Association between serum apolipoprotein E and cognitive function in Chinese patients with temporal lobe epilepsy.

OBJECTIVE: To investigate the effect of serum apolipoprotein E (APOE) levels on cognitive function in patients with temporal lobe epilepsy (TLE). METHODS: Clinical data were collected from 190 subjects including 110 TLE patients and 80 healthy people. Cognitive function was assessed using the Addenbrooke's Cognitive Examination Revised (ACE-R) scale. Serum levels of APOE were measured using ELISA kits. Genotyping of APOE in peripheral blood was detected by microarray hybridization. RESULTS: Patients with TLE had significantly lower ACE-R total score, memory and verbal fluency scores compared to the healthy group. Serum levels of APOE were significantly higher in TLE patients than in the healthy subjects. Serum APOE levels were significantly negatively correlated with ACE-R total score, memory and verbal fluency scores. The cognitive function score of TLE with APOE ε4 allele was lower than that of TLE without APOE ε4 allele. SIGNIFICANCE: Our study showed that serum APOE levels were higher in TLE patients than in the healthy population. And serum APOE levels were associated with cognitive dysfunction in TLE patients. APOE ε4 allele carriers have poor cognitive function in TLE patients.

Construction and verification of risk predicting models to evaluate the possibility of hydrocephalus following aneurysmal subarachnoid hemorrhage.

BACKGROUND: Hydrocephalus following a ruptured aneurysm portends a poor prognosis. The authors aimed to establish a nomogram to predict the risk of hydrocephalus after aneurysmal subarachnoid hemorrhage (aSAH). METHODS: A total of 421 patients with aSAH who were diagnosed by digital subtraction angiography in The General Hospital of Northern Theater Command center from January 2020 to June 2021 were screened to establish the training cohort. An additional 135 patients who enrolled between July 2021 and May 2022 were used for the validation cohort. Variate difference analysis and stepwise logistic regression (model A) and univariate and multivariate logistic regressions (model B) were respectively used to construct two models. Then, the net reclassification improvement (NRI), integrated discrimination improvement (IDI), and receiver operating characteristic (ROC) curve were used to compare the predictive abilities of the two models. Finally, two nomograms were constructed and externally validated. RESULTS: After screening, 556 patients were included. The area under the ROC curve of models A and B in the training cohort were respectively 0.884 (95 % confidence interval [CI]: 0.847-0.921) and 0.834 (95 % CI: 0.787-0.881). The prediction ability of the model A was superior to model B (NRI > 0, IDI > 0, p < 0.05). The C-index of models A and B was 0.8835 and 0.8392, respectively. Regarding clinical usefulness, the two models offered a net benefit with a threshold probability of between 0.12 and 1 in the decision curve analysis, suggesting that the two models can accurately predict hydrocephalus events. CONCLUSIONS: Both models have good prediction accuracy. Compared with model B, model A has better discrimination and calibration. Further, the easy-to-use nomogram can help neurosurgeons to make rapid clinical decisions and apply early treatment measures in high-risk groups, which ultimately benefits patients.

High-altitude cerebral hypoxia promotes mitochondrial dysfunction and apoptosis of mouse neurons.

Introduction: Neuronal cell death is an important factor in the pathogenesis of acute high-altitude cerebral hypoxia; however, the underlying molecular mechanism remains unclear. In this study, we tested if high-altitude hypoxia (HAH) causes neuronal death and mitochondrial dysfunction using various in vivo and in vitro approaches. Methods: Acute high-altitude cerebral hypoxia was induced by hypobaric hypoxia chamber in male mice. we explored the mechanisms of neuronal cell death using immunofluorescence, western blotting, transmission electron microscopy, and flow cytometry. Next, mitochondrial function and morphology were observed using Jc-1 staining, seahorse assay, western blotting, MitoTracker staining, and transmission electron microscopy. Moreover, open field test, elevated plus test, and Morris water maze were applied for animal behavior. Results: Results revealed that HAH disrupted mitochondrial function and promoted neuronal apoptosis and necroptosis both in HT-22 cells and in mouse hippocampal neurons. Moreover, the mitochondrial membrane potential and adenosine triphosphate production decreased in neurons after HAH, while oxidative stress and mitochondrial fission increased. Behavioral studies suggested that HAH induced anxiety-like behavior and impaired spatial memory, while it had no effect on athletic ability. Discussion: These findings demonstrated that HAH promotes mitochondrial dysfunction and apoptosis of mouse neurons, thus providing new insights into the role of mitochondrial function and neuronal cell death in acute high-altitude cerebral hypoxia.

