Astragaloside IV mediates radiation-induced neuronal damage through activation of BDNF-TrkB signaling.

BACKGROUND: Electromagnetic radiation is relevant to human life, and radiation can trigger neurodegenerative diseases by altering the function of the central nervous system through oxidative stress, mitochondrial dysfunction, and protein degradation. Astragaloside IV (AS-IV) is anti-oxidative, anti-apoptotic, activates the BDNF-TrkB pathway and enhances synaptic plasticity in radiated mice, which can exert its neuroprotection. However, the exact molecular mechanisms are still unclear. PURPOSE: This study investigated whether AS-IV could play a neuroprotective role by regulating BDNF-TrkB pathway in radiation damage and its underlying molecular mechanisms. METHODS: Transgenic mice (Thy1-YFP line H) were injected with AS-IV (40 mg/kg/day body weight) by intraperitoneal injection daily for 4 weeks, followed by X-rays. PC12 cells and primary cortical neurons were also exposed to UVA after 24 h of AS-IV treatment (25 µg/ml and 50 µg/ml) in vitro. The impact of radiation on learning and cognitive functions was visualized in the Morris water maze assay. Subsequently, Immunofluorescence and Golgi-Cox staining analyses were utilized to investigate the structural damage of neuronal dendrites and the density of dendritic spines. Transmission electron microscopy was performed to examine how the radiation affected the ultrastructure of neurons. Finally, western blotting analysis and Quantitative RT-PCR were used to evaluate the expression levels and locations of proteins in vitro and in vivo. RESULTS: Radiation induced BDNF-TrkB signaling dysregulation and decreased the levels of neuron-related functional genes (Ngf, Bdnf, Gap-43, Ras, Psd-95, Arc, Creb, c-Fos), PSD-95 and F-actin, which subsequently led to damage of neuronal ultrastructure and dendrites, loss of dendritic spines, and decreased dendritic complexity index, contributing to spatial learning and memory deficits. These abnormalities were prevented by AS-IV treatment. In addition, TrkB receptor antagonists antagonized these neuroprotective actions of AS-IV. 7,8-dihydroxyflavone and AS-IV had neuroprotective effects after radiation. CONCLUSION: AS-IV inhibits morphological damage of neurons and cognitive dysfunction in mice after radiation exposure, resulting in a neuroprotective effect, which were mediated by activating the BDNF-TrkB pathway.

The Role of the Orexin System in Craniocerebral Trauma-Induced Epilepsy in Mice.

BACKGROUND: Following traumatic brain injury (TBI), an imbalance arises in the central nervous system within the hippocampus region, resulting in the proliferation of mossy cell fibers, causing abnormal membrane discharge. Moreover, disruptions in cellular neurotransmitter secretion induce post-traumatic epilepsy. Extensive experimental and clinical data indicate that the orexin system plays a regulatory role in the hippocampal central nervous system, but the specific regulatory effects are unclear. Therefore, further experimental evaluation of its relevance is needed. OBJECTIVE: This study aims to investigate the effects of orexin receptor agonists (OXA) on the seizure threshold and intensity in controlled cortical impact (CCI) mice, and to understand the role of the orexin system in post-traumatic epilepsy (PTE). METHODS: Male C57BL/6 mice weighing 18-22 g were randomly divided into three groups: Sham, CCI, and CCI+OXA. The three groups of mice were sequentially constructed with models, implanted with electrodes, and established drug-delivery cannulas. After a 30-day recovery, the Sham and CCI groups were injected with physiological saline through the administration cannulas, while the CCI+OXA group was injected with OXA. Subsequently, all mice underwent electrical stimulation every 30 minutes for a total of 15 times. Epileptic susceptibility, duration, intensity, and cognitive changes were observed. Concurrently, the expression levels and changes of GABAergic neurons in the hippocampus of each group were examined by immunofluorescence. RESULTS: Injecting OXA into hippocampal CA1 reduces the threshold of post-traumatic seizures, prolongs the post-discharge duration, prolongs seizure duration, reduces cognitive ability, and exacerbates the loss of GABAergic neurons in the hippocampal region. CONCLUSIONS: Based on the results, we can find that injecting OXA antagonists into the CA1 region of the hippocampus can treat or prevent the occurrence and progression of post-traumatic epilepsy.

