Senolytic and senomorphic agent procyanidin C1 alleviates structural and functional decline in the aged retina.

Increased cellular senescence burden contributes in part to age-related organ dysfunction and pathologies. In our study, using mouse models of natural aging, we observed structural and functional decline in the aged retina, which was accompanied by the accumulation of senescent cells and senescence-associated secretory phenotype factors. We further validated the senolytic and senomorphic properties of procyanidin C1 (PCC1) both in vitro and in vivo, the long-term treatment of which ameliorated age-related retinal impairment. Through high-throughput single-cell RNA sequencing (scRNA-seq), we comprehensively characterized the retinal landscape after PCC1 administration and deciphered the molecular basis underlying the senescence burden increment and elimination. By exploring the scRNA-seq database of age-related retinal disorders, we revealed the role of cellular senescence and the therapeutic potential of PCC1 in these pathologies. Overall, these results indicate the therapeutic effects of PCC1 on the aged retina and its potential use for treating age-related retinal disorders.

Empagliflozin targets Mfn1 and Opa1 to attenuate microglia-mediated neuroinflammation in retinal ischemia and reperfusion injury.

BACKGROUND: Neuroinflammation and mitochondrial dysfunction play crucial roles in retinal ischemia and reperfusion (IR) injury. Recent studies have identified mitochondrial function as a promising target for immunomodulation. Empagliflozin (EMPA), an anti-diabetic drug, has exhibited great potential as both an anti-inflammatory agent and a protector of mitochondrial health. This study aimed to assess the therapeutic efficacy of EMPA in retinal IR injury. METHODS: To evaluate the protective effects of EMPA, the drug was injected into the vitreous body of mice post-retinal IR. Single-cell RNA sequencing (scRNA-seq) analysis was conducted to uncover the underlying mechanisms, and the results were further validated through in vivo and in vitro experiments. RESULTS: EMPA effectively protected retinal ganglion cells (RGCs) from IR injury by attenuating local retinal inflammation. The scRNA-seq analysis revealed that EMPA downregulated the nucleotide-binding domain and leucine-rich repeat containing protein 3 (NLRP3) signaling pathway and restored mitochondrial dynamics by upregulating the expression of mitochondrial fusion-related genes, Mitofusin 1 (Mfn1) and optic atrophy 1 (Opa1). These findings were further corroborated by Western blotting. In vitro experiments provided additional insights, demonstrating that EMPA suppressed lipopolysaccharide (LPS)-induced cell inflammation and NLRP3 inflammasome activation. Moreover, EMPA enhanced mitochondrial fusion, neutralized mitochondrial reactive oxygen species (mtROS), and restored mitochondrial membrane potential (MMP) in BV2 microglia. Notably, genetic ablation of Mfn1 or Opa1 abolished the anti-inflammatory effects of EMPA. CONCLUSIONS: Our findings highlight the positive contribution of Mfn1 and Opa1 to the anti-inflammatory therapeutic effect of EMPA. By restoring mitochondrial dynamics, EMPA effectively mitigates microglia-mediated neuroinflammation and prevents RGC loss in retinal IR injury.

N,N-Dimethyl-3ß-hydroxycholenamide attenuates neuronal death and retinal inflammation in retinal ischemia/reperfusion injury by inhibiting Ninjurin 1.

BACKGROUND: Retinal ischemia-reperfusion (RIR) injury refers to an obstruction in the retinal blood supply followed by reperfusion. Although the molecular mechanism underlying the ischemic pathological cascade is not fully understood, neuroinflammation plays a crucial part in the mortality of retinal ganglion cells. METHODS: Single-cell RNA sequencing (scRNA-seq), molecular docking, and transfection assay were used to explore the effectiveness and pathogenesis of N,N-dimethyl-3ß-hydroxycholenamide (DMHCA)-treated mice with RIR injury and DMHCA-treated microglia after oxygen and glucose deprivation/reoxygenation (OGD/R). RESULTS: DMHCA could suppress inflammatory gene expression and attenuate neuronal lesions, restoring the retinal structure in vivo. Using scRNA-seq on the retina of DMHCA-treated mice, we provided novel insights into RIR immunity and demonstrated nerve injury-induced protein 1 (Ninjurin1/Ninj 1) as a promising treatment target for RIR. Moreover, the expression of Ninj1, which was increased in RIR injury and OGD/R-treated microglia, was downregulated in the DMHCA-treated group. DMHCA suppressed the activation of the nuclear factor kappa B (NF-κB) pathways induced by OGD/R, which was undermined by the NF-κB pathway agonist betulinic acid. Overexpressed Ninj1 reversed the anti-inflammatory and anti-apoptotic function of DMHCA. Molecular docking indicated that for Ninj1, DMHCA had a low binding energy of - 6.6 kcal/mol, suggesting highly stable binding. CONCLUSION: Ninj1 may play a pivotal role in microglia-mediated inflammation, while DMHCA could be a potential treatment strategy against RIR injury.

