Differential Efficacy of Small Molecules Dynasore and Mdivi-1 for the Treatment of Dry Eye Epitheliopathy or as a Countermeasure for Nitrogen Mustard Exposure of the Ocular Surface.

The ocular surface comprises the wet mucosal epithelia of the cornea and conjunctiva, the associated glands, and the overlying tear film. Epitheliopathy is the common pathologic outcome when the ocular surface is subjected to oxidative stress. Whether different stresses act via the same or different mechanisms is not known. Dynasore and dyngo-4a, small molecules developed to inhibit the GTPase activity of classic dynamins DNM1, DNM2, and DNM3, but not mdivi-1, a specific inhibitor of DNM1L, protect corneal epithelial cells exposed to the oxidant tert-butyl hydroperoxide (tBHP). Here we report that, while dyngo-4a is the more potent inhibitor of endocytosis, dynasore is the better cytoprotectant. Dynasore also protects corneal epithelial cells against exposure to high salt in an in vitro model of dysfunctional tears in dry eye. We now validate this finding in vivo, demonstrating that dynasore protects against epitheliopathy in a mouse model of dry eye. Knockdown of classic dynamin DNM2 was also cytoprotective against tBHP exposure, suggesting that dynasore's effect is at least partially on target. Like tBHP and high salt, exposure of corneal epithelial cells to nitrogen mustard upregulated the unfolded protein response and inflammatory markers, but dynasore did not protect against nitrogen mustard exposure. In contrast, mdivi-1 was cytoprotective. Interestingly, mdivi-1 did not inhibit the nitrogen mustard-induced expression of inflammatory cytokines. We conclude that exposure to tBHP or nitrogen mustard, two different oxidative stress agents, cause corneal epitheliopathy via different pathologic pathways. SIGNIFICANCE STATEMENT: Results presented in this paper, for the first time, implicate the dynamin DNM2 in ocular surface epitheliopathy. The findings suggest that dynasore could serve as a new topical treatment for dry eye epitheliopathy and that mdivi-1 could serve as a medical countermeasure for epitheliopathy due to nitrogen mustard exposure, with potentially increased efficacy when combined with anti-inflammatory agents and/or UPR modulators.

DZ2002 alleviates corneal angiogenesis and inflammation in rodent models of dry eye disease via regulating STAT3-PI3K-Akt-NF-κB pathway.

Dry eye disease (DED) is a prevalent ocular disorder with a multifactorial etiology. The pre-angiogenic and pre-inflammatory milieu of the ocular surface plays a critical role in its pathogenesis. DZ2002 is a reversible type III S-adenosyl-L-homocysteine hydrolase (SAHH) inhibitor, which has shown excellent anti-inflammatory and immunosuppressive activities in vivo and in vitro. In this study, we evaluated the therapeutic potential of DZ2002 in rodent models of DED. SCOP-induced dry eye models were established in female rats and mice, while BAC-induced dry eye model was established in female rats. DZ2002 was administered as eye drops (0.25%, 1%) four times daily (20 µL per eye) for 7 or 14 consecutive days. We showed that topical application of DZ2002 concentration-dependently reduced corneal neovascularization and corneal opacity, as well as alleviated conjunctival irritation in both DED models. Furthermore, we observed that DZ2002 treatment decreased the expression of genes associated with angiogenesis and the levels of inflammation in the cornea and conjunctiva. Moreover, DZ2002 treatment in the BAC-induced DED model abolished the activation of the STAT3-PI3K-Akt-NF-κB pathways in corneal tissues. We also found that DZ2002 significantly inhibited the proliferation, migration, and tube formation of human umbilical endothelial cells (HUVECs) while downregulating the activation of the STAT3-PI3K-Akt-NF-κB pathway. These results suggest that DZ2002 exerts a therapeutic effect on corneal angiogenesis in DED, potentially by preventing the upregulation of the STAT3-PI3K-Akt-NF-κB pathways. Collectively, DZ2002 is a promising candidate for ophthalmic therapy, particularly in treating DED.

Cytisine eye drops for benzalkonium chloride-induced dry eye: safety and efficacy evaluation.

