Massive congenital immature teratoma of the lateral ventricle in a 33-day infant comorbidity with atrial septal defect.

Congenital teratomas are extremely rare and mainly midline tumors arising in the pineal regions in childhood brain tumors which are rarer cases occur in the lateral ventricle. Atrial septal defect (ASD) is detected in approximately 0.15% of newborns. We report an intracranial massive immature teratoma of the lateral ventricle in a 33-day-old infant on account of its rare location, comorbidity, and rapidly increasing size after surgery. Based on our information, this was the first case of congenital immature teratoma of the lateral ventricle comorbidity with ASD.

Linear scleroderma in a child with central nervous system involvement: clinical and radiological features.

Linear scleroderma is the most common type of localized scleroderma in children. Lesions rarely involve areas other than the skin, and nervous system involvement is even rare. We reported a case of a 6-year-old girl who was admitted to the hospital with recurrent seizures for 4 weeks. Before that, she had left frontal plaques for more than 1 year. Radiological imaging of the brain showed multiple abnormal lesions and skin biopsy of the plaques indicated scleroderma. After drug therapy, the girl had no recurrence of epilepsy, and no obvious abnormalities were found in the reexamination of neuroimaging. We performed further radiological examination on this patient and reviewed the literatures for this rare case.

Electrochemical biosensing of circulating microRNA-21 in cerebrospinal fluid of medulloblastoma patients through target-induced redox signal amplification.

Monitoring of cerebrospinal fluid (CSF) microRNAs (miRs) offers a promising option for the diagnosis and management of patients with central nervous system tumors. However, the sensitive detection of miRs in clinical CSF samples has been hindered by the ultra-low abundance of target miRs. Here, we report an electrochemical biosensor for the highly sensitive label-free detection of CSF miR-21 relying on target-induced redox signal amplification (eTIRSA). The biosensor was developed by covalently assembling the capture stands partially complementary to miR-21 on the gold nanoparticle-coated glassy carbon electrode. In the presence of miR-21, the short capture stand hybridized with the partial bases of miR-21, allowing the rest sequence of the target molecule to further bind with a long guanine-rich sequence which could specifically adsorb a number of methylene blue indicators, thus generating an amplified electrochemical redox signal, typically at a working potential of - 0.19 V (vs. SCE). The response of the surface-bound methylene blue indicators was positively correlated to the concentration of miR-21, providing a dynamic range of 0.5-80 pM and a limit of detection down to 56 fM. Moreover, the eTIRSA biosensor had high specificity with single-base resolution and exhibited good performance for label-free quantification of miR-21 in medulloblastoma cell extracts and clinical CSF samples and for accurate discrimination of medulloblastoma against non-cancer controls, indicating its potential application in CSF miR-based liquid biopsy of brain cancers.

Metabolomic Characterization of Cerebrospinal Fluid from Intracranial Bacterial Infection Pediatric Patients: A Pilot Study.

Intracranial bacterial infection remains a major cause of morbidity and mortality in neurosurgical cases. Metabolomic profiling of cerebrospinal fluid (CSF) holds great promise to gain insights into the pathogenesis of central neural system (CNS) bacterial infections. In this pilot study, we analyzed the metabolites in CSF of CNS infection patients and controls in a pseudo-targeted manner, aiming at elucidating the metabolic dysregulation in response to postoperative intracranial bacterial infection of pediatric cases. Untargeted analysis uncovered 597 metabolites, and screened out 206 differential metabolites in case of infection. Targeted verification and pathway analysis filtered out the glycolysis, amino acids metabolism and purine metabolism pathways as potential pathological pathways. These perturbed pathways are involved in the infection-induced oxidative stress and immune response. Characterization of the infection-induced metabolic changes can provide robust biomarkers of CNS bacterial infection for clinical diagnosis, novel pathways for pathological investigation, and new targets for treatment.

Circulating apelin, chemerin and omentin levels in patients with gestational diabetes mellitus: a systematic review and meta-analysis.

