Clinical characterization of EFHD2 (swiprosin-1) in Glioma-associated macrophages and its role in regulation of immunosuppression.

Glioblastoma has been extensively studied due to its high mortality and short survival. The evolution mechanism of tumor-associated macrophages (TAMs) to Glioma-associated microglia and macrophages (GAMs) in the tumor microenvironment (TME) remains to be elucidated. The tumor cell-to-cell interaction patterns have not been well defined yet. The EF-Hand Domain Family Member D2 (EFHD2) has been reported to be differentially expressed as an immunomodulatory molecule in a variety of cancers. But large-scale clinical data from multiple ethnic communities have not been used to investigate the role of EFHD2 in glioma. RNA-seq data from 313 or 657 glioma patients from the Chinese Glioma Genome Atlas (CGGA) database and 603 glioma patients from the Cancer Genome Atlas (TCGA) database were analyzed retrospectively. Cell localization was performed using single-cell sequencing data from the CGGA database and the GSE131928 dataset. Mouse glioma cell lines and primary macrophages isolated from Efhd2 knockout mice were co-cultured to validate the immunomodulatory effects of EFHD2 on macrophages and the remodeling of TME of glioblastoma. EFHD2 is enriched in high-grade gliomas, isocitrate dehydrogenase wild-type, and 1p/19q non-co-deficient gliomas. It is a potential biomarker of glioma-proneuronal subtypes and an independent prognostic factor for overall survival in patients with malignant glioblastoma. EFHD2 regulates the monocyte-macrophage system function and positively correlates with immunosuppressive checkpoints. Further experimental data demonstrates that Efhd2 influences the polarization state of GAMs and inhibits the secretion of TGF-ß1. In vitro experiments have revealed that macrophages lacking Efhd2 suppress the vitality of two glioma cell lines and decelerate the growth of glioma xenografts. In conclusion, EFHD2 promises to be a key target for TME-related immunotherapy.

[Mechanism of Guizhi Gancao Decoction against myocardial ischemia-reperfusion injury based on network pharmacology and experimental verification].

This study employed network pharmacology to investigate the effect of Guizhi Gancao Decoction(GGD) on myocardial ischemia-reperfusion injury(MI/RI) in rats and decipher the underlying mechanism. Firstly, the chemical components and targets of GGD against MI/RI were searched against the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), SwissTargetPrediction, and available articles. STRING and Cytoscape 3.7.2 were used to establish the protein-protein interaction(PPI) network for the common targets, and then Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses were carried out for the core targets. The "drug-active component-target-pathway" network was built. Furthermore, molecular docking between key active components and targets was conducted in AutoDock Vina. Finally, the rat model of MI/RI was established, and the myocardial infarction area was measured. Hematoxylin-eosin(HE) staining and transmission electron microscopy(TEM) were employed to detect cardiomyocyte pathology and ultrastructural changes. Western blot was employed to determine the expression of related proteins in the myocardial tissue. A total of 75 chemical components of GGD were screened out, corresponding to 318 targets. The PPI network revealed 46 core targets such as tumor protein p53(TP53), serine/threonine kinase 1(AKT1), signal transducer and activator of transcription 3(STAT3), non-receptor tyrosine kinase(SRC), mitogen-activated protein kinase 1(MAPK1), MAPK3, and tumor necrosis factor(TNF). According to GO and KEGG enrichment analyses, the core targets mainly affected the cell proliferation and migration, signal transduction, apoptosis, and transcription, involving advanced glycation end products-receptor(AGE-RAGE), MAPK and other signaling pathways in cancers and diabetes complications. The molecular docking results showed that the core components of GGD, such as licochalcone A,(+)-catechin, and cinnamaldehyde, had strong binding activities with the core target proteins, such as MAPK1 and MAPK3. The results of animal experiments showed that compared with the model group, GGD significantly increase superoxide dismutase, decreased malondialdehyde, lactate dehydrogenase, and creatine kinase-MB, and reduced the area of myocardial infarction. HE staining and TEM results showed that GGD pretreatment restored the structure of cardiomyocytes and alleviated the pathological changes and ultrastructural damage of mitochondria in the model group. In addition, GGD significantly down-regulated the phosphorylation of c-Jun N-terminal kinase and p38 and up-regulate that of extracellular regulated kinases 1/2 in the myocardial tissue. The results suggested that GGD may exert the anti-MI/RI effect by regulating the MAPK signaling pathway via the synergistic effects of Cinnamomi Ramulus and Glycyrrhizae Radix et Rhizoma.

