Microfluidic Fabricated Liposomes for Nutlin-3a Ocular Delivery as Potential Candidate for Proliferative Vitreoretinal Diseases Treatment.

Purpose: Proliferative vitreoretinal diseases (PVDs) represent a heterogeneous group of pathologies characterized by the presence of retinal proliferative membranes, in whose development retinal pigment epithelium (RPE) is deeply involved. As the only effective treatment for PVDs at present is surgery, we aimed to investigate the potential therapeutic activity of Nutlin-3a, a small non-genotoxic inhibitor of the MDM2/p53 interaction, on ARPE-19 cell line and on human RPE primary cells, as in vitro models of RPE and, more importantly, to formulate and evaluate Nutlin-3a loaded liposomes designed for ophthalmic administration. Methods: Liposomes were produced using an innovative approach by a microfluidic device under selection of different conditions. Liposome size distribution was evaluated by photon correlation spectroscopy and centrifugal field flow fractionation, while the liposome structure was studied by transmission electron microscopy and Fourier-transform infrared spectroscopy. The Nutlin-3a entrapment capacity was evaluated by ultrafiltration and HPLC. Nutlin-3a biological effectiveness as a solution or loaded in liposomes was evaluated by viability, proliferation, apoptosis and migration assays and by morphological analysis. Results: The microfluidic formulative study enabled the selection of liposomes composed of phosphatidylcholine (PC) 5.4 or 8.2 mg/mL and 10% ethanol, characterized by roundish vesicular structures with 150-250 nm mean diameters. Particularly, liposomes based on the lower PC concentration were characterized by higher stability. Nutlin-3a was effectively encapsulated in liposomes and was able to induce a significant reduction of viability and migration in RPE cell models. Conclusion: Our results lay the basis for a possible use of liposomes for the ocular delivery of Nutlin-3a.

Hemoglobin levels are associated with retinal vascular caliber in a middle-aged birth cohort.

Vascular and neural structures of the retina can be visualized non-invasively and used to predict ocular and systemic pathologies. We set out to evaluate the association of hemoglobin (Hb) levels within the national reference interval with retinal vascular caliber, optical coherence tomography (OCT) and visual field (VF) parameters in the Northern Finland 1966 Birth Cohort (n = 2319, 42.1% male, average age 47 years). The studied parameters were evaluated in Hb quintiles and multivariable linear regression models. The lowest Hb quintile of both sexes presented the narrowest central retinal vein equivalent (CRVE) and the healthiest cardiometabolic profile compared to the other Hb quintiles. In the regression models, CRVE associated positively with Hb levels in both sexes, (Bmales = 0.068 [0.001; 0.135], Bfemales = 0.087 [0.033; 0.140]), after being adjusted for key cardiometabolic and inflammatory parameters, smoking status, and fellow vessel caliber. No statistically significant associations of Hb levels with central retinal artery equivalent, OCT or VF parameters were detected. In conclusion, Hb levels were positively and specifically associated with CRVE, indicating that Hb levels are an independent factor affecting CRVE and the effect is in parallel with established risk factors for cardiometabolic diseases.

Marine Natural Products Rescuing the Eye: A Narrative Review.

Different degrees of visual impairment lead to a decrease in patient wellbeing, which has an adverse effect on many facets of social and professional life. Eye disorders can affect several parts of the eye, most notably the retina and the cornea, and the impacted areas might share a common form of cellular damage or dysfunction (such as inflammation, oxidative stress and neuronal degeneration). Considering that marine organisms inhabit a broad variety of marine habitats, they display a great degree of chemical diversity. As a result, molecules with a marine origin are receiving more and more attention in the hopes of developing novel therapeutic approaches. For instance, fucoxanthin has been demonstrated to be effective in protecting the retina against photo-induced damage, while largazole, astaxanthin and spirulina have all shown antioxidant, anti-inflammatory and antiapoptotic activities that can be useful for the management of several ocular diseases, such as age-related macular degeneration and ocular surface disorders. The aim of this review is to analyze the scientific literature relating to the therapeutic effects on the eye of the main natural marine products, focusing on their mechanism of action and potential clinical uses for the management of ocular diseases.

Can (Natural) deep eutectic systems increase the efficacy of ocular therapeutics?

