Functional alterations of the brain default mode network and somatosensory system in trigeminal neuralgia.

Mapping the localization of the functional brain regions in trigeminal neuralgia (TN) patients is still lacking. The study aimed to explore the functional brain alterations and influencing factors in TN patients using functional brain imaging techniques. All participants underwent functional brain imaging to collect resting-state brain activity. The significant differences in regional homogeneity (ReHo) and amplitude of low frequency (ALFF) between the TN and control groups were calculated. After familywise error (FWE) correction, the differential brain regions in ReHo values between the two groups were mainly located in bilateral middle frontal gyrus, bilateral inferior cerebellum, right superior orbital frontal gyrus, right postcentral gyrus, left inferior temporal gyrus, left middle temporal gyrus, and left gyrus rectus. The differential brain regions in ALFF values between the two groups were mainly located in the left triangular inferior frontal gyrus, left supplementary motor area, right supramarginal gyrus, and right middle frontal gyrus. With the functional impairment of the central pain area, the active areas controlling memory and emotion also change during the progression of TN. There may be different central mechanisms in TN patients of different sexes, affected sides, and degrees of nerve damage. The exact central mechanisms remain to be elucidated.

PSMC2 promotes glioma progression by regulating immune microenvironment and PI3K/AKT/mTOR pathway.

BACKGROUND: Glioma, the most frequent and malignant central nervous system (CNS) cancer, has a bad outcome. Proteasome 26S subunit ATPase 2 (PSMC2) is an essential part of the 26S proteasome and promotes the development of several tumors. However, the pathway and function of PSMC2 in glioma have not been unelucidated. METHODS: This study analyzed PSMC2 expression in glioma tissues and its predictive significance for patients. We examined the link between PSMC2 and DNA methylation, immune cell infiltration, tumor immune cycle, immune cell homeostasis, and immune checkpoints. Subsequently, immunohistochemistry and in vitro trials were employed to validate the expression, prognostic potential, and function of PSMC2 in glioma. The mechanisms of PSMC2 in glioma were further explored. RESULTS: Our study revealed that PSMC2 expression increased in glioma tissues contrasted with healthy tissues, and patients with high PSMC2 glioma exhibited poor overall survival (OS) compared to the low-PSMC2 group. Immune profile analysis revealed that PSMC2 was positively related to immunosuppressive cell infiltration and immune checkpoints and adversely related to the cancer immune cycle and immune cell homeostasis. In cell-based investigations, the inhibition of PSMC2 was found to effectively suppress the aggressiveness and proliferation of glioma cell lines while also enhancing cell cycle arrest and promoting cell death. Gene Set Enrichment Analysis (GSEA), Gene Set Variation Analysis (GSVA), and in vitro experiments showed that PSMC2 promoted glioma development through the PI3K/AKT/mTOR pathway. CONCLUSIONS: PSMC2 was upregulated in glioma and promoted cancer progression by modulating the tumor immune microenvironment, cancer cell biological behavior, immune cell homeostasis, and the PI3K/AKT/mTOR pathway, providing a new option to treat glioma.

Exosomes derived from human umbilical cord mesenchymal stem cells decrease neuroinflammation and facilitate the restoration of nerve function in rats suffering from intracerebral hemorrhage.

Exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSC-ex) have become a hopeful substitute for whole-cell therapy due to their minimal immunogenicity and tumorigenicity. The present study aimed to investigate the hypothesis that hUCMSC-ex can alleviate excessive inflammation resulting from intracerebral hemorrhage (ICH) and facilitate the rehabilitation of the nervous system in rats. In vivo, hemorrhagic stroke was induced by injecting collagenase IV into the striatum of rats using stereotactic techniques. hUCMSC-ex were injected via the tail vein at 6 h after ICH model establishment at a dosage of 200 µg. In vitro, astrocytes were pretreated with hUCMSC-ex and then stimulated with hemin (20 µmol/mL) to establish an ICH cell model. The expression of TLR4/NF-κB signaling pathway proteins and inflammatory factors, including TNF-α, IL-1ß, and IL-10, was assessed both in vivo and in vitro to investigate the impact of hUCMSC-ex on inflammation. The neurological function of the ICH rats was evaluated using the corner turn test, forelimb placement test, Longa score, and Bederson score on the 1st, 3rd, and 5th day. Additionally, RT-PCR was employed to examine the mRNA expression of TLR4 following hUCMSC-ex treatment. The findings demonstrated that hUCMSC-ex downregulated the protein expression of TLR4, NF-κB/P65, and p-P65, reduced the levels of pro-inflammatory cytokines TNF-α and IL-1ß, and increased the expression of the anti-inflammatory cytokine IL-10. Ultimately, the administration of hUCMSC-ex improved the behavioral performance of the ICH rats. However, the results of PT-PCR indicated that hUCMSC-ex did not affect the expression of TLR4 mRNA induced by ICH, suggesting that hUCMSCs-ex may inhibit TLR4 translation rather than transcription, thereby suppressing the TLR4/NF-κB signaling pathway. We can conclude that hUCMSC-ex mitigates hyperinflammation following ICH by inhibiting the TLR4/NF-κB signaling pathway. This study provides preclinical evidence for the potential future application of hUCMSC-ex in the treatment of cerebral injury.

Exploring the therapeutic potential of cannabidiol for sleep deprivation-induced hyperalgesia.

Hyperalgesia resulting from sleep deprivation (SD) poses a significant a global public health challenge with limited treatment options. The nucleus accumbens (NAc) plays a crucial role in the modulation of pain and sleep, with its activity regulated by two distinct types of medium spiny neurons (MSNs) expressing dopamine 1 or dopamine 2 (D1-or D2) receptors (referred to as D1-MSNs and D2-MSNs, respectively). However, the specific involvement of the NAc in SD-induced hyperalgesia remains uncertain. Cannabidiol (CBD), a nonpsychoactive phytocannabinoid, has demonstrated analgesic effects in clinical and preclinical studies. Nevertheless, its potency in addressing this particular issue remains to be determined. Here, we report that SD induced a pronounced pronociceptive effect attributed to the heightened intrinsic excitability of D2-MSNs within the NAc in Male C57BL/6N mice. CBD (30 mg/kg, i.p.) exhibited an anti-hyperalgesic effect. CBD significantly improved the thresholds for thermal and mechanical pain and increased wakefulness by reducing delta power. Additionally, CBD inhibited the intrinsic excitability of D2-MSNs both in vitro and in vivo. Bilateral microinjection of the selective D2 receptor antagonist raclopride into the NAc partially reversed the antinociceptive effect of CBD. Thus, these findings strongly suggested that SD activates NAc D2-MSNs, contributing heightened to pain sensitivity. CBD exhibits antinociceptive effects by activating D2R, thereby inhibiting the excitability of D2-MSNs and promoting wakefulness under SD conditions.

Causal Relationship between Parkinson's Disease with Heart and Vascular Disease: A Two-Sample Mendelian Randomization Study.

INTRODUCTION: The aim of this study was to investigate the causal relationship between Parkinson's disease (PD) and myocardial infarction (MI), atrial fibrillation and flutter (AF), and venous thromboembolism (VTE) by Mendelian randomization (MR) analysis. METHODS: By using data from publicly available genome-wide association studies from databases, single nucleotide polymorphisms were screened as instrumental variables, and the MR analysis was finished by inverse-variance weighted (IVW), MR-egger, weighted median methods. RESULTS: The primary IVW method showed a negative association between genetically predicted PD and risk of MI (OR = 0.9989; 95% CI: 0.9980-0.9998; p = 0.02). However, PD was not significantly associated with AF or VTE. CONCLUSION: This study suggests a negative association between PD with MI, which implies that PD has a protective effect on MI.

Integrating Network Pharmacology and Experimental Verification to Explore the Pharmacological Mechanisms of Radix Paeoniae Rubra Against Glioma.

