UTX inhibition suppresses proliferation and promotes apoptosis in patient-derived glioblastoma stem cells by modulating periostin expression.

Glioblastoma stem cells (GSCs) exert a crucial influence on glioblastoma (GBM) development, progression, resistance to therapy, and recurrence, making them an attractive target for drug discovery. UTX, a histone H3K27 demethylase, participates in regulating multiple cancer types. However, its functional role in GSCs remains insufficiently explored. This study aims to investigate the role and regulatory mechanism of UTX on GSCs. Analysis of TCGA data revealed heightened UTX expression in glioma, inversely correlating with overall survival. Inhibiting UTX suppressed GBM cell growth and induced apoptosis. Subsequently, we cultured primary GSCs from three patients, observing that UTX inhibition suppressed cell proliferation and induced apoptosis. RNA-seq was performed to analyze the gene expression changes after silencing UTX in GSCs. The results indicated that UTX-mediated genes were strongly correlated with GBM progression and regulatory tumor microenvironment. The transwell co-cultured experiment showed that silencing UTX in the transwell chamber GSCs inhibited the well plate cell proliferation. Protein-protein interaction analysis revealed that periostin (POSTN) played a role in the UTX-mediated transcriptional regulatory network. Replenishing POSTN reversed the effects of UTX inhibition on GSC proliferation and apoptosis. Our study demonstrated that UTX inhibition hindered POSTN expression by enhancing the H3K27me2/3 level, eventually resulting in inhibiting proliferation and promoting apoptosis of patient-derived GSCs. Our findings may provide a novel and effective strategy for the treatment of GBM.

Cross-platform validation of neurotransmitter release impairments in schizophrenia patient-derived NRXN1-mutant neurons.

Heterozygous NRXN1 deletions constitute the most prevalent currently known single-gene mutation associated with schizophrenia, and additionally predispose to multiple other neurodevelopmental disorders. Engineered heterozygous NRXN1 deletions impaired neurotransmitter release in human neurons, suggesting a synaptic pathophysiological mechanism. Utilizing this observation for drug discovery, however, requires confidence in its robustness and validity. Here, we describe a multicenter effort to test the generality of this pivotal observation, using independent analyses at two laboratories of patient-derived and newly engineered human neurons with heterozygous NRXN1 deletions. Using neurons transdifferentiated from induced pluripotent stem cells that were derived from schizophrenia patients carrying heterozygous NRXN1 deletions, we observed the same synaptic impairment as in engineered NRXN1-deficient neurons. This impairment manifested as a large decrease in spontaneous synaptic events, in evoked synaptic responses, and in synaptic paired-pulse depression. Nrxn1-deficient mouse neurons generated from embryonic stem cells by the same method as human neurons did not exhibit impaired neurotransmitter release, suggesting a human-specific phenotype. Human NRXN1 deletions produced a reproducible increase in the levels of CASK, an intracellular NRXN1-binding protein, and were associated with characteristic gene-expression changes. Thus, heterozygous NRXN1 deletions robustly impair synaptic function in human neurons regardless of genetic background, enabling future drug discovery efforts.

CCN3/NOV Regulates Proliferation and Neuronal Differentiation in Mouse Hippocampal Neural Stem Cells via the Activation of the Notch/PTEN/AKT Pathway.

