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Ischemia-reperfusion (I/R) is a common pathology when the blood supply to an organ was disrupted and then restored. During the reperfusion process, inflammation and tissue injury were triggered, which were mediated by immunocytes and cytokines. However, the mechanisms initiating I/R-induced inflammation and driving immunocytes activation remained largely unknown. In this study, we identified long non-coding RNA (lncRNA)-H19 as the key onset of I/R-induced inflammation. We found that I/R increased lncRNA-H19 expression to significantly promote NLRP3/6 inflammasome imbalance and resulted in microglial pyroptosis, cytokines overproduction, and neuronal death. These damages were effectively inhibited by lncRNA-H19 knockout. Specifically, lncRNA-H19 functioned via sponging miR-21 to facilitate PDCD4 expression and formed a competing endogenous RNA network (ceRNET) in ischemic cascade. LncRNA H19/miR-21/PDCD4 ceRNET can directly regulate I/R-induced sterile inflammation and neuronal lesion in vivo. We thus propose that lncRNA-H19 is a previously unknown danger signals in the molecular and immunological pathways of I/R injury, and pharmacological approaches to inhibit H19 seem likely to become treatment modalities for patients in the near future based on these mechanistic findings.

Neuroinflammation is a complex inflammatory process in the nervous system that is expected to play a significant role in neurological diseases. Necroptosis is a kind of necrosis that triggers innate immune responses by rupturing dead cells and releasing intracellular components; it can be caused by Toll-like receptor (TLR)-3 and TLR-4 agonists, tumor necrosis factor (TNF), certain microbial infections, and T cell receptors. Necroptosis signaling is modulated by receptor-interacting protein kinase (RIPK) 1 when the activity of caspase-8 becomes compromised. Activated death receptors (DRs) cause the activation of RIPK1 and the RIPK1 kinase activity-dependent formation of an RIPK1-RIPK3-mixed lineage kinase domain-like protein (MLKL), which is complex II. RIPK3 phosphorylates MLKL, ultimately leading to necrosis through plasma membrane disruption and cell lysis. Current studies suggest that necroptosis is associated with the pathogenesis of neuroinflammatory diseases, such as Alzheimer’s disease, Parkinson’s disease, and traumatic brain injury. Inhibitors of necroptosis, such as necrostatin-1 (Nec-1) and stable variant of Nec (Nec-1s), have been proven to be effective in many neurological diseases. The purpose of this article is to illuminate the mechanism underlying necroptosis and the important role that necroptosis plays in neuroinflammatory diseases. Overall, this article shows a potential therapeutic strategy in which targeting necroptotic factors may improve the pathological changes and clinical symptoms of neuroinflammatory disorders.

Long noncoding RNAs (lncRNAs) are transcripts with low protein-coding potential but occupy a large part of transcriptional output. Their roles include regulating gene expression at the epigenetic, transcriptional, and post-transcriptional level in cellular homeostasis. However, lncRNA studies are still in their infancy and the functions of the vast majority of lncRNA transcripts remain unknown. It is generally known that the function of the human nervous system largely relies on the precise regulation of gene expression. Various studies have shown that lncRNAs have a significant impact on normal neural development and on the development and progression of neurodegenerative diseases. In this review, we focused on recent studies associated with lncRNAs in neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), frontotemporal lobar degeneration (FTLD), and glaucoma. Glaucoma, caused by unexplained ganglion cell lesion and apoptosis, is now labeled as a chronic neurodegenerative disorder [ 1 ], and therefore, we discussed the association of lncRNAs with glaucoma as well. We illustrate the role of some specific lncRNAs, which may provide new insights into our understanding of the etiology and pathophysiology of the neurodegenerative diseases mentioned above.

