Dry eye disease (DED) affects up to 50 % of the global population, leading to serious discomforts that affect patients' quality of life. In the multifactorial etiology of DED, oxidative stress is at the core, initiating a sequence of inflammatory responses and surface damage via a vicious cycle. However, current therapies merely have a narrow focus on inflammation. In this study, we developed a novel antioxidative eye drop, ethylenediamine (EDA)-modified C70 fullerene derivatives (abbreviated as FN-EDA), to break this vicious cycle. FN-EDA was successfully synthesized by modifying C70 fullerene with multiple ethylenediamine (EDA) groups, resulting in enhanced water solubility and a positive charge. This modification significantly improved ocular surface retention time, cellular uptake, and lysosomal escape in vitro. Therapeutically, FN-EDA significantly alleviated dry eye disease (DED) in a mouse model. It reduced corneal epithelial damage by 3.8-fold compared to 0.05 % cyclosporine A (CsA) and restored tear secretion to approximately 65 % of the normal level. Mechanistically, both in vivo and in vitro results demonstrate that FN-EDA is endowed with superior biological activity in effectively scavenging excessive oxidative stress, down-regulating proinflammatory cytokines expression, and promoting epithelial barrier reconstruction, even recovering corneal innervation. Thus, our findings open an avenue to make this multi-functional eye drop a promising candidate for DED.

Dry eye disease (DED) is a multifactorial disorder that disturbs ocular surface equilibrium, considerably diminishing quality of life. Present therapies only offer symptomatic alleviation. Stem cell treatment, especially mesenchymal stem cells (MSCs), has surfaced as a viable approach for tissue regeneration and immunological regulation in DED. Preclinical and early clinical investigations indicate that MSCs can improve lacrimal gland functionality, diminish inflammation, and facilitate corneal regeneration. Nonetheless, obstacles persist in enhancing MSC viability, determining the optimal MSC source, and guaranteeing sustained therapeutic effectiveness. Additional extensive randomized clinical trials are required to confirm the efficacy of MSC-based therapies for severe DED.

Chronic ocular graft-versus-host disease (oGVHD) is one of the most common complications after allogeneic hematopoietic stem cell transplantation (aHSCT). Recent studies indicate that desiccating stress by air-conditioning in transplantation wards increases the incidence of oGVHD. To test the hypothesis that experimental desiccating stress is a risk factor for oGVHD a mouse model of oGVHD was subjected to experimental desiccating stress.

A previously established chemo-induced minor-mismatch mouse model of oGVHD was used. One group was challenged with desiccating stress for 18 days and compared to non-desiccated GVHD animals. Clinical phenotyping was performed weekly and ocular tissue and regional lymph nodes were collected on days 7 and 28 for flow-cytometry, tear film cytokine analysis, histology for corneal lymphatics and dendritic cell counts, and corneal gene expression.

Desiccating stress leads to significant earlier and more severe systemic and oGVHD accompanied by higher numbers of activated corneal dendritic cells, higher expression of TNF in tear film and earlier corneal lymphangiogenesis. Gene expression analysis suggests that systemic GVHD severity may influence oGVHD. Different inflammatory pathways are upregulated at d28 following desiccating stress in contrast to non-desiccated GVHD.

The data presented strengthens the hypothesis, that desiccating stress during aHSCT is a risk factor for oGVHD. Together with already published clinical data, there is increasing evidence that implicates protecting patients from desiccation during the engraftment of allogeneic hematopoietic stem cells. Furthermore, specific prophylactic therapies should be developed and tested to reduce the incidence and severity of oGVHD.

Dry eye disease (DED) is a multifactorial illness affecting tears and the ocular surface. The neurokinin 1 receptor (NK1R) is a target for controlling T helper 17 (Th17) and regulatory T cell (Treg) imbalances. This work creates a silk fibroin (SF) nanoparticle hydrogel that targets NK1R with CP-99,994 (CP). Combining CP and SF to generate stable nanoparticles while integrating a flexible hydrogel material results in a sustained-release ophthalmic drop formulation (SF@CP@Gel), which provides a long-lasting ocular formulation with anti-inflammatory and reparative properties. SF@CP@Gel could maintain a stable CP concentration for 25 h with detectable biological activity. The cell counting kit-8 and 2,7-DHL-DA results reveal that SF@CP@Gel has no cytotoxic effect on human corneal epithelial cells (HCECs) and decreases the reactive oxygen species level in oxidatively damaged HCECs. Cell scratch assays demonstrate that SF@CP@Gel can greatly increase HCEC migration and proliferation within 24 h. Furthermore, in vivo therapy with topical SF@CP@Gel twice daily markedly reduce clinical symptoms by reducing the amount of pathogenic Th17 cells while efficiently restoring Treg activity. In summary, this work reveals that SF@CP@Gel might attenuate DED by inhibiting NK1R-mediated SP signaling and thereby modulating the Th17/Treg ratio, a potential anti-inflammatory and repair treatment method for DED.

To investigate the ocular surface changes during progress of the Sjögren's Syndrome (SS), using a previously described IL14α transgenic mice (IL14α TG) SS model.

The ocular surface of IL14α TG and C57BL/6 wild-type (WT) female mice were evaluated at the age of six, nine, 12, 15, and 18 months. Slit lamp microscopy observation, Oregon green dextran staining, Schirmer test, and periodic-acid-Schiff staining were assessed. Immunohistochemistry, immunofluorescence, and associated gene expression analysis by qPCR and ELISA were performed in cornea, conjunctiva, and lacrimal grand at different ages of the mice. Masson's trichome staining was conducted on lacrimal gland cryosections.

Compared with C57BL/6 WT mice, IL14α TG mice showed corneal barrier function damage and losses in conjunctival goblet cell density starting at nine months, whereas decreases in tear secretion started at 18 months of age. Significant increases in CD4+ T cell infiltration in the conjunctiva of IL14α TG mice was first observed at 6 months. Higher expression levels of inflammatory cytokines IL-17A, IFN-γ, IL-1β, and TNF-α in the conjunctiva, whereas MUC5AC and MUC5B had lower expression levels at nine months in the IL14α TG mice. However, lacrimal gland function-associated gene expression levels mostly decreased in IL14α TG mice at 12 months of age.

Ocular surface tissue changes were involved in SS-like dry eye in a time-dependent manner in IL14α TG mice, and conjunctival T-cell infiltration may contribute to ocular surface pathological changes in an early stage of SS-related dry eye.

