Proteomic analysis of human lacrimal and tear fluid in dry eye disease

Jung, Jae Hun; Ji, Yong Woo; Hwang, Ho Sik; Oh, Jae Won; Kim, Hyeon Chang; Kim, Kwang Pyo

doi:10.1038/s41598-017-13817-y

Cited by 70 publications

(60 citation statements)

References 51 publications

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“…In accordance with these data, it is true that the number of immunoinflammatory molecule expressions are three times higher in the LGs compared with the ocular surface. 34 HIF-1α has been reported to promote cell survival of immune and nonimmune cells during hypoxia. 35 Our previous report has shown that HIF-1α mediated autophagy signals promote acinar cell survival during desiccating stress.…”

Section: Discussionmentioning

confidence: 99%

HIF1α-mediated TRAIL Expression Regulates Lacrimal Gland Inflammation in Dry Eye Disease

Lee

Choi

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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The purpose of this study was to investigate the expression of death ligands in the lacrimal glands (LGs), identify upstream factors that regulate their expression, and determine the functional roles of these factors in the pathogenesis of dry eye disease (DED). METHODS. For DED experiment, ex vivo coculture system with LG and in vivo murine model using a controlled environment chamber were utilized. C57BL/6 mice and hypoxiainducible factor (HIF)-1α conditional knockout (CKO) mice were used. Immunohistochemical staining, polymerase chain reaction, and immunoblotting were performed to determine levels of death ligands including tumor necrosis factor-related apoptosisinducing ligand (TRAIL) in DED-induced LGs. Additionally, acinar cell and CD45 + cell apoptosis was determined with neutralizing TRAIL treatment. RESULTS. Desiccating stress significantly increased HIF-1α expression in LG-acinar cells. Furthermore, HIF-1α deficiency significantly enhanced the infiltration of CD45 + inflammatory cells in LG and induced LG-acinar cell death. Meanwhile, only TRAIL expression was increased in DED-LG, but abrogated in HIF-1α CKO. Interestingly, the main source of TRAIL was the CD45-LG-acinar cells, but not CD45 + immune cells after DED induction. Using ex vivo coculture system, we confirmed LG-induced apoptosis of immune cells via HIF-1α-mediated TRAIL secretion following DED. Consistent with ex vivo, the insufficiency of HIF-1α and TRAIL enhanced recruitment of inflammatory cells to the LG and subsequently exacerbated ocular surface damage in DED mice. CONCLUSIONS. Our findings offer novel insight into the regulatory function of acinar cellderived TRAIL in limiting inflammatory damage and could be implicated in the development of potential therapeutic strategies for DED.

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Section: Discussionmentioning

confidence: 99%

HIF1α-mediated TRAIL Expression Regulates Lacrimal Gland Inflammation in Dry Eye Disease

Lee

Choi

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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“…26,27 A recent human study reported protein changes in the lacrimal and tear fluid of patients with dry eye. 28 Therefore, to understand the pathophysiologic changes of the lacrimal gland and its role as a possible target organ during crosstalk between the gut microbiome and the immune system, we investigated the mechanism by which IRT5 probiotics alter the gut microbiota and the proteome of the extraorbital lacrimal glands in a mouse model of Sjögren syndrome.…”

mentioning

confidence: 99%

IRT5 Probiotics Changes Immune Modulatory Protein Expression in the Extraorbital Lacrimal Glands of an Autoimmune Dry Eye Mouse Model

Choi

Ryu

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Purpose While the association between the gut microbiome and the immune system has been studied in autoimmune disorders, little is known about ocular disease. Previously we reported that IRT5, a mixture of five probiotic strains, could suppress autoimmune dry eye. In this study, we investigated the mechanism by which IRT5 performs its immunomodulatory function in a mouse model of autoimmune dry eye. Methods NOD.B10.H2b mice were used as an autoimmune dry eye model. Either IRT5 or PBS was gavaged orally for 3 weeks, with or without 5 days of antibiotic pretreatment. The effects on clinical features, extraorbital lacrimal gland and spleen proteins, and fecal microbiota were analyzed. Results The ocular staining score was lower, and tear secretion was higher, in the IRT5-treated groups than in the PBS-treated groups. After IRT5 treatment, the downregulated lacrimal gland proteins were enriched in the biological processes of defense response and immune system process. The relative abundances of 33 operational taxonomic units were higher, and 53 were lower, in the feces of the IRT5-treated groups than in those of the PBS-treated groups. IRT5 administration without antibiotic pretreatment also showed immunomodulatory functions with increases in the Lactobacillus helveticus group and Lactobacillus hamsteri . Additional proteomic assays revealed a decrease of proteins related to antigen-presenting processes in the CD11b + and CD11c + cells of spleen in the IRT5-treated groups. Conclusions Changes in the gut microbiome after IRT5 treatment improved clinical manifestations in the autoimmune dry eye model via the downregulation of antigen-presenting processes in immune networks.

