Chronic Sleep Deprivation Impairs Visual Functions via Oxidative Damage in Mice.

Sleep deprivation (SD) is a global public health burden, and has a detrimental role in the nervous system. Retina is an important part of the central nervous system; however, whether SD affects retinal structures and functions remains largely unknown. Herein, chronic SD mouse model indicated that loss of sleep for 4 months could result in reductions in the visual functions, but without obvious morphologic changes of the retina. Ultrastructural analysis by transmission electron microscope revealed the deterioration of mitochondria, which was accompanied with the decrease of multiple mitochondrial proteins in the retina. Mechanistically, oxidative stress was provoked by chronic SD, which could be ameliorated after rest, and thus restore retinal homeostasis. Moreover, the supplementation of two antioxidants, α-lipoic acid and N-acetyl-l-cysteine, could reduce retinal reactive oxygen species, repair damaged mitochondria, and, as a result, improve the retinal functions. Overall, this work demonstrated the essential roles of sleep in maintaining the integrity and health of the retina. More importantly, it points towards supplementation of antioxidants as an effective intervention strategy for people experiencing sleep shortages.

Uveal melanoma distant metastasis prediction system: A retrospective observational study based on machine learning.

Uveal melanoma (UM) patients face a significant risk of distant metastasis, closely tied to a poor prognosis. Despite this, there is a dearth of research utilizing big data to predict UM distant metastasis. This study leveraged machine learning methods on the Surveillance, Epidemiology, and End Results (SEER) database to forecast the risk probability of distant metastasis. Therefore, the information on UM patients from the SEER database (2000-2020) was split into a 7:3 ratio training set and an internal test set based on distant metastasis presence. Univariate and multivariate logistic regression analyses assessed distant metastasis risk factors. Six machine learning methods constructed a predictive model post-feature variable selection. The model evaluation identified the multilayer perceptron (MLP) as optimal. Shapley additive explanations (SHAP) interpreted the chosen model. A web-based calculator personalized risk probabilities for UM patients. The results show that nine feature variables contributed to the machine learning model. The MLP model demonstrated superior predictive accuracy (Precision = 0.788; ROC AUC = 0.876; PR AUC = 0.788). Grade recode, age, primary site, time from diagnosis to treatment initiation, and total number of malignant tumors were identified as distant metastasis risk factors. Diagnostic method, laterality, rural-urban continuum code, and radiation recode emerged as protective factors. The developed web calculator utilizes the MLP model for personalized risk assessments. In conclusion, the MLP machine learning model emerges as the optimal tool for predicting distant metastasis in UM patients. This model facilitates personalized risk assessments, empowering early and tailored treatment strategies.

Drug-associated glaucoma: A real-world study based on the Food and Drug Administration adverse event reporting system database.

BACKGROUND: This study aims to assess the risk of drug-associated glaucoma and track its epidemiological characteristics using real-world data. METHODS: Adverse event reports from the Food and Drug Administration Adverse Event Reporting System (FAERS) from January 2004 to December 2023 were analysed. Disproportionality analysis and the Bayesian Confidence Propagation Neural Network algorithm were used. The study classified drugs associated with glaucoma, assessed risk levels, and compared drug-induced times across different categories. RESULTS: Eight hundred and five drugs were linked to glaucoma in the FAERS database. Disproportionality analysis identified 46 drugs with significant risk, mainly adrenergic medications (clobetasol propionate, fluocinolone acetonide), antihypertensives (hydrochlorothiazide), insulin (insulin human), anticholinergics (umeclidinium, darifenacin), VEGF inhibitors (brolucizumab, faricimab), and psychotropics (topiramate, ziprasidone). The top three high-risk drugs were clobetasol propionate, umeclidinium, and fluocinolone acetonide. The shortest drug-induced times were observed with indacaterol, salmeterol, and umeclidinium. Anticholinergic medications had the shortest drug-induced time among all categories. Females (62.5%) and the elderly (average age 63.5 ± 16.8 years) were predominantly affected. Reports of drug-associated glaucoma increased over the years. CONCLUSION: Preventing drug-associated glaucoma is more effective than treatment. Identifying the risk and drug-induced times of systemic and ophthalmic drugs can reduce occurrence risk. Clinical practitioners should be vigilant and inform patients of these risks.

