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Persistent poly (ADP‐ribose) polymerase 1 (PARP‐1) activation has proven detrimental and can lead to PARP‐1‐dependent cell death. Mitochondria‐associated endoplasmic reticulum (ER) membranes (MAMs) serve as essential hubs for many biological pathways, such as autophagy and mitochondria fission and fusion. This study aimed to alleviate the effects of hydrogen peroxide (H2O2)‐induced persistent PARP‐1 activation and MAM dysregulation by the usage of a PARP‐1 inhibitor. Results showed that receptor‐interacting protein kinase (RIPK) 1 inhibitor (necrostatin‐1) and PARP‐1 inhibitor (olaparib) protected retinal precursor cells from H2O2‐induced death, while a pan‐caspase inhibitor (Z‐VAD‐FMK) failed to protect R28 cells. Olaparib also alleviated H2O2‐induced MAM dysregulation, as evidenced by decreased VDAC1/ITPR3 interactions and reduced mitochondrial membrane potential collapse. Additionally, olaparib also inhibited H2O2‐induced autophagy. Inhibiting autophagic flux increased MAM signaling under both normal and oxidative conditions. Furthermore, H2O2 treatment caused a reduction in the protein level of mitofusin‐2 (MFN2) in a dose‐ and time‐dependent manner. Mfn2 knockdown was found to further magnify MAM dysregulation and mitochondrial dysfunction under normal and oxidative conditions. Mfn2 overexpression surprisingly enhanced H2O2‐induced MAM signaling and failed to rescue H2O2‐induced mitochondrial dysfunction. These results indicate that MAMs probably serve as a membrane source for oxidative stress‐associated autophagy. MAM dysregulation also contributed to H2O2‐induced PARP‐1‐dependent cell death. However, more studies are required to decipher the link between the modulation of Mfn2 expression, changes in MAM integrity, and alterations in mitochondrial performances. [ABSTRACT FROM AUTHOR]

As the main loading‐bearing tissue of eye, sclera exerts an important role in the pathophysiology of glaucoma. Intraocular pressure (IOP) generates mechanical strain on sclera. Recent studies have demonstrated that sclera, especially the peripapillary sclera, undergoes complicated remodelling under the mechanical strain. However, the mechanisms of the hypertensive scleral remodelling in human eyes remained uncertain. In this study, peripapillary human scleral fibroblasts (ppHSFs) were applied cyclic mechanical strain by Flexcell‐5000™ tension system. We found that CXC‐ ligands and CXCR2 were differentially expressed after strain. Increased cell proliferation and inhibited cell motility were observed when CXCR2 was upregulated under the strain, whereas cell proliferation and motility did not have a significant change when CXCR2 was knocked down. CXCR2 could facilitate cell proliferation ability, modulate the mRNA and protein expressions of type I collagen and matrix metalloproteinase 2 via JAK1/2‐STAT3 signalling pathway. In addition, CXCR2 might inhibit cell migration via FAK/MLC2 pathway. Taken together, CXCR2 regulated protein production and affected cell behaviours of ppHSFs. It might be a potential therapeutic target for the hypertensive scleral remodelling. [ABSTRACT FROM AUTHOR]

Purpose: To investigate activation of the lesion projection zone (LPZ) in the primary visual cortex during end‐stage glaucoma using functional magnetic resonance imaging (fMRI), as well as the relationship between fMRI responses and clinical data. Methods: Twelve subjects with bilateral end‐stage glaucoma (group A), 12 with unilateral end‐stage glaucoma (group B) and 12 healthy controls (group C) were enrolled. fMRI was performed under two testing stimuli conditions: passive viewing of a full‐field flickering checkerboard and active viewing of a one‐back task with scene images. In fMRI analysis, the primary visual cortex was divided into six regions of interest (ROIs). The beta values of the six ROIs were compared across the three groups using one‐way analysis of variance under two viewing conditions. Associations between the fMRI beta value and clinical data including multifocal electroretinogram (mfERG), microperimeter‐1 and optical coherence tomography were analysed by Spearman correlation. Results: The beta values for ROIs 1–3 representing the LPZ were significantly different between the three groups under active viewing conditions, whereas no significant changes were detected under passive viewing. In group A, there were significant differences between all six ROIs for the two viewing conditions, while no significant differences were found in groups B and C. In group A, the P‐wave amplitudes of the mfERG was significantly correlated with the beta values of ROIs 1 and 2 under active viewing. In addition, the P‐wave latencies of the mfERG were significantly correlated with the beta values for ROIs 2–5. No associations were found between fMRI beta values and clinical data in groups B and C. Conclusions: Activation of the LPZ in the primary visual cortex was observed in patients with bilateral end‐stage glaucoma under active viewing conditions. These changes were correlated with residual retinal function. [ABSTRACT FROM AUTHOR]