Glioma has a high mortality and can hardly be completely cured. Radix Paeoniae Rubra (RPR) is a prevalent component in traditional Chinese medicine used for tumor treatments. We explored the mechanism of RPR in treating glioma using network pharmacology and experiments. A network pharmacology approach was used to screen active ingredients, targets of RPR and glioma. We then constructed a herb-active ingredient-target-pathway network and conducted protein-protein interaction (PPI) network analysis, as well as Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Molecular docking was also performed. Using CCK-8, colony formation, and xenograft experiments, we evaluated the effect of RPR on glioma. The involved pathway and proteins were identified by Western blot. From public databases, we identified nine active RPR ingredients and 40 overlapping targets among 109 RPR targets and 1360 glioma-associated targets. The PPI analysis revealed ten targets, such as AKT1, TP53, and VEGFA, which were identified as hub genes. The results from GO and KEGG analysis highlighted the involvement of the PI3K/AKT pathway. A herb-active ingredient-target-pathway network was constructed. By docking molecular structures, six suitable conformations have been identified. The RPR extract demonstrated anti-tumor properties by inhibiting glioma cell proliferation in vitro and in vivo, likely achieved by suppressing the phosphorylation of the PI3K/AKT signaling pathway. RPR concurrently downregulated the phosphorylation level of AKT1 and the protein expression level of VEGFA, while upregulating the expression of P53 in the U251 cell line. Utilizing network pharmacology and molecular docking, our study not only predicted the impact of RPR on glioma but also delineated the herb-active ingredient-target-pathway network. Experimentally, we confirmed that RPR may exert its anti-tumor properties by inhibiting the phosphorylation of the PI3K/AKT pathway, including AKT1, and by regulating the expression levels of VEGFA and P53.

Exosomes derived from human umbilical cord mesenchymal stem cells pretreated by monosialoteterahexosyl ganglioside alleviate intracerebral hemorrhage by down-regulating autophagy.

PURPOSE: Intracerebral hemorrhage (ICH) results in substantial morbidity, mortality, and disability. Depleting neural cells in advanced stages of ICH poses a significant challenge to recovery. The objective of our research is to investigate the potential advantages and underlying mechanism of exosomes obtained from human umbilical cord mesenchymal stem cells (hUMSCs) pretreated with monosialoteterahexosyl ganglioside (GM1) in the prevention of secondary brain injury (SBI) resulting from ICH. PATIENTS AND METHODS: In vitro, hUMSCs were cultured and induced to differentiate into neuron-like cells after they were pretreated with 150 µg/mL GM1. The exosomes extracted from the culture medium following a 6-h pretreatment with 150 µg/mL GM1 were used as the treatment group. Striatal infusion of collagenase and hemoglobin (Hemin) was used to establish in vivo and in vitro models of ICH. RESULTS: After being exposed to 150 µg/mL GM1 for 6 h, specific cells displayed typical neuron-like cell morphology and expressed neuron-specific enolase (NSE). The rate of differentiation into neuron-like cells was up to (15.9 ± 5.8) %, and the synthesis of N-Acetylgalactosaminyltransferase (GalNAcT), which is upstream of GM1, was detected by Western blot. This study presented an increase in the synthesis of GalNAcT. Compared with the ICH group, apoptosis in the treatment group was remarkably reduced, as detected by TUNEL, and mitochondrial membrane potential was restored by JC-1. Additionally, Western blot revealed the restoration of up-regulated autophagy markers Beclin-1 and LC3 and the down-regulation of autophagy marker p62 after ICH. CONCLUSION: These findings suggest that GM1 is an effective agent to induce the differentiation of hUMSCs into neuron-like cells. GM1 can potentially increase GalNAcT production through "positive feedback", which generates more GM1 and promotes the differentiation of hUMSCs. After pretreatment with GM1, exosomes derived from hUMSCs (hUMSCs-Exos) demonstrate a neuroprotective effect by inhibiting autophagy in the ICH model. This study reveals the potential mechanism by which GM1 induces differentiation of hUMSCs into neuron-like cells and confirms the therapeutic effect of hUMSCs-Exos pretreated by GM1 (GM1-Exos) on an ICH model, potentially offering a new direction for stem cell therapy in ICH.

An association between ATP7B expression and human cancer prognosis and immunotherapy: a pan-cancer perspective.

