Yisheng Zhong

Pigment epithelium derived factor as an anti-inflammatory factor against decrease of glutamine synthetase expression in retinal Müller cells under high glucose conditions

BackgroundThe pathogenesis of diabetic retinopathy (DR) is similar to that of a chronic inflammatory disease. A predominant function of Müller cells is to regulate glutamate levels, but in DR the function is compromised. The present study was performed to investigate the role of pigment epithelial derived factor (PEDF) on the expression of glutamine synthetase (GS) in rat retinal Müller cells under high glucose conditions, and to study the possible mechanism for PEDF against decrease of GS expression in retinal Müller cells under high glucose conditions.MethodsThe role of PEDF on the expressions of GS and interleukin-1ß (IL-1ß) in retinal Müller cells under normal and high glucose conditions was measured by western blotting, real-time RT-PCR, or immunocytochemistry. In order to confirm the effect of PEDF on GS against the role of IL-1ß, the PEDF siRNA method was used.ResultsHigh glucose increased the expression of IL-1ß, but decreased the expressions of GS and PEDF in retinal Müller cells. PEDF increased the expression of GS and decreased the expression of IL-1ß in retinal Müller cells under high glucose conditions. The effect of IL-1ß on expression of GS was inhibited by PEDF. Moreover, down-regulation of PEDF expression by siRNA resulted in significantly increasing the expression of IL-1ß, but decreasing the expression of GS in retinal Müller cells.ConclusionsPEDF increases expression of GS against the effect of IL-1ß in retinal Müller cells under high glucose conditions. These findings suggested that PEDF may act as an anti-inflammatory factor against decrease of GS expression in retinal Müller cells in diabetic retinopathy.

Relevant variations and neuroprotecive effect of hydrogen sulfide in a rat glaucoma model

Glaucoma is an irreversible and blinding neurodegenerative disease of the eye, and is characterized by progressive loss of retinal ganglion cells (RGCs). Since endogenous hydrogen sulfide (H2S) was reported to be involved in neurodegeneration in the central nervous system, the authors aimed to develop a chronic ocular hypertension (COH) rat model simulating glaucoma and therein test the H2S level together with the retinal protein expressions of related synthases, and further investigated the effect of exogenous H2S supplement on RGC survival. COH rat model was induced by cross-linking hydrogel injection into anterior chamber, and the performance of the model was assessed by intraocular pressure (IOP) measurement, RGC counting and retinal morphological analysis. Endogenous H2S level was detected along with the retinal protein expressions of H2S-related synthases cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST) in the COH rats. Retinal H2S level and RGC survival were evaluated again after NaHS (a H2S donor) treatment in the COH rats. The results showed that the COH model succeeded in simulating glaucoma features, and retinal H2S level decreased significantly when the retinal protein expressions of CBS, CSE and 3-MST were downregulated generally in the COH rats. Furthermore, the decrease of retinal H2S level and loss of RGCs were both improved by NaHS treatment in experimental glaucoma, without obvious variation of IOP. Our study revealed that the intracameral injection of cross-linking hydrogel worked efficiently in modeling glaucoma, and H2S had protective effect on RGCs and might be involved in the pathological mechanism of glaucomatous neuropathy.

Peripapillary Choroidal Thickness and Open-Angle Glaucoma: A Meta-Analysis

Purpose. To investigate the potential relationship between open-angle glaucoma (OAG) and peripapillary choroidal thickness (PPCT). Materials and Methods. Relevant publications were searched systematically through various databases from inception to January 2016. Studies comparing PPCT in OAG patients and healthy controls were retrieved. All qualified articles were analyzed using Stata 14.0 and Revman 5.3 software. Results. A total of 13 studies were identified for inclusion. There was a significant reduction of average PPCT in OAG patients compared to control participants (WMD = −24.07, 95% CI: −34.29, −13.85). Reduction of PPCT was significant in the superior (WMD = −28.87, 95% CI: −44.96, −12.78) and nasal (WMD = −21.75, 95% CI: −41.52, −1.98) sectors, but there was no significant reduction of PPCT in the inferior (WMD = −9.57, 95% CI: −36.55, 17.40) and temporal (WMD = −13.85, 95% CI: −35.40, 7.70) sectors. No obvious publication bias was detected. Conclusions. This meta-analysis suggests that open-angle glaucoma patients have significantly decreased peripapillary choroidal thickness compared to healthy individuals. Peripapillary choroidal thickness measured by optical coherence tomography may be an important parameter to consider in open-angle glaucoma.

Color Doppler Imaging Analysis of Ocular Blood Flow Velocities in Normal Tension Glaucoma Patients: A Meta-Analysis.