Dry eye disease (DED) is a complicated disorder that impacts ocular surface and tear-film stability. Inflammation has recently been reported as the core mechanism and main therapeutic target of DED. Although anti-inflammatory drugs have been developed, they still have limited efficacy and various side effects. Recent reports have suggested that kinase inhibitors are beneficial for relieving inflammation. Therefore, this study aimed to investigate the anti-inflammatory effects of LCB 03-0110, a multi-tyrosine kinase inhibitor, on representative cell-based models (HCE- 2 and Th17 cells) of DED. While tacrolimus and tofacitinib, two different anti-inflammatory drugs that have entered clinical trials for DED treatment, did not induce any anti-inflammatory responses in HCE-2 cells, LCB 03-0110 significantly suppressed the phosphorylation of P38 and ERK and reduced the expression levels of IL-6 and IL-8 in HCE-2 cells treated with either LPS or poly(I:C). Moreover, LCB 03-0110 notably decreased the expression level of IL-17A in Th17 cells in a dose-dependent manner, whereas tofacitinib promoted IL-17A production at low concentrations but inhibited its expression at concentrations greater than 1 μM. In addition, LCB 03-0110 was found to be non-toxic to both HCE-2 and Th17 cells. In conclusion, these results suggest that LCB 03-0110 would be a promising drug candidate for the treatment of DED because of its advantages over tacrolimus and tofacitinib.

Background/Objectives: This study aimed to evaluate the therapeutic effects of combined 5% lifitegrast (LF) and tocopherol (TCP) eye drops in a murine experimental dry eye (EDE) model. Methods: Female C57BL/6 were divided into seven groups: untreated controls, EDE control, EDE + 0.05% cyclosporin A (CsA), EDE + tocopherol (TCP), EDE + 5% LF, EDE + 5% LF + TCP (once daily), and EDE + 5% LF + TCP (twice daily). Clinical parameters (tear volume, tear break-up time (TBUT), corneal fluorescein staining score (CFSS), tear film lipid layer grade (TFLLG)) were assessed on days 7 and 14. Goblet cell density in the conjunctiva, CD4+ IFN-γ+ T cells, interleukin levels, reactive oxygen species (ROS) levels, and corneal apoptotic cells were analyzed on day 14. Results: Monotherapy with 0.05% CsA and LF showed improvements in all clinical parameters compared to the EDE control (p < 0.05). Combination therapy groups demonstrated superior improvements in clinical parameters compared to the EDE control, 0.05% CsA, and 5% LF groups. CD4+ IFN-γ+ T cell percentages and ROS levels in the cornea and conjunctiva were markedly reduced in the combination groups compared with the 0.05% CsA and 5% LF groups (p < 0.01). Furthermore, corneal apoptotic cells significantly decreased in the combination groups compared to the 0.05% CsA and TCP groups (p < 0.05). Conclusions: Combined 5% LF and TCP eye drops improved tear film parameters and reduced inflammatory and oxidative stress markers. The combination therapy can mitigate ocular surface damage by managing inflammation and oxidative stress in dry eye.

Dry eye disease (DED) is a common multifactorial disorder characterized by a deficiency in the quality and/or quantity of tear fluid. Tear hyperosmolarity, the dysfunction of ion channel proteins, and eye inflammation are primarily responsible for the development and progression of DED. Alterations in the structure and/or function of ion channel receptors (transient receptor potential ankyrin 1 (TRPA1), transient receptor potential melastatin 8 (TRPM8), transient receptor potential vanilloid 1 and 4 (TRPV1 and TRPV4)), and consequent hyperosmolarity of the tears represent the initial step in the development and progression of DED. Hyperosmolarity triggers the activation of ion channel-dependent signaling pathways in corneal epithelial cells and eye-infiltrated immune cells, leading to the activation of transcriptional factors that enhance the expression of genes regulating inflammatory cytokine production, resulting in a potent inflammatory response in the eyes of DED patients. A persistent and untreated detrimental immune response further modifies the structure and function of ion channel proteins, perpetuating tear hyperosmolarity and exacerbating DED symptoms. Accordingly, suppressing immune cell-driven eye inflammation and alleviating tear hyperosmolarity through the modulation of ion channels in DED patients holds promise for developing new therapeutic strategies. Here, we summarize current knowledge about the molecular mechanisms responsible for the inflammation-induced modification of ion channels leading to tear hyperosmolarity and immune cell dysfunction in DED patients. We also emphasize the therapeutic potential of the newly designed immunomodulatory and hypo-osmotic solution d-MAPPS™ Hypo-Osmotic Ophthalmic Solution, which can activate TRPV4 in corneal epithelial cells, stabilize the tear film, enhance natural cytokine communication, and suppress detrimental immune responses, an important novel approach for DED treatment.

As a common complication of Sjogren syndrome (SS), SS-related dry eye disease (SS-DED) significantly affects the patients' quality of life. Pro-inflammatory cytokines in tears are widely believed to play a crucial role in the pathogenesis of SS-DED. A systematic literature review with meta-analyses was conducted to provide a quantitative summary of tear cytokine levels in SS-DED compared with non-SS-DED and healthy controls.

The PubMed, Embase, Web of Science, Ovid, and Scopus databases were searched until June 2022. Original case-control studies investigating tear cytokines in SS-DED patients compared with non-SS-DED or healthy individuals were included. Differences of cytokines levels were compared with random-effects standardized mean differences ± 95% confidence intervals calculated as the effect size.

A total of 15 articles, 809 subjects (302 for SS-DED, 220 for non-SS-DED, and 287 for healthy controls) were included in the study. SS-DED patients had higher tear levels of interferon-gamma, interleukin (IL)-17, IL-1β, IL-2, IL-4, IL-6, and IL-8 as compared to healthy controls. As for comparison between SS-DED and non-SS-DED group, the levels of IL-12p70, IL-17, IL-4, IL-6, IL-8, and tumor necrosis factor-alpha were significantly higher in SS-DED patients compared with the non-SS-DED group. The level of epidermal growth factor was significantly lower in SS-DED patients compared with both non-SS-DED patients and healthy controls.

The findings from this study provide evidence for levels of tear cytokines in SS-DED to become potential diagnostic biomarkers or therapeutic targets. Further studies with a higher number of subjects and improved quality are necessary.

Substance P is a neuropeptide expressed by nerves and an array of cells that serves as a critical mediator of neuroinflammation. Our recent work has demonstrated that blocking the preferred receptor for substance P, neurokinin 1 receptor, effectively suppresses the induction of acute dry eye disease by preserving regulatory T-cell function, while inhibiting antigen-presenting cell maturation and subsequent generation of effector Th17 cells. Clinically, dry eye disease is a chronic disorder characterized by sustained ocular surface inflammation, which is mediated by long-lived memory Th17 cells demonstrated in our well-established chronic dry eye disease model. The present study aimed to further understand the function of substance P in the chronic phase of dry eye disease and its role in regulating the underlying pathogenic memory Th17. In vitro culture of effector T cells isolated from acute dry eye disease with substance P led to an enhanced conversion of effector Th17 to memory Th17, while culturing memory T cells isolated from chronic dry eye disease with substance P effectively preserved the memory Th17 cells. In contrast, the addition of a neurokinin 1 receptor antagonist in the cultures abolished the substance P-mediated effects. Furthermore, in vivo treatment with the neurokinin 1 receptor antagonist during the resolution phase of acute dry eye disease significantly suppressed memory Th17 generation, and treatment in the chronic phase of dry eye disease disrupted the maintenance of memory Th17. Taken together, our results demonstrate that increased expression of substance P promotes memory Th17 generation and maintenance in chronic dry eye disease, and thus blockade of substance P represents a novel promising memory Th17-targeting strategy in treating chronic ocular surface inflammation.