Because retinitis pigmentosa (RP) has been shown to cause degenerative changes in the entire visual pathway, there is an urgent need to perform longitudinal assessments of RP‐induced degeneration and identify imaging protocols to detect this degeneration as early as possible. In this study, we assessed a transgenic rat model of RP by using complementary noninvasive magnetic resonance imaging techniques, namely, proton magnetic resonance spectroscopy (1H‐MRS), to investigate the metabolic changes in RP. Our study demonstrated decreased concentrations and ratios to creatine (Cr) of N‐acetylaspartate (NAA), glutamate (Glu), γ‐aminobutyric acid (GABA), and taurine (Tau), whereas myo‐inositol (Ins) and choline (Cho) were increased in the visual cortex of Royal College of Surgeons (RCS) rats compared with control rats (p < 0.05). Furthermore, with the progression of RP, the concentrations of NAA, Glu, GABA, and Tau, and the ratios of GABA/Cr and Tau/Cr significantly decreased over time, whereas the concentrations of Ins and Cho and the ratio of Ins/Cr significantly increased over time (p < 0.05). In addition, in RCS rats, NAA/Cr decreased significantly from 3 to 4 months postnatal (p < 0.001), and Cho/Cr increased significantly from 4 to 5 months postnatal (p = 0.005). Meanwhile, the 1H‐MRS indicators in 5‐month postnatal RCS rats could be confirmed by immunohistochemical staining. In conclusion, with the progression of RP, the metabolic alterations in the visual cortex indicated progressive reprogramming with the decrease of neurons and axons, accompanied by the proliferation of gliocytes. [ABSTRACT FROM AUTHOR]

Caveolin‐1(Cav‐1) is involved in lipid metabolism and energy homeostasis, which is important for the energetically demanding retina. Although retinal function deficits were noted in Cav‐1 knockout (Cav‐1‐/‐) mice, the underlying causes remain largely unknown. Here, we investigate if the disruption in energy homeostasis presents a potential mechanism for retinal function deficits in Cav‐1‐/‐ retina and if it can be ameliorated by nicotinamide (NAM). In this study, NAM was administrated orally for 2 weeks in Cav‐1‐/‐ mice before experiments. Oxidative lipidomics was conducted to detect the oxylipin changes, the retinal energy flux was measured by seahorse assay, and the retinal function was assessed by electroretinogram (ERG). Cav‐1 deficiency induced the dysregulation of oxidative lipidomics and reduction in energy consumption/production in the retina by decreasing Na+/K+‐ATPase, oxidative phosphorylation CII, cytochrome c, and oxygen consumption rate (OCR). A decrease in Sirt1 was also detected. Therapeutic administration of NAM significantly increased Sirt1 expression and improved energy deficiency by increasing Na+/K+‐ATPase, cytochrome c, and OCR. The dysregulation of oxidative lipidomics was partially recovered, and the retinal function was improved as assessed by ERG compared to Cav‐1‐/‐ mice. Our study demonstrated the dysregulation of oxidative lipidomics in Cav‐1‐/‐ retina and established a link between energy deficiency and retinal function deficits in Cav‐1‐/‐ mice. Administration of NAM ameliorated energy deficiency, increased the expression of Sirt1, and improved retinal function, which presents a potential therapeutic strategy for Cav‐1 deficiency‐induced retinal function deficits. [ABSTRACT FROM AUTHOR]

Background and Purpose: The aim of this study is to investigate the vasorelaxant effect of exendin-4, a GLP-1 receptor agonist on retinal capillaries under normal and ischaemia-reperfusion (I/R) conditions.Experimental Approach: Capillary diameters in the whole-mounted retina were directly observed using infrared differential interference contrast microscopy. A model of retinal I/R was established inraats,using high perfusion pressure in an anterior chamber. To assess the effects of exendin-4, it was administered through subcutaneous injection, intravitreal injection, or eye drops. The underlying mechanism was explored by immunofluorescence, qPCR, and capillary western blots.Key Results: Immunofluorescence staining showed that GLP-1 receptors were expressed in endothelial cells of retinal capillaries. Exendin-4 relaxed the capillaries precontracted by noradrenaline, an effect abolished by denuding endothelium with CHAPS and inhibited by GLP-1 receptor antagonist exendin-9-39, endothelial NOS (eNOS) inhibitor l-NAME, and the guanylate cyclase blocker ODQ but not by a COX inhibitor, indomethacin. Retinal capillaries were constricted in I/R injury, an effect reversed by perfusion of exendin-4. Expression of PI3K and Akt, phosphorylation level of eNOS and NO production after I/R were lower than that in the normal control group. Administration of exendin-4 improved the changes.Conclusion and Implications: Exendin-4 can restore injured microvascular patency in I/R. Exendin-4 may regulate retinal capillaries through the GLP-1 receptor-PI3K/Akt-eNOS/NO-cGMP pathway. Therefore, exendin-4 may be an effective treatment for improving tissue perfusion in I/R-related conditions. [ABSTRACT FROM AUTHOR]