This experiment aimed to investigate the feasibility of cytisine (CYT) in treating eye diseases with ocular topical application. An in vitro cytotoxicity test, a hen's egg test-chorioallantoic membrane (HET-CAM), and a mouse eye tolerance test were used to fully reveal the ocular safety profiles of CYT. For the efficacy evaluations, CYT's effects on cell wound healing, against H2O2-induced oxidative stress damages on cells, and on benzalkonium chloride (BAC)-induced dry eye disease (DED) in mice were evaluated. Results showed that CYT did not show any cytotoxicities at concentrations no higher than 250 µg/ml, while lipoic acid (α-LA) at 250 µg/ml and BAC at 1.25 µg/ml showed significant cytotoxicities within 48 h incubation. The HET-CAM and mouse eye tolerance test confirmed that 0.5% CYT eye drops demonstrated good safety characteristics. Efficacy evaluations showed that CTY significantly promoted cell migration and wound healing. CYT significantly improved cell survival against H2O2-induced oxidative stress damage by reversing the imbalance between the reactive oxygen species (ROS) and antioxidant defense mechanisms. The animal evaluation of the BAC-induced dry eye model revealed that CYT demonstrated a strong treatment effect, including reversing ocular surface damages, recovering corneal sensitivity, and inhibiting neovascularization; HMGB1/NF-κB signaling was involved in this DED treatment by CTY. In conclusion, CYT had strong experimental treatment efficacy against DED with good ocular safety profiles, and it might be a novel and promising drug for DED.

PM2.5 exposure increases dry eye disease risks through corneal epithelial inflammation and mitochondrial dysfunctions.

Dry eye disease (DED) is the most common disease affecting vision and quality of life. PM2.5 was a potential risk of DED. Herein, we conducted animal exposure and cell-based studies to evaluate the pathogenic effect of PM2.5 exposure on the ocular surface and DED etiological mechanisms. C57 mice were exposed to filtered air and PM2.5 aerosol. We assessed health conditions and inflammation of the ocular surface by corneal fluorescein staining and immunohistochemistry. In parallel, cultured human corneal epithelial cells (HCETs) were treated with PM2.5, followed by characterization of cell viability, intracellular ATP level, mitochondrial activities, and expression level of DED relevant mRNA and proteins. In mice, PM2.5 exposure induced severe superficial punctate keratopathy and inflammation in their cornea. In HCETs, cell proliferation and ROS generation followed dose-response and time-dependent manner; meanwhile, mitochondrial ROS (mtROS) level increased and mitochondrial membrane potential (MMP) level decreased. Inflammation cascade was triggered even after short-term exposure. The reduction of ATP production was alleviated with Nrf2 overexpression, NF-κB P65 knockdown, or ROS clearance. Nrf2 overexpression and P65 knockdown reduced inflammatory reaction through decreasing expression of P65 and increasing of Nrf2, respectively. They partly alleviated changes of ROS/mtROS/MMP. This research proved that PM2.5 would cause DED-related inflammation reaction on corneal epithelial cells and further explored its mechanism: ROS from mitochondrial dysfunctions of corneal epithelial cells after PM2.5 exposure partly inhibited the expression of anti-inflammatory protein Nrf2 led the activation of inflammatory protein P65 and its downstream molecules, which finally caused inflammation reaction.

Lactobacillus fermentum HY7302 Improves Dry Eye Symptoms in a Mouse Model of Benzalkonium Chloride-Induced Eye Dysfunction and Human Conjunctiva Epithelial Cells.

(1) We investigated the effects of the Lactobacillus fermentum HY7302 (HY7302) in a mouse model of benzalkonium chloride (BAC)-induced dry eye, and the possibility of using HY7302 as a food supplement for preventing dry eye. (2) The ocular surface of Balb/c mice was exposed to 0.2% BAC for 14 days to induce dry eye (n = 8), and the control group was treated with the same amount of saline (n = 8). HY7302 (1 × 109 CFU/kg/day, 14 days, n = 8) was orally administered daily to the mice, and omega-3 (200 mg/kg/day) was used as a positive control. To understand the mechanisms by which HY7302 inhibits BAC-induced dry eye, we performed an in vitro study using a human conjunctival cell line (clone-1-5c-4). (3) The probiotic HY7302 improved the BAC-induced decreases in the corneal fluorescein score and tear break-up time. In addition, the lactic acid bacteria increased tear production and improved the detached epithelium. Moreover, HY7302 lowered the BAC-induced increases in reactive oxygen species production in a conjunctival cell line and regulated the expression of several apoptosis-related factors, including phosphorylated protein kinase B (AKT), B-cell lymphoma protein 2 (Bcl-2), and activated caspase 3. Also, HY7302 alleviated the expression of pro-inflammatory cytokines, such as interleukin-1ß (IL-1ß), IL-6, and IL-8, and also regulated the matrix metallopeptidase-9 production in the conjunctival cell line. (4) In this study, we showed that L. fermentum HY7302 helps prevent dry eye disease by regulating the expression of pro-inflammatory and apoptotic factors, and could be used as a new functional food composition to prevent dry eye disease.