BACKGROUND: The available data on the significance of circulating apelin, chemerin and omentin in women with gestational diabetes mellitus (GDM) are inconsistent. This analysis includes a systematic review of the evidence associating the serum concentrations of these adipokines with GDM. METHODS: Publications through December 2019 were retrieved from PubMed, Embase, the Cochrane Library, and Web of Science. Subgroup analysis and meta-regression were conducted to evaluate sources of heterogeneity. RESULTS: Analysis of 20 studies, including 1493 GDM patients and 1488 normal pregnant women did not find significant differences in circulating apelin and chemerin levels (apelin standardized mean difference [SMD] = 0.43, 95% confidence interval (CI): - 0.40 to 1.26, P = 0.31; chemerin SMD = 0.77, 95% CI - 0.07 to 1.61, P = 0.07). Circulating omentin was significantly lower in women with GDM than in healthy controls (SMD = - 0.72, 95% CI - 1.26 to - 0.19, P = 0.007). Publication bias was not found; sensitivity analysis confirmed the robustness of the pooled results. CONCLUSIONS: Circulating omentin was decreased in GDM patients, but apelin and chemerin levels were not changed. The results suggest that omentin has potential as a novel biomarker for the prediction and early diagnosis of GDM.

Detection and Inhibition of Bacteria on a Dual-Functional Silver Platform.

Detection and inhibition of bacteria are universally required in clinics and daily life for health care. Developing a dual-functional material is challenging and in demand, engaging advanced applications for both defined bioanalysis and targeted biotoxicity. Herein, magnetic silver nanoshells are designed as a multifunctional platform for the detection and inhibition of bacteria. The optimized magnetic silver nanoshells enable direct laser desorption/ionization mass spectrometry based metabolic analysis of bacteria (≈10 µL-1 ), in complex biofluids. The serum infection process (0-10 h) is monitored by statistics toward clinical classification. Moreover, magnetic silver nanoshells facilitate surface adhesion on bacteria due to nanoscale surface roughness and thus display long-term antibacterial effects. Bacteria metabolism is studied with metabolic biomarkers (e.g., malate and lysine) identified during inhibition, showing cell membrane destruction and dysfunctional protein synthesis mechanisms. This work not only guides the design of material-based approaches for bioanalysis and biotoxicity, but contributes to bacteria-related diagnosis by using specific metabolic biomarkers for sensitive detection and new insights by monitoring metabolomic change of bacteria for antibacterial applications.

Hematopoietic stem/progenitor cell differentiation towards myeloid lineage is modulated by LIGHT/LIGHT receptor signaling.

The cytokine LT-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator on T cells (LIGHT) is a member of the tumor necrosis factor (TNF) superfamily. It is expressed primarily on activated T lymphocytes, and detectable on monocytes, granulocytes, and immune dendritic cells. It mainly plays a role in immune regulation including T cell activation and dendritic cell maturation. We recently reported its role as an inducer in embryonic stem cell differentiation, but its role in regulation of adult stem cell has not been defined. In the present study, we examined the expression of LIGHT receptor in Lin- c-kit+ Sca-1+ hematopoietic stem/progenitor cells (HSC/HPCs). We found that HSC express HVEM, a LIGHT receptor, on its surface. We further identified the role of LIGHT in promoting myeloid differentiation of HSCs driven by granulocyte-monocyte colony stimulating factor (GM-CSF). Further studies showed that LIGHT enhances both GM-CSF and GM-CSF receptor (GM-CSFR) expression in HSCs. LIGHT stimulation increases PU.1 expression in HSC/HPCs. In vivo administration of LIGHT increases the colony-forming unit-granulocyte/monocyte (CFU-GM) colony formation and plasma GM-CSF level. Altogether, the data suggest LIGHT promote myeloid differentiation of HSC/HPCs.

Hepatic regenerative potential of mouse bone marrow very small embryonic-like stem cells.

Very small embryonic-like stem cells (VSELs) are a Sca-1 (+) Lin(-) CD45(-) cell population that has been isolated from the bone marrow of mice. The similarities and differences between the mRNA profiles of VSELs and embryonic stem (ES) cells have not yet been defined. Here, we report the whole genome gene expression profile of VSELs and ES cells. We analyzed the global gene expression of VSELs and compared it with ES cells by microarray analysis. We observed that 9,521 genes are expressed in both VSELs and ES cells, 1,159 genes are expressed uniquely in VSELs, and 420 genes are expressed uniquely in ES cells. We found that although VSELs are similar to ES cells in their expression of genes associated with stem cell behavior and pluripotency, there are also differences in their mRNA expression. We further analyzed the expression of stem cell-associated genes in VSELs and ES cells, and found that there were differences in these genes. For instance, the Pkd2 and Yap1 gene were reduced in their expression in VSELs when compared with ES cells. But we also found Zfp54 gene expression was higher in VSELs compared with ES cells. More interestingly, we demonstrated that VSELs express c-kit, the stem cell factor (SCF) receptor. In vitro, SCF promoted VSEL differentiation into hepatic colonies in the presence of hepatocyte growth factor. In vivo, transplantation of VSELs directly into CCl4-induced injured livers significantly reduced serum ALT and AST levels. Therefore, these data suggest that VSELs play a role in the repair of injured livers.