Characteristics and Neural Mechanisms of Sleep-Wake Disturbances After Traumatic Brain Injury.

Sleep-wake disturbances (SWDs) are one of the most common complaints following traumatic brain injury (TBI). The high prevalence and socioeconomic burden of SWDs post-TBI have only been recognized in the past decade. Common SWDs induced by TBI include excessive daytime sleepiness (EDS), hypersomnia, insomnia, obstructive sleep apnea (OSA), and circadian rhythm sleep disorders. Sleep disturbances can significantly compromise quality of life, strain interpersonal relationships, diminish work productivity, exacerbate other clinical conditions, and impede the rehabilitation process of TBI patients. Consequently, the prompt regulation and enhancement of sleep homeostasis in TBI patients is of paramount importance. Although studies have shown that abnormal neural network function, neuroendocrine changes, disturbance of sleep-wake regulators, and immune inflammatory responses related to brain structural damage induced by TBI are involved in the development of SWDs, the exact neuropathological mechanisms are still poorly understood. Therefore, we systematically review the current clinical and experimental studies on the characteristics and possible neural mechanisms of post-TBI SWDs. Elucidating the neural underpinnings of post-TBI SWDs holds the potential to diversify and enhance therapeutic approaches for these conditions. Such advancements could hasten the recuperation of TBI patients and ameliorate their overall quality of life. It is our aspiration that departments specializing in neurosurgery, rehabilitation, and neuropsychiatry will be able to recognize and address these conditions promptly, thereby facilitating the healing journey of affected individuals.

Neuroprotective Effects of Vinpocetine Against Ischemia-Reperfusion Injury Via Inhibiting NLRP3 Inflammasome Signaling Pathway.

Ischemic stroke is one of the main causes of serious disability and death worldwide. NLRP3 inflammasome is an intracellular pattern recognition receptor composed of polyprotein complex, which participates in mediating a series of inflammatory responses and is considered as a potential target for the treatment of ischemic stroke. Vinpocetine, a derivative of vincamine, has been widely used in the prevention and treatment of ischemic stroke. However, the therapeutic mechanism of vinpocetine is not clear, and its effect on NLRP3 inflammasome remains to be determined. In this study, we used the mouse model of transient middle cerebral artery occlusion (tMCAO) to simulate the occurrence of ischemic stroke. Different doses of vinpocetine (5, 10, 15 mg/kg/d) were injected intraperitoneally for 3 days after ischemia-reperfusion in mice. The effects of different doses of vinpocetine on the degree of ischemia-reperfusion injury in mice were observed by TTC staining and modified neurological severity score scale, and the optimal dose was determined. Then, based on this optimal dose, we observed the effects of vinpocetine on apoptosis, microglial proliferation and NLRP3 inflammasome. In addition, we compared the effects of vinpocetine and MCC950 (a specific inhibitor of NLRP3 inflammasome) on NLRP3 inflammasome. Our results show that vinpocetine can effectively reduce the infarct volume and promote the recovery of behavioral function in stroke mice, and the maximal beneficial effects were observed at the dose of 10 mg/kg/d. Vinpocetine can effectively inhibit the apoptosis of peri-infarct neurons, promote the expression of Bcl-2, inhibit the expression of Bax and Cleaved Caspase-3, and reduce the proliferation of peri-infarct microglia. In addition, vinpocetine, like MCC950, can reduce the expression of NLRP3 inflammasome. Therefore, vinpocetine can effectively alleviate the ischemia-reperfusion injury in mice, and the inhibition of NLRP3 inflammasome may be an important therapeutic mechanism of vinpocetine.