The role of dynamin-related protein 1 in cerebral ischemia/hypoxia injury.

Mitochondrial dysfunction, especially in terms of mitochondrial dynamics, has been reported to be closely associated with neuronal outcomes and neurological impairment in cerebral ischemia/hypoxia injury. Dynamin-related protein 1 (Drp1) is a cytoplasmic GTPase that mediates mitochondrial fission and participates in neuronal cell death, calcium signaling, and oxidative stress. The neuroprotective role of Drp1 inhibition has been confirmed in several central nervous system disease models, demonstrating that targeting Drp1 may shed light on novel approaches for the treatment of cerebral ischemia/hypoxia injury. In this review, we aimed to highlight the roles of Drp1 in programmed cell death, oxidative stress, mitophagy, and mitochondrial function to provide a better understanding of mitochondrial disturbances in cerebral ischemia/hypoxia injury, and we also summarize the advances in novel chemical compounds targeting Drp1 to provide new insights into potential therapies for cerebral ischemia/hypoxia injury.

Clinical effectiveness of nimodipine for the prevention of poor outcome after aneurysmal subarachnoid hemorrhage: A systematic review and meta-analysis.

Objective: In clinical practice, nimodipine is used to control cerebral vasospasm (CVS), which is one of the major causes of severe disability and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH). However, the exact efficacy of nimodipine use for patients with aSAH is still controversial due to the lack of sufficient and up-to-date evidence. Methods: In this meta-analysis, the latest databases of the Cochrane Central Register of Controlled Trials, PubMed-Medline, Web of Science, Embase, Scopus, and OVID-Medline were comprehensively searched for retrieving all randomized controlled trials (RCTs) regarding the efficacy of nimodipine in patients with aSAH. The primary outcome was a poor outcome, and the secondary outcomes were mortality and cerebral vasospasm (CVS). After detailed statistical analysis of different outcome variables, further evidence quality evaluation and recommendation grade assessment were carried out. Results: Approximately 13 RCTs met the inclusion criteria, and a total of 1,727 patients were included. Meta-analysis showed that a poor outcome was significantly reduced in the nimodipine group [RR, 0.69 (0.60-0.78); I2 = 29%]. Moreover, nimodipine also dramatically decreased the mortality [RR, 0.50 (0.32-0.78); I2 = 62%] and the incidence of CVS [RR, 0.68 (0.46-0.99); I2 = 57%]. Remarkably, we found a poor outcome and mortality were both significantly lower among patients with aSAH, with the mean age < 50 than that mean age ≥ 50 by subgroup analysis. Furthermore, the evidence grading of a poor outcome and its age subgroup in this study was assessed as high. Conclusion: Nimodipine can significantly reduce the incidence of a poor outcome, mortality, and CVS in patients with aSAH. Moreover, we strongly recommend that patients with aSAH, especially those younger than 50 years old, should use nimodipine as early as possible in order to achieve a better clinical outcome, whether oral medication or endovascular direct medication. Systematic review registration: www.york.ac.uk/inst/crd, identifier: CRD42022334619.

Relationship between recurrent ischemic events in cerebrovascular disease and cytochrome P450 2C19 gene polymorphism on the basis of thrombelastography.

BACKGROUND: Recurrent ischemic events in cerebrovascular disease present a difficult problem in clinical practice. The predictive value of cytochrome P450 2C19 (CYP2C19) gene polymorphism and high platelet reactivity for recurrent ischemic events in cerebrovascular disease is not clear. METHODS: A total of 295 patients with acute ischemic cerebrovascular disease admitted to the cerebrovascular disease center of Northern Theater General Hospital between January 1, 2020 and February 2, 2021 were enrolled in this study. Thrombelastography (TEG) was used to detect platelet reactivity and CYP2C19 gene polymorphism. RESULTS: Among the 118 noncarriers, 97 had normal platelet reactivity and 21 had high platelet reactivity. Of the 177 carriers, 120 showed normal platelet reactivity and 57 showed high platelet reactivity. The area under the curve (AUC) of CYP2C19 gene polymorphism in predicting recurrent ischemic events was 0.66. The regression coefficients of hypertension, stroke history, carriers, and high platelet reactivity with recurrent ischemic events were 0.341, 0.402, 0.358, and 0.281, respectively, with significant positive correlation (P<0.05). CONCLUSIONS: Hypertension, stroke history, carriers, and high platelet reactivity are all independent risk factors for recurrent ischemic events. CYP2C19 gene polymorphism and high platelet reactivity can be used as effective predictors of recurrent ischemic events in clinical cerebrovascular disease.