IL-1/IL-1R signaling induced by all-trans-retinal contributes to complement alternative pathway activation in retinal pigment epithelium.

The underlying mechanisms of complement activation in Stargardt disease type 1 (STGD1) and age-related macular degeneration (AMD) are not fully understood. Overaccumulation of all-trans-retinal (atRAL) has been proposed as the pathogenic factor in both diseases. By incubating retinal pigment epithelium (RPE) cells with atRAL, we showed that C5b-9 membrane attack complexes (MACs) were generated mainly through complement alternative pathway. An increase in complement factor B (CFB) expression as well as downregulation of complement regulatory proteins CD46, CD55, CD59, and CFH were observed in RPE cells after atRAL treatment. Furthermore, interleukin-1ß production was provoked in both atRAL-treated RPE cells and microglia/macrophages. Coincubation of RPE cells with interleukin-1 receptor antagonist (IL1Ra) and atRAL ameliorated complement activation and downregulated CFB expression by attenuating both p38 and c-Jun N-terminal kinase (JNK) signaling pathways. Our findings demonstrate that atRAL induces an autocrine/paracrine IL-1/IL-1R signaling to promote complement alternative pathway activation in RPE cells and provide a novel perspective on the pathomechanism of macular degeneration.

Hypoxic postconditioning activates the Wnt/ß-catenin pathway and protects against transient global cerebral ischemia through Dkk1 Inhibition and GSK-3ß inactivation.

The Wingless/Int (Wnt)/ß-catenin pathway plays an essential role in cell survival. Although postconditioning with 8% oxygen can alleviate transient global cerebral ischemia (tGCI)-induced neuronal damage in hippocampal CA1 subregion in adult rats as demonstrated by our previous studies, little is understood about the role of Wnt/ß-catenin pathway in hypoxic postconditioning (HPC)-induced neuroprotection. This study tried to investigate the involvement of Wnt/ß-catenin pathway in HPC-induced neuroprotection against tGCI and explore the underlying molecular mechanism thereof. We observed that HPC elevated nuclear ß-catenin level as well as increased Wnt3a and decreased Dickkopf-1 (Dkk1) expression in CA1 after tGCI. Accordingly, HPC enhanced the expression of survivin and reduced the ratio of B-cell lymphoma/lewkmia-2 (Bcl-2)-associated X protein (Bax) to Bcl-2 following reperfusion. Moreover, our study has shown that these effects of HPC were abolished by lentivirus-mediated overexpression of Dkk1, and that the overexpression of Dkk1 completely reversed HPC-induced neuroprotection. Furthermore, HPC suppressed the activity of glycogen synthase kinase-3ß (GSK-3ß) in CA1 after tGCI, and the inhibition of GSK-3ß activity with SB216763 increased the nuclear accumulation of ß-catenin, up-regulated the expression of survivin, and reduced the ratio of Bax to Bcl-2, thus preventing the delayed neuronal death after tGCI. Finally, the administration of LY294002, an inhibitor of PI3K, increased GSK-3ß activity and blocked nuclear ß-catenin accumulation, thereby decreasing survivin expression and elevating the Bax-to-Bcl-2 ratio after HPC. These results suggest that activation of the Wnt/ß-catenin pathway through Dkk1 inhibition and PI3K/protein kinase B pathway-mediated GSK-3ß inactivation contributes to the neuroprotection of HPC against tGCI.-Zhan, L., Liu, D., Wen, H., Hu, J., Pang, T., Sun, W., Xu, E. Hypoxic postconditioning activates the Wnt/ß-catenin pathway and protects against transient global cerebral ischemia through Dkk1 inhibition and GSK-3ß inactivation.

Multifaceted mitochondrial as a novel therapeutic target in dry eye: insights and interventions.