Dry eye disease (DED) is characterized by a dysfunctional tear film in which the corneal epithelium and its abundant nerves are affected by ocular desiccation and inflammation. Although adaptive immunity and specifically CD4+ T cells play a role in DED pathogenesis, the exact contribution of these cells to corneal epithelial and neural damage remains undetermined. To address this, we explored the progression of a surgical DED model in wild-type (WT) and T cell-deficient mice. We observed that adaptive immune-deficient mice developed all aspects of DED comparably to WT mice except for the absence of functional and morphological corneal nerve changes, nerve damage-associated transcriptomic signature in the trigeminal ganglia, and sustained tear cytokine levels. Adoptive transfer of CD4+ T cells from WT DED mice to T cell-deficient mice reproduced corneal nerve damage but not epitheliopathy. Conversely, T cell-deficient mice reconstituted solely with naïve CD4+ T cells developed corneal nerve impairment and epitheliopathy upon DED induction, thus replicating the WT DED phenotype. Collectively, our data show that while corneal neuropathy is driven by CD4+ T cells in DED, corneal epithelial damage develops independently of the adaptive immune response. These findings have implications for T cell-targeting therapies currently in use for DED.

To evaluate the effects of dry eye on conjunctival immune cell number and transcriptional profiles with attention to mononuclear phagocytes.

Expression profiling was performed by single-cell RNA sequencing on sorted conjunctival immune cells from non-stressed and C57BL/6 mice subjected to desiccating stress (DS). Monocle 3 modeled cell trajectory, scATAC-seq assessed chromatin accessibility and IPA identified canonical pathways. Inflammation and goblet cells were measured after depletion of MRC1+ MΦs with mannosylated clodronate liposomes.

Mononuclear phagocytes (monocytes, MΦs, DCs) comprised 72 % of immune cells and showed the greatest changes with DS. Distinct DS induced gene expression patterns were seen in phagocytes classified by expression of Ccr2 and [Timd4, Lyve1, Folr2 (TLR)]. Expression of phagocytosis/efferocytosis genes increased in TLF+CCR2- MΦs. Monocytes showed the highest expression of Ace, Cx3cr1, Vegfa, Ifngr1,2, and Stat1 and TLF-CCR2+ cells expressed higher levels of inflammatory mediators (Il1a, Il1b, Il1rn, Nfkb1, Ccl5, MHCII, Cd80, Cxcl10, Icam1). A trajectory from monocyte precursors branched to terminate in regulatory MΦs or in mDCs via transitional MΦ and cDC clusters. Activated pathways in TLF+ cells include phagocytosis, PPAR/RXRα activation, IL-10 signaling, alternate MΦ activation, while inflammatory pathways were suppressed. Depletion of MRC1+ MΦs increased IL-17 and IFN-γ expression and cytokine-expressing T cells, reduced IL-10 and worsened goblet loss.

Dryness stimulates distinct gene expression patterns in conjunctival phagocytes, increasing expression of regulatory genes in TLF+ cells regulated in part by RXRα, and inflammatory genes in CCR2+ cells. Regulatory MΦs depletion worsens DS induced inflammation and goblet cell loss.

Tissue-specific delivery of oligonucleotide therapeutics beyond the liver remains a key challenge in nucleic acid drug development. To address this issue, exploiting exosomes as a novel carrier has emerged as a promising approach for efficient nucleic acid drug delivery. However, current exosome-based delivery systems still face multiple hurdles in their clinical applications. Herein, this work presents a strategy for constructing a hybrid exosome vehicle (HEV) through a DNA zipper-mediated membrane fusion approach for tissue-specific siRNA delivery. As a proof-of-concept, this work successfully fuses a liposome encapsulating anti-NFKBIZ siRNAs with corneal epithelium cell (CEC)-derived exosomes to form a HEV construct for the treatment of dry eye disease (DED). With homing characteristics inherited from exosomes, the siRNA-bearing HEV can target its parent cells and efficiently deliver the siRNA payloads to the cornea. Subsequently, the NFKBIZ gene silencing significantly reduces pro-inflammatory cytokine secretions from the ocular surface, reshapes its inflammatory microenvironment, and ultimately achieves an excellent therapeutic outcome in a DED mouse model. As a versatile platform, this hybrid exosome with targeting capability and designed therapeutic siRNAs may hold great potential in various disease treatments.

Immunopeptides have low toxicity, low immunogenicity and targeting, and broad application prospects in drug delivery and assembly, which are diverse in application strategies and drug combinations. Immunopeptides are particularly important for regulating ocular immune homeostasis, as the eye is an immune-privileged organ. Immunopeptides have advantages in adaptive immunity and innate immunity, treating eye immune-related diseases by regulating T cells, B cells, immune checkpoints, and cytokines. This article summarizes the application strategies of immunopeptides in innate immunity and adaptive immunity, including autoimmunity, infection, vaccine strategies, and tumors. Furthermore, it focuses on the mechanisms of immunopeptides in mediating ocular immunity (autoimmune diseases, inflammatory storms, and tumors). Moreover, it reviews immunopeptides' application strategies and the therapeutic potential of immunopeptides in the eye. We expect the immune peptide to get attention in treating eye diseases and to provide a direction for eye disease immune peptide research.

Dry eye is a chronic and multifactorial ocular surface disease caused by tear film instability or imbalance in the microenvironment of the ocular surface. It can lead to various discomforts such as inflammation of the ocular surface and visual issues. However, the mechanism of dry eye is not clear, which results in dry eye being only relieved but not cured in clinical practice. Finding multiple environmental pathways for dry eye and exploring the pathogenesis of dry eye have become the focus of research. Studies have found that changes in microbiota may be related to the occurrence and development of dry eye disease.

Entered the keywords "Dry eye", "Microbiota", "Bacteria" through PUBMED, summarised the articles that meet the inclusion criteria and then filtered them while the publication time range of the literature was defined in the past 5 years, with a deadline of 2023.A total of 13 clinical and 1 animal-related research articles were screened out and included in the summary.

Study found that different components of bacteria can induce ocular immune responses through different receptors present on the ocular surface, thereby leading to an imbalance in the ocular surface microenvironment. Changes in the ocular surface microbiota and gut microbiota were also found when dry eye syndrome occurs, including changes in diversity, an increase in pro-inflammatory bacteria, and a decrease in short-chain fatty acid-related bacterial genera that produce anti-inflammatory effects. Fecal microbiota transplantation or probiotic intervention can alleviate signs of inflammation on the ocular surface of dry eye animal models.

By summarizing the changes in the ocular surface and intestinal microbiota when dry eye occurs, it is speculated and concluded that the intestine may affect the occurrence of eye diseases such as dry eye through several pathways and mechanisms, such as the occurrence of abnormal immune responses, microbiota metabolites- intervention of short-chain fatty acids, imbalance of pro-inflammatory and anti-inflammatory factors, and release of neurotransmitters, etc. Analyzing the correlation between the intestinal tract and the eyes from the perspective of microbiota can provide a theoretical basis and a new idea for relieving dry eyes in multiple ways in the future.

