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Biomaterials Aug 2021Defective cellular metabolism, impaired mitochondrial function, and increased cell death are major problems that adversely affect donor tissues during hypothermic...
Defective cellular metabolism, impaired mitochondrial function, and increased cell death are major problems that adversely affect donor tissues during hypothermic preservation prior to transplantation. These problems are thought to arise from accumulated reactive oxygen species (ROS) inside cells. Oxidative stress acting on the cells of organs and tissues preserved in hypothermic conditions before surgery, as is the case for cornea transplantation, is thought to be a major reason behind cell death prior to surgery and decreased graft survival after transplantation. We have recently discovered that ubiquinol - the reduced and active form of coenzyme Q10 and a powerful antioxidant - significantly enhances mitochondrial function and reduces apoptosis in human donor corneal endothelial cells. However, ubiquinol is highly lipophilic, underscoring the need for an aqueous-based formulation of this molecule. Herein, we report a highly dispersible and stable formulation comprising a complex of ubiquinol and gamma cyclodextrin (γ-CD) for use in aqueous-phase ophthalmic products. Docking studies showed that γ-CD has the strongest binding affinity with ubiquinol compared to α- or β-CD. Complexed ubiquinol showed significantly higher stability compared to free ubiquinol in different aqueous ophthalmic products including Optisol-GS® corneal storage medium, balanced salt solution for intraocular irrigation, and topical Refresh® artificial tear eye drops. Greater ROS scavenging activity was noted in a cell model with high basal metabolism and ROS generation (A549) and in HCEC-B4G12 human corneal endothelial cells after treatment with ubiquinol/γ-CD compared to free ubiquinol. Furthermore, complexed ubiquinol was more effective at lowering ROS, and at far lower concentrations, compared to free ubiquinol. Complexed ubiquinol inhibited lipid peroxidation and protected HCEC-B4G12 cells against erastin-induced ferroptosis. No evidence of cellular toxicity was detected in HCEC-B4G12 cells after treatment with complexed ubiquinol. Using a vertical diffusion system, a topically applied inclusion complex of γ-CD and a lipophilic dye (coumarin-6) demonstrated transcorneal penetrance in porcine corneas and the capacity for the γ-CD vehicle to deliver drug to the corneal endothelium. Using the same model, topically applied ubiquinol/γ-CD complex penetrated the entire thickness of human donor corneas with markedly greater ubiquinol retention in the endothelium compared to free ubiquinol. Lastly, the penetrance of ubiquinol/γ-CD complex was assayed using human donor corneas preserved for 7 days in Optisol-GS® per standard industry practices, and demonstrated higher amounts of ubiquinol retained in the corneal endothelium compared to free ubiquinol. In summary, ubiquinol complexed with γ-CD is a highly stable composition that can be incorporated into a variety of aqueous-phase products for ophthalmic use including donor corneal storage media and topical eye drops to scavenge ROS and protect corneal endothelial cells against oxidative damage.
Topics: Animals; Cornea; Corneal Transplantation; Culture Media, Serum-Free; Dextrans; Endothelial Cells; Endothelium, Corneal; Gentamicins; Humans; Organ Preservation; Swine; Ubiquinone
PubMed: 34087583
DOI: 10.1016/j.biomaterials.2021.120842 -
Taiwan Journal of Ophthalmology 2023To assess the extent of inferior fornix shortening in conjunctivochalasis (CCh) and to evaluate whether fornix deepening reconstruction can restore the fornix tear...
PURPOSE
To assess the extent of inferior fornix shortening in conjunctivochalasis (CCh) and to evaluate whether fornix deepening reconstruction can restore the fornix tear reservoir in patients with CCh.
MATERIALS AND METHODS
This was a retrospective review of five patients (3 unilateral and 2 bilateral eyes, total 7 eyes) with CCh who underwent fornix deepening reconstruction with conjunctival recession and amniotic membrane transplantation. Postsurgical outcome measures included changes in fornix depth with correlation to basal tear volumes, symptoms, corneal staining, and conjunctival inflammation.
RESULTS
For the three patients with unilateral surgery, both the fornix depth (8.3 ± 1.5 mm) and wetting length (9.3 ± 8.5 mm) of the operative eyes were less than the fellow eyes (10.3 ± 1.5 mm and 10.3 ± 8.5 mm, respectively). At 5.3 ± 2.7 months (range 1.7-8.7) postoperatively, the fornix depth increased significantly by 2.0 ± 1.1 mm ( = 0.02). Deepening of the fornix depth was accompanied by overwhelming symptomatic relief (91.5%) that could be subdivided into complete relief (87.5%) and partial relief (4%) of symptoms, with blurred vision being the most notably relieved symptom ( = 0.03). Furthermore, superficial punctate keratitis and conjunctival inflammation were significantly improved at follow-up ( = 0.008 and 0.05, respectively).
