Ocular complications of diabetes mellitus (DM) are the leading cause of vision loss. Ocular inflammation often occurs in the early stage of DM; however, there are no proven quantitative methods to evaluate the inflammatory status of eyes in DM. The 18 kDa translocator protein (TSPO) is an evolutionarily conserved cholesterol binding protein localized in the outer mitochondrial membrane. It is a biomarker of activated microglia/macrophages; however, its role in ocular inflammation is unclear. In this study, fluorine-18-DPA-714 ([18F]-DPA-714) was evaluated as a specific TSPO probe by cell uptake, cell binding assays and micro positron emission tomography (microPET) imaging in both in vitro and in vivo models. Primary microglia/macrophages (PMs) extracted from the cornea, retina, choroid or sclera of neonatal rats with or without high glucose (50 mM) treatment were used as the in vitro model. Sprague-Dawley (SD) rats that received an intraperitoneal administration of streptozotocin (STZ, 60 mg/kg once) were used as the in vivo model. Increased cell uptake and high binding affinity of [18F]-DPA-714 were observed in primary PMs under hyperglycemic stress. These findings were consistent with cellular morphological changes, cell activation, and TSPO up-regulation. [18F]-DPA-714 PET imaging and biodistribution in the eyes of DM rats revealed that inflammation initiates in microglia/macrophages in the early stages (3 weeks and 6 weeks), corresponding with up-regulated TSPO levels. Thus, [18F]-DPA-714 microPET imaging may be an effective approach for the early evaluation of ocular inflammation in DM.

BACKGROUND: The aim of this study was to report the clinical profile of new-onset and relapse of uveitis following rapid spreading of coronavirus disease 2019 (COVID-19) infection due to change of anti-COVID-19 policies in China and investigate potential risk factors for inflammation relapse.
METHODS: In this retrospective case-control study, patients with new-onset or a history of uveitis between December 23, 2022, and February 28, 2023, were included to assess the influence of COVID-19 infection on uveitis. Detailed information on demographic data, clinical characteristics, treatment measures, treatment response, and ocular inflammatory status before and after COVID-19 infection was collected.
RESULTS: This study included 349 patients with a history of uveitis. The uveitis relapse rate was higher (28.8%, n = 288) in those with COVID-19 infection than in patients without COVID-19 infection (14.8%, n = 61) (P = 0.024). Among the relapse cases, 50.8% experienced a relapse of anterior uveitis, while 49.2% had a relapse of uveitis involving the posterior segment. Multivariable regression analysis indicated a positive correlation between disease duration and uveitis relapse, while the last relapse exceeding one year before COVID-19 infection and the use of methotrexate during COVID-19 infection were negatively correlated with relapse of uveitis. Thirteen patients who developed new-onset uveitis following COVID-19 infection were included; among them, three (23.1%) had anterior uveitis and 10 (76.9%) had uveitis affecting the posterior segment. Regarding cases involving the posterior segment, four patients (30.8%) were diagnosed with Vogt-Koyanagi-Harada disease.
CONCLUSIONS: COVID-19 infection increases the rate of uveitis relapse. Long disease duration is a risk factor, while time since the last relapse more than 1 year and methotrexate use are protective factors against uveitis relapse.