Dry eye, recognized as the most prevalent ocular surface disorder, has risen to prominence as a significant public health issue, adversely impacting the quality of life for individuals across the globe. Despite decades of extensive research into the chronic inflammation that characterizes dry eye, the intricate mechanisms fueling this persistent inflammatory state remain incompletely understood. Among the various cellular components under investigation, mitochondria-essential for cellular energy production and homeostasis-have attracted increasing attention for their role in dry eye pathogenesis. This involvement points to mechanisms such as oxidative stress, apoptosis, and sustained inflammation, which are central to the progression of the disease. This review aims to provide a thorough exploration of mitochondrial dysfunction in dry eye, shedding light on the critical roles played by mitochondrial oxidative stress, apoptosis, and mitochondrial DNA damage. It delves into the mechanisms through which diverse pathogenic factors may trigger mitochondrial dysfunction, thereby contributing to the onset and exacerbation of dry eye. Furthermore, it lays the groundwork for an overview of current therapeutic strategies that specifically target mitochondrial dysfunction, underscoring their potential in managing this complex condition. By spotlighting this burgeoning area of research, our review seeks to catalyze the development of innovative drug discovery and therapeutic approaches. The ultimate goal is to unlock promising avenues for the future management of dry eye, potentially revolutionizing treatment paradigms and improving patient outcomes. Through this comprehensive examination, we endeavor to enrich the scientific community's understanding of dry eye and inspire novel interventions that address the underlying mitochondrial dysfunctions contributing to this widespread disorder.

Unleashing Novel Therapeutic Strategies for Dry Eye: Targeting ROS and the cGAS-STING Signaling Pathway with Tetrahedral Framework Nucleic Acids.

Dry eye affects majority of the global population, causing significant discomfort or even visual impairment, of which inflammation plays a crucial role in the deterioration process. This highlights the need for effective and safe anti-inflammatory treatments to achieve satisfactory therapeutic outcomes. This study focuses on the potential of tetrahedral framework nucleic acids (tFNA), a self-assembled nucleic acid material, as a simple and rapid treatment for oxidative stress and inflammation-induced disorders associated with dry eye. Mechanistically, tFNA is found to effectively alleviate dry eye damage by promoting corneal epithelial healing, restoring goblet cell function, and facilitating tear secretion recovery. Through RNA-seq analysis, it is observed that tFNA treatment normalizes the expression levels of most genes. Further exploration of the mechanism reveals that tFNA reduces excessive production of reactive oxygen species and modulates the inflammatory microenvironment, especially through cGAS-STING pathway thereby levels of inflammatory cytokines, including MMP9 and IL-6, are reduced. Additionally, tFNA demonstrates excellent safety performance without causing damage to the eye. Importantly, this study represents a successful application of nanophase materials with nucleic acid biological features for the effective treatment of dry eye, highlighting the potential clinical use of tFNA in the treatment of dry eye.

Targeting Nrf2 signaling in dry eye.

Dry eye, the most common ocular surface disease, can cause ocular surface tissue damage and discomfort symptoms and seriously affect people's quality of life. The etiology of dry eye is diverse, and its pathogenesis is complex. The oxidative stress reaction is considered to be among the important factors in the pathogenesis of dry eye. Therefore, activating the antioxidant system has a potential therapeutic effect on dry eye. Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway is considered the most important antioxidant pathway in the body. The activation of the Nrf2 signaling pathway and its interaction with other pathways are important mechanisms to prevent the occurrence and development of dry eye. This review describes the structure and function of Nrf2, summarizes the changes in the oxidative stress response in dry eye, focuses on the potential mechanism of the Nrf2 signaling pathway in the treatment of dry eye, and, finally, summarizes the drugs that activate the Nrf2 signaling pathway in the treatment of dry eye.

Revamping anti-cGAS-STING therapy via an injectable thermo-responsive supramolecular hydrogel for pathological retinal angiogenesis.