BACKGROUND: ATP7B is a copper-transporting protein that contributes to the chemo-resistance of human cancer cells. It remains unclear what the molecular mechanisms behind ATP7B are in cancer, as well as its role in human pan-cancer studies. METHODS: Our study evaluated the differential expression of ATP7B in cancer and paracancerous tissues based on RNA sequencing data from the GTEx and TCGA. Kaplan-Meier and Cox proportional hazards regressions were used to estimate prognostic factors associated with ATP7B.The correlations between the expression of ATP7B and immune cell infiltration, tumor mutation burden, microsatellite instability and immune checkpoint molecules were analyzed. Co-expression networks and mutations in ATP7B were analyzed using the web tools. An analysis of ATP7B expression difference on drug sensitivity on tumor cells was performed using the CTRP, GDSC and CMap database. RESULTS: ATP7B expression differed significantly between cancerous and paracancerous tissues. The abnormal expression of ATP7B was linked to prognosis in LGG and KIRC. Infiltration of immune cells, tumor mutation burden, microsatellite instability and immunomodulators had all been linked to certain types of cancer. Cancer cells exhibited a correlation between ATP7B expression and drug sensitivity. CONCLUSION: ATP7B might be an immunotherapeutic and prognostic biomarker based on its involvement in cancer occurrence and development.

Influence of ferroptosis indicators on the stability of atherosclerotic plaque.

Ferroptosis is a new form of cell death that is unique and closely related to iron concentration, and reactive oxygen species (ROS) production. We investigated the indicators of ferroptosis between vulnerable plaque and stable plaque in atherosclerotic. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to detect the expression of the ferroptosis-related genes and proteins and extracellular matrix stability-related genes and proteins (FN, CoL-1). Superoxide dismutase (SOD) activities, glutathione peroxidase (GSH) and malondialdehyde (MDA) were detected by ELISA. The commercially available kit was used to detect Fe2+ concentration in tissue. DCFH-DA fluorescent probe was used to detect the ROS levels. H&E stain, Masson trichrome stain, and Oil Red O stain were used to detect pathological states in vulnerable plaque and stable plaque. Tissue localization and positive rate of GPX4, SLC7A11, COX-2, FN, and COL-1 were evaluated by immunohistochemistry. The results showed a significant increase in the expression of COX2 and a significant decrease in the expression of GPX4 and SLC7A11 in genes related to ferroptosis in vulnerable plaque compared with stable plaque. Pathologic results showed vulnerable plaque with higher levels of inflammatory cell infiltration, more diffuse collagen fibers, and larger particles of lipid droplets. Concentrations of the antioxidant metabolites SOD and GSH were significantly reduced and concentrations of the oxidative metabolites MDA and Fe2+ were significantly increased in vulnerable plaque compared with stable plaque. The expression of FN and CoL-1 was significantly reduced in genes related to extracellular matrix stability in vulnerable plaque. Taken together, these findings indicate that the degree of ferroptosis in vulnerable plaque is higher than that in stable plaque, suggesting that changes in indicators of ferroptosis may affect carotid atherosclerotic plaque stability, target spot in the ferroptosis signaling pathway may provide further theoretical basis for the clinical treatment of carotid atherosclerosis.

STEAP3 is a prognostic biomarker that promotes glioma progression by regulating immune microenvironment and PI3K-AKT pathway.

BACKGROUND: STEAP3 is a metal reductase located on the plasma membrane close to the nucleus and vesicles. Despite numerous studies indicating the involvement of STEAP3 in tumor advancement, the prognostic value of STEAP3 in glioma and the related mechanisms have not been fully investigated. METHODS: Initially, we examined the correlation between STEAP3 expression and the survival rate in various glioma datasets. To assess the prognostic capability of STEAP3 for one-year, three-year, and five-year survival, we created receiver operating characteristic (ROC) curves and nomograms. Additionally, an investigation was carried out to examine the mechanisms that contribute to the involvement of STEAP3 in gliomas, including immune and enrichment analysis. To confirm the expression of STEAP3 in LGG and GBM, tumor tissue samples were gathered, and cell experiments were conducted to explore the impacts of STEAP3. The function of STEAP3 in the tumor immune microenvironment was assessed using the M2 macrophage infiltration assay. RESULTS: We found that STEAP3 expressed differently in group with different age, tumor grade IDH and 1p19q status. The analysis of survival illustrated that glioma patients with high level of STEAP3 experienced shorter survival durations, especially for IDH-mutant astrocytoma. Cox analysis demonstrated that STEAP3 had potential to act as an independent prognostic factor for glioma. The predictive value of STEAP3 for glioma prognosis was demonstrated by ROC curves and nomogram. Immune analysis showed that STEAP3 may lead to a suppressive immune microenvironment through the control of immunosuppressive cell infiltration and Cancer-Immunity Cycle. Combining enrichment analysis and cell experiments, we discovered that STEAP3 can promote glioma progression through regulation of PI3K-AKT pathway and M2 macrophage infiltration. CONCLUSION: STEAP3 plays significant roles in the advancement of glioma by regulating immune microenvironment and PI3K-AKT pathway. It has the potential to serve as a therapy target for glioma.