Axons of adult neurons in the mammalian central nervous system generally fail to regenerate by themselves, and few if any therapeutic options exist to reverse this situation. Due to a weak intrinsic potential for axon growth and the presence of strong extrinsic inhibitors, retinal ganglion cells (RGCs) cannot regenerate their axons spontaneously after optic nerve injury and eventually undergo apoptosis, resulting in permanent visual dysfunction. Regarding the extracellular environment, research to date has generally focused on glial cells and inflammatory cells, while few studies have discussed the potentially significant role of interneurons that make direct connections with RGCs as part of the complex retinal circuitry. In this study, we provide a novel angle to summarize these extracellular influences following optic nerve injury as “intercellular interactions” with RGCs and classify these interactions as synaptic and non-synaptic. By discussing current knowledge of non-synaptic (glial cells and inflammatory cells) and synaptic (mostly amacrine cells and bipolar cells) interactions, we hope to accentuate the previously neglected but significant effects of pre-synaptic interneurons and bring unique insights into future pursuit of optic nerve regeneration and visual function recovery.

Acute glaucoma is a sight-threatening condition characterized by a sudden and substantial rise in intraocular pressure (IOP) and consequent retinal ganglion cell (RGC) death. Angle closure glaucoma, a common cause of glaucoma in Asia that affects tens of millions of people worldwide, often presents acutely with loss of vision, pain, and high IOP. Even when medical and surgical treatment is available, acute angle closure glaucoma can cause permanent and irreversible loss of vision. Toll-like receptor 4 (TLR4) signaling has been previously implicated in the pathogenesis of IOP-induced RGC death, although the underlying mechanisms are largely unknown. In the present study, we used an acute IOP elevation/glaucoma model to investigate the underlying mechanism of RGC death. We found that TLR4 leads to increased caspase-8 expression; this elevation increases IL-1β expression and RGC death via a caspase-1–dependent pathway involving Nod-like receptor family, pyrin domain containing 1 (NLRP1)/NLRP3 inflammasomes and a caspase-1–independent pathway. We show that inhibition of caspase-8 activation significantly attenuates RGC death by down-regulating the activation of NLRP1 and NLRP3, thus demonstrating the pivotal role of caspase-8 in the TLR4-mediated activation of inflammasomes. These findings demonstrate collectively a critical role of caspase-8 in transducing TLR4-mediated IL-1β production and RGC death and highlight signal transduction in a caspase-1–dependent NLRP1/NLRP3 inflammasome pathway and a caspase-1–independent pathway in acute glaucoma. These results provide new insight into the pathogenesis of glaucoma and point to a treatment strategy.

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.

Background The aim of this study was to establish a complete retinal cell atlas of ischemia–reperfusion injury by single-cell RNA sequencing, and to explore the underlying mechanism of retinal ischemia–reperfusion injury in mice. Methods Single-cell RNA sequencing was used to evaluate changes in the mouse retinal ischemia reperfusion model. In vivo and in vitro experiments were performed to verify the protective effect of inhibiting ferroptosis in retinal ischemia–reperfusion injury. Results After ischemia–reperfusion injury, retinal cells were significantly reduced, accompanied by the activation of myeloid and a large amount of blood-derived immune cell infiltration. The IFNG, MAPK and NFKB signaling pathways in retinal neuronal cells, together with the TNF signaling pathway in myeloid give rise to a strong inflammatory response in the I/R state. Besides, the expression of genes implicating iron metabolism, oxidative stress and multiple programed cell death pathways have changed in cell subtypes described above. Especially the ferroptosis-related genes and blocking this process could apparently alleviate the inflammatory immune responses and enhance retinal ganglion cells survival. Conclusions We established a comprehensive landscape of mouse retinal ischemia–reperfusion injury at the single-cell level, revealing the important role of ferroptosis during this injury, and targeted inhibition of ferroptosis can effectively protect retinal structure and function.