Myeloid derived suppressor cells (MDSCs) are a heterogenous population of immature hematopoietic precursors with known immunoregulatory functions. The immunosuppressive role of MDSCs has been highlighted in several inflammatory ophthalmic disorders; however, their therapeutic application in suppressing the immune-mediated changes in dry eye disease (DED) has not been studied. We observed significant reduction in antigen presenting cell (APC) frequencies and their maturation in the presence of MDSCs. Moreover, co-culturing MDSCs with T helper 17 cells (Th17) resulted in reduced Th17 frequencies and their IL-17 expression. On the contrary, MDSCs maintained regulatory T cell frequencies and enhanced their function in-vitro. Furthermore, we delineated the role of interleukin-10 (IL-10) secreted by MDSCs in their immunoregulatory functions. We confirmed these results by flow cytometry analysis and observed that treatment with MDSCs in DED mice effectively suppressed the maturation of APCs, pathogenic Th17 response, and maintained Treg function and significantly ameliorated the disease. The results in this study highlight the potential therapeutic application of MDSCs in treating refractory DED.

The aim of this study was to observe the expression of interleukin (IL)-17 and intercellular adhesion molecule (ICAM)-1 in conjunctivochalasis (CCH) and to analyze the correlations between cytokines and the severity of CCH.

Serum samples were collected from 22 patients with CCH and 18 normal controls (NCs). The Ocular Surface Disease Index, tear film break-up time, Schirmer I test, and corneal fluorescein staining were used to evaluate the ocular surface signs and symptoms. The concentrations of IL-17, IL-23, and ICAM-1 in serum and cellular supernatants were measured by enzyme-linked immunosorbent assays, and the gene expression levels of cytokines were measured by a quantitative real-time polymerase chain reaction. The relationships between serum concentrations of IL-17, IL-23, and ICAM-1 with clinical ocular surface parameters in CCH were analyzed using the Spearman correlation analysis.

The concentrations of IL-17 and ICAM-1 in serum and cellular supernatants of CCH were significantly higher than those of NCs (all P < 0.001). The concentrations of IL-23 in serum and cellular supernatants of CCH showed no significant difference from those of NCs ( P > 0.05). The mRNA expression levels of IL-17 and ICAM-1 in conjunctival fibroblasts of CCH were significantly higher than those of NCs (all P < 0.001). The mRNA expression of IL-23 in conjunctival fibroblasts of CCH was higher than that of NCs, without a significant difference ( P > 0.05). Furthermore, the serum concentrations of IL-17 and ICAM-1 were positively correlated with Ocular Surface Disease Index and fluorescein staining (all P < 0.05), and negatively correlated with break-up time and Schirmer I test of CCH (all P < 0.05).

The expression levels of IL-17 and ICAM-1 were significantly increased in CCH serum and associated with the disease severity. We postulate that IL-17 and ICAM-1 may play a role in the pathogenesis of CCH. IL-17 and ICAM-1 antagonists may be a potential treatment option for CCH in the future.

Herpes simplex virus (HSV) infection of the cornea, uvea, and retina is the leading infectious cause of blindness worldwide. This study examined the effects of retinoic acid (RA) on the protein levels of interleukin (IL)-17A and IL-23 cytokines with known proinflammatory effects and toll-like receptor 3 (TLR3) messenger RNA (mRNA) expression in retinal pigment epithelial (ARPE-19) cells treated with HSV-1-infected cell protein 0 (ICP0).

We used 3-[4.5-dimethylthiazol-2-yl]-2.5-diphenyl tetrazolium bromide assay to calculate the half maximal inhibitory concentration (IC50) doses of RA and ICP0 in ARPE-19 cells. At the end of 24 hours, protein levels of IL-17A and IL-23 were analyzed using enzyme-linked immunosorbent assay. TLR3 mRNA expression levels were also calculated using reverse transcription-polymerase chain reaction (RT-PCR).

RA administration decreased IL-17A levels, which were elevated by ICP0. The IL-23 levels were similar between the ICP0-treated and control groups, but the difference was significant between the ICP0-treated group and RA+ICP0 combination. These results showed that RA can significantly increase IL-23 levels in the presence of ICP0. Although ICP0 dramatically increased TLR3 mRNA expression compared with that in the control group, the RA+ICP0 combination returned TLR3 mRNA expression to a level similar to that in the control group (P = 0.419).

RA may potentially neutralize HSV-1 ICP0 negative effects in ARPE-19 cells.

Changes in the bacterial flora in the gut, also described as gut microbiota, are readily acknowledged to be associated with several systemic diseases, especially those with an inflammatory, neuronal, psychological or hormonal factor involved in the pathogenesis and/or the perception of the disease. Maintaining ocular surface homeostasis is also based on all these four factors, and there is accumulating evidence in the literature on the relationship between gut microbiota and ocular surface diseases. The mechanisms involved are mostly interconnected due to the interaction of central and peripheral neuronal networks, inflammatory effectors and the hormonal system. A better understanding of the influence of the gut microbiota on the maintenance of ocular surface homeostasis, and on the onset or persistence of ocular surface disorders could bring new insights and help elucidate the epidemiology and pathology of ocular surface dynamics in health and disease. Revealing the exact nature of these associations could be of paramount importance for developing a holistic approach using highly promising new therapeutic strategies targeting ocular surface diseases.

Meibomian gland dysfunction (MGD) is a leading cause of dry eye disease and one of the most common ophthalmic conditions encountered in eye clinics worldwide. These holocrine glands are situated in the eyelid, where they produce specialized lipids, or meibum, needed to lubricate the eye surface and slow tear film evaporation - functions which are critical to preserving high-resolution vision. MGD results in tear instability, rapid tear evaporation, changes in local microflora, and dry eye disease, amongst other pathological entities. While studies identifying the mechanisms of MGD have generally focused on gland obstruction, we now know that age is a major risk factor for MGD that is associated with abnormal cell differentiation and renewal. It is also now appreciated that immune-inflammatory disorders, such as certain autoimmune diseases and atopy, may trigger MGD, as demonstrated through a T cell-driven neutrophil response. Here, we independently discuss the underlying roles of gland and immune related factors in MGD, as well as the integration of these two distinct mechanisms into a unified perspective that may aid future studies. From this unique standpoint, we propose a revised model in which glandular dysfunction and immunopathogenic pathways are not primary versus secondary contributors in MGD, but are fluid, interactive, and dynamic, which we likened to the Yin and Yang of MGD.

We investigated the effects of vitamin D on the ocular surface, tear functions, corneal imaging, and tear film cytokine levels.

Fifty-two patients with vitamin D levels were examined in 3 groups according to serum vitamin D levels; 28 in group 1 (<12 ng/ml), 10 in group 2 (12-20 ng/ml), and 14 in group 3 (>20 ng/ml). Ocular surface disease index (OSDI), tear break up time (BUT), lissamine green (LG) staining, Schirmer test, in vivo confocal microscopy (IVCM), and tear collection for cytokine analysis were performed.