Retinal neovascularization is a leading cause of blindness. While current anti-VEGF drugs effectively inhibit pathological angiogenesis, some patients develop resistance or reduced responsiveness to treatments over time, leading to diminished effectiveness. In this study, we identified high activation of the cGAS-STING signaling pathway, which exacerbated pathological neovascularization and vessel leakage. We developed an injectable thermo-responsive supramolecular hydrogel loaded with an anti-STING drug. The hydrogel, made of Pluronic F127 (PF·127) consisting of poly(ethylene oxide) and poly(propylene oxide) units, demonstrated excellent transparency and biocompatibility. Importantly, the thermo-sensitive property allowed for precise spatial release of the drug, extending the effective treatment duration of C-176, which suppressed STING activation in the retina, reduced inflammation, and protected retinal tissue. HydroC-176 effectively inhibited microglial cell infiltration and the release of inflammatory angiogenic factors, highlighting its enhanced efficacy. While demonstrating slightly lower effectiveness compared to traditional anti-VEGF therapy, HydroC-176 exhibited more robust capabilities in regulating ocular microenvironmental inflammation. This approach may assist in enhancing the sensitivity and effectiveness of anti-VEGF therapy for reducing ocular inflammation, potentially improving patients' response to traditional treatment. These results have suggested innovative and comprehensive strategies for the management of retinal neovascularization.

Advances and prospects of multi-modal ophthalmic artificial intelligence based on deep learning: a review.

BACKGROUND: In recent years, ophthalmology has emerged as a new frontier in medical artificial intelligence (AI) with multi-modal AI in ophthalmology garnering significant attention across interdisciplinary research. This integration of various types and data models holds paramount importance as it enables the provision of detailed and precise information for diagnosing eye and vision diseases. By leveraging multi-modal ophthalmology AI techniques, clinicians can enhance the accuracy and efficiency of diagnoses, and thus reduce the risks associated with misdiagnosis and oversight while also enabling more precise management of eye and vision health. However, the widespread adoption of multi-modal ophthalmology poses significant challenges. MAIN TEXT: In this review, we first summarize comprehensively the concept of modalities in the field of ophthalmology, the forms of fusion between modalities, and the progress of multi-modal ophthalmic AI technology. Finally, we discuss the challenges of current multi-modal AI technology applications in ophthalmology and future feasible research directions. CONCLUSION: In the field of ophthalmic AI, evidence suggests that when utilizing multi-modal data, deep learning-based multi-modal AI technology exhibits excellent diagnostic efficacy in assisting the diagnosis of various ophthalmic diseases. Particularly, in the current era marked by the proliferation of large-scale models, multi-modal techniques represent the most promising and advantageous solution for addressing the diagnosis of various ophthalmic diseases from a comprehensive perspective. However, it must be acknowledged that there are still numerous challenges associated with the application of multi-modal techniques in ophthalmic AI before they can be effectively employed in the clinical setting.

Accurate detection and grading of pterygium through smartphone by a fusion training model.

BACKGROUND/AIMS: To improve the accuracy of pterygium screening and detection through smartphones, we established a fusion training model by blending a large number of slit-lamp image data with a small proportion of smartphone data. METHOD: Two datasets were used, a slit-lamp image dataset containing 20 987 images and a smartphone-based image dataset containing 1094 images. The RFRC (Faster RCNN based on ResNet101) model for the detection model. The SRU-Net (U-Net based on SE-ResNeXt50) for the segmentation models. The open-cv algorithm measured the width, length and area of pterygium in the cornea. RESULTS: The detection model (trained by slit-lamp images) obtained the mean accuracy of 95.24%. The fusion segmentation model (trained by smartphone and slit-lamp images) achieved a microaverage F1 score of 0.8981, sensitivity of 0.8709, specificity of 0.9668 and area under the curve (AUC) of 0.9295. Compared with the same group of patients' smartphone and slit-lamp images, the fusion model performance in smartphone-based images (F1 score of 0.9313, sensitivity of 0.9360, specificity of 0.9613, AUC of 0.9426, accuracy of 92.38%) is close to the model (trained by slit-lamp images) in slit-lamp images (F1 score of 0.9448, sensitivity of 0.9165, specificity of 0.9689, AUC of 0.9569 and accuracy of 94.29%). CONCLUSION: Our fusion model method got high pterygium detection and grading accuracy in insufficient smartphone data, and its performance is comparable to experienced ophthalmologists and works well in different smartphone brands.

