Adenylate kinase 4 promotes neuronal energy metabolism and mitophagy in early cerebral ischemia via Parkin/PKM2 pathway.

Mitochondrial dysfunction is closely related to brain injury and neurological dysfunction in ischemic stroke. Adenylate kinase 4 (AK4) plays a critical role in energy metabolism and mitochondrial homeostasis. However, the underlying mechanisms remain unclear. In the present study, we demonstrated an important role of AK4 in mitochondrial dysfunction in the early cerebral ischemia. Early focal cerebral ischemia induced decrease of AK4 protein expression in ischemic hemispheric brain tissue in mice. Exposure of cultured primary neuron to oxygen-glucose deprivation (OGD) also induced AK4 downregulation. Overexpression of AK4 in neuron using adeno-associated virus (AAV-AK4) in mice promoted neuronal survival reflected by decreased infarction volume and TUNEL staining. AK4 overexpression inhibited mitochondrial decline and downregulation of energy metabolism-associated proteins (p-AMPK and ATP1A3) induced by MCAO. Moreover, AK4 knock-in using lentivirus carried AK4 vector (LV-AK4) induced energy metabolism shift from glycolysis to oxidation in neuron. Using transmission electron microscope and western blot, we revealed that AK4 overexpression promoted mitophagy and mitophagy-associated proteins expression PINK1 and Parkin after MCAO. Mass spectrometry and co-immunoprecipitation revealed an interaction between AK4 and PKM2. Mechanistically, AK4 indirectly decreased PKM2 expression via enhancing its ubiquitination by increasing the interaction between PKM2 and its ubiquitin E3 ligase Parkin, and inhibits Parkin downregulation. In conclusion, our data demonstrate that AK4/ Parkin /PKM axis prevents cerebral ischemia damage via regulation of neuronal energy metabolism model and mitophagy. AK4 was a new target for intervention of early ischemic neuron injury.

Protective Effect of Hop Ethyl Acetate Extract on Corticosterone-Induced PC12 and Improvement of Depression-like Behavior in Mice.

Depression is a common mental disorder. In recent years, more and more attention has been paid to depression and its etiology and pathogenesis. This review aims to explore the neuroprotective and antidepressant effects of hop components. By establishing an in vitro cell damage model using PC12 cells induced by corticosterone (CORT) and an in vivo depression model through the intracranial injection of lipopolysaccharide (LPS) in mice, hop ethyl acetate extract (HEA) was used to study the protective effect and mechanism of HEA on neuronal cells in vitro and the antidepression effect and mechanism in vivo. The results showed that HEA increased the survival and decreased the rate of lactate dehydrogenase (LDH) release, apoptosis, and the ROS and NO content of CORT-induced PC12 cells. HEA alleviated depressive-like behavior, neuroinflammation, reduction of norepinephrine, and dendritic spines induced by intracerebroventricular injection of LPS in mice and increases the expression levels of BDNF, SNAP 25, and TrkB proteins without any significant side effects or toxicity. Hops demonstrated significant comprehensive utilization value, and this work provided an experimental basis for the role of hops in the treatment of depression and provided a basis for the development of HEA for antidepressant drugs or dietary therapy products.

Development and external validation of a novel score for predicting postoperative 30­day mortality in tumor craniotomy patients: A cross­sectional diagnostic study.

The identification of patients with craniotomy at high risk for postoperative 30-day mortality may contribute to achieving targeted delivery of interventions. The present study aimed to develop a personalized nomogram and scoring system for predicting the risk of postoperative 30-day mortality in such patients. In this retrospective cross-sectional study, 18,642 patients with craniotomy were stratified into a training cohort (n=7,800; year of surgery, 2012-2013) and an external validation cohort (n=10,842; year of surgery, 2014-2015). The least absolute shrinkage and selection operator (LASSO) model was used to select the most important variables among the candidate variables. Furthermore, a stepwise logistic regression model was established to screen out the risk factors based on the predictors chosen by the LASSO model. The model and a nomogram were constructed. The area under the receiver operating characteristic (ROC) curve (AUC) and calibration plot analysis were used to assess the model's discrimination ability and accuracy. The associated risk factors were categorized according to clinical cutoff points to create a scoring model for postoperative 30-day mortality. The total score was divided into four risk categories: Extremely high, high, intermediate and low risk. The postoperative 30-day mortality rates were 2.43 and 2.58% in the training and validation cohort, respectively. A simple nomogram and scoring system were developed for predicting the risk of postoperative 30-day mortality according to the white blood cell count; hematocrit and blood urea nitrogen levels; age range; functional health status; and incidence of disseminated cancer cells. The ROC AUC of the nomogram was 0.795 (95% CI: 0.764 to 0.826) in the training cohort and it was 0.738 (95% CI: 0.7091 to 0.7674) in the validation cohort. The calibration demonstrated a perfect fit between the predicted 30-day mortality risk and the observed 30-day mortality risk. Low, intermediate, high and extremely high risk statuses for 30-day mortality were associated with total scores of (-1.5 to -1), (-0.5 to 0.5), (1 to 2) and (2.5 to 9), respectively. A personalized nomogram and scoring system for predicting postoperative 30-day mortality in adult patients who underwent craniotomy were developed and validated, and individuals at high risk of 30-day mortality were able to be identified.