The mean OSDI score was 35.2 ± 23.3, 36.2 ± 17.7, 24.4 ± 18.2 (p = .253), TBUT was 6.7 ± 2.5 sec, 9.3 ± 1.8 sec, 11.1 ± 2.8 sec (p < .001), Schirmer test was 16.7 ± 8.5 mm, 18.7 ± 7.6 mm, and 20.2 ± 7 mm (p = .254), median LG staining grade was 1 (0-3), 1 (0-2), 0 (0-1) (p = .008) in group 1, group 2, and group 3, respectively. Basal epithelial cell density was 4 027 ± 512 cells/mm2, 4 673 ± 451 cells/mm2, 5 067 ± 817 cells/mm2 (p = < 0.001), sub-basal nerve density was 978 ± 204 μm/frame, 1 236 ± 172 μm/frame, 1 425 ± 290 μm/frame (p = <0.001), median number of long nerve fibers was 3 (2-4) nerve/frame, 4 (3-4) nerve/frame, 4 (3-6) nerve/frame (p = .001), and median grade of nerve fiber tortuosity was 2 (0-3), 2.5 (2-3), 3 (2-4) (p < .001) in group 1, group 2, and group 3, respectively. Mean IL-1 β (82.62 ± 15.26, 85.57 ± 17.41, and 66.44 ± 11 ng/ml in group 1, 2 and 3, respectively, p = .002), IL-17 (77.80 ± 24.91, 64.46 ± 25.47, 55.42 ± 12.05 ng/ml in group 1, 2 and 3, respectively, p = .012), and IL-2 (75.7 ± 18.4, 66.13 ± 26.78, and 59.65 ± 16.04 ng/ml in group 1, 2 and 3, respectively, p = .048) levels were significantly lower in group 3, whereas, IL-13 levels were significantly higher in group 3 (16.12 ± 5.24, 19.20 ± 4.90, and 21.6 ± 5.55 ng/ml in groups 1, 2, and 3, respectively, p = .010).

Vitamin D deficiency/insufficiency is associated with ocular surface changes shown with significant TBUT, LG staining, and tear film cytokine contents. Besides, significant corneal basal epithelial, sub-basal nerve density, and structural sub-basal nerve changes were associated with lower Vitamin D levels.

The purpose of this study was to extensively evaluate the efficacy of integrin αvβ3 antagonists for the treatment of experimental dry eye (EDE).

Vitronectin, an αvβ3 ligand, was used to induce tumor necrosis factor-α gene expression in human THP-1 macrophages. To induce EDE, C57BL/6 mice were housed in a low-humidity controlled environment chamber and injected subcutaneously with scopolamine for 7 days. Subsequently, αvβ3 antagonists, including RGDfD, c(RGDfD), c(RGDiD), c(RGDfK), ATN-161, SB273005, and cilengitide, were administered topically to EDE animals under controlled environment chamber conditions. Corneal epithelial damage in EDE was assessed by fluorescein staining. The density of conjunctival goblet cells and secretion of tears was measured by period acid-Schiff staining and phenol red-impregnated cotton threads, respectively. Inflammation markers, including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, IL-17A, and metalloproteinase (MMP)-9, in the pooled cornea and conjunctiva tissues were examined by real-time polymerase chain reaction.

The inhibitory effects of αvβ3 antagonists on the vitronectin-induced tumor necrosis factor-α gene expression and integrin-mediated inflammatory signaling were validated in THP-1 macrophages. αvβ3 antagonists ameliorated the impairment of the corneal epithelial barrier with varying therapeutic efficacies, compared with vehicle-treated mice. c(RGDfD) and c(RGDiD) significantly protected against goblet cell loss, tear reduction, and proinflammatory gene expression in EDE.

Topical applications of αvβ3 antagonists yield therapeutic benefits in EDE by promoting corneal epithelial defect healing and reducing inflammation. Antagonistic targeting αvβ3 may be a novel promising strategy to treat patients with dry eye disease.

Systemic Lupus Erythematosus (SLE) is a complex autoimmune disorder characterized by immune dysregulation and multi-organ involvement. In this concise brief review, we highlight key insights into Ocular Systemic Lupus Erythematosus (SLE), an intricate autoimmune disorder with diverse organ involvement. Emphasizing the formation of autoantibodies and immune complex deposition, we delve into the inflammation and damage affecting ocular structures. Clinical presentations, ranging from mild dry eye syndrome to severe conditions like retinal vasculitis, necessitate a comprehensive diagnostic approach, including clinical exams, serological testing, and imaging studies. Differential diagnosis involves distinguishing SLE-related ocular manifestations from other autoimmune and non-inflammatory ocular conditions. The multidisciplinary management approach, involving rheumatologists, ophthalmologists, and immunologists, tailors treatment based on ocular involvement severity, encompassing corticosteroids, immunosuppressive agents, and biologics. Follow-up is crucial for monitoring disease progression and treatment response. Future perspectives revolve around advancing molecular understanding, refining diagnostic tools, and exploring targeted therapies. Novel research areas include genetic factors, microbiome composition, and biotechnology for tailored and effective SLE ocular treatments.

Dry eye (DE) is a multifactorial ocular surface disease characterised by an imbalance in tear homeostasis. The pathogenesis of DE is complex and related to environmental, immunological (e.g., T helper 17 cells) and other factors. However, the DE disease pathogenesis remains unclear, thereby affecting its clinical treatment. This study aimed to explore the mechanism through which prostaglandin E2 (PGE2) affects DE inflammation by regulating Th17. The DE mouse model was established through subcutaneous injection of scopolamine hydrobromide. The tear secretion test and break-up time (BUT) method were used to detect tear secretion and tear film BUT, respectively. Enzyme-linked immunosorbent assay (ELISA) was used to detect the concentrations of PGE2, interleukin (IL)-17, IL-6 and tumour necrosis factor (TNF-α) in tear fluid and those of PGE2 and IL-17 in the serum. RT-qPCR and western blotting were used to test the mRNA and protein expression levels of IL-17 and retinoid-related orphan receptor-γt (RORγt). PGE2 was highly expressed in the DE mouse model. The mRNA and protein levels of IL-17 and the key Th17 transcription factor RORγt were increased in tissues of the DE mice. Moreover, PGE2 promoted tear secretion, reduced the BUT, increased the IL-17 concentration in tears and increased the Th17 cell proportion in DE, whereas the PGE2 receptor inhibitor AH6809 reversed the effects of PGE2 on tear secretion, BUT, and the Th17 cell proportion in draining lymph node (DLN) cells. Taken together, the study findings indicate that PGE2 could induce DE-related symptoms by promoting Th17 differentiation.

Dry eye disease (DED) is a commonly reported ocular complaint that has garnered significant attention in recent research. The global occurrence of DED ranges from 5% to 50%, impacting a substantial proportion of individuals worldwide with increasing frequency. Although topical administration remains the mainstream drug delivery method for ocular diseases, it suffers from drawbacks such as low bioavailability, rapid drug metabolism, and frequent administration requirements. Fortunately, the advancements in nanomedicine offer effective solutions to address the aforementioned issues and provide significant assistance in the treatment of DED.

