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Age-related macular degeneration (AMD) is a common cause of visual impairment in the elderly. There are very limited therapeutic options for AMD with the predominant therapies targeting vascular endothelial growth factor (VEGF) in the retina of patients afflicted with wet AMD. Hence, it is important to remind readers, especially those interested in AMD, about current studies that may help to develop novel therapies for other stages of AMD. This study, therefore, provides a comprehensive review of studies on human specimens as well as rodent models of the disease, to identify and analyze the molecular mechanisms behind AMD development and progression. The evaluation of this information highlights the central role that oxidative damage in the retina plays in contributing to major pathways, including inflammation and angiogenesis, found in the AMD phenotype. Following on the debate of oxidative stress as the earliest injury in the AMD pathogenesis, we demonstrated how the targeting of oxidative stress-associated pathways, such as autophagy and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, might be the futuristic direction to explore in the search of an effective treatment for AMD, as the dysregulation of these mechanisms is crucial to oxidative injury in the retina. In addition, animal models of AMD have been discussed in great detail, with their strengths and pitfalls included, to assist inform in the selection of suitable models for investigating any of the molecular mechanisms.

Ischemia is a common pathological condition present in many neurodegenerative diseases, including ischemic stroke, retinal vascular occlusion, diabetic retinopathy, and glaucoma, threatening the sight and lives of millions of people globally. Ischemia can trigger excessive oxidative stress, inflammation, and vascular dysfunction, leading to the disruption of tissue homeostasis and, ultimately, cell death. Current therapies are very limited and have a narrow time window for effective treatment. Thus, there is an urgent need to develop more effective therapeutic options for ischemia-induced neural injuries. With emerging reports on the pharmacological properties of natural flavonoids, these compounds present potent antioxidative, anti-inflammatory, and antiapoptotic agents for the treatment of ischemic insults. Three major active flavonoids, baicalein, baicalin, and wogonin, have been extracted from Scutellaria baicalensis Georgi (S. baicalensis); all of which are reported to have low cytotoxicity. They have been demonstrated to exert promising pharmacological capabilities in preventing cell and tissue damage. This review focuses on the therapeutic potentials of these flavonoids against ischemia-induced neurotoxicity and damage in the brain and retina. The bioactivity and bioavailability of baicalein, baicalin, and wogonin are also discussed. It is with hope that the therapeutic potential of these flavonoids can be utilized and developed as natural treatments for ischemia-induced injuries of the central nervous system (CNS).

Uveitis is a group of sight-threatening ocular inflammatory diseases, potentially leading to permanent vision loss in patients. However, it remains largely unknown how uveitis causes retinal malfunction and vision loss. Endotoxin-induced uveitis (EIU) in rodents is a good animal model to study uveitis and associated acute retinal inflammation. To understand the pathogenic mechanism of uveitis and screen potential targets for treatment, we analyzed the retinal proteomic profile of the EIU mouse model using a data-independent acquisition-based mass spectrometry (SWATH-MS). After systemic LPS administration, we observed activation of microglial cells accompanied with the elevation of pro-inflammatory mediators and visual function declines. In total, we observed 79 upregulated and 90 downregulated differentially expressed proteins (DEPs). Among the DEPs, we found that histone family members (histone H1, H2A, H2B) and blood proteins including haptoglobin (HP), hemopexin (HPX), and fibrinogen gamma chain (FGG) were dramatically increased in EIU groups relative to those in control groups. We identified phototransduction and synaptic vesicle cycle as the top two significant KEGG pathways. Moreover, canonical pathway analysis on DEPs using Ingenuity Pathway Analysis revealed top three most significant enriched pathways related to acute phase response signaling, synaptogenesis signaling, and eif2 signaling. We further confirmed upregulation of several DEPs associated with the acute phase response signaling including HP, HPX, and FGG in LPS-treated retinas by qPCR and Western blot. In summary, this study serves as the first report to detect retinal proteome changes in the EIU model. The study provides several potential candidates for exploring the mechanism and novel therapeutic targets for uveitis and other retinal inflammatory diseases.

