Ziyu Yu

All Publications

• An NF-1 heterozygote Ossabaw pig line lacks optic pathway gliomas but leads to RGC deficiency in the adult Yu, Z., Li, B., Heng, K., Saenz, Y., Cheney, D., Watson, A., Goldberg, J. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2024

  View details for Web of Science ID 001313316208064

• Single-cell transcriptomic Atlas of aging macaque ocular outflow tissues. Protein & cell Wu, J., Wang, C., Sun, S., Ren, T., Pan, L., Liu, H., Hou, S., Wu, S., Yan, X., Zhang, J., Zhao, X., Liu, W., Zhu, S., Wei, S., Zhang, C., Jia, X., Zhang, Q., Yu, Z., Zhuo, Y., Zhao, Q., Yang, C., Wang, N. 2024

  Abstract

  The progressive degradation in the trabecular meshwork (TM) is related to age-related ocular diseases like primary open-angle glaucoma. However, the molecular basis and biological significance of the aging process in TM have not been fully elucidated. Here, we established a dynamic single-cell transcriptomic landscape of aged macaque TM, wherein we classified the outflow tissue into 12 cell subtypes and identified mitochondrial dysfunction as a prominent feature of TM aging. Furthermore, we divided TM cells into 13 clusters and performed an in- depth analysis on cluster 0, which had the highest aging score and the most significant changes in cell proportions between the two groups. Ultimately, we found that the APOE gene was an important differentially expressed gene in cluster 0 during the aging process, highlighting the close relationship between cell migration and extracellular matrix regulation, and TM function. Our work further demonstrated that silencing the APOE gene could increase migration and reduce apoptosis by releasing the inhibition on the PI3K-AKT pathway and downregulating the expression of extracellular matrix components, thereby increasing the aqueous outflow rate and maintaining intraocular pressure within the normal range. Our work provides valuable insights for future clinical diagnosis and treatment of glaucoma.

  View details for DOI 10.1093/procel/pwad067

  View details for PubMedID 38366188

• Discovery of Clinical Manifestations in Spontaneous Glaucoma Suspect Nonhuman Primates. Ophthalmic research Jia, X., Yu, Z., Wu, J., Hou, S., Du, Y., Zhu, Y., Li, Z., Tu, S., Zhao, L., Su, W., Wang, N., Zhuo, Y. 2023; 66 (1): 1406-1416

  Abstract

  The primary aim of this study was to assess the longitudinal changes in retinal nerve fiber layer (RNFL) thickness and relative ONH parameters using spectral-domain optical coherence tomography (SD-OCT) in the living eyes of nonhuman primates with spontaneous glaucoma.Totally 9 macaque subjects underwent a standard fundus photo and OCT examination, including 3 adult monkeys with stable elevated intraocular pressure (IOP) as the glaucoma suspect group and 6 normal IOP monkeys as the control group. Each eye of primates with IOP measurement was repeated three times. OCT measurements recorded RNFL, Bruch's membrane opening (BMO) minimum rim width (MRW). The follow-up scan of glaucomatous subjects was undergone in 10 months.The mean ages of glaucoma and healthy subjects are 19.33 ± 0.33 and 20.5 ± 1.46 years. Elevated IOP was achieved in three nonhuman primate eyes with an average increase of 10 mm Hg over the study period. Elevated IOP was associated with decreased RNFL thickness in all the regions and decreased RNFL phase retardation in the superior and inferior regions. When averaged over the entire retinal area, only the whole RNFL and temporal regions showed a significant decrease. The mean IPL thicknesses are 87.17 ± 2.15 μm in glaucomatous and 93.33 ± 1.51 μm in healthy eyes (p = 0.03). Lamina cribrosa parameters are measured from the OCT images and showed significant differences between glaucoma primates and normal primates.Of the measured parameters, decreased RNFL and MRW were correlated with glaucomatous damage. Natural glaucoma primate can be a natural glaucoma model which is closer to glaucoma in humans.

  View details for DOI 10.1159/000533865

  View details for PubMedID 37926084

• Identification and validation of key biomarkers and potential therapeutic targets for primary open-angle glaucoma. Science China. Life sciences Wu, J., Lin, C., Yang, C., Pan, L., Liu, H., Zhu, S., Wei, S., Jia, X., Zhang, Q., Yu, Z., Zhao, X., Liu, W., Zhuo, Y., Wang, N. 2023

  Abstract

  Primary open-angle glaucoma (POAG) is a prevalent cause of blindness worldwide, resulting in degeneration of retinal ganglion cells and permanent damage to the optic nerve. However, the underlying pathogenetic mechanisms of POAG are currently indistinct, and there has been no effective nonsurgical treatment regimen. The objective of this study is to identify novel biomarkers and potential therapeutic targets for POAG. The mRNA expression microarray datasets GSE27276 and GSE138125, as well as the single-cell high-throughput RNA sequencing (scRNA-seq) dataset GSE148371 were utilized to screen POAG-related differentially expressed genes (DEGs). Functional enrichment analyses, protein-protein interaction (PPI) analysis, and weighted gene co-expression network analysis (WGCNA) of the DEGs were performed. Subsequently, the hub genes were validated at a single-cell level, where trabecular cells were annotated, and the mRNA expression levels of target genes in different cell clusters were analyzed. Immunofluorescence and quantitative real-time PCR (qPCR) were performed for further validation. DEGs analysis identified 43 downregulated and 32 upregulated genes in POAG, which were mainly enriched in immune-related pathways, oxidative stress, and endoplasmic reticulum (ER) stress. PPI networks showed that FN1 and DUSP1 were the central hub nodes, while GPX3 and VAV3 were screened out as hub genes through WGCNA and subsequently validated by qPCR. Finally, FN1, GPX3, and VAV3 were determined to be pivotal core genes via single-cell validation. The relevant biomarkers involved in the pathogenesis of POAG, may serve as potential therapeutic targets. Further studies are necessary to unveil the mechanisms underlying the expression variations of these genes in POAG.