BACKGROUND: Corneal neovascularization (CoNV) threatens vision by disrupting corneal avascularity, however, current treatments, including pharmacotherapy and surgery, are hindered by limitations in efficacy and adverse effects. Minocycline, known for its anti-inflammatory properties, could suppress CoNV but faces challenges in effective delivery due to the cornea\'s unique structure. Therefore, in this study a novel drug delivery system using minocycline-loaded nano-hydroxyapatite/poly (lactic-co-glycolic acid) (nHAP/PLGA) nanoparticles was developed to improve treatment outcomes for CoNV.
RESULTS: Ultra-small nHAP was synthesized using high gravity technology, then encapsulated in PLGA by a double emulsion method to form nHAP/PLGA microspheres, attenuating the acidic by-products of PLGA degradation. The MINO@PLGA nanocomplex, featuring sustained release and permeation properties, demonstrated an efficient delivery system for minocycline that significantly inhibited the CoNV area in an alkali-burn model without exhibiting apparent cytotoxicity. On day 14, the in vivo microscope examination and ex vivo CD31 staining corroborated the inhibition of neovascularization, with the significantly smaller CoNV area (29.40% ± 6.55%) in the MINO@PLGA Tid group (three times daily) than that of the control group (86.81% ± 15.71%), the MINO group (72.42% ± 30.15%), and the PLGA group (86.87% ± 14.94%) (p < 0.05). Fluorescein sodium staining show MINO@PLGA treatments, administered once daily (Qd) and three times daily (Tid) demonstrated rapid corneal epithelial healing while the Alkali injury group and the DEX group showed longer healing times (p < 0.05). Additionally, compared to the control group, treatments with dexamethasone, MINO, and MINO@PLGA were associated with an increased expression of TGF-β as evidenced by immunofluorescence, while the levels of pro-inflammatory cytokines IL-1β and TNF-α demonstrated a significant decrease following alkali burn. Safety evaluations, including assessments of renal and hepatic biomarkers, along with H&E staining of major organs, revealed no significant cytotoxicity of the MINO@PLGA nanocomplex in vivo.
CONCLUSIONS: The novel MINO@PLGA nanocomplex, comprising minocycline-loaded nHAP/PLGA microspheres, has shown a substantial capacity for preventing CoNV. This study confirms the complex\'s ability to downregulate inflammatory pathways, significantly reducing CoNV with minimal cytotoxicity and high biosafety in vivo. Given these findings, MINO@PLGA stands as a highly promising candidate for ocular conditions characterized by CoNV.

Currently, the marketed ophthalmic preparations of pranoprofen (PF) are mainly eye drops, but due to the special clearance mechanism of the eye and corneal reflex, the contact time between the drug and the focal site is short, most of the drug is lost, and the bioavailability is less than 5%. In the present study, an in situ gel eye drop containing no bacteriostatic agent and sensitive to temperature and ions was designed for delivery of PF. It was demonstrated to meet the criteria for ophthalmic preparations by characterization such as appearance content sterility. Ocular irritation tests showed a favorable safety profile. In vivo ocular retention time experiments showed that the ocular retention time of the pranoprofen gel was 4.41 times longer than that of commercially available drops (Pranopulin®), and the nasal tear excretion of the pranoprofen gel was lower than that of Pranopulin®, which suggests that the drug loss was reduced relative to that of the drops. The efficacy of the pranoprofen gel against tincture of cayenne pepper-induced corneal and conjunctival inflammation was examined using Pranopulin® as a control and in conjunction with inflammation scores, H&E slice results, and levels of IL-1β, IL-6, and TNF-α. The results showed that pranoprofen gel and Pranololin® had significant efficacy in the treatment of corneal and conjunctival inflammation, and the anti-inflammatory effect of pranoprofen gel was superior to that of Pranololin®. This study provides a new option for the treatment of corneal and conjunctival inflammation.

BACKGROUND: The management of post-refractive surgery dry eye disease (DED) can be challenging in clinical practice, and patients usually show an incomplete response to traditional artificial tears, especially when it is complicated with ocular pain. Therefore, we aim to investigate the efficacy of combined topical 0.05% cyclosporine A and 0.1% sodium hyaluronate treatment in post-refractive surgery DED patients with ocular pain unresponsive to traditional artificial tears.
METHODS: We enrolled 30 patients with post-refractive surgery DED with ocular pain who were unresponsive to traditional artificial tears. Topical 0.05% cyclosporine A and 0.1% sodium hyaluronate were used for 3 months. They were evaluated at baseline and 1 and 3 months for dry eye and ocular pain symptoms and objective parameters, including Numerical Rating Scale (NRS), Neuropathic Pain Symptom Inventory modified for the Eye (NPSI-Eye), tear break-up time (TBUT), Schirmer I test (SIt), corneal fluorescein staining (CFS), corneal sensitivity, and corneal nerve morphology. In addition, tear levels of inflammatory cytokines and neuropeptides were measured using the Luminex assay.
RESULTS: After 3 months of treatment, patients showed a statistically significant improvement in the ocular surface disease index (OSDI), TBUT, SIt, CFS, and corneal sensitivity (all P < 0.01) using linear mixed models. As for ocular pain parameters, the NRS and NPSI-Eye scores were significantly reduced (both P < 0.05) and positively correlated with the OSDI and CFS scores. Additionally, tear IL-1β, IL-6, and TNF-α levels were improved better than pre-treatment (P = 0.01, 0.03, 0.02, respectively).
CONCLUSIONS: In patients with post-refractive surgery DED with ocular pain, combined topical 0.05% cyclosporine A and 0.1% sodium hyaluronate treatment improved tear film stability, dry eye discomfort, and ocular pain, effectively controlling ocular inflammation.
BACKGROUND: Registration number: NCT06043908.