Protocol for laser-induced chronic ocular hypertension and intracameral injection in nonhuman primates.

Laser-induced hypertension in nonhuman primates is used to mimic human glaucoma, the leading cause of irreversible blindness. In this protocol, we detail steps for laser-induced ocular hypertension in nonhuman primates by laser photocoagulation of the trabecular meshwork and subsequent intracameral injection. We further describe recording and evaluation of intraocular pressure changes and peripapillary retinal nerve fiber layer thickness. This protocol can assist researchers improve the success rate and repeatability of the procedure and reduce the number of nonhuman primates needed. For complete details on the use and execution of this protocol, please refer to Sun et al. (2022).

Erratum: Long-term and potent IOP-lowering effect of IκBα-siRNA in a nonhuman primate model of chronic ocular hypertension.

[This corrects the article DOI: 10.1016/j.isci.2022.104149.].

Long-term and potent IOP-lowering effect of IκBα-siRNA in a nonhuman primate model of chronic ocular hypertension.

Glaucoma is one of the most common causes of irreversible blindness. It is acknowledged that lowering intraocular pressure (IOP) is the effective treatment to slow glaucoma disease progression. The main obstacle of existing drugs is that the effect of reducing IOP does not last long. Degradation of IκB stimulates the transcription of NF-κB, which could upregulate the expression of matrix metalloproteinases (MMPs). Whether a IκB-targeted gene therapy works in glaucoma is unclear. Here, we established a chronic ocular hypertension (COHT) model in rhesus monkey by laser photocoagulation and verified that intracameral delivery of IκBα-siRNA showed long-lasting and potent effects of reducing IOP without obvious inflammation in monkeys with COHT. We also verified that IκBα-siRNA could increase the expressions of MMP2 and MMP9 by knocking down IκBα in vitro and in vivo. Our results in nonhuman primates indicated that IκBα-siRNA may become a promising therapeutic approach for the treatment of glaucoma.

Relative peripheral refraction characteristics and their relationship with retinal microvasculature in young adults: Using a novel quantitative approach.

AIM: To analyze relative peripheral refraction (RPR) characteristics in young adults and to investigate the relationship between RPR and retinal microvasculature using multispectral refractive tomography (MRT), a novel quantitative approach. METHODS: This cross-sectional study included 278 eyes of 139 young adults. All eyes underwent complete ophthalmic examinations, including MRT, optical coherence tomography angiography (OCTA) and other ocular examinations. Refraction difference values (RDVs) among different rings/sectors were compared using one-way ANOVA in bilateral eyes. Stepwise multiple linear regression analyses were performed between ∆RDV in different rings and ∆density/thickness value in OCTA. RESULTS: Among the different rings, the 30°-45°/45°-53° RDV was significantly greater than the inner rings in both eyes. Among the different sectors, RDV in the superior sector was most significantly reduced among all sectors, and RDV in the nasal sector was significantly greater than that in the temporal sector. In the stepwise multiple linear regression analyses, ∆RDV was negatively correlated with ∆radial peripapillary capillary plexus density and ∆macular thickness. CONCLUSIONS: MRT may be a useful tool in RPR quantitative assessment. RPR and some OCTA indexes might be closely correlated. Further research should be conducted to investigate the relationships among these indexes in young adults.

Disease burden of age-related macular degeneration in China from 1990 to 2019: findings from the global burden of disease study.

BACKGROUND: To evaluate the disease burden of age-related macular degeneration (AMD) in terms of disability-adjusted life years (DALY) in China from 1990 to 2019. METHODS: Prevalence of blindness and vision loss due to AMD and DALY number, rate, and age-standardized rates of AMD were collected from the Global Burden of Disease Study 2019 database. The characters of variables were analyzed between China and its neighboring countries. RESULTS: From 1990 to 2019, the all-age number and rate for AMD prevalence and DALYs increased significantly in China, while the age standardized DALYs rate in 2019 showed a decrease of 3.63% compared with that in 1990. Females were found to have a higher prevalence and DALYs than males. The 65-69 age group had the highest AMD DALYs number, while the DALYs rate showed a positive association with age. In 2019, when compared to neighboring countries, the age standardized prevalence rate of AMD in China was ranked second after Pakistan, while the age standardized DALYs rate ranked second after Pakistan and India. CONCLUSIONS: Despite a small decrease in age standardized DALYs rate in China in the past three decades, the disease burden of AMD is still considerable and much higher compared to neighboring developed countries. Optimizing health services allocation is needed to further reduce this burden.

Global disease burden of uncorrected refractive error among adolescents from 1990 to 2019.

