder adults. Besides, there was a significant synergistic interaction between SVI and SCC on PFI, which indicated the improvement of SVI and SCC may be beneficial for the prevention of PFI. For the elderly, especially those with multiple disabilities, comprehensive and targeted approaches are imperative to foster their overall well-being and health.

Clinical observation of phacoemulsification under the low perfusion pattern and low negative pressure in patients with low corneal endothelial cell density.

BACKGROUND: To observe the safety and effect of phacoemulsification combined with intraocular lens (IOL) implantation in patients with low corneal endothelial cell density (CD) under the low perfusion pattern with low negative pressure. METHODS: In this retrospective case series study, a total of 16 patients (17 eyes) were studied. They had all been diagnosed with low corneal endothelial (CD) and cataracts in the First Affiliated Hospital of Fujian Medical University from December 2019 to October 2021. They underwent phacoemulsification combined with IOL implantation under the low perfusion pattern with low negative pressure. The variations of corneal endothelial( CD), coefficient of variation (CV) of the cell area, central corneal thickness (CCT), visual acuity, and intraocular pressure before and after the operation were observed and assessed. Then a paired t-test, repeated measures analysis of variance, and Pearson correlation analysis were adopted for data analysis. RESULTS: The mean intraocular pressure of the 17 eyes was 16.88 ± 6.47 mmHg before the operation and 14.41 ± 3.10 mmHg after the operation, showing a statistically significant difference of t = 2.222, and p = 0.041. Before the operation, the mean visual acuity was 0.16 ± 0.09, and after the operation, it was 0.45 ± 0.16, displaying a statistically significant difference of t = -9.917, p < 0.001. Before and after the operation, four of the 17 eyes had no detectable CD. The mean CD of the other 13 eyes at one month after the operation (644.308 ± 106.24 cells/mm2) was lower than that before the operation (709.62 ± 119.19 cells/mm2), and the differences were statistically significant (F = 20.044, p < 0.001). However, no statistically significant differences were found in the mean CV before the operation (31.23 ± 4.21), and at one month after the operation (32.62 ± 3.80; F = 2.130, p = 0.157). Moreover, the mean CCT of 14 eyes at one month after the operation (562.72 ± 27.82 µm) was larger than that before the operation (534.79 ± 24.69 µm). CONCLUSIONS: The low perfusion pattern with low negative pressure is safe and effective for corneal endothelial dysfunction patients complicated with cataracts.

Optical Coherence Tomography Angiography in Posner-Schlossman Syndrome - A Preliminary Study.

PURPOSE: To evaluate vessel density (VD) and structural features in Posner-Schlossman syndrome (PSS) patients' eyes using optical coherence tomography angiography (OCTA). METHODS: An observational study was conducted among 23 affected eyes (group A), 23 contralateral unaffected eyes (group B), and 23 control eyes (group C). RESULT: The macular superficial, macular deep, and optic nerve head (ONH) VD of group A were 45.26 ± 5.80, 46.78 ± 6.96, and 46.10 ± 4.22, respectively. The macular superficial VD, macular deep VD, and retinal thickness of group A were significantly lower than those of group C (all P < .05). The retinal nerve fiber layer thickness of group A decreased in the superior and inferior sections. The macular superficial VD had the highest diagnostic value (area under curve = 0.989) for PSS. CONCLUSION: OCTA can detect the fundus change in the macular and ONH regions of the PSS's affected eyes.

Structure‒function‒pathogenicity analysis of C-terminal myocilin missense variants based on experiments and 3D models.

MYOC is a common pathogenic gene for primary open-angle glaucoma and encodes the protein named myocilin. Multiple MYOC variations have been found, with different clinical significance. However, the pathogenesis of glaucoma induced by MYOC mutations has not been fully clarified. Here, we analyze the molecular and cellular biological differences caused by multiple variant myocilins, including protein secretion characteristics, structural changes, subcellular localization, cellular autophagic activity and oxidative stress. Denaturing and nondenaturing electrophoresis showed myocilin to be a secreted protein with the tendency to self-oligomerize. The full-length myocilin and its C-terminal cleavage fragment are secreted. Secretion analysis of 23 variant myocilins indicated that secretion defects are closely related to the pathogenicity of MYOC variants. Structural analysis showed that the alteration of steric clash is associated with the secretion characteristics and pathogenicity of myocilin variants. Immunocytochemistry results demonstrated that mutated myocilins are retained in the endoplasmic reticulum and disrupt autophagy. MTT assay, MitoTracker staining, and DCFH-DA staining showed increased oxidative injury in cells expressing MYOC mutants. Taken together, MYOC mutations are able to induce cell dysfunction via secretion defects and intracellular accumulation resulting from steric clash alterations.

