NADPH and NAC synergistically inhibits chronic ocular hypertension-induced neurodegeneration and neuroinflammation through regulating p38/MAPK pathway and peroxidation.

Glaucoma, the leading cause of irreversible blindness worldwide, is characterized by neurodegeneration and neuroinflammation with retinal NAD/NADP and GSH decline. Nicotinamide adenine dinucleotide (NAD)/NAD phosphate (NADP) and glutathione (GSH) are two redox reducers in neuronal and glial metabolism. However, therapeutic strategies targeting NAD/NADP or GSH do not exert ideal effects, and the underlying mechanisms are still poorly understood. We assessed morphological changes in retinal ganglion cells (RGCs), the affected neurons in glaucoma, and Müller cells, the major glial cells in the retina, as well as the levels of phosphorylated p38 (p-p38) and Caspase-3 in glaucoma patients. We constructed a modified chronic ocular hypertensive rat model and an oxygen-glucose deprivation (OGD) cell model. After applying NADPH and N-acetylcysteine (NAC), a precursor to cysteine, the rate-limiting substrate in GSH biosynthesis, to cells, apoptosis, axonal damage and peroxidation were reduced in the RGCs of the NAC group and p-p38 levels were decreased in the RGCs of the NADPH group, while in stimulated Müller cells cultured individually or cocultured with RGCs, gliosis and p38/MAPK, rather than JNK/MAPK, activation were inhibited. The results were more synergistic in the rat model, where either NADPH or NAC showed crossover effects on inhibiting peroxidation and p38/MAPK pathway activation. Moreover, the combination of NADPH and NAC ameliorated RGC electrophysiological function and prevented Müller cell gliosis to the greatest extent. These data illustrated conjoined mechanisms in glaucomatous RGC injury and Müller cell gliosis and suggested that NADPH and NAC collaborate as a neuroprotective and anti-inflammatory combination treatment for glaucoma and other underlying human neurodegenerative diseases.

Comparison Between Two Types of Viral-Induced Anterior Uveitis In Vitro and In Vivo: A Stronger Response in Herpes Simplex Virus Type 1 Than in Murine Cytomegalovirus.

Purpose: To observe the similarities and differences between herpes simplex virus type 1 (HSV-1) and murine cytomegalovirus (MCMV)-induced viral anterior uveitis (VAU), both in vitro and in vivo. Methods: Primary rat trabecular meshwork cells (RTMCs) were infected by HSV-1 or MCMV to clarify the pattern of virus replication and the effect on cells. In vivo, intracameral injection of HSV-1 or MCMV was performed to establish the VAU rat models. The clinical manifestation, intraocular pressure (IOP), histological characteristics, ultrastructural changes, and the expression of inflammatory cytokines in the anterior segment were observed and compared between these two types of VAU models. Results: Both viruses could infect the RTMCs but HSV-1 exhibited an earlier and greater cytopathic effect in vitro. In vivo, both VAU rats showed typical acute VAU signs, and the IOP elevation seemed to be correlated with the inflammatory progression. Histopathological findings and ultrastructural changes revealed tissue damage and cell infiltration in the anterior chamber angle. In both models, similar proinflammatory cytokines were upregulated. HSV-1 and MCMV viral particles were identified under transmission electron microscopy. Conclusions: HSV-1 and MCMV infection share certain similarities but have significant differences both in vitro and in vivo. HSV-1 usually has a stronger anterior segment inflammation with a longer duration compared with MCMV in VAU models. Our results provided a valuable animal model for investigating pathogenesis and exploring therapeutic strategies for clinical VAU.

Overview and update on cytomegalovirus-associated anterior uveitis and glaucoma.

Cytomegalovirus anterior uveitis is the most common ocular inflammatory disease caused by cytomegalovirus infection. It mainly occurs in middle-aged males with competent immunologic function, and the incidence is higher in Asia. The clinical manifestations vary from Posner-Schlossman syndrome and corneal endotheliitis to Fuchs uveitis syndrome, and are often accompanied by intraocular hypertension. Secondary glaucoma is a potentially blinding ocular complication with a pathogenesis that includes complicated immunological factors, intraocular inflammation, different types of angle abnormalities, and the administration of steroids, which may result in physical discomfort and visual impairment. Diagnostic tests, such as the polymerase chain reaction, optical coherence tomography, ocular microscopy, and confocal microscopy, might help in identifying anterior uveitis caused by other viruses. Combinations of antiviral medications and anti-inflammatory agents are effective treatments. If pharmacological therapy cannot reduce intraocular pressure or slow the progression of glaucomatous optic neuropathy, surgical intervention is required as a last resort.

Analysis of macular microvasculature with optical coherence tomography angiography for migraine: A systematic review and meta-analysis.

