Mitochondrial Inhibitor Rotenone Triggers and Enhances Neuronal Ferroptosis Following Intracerebral Hemorrhage.

Ferroptosis, a form of regulatory non-apoptotic cell death driven by iron-dependent lipid peroxidation, accounts for more than 80% of the total types of neuronal death in the acute phase of intracerebral hemorrhage (ICH). Mitochondria have essential roles in energy production, macromolecule synthesis, cellular metabolism, and cell death regulation. However, its role in ferroptosis remains unclear and somewhat controversial, especially in ICH. This study aimed to investigate whether damaged mitochondria could trigger and enhance neuronal ferroptosis in ICH. The isobaric tag for relative and absolute quantitation proteomics on human ICH samples suggested that ICH caused significant damage to the mitochondria, which presented ferroptosis-like morphology under electron microscopy. Subsequently, use of the mitochondrial special inhibitor Rotenone (Rot) to induce mitochondrial damage showed that it has significant dose-dependent toxicity on primary neurons. Single Rot administration markedly inhibited neuronal viability, promoted iron accumulation, increased malondialdehyde (MDA) contents, decreased total superoxide dismutase (SOD) activity, and downregulated ferroptosis-related proteins RPL8, COX-2, xCT, ASCL4, and GPX4 in primary neurons. Moreover, Rot enhanced these changes via hemin and autologous blood administration in primary neurons and mice, mimicking the in vitro and in vivo ICH models, respectively. Furthermore, Rot exacerbated the ICH-induced hemorrhagic volumes, brain edema, and neurological deficits in mice. Together, our data revealed that ICH induced significant mitochondrial dysfunction and that mitochondrial inhibitor Rot can trigger and enhance neuronal ferroptosis.

Combining ultrasound with bio-indicators reveals progression of carotid stenosis.

BACKGROUND: Carotid artery stenosis (CAS) is one of the leading causes of ischemic stroke. However, knowledge of the changes in the plaque itself is lacking. Information about the ultrasound and clinical features of CAS will help elucidate the changes in prognostic and risk factors. METHODS: We evaluated 736 patients with carotid stenosis for an average 18-month follow-up. According to their degree of CAS stenosis, patients were allocated to one of three groups: regression (n=125), stable (n=443), or progression (n=168). An ordinal regression analysis was used to determine the risk factors for atherosclerosis progression. A logistic regression was subsequently applied to investigate the effects of CAS stenosis on cerebrovascular events after adjusting for various factors. RESULTS: The progression group had more male patients (P=0.02), hypoechoic plaque (P<0.01), high-risk high sensitivity C-reactive protein (hs-CRP) (P=0.02), ulcerative plaque (P=0.05), and hyperlipidemia (P=0.05) than the other two groups. There were no significant differences in residual ultrasound and clinical features among the three groups, including age, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), intima-media thickness (IMT), body mass index (BMI), diabetes mellitus (DM), hypertension (HTN), coronary heart disease (CHD), statin use, ulcerative plaque. The ordinal regression analysis identified hypoechoic plaque (OR, 1.53; 95% CI: 1.14-2.05; P<0.01) and high-risk hs-CRP (OR, 1.75; 95% CI: 1.17-2.61; P<0.01) as independent risk factors for CAS progression. Logistic regression analysis revealed that the stroke/transient ischemic attack adjusted odds ratio was 1.80 (95% CI: 1.03-3.13) in the progression group. CONCLUSIONS: High-risk hs-CRP and hypoechoic plaque are independently associated with CAS progression. The progression of carotid stenosis is associated with a high risk of cerebrovascular events.

Proteomic Analysis of Perihematoma Tissue from Patients with Intracerebral Hemorrhage Using iTRAQ-Based Quantitative Proteomics.