Neural stem cells (NSCs) persist in the subgranular zone (SGZ) throughout the lifespan and hold immense potential for the repair and regeneration of the central nervous system, including hippocampal-related diseases. Several studies have demonstrated that cellular communication network protein 3 (CCN3) regulates multiple types of stem cells. However, the role of CCN3 in NSCs remains unknown. In this study, we identified CCN3 expression in mouse hippocampal NSCs and observed that supplementing CCN3 improved cell viability in a concentration-dependent manner. Additionally, in vivo results showed that the injection of CCN3 in the dentate gyrus (DG) increased Ki-67- and SOX2-positive cells while decreasing neuron-specific class III beta-tubulin (Tuj1) and doublecortin (DCX)-positive cells. Consistently with the in vivo results, supplementing CCN3 in the medium increased the number of BrdU and Ki-67 cells and the proliferation index but decreased the number of Tuj1 and DCX cells. Conversely, both the in vivo and in vitro knockdown of the Ccn3 gene in NSCs had opposite effects. Further investigations revealed that CCN3 promoted cleaved Notch1 (NICD) expression, leading to the suppression of PTEN expression and eventual promotion of AKT activation. In contrast, Ccn3 knockdown inhibited the activation of the Notch/PTEN/AKT pathway. Finally, the effects of changes in CCN3 protein expression on NSC proliferation and differentiation were eliminated by FLI-06 (a Notch inhibitor) and VO-OH (a PTEN inhibitor). Our findings imply that while promoting proliferation, CCN3 inhibits the neuronal differentiation of mouse hippocampal NSCs and that the Notch/PTEN/AKT pathway may be a potential intracellular target of CCN3. Our findings may help develop strategies to enhance the intrinsic potential for brain regeneration after injuries, particularly stem cell treatment for hippocampal-related diseases.

Deltapine 15 contributes to the genomic architecture of modern upland cotton cultivars.

Foundation parents play a critical role in the genetic constituents of the derived genotypes. Deltapine-15 (DLP-15), introduced to China in 1950, is one of the most commonly used parents for early breeding programs in China. However, the formation and inheritance patterns of genomic constituents have not been studied. Therefore, this study aimed at understanding and exploring the genomic architecture of 146 DLP-15 derived cultivars with a common foundation parent DLP-15. Population structure based on sequencing data clustered genotypes into two groups (G1 and G2) supported by principal component analysis. Further exploration led to the identification of Chr-A08 with significantly differentiated regions between two groups. Moreover, we identified genome-wide identity by descent (IBD) segments (840 segments) to understand the genomic inheritance pattern in DLP-15 derived cultivars, spanning the 20-95 Mb region on Chr-A08. Interestingly, Chr-A08 depicted a unique inheritance pattern from DLP-15 to its derived cultivars. IBD-segment-based haplotype analysis suggested significant differences among the two groups. Phenotypic trait association with DLP-derived haplotypes concerning Chr-A08 suggested a significant increase in yield and fiber quality. Furthermore, distinguished IBD segments overlapped with previously reported QTLs concerning fiber yield and quality. Our results systematically identified genomic signatures transmitted from the foundation parent DLP-15 to its derived cultivars and provided a basis for further exploiting excellent haplotypes associated with DLP-15.

Activation of metabotropic glutamate receptor 4 regulates proliferation and neural differentiation in neural stem/progenitor cells of the rat subventricular zone and increases phosphatase and tensin homolog protein expression.

Neural stem/progenitor cells (NSPCs) persist in the mammalian subventricular zone throughout life, where they can be activated in response to physiological and pathophysiological stimuli. A recent study indicates metabotropic glutamate receptor 4 (mGluR4) is involved in regulating NSPCs behaviors. Therefore, defining mGluR4 function in NSPCs is necessary for determining novel strategies to enhance the intrinsic potential for brain regeneration after injuries. In this study, mGluR4 was functionally expressed in SVZ-derived NSPCs from male Sprague-Dawley rats, in which the cyclic adenosine monophosphate concentration was reduced after treatment with the mGluR4-specific agonist VU0155041. Additionally, lateral ventricle injection of VU0155041 significantly decreased 5-bromo-2'-deoxyuridine (BrdU)+ and Ki67+ cells, while increased Doublecortin (DCX)/BrdU double-positive cells in SVZ. In cultured NSPCs, mGluR4 activation decreased the ratio of BrdU+ cells, G2/M-phase cells, and inhibited Cyclin D1 expression, whereas it increased neuron-specific class III ß-tubulin (Tuj1) expression and the number of Tuj1, DCX, and PSA-NCAM-positive cells. However, pharmacological blocking mGluR4 with the antagonist MSOP or knockdown of mGluR4 abolished the effects of VU0155041 on NSPCs proliferation and neuronal differentiation. Further investigation demonstrated that VU0155041 treatment down-regulated AKT phosphorylation and up-regulated expression of the phosphatase and tensin homolog protein (PTEN) in NSPCs culture. Moreover VU0155041-induced proliferating inhibition and neuronal differentiating amplification in NSPCs were significantly hampered by VO-OHpic, a PTEN inhibitor. We conclude that activation of mGluR4 in SVZ-derived NSPCs suppresses proliferation and enhances their neuronal differentiation, and regulation of PTEN may be involved as a potential intracellular target of mGluR4 signal. Cover Image for this issue: https://doi.org/10.1111/jnc.15052.