PURPOSE: To compare the corneal biomechanical properties before and after small incision lenticule extraction (SMILE) and femtosecond laser-assisted LASIK in different levels of myopia with the Ocular Response Analyzer (Reichert Ophthalmic Instruments, Depew, NY). METHODS: A total of 187 and 79 eyes that received SMILE or LASIK, respectively, between January and June 2013 at Zhongshan Ophthalmic Center were enrolled in this study. Patients were grouped according to surgery type (SMILE or LASIK) and −6.00 diopters (D) or less (⩽ −6.00 D) or myopia greater than −6.00 D (>−6.00 D). Corneal hysteresis, corneal resistance factor, and 37 waveform parameters were recorded and compared preoperatively and at 1 week and 1 and 3 months postoperatively. RESULTS: There was a significant decrease of corneal hysteresis, corneal resistance factor, p1area, and p2area, and an increase of path1 and path2 in both SMILE and LASIK. In myopia −6.00 D or less, the differences between SMILE and LASIK were not significant (There was a significant decrease of corneal hysteresis, corneal resistance factor, p1area, and p2area, and an increase of path1 and path2 in both SMILE and LASIK. In myopia −6.00 D or less, the differences between SMILE and LASIK were not significant ( P > .05), but in myopia greater than −6.00 D, the corneal hysteresis, corneal resistance factor, p1area, and p2area decreased significantly more in LASIK than in SMILE ( P < .05). CONCLUSIONS: When comparing SMILE with LASIK, myopia was greater than −6.00 D, and the corneal hysteresis, corneal resistance factor, p1area, and p2area decrease was less after SMILE. [[ J Refract Surg . 2014;30(10):702–707.]

AimTo investigate the effect of the Defocus Incorporated Soft Contact (DISC) lenses on myopia progression and choroidal thickness (ChT) of Chinese mainland children over a period of 12 months.MethodsThis was a prospective double-blind randomised controlled trial involving 84 myopic children. Subjects were randomly assigned to use of either DISC or single vision contact lens (SVL). Cycloplegic spherical equivalent refraction (SER), axial length (AL) and ChT were measured at 6 and 12 months.ResultsFor 12 months, the average changes in SER and AL in the DISC group were (−0.50±0.41) D and (0.22±0.13) mm. Corresponding values in the SVL group were (−1.23±0.50) D and (0.49±0.15) mm. Myopia control efficacy in SER was 59% and 55% in AL. For those aged under 10, myopia control efficacy in SER is higher at 95% in 6 months and 71.4% in 12 months. ChT increased by 0.16±24.46 µm in the DISC group, while in contrast, it thinned in the SVL group (−9.11±32.25 µm) after 12 months. ChT changes demonstrated a significant negative association with AL over 12 months in the DISC group but not in the SVL group. In contrast, ChT change over 12 months was significantly negatively associated with initial ChT in the SVL group, but not in the DISC group.ConclusionsDISC lenses effectively slowed myopia progression and AL compared with SVL, especially for younger children. Myopia defocus treatment changes the original intrinsic relationship between ChT and myopia progression, providing strong evidence that myopia defocus design controls myopia progression by changing ChT.