Purpose: It has been hypothesised that uric acid (UA) has a protective effect against oxidative damage in the central nervous system. Therefore, we investigated serum UA concentrations in patients with primary open‐angle glaucoma (POAG) and explored the relationship between serum UA concentration and glaucoma severity. Methods: This prospective, cross‐sectional, case–control study was conducted in 163 POAG patients and 103 normal controls. Clinical and demographic information was obtained from the medical data platform of the Eye & ENT Hospital of Fudan University, Shanghai, China. The POAG patients were categorised into mild [median deviation (MD) ≤ 6.00 dB], moderate (MD > 6 Db–≥12 dB) and severe (MD > 12 dB) subgroups, based on their visual field MD results. Results: The level of serum UA in the POAG group (0.321 ± 0.084 mmol/l) was approximately 12.77% lower (p < 0.001) than that of the control group (0.362 ± 0.053 mmol/l). The UA/creatinine (Cr) ratio was approximately 14.99% lower (p < 0.001) in patients with POAG (4.47 ± 1.15), compared with the control group (5.14 ± 1.05). The mean level of UA was lowest in the severe POAG group, followed by the moderate POAG group, and the mild POAG group (p < 0.001). A similar trend was observed when UA levels were compared between the POAG and control groups in males. Multivariate regression analyses showed a significant negative correlation between UA and vertical cup–disc ratio (B = −0.320, p = 0.034), and UA and MD (B = −0.441, p = 0.031) in males. Conclusion: Primary open‐angle glaucoma patients have lower UA levels; however, a negative association between UA levels and disease severity was evident in male patients. [ABSTRACT FROM AUTHOR]

Purpose The enlargement of optic nerve sheath diameter (ONSD) has been proven to be related with raised intracranial pressure (ICP). No prospective study has been focused on utilizing retrobulbar ultrasonography in optic disc oedema patient presented to ophthalmologist. Methods High-resolution transbulbar ultrasonography was performed in a cohort of patient presented with bilateral optic disc oedema. The subarachnoid space of optic nerve (SAS), ONSD and optic nerve diameter (OND) was measured prior to other ancillaries including lumbar puncture. Subjects were classified into increased intracranial pressure (IIP) and normal intracranial pressure (NIP) group according to the open cerebrospinal fluid pressure more than 200 mm H20. The SAS, ONSD and OND were compared between groups and with normal control. The sensitivity of SAS or ONSD change for predicating intracranial hypertension was assessed. Results A total of 20 IIP, 25 NIP patients and 25 normal controls were evaluated. The mean SAS and ONSD measured in idiopathic intracranial hypertension group was significantly increased than that of NIP and controls (p < 0.001), whereas the OND showed no statistic difference between each group. The sensitivities using the SAS and ONSD for differentiating increased ICP in optic disc oedema patients were 0.99 and 0.97, respectively. Conclusions The enlarged SAS and ONSD measured by high-resolution transbulbar sonography are very sensitive parameters to predicate increased ICP in bilateral optic disc oedema patients. [ABSTRACT FROM AUTHOR]

This study aimed to explore the optimal dose and manner of administration for visualization of the auditory pathway on manganese-enhanced MRI (ME MRI). Twenty-four healthy male Sprague-Dawley rats were randomly divided into three experimental groups ( n = 8 for Groups A, B and C). The rats in Groups A, B and C were subjected to MnCl2 injection through the tympanum, inner ear endolymph and perilymph, respectively (0.2 M for four rats and 0.4 M for the others in each group) and observed at 1, 2, 3, 4, 7 and 10 days after the operation with 3.0 T MRI. The signal intensity (SI) and dynamic changes of the auditory pathways at various times, and at two doses through three injection routes, were compared by statistical analysis. Administration of MnCl2 through the perilymph best showed the complete auditory pathway ( P < 0.01), whereas administration though the tympanum only demonstrated part of the pathway. The SI was highest at 24 h after administration of the tracer and began to decline at 48 h. The SI of the auditory cortex was higher after the injection of 0.4 M MnCl2 than that of 0.2 M MnCl2. ME MRI best demonstrated the whole auditory pathway at 24 h after the injection of 0.4 M MnCl2 through the perilymph in the rat, which provided an optimal method for the study of ME MRI of the auditory pathway in the animal model. [ABSTRACT FROM AUTHOR]