DED is considered a multifactorial disease of the ocular surface and tear film, in which the integrity of tear film function and structure plays a crucial role in maintaining the homeostasis of the ocular surface. The conventional treatment for DED involves the utilization of artificial tear products, cyclosporin, corticosteroids, mucin secretagogues, and nonsteroidal anti-inflammatory drugs. Furthermore, nanomedicine is presently a significant field of study, with numerous clinical trials underway for various nanotherapeutics including nanoemulsions, nanosuspensions, liposomes, and micelles. Notably, some of these innovative nanoformulations have already received FDA approval as novel remedies for DED, and the advancement of nanomedicine is poised to offer enhanced prospects to solve the shortcomings of existing treatments for DED partially.

This article provides an overview of the latest advancements in nanomedicine for DED treatment, while the field of DED treatment is expected to witness a remarkable breakthrough shortly with the development of nanomedicine, bringing promising prospects for patients worldwide suffering conditions.

Dry eye disease (DED) is a growing health concern that impacts millions of individuals every year, and is associated with corneal injury, excessive oxidative stress and inflammation. Current therapeutic strategies, including artificial tears and anti-inflammatory agents, are unable to achieve a permanent clinical cure due to their temporary nature or adverse side effects. Therefore, here, we investigated the effectiveness of the topical administration of programmed death-ligand 1 (PD-L1) in the mouse model of DED. The model was generated in C57BL/6 mice by excising the extra orbital lacrimal gland and causing desiccation stress with scopolamine injections. Subsequently, either phosphate-buffered saline (3 µL/eye) or PD-L1 (0.5 µg/mL) was topically administered for 10 days. Tear volume was evaluated with phenol red thread, and corneal fluorescein staining was observed to quantify the corneal epithelial defect. Corneas were collected for histological analysis, and the expression levels of inflammatory signaling proteins such as CD4, CD3e, IL-17, IL-1β, pIkB-α, pNF-kB and pERK1/2 were assessed through immunofluorescence and Western blot techniques. Our results demonstrate that desiccating stress-induced corneal epithelial defect and tear secretion were significantly improved by topical PD-L1 and could reduce corneal CD4+ T cell infiltration, inflammation and apoptosis in a DED mouse model by downregulating IL-17 production and ERK1/2-NFkB pathways.

To investigate the impact of transmembrane protein CMTM6 on the pathogenesis of dry eye disease (DED) and elucidate its potential mechanisms.

CMTM6 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.

CMTM6 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.

The 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.

This study is mainly based on T helper type 17 (Th17) cells analysis of the mechanism of prostaglandin E2 (PGE2) promoting the progression of dry eye (DE). Scopolamine and dry environment were used to induce mice DE model. Celecoxib was used to inhibit PGE2. Corneal epithelial cells and CD4+ T cells were used to construct a co-culture system. The osmotic pressure was increased by adding NaCl to simulate DE in vitro. AH6809 and E7046 were used to pre-culture to inhibit EP2/4 in T cells to verify the effect of exogenous PGE2 on Th17 cell differentiation and corneal epithelial cell apoptosis. The function of Th17 cells was analyzed by detecting RORγt and interleukin-17 (IL-17). PGE2 was instilled on the ocular surface to induce DE symptoms of mice. AH6809 and E7046 were used to inhibit EP2/4. The corneal epithelial cell apoptosis was observed by TUNEL. The proportion of Th17 cells in corneal tissue and draining lymph nodes (DLNs) was detected by flow cytometry. In DE mice, the concentration of PGE2 and IL-17 increased in tears, and the proportion of Th17 increased, while inhibition of PGE2 alleviated the symptoms of DE and inhibited Th17 differentiation. Hypertonic environment induces corneal epithelial cells to secrete PGE2. PGE2 promoted the expression of EP2/4 and the differentiation of Th17 cells in vitro. The hypertonic environment promoted PGE2 level and the apoptosis of corneal epithelial cells in the co-culture system. PGE2 alone did not cause corneal epithelial cell apoptosis, while PGE2 promoted apoptosis by promoting Th17. Blocking EP2/4 reduced the induction of Th17 differentiation by PGE2 and the promoted corneal epithelial cell apoptosis. Animal experiments showed that exogenous PGE2 induced DE symptoms. Blocking EP2/4 not only inhibited the proportion of Th17, but also alleviated the apoptosis of corneal epithelial cells caused by PGE2. PGE2 induces aggravation of inflammation by promoting the level of Th17 in the ocular surface, and causes corneal epithelial cell apoptosis, thereby participating in the progression of DE.

This study aimed to analyze the differences in the expression of pain-related genes in conjunctival epithelial cells among symptomatic contact lens (CL) wearers (SCLWs), asymptomatic CL wearers (ACLWs), and non-CL wearers (non-CLWs).

For this study, 60 participants (20 non-CLWs, 40 CLWs) were enrolled. The CLW group comprised 20 ACLWs and 20 SCLWs according to the Contact Lens Dry Eye Questionnaire short form©. Conjunctival cells were collected using impression cytology, and RNA was isolated and used to determine the expression levels of 85 human genes involved in neuropathic and inflammatory pain. The effects of CL wear and discomfort were evaluated using mixed-effects ANOVA with partially nested fixed-effects model. Gene set enrichment analysis was performed to assign biological meaning to sets of differentially expressed genes.

Six genes (CD200, EDN1, GRIN1, PTGS1, P2RX7, and TNF) were significantly upregulated in CLWs compared to non-CLWs. Eleven genes (ADORA1, BDKRB1, CACNA1B, DBH, GRIN1, GRM1, HTR1A, PDYN, PTGS1, P2RX3, and TNF) were downregulated in SCLWs compared to ACLWs. These genes were mainly related to pain, synaptic transmission and signaling, ion transport, calcium transport and concentration, and cell-cell signaling.

CL wear modified the expression of pain- and inflammation-related genes in conjunctival epithelial cells. These changes may be in part, along with other mechanisms, responsible for CL discomfort in SCLWs.

Meibomian gland dysfunction (MGD) leads to meibum stasis and pathogenic bacteria proliferation. We determined meibum microbiota via next-generation sequencing (NGS) and examined their association with tear cytokine levels in patients with MGD. This cross-sectional study included 44 moderate-severe patients with MGD and 44 healthy controls (HCs). All volunteers underwent assessment with the ocular surface disease index questionnaire, Schirmer without anesthesia, tear break-up time, Oxford grading of ocular surface staining, and lid and meibum features. Sample collection included tears for cytokine detection and meibum for 16S rRNA NGS. No significant differences were observed in the α-diversity of patients with MGD compared with that in HCs. However, Simpson's index showed significantly decreased α-diversity for severe MGD than for moderate MGD (p = 0.045). Principal coordinate analysis showed no significant differences in β-diversity in meibum samples from patients with MGD and HCs. Patients with MGD had significantly higher relative abundances of Bacteroides (8.54% vs. 6.00%, p = 0.015) and Novosphingobium (0.14% vs. 0.004%, p = 0.012) than the HCs. Significantly higher interleukin (IL)-17A was detected in the MGD group than in the HC group, particularly for severe MGD (p = 0.008). Although Bacteroides was more abundant in the MGD group than in the HC group, it was not positively correlated with IL-17A. The relationship between core meibum microbiota and tear cytokine levels remains unclear. However, increased Bacteroides and Novosphingobium abundance may be critical in MGD pathophysiology.

