Epigenetic Landscape Analysis of the Long Non-Coding RNA and Messenger RNA in a Mouse Model of Corneal Alkali Burns

Jiang, Li; He, Weiqun; Tang, Fen; Tang, Ningning; Huang, Guangyi; Huang, Wei; Wu, Xiaonian; Guan, Jianpei; Zeng, Siming; Li, Min; Chen, Qi; Zhang, Mingyuan; Zhong, Haibin; Lan, Qianqian; Cui, Ling; Li, Lili; Xu, Fan

doi:10.1167/iovs.62.4.28

Cited by 7 publications

(3 citation statements)

References 40 publications

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“…Several pathways actively partake in sustaining inflammation of the cornea in CAB models (Figure 2c). For example, alkali exposure induces p38 mitogen-activated protein kinase (MAPK) signaling which activates the downstream effector MAPK-activated protein kinase-2 (MK2) to selectively augment IL-6, IL-1β, MIP-1α, ICAM-1, and VCAM-1 production, thereby significantly increasing leukocyte accumulation [16,57]. In addition, signal transducer and activator of transcription 3 (STAT3) signaling in alkali-induced corneal inflammation was highlighted when its pharmacological inhibition reduced VEGF, MMP-2, MMP-9 and TGF-β1 expression, possibly by attenuating MCP-1 production to decrease macrophage infiltration [18].…”

Section: Inflammatory Milieumentioning

confidence: 99%

Pathogenesis of Alkali Injury-Induced Limbal Stem Cell Deficiency: A Literature Survey of Animal Models

Sprogyte

Park

Girolamo

2023

Cells

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Limbal stem cell deficiency (LSCD) is a debilitating ocular surface disease that eventuates from a depleted or dysfunctional limbal epithelial stem cell (LESC) pool, resulting in corneal epithelial failure and blindness. The leading cause of LSCD is a chemical burn, with alkali substances being the most common inciting agents. Characteristic features of alkali-induced LSCD include corneal conjunctivalization, inflammation, neovascularization and fibrosis. Over the past decades, animal models of corneal alkali burn and alkali-induced LSCD have been instrumental in improving our understanding of the pathophysiological mechanisms responsible for disease development. Through these paradigms, important insights have been gained with regards to signaling pathways that drive inflammation, neovascularization and fibrosis, including NF-κB, ERK, p38 MAPK, JNK, STAT3, PI3K/AKT, mTOR and WNT/β-catenin cascades. Nonetheless, the molecular and cellular events that underpin re-epithelialization and those that govern long-term epithelial behavior are poorly understood. This review provides an overview of the current mechanistic insights into the pathophysiology of alkali-induced LSCD. Moreover, we highlight limitations regarding existing animal models and knowledge gaps which, if addressed, would facilitate development of more efficacious therapeutic strategies for patients with alkali-induced LSCD.

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Section: Inflammatory Milieumentioning

confidence: 99%

Pathogenesis of Alkali Injury-Induced Limbal Stem Cell Deficiency: A Literature Survey of Animal Models

Sprogyte

Park

Girolamo

2023

Cells

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“…Long non-coding ribonucleic acids (RNAs) (lncRNAs), which consist of more than 200 nucleotides, are involved in protein translation and messenger RNA (mRNA) decay, which play important roles in regulating inflammatory pathways (16,17). A growing number of studies has revealed that some lncRNAs participate in the pathogenesis of multiple diseases, including cancer, ocular alkali burns, and Sjögren's syndrome by regulating mRNA directly or indirectly (18)(19)(20). Long non-coding ribonucleic acids regulate gene expression through epigenetic regulation, transcriptional regulation, and post-transcriptional regulation, thus participating in various biological processes (BP) such as cell proliferation, differentiation, and apoptosis (21)(22)(23)(24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