Nuclear transport of phosphorylated LanCL2 promotes invadopodia formation and tumor progression of glioblastoma by activating STAT3/Cortactin signaling.

INTRODUCTION: Our previous study showed that the abscisic acid receptor lanthionine synthetase C-like 2 (LanCL2) is a significant prognostic factor for overall survival in young glioblastoma patients. However, the role of LanCL2 in glioblastoma remains unclear yet. OBJECTIVES: This study aims to investigate the role of LanCL2 in regulating in-vitro cell invasion and in-vivo tumor progression of glioblastoma and its underlying mechanism. METHODS: Tyrosine 198 or 295 residue of LanCL2 was mutated using site-directed mutagenesis to block its phosphorylation. The role of LanCL2 in glioblastoma was investigated using transwell or 3D invasion assay, matrix degradation assay and intracranial xenograft model. RESULTS: This study showed that nuclear transport of LanCL2 was enhanced by overexpression of LanCL2 or its ligand abscisic acid in glioblastoma cells. Knockdown of LanCL2 suppressed migration, invasion and invadopodia formation of glioblastoma cells, whereas overexpression of wild-type LanCL2 enhanced them. Blocking of Tyr295 residue phosphorylation of LanCL2 impeded its nuclear transport, retarded glioblastoma cell motility and invadopodia formation, and deceased the phosphorylation of Cortactin and STAT3. c-Met was identified as the upstream tyrosine kinase of Tyr295 residue of LanCL2, and inhibition of c-Met markedly suppressed the nuclear transport of LanCL2. Moreover, overexpression of wild-type LanCL2 significantly promoted orthotopic tumor growth of glioblastoma in vivo and led to poor survival of mice with median survival time of 33.5 days, whereas Tyr295 mutation rescued it with median survival time of 49 days. CONCLUSION: Our findings suggested that Tyr295 phosphorylation is crucial to the activation and nuclear transport of LanCL2, as well as invadopodia formation and tumor progression of glioblastoma, providing the evidence of a novel signaling axis c-Met/LanCL2/STAT3/Cortactin and the first observation of the importance of Tyr295 phosphorylation to LanCL2.

Diterpenoid honatisine overcomes temozolomide resistance in glioblastoma by inducing mitonuclear protein imbalance through disruption of TFAM-mediated mtDNA transcription.

BACKGROUND: Glioblastoma (GBM) represents as the most formidable intracranial malignancy. The systematic exploration of natural compounds for their potential applications in GBM therapy has emerged as a pivotal and fruitful avenue of research. PURPOSE: In the present study, a panel of 96 diterpenoids was systematically evaluated as a repository of potential antitumour agents. The primary objective was to discern their potency in overcoming resistance to temozolomide (TMZ). Through an extensive screening process, honatisine, a heptacyclic diterpenoid alkaloid, emerged as the most robust candidate. Notably, honatisine exhibited remarkable efficacy in patient-derived primary and recurrent GBM strains. Subsequently, we subjected this compound to comprehensive scrutiny, encompassing GBM cultured spheres, GBM organoids (GBOs), TMZ-resistant GBM cell lines, and orthotopic xenograft mouse models of GBM cells. RESULTS: Our investigative efforts delved into the mechanistic underpinnings of honatisine's impact. It was discerned that honatisine prompted mitonuclear protein imbalance and elicited the mitochondrial unfolded protein response (UPRmt). This effect was mediated through the selective depletion of mitochondrial DNA (mtDNA)-encoded subunits, with a particular emphasis on the diminution of mitochondrial transcription factor A (TFAM). The ultimate outcome was the instigation of deleterious mitochondrial dysfunction, culminating in apoptosis. Molecular docking and surface plasmon resonance (SPR) experiments validated honatisine's binding affinity to TFAM within its HMG-box B domain. This binding may promote phosphorylation of TFAM and obstruct the interaction of TFAM bound to heavy strand promoter 1 (HSP1), thereby enhancing Lon-mediated TFAM degradation. Finally, in vivo experiments confirmed honatisine's antiglioma properties. Our comprehensive toxicological assessments underscored its mild toxicity profile, emphasizing the necessity for a thorough evaluation of honatisine as a novel antiglioma agent. CONCLUSION: In summary, our data provide new insights into the therapeutic mechanisms underlying honatisine's selective inducetion of apoptosis and its ability to overcome chemotherapy resistance in GBM. These actions are mediated through the disruption of mitochondrial proteostasis and function, achieved by the inhibition of TFAM-mediated mtDNA transcription. This study highlights honatisine's potential as a promising agent for glioblastoma therapy, underscoring the need for further exploration and investigation.

