Thymoquinone in Ocular Neurodegeneration: Modulation of Pathological Mechanisms via Multiple Pathways.

Thymoquinone is a naturally occurring compound and is the major component of Nigella sativa, also known as black seed or black cumin. For centuries thymoquinone has been used especially in the Middle East traditionally to treat wounds, asthma, allergies, fever, headache, cough, hypertension, and diabetes. Studies have suggested beneficial effects of thymoquinone to be attributed to its antioxidant, antibacterial, anti-oxidative stress, anti-inflammatory, and neuroprotective properties. Recently, there has been a surge of interest in thymoquinone as a treatment for neurodegeneration in the brain, such as that seen in Alzheimer's (AD) and Parkinson's diseases (PD). In vitro and in vivo studies on animal models of AD and PD suggest the main neuroprotective mechanisms are based on the anti-inflammatory and anti-oxidative properties of thymoquinone. Neurodegenerative conditions of the eye, such as Age-related Macular Degeneration (AMD) and glaucoma share at least in part similar mechanisms of neuronal cell death with those occurring in AD and PD. This review aims to summarize and critically analyze the evidence to date of the effects and potential neuroprotective actions of thymoquinone in the eye and ocular neurodegenerations.

Discovering the Potential of Natural Antioxidants in Age-Related Macular Degeneration: A Review.

Age-related macular degeneration (AMD) is a multifactorial disease associated with anatomical changes in the inner retina. Despite tremendous advances in clinical care, there is currently no cure for AMD. This review aims to evaluate the published literature on the therapeutic roles of natural antioxidants in AMD. A literature search of PubMed, Web of Science and Google Scholar for peer-reviewed articles published between 1 January 2011 and 31 October 2021 was undertaken. A total of 82 preclinical and 18 clinical studies were eligible for inclusion in this review. We identified active compounds, carotenoids, extracts and polysaccharides, flavonoids, formulations, vitamins and whole foods with potential therapeutic roles in AMD. We evaluated the integral cellular signaling pathways including the activation of antioxidant pathways and angiogenesis pathways orchestrating their mode of action. In conclusion, we examined the therapeutic roles of natural antioxidants in AMD which warrant further study for application in clinical practice. Our current understanding is that natural antioxidants have the potential to improve or halt the progression of AMD, and tailoring therapeutics to the specific disease stages may be the key to preventing irreversible vision loss.

The application of clinical registries in ophthalmic trauma-the International Globe and Adnexal Trauma Epidemiology Study (IGATES).

Ophthalmic trauma is a leading cause of preventable monocular blindness worldwide. The prevalence of ophthalmic trauma varies considerably based on geographic location, socio-economic status, age groups, occupation, and cultural practices such as firework celebrations. Clinical registries are known to be valuable in guiding the diagnosis, management, and prognostication of complex diseases. However, there is currently a lack of a centralized international data repository for ophthalmic trauma. We draw lessons from past and existing clinical registries related to ophthalmology and propose a new suitable international multicenter clinical registry for ophthalmic trauma: the International Globe and Adnexal Trauma Epidemiology Study (IGATES). IGATES is hosted on a secure web-based platform which exhibits user-friendly smart features, an integrated Ocular Trauma Score (OTS) prognosis calculator, efficient data collection points, and schematic graphical software. IGATES currently has 37 participating centers globally. The data collected through IGATES will be primarily used to develop a more robust and improved ophthalmic trauma prognostic classification system, the Ocular Trauma Score-2 (OTS-2), which builds on previous systems such as the Birmingham Eye Trauma Terminology System (BETTS) and Ocular Trauma Score (OTS). Furthermore, IGATES will act as a springboard for further research into the epidemiology, diagnosis, and management of ophthalmic trauma. Ultimately, IGATES serves to advance the field of ophthalmic trauma and improve the care that patients with ophthalmic trauma receive.

Epidemiology and outcomes of open globe injuries: the international globe and adnexal trauma epidemiology study (IGATES).