Background. To evaluate the potential diagnostic value of CDI of retrobulbar hemodynamic changes in NTG patients. Methods. Relevant publications which included PSV, EDV, and RI of OA, CRA, NPCA, and TPCA in NTG patients and normal controls measured by CDI were retrieved from the Cochrane Central Register of Controlled Trials, PubMed, the ISI Web of Knowledge, and EMBASE from 1990 to 2014. Subgroup analyses were made based on IOP-lowering medications uses. Result. In OA, there was significant decrease of PSV with moderate heterogeneity (P < 0.00001, I 2 = 49%) and significant decrease of EDV with significant heterogeneity (P = 0.0005, I 2 = 87%) in NTG patients. In CRA, similar results of PSV (P < 0.00001, I 2 = 42%) and EDV (P < 0.00001, I 2 = 80%) were detected. Significant decrease of PSV and EDV with significant heterogeneity was also found in both NPCA (P < 0.0001, I 2 = 70%; P < 0.0001, I 2 = 76%; resp.) and TPCA (P < 0.00001, I 2 = 54%; P < 0.00001, I 2 = 65%; resp.). Statistically significant increases of RI were found in CRA (P = 0.0002, I 2 = 89%) and TPCA (P = 0.02, I 2 = 81%) with significant heterogeneities, though RI in OA (P = 0.25, I 2 = 94%) and in NPCA (P = 0.15, I 2 = 86%) showed no statistical changes with significant heterogeneities. Conclusions. Ischemic change of retrobulbar hemodynamics is one of the important manifestations of NTG. Hemodynamic parameters measured by CDI might be potential diagnostic tools for NTG.

Intravitreal Ranibizumab Injection as an Adjuvant in the Treatment of Neovascular Glaucoma Accompanied by Vitreous Hemorrhage after Diabetic Vitrectomy

Purpose. To determine the efficacy of intravitreal ranibizumab injection as adjuvant therapy in the treatment of neovascular glaucoma (NVG) accompanied by postvitrectomy diabetic vitreous hemorrhage (PDVH). Methods. Eighteen NVG patients (18 eyes) accompanied by PDVH were enrolled in this prospective, monocenter, 12-month, interventional case series. The consecutive 18 patients with an IOP ≥ 25 mmHg despite being treated with the maximum medical therapy were treated with intravitreal ranibizumab injections. Vitreous surgery or/with Ahmed valve implantation were indicated if no clinical improvement in vitreous haemorrhage and uncontrolled IOP was shown. Results. Ten patients got clear vitreous and controlled IOP only with 2.7 ± 1.8 injections of ranibizumab without additional surgery. Vitrectomy or/with Ahmed valve implantation was administered in the other 8 eyes due to uncontrolled VH and IOP. At follow-up month 12, all the 18 eyes gained clear vitreous. At month 12 BCVA improved significantly compared to baseline. The baseline and follow-up at month 12 IOP/medication usage were 36.7 ± 8.1 mmHg on 3.4 ± 0.7 medications and 16.2 ± 4.9 mmHg on 0.67 ± 0.77 medications, respectively. Conclusions. The findings suggest that intravitreal ranibizumab injection as adjuvant therapy for treatment of NVG accompanied by PDVH may be safe and potentially effective. This clinical trial is registered with NCT02647515.

Hydrogen sulfide supplement attenuates the apoptosis of retinal ganglion cells in experimental glaucoma

ABSTRACT Glaucoma is a group of neurodegenerative eye diseases characterized by progressive impairment of visual function due to loss of retinal ganglion cells (RGC). As hydrogen sulfide (H2S) was reported to play a role in the process of glaucomatous neuropathy and improve RGC survival in experimental glaucoma, the authors aimed to investigate the anti‐apoptosis effect of H2S supplement in a rat glaucoma model, and further tried to explore the involved factors in the neuroprotection. A chronic ocular hypertension (COH) rat model induced by intracameral injection of cross‐linking hydrogel was employed to simulate glaucoma and 288 rats were subjected to experimental procedures in the present study. After 4 weeks of sodium hydrosulfide (NaHS) administration following COH induction, the apoptosis of RGC isolated from experimented rats as well as apoptosis of neurons in ganglion cell layer (GCL), intrinsic apoptotic pathway activity, mitochondrial function, glial activation, NF‐&kgr;B pathway activity, NADPH oxidase activity, autophagy activity and TNF‐&agr; level in retina were evaluated. The results showed that H2S supplement effectively attenuated the apoptosis of RGC in experimental glaucoma, and the neuroprotection by H2S might correlate with preservation of mitochondrial function, attenuation of oxidative stress, suppression of glial activation, inhibition of inflammatory pathways and downregulation of autophagy. Our study indicated that H2S supplement resulted in significant neuroprotection through attenuation of RGC apoptosis which might be linked with multiple factors in experimental glaucoma. The new therapeutic strategy might potentially contribute to benefit glaucoma treatment, which is worth further concerns. HIGHLIGHTSAimed to investigate how H2S took part in the neuroprotection of glaucoma.H2S supplement attenuated the apoptosis of RGC in experimental glaucoma.Various factors might be involved in the protection by H2S on RGC.

Flt3 Regulation in the Mononuclear Phagocyte System Promotes Ocular Neovascularization.