Arylsulfatase D is a prognostic biomarker that promotes glioma cells progression through JAK2/STAT3 pathway and M2 macrophage infiltration.

Background: Arylsulfatase D (ARSD) belongs to the sulfatase family and plays a crucial role in maintaining the proper structure of bone and cartilage matrix. Although several researches have revealed the functions of ARSD in tumor progression, the prognostic value of ARSD in glioma and the related mechanisms have not been fully investigated. Methods: We performed a pan-cancer analysis of ARSD, and investigated the relationship between expression of ARSD and overall survival (OS) in multiple glioma datasets. ROC curves and nomograms were created to investigate the predictive capacity of ARSD. Immune and analysis were conducted to investigate the mechanisms underlying the roles of ARSD in glioma. Glioma tissue samples were collected to verify the expression of ARSD in glioma, while the functions of ARSD were explored using cell experiment. M2 macrophage infiltration assay was used to determine the relation between ARSD and tumor immune microenvironment. Results: Survival analysis indicated that individuals with high ARSD expression in glioma had a shorter survival time. Cox analysis showed that ARSD had a good ability for predicting prognosis in glioma. Immune analysis suggested that ARSD could regulate immune cell infiltration and affect the Cancer-Immunity Cycle to create an immunosuppressive environment. Combined with cell experiment and bioinformatic analysis, we found that ARSD can promote glioma progression through regulation of JAK2/STAT3 pathway and M2 macrophage infiltration. Conclusion: Our study found that ARSD can promote glioma development by regulating immune microenvironment and JAK2/STAT3 signaling pathway, which provided a potential therapy target for glioma treatment.

RPA3 promotes the proliferation, migration, and invasion of gliomas by activating the PI3K-AKT-mTOR pathway.

Gliomas are the most common primary malignant brain tumors, with a poor prognosis and high mortality, and there is no effective treatment regimen. A number of studies have shown that replication protein A3 (RPA3) can regulate DNA replication and that the abnormal expression of RPA3 can lead to genomic instability and induce the development of a variety of tumors. However, the relationship between RPA3 and gliomas and the mechanism of action remains unclear. In this study, we investigated the role of RPA3 in the development of gliomas and the possible mechanism. The Chinese Glioma Genome Atlas (CGGA), The Cancer Genome Atlas (TCGA), and the Gene Expression Omnibus (GEO) databases were used to analyze the expression level of RPA3 and its correlation with clinical prognosis. A univariate Cox regression model was established to predict the prognosis of glioma patients and analyze the correlation between RPA3 and immune cell infiltration and activation. Immunohistochemistry, RT-PCR, and Western blot (WB) were used to detect the expression of RPA3 in glioma specimens. After knocking down and overexpressing RPA3 with plasmids, effects on glioma cell proliferation, migration and invasive capacity were investigated in vitro. The possible molecular mechanisms were analyzed using WB. Results showed that the expression of RPA3 in glioma tissue and cells was significantly higher than that in normal glial cells and was positively correlated with the poor prognosis of patients with gliomas. The overexpression of RPA3 expression activated the phosphatidylinositol 3-kinase (PI3K)-AKT-mammalian target of the rapamycin (mTOR) pathway by promoting the phosphorylation of PI3K, AKT, and mTOR, thereby promoting the proliferation, migration and invasion of glioma cells. In conclusion, RPA3 is highly expressed in gliomas and promotes the proliferation, migration and invasion of gliomas by activating the PI3K-AKT-mTOR pathway. Therefore, RPA3 may be a prognostic biomarker and therapeutic target for gliomas.

Prognostic factors and Doxorubicin involved in malignant progression of meningioma.