PURPOSE: To detail the methodology for a novel ocular trauma registry and utilize the registry to determine the demographics, nature of injury, and associations of severe visual loss for open globe injuries (OGI). METHODS: Thirteen hospitals in 7 countries used International Globe and Adnexal Trauma Epidemiology Study (IGATES) platform. Patients presenting between April 2009 and 2020 with OGI (with or without) adnexal involvement or intraocular foreign body (IOFB) were included. RESULTS: Analyses of presenting and final VA, using "severe vision loss" (VA ≤ 6/60) and "no severe loss" (VA > 6/60), were performed. Four hundred fifty-four (64%) patients had VA < 6/60 at presentation and 327 (44.8%) at final follow-up, with a highly significant association between presenting and final VA (p < 0.0001). From the cohort of 746 patients, 37 were missing VA at presentation and 16 at follow-up and complete clinical data was available for 354 patients. The male to female ratio is 6:1, and mean age 36.0 ± 20.0 years old. Relative afferent pupillary defect (RAPD), zone III injury, IOFB, and eyelid injury at presentation were recorded in 50 (6.7%), 55 (7.8%), 97 (13%), and 87 (11.7%) patients, respectively, and were significantly associated with VA < 6/60 at follow-up. Older age, ≥ 61 years, was associated with 3.39 times (95% CI: 1.95-5.89) higher risk than ≤20-year-old patients (p < 0.0001) and males 0.424 times (95% CI: 0.27-0.70) lower risk than female (p = 0.0001) of severe vision loss (SVL). CONCLUSION: In OGIs from 13 hospitals, female gender, older age, zone III injury, eyelid injury, and IOFB were associated with higher risk of visual outcome of SVL.

Comparative cohorts of retinopathy of prematurity outcomes of differing oxygen saturation: real-world outcomes.

OBJECTIVE: An ongoing third epidemic of retinopathy of prematurity (ROP) is contributed largely by developing nations. We describe a cohort of infants in a single neonatal unit where two limits of oxygen saturation were administered, to show real-world outcomes from trend in neonatology for higher oxygen to improve survival. METHODS AND ANALYSIS: This retrospective, comparative study of prospectively collected data in an ROP screening programme included infants indicated by gestational age ≤32 weeks, birth weight <1501 g, ventilation for 7 days or requiring oxygen >1 month, who underwent dilated fundoscopic examination from age 4 weeks, every 2 weeks until full retinal vascularisation. Infants with ROP were examined weekly and treated where indicated. Data were divided into two epochs. Epoch 1 oxygen saturation targets were [88-92%], epoch 2 targets [90-95% (99%)] with allowance of increase to 20% for several hours after procedures. Outcome measures included development of ROP, treatment, mortality, sepsis and intraventricular haemorrhage. RESULTS: A total of 651 infants underwent examination between 2003 and 2016. The incidence of ROP in epoch 1 was 29.1% and epoch 2 was 29.3% (p=0.24). ROP progression doubled in epoch 2 (5 vs 11%, p=0.006), proportion of cases treated halved (14% vs 6%, p=0.0005), sepsis was halved (78.5% vs 41.2%, p<0.0001) and intraventricular haemorrhage doubled (20.2% vs 43.8%, p=0.0001) in epoch 2. Mortality was 4% and 0% in epochs 1 and 2, respectively. CONCLUSION: Incidence of ROP did not differ, although ROP cases that worsened doubled with higher oxygen targets. ROP cases requiring treatment decreased, as did sepsis and mortality. Intraventricular haemorrhage cases doubled.

Premature Ocular Aging Features in Childhood Acute Lymphoblastic Leukemia Survivors.