Activation of type 4 metabotropic glutamate receptor promotes cell apoptosis and inhibits proliferation in bladder cancer.

Bladder cancer, the second most common genitourinary malignancy, severely endangers the human health. Rising evidence suggests that metabotropic glutamate receptors (mGluRs) are involve in tumor progression. In this study, we observed that metabotropic glutamate receptor 4 (mGluR4) was functionally expressed in normal and cancerous bladder cells and its expression was positively correlated with high bladder cancer grading. We further confirmed that the activation of mGluR4 by VU0155041, an mGluR4-specific agonist, decreased cyclic adenosine monophosphate (cAMP) concentration and cell viability, promoted apoptosis and inhibited proliferation in bladder cancer cells, whereas MSOP (group III mGluR antagonist) or mGluR4 knockdown eliminated the effects of mGluR4 activity. Western blotting revealed the decreased cyclin D1 expression, increased procaspase-8/9/3 cleavage, and unbalanced Bcl-2/Bax expression in bladder cancer cell lines after mGluR4 activation, and likewise MSOP and mGluR4 knockdown abrogated the actions of mGluR4 activity. In vivo study showed that mGluR4 activation significantly inhibited tumor growth of bladder cancer via suppressing proliferation and promoting apoptosis. Furthermore, upregulation of phosphatase and tensin homolog (PTEN) and inhibition of Akt phosphorylation were also observed after mGluR4 activation. Similar with VU0155041, the Akt-specific inhibitor markedly promoted apoptosis and inhibited proliferation. Nevertheless, the PTEN-specific inhibitor significantly abolished the mGluR4 activation-induced cell apoptosis and proliferative inhibition in bladder cancer cell lines. These results indicate that mGluR4 can regulate the switch between survival and death via the cAMP/PTEN/AKT signaling pathway in bladder cancer cells. Our findings suggest that mGluR4 has diagnostic and prognostic potential for bladder cancer, and the development of mGluR4 agonist may be a promising strategy for bladder cancer treatment.

Rapid estimation of bathymetry from multispectral imagery without in situ bathymetry data.

Optimization-based semi-analytical methods (OSMs) and empirical methods (EMs) have been developed to derive bathymetry maps from satellite-based multispectral data of coral reefs, allowing for the management, monitoring, and protection of coral reefs. However, OSMs are often criticized due to the time-consuming requirements of iterative computations, yet they are praised for working without the need for in situ bathymetry data. EMs are praised for their time-saving characteristics and criticized for their need for in situ measurements. To estimate the water depth from multispectral data quickly without in situ bathymetry data, we provide a new EM that combines our previously developed OSM called the unmixing-based multispectral optimization process exemplar method (UMOPE) and an EM called Stumpf's ratio method (SRM). In the new method, reflectance values from a small number of sampled pixels and the corresponding water depths estimated by UMOPE are used to determine the regression parameters for SRM. Thus, SRM determines the upper limit of accuracy for the new method, and UMOPE determines the possibility of reaching the upper limit. The new method was evaluated using three types of imagery of Xisha Islands, namely, WorldView-2 imagery with three traditional visible bands (WV-2a), Landsat 8 imagery with four visible bands, and WV-2 imagery with six visible bands (WV-2b). The results show that the new method can perform as well as SRM for Landsat 8 data and WV-2b data with similar root mean square error values at different depths. The lack of a coastal band in WV-2a imagery may cause large errors for the new method in deep water regions, especially when the water-leaving reflectance is noise perturbed. We found that even though the depths estimated by UMOPE are not error free at different ranges of water depth, if the regression line between the depths estimated by UMOPE and the measured depths is near the 1:1 line, the new method can perform as well as SRM. The new method may facilitate the rapid estimation of bathymetry from free Landsat 8 data of optically shallow waters around the world without in situ bathymetry data.