Meningioma was the most primary intracranial tumor, but the molecular characteristics and the treatment of malignant meningioma were still unclear. Nine malignant progression-related genes based prognostic signatures were identified by transcriptome analysis between benign meningioma and malignant meningioma. The external dataset GEO136661 and quantitative Real-time Polymerase Chain Reaction were used to verify the prognostic factors. has-miR-3605-5p, hsa-miR-664b-5p, PNRC2, BTBD8, EXTL2, SLFN13, DGKD, NSD2, and BVES were closed with malignant progression. Moreover, Doxorubicin was identified by Connectivity Map website with the differential malignant progression-related genes. CCK-8 assay, Edu assay, wound healing assay, and trans-well experiment were used to reveal that Doxorubicin could inhibit proliferation, migration and invasion of IOMM-Lee Cells.

Atorvastatin prevents endoplasmic reticulum stress-mediated apoptosis via the Nrf2/HO-1 signaling pathway in TBI mice.

BACKGROUND: Our present study evaluated the neuroprotection effects of atorvastatin by inhibiting TBI-induced ER stress, as well as the potential role of the Nrf2/HO-1 pathway in experimental TBI. METHODS: First, the mice were divided into four groups:sham, TBI, TBI+Vehicle and TBI+atorvastatin groups. The mice received atorvastatin (10 mg/kg/day) through intragastric gavage once a day for 3 days before TBI. In addition, Nrf2 WT and Nrf2 knockout mice were randomly divided into four groups: Nrf2+/+ TBI, Nrf2+/+ TBI+atorvastatin, Nrf2-/- TBI, and Nrf2-/- TBI+atorvastatin groups. Several neurobehavioral parameters were assessed post-TBI using mNSS, brain edema and the rotarod test, and the brain was isolated for molecular and biochemical analysis conducted through TUNEL staining and western blotting. . RESULTS: The results showed that atorvastatin treatment significantly improved neurological deficits, alleviated brain edema, and apoptosis caused by TBI. Western blotting analysis showed that atorvastatin significantly suppressed ER stress and its related apoptotic pathway after TBI, which may be associated with the further activation of the Nrf2/HO-1 pathway. However, compared with the Nrf2+/+ TBI+Vehicle group, Nrf2 deficiency further aggravated neurological deficits and promoted ER stress-mediated apoptosis induced by TBI. Interestingly, atorvastatin failed to improve neurological deficits but reversed apoptosis, and the loss of the beneficial properties of anti-ER stress in the Nrf2-/- TBI mice. . CONCLUSIONS: The results indicated that atorvastatin improves the neurologic functions and protects the brain from injury in the Nrf2+/+ TBI mice, primarily by counteracting ER stress-mediated apoptosis, which may be achieved through the activation of the Nrf2/HO-1 signaling pathway.

A combination of umbilical cord mesenchymal stem cells and monosialotetrahexosy 1 ganglioside alleviates neuroinflammation in traumatic brain injury.

Neuro-inflammation and activated microglia play important roles in neuron damage in the traumatic brain injury (TBI). In this study, we determined the effect of neural network reconstruction after human umbilical cord mesenchymal stem cells (UMSCs) combined with monosialotetrahexosy 1 ganglioside (GM1) transplantation and the effect on the neuro-inflammation and polarization of microglia in a rat model of TBI, which was established in male rats using a fluid percussion brain injury device. Rats survived until day 7 after TBI were randomly treated with normal control (NC), saline (NS), GM1, UMSCs, and GM1 plus UMSCs. Modified neurological severity score (mNSS) was assessed on days 7 and 14, and the brain tissue of the injured region was collected. Immunofluorescence, RT-PCR, and western blot analysis found that inhibitory neuro-inflammatory cytokines TGF-ß and CD163 protein expression levels in injured brain tissues were significantly increased in rats treated with GM1 + UMSCs, GM1, or UMSCs and were up-regulated compared to saline-treated rats. Neuro-inflammatory cytokines IL-6, COX-2 and iNOS protein expressions were down-regulated compared to rats treated with saline. The protein expression levels of NE, NF-200, MAP-2 and ß-tubulin III were increased in the injured brain tissues from rats treated with GM1 + UMSCs, or GM1 and UMSCs alone compared to those in the rats treated with NS. The protein expression levels in rats treated with GM1 plus UMSCs were most significant on day 7 following UMSC transplantation. The rats treated with GM1 plus UMSCs had the lowest mNSS compared with that in the other groups. These data suggest that UMSCs and GM1 promote neural network reconstruction and reduce the neuro-inflammation and neurodegeneration through coordinating injury local immune inflammatory microenvironment to promote the recovery of neurological functions in the TBI.