Purpose: Childhood cancer survivors (CCS) demonstrate features of premature aging in a multitude of organ systems. The aim of this pilot study is to determine the presence of premature ocular aging features in CCS, specifically childhood acute lymphoblastic leukemia (ALL) survivors. Methods: This prospective case-control study was conducted over a period of 21 months, starting July 2015 till March 2017. A total of 59 childhood ALL survivors who attended the Paediatric Oncology Clinic of University Malaya Medical Centre (UMMC) and 48 age, race, and gender-matched controls went through a series of ocular examinations and tests. Inclusion criteria used to recruit survivors were age above 16 years, history of ALL in childhood, completion of treatment for ALL, and a remission period of at least 5 years. Patients with ocular disease and those who received hematopoietic stem cell transplantation were excluded. The parameters measured were visual acuity, amplitude of accommodation, pupil cycle time (PCT), and tear break-up time (TBUT). Results: Survivors of childhood ALL demonstrated significant differences in amplitude of accommodation, PCT, and TBUT compared to age-matched controls. Survivors had a lower median (interquartile range [IQR]) amplitude of accommodation compared to controls (11.0 D [9.0-13.0] vs. 12.0 D [10.5-15]; p = 0.045). Survivors also showed a longer median (IQR) PCT in comparison to controls (931.00 mseconds (857.00-1063.00) vs. 875.50 mseconds (825.75-966.00); p = 0.024). In addition, median (IQR) TBUT was worse in survivors in comparison to the control group (9 seconds [6-13] vs. 11 seconds [10-15]; p = 0.001). Conclusion: Survivors of childhood ALL demonstrate premature ocular aging features compared to age-matched controls. Thus, survivors may benefit from having ocular examinations as part of their routine late-effects screening to detect age-related ocular morbidities early in its course.

Secretory proteostasis of the retinal pigmented epithelium: Impairment links to age-related macular degeneration.

Secretory proteostasis integrates protein synthesis, processing, folding and trafficking pathways that are essential for efficient cellular secretion. For the retinal pigment epithelium (RPE), secretory proteostasis is of vital importance for the maintenance of the structural and functional integrity of apical (photoreceptors) and basal (Bruch's membrane/choroidal blood supply) sides of the environment it resides in. This integrity is achieved through functions governed by RPE secreted proteins, which include extracellular matrix modelling/remodelling, angiogenesis and immune response modulation. Impaired RPE secretory proteostasis affects not only the extracellular environment, but leads to intracellular protein aggregation and ER-stress with subsequent cell death. Ample recent evidence implicates dysregulated proteostasis as a key factor in the development of age-related macular degeneration (AMD), the leading cause of blindness in the developed world, and research aiming to characterise the roles of various proteins implicated in AMD-associated dysregulated proteostasis unveiled unexpected facets of the mechanisms involved in degenerative pathogenesis. This review analyses cellular processes unveiled by the study of the top 200 transcripts most abundantly expressed by the RPE/choroid in the light of the specialised secretory nature of the RPE. Functional roles of these proteins and the mechanisms of their impaired secretion, due to age and genetic-related causes, are analysed in relation to AMD development. Understanding the importance of RPE secretory proteostasis in relation to maintaining retinal health and how it becomes impaired in disease is of paramount importance for the development and assessment of future therapeutic advancements involving gene and cell therapies.

Advanced glycation end products-related modulation of cathepsin L and NF-κB signalling effectors in retinal pigment epithelium lead to augmented response to TNFα.

The retinal pigment epithelium (RPE) plays a central role in neuroretinal homoeostasis throughout life. Altered proteolysis and inflammatory processes involving RPE contribute to the pathophysiology of age-related macular degeneration (AMD), but the link between these remains elusive. We report for the first time the effect of advanced glycation end products (AGE)-known to accumulate on the ageing RPE's underlying Bruch's membrane in situ-on both key lysosomal cathepsins and NF-κB signalling in RPE. Cathepsin L activity and NF-κB effector levels decreased significantly following 2-week AGE exposure. Chemical cathepsin L inhibition also decreased total p65 protein levels, indicating that AGE-related change of NF-κB effectors in RPE cells may be modulated by cathepsin L. However, upon TNFα stimulation, AGE-exposed cells had significantly higher ratio of phospho-p65(Ser536)/total p65 compared to non-AGEd controls, with an even higher fold increase than in the presence of cathepsin L inhibition alone. Increased proportion of active p65 indicates an AGE-related activation of NF-κB signalling in a higher proportion of cells and/or an enhanced response to TNFα. Thus, NF-κB signalling modulation in the AGEd environment, partially regulated via cathepsin L, is employed by RPE cells as a protective (para-inflammatory) mechanism but renders them more responsive to pro-inflammatory stimuli.