Recombinant Human Clusterin Seals Damage to the Ocular Surface Barrier in a Mouse Model of Ophthalmic Preservative-Induced Epitheliopathy.

There is a significant unmet need for therapeutics to treat ocular surface barrier damage, also called epitheliopathy, due to dry eye and related diseases. We recently reported that the natural tear glycoprotein CLU (clusterin), a molecular chaperone and matrix metalloproteinase inhibitor, seals and heals epitheliopathy in mice subjected to desiccating stress in a model of aqueous-deficient/evaporative dry eye. Here we investigated CLU sealing using a second model with features of ophthalmic preservative-induced dry eye. The ocular surface was stressed by topical application of the ophthalmic preservative benzalkonium chloride (BAC). Then eyes were treated with CLU and sealing was evaluated immediately by quantification of clinical dye uptake. A commercial recombinant form of human CLU (rhCLU), as well as an rhCLU form produced in our laboratory, designed to be compatible with U.S. Food and Drug Administration guidelines on current Good Manufacturing Practices (cGMP), were as effective as natural plasma-derived human CLU (pCLU) in sealing the damaged ocular surface barrier. In contrast, two other proteins found in tears: TIMP1 and LCN1 (tear lipocalin), exhibited no sealing activity. The efficacy and selectivity of rhCLU for sealing of the damaged ocular surface epithelial barrier suggests that it could be of therapeutic value in treating BAC-induced epitheliopathy and related diseases.

The Anti-Inflammatory Effect of Multi-Wavelength Light-Emitting Diode Irradiation Attenuates Dry Eye Symptoms in a Scopolamine-Induced Mouse Model of Dry Eye.

Dry eye disease is a common condition in patients of all ages, causing discomfort and potential visual problems. Current treatments, including artificial tears and anti-inflammatory drugs, have certain limitations, encouraging research into alternative therapies. We investigated the therapeutic potential of multi-wavelength light-emitting diode (LED) irradiation of mice with dry eye. First, we showed that multi-wavelength LED irradiation was non-toxic to human corneal epithelial cells and improved cell viability. We then used a scopolamine-induced mouse model of dry eye to assess the effects of multi-wavelength LED irradiation on various clinical parameters. This treatment increased the tear volume and reduced corneal irregularity, thus improving dry eye. Histological analysis revealed that multi-wavelength LED irradiation protected against corneal epithelial damage and the associated reduction in epithelial thickness and would thus improve the corneal health of dry eye patients. Multi-wavelength LED irradiation significantly reduced the corneal levels of pro-inflammatory cytokines IL-6, IL-1ß, and TNF-α; the treatment was thus anti-inflammatory. Our results suggest that multi-wavelength LED irradiation may serve as a safe and effective treatment for dry eye, alleviating symptoms, reducing inflammation, and promoting corneal health.

The Lubricating Effect of Eye Drops Containing Hyaluronic Acid and Mallow Extract in Patients with Dry Eye Disease-A Pilot Study.

Background and Objectives: Mucilaginous substances from plants are known to be able to support the lubricating effect of hyaluronic acid (HA) in dry eye disease (DED). In this pilot study, the combined lubricating effect of HA and mallow extract (Malva sylvestris L.) in patients with DED was assessed. Materials and Methods: Twenty patients at five ophthalmological practices in Italy were treated with eye drops containing HA and mallow extract on the one hand, and with eye drops containing HA only, on the other hand, in a two-period crossover design. As primary endpoints, the tear film breakup time (TBUT), the reduction of lissamine green staining of the ocular surface (Oxford Scheme, OS), and the safety and efficacy assessment by the ophthalmologists were evaluated. As secondary variables, the patient symptom score, the ocular surface index (OSDI) and the satisfaction, preference and efficacy assessment by the patients were evaluated. All data were analysed descriptively in addition to an exploratory analysis being made of the target variables. Results: Both products were well-tolerated. There were no statistically significant differences with regard to the TBUT, OS and OSDI between the two treatments. Anyway, the efficacy and safety assessments by the ophthalmologists and the patients showed results in favour of the combined product. Conclusion: The addition of mallow extract to HA-containing eye drops enhances the treatment of DED, at least with respect to subjective measurements. Further assessments will have to be done to prove and explain this observation in terms of measurable parameters, e.g., markers for inflammatory cytokines.