Purpose To investigate and compare the 24-hr intra-ocular pressure ( IOP) pattern among different severities of glaucomatous optic neuropathy ( GON) together with different subtypes of primary open-angle glaucoma ( POAG). Methods The IOPs of untreated patients with POAG were measured every 2 hrs over a 24-hr period. Subjects were divided into mild, moderate and severe groups according to the glaucoma staging system 2. The two POAG subtypes, normal tension glaucoma ( NTG) and hypertension glaucoma ( HTG) were classified according to peak IOP values throughout the 24-hr period. The 24-hr IOP curves were obtained based on the average IOP value at each time-point. The mean, peak, trough and fluctuation of IOP together with the diurnal-to-nocturnal IOP change were calculated and compared among different groups. Results A total of 160 POAG patients (84 NTG and 76 HTG) were enrolled in the study. Generally, IOP decreased in the diurnal period and increased progressively during the nocturnal period, with peak IOP occurring from 2:00 AM to 10:00 AM. The average IOP values at all time-points were significantly higher in the mild group compared to the moderate and severe groups (p < 0.05). Compared with the NTG subjects, the IOP parameters including mean, peak, trough and fluctuation were significantly higher in the HTG subjects (p < 0.001), and IOP increased more predominantly in the HTG subtype during the nocturnal period. Conclusions There was some regularity in the 24-hr IOP pattern in POAG, but different severities of GON and different subtypes might present different characteristics. Other non- IOP factors may lead to pathological IOP fluctuation and could be correlated with GON. [ABSTRACT FROM AUTHOR]

Neovascularization (NV), as a cardinal complication of several ocular diseases, has been intensively studied, and research has shown its close association with inflammation and immune cells. In the present study, the role of interleukin-17A (IL-17A) in angiogenesis in the process of ocular NV both in vivo and in vitro was investigated. Also, a paracrine role of IL-17A was demonstrated in the crosstalk between endothelial cells and macrophages in angiogenesis. In the retinas of mice with retinopathy of prematurity, the IL-17A expression increased significantly at postnatal day 15 (P15) and P18 during retinal NV. Mice given IL-17A neutralizing antibody (NAb) developed significantly reduced choroidal NV and retinal NV. Studies on vascular endothelial growth factor (VEGF) over-expressing mice suggested that IL-17A modulated NV through the VEGF pathway. Furthermore, IL-17A deficiency shifted macrophage polarization toward an M2 phenotype during retinal NV with significantly reduced M1 cytokine expression compared with wild-type controls. In vitro assays revealed that IL-17A treated macrophage supernatant gave rise to elevated human umbilical vascular endothelial cell proliferation, tube formation and VEGF receptor 1 and receptor 2 expression. Therefore, IL-17A could potentially serve as a novel target for treating ocular NV diseases. The limitation of this study involved the potential mechanisms, such as which transcription accounted for macrophage polarization and how the subsequent cytokines were modulated when macrophages were polarized. Further studies need to be undertaken to definitively determine the extent to which IL-17A neutralizing anti-angiogenic activity depends on macrophage modulation compared with anti-VEGF treatment. [ABSTRACT FROM AUTHOR]

Glaucoma is now viewed not just a disease of the eye but also a disease of the brain. The prognosis of glaucoma critically depends on how early the disease can be detected. However, early glaucomatous loss of the laminar functions in the human lateral geniculate nucleus (LGN) and superior colliculus (SC) remains difficult to detect and poorly understood. Using functional MRI, we measured neural signals from different layers of the LGN and SC, as well as from the early visual cortices (V1, V2 and MT), in patients with early-stage glaucoma and normal controls. Compared to normal controls, early glaucoma patients showed more reduction of response to transient achromatic stimuli than to sustained chromatic stimuli in the magnocellular layers of the LGN, as well as in the superficial layer of the SC. Magnocellular responses in the LGN were also significantly correlated with the degree of behavioral deficits to the glaucomatous eye. Finally, early glaucoma patients showed no reduction of fMRI response in the early visual cortex. These findings demonstrate that 'large cells' in the human LGN and SC suffer selective loss of response to transient achromatic stimuli at the early stage of glaucoma. Hum Brain Mapp 37:558-569, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Many clinical and fundamental studies have shown that high myopia ( HM) and glaucoma are closely associated. In particular, the occurrence and progression of primary open-angle glaucoma interact with the progression of HM. Two hypotheses have been proposed to explain the association between the two disorders: the hypertension gene theory and the collagen-related gene theory. HM and primary open-angle glaucoma patients show similar collagen changes and hypersensitive responses to glucocorticoids. Consequently, these common features may hold key information regarding their underlying mechanisms. Advances in life sciences, such as molecular genetics, provide opportunities for clarifying their association at the molecular level. This article reviews available research on the association between these two disorders from the perspectives of epidemiology, clinical manifestation, diagnosis and pathogenic mechanisms. [ABSTRACT FROM AUTHOR]