  View details for DOI 10.1007/s11427-022-2344-5

  View details for PubMedID 37610681

  View details for PubMedCentralID 64704

• Single-cell RNA sequencing reveals a landscape and targeted treatment of ferroptosis in retinal ischemia/reperfusion injury. Journal of neuroinflammation Li, Y., Wen, Y., Liu, X., Li, Z., Lin, B., Deng, C., Yu, Z., Zhu, Y., Zhao, L., Su, W., Zhuo, Y. 2022; 19 (1): 261

  Abstract

  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.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.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.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.

  View details for DOI 10.1186/s12974-022-02621-9

  View details for PubMedID 36289494

  View details for PubMedCentralID PMC9597965

• TNF-alpha stimulation enhances the neuroprotective effects of gingival MSCs derived exosomes in retinal ischemia-reperfusion injury via the MEG3/miR-21a-5p axis BIOMATERIALS Yu, Z., Wen, Y., Jiang, N., Li, Z., Guan, J., Zhang, Y., Deng, C., Zhao, L., Zheng, S., Zhu, Y., Su, W., Zhuo, Y. 2022; 284: 121484

  Abstract

  Retinal ischemia-reperfusion injury (IRI) is one of the main pathogenic mechanisms of glaucoma, which are largely unknown, including neuroinflammation and neuronal death in the pathological process. In our previous studies, mesenchymal stem cells (MSCs) have been reported to play anti-inflammatory and neuroprotective roles. Additionally, conditioned culture medium (CM) of MSCs stimulated by TNF-α have achieved better antiallergic effects in an experimental allergic conjunctivitis mouse model. However, there is an urgent need for cell-free therapy approaches, like exosomes, to reduce the side effects of autoimmunity. The present study aimed to elucidate the pathways involving TNF-α-stimulated gingival MSC (GMSC)-exosomes (TG-exos), in modulating inflammatory microglia and alleviating apoptosis. In this study, exosomes from the CM of GMSCs were isolated by ultracentrifugation and were injected into the vitreous of mice. The results showed that intraocular injection of TG-exos into mice with IRI notably reduced inflammation and cell loss than that with G-exos (GMSC-exosomes). Similar results were observed in vitro. Additionally, with the microRNA (miR) arrays, it was found that miR-21-5p acted as a crucial factor in TG-exos for neuroprotection and anti-inflammation. Following target prediction and dual-luciferase assay suggested that miR-21-5p played a role by combining with programmed cell death 4 (PDCD4), which was regulated by the long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3) as a competing endogenous RNA (ceRNA). This study demonstrates a new therapeutic pathway for neuroprotection against IRI by delivering miR-21-5p-enriched exosomes through MEG3/miR-21-5p/PDCD4 axis and paves the way for the establishment of a cell-free therapeutic approach for glaucoma.

  View details for DOI 10.1016/j.biomaterials.2022.121484

  View details for Web of Science ID 000792093700002

  View details for PubMedID 35378413

• Necroptosis: A Novel Pathway in Neuroinflammation. Frontiers in pharmacology Yu, Z., Jiang, N., Su, W., Zhuo, Y. 2021; 12: 701564

  Abstract

  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.

  View details for DOI 10.3389/fphar.2021.701564

  View details for PubMedID 34322024

  View details for PubMedCentralID PMC8311004

• Laquinimod exerts anti-inflammatory and antiapoptotic effects in retinal ischemia/reperfusion injury. International immunopharmacology Jiang, N., Li, Z., Li, Z., Zhang, Y., Yu, Z., Wan, P., Zhu, Y., Li, Y., Su, W., Zhuo, Y. 2020; 88: 106989

  Abstract

  Retinal ischemia/reperfusion (I/R) occurs in various vision disabled ocular diseases, involved in acute glaucoma, diabetic retinopathy, ischemic optic neuropathy, hypertensive retinopathy and retinal vascular occlusion. Laquinimod (LQ), a new type of immunosuppressant, has been reported to exert anti-inflammatory effects on autoimmune diseases. This research aims to investigate the protective effect of LQ on I/R damage by focusing on inhibiting dysregulated neuroinflammation and neuronal apoptosis. In our study, mice were treated with LQ after high intraocular pressure (IOP)-induced retinal I/R injury. The data showed that LQ significantly attenuated high IOP-induced retinal ganglion cell (RGC) death and inner plexiform layer (IPL) thinning and inhibited microglial activation. The results of qRT-PCR, flow cytometry and Luminex multiplex assays demonstrated the anti-inflammatory action of LQ in BV2 cells stimulated with lipopolysaccharide (LPS). In addition, primary RGC apoptosis induced by oxygen-glucose deprivation/reperfusion (OGD/R) was also directly suppressed by LQ. Importantly, LQ inhibited the expression of cleaved caspase-8 and the downstream NLRP3 inflammasome and IL-1β. In conclusion, our findings offer the first evidence that LQ treatment prevents retinal I/R damage. Furthermore, LQ could directly inhibit RGC apoptosis. Caspase-8 activation and subsequent inflammation can also be suppressed by LQ, which suggests that LQ may act through inhibiting the caspase-8 pathway. This study demonstrates a new mechanism of LQ and provides beneficial preclinical data for the clinical application of LQ.

  View details for DOI 10.1016/j.intimp.2020.106989

  View details for PubMedID 33182069