Interleukin-20 is involved in dry eye disease and is a potential therapeutic target.

BACKGROUND: Dry eye disease (DED) is a common disease in ophthalmology, affecting millions of people worldwide. Recent studies have shown that inflammation is the core mechanism of DED. IL-20 is a proinflammatory cytokine involved in various inflammatory diseases. Therefore, we aimed to explore the role of this cytokine in the pathogenesis of DED and evaluate the therapeutic potential of the anti-IL-20 monoclonal antibody (mAb) 7E for DED treatment. METHODS: Clinical tear samples from patients with DED and non-DED controls were collected and their IL-20 protein levels were determined. We established three DED animal models to explore the role of IL-20 and the efficacy of IL-20 antibody in DED. Benzalkonium chloride (BAC)-induced over-evaporative DED, extra-orbital lacrimal gland excision (LGE)-induced aqueous tear-deficient DED, and desiccating stress (DS)-induced combined over-evaporative and aqueous tear-deficient DED animal models were established to investigate the role of IL-20. The anti-IL-20 antibody 7E was established to neutralize IL-20 activity. The effects of IL-20 or 7E on human corneal epithelial cells and macrophages under hyperosmotic stress were analyzed. 7E was topically applied to eyes to evaluate the therapeutic effects in the DED animal models. RESULTS: IL-20 was significantly upregulated in the tears of patients with DED and in the tears and corneas of DED animal models. Under hyperosmotic stress, IL-20 expression was induced via NFAT5 activation in corneal epithelial cells. 7E suppressed hyperosmotic stress-induced activation of macrophages. IL-20 induced cell death in corneal epithelial cells and 7E protected cells from hyperosmotic stress-induced cell death. Blocking IL-20 signaling with 7E protected mice from BAC-induced, LGE-induced, and DS-induced DED by reducing DED symptoms and inhibiting inflammatory responses, macrophage infiltration, apoptosis, and Th17 populations in the conjunctiva and draining lymph nodes. CONCLUSIONS: Our results demonstrated the functions of IL-20 in DED and presented a potential therapeutic option for this condition.

The use of androgen deprivation therapy for prostate cancer and its effect on the subsequent dry eye disease: a population-based cohort study.

This study aimed to investigate the influence of androgen deprivation therapy (ADT) for the development of dry eye disease (DED) in subjects with prostate cancer via the use of national health insurance research database (NHIRD) of Taiwan. A retrospective cohort study was conducted and patients were selected as prostate cancer with ADT according to diagnostic and procedure codes. Each participant in that group was then matched to one patient with prostate cancer but without ADT and two subject s without prostate cancer and ADT. And a total of 1791, 1791 and 3582 participants were enrolled in each group. The primary outcome was set as the DED development according to the diagnostic codes. Cox proportional hazard regression was applied to calculate the adjusted hazard ratio (aHR) and 95% confidence interval (CI) of ADT and other parameters for DED development. There were 228, 126 and 95 new events of DED developed in the control group, the prostate cancer without ADT group and the prostate cancer with ADT group. The rate of DED in the prostate cancer with ADT group (aHR: 0.980, 95% CI: 0.771-1.246, P= 0.8696) and Prostate cancer without ADT group (aHR: 1.064, 95% CI: 0.855-1.325, P= 0.5766) were not significantly different compared to the control group. In addition, the patients aged 70-79 years old demonstrated a significantly higher incidence of developing DED compared to those aged 50-59 years old (aHR: 1.885, 95% CI: 1.188-2.989, P= 0.0071). In conclusion, the use of ADT did not alter the incidence of subsequent DED.

Recombinant Human Thymosin ß4 (rhTß4) Modulates the Anti-Inflammatory Responses to Alleviate Benzalkonium Chloride (BAC)-Induced Dry Eye Disease.