Dry eye disease (DED) is a multifactorial disease in ocular surface, and inflammation plays an etiological role. Berberine (BBR) has shown efficacy in treating inflammatory diseases. Yet, there was no adequate information related to the therapeutic effects of BBR for DED.

To detect the effects and explore the potential mechanisms of BBR on DED.

In vitro, in vivo study and network pharmacology analysis were involved.

The human corneal epithelium cells viability was evaluated with different concentrations of BBR. Dry eye murine model was established by exposing to the desiccating stress, and Ciclosporin (CSA), BBR eye drops or vehicle were topical administration for 7 days. The phenol red cotton tests, Oregon-green-dextran staining and Periodic acid-Schiff staining were performed and evaluated the dry eye after treatment. Inflammation and apoptosis levels of ocular surface were quantified. The potential targets related to berberine and dry eye were collected from databases. The Protein-Protein interaction network analysis and GO & KEGG enrichment analysis were realized by STRING database, Metascape platform and Cytoscape software to find core targets and signaling pathways. The SchrÖdinger software was used to molecular docking and PyMOL software to visualization. Finally, the levels of PI3K/AKT/NFκB and MAPK pathways were detected.

The data revealed BBR could rescue impaired HCE under hyperosmotic conditions. In addition, BBR eye drops could ameliorate dry eye. And BBR eye drops suppressed the inflammatory factors and CD4+T cells infiltration in conjunctiva. Besides, BBR eye drops protected ocular surface by avoiding the severe apoptosis and decreasing the level of MMP-3 and MMP-9. 148 common targets intersection between BBR and dry eye were found via network pharmacology analysis. Core proteins and core pathways were identified through PPI and GO&KEGG enrichment analysis. Molecular docking displayed excellent binding between BBR and those core targets. Finally, in vivo study verified that BBR eye drops had a therapeutic effect in dry eye by inhibiting PI3K/AKT/NFκB and MAPK pathways.

The research provided convincing evidence that BBR could be a candidate drug for dry eye.

Dry eye disease (DED) is a multifactorial disorder of the lacrimal system and ocular surface, characterized by a deficiency in the quality and/or quantity of the tear fluid. The multifactorial nature of DED encompasses a number of interconnected underlying pathologies, including loss of homeostasis, instability and hyperosmolarity of the tears, and the induction and propagation of detrimental inflammatory responses in the eyes, which finally results in the development of neurosensory dysfunction and visual disruption. Dryness, grittiness, scratchiness, discomfort, inflammation, burning, watering, ocular fatigue, pain, and decreased functional visual acuity are common symptoms of DED. Eye dysfunction drastically attenuates patients' quality of life. Accordingly, a better understanding of the pathogenic processes that regulate the development and progression of DED is crucially important for the establishment of new and more effective DED-related treatment approaches, which would significantly improve the quality of life of DED patients. Since the process of osmoregulation, which guards the ocular surface epithelia and maintains normal vision, is affected when the osmolarity of the tears is greater than that of the epithelial cells, tear hyperosmolarity (THO) is considered an initial, important step in the development, progression, and aggravation of DED. In order to delineate the role of THO in the pathogenesis of DED, in this review article, we summarize current knowledge related to the molecular mechanisms responsible for the development of THO-induced pathological changes in the eyes of DED patients, and we briefly discuss the therapeutic potential of hypo-osmotic eye drops in DED treatment.

People with diabetes mellitus (DM) are at an increased risk for developing dry eye disease (DED). However, the mechanisms underlying this phenomenon remain unclear. Recent studies have found that the ocular surface microbiota (OSM) differs significantly between patients with DED and healthy people, suggesting that OSM dysbiosis may contribute to the pathogenesis of DED. This hypothesis provides a new possible explanation for why diabetic patients have a higher prevalence of DED than healthy people. The high-glucose environment and the subsequent pathological changes on the ocular surface can cause OSM dysbiosis. The unbalanced microbiota then promotes ocular surface inflammation and alters tear composition, which disturbs the homeostasis of the ocular surface. This "high glucose-OSM dysbiosis" pathway in the pathogenesis of DED with DM (DM-DED) is discussed in this review.

Corneal epithelial barrier function is important to maintain corneal homeostasis and is impaired by inflammation. We aimed to investigate the localization of semaphorin 4D (Sema4D) in the cornea, and its effects on the barrier function of cultured corneal epithelial cells.

The expressions of semaphorin4 D and its receptor in the murine cornea were examined by immunoblot, immunofluorescent staining and confocal microscopy observations. Human corneal epithelial (HCE) cells stimulated by TNF-α or IL-1β were cultured with or without Sema4D. Cell viability was examined by CCK8, cell migration was evaluated by scratch wound assay, and barrier function was assessed by transepithelial electrical resistance (TEER) and Dextran-FITC permeability assay. The expression of tight junction proteins in HCE cells was examined by immunoblot, immunofluorescent staining and qRT-PCR.

We demonstrated that the protein of Sema4D and its receptor, plexin-B1, was expressed in murine cornea. Sema4D induced an increase in the TEER and a decrease in the permeability of HCE cells. It also induced the expression of tight junction protein ZO-1, occludin and claudin-1 in HCE cells. Furthermore, under stimulation of TNF-α or IL-1β, Sema4D treatment could inhibit the decreased TEER and the elevated permeability of HCE cells.

Sema4D is located distinctly in corneal epithelial cells and promoted their barrier function by increasing the expression of tight junction proteins. Sema4D may act as a preventive for maintaining corneal epithelial barrier function during ocular inflammation.

To investigate clinical characteristics and tear film biomarkers of patients with chronic dry eye disease (DED) following femtosecond laser-assisted laser in situ keratomileusis (FS-LASIK).

Patients were divided into the chronic DED after FS-LASIK (n = 36), DED without FS-LASIK (n = 39), and normal control (without FS-LASIK; n = 34) groups. Dry eye, pain, and psychological-related symptoms were evaluated using the Ocular Surface Disease Index (OSDI), Numerical Rating Scale (NRS), Neuropathic Pain Symptom Inventory Modified for the Eye (NPSI-Eye), and Hamilton Anxiety Rating Scale (HAMA) questionnaires. Ocular surface parameters, tear cytokines, and neuropeptide concentrations were evaluated with specific tests.

The DED after FS-LASIK group showed higher corneal fluorescein staining scores, but lower OSDI and NPSI-Eye scores than the DED without FS-LASIK group (all P < .05). Corneal sensitivity and nerve density decreased in the DED after FS-LASIK group (all P < .01). Granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-17A, IL-23, alpha-melanocyte stimulating hormone (α-MSH), oxytocin, and substance P levels were highest in the DED after FS-LASIK group, followed by the DED without FS-LASIK and normal control groups (all P < .05). Interferon-γ and neurotensin levels were only significantly higher in the DED after FS-LASIK group (all P < .05).