Clinical application of the CO2 laser in Ab externo Schlemm's canal surgery.

Purpose: This study aimed to investigate the clinical application of laser as a knife in Ab externo Schlemm's canal (SC) surgery and compare the efficacy and safety of the CO2 laser with the conventional procedure using a surgical knife. Methods: Patients who underwent either canaloplasty or trabeculotomy with CO2 laser system which was used to locate and ablate the outer wall of SC at the time interval between May 2020 and May 2021 were identified, their medical files were reviewed, and their results were compared with conventional surgery group who underwent canaloplasty or trabeculotomy with conventional surgical knife at the same time period. The following datas were conducted and compared: age, sex, intraocular pressure (IOP), number of drugs, best-corrected visual acuity (BCVA), mean deviation and pattern standard deviation of visual field examination, SC opening related complications. Results: A total of 49 patients (49 eyes) were included in this study, including 23 in the Laser surgery group and 26 in the conventional surgery group. Time for SC opening was 49.33 ± 25.23 s and 116.50 ± 31.79 s for laser surgery group and conventional surgery group, respectively. This difference between the two groups was statistically significant (P < 0.01). Hemorrhage occurred in five eyes during ablation for the laser surgery group and in 24 eyes for the conventional surgery group. In addition, anterior chamber penetration occurred in two cases for the laser surgery group and in six cases for the conventional surgery group. The success rate of identifying and opening outer wall of SC was 91.30% (21 eyes) for the laser surgery group and 76.92% (20 eyes) for the conventional surgery group. The difference between preoperative and postoperative intraocular pressure for each group was statistically significant (P < 0.01), and there were no statistically significant differences across the two groups in terms of postoperative IOP (P = 0.238) and BCVA (P = 0.389). Conclusion: Compared with the conventional procedure using a surgical knife, CO2 laser-assisted ablation of the outer wall of SC was less time-consuming and less technically challenging. CO2 laser-assisted ablation also resulted in fewer complications. Furthermore, it had a shorter learning curve and a higher success rate of identifying and opening SC.

Clinical outcomes and complications between FLACS and conventional phacoemulsification cataract surgery: a PRISMA-compliant Meta-analysis of 25 randomized controlled trials.

AIM: To update and investigate the clinical outcomes and complications between femtosecond laser-assisted cataract surgery (FLACS) and conventional phacoemulsification cataract surgery (CPCS). METHODS: A Meta-analysis was performed using databases, including Pubmed, Embase, and the Cochrane library. At least one of the clinical outcomes and/or complications data in each included randomized controlled trials (RCT) was reported. The quality of the RCT was assessed with the Cochrane risk assessments tool. RESULTS: Overall, 25 RCTs including 3781 eyes were included. No statistically significant difference detected between FLACS and CPCS in terms of corrected distant visual acuity (CDVA), uncorrected distant visual acuity (UDVA), and central corneal thickness (CCT) at the long-term follow up, although FLACS showed better CDVA at 1wk postoperatively, and less increase in CCT at 1d and 1wk. FLACS had better postoperative endothelial cell count (ECC) at 1 and 4-6wk, while there was no significantly difference between FLACS and CPCS at 1d, 3 and 6mo [weighted mean difference (WMD): 51.54, 95% confidence interval (CI): -5.46 to 108.54, P=0.08; WMD: 48.52, 95%CI: -17.54 to 114.58, P=0.15; WMD: 12.17, 95%CI: -48.61 to 72.94, P=0.69, respectively]. Postoperative endothelial cell loss (ECL) of the FLACS was significantly lower than that of the CPCS at 1, 4-6wk, and 3mo (P=0.02, 0.008, 0.03, respectively). However, there was no significant difference between two groups at 6mo (WMD: -30.36, 95%CI: -78.84 to 18.12, P=0.22). No significant difference was discovered with respect to the macular edema [odds ratio (OR): 0.93, 95%CI: 0.42 to 2.05, P=0.85], capsular complication excluding posterior capsular tears (OR: 0.79, 95%CI: 0.42 to 1.50, P=0.47) and intraocular pressure change (OR: 0.82, 95%CI: 0.39 to 1.72, P=0.60). However, posterior capsular tears were more common in CPCS group (OR: 0.12, 95%CI: 0.01 to 0.98, P=0.05). The effective phacoemulsification times were significantly lower in the FLACS group compared to the CPCS group (WMD: -0.78, 95%CI: -1.23 to -0.34, P=0.0006). CONCLUSION: No statistically significant difference is discovered between FLACS and CPCS in clinical outcomes at the long-term follow up. However, higher rate of posterior capsular tears is detected in patients receiving CPCS.

