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.
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 β-cells. By culturing rat pancreatic β-cells (INS-1) cells in high-glucose media, we identified a source of increased miR-15a in the blood as exosomes secreted by pancreatic β-cells. We postulate that miR-15a, produced in pancreatic β-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 β-cell-specific miR-15a
mice.
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.
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.
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.
•· The retinal pigment epithelium (RPE) spends a huge amount of cellular energy for producing its secretome.•Multiple pathways are employed to allow protein release from RPE cells.•RPE secretory proteins govern multiple processes (apical/basolateral ECM (re)modelling, angiogenesis, immune response).•Altered RPE secretory proteostasis contributes to age- and disease-associated loss of retinal integrity.•Mutated secreted proteins cause intracellular proteotoxicity and ER stress, alongside extracellular proteolytic imbalance.
Thymoquinone is a naturally occurring compound and is the major component of
, 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).
and
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.
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.
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.
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.
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.
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.
Abstract
Background and Aims
Intravenous (IV) anti-vascular endothelial growth factor(VEGF) is a potent anti-angiogenic factor for the treatment of solid tumours. While, intravitreal anti-VEGF ...injection is used in the treatment for macular and retinal diseases. The effects of IV anti-VEGF agents are well documented to cause hypertension, renal impairment and proteinuria. However only few reports showed the significance of intravitreal anti-VEGF injection causing minimal change disease (MCD) and acute kidney injury (AKI). Hence, this study is to determine the outcome of renal function following intravitreal anti-VEGF injection.
Method
This is a prospective, cross sectional study recruiting patients from ophthalmology day-care operation theatre that were scheduled for intravitreal anti-VEGF injection in University Malaya Medical Centre (UMMC). On the day of the injection of anti-VEGF, patients’ demographic data (age, gender, medical background, medications), blood pressure, height, weight and investigations for serum creatinine and urine protein creatinine ratio (PCR) were collected. Following these, they will receive the intravitreal anti-VEGF as per schedule. All these patients were given a follow-up within 72hours to reassess blood pressure, serum creatinine and urine PCR.
Results
A total of 90 patients were recruited. However, 15 patients were subsequently excluded as there was no repeated serum creatinine at 72-hours post treatment. Their mean age was 67.25 ± 10.41. Among all, 3 patients had significance increased in serum creatinine (4%) with significance changed of urine PCR post treatment. Table 1 showed baseline parameters prior to treatment and table 2 was post treatment parameters.
Higher serum creatinine and proteinuria pre intravitreal anti-VEGF were identified to have higher OR of 1.018 (95% CI 1.001-1.035) (p=0.043) and OR 1.004 (1.000-1.007) (p=0.025) respectively among those who developed AKI. In assessing the association between higher pre-treatment creatinine and proteinuria (independent variable) and development of AKI (dependent variable) estimated by logistic regression with no AKI as a reference group we found that there were no significance.
Conclusion
Following intravitreal anti-VEGF administration, there were no significant changes in blood pressure. However, 4% from our cohort had AKI and worsening proteinuria at 72 hours post treatment. These patients had higher serum creatinine and proteinuria prior to treatment. However, our study is underpowered to establish the relationship between intravitreal anti-VEGF and development of AKI. Further study with larger sample size and longer-term outcome is needed.
Variable
No AKI (n=72)
AKI (n=3)
p value (95% CI)
Underlying Diabetes Mellitus
56/72 (77.78%)
3/3 (100%)
0.598
Height
161.18 ± 8.38
164 ± 1.00
0.565 (-12.52-6.89)
Weight
69.92 ± 13.86
60.37 ± 5.29
0.241 (-6.54-25.63)
Systolic BP pre injection
142.01 ± 18.50
141.67 ± 9.29
0.974 (-21.15-21.85)
Diastolic BP pre- injection
71.58 ± 11.29
76.00 ± 7.21
0.505 (-17.56-8.73)
Creatinine pre-injection
91.92 ± 41.87
159.33 ± 123.62
0.015 (-121.54- -13.29)
uPCR pre injection
91.66 ± 176.81
437.30 ± 527.54
0.004 (-575.06- -116.22)
Table 1:
Baseline parameters before intravitreal anti-VEGF injection among the patients that developed AKI vs no-AKI.
Variable
No AKI (n=72)
AKI (n=3)
p value (95% CI)
Systolic BP post injection
141.14 ± 21.53
139.67 ± 17.47
0.907 (-23.69-26.63)
Diastolic BP post injection
71.72 ± 10.51
70.33 ± 6.66
0.822 (6.14 - -10.86)
Creatinine post injection
90.56 ± 41.18
209.67 ± 159.66
<0.001 (28.55- -176.01)
uPCR post injection
97.16 ± 266.02
639.00 ± 795.88
0.003 (173.52- -887.83)
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