Dry eye disease (DED) is a multifactorial ocular disorder that interferes with daily living and reduces quality of life. However, there is no most ideal therapeutic treatment to address all the deleterious defects of DED. The purpose of this study was to investigate the ability of recombinant human thymosin ß4 (rhTß4) to promote healing in a benzalkonium chloride (BAC)-induced mice DED model and the anti-inflammatory effects involved in that process. Eye drops consisting of 0.05% and 0.1% rhTß4 were used for treatment of DED. Tear volume and corneal staining scores were measured after 7 days. Periodic acid-Schiff staining for gobleT cells in conjunctiva, immunohistochemical staining for CD4+ T cells, TUNEL assay for apoptotic positive cells in cornea and conjunctiva, qRT-PCR and ELISA assays for multiple cytokines were performed. All clinical parameters showed improvement in both the 0.05% and 0.1% rhTß4 groups. Specifically, topical application of rhTß4 significantly increased conjunctival gobleT cells and reduced apoptotic cells in conjunctiva. Mechanically, the rhTß4 groups showed significantly reduced inflammatory cytokine levels and CD4+ T cells in conjunctiva by blocking NF-κB (nuclear factor kappa B) activation, suggesting that 0.05-0.1% rhTß4 eye drops may be used as a potential therapeutic treatment for DED.

Therapeutic Effects of Acer palmatum Thumb. Leaf Extract (KIOM-2015E) on Benzalkonium Chloride-Induced Dry Eye in a Mouse Model.

We determined the effects of two extracts from Acer palmatum Thumb. leaves (hot water extract KIOM-2015EW and 25% ethanol extract KIOM-2015EE) in a benzalkonium chloride (BAC)-induced dry eye mouse model. Dry eye was induced by 0.2% BAC for 2 weeks, followed by treatment three times (eye drop) or once (oral administration) daily with KIOM-2015E for 2 weeks. Treatment with both KIOM-2015EE and KIOM-2015EW resulted in a marked increase in tear volume production for the 4 days of treatment. The Lissamine Green staining score, TUNEL-positive cells, and inflammatory index were significantly decreased after 2 weeks. Topical KIOM-2015EE administration exhibited a greater improvement in decreasing the ocular surface staining scores, inflammation, dead cells, and increasing tear production in a dose-dependent manner compared with the other groups. Furthermore, KIOM-2015E significantly reduced the phosphorylation of NF-κB, which was activated in the BAC-treated cornea. Topical administration was much more effective than oral administration for KIOM-2015E and KIOM-2015EE was more effective than KIOM-2015EW. Application of KIOM-2015E resulted in clinical improvement, inhibited the inflammatory response, and alleviated signs of dry eye. These results indicate that KIOM-2015E has potential as a therapeutic agent for the clinical treatment of dry eye.

Ocular manifestations of systemic isotretinoin in patients with acne: a systemic review and meta-analysis.

PURPOSE: To examine the effects of systemic isotretinoin treatment on the eye using several ocular examination parameters. METHODS: We conducted a systemic review for literature published up to June 2021 in both PubMed and Web of Science databases. We included prospective observational or interventional studies evaluating ocular manifestations of isotretinoin in acne patients. The primary outcome measures were anaesthetized and non-anaesthetized Schirmer test, tear break-up time (TBUT), central corneal thickness (CCT), average retinal nerve fibre layer (RNFL) thickness, ganglion cell-inner plexiform layer (GC-IP) thickness, subfoveal choroidal thickness, axial length, ocular surface disease index (OSDI), meibomian gland expression (MGE) and conjunctival stain. The National Institute of Health (NIH) quality assessment tools were used to assess the data quality. The effect size used to analyse the included studies was the weighted mean difference (WMD) and its related confidence intervals (95%CIs). RESULTS: Twenty-one publications involving 1105 eyes of 842 participants met the inclusion criteria. Isotretinoin use was significantly associated with reduction in the scores of anaesthetized Schirmer (WMD = -2.23, 95%CI: -3.28 to -1.18), non-anaesthetized Schirmer (WMD = -3.74, 95%CI: -4.23 to -3.25), TBUT (WMD = -3.47, 95%CI: -5.09 to -1.86), and CCT (WMD= -7.39, 95%CI: -13.91 to -0.88). Isotretinoin use was significantly associated with increase of OSDI (WMD = 18.29, 95%CI: 7.54-29.03), MGE (WMD = 1.02, 95%CI: 0.70-1.33) and conjunctival stain scores (WMD = 0.61, 95%CI: 0.47-0.76). No significant change was noted in RNFL thickness (WMD = -0.64, 95%CI: -1.80 to 0.51); GC-IP thickness (WMD = 0.42, 95%CI: -1.08 to 1.92); subfoveal choroidal thickness (WMD = -1.80, 95%CI: -6.69 to 3.09), and axial length (WMD = 0.08, 95%CI: -0.19 to 0.35). A significant heterogeneity was found between the study estimates in each of anaesthetized Schirmer, TBUT, MGE, OSDI, and conjunctival stain tests. CONCLUSION: Isotretinoin use results in a statistically significant reduction of the central corneal thickness, TBUT, and Schirmer test scores. A statistically significant increase in MGE, OSDI and conjunctival stain scores was found. No statistically significant change of average RNFL, GC-IP thickness, subfoveal choroidal thickness, or axial length was observed. Further well-designed studies should evaluate the long-term effect of isotretinoin on the eye and reach a firmer conclusion.