Effects of Zhuang medicine compound Xiancao Granule on diabetic kidney disease: A multi-omics analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetic kidney disease (DKD) poses a severe threat to human health. Compound Xiancao Granule (CXCG), a classic Zhuang medicinal formula, is reported as highly effective in treating DKD. However, the mechanisms underlying the action of CXCG in DKD remain unclear. AIM OF THE STUDY: This study aimed to investigate the mechanisms of action of CXCG against DKD using multi-omics analysis, including 16s rRNA sequencing, metabolomics, and transcriptomics. MATERIALS AND METHODS: The chemical compounds of CXCG were identified using ultra-high- performance liquid chromatography quadrupole/electrostatic field orbital trap high-resolution mass spectrometry analysis. A rat model of DKD was established by combining nephrectomy of the left kidney, high-fat diet, and streptozotocin. The therapeutic effects of CXCG on DKD were assessed based on body weight, blood glucose level, renal function, inflammatory cytokine levels, and histological staining. Subsequently, 16s rRNA sequencing, liquid chromatography-tandem mass spectrometry untargeted metabolomic profiling, and RNA sequencing analysis were used to investigate the mechanisms of action of CXCG in DKD. Spearman's correlation analysis was performed to elucidate the correlations between efficacy indicators, gut microbiota, metabolites, and inflammation-related genes. RESULTS: A total of 118 compounds were identified in CXCG. CXCG significantly ameliorated glucose metabolism disorders, improved renal function, attenuated inflammation, and delayed renal pathological changes in DKD rats. CXCG modulated gut microbiota dysbiosis, including Alloprevotella, Oscillibacter, Anaeroplasma, Anaerotruncus, and Faecalibacterium. In addition, metabolic disruption in DKD rats was regulated by CXCG, which is involved in the metabolism of carbohydrates and amino acids. Transcriptome analysis showed that CXCG affected DKD mainly by regulating inflammation-related genes and pathways, such as the PI3K/Akt and MAPK signaling pathways. Furthermore, there were significant correlations between efficacy indicators, gut microbiota, metabolites, and genes. CONCLUSION: This multi-omics association study provides novel insights into the effects of CXCG on DKD by remodeling the gut microbiota structure and restoring the metabolic homeostasis through the regulation of carbohydrate metabolism, amino acid metabolism, and inflammation-related pathways, highlighting a potential therapeutic strategy for DKD.

Ferroptosis: A new view on the prevention and treatment of diabetic kidney disease with traditional Chinese medicine.

Diabetic kidney disease is one of the complications of diabetes mellitus, which can eventually progress to end-stage kidney disease. The increasing prevalence of diabetic kidney disease has brought huge economic burden to society and seriously jeopardized public health. Ferroptosis is an iron-dependent, non-apoptosis-regulated form of cell death. The regulation of ferroptosis involves different molecular mechanisms and multiple cellular metabolic pathways. In recent years, ferroptosis has been proved to be closely related to the occurrence and development of diabetic kidney disease, and can interact with pathological changes such as fibrosis, inflammation, oxidative stress, and disorders of glucose and lipid metabolism, destroying the structure, form and function of the inherent cells of the kidney, and promoting the progression of the disease. Traditional Chinese medicine has a long history of treating diabetic kidney disease with remarkable curative effect. Current scholars have shown that the oral administration of traditional Chinese medicine and the external treatment of Chinese medicine can regulate GPX4, Nrf2, ACSL4, PTGS2, TFR1 and other key signaling molecules, curb ferroptosis, and prevent the progressive deterioration of diabetic kidney disease. In this paper, the mechanism of ferroptosis and diabetic kidney disease and the prevention and treatment of traditional Chinese medicine are analyzed and summarized, in order to provide new ideas and new plans for the treatment of diabetic kidney disease.