Humidified versus nonhumidified low-flow oxygen therapy in children with Pierre-Robin syndrome: Study protocol for a randomised controlled trial.

AIMS AND OBJECTIVES: To evaluate the necessity of oxygen humidification for low-flow oxygen therapy in children with Pierre-Robin syndrome. BACKGROUND: Whether to carry out humidification or not in the low-flow oxygen delivery remains unclear, and currently, there is no published study on this issue in the population of children. Therefore, it is necessary to conduct more studies to elucidate this issue. DESIGN: A randomised controlled trial. METHODS: We attempt to report this randomised controlled trial to comply with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT). 188 children with Pierre-Robin syndrome will be expected to inclusion. The participants will be randomly divided into the humidified group (n = 94) and nonhumidified group (n = 94) at a ratio of 1:1. For humidified group, the oxygen will be routinely humidified with disposable bottle containing sterile water, whereas for nonhumidified group, the oxygen will not be humidified. Average arterial oxygen partial pressure (PaO2 ) and carbon dioxide partial pressure (PaCO2 ), incidence of ventilator-associated pneumonia (VAP), nasal cavity dryness, nasal mucosal bleeding and bacterial contamination of the humidified bottle, the cost of nasal oxygen therapy and duration of ICU stay are collected and analysed. RESULTS: The study is planned to start in May 2019, and the results will be expected in July 2020. CONCLUSIONS: This study is expected to provide a credible evidence on the necessity of routine oxygen humidification in low-flow oxygen delivery. RELEVANCE TO CLINICAL PRACTICE: Understanding the role of oxygen humidification and no humidification for low-flow oxygen therapy in the population of children is beneficial to the nursing care of healthcare providers in clinical setting.

Placement of peripherally inserted central catheter through upper versus lower limb vein in neonates: A meta-analysis of randomized controlled trials.

AIM: Peripherally inserted central catheter (PICC) is an important treatment for the drug and nutrition administration in neonates. We aimed to evaluate the effects and safety of PICC placement through upper versus lower limb vein in neonates, to provide insights into the clinical PICC nursing care. DESIGN: A meta-analysis. METHODS: We searched the Cochrane Library, Web of Science, PubMed, Science Direct, China national knowledge infrastructure, Wanfang Data Knowledge Service Platform, China Weipu Database, China Biomedical Literature Database for published randomized controlled trials (RCTs) on the placement of PICC via upper limb and lower limb venipuncture. Two reviewers independently evaluated and cross-checked the quality of the included studies in accordance with the quality standards of the Cochrane Manual. We used RevMan 5.3 software for statistical processing. RESULTS: A total of 12 RCTs were included in this meta-analysis. Meta-analysis indicated that compared with upper limb veins, PICC insertion through lower limb veins is beneficial to increase the one-time puncture success rate (relative risk [RR]  =  0.73, 95% confidence interval [CI]: 0.68-0.79) and the indwelling time (mean difference [MD] =  -3.60, 95% CI: -5.35 to -1.86), reduce the operation time (MD =  10.37, 95% CI: 7.48-13.26), estimated bleeding volume (MD =  0.55, 95% CI: 0.34-0.75), incidence of catheter ectopia (RR  =  2.46, 95% CI: 1.81-3.35), PICC-associated infection (RR  =  2.82, 95% CI: 1.65-4.83), exosmosis (RR  =  2.45, 95% CI: 1.49-4.04, p < .001) and phlebitis (RR  =  1.40, 95% CI: 1.03-1.90). No significant difference in the Incidence of catheter obstruction between the upper and lower limb veins (RR  =  1.20, 95% CI: 0.73-1.97, p = .48) was found. PUBLIC CONTRIBUTION: There are certain advantages in neonatal PICC puncture through the lower limb vein. The lower limb vein may be the preferred choice for neonatal PICC puncture.

Integrating network pharmacology and bioinformatics to explore and experimentally verify the regulatory effect of Buyang Huanwu decoction on glycolysis and angiogenesis after cerebral infarction.