Protective Effects of Trimetazidine in Retarding Selenite-Induced Lens Opacification.

Purpose: Cataracts are the leading cause of vision loss worldwide, and the over-production of reactive oxygen species (ROS) is the foremost underlying cause of cataracts. Reducing ROS levels can efficiently prevent lens opacification, as evidenced by many studies. Here, we inhibited ROS overproduction with trimetazidine (TMZ), which is an antioxidant, to explore the therapeutic effects of TMZ and the mechanism of lens opacification.Materials and methods: Sodium selenite-induced cataract formation resulted in a significant loss of lens transparency. This effect could be efficiently rescued by TMZ, which was further found to be an inhibitor of ROS production, as determined by assaying oxidative stress-related parameters (SOD activity, MDA, ·OH and H2O2 levels) during cataract formation. The experimental protocols involving animal research were approved by the Animal Care and Ethics Committee of Wenzhou Medical University and conducted according to the Association for Research in Vision and Ophthalmology under the guidelines of the Animal Welfare Act (SYXK 2015-0009).Results: Our study found that TMZ can retard the onset and progression of lens opacification in vivo in experiments using Sprague-Dawley (SD) suckling rats and can rescue the morphology of HLEB3 cells in vitro. The flow cytometry and DNA fragmentation assays showed that TMZ could prevent sodium selenite-induced apoptosis. The western blot analysing showed that the levels of apoptosis-associated Bcl-2 and Nrf2 were dramatically decreased following the sodium selenite treatment. In addition, the bisulfate DNA sequencing revealed that the demethylation of CpGs in the promoter region of Keap1 was stimulated, and that this demethylation could be inhibited by TMZ by rescuing the Nrf2 expression level.Conclusions: Our findings indicate that the antioxidant TMZ strongly reduces ROS production, which ultimately delays the progression of cataract formation, suggesting that treatment with TMZ represents a novel, promising antioxidant protection to retard cataract formation.

Effects of etanercept on the apoptosis of ganglion cells and expression of Fas, TNF-α, caspase-8 in the retina of diabetic rats.

AIM: To evaluate the effects of etanercept on the expression of Fas, tumor necrosis factor-alpha (TNF-α) and caspase-8 in the early stage of the apoptotic pathway in diabetic rats, and to explore the therapeutic effect of etanercept on diabetic retinopathy. METHODS: A total of 60 Sprague-Dawley (SD) rats were randomly and evenly divided into 3 groups with 20 rats each, including control group, and diabetic groups with or without treatment. Streptozotocin (STZ)-induced diabetic rats were established for diabetic groups. Blood glucose and body weight were measured weekly. All the rats were sacrificed at the 12wk after treatment. The expressions of Fas, TNF-α and caspase-8 in rat retina were quantitatively detected by PCR and Western blot. The leakage of Evan blue was adopted to measure the retinal vascular leakage quantitatively, and to compare it among different groups. TUNEL method was used to compare the amount of apoptotic bodies quantitatively in rat retina ganglion cells under electron microscope. RESULTS: The expressions of Fas, TNF-α and caspase-8 in each group were compared via PCR and Western blot, in which the diabetic group with treatment was lower than those without treatment (P<0.01), but all the diabetic groups were higher than the control group (P<0.01). Evans blue leakage in the diabetic treatment group was lower than those without treatment (P<0.01), but those in the control group was the lowest compared with the other two groups (P<0.01). TUNEL method showed that the apoptotic bodies of retina in the diabetic treatment group was lower than those without treatment (P<0.01), while those in the control group was the lowest compared with the other two groups (P<0.01). CONCLUSION: Etanercept can effectively reduce the expression of Fas, TNF-α and caspase-8, as well as the retinal leakage and retinal cell apoptosis in diabetic rats.