Drug-Related Keratitis: A Real-World FDA Adverse Event Reporting System Database Study.

Purpose: This study aimed to assess the drug risk of drug-related keratitis and track the epidemiological characteristics of drug-related keratitis. Methods: This study analyzed data from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database from January 2004 to December 2023. A disproportionality analysis was conducted to assess drug-related keratitis with positive signals, and drugs were classified and assessed with regard to their drug-induced timing and risk of drug-related keratitis. Results: A total of 1606 drugs were reported to pose a risk of drug-related keratitis in the FAERS database, and, after disproportionality analysis and screening, 17 drugs were found to significantly increase the risk of drug-related keratitis. Among them, seven were ophthalmic medications, including dorzolamide (reporting odds ratio [ROR] = 3695.82), travoprost (ROR = 2287.27), and brimonidine (ROR = 2118.52), and 10 were non-ophthalmic medications, including tralokinumab (ROR = 2609.12), trazodone (ROR = 2377.07), and belantamab mafodotin (ROR = 680.28). The top three drugs having the highest risk of drug-related keratitis were dorzolamide (Bayesian confidence propagation neural network [BCPNN] = 11.71), trazodone (BCPNN = 11.11), and tralokinumab (BCPNN = 11.08). The drug-induced times for non-ophthalmic medications were significantly shorter than those for ophthalmic medications (mean days, 141.02 vs. 321.96, respectively; P < 0.001). The incidence of drug-related keratitis reached its peak in 2023. Conclusions: Prevention of drug-related keratitis is more important than treatment. Identifying the specific risks and timing of drug-induced keratitis can support the development of preventive measures. Translational Relevance: Identifying the specific drugs related to medication-related keratitis is of significant importance for drug vigilance in the occurrence of drug-related keratitis.

Psychometric validation of the Chinese version of the dry eye-related quality-of-life score questionnaire.

AIM: To psychometrically validate the Chinese version of the dry eye-related quality-of-life score questionnaire (DEQS-CHN) among Chinese patients with dry eye. METHODS: This study involved 231 participants, including 191 with dry eye disease (DED) comprising the dry eye disease group, and 40 healthy participants forming the control group. Participants were required to complete the DEQS-CHN, and Chinese dry eye questionnaire and undergo clinical tests including the fluorescein breakup time (FBUT), corneal fluorescein staining (CFS), and Schirmer I test. To assess the internal consistency and retest reliability, Cronbach's α and the intraclass correlation coefficient (ICC) were employed. Content validity was assessed by item-level content validity index (ICV) and an average scale-level content validity index (S-CVI/Ave). Construct validity was assessed by confirmatory factor analysis. The concurrent validity was assessed by calculating correlations between DEQS-CHN and Chinese dry eye questionnaire. Discriminative validity was evaluated through non-parametric tests, with receiver operating characteristic (ROC) curve serving as conclusive indicators of the questionnaire's distinguishing capability. RESULTS: The Cronbach's α coefficients for frequency and degree of ocular symptoms, impact on daily life, and summary score were 0.736, 0.704, 0.811, 0.818, 0.861, and 0.860, respectively, and the ICC were 0.611, 0.677, 0.715, 0.769, 0.711, and 0.779, respectively. All I-CVI scores ranged from 0.833 to 1.000, with an S-CVI/Ave of 0.956. Confirmatory factor analysis results exhibited a well-fitting model consistent with the original questionnaire [χ 2/df=2.653, incremental fit index (IFI)=0.924, comparative fit index (CFI)=0.924, Tucker-Lewis index (TLI)=0.909, and root mean square error of approximation (RMSEA)=0.065]. There was a moderate positive correlation between the DEQS-CHN and the Chinese dry eye questionnaire (r 2=0.588). The dry eye group demonstrated significantly higher scores compared to the control group, and the area under the curve (AUC) value was 0.8092. CONCLUSION: The DEQS-CHN has been demonstrated as a valid and reliable instrument for assessing the impact of dry eye disease on the quality of life among Chinese individuals with DED.