ETHNOPHARMACOLOGICAL RELEVANCE: Promoting the recovery of cerebral blood circulation after cerebral infarction (CI) is an important intervention. Buyang Huanwu decoction (BHD) is a classic prescription for treating CI that promotes angiogenesis. Cytoplasmic glycolysis ischaemic-region cells after CI may be highly activated to maintain metabolic activity under hypoxia. From the perspective of long-term maintenance of glycolytic metabolism in the ischaemic area after CI, it may be beneficial to promote angiogenesis and maintain glial cell activation and neuronal survival. In this context, the regulatory relationship of lncRNAs and miRNAs with mRNAs is worthy of attention. Mining the competitive binding relationships among RNAs will aid in the screening of key gene targets post-CI. In this study, network pharmacology and bioinformatics were used to construct a ceRNA network, screen key targets, and explore the effect of glycolysis on angiogenesis during BHD-mediated CI regulation. AIM OF THE STUDY: This study aimed to explore the effect of BHD on angiogenesis after glycolysis regulation in CI. MATERIALS AND METHODS: According to the 21 active BHD ingredients we identified by our research team, we conducted network pharmacology. BHD targets that can regulate glycolysis and angiogenesis after CI were screened from the GeneCards, CTD and OMIM databases. We retrieved CI-related datasets from the GEO database and screened for differentially expressed lncRNAs and miRNAs. LncRNA‒miRNA-mRNA/TF targeting relationships were screened and organized with the miRcode, miRDB, TargetScan, miRWalk, and TransmiR v2.0 databases. Cytoscape was used to construct an lncRNA‒miRNA-mRNA/TF ceRNA network. Through BioGPS, key mRNAs/TFs in the network were screened for enrichment analysis. Animal experiments were then conducted to validate some key mRNAs/TFs and enriched signalling pathways. RESULTS: PFKFB3 and other genes may help regulate glycolysis and angiogenesis through AMPK and other signalling pathways. The anti-CI effect of BHD may involve maintaining activation of genes such as AMPK and PFKFB3 in the ischaemic cortex, maintaining moderate glycolysis levels in brain tissue, and promoting angiogenesis. CONCLUSION: BHD can regulate glycolysis and promote angiogenesis after CI through multiple pathways and targets, in which AMPK signalling pathway activation may be important.

Study on the molecular mechanisms of Liuwei Dihuang decoction against aging-related cognitive impairment based on network pharmacology and experimental verification.

Objective: Based on network pharmacology and experimental validation, this study aimed to screen the potential targets of Liuwei Dihuang decoction (LW) against mild cognitive impairment (MCI). Methods: Based on network pharmacology, this study preliminarily explored the targets and molecular mechanisms of LW in the treatment of MCI. The results showed that the mechanism of action of LW against MCI may be related to the cAMP pathway. Then, an aging cell and animal model was established to further verify its molecular mechanism. Results: A total of 23 active ingredients were identified in LW. In addition, through network pharmacological analysis, we found 22 anti-MCI active ingredients in LW, of which alisol B had the most significant effect, and predicted the potential mechanism pathway by which LW may improve MCI through the cAMP signaling pathway. Further in vivo and in vitro experiments confirmed that LW can alleviate cognitive dysfunction in aging mice and reduce D-galactose-induced senescent cells, which may be through activation of the cAMP/PKA/CREB signaling pathway. Conclusion: This study found that the traditional Chinese medicine formula LW may play a role in improving MCI by regulating the cAMP/PKA/CREB signaling pathway, which provides a reference for further clinical research on the anti-MCI effect of LW and its molecular mechanism.

Buyang Huanwu decoction promotes angiogenesis after cerebral ischemia through modulating caveolin-1-mediated exosome MALAT1/YAP1/HIF-1α axis.