Jujuboside B inhibits febrile seizure by modulating AMPA receptor activity.

ETHNOPHARMACOLOGICAL RELEVANCE: Febrile seizure is a common neurologic disorder with limited treatment occurring in infants and children under the age of five. Jujuboside B (JuB) is a main bioactive saponin component isolated from the Chinese anti-insomnia herbal medicine Ziziphi Spinosae Semen (ZSS), seed of Ziziphus jujuba Mill, which has been proved to exhibit neuroprotective effects recently. AIM OF THE STUDY: In this study, we aimed at elucidating the effect of JuB on suppressing febrile seizure and the potential mechanisms. METHODS: Electroencephalogram (EEG) recording was used to monitor the severity of febrile seizures. The JuB in the brain was identified by mass spectrometry. Neuronal excitability was investigated using patch clamp. RESULTS: JuB (30 mg/kg) significantly prolonged seizure latency and reduced the severity in hyperthermia-induced seizures model mice. Hippocampal neuronal excitability was significantly decreased by JuB. And JuB significantly reduced the excitatory synaptic transmission mediated by α-amino-3-hydroxy-5-methyl-4-iso-xazolepropionic acid receptor (AMPAR), including evoked excitatory postsynaptic currents (eEPSCs), and miniature EPSCs (mEPSCs) in hippocampal neurons. Furthermore, JuB also significantly inhibited recombinant GluA1 and GluA2 mediated AMPA current in HEK293 cell and decreased the upregulation of [Ca2+]i induced by AMPA in primary cultured cortex neurons. CONCLUSIONS: JuB suppressed the excitability of hippocampal neurons by inhibiting the activity of AMPAR and reducing the intracellular free calcium, thereby relieving febrile seizures.

Intracranial penetrating injury by clothes fork in an infant: case report and review of the literature.

Nonmissile intracranial penetrating injury (IPI) in pediatric population is rare. Here, we report the exceedingly rare case of a 5-month-old infant sustained by a metallic clothes fork penetrating into his left forehead. The little baby was identified to carry a traumatic hemorrhagic shock, and a multidisciplinary team (MDT) was immediately established response for whole-course evaluation and decision-making. Computed tomography revealed that the clothes fork had impaled into the left frontal bone and brain parenchyma with about 3.2 cm inside the cranial vault. The infant underwent emergency surgery, and the clothes fork was removed jointly by MDT members under general anesthesia in the retrograde direction. His recovery was uneventful and was followed up 2 years without growth and developmental abnormality. As an extremely rare entity with distinct age-related characteristics, a MDT approach is a best choice and effective strategy to manage infant nonmissile IPI, including preoperative management, surgical treatment, and even following rehabilitation.

A novel necroptosis-related gene signature for predict prognosis of glioma based on single-cell and bulk RNA sequencing.

Background: Glioma is the most fatal neoplasm among the primary intracranial cancers. Necroptosis, a form of programmed cell death, is correlated with tumor progression and immune response. But, the role of necroptosis-related genes (NRGs) in glioma has not been well-uncovered. Methods: Single-cell and bulk RNA sequencing data, obtained from publicly accessed databases, were used to establish a necroptosis-related gene signature for predicting the prognosis of glioma patients. Multiple bioinformatics algorithms were conducted to evaluate the efficacy of the signature. The relative mRNA level of each signature gene was validated by quantitative real-time reverse transcription PCR (qRT-PCR) in glioma cell lines compared to human astrocytes. Results: In this predicted prognosis model, patients with a high risk score showed a shorter overall survival, which was verified in the testing cohorts. The signature risk score was positively related with immune cell infiltration and some immune check points, such as CD276 (B7-H3), CD152 (CTLA-4), CD223 (LAG-3), and CD274 (PD-L1). Single-cell RNA sequencing analysis confirmed that the glioma microenvironment consists of various immune cells with different markers. The eight NRGs of the signature were detected to be expressed in several immune cells. QRT-PCR results verified that all the eight signature genes were differentially expressed between human astrocytes and glioma cells. Conclusion: The eight NRGs correlate with the immune microenvironment of glioma according to our bioinformatics analysis. This necroptosis-related gene signature may evaluate the precise methodology of predicting prognosis of glioma and provide a novel thought in glioma investigation.

