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19 pages, 5224 KiB

Open AccessArticle

Comparative Analysis of Age-Related Changes in Lacrimal Glands and Meibomian Glands of a C57BL/6 Male Mouse Model

by Chang Ho Yoon, Jin Suk Ryu, Ho Sik Hwang and Mee Kum Kim

Int. J. Mol. Sci. 2020, 21(11), 4169; https://doi.org/10.3390/ijms21114169 - 11 Jun 2020

Cited by 27 | Viewed by 3570

Abstract

It is not known how biological changes in the lacrimal (LGs) and meibomian (MGs) glands contribute to dry eye disease (DED) in a time-dependent manner. In this study, we investigated time-sequenced changes in the inflammation, oxidative stress, and senescence of stem cells in [...] Read more.

It is not known how biological changes in the lacrimal (LGs) and meibomian (MGs) glands contribute to dry eye disease (DED) in a time-dependent manner. In this study, we investigated time-sequenced changes in the inflammation, oxidative stress, and senescence of stem cells in both glands of an aging-related DED mouse model. Eight-week (8W)-, one-year (1Y)-, and two-year (2Y)-old C57BL/6 male mice were used. MG areas of the upper and lower eyelids were analyzed by transillumination meibography imaging. The number of CD45⁺, 8-OHdG⁺, Ki-67⁺, and BrdU⁺ cells was compared in both glands. Increased corneal staining and decreased tear secretion were observed in aged mice. The MG dropout area increased with aging, and the age-adjusted MG area in lower lids was negatively correlated with the National Eye Institute (NEI) score. Increased CD4⁺ interferon (IFN)-γ⁺ cells in LGs were found in both aged mice. An increase in 8-OHdG⁺ cells in both glands was evident in 2Y-old mice. Reduced Ki-67⁺ cells, but no change in CD45⁺ cells, was observed in the MGs of 1Y-old mice. Increased BrdU⁺ cells were observed in the LGs of aged mice. This suggests that age-dependent DED in C57BL/6 mice is related to inflammation of the LGs, the development of MG atrophy, and oxidative stress in both glands. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders 2.0)

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14 pages, 3702 KiB

Open AccessArticle

The Effects of High Molecular Weight Hyaluronic Acid Eye Drop Application in Environmental Dry Eye Stress Model Mice

by Takashi Kojima, Taeko Nagata, Haruka Kudo, Wolfgang G. K. Müller-Lierheim, Gysbert-Botho van Setten, Murat Dogru and Kazuo Tsubota

Int. J. Mol. Sci. 2020, 21(10), 3516; https://doi.org/10.3390/ijms21103516 - 15 May 2020

Cited by 38 | Viewed by 6748

Abstract

Hyaluronic acid (HA) ophthalmic solution is widely used in dry eye treatment worldwide. However, there are no reports comparing the dry eye treatment effects of high molecular weight HA with low molecular weight HA. Sixty eight-week-old C57BL/6 mice were assigned to the following [...] Read more.

Hyaluronic acid (HA) ophthalmic solution is widely used in dry eye treatment worldwide. However, there are no reports comparing the dry eye treatment effects of high molecular weight HA with low molecular weight HA. Sixty eight-week-old C57BL/6 mice were assigned to the following 6 groups and exposed to environmental dry eye stress (EDES) that mimics office work environment: (1) 0.1% low molecular weight HA (LMWHA) eye drops, (2) 0.3% LMWHA eye drops, (3) 3% diquafosol sodium (DQ) eye drops, (4) 0.15% high molecular weight HA (HMWHA) eye drops, (5) no treatment with exposure to EDES (EDES+/Treatment−), and (6) no treatment without exposure to EDES (EDES−/Treatment−). After EDES, the HMWHA group had significantly longer break-up time (BUT) than the 0.1%, 0.3% LMWHA groups and the DQ group. After EDES, the HMWHA group had significantly lower lissamine green staining scores than the LMWHA and DQ groups. Subepithelial presumed dendritic cell density in the HMWHA group was significantly lower than the EDES+/Treatment− group. After EDES exposure, Conjunctival Muc5AC mRNA expression in the HMWHA group was significantly higher than the 0.1 and 0.3% LMWHA groups. Ophthalmic HMWHA solution may have a better dry eye treatment effect than LMWHA or DQ solution, owing to its anti-inflammatory effect. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders 2.0)

