Abnormal H3K4 enzyme catalytic activity and neuronal morphology caused by ASH1L mutations in individuals with Tourette syndrome.

ASH1L potentially contributes to Tourette syndrome (TS) and other neuropsychiatric disorders, as our previous studies have shown. It regulates essential developmental genes by counteracting polycomb-mediated transcriptional repression, which restricts chromatin accessibility at target genes. ASH1L is highly expressed in the adult brain, playing a crucial role in the early stage. However, it remains unclear how ASH1L mutations carried by patients with TS participate in regulating neuronal growth processes leading to TS traits. Five TS families recruited in our study underwent comprehensive physical examinations and questionnaires to record clinical phenotypes and environmental impact factors. We validated the variants via Sanger sequencing and constructed two mutants near the catalytic domain of ASH1L. We conducted molecular modeling, in vitro assays, and primary neuron cultures to find the role of ASH1L in neuronal development and its correlation with TS. In this study, we validated five pathogenic ASH1L rare variants and observed symptoms in patients with simple tics and behavioral comorbidities. Mutations near the catalytic domain of TS patients cause mental state abnormalities and disrupt ASH1L function by destabilizing its spatial conformation, leading to decreased activity of catalytic H3K4, thereby affecting the neurite growth. We need to conduct larger-scale studies on TS patients and perform additional neurological evaluations on mature neurons. We first reported the effects of ASH1L mutations in TS patients, including phenotypic heterogeneity, protein function, and neurological growth. This information contributes to understanding the neurodevelopmental pathogenesis of TS in patients with ASH1L mutations.

Cathodal bilateral transcranial direct-current stimulation regulates selenium to confer neuroprotection after rat cerebral ischaemia-reperfusion injury.

Non-invasive transcranial direct-current stimulation (tDCS) is a safe ischaemic stroke therapy. Cathodal bilateral tDCS (BtDCS) is a modified tDCS approach established by us recently. Because selenium (Se) plays a crucial role in cerebral ischaemic injury, we investigated whether cathodal BtDCS conferred neuroprotection via regulating Se-dependent signalling in rat cerebral ischaemia-reperfusion (I/R) injury. We first showed that the levels of Se and its transport protein selenoprotein P (SEPP1) were reduced in the rat cortical penumbra following I/R, whereas cathodal BtDCS prevented the reduction of Se and SEPP1. Interestingly, direct-current stimulation (DCS) increased SEPP1 level in cultured astrocytes subjected to oxygen-glucose deprivation reoxygenation (OGD/R) but had no effect on SEPP1 level in OGD/R-insulted neurons, indicating that DCS may increase Se in ischaemic neurons by enhancing the synthesis and secretion of SEPP1 in astrocytes. We then revealed that DCS reduced the number of injured mitochondria in OGD/R-insulted neurons cocultured with astrocytes. DCS and BtDCS prevented the reduction of the mitochondrial quality-control signalling, vesicle-associated membrane protein 2 (VAMP2) and syntaxin-4 (STX4), in OGD/R-insulted neurons cocultured with astrocytes and the ischaemic brain respectively. Under the same experimental conditions, downregulation of SEPP1 blocked DCS- and BtDCS-induced upregulation of VAMP2 and STX4. Finally, we demonstrated that cathodal BtDCS increased Se to reduce infract volume following I/R. Together, the present study uncovered a molecular mechanism by which cathodal BtDCS confers neuroprotection through increasing SEPP1 in astrocytes and subsequent upregulation of SEPP1/VAMP2/STX4 signalling in ischaemic neurons after rat cerebral I/R injury. KEY POINTS: Cathodal bilateral transcranial direct-current stimulation (BtDCS) prevents the reduction of selenium (Se) and selenoprotein P in the ischaemic penumbra. Se plays a crucial role in cerebral ischaemia injury. Direct-current stimulation reduces mitochondria injury and blocks the reduction of vesicle-associated membrane protein 2 (VAMP2) and syntaxin-4 (STX4) in oxygen-glucose deprivation reoxygenation-insulted neurons following coculturing with astrocytes. Cathodal BtDCS regulates Se/VAMP2/STX4 signalling to confer neuroprotection after ischaemia.

Epigenetic alterations and advancement of lymphoma treatment.