Identification of a novel idiopathic congenital nystagmus­causing missense mutation, p.G296C, in the FRMD7 gene.

Exploring the genetic basis for idiopathic congenital nystagmus is critical for improving our understanding of its molecular pathogenesis. In the present study, direct sequencing using gene specific primers was performed in order to identify the causative mutations in two brothers from a Chinese family who had been diagnosed with idiopathic congenital nystagmus. A comprehensive ophthalmological examination, including eye movement recordings, fundus examination, and retinal optical coherence tomography imaging was also conducted, to characterize the disease phenotype. The results revealed that the two brothers exhibited clear signs of nystagmus without any other ocular anomalies. Direct sequencing revealed a G to T transition (c.886G>T) in exon 9 of the four­point­one, ezrin, radixin, moesin domain­containing 7 (FRMD7) gene, which resulted in a conservative substitution of glycine to cysteine at codon 296 (p.G296C), leading to idiopathic congenital nystagmus in the two affected brothers. c.886G>T is a novel idiopathic congenital nystagmus­inducing mutation in the FRMD7 gene. This finding expands the spectrum of known gene mutations in idiopathic congenital nystagmus, and may be useful for faster gene diagnosis, prenatal testing, the development of potential gene therapies, and for improving the understanding of the molecular pathogenesis of idiopathic congenital nystagmus.

A recurrent G367R mutation in MYOC associated with juvenile open angle glaucoma in a large Chinese family.

AIM: To identify the mutations of MYOC, OPTN, CYP1B1 and WDR36 in a large Chinese family affected by juvenile open angle glaucoma (JOAG). METHODS: Of 114 members of one family were recruited in this study. Blood samples from twelve members of this pedigree were collected for further research. As a control, 100 unrelated subjects were recruited from the same hospital. The exon and flanking intron sequences of candidate genes were amplified using the polymerase chain reaction and direct DNA sequencing. RESULTS: The proband (III:10) was a seventy-three years old woman with binocular JOAG at the age of 31. A recurrent heterozygous mutation (c.1099G>A) of MYOC was identified in the three JOAG patients and another suspect. This transition was located in the first base pair of codon 367 (GGA>AGA) in exon 3 of MYOC and was predicted to be a missense substitution of glycine to arginine (p.G367R) in myocilin. Mutations in OPTN, CYP1B1 or WDR36 were not detected in this study. The G367R mutation was not present in unaffected family members or in 100 ethnically matched controls. Other variants of the coding regions of candidate genes were not detected in all participants. To date, this family was the largest to have been identified as carrying a certain MYOC mutation in China, further evidence of a founder effect for the G367R MYOC mutant was provided by our data. CONCLUSION: A MYOC c.1099G>A mutation in an autosomal dominant JOAG family is identified and the characteristic phenotypes among the patients are summarized. Genetic testing could be utilized in high-risk populations and be helpful not only for genetic counseling, but also for early diagnosis and treatment of affected patients or carriers of inherited JOAG.

Identification of a novel GJA3 mutation in a large Chinese family with congenital cataract using targeted exome sequencing.

Autosomal dominant congenital cataract (ADCC) is a clinically and genetically heterogeneous ocular disease in children that results in serious visual impairments or even blindness. Targeted exome sequencing (TES) is an efficient method used for genetic diagnoses of inherited diseases. In the present study, we used a custom-made TES panel to identify the genetic defect of a four-generation Chinese family with bilateral pulverulent nuclear cataracts. A novel heterozygous missense mutation c.443C>T (p. T148I) in GJA3 was identified. The results of the bioinformatic analysis showed that the mutation was deleterious to the structure and hemichannel function of Cx46 encoded by GJA3. Plasmids expressing wild-type and mutant human Cx46 were constructed and ectopically expressed in human lens epithelial cells (HLECs) or human embryonic kidney (HEK-293) cells. Fluorescent images indicated aggregated signals of mutant protein in the cytoplasm, and a higher protein level was also detected in T148I stable cell lines. In summary, we identified a novel mutation in GJA3 for ADCC, which provided molecular insights into the pathogenic mechanism of ADCC.