Cell autonomous role of leucine-rich repeat kinase in protection of dopaminergic neuron survival.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease (PD), which is the leading neurodegenerative movement disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). However, whether LRRK2 mutations cause PD and degeneration of DA neurons via a toxic gain-of-function or a loss-of-function mechanism is unresolved and has pivotal implications for LRRK2-based PD therapies. In this study, we investigate whether LRRK2 and its functional homologue LRRK1 play an essential, intrinsic role in DA neuron survival through the development of DA neuron-specific LRRK conditional double knockout (cDKO) mice. We first generated and characterized floxed LRRK1 and LRRK2 mice and then confirmed that germline deletions of the floxed LRRK1 and LRRK2 alleles result in null mutations, as evidenced by the absence of LRRK1 and LRRK2 mRNA and protein in the respective homozygous deleted mutant mice. We further examined the specificity of Cre-mediated recombination driven by the dopamine transporter-Cre (DAT-Cre) knockin (KI) allele using a GFP reporter line and confirmed that DAT-Cre-mediated recombination is restricted to DA neurons in the SNpc. Crossing these validated floxed LRRK1 and LRRK2 mice with DAT-Cre KI mice, we then generated DA neuron-restricted LRRK cDKO mice and further showed that levels of LRRK1 and LRRK2 are reduced in dissected ventral midbrains of LRRK cDKO mice. While DA neuron-restricted LRRK cDKO mice of both sexes exhibit normal mortality and body weight, they develop age-dependent loss of DA neurons in the SNpc, as demonstrated by the progressive reduction of DA neurons in the SNpc of LRRK cDKO mice at the ages of 20 and 24 months but the unaffected number of DA neurons at the age of 15 months. Moreover, DA neurodegeneration is accompanied with increases of apoptosis and elevated microgliosis in the SNpc as well as decreases of DA terminals in the striatum, and is preceded by impaired motor coordination. Taken together, these findings provide the unequivocal evidence for the importance of LRRK in DA neurons and raise the possibility that LRRK2 mutations may impair its protection of DA neurons, leading to DA neurodegeneration in PD.

Does right hemisphere compensate for the left in school-age children with large left middle fossa arachnoid cysts?

BACKGROUND: To assess the cognitive function changes and brain network neuroplasticity in school-age children having large (diameter > 5 cm) left middle fossa arachnoid cyst (MFACs). METHODS: Eleven patients and 22 normal controls (NC) between 6 and 14 years of age were included. The CNS Vital Signs (CNS VS) were administered for cognitive assessment. The differences of cognitive data and functional connectivity (FC) in resting-state functional magnetic resonance imaging (rs-fMRI) were compared between the patient group and the NC group. The correlations between the altered FC and cognitive data in the patient group were assessed. RESULTS: Patient group had significantly poorer attention (including Complex Attention, Sustained Attention, Simple Attention, Cognitive Flexibility, and Executive Function) and memory function (Visual Memory and Working Memory) than the NC group (uncorrected p-value, p-unc < 0.05). Whole-brain local correlation (LCOR) analysis showed an extensively lower LCOR in the patient group (voxel threshold p-unc < 0.001, cluster-size threshold of false discovery rate adjusted p (p-FDR) < 0.001). Functional connectivity (FC) analysis showed that bilateral frontal and temporal lobes connectivity in the patient group was significantly lower than the NC group (p-FDR < 0.05). Seed-based FC analysis indicated that there was altered FC between the right temporal lobe and the left temporal-parietal/temporal-occipital area (p-FDR < 0.05). In the patient group, most of the altered FC had a negative correlation to the cognitive score, while the FC in the right temporal lobe-left temporal-occipital area positively correlated to Verbal/Visual Memory (r = 0.41-0.60, p-FDR < 0.05). In correlation analysis between clinical data and cognitive score, the only significant result was a low correlation between cyst size and Reaction Time (-0.30--0.36, P-FDR < 0.05). CONCLUSIONS: School-aged children with large left MFAC showed significantly lower cognitive performance primarily in attention and memory domains. Distinct from neuroplasticity in a unilateral brain lesion, compensation in the healthy hemisphere in MFAC patients was sparse.