Adverse events of topical ocular prostaglandin medications for glaucoma treatment: a pharmacovigilance study based on the FAERS database.

Background: As prostaglandin medications, crucial in glaucoma treatment, become more widely used, their local adverse events are increasingly observed. Objectives: To evaluate the common adverse events of four clinically commonly used prostaglandin F (FP) receptor agonists in the treatment of glaucoma in the Food and Drug Administration Adverse Event Reporting System (FAERS) database. Design: We screened and analyzed the generic and brand names of latanoprost, bimatoprost, travoprost, and tafluprost in the FAERS database and summarized and cleaned the baseline information of subjects receiving the above-mentioned drugs. Methods: Perform descriptive statistical analysis on the baseline information of subjects using the drugs. Conduct disproportionality analysis of drug-related adverse events. The criteria for positive signals of adverse events are established by simultaneously meeting the thresholds set by four methods: the ratio of reported odds, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker. Additionally, assess the cumulative risk curves for drug-induced time of the aforementioned drugs and use one-way ANOVA to compare differences in drug-induced time across different groups. Results: The study included 1567 latanoprost, 1517 bimatoprost, 696 travoprost, and 82 tafluprost subjects. Adverse events mainly affected eye disorders, with significant issues in iris hyperpigmentation, ocular pemphigoid, corneal endothelial cell loss, periorbital fat atrophy, corneal irritation, eyelash growth, and ocular hyperemia. The time to onset varied among drugs, with latanoprost showing the longest (mean days = 344.37) and bimatoprost the shortest duration (mean days = 155.65; p < 0.001). Conclusion: Although signal detection analysis based on the FAERS database cannot establish a definitive causal relationship, our study found that FP receptor agonists used in glaucoma can cause various adverse events. Assessing their clinical suitability and potential side effects is crucial for providing personalized treatment and ensuring medication safety.

Understanding side effects of eye drops for glaucoma: a study using the FAERS database Why was the study done? Prostaglandin medications are crucial in treating glaucoma but can cause local adverse events. As the use of these medications increases, it's important to understand their common side effects. The Food and Drug Administration Adverse Event Reporting System (FAERS) is a database that contains adverse event reports, medication error reports and product quality complaints resulting in adverse events that were submitted to the Food and Drug Administration. What did the researchers do? We analyzed the FAERS database to evaluate the common adverse events of four prostaglandin medications commonly used to treat glaucoma: latanoprost, bimatoprost, travoprost, and tafluprost. What did the researchers find? The study included 1567 latanoprost users, 1517 bimatoprost users, 696 travoprost users, and 82 tafluprost users. The main adverse events affected eye disorders, with significant issues including iris hyperpigmentation, ocular pemphigoid, corneal endothelial cell loss, periorbital fat atrophy, corneal irritation, eyelash growth, and ocular hyperemia. The time to onset varied among drugs, with latanoprost showing the longest and bimatoprost the shortest duration. What do the findings mean? Although signal detection analysis from the FAERS database cannot establish a definitive causal relationship, prostaglandin medications used in glaucoma treatment can cause various ocular adverse events during long-term use. Understanding these side effects is crucial for providing personalized treatment and ensuring medication safety.

Real-World Large Sample Assessment of Drug-related Dry Eye Risk: Based on the FDA Adverse Event Reporting System Database.