Intracerebral hemorrhage is a complicated disorder with limited proven prognostic and therapeutic targets and elusive mechanisms. With proteomic methods, we aimed to explore the global protein expression profile of perihematomal tissue from ICH patients and identify potential pathophysiological pathways and protein markers. Using iTRAQ-labeling quantitative proteomics technology, four ICH brain sample and four non-ICH brain samples were analyzed. Among the 3740 quantifiable proteins, 884 were dysregulated in the patients compared to those in the controls (p < 0.05). After bioinformatics analysis, the differentially expressed proteins were found to be mostly involved in hemostatic processes, nutrient metabolism signaling pathways, and antioxidation pathways. Moreover, fibronectin 1 was revealed to be at the center of the protein-protein interaction networks. In summary, the potential pathways and brain protein markers that could potentially be used to predict the prognosis of ICH were obtained from the altered proteomic profile of perihematomal tissue. Thus, these data may yield novel insights into the mechanisms of ICH-induced secondary brain injury.

AEBP1 as a potential immune-related prognostic biomarker in glioblastoma: a bioinformatic analyses.

BACKGROUND: Adipocyte enhancer binding protein 1 (AEBP1) has been shown to be closely related to cancer progression; however research on its potential role in glioblastoma (GBM) remains limited. METHODS: Following an expression analysis of AEBP1 in GBM through the Oncomine database, other critical findings were accessed via The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx) databases. Specifically, in addition to identifying differentially expressed genes, the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) were further investigated. Additionally, a gene set enrichment analysis (GSEA) was performed to examine the enrichment pathways in the AEBP1 high-expression group. To examine the prognostic role of AEBP1 in GBM, survival information was obtained from the Chinese Glioma Genome Atlas (CGGA) database. Finally, the relationship between the expression of AEBP1 and immune infiltration in GBM was examined by using the "Gene Module", "Survival Module", and "SCNA Module" on the website "Tumor Immune Estimation Resource (TIMER)". RESULTS: The Oncomine database revealed that AEBP1 was highly expressed in GBM. The prognostic analyses of 4 independent databases (i.e., TCGA, GTEx, Oncomine, and CGGA) revealed that AEBP1 was an independent predictable marker of GBM. The results of the GSEA showed that protein export, prion disease, cytokine receptor interaction, hematopoietic cell lineage, cell adhesion molecules, apoptosis, and the complement and coagulation cascades were differentially enriched in highly expressed AEBP1 phenotypes. Hence the conclusion is that the high expression of AEBP1 is closely correlated to poor prognosis of GBM. The immune analysis demonstrated that AEBP1 copy number alteration might affect immune infiltration in GBM tissues, and thus the survival outcomes of GBM patients. CONCLUSIONS: High AEBP1 expression in GBM is closely correlated to patient prognosis. AEBP1 is a potential therapeutic target for the inhibition of cancerous progression and the development of new immunotherapies for GBM.

Inhibition of neuronal ferroptosis in the acute phase of intracerebral hemorrhage shows long-term cerebroprotective effects.

Intracerebral hemorrhage (ICH) is a devastating subtype of stroke because it has few viable therapeutic options to intervene against primary or second brain injury. Recently, evidence has suggested that ferroptosis, a nonapoptotic form of cell death, is involved in ICH. In this study, we examined whether ICH-induced neuron death is partly ferroptotic in humans and assessed its temporal and spatial characteristics in mice. Furthermore, the ferroptosis inhibitor ferrostatin-1 (Fer-1) was used to examine the role of ferroptosis after ICH. Fold changes in ferroptosis-related gene expression, intracellular iron levels, malondialdehyde (MDA) levels, and both protein levels and cellular localization of cyclooxygenase-2 (COX-2) were measured to monitor ferroptosis. Transmission electron microscopy (TEM) was also performed to examine the ultrastructure of cells after ICH. We found that the expression level of prostaglandin-endoperoxide synthase (PTGS2) was increased in both in vitro and in vivo ICH models; by comparison, expression level of RPL8 was increased in human brain tissue. In mice, iron and MDA levels were significantly increased 3 h after ICH; COX-2 levels were increased at 12 h after ICH and peaked at 3 days after ICH; COX-2 colocalized with NeuN (a neuronal biomarker); and TEM showed that shrunken mitochondria were found at 3 h, 3 days, and 7 days after ICH. Moreover, ICH-induced neurological deficits, memory impairment and brain atrophy were reduced by Fer-1 treatment. Our results demonstrated that neuronal ferroptosis occurs during the acute phase of ICH in brain areas distant from the hematoma and that inhibition of ferroptosis by Fer-1 exerted a long-term cerebroprotective effect.