Luteolin overcomes acquired resistance to osimertinib in non-small cell lung cancer cells by targeting the HGF-MET-Akt pathway.

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has overcome the acquired resistance of first- and second-generation EGFR-TKIs due to the EGFR T790M mutation in non-small cell lung cancer (NSCLC). However, acquired resistance to osimertinib remains a significant clinical challenge. Luteolin, a natural flavonoid from traditional Chinese medicine, has exerted antitumor effects in various tumors. In this study, we investigated whether the natural flavonoid luteolin can enhance the antitumor effects of osimertinib in NSCLC cells. We established an acquired osimertinib-resistant cell line, H1975/OR, and evaluated the effects of luteolin and osimertinib alone and in combination on proliferation, migration, invasion, and apoptosis of H1975/OR cells. The potential mechanisms by which the combination of luteolin and osimertinib exert their effects were investigated by PCR, western blot, gene silencing, molecular docking, SPR and kinase activity analysis. The combination of luteolin and osimertinib inhibited the proliferation, migration, and invasion of H1975/OR cells and promoted apoptosis. We identified mesenchymal-epithelial transition factor (MET) amplification and overactivation as important resistance mechanisms of H1975/OR cells. The combination downregulated the gene and protein expression of MET and inhibited its protein phosphorylation, thereby blocking the activation of the downstream Akt pathway. Additionally, the mediated effects of MET on the synergistic effect of luteolin and osimertinib were confirmed by silencing of MET. Luteolin strongly bound with nonphosphorylated MET by occupying the active pocket of MET and inhibiting its activation. Notably, the combination also downregulated the expression of autocrine hepatocyte growth factor (HGF), the sole ligand of MET. In conclusion, luteolin can synergize with osimertinib to overcome MET amplification and overactivation-induced acquired resistance to osimertinib by suppressing the HGF-MET-Akt pathway, suggesting the clinical potential of combining luteolin with osimertinib in NSCLC patients with acquired resistance.

Association between preoperative serum sodium and postoperative 30-day mortality in adult patients with tumor craniotomy.

BACKGROUND: Limited data exist regarding preoperative serum sodium (Na) and 30-day mortality in adult patients with tumor craniotomy. Therefore, this study investigates their relationship. METHODS: A secondary retrospective analysis was performed using data from the ACS NSQIP database (2012-2015). The principal exposure was preoperative Na. The outcome measure was 30-day postoperative mortality. Binary logistic regression modeling was conducted to explore the link between them, and a generalized additive model and smooth curve fitting were applied to evaluate the potential association and its explicit curve shape. We also conducted sensitivity analyses and subgroup analyses. RESULTS: A total of 17,844 patients (47.59% male) were included in our analysis. The mean preoperative Na was 138.63 ± 3.23 mmol/L. The 30-day mortality was 2.54% (455/17,844). After adjusting for covariates, we found that preoperative Na was negative associated with 30-day mortality. (OR = 0.967, 95% CI:0.941, 0.994). For patients with Na ≤ 140, each increase Na was related to a 7.1% decreased 30-day mortality (OR = 0.929, 95% CI:0.898, 0.961); for cases with Na > 140, each increased Na unit was related to a 8.8% increase 30-day mortality (OR = 1.088, 95% CI:1.019, 1.162). The sensitivity analysis and subgroup analysis indicated that the results were robust. CONCLUSIONS: This study shows a positive and nonlinear association between preoperative Na and postoperative 30-day mortality in adult patients with tumor craniotomy. Appropriate preoperative Na management and maintenance of serum Na near the inflection point (140) may reduce 30-day mortality.

miR­137 is a diagnostic tumor­suppressive miRNA that targets SPHK2 to promote M1­type tumor­associated macrophage polarization.