A cysteine-rich secretory protein involves in phytohormone melatonin mediated plant resistance to CGMMV.

BACKGROUND: Melatonin is considered to be a polyfunctional master regulator in animals and higher plants. Exogenous melatonin inhibits plant infection by multiple diseases; however, the role of melatonin in Cucumber green mottle mosaic virus (CGMMV) infection remains unknown. RESULTS: In this study, we demonstrated that exogenous melatonin treatment can effectively control CGMMV infection. The greatest control effect was achieved by 3 days of root irrigation at a melatonin concentration of 50 µM. Exogenous melatonin showed preventive and therapeutic effects against CGMMV infection at early stage in tobacco and cucumber. We utilized RNA sequencing technology to compare the expression profiles of mock-inoculated, CGMMV-infected, and melatonin+CGMMV-infected tobacco leaves. Defense-related gene CRISP1 was specifically upregulated in response to melatonin, but not to salicylic acid (SA). Silencing CRISP1 enhanced the preventive effects of melatonin on CGMMV infection, but had no effect on CGMMV infection. We also found exogenous melatonin has preventive effects against another Tobamovirus, Pepper mild mottle virus (PMMoV) infection. CONCLUSIONS: Together, these results indicate that exogenous melatonin controls two Tobamovirus infections and inhibition of CRISP1 enhanced melatonin control effects against CGMMV infection, which may lead to the development of a novel melatonin treatment for Tobamovirus control.

A systematic review and meta-analysis of outcomes between dusting and fragmentation in retrograde intrarenal surgery.

OBJECTIVES: Comparing stone-free rates and associated outcome measures between two surgical modalities of lithotripsy fragmentation and removal or spontaneous passage of dust during retrograde intrarenal surgery (RIRS). METHODS: In March 2023, we conducted a literature search in several widely used databases worldwide, including PubMed, Embase, and Google Scholar. We only considered English articles and excluded pediatric patients. Reviews and protocols without any published data were excluded. We also excluded articles with conference abstracts and irrelevant content. We used the Cochran-Mantel-Haenszel method and random-effects models to assess inverse variances and 95% confidence intervals (CIs) for mean differences in categorical variables. The results were reported as odds ratios (ORs) and 95% CIs. Statistical significance was set at p < 0.05. RESULTS: Our final meta-analysis included nine articles, comprising two randomized controlled trials (RCTs) and seven cohort studies. The total number of patients included in these studies was 1326, and all studies used holmium laser lithotripsy. The pooled analysis of the dust and fragmentation groups showed that the fragmentation group had a higher stone-free rate (OR 0.6; 95% CI 0.41 - 0.89; p = 0.01); the dust group had a shorter operative time (WMD - 11.6 min; 95% CI - 19.56 - -3.63; p = 0.004); and the dust group had a higher retreatment rate (OR 2.03; 95% CI 1.31 - 3.13; p = 0.001). There was no statistically significant difference between the two groups in terms of length of hospital stay, overall complications, or postoperative fever. CONCLUSIONS: Our results showed that both procedures could be safely and effectively used for upper ureteral and renal calculi lithotripsy, the dust group had potential advantages over the fragmentation group in terms of the operation time, and the fragmentation group had certain advantages in terms of stone-free rate and retreatment rate.

Saikosaponin D alleviates cancer cachexia by directly inhibiting STAT3.