Intractable Hiccups Associated with Chiari Type I Malformation: Case Report and Literature Review.

BACKGROUND: The authors report the case of a 34-year-old man who presented with intractable hiccups. The imaging examination showed that the patient was suffering from syringomyelia associated with Chiari type I malformation. CASE DESCRIPTIONS: The patient underwent posterior fossa decompression combined with bilateral tonsillectomy and duroplasty. The intractable hiccups completely resolved 1 week after operation and had not recurred at 2 months after surgery. Postoperative magnetic resonance imaging showed the atrophy of the tonsils of the cerebellum and disappearance of the cavities of the spinal cord. CONCLUSIONS: Intractable hiccups as the main symptoms of Chiari type I malformation are extremely rare in the clinic. Decompression surgery should be an appropriate method to relieve the symptoms.

Long-Term Therapeutic Effect of Microvascular Decompression for Trigeminal Neuralgia: Kaplan-Meier Analysis in a Consecutive Series of 425 Patients.

AIM: To evaluate the long-term efficacy and safety of microvascular decompression (MVD) for treating trigeminal neuralgia (TN), and identify the predictors of pain relief. MATERIAL AND METHODS: A total of 425 patients who underwent surgery between 1991 and 2011 for idiopathic TN were included in this study. Pain outcome was graded using the Barrow Neurological Institute pain scale and success was defined as complete pain relief without medication. A Kaplan-Meier survival curve was generated. Univariate analysis and Cox proportional-hazards regression were performed to identify factors associated with the maintenance of long-term pain relief. RESULTS: The cure rate was 89.3% at 1 year, 80.5% at 3 years, 75.6% at 5 years, and 71.2% at 8 years. Typical clinical presentation, arterial vessel compression, and age ? 60 years at the time of surgery were independent predictors of an excellent outcome. Gender, side, branches involved, symptom duration, hypertension, previously failed surgery, and number of conflicted vessels had no prognostic value. A total of 36 patients (8.47%) developed permanent cranial nerve injury and general complications and the mortality rate was 0.24%. CONCLUSION: MVD has positive effects for TN treatment, with persistent pain relief achieved in 71.2% of patients 8 years after the procedure. Long-term pain remission may be related to typical clinical presentation, an arterial conflicted vessel, and age ? 60 years at the time of surgery.

Microvascular decompression for hemifacial spasm: can intraoperative lateral spread response monitoring improve surgical efficacy?

OBJECTIVE The purpose of this study was to evaluate whether intraoperative monitoring of lateral spread response (LSR) improves the efficacy of microvascular decompression (MVD) for hemifacial spasm (HFS). METHODS In this prospective study, patients undergoing MVD for HFS were assigned to one of 2 groups, Group A (MVD with intraoperative LSR monitoring) or Group B (MVD without LSR monitoring). Clinical outcome at 12 months after surgery was assessed through telephone survey. Data analysis was performed to investigate the effect of intraoperative LSR monitoring on efficacy of MVD. RESULTS A total of 283 patients were enrolled in the study, 145 in Group A and 138 in Group B. There was no statistically significant difference between the 2 groups with respect to the percentage of patients who had spasm relief at either 1 week (Group A 87.59% vs Group B 83.33%; p = 0.317) or 1 year (93.1% vs 94.2%; p = 0.809) after surgery. A clear-cut elimination of LSR during surgery was observed in 131 (90.34%) of 145 patients; LSR persisted in 14 patients (9.66%) at the end of the surgical procedure. Disappearance of LSR correlated with spasm-free status at 1 week postoperatively (p = 0.017) but not at 1 year postoperatively (p = 0.249). CONCLUSIONS Intraoperative LSR monitoring does not appear to provide significant benefit with respect to the outcome of MVD for HFS in skilled hands. Persistence of LSR does not always correlate with poor outcome, and LSR elimination should not be pursued in all patients after verification of complete decompression.