BACKGROUND: Angiogenesis is an effective method for promoting neurological function recovery after cerebral ischemia (CI). Buyang Huanwu decoction (BHD) is a traditional Chinese medicinal recipe that is frequently employed for CI treatment. Previous investigations have validated that it promotes angiogenesis following CI. Nevertheless, the precise mechanism by which it does this has yet to be completely understood. OBJECTIVE: This study aims to examine the underlying mechanism through which BHD facilitates angiogenesis following CI by regulating the exosomal MALAT1/YAP1/HIF-1α signaling axis, specifically via the involvement of caveolin-1 (Cav1), an endocytosis-associated protein. METHODS: A CI model was created using middle cerebral artery occlusion (MCAO). Following the administration of multiple doses of BHD, various parameters, including the neurobehavioral score, pathological damage, and angiogenesis, were assessed in each group of mice to identify the optimal dosage of BHD for treating CI. The molecular processes underlying the angiogenic implications of BHD following CI were investigated exhaustively by employing single-cell sequencing. Finally, the involvement of Cav1 was confirmed in Cav1 knockout mice and Cav1-silenced stably transfected strains to validate the mechanism by which BHD increases angiogenesis following CI. RESULTS: BHD could promote angiogenesis after CI. Single-cell sequencing results suggested that its potential mechanism of action might be connected with Cav1 and the exosomal MALAT1/YAP1/HIF-1α signaling axis. BHD could promote angiogenesis after CI by regulating the exosomal MALAT1/YAP1/HIF-1α axis through Cav1, as validated in vivo and in vitro experiments. Accordingly, Cav1 may be a key target of BHD in promoting angiogenesis after CI. CONCLUSION: This investigation represents the initial attempt to comprehensively ascertain the underlying mechanism of action of BHD in treating CI using single-cell sequencing, gene-knockout mice, and stable transfected cell lines, potentially associated with the modulation of the exosomal MALAT1/YAP1/HIF-1α axis by Cav1. Our findings offer novel empirical evidence for unraveling the regulatory pathways through which Cav1 participates in angiogenesis following CI and shed light on the potential mechanisms of BHD.

Efficient generation of functional neurons from mouse embryonic stem cells via neurogenin-2 expression.

The production of induced neuronal (iN) cells from human embryonic stem cells (ESCs) and induced pluripotent stem cells by the forced expression of proneural transcription factors is rapid, efficient and reproducible. The ability to generate large numbers of human neurons in such a robust manner enables large-scale studies of human neural differentiation and neuropsychiatric diseases. Surprisingly, similar transcription factor-based approaches for converting mouse ESCs into iN cells have been challenging, primarily because of low cell survival. Here, we provide a detailed approach for the efficient and reproducible generation of functional iN cells from mouse ESC cultures by the genetically induced expression of neurogenin-2. The resulting iN cells display mature pre- and postsynaptic specializations and form synaptic networks. Our method provides the basis for studying neuronal development and enables the direct comparison of cellular phenotypes in mouse and human neurons generated in an equivalent way. The procedure requires 14 d and can be carried out by users with expertise in stem cell culture.

Parathyroid Hormone-Related Protein Promotes the Proliferation of Patient-Derived Glioblastoma Stem Cells via Activating cAMP/PKA Signaling Pathway.

Background and Objectives: Glioblastoma (GBM) is an aggressive primary brain tumor characterized by its heterogeneity and high recurrence and lethality rates. Glioblastoma stem cells (GSCs) play a crucial role in therapy resistance and tumor recurrence. Therefore, targeting GSCs is a key objective in developing effective treatments for GBM. The role of Parathyroid hormone-related peptide (PTHrP) in GBM and its impact on GSCs remains unclear. This study aimed to investigate the effect of PTHrP on GSCs and its potential as a therapeutic target for GBM. Methods and Results: Using the Cancer Genome Atlas (TCGA) database, we found higher expression of PTHrP in GBM, which correlated inversely with survival. GSCs were established from three human GBM samples obtained after surgical resection. Exposure to recombinant human PTHrP protein (rPTHrP) at different concentrations significantly enhanced GSCs viability. Knockdown of PTHrP using target-specific siRNA (siPTHrP) inhibited tumorsphere formation and reduced the number of BrdU-positive cells. In an orthotopic xenograft mouse model, suppression of PTHrP expression led to significant inhibition of tumor growth. The addition of rPTHrP in the growth medium counteracted the antiproliferative effect of siPTHrP. Further investigation revealed that PTHrP increased cAMP concentration and activated the PKA signaling pathway. Treatment with forskolin, an adenylyl cyclase activator, nullified the antiproliferative effect of siPTHrP. Conclusions: Our findings demonstrate that PTHrP promotes the proliferation of patient-derived GSCs by activating the cAMP/PKA signaling pathway. These results uncover a novel role for PTHrP and suggest its potential as a therapeutic target for GBM treatment.