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10 pages, 1426 KiB

Open AccessCommunication

Evaluation of Cell Harvesting Techniques to Optimize Lipidomic Analysis from Human Meibomian Gland Epithelial Cells in Culture

by Jillian F. Ziemanski, Jianzhong Chen and Kelly K. Nichols

Int. J. Mol. Sci. 2020, 21(9), 3277; https://doi.org/10.3390/ijms21093277 - 06 May 2020

Cited by 8 | Viewed by 2791

Abstract

The lipidomic analysis of immortalized human meibomian gland epithelial cells (HMGECs) has been proposed as a preclinical model to study meibomian gland dysfunction. An in vitro study was conducted to evaluate neutral lipid recovery following three harvesting techniques and to identify candidate lipid [...] Read more.

The lipidomic analysis of immortalized human meibomian gland epithelial cells (HMGECs) has been proposed as a preclinical model to study meibomian gland dysfunction. An in vitro study was conducted to evaluate neutral lipid recovery following three harvesting techniques and to identify candidate lipid biomarkers of HMGECs. HMGECs were cultured in serum-containing media for two days to promote lipid production. Cells were either harvested by 0.25% trypsin–ethylenediaminetetraacetic acid (EDTA), harvested by 10 mM EDTA, or simultaneously harvested and extracted by 2:1 chloroform–methanol (CM). After extraction by a modified Folch technique, the nonpolar phase was processed and infused into a TripleTOF 5600 mass spectrometer (Sciex, Framingham, MA, USA) with electrospray ionization. MS and MS/MS^all spectra were acquired. Nonpolar cholesteryl esters (CEs) were consistently detected in all samples, while wax esters were not. Only small differences in two out of twenty CEs were detected between harvesting methods. CM yielded less CE18:1 than the other methods but greater CE20:4 than the trypsin–EDTA method (p < 0.05 for all). Similar to human meibum, very long-chain CEs with carbon number (n_c) ≥ 24 were detected in all samples and may serve as HMGEC lipid biomarkers. Further work is needed to address the absence of wax esters. Overall, the three harvesting methods are reasonably equivalent, though CM promotes much better efficiency and is recommended for higher throughput. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders 2.0)

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22 pages, 7084 KiB

Open AccessArticle

A Multivalent ICAM-1 Binding Nanoparticle which Inhibits ICAM-1 and LFA-1 Interaction Represents a New Tool for the Investigation of Autoimmune-Mediated Dry Eye

by Pang-Yu Hsueh, Yaping Ju, Adrianna Vega, Maria C. Edman, J. Andrew MacKay and Sarah F. Hamm-Alvarez

Int. J. Mol. Sci. 2020, 21(8), 2758; https://doi.org/10.3390/ijms21082758 - 15 Apr 2020

Cited by 13 | Viewed by 4485

Abstract

The autoimmune disorder, Sjögren’s syndrome (SS), is characterized by lymphocytic infiltration and loss of function of exocrine glands such as the lacrimal gland (LG) and salivary gland. SS-associated changes in the LG are associated with the development of autoimmune-mediated dry eye disease. We [...] Read more.