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“…The LC-QqQ-MS-based MRM verification for enzymes in the SL metabolism pathway was performed using 100 μg protein samples from DLD-1 and DLD-1/5-FU cells in triplicate. The pair of m/z values that are isolated in Q1 and Q3 and optimized collisional energy were referred to the Human SRMAtlas database 21,67 . Peptides were separated on an Agilent 1290 LC RP-HPLC equipped with a RP-HPLC column (150 × 2.1 mm ID, Agilent Zorbax Eclipse Plus C18 Rapid Resolution HD, 1.8 μm particles), and an Agilent 6490 triple-quadrupole mass spectrometer using a gradient from 5% to 40% solvent B (90% ACN, 0.1% formic acid) over 40 min.…”

Section: Verification Of Sphingolipid-related Enzymes By Mrm Analysismentioning

confidence: 99%

Comparative lipidomics of 5-Fluorouracil–sensitive and –resistant colorectal cancer cells reveals altered sphingomyelin and ceramide controlled by acid sphingomyelinase (SMPD1)

Jung

Taniguchi

Lee

et al. 2020

Sci Rep

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5-Fluorouracil (5-FU)is a chemotherapeutic drug widely used to treat colorectal cancer. 5-FU is known to gradually lose its efficacy in treating colorectal cancer following the acquisition of resistance. We investigated the mechanism of 5-FU resistance using comprehensive lipidomic approaches. We performed lipidomic analysis on 5-FU-resistant (DLD-1/5-FU) and -sensitive (DLD-1) colorectal cancer cells using MALDI-MS and LC-MRM-MS. In particular, sphingomyelin (SM) species were significantly up-regulated in 5-FU-resistant cells in MALDI-TOF analysis. Further, we quantified sphingolipids including SM and Ceramide (Cer) using Multiple Reaction Monitoring (MRM), as they play a vital role in drug resistance. We found that 5-FU resistance in DLD-1/5-FU colorectal cancer cells was mainly associated with SM increase and Cer decrease, which are controlled by acid sphingomyelinase (SMPD1). In addition, reduction of SMPD1 expression was confirmed by LC-MRM-MS analysis and the effect of SMPD1 in drug resistance was assessed by treating DLD-1 cells with siRNA-SMPD1. Furthermore, clinical colorectal cancer data set analysis showed that down-regulation of SMPD1 was associated with resistance to chemotherapy regimens that include 5-FU. Thus, from our study, we propose that SM/Cer and SMPD1 are new potential target molecules for therapeutic strategies to overcome 5-FU resistance.Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality in both men and women 1 . Although there are other drugs for treatment of CRC, 5-Fluorouracil (5-FU) is widely used and is positioned as a first-line chemotherapy. 5-FU was developed as an inhibitor of thymidylate synthase (TS), which results in suppression of thymine synthase, resulting in cell death 2 . The mechanism involves misincorporation of a pyrimidine analogue into RNA and DNA in place of uracil or thymine, respectively 3 . Despite the effectiveness of 5-FU, drug resistance remains a significant limitation. To overcome this drug resistance, many researchers have tried to identify potential genes and proteins involved in mediating 5-FU resistance, using emerging technologies such as microarray profiling 4 and whole genome sequencing 5 . For instance, the alteration of drug influx and efflux by the ABCC5 membrane protein and mutation of the drug target 6 may lead to 5-FU resistance. Furthermore, accumulation of TS protein and elevated activity of deoxyuridine triphosphatase are expected to cause 5-FU resistance www.nature.com/scientificreports www.nature.com/scientificreports/ in CRC. Although various target genes are involved, the detailed 5-FU-resistance mechanism has not been fully elucidated. Therefore, new strategies for therapy and resistance reversal are urgently needed.Various lipidomic approaches have revealed that lipids play key roles in various phenomena in living cells including oncogenesis 7,8 , apoptosis 9 , and drug resistance 10-12 . Alterations in levels of glycerophospholipids (GPs) such as phosphatidylcholine (PC) and phosphatidylethanolamine (PE) h...

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Proteomic analysis of human lacrimal and tear fluid in dry eye disease

Cited by 70 publications

References 51 publications

HIF1α-mediated TRAIL Expression Regulates Lacrimal Gland Inflammation in Dry Eye Disease

HIF1α-mediated TRAIL Expression Regulates Lacrimal Gland Inflammation in Dry Eye Disease

IRT5 Probiotics Changes Immune Modulatory Protein Expression in the Extraorbital Lacrimal Glands of an Autoimmune Dry Eye Mouse Model

Comparative lipidomics of 5-Fluorouracil–sensitive and –resistant colorectal cancer cells reveals altered sphingomyelin and ceramide controlled by acid sphingomyelinase (SMPD1)

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