Current modalities for diagnosing carotid cavernous fistula (CCF) are inaccurate in analysing retinal microcirculations and nerve fibre changes. Retinal microvascular and neural alterations occur in CCF patients and can be quantitatively measured using optical coherence tomography angiography (OCTA). We measured the neurovascular changes in the eyes of CCF patients and used OCTA as a supplementary method.
This cross-sectional study studied 54 eyes of 27 unilateral CCF subjects and 54 eyes of 27 healthy age- and sex-matched controls. OCTA parameters in the macula and optic nerve head (ONH) were analysed using a one-way analysis of variance with further Bonferroni corrections. Parameters with statistical significance were included in a multivariable binary logistic regression analysis and receiver operating characteristic (ROC) curves were generated.
There was significantly less deep-vessel density (DVD) and ONH-associated capillary density in both eyes of CCF patients than in controls, while the differences between the affected and contralateral eyes were insignificant. The retinal nerve fibre layer and ganglion cell complex thickness were lower in the affected eyes than in the contralateral or controlled eyes. ROC curves identified DVD and ONH-associated capillary density as significant parameters in both eyes of CCF patients.
The retinal microvascular circulation was affected in both eyes of unilateral CCF patients. Microvascular alterations occurred before retinal neural damage. This quantitative study suggests a supplementary measurement for diagnosing CCF and detecting early neurovascular impairments.

Stroke, the leading cause of long-term disability worldwide, is caused by the blockage or hemorage of cerebral arteries. The resultant cerebral ischemia causes local neuronal death and brain injury. Histone deacetylase 9 (HDAC9) has been reported to be elevated in ischemic brain injury, but its mechanism in stroke is still enigmatic. The present study aimed to unveil the manner of regulation of HDAC9 expression and the effect of HDAC9 activation on neuronal function in cerebral ischemia. MicroRNAs (miRNAs) targeting HDAC9 were predicted utilizing bioinformatics analysis. We then constructed the oxygen glucose deprivation (OGD) cell model and the middle cerebral artery occlusion (MCAO) rat model, and elucidated the expression of CCCTC binding factor (CTCF)/miR-383-5p/HDAC9. Targeting between miR-383-5p and HDAC9 was verified by dual-luciferase reporter assay and RNAi. After conducting an overexpression/knockdown assay, we assessed neuronal impairment and brain injury. We found that CTCF inhibited miR-383-5p expression via its enrichment in the promoter region of miR-383-5p, whereas the miR-383-5p targeted and inhibited HDAC9 expression. In the OGD model and the MCAO model, we confirmed that elevation of HDAC9 regulated by the CTCF/miR-383-5p/HDAC9 pathway mediated apoptosis induced by endoplasmic reticulum stress, while reduction of HDAC9 alleviated apoptosis and the symptoms of cerebral infarction in MCAO rats. Thus, the CTCF/miR-383-5p/HDAC9 pathway may present a target for drug development against ischemic brain injury.

Background: Widespread neural and microvascular injuries are common in chronic kidney disease (CKD), increasing risks of neurovascular complications and mortality. Early detection of such changes helps assess the risks of neurovascular complications for CKD patients. As an extension of central nervous system, the retina provides a characteristic window to observe neurovascular alterations in CKD. This study aimed to determine the presence of retinal neurovascular impairment in different stages of CKD. Methods: One hundred fifteen non-diabetic and non-dialytic CKD patients of all stages and a control group of 35 healthy subjects were included. Retinal neural and microvascular parameters were obtained by optical coherence tomography angiography (OCTA) examination. Results: CKD 1-2 group (versus control group) had greater odds of having decreased retinal ganglion cell-inner plexiform layer thickness (GC-IPLt) (odds ratio [OR]: 0.92; 95% confidence interval [CI]: 0.86-0.98), increased ganglion cell complex-focal loss volume (GCC-FLV) (OR: 3.51; 95% CI: 1.27-9.67), and GCC-global loss volume (GCC-GLV) (OR: 2.48; 95% CI: 1.27-4.82). The presence of advanced stages of CKD (CKD 3-5 group versus CKD 1-2 group) had greater odds of having decreased retinal vessel density in superficial vascular plexus (SVP)-WholeImage (OR: 0.77, 95% CI: 0.63-0.92), SVP-ParaFovea (OR: 0.83, 95% CI: 0.71-0.97), SVP-ParaFovea (OR: 0.76, 95% CI: 0.63-0.91), deep vascular plexus (DVP)-WholeImage (OR: 0.89, 95% CI: 0.81-0.98), DVP-ParaFovea (OR: 0.88, 95% CI: 0.78-0.99), and DVP-PeriFovea (OR: 0.90, 95% CI: 0.83-0.98). Besides, stepwise multivariate linear regression among CKD patients showed that β2-microglobulin was negatively associated with GC-IPLt (β: -0.294; 95% CI: -0.469 ∼ -0.118), and parathyroid hormone was positively associated with increased GCC-FLV (β: 0.004; 95% CI: 0.002∼0.006) and GCC-GLV (β: 0.007; 95% CI: 0.004∼0.01). Urine protein to creatinine ratio was positively associated with increased GCC-FLV (β: 0.003; 95% CI: 0.001∼0.004) and GCC-GLV (β: 0.003; 95% CI: 0.001∼0.006). Conclusion: Retinal neuronal impairment is present in early stages of CKD (stages 1-2), and it is associated with accumulation of uremic toxins and higher UACR, while retinal microvascular hypoperfusion, which is associated with worse eGFR, was only observed in relatively advanced stages of CKD (stages 3-5). The results highlight the importance of monitoring retinal neurovascular impairment in different stages of CKD.