Cancer cachexia is a metabolic syndrome that is characterized by progressive loss of skeletal muscle mass, and effective therapeutics have yet to be developed. Saikosaponin D (SSD), a major bioactive component of Radix Bupleuri, exhibits antiinflammatory, anti-tumor, anti-oxidant, anti-viral, and hepatoprotective effects. In this study, we demonstrated that SSD is a promising agent for the treatment of cancer cachexia. SSD could alleviate TCM-induced myotube atrophy and inhibit the expression of E3 ubiquitin ligases muscle RING-finger containing protein-1 (MuRF1) and muscle atrophy Fbox protein (Atrogin-1/MAFbx) in vitro. Moreover, SSD suppressed the progression of cancer cachexia, with significant improvements in the loss of body weight, gastrocnemius muscle, and tibialis anterior muscle mass in vivo. Mechanism investigations demonstrated that SSD could directly bind to STAT3 and specifically inhibit its phosphorylation as well as its transcriptional activity. Overexpression of STAT3 partially abolished the inhibitory effect of SSD on myotube atrophy, indicating that the therapeutic effect of SSD was attributed to STAT3 inhibition. These findings provide novel strategies for treatment of cancer cachexia by targeting STAT3, and SSD may be a promising drug candidate for cancer cachexia.

Ultrastable Polyoxometalate-Encapsulated Supramolecular Metal-Organic Nanotubes for Single-Crystal Proton Conduction.

Two unique polyoxometalate (POM)-encapsulated tubular materials with the formula K(H2O)6[M6(btp)6(H2O)22](P2W18O62)3(Hbtp)5(btp)3·52H2O [M = Mn (1) and Co (2); btp = 2,6-bis(1,2,4-triazol-1-yl)pyridine] were designed and synthesized based on the Dawson POM and V-type btp ligand, as confirmed by IR, X-ray diffraction (XRD), and element analysis. Single-crystal XRD analyses of compound 1 show that two kinds of remarkable metal-organic supramolecular nanotubes, including trigonal and hexagonal nanotubes, are constructed along the c-axis direction via π···π-packing interactions between {Mn3(btp)3} rings and the btp ligands, of which [α-P2W18O62]6- anions are confined in channels, making the entire structure extraordinarily stable. Meanwhile, the coordinated [α-P2W18O62]6- anion within the hexagonal channel makes the channel highly hydrophilic and attracts a number of guest water molecules to fill in the free space, conducive to proton transport. Therefore, the single-crystal sample of 1 exhibits a high proton conductivity of 6.39 × 10-3 S cm-1 along one-dimensional channels, 30 times higher than that of a pellet sample at 358 K and 98% relative humidity.

ARG1 as a promising biomarker for sepsis diagnosis and prognosis: evidence from WGCNA and PPI network.

BACKGROUND: Sepsis is a life-threatening multi-organ dysfunction caused by the dysregulated host response to infection. Sepsis remains a major global concern with high mortality and morbidity, while management of sepsis patients relies heavily on early recognition and rapid stratification. This study aims to identify the crucial genes and biomarkers for sepsis which could guide clinicians to make rapid diagnosis and prognostication. METHODS: Preliminary analysis of multiple global datasets, including 170 samples from patients with sepsis and 110 healthy control samples, revealed common differentially expressed genes (DEGs) in peripheral blood of patients with sepsis. After Gene Oncology (GO) and pathway analysis, the Weighted Gene Correlation Network Analysis (WGCNA) was used to screen for genes most related with clinical diagnosis. Also, the Protein-Protein Interaction Network (PPI Network) was constructed based on the DEGs and the hub genes were found. The results of WGCNA and PPI network were compared and one shared gene was discovered. Then more datasets of 728 experimental samples and 355 control samples were used to prove the diagnostic and prognostic value of this gene. Last, we used real-time PCR to confirm the bioinformatic results. RESULTS: Four hundred forty-four common differentially expressed genes in the blood of sepsis patients from different ethnicities were identified. Fifteen genes most related with clinical diagnosis were found by WGCNA, and 24 hub genes with most node degrees were identified by PPI network. ARG1 turned out to be the unique overlapped gene. Further analysis using more datasets showed that ARG1 was not only sharply up-regulated in sepsis than in healthy controls, but also significantly high-expressed in septic shock than in non-septic shock, significantly high-expressed in severe or lethal sepsis than in uncomplicated sepsis, and significantly high-expressed in non-responders than in responders upon early treatment. These all demonstrate the performance of ARG1 as a key biomarker. Last, the up-regulation of ARG1 in the blood was confirmed experimentally. CONCLUSIONS: We identified crucial genes that may play significant roles in sepsis by WGCNA and PPI network. ARG1 was the only overlapped gene in both results and could be used to make an accurate diagnosis, discriminate the severity and predict the treatment response of sepsis.