PURPOSE AND DESIGN: This study aimed to evaluate the risk of drug-related dry eye using real-world data, underscoring the significance of tracing pharmacological etiology for distinct clinical types of dry eye. METHODS: Analyzing adverse event reports in the Food and Drug Administration Adverse Event Reporting System (FAERS) from January 2004 to September 2023, we employed disproportionality analysis and the Bayesian confidence propagation neural network algorithm. The analysis involved categorizing drugs causing dry eye, assessing risk levels, and conducting segmental assessments based on the time of onset of drug-related dry eye adverse reactions. RESULTS: In the FAERS database, adverse reactions related to dry eye were linked to 1160 drugs. Disproportionality analysis identified 33 drugs with significant risk, notably in ophthalmic (brimonidine, bimatoprost), oncology (tisotumab vedotin, erdafitinib), and other medications (isotretinoin, oxymetazoline). The top three drugs with the highest risk of drug-related dry eye are isotretinoin (Bayesian confidence propagation neural network (BCPNN) = 6.88), tisotumab vedotin (BCPNN = 6.88), and brimonidine (BCPNN = 6.77). Among different categories of drugs, respiratory medications have the shortest mean onset time for drug-related dry eye, averaging 50.99 days. The prevalence skewed towards females (69.9 %), particularly in menopausal and elderly individuals (45-70 years old, mean age 54.7 ± 18.2). Reports of drug-related dry eye adverse reactions showed an annual increase. CONCLUSION: Informed clinical decision-making is crucial for preventing drug-related dry eye. Assessing the risk of dry eyes associated with both local and systemic medications helps optimize treatment and provide necessary cautionary information.

The cGAS-STING pathway-dependent sensing of mitochondrial DNA mediates ocular surface inflammation.

The innate immune response is the main pathophysiological process of ocular surface diseases exposed to multiple environmental stresses. The epithelium is central to the innate immune response, but whether and how innate immunity is initiated by ocular epithelial cells in response to various environmental stresses in ocular surface diseases, such as dry eye, is still unclear. By utilizing two classic experimental dry eye models-a mouse ocular surface treated with benzalkonium chloride (BAC) and a mouse model with surgically removed extraorbital lachrymal glands, as well as dry eye patient samples-along with human corneal epithelial cells (HCE) exposed to hyperosmolarity, we have discovered a novel innate immune pathway in ocular surface epithelial cells. Under stress, mitochondrial DNA (mtDNA) was released into the cytoplasm through the mitochondrial permeability transition pore (mPTP) and further activated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, aggravating downstream inflammatory responses and ocular surface damage. Genetic deletion or pharmacological suppression of STING and inhibition of mtDNA release reduced inflammatory responses, whereas mtDNA transfection supported cytoplasmic mtDNA-induced inflammatory responses by activating the cGAS-STING pathway. Our study clarified the cGAS-STING pathway-dependent sensing of mitochondrial DNA-mediated ocular surface inflammation, which elucidated a new mechanism of ocular surface diseases in response to multiple environmental stresses.

Berberine ameliorate inflammation and apoptosis via modulating PI3K/AKT/NFκB and MAPK pathway on dry eye.

BACKGROUND: Dry eye disease (DED) is a multifactorial disease in ocular surface, and inflammation plays an etiological role. Berberine (BBR) has shown efficacy in treating inflammatory diseases. Yet, there was no adequate information related to the therapeutic effects of BBR for DED. PURPOSE: To detect the effects and explore the potential mechanisms of BBR on DED. STUDY DESIGN: In vitro, in vivo study and network pharmacology analysis were involved. METHOD: The human corneal epithelium cells viability was evaluated with different concentrations of BBR. Dry eye murine model was established by exposing to the desiccating stress, and Ciclosporin (CSA), BBR eye drops or vehicle were topical administration for 7 days. The phenol red cotton tests, Oregon-green-dextran staining and Periodic acid-Schiff staining were performed and evaluated the dry eye after treatment. Inflammation and apoptosis levels of ocular surface were quantified. The potential targets related to berberine and dry eye were collected from databases. The Protein-Protein interaction network analysis and GO & KEGG enrichment analysis were realized by STRING database, Metascape platform and Cytoscape software to find core targets and signaling pathways. The SchrÖdinger software was used to molecular docking and PyMOL software to visualization. Finally, the levels of PI3K/AKT/NFκB and MAPK pathways were detected. RESULT: The data revealed BBR could rescue impaired HCE under hyperosmotic conditions. In addition, BBR eye drops could ameliorate dry eye. And BBR eye drops suppressed the inflammatory factors and CD4+T cells infiltration in conjunctiva. Besides, BBR eye drops protected ocular surface by avoiding the severe apoptosis and decreasing the level of MMP-3 and MMP-9. 148 common targets intersection between BBR and dry eye were found via network pharmacology analysis. Core proteins and core pathways were identified through PPI and GO&KEGG enrichment analysis. Molecular docking displayed excellent binding between BBR and those core targets. Finally, in vivo study verified that BBR eye drops had a therapeutic effect in dry eye by inhibiting PI3K/AKT/NFκB and MAPK pathways. CONCLUSION: The research provided convincing evidence that BBR could be a candidate drug for dry eye.