Herein, we report a facile method for converting carboxylate-containing indomethacin (Idm) into a cyclooxygenase-2 (COX-2) selective inhibitor via the amidation of an unnatural peptide sequence (Nal-Nal-Asp). The resulting indomethacin amides (i.e., Idm-Nal-Nal-Asp) have high selectivity for COX-2, and can self-assemble into a one-component supramolecular hydrogel that acts as a \'self-delivery\' system for boosting anti-inflammatory efficacy. Self-assembled Idm-Nal-Nal-Asp hydrogel robustly inhibits COX-2 expression in lipopolysaccharide (LPS)-activated Raw 264.7 macrophages while also exhibits superior anti-inflammatory and antioxidant activities via reactive oxygen species (ROS)-related NF-κB and Nrf2/HO-1 pathways. Moreover, a rabbit model of endotoxin-induced uveitis (EIU) reveals that the Idm-Nal-Nal-Asp hydrogel outperforms clinically used 0.1 wt% diclofenac sodium eye drops in terms of in vivo anti-inflammatory efficacy via topical instillation route. As a rational approach to designing and applying COX-2 selective inhibitors, this work presents a simple method for converting non-selective nonsteriodal anti-inflammatory drugs (NSAIDs) into highly selective COX-2 inhibitors that can self-assemble into supramolecular hydrogel for anti-inflammation applications.

Cyclic GMP-AMP (cGAMP) synthase (cGAS), a sensor of cytosolic DNA, recognizes cytoplasmic nucleic acids to activate the innate immune responses via generation of the second messenger cGAMP and subsequent activation of the stimulator of interferon genes (STINGs). The cGAS-STING signaling has multiple immunologic and physiological functions in all human vital organs. It mediates protective innate immune defense against DNA-containing pathogen infection, confers intrinsic antitumor immunity via detecting tumor-derived DNA, and gives rise to autoimmune and inflammatory diseases upon aberrant activation by cytosolic leakage of self-genomic and mitochondrial DNA. Disruptions in these functions are associated with the pathophysiology of various immunologic and neurodegenerative diseases. Recent evidence indicates important roles of the cGAS-STING signaling in mediating inflammatory responses in ocular inflammatory and inflammation-associated diseases, such as keratitis, diabetic retinopathy, age-related macular degeneration, and uveitis. In this review, we summarize the recently emerging evidence of cGAS-STING signaling in mediating ocular inflammatory responses and affecting pathogenesis of these complex eye diseases. We attempt to provide insightful perspectives on future directions of investigating cGAS-STING signaling in ocular inflammation. Understanding how cGAS-STING signaling is modulated to mediate ocular inflammatory responses would allow future development of novel therapeutic strategies to treat ocular inflammation and autoimmunity.