The present study investigated the expression level of microRNA (miR)-137 in glioma tissues and cell lines and explored its potential diagnostic significance as well as its function effects on glioma cells. miR-137 expression level was detected in glioma tissues using in situ hybridization, and in glioma cell lines using reverse transcription-quantitative PCR (RT-qPCR). The diagnostic significance of miR-137 in glioma was assessed using receiver operating characteristic curve analyses. Quantibody® Human Inflammation Array 1 was used to evaluate the impact of ectopic miR-137 expression on release of cytokines in glioma cell lines. IL-13, TNF-α and IFN-γ levels were detected using ELISA. To confirm that sphingosine kinase 2 (SPHK2) is a target of miR-137, RT-qPCR, western blot analysis and dual-luciferase assay were adopted. The results demonstrated that miR-137 expression was downregulated in both glioma tissues and cell lines. Downregulation of miR-137 was significantly associated with high grade gliomas. Additionally, it was found that overexpression of miR-137 reduced IL-13, but promoted TNFα and IFN-γ production. SPHK2 knockdown inhibited IL-13 release, promoted TNF-α and IFN-γ production. SPHK2 was a direct target of miR-137. Collectively, the results of the present study indicated that miR-137 expression plays a tumor-suppressive role in glioma. It is downregulated in glioma and may promote M1-type TAMs polarization, and may be a diagnostic biomarker and potential therapeutic strategy for glioma treatment in the future.

Integration analysis using bioinformatics and experimental validation on the clinical and biological significance of TSLP in cancers.

Thymic stromal lymphopoietin (TSLP) has significantly impacted the development and progression of various neoplastic disorders. To comprehensively evaluate the diverse significance of TSLP in malignant tumors, we first integrative analyze the TSLP expression level in paired and unpaired pan-cancer tissue and cell line, compared against the normal tissue. The correlation between TSLP expression, molecular subtypes, immune subtypes, diagnostic value, and prognostic value in pan-cancer was also investigated. We then explored the impact of TSLP expression on multifaced immune cell infiltration and subsequent clinical outcomes in lung adenocarcinoma (LUAD) patients. and conducted cellular experiments to functionally examine the effect of TSLP on cell proliferation, apoptosis, cell cycle, migration, and invasion in LUAD. The anti-neoplastic mechanism of TSLP was further investigated by qRT-PCR and western blotting. Our findings reveal that TSLP expression is abnormally low in various cancers compared to normal tissue and is associated with different molecular and immune subtypes of cancers. Moreover, ROC and survival analysis results suggest that TSLP expression is correlated with the diagnostic, prognostic, clinical features, and immune cells of LUAD patients. Cell experiments showed that overexpression of TSLP elicited a significant reduction in LUAD cell viability, promoted cell apoptosis, impeded cell cycle progression in the G2/M phase, and inhibited cell migration and invasion. In addition, TSLP inhibited LUAD progression through the JAK1/STAT3 signaling pathway. Therefore, targeting TSLP shows potential as a therapeutic strategy for pan-cancer, particularly for LUAD, and as a biomarker for predicting the prognosis of this malignancy.

The role and regulatory mechanism of HIF-1α in myocardial injury in rats undergoing cardiopulmonary bypass.

BACKGROUND: Hypoxia-inducible factor-1alpha (HIF-1α) is a transcription factor implicated in physiological and pathological responses to hypoxia. The present study aims to investigate the effect and mechanism of HIF-1α on cardiopulmonary bypass (CPB)-related myocardial injury, thereby conferring a theoretical basis for the clinical treatment of myocardial injury in CPB. METHODS: An experimental model of CPB was established in rats by surgery. Adenovirus-packaged overexpression vectors and antiagomiRNA were used to overexpress HIF-1α and NR4A1 or inhibit miR-124-3p expression in rat myocardial tissues, respectively. qRT-PCR and Western blot detected HIF-1α, miR-124-3p, and NR4A1 expression in myocardial tissues. The rat cardiac function was monitored through an echocardiogram. The rat plasma at different stages of CPB was collected, followed by the detection of IL-6, cTnT, CK-MB, and IL-1ß. TUNEL staining measured apoptosis in myocardial tissues. ChIP assay analysed the enrichment of HIF-1α on the miR-124-3p promoter. The binding relationships between HIF-1α and miR-124-3p promoter sequence and between miR-124-3p and NR4A1 3'UTR sequence were confirmed by dual-luciferase reporter assay. RESULTS: HIF-1α expression had no significant change after CPB modelling. Overexpression of HIF-1α improved the cardiac function of CPB rats, decreased plasma IL-6, cTnT, CK-MB, and IL-1ß levels, and reduced TUNEL-positive myocardial cells. HIF-1α was enriched on the miR-124-3p promoter and promoted miR-124-3p expression. miR-124-3p bound to NR4A1 3'UTR sequence and targeted NR4A1 expression. Inhibition of miR-124-3p or overexpression of NR4A1 partially reversed the ameliorative effect of HIF-1α overexpression on myocardial injury in CPB rats. CONCLUSION: Overexpression of HIF-1α can improve myocardial injury in CPB rats via the miR-124-3p/NR4A1 axis.