Discovery of 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalen-4-carboxamides as potent and selective CB2 receptor agonists.

The design and synthesis of novel 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalen-4-carboxamide CB2 selective ligands for the potential treatment of pain is described. Compound (R,R)-25 has good balance between CB2 agonist potency and selectivity over CB1, and possesses overall favorable pharmaceutical properties. It also demonstrated robust in vivo efficacy mediated via CB2 activation in the rodent models of inflammatory and osteoarthritis pain after oral administration.

Inhibition of Mas G-protein signaling improves coronary blood flow, reduces myocardial infarct size, and provides long-term cardioprotection.

The Mas receptor is a class I G-protein-coupled receptor that is expressed in brain, testis, heart, and kidney. The intracellular signaling pathways activated downstream of Mas are still largely unknown. In the present study, we examined the expression pattern and signaling of Mas in the heart and assessed the participation of Mas in cardiac ischemia-reperfusion injury. Mas mRNA and protein were present in all chambers of human hearts, with cardiomyocytes and coronary arteries being sites of enriched expression. Expression of Mas in either HEK293 cells or cardiac myocytes resulted in constitutive coupling to the G(q) protein, which in turn activated phospholipase C and caused inositol phosphate accumulation. To generate chemical tools for use in probing the function of Mas, we performed a library screen and chemistry optimization program to identify potent and selective nonpeptide agonists and inverse agonists. Mas agonists activated G(q) signaling in a dose-dependent manner and reduced coronary blood flow in isolated mouse and rat hearts. Conversely, treatment of isolated rat hearts with Mas inverse agonists improved coronary flow, reduced arrhythmias, and provided cardioprotection from ischemia-reperfusion injury, an effect that was due, at least in part, to decreased cardiomyocyte apoptosis. Participation of Mas in ischemia-reperfusion injury was confirmed in Mas knockout mice, which had reduced infarct size relative to mice with normal Mas expression. These results suggest that activation of Mas during myocardial infarction contributes to ischemia-reperfusion injury and further suggest that inhibition of Mas-G(q) signaling may provide a new therapeutic strategy directed at cardioprotection.

BTBD10 inhibits glioma tumorigenesis by downregulating cyclin D1 and p-Akt.

The aim of this study was to investigate the role of BTBD10 in glioma tumorigenesis. The mRNA and protein levels of BTBD10 in 52 glioma tissues and eight normal brain tissues were determined using reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis, respectively. U251 human glioblastoma cells were infected with BTBD10-expressing or control lentiviruses. Cell growth was evaluated using the methyl thiazolyl tetrazolium (MTT) assay. Cell apoptosis and cell cycle distribution were analyzed using flow cytometry. Cyclin D1 and p-Akt levels were determined using western blot analysis. The results showed that BTBD10 mRNA and protein levels were significantly lower in glioma tissues than in normal brain tissues. Additionally, BTBD10 levels were significantly lower in high-grade gliomas than in low-grade tumors. Compared with control cells, U251 cells overexpressing BTBD10 exhibited decreased cell proliferation, increased cell accumulation at the G0/G1 phase, increased cell apoptosis, and decreased levels of cyclin D1 and p-Akt. These findings show that BTBD10 is downregulated in human glioma tissue and that BTBD10 expression negatively correlates with the pathological grade of the tumor. Furthermore, BTBD10 overexpression inhibits proliferation, induces G0/G1 arrest, and promotes apoptosis in human glioblastoma cells by downregulating cyclin D1- and Akt-dependent signaling pathways.

Nonenzymatic Multiamplified Electrochemical Detection of Medulloblastoma-Relevant MicroRNAs from Cerebrospinal Fluid.