Polydatin alleviates DSS- and TNBS-induced colitis by suppressing Th17 cell differentiation via directly inhibiting STAT3.

Inflammatory bowel disease (IBD) is a non-specific chronic intestinal inflammatory disease, often presenting with abdominal pain, diarrhea, bloody stool, anorexia, and body loss. It is difficult to cure completely and a promising treatment is urgently needed. Natural compounds can offer promising chemical agents for treatment of diseases. Polydatin is a natural ingredient extracted from the dried rhizome of Polygonum cuspidatum, which has anti-inflammatory, anti-tumor, and dementia protection activities. The purpose of this study was to evaluate the therapeutic effect of polydatin on IBD and explore its possible mechanism. We found that polydatin could effectively suppress the differentiation of Th17 cells in vitro, but had no effect on the differentiation of Treg cells. Polydatin significantly alleviated colitis induced by dextran sulfate sodium (DSS) and 2, 4, 6-trinitrobenzenesulfonic acid (TNBS) in mice, and dramatically decreased the proportion of Th17 cells in spleen and mesenteric lymph nodes. Mechanism investigations revealed that polydatin specifically inhibited signal transducer and activator of transcription 3 (STAT3) phosphorylation by directly binding to STAT3, leading to Th17 cell reduction and thereby alleviating colitis. These findings provide novel insights into the anti-colitis effect of polydatin, which may be a promising drug candidate for the treatment of IBD.

[Research progress on activities and mechanisms of anti-hepatitis B virus drugs].

Hepatitis B virus(HBV) is the pathogen causing hepatitis B, which is characterized by strong infectivity, high incidence, and widespread prevalence and has seriously threatened human health and affected their quality of life. Anti-HBV drugs in western medicine mainly include nucleosides(nucleic acids) and interferons, among which nucleosides(nucleic acids) are used more often. Due to the easy development of drug resistance, their therapeutic effects are not remarkable. Interferons can easily cause serious adverse reactions such as liver injury. Anti-HBV drugs in traditional Chinese medicine mainly include single Chinese herbs(Artemisiae Scopariae Herba, Artemisiae Annuae Herba, Salviae Miltiorrhizae Radix et Rhizoma, etc.) and Chinese herbal compounds(Yinchenhao Decoction, Xiaochaihu Decoction, Tiaogan Huaxian Pills, etc.), whose chemical compositions and action targets have not been fully identified. The combined medication is better than single medication, in that the former can improve drug resistance, make up each other's deficiencies, reduce adverse reactions, and prolong the action time. This study reviewed the anti-HBV activities and mechanisms of western drugs, Chinese herbs, and combined medications, in order to provide reference for the development and research of new anti-HBV drugs.

Isopolymolybdate-Based Cobalt/Nickel Coordination Polymers Constructed by V-Type N-Donor Ligands.