Lymphomas, complex and heterogeneous malignant tumors, originate from the lymphopoietic system. These tumors are notorious for their high recurrence rates and resistance to treatment, which leads to poor prognoses. As ongoing research has shown, epigenetic modifications like DNA methylation, histone modifications, non-coding RNA regulation, and RNA modifications play crucial roles in lymphoma pathogenesis. Epigenetic modification-targeting drugs have exhibited therapeutic efficacy and tolerability in both monotherapy and combination lymphoma therapy. This review discusses pathogenic mechanisms and potential epigenetic therapeutic targets in common lymphomas, offering new avenues for lymphoma diagnosis and treatment. We also discuss the shortcomings of current lymphoma treatments, while suggesting potential areas for future research, in order to improve the prediction and prognosis of lymphoma.

Surfeit Locus Protein 4 as a Novel Target for Therapeutic Intervention in Cerebral Ischemia-Reperfusion Injury.

Surfeit locus protein 4 (SURF4) functions as a cargo receptor that is capable of transporting newly formed proteins from the lumen of the endoplasmic reticulum into vesicles and Golgi bodies. However, the role of SURF4 in the central nervous system remains unclear. The aim of this study is to investigate the role of SURF4 and its underlying mechanisms in cerebral ischemia/reperfusion (I/R) injury in rats, and whether it can be used effectively for novel therapeutic intervention. We also examined whether transcranial direct-current stimulation (tDCS) can exert a neuroprotective effect via SURF4-dependent signalling. Following cerebral I/R injury in rats, a significant increase was observed in the expression of SURF4. In both I/R injury and oxygen-glucose deprivation (OGD) insult, suppressing the expression of SURF4 demonstrated a neuroprotective effect, while overexpression of SURF4 resulted in increased neuronal death. We further showed that the levels of nerve growth factor precursor (proNGF), p75 neurotrophin receptor (p75NTR), sortilin, and PTEN were increased following cerebral I/R injury, and that SURF4 acted through the PTEN/proNGF signal pathway to regulate neuronal viability. We demonstrated that tDCS treatment reduced SURF4 expression and decreased the infarct volume after cerebral I/R injury. Together, this study indicates that SURF4 plays a critical role in ischemic neuronal injury and may serve as a molecular target for the development of therapeutic strategies in acute ischemic stroke.

Upregulation of mitochondrial PGK1 by ROS-TBC1D15 pathway promotes neuronal death after oxygen-glucose deprivation/reoxygenation injury.

Phosphoglycerate kinase 1 (PGK1) is extensively located in the cytosol and mitochondria. The role of PGK1 in ischemic neuronal injury remains elusive. In the in vitro model of oxygen-glucose deprivation/reoxygenation (OGD/R), we showed that PGK1 expression was increased in cortical neurons. Knockdown of PGK1 led to a reduction of OGD/R-induced neuronal death. The expression of cytosolic PGK1 was reduced, but the levels of mitochondrial PGK1 were increased in OGD/R-insulted neurons. Inhibiting the activity of mitochondrial PGK1 alleviated the neuronal injury after OGD/R insult. We further showed that the protein levels of TBC domain family member 15 (TBC1D15) were decreased in OGD/R-insulted neurons. Knockdown of TBC1D15 led to increased levels of mitochondrial PGK1 after OGD/R insult in cortical neurons. Moreover, increased reactive oxygen species (ROS) resulted in a reduction of TBC1D15 in OGD/R-insulted neurons. These results suggest that the upregulation of mitochondrial PGK1 by ROS-TBC1D15 signaling pathway promotes neuronal death after OGD/R injury. Mitochondrial PGK1 may act as a regulator of neuronal survival and interventions in the PGK1-dependent pathway may be a potential therapeutic strategy.

FLAIR-hyperintense lesions in anti-MOG-associated encephalitis with seizures overlaying anti-N-methyl-D-aspartate receptor encephalitis: A case report.