National Brain Tumour Registry of China (NBTRC) statistical report of primary brain tumours diagnosed in China in years 2019-2020.

Background: The lack of a well-designed brain tumour registry with standardized pathological diagnoses in underdeveloped countries hinders the ability to compare epidemiologic data across the globe. The National Brain Tumour Registry of China (NBTRC), created in January 2018, is the first multi-hospital-based brain tumour registry in China. Patient data reported to the NBTRC in years 2019-2020 were assessed. Methods: Tumour pathology was based on the 2016 World Health Organization (WHO) classification of tumours of the central nervous system and ICD-O-3. The anatomical site was coded per the Surveillance, Epidemiology, and End Results (SEER) solid tumour module (version of July 2019). The cases were tabulated by histology and anatomical site. Categorical variables were reported as numbers (percentages). The distribution of tumours by age (0-14, 15-19, 20-39, 40-64, and 65+ years) was analysed. Findings: There were a total of 25,537 brain tumours, foremost among them meningioma (23.63%), followed by tumours of the pituitary (23.42%), and nerve sheath tumours (9.09%). Glioblastoma, the most common and lethal form of primary brain cancer in adults, represented 8.56% of all cases. Of note, 6.48% of the malignant tumours were located in the brain stem. The percentage of malignant brain tumours decreased with increasing age, 24.08% in adults (40+ years), 30.25% in young adults (20-39 years), 35.27% in adolescents (15-19 years), and 49.83% in children (0-14 years). Among the 2107 paediatric patients, the most common sites were ventricle (17.19%), brainstem (14.03%), pituitary and craniopharyngeal duct (13.4%), and cerebellum (12.3%), a distribution that differed from that of the entire cohort. The histology distribution was also unique in children, with glioblastoma much less incident compared to the whole cohort (3% vs. 8.47%, p < 0.01). 58.80% of all patients chose higher-level neurosurgical hospitals outside of their province of residence. The median in-hospital length of stay (LOS) for the various pathologies ranged from 11 to 19 days. Interpretation: The histological and anatomical site distribution of brain tumours in the NBTRC was statistically different in the subgroup of children (0-14 years). Patient choice of pursuing trans-provincial treatment was common and the in-hospital LOS was longer compared to that reported in similar European and American patient populations, which merits further attention. Funding: The National Key Research and Development Program of China (2015BAI12B04, 2013BAI09B03, 2014BAI04B01, and 2021YFF1201104) and Chinese National Natural Science Foundation of China (81971668).

Cerebral Autoregulation Status in Relation to Brain Injury on Electroencephalogram and Magnetic Resonance Imaging in Children Following Cardiac Surgery.

Background Disturbed cerebral autoregulation has been reported in children with congenital heart disease before and during cardiopulmonary bypass surgery, but not after. We sought to characterize the cerebral autoregulation status in the early postoperative period in relation to perioperative variables and brain injuries. Methods and Results A prospective and observational study was conducted in 80 patients in the first 48 hours following cardiac surgery. Cerebral oximetry/pressure index (COPI) was retrospectively calculated as a moving linear correlation coefficient between mean arterial blood pressure and cerebral oxygen saturation. Disturbed autoregulation was defined as COPI >0.3. Correlations of COPI with demographic and perioperative variables as well as brain injuries on electroencephalogram and magnetic resonance imaging and early outcomes were analyzed. Thirty-six (45%) patients had periods of abnormal COPI for 7.81 hours (3.38 hours) either at hypotension (median <45 mm Hg) or hypertension (median >90 mm Hg) or both. Overall, COPI became significantly lower over time, suggesting improved autoregulatory status during the 48 postoperative hours. All of the demographic and perioperative variables were significantly associated with COPI, which in turn was associated with the degree of brain injuries and early outcomes. Conclusions Children with congenital heart disease following cardiac surgery often have disturbed autoregulation. Cerebral autoregulation is at least partly the underlying mechanism of brain injury in those children. Careful clinical management to manipulate the related and modifiable factors, particularly arterial blood pressure, may help to maintain adequate cerebral perfusion and reduce brain injury early after cardiopulmonary bypass surgery. Further studies are warranted to determine the significance of impaired cerebral autoregulation in relation to long-term neurodevelopment outcomes.

Perioperative EEG background and discharge abnormalities in children undergoing cardiac surgery: a prospective single-centre observational study.