Four novel isopolymolybdate-based coordination polymers (CPs), constructed from 2,6-bis(1,2,4-triazol-1-yl)pyridine (btp), 1,3-bis(4H-1,2,4-triazol-4-yl)benzene (btb), and 3,5-bis(1-imidazolium)pyridine (bip), have been synthesized under a hydrothermal method: {[Co(btp)(H2O)2(ß-Mo8O26)0.5]·3H2O}n (1), [Ni(btp)(H4Mo6O22)0.5]n (2), [Co(btb)(H2O)(ß-Mo8O26)0.5]n (3), and {[Co(Hbip)2(H2O)2(γ-Mo8O26)]·6H2O}n (4). Complex 1 exhibits one 3D framework with an unexpected 3-nodal 2,4,6-c net topology containing the 1D {ß-Mo8O26}n chains, 6-connected CoII centers, and V-type coordinated btp ligands. The neighboring [Mo6O22]4- anions of complex 2 are bridged by the NiII centers to build one 2D {Ni2(Mo6O22)} network, which is arranged into the 3D framework through the weak π···π stacking interactions. In compound 3, one 3D framework is formed by the adjacent 1D {Co2(btp)2}n chains connected by {ß-Mo8O26}n units, which demonstrates a rare 4,6-c fsc topology. In complex 4, one 2D {Co(Hbip)2(γ-Mo8O26)} layer with a (4, 4) network is connected to one 3D hydrogen-bonding framework via N-H···O and O-H···O hydrogen bonds. Magnetic data indicate that complexes 1 and 4 exhibit antiferromagnetic behaviors, whereas complexes 2 and 3 reveal spin-canting magnetic behavior and metamagnetic behavior, respectively. In addition, the proton conductivity of complexes 3 and 4 was investigated, showing that compound 4 has good proton conductivity at 85 °C and a relative humidity of 98% RH.

RNA-binding protein HuR regulates translation of vitamin D receptor modulating rapid epithelial restitution after wounding.

Homeostasis of the intestinal epithelium is tightly regulated by numerous extracellular and intracellular factors including vitamin D and the vitamin D receptor (VDR). VDR is highly expressed in the intestinal epithelium and is implicated in many aspects of gut mucosal pathophysiology, but the exact mechanism that controls VDR expression remains largely unknown. The RNA-binding protein human antigen R (HuR) regulates the stability and translation of target mRNAs and thus modulates various cellular processes and functions. Here we report a novel role of HuR in the posttranscriptional control of VDR expression in the intestinal epithelium. The levels of VDR in the intestinal mucosa decreased significantly in mice with ablated HuR, compared with control mice. HuR silencing in cultured intestinal epithelial cells (IECs) also reduced VDR levels, whereas HuR overexpression increased VDR abundance; neither intervention changed cellular Vdr mRNA content. Mechanistically, HuR bound to Vdr mRNA via its 3'-untranslated region (UTR) and enhanced VDR translation in IECs. Moreover, VDR silencing not only inhibited IEC migration over the wounded area in control cells but also prevented the increased migration in cells overexpressing HuR, although it did not alter IEC proliferation in vitro and growth of intestinal organoids ex vivo. The human intestinal mucosa from patients with inflammatory bowel diseases exhibited decreased levels of both HuR and VDR. These results indicate that HuR enhances VDR translation by directly interacting with its mRNA via 3'-UTR and that induced VDR by HuR is crucial for rapid intestinal epithelial restitution after wounding.

Icariin Ameliorates Amyloid Pathologies by Maintaining Homeostasis of Autophagic Systems in Aß1-42-Injected Rats.

Macroautophagy, a sole pathway for dysfunctional organelles or aggregated proteins turnover, has been implicated in the early development of Alzheimer's disease (AD). Previous studies have found that reversal of autophagy dysfunction in APP transgenic mice ameliorates amyloid pathologies. Icariin (ICA), the main component from traditional Chinese herb Epimedium brevicornu Maxim., can reduce accumulations of amyloid-ß (Aß) peptide in vivo and in vitro, but the mechanism remains unclear. Here, we explored the effects of ICA on autophagy-lysosomal pathway in intracerebroventricular (icv) injection of human Aß1-42 peptide rats. We demonstrated that feeding the rats with ICA (30 mg/kg, 60 mg/kg and 90 mg/kg rat, per os) for 4 weeks rescued the Aß1-42-induced spatial memory impairments, reduced endogenous rat Aß42 tested by ELISA and decreased Aß accumulation using 6E10 antibody. Furthermore, Aß1-42 induced strong autophagy response, however ICA decreased the levels of microtubule-associated protein 1 light chain 3 (LC3) II/LC3I, Beclin1, Cathepsin D (Cat D) and brain lysosomal Cathepsin D activity. We also observed that ICA enhanced the phosphorylation of protein kinase B (PKB/AKT) and p70 ribosomal protein S6 kinase (p70S6K). In addition, ICA arrested Aß1-42-induced cells loss, mitochondrias damage, nuclear membranes unclear and abundant nucleas chromatin agglutinates in hippocampus, lessened the expression of Cleaved-caspase-3, brain oxidative stress, astroglial activation. These findings suggest that ICA can ameliorate amyloid pathologies with improving autophagy-lysosome function and Chinese materia medica may be potential for AD treatment.

