Anti-inflammatory effect of hydroxyproline-GQDGLAGPK in desiccation stress-induced experimental dry eye mouse.
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ABSTRACT:
SUBMITTER: Lee H
PROVIDER: S-EPMC5547052 | biostudies-other | 2017 Aug
REPOSITORIES: biostudies-other
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Project description:ObjectiveTo investigate the clinical effects of IRT5 probiotics in the environmental dry eye model.MethodsEight week old male C57BL/6 mice were randomly divided into two groups; control group (n = 16) received oral gavage of 300 μL phosphate-buffered saline (PBS) alone once daily, IRT5 group (n = 9) received oral gavage of 1 x 109 CFU IRT5 probiotics powder in 300 μL PBS once daily, both groups for 11 to 12 days. Simultaneously, all mice underwent dry eye induction. Tear secretion, corneal staining and conjunctival goblet cell density were evaluated. Quantative real-time polymerase chain reaction (RT-PCR) for inflammation-related markers was performed. 16S ribosomal RNA of fecal microbiome was analyzed and compositional difference, alpha and beta diversities were assessed.ResultsThere was no difference in NEI score but significant increase in tear secretion was observed in IRT5 group (p < 0.001). There was no significant difference in goblet cell density between groups. Quantative RT-PCR of cornea and conjunctiva revealed increased TNF-α expression in IRT5 group (p < 0.001) whereas other markers did not significantly differ from control. IRT5 group had significantly increased species diversity by Shannon index (p = 0.041). Beta diversity of genus by UniFrac principle coordinates analysis showed significant distance between groups (p = 0.001). Compositional differences between groups were observed and some were significantly associated with tear secretion. Multivariate linear regression analysis revealed Christensenellaceae (p = 0.009), Lactobacillus Helveticus group (p = 0.002) and PAC001797_s (p = 0.011) to strongly influence tear secretion.ConclusionIn experimental dry eye model, IRT5 probiotics treatment partially improves experimental dry eye by increasing tear secretion which was associated with and influenced by the change in intestinal microbiome. Also, intestinal microbiome may affect the lacrimal gland through a different mechanism other than regulating inflammation.
| S-EPMC7707591 | biostudies-literature
Project description:The aim of the present study was to investigate the anti-inflammatory effects of glycine thymosin ?4 (Gly-T?4) eye drops, and to compare the efficacy of topical Gly-T?4 with Cyclosporine A (CsA) in a mouse model of experimental dry eye (EDE). Eye drops consisting of balanced salt solution (BSS), 0.1% Gly-T?4 or 0.05% CsA were used for treatment of EDE. Tear volume, tear film break-up time and corneal staining scores were measured after 7 and 14 days. Periodic acid-Schiff staining for conjunctival gobleT cells, TUNEL assay for corneal apoptotic positive cells, multiplex immunobead assay for interleukin (IL)-1?, IL-6, tumor necrosis factor-? and interferon-? levels, and flow cytometry for CD4+/CCR5+ T cells were performed after 14 days. All clinical parameters showed improvement in the Gly-T?4 and CsA groups (all P<0.05). Significantly increased conjunctival gobleT cells and decreased corneal TUNEL positive cells were observed in the Gly-T?4 and CsA groups. The Gly-T?4 and CsA treated groups showed significantly reduced inflammatory cytokine levels and T cells in the conjunctiva compared with the EDE and BSS groups (all P<0.05). However, there were no significant differences observed in the inflammatory and clinical parameters between the Gly-T?4 and CsA treatment groups. Topical application of 0.1% Gly-T?4 significantly reduced inflammation on the ocular surface, as well as clinical parameters of EDE, with a similar efficacy to that of 0.05% CsA emulsions, suggesting that Gly-T?4 eye drops may be used as a therapeutic agent for treatment of dry eye disease.
| S-EPMC7201140 | biostudies-literature
Project description:Dry eye disease (DED) impacts ≈30% of the world's population and causes serious ocular discomfort and even visual impairment. Inflammation is one core cause of the DED vicious cycle, a multifactorial deterioration in DED process. However, there are also reactive oxygen species (ROS) regulating inflammation and other points in the cycle from the upstream, leading to treatment failure of current therapies merely targeting inflammation. Accordingly, the authors develop micelle-based eye drops (more specifically p38 mitogen-activated protein kinases (MAPK) inhibitor Losmapimod (Los)-loaded and ROS scavenger Tempo (Tem)-conjugated cationic polypeptide micelles, designated as MTem/Los) for safe and efficient DED management. Cationic MTem/Los improve ocular retention of conjugated water-soluble Tem and loaded water-insoluble Los via electrostatic interaction with negatively charged mucin on the cornea, enabling an increase in therapeutic efficiency and a decrease in dosing frequency. Mechanistically, MTem/Los effectively decrease ROS over-production, reduce the expression of proinflammatory cytokines and chemokines, restrain macrophage proinflammatory phenotypic transformation, and inhibit cell apoptosis. Therapeutically, the dual-functional MTem/Los suppress the inflammatory response, reverse corneal epithelial defect, save goblet cell dysfunction, and recover tear secretion, thus breaking the vicious cycle and alleviating the DED. Moreover, MTem/Los exhibit excellent biocompatibility and tolerability for potential application as a simple and rapid treatment of oxidative stress- and inflammation-induced disorders, including DED.