Central corneal thickness changes and horizontal corneal diameter in premature infants: A prospective analysis.

To report observations of horizontal corneal diameter (HCD) and central corneal thickness (CCT) changes in premature infants with stable optic disc cupping and intraocular pressures (IOPs). The HCD and CCT at term serve as a baseline for premature infants.Sixty-three premature infants were enrolled in a prospective case series. HCD, CCT, and IOP were measured. RetCam images of the optic discs were used to evaluate the cup-disc ratio (CDR) and read by an independent masked observer. Data were collected at between preterm (32-36 weeks) and again at term (37-41 weeks) postconceptual age. Left eye measurements were used for statistical analysis. Left eye findings were combined to construct predictive models for HCD and CCT.The mean HCD was 9.1 mm (standard deviation [SD] = 0.7 mm) at preterm and 10.0 mm (SD = 0.52 mm) at term. The mean CCT preterm was 618.8 (SD = 72.9) µm and at term 563.9 (SD = 50.7) µm, respectively. The average preterm CDR was 0.31 and at maturity was 0.33. Average IOP of preterm and term was 13.1 and 14.11 mm Hg, respectively. There was significant linear correlation between HCD with the postmenstrual age (r = 0.40, P < .01) and the head circumference (r = 0.33, P < .05). Predictive models were constructed for HCD (R = 0.52, 0.2 mm/wk) and CCT (R = 0.23, -11.4 µm/wk) with postconceptual ages.The HCD and CCT variation did not affect IOP reading over time. CCT was not correlated with birth parameters and decreased as the infant reached term. Corneal diameter correlated with gestational age at birth and head circumference.

A rare case of solitary unifocal Langerhans cell histiocytosis with orbital extension: Diagnostic dilemma.

Langerhans cell histiocytosis (LCH) is rarely encountered in ophthalmology practice. It is a spectrum of disorder characterized by accumulation of histiocytes in various tissues. Diagnosis is challenging as it may simulate periorbital hematoma, rhabdomyosarcoma, and neuroblastoma. We report a case of unifocal LCH with orbital extension. Diagnosis was obtained from incisional biopsy, and histopathological examination showed numerous histiocytes with eosinophilic infiltrations. The presence of Langerhans cells was confirmed by the presence of protein S-100, CD1a, and/or Langerin (CD207). Treatment depends on the degree of organ involvement. She responded well to cytotoxic drugs and steroids. This emphasized that prompt tissue diagnosis is crucial for early management.

Association of glycemic control with progression of diabetic retinopathy in type 2 diabetes mellitus patients in Malaysia

Abstract The risk of having microvascular complication is high among Type 2 Diabetes Mellitus (T2DM) patients. However, factors associated with the glycemic control and progression of diabetic retinopathy (DR) in T2DM patients is limited. This study aims to determine association between anti-diabetic agents, glycemic control and progression of diabetic retinopathy in a Malaysian population. A retrospective study conducted in a tertiary teaching hospital in Malaysia, from January 2009 until March 2014. This study enrolled 104 patients aged 40-84 years, with a mean age 63.12 ± 9.18 years. patients had non-proliferative diabetic retinopathy (NPDR, 77%) and 35% had proliferative diabetic retinopathy (PDR). Diabetic macula edema (DME) was present in 20% of NPDR patients, compared with 7% in PDR. Alpha-glucosidase inhibitor (p=0.012), age (p=0.014) and number of antidiabetic agents used (p=0.015) were significantly associated with stages of diabetic retinopathy. Family history of T2DM (p=0.039) was associated with DME. Identifying factors influencing the progression of diabetic retinopathy may aid in optimizing the therapeutic effects of anti-diabetic agents in T2DM patients.

Exosomal MicroRNA-15a Transfer from the Pancreas Augments Diabetic Complications by Inducing Oxidative Stress.