BACKGROUND: We analysed the characteristics of abnormal electroencephalogram (EEG) patterns before, during, and 48 h after cardiac surgery in patients with heterogeneous congenital heart disease to assess their relationship to demographic and perioperative variables and to early patient outcomes. METHODS: In 437 patients enrolled in a single centre, EEG was evaluated for background (including sleep-wake cycle) and discharge (seizures, spikes/sharp waves, pathological delta brushes) abnormalities. Clinical data (arterial blood pressure, doses of inotropic drugs, and serum lactate concentrations) were recorded every 3 h. Postoperative brain MRI was performed before discharge. RESULTS: Preoperative, intraoperative, and postoperative EEG was monitored in 139, 215, and 437 patients, respectively. Patients with a degree of preoperative background abnormalities (n=40) had more severe intraoperative and postoperative EEG abnormalities (P<0.0001). Intraoperatively, 106/215 (49.3%) patients progressed into an isoelectric EEG. Longer durations of isoelectric EEG were associated with more severe postoperative EEG abnormalities and brain injury on MRI (Ps≤0.003). Postoperative background abnormalities occurred in 218/437 (49.9%) patients, and 119 (54.6%) of them had not recovered after surgery. Seizures occurred in 36/437 (8.2%) patients, spikes/sharp waves in 359/437 (82.2%), and pathological delta brushes in 9/437 (2.0%). Postoperative EEG abnormalities correlated with degree of brain injury on MRI (Ps≤0.02). Demographic and perioperative variables were significantly correlated with postoperative EEG abnormalities, which in turn correlated with adverse clinical outcomes. CONCLUSIONS: Perioperative EEG abnormalities occurred frequently and correlated with numerous demographic and perioperative variables and adversely correlated with postoperative EEG abnormalities and early outcomes. The relation of EEG background and discharge abnormalities with long-term neurodevelopmental outcomes remains to be explored.

USP39-mediated deubiquitination of Cyclin B1 promotes tumor cell proliferation and glioma progression.

BACKGROUND: The elevated Cyclin B1 expression contributes to various tumorigenesis and poor prognosis. Cyclin B1 expression could be regulated by ubiquitination and deubiquitination. However, the mechanism of how Cyclin B1 is deubiquitinated and its roles in human glioma remain unclear. METHODS: Co-immunoprecipitation and other assays were performed to detect the interacting of Cyclin B1 and USP39. A series of in vitro and in vivo experiments were performed to investigate the effect of USP39 on the tumorigenicity of tumor cells. RESULTS: USP39 interacts with Cyclin B1 and stabilizes its expression by deubiquitinating Cyclin B1. Notably, USP39 cleaves the K29-linked polyubiquitin chain on Cyclin B1 at Lys242. Additionally, overexpression of Cyclin B1 rescues the arrested cell cycle at G2/M transition and the suppressed proliferation of glioma cells caused by USP39 knockdown in vitro. Furthermore, USP39 promotes the growth of glioma xenograft in subcutaneous and in situ of nude mice. Finally, in human tumor specimens, the expression levels of USP39 and Cyclin B1 are positively relevant. CONCLUSION: Our data support the evidence that USP39 acts a novel deubiquitinating enzyme of Cyclin B1 and promoted tumor cell proliferation at least in part through Cyclin B1 stabilization, represents a promising therapeutic strategy for tumor patients.

Research Progress on the Etiology and Pathogenesis of Alzheimer's Disease from the Perspective of Chronic Stress.

Due to its extremely complex pathogenesis, no effective drugs to prevent, delay progression, or cure Alzheimer's disease (AD) exist at present. The main pathological features of AD are senile plaques composed of ß-amyloid, neurofibrillary tangles formed by hyperphosphorylation of the tau protein, and degeneration or loss of neurons in the brain. Many risk factors associated with the onset of AD, including gene mutations, aging, traumatic brain injury, endocrine and cardiovascular diseases, education level, and obesity. Growing evidence points to chronic stress as one of the major risk factors for AD, as it can promote the onset and development of AD-related pathologies via a mechanism that is not well known. The use of murine stress models, including restraint, social isolation, noise, and unpredictable stress, has contributed to improving our understanding of the relationship between chronic stress and AD. This review summarizes the evidence derived from murine models on the pathological features associated with AD and the related molecular mechanisms induced by chronic stress. These results not only provide a retrospective interpretation for understanding the pathogenesis of AD, but also provide a window of opportunity for more effective preventive and identifying therapeutic strategies for stress-induced AD.