Buyang Huanwu Decoction alleviates cerebral ischemic injury through modulating caveolin-1-mediated mitochondrial quality control.

Introduction: Mitochondrial quality control (MQC) is an important mechanism of neural repair after cerebral ischemia (CI). Recent studies have shown that caveolin-1 (Cav-1) is an important signaling molecule in the process of CI injury, but its mechanism of regulating MQC after CI is still unclear. Buyang Huanwu Decoction (BHD) is a classic traditional Chinese medicine formula that is often used to treat CI. Unfortunately, its mechanism of action is still obscure. Methods: In this study, we tested the hypothesis that BHD can regulate MQC through Cav-1 and exert an anti-cerebral ischemia injury effect. We used Cav-1 knockout mice and their homologous wild-type mice, replicated middle cerebral artery occlusion (MCAO) model and BHD intervention. Neurobehavioral scores and pathological detection were used to evaluate neurological function and neuron damage, transmission electron microscopy and enzymology detection of mitochondrial damage. Finally, western blot and RT-qPCR expression of MQC-related molecules were tested. Results: After CI, mice showed neurologic impairment, neuronal damage, and significant destruction of mitochondrial morphology and function, and MQC was imbalanced. Cav-1 deletion aggravated the damage to neurological function, neurons, mitochondrial morphology and mitochondrial function after CI, aggravated the imbalance of mitochondrial dynamics, and inhibited mitophagy and biosynthesis. BHD can maintain MQC homeostasis after CI through Cav-1 and improve CI injury. Discussion: Cav-1 can affect CI injury by regulating MQC, and this mechanism may be another target of BHD for anti-cerebral ischemia injury.

A UPLC-Q-TOF/MS and network pharmacology method to explore the mechanism of Anhua fuzhuan tea intervention in nonalcoholic fatty liver disease.

The possible mechanism by which the active components of Anhua fuzhuan tea act on FAM in NAFLD lesions was investigated. 83 components of Anhua fuzhuan tea were analysed by UPLC-Q-TOF/MS. Luteolin-7-rutinoside and other compounds were first discovered in fuzhuan tea. According to the TCMSP database and the Molinspiration website tool to predict and review the literature reports, 78 compounds were identified in fuzhuan tea with possible biological activities. The PharmMapper, Swiss target prediction, and SuperPred databases were used to predict the action targets of biologically active compounds. The GeneCards, CTD, and OMIM databases were mined for NAFLD and FAM genes. Then, a fuzhuan Tea-NAFLD-FAM Venn diagram was constructed. Using the STRING database and CytoHubba program of Cytoscape software, protein interaction analysis was performed, and 16 key genes, including PPARG, were screened. GO function and KEGG enrichment analyses of the screened key genes showed that Anhua fuzhuan tea may regulate FAM in the process of NAFLD through the AMPK signalling pathway, nonalcoholic fatty liver disease pathway, etc. After constructing an active ingredient-key target-pathway map with Cytoscape software, combined with literature reports and BioGPS database analysis, we believe that among the 16 key genes, SREBF1, FASN, ACADM, HMGCR, and FABP1 have potential in the treatment of NAFLD. Animal experiments confirmed the effect of Anhua fuzhuan tea in improving NAFLD and confirmed that this tea can interfere with the gene expression of the above five targets by the AMPK/PPAR pathway, providing support for Anhua fuzhuan tea interfering with FAM in NAFLD lesions.

Integrative analyses highlight functional regulatory variants associated with neuropsychiatric diseases.