Leukocyte as an Independent Predictor of Lower-Extremity Deep Venous Thrombosis in Elderly Patients With Primary Intracerebral Hemorrhage.

Objective: Due to the interaction of leukocytes with platelets and coagulation factors, they may in turn play a role in hemostasis or the formation of thrombi. This study aimed to investigate the association of leukocytosis on admission with an increased risk of acute lower-extremity deep venous thrombosis (LEDVT) in elderly patients with primary intracerebral hemorrhage (ICH). Methods: This was a single-center, retrospective observational study of consecutive patients observed with spontaneous ICH aged 60 years or above at Lanzhou University Second Hospital from January 2017 to September 2021. Clinical data and demographic information were collected and analyzed. Univariate and multivariate analyses were conducted to identify independent risk factors of acute LEDVT. One-to-one matching was implemented to balance important patient characteristics by the groups' propensity score matching (PSM) analysis. Results: A total of 371 elderly patients with primary ICH fulfilled requirements for inclusion and exclusion, of whom 33 (8.89%) experienced LEDVT. Leukocyte counts were statistically higher in the LEDVT group compared to the non-LEDVT group [12.89 (8.80-14.61) × 109 cells/L vs. 8.31 (6.60-10.75) × 109 cells /L, p < 0.001]. Multivariate logistic regression models adjusted for several potential confounding factors were performed, and leukocytes were consistently a significant independent predictor of LEDVT. The optimal cut-off value of leukocyte counts calculated from the receiver operating characteristic (ROC) curve to predict LEDVT was 10.22 × 109 cells /L (area under the curve:0.714, 95%CI 0.665-0.759; the sensitivity was 72.73%; the specificity was 71.01%) in elderly patients with primary ICH. After one-to-one PSM, compared to the matched non-LEDVT group, the matched LEDVT group had significantly higher leukocyte counts [11.98 (8.40-13.94) × 109 cells/L vs. 6.12 (4.68-12.00) × 109 cells/L, p = 0.003]. After PSM, the ROC curve was plotted for leukocytes as a predictor of LEDVT, with an AUC of 0.722 (95%CI 0.593-0.828, p = 0.001; the sensitivity was 87.10%, and the specificity was 61.29%). Elevated leukocytes remained independently significant as predictors of LEDVT in elderly patients with primary ICH. Conclusion: Leukocyte at admission is an independent risk factor of LEDVT in elderly patients with primary ICH.

Ki20227 aggravates apoptosis, inflammatory response, and oxidative stress after focal cerebral ischemia injury.

The survival of microglia depends on the colony-stimulating factor-1 receptor (CSF1R) signaling pathway under physiological conditions. Ki20227 is a highly selective CSF1R inhibitor that has been shown to change the morphology of microglia. However, the effects of Ki20227 on the progression of ischemic stroke are unclear. In this study, male C57BL/6 mouse models of focal cerebral ischemic injury were established through the occlusion of the middle cerebral artery and then administered 3 mg/g Ki20227 for 3 successive days. The results revealed that the number of ionized calcium-binding adaptor molecule 1/bromodeoxyuridine double positive cells in the infarct tissue was reduced, the degree of edema was increased, neurological deficits were aggravated, infarct volume was increased, and the number of peri-infarct Nissl bodies was reduced. The number of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells in the peri-infarct tissue was increased. The expression levels of Bax and Cleaved caspase-3 were up-regulated. Bcl-2 expression was downregulated. The expression levels of inflammatory factors and oxidative stress-associated factors were increased. These findings suggested that Ki20227 blocked microglial proliferation and aggravated the pathological progression of ischemia/reperfusion injury in a transient middle cerebral artery occlusion model. This study was approved by the Animal Ethics Committee of Lanzhou University Second Hospital (approval No. D2020-68) on March 6, 2020.