Utility of Contrast-Enhanced Ultrasound for the Assessment of Skeletal Muscle Perfusion in Diabetes Mellitus: A Meta-Analysis.

BACKGROUND This study evaluated the effectiveness of contrast-enhanced ultrasonography for the assessment of skeletal muscle perfusion in diabetes mellites. MATERIAL AND METHODS Electronic databases (Embase, Google Scholar, Ovid, and PubMed) were searched for required articles, and studies were selected by following pre-determined eligibility criteria. Meta-analyses of mean differences or standardized mean differences (SMD) were performed to evaluate the significance of difference in contrast-enhanced ultrasonography measured muscle perfusion indices between patients with diabetes and healthy individuals or between basal and final values of perfusion indices after insulin manipulation or physical exercise in patients with diabetes or healthy individuals. RESULTS There were 15 studies included, with 279 patients with diabetes and 230 healthy individuals in total. The age of the study patients with diabetes mellitus was 55.8 years (95% CI: 49.6 years, 61.9 years) and these patients had disease for 11.4 years (95% CI: 7.7 years, 15.1 years). The percentage of males in group of patients with diabetes was 66% (95% CI: 49%, 84%), body mass index was 29.4 kg/m² (95% CI: 26.5 kg/m², 32.3 kg/m²), hemoglobin A1c was 7.3% (95% CI: 6.7%, 7.9%), and fasting plasma glucose was 149 kg/m² (95% CI: 118 kg/m², 179 kg/m²). Time to peak intensity after provocation was significantly higher in patients with diabetes than in healthy individuals (SMD 1.18 [95% CI: 0.60, 1.76]; P<0.00001). In patients with diabetes, insulin administration did not improve contrast-enhanced ultrasonography measured muscle perfusion indices but exercise improved muscle perfusion but at a level that was statistically non-significant (SMD between basal and post-exercise values (1.03 [95% CI: -0.14, 2.20]; P=0.08). In healthy individuals, lipids in addition to insulin administration was associated with significantly reduced blood volume and blood flow. CONCLUSIONS Our review showed that the use of contrast-enhanced ultrasonography showed that diabetes mellitus was associated with altered muscle perfusion in which insulin-mediated metabolic changes played an important role.

[Identification and determination of phenolic acids and flavonoids in Artemisiae Argyi Folium by UPLC-DAD-MS].

The study aims to qualitatively and quantitatively analyze phenolic acids and flavonoids in Artemisiae Argyi Folium cultivated in Qichun(Qiai) for the quality control of this genuine regional herbs. UPLC-LTQ-Orbitrap-MS was used for rapid separation and structural identification of the constituents. Samples were separated on an UPLC column(2. 1 mm×100 mm,1. 8 µm) by gradient elution using 0. 1% formic acid and acetonitrile as mobile phases at a flow rate of 0. 4 m L·min-1. By UPLC-LTQ-Orbitrap-MS,16 compounds including phenolic acids and flavonoids were identified by comparison with reference standards or literature data. For quantitative analysis,12 identified compounds were simultaneously determined by UPLC-DAD at wavelengths of 330 nm. The method was validated with respect to linearity,precision,repeatability,stability and recovery. The contents of these compounds were found to differ significantly between the samples from Qichun and other areas. This strategy was novel,effective and straightforward,which provided a potential approach for holistic quality control of Qiai.