| S-EPMC9189644 | biostudies-literature
Project description:BackgroundTo investigate the anti-inflammatory and antioxidative effects of gallic acid (GA) on human corneal epithelial cells (HCECs) and RAW264.7 macrophages as well as its therapeutic effects in an experimental dry eye (EDE) mouse model.MethodsA cell counting kit-8 (CCK-8) assay was used to test the cytotoxicity of GA. The effect of GA on cell migration was evaluated using a scratch wound healing assay. The anti-inflammatory and antioxidative effects of GA in vitro were tested using a hypertonic model (HCECs) and an inflammatory model (RAW264.7 cells). The in vivo biocompatibility of GA was detected by irritation tests in rabbits, whereas the preventive and therapeutic effect of GA in vivo was evaluated using a mouse model of EDE.ResultsIn the range of 0-100 μM, GA showed no cytotoxicity in RAW264.7 cells or HCECs and did not delay the HCECs monolayer wound healing within 24 h. Ocular tolerance to GA in the in vivo irritation test was good after seven days. In terms of antioxidative activity, GA significantly reduced the intracellular reactive oxygen species (ROS) in lipopolysaccharide (LPS) activated RAW264.7 macrophages and HCECs exposed to hyperosmotic stress. Furthermore, after pre-treatment with GA, the expression levels of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NADPH quinone oxidoreductase-1 (NQO-1) were significantly upregulated in RAW264.7 macrophages. GA also exhibits excellent anti-inflammatory properties. This is mainly demonstrated by the ability of GA to effectively downregulate the nuclear transcription factor-κB (NF-κB) pathway in LPS-activated RAW264.7 macrophages and to reduce inflammatory factors, such as nitric oxide (NO), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α). In vivo efficacy testing results in a mouse model of EDE showed that GA can effectively prevent and inhibit the apoptosis of corneal epithelial cells (CECs), reduce inflammatory factors in the cornea and conjunctiva as well as protect goblet cells.ConclusionIn vitro and in vivo results indicate that GA possesses potent anti-inflammatory and antioxidative properties with no apparent cytotoxicity within the range of 0-100 μM. It is a promising eye drop formulation for the effective prevention and treatment of dry eye disease (DED).
| S-EPMC10150500 | biostudies-literature
Project description:The goal of this study was to explore the specific signaling pathways related to inflammation in two experimental mouse dry eye (EDE) models. Female C57BL/6 mice housed for 10 days in a controlled desiccative environment were either treated with scopolamine (EDE-1; n = 18) or subjected to extraorbital lacrimal gland excision bilaterally (EDE-2; n = 10). Non-induced mice (n = 20) served as healthy controls. A corneal fluorescein staining (CFS) scoring was used at baseline through to day (D) 10 to evaluate epitheliopathy. At D10, corneas and conjunctivas were collected for multiplexed transcriptomic analysis with the NanoString® mouse inflammatory CodeSet. Both EDE-1 and EDE-2 mice presented a change in corneal integrity, with a significant increase in CFS scores at D10. More gene transcripts were identified in EDE-2 compared with EDE-1 (116 vs. 96, respectively), and only a few were common to both models, 13 for the cornea and 6 for the conjunctiva. The gene functional annotation analysis revealed that the same inflammatory pathways were involved in both models. Comparative profiling of gene expression in the two EDE models leads to the identification of various targets and signaling pathways, which can be extrapolated to and confirmed in human disease.
| S-EPMC8509332 | biostudies-literature
Project description:Dry eye from Sjögren's syndrome is a multifactorial disease that results in dysfunction of the lacrimal functional unit. Studies have shown changes in tear composition, including inflammatory cytokines, chemokines, and metalloproteinase. T-lymphocytes have been shown to increase in the conjunctiva and lacrimal glands in patient and animal models. This inflammation is in part responsible for the pathogenesis of the disease, which results in symptoms of eye irritation, ocular surface epithelial disease, and loss of corneal barrier function. There are a number of anti-inflammatory approaches for treating this disease. The current study reviews details of immune response and anti-inflammatory therapies used to control this disease.