The effects of the systemic isotretinoin treatment on ocular surface and meibomian glands: a prospective longitudinal study.

PURPOSE: To assess the effects of systemic isotretinoin therapy (SIT) on the ocular surface, meibomian glands (MG) and cornea microstructure in acne vulgaris (AV) patients. METHODS: Patients with AV (n = 20) and healthy controls (n = 20) were enrolled in the study. All participants underwent ocular surface tests in the order of ocular surface disease index (OSDI) questionnaire, corneal sensitivity, tear break-up time (BUT), fluorescein and lissamine green (LG) staining and Schirmer II test with anaesthesia. MG alterations were evaluated with meibography for upper (UE) and lower eyelids (LE) separately. Corneal basal epithelium and subbasal nerve plexus (SNP) were evaluated using In Vivo Confocal Microscopy (IVCM). RESULTS: Schirmer II test with anaesthesia, BUT, corneal sensitivity, fluorescein and LG staining grades and OSDI score results showed no difference between the control group and the baseline of the patient group. Whereas the meibomian gland dysfunction (MGD) grades, UE and LE meiboscores were higher in the patient group at the baseline (p = 0.013, p = 0.004, p = 0.008 respectively). The Control group possessed higher numbers of total and long nerve fibres compared with patients at the baseline (p ≤ 0.001 for both two values). Compared to the baseline and the third month, BUT decreased and fluorescein staining grades increased (p = 0.017 and p = 0.043, respectively). MGD grades, UE and LE meiboscores increased in the third month compared to the baseline (p < 0.001, p < 0.001, p = 0.008 respectively). Basal epithelial cell density (BECD) decreased in the third month of SIT (p = 0.043). CONCLUSIONS: This prospective study showed that systemic Isotretinoin treatment effects not only ocular surface parameters but also corneal and Meibomian glands structure. Considering early alterations in the course of treatment, ophthalmological assessment and follow-up during SIT are mandatory.

Tear meniscus, corneal topographic and aberrometric changes after botulinum toxin-a injection in patients with blepharospasm and hemifacial spasm.

PURPOSE: To investigate the effect of botulinum neurotoxin-A (BTX-A) treatment on dry eye symptoms, tear meniscus, corneal topography and corneal aberrometry in patients with benign essential blepharospasm (BEB) and hemifacial spasm (HFS). MATERIALS AND METHODS: This prospective study comprised of 6 patients with BEB and 20 patients with HFS. Tear meniscus height (TMH) and depth (TMD), tear break-up time (TBUT), corneal fluorescein staining score (CFSS), Schirmer I test, ocular surface disease index (OSDI) score, corneal topography [corneal power of flat axis (K1), corneal power of steep axis (K2), mean corneal power (Km), astigmatism and thinnest pachymetry] and anterior corneal aberrometry [spherical aberration (SA), vertical coma (vcoma), horizontal coma (hcoma), higher order root mean square (hRMS) and total RMS] were evaluated before BTX-A treatment, 3 weeks after BTX-A treatment and 2 months after BTX-A treatment. RESULTS: Six patients with BEB and 20 patients with HFS treated with BTX-A were evaluated in this study. Twenty contralateral spasm free eyes of 20 HFS patients were taken as control group. TMH and TMD were found to be significantly higher in eyes with spasm at both 3 weeks and 2 months after injection (TMH: 279.0 ± 123.2 at pretreatment, 380.5 ± 174.7 at third week and 317.0 ± 125.5 at second month p < 0.001 and p = 0.02, respectively), (TMD: 183.7 ± 59.7 at pretreatment, 235.7 ± 91.1 at third week and 209.8 ± 77.1 at second month p < 0.01 and p = 0.015, respectively). TBUT, CFSS, Schirmer I test values were similar (p > 0.05). OSDI scores decreased significantly from 29.6 ± 25.3 to 19.8 ± 20. p = 0.03 at third week and increased again by second month. K2 (43.9 ± 1.7 vs. 43.7 ± 1.6, p = 0.03) and astigmatism (0.8 ± 0.5 vs. 0.6 ± 0.4, p = 0.04) values were significantly lower at third week and increased again by second month. Pachymetry and aberrometric values did not change significantly. In the control group only Schirmer I test value decreased significantly at second month (10.5 ± 6.5 vs. 7.2 ± 5.6, p = 0.008), other parameters did not change. CONCLUSION: BTX-A injection increases tear meniscus and decrease symptoms related to dry eye disease in BEB and HFS patients. It decrease astigmatism and keratometry values, it does not cause a significant change in corneal aberrations. However the positive effects of BTX-A injection on ocular surface is temporary.