Cordycepin confers neuroprotection in mice models of intracerebral hemorrhage via suppressing NLRP3 inflammasome activation.

Neuroinflammation has been recognized as a major contributor to brain injury caused by intracerebral hemorrhage (ICH). Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome acts as an important mediator of inflammatory response in various inflammation-related diseases including hemorrhagic insults. Cordycepin has recently been shown to possess anti-inflammatory effect; however, its role and the possible underlying mechanisms in ICH remain unclear. This study was designed to investigate the neuroprotective effect of cordycepin in mice models of ICH and to elucidate the underlying molecular mechanisms. ICH was induced in male ICR mice by injecting autologous blood infusion stereotactically. Cordycepin was then given intraperitoneally (i.p.) at 30 min after ICH induction. The results demonstrated that NLRP3 inflammasome was activated and exacerbated the inflammatory progression after ICH. Cordycepin treatment significantly alleviated neurological deficits, brain edema, and perihematomal tissue damage following ICH. These changes were accompanied by downregulated NLRP3 inflammasome components expression and a reduction of production and release of inflammasome substrates interleukin-1beta (IL-1ß) and interleukin-18 (IL-18). Furthermore, cordycepin ameliorated neuronal death in the perihematomal regions, accompanied by a large reduction in the expression of high-mobility group protein B 1 (HMGB1) post-ICH. In conclusion, this study provides in vivo evidence that cordycepin confers neuroprotective effect in the models of ICH, possibly through the suppression of NLRP3 inflammasome activation.

Clinical features and long-term surgical outcomes in 39 patients withtumor-related trigeminal neuralgia compared with 360 patients with idiopathic trigeminal neuralgia.

OBJECTIVE: The purpose of this study was to compare clinical features, long-term surgical outcomes between patients with idiopathic and tumor-related trigeminal neuralgia (TN), and to identify factors associated with the maintenance of permanent pain-free state. METHODS: Between January 2003 and December 2013, 360 patients with idiopathic TN and 39 patients with tumor-related TN who had undergone microsurgery were retrospectively studied. Kaplan-Meier survival curves were generated and compared by Log-rank test, and the possible prognostic factors were analyzed by the Cox proportional-hazards regression. RESULTS: Patients with tumor-related TN exhibited a younger age of pain onset (46.28 ± 18.18y vs. 53.03 ± 11.90y, p = .006), a briefer symptom duration (3.20 ± 4.38y vs. 7.01 ± 6.04y, p = .000), and much more preoperative neuropathic deficits (61.54%% vs. 24.17%%, p = .000), as compared with patients with idiopathic TN. Using Kaplan-Meier analysis, we found microsurgery was effective in 72.3% of patients with idiopathic TN, and in 86.4% of cases with tumor-related TN at six years follow-up postoperatively. Prognostic analysis suggested that a clear-cut neurovascular compression in patients with idiopathic TN (HR = 3.098, 95%CI: 1.800-5.311; p = .000) and total tumor removal in patients with tumor secondary TN (HR = 7.662, 95%CI: 0.098-36.574; p = .044) were positively correlated with excellent long-term outcomes. CONCLUSIONS: The occurrences of TN at younger age, a shorter duration and preponderance of preclinical neuropathic symptoms are the characteristics of TN patients secondary to intracranial tumor, in contrast to patients with TN caused by a compressed vessel. Microsurgery is an effective and safe treatment modality for TN regardless of the disease etiology, the involvement of a clear-cut vascular offender and total tumor resection are the most important predictors of excellent outcome for microsurgery in idiopathic and tumor-related TN patients, respectively.

Ghrelin Attenuates Intestinal Barrier Dysfunction Following Intracerebral Hemorrhage in Mice.