Background The interaction of copolymer-1-activated T cells and microglia on retinal ganglion cells survival in vitro was explored. Methods Copolymer-1-specific T cells were made by repeated copolymer-1 stimulation of T cells, microglia were isolated from the retinas of newborn rats, and then, they were co-cultured (the experimental group) for 48 h. Retinal ganglion cells were collected from the retinas of adult rats, purified, and then, the supernatants from different groups were added. After 72 h, terminal-deoxynucleotidyl transferase-mediated d-UTP nick end labelling analysis was used to observe retinal ganglion cell apoptosis, and reverse transcription polymerase chain reaction was used to test messenger RNA expression of Caspase-3 and Caspase-8. The levels of cytokines, including insulin-like growth factor-1, brain-derived neurotrophic factor, tumour necrosis factor-α and interleukin-10, in the supernatants were examined by enzyme-linked immunosorbent assay to explore the possible mechanisms undergoing. Results After 72 h, the mean retinal ganglion cell apoptosis rate in the experimental group was the lowest (25.36%) among the groups. The messenger RNA expression of Caspase-3 and Caspase-8 in this group was significantly lower than that of the control groups (both P < 0.05). The secretion of interlekin-10 and brain-derived neurotrophic factor, insulin-like growth factor-1 and tumour necrosis factor-α in the supernatant of the experimental group were higher than that of the control groups (both P < 0.05) after co-culture. Conclusions The interaction of copolymer-1-specific T cells with microglia could reduce retinal ganglion cell apoptosis. The related immune mechanisms were complicated. Upregulation of brain-derived neurotrophic factor and insulin-like growth factor-1, and the balance of some pro-inflammatory and anti-inflammatory cytokines may be involved in this protective autoimmunity. [ABSTRACT FROM AUTHOR]

Objective To investigate the responses of lateral geniculate nucleus (LGN) astrocytes to experimental glaucoma in monkeys. Animal studied Rhesus monkeys ( Macaca mulatta). Procedures Unilateral chronic elevation of intraocular pressure (IOP) was induced in six rhesus monkeys by laser photocoagulation of the trabecular meshwork. Four normal monkeys were used as controls. Immunohistochemistry with antibodies to glial fibrillary acidic protein (GFAP), S100β and parvalbumin was used to specifically label astrocytes and neurons in the LGN. The relative immunointensity (RI) of GFAP was defined as the ratio of intensity between each region of interest to a reference field and compared between the experimental and control groups as a function of percentage optic nerve fiber loss. Ultrastructural changes of LGN astrocytes were examined by transmission electron microscopy. Results An increase in GFAP and S100β immunoreactivity was observed in the LGN layers receiving projections from the experimental glaucoma eyes. Quantitative analysis revealed that the RI of GFAP in both the magnocellular and parvocellular layers connected to the glaucomatous eyes increased in a linear fashion with increasing optic nerve fiber loss. Compared to controls, the RI of GFAP was also moderately elevated in LGN layers connected to the fellow nonglaucomatous eyes. Ultrastructurally, accumulation of glial filaments that occurred throughout the perikaryon and extended into the process in reactive astrocytes was observed in LGN layers of glaucomatous monkeys. Conclusions Reactive astrogliosis occurs in the magnocellular and parvocellular LGN layers of monkeys with unilateral glaucoma. Astrocytes may play an important role in the regulation of LGN microenvironment in glaucoma. [ABSTRACT FROM AUTHOR]

The article discusses the retrospective study that outlines the changes of anterior segment parameters in primary angle closure of patient with axial myopia. It mentions that myopic primary angle-closure patients had no significant differences in anterior segment parameters compared with emmetropic and hyperopic counterparts. It outlines the classification of primary angle-closure diseases including angle-closure suspect, primary angle closure and primary angle-closure glaucoma.