The eye is one of the most complex organs in the human body, with a unique anatomy and physiology, being divided into anterior and posterior segments. Ocular diseases can occur in both segments, but different diseases affect different segments. Glaucoma and cataracts affect the anterior segment, while macular degeneration and diabetic retinopathy occur in the posterior segment. The easiest approach to treat ocular diseases, especially in the anterior segment, is through the administration of topical eye drops, but this route presents many constraints, namely precorneal dynamic and static ocular barriers. On the other hand, the delivery of drugs to the posterior segment of the eye is far more challenging and is mainly performed by the intravitreal route. However, it can lead to severe complications such as retinal detachment, endophthalmitis, increased intraocular pressure and haemorrhage. The design of new drug delivery systems for the anterior segment is very challenging, but targeting the posterior one is even more difficult and little progress has been made. In this review we will discuss various strategies including the incorporation of additives in the formulations, such as viscosity, permeability, and solubility enhancers, namely based on Deep eutectic systems (DES). Natural deep eutectic systems (NADES) have emerged to solve several problems encountered in pharmaceutical industry, regarding the pharmacokinetic and pharmacodynamic properties of drugs. NADES can contribute to the design of advanced technologies for ocular therapeutics, including hydrogels and nanomaterials. Here in, we revise some applications of (NA)DES in the development of new drug delivery systems that can be translated into the ophthalmology field.

Painful Eyes in Neurology Clinic: A Guide for Neurologists.

Eye pain is a common complaint among patients presenting to the neurology clinic. It can be related to neurologic diseases, but it can also be a localized eye condition. Such disorders can be misleading, as their benign appearance might mask more grave underlying conditions, potentially leading to misdiagnoses or delayed treatment. Clinicians should be aware of the specific neurologic or systemic disorders (eg, demyelinating diseases or vascular abnormalities) that might first manifest as eye pain. Formal ophthalmic consultation is recommended for patients presenting with eye pain as the predominant complaint especially when red flags for more serious pathology are present.

The Hippo signalling pathway and its impact on eye diseases.

The Hippo signalling pathway, an evolutionarily conserved kinase cascade, has been shown to be crucial for cell fate determination, homeostasis and tissue regeneration. Recent experimental and clinical studies have demonstrated that the Hippo signalling pathway is involved in the pathophysiology of ocular diseases. This article provides the first systematic review of studies on the regulatory and functional roles of mammalian Hippo signalling systems in eye diseases. More comprehensive studies on this pathway are required for a better understanding of the pathophysiology of eye diseases and the development of effective therapies.

Susceptibility of optic nerve head in children with posture-related elevation of intraocular pressure.

BACKGROUND/AIMS: This work aimed to investigate changes in optic nerve head (ONH) morphometry based on Bruch membrane opening in children with extensive nocturnal intraocular pressure (IOP) elevations. METHODS: The course of Bruch membrane opening-based optic nerve head (ONH) morphometry was analysed in thirty-two patients younger than 18 years with evaluable SD-OCT examinations of the ONH and nocturnal posture-dependent IOP elevation above 25 mmHg. Longitudinal changes in neuroretinal rim tissue, as measured by Bruch Membrane opening minimum rim width (BMO-MRW) and peripapillary retinal nerve fiber layer (RNFL) thickness, were assessed. RESULTS: One year after the 24 h IOP measurement, global BMO-MRW (- 1.61 ± 16.8 µm, n.s.; p = 0.611) and RNFL (+ 0.64 ± 3.17 µm; n.s.; p = 0.292) measurements were not significantly different from the baseline. No significant BMO-MRW reduction (- 3.91 ± 24.3 µm; n.s. p = 0.458) or deviation in RNFL thickness (+ 1.10 ± 3.52 µm) was observed at the four-year follow-up. Absolute IOP values measured in the supine position did not correlate with changes in global BMO-MRW or RNFL thickness. CONCLUSION: Posture-dependent IOP elevations do not seem to influence retinal nerve fibre layer thickness or Bruch membrane opening-based morphometric data in childhood.

No side effects on rabbit retina or vitreous microenvironment by nd:YAG laser vitreolysis.

BACKGROUND: To explore the safety of Neodymium:Yttrium-aluminum-garnet (Nd:YAG) laser vitreolysis based on the histological examination of the retina and the alteration of vitreous cytokines in the rabbits. METHODS: Nine male New Zealand rabbits underwent Nd:YAG laser vitreolysis of 10 mJ x 500 pulses in the left eyes, while the right eyes were used as controls. Intraocular pressure, color fundus photography, and ultrasound B scan were measured before, as well as 1 day, 4 weeks, and 12 weeks after Nd:YAG laser vitreolysis. Three rabbits were euthanized 1 day, 4 weeks, and 12 weeks after treatment, respectively. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and hematoxylin-eosin (H&E) staining were used to look for pathological changes in the retina. An enzyme-linked immunosorbent assay (ELISA) was utilized to detect the expression of vascular endothelial growth factor (VEGF) and some inflammatory cytokines, including interferon inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1) and interlenkin 6 (IL-6) in the vitreous humor. The ascorbic acid (AsA) and total reactive antioxidant potential (TRAP) in the vitreous humor were also measured. RESULTS: Following Nd:YAG laser vitreolysis, the levels of VEGF, IP-10, MCP-1, IL6, AsA, and TRAP in the vitreous humor did not change substantially (P > 0.05). There were no detectable pathological changes in the retinal tissues, and no apoptotic signal was found. CONCLUSIONS: Rabbits tolerate Nd:YAG laser vitreolysis without observable impact on retinal tissue or the microenvironment of the vitreous.