Uveitis is a major cause of vision impairment worldwide. Current treatments have limited effectiveness but severe complications. Mannose binding lectin (MBL) is an important protein of the innate immune system that binds to TLR4 and suppresses LPS-induced inflammatory cytokine secretion. MBL-mediated inhibition of inflammation via the TLR4 pathway and MBL-derived peptides might be a potential therapeutics. In this study, we designed a novel MBL-derived peptide, WP-17, targeting TLR4. Bioinformatics analysis was conducted for the sequence, structure and biological properties of WP-17. The binding of WP-17 to THP-1 cells was analyzed using flow cytometry. Signaling molecules were analyzed by western blotting, and activation of NF-κB was measured by immunofluorescence-histochemical analysis. Effects of WP-17 were studied in vitro using LPS-stimulated THP-1 cells and in vivo in endotoxin-induced uveitis (EIU). Our results showed that WP-17 could bind to TLR4 expressed on macrophages, thus downregulating the expression levels of MyD88, IRAK-4, and TRAF-6, and inhibiting the downstream NF-kB signaling pathway and LPS-induced expression of TNF-α and IL-6 in THP-1 cells. Moreover, in EIU rats, intravitreal pretreatment with WP-17 demonstrated significant inhibitory effects on ocular inflammation, attenuating the clinical and histopathological manifestations of uveitis, reducing protein leakage and cell infiltration into the aqueous humor, and suppressing TNF-α and IL-6 production in ocular tissues. In summary, our study provides the first evidence of a novel MBL-derived peptide that suppressed activation of the NF-кB pathway by targeting TLR4. The peptide effectively inhibited rat uveitis and may be a promising candidate for the management of ocular inflammatory diseases.

OBJECTIVE: The purpose of the study was to describe the cases of intraocular inflammation following COVID-19 vaccination (Comirnaty mRNA vaccine and CoronaVac vaccine) in Hong Kong.
METHODS: This was a retrospective case series.
RESULTS: This series includes 16 eyes among 10 female patients, with a mean age of 49.4 ± 17.4 years. Eight patients (80%) received the Pfizer-BioNTech mRNA vaccination. Anterior uveitis was the most common presentation of postvaccination uveitis (50%) observed in our series, followed by intermediate uveitis (30%) and posterior uveitis (20%), respectively. A case of retinal vasculitis in the form of frosted branch angiitis, previously only reported following COVID-19 infection, was observed following COVID-19 vaccination. The median time from vaccination to uveitis onset was 15.2 days (range: 0-6 weeks). Inflammation in 11 out 16 eyes (68.75%) was completely resolved with topical steroids.
CONCLUSIONS: Anterior uveitis was the predominant presentations of uveitis flare-ups following COVID-19 in our case series, followed by intermediate uveitis. Aligning with the current global literature concerning this issue, most of the uveitis attacks presented as anterior uveitis and were completely resolved with topical steroids. Consequently, the risk of uveitis flare-ups should not deter the public from receiving COVID-19 vaccines.

OBJECTIVE: Sjogren\'s syndrome (SS) is a chronic autoimmune disease, particularly involving the lacrimal and salivary glands, with dryness as the main symptom. To date, the pathogenesis of SS is not fully understood. Recently, numerous miRNAs were implicated in SS etiology and pathogenesis.
METHODS: Ocular wash was collected from SS patients and healthy controls. INF-γ-treated salivary gland epithelial cells (SGECs) were utilized as SS in vitro models. Expressions of miR-223-3p and inositol 1,4,5-trisphosphate receptor type 3 (ITPR3) in ocular wash specimens and cells were measured by RT-qPCR assay and western blot analysis, respectively. ELISA assay was exploited to detect IL-6, IL-12, and TNF-γ levels. CCK-8, flow cytometry, and western blot assay were exploited to determine cell viability, apoptosis, and apoptosis-related protein levels.
RESULTS: ITPR3 was a direct downstream gene of miR-223-3p and negatively modulated by miR-223- 3p. MiR-223-3p increased while ITPR3 decreased in samples from SS patients and INF-γ-induced SGECs. miR-223-3p knockdown facilitated INF-γ-induced SGECs cell viability and restrained apoptosis and inflammation response through the NF-κB pathway.
CONCLUSIONS: MiRNA-223-3p is implicated in the process of SS initiation and development. It may become one of the targets for the treatment of SS in the future, as well as a possible indicator for clinical monitoring of disease activity.