Neuregulin-1 Promotes Myocardial Angiogenesis in the Rat Model of Diabetic Cardiomyopathy.

BACKGROUND/AIMS: Microvascular insufficiency takes a critical role in the development of diabetic cardiomyopathy (DCM). So this study was designed to investigate the effects of Neuregulin-1 (NRG-1) treatment on myocardial angiogenesis and the changes of VEGF/Flk1 and Ang-1/Tie-2 signaling in the rat model of DCM. METHODS: Diabetic rats were induced by a single intraperitoneal injection of Streptozotocin. 12 weeks after the diabetes induction, the rats with NRG-1 treatment were treated with tail vein injection of NRG-1 at the dose of 10µg/kg/d for consecutive 10 days. Cardiac function was assessed using catheter MPA cardiac function analysis system. Myocardial blood flow (MBF) was assessed with stable-isotope labeled microspheres. Capillary density was measured by CD31 immunohistochemistry. The protein expression and receptors phosphorylation were assessed using western blot. RESULTS: Left ventricular function, capillary density and MBF were significantly reduced in DCM group when compared with those in the control group (P< 0.01, P< 0.01 and P< 0.05 respectively). Left ventricular function and capillary density were significantly increased in NRG-1 treatment group when compared with those in the DCM group (P< 0.05 and P< 0.05 respectively). The expression of VEGF and Ang-1 and the phosphorylation of Flk1 and Tie-1 were significantly decreased in DCM group as compared with those in the control group. However, those in the NRG-1 treatment group were significantly increased as compared with those in the DCM group. In vitro, NRG-1 treatment increased significantly the expression of VEGF and Ang-1 in human coronary artery smooth muscle cells. CONCLUSIONS: NRG-1 can increase the myocardial angiogenesis of DCM, probably via the direct effects of NRG-1 and via the increasing expression of VEGF and Ang-1. These findings may contribute to developing a novel approach to reverse the impaired angiogenic responses in diabetes or coronary artery disease.

Propofol attenuates H2O2-induced oxidative stress and apoptosis via the mitochondria- and ER-medicated pathways in neonatal rat cardiomyocytes.

Previous studies have shown that propofol, an intravenous anesthetic commonly used in clinical practice, protects the myocardium from injury. Mitochondria- and endoplasmic reticulum (ER)-mediated oxidative stress and apoptosis are two important signaling pathways involved in myocardial injury and protection. The present study aimed to test the hypothesis that propofol could exert a cardio-protective effect via the above two pathways. Cultured neonatal rat cardiomyocytes were treated with culture medium (control group), H2O2 at 500 µM (H2O2 group), propofol at 50 µM (propofol group), and H2O2 plus propofol (H2O2 + propofol group), respectively. The oxidative stress, mitochondrial membrane potential (ΔΨm) and apoptosis of the cardiomyocytes were evaluated by a series of assays including ELISA, flow cytometry, immunofluorescence microscopy and Western blotting. Propofol significantly suppressed the H2O2-induced elevations in the activities of caspases 3, 8, 9 and 12, the ratio of Bax/Bcl-2, and cell apoptosis. Propofol also inhibited the H2O2-induced reactive oxygen species (ROS) generation, lactic dehydrogenase (LDH) release and mitochondrial transmembrane potential (ΔΨm) depolarization, and restored the H2O2-induced reductions of glutathione (GSH) and superoxide dismutase (SOD). In addition, propofol decreased the expressions of glucose-regulated protein 78 kDa (Grp78) and inositol-requiring enzyme 1α (IRE1α), two important signaling molecules in the ER-mediated apoptosis pathway. Propofol protects cardiomyocytes from H2O2-induced injury by inhibiting the mitochondria- and ER-mediated apoptosis signaling pathways.

Glycine induces bidirectional modifications in N-methyl-D-aspartate receptor-mediated synaptic responses in hippocampal CA1 neurons.