AIMS: MicroRNAs (miRNAs), one type of noncoding RNA, modulate post-transcriptional gene expression in various pathogenic pathways in type 2 diabetes (T2D). Currently, little is known about how miRNAs influence disease pathogenesis by targeting cells at a distance. The purpose of this study was to investigate the role of exosomal miRNAs during T2D. RESULTS: We show that miR-15a is increased in the plasma of diabetic patients, correlating with disease severity. miR-15 plays an important role in insulin production in pancreatic ß-cells. By culturing rat pancreatic ß-cells (INS-1) cells in high-glucose media, we identified a source of increased miR-15a in the blood as exosomes secreted by pancreatic ß-cells. We postulate that miR-15a, produced in pancreatic ß-cells, can enter the bloodstream and contribute to retinal injury. miR-15a overexpression in Müller cells can be induced by exposing Müller cells to exosomes derived from INS-1 cells under high-glucose conditions and results in oxidative stress by targeting Akt3, which leads to apoptotic cell death. The in vivo relevance of these findings is supported by results from high-fat diet and pancreatic ß-cell-specific miR-15a-/- mice. INNOVATION: This study highlights an important and underappreciated mechanism of remote cell-cell communication (exosomal transfer of miRNA) and its influence on the development of T2D complications. CONCLUSION: Our findings suggest that circulating miR-15a contributes to the pathogenesis of diabetes and supports the concept that miRNAs released by one cell type can travel through the circulation and play a role in disease progression via their transfer to different cell types, inducing oxidative stress and cell injury. Antioxid. Redox Signal. 27, 913-930.

Effect of Nocturnal Intermittent Peritoneal Dialysis on Intraocular Pressure and Anterior Segment Optical Coherence Tomography Parameters.

PURPOSE: To evaluate the effect of nocturnal intermittent peritoneal dialysis (NIPD) on intraocular pressure (IOP) and anterior segment optical coherence tomography (ASOCT) parameters. Systemic changes associated with NIPD were also analyzed. METHODS: Observational study. Nonglaucomatous patients on NIPD underwent systemic and ocular assessment including mean arterial pressure (MAP), body weight, serum osmolarity, visual acuity, IOP measurement, and ASOCT within 2 hours both before and after NIPD. The Zhongshan Angle Assessment Program (ZAAP) was used to measure ASOCT parameters including anterior chamber depth, anterior chamber width, anterior chamber area, anterior chamber volume, lens vault, angle opening distance, trabecular-iris space area, and angle recess area. T tests and Pearson correlation tests were performed with P<0.05 considered statistically significant. RESULTS: A total of 46 eyes from 46 patients were included in the analysis. There were statistically significant reductions in IOP (-1.8±0.6 mm Hg, P=0.003), MAP (-11.9±3.1 mm Hg, P<0.001), body weight (-0.7±2.8 kg, P<0.001), and serum osmolarity (-3.4±2.0 mOsm/L, P=0.002) after NIPD. All the ASOCT parameters did not have any statistically significant changes after NIPD. There were no statistically significant correlations between the changes in IOP, MAP, body weight, and serum osmolarity (all P>0.05). CONCLUSIONS: NIPD results in reductions in IOP, MAP, body weight, and serum osmolarity in nonglaucomatous patients.

Endoscopic transnasal removal of an intraconal foreign body using an image-guided surgical system.

Foreign bodies lodged in the intraconal space of the orbit pose a surgical challenge due to its deep location behind the globe. Image-guided endoscopic transnasal surgery facilitates the localization of the metallic foreign bodies and enables its safe removal with minimal surrounding tissue damage and optic nerve injury.

Caffeic acid phenethyl ester (CAPE): scavenger of peroxynitrite in vitro and in sepsis models.