RATIONALE: FLAIR-hyperintense lesions in anti-myelin oligodendrocyte glycoprotein (MOG)-associated encephalitis with seizures (FLAMES) is a rare clinical phenotype of anti-MOG; immunoglobulin G-associated disease is often misdiagnosed as viral encephalitis in the early stages. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune encephalitis caused by antibodies targeting the GluN1 subunit of the NMDAR. The coexistence of anti-NMDAR encephalitis and FLAMES is very rare. PATIENT CONCERNS: A 20-year-old female patient initially presented with seizures accompanied by daytime sleepiness. DIAGNOSES: Magnetic resonance imaging revealed FLAIR-hyperintense lesions in unilateral cerebral cortex. NMDAR antibodies was positive in the cerebrospinal fluid and MOG antibodies in the serum. INTERVENTIONS: Steroid therapy was administrated. OUTCOMES: The symptoms completely relieved. At 6-month follow-up, the patient's condition remained stable. Magnetic resonance imaging showed no abnormalities in the unilateral cerebral cortex. CONCLUSION: When a patient with anti-NMDAR encephalitis or FLAMES is encountered in clinical practice, the coexistence of these diseases with double-positive anti-NMDAR and MOG antibodies should be considered and adopt appropriate evaluation and treatment.

Exploring the anti-glioma mechanism of the active components of Cortex Periplocae based on network pharmacology and iTRAQ proteomics in vitro.

BACKGROUND: The active components of Cortex Periplocae (CP) exert antitumor properties in many cancers. However, little is known about their effects on glioma or the related underlying mechanisms. OBJECTIVES: The study investigated the underlying mechanism of CP in treating glioma. MATERIAL AND METHODS: The U251 and TG905 cells were treated with an ethanol extract from CP. Cell proliferation was detected using Cell Counting Kit-8 (CCK-8) and a colony formation assay. The flow cytometric analysis was applied to explore the induction of cell cycle arrest and apoptosis. The expression levels of cell cycleand apoptosis-associated proteins were measured with western blot. A network pharmacology method was performed to predict the potential mechanism underlying the effects of the active components of CP on glioma. Then, isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomics analysis was used to verify the differentially expressed proteins and pathways in order to reveal the underlying mechanisms. Furthermore, to determine the iTRAQ results, 6 candidate proteins were chosen for quantification using parallel reaction monitoring (PRM). RESULTS: The CP extract inhibited the proliferation of U251 and TG905 cells and induced cell cycle arrest and apoptosis. There are 16 active compounds of CP. The antitumor mechanism of CP may be related to the apoptosis pathway, p53 signaling pathway, PI3K-AKT pathway, or transcriptional misregulation in cancer pathway. Six proteins (HSP90AB1, TOP2A, ATP1A1, TGFß1, ATP1B1, and TYMS) were determined to be key factors involved in regulating CP in glioma. CONCLUSIONS: Our research revealed the underlying mechanism of CP in treating glioma using integrated network pharmacology and iTRAQ-based quantitative proteomics technology.

Inhibition of hyaluronic acid degradation pathway suppresses glioma progression by inducing apoptosis and cell cycle arrest.

BACKGROUND: Abnormal hyaluronic acid (HA) metabolism is a major factor in tumor progression, and the metabolic regulation of HA mainly includes HA biosynthesis and catabolism. In glioma, abnormal HA biosynthesis is intimately involved in glioma malignant biological properties and the formation of immunosuppressive microenvironment; however, the role of abnormal HA catabolism in glioma remains unclear. METHODS: HA catabolism is dependent on hyaluronidase. In TCGA and GEPIA databases, we found that among the 6 human hyaluronidases (HYAL1, HYAL2, HYAL3, HYAL4, HYALP1, SPAM1), only HYAL2 expression was highest in glioma. Next, TCGA and CGGA database were further used to explore the correlation of HYAL2 expression with glioma prognosis. Then, the mRNA expression and protein level of HYAL2 was determined by qRT-PCR, Western blot and Immunohistochemical staining in glioma cells and glioma tissues, respectively. The MTT, EdU and Colony formation assay were used to measure the effect of HYAL2 knockdown on glioma. The GSEA enrichment analysis was performed to explore the potential pathway regulated by HYAL2 in glioma, in addition, the HYAL2-regulated signaling pathways were detected by flow cytometry and Western blot. Finally, small molecule compounds targeting HYAL2 in glioma were screened by Cmap analysis. RESULTS: In the present study, we confirmed that Hyaluronidase 2 (HYAL2) is abnormally overexpressed in glioma. Moreover, we found that HYAL2 overexpression is associated with multiple glioma clinical traits and acts as a key indicator for glioma prognosis. Targeting HYAL2 could inhibit glioma progression by inducing glioma cell apoptosis and cell cycle arrest. CONCLUSION: Collectively, these observations suggest that HYAL2 overexpression could promote glioma progression. Thus, treatments that disrupt HA catabolism by altering HYAL2 expression may serve as effective strategies for glioma treatment.