Glycine can persistently potentiate or depress AMPA responses through differential actions on two binding sites: NMDA and glycine receptors. Whether glycine can induce long-lasting modifications in NMDA responses, however, remains unknown. Here, we report that glycine induces long-term potentiation (LTP) or long-term depression (LTD) of NMDA responses (Gly-LTP(NMDA) or Gly-LTD(NMDA)) in a dose-dependent manner in hippocampal CA1 neurons. These modifications of NMDA responses depend on NMDAR activation. In addition, the induction of Gly-LTP(NMDA) requires binding of glycine with NMDARs, whereas Gly-LTD(NMDA) requires that glycine bind with both sites on NMDARs and GlyRs. Moreover, activity-dependent exocytosis and endocytosis of postsynaptic NMDARs underlie glycine-induced bidirectional modification of NMDA excitatory postsynaptic currents. Thus, we conclude that glycine at different levels induces bidirectional plasticity of NMDA responses through differentially regulating NMDA receptor trafficking. Our present findings reveal important functions of the two glycine binding sites in gating the direction of synaptic plasticity in NMDA responses.

GATA-1 directly regulates Nanog in mouse embryonic stem cells.

Nanog safeguards pluripotency in mouse embryonic stem cells (mESCs). Insight into the regulation of Nanog is important for a better understanding of the molecular mechanisms that control pluripotency of mESCs. In a silico analysis, we identify four GATA-1 putative binding sites in Nanog proximal promoter. The Nanog promoter activity can be significantly repressed by ectopic expression of GATA-1 evidenced by a promoter reporter assay. Mutation studies reveal that one of the four putative binding sites counts for GATA-1 repressing Nanog promoter activity. Direct binding of GATA-1 on Nanog proximal promoter is confirmed by electrophoretic mobility shift assay and chromatin immunoprecipitation. Our data provide new insights into the expanded regulatory circuitry that coordinates Nanog expression.

Hesx1 enhances pluripotency by working downstream of multiple pluripotency-associated signaling pathways.

Hesx1, a homeobox gene expressed in embryonic stem cells (ESCs), has been implicated in the core transcription factors governing the pluripotent state. However, data about the underlying mechanism of how Hesx1 is involved in maintaining pluripotency is still scarce. In this study, we find Hesx1 responds to multiple pluripotency-related pathway inhibitors as well as LIF stimulation. Particularly, the expression of Hesx1 can be readily induced by dual inhibition (2i) of glycogen synthase kinase 3 and mitogen-activated protein kinase. Forced expression of Hesx1 can partially compensate for the withdrawal of either LIF or each component of 2i. We also demonstrate that LIF and each inhibitor of 2i can induce Hesx1 independent of one another. We tentatively put forward that Hesx1 is a common downstream target of LIF- and 2i-mediated self-renewal signaling pathways and plays an important role in maintaining ESC identity. Our study extends the methods of identifying the missing crucial factors in establishing ESC pluripotency.

[Inhibition of sanguinarine on S180 subcutaneously implanted tumors in mice].

OBJECTIVE: To investigate the inhibition of sanguinarine on S180 sarcoma in mice and the effect of angiogenesis. METHODS: S180 subcutaneous implanted tumor model mice were randomly divided into six groups: control group, cyclophosphamide (CTX) group, sanguinarine (10, 20 and 40 mg/kg) groups and combination group. The mice were sacrificed on the 10th day to measure the tumor weight and volumes, and caculate the tumor growth inhibition. Histopathology was performed, while immunohistochemistry was applied for assessment of MVD (microvascular density) and the expression of VEGF (vascular endothelial growth factor). RESULTS: The growth of tumors were significantly inhibited in the treatment groups (CTX group, sanguinarine 20 and 40 mg/kg groups, and combination group). HE staining showed tumor cell atypia and pathologic micosis were lower than that of the control group. Scattered and fusion of the slice necrosis foci were observed in the treatment groups. CTX, sanguinarine (20 and 40 mg/kg) and combination significantly reduced the expression of MVD and VEGF compared with the control group (P < 0.01, P < 0.05). CONCLUSION: Sanguinarine can effectively inhibit the growth of S180 implanted tumors via reducing MVD and the expression of VEGF, which is associated with its anti-angiogenesis.