Diquafosol Sodium Inhibits Apoptosis and Inflammation of Corneal Epithelial Cells Via Activation of Erk1/2 and RSK: In Vitro and In Vivo Dry Eye Model

Park, Jin Hyoung; Moon, S.-J.; Kang, Dong Hyun; Um, Hyun Jun; Kang, Suk-Yun; Kim, Jae Yong; Tchah, Hungwon

doi:10.1167/iovs.17-22925

Cited by 41 publications

(29 citation statements)

References 34 publications

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“…Our f indings demonstrate that hyperosmotic stress induces inflammation, and diquafosol is an effective agent that protects HCECs from hyperosmotic stress-induced inflammation. These results are consistent with previous studies in which the secretion of inf lammatory cytokines was signif icantly reduced in desiccation stress-induced dry eye models [25]. Results showing that diquafosol inhibits the production of inflammatory cytokines in a variety of dry eye models suggest that diquafosol may exert anti-inf lammatory effects on various pathogenic factors associated with dry eye syndrome, such as tear hyperosmolarity or dry conditions.…”

Section: Discussionsupporting

confidence: 92%

Effect of Diquafosol on Hyperosmotic Stress-induced Tumor Necrosis Factor-α and Interleukin-6 Expression in Human Corneal Epithelial Cells

Kim

Yang

Nguyen

et al. 2020

Korean J Ophthalmol

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Purpose: Diquafosol is a pharmaceutical drug used for dry eye treatment with a novel mechanism of action. It is a purinergic P2Y2 receptor agonist that promotes the secretion of tears and healing of corneal epithelial wounds. However, its inhibitory effect on hyperosmotic stress-induced inflammation in human corneal epithelial cells (HCECs) remains unclear. Methods: A hyperosmotic stress model was established by transferring HCECs from isosmotic (312 mOsm/kg to hyperosmotic medium (500 mOsm/kg). HCECs were incubated with 500 mOsm/kg hyperosmotic medium for 30 minutes, and then treated with diquafosol (0.6-6 mg/mL) for 4 or 24 hours. Cells were then harvested and analyzed by western blot, immunocytochemistry, and real-time polymerase chain reaction to evaluate the expression of interleukin-6, tumor necrosis factor-alpha, and the phosphorylation status of nuclear factor-kappa B. Results: Diquafosol significantly decreased the mRNA and protein expression of hyperosmotic stress-induced tumor necrosis factor-alpha and interleukin-6. These results were supported by immunofluorescence staining and quantitative real-time polymerase chain reaction analysis. Furthermore, diquafosol inhibits nuclear factor-kappa B activation by suppressing the phosphorylation and degradation of the inhibitor of кB. Conclusions: This study shows that diquafosol inhibits nuclear factor-kappa B signaling and inflammatory factors induced by hyperosmotic stress in HCECs. This suggests that using diquafosol for the improvement of dry eye syndrome could be effective in the treatment of inflammation-related corneal and conjunctival diseases.

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Section: Discussionsupporting

confidence: 92%

Effect of Diquafosol on Hyperosmotic Stress-induced Tumor Necrosis Factor-α and Interleukin-6 Expression in Human Corneal Epithelial Cells

Kim

Yang

Nguyen

et al. 2020

Korean J Ophthalmol

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“…Inhibiting tear secretion by systemic administration of the muscarinic cholinergic antagonist scopolamine produced keratoconjunctivitis sicca that mimics human dry eye. This scopolamine-induced dry eye model is commonly used animal model in DED research [22,[24][25][26][27]. We demonstrated that the oxidation product 8-OHdG accumulated in the corneal epithelial cells of this model.…”

Section: Plos Onementioning

confidence: 73%

NFE2L2 activator RS9 protects against corneal epithelial cell damage in dry eye models