Bilateral transcranial direct-current stimulation promotes migration of subventricular zone-derived neuroblasts toward ischemic brain.

Ischemic insult stimulates proliferation of neural stem cells (NSCs) in the subventricular zone (SVZ) after stroke. However, only a fraction of NSC-derived neuroblasts from SVZ migrate toward poststroke brain region. We have previously reported that direct-current stimulation guides NSC migration toward the cathode in vitro. Accordingly, we set up a new method of transcranial direct-current stimulation (tDCS), in which the cathodal electrode is placed on the ischemic hemisphere and anodal electrode on the contralateral hemisphere of rats subjected to ischemia-reperfusion injury. We show that the application of this bilateral tDCS (BtDCS) promotes the migration of NSC-derived neuroblasts from SVZ toward the cathode direction into poststroke striatum. Reversing the position of the electrodes blocks the effect of BtDCS on the migration of neuroblasts from SVZ. BtDCS protects against neuronal death and improves the functional recovery of stroke animals. Thus, the migration of NSC-derived neuroblasts from SVZ toward poststroke brain region contributes to the effect of BtDCS against ischemia-induced neuronal death, supporting a potential development of noninvasive BtDCS as an endogenous neurogenesis-based stroke therapy.

Transcranial direct-current stimulation confers neuroprotection by regulating isoleucine-dependent signalling after rat cerebral ischemia-reperfusion injury.

Isoleucine is a branched chain amino acid. The role of isoleucine in cerebral ischemia-reperfusion injury remains unclear. Here, we show that the concentration of isoleucine is decreased in cerebrospinal fluid in a rat model of cerebral ischemia-reperfusion injury, the rat middle cerebral artery occlusion (MCAO). To our surprise, the level of intraneuronal isoleucine is increased in an in vitro model of cerebral ischemia injury, the oxygen-glucose deprivation (OGD). We found that the increased activity of LAT1, an L-type amino acid transporter 1, leads to the elevation of intraneuronal isoleucine after OGD insult. Reducing the level of intraneuronal isoleucine promotes cell survival after cerebral ischemia-reperfusion injury, but supplementing isoleucine aggravates the neuronal damage. To understand how isoleucine promotes ischemia-induced neuronal death, we reveal that isoleucine acts upstream to reduce the expression of CBFB (core binding factor ß, a transcript factor involved in cell development and growth) and that the phosphatase PTEN acts downstream of CBFB to mediate isoleucine-induced neuronal damage after OGD insult. Interestingly, we demonstrate that direct-current stimulation reduces the level of intraneuronal isoleucine in cortical cultures subjected to OGD and that transcranial direct-current stimulation (tDCS) decreases the cerebral infarct volume of MCAO rat through reducing LAT1-depencent increase of intraneuronal isoleucine. Together, these results lead us to conclude that LAT1 over activation-dependent isoleucine-CBFB-PTEN signal transduction pathway may mediate ischemic neuronal injury and that tDCS exerts its neuroprotective effect by suppressing LAT1 over activation-dependent signalling after cerebral ischemia-reperfusion injury.

tDCS Regulates ASBT-3-OxoLCA-PLOD2-PTEN Signaling Pathway to Confer Neuroprotection Following Rat Cerebral Ischemia-Reperfusion Injury.

Humans exhibit a rich intestinal microbiome that contain high levels of bacteria capable of producing 3-oxo-lithocholic acid (3-oxoLCA) and other secondary bile acids (BAs). The molecular mechanism mediating the role of 3-oxoLCA in cerebral ischemia-reperfusion (I/R) injury remains unclear. We investigated the role of 3-oxoLCA in a rat cerebral I/R injury model. We found that the concentrations of 3-oxoLCA within the cerebrospinal fluid were increased following I/R. In the in vitro oxygen-glucose deprivation (OGD) model, the levels of intraneuronal 3-oxoLCA was elevated following OGD insult. We showed that the increase of membrane ASBT (apical sodium-dependent bile acid transporter) contributed to OGD-induced elevation of intraneuronal 3-oxoLCA. Increasing intraneuronal 3-oxoLCA promoted ischemia-induced neuronal death, whereas reducing 3-oxoLCA levels were neuroprotective. Our results revealed that PLOD2 (procollagen-lysine, 2-oxoglutarate 5-dioxygenases 2) functioned upstream of PTEN (the phosphatase and tensin homolog deleted on chromosome 10) and downstream of 3-oxoLCA to promote OGD-induced neuronal injury. We further demonstrated that direct-current stimulation (DCS) decreased the levels of intraneuronal 3-oxoLCA and membrane ASBT in OGD-insulted neurons, while bilateral transcranial DCS (tDCS) reduced brain infarct volume following I/R by inhibiting ASBT. Together, these data suggest that increased expression of ASBT promotes neuronal death via 3-oxoLCA-PLOD2-PTEN signaling pathway. Importantly, bilateral tDCS suppresses ischemia-induced increase of ASBT, thereby conferring neuroprotection after cerebral I/R injury.