The vitreous humor (VH) is a transparent gelatin-like substance that occupies two-thirds of the eyeball and undergoes the most significant changes during eye elongation. Quantitative proteomics on the normal growth period in the VH could provide new insights into understanding its progression mechanism in the early stages of myopia. In this study, a data-independent acquisition (SWATH-MS) was combined with targeted LC-ESI-MS/MS to identify and quantify the relative protein changes in the vitreous during the normal growth period (4, 7, 14, 21 and 28 days old) in the chick model. Chicks were raised under normal growing conditions (12/12 h Dark/light cycle) for 28 days, where ocular measurements, including refractive and biometric measurements, were performed on days 4 (baseline), 7, 14, 21 and 28 (n = 6 chicks at each time point). Extracted vitreous proteins from individual animals were digested and pooled into a left eye pool and a right pool at each time point for protein analysis. The vitreous proteome for chicks was generated using an information-dependent acquisition (IDA) method by combining injections from individual time points. Using individual pool samples, SWATH-MS was employed to quantify proteins between each time point. DEPs were subsequently confirmed in separate batches of animals individually on random eyes (n = 4) using MRMHR between day 7 and day 14. Refraction and vitreous chamber depth (VCD) were found to be significantly changed (p < 0.05, n = 6 at each time point) during the period. A comprehensive vitreous protein ion library was built with 1576 non-redundant proteins (22987 distinct peptides) identified at a 1% false discovery rate (FDR). A total of 12 up-regulated and 26 down-regulated proteins were found across all time points compared to day 7 using SWATH-MS. Several DEPs, such as alpha-fetoprotein, the cadherin family group, neurocan, and reelin, involved in structural and growth-related pathways, were validated for the first time using MRMHR under this experimental condition. This study provided the first comprehensive spectral library of the vitreous for chicks during normal growth as well as a list of potential growth-related protein biomarker candidates using SWATH-MS and MRMHR during the emmetropization period.

Most of the previous myopic animal studies employed a single-candidate approach and lower resolution proteomics approaches that were difficult to detect minor changes, and generated limited systems-wide biological information. Hence, a complete picture of molecular events in the retina involving myopic development is lacking. Here, to investigate comprehensive retinal protein alternations and underlying molecular events in the early myopic stage, we performed a data-independent Sequential Window Acquisition of all Theoretical Mass Spectra (SWATH) based proteomic analysis coupled with different bioinformatics tools in pigmented guinea pigs after 4-day lens-induced myopia (LIM). Myopic eyes compared to untreated contralateral control eyes caused significant changes in refractive error and choroid thickness (p < 0.05, n = 5). Relative elongation of axial length and the vitreous chamber depth were also observed. Using pooled samples from all individuals (n = 10) to build a species-specific retinal ion library for SWATH analysis, 3202 non-redundant proteins (with 24,616 peptides) were identified at 1% global FDR. For quantitative analysis, the 10 individual retinal samples (5 pairs) were analyzed using a high resolution Triple-TOF 6600 mass spectrometry (MS) with technical replicates. In total, 37 up-regulated and 21 down-regulated proteins were found significantly changed after LIM treatment (log2 ratio (T/C) > 0.26 or < −0.26; p ≤ 0.05). Data are accepted via ProteomeXchange with identifier PXD025003. Through Ingenuity Pathways Analysis (IPA), “lipid metabolism” was found as the top function associated with the differentially expressed proteins. Based on the protein abundance and peptide sequences, expression patterns of two regulated proteins (SLC6A6 and PTGES2) identified in this pathway were further successfully validated with high confidence (p < 0.05) using a novel Multiple Reaction Monitoring (MRM) assay on a QTRAP 6500+ MS. In summary, through an integrated discovery and targeted proteomic approach, this study serves as the first report to detect and confirm novel retinal protein changes and significant biological functions in the early LIM mammalian guinea pigs. The study provides new workflow and insights for further research to myopia control.