Objective: This study aimed to evaluate the features of macular microvasculature with optical coherence tomography angiography (OCTA) among migraine patients. Methods: We systematically searched PubMed, Web of Science, Embase, and Cochrane Library for studies that evaluated the macular microvasculature of migraine patients. The weighted mean differences (WMDs) of the foveal avascular zone (FAZ), foveal superficial capillary plexus (SCP) vessel density (VD), parafoveal SCP VD, foveal deep capillary plexus (DCP) VD, and parafoveal DCP VD with 95% confidence intervals (CIs) among migraine with aura (MA) group, migraine without aura (MO) group, and healthy controls (HC) group were analyzed using a random-effect model. P < 0.05 was considered significant in statistical analyses. Publication bias was assessed using funnel plots and statistical tests (Egger's test and Begg's test). Results: Nine studies covering 675 individuals were enrolled in this meta-analysis ultimately. The FAZ of MA patients was not significantly different from HC (WMD = 0.04, 95% CI -0.00 to 0.09). However, the FAZ of MA was significantly larger than that of HC after correction of publication bias by trim and fill method (WMD = 1.03, 95% CI 0.99 to 1.08). The FAZ of MO patients was similar to that of HC (WMD = 0.03, 95% CI -0.00 to 0.07), while smaller than that of MA patients (WMD = 0.05, 95% CI 0.01 to 0.09). VD of the SCP, either in the foveal or parafoveal area, was not significantly different among the three groups. As for DCP, VD in MA patients was lower when compared with HC in the parafovea (WMD = -1.20, 95% CI -1.88 to -0.51). Conclusions: We found that there was a larger FAZ in MA compared with HC after adjusting for publication bias. The FAZ in MO was not significantly different from that in HC, but significantly lower than that in MA. There was no significant difference in either foveal or parafoveal VD of SCP among MA, MO, and HC participants, while the parafoveal VD of the DCP in MA was lower than that of the HC.

Inhibiting multiple forms of cell death optimizes ganglion cells survival after retinal ischemia reperfusion injury.

Progressive retinal ganglion cells (RGCs) death that triggered by retinal ischemia reperfusion (IR), leads to irreversible visual impairment and blindness, but our knowledge of post-IR neuronal death and related mechanisms is limited. In this study, we first demonstrated that apart from necroptosis, which occurs before apoptosis, ferroptosis, which is characterized by iron deposition and lipid peroxidation, is involved in the whole course of retinal IR in mice. Correspondingly, all three types of RGCs death were found in retina samples from human glaucoma donors. Further, inhibitors of apoptosis, necroptosis, and ferroptosis (z-VAD-FMK, Necrostatin-1, and Ferrostatin-1, respectively) all exhibited marked RGC protection against IR both in mice and primary cultured RGCs, with Ferrostatin-1 conferring the best therapeutic effect, suggesting ferroptosis plays a more prominent role in the process of RGC death. We also found that activated microglia, Müller cells, immune responses, and intracellular reactive oxygen species accumulation following IR were significantly mitigated after each inhibitor treatment, albeit to varying degrees. Moreover, Ferrostatin-1 in combination with z-VAD-FMK and Necrostatin-1 prevented IR-induced RGC death better than any inhibitor alone. These findings stand to advance our knowledge of the post-IR RGC death cascade and guide future therapy for RGC protection.

Corneal in vivo Confocal Microscopy for Assessment of Non-Neurological Autoimmune Diseases: A Meta-Analysis.

Purpose: This study aimed to evaluate the features of corneal nerve with in vivo confocal microscopy (IVCM) among patients with non-neurological autoimmune (NNAI) diseases. Methods: We systematically searched PubMed, Web of Science, and Cochrane Central Register of Controlled Trials for studies published until May 2021. The weighted mean differences (WMDs) of corneal nerve fiber length (CNFL), corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), tortuosity, reflectivity, and beadings per 100 µm with a 95% CI between NNAI and control group were analyzed using a random-effects model. Results: The results showed 37 studies involving collective totals of 1,423 patients and 1,059 healthy controls were ultimately included in this meta-analysis. The pooled results manifested significantly decreased CNFL (WMD: -3.94, 95% CI: -4.77--3.12), CNFD (WMD: -6.62, 95% CI: -8.4--4.85), and CNBD (WMD: -9.89, 95% CI: -14--5.79) in NNAI patients. In addition, the NNAI group showed more tortuous corneal nerve (WMD: 1.19, 95% CI:0.57-1.81). The comparison between NNAI patients and healthy controls in beadings per 100 µm corneal nerve length was inconsistent. No significant difference was found in the corneal nerve fiber reflectivity between NNAI and the control group (WMD: -0.21, 95% CI: -0.65-0.24, P = 0.361). Conclusions: The parameters and morphology of corneal nerves observed by IVCM proved to be different in NNAI patients from healthy controls, suggesting that IVCM may be a non-invasive technique for identification and surveillance of NNAI diseases.