Noncoding variants of presumed regulatory function contribute to the heritability of neuropsychiatric disease. A total of 2,221 noncoding variants connected to risk for ten neuropsychiatric disorders, including autism spectrum disorder, attention deficit hyperactivity disorder, bipolar disorder, borderline personality disorder, major depression, generalized anxiety disorder, panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder and schizophrenia, were studied in developing human neural cells. Integrating epigenomic and transcriptomic data with massively parallel reporter assays identified differentially-active single-nucleotide variants (daSNVs) in specific neural cell types. Expression-gene mapping, network analyses and chromatin looping nominated candidate disease-relevant target genes modulated by these daSNVs. Follow-up integration of daSNV gene editing with clinical cohort analyses suggested that magnesium transport dysfunction may increase neuropsychiatric disease risk and indicated that common genetic pathomechanisms may mediate specific symptoms that are shared across multiple neuropsychiatric diseases.

Humidified versus nonhumidified low-flow oxygen therapy in children with Pierre-Robin syndrome: A randomized controlled trial.

BACKGROUND: Humidification is an important process in clinical oxygen therapy. We aimed to evaluate the effects and safety of humidified versus nonhumidified low-flow oxygen therapy in children with Pierre-Robin syndrome. METHODS: This study was an open-label, single-centered randomized controlled trial (RCT) with a parallel group design. The study protocol has been registered in Chinese Clinical Trial Registry (ChiCTR1900021584). The children were randomized to the humidified versus nonhumidified groups. Average arterial oxygen partial pressure (PaO2) and carbon dioxide partial pressure (PaCO2), incidence of ventilator-associated pneumonia (VAP), nasal cavity dryness, nasal mucosal bleeding and bacterial contamination of the humidified bottle, the cost of nasal oxygen therapy and duration of intensive care unit (ICU) stay were analyzed. RESULTS: A total of 213 children with Pierre-Robin syndrome were included. There were no significant differences in the gender, age, weight, prematurity, duration of anesthesia and surgery duration of mandibular traction between humidified group and nonhumidified group (all P > .05). No significant differences in the average arterial PaO2 and PaCO2 level on the postoperative day 1, 2, and ICU discharge between humidified group and nonhumidified group were found (all P > .05). There were no significant differences in the incidence of nasal cavity dryness, nasal mucosal bleeding, bacterial contamination and VAP, the duration of ICU stay between humidified group and nonhumidified group (all P > .05). The cost of nasal oxygen therapy in the humidified group was significantly less than that of nonhumidified group (P = .013). CONCLUSIONS: Humidifying the oxygen with cold sterile water in the low-flow oxygen therapy in children may be not necessary. Future RCTs with lager sample size and rigorous design are warranted to further elucidate the effects and safety of humidified versus nonhumidified low-flow oxygen therapy.

Periostin attenuates oxygen and glucose deprivation-induced death of mouse neural stem cells via inhibition of p38 MAPK activation.

Promoting neural stem cells (NSCs) survival in the harsh niche is essential to cell replacement therapy for various central nervous system diseases. As an integral component of the extracellular matrix, Periostin (POSTN) has been shown to protect various cell types from hypoxia-ischemia damage. This study aimed to investigate the neuroprotective effects of POSTN on NSCs injury induced by oxygen and glucose deprivation (OGD). Under challenge with OGD, cell viability significantly decreased in cultured mouse NSCs, and supplement POSTN rescued cell viability in a concentration-dependent manner, as shown by CCK-8. TUNEL and propidium iodide/Hoechst staining showed that POSTN pretreatment protected NSCs against OGD-induced apoptosis. Western blot assay demonstrated that POSTN pretreatment inhibited cleavage of caspase-3 and restored the balance of Bcl-2/Bax. And pretreatment with cilengitide (an inhibitor of POSTN receptors) abolished the protective effect of POSTN. Further investigation demonstrated that supplement POSTN inhibited phosphorylation of p38 in a concentration-dependent manner. Moreover, the neuroprotective effect of POSTN was hampered by anisomycin, an activator of p38. We conclude that POSTN pretreatment in cultured mouse NSCs mitigated OGD-induced cell death, and inhibition of the p38 MAPK pathway might be one of the underlying mechanisms. Our findings may provide a novel strategy for enhancing both endogenous and exogenous NSCs survival after ischemia and hypoxia injury.