CONCLUSION
Deepening of the fornix to restore the tear reservoir is an important surgical objective that may change the tear hydrodynamic state to provide a stable tear film and improve outcomes in CCh.
PubMed: 37252158
DOI: 10.4103/tjo.tjo_28_22 -
The Journal of Biological Chemistry 2021Lipids in complex, protein-enriched films at air/liquid interfaces reduce surface tension. In the absence of this benefit, the light refracting and immunoprotective tear...
Lipids in complex, protein-enriched films at air/liquid interfaces reduce surface tension. In the absence of this benefit, the light refracting and immunoprotective tear film on eyes would collapse. Premature collapse, coupled with chronic inflammation compromising visual acuity, is a hallmark of dry eye disease affecting 7 to 10% of individuals worldwide. Although collapse seems independent of mutation (unlike newborn lung alveoli), selective proteome and possible lipidome changes have been noted. These include elevated tissue transglutaminase and consequent inactivation through C-terminal cross-linking of the tear mitogen lacritin, leading to significant loss of lacritin monomer. Lacritin monomer restores homeostasis via autophagy and mitochondrial fusion and promotes basal tearing. Here, we discover that lacritin monomer C-terminal processing, inclusive of cysteine, serine, and metalloproteinase activity, generates cationic amphipathic α-helical proteoforms. Such proteoforms (using synthetic peptide surrogates) act like alveolar surfactant proteins to rapidly bind and stabilize the tear lipid layer. Immunodepletion of C- but not N-terminal proteoforms nor intact lacritin, from normal human tears promotes loss of stability akin to human dry eye tears. Stability of these and dry eye tears is rescuable with C- but not N-terminal proteoforms. Repeated topical application in rabbits reveals a proteoform turnover time of 7 to 33 h with gradual loss from human tear lipid that retains bioactivity without further processing. Thus, the processed C-terminus of lacritin that is deficient or absent in dry eye tears appears to play a key role in preventing tear film collapse and as a natural slow release mechanism that restores epithelial homeostasis.
Topics: Animals; Disease Models, Animal; Dry Eye Syndromes; Eye Proteins; Glycoproteins; Humans; Meibomian Glands; Protein Isoforms; Rabbits; Tears
PubMed: 33187980
DOI: 10.1074/jbc.RA120.015833 -
Journal of Optometry 2020Evaluations of tear functions frequently involve some form of voluntary control over blink behaviour. To the degree that voluntary control of blinking risks departure... (Review)
Review
Evaluations of tear functions frequently involve some form of voluntary control over blink behaviour. To the degree that voluntary control of blinking risks departure from normal-range spontaneous blinking, the tear function findings from such studies may be confounded. Even subject awareness that blinking is being assessed may influence findings if such awareness results in any degree of voluntary control. Ideally, the influence on blink rate and tear functions induced by therapeutic or experimental interventions could be measured against a normal-range baseline spontaneous blink rate in order that any differences found could be validly attributed to those interventions. Sometimes pre-intervention 'rest-related' baseline blink rates have been incorrectly described as 'basal' blink rates without specification of pre-intervention conditions of 'rest' or consideration of any contributions from voluntary control. Also, studies which use only blink rates to measure blink efficiency ignore the critically important contribution of incomplete blinking to blink inefficiency. This review finds that the assessment of normal-range spontaneous blink rates depends on measurement conditions which have frequently been ignored previously. For example, normal-range spontaneous blink rates appear more likely to occur with fixation targets which have a disengaged affect and an associated neutral influence on and from dopamine activity. Ideally, fixation targets should also involve minimal cognitive loading and vision demands. In addition, normal-range (symptom free) spontaneous blink rates are more likely to be assessed in a comfortable ambient environment without subject awareness that blink behaviour is being assessed and when voluntary blinking is not involved.
Topics: Blinking; Dopamine; Dry Eye Syndromes; Humans; Tears
PubMed: 31992536
DOI: 10.1016/j.optom.2019.09.002 -
Therapeutic Advances in Ophthalmology 2018The aim of this study is to evaluate the difference between reflex and basal tear osmolarity among healthy normal subjects.
PURPOSE
The aim of this study is to evaluate the difference between reflex and basal tear osmolarity among healthy normal subjects.