Retinal ischemia is a common cause of many retinal diseases, leading to irreversible vision impairment and blindness. Excessive neuroinflammation, including microglial activation and T-cell responses, has been identified as a critical factor associated with neurodegeneration in retinal ischemia. Baicalein is a natural flavonoid reported to have broad anti-inflammatory and neuroprotective bioactivities. Herein, the effects of baicalein on microglia activation in vitro and in vivo were investigated. We found that baicalein exhibited robust anti-inflammatory effect on cultured human and mouse microglia, as demonstrated by decreased induction of pro-inflammatory cytokines and the phosphorylation of phosphoinositide 3-kinase (PI3K) and nuclear factor kappa B (NFκB). Proteomic analysis further unraveled baicalein’s effect on modulating IL-17 signaling pathways and its upstream regulator IL-1β. Intravitreal administration of baicalein in the mouse model of retinal ischemia/reperfusion (I/R) injury attenuated microglial activation and retinal T-cell infiltration, particularly the T helper 17 cells. Additionally, baicalein was shown to exert neuroprotective effects by significantly reducing the retinal ganglion cell (RGC) loss after I/R injury, leading to an improved retinal function and spatial vision. These results suggest that baicalein, a natural flavonoid, acts as a negative regulator of activated microglia and immune responses both in vitro and in vivo , effectively alleviating neurodegeneration in retinal I/R injury. This finding indicates that baicalein could be a potential therapeutic agent against currently incurable degenerative retinal diseases.

Mechanical tissue stresses are important contributors to the increased risk of sight-threatening pathology in larger, more myopic eyes. The contribution of altered ocular vasculature to the development of this pathology is less well defined. The current study investigated the impact of eye size on the superficial vasculature of the macula. Subjects (n = 104) aged 18–50, with no history of ocular or vascular disease, or myopia control, were recruited from university staff and student populations in Australia and Hong Kong. Refractive error, ocular size, retinal morphology and vascular morphology were quantified through open field autorefraction, ocular biometry and ocular coherence tomography angiography. Morphology of the superficial retinal capillary plexus was assessed over a 3 × 3 mm fovea-centred area. Perfusion area and vessel length densities were analysed relative to axial eye length and retinal thickness. A significant inverse association was found between axial length and vascular density measures (perfusion area density r2 = 0.186, p < 0.001; and vessel length density r2 = 0.102, p = 0.001). Perfusion area and vessel length densities were reduced by 5.8% (p = 0.001) in the longest, relative to the shortest, eyes. The aggregated ganglion cell layer inner plexiform layer thickness was also inversely associated with eye size (r2 = 0.083, p = 0.003), and reduced, by 8.1% (p < 0.001), in the longest eyes. An inverse association of eye size and superficial retinal vasculature density, that is not simply explained by retinal expansion or image magnification factors, was confirmed. These data support the hypothesis that ongoing metabolic challenges may underlie the development of myopia-related and -associated pathology in larger eyes.

In age-related macular degeneration (AMD), hydroquinone (HQ)-induced oxidative damage in retinal pigment epithelium (RPE) is believed to be an early event contributing to dysregulation of inflammatory cytokines and vascular endothelial growth factor (VEGF) homeostasis. However, the roles of antioxidant mechanisms, such as autophagy and the ubiquitin-proteasome system, in modulating HQ-induced oxidative damage in RPE is not well-understood. This study utilized an in-vitro AMD model involving the incubation of human RPE cells (ARPE-19) with HQ. In comparison to hydrogen peroxide (H2O2), HQ induced fewer reactive oxygen species (ROS) but more oxidative damage as characterized by protein carbonyl levels, mitochondrial dysfunction, and the loss of cell viability. HQ blocked the autophagy flux and increased proteasome activity, whereas H2O2 did the opposite. Moreover, the lysosomal membrane-stabilizing protein LAMP2 and cathepsin D levels declined with HQ exposure, suggesting loss of lysosomal membrane integrity and function. Accordingly, HQ induced lysosomal alkalization, thereby compromising the acidic pH needed for optimal lysosomal degradation. Pretreatment with MG132, a proteasome inhibitor and lysosomal stabilizer, upregulated LAMP2 and autophagy and prevented HQ-induced oxidative damage in wildtype RPE cells but not cells transfected with shRNA against ATG5. This study demonstrated that lysosomal dysfunction underlies autophagy defects and oxidative damage induced by HQ in human RPE cells and supports lysosomal stabilization with the proteasome inhibitor MG132 as a potential remedy for oxidative damage in RPE and AMD.