MAP4K4 induces early blood-brain barrier damage in a murine subarachnoid hemorrhage model.

Sterile-20-like mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is expressed in endothelial cells and activates inflammatory vascular damage. Endothelial cells are important components of the blood-brain barrier. To investigate whether MAP4K4 plays a role in the pathophysiology of subarachnoid hemorrhage, we evaluated the time-course expression of MAP4K4 after subarachnoid hemorrhage. A subarachnoid hemorrhage model was established using the intravascular perforation method. The model mice were assigned to four groups: MAP4K4 recombinant protein, scramble small interfering RNA, and MAP4K4 small interfering RNA were delivered by intracerebroventricular injection, while PF-06260933, a small-molecule inhibitor of MAP4K4, was administrated orally. Neurological score assessments, brain water assessments, Evans blue extravasation, immunofluorescence, western blot assay, and gelatin zymography were performed to analyze neurological outcomes and mechanisms of vascular damage. MAP4K4 expression was elevated in the cortex at 24 hours after subarachnoid hemorrhage, and colocalized with endothelial markers. MAP4K4 recombinant protein aggravated neurological impairment, brain edema, and blood-brain barrier damage; upregulated the expression of phosphorylated nuclear factor kappa B (p-p65) and matrix metalloproteinase 9 (MMP9); and degraded tight junction proteins (ZO-1 and claudin 5). Injection with MAP4K4 small interfering RNA reversed these effects. Furthermore, administration of the MAP4K4 inhibitor PF-06260933 reduced blood-brain barrier damage in mice, promoted the recovery of neurological function, and reduced p-p65 and MMP9 protein expression. Taken together, the results further illustrate that MAP4K4 causes early blood-brain barrier damage after subarachnoid hemorrhage. The mechanism can be confirmed by inhibiting the MAP4K4/NF-κB/MMP9 pathway. All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of General Hospital of Northern Theater Command (No. 2018002) on January 15, 2018.

NEK7 Coordinates Rapid Neuroinflammation After Subarachnoid Hemorrhage in Mice.

Background: Subarachnoid hemorrhage (SAH) is a devastating disease which leads to high morbidity and mortality. Recent studies have indicated that, never in mitosis gene A-related expressed kinase 7 (NEK7), is involved in NLRP3 (NLR family, pyrin domain containing 3) associated inflammation, which may result in subsequent cellular and vascular damage. The aim of this study was to investigate whether NEK7 is involved in the pathophysiology of subarachnoid hemorrhage. Methods: 455 adult male C57B6J mice, weighing 22 to 30 g, were used to investigate the time course of NEK7 expression in the ipsilateral cortex after SAH, and to investigate the intrinsic function and mechanism of NEK7. A vascular puncture model was used to create the mouse SAH model, and intracerebroventricular injection was used to deliver NEK7 recombinant protein, NEK7 small interfering RNA, nigericin, and MCC950. Neurological score, brain water content, Evans blue extravasation, immunofluorescence, and western blot were evaluated for neurological outcome, neuronal apoptosis, blood-brain barrier damage, microglia accumulation, and the mechanism of NEK7 and NLRP3 activation. Results: Our results exhibited that intrinsic NEK7 was elevated after SAH in the cortex of the left/ipsilateral hemisphere and was colocalized with microglia, endothelial cells, neuron, astrocyte, and oligodendrocyte, and highly expressed in microglia and endothelial cells after SAH. NEK7 recombinant protein aggravated neurological deficits, brain edema, neuronal apoptosis, BBB permeability, microglial accumulation, and activated caspase-1 and IL-1ß maturation, while NEK7 small interfering RNA injection reversed those effects. Nigericin administration enhanced ASC oligomerization, caspase-1 and IL-1ß maturation without increasing the protein level of NLRP3, and ASC oligomerization and caspase-1 IL-1ß maturation reduced when combined with NEK7 knockdown or MCC950 delivery. We found the level of NEK7 expression increased after SAH and could activate the downstream NLRP3 pathway to induce caspase-1, IL-1ß expression and then increased the BBB opening, microglia accumulation and neuronal apoptosis after SAH. Conclusions: This study demonstrated for the first time that NEK7 mediated the harmful effects of neuronal apoptosis and BBB disruption after SAH, which may potentially be mediated by the NEK7/NLRP3 signal. NEK7 served as a co-component for NLRP3 inflammasome activation after SAH. NEK7 may be a promising target on the management of SAH patients.