MAP4Ks inhibition promotes retinal neuron regeneration from Müller glia in adult mice.

Mammalian Müller glia (MG) possess limited regenerative capacities. However, the intrinsic capacity of mammalian MG to transdifferentiate to generate mature neurons without transgenic manipulations remains speculative. Here we show that MAP4K4, MAP4K6 and MAP4K7, which are conserved Misshapen subfamily of ste20 kinases homologs, repress YAP activity in mammalian MG and therefore restrict their ability to be reprogrammed. However, by treating with a small molecule inhibitor of MAP4K4/6/7, mouse MG regain their ability to proliferate and enter into a retinal progenitor cell (RPC)-like state after NMDA-induced retinal damage; such plasticity was lost in YAP knockout MG. Moreover, spontaneous trans-differentiation of MG into retinal neurons expressing both amacrine and retinal ganglion cell (RGC) markers occurs after inhibitor withdrawal. Taken together, these findings suggest that MAP4Ks block the reprogramming capacity of MG in a YAP-dependent manner in adult mammals, which provides a novel avenue for the pharmaceutical induction of retinal regeneration in vivo.

Can the cGAS-STING Pathway Play a Role in the Dry Eye?

Dry eye is one of the most common ocular surface diseases in the world and seriously affects the quality of life of patients. As an immune-related disease, the mechanism of dry eye has still not been fully elucidated. The cGAS-STING pathway is a recently discovered pathway that plays an important role in autoimmune and inflammatory diseases by recognizing dsDNA. As an important signal to initiate inflammation, the release of dsDNA is associated with dry eye. Herein, we focused on the pathophysiology of the immune-inflammatory response in the pathogenesis of dry eye, attempted to gain insight into the involvement of dsDNA in the dry eye immune response, and investigated the mechanism of the cGAS-STING pathway involved in the immune-inflammatory response. We further proposed that the cGAS-STING pathway may participate in dry eye as a new mechanism linking dry eye and the immune-inflammatory response, thus providing a new direction for the mechanistic exploration of dry eye.

Obstructive Sleep Apnea Affects Lacrimal Gland Function.

PURPOSE: To determine the effect of obstructive sleep apnea syndrome (OSA) on lacrimal gland function and its mechanism. METHODS: Male mice aged seven to eight weeks were housed in cages with cyclic intermittent hypoxia to mimic OSA, and the control group was kept in a normal environment. Slit-lamp observation, fluorescein staining, and corneal sensitivity detection are used to assess cornea changes. Tear secretion was detected by phenol red cotton thread, and the pathological changes of lacrimal gland were observed by hematoxylin and eosin staining, oil red O staining, cholesterol and triglyceride kits, immunofluorescence staining, immunohistochemical staining, real-time polymerase chain reaction, transmission electron microscopy, and Western blot. RESULTS: Studies revealed a decreased tear secretion, corneal epithelial defects and corneal hypersensitivity. Myoepithelial cell damage, abnormal lipid accumulation, reduced cell proliferation, increased apoptosis and inflammatory cell infiltration in the lacrimal gland were also seen. Hifα and NF-κB signaling pathways, moreover, were activated, while Pparα was downregulated, in the lacrimal glands of OSA mice. Fenofibrate treatment significantly alleviated pathological changes of the lacrimal gland induced by OSA. CONCLUSION: OSA disturbs the Hifα/Pparα/NF-κB signaling axis, which affects lacrimal gland structure and function and induces dry eye.