The autoimmune disorder, Sjögren’s syndrome (SS), is characterized by lymphocytic infiltration and loss of function of exocrine glands such as the lacrimal gland (LG) and salivary gland. SS-associated changes in the LG are associated with the development of autoimmune-mediated dry eye disease. We have previously reported the accumulation of intercellular adhesion molecule 1 (ICAM-1) in the LG of Non-Obese Diabetic (NOD) mice, a murine model of autoimmune-mediated dry eye in SS, in both LG acinar cells and infiltrating lymphocytes. ICAM-1 initiates T-cell activation and can trigger T-cell migration through binding to lymphocyte function-associated 1 antigen (LFA). To modulate this interaction, this study introduces a new tool, a multivalent biopolymeric nanoparticle assembled from a diblock elastin-like polypeptide (ELP) using the S48I48 (SI) ELP scaffold fused with a mouse ICAM-1 targeting peptide to form IBP-SI. IBP-SI forms a multivalent, monodisperse nanoparticle with a radius of 21.9 nm. Unlike the parent SI, IBP-SI binds mouse ICAM-1 and is internalized by endocytosis into transfected HeLa cells before it accumulates in lysosomes. In vitro assays measuring lymphocyte adhesion to Tumor Necrosis Factor TNF-α-treated bEnd.3 cells, which express high levels of ICAM-1, show that adhesion is inhibited by IBP-SI but not by SI, with IC₅₀ values of 62.7 μM and 81.2 μM, respectively, in two different assay formats. IBP-SI, but not SI, also blocked T-cell proliferation in a mixed lymphocyte reaction by 74% relative to proliferation in an untreated mixed cell reaction. These data suggest that a biopolymeric nanoparticle with affinity for ICAM-1 can disrupt ICAM-1 and LFA interactions in vitro and may have further utility as an in vivo tool or potential therapeutic. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders 2.0)

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10 pages, 2051 KiB

Open AccessArticle

Alpha-Lipoic Acid Ameliorates Radiation-Induced Lacrimal Gland Injury through NFAT5-Dependent Signaling

by Hyuna Kim, Woong-Sun Yoo, Jung Hwa Jung, Bae Kwon Jeong, Seung Hoon Woo, Jin Hyun Kim and Seong Jae Kim

Int. J. Mol. Sci. 2019, 20(22), 5691; https://doi.org/10.3390/ijms20225691 - 13 Nov 2019

Cited by 18 | Viewed by 2701

Abstract

Dry eye syndrome related to radiation therapy is relatively common and can severely impair a patient’s daily life. The nuclear factor of activated T cells 5(NFAT5) is well known for its osmoprotective effect under hyperosmolar conditions, and it also has immune-modulating functions. We [...] Read more.

Dry eye syndrome related to radiation therapy is relatively common and can severely impair a patient’s daily life. The nuclear factor of activated T cells 5(NFAT5) is well known for its osmoprotective effect under hyperosmolar conditions, and it also has immune-modulating functions. We investigated the role of NFAT5 and the protective effect of α-lipoic acid(ALA) on radiation-induced lacrimal gland (LG) injuries. Rats were assigned to control, ALA only, radiation only, and ALA administered prior to irradiation groups. The head and neck area, including the LG, was evenly irradiated with 2 Gy/minute using a photon 6-MV linear accelerator. NFAT5 expression was enhanced and localized in the LG tissue after irradiation and was related to cellular apoptosis. ALA had a protective effect on radiation-induced LG injury through the inhibition of NFAT5 expression and NFAT5-dependent signaling pathways. Functional radiation–induced damage of the LG and cornea was also restored with ALA treatment. NFAT5 expression and its dependent signaling pathways were deeply related to radiation-induced dry eye, and the condition was improved by ALA treatment. Our results suggest a potential role of NFAT5 and NF-κB in the proinflammatory effect in LGs and cornea, which offers a target for new therapies to treat dry eye syndrome. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders 2.0)

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12 pages, 2951 KiB

Open AccessArticle

The Effect of Long-Term Use of an Eyewash Solution on the Ocular Surface Mucin Layer

by Hiroyuki Yazu, Naoyuki Kozuki, Murat Dogru, Ayako Shibasaki and Hiroshi Fujishima

Int. J. Mol. Sci. 2019, 20(20), 5078; https://doi.org/10.3390/ijms20205078 - 13 Oct 2019

Cited by 5 | Viewed by 3565

Abstract

The use of eyewash solutions in Japan, especially in patients with allergic conjunctivitis and contact lens wearers, has been increasing. Our aim was to investigate how the use of preservative-free eyewash solution in healthy eyes for one month affects corneal safety and ocular [...] Read more.