METHOD
The right eyes of 20 healthy normal male subjects aged 20 to 40 years were recruited for this study. The inclusion criteria for the subjects were the Ocular Surface Disease Index questionnaire score of less than 12 and wetting length of the phenol red thread of more than 10 mm. Tear film osmolarity was assessed using TearLab osmometer. Basic tear osmolarity was measured normally without inducing any irritation to the eye. In order to stimulate reflex tear, subjects were asked to open their eye as long as they can till they feel ocular surface irritation (minimum 20 s).
RESULTS
The mean score on the Ocular Surface Disease Index questionnaire was 5.5 ± 3. The mean value obtained from the phenol red thread was 21 ± 4.5 mm. There were no statistically significant differences between the osmolarity readings of basal and reflex tear osmolarity ( > 0.05). The mean value was 308 ± 12 and 306 ± 9 mOsm/l for basic and reflex tear osmolarity, respectively.
CONCLUSION
This study found that the osmolarity of the basal and reflex tears fell within the same range. The values found in this study are in agreement with published results for normal subjects.
PubMed: 30151502
DOI: 10.1177/2515841418794886 -
Journal of Ocular Pharmacology and... Nov 2019The study establishes normative data of tear volume (TV) and tear turnover rate (TTR) in healthy dogs and cats, 2 species commonly used for translational research in...
The study establishes normative data of tear volume (TV) and tear turnover rate (TTR) in healthy dogs and cats, 2 species commonly used for translational research in ophthalmology. Thirty-six dogs and 24 cats were enrolled, encompassing a variety of breeds with diverse skull conformations (brachycephalic, mesocephalic, and dolichocephalic). Two microliters of 10% fluorescein were instilled onto the upper bulbar conjunctiva of both eyes, followed by tear collection with 2-μL capillary tubes at 0, 2, 4, 6, 10, 15, and 20 min. Fluorescein concentrations were measured with a computerized scanning ocular fluorophotometer. The TV and TTR were estimated based upon nonlinear mixed-effects analysis of fluorescein decay curves. In dogs, median (interquartile range) TV, basal TTR (bTTR), and reflex TTR (rTTR) were 65.3 μL (42.3-87.9), 12.2%/min (3.7-22.1), and 50.0%/min (25.9-172.3), respectively. In cats, median (interquartile range) TV, bTTR, and rTTR were 32.1 μL (29.5-39.9), 10.9%/min (3.0-23.7), and 50.0%/min (28.4-89.4), respectively. Body weight ( = 0.44) and age ( = 0.30) were positively correlated ( ≤ 0.019) with TV in dogs. Age was negatively correlated ( ≤ 0.018) with TTR in dogs ( = -0.33) and cats ( = -0.24). However, TV and TTR were not associated with skull conformation in either species. Dogs have greater TV than cats but similar basal and rTTR. Tear parameters were impacted by body weight and age, but not by skull conformation. In both clinical and research settings, successive lacrimal tests should be spaced by ≥10 min to provide sufficient time for the tear film to replenish, as bTTR is ∼11%/min-12%/min in both species.
Topics: Animals; Cats; Dogs; Fluorophotometry; Humans; Tears
PubMed: 31381493
DOI: 10.1089/jop.2019.0038 -
Advances in Experimental Medicine and... 2020Homeostasis and visual acuity of the surface of the eye are dependent on tears, a thin film comprising at least 1800 different extracellular proteins and numerous... (Review)
Review
Homeostasis and visual acuity of the surface of the eye are dependent on tears, a thin film comprising at least 1800 different extracellular proteins and numerous species of lipids through which 80% of entering light is refracted at the air interface. Loss of homeostasis in dry eye disease affects 5-7% of the world's population, yet little is known about key molecular players. Our story began as an unbiased screen for regulators of tearing that led to the discovery of homeostasis-restorative 'lacritin', a tear protein whose active form is selectively deficient in dry eye. Heparanase acts as a novel 'on-switch' for lacritin ligation of syndecan-1 necessary to trigger basal tearing, as well as pertussis toxin-sensitive and FOXO-dependent signaling pathways for healing of inflammation-damaged epithelia and restoring epithelial oxidative phosphorylation by mitochondrial fusion downstream of transiently accelerated autophagy. A phase 2 clinical trial has tested the applicability of this mechanism to the resolution of dry eye disease. Results are not yet available. With lacritin proteoforms detected in cerebral spinal fluid, plasma, and urine, the capacity of the lacritin-syndecan-1-heparanase axis to restore homeostasis might have wide systemic relevance to other organs.