The sensitive analysis of microRNAs (miRNAs) in cerebrospinal fluid (CSF) holds promise for the minimally invasive early diagnosis of brain cancers such as pediatric medulloblastoma but remains challenging due partially to a lack of facile yet sensitive sensing methods. Herein, an enzyme-free triple-signal amplification electrochemical assay for miRNA was developed by integrating the target-triggered cyclic strand-displacement reaction (TCSDR), hybridization chain reaction (HCR), and methylene blue (MB) intercalation. In this assay, the presence of target miRNA (miR-9) initiated the TCSDR and produced primers that triggered the subsequent HCR amplification to generate copious double-stranded DNAs (dsDNAs) on the electrode surface. Intercalation of a large number of MB reporters into the long nicked double helixes of dsDNAs yielded a more enhanced signal of differential pulse voltammetry. The enzyme-free multiple-amplification approach allowed for highly sensitive (detection limit: 6.5 fM) and sequence-specific (single-base mismatch resolution) detection of miR-9 from tumor cells and human CSF with minimal sample consumption (10 µL). Moreover, the clinical utilization of this method was documented by accurate discrimination of five medulloblastoma patients from the nontumoral controls. In light of its sensitivity, specificity, and convenience of use, this electrochemical method was expected to facilitate the early detection of malignant brain tumors.

Establishment of a prognostic-related microRNAs risk model for glioma by bioinformatics analysis.

BACKGROUND: To explore the specific prognosis related microRNAs (miRNAs) of glioma. METHODS: The miRNA-Seq data and clinical information of glioma patients were downloaded from the TCGA (510 cases) and GEO (GSE112009, 25 cases) database. LASSO & COX regression was used to develop a miRNA-based model for predicting patient survival in the training set (n=255), to carry out glioma prognostic related miRNAs screening, and to construct a linear risk model based on the expression profiles of seven miRNAs. COX regression analysis was used to determine whether the miRNAs risk model was an independent prognostic factor. RESULTS: Seven survival-related miRNAs (miR-140-5p, miR-145-5p, miR-148a-3p, miR-183-5p, miR-222-3p, miR-223-3p, and miR-374a-5p) were identified in the training set. This showed that the overall survival time of the high-risk group was significantly lower than that of the low-risk group in the training set, prediction set, and validation set (P<0.05). Further analysis revealed that age and Karnofsky score both affected the risk of glioma. By crossing seven potential target genes of microRNAs, 620 effective target genes were obtained and GO analysis showed that these were related to the positive regulation of cell migration, neuron migration, and the response of transforming growth factor, and KEGG analysis showed they were related to the TGF-beta signaling pathway, MAPK signaling, and AGE-RAGE signaling pathway in diabetic complications. CONCLUSIONS: Seven miRNAs which regulate target genes to participate in related signaling pathways and lead to a poor prognosis were identified as biomarkers of glioma.

Hypoxia- and dexamethasone-dependent HIF1α-glucocorticoid receptor interaction leads to degradation of glucocorticoid receptor in pituitary adenomas.

Cushing disease has a very high mortality rate and glucocorticoid resistance caused by GR down-regulation is one major reason of mortality. Although HIF1α signaling and GR signaling are involved in the pathogenesis of pituitary adenomas, it's unclear whether and how these two essential pathways could cross-talk with each other. Here, we performed a comprehensive study to investigate the reciprocal effects of HIF1α and GR on each other in AtT20 cell lines and explored the potential therapeutic effect of HIF1α inhibitor in in-vivo mouse model. We find that hypoxia up-regulated the promoter activity, mRNA and protein levels of GR and the induced GR protein was localized in cytosol. On the other hand, GR activation by its agonist DEX increased HIF1α protein through post-transcriptional mechanism. However, hypoxia and DEX show differential synergistic effects on HIF1α and GR. In hypoxia-DEX condition, HIF1α protein was further up-regulated but mainly localized in cytosol while GR was trapped and degraded in cytosol via UPS pathway. Further Co-IP experiments demonstrate that DNA binding domain of GR can interact with PASb domain of HIF1α. In a in-vivo mouse model of Cushing's disease, HIF1α inhibitor reduced HIF1α and GR protein levels, reduced tumor size and lowered the plasma concentrations of ACTH and corticosterone. In summary, we find that a novel HIF1α-GR crosstalk contributes to the pathogenesis of pituitary adenomas and HIF1α inhibitor shows potential therapeutic effects for Cushing's disease.

Potent tricyclic pyrazole tetrazole agonists of the nicotinic acid receptor (GPR109a).