Postoperative prognostic nomogram for adult grade II/III astrocytoma in the Chinese Han population.

Background: Prognostic models of glioma have been the focus of many studies. However, most of them are based on Western populations. Additionally, because of the complexity of healthcare data in China, it is important to select a suitable model based on existing clinical data. This study aimed to develop and independently validate a nomogram for predicting the overall survival (OS) with newly diagnosed grade II/III astrocytoma after surgery. Methods: Data of 472 patients with astrocytoma (grades II-III) were collected from Qilu Hospital as training cohort while data of 250 participants from Linyi People's Hospital were collected as validation cohort. Cox proportional hazards model was used to construct the nomogram and individually predicted 1-, 3-, and 5-year survival probabilities. Calibration ability, and discrimination ability were analyzed in both training and validation cohort. Results: Overall survival was negatively associated with histopathology, age, subtotal resection, multiple tumors, lower KPS and midline tumors. Internal validation and external validation showed good discrimination (The C-index for 1-, 3-, and 5-year survival were 0.791, 0.748, 0.733 in internal validation and 0.754, 0.735, 0.730 in external validation, respectively). The calibration curves showed good agreement between the predicted and actual 1-, 3-, and 5-year OS rates. Conclusion: This is the first nomogram study that integrates common clinicopathological factors to provide an individual probabilistic prognosis prediction for Chinese Han patients with astrocytoma (grades II-III). This model can serve as an easy-to-use tool to advise patients and establish optimized surveillance approaches after surgery. Supplementary Information: The online version contains supplementary material available at 10.1007/s13755-023-00223-0.

RNA-seq analysis reveals candidate genes associated with proliferation, invasion, and migration in BCL11A knockdown B-NHL cell lines.

B-cell lymphoma/leukemia 11A (BCL11A) is highly expressed in B-cell non-Hodgkin lymphoma (B-NHL), blocks cell differentiation, and inhibits cell apoptosis. However, little is known about BCL11A in the proliferation, invasion, and migration of B-NHL cells. Here, we found increased expression of BCL11A in B-NHL patients and cell lines. Knockdown of BCL11A suppressed the proliferation, invasion, and migration of B-NHL cells in vitro and reduced tumor growth in vivo. RNA sequencing (RNA-seq) and KEGG pathway analysis demonstrated that BCL11A-targeted genes were significantly enriched in the PI3K/AKT signaling pathway, focal adhesion, and extracellular matrix (ECM)-receptor interaction (including COL4A1, COL4A2, FN1, SPP1), and SPP1 was the most significantly downregulated gene. qRT‒PCR, western blotting, and immunohistochemistry revealed that silencing BCL11A reduced the expression level of SPP1 in Raji cells. Our study suggested that high level of BCL11A may promote B-NHL proliferation, invasion, and migration, and the BCL11A-SPP1 regulatory axis may play an important role in Burkitt's lymphoma.

Network pharmacology and molecular docking combined with widely targeted metabolomics to elucidate the potential compounds and targets of Euphorbia helioscopia seeds for the treatment of pulmonary fibrosis.