Patients with chronic DED after FS-LASIK showed milder ocular symptoms, greater epithelial damage, and higher levels of tear inflammatory cytokines and neuropeptides than patients with DED without FS-LASIK, indicating that the nervous and immune systems may play significant roles in FS-LASIK-related chronic DED development. [J Refract Surg. 2023;39(8):556-563.].

Corneal diseases affect 4.2 million people worldwide and are a leading cause of vision impairment and blindness. Current treatments for corneal diseases, such as antibiotics, steroids, and surgical interventions, have numerous disadvantages and challenges. Thus, there is an urgent need for more effective therapies. Although the pathogenesis of corneal diseases is not fully understood, it is known that injury caused by various stresses and postinjury healing, such as epithelial renewal, inflammation, stromal fibrosis, and neovascularization, are highly involved. Mammalian target of rapamycin (mTOR) is a key regulator of cell growth, metabolism, and the immune response. Recent studies have revealed that activation of mTOR signalling extensively contributes to the pathogenesis of various corneal diseases, and inhibition of mTOR with rapamycin achieves promising outcomes, supporting the potential of mTOR as a therapeutic target. In this review, we detail the function of mTOR in corneal diseases and how these characteristics contribute to disease treatment using mTOR-targeted drugs.

Introduction Dry eye disease affects a substantial number of individuals globally and significantly impacts their quality of life and productivity. Understanding the underlying mechanisms and managing dry eye disease poses substantial challenges. Recent research has highlighted the involvement of various inflammatory mediators in the pathogenesis of dry eye disease, including the cytokines interferon (IFN)-γ and interleukin (IL)-17. Activation of stress signaling pathways and residential immune cells on the ocular epithelial surface ignites epithelial changes, destabilizes tear film, amplifies inflammation and creates an endless loop. Lutein is a β-carotenoid antioxidant which has been proven to be beneficial in many ocular diseases due to its protective and anti-inflammatory effect induced by various stimulators. Lutein also acts as a direct and indirect antioxidant agent, suppressing oxidative stress and mitigating oxidative damage. The purpose of this research is to investigate the potential therapeutic effects of lutein in a mouse model of dry eye, aiming to elucidate its impact on ocular manifestation, goblet cells count, IFN-γ and IL-17 level. Methods Desiccating stress was induced in C57BL/6 mice. In a separate group, lutein was administered subcutaneously on a daily basis throughout the experimental period. Clinical manifestations of dry eye, including ocular surface changes, were documented photographically. Goblet cell concentration was assessed through Periodic Acid-Schiff (PAS) staining, and the levels of IFN-γ and IL-17 were measured using enzyme-linked immunosorbent assay (ELISA). Data obtained from these assessments were compared between the experimental groups to determine the potential effects of lutein on dry eye pathology and cytokine levels. Results Significant differences were observed in clinical observations and goblet cell concentrations among the groups; however, no statistically significant differences were found in the levels of IFN-γ and IL-17 between the groups. The untreated group exhibited significantly higher opacities and irregularities compared to the lutein-treated group, whereas the mean goblet cell count was highest in the lutein-treated group. Conclusion Lutein administration improves clinical observations and goblet cell concentrations in a mouse model of dry eye. The treated group exhibited improved ocular surface integrity, but no significant differences in the tested cytokine levels were observed. These findings suggest that lutein supplementation could be a promising therapeutic option for managing dry eye disease. Further research is needed to understand the underlying mechanisms and long-term effects of lutein in dry eye management.

Dry eye disease (DED) is a multifactorial ocular surface disorder arising from numerous interrelated underlying pathologies that trigger a self-perpetuating cycle of instability, hyperosmolarity, and ocular surface damage. Associated ocular discomfort and visual disturbance contribute negatively to quality of life. Ocular surface inflammation has been increasingly recognised as playing a key role in the pathophysiology of chronic DED. Current readily available anti-inflammatory agents successfully relieve symptoms, but often without addressing the underlying pathophysiological mechanism. The NOD-like receptor protein-3 (NLRP3) inflammasome pathway has recently been implicated as a key driver of ocular surface inflammation, as reported in pre-clinical and clinical studies of DED. This review discusses the intimate relationship between DED and inflammation, highlights the involvement of the inflammasome in the development of DED, describes existing anti-inflammatory therapies and their limitations, and evaluates the potential of the inflammasome in the context of the existing anti-inflammatory therapeutic landscape as a therapeutic target for effective treatment of the disease.

Sjögren's syndrome (SS) is an inflammatory autoimmune disease characterized by high levels of chronic lymphocyte infiltration. Differences and dysfunction in the gut microbiota and metabolites may be closely related to the pathogenesis of SS. The purpose of this study was to reveal the relationship between the gut microbiota and metabolome in NOD mice as a model of SS and the role of FuFang Runzaoling (FRZ), which is a clinically effective in treating SS.

NOD mice were gavaged with FRZ for 10 weeks. The ingested volume of drinking water, submandibular gland index, pathologic changes of the submandibular glands, and serum cytokines interleukin (IL)-6, IL-10, IL-17 A, and tumor necrosis factor-alpha (TNF-α) were determined. The roles of FRZ on gut microbiota and fecal metabolites were explored by 16 S rRNA gene sequencing and liquid chromatography-mass spectrometry (LC-MC), respectively. The correlation between them was determined by Pearson correlation analysis.

Compared with the model group, the drinking water volume of NOD mice treated with FRZ increased and the submandibular gland index decreased. FRZ effectively ameliorated lymphocyte infiltration in the small submandibular glands in mice. Serum levels of IL-6, TNF-α, and IL-17 A decreased, and IL-10 increased. The Firmicutes/Bacteroidetes ratio in the FRZ treatment group was higher. FRZ significantly downregulated the relative abundance of the family Bacteroidaceae and genus Bacteroides, and significantly upregulated the relative abundance of genus Lachnospiraceae_UCG-001. Orthogonal projections to latent structures discriminant analysis (OPLS-DA) revealed the significant change in fecal metabolites after FRZ treatment. Based on criteria of OPLS-DA variable influence on projection > 1, P < 0.05, and fragmentation score > 50, a total of 109 metabolites in the FRZ-H group were differentially regulated (47 downregulated and 62 upregulated) compared to their expressions in the model group. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed enriched metabolic of sphingolipid metabolism, retrograde endocannabinoid signaling, GABAergic synapse, necroptosis, arginine biosynthesis, and metabolism of histidine, alanine, aspartate, and glutamate. Correlation analysis between gut microbiota and fecal metabolites suggested that the enriched bacteria were related to many key metabolites.

Taken together, we found FRZ could reduce the inflammatory responses in NOD mice by regulating the gut microbiota, fecal metabolites, and their correlation to emerge a therapeutic effect on mice with SS. This will lay the foundation for the further studies and applications of FRZ, and the use of gut microbiotas as drug targets to treat SS.