Glaucoma is a leading cause of irreversible blindness. Injury of retinal ganglion cells (RGCs) accounts for visual impairment of glaucoma. Here, we report rapamycin protects RGCs from death in experimental glaucoma model and the underlying mechanisms. Our results showed that treatment with rapamycin dramatically promote RGCs survival in a rat chronic ocular hypertension model. This protective action appears to be attributable to inhibition of neurotoxic mediators release and/or direct suppression of RGC apoptosis. In support of this mechanism, in vitro, rapamycin significantly inhibits the production of NO, TNF-α in BV2 microglials by modulating NF-κB signaling. In experimental animals, treatment with rapamycin also dramatically inhibited the activation of microglials. In primary RGCs, rapamycin was capable of direct suppression the apoptosis of primary RGCs induced by glutamate. Mechanistically, rapamycin-mediated suppression of RGCs apoptosis is by sparing phosphorylation of Akt at a site critical for maintenance of its survival-promoting activity in cell and animal model. These results demonstrate that rapamycin is neuroprotective in experimental glaucoma, possibly via decreasing neurotoxic releasing and suppressing directly apoptosis of RGCs.

Patients with high myopia have an increased lifetime risk of complications. The prevalence patterns of high myopia in children and adolescents in southern China are unclear. Early identification of high-risk individuals is critical for reducing the occurrence and development of high myopia and avoiding the resulting complications. This study aimed to determine the prevalence of high myopia in children and adolescents in southern China via real-world screening data and to predict its onset by studying the risk factors for high myopia based on machine learning. This retrospective school-based study was conducted in 13 cities with different gross domestic products in southern China. Through data acquisition and filtering, we analyzed the prevalence of high myopia and its association with age, school stage, gross domestic product, and risk factors. A random forest algorithm was used to predict high myopia among schoolchildren and then assessed in an independent hold-out group. There were 1,285,609 participants (mean age 11.80, SD 3.07, range 6-20 years), of whom 658,516 (51.2%) were male. The overall prevalence of high myopia was 4.48% (2019), 4.88% (2020), and 3.17% (2021), with an increasing trend from the age of 11 to 17 years. The rates of high myopia increased from elementary schools to high schools but decreased at all school stages from 2019 to 2021. The coastal and southern cities had a higher proportion of high myopia, with an overall prevalence between 2.60% and 5.83%. Age, uncorrected distance visual acuity, and spherical equivalents were predictive factors for high myopia onset in schoolchildren. The random forest algorithm achieved a high accuracy of 0.948. The area under the receiver operator characteristic curve (AUC) was 0.975. Both indicated sufficient model efficacy. The performance of the model was validated in an external test with high accuracy (0.971) and a high AUC (0.957). High myopia had a high incidence in Guangdong Province. Its onset in children and adolescents was well predicted with the random forest algorithm. Efficient use of real-world data can contribute to the prevention and early diagnosis of high myopia.

The process of aging exerts profound effects on various physiological systems, leading to the progression of chronic degenerative disorders and pathologies associated with advancing age. Cellular senescence plays a central role in the aging process and the onset of various eye conditions associated with advancing age, including age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma, cataracts, and ocular surface disorders. The accumulation of senescent cells (SnCs) and their secretion of pro-inflammatory and tissue-remodeling factors, collectively known as the senescence-associated secretory phenotype (SASP), exacerbate chronic inflammation, oxidative stress, and tissue dysfunction, contributing to disease progression. This study is the first to systematically integrate the multifaceted mechanisms of cellular senescence in ocular diseases, revealing differential regulatory mechanisms of specific signaling pathways across different ocular pathologies, thereby providing novel insights into the pathogenesis of these disorders. SnC-targeted therapies such as senolytics, senomorphics, SASP modulators, mitochondrial-targeted antioxidants, and epigenetic reprogramming are emerging as regenerative therapies, demonstrating potent anti-inflammatory effects, restoration of normal tissue physiology, and successful regeneration of ocular defects in preclinical models and clinical trials, while slowing senescence-associated disease progression. This review not only summarizes the role of cellular senescence in ocular diseases but also delves into potential therapeutic strategies, particularly highlighting novel perspectives for root-cause-targeted therapies from the unique angle of senescence biology, which may pioneer new directions for the treatment of ocular pathologies.