Intraocular pressure changes before and after a femtosecond laser procedure for cataract surgery.

This study aimed to evaluate the changes in intraocular pressure (IOP) before and after femtosecond laser capsulorhexis and lens fragmentation for cataract surgery. We measured the IOP before, immediately, 30 min, and 1 h after the laser procedure in 47 eyes of 47 patients who underwent the femtosecond laser procedure. The mean IOP was 17.51 ± 3.28 mmHg, 30.23 ± 6.70 mmHg, 17.96 ± 3.75 mmHg, and 21.77 ± 5.88 mmHg before, immediately after, 30 min after, and 1 h after the laser procedure, respectively. The mean IOP significantly increased immediately (adjusted P < 0.001) and 1 h (adjusted P = 0.001) after the laser procedure compared with the pre-laser IOP. The mean IOP at 30 min after the laser procedure was significantly lower than that immediately after the procedure (adjusted P < 0.001). However, the IOP 1 h after the laser procedure became higher than that 30 min after the laser procedure. Additionally, the IOP 1 h after the laser procedure was positively correlated with the baseline IOP and negatively correlated with the axial length. In conclusion, this study demonstrated that cataract surgery should be commenced within 30 min after the femtosecond laser procedure to ensure a safe cataract surgery that reduces the risk of increased intraocular pressure.

Effects of propofol, desflurane, and spinal anesthesia on intraocular pressure during lumbar disc herniation surgery: a randomized controlled study.

OBJECTIVE: This study aims to evaluate the effects of total intravenous anesthesia (propofol), volatile anesthesia (desflurane), and spinal anesthesia on intraocular pressure (IOP) during lumbar disc herniation surgery in the prone position. PATIENTS AND METHODS: This randomized controlled trial was conducted between January 2022 and January 2023. The study included 75 patients with lumbar disc herniation between the ages of 18-75, with the American Society of Anesthesiologists (ASA) 1-2. The patients were randomly divided into 3 groups: propofol, desflurane, and spinal. IOP was measured at 5-time points throughout surgery, including baseline (T1), 10 minutes after anesthesia (T2), 10 minutes after prone positioning (T3: early prone), 30 minutes after prone positioning (T4: late prone), and 10 minutes after returning to the supine position (T5). Hemodynamic parameters were measured at these time points. Hemoglobin and hematocrit values were measured preoperatively and on the first postoperative day. RESULTS: There were 25 patients in each group. The groups were similar in terms of all characteristics except for weight and body mass index, which were lower in the spinal group. Propofol recipients had significantly higher T3 (prone) IOP compared to desflurane recipients (p = 0.001). We found no significant differences between groups in terms of T1, T2, T4, and T5 IOP. Multivariable linear regression revealed that diabetes mellitus (p = 0.016) and high T1 IOP (p = 0.001) were independently associated with higher T3 IOP. In addition, we found that the desflurane (p < 0.001) and spinal (p = 0.002) groups had significantly lower T3 IOP compared to propofol recipients after adjusting for diabetes mellitus and T1 IOP. CONCLUSIONS: Our findings suggest that volatile anesthesia (desflurane) and spinal anesthesia are linked to lower IOP in the prone position among patients undergoing spinal surgery, in comparison to those receiving total intravenous anesthesia. There is a need to test the results with more comprehensive, population-based studies in different patient groups. ClinicalTrials gov ID: NCT06070480.

Association of Long-Term Exposure to Ambient Air Pollution With the Risk of Acute Primary Angle Closure.

Purpose: The purpose of this study was to investigate the association between long-term exposure to ambient air pollutants and the risk of acute primary angle closure (APAC). Methods: Two hundred eighty-one (281) patients with APAC and 730 age- and sex-matched controls hospitalized between January 2017 and December 2019 were enrolled in this retrospective case-control study. Residential exposure to ambient air pollutants, including fine particulate matter (PM2.5), inhalable particulate (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2), and ozone were estimated by satellite-models or ground measurement. Multivariate regression analyses explored the association between annual air pollutants exposure and the risk of APAC. Results: Of the 1011 participants (31.1% were male subjects), the average age was 64.0 years. Long-term exposure to PM2.5, PM10, and SO2 were significantly associated with an increased risk of APAC. The adjusted odds ratios (aORs) for each interquartile range (IQR) increment of PM2.5, PM10, and SO2 were 1.28 (95% confidence interval [CI] = 1.06-1.57), 1.26 (95% CI = 1.06-1.50), and 1.30 (95% CI = 1.04-1.62) separately, after controlling for confounders. Robust associations were observed for a longer lag 2-year exposure. Conclusions: Long-term exposure to PM2.5, PM10, and SO2 was associated with an increased risk of APAC in a Chinese population. Our findings provide epidemiological implications on the adverse effects of air pollution on ocular diseases. Translational Relevance: Long-term exposure to ambient air pollutants increased the risk of APAC.