Melatonin Attenuates White Matter Injury via Reducing Oligodendrocyte Apoptosis After Subarachnoid Hemorrhage in Mice.

AIM: To determine whether melatonin (MLT) mitigates white matter (WM) injury by attenuating NOD-like receptor family pyrin domain-containing 3 (NLRP3)-associated oligodendrocyte apoptosis after subarachnoid hemorrhage (SAH). MATERIAL AND METHODS: SAH model C57BL/6J mice were created using an endovascular perforation technique. The mice were injected intraperitoneally with MLT at doses of 50 mg/kg, 150 mg/kg and 300 mg/kg. The animals were evaluated for neurological outcomes according to neurological score, brain water content, myelin degradation, amyloid precursor protein (APP) accumulation, apoptosis, and levels of NLRP3, caspase-1, interleukin-1?, Bcl-2, and Bcl-2-interacting mediator of cell death (Bim) expression after SAH. RESULTS: MLT at a dose of 50 mg/kg improved neurological score, alleviated brain edema, and reduced WM injury. In addition, loss of myelin basic protein (MBP) and accumulation of APP, and expression in the ipsilateral/left hemisphere were found after SAH, and were reversed by MLT treatment. NLRP3 signal activation was found in microglia and apoptosis in oligodendrocytes were observed after SAH. MLT reduced oligodendrocyte apoptosis by regulating Bim and Bcl-2. CONCLUSION: Results of this study indicated that MLT exerts a WM-protective effect in SAH pathophysiology, possibly by attenuating apoptosis in oligodendrocytes.

SRY-related high-mobility-group box 4: Crucial regulators of the EMT in cancer.

The epithelial-mesenchymal transition (EMT) is a process of cell transformation under certain physiological and pathological states in which epithelial cells are transformed into mesenchymal cells with fibroblast-like properties, which confers upon them the increased invasion and migration capabilities of cancer cells. Previous studies have demonstrated that SRY-related high-mobility-group box 4 (Sox4) protein coordinates EMT-related pathways and EMT-related transcription factors, thereby regulating the EMT process. The focus of this review is to evaluate recent advances regarding the role of Sox4 protein in the cancer EMT. First, we provide an overview of the general background of Sox4 (structure and function) and the EMT in cancer. Next, we introduce the interactions between Sox4 protein and various factors during cancer EMT. Finally, we suggest directions for future investigations. In general, the information compiled in this paper should serve as a comprehensive repository of information on the subject matter and contribute to the design of other research and future efforts to develop therapeutic strategies that target the Sox4 protein.

Naringin suppresses the development of glioblastoma by inhibiting FAK activity.

As the most common and lethal primary malignant brain cancer, glioblastoma is hard to timely diagnose and sensitive therapeutic monitoring. It is essential to develop new and effective drugs for glioblastoma multiform. Naringin belongs to citrus flavonoids and was found to display strong anti-inflammatory, antioxidant and antitumor activities. In this report, we found that naringin can specifically inhibit the kinase activity of FAK and suppress the FAKp-Try397and its downstream pathway in glioblastoma cells. Our study showed out that naringin can inhibit cell proliferation by inhibiting FAK/cyclin D1 pathway, promote cell apoptosis through influencing FAK/bads pathway, at the same time, it can also inhibit cell invasion and metastasis by inhibiting the FAK/mmps pathway. All these showed that naringin exerts the anti-tumor effects in U87 MG by inhibiting the kinase activity of FAK.

Epigenetic Suppression of GADs Expression is Involved in Temporal Lobe Epilepsy and Pilocarpine-Induced Mice Epilepsy.