Tricyclic pyrazole tetrazoles which are potent partial agonists of the high affinity niacin receptor, GPR109a, have been discovered and optimized. One of these compounds has proven to be effective at lowering free fatty acids in vitro and in vivo.

A Biomimetic Plasmonic Nanoreactor for Reliable Metabolite Detection.

Reliable monitoring of metabolites in biofluids is critical for diagnosis, treatment, and long-term management of various diseases. Although widely used, existing enzymatic metabolite assays face challenges in clinical practice primarily due to the susceptibility of enzyme activity to external conditions and the low sensitivity of sensing strategies. Inspired by the micro/nanoscale confined catalytic environment in living cells, the coencapsulation of oxidoreductase and metal nanoparticles within the nanopores of macroporous silica foams to fabricate all-in-one bio-nanoreactors is reported herein for use in surface-enhanced Raman scattering (SERS)-based metabolic assays. The enhancement of catalytical activity and stability of enzyme against high temperatures, long-time storage or proteolytic agents are demonstrated. The nanoreactors recognize and catalyze oxidation of the metabolite, and provide ratiometric SERS response in the presence of the enzymatic by-product H2O2, enabling sensitive metabolite quantification in a "sample in and answer out" manner. The nanoreactor makes any oxidoreductase-responsible metabolite a candidate for quantitative SERS sensing, as shown for glucose and lactate. Glucose levels of patients with bacterial infection are accurately analyzed with only 20 µL of cerebrospinal fluids, indicating the potential application of the nanoreactor in vitro clinical testing.

5-N,N-Disubstituted 5-aminopyrazole-3-carboxylic acids are highly potent agonists of GPR109b.

A series of 5-N,N-disubstituted-5-aminopyrazole-3-carboxylic acids were prepared and found to act as highly potent and selective agonists of the G-Protein Coupled Receptor (GPCR) GPR109b, a low affinity receptor for niacin and some aromatic d-amino acids. Little activity was observed at the highly homologous higher affinity niacin receptor, GPR109a.

A role for intestinal endocrine cell-expressed g protein-coupled receptor 119 in glycemic control by enhancing glucagon-like Peptide-1 and glucose-dependent insulinotropic Peptide release.

We recently showed that activation of G protein-coupled receptor 119 (GPR119) (also termed glucose dependent insulinotropic receptor) improves glucose homeostasis via direct cAMP-mediated enhancement of glucose-dependent insulin release in pancreatic beta-cells. Here we show that GPR119 also stimulates incretin hormone release and thus may regulate glucose homeostasis by this additional mechanism. GPR119 mRNA was found to be expressed at significant levels in intestinal subregions that produce glucose-dependent insulinotropic peptide and glucagon-like peptide (GLP)-1. Furthermore, in situ hybridization studies indicated that most GLP-1-producing cells coexpress GPR119 mRNA. In GLUTag cells, a well-established model of intestinal L-cell function, the potent GPR119 agonist AR231453 stimulated cAMP accumulation and GLP-1 release. When administered in mice, AR231453 increased active GLP-1 levels within 2 min after oral glucose delivery and substantially enhanced total glucose-dependent insulinotropic peptide levels. Blockade of GLP-1 receptor signaling with exendin(9-39) reduced the ability of AR231453 to improve glucose tolerance in mice. Conversely, combined administration of AR231453 and the DPP-4 inhibitor sitagliptin to wild-type mice significantly amplified both plasma GLP-1 levels and oral glucose tolerance, relative to either agent alone. In mice lacking GPR119, no such enhancement was seen. Thus, GPR119 regulates glucose tolerance by acting on intestinal endocrine cells as well as pancreatic beta-cells. These data also suggest that combined stimulation of incretin hormone release and protection against incretin hormone degradation may be an effective antidiabetic strategy.

Role of GPR81 in lactate-mediated reduction of adipose lipolysis.

Heavy exercise or oxygen deficit often links with higher levels of arterial lactate and lower levels of plasma free fatty acids (FFA). Treatment with lactate reduces circulating levels of FFA in vivo and lipolysis in adipose tissues in vitro. However, the underlying mechanism has remained unclear. Here we employ pharmacological and genetic approaches to show that GPR81, an orphan G-protein-coupled receptor with relatively restricted expression in the adipose tissues, functions as a receptor for lactate and can mediate an anti-lipolytic effect of lactate. GPR81 may thus function as a sensor of lactate that can modulate the FFA pool under exercise or conditions of oxygen deficit.