Fms-like tyrosine kinase 3 (Flt3), a tyrosine kinase receptor expressed in CD34+ hematopoietic stem/progenitor cells, is important for both normal myeloid and lymphoid differentiation. It has been implicated in mice and humans for potential multilineage differentiation. We found that mice deficient in Flt3 or mice that received an Flt3 inhibitor (AC220) showed significantly reduced areas of ischemia-induced retinal neovascularization (RNV) and laser-induced choroidal NV (CNV) (P < 0.05). Increased Flt3 expression at the protein level was detected in retinas of oxygen-induced retinopathy (OIR) mice at P15 and P18 during retinal NV (RNV) progression. We subsequently found that macrophages (Mphi) polarization was regulated at the site of CNV in Flt3-deficient mice. Flow cytometry analysis demonstrated that Flt3 deficiency shifted Mphi polarization towards an M2 phenotype during RNV with significant reduction in M1 cytokine expression when compared to the wild-type controls (P < 0.05). Based on the above findings, we concluded that Flt3 inhibition alleviated ocular NV by promoting a Mphi polarization shift towards the M2 phenotype. Therapies targeting Flt3 may provide a new approach for the treatment of ocular NV.

Inhibition of integrin α5β1 ameliorates VEGF-induced retinal neovascularization and leakage by suppressing NLRP3 inflammasome signaling in a mouse model

PurposeTo assess the effect of inhibiting integrin α5β1 by ATN-161 on vascular endothelial growth factor (VEGF)-induced neovascularization (NV) and leakage causing retinal detachment in adult Tet/opsin/VEGF transgenic mice, and characterize the underlying mechanism of its function.MethodRetinas from adult Tet/opsin/VEGF transgenic mice and human retinal endothelial cells (HRECs) exposed to VEGF (treated with ATN-161 or PBS) were used to carry out immunofluorescence, RT-PCR and western blot to examine expression levels of integrin α5β1 and the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome. Retinal frozen section analysis was used to assess NV and leakage causing retinal detachment.ResultsIn comparison to normal-treated mice, doxycycline-treated Tet/opsin/VEGF transgenic mice showed severe retinal detachment and higher integrin α5β1 expression. Furthermore, the retinal detachment was inhibited significantly by ATN-161. Additionally, ATN-161 treatment was associated with a conspicuous reduction in NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), cleaved caspase-1, and mature interleukin-1β expression levels in the retinas of Tet/opsin/VEGF transgenic mice treated with doxycycline as well as in HRECs exposed to VEGF.ConclusionATN-161, an antagonist of integrin α5β1, is a promising treatment for retinal neovascularization (RNV), and its retinal protection role appears to take effect through inhibition of NLRP3 inflammasome activity.

Concordance of 24‑h intraocular pressure curve in patients with untreated unilateral primary open‑angle glaucoma

The present study aimed to assess the concordance of 24-h intraocular pressure (IOP) curves between glaucomatous and contralateral eyes for patients with untreated unilateral primary open-angle glaucoma (POAG). A total of 32 patients with unilateral POAG and 32 age-matched normal subjects were enrolled. The IOP measurements were performed every 2 h over a 24-h period. The concordance of the 24-h IOP curves was assessed via the correlation coefficient (r), intraclass correlation coefficient (ICC) and repeated-measures analysis of variance (ANOVA). No significant difference was identified between all IOPs, as well as the mean, peak and trough IOP or IOP fluctuations of the paired eyes in the two groups. The strength of association of all IOPs was moderate in the glaucoma group (r, 0.752-0.867) and the normal controls (r, 0.625-0.873). IOP readings at each time-point indicated a high agreement in the glaucoma group (ICC, 0.857-0.929) and the normal controls (ICC, 0.768-0.932). Repeated-measures ANOVA indicated that the 24-h IOP curves of the paired eyes had parallel profiles in the two study groups (P=0.837 and P=0.897, respectively). The glaucoma patients had significantly higher proportions of all IOPs displaying absolute differences of ≥2 and ≥3 mmHg (46.09 vs. 35.68%, P<0.001; 29.69 vs. 12.50%, P<0.001, respectively). In conclusion, the 24-h IOP curves of the paired eyes had parallel profiles in unilateral glaucoma patients and normal subjects. However, unilateral glaucoma patients had a significantly larger proportion of IOP differences of ≥2 and ≥3 mmHg.

Effect of Adenosine and Adenosine Receptor Antagonists on Retinal Müller Cell Inwardly Rectifying Potassium Channels under Exogenous Glutamate Stimulation

The vitreousness of glaucoma subjects contains elevated glutamate, and excessive extracellular glutamate is toxic to retinal neurons. Therefore, glutamate clearance is potentially impaired in the retina of glaucoma subjects. Müller cells play an important role in maintaining low extracellular levels of neurotransmitters, such as glutamate. A better understanding of the cross-talk between adenosine and glutamate may provide a better characterization of the regulatory network in Müller cells. Here, Müller cells were purified from the rat retina on postnatal day 5 using the papain digestion method. Application of increasing concentrations of glutamate (0-20 mmol/L) caused a dose-dependent decrease in the expression levels of Kir4.1, Kir2.1, GLAST, and GS. Exogenous adenosine regulated Kir channels and subsequently promoted GLAST and GS expression levels in Müller cells under exogenous glutamate stimulation. These effects were partly dependent on adenosine receptors.