Revolutionizing eye care: the game-changing applications of nano-antioxidants in ophthalmology.

Since the theory of free radical-induced aging was proposed in 1956, it has been constantly proven that reactive oxygen species (ROS) produced by oxidative stress play a vital role in the occurrence and progression of eye diseases. However, the inherent limitations of traditional drug therapy hindered the development of ophthalmic disease treatment. In recent years, great achievements have been made in the research of nanomedicine, which promotes the rapid development of safe theranostics in ophthalmology. In this review, we focus on the applications of antioxidant nanomedicine in the treatment of ophthalmology. The eye diseases were mainly classified into two categories: ocular surface diseases and posterior eye diseases. In each part, we first introduced the pathology of specific diseases about oxidative stress, and then presented the representative application examples of nano-antioxidants in eye disease therapy. Meanwhile, the nanocarriers that were used, the mechanism of function, and the therapeutic effect were also presented. Finally, we summarized the latest research progress and limitations of antioxidant nanomedicine for eye disease treatment and put forward the prospects of future development.

Functions of mucosal associated invariant T cells in eye diseases.

Mucosal-associated invariant T (MAIT) cells are a unique subset of T cells that recognizes metabolites derived from the vitamin B2 biosynthetic pathway. Since the identification of cognate antigens for MAIT cells, knowledge of the functions of MAIT cells in cancer, autoimmunity, and infectious diseases has been rapidly expanding. Recently, MAIT cells have been found to contribute to visual protection against autoimmunity in the eye. The protective functions of MAIT cells are induced by T-cell receptor (TCR)-mediated activation. However, the underlying mechanisms remain unclear. Thus, this mini-review aims to discuss our findings and the complexity of MAIT cell-mediated immune regulation in the eye.

[Hyperbaric oxygen therapy and eye disease: Review of the literature]. / Oxygénothérapie hyperbare et maladies oculaires : une revue de la littérature.

Hyperbaric oxygen therapy consists of breathing 100% oxygen continuously or intermittently in a chamber at a pressure equal to or greater than 1.4 absolute atmospheres. Indicated for the emergency treatment of carbon monoxide poisoning and other medical-surgical pathologies such as gas embolism or necrotizing soft-tissue infections, various studies have shown a beneficial effect of hyperbaric oxygen therapy in certain ocular pathologies, notably of microcirculatory origin, such as central retinal artery occlusion or macular edema linked to retinal vein occlusions. In addition, hyperbaric oxygen might represent an alternative treatment for ocular quinine toxicity and might also be useful as an adjuvant to surgery and antibiotics in cases of periorbital necrotizing fasciitis. On the other hand, oxygen in high concentrations has toxic ocular effects due to the production of reactive oxygen derivatives.

Options for Topical Treatment of Oxidative Eye Diseases with a Special Focus on Retinopathies.

Antioxidants, usually administered orally through the systemic route, are known to counteract the harmful effects of oxidative stress on retinal cells. The formulation of these antioxidants as eye drops might offer a new option in the treatment of oxidative retinopathies. In this review, we will focus on the use of some of the most potent antioxidants in treating retinal neuropathies. Melatonin, known for its neuroprotective qualities, may mitigate oxidative damage in the retina. N-acetyl-cysteine (NAC), a precursor to glutathione, enhances the endogenous antioxidant defense system, potentially reducing retinal oxidative stress. Idebenone, a synthetic analogue of coenzyme Q10, and edaravone, a free radical scavenger, contribute to cellular protection against oxidative injury. Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, possesses anti-inflammatory and antioxidant effects that could be beneficial in cases of retinopathy. Formulating these antioxidants as eye drops presents a localized and targeted delivery method, ensuring effective concentrations reach the retina. This approach might minimize systemic side effects and enhance therapeutic efficacy. In this paper, we also introduce a relatively new strategy: the alkylation of two antioxidants, namely, edaravone and EGCG, to improve their insertion into the lipid bilayer of liposomes or even directly into cellular membranes, facilitating their crossing of epithelial barriers and targeting the posterior segment of the eye. The synergistic action of these antioxidants may offer a multifaceted defense against oxidative damage, holding potential for the treatment and management of oxidative retinopathies. Further research and clinical trials will be necessary to validate the safety and efficacy of these formulations, but the prospect of antioxidant-based eye drops represents a promising avenue for future ocular therapies.