| S-EPMC4128848 | biostudies-literature
Project description:The aim of this study was to assess the anti-inflammatory and anti-apoptotic effects of KIOM-2015EW, the hot-water extract of maple leaves in hyperosmolar stress (HOS)-induced human corneal epithelial cells (HCECs). HCECs were exposed to hyperosmolar medium and exposed to KIOM-2015EW with or without the hyperosmolar media. Tumor necrosis factor (TNF)-?, interleukin (IL)-1?, and IL-6 production and apoptosis were observed, and the activation of mitogen-activated protein kinases (MAPKs) including extracellular signal regulated kinase (ERK), p38 and c-JUN N-terminal kinase (JNK) signaling and nuclear factor (NF)-?B was confirmed. Compared to isomolar medium, the induction of cell cytotoxicity significantly increased in HCECs exposed to hyperosmolar medium in a time-dependent manner. KIOM-2015EW-treatment significantly reduced the mRNA and protein expression of pro-inflammatory mediators and apoptosis. KIOM-2015EW-treatment inhibited HOS-induced MAPK signaling activation. Additionally, the HOS-induced increase in NF-?B phosphorylation was attenuated by KIOM-2015EW. The results demonstrated that KIOM-2015EW protects the ocular surface by suppressing inflammation in dry eye disease, and suggest that KIOM-2015EW may be used to treat several ocular surface diseases where inflammation plays a key role.
| S-EPMC5872700 | biostudies-literature
Project description:Dry eye disease (DED) is a complex multifactorial disease showing heterogenous symptoms, including dryness, photophobia, ocular discomfort, irritation and burning but also pain. These symptoms can affect visual function leading to restrictions in daily life activities and reduction in work productivity with a consequently high impact on quality of life. Several pathological mechanisms contribute to the disease: evaporative water loss leads to impairment and loss of tear homeostasis inducing either directly or indirectly to inflammation, in a self-perpetuating vicious cycle. Dysregulated ocular immune responses result in ocular surface damage, which further contributes to DED pathogenesis. Currently, DED treatment is based on a flexible stepwise approach to identify the most beneficial intervention. Although most of the available treatments may control to a certain extent some signs and symptoms of DED, they show significant limitations and do not completely address the needs of patients suffering from DED. This review provides an overview of the emerging experimental therapies for DED. Several promising therapeutic strategies are under development with the aim of dampening inflammation and restoring the homeostasis of the ocular surface microenvironment. Results from early phase clinical trials, testing the effects of EnaC blockers, TRPM8 agonist or mesenchymal stem cells in DED patients, are especially awaited to demonstrate their therapeutic value for the treatment of DED. Moreover, the most advanced experimental strategies in the pipeline for DED, tivanisiran, IL-1R antagonist EBI-005 and SkQ1, are being tested in Phase III clinical trials, still ongoing. Nevertheless, although promising results, further studies are still needed to confirm efficacy and safety of the new emerging therapies for DED.
| S-EPMC8001578 | biostudies-literature
Project description:PurposeTo investigate the impact of transmembrane protein CMTM6 on the pathogenesis of dry eye disease (DED) and elucidate its potential mechanisms.MethodsCMTM6 expression was confirmed by database analysis, real-time polymerase chain reaction (RT-PCR), western blot, and immunohistochemistry. Tear secretion was measured using the phenol red thread test. Immune cell infiltration was assessed through flow cytometry. Barrier function was evaluated by fluorescein sodium staining, immunofluorescence staining of zonula occludens 1 (ZO-1), and electric cell-substrate impedance sensing (ECIS) assessment. For silencing CMTM6 expression, siRNA and shRNA were employed, along with lentiviral vector-mediated overexpression of CMTM6. Proinflammatory cytokine levels were analyzed by RT-PCR and cytometric bead array (CBA) analysis.ResultsCMTM6 showed high expression in healthy human and mouse corneal and conjunctival epithelium but was notably reduced in DED. Notably, this downregulation was correlated with disease severity. Cmtm6-/- dry eye (DE) mice displayed reduced tear secretion, severe corneal epithelial defects, decreased conjunctival goblet cell density, and upregulated inflammatory response. Additionally, Cmtm6-/- DE mice and CMTM6 knockdown human corneal epithelial cell-transformed (HCE-T) cells showed more severe barrier disruption and reduced expression of ZO-1. Knockdown of CMTM6 in HCE-T cells increased inflammatory responses induced by hyperosmotic stress, which was significantly mitigated by CMTM6 overexpression. Moreover, the level of phospho-p65 in hyperosmolarity-stimulated HCE-T cells increased after silencing CMTM6. Nuclear factor kappa B (NF-κB) p65 inhibition (JSH-23) reversed the excessive inflammatory responses caused by hyperosmolarity in CMTM6 knockdown HCE-T cells.ConclusionsThe reduction in CMTM6 expression on the ocular surface contributes to the pathogenesis of DED. The CMTM6-NF-κB p65 signaling pathway may serve as a promising therapeutic target for DED.
| S-EPMC10768713 | biostudies-literature
Project description: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.
| S-EPMC8703135 | biostudies-literature