The use of eyewash solutions in Japan, especially in patients with allergic conjunctivitis and contact lens wearers, has been increasing. Our aim was to investigate how the use of preservative-free eyewash solution in healthy eyes for one month affects corneal safety and ocular surface mucin. We analyzed 42 eyes of 21 individuals (17 males, four females; mean age: 36.1 ± 7.4 years) without ocular allergies, dry eyes, or other ocular diseases through a prospective study. Eyes were randomized to a wash group (group one) and a nonwash follow up group (group two). We evaluated the dry eye-related quality-of-life score (DEQS), tear film breakup time (TBUT), fluorescein staining score, mRNA expression of MUC5AC and MUC16, MUC16 immunohistochemistry, and MUC5AC periodic acid Schiff (PAS) staining. There was a significant decrease in DEQS scores after one month of eyewash use (p < 0.05). There were no significant differences in other evaluation items that were analyzed (all p > 0.05). Furthermore, no significant differences were observed between group one and group two in all endpoints (all p > 0.05). The results suggest that one month use of a nonpreserved eyewash solution has no detrimental effects on the tear film and the ocular surface mucins. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders 2.0)

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15 pages, 2415 KiB

Open AccessArticle

The Effects of Rebamipide 2% Ophthalmic Solution Application on Murine Subbasal Corneal Nerves After Environmental Dry Eye Stress

by Cem Simsek, Takashi Kojima, Shigeru Nakamura, Murat Dogru and Kazuo Tsubota

Int. J. Mol. Sci. 2019, 20(16), 4031; https://doi.org/10.3390/ijms20164031 - 18 Aug 2019

Cited by 5 | Viewed by 4937

Abstract

Rebamipide ophthalmic solution is a mucin secretagogue which is an important therapeutic agent in the treatment of dry eye. It has been noted that dry eye in office workers is associated with a decrease in secretory mucin. This study aimed to evaluate the [...] Read more.

Rebamipide ophthalmic solution is a mucin secretagogue which is an important therapeutic agent in the treatment of dry eye. It has been noted that dry eye in office workers is associated with a decrease in secretory mucin. This study aimed to evaluate the effects of 2% rebamipide ophthalmic solution in mice subjected to environmental dry eye stress (EDES), which mimics the conditions of office workers. Thirty eyes from thirty BALB/c mice (eight-week-old males) were divided into three treatment groups: artificial tear (vehicle), 2% rebamipide ophthalmic solution, and 0.1% hyaluronic acid (HA) ophthalmic solution. After four days of pretreatment, mice were exposed to EDES for three days. The corneal subbasal nerve and inflammatory cells were then examined using in vivo confocal microscopy. Following EDES exposure, the lissamine green staining score was significantly lower and corneal sensitivity was more preserved in the 2% rebamipide group than in the HA group. In addition, the subbasal nerve fiber density was significantly higher and the DC density was significantly lower in the 2% rebamipide group than in the HA group. Overall, the topical rebamipide ophthalmic solution showed more favorable therapeutic effects when compared to the HA ophthalmic solution in a mouse model of EDES, likely owing to its anti-inflammatory and neuroprotective effects. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders 2.0)

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Review

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16 pages, 1048 KiB

Open AccessReview

Autoimmune Epithelitis and Chronic Inflammation in Sjögren’s Syndrome-Related Dry Eye Disease

by Yoko Ogawa, Tsutomu Takeuchi and Kazuo Tsubota

Int. J. Mol. Sci. 2021, 22(21), 11820; https://doi.org/10.3390/ijms222111820 - 30 Oct 2021

Cited by 13 | Viewed by 3732

Abstract

Autoimmune epithelitis and chronic inflammation are one of the characteristic features of the immune pathogenesis of Sjögren’s syndrome (SS)-related dry eye disease. Autoimmune epithelitis can cause the dysfunction of the excretion of tear fluid and mucin from the lacrimal glands and conjunctival epithelia [...] Read more.