Recent studies have shown that histone acetylation is involved with the regulation of enzyme glutamate decarboxylases (GADs), including GAD67 and GAD65. Here, we investigated the histone acetylation modifications of GADs in the pathogenesis of epilepsy and explored the therapeutic effect of a novel second-generation histone deacetylase inhibitor (HDACi) JNJ-26481585 in epilepsy animals. We revealed the suppression of GADs protein and mRNA level, and histone hypoacetylation in patients with temporal lobe epilepsy and pilocarpine-induced epilepsy mice model. Double-immunofluorescence also indicated that the hypoacetyl-H3 was located in hippocampal GAD67/GAD65 positive neurons in epilepsy mice. JNJ-26481585 significantly reversed the decrease of the GAD67/GAD65 both protein and mRNA levels, and the histone hypoacetylation of GABAergic neurons in epilepsy mice. Meanwhile, single-cell real-time PCR performed in GFP-GAD67/GAD65 transgenic mice demonstrated that JNJ-26481585 induced increase of GAD67/GAD65 mRNA level in GABAergic neurons. Furthermore, JNJ-26481585 significantly alleviated the epileptic seizures in mice model. Together, our findings demonstrate inhibition of GADs gene via histone acetylation plays an important role in the pathgenesis of epilepsy, and suggest JNJ-26481585 as a promising therapeutic strategy for epilepsy.

Rutin Inhibits Neuroinflammation and Provides Neuroprotection in an Experimental Rat Model of Subarachnoid Hemorrhage, Possibly Through Suppressing the RAGE-NF-κB Inflammatory Signaling Pathway.

As is known to all, neuroinflammation plays a vital role in early brain injury pathogenesis following subarachnoid hemorrhage (SAH). It has been shown that rutin have a property of inhibiting inflammation in many kinds of animal models. However, the effect of rutin on neuroinflammation after SAH remains uninvestigated. In this study, we investigated the potential effects of rutin on neuroinflammation and the underlying mechanism in an experimental rat model of SAH performed by endovascular perforation. Adult male SD rats were randomly divided into three groups, including sham group, SAH + vehicle group and SAH + rutin group (50 mg/kg) intraperitoneally (i.p.) administered at 30 min after SAH. After sacrificed at 24 h after SAH, all rats were examined by following tests, including neurologic scores, blood-brain barrier permeability, brain water content and neuronal cell death in cerebral cortex. The level of inflammation in brain was estimated by means of multiple molecules, including RAGE, NF-κB, and inflammation cytokines. Our results indicated that rutin could significantly downregulate the increased level of REGE, NF-κB and inflammatory cytokines in protein level. In addition, rutin could also ameliorate a series of secondary brain injuries such as brain edema, destruction of blood-brain barrier, neurological deficits and neuronal death. This study indicated that rutin administration had a neuroprotective effect in an experimental rat model of SAH, possibly through inhibiting RAGE-NF-κB mediated inflammation signaling pathway.

Smilax glabra Roxb targets Akt(p-Thr308) and inhibits Akt-mediated signaling pathways in SGC7901 cells.

BACKGROUND: Smilax glabra Roxb (SGR) as a novel anti-tumor agent has been paid attention in several types of cancer cells. However, the effect of SGR on SGC7901 cells has not been investigated. PURPOSE: We investigate the effect and potential mechanisms of SGR on SGC7901 cells in this study. METHODS: Three kinds of gastric cancer cell lines (BGC823, SGC7901 and MKN45) and one kind of human embryonic kidney cell line (HEK293) were exposed to varying concentrations of SRG. Then, we observed the effect of SRG on these cell lines and the changes on proliferation, invasion and apoptosis. Finally, we detected the signaling pathway in which SGR may involve. RESULTS: SGR effectively suppressed the proliferation of SGC7901 cell lines by inhibiting the phosphorylation of Akt (Thr308). Moreover, we found SGR could significantly induce SGC7901 cell lines apoptosis by inhibiting Akt(p-Thr308)/Bad pathway and inhibit its migration and invasion partly by inhibiting Akt(p-Thr308)/MMPs pathway. DISCUSSION: SGR could effectively suppress the proliferation and invasion of SGC7901 cell lines by inhibiting the phosphorylation of Akt (Thr308) and its downstream relative pathways. CONCLUSION: SGR could effectively suppress the phosphorylation of Akt (Thr308) and then inhibit the proliferation and invasion of SGC7901 cell and enhance its apoptosis through Akt-mediated signaling pathways.