BACKGROUND: The whole herb of Euphorbia helioscopia has been traditionally used for treating pulmonary tuberculosis, malaria, warts, lung cancer and bacillary dysentery for a long time in China. However, E. helioscopia seeds are often discarded and its medicinal value is often ignored, resulting in a waste of resources. METHOD: In this work, widely targeted metabolomics based on UPLC-ESI-QTRAP-MS/MS methods and metware database (MWDB) were firstly used to identify the chemical compositions of EHS. Besides, network pharmacology, molecular docking and molecular dynamics simulation were performed for elucidating the potential compounds and targets of E. helioscopia seeds for the treatment of pulmonary fibrosis via common database (like TCMSP, Genecards, DAVID, STRING) and common software (like Sybyl, Cytoscape, Pymol and Schrödinger). RESULT: The results of widely targeted metabolomics showed 231 compounds including 12 categories were identified. The highest content compositions are lipids (33.89%) followed by amino acids and derivatives (21.78%), nucleotides and derivatives (15.73%), as well as the content of functional ingredients like phenolic acids (7.33%), alkaloids (7.03%) and flavonoids (4.51%) are relatively high. Besides, the results of network pharmacology and molecular docking showed that EHS presented anti-pulmonary fibrosis medicinal value through multi-ingredients, multi-targets and multi-pathways approach. Key ingredients including 9-Hydroxy-12-oxo-15(Z)-octadecenoic acid, Nordihydrocapsiate, 1-O-Salicyl-d-glucose, 9-(Arabinosyl)hypoxanthine, Xanthosine and Galangin-7-O-glucoside. Key targets including SRC, HSP90AA1, AKT1, EGFR, JUN, EP300 and VEGFA, and key signaling pathways mainly related to AGE-RAGE, EGFR tyrosine kinase inhibitor resistance, VEGF and HIF-1 signaling pathway. Molecular dynamics simulation showed that HSP90AA1 and 9-Hydroxy-12-oxo-15(Z)-octadecenoic complex (with the highest docking score) have a stable combination effect. CONCLUSION: In conclusion, this study revealed the chemical compositions of EHS and its anti-pulmonary fibrosis medicinal effect for the first time, it will provide scientific insight for the development of EHS as medicinal resource.

Targeting copper death genotyping associated gene RARRES2 suppresses glioblastoma progression and macrophages infiltration.

BACKGROUND: Copper homeostasis is associated with malignant biological behavior in various tumors. The excessive accumulation of copper can induce tumor death, which is named cuproptosis, and it is also closely related to tumor progression and the formation of the immune microenvironment. However, the associations of cuproptosis with glioblastoma (GBM) prognosis and microenvironment construction are poorly understood. METHOD: First, TCGA and GEO (GSE83300, GSE74187) merged datasets were used to analyze the association of cuproptosis-related genes (CRGs) with GBM. Then, we performed cluster analysis of CRGs in GBM from the GEO (GSE83300, GSE74187) and TCGA merged datasets. Subsequently, the prognostic risk model was constructed by least absolute shrinkage and selection operator (LASSO) according to gene expression features in CRG clusters. Next, we performed a series of in-depth analyses, including tumor mutational burden (TMB) analysis, cluster analysis, and GBM IDH status prediction. Finally, RARRES2 was identified as a target gene for GBM treatment, especially IDH wild-type GBM. In addition, we further analyzed the correlation of CRG clusters and RARRES2 expression with the GBM immune microenvironment by ESTIMATE and CIBERSORT analyses. In vitro experiments were conducted to demonstrate that targeting RARRES2 inhibits glioblastoma progression and macrophage infiltration, particularly IDH wild-type GBM. RESULTS: In the present study, we demonstrated that the CRG cluster was closely related to GBM prognosis and immune cell infiltration. Moreover, the prognostic risk model constructed with the three genes (MMP19, G0S2, RARRES2) associated with the CRG clusters could well evaluate the prognosis and immune cell infiltration in GBM. Subsequently, after further analyzing the tumor mutational burden (TMB) in GBM, we confirmed that RARRES2 in the prognostic risk model could be used as a crucial gene signature to predict the prognosis, immune cell infiltration and IDH status of GBM patients. CONCLUSION: This study fully revealed the potential clinical impact of CRGs on GBM prognosis and the microenvironment, and determined the effect of the crucial gene (RARRES2) on the prognosis and tumor microenvironment construction of GBM, meanwhile, our study also revealed over-expressed RARRES2 is related to the IDH satus of GBM, which provides a novel strategy for the treatment of GBM, particularly IDH wild-type GBM.

Tenecteplase versus alteplase in acute ischaemic cerebrovascular events (TRACE-2): a phase 3, multicentre, open-label, randomised controlled, non-inferiority trial.