CCNB2 is a novel prognostic factor and a potential therapeutic target in low-grade glioma.

BACKGROUND: Cyclin B2 (CCNB2) is an important component of the cyclin pathway and plays a key role in the occurrence and development of cancer. However, the correlation between prognosis of low-grade glioma (LGG), CCNB2, and tumor infiltrating lymphocytes is not clear. METHODS: The expression of CCNB2 in LGG was queried in Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and TIMER databases. The relationships between CCNB2 and the clinicopathological features of LGG were analyzed using the Chinese Glioma Genome Atlas (CGGA) database. The relationship between CCNB2 expression and overall survival (OS) was evaluated by GEPIA2. The correlation between CCNB2 and LGG immune infiltration was analyzed by the TIMER database. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect CCNB2 expression. RESULTS: The expression of CCNB2 differed across different tumor tissues, but was higher in LGG than in normal tissues. LGG patients with high expression of CCNB2 have poorer prognosis. The expression of CCNB2 was correlated with age, WHO grade, IDH mutational status, 1p/19q codeletion status, and other clinicopathological features. The expression of CCNB2 in LGG was positively correlated with the infiltration level of B cells, dendritic cells, and macrophages. qRT-PCR results revealed that the expression of CCNB2 in LGG tissues was higher than normal tissues and higher expression of CCNB2 was associated with worse prognosis. CONCLUSION: CCNB2 may be used as a potential biomarker to determine the prognosis of LGG and is also related to immune infiltration.

Adequacy of health literacy and its effect on diabetes self-management: a meta-analysis.

This study evaluated the role of health literacy (HL) in the self-management of diabetes. A literature search was conducted in electronic databases and studies were selected using precise eligibility criteria. A meta-analysis was conducted to estimate the HL adequacy rate, factors affecting the adequacy of HL and correlations between HL and diabetes self-management variables. Thirty-three studies were included in the analysis. The HL adequacy rate was 67% (95% confidence interval (CI) 57, 76). Compared with patients with inadequate HL, patients with adequate HL were younger (mean difference -5.2 years; 95% CI -7.2, -3.2; P<0.00001), more likely to have a high school or higher level of education (odds ratio (OR) 8.39; 95% CI 5.03, 13.99]; P<0.00001) and were less likely to belong to a low-income group (OR 0.36; 95% CI 0.23, 0.56; P<0.00001). HL was positively correlated with self-monitoring (r=0.19; 95% CI 0.11, 0.27; P<0.00001), dietary and physical care (r=0.12; 95% CI 0.07, 0.18; P=0.009), diabetes knowledge (r=0.29; 95% CI 0.09, 0.45; P<0.001), self-efficacy (r=0.28; 95% CI 0.15, 0.41; P<0.00001), self-care (0.24; 95% CI 0.16, 0.31; P<0.00001), formal education (r=0.35; 95% CI 0.18, 0.53; P<0.00001) and social support (r=0.2; 95% CI 0.07, 0.33; P<0.00001). Patient age (r=-0.28; 95% CI -0.39, -0.17; P<0.00001) was inversely correlated with HL. In conclusion, 67% of diabetes patients had adequate HL, with a higher rate among better educated and higher income groups. HL had a statistically significant but weak positive correlation with diabetes self-management variables.

Pharmacological Targeting of CSF1R Inhibits Microglial Proliferation and Aggravates the Progression of Cerebral Ischemic Pathology.