Autoimmune epithelitis and chronic inflammation are one of the characteristic features of the immune pathogenesis of Sjögren’s syndrome (SS)-related dry eye disease. Autoimmune epithelitis can cause the dysfunction of the excretion of tear fluid and mucin from the lacrimal glands and conjunctival epithelia and meibum from the meibomian glands. The lacrimal gland and conjunctival epithelia express major histocompatibility complex class II or human leukocyte antigen-DR and costimulatory molecules, acting as nonprofessional antigen-presenting cells for T cell and B cell activation in SS. Ocular surface epithelium dysfunction can lead to dry eye disease in SS. Considering the mechanisms underlying SS-related dry eye disease, this review highlights autoimmune epithelitis of the ocular surface, chronic inflammation, and several other molecules in the tear film, cornea, conjunctiva, lacrimal glands, and meibomian glands that represent potential targets in the treatment of SS-related dry eye disease. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders 2.0)

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14 pages, 4295 KiB

Open AccessReview

Immune Checkpoints Contribute Corneal Immune Privilege: Implications for Dry Eye Associated with Checkpoint Inhibitors

by Junko Hori, Tomoyuki Kunishige and Yuji Nakano

Int. J. Mol. Sci. 2020, 21(11), 3962; https://doi.org/10.3390/ijms21113962 - 31 May 2020

Cited by 18 | Viewed by 3924

Abstract

The eye is provided with immune protection against pathogens in a manner that greatly reduces the threat of inflammation-induced vision loss. Immune-mediated inflammation and allograft rejection are greatly reduced in the eye, a phenomenon called ‘immune privilege’. Corneal tissue has inherent immune privilege [...] Read more.

The eye is provided with immune protection against pathogens in a manner that greatly reduces the threat of inflammation-induced vision loss. Immune-mediated inflammation and allograft rejection are greatly reduced in the eye, a phenomenon called ‘immune privilege’. Corneal tissue has inherent immune privilege properties with underlying three mechanisms: (1) anatomical, cellular, and molecular barriers in the cornea; (2) an immunosuppressive microenvironment; and (3) tolerance related to regulatory T cells and anterior chamber-associated immune deviation. This review describes the molecular mechanisms of the immunosuppressive microenvironment and regulatory T cells in the cornea that have been elucidated from animal models of ocular inflammation, especially those involving corneal transplantation, it also provides an update on immune checkpoint molecules in corneal and systemic immune regulation, and its relevance for dry eye associated with checkpoint inhibitor therapy. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders 2.0)

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17 pages, 3288 KiB

Open AccessReview

Dry Eye Disease and Tear Cytokine Levels—A Meta-Analysis

by Matilde Roda, Ivan Corazza, Maria Letizia Bacchi Reggiani, Marco Pellegrini, Leonardo Taroni, Giuseppe Giannaccare and Piera Versura

Int. J. Mol. Sci. 2020, 21(9), 3111; https://doi.org/10.3390/ijms21093111 - 28 Apr 2020

Cited by 74 | Viewed by 4771

Abstract

Background—It is recognized that inflammation is an underlying cause of dry eye disease (DED), with cytokine release involved. We systematically reviewed literature with meta-analyses to quantitatively summarize the levels of tear cytokines in DED. Methods—The PubMed, Embase, Web of Science, Ovid, Cochrane, and [...] Read more.