Nivolumab-Related Dry Mouth and Dry Eye: Cross-Sectional Study.

To evaluate ICIs related dry eye and dry mouth in nivolumab therapy, 24 patients receiving nivolumab (group 1), 30 patients in remission without treatment for 6 months (group 2), 30 healthy participants (group 3) were cross-sectionally examined. Schirmer's 1, 2, TSH blood tests, serological analysis, salivary flow scintigraphy and minor-salivary gland biopsy were performed. Schirmer's tests were performed with anesthetic (1) and without anesthetic (2). Schirmer's scores were lower in group 1 with more frequent reduced tear production (p < 0.001). TSH levels negatively correlated with Schirmer's scores. Functional insufficiency was detected by salivary flow scintigraphy in 7 out of 10 patients with Schirmer's test positivity. In Schirmer's positive patients, lymphocytic sialadenitis was confirmed in 4 patients (focus score > 1) and CD4 T lymphocyte precipitation was observed in 6 patients. Nivolumab therapy may be associated with ICIs related immune sicca.

α-MSH ameliorates corneal surface dysfunction in scopolamine-induced dry eye rats and human corneal epithelial cells via enhancing EGFR expression.

Dry eye (DE) is a chronic, multifactorial ocular surface disease associated with visual disturbance, tear film instability, hyperosmolarity, ocular surface inflammation and damage. Effective intervention is necessary to control this disease. In this study we topically applied α-melanocyte stimulating hormone (α-MSH) on the ocular surface of scopolamine-induced DE rats and found that it promoted tear secretion, reduced tear breakup time and fluorescein sodium staining and increased the number of conjunctival goblet cells. To investigate the mechanism, protein array was conducted, which showed that α-MSH exerted its effects via epithelial growth factor receptor (EGFR) in the JAK-STAT signaling pathway. Furthermore, in vitro experiments showed that α-MSH protected human corneal epithelial cells (hCECs) by maintaining their migration ability and viability and decreasing apoptosis. However, blockade of EGFR abolished these protective effects. Moreover, α-MSH decreased the level of autophagy in benzalkonium chloride (BAC)-stressed hCECs via EGFR. These results demonstrated that α-MSH ameliorated lesions and restored ocular surface functions by upregulating EGFR expression.

Melatonin ameliorates oxidative stress-mediated injuries through induction of HO-1 and restores autophagic flux in dry eye.