et al. 2020

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Oxidative stress may cause ocular surface damage during the development of dry eye. Mammalian cells have defense systems against oxidative stress. A central regulator of the stress response is nuclear factor-erythroid 2-related factor 2 (NFE2L2). NFE2L2 is activated by the novel triterpenoid RS9 (a biotransformation compound of RTA 402). The purpose of this study was to assess the efficacy of RS9 against dry eye using in vitro and in vivo models. Bioactivity was estimated by the induction of mRNAs for two NFE2L2-targeted genes: NQO1 (prevents radical species) and GCLC (glutathione synthesis), using a corneal epithelial cell line (HCE-T). Protection against oxidation and cell damage was tested in vitro by culturing cells under hyperosmotic stress or by the addition of menadione, a generator of reactive oxygen species (ROS). Dry eye in vivo was induced by the injection of scopolamine into rats. Then, 930 nM of RS9 was applied to both eyes for 2 weeks. Oxidative stress was measured by the accumulation of 8-hydroxy-2'-deoxyguanosine (8-OHdG). Corneal wound healing was measured by scoring for superficial punctate keratitis (SPK). Corneal epithelial cell densities were evaluated histologically. RS9 and RTA 402 induced the expression of NQO1 and GCLC mRNAs in HCE-T cells. And both compounds suppressed hyperosmotic-ROS generation and menadione induced cellular damage. However RS9 had a stronger protective effect than RTA 402. Ocular instillation of RS9 also significantly upregulated the expression of Nqo1 mRNA in the corneal epithelium. Accumulation of 8-OHdG, increase of SPK scores and decrement of basal cell density were observed in corneal epithelium from scopolamine-injected rats. These changes were significantly ameliorated by the topical administration of RS9. RS9 induced Nfe2l2 activation and Nfe2l2-targeted genes, reduced oxidation, and ameliorated symptoms of dry eye using in vitro and in vivo models. Thus, RS9 might be a potent candidate agent against dry eye disease.

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“…At present, the main clinical application of tear substitutes to relieve dry eye symptoms, but cannot effectively cure dry eye syndrome 3 . Inflammatory response, apoptosis, and changes in sex hormone levels are all associated with the development of dry eye syndrome, and inflammation is considered to be the most important factor in the pathogenesis of dry eye syndrome 4,5 …”

Section: Introductionmentioning

confidence: 99%

“…3 Inflammatory response, apoptosis, and changes in sex hormone levels are all associated with the development of dry eye syndrome, and inflammation is considered to be the most important factor in the pathogenesis of dry eye syndrome. 4,5 Interleukin-1 receptor-associated kinase 1 (IRAK1) is a serinethreonine kinase that mediates Toll-like receptors (TLR) and IL-1 signaling pathways. These signaling pathways are critical for regulating immune responses and inflammatory processes.…”

mentioning

confidence: 99%

The expression of miRNA‐146a‐5p and its mechanism of treating dry eye syndrome

Yin

Zhang

et al. 2020

Clinical Laboratory Analysis

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Objective Dry eye syndrome in which tear fluid quality or abnormality, or kinetic abnormality is caused by various reasons, resulting in decreased tear film stability. In recent years, more and more results from the studies indicate that miRNA alterations are involved in dry eye syndrome. And miRNA‐146a‐5p is a key regulator to regulate the inflammatory response. In this paper, we demonstrated whether miRNA‐146a‐5p could cure dry eye syndrome by regulating target genes based on network analysis. Methods In current study, we collected the blood of patients with dry eye disease served as a model group; the blood of healthy people was served as control group. The expression of miRNA‐146a‐5p in the patients was detected by RT‐PCR, the genes controlled by miRNA‐146a‐5p were predicted by TargetScan, miRDB, miRWalk, and PicTar databases, and the genes regulated by miRNA‐146a‐5p which relative with dry eye disease were selected by drawing Venn diagram. Results The comparison of the general information between patients and healthy people was no significant difference, and it indicated that the two groups were comparable. The results of databases showed that IRAK1 was one of the target genes regulated by miRNA‐146a‐5p, and it is related to dry eye disease. The expression of miRNA‐146a‐5p was negatively related to IRAK1 mRNA and protein, while IRAK1 had a positive correlation with IL‐6, TNF‐α, and CBP proteins. Conclusion These results emphasized that miRNA‐146a‐5p could inhibit the expression of IRAK1, IL‐6, TNF‐α, and CBP to help reduce the inflammatory response in dry eye syndrome.

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Diquafosol Sodium Inhibits Apoptosis and Inflammation of Corneal Epithelial Cells Via Activation of Erk1/2 and RSK: In Vitro and In Vivo Dry Eye Model

Cited by 41 publications

References 34 publications

Effect of Diquafosol on Hyperosmotic Stress-induced Tumor Necrosis Factor-α and Interleukin-6 Expression in Human Corneal Epithelial Cells

Effect of Diquafosol on Hyperosmotic Stress-induced Tumor Necrosis Factor-α and Interleukin-6 Expression in Human Corneal Epithelial Cells

NFE2L2 activator RS9 protects against corneal epithelial cell damage in dry eye models

The expression of miRNA‐146a‐5p and its mechanism of treating dry eye syndrome

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