BACKGROUND: There is increasing interest in replacing alteplase with tenecteplase as the preferred thrombolytic treatment for patients with acute ischaemic stroke. We aimed to establish the non-inferiority of tenecteplase to alteplase for these patients. METHODS: In this multicentre, prospective, open-label, blinded-endpoint, randomised controlled, non-inferiority trial, adults with an acute ischaemic stroke who were eligible for standard intravenous thrombolysis but ineligible for endovascular thrombectomy were enrolled from 53 centres in China and randomly assigned (1:1) to receive intravenous tenecteplase (0·25 mg/kg, maximum dose of 25 mg) or intravenous alteplase (0·9 mg/kg, maximum dose of 90 mg). Participants had to be able to receive treatment within 4·5 h of stroke, have a modified Rankin Scale (mRS) score of no more than 1 before enrolment, and have a National Institutes of Health Stroke Scale score of 5-25. Patients and treating clinicians were not masked to group assignment; clinicians evaluating outcomes were masked to treatment type. The primary efficacy outcome was the proportion of participants who had a mRS score of 0-1 at 90 days, assessed in the modified intention-to-treat population (all randomly assigned participants who received the allocated thrombolytic), with a non-inferiority margin of 0·937 for the risk ratio (RR). The primary safety outcome was symptomatic intracranial haemorrhage within 36 h, assessed in all participants who received study drug and had a safety assessment available. The trial is registered with ClinicalTrials.gov, NCT04797013, and has been completed. FINDINGS: Between June 12, 2021, and May 29, 2022, 1430 participants were enrolled and randomly assigned to tenecteplase (n=716) or alteplase (n=714). Six patients assigned to tenecteplase and seven to alteplase did not receive study product, and five participants in the tenecteplase group and 11 in the alteplase group were lost to follow-up at 90 days. The primary outcome in the modified intention-to-treat population occurred in 439 (62%) of 705 in the tenecteplase group versus 405 (58%) of 696 in the alteplase group (RR 1·07, 95% CI 0·98-1·16). The lower limit of the RR's 95% CI was greater than the non-inferiority margin. Symptomatic intracranial haemorrhage within 36 h was observed in 15 (2%) of 711 in the tenecteplase group and 13 (2%) of 706 in the alteplase group (RR 1·18, 95% CI 0·56-2·50). Mortality within 90 days occurred in 46 (7%) individuals in the tenecteplase group versus 35 (5%) in the alteplase group (RR 1·31, 95% CI 0·86-2·01). INTERPRETATION: Tenecteplase was non-inferior to alteplase in people with ischaemic stroke who were eligible for standard intravenous thrombolytic but ineligible for or refused endovascular thrombectomy. FUNDING: National Science and Technology Major Project, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, National Natural Science Foundation of China, and China Shijiazhuang Pharmaceutical Company Recomgen Pharmaceutical (Guangzhou).

CYP2C8 and CYP2J2 gene variations increase the risk of hypertensive intracerebral hemorrhage.

PURPOSE: Many studies have shown that cytochrome P450 (CYP) gene polymorphisms are usually associated with an increased risk of cardiovascular and cerebrovascular diseases. To explore the association of CYP2C8 and CYP2J2 gene polymorphisms with hypertensive intracerebral hemorrhage (HICH) in the Han Chinese population. METHODS: Forty HICH patients and 40 control subjects were recruited for this study. Two single nucleotide polymorphisms (SNP) (rs1058932, rs2275622) in the CYP2C8 gene and two SNPs (rs2271800, rs1155002) in the CYP2J2 gene were selected for genotyping by direct sequencing. Statistical analysis was applied to examine the effect of genetic variation on HICH. RESULTS: We found that variant alleles of CYP2C8 rs1058932 (A) and rs2275622 (C) were both significantly associated with HICH, especially in females. We also found significant associations of CYP2C8 rs1058932 (A) and rs2275622 (C) variant alleles with poor outcomes in HICH patients, especially in males. CONCLUSIONS: CYP2C8 gene polymorphisms might increase the risk of HICH in the Han Chinese population and might lead to poor outcomes. This finding adds to the body of literature supporting novel therapeutic strategies for HICH.

Clinical exome sequencing identifies novel compound heterozygous mutations of the POMT2 gene in patients with limb-girdle muscular dystrophy.