Background—It is recognized that inflammation is an underlying cause of dry eye disease (DED), with cytokine release involved. We systematically reviewed literature with meta-analyses to quantitatively summarize the levels of tear cytokines in DED. Methods—The PubMed, Embase, Web of Science, Ovid, Cochrane, and Scopus databases were reviewed until September 2019, and original articles investigating tear cytokines in DED patients were included. Differences of cytokines levels of DED patients and controls were summarized by standardized mean differences (SMD) using a random effects model. Study quality was assessed by applying Newcastle-Ottawa-Scale and the GRADE quality score. Methods of analytical procedures were included as covariate. Results—Thirteen articles investigating 342 DED patients and 205 healthy controls were included in the meta-analysis. The overall methodological quality of these studies was moderate. Systematic review of the selected articles revealed that DED patients had higher tear levels of interleukin (IL)-1β, IL-6, chemokine IL-8, IL-10, interferon-γ, IFN-γ, and tumor necrosis factor-α, TNF-α as compared to controls. Evidence was less strong for IL-2 and IL-17A. Conclusions—Data show that levels of tear cytokines in DED and control display a great variability, and further studies of higher quality enrolling a higher number of subjects are needed, to define a cut-off value. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders 2.0)

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14 pages, 2652 KiB

Open AccessReview

Contribution of Mucins towards the Physical Properties of the Tear Film: A Modern Update

by Georgi As. Georgiev, Petar Eftimov and Norihiko Yokoi

Int. J. Mol. Sci. 2019, 20(24), 6132; https://doi.org/10.3390/ijms20246132 - 05 Dec 2019

Cited by 57 | Viewed by 5857

Abstract

Instability of the tear film (TF) protecting the ocular surface results in dry eye syndrome (DES), the most prevalent public health ophthalmic disease affecting the quality of life of 10 to 30% of the human population worldwide. Although the impact of the tear [...] Read more.

Instability of the tear film (TF) protecting the ocular surface results in dry eye syndrome (DES), the most prevalent public health ophthalmic disease affecting the quality of life of 10 to 30% of the human population worldwide. Although the impact of the tear film lipid layer (TFLL) and of the aqueous tears (AT) to the TF stability is extensively studied, in contrast the contribution of the secretory mucins (SM) and of the membrane-associated mucins (MAM), i.e., one of the most abundant molecular classes in AT and in the corneal epithelium respectively, remains poorly defined. However, it is well known that in DES both types of mucins are quantitatively or qualitatively deficient. Numerous studies since the 1990s until now have proposed direct involvement of SM and MAM in the material properties (viscoelasticity, hydration, and protection of the ocular surface; synergistic cooperation with the rest of the TF layers; etc.) and stability of TF. These theories will be reviewed here in the context of the classical and modern in vitro and in vivo results that allow their reappraisal and in view of the novel mucin secretion enhancing pharmaceuticals, which have opened innovative routes for the therapy of DES. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders 2.0)

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18 pages, 2333 KiB

Open AccessReview

Tear Metabolomics in Dry Eye Disease: A Review

by Mazyar Yazdani, Katja Benedikte Prestø Elgstøen, Helge Rootwelt, Aboulghassem Shahdadfar, Øygunn Aass Utheim and Tor Paaske Utheim

Int. J. Mol. Sci. 2019, 20(15), 3755; https://doi.org/10.3390/ijms20153755 - 01 Aug 2019

Cited by 60 | Viewed by 14926

Abstract

Dry eye disease (DED) is a multifactorial syndrome that can be caused by alteration in the quality or quantity of the precorneal tear film. It is considered one of the most common ocular conditions leading patients to seek eye care. The current method [...] Read more.

Dry eye disease (DED) is a multifactorial syndrome that can be caused by alteration in the quality or quantity of the precorneal tear film. It is considered one of the most common ocular conditions leading patients to seek eye care. The current method for diagnostic evaluations and follow-up examinations of DED is a combination of clinical signs and symptoms determined by clinical tests and questionnaires, respectively. The application of powerful omics technologies has opened new avenues toward analysis of subjects in health and disease. Metabolomics is a new emerging and complementary research discipline to all modern omics in the comprehensive analysis of biological systems. The identification of distinct metabolites and integrated metabolic profiles in patients can potentially inform clinicians at an early stage or during monitoring of disease progression, enhancing diagnosis, prognosis, and the choice of therapy. In ophthalmology, metabolomics has gained considerable attention over the past decade but very limited such studies have been reported on DED. This paper aims to review the application of tear metabolomics in DED. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders 2.0)

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