Excessive free radical production by immune cells has been linked to cell death and tissue injury during sepsis. Peroxynitrite is a short-lived oxidant and a potent inducer of cell death that has been identified in several pathological conditions. Caffeic acid phenethyl ester (CAPE) is an active component of honeybee products and exhibits antioxidant, anti-inflammatory, and immunomodulatory activities. The present study examined the ability of CAPE to scavenge peroxynitrite in RAW 264.7 murine macrophages stimulated with lipopolysaccharide/interferon-γ that was used as an in vitro model. Conversion of 123-dihydrorhodamine to its oxidation product 123-rhodamine was used to measure peroxynitrite production. Two mouse models of sepsis (endotoxemia and cecal ligation and puncture) were used as in vivo models. The level of serum 3-nitrotyrosine was used as an in vivo marker of peroxynitrite. The results demonstrated that CAPE significantly improved the viability of lipopolysaccharide/interferon-γ-treated RAW 264.7 cells and significantly inhibited nitric oxide production, with effects similar to those observed with an inhibitor of inducible nitric oxide synthase (1400W). In addition, CAPE exclusively inhibited the synthesis of peroxynitrite from the artificial substrate SIN-1 and directly prevented the peroxynitrite-mediated conversion of dihydrorhodamine-123 to its fluorescent oxidation product rhodamine-123. In both sepsis models, CAPE inhibited cellular peroxynitrite synthesis, as evidenced by the absence of serum 3-nitrotyrosine, an in vivo marker of peroxynitrite. Thus, CAPE attenuates the inflammatory responses that lead to cell damage and, potentially, cell death through suppression of the production of cytotoxic molecules such as nitric oxide and peroxynitrite. These observations provide evidence of the therapeutic potential of CAPE treatment for a wide range of inflammatory disorders.

Bone Remodeling in Choroidal Osteoma Monitored by Fundus Photography and Spectral-Domain Optical Coherence Tomography.

Choroidal osteoma is a benign ossifying tumor of the choroid, consisting of mature bone tissue. It has been described to enlarge and evolve at varying rates over time. Here, we report and quantify the progression of a unilateral choroidal osteoma in a 7-year-old boy by fundus photography, and document tumor remodeling by spectral domain optical coherence tomography images.

AAV-mediated gene transfer of human X-linked inhibitor of apoptosis protects against oxidative cell death in human RPE cells.

PURPOSE: To determine whether human X-linked inhibitor of apoptosis (XIAP) enhances the survival of cultured human retinal pigment epithelial cells exposed to H(2)O(2). METHODS: ARPE-19 cells were exposed to H(2)O(2) to induce oxidative cell death. Intracellular reactive oxygen species (ROS) were measured using 2',7'-dichlorofluorescein diacetate. MTT assay was performed to quantify mitochondrial stress. Cell apoptosis was determined by TUNEL assay. Human XIAP was delivered with bicistronic expression of green fluorescent protein (GFP), using recombinant adeno-associated virus (AAV-XIAP-GFP). The null vector, containing identical sequences but without XIAP, was used as a control (AAV-NULL-GFP). Transduced cells underwent fluorescence-activated cell sorting. XIAP overexpression was examined by immunostaining and Western blot analysis. RESULTS: ARPE-19 cells exposed to 0.25 mM H(2)O(2) for 1 hour showed increased TUNEL staining compared with nonstressed cells (17 ± 1.4 vs. 1.8 ± 0.4 cells per 20 × field; P = 0.000006), accompanied by a significant increase in intracellular ROS (207 ± 46% vs. 100 ± 9.5%; P = 0.0002). The AAV-XIAP-GFP transduced cells had 11-fold higher XIAP expression than the AAV-NULL-GFP controls (1300 ± 126% vs. 120 ± 10%; P = 0.0006). XIAP over-expression significantly reduced the number of apoptotic cells after stress compared with the AAV-NULL-GFP controls (3.2 ± 0.6 vs. 18 ± 1.6 cells per 20 × field; P = 0.00003). Mitochondrial stress was reduced by AAV-XIAP-GFP, but did not reach a statistical significance (68 ± 3.5% vs. 74 ± 3.8%; P = 0.24). CONCLUSIONS: Overexpression of human XIAP protects ARPE-19 cells against H(2)O(2)-induced oxidative cell death by acting downstream on the apoptotic pathway. XIAP gene therapy using AAV may provide a means of reducing the effect of oxidative stress to RPE cells in age-related macular degeneration.