OBJECTIVE: Mutations in protein O-mannosyltransferase 2 (POMT2) (MIM#607439) have been identified in severe congenital muscular dystrophy such as Walker-Warburg syndrome (WWS) and milder limb-girdle muscular dystrophy type 2N (LGMD2N). The aim of this study is to investigate the genetic causes in patients with LGMD2N. METHODS: Three patients diagnosed with mild limb-girdle muscular dystrophy were recruited. The genetically pathogenic variant was identified by clinical exome sequencing, and healthy controls were verified by Sanger sequencing. RESULTS: Novel compound heterozygous mutations c.800A > G and c.1074_1075delinsAT of POMT2 were revealed in one affected individual by clinical exome sequencing. There was no report of these two variants and predicted to be highly damaging to the function of the POMT2. CONCLUSION: The novel variants extend the spectrum of POMT2 mutations, which promotes the prognostic value of testing for POMT2 mutations in patients with LGMD2N.

CircHIPK3 promotes neuroinflammation through regulation of the miR-124-3p/STAT3/NLRP3 signaling pathway in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is characterized as a neurodegenerative disease; however, the mechanisms regarding its pathogenesis have not been fully explored. OBJECTIVES: To explore the role of circular RNA homeodomain interacting protein kinase 3 (circHIPK3) in the progression of PD. MATERIAL AND METHODS: The circHIPK3 and microRNA-124 (miR-124) expression in human serum and cerebral fluid was detected using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) in 92 PD patients and 95 controls. The circHIPK3 was overexpressed and/or silenced in cells to explore its molecular mechanisms and effects on neuroinflammation. The production of intracellular reactive oxygen species (ROS) was assessed using 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. Interleukin 6 (IL-6), IL-1ß and tumor necrosis factor alpha (TNF-α) production in BV2 cells after the indicated treatment was measured using enzyme-linked immunosorbent assay (ELISA). The protein expression of microglia markers (cluster of differentiation molecule 11b (CD11b) and ionized calcium-binding adapter molecule 1 (Iba-1)), pyroptosis-related factors, NLR family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing C-terminal caspase recruitment domain (ASC), and caspase-1, signal transducer and activator of transcription 3 (STAT3), and phosphorylated STAT3 (p-STAT3) were examined using western blot analysis. Furthermore, the interaction between circHIPK3, miR-124 and STAT3 was predicted with bioinformatics and examined using fluorescence in situ hybridization (FISH), luciferase reporter assays, RNA pull-down, and RNA immunoprecipitation (RIP). RESULTS: The expression of circHIPK3 in human serum and cerebral fluids was significantly higher than in controls, whereas miR-124 expression was drastically reduced. In addition, lipopolysaccharide (LPS)-treated BV2 cells exhibited higher expression of circHIPK3 and lower miR-124 expression. The SH-SY5Y cells exhibited a significantly impaired viability and elevated apoptotic rate, along with an upregulation of circHIPK3 and a downregulation of miR-124 expression after being treated with supernatants collected from LPS-treated BV2 cells. The upregulation of circHIPK3 increased IL-6, IL-1ß and TNF-α secretion in BV2 cells. The protein expressions of microglia markers (CD11b and Iba-1), as well as pyroptosis-related factors, NLRP3, caspase-1, and ASC, were also increased following the expression of circHIPK3. All these effects were reversed by the addition of miR-124. CONCLUSIONS: The circHIPK3 enhances neuroinflammation by sponging miR-124 and regulating the miR-124-mediated STAT3/NALP3 pathway in PD.

Clinical Exome Sequencing Identifies NDP Gene Variants in Two Chinese Families with X-Linked Norrie Disease.

Purpose: To explore the genetic defects in two Chinese families with X-linked Norrie disease (ND). Methods: We analyzed two Chinese families with ND at molecular level through clinical exome sequencing and the variations were identified by Sanger sequencing. Results: Two genetic variations were found in the NDP gene by clinical exome sequencing, a partial deletion of 801 bp contained the whole exon 2 and a missense variant (164G>A) within codon 55 that resulted in the interchange of cysteine by phenylalanine. Clinical findings were more severe in the patients who presented the missense variant. Conclusion: We report two genetic variations in the NDP gene in Chinese that extend the mutational and phenotypic spectra of NDP gene, and also demonstrate the feasibility of clinical exome sequencing in application of molecular diagnosis.