This study aimed to investigate the protective effect of melatonin on the corneal epithelium in dry eye disease(DED) and explore its underlying mechanism. Human corneal epithelial(HCE) cells was exposure to t-butylhydroperoxide(tBH), C57BL/6 mice were injected of subcutaneous scopolamine to imitate DED. Melatonin was used both in vivo and in vitro. Cell viability was detected by Cell Counting Kit-8 assay and Lactate Dehydrogenase Leakage. The change of cellular reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP), and apoptosis was analyzed by flow cytometry. Western blot assays and immunofluorescence were carried out to measure protein changes. mRNA expression was investigated by RNA sequencing (RNA-Seq) and quantitative real-time PCR. The change of autophagic flux were observed through mCherry-GFP-LC3 transfection and electron microscopy(TEM). Clinical parameters of corneal epithelium defects, conjunctival goblet cells, tear volume, and level of ocular surface inflammation was recorded. Melatonin was able to reduce excessive ROS production and maintain mitochondrial function. TEM assay found melatonin rescued impaired autophagic flux under tBH. Moreover, melatonin significantly preserved cell viability, abolished LDH release, and decreased apoptosis. RNA-Seq indicated that melatonin greatly activating hemeoxygenase-1 (HO-1) expression. Interestingly, HO-1 ablation largely attenuated its protective effects. Besides, in dry eye mouse model, intraperitoneal injection of melatonin showed greatly improved clinical parameters, inhibited activated NLRP3 inflammation cascade, and increased density of goblet cells and tear volume. Thus, melatonin protects corneal epithelial cells from oxidative damage, maintain normal level of autophagy, and reduce inflammation via trigging HO-1 expression in DED.

Influence of Different Antidepressants on Ocular Surface in Patients With Major Depressive Disorder.

PURPOSE: Several studies have previously reported the association between dry eye and depression along with the treatment of depression. The aim of this study was to investigate the effects of different antidepressant drugs on tear parameters in patients with major depressive disorder. METHODS: We recruited 132 patients who were using different antidepressants and 58 healthy controls. Venlafaxine, duloxetine, escitalopram, and sertraline were used by 34, 28, 36, and 34 patients, respectively. The participants filled out and completed the Beck Depression Scale. We recorded Schirmer test, tear breakup time (TBUT) and corneal staining values of the participants. The Ocular Surface Disease Index was completed by the participants. In addition, we evaluated the tear meniscus parameters by using anterior segment optical coherence tomography. RESULTS: All conventional dry eye tests and tear meniscus parameters were significantly lesser in the depression group than in the control group (Schirmer test, 11.41 ± 6.73 mm and 22.53 ± 4.98 mm; TBUT, 5.29 ± 2.92 seconds and 13.38 ± 1.72; Corneal staining, tear meniscus area, 0.026 ± 0.012 mm2 and 0.11 ± 0.025 mm2; tear meniscus depth, 182.75 ± 78.79 µm and 257.48 ± 90.1 µm; tear meniscus height, 290.3 ± 133.63 µm and 459.78 ± 180.26 µm, in patients and controls, respectively). The tear parameters of the duloxetine group were lowest among the drug groups and Schirmer test, and TBUT of the venlafaxine group was statistically significantly different from the duloxetine group (P = 0.028 and P = 0.017, respectively). Ocular Surface Disease Index score of the depression group was significantly higher than the control group (31.12 ± 21.15 and 17.43 ± 11.75 in depression and control group, respectively.). CONCLUSIONS: We found that the usage of selective serotonin reuptake inhibitors and serotonin noradrenaline reuptake inhibitors affects the ocular surface by a mechanism other than the anticholinergic system. Besides serotonin blockage, the noradrenaline blockade of serotonin noradrenaline reuptake inhibitors may increase the dry eye findings on the ocular surface.

Retrospective analysis of adverse events with dupilumab reported to the United States Food and Drug Administration.

BACKGROUND: Atopic dermatitis (AD) is one of the most common inflammatory skin diseases and has aesthetic, physical, and emotional-social sequelae when left untreated. OBJECTIVE: To classify the most common adverse reactions associated with dupilumab treatment in patients with AD. METHODS: The United States Food and Drug Administration Adverse Event Reporting (FAERS) database was analyzed for common adverse reactions associated with dupilumab, topical pimecrolimus, and topical tacrolimus. Phase III clinical trial data were used to compare the rate of herpes infections between the treatment group and placebo group. RESULTS: The most common adverse reaction associated with dupilumab was ocular complications. Herpes infections were extremely rare in the patients with AD being treated with dupilumab. LIMITATIONS: Prescribing information for dupilumab, topical pimecrolimus, and topical tacrolimus is not available. Adverse effects are reported by patients, health care providers, and pharmaceutical companies, they have not been corroborated. CONCLUSIONS: Ocular complications are the most common complication associated with dupilumab. The rate of herpes infection is low in patients being treated with dupilumab, topical pimecrolimus, and topical tacrolimus. There is no significant difference for the rate of herpes infection between, placebo, dupilumab, topical pimecrolimus, and the topical tacrolimus treatment group, suggesting that dupilumab does not affect herpes infection rates.