Topics: Dry Eye Syndromes; Glucuronidase; Glycoproteins; Homeostasis; Humans; Syndecan-1; Tears
PubMed: 32274735
DOI: 10.1007/978-3-030-34521-1_31 -
Maxillofacial Plastic and... Dec 2015Dry eye syndrome is a relatively common disease of the tears and ocular surfaces that results in discomfort, visual disturbance, and tear film instability with possible... (Review)
Review
Dry eye syndrome is a relatively common disease of the tears and ocular surfaces that results in discomfort, visual disturbance, and tear film instability with possible damage to the ocular surfaces. Microvascular submandibular gland (SMG) transfer offers a surgical alternative for a permanent autologous substitution of tears using the basal secretion of a transplanted SMG. Long-term follow-up reveals that this technique is a lasting and effective solution for patients with severe dry eye syndrome. The uncomfortable symptoms were relieved, and the frequency of use of pharmaceutical tear substitutes was reduced. Objective examination showed significant improvement in tear film and some features of ocular surface such as breakup time of tear film and corneal staining. Patients may suffer from obstruction of Wharton's duct or epiphora after surgery. Activation of secretion-related receptors could improve the early hypofunction of the denervated SMG and prevent the duct obstruction. Reduction surgery, partial SMG transplantation, uses of atropine gel or Botulinum toxin A could be the choices of treatment for epiphora.
PubMed: 25664315
DOI: 10.1186/s40902-015-0006-4 -
Transactions of the American... 1985Tear analysis in contact lens wearers was compared with tear analysis in aphakics without contact lens wear and normal phakic patients. Subjects were divided into five... (Comparative Study)
Comparative Study Review
Tear analysis in contact lens wearers was compared with tear analysis in aphakics without contact lens wear and normal phakic patients. Subjects were divided into five groups: group 1, aphakic without contact lens; group 2, phakic with daily-wear hard contact lens; group 3, phakic with daily-wear soft contact lens; group 4, phakic with extended-wear soft contact lens; and group 5, aphakic with extended-wear soft contact lens. The experimental groups were compared with age- and sex-matched control groups for statistical analysis of tear variables by means of the Student's t-test. The variables measured were tear osmolarity, tear albumin, and lysozyme and lactoferrin concentrations in basal and reflex tears. Highly significant elevations of tear osmolarity were found in aphakic subjects without contact lenses. Less significant differences in tear osmolarity were found in phakic subjects with hard daily-wear lenses or with extended-wear soft lenses. Tear albumin, lysozyme, and lactoferrin in basal and reflex tears were not significantly different in the different groups of contact lens wearers or in the group of aphakic subjects without contact lenses compared with their control groups. Individual variations in tear albumin, lysozyme, and lactoferrin appeared to be responsible for the inability to demonstrate significant differences in tear composition in association with the wearing of different types of contact lenses. Older and aphakic patients demonstrated a tendency to have increased concentrations of proteins in the tears compared with younger, phakic contact lens wearers and normal controls without contact lenses.
Topics: Adolescent; Adult; Age Factors; Aged; Albumins; Aphakia, Postcataract; Contact Lenses; Contact Lenses, Extended-Wear; Contact Lenses, Hydrophilic; Female; Humans; Immunoglobulins; Lactoferrin; Lipids; Male; Middle Aged; Mucins; Muramidase; Proteins; Tears
PubMed: 3914131
DOI: No ID Found -
Journal of Research in Medical Sciences... Aug 2014Ramadan fasting may alter a variety of physiological parameters which by themselves influence ocular system. Here, we review the effects of Ramadan fasting on the health... (Review)
Review
BACKGROUND
Ramadan fasting may alter a variety of physiological parameters which by themselves influence ocular system. Here, we review the effects of Ramadan fasting on the health and function of the eye.
MATERIALS AND METHODS
Literature records in PubMed/MEDLINE, Web of Science, EMBASE, Google Scholar, and Iran Medex databases as well as proceedings of related meetings from January 1986 to March 2014 were systematically reviewed. The search key words was based on the terms "Ramadan Fasting," "Ramadan," "Islamic Fasting," "Fasting in Ramadan" accompanied with one of the eye, tear drop, myopia, intraocular pressure (IOP), tear break up time, basal tear secretion, refractive error, and visual acuity.
RESULTS
Predawn water loading and dehydration in the evening are shown to increase and decrease IOP and tear secretion, respectively. Ocular blood flow is changed in Ramadan fasting, and patients with ocular vein occlusion may experience more frequent attacks. There are no or minimal fluctuations in visual acuity and refractive errors, but most of them are decompensated after Ramadan.
CONCLUSION
Although the influence of fasting in different eye parameters is evaluated in several studies, there are no or only limited studies conducted on patients suffering from glaucoma, damage to ophthalmic vasculature, tear dysfunction, and minimal visual acuity. Such studies are required to make a definite decision before fasting is declared harmless to these patients.
PubMed: 25422666
DOI: No ID Found