Ischemic stroke can induce rapid activation of the microglia. It has been reported that the microglia's survival is dependent on colony-stimulating factor 1 receptor (CSF1R) signaling and that pharmacological inhibition of CSF1R leads to morphological changes in the microglia in the healthy brain. However, the impact of CSF1R inhibition on neuronal structures and motor ability after ischemia-reperfusion remains unclear. In this study, we investigated microglial de-ramification, proliferation, and activation after inhibition of CSF1R by a tyrosine kinase inhibitor (ki20227) in a mouse model of global cerebral ischemia induced by bilateral common carotid artery ligation (BCAL). In addition to microglial morphology, we evaluated the mRNA expression of cytokines, chemokines, and inflammatory receptors. Our results show that pharmacological inhibition of CSF1R in ischemic mice resulted in the blockade of microglial proliferation and a shift in microglial morphology reflected by excessive de-ramification and a more activated phenotype accompanied by an enhanced innate immune response. Furthermore, we show that pharmacological inhibition of CSF1R in ischemic mice resulted in the aggravation of neuronal degeneration and behavioral impairment. Intravital two-photon imaging revealed that although pharmacological inhibition of CSF1R did not affect the recovery of dendritic structures, it caused a significant increase in spine elimination during reperfusion in ischemic mice. These findings suggest that pharmacological inhibition of CSF1R induces a blockade of microglial proliferation and causes acute activation of the microglia accompanied by a severe inflammatory response. It aggravates neuronal degeneration, loss of dendritic spines, and behavioral deficits after transient global cerebral ischemia.

Bilateral Dysplastic Gangliocytoma with Concurrent Polyostotic Fibrous Dysplasia: A Case Report and Literature Review.

BACKGROUND: Dysplastic gangliocytoma is a sporadic cerebellar benign tumor with the characteristics of hamartoma and true tumor, also known as Lhermitte-Duclos disease (LDD). Bone fibrous dysplasia (FD) is a slowly progressive self-limited benign bone tissue disease. Cowden syndrome, an autosomal dominant genetic disorder caused by germline mutations in the PTEN gene, is considered to be closely related to dysplastic gangliocytoma. McCune-Albright syndrome is a disease characterized by café-au-lait skin macules, polyostotic FD, and precocious puberty. The etiologic mechanism of both conditions is not yet clear. We report a rare case of bilateral dysplastic gangliocytoma with concurrent polyostotic FD. CASE DESCRIPTION: We describe a 16-year-old boy with both LDD and FD. He presented for medical examination with headache and poor eyesight. Magnetic resonance imaging revealed proliferation of the skull and abnormal signals in the cerebellum, and supratentorial hydrocephalus. Subtotal resection of the cerebellar tumor was performed, and the diagnosis of LDD and FD was confirmed by histopathology. No other abnormal changes were found in systemic medical examination and no PTEN gene mutation was found in the genetic analysis; therefore, the diagnoses of Cowden syndrome and McCune-Albright syndrome were excluded. CONCLUSIONS: LDD and FD are 2 rare diseases, and the simultaneous occurrence of the 2 conditions has not been reported before, to our knowledge. Our report challenges the etiology of the 2 diseases and the relationship between them, hoping to provide a reference for the study of the 2 diseases.

HDAC4 gene silencing alleviates epilepsy by inhibition of GABA in a rat model.

OBJECTIVES: Despite the availability of effective antiepileptic drugs, epileptic patients still suffer from intractable seizures and adverse events. Better control of both seizures and fewer side effects is needed in order to enhance the patient's quality of life. We performed the present study with an attempt to explore the effect that HDAC4 gene silencing would have on epilepsy simulated by model rats. Furthermore, the study made additional analysis on the relativity of the HDAC4 gene in regard to its relationship with the gamma-aminobutyric acid (GABA) signaling pathway. MATERIALS AND METHODS: Tremor rats were prepared in order to establish the epilepsy model. The rats would go on to be treated with si-HDAC4 in order to identify roles of the HDAC4 in levels of GABAARα1, GABAARα4, GAD65, GAT-1, and GAT-3. Finally, both electroencephalogram behavior and cognitive function of the rats following the treatment of si-HDAC4 were observed. RESULTS: Levels of the GABAARα1 and GABAARα4 showed an evident increase, while GAD65, GAT-1, and GAT-3 displayed a decline in the epilepsy rats treated with the aforementioned si-HDAC4 when compared with the epilepsy rats. After injection of si-HDAC4, the epilepsy rats presented with a reduction in seizure degree, latency and duration of seizure, amount of scattered epileptic waves, and occurrence of epilepsy, with an improvement in their cognitive function. CONCLUSION: The study highlighted the role that HDAC4 gene silencing played in easing the cases of epilepsy found in the model rats. This was shown to have occurred through the upregulation of both GABAARα1 and GABAARα4 levels, as well as in the downregulation of GAD65, GAT-1, and GAT-3 levels. The evidence provided shows that the HDAC4 gene is likely to present as a new objective in further experimentation in the treatment of epilepsy.