Diabetic neuropathic pain is characterized by spontaneous pain with hyperalgesia and allodynia. We investigated whether (-)-epigallocatechin-3-O-gallate could improve diabetic neuropathic pain development through hypoglycemic, hypolipidemic, antioxidant, and anti-inflammatory effects. Diabetes was induced in rats by streptozotocin (55 mg/kg/once) and treated with (-)-epigallocatechin-3-O-gallate (25 mg/kg/orally/once/daily/5 weeks). Diabetic rats showed an increase in serum levels of glucose, nitric oxide, triglyceride, total cholesterol, and low-density lipoprotein-cholesterol with a decrease in high-density lipoprotein-cholesterol and body weight. Also, there was an elevation in brain malondialdehyde with a marked reduction in brain levels of glutathione, superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase. Furthermore, diabetic rats showed a clear reduction in plasma levels of insulin and an increase in plasma cytokines (interleukin-6 and tumor necrosis factor-α). Moreover, diabetic rats exhibited hyperalgesia as indicated by a hot plate, tail immersion, formalin, and carrageenan-induced edema tests as well as brain histopathological changes (neuron degeneration, gliosis, astrocytosis, congestion and hemorrhage). (-)-Epigallocatechin-3-O-gallate treatment ameliorated alterations in body weight, biochemical parameters, pain sensation, and histopathological changes in brain tissue. (-)-Epigallocatechin-3-O-gallate offers promising hypoglycemic, hypolipidemic, antioxidant and anti-inflammatory effects, which can prevent the development and progression of diabetic neuropathic pain.

DNA 5-hydroxymethylcytosine (5hmC), converted from 5-methylcytosine (5mC), is highly enriched in the central nervous system and is dynamically regulated during neural development and metabolic disorders. However, whether and how neural 5hmC is involved in metabolic disorders shows little evidence. In this study, significant downregulation of the DNA 5hmC were observed in the cerebral cortex of HFD-induced diabetic mice, while phosphated AMP-activated protein kinase (p-AMPK) and ten-eleven translocation 2 (TET2) reduced, and mitochondrial dysfunction. We futher demonstrated that dysregulation of 5hmC preceded mitochondrial dysfunction in palmitic acid-treated HT22 cells and decreased level of 5hmC led to mitochondrial respiratory activity and apoptosis in HT22 cells. Taken together, our results reveal that neural 5hmC undergoes remodeling during HFD-induced metabolic disorder, and 5hmC downregulation significantly impacts on mitochondrial respiration and cell apoptosis. This study suggests a novel link between metabolic disorder and neural impairment through neural DNA 5hmC remodeling and resultant mitochondrial dysfunction.

Obesity is closely associated to several diseases such as type 2 diabetes, cardiovascular disease, hepatic steatosis, airway disease, neurodegeneration, biliary diseases and certain cancers. It is, therefore, of importance to assess the role of nutrition in disease prevention as well as its effect in the course of such pathologies. In the present study, we addressed the impact of the exposure to different obesogenic diets in the mice brains phosphoproteome. To analyze if the obesity could be able to modify the protein pattern expression of brain neurons, obesity was induced in two different groups of mice. One group of mice was fed with hyperglycemic diet (HGD) and the other one was fed with high-fat diet (HFD), both for 12 weeks. A control group of lean mice was fed with a standard diet (SD). Metabolic parameters were measured before sacrifice, and brains were harvested for label-free phosphoproteomic analysis. Mice brains were analyzed to find differences, if any, in protein phosphorylation. Interestingly, the changes were independent of the obesogenic diet as no changes were detected between the two obese groups. Dephosphorylation of proteins involved in neuronal development (among others SYNGAP1 and PPP1R9B), in vesicle trafficking (for example SNAP91 and AMPH) and in cytoskeletal functions (for example, CLASP2 and GSK3B) was identified, while increased phosphorylation was detected for microtubule proteins (such as MAP2 and MAPT). Phospho site analysis of the mouse brain proteome reveals important changes that point to a connection between diet-induced obesity and impairment of neuronal functions and signaling.

Excessive exposure to infrasound, a kind of low-frequency but high-intensity sound noise generated by heavy transportations and machineries, can cause vibroacoustic disease which is a progressive and systemic disease, and finally results in the dysfunction of central nervous system. Our previous studies have demonstrated that glial cell-mediated inflammation may contribute to infrasound-induced neuronal impairment, but the underlying mechanisms are not fully understood. Here, we show that cannabinoid (CB) receptors may be involved in infrasound-induced neuronal injury. After exposure to infrasound at 16 Hz and 130 dB for 1-14 days, the expression of CB receptors in rat hippocampi was gradually but significantly decreased. Their expression levels reached the minimum after 7- to 14-day exposure during which the maximum number of apoptotic cells was observed in the CA1. 2-Arachidonoylglycerol (2-AG), an endogenous agonist for CB receptors, reduced the number of infrasound-triggered apoptotic cells, which, however, could be further increased by CB receptor antagonist AM251. In animal behavior performance test, 2-AG ameliorated the infrasound-impaired learning and memory abilities of rats, whereas AM251 aggravated the infrasound-impaired learning and memory abilities of rats. Furthermore, the levels of proinflammatory cytokines tumor necrosis factor alpha and interleukin-1β in the CA1 were upregulated after infrasound exposure, which were attenuated by 2-AG but further increased by AM251. Thus, our results provide the first evidence that CB receptors may be involved in infrasound-induced neuronal impairment possibly by affecting the release of proinflammatory cytokines.