Intestinal barrier dysfunction remains a critical problem in patients with intracerebral hemorrhage (ICH) and is associated with poor prognosis. Ghrelin, a brain-gut peptide, has been shown to exert protection in animal models of gastrointestinal injury. However, the effect of ghrelin on intestinal barrier dysfunction post-ICH and its possible underlying mechanisms are still unknown. This study was designed to investigate whether ghrelin administration attenuates intestinal barrier dysfunction in experimental ICH using an intrastriatal autologous blood infusion mouse model. Our data showed that treatment with ghrelin markedly attenuated intestinal mucosal injury at both histomorphometric and ultrastructural levels post-ICH. Ghrelin reduced ICH-induced intestinal permeability according to fluorescein isothiocyanate conjugated-dextran (FITC-D) and Evans blue extravasation assays. Concomitantly, the intestinal tight junction-related protein markers, Zonula occludens-1 (ZO-1) and claudin-5 were upregulated by ghrelin post-ICH. Additionally, ghrelin reduced intestinal intercellular adhesion molecule-1 (ICAM-1) expression at the mRNA and protein levels following ICH. Furthermore, ghrelin suppressed the translocation of intestinal endotoxin post-ICH. These changes were accompanied by improved survival rates and an attenuation of body weight loss post-ICH. In conclusion, our results suggest that ghrelin reduced intestinal barrier dysfunction, thereby reducing mortality and weight loss, indicating that ghrelin is a potential therapeutic agent in ICH-induced intestinal barrier dysfunction therapy.

Structural brain alterations in hemifacial spasm: A voxel-based morphometry and diffusion tensor imaging study.

OBJECTIVE: Hemifacial spasm (HFS) is characterized by involuntary, irregular clonic or tonic movement of muscles innervated by the facial nerve. We evaluated structural reorganization in brain gray matter and white matter and whether neuroplasticity is linked to clinical features in HFS patients. METHODS: High-resolution structural magnetic resonance imaging and diffusion tensor imaging data were acquired by 3.0 T MRI from 42 patients with HFS and 30 healthy subjects. The severity of the spasm was assessed according to Jankovic disability rating scale. Voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) analysis were performed to identify regional grey matter volume (GMV) changes and whole-brain microstructural integrity disruption measured by fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). RESULTS: The VBM analysis showed that patients with HFS reduced GMV in the right inferior parietal lobule and increased GMV in the cerebellar lobule VIII, when compared with healthy subjects. Furthermore, within the HFS disease group, GMV decreased with the disease duration in the right inferior parietal lobule. TBSS did not identify group differences in diffusivity parameters. CONCLUSIONS: While no white matter integrity disruption was detected in the brain of patients with HFS, our study identified evident GMV changes in brain areas which were known to be involved in motor control. SIGNIFICANCE: Our results suggest that HFS, a chronic neurovascular conflict disease, is related to structural reorganization in the brain.

Altered spontaneous brain activity in patients with hemifacial spasm: a resting-state functional MRI study.

Resting-state functional magnetic resonance imaging (fMRI) has been used to detect the alterations of spontaneous neuronal activity in various neurological and neuropsychiatric diseases, but rarely in hemifacial spasm (HFS), a nervous system disorder. We used resting-state fMRI with regional homogeneity (ReHo) analysis to investigate changes in spontaneous brain activity of patients with HFS and to determine the relationship of these functional changes with clinical features. Thirty patients with HFS and 33 age-, sex-, and education-matched healthy controls were included in this study. Compared with controls, HFS patients had significantly decreased ReHo values in left middle frontal gyrus (MFG), left medial cingulate cortex (MCC), left lingual gyrus, right superior temporal gyrus (STG) and right precuneus; and increased ReHo values in left precentral gyrus, anterior cingulate cortex (ACC), right brainstem, and right cerebellum. Furthermore, the mean ReHo value in brainstem showed a positive correlation with the spasm severity (r = 0.404, p = 0.027), and the mean ReHo value in MFG was inversely related with spasm severity in HFS group (r = -0.398, p = 0.028). This study reveals that HFS is associated with abnormal spontaneous brain activity in brain regions most involved in motor control and blinking movement. The disturbances of spontaneous brain activity reflected by ReHo measurements may provide insights into the neurological pathophysiology of HFS.