Development and validation of AKI prediction model in postoperative critically ill patients: a multicenter cohort study.

BACKGROUND: Acute kidney injury (AKI) is a common complication, especially among postoperative critically ill patients. Early identification of AKI is essential for reducing mortality. METHODS: Multicenter data were used to develop an AKI prediction model for critically ill postoperative patients. A total of 1731 patients admitted to intensive care units (ICUs) were divided into a development set (n=1196) and a validation set (n=535) according to the principle of 7:3 randomization. Multivariate logistic regression analysis was performed on the predictors identified by univariate analysis, and a nomogram was created based on the predictors. The area under the receiver operating characteristic curve (AUROC) was used to assess the discrimination of the model. Calibration curves were generated, and the Hosmer-Lemeshow (HL) goodness of fit test was carried out. Decision curve analysis (DCA) was performed to assess the net clinical benefit. RESULTS: The final model included 7 predictors: age, emergency surgery, abnormal basal creatinine level (BCr), chronic kidney disease (CKD), use of nephrotoxic drugs, diuretic use, and the Sequential Organ Failure Assessment (SOFA) score. A nomogram was drawn based on the predictors. The AUROC of the model in the development set was 0.725 (95% confidence interval (CI): 0.696-0.754). In the validation set, the AUROC was 0.706 (95% CI: 0.656-0.744). The model showed good discrimination (>70%) in both sets, and the HL test indicated that the model fit was good (P>0.05). DCA showed that our model is clinically useful. CONCLUSION: The novel prediction model can be used to identify high-risk postoperative patients and provide a scientific and effective basis for clinicians to identify AKI early with a nomogram.

CASP6 predicts poor prognosis in glioma and correlates with tumor immune microenvironment.

Background: Glioma is an aggressive tumor of the central nervous system. Caspase-6 (CASP6) plays a crucial role in cell pyroptosis and is a central protein involved in many cellular signaling pathways. However, the association between CASP6 and prognosis of glioma patients remains unclear. Methods: Four bioinformatic databases were analyzed to identify differentially expressed genes (DEGs) between glioma and healthy tissues. Eighty-one protein-coding pyroptosis-related genes (PRGs) were obtained from the GeneCards database. The pyroptosis-related DEGs (PRDEGs) were extracted from each dataset, and CASP6 was found to be aberrantly expressed in glioma. We then investigated the biological functions of CASP6 and the relationship between CASP6 expression and the tumor microenvironment and immunocyte infiltration. The half maximal inhibitory concentration of temozolomide and the response to immune checkpoint blockade in the high- and low-CASP6 expression groups were estimated using relevant bioinformatic algorithms. Quantitative real-time reverse transcription PCR and western blotting were carried out to confirm the different expression levels of CASP6 between human astrocytes and glioma cell lines (U251 and T98G). We determined the role of CASP6 in the tumorigenesis of glioma by knocking down CASP6 in U251 and T98G cell lines. Results: We found that CASP6 was overexpressed in glioma samples and in glioma cell lines. CASP6 expression in patients with glioma correlated negatively with overall survival. In addition, CASP6 expression correlated positively with the degree of glioma progression. Functional analysis indicated that CASP6 was primarily involved in the immune response and antigen processing and presentation. Patients with high CASP6 levels responded more favorably to temozolomide, while patients with low expression of CASP6 had a better response to immunotherapy. Finally, in vitro experiments showed that CASP6 knockdown inhibited glioma proliferation. Conclusions: The pyroptosis-related gene CASP6 might represent a sensitive prognostic marker for patients with glioma and might predict their response of immunotherapy and temozolomide therapy. Our results might lead to more precise immunotherapeutic strategies for patients with glioma.