Long Non-coding RNAs Gabarapl2 and Chrnb2 Positively Regulate Inflammatory Signaling in a Mouse Model of Dry Eye

et al. 2021

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Purpose: To elucidate the expression profile and the potential role of long non-coding ribonucleic acids (RNAs) (lncRNAs) in a dry eye disease (DED) model.Methods: A DED model was established in C57BL/6J mice with 0.2% benzalkonium chloride (BAC) twice a day for 14 days. The differentially expressed lncRNAs were detected by RNA-seq technology (Gene Expression Omnibus, GEO GSE186450) and the aberrantly expressed lncRNAs were further verified by RT-qPCR. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to predicate the related candidate genes and potential pathological pathways. Cells from a human corneal epithelial cell line (HCECs) were cultured under hyperosmolarity. The regulation of inflammatory factors by silencing potential targeted lncRNAs was verified in vitro in HCECs.Results: In our study, a significant increase in corneal fluorescence staining and a reduction in tear production were observed in DED mice at all follow-ups compared with the controls, and the differences were increasing over time. In total, 2,649 upregulated and 704 downregulated lncRNAs were identified in DED mice. We selected six aberrantly expressed and most abundant lncRNAs and performed RT-qPCR using the samples for RNA-seq. Chrnb2, Gabarapl2, and Usp31 were thereby confirmed as the most significantly altered lncRNAs. Pathway analysis revealed that the neuroactive ligand–receptor interaction signaling pathway was the most enriched, followed by the calcium signaling pathway and cytokine–cytokine receptor interaction. Following treatment of Gabarapl2 siRNA and Chrnb2 siRNA, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 were significantly downregulated in the HCECs.Conclusion: Our study suggests that Chrnb2 and Gabarapl2 may be involved in the inflammation response by regulating TNF-α, IL-1β, and IL-6 in DED. These candidate lncRNAs may be both potential biomarkers and therapeutic targets for DED.

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“… 7 Most studies examining alkali-burned corneas have focused on RNA or protein levels. In previous related studies, various techniques, such as circRNA microarray analysis, 8 transcriptome sequencing, 9 and quantitative proteomics, 10 were used to identify dysregulated molecules in corneal tissues after alkali exposure. However, studies on the integration and analysis of the transcriptomics and proteomics data of mouse alkali-burned corneas are limited.…”

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confidence: 99%

Exploring Corneal Neovascularization: An Integrated Approach Using Transcriptomics and Proteomics in an Alkali Burn Mouse Model

Wang,

Deng,

et al. 2024

Invest. Ophthalmol. Vis. Sci.

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Purpose Corneal neovascularization (CNV) impairs corneal transparency and visual acuity. The study aims to deepen our understanding of the molecules involved in CNV induced by alkali burns, facilitate a better grasp of CNV mechanisms, and uncover potential therapeutic targets. Methods Eighty-four mice were selected for establishing CNV models via alkali burns. On days 3, 7, and 14 after the burns, corneal observations and histological investigations were conducted. An integrated analysis of RNA sequencing (RNA-seq)-based transcriptomics and label-free quantitative proteomics was performed in both normal and burned corneas. Bioinformatics approaches, encompassing Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, were applied to discern differentially expressed genes (DEGs) and crucial signaling pathways. Four potentially CNV-related genes were validated using quantitative real-time PCR (qRT-PCR) and Western blot. Results Significant CNV was observed on the seventh day. Forty-one genes were differentially expressed in neovascularized corneas, with 15 upregulated and 26 downregulated at both mRNA and protein levels. Bioinformatics analysis revealed that these DEGs participated in diverse biological processes, encompassing retinol and retinoic acid metabolism, neutrophil chemotaxis, and actin filament assembly, along with significant enrichment pathways like cytochrome P450, tyrosine, and phenylalanine metabolism. The upregulation of lymphocyte cytosolic protein 1 ( LCP1 ) and cysteine and glycine-rich protein 2 ( CSRP2 ) genes and the downregulation of transglutaminase 2 ( TGM2 ) and transforming growth factor-beta-induced ( TGFBI ) genes were confirmed. Conclusions We analyzed gene expression differences in mouse corneas 7 days after alkali burns, finding 41 genes with altered expression. The exact role of these genes in CNV is not fully understood, but exploring angiogenesis-related molecules offers potential for CNV treatment or prevention.

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Epigenetic Landscape Analysis of the Long Non-Coding RNA and Messenger RNA in a Mouse Model of Corneal Alkali Burns

Cited by 7 publications

References 40 publications

Pathogenesis of Alkali Injury-Induced Limbal Stem Cell Deficiency: A Literature Survey of Animal Models

Pathogenesis of Alkali Injury-Induced Limbal Stem Cell Deficiency: A Literature Survey of Animal Models

Long Non-coding RNAs Gabarapl2 and Chrnb2 Positively Regulate Inflammatory Signaling in a Mouse Model of Dry Eye

Exploring Corneal Neovascularization: An Integrated Approach Using Transcriptomics and Proteomics in an Alkali Burn Mouse Model

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