Bis(1,10-phenanthroline-κ2 N,N′)(sulfato-κ2 O,O′)nickel(II) ethane-1,2-diol solvate

In the title compound, [Ni(SO4)(C12H8N2)2]·C2H6O2, the coordination polyhedron around the Ni2+ ion is a distorted octahedron, with four N atoms from two phenanthroline groups and two O atoms from a bidentate sulfate ligand. The Ni2+ ion lies on a special position of site symmetry 2. Inter­molecular O—H⋯O hydrogen bonds help to stabilize the structure. The OH group of the ethane-1,2-diol solvent is disordered over two positions with equal occupancy

Characteristic Analysis from Excessive to Deficient Syndromes in Hepatocarcinoma