BACKGROUND: To estimate the global disease burden of uncorrected refractive error (URE) among adolescents and assess the contributions of various risk factors to disability-adjusted life-years (DALYs) due to URE. METHODS: Global, regional and country-level DALY numbers and rates due to URE among adolescents were acquired from the Global Burden of Disease Study 2019 database. Human Development Index (HDI), Socio-Demographic Index (SDI) and other country-level data were obtained from other open databases as potential indicators. Regression analysis was used to evaluate associations between DALY rates among adolescents and potential predictors. RESULTS: Global DALYs due to URE among adolescents rose by 8% between 1990 and 2019 but moderately decreased by 4.8% during this period after adjusting for population size. Female adolescents showed higher DALY rates. DALY rates sharply increased from 5 to 9 years of age, then rose more slowly, reaching a plateau before 20 years of age. Country-level DALY rates in 2019 were positively associated with HDI, SDI, and urbanization rates but negatively correlated with primary school dropout rates. Higher disease burden of adolescents visually impaired from URE was associated with lower primary school dropout rates (ß = - 0.257, 95% CI - 0.376 to - 0.138, P < 0.001) and higher urbanization rates (ß = 0.257, 95% CI 0.067 to 0.256, P = 0.001). CONCLUSIONS: Higher socioeconomic status, urbanization rates and education levels are associated with a heavier disease burden of URE among adolescents. The findings of this study can provide a reference for policy making on resource allocation for URE prevention and control in teenagers.

A Quantitative Comparison of Multispectral Refraction Topography and Autorefractometer in Young Adults.

Purpose: Purpose of this study is to evaluate the measuring consistency of central refraction between multispectral refraction topography (MRT) and autorefractometry. Methods: This was a descriptive cross-sectional study including subjects in Sun Yat-sen Memorial Hospital from September 1, 2020, to December 31, 2020, ages 20 to 35 years with a best corrected visual acuity of 20/20 or better. All patients underwent cycloplegia, and the refractive status was estimated with autorefractometer, experienced optometrist and MRT. We analyzed the central refraction of the autorefractometer and MRT. The repeatability and reproducibility of values measured using both devices were evaluated using intraclass correlation coefficients (ICCs). Results: A total of 145 subjects ages 20 to 35 (290 eyes) were enrolled. The mean central refraction of the autorefractometer was -4.69 ± 2.64 diopters (D) (range -9.50 to +4.75 D), while the mean central refraction of MRT was -4.49 ± 2.61 diopters (D) (range -8.79 to +5.02 D). Pearson correlation analysis revealed a high correlation between the two devices. The intraclass correlation coefficient (ICC) also showed high agreement. The intrarater and interrater ICC values of central refraction were more than 0.90 in both devices and conditions. At the same time, the mean central refraction of experienced optometrist was -4.74 ± 2.66 diopters (D) (range -9.50 to +4.75D). The intra-class correlation coefficient of central refraction measured by MRT and subjective refraction was 0.939. Conclusions: Results revealed that autorefractometry, experienced optometrist and MRT show high agreement in measuring central refraction. MRT could provide a potential objective method to assess peripheral refraction.

The incidence and risk factors of neovascular glaucoma secondary to proliferative diabetic retinopathy after vitrectomy.

OBJECTIVE: The incidence and risk factors of neovascular glaucoma (NVG) secondary proliferative diabetic retinopathy (PDR) after pars plana vitrectomy (PPV) are unclear and reports in the published literature are inconsistent. Therefore, a systematic review and meta-analysis were conducted to clarify the risk factors associated with neovascular glaucoma. METHODS: PubMed, Embase, and The Cochrane Library were systematically searched without language limitations for studies related to NVG after PPV in PDR patients. We used R software to fit the correlation between incidence and the date of publication for studies and performed a Spearman analysis. For binary and continuous variables, the odds ratios (ORs) with 95% confidence intervals (CIs) were pooled, respectively, using Review Manager 5.3 (The Cochrane Collaboration). RESULTS: Twenty-six studies with 5161 patients were included in our meta-analysis. The overall pooled incidence of NVG after PPV in PDR patients was 6% (95% CI, 0.05-0.07, p-value < 0.00001). Pooled estimates indicated a positive correlation for NVG after PPV in PDR patients with higher baseline IOP (OR, 1.26; 95%CI,0.56-1.95, p-value = 0.0004), preoperative iris neovascularization (INV) (OR, 5.66; 95% CI, 2.10-15.23, p-value = 0.0006), preoperative or intraoperative combined cataract surgery (OR, 2.00; 95% CI, 1.15-3.46, p-value = 0.01), postoperative vitreous hemorrhage (VH) (OR, 3.53; 95% CI, 1.63-7.66, p-value = 0.001), and a negative correlation with age (OR, -2.90; 95%CI, -5.00 to -0.81, p-value < 0.007). CONCLUSION: Our systematic review and meta-analysis indicated that the main risk factors for NVG after PPV in PDR patients included higher baseline IOP, preoperative INV, preoperative or intraoperative combined cataract surgery, postoperative VH, and was negatively correlated with age.