Traumatic bifrontoparietal extradural hematomas with detachment of superior sagittal sinus: a case report and review of the literature.

A 45-year-old man suffered bifrontoparietal extradural hematoma resulting from head injury, which cause superior sagittal sinus detachment from its subperiosteal loggia. We present the patient who was treated by early surgical evacuation of the hematoma with an excellent outcome and we also perform a review of the current literature.

Multiple myeloma with pathologically proven skull plasmacytoma after a mild head injury: Case report.

RATIONALE: MM is a malignant tumor originating from the plasma cells of the bone marrow. Central nervous system myelomatosis is very rare and may be a complication of MM. PATIENT CONCERNS: A 60-year-old man presented with a slowly growing soft mass at his right frontal scalp after a mild head injury 6 months ago. DIAGNOSES: Neuroradiological examinations revealed a solid intracranial-extracranial mass with an osteolytic lesion in the skull. Histopathological examination showed skull plasmacytoma, and postoperative examinations revealed multiple myeloma. INTERVENTIONS: The tumor was completely removed and the skull defect repaired with the titanium mesh. Then, chemotherapy was initiated after surgery with bortezomib and dexamethasone. OUTCOMES: The patient received eight chemotherapies within one year after surgery. LESSONS: Despite a history of head injury, a differential diagnosis should be kept in mind during the diagnosis of solid intracranial-extracranial masses, especially in the presence of osteolytic skull at the lesioned site.

Exogenous Neural Stem Cells Transplantation as a Potential Therapy for Photothrombotic Ischemia Stroke in Kunming Mice Model.

Stroke is considered as the second leading cause of death worldwide. The survivors of stroke experience different levels of impairment in brain function resulting in debilitating disabilities. Current therapies for stroke are primarily palliative and may be effective in only a small population of stroke patients. In this study, we explore the transplantation of exogenous neural stem cells (NSCs) as the potential therapy for the photothrombotic ischemia stroke in a Kunming mice model. After stroke, mice receiving NSC transplantation demonstrated a better recovery of brain function during the neurobehavioral tests. Histology analysis of the brain samples from NSC transplanted mice demonstrated a reduction of brain damage caused by stroke. Moreover, immunofluorescence assay for biomarkers in brain sections confirmed that transplanted NSCs indeed differentiated to neurons and astrocytes, consistent with the improved brain function after stroke. Taken together, our data suggested that exogenous NSC transplantation could be a promising therapy for stroke.

Neural stem cell transplantation promotes behavioral recovery in a photothrombosis stroke model.

Stem cell-based therapy provides a promising approach for treat stroke. Neural stem cells isolated from mice hippocampus possessing the capacity of differentiate into neurons and astrocytes both in vitro and vivo. Here, we investigated the capability of neural stem cell transplantation in photothrombosis stroke model. Nissl staining revealed that the cortical infarct significantly decreased by 16.32% (Vehicle: 27.93le: an mm(3), n=6, NSC: 23.37le: ai mm(3), n=6, P<0.05) in the NSC group compared with the vehicle. More over transplantation of neural stem cells significantly (P<0.01) improved neurological performance compared with vehicle. These results indicate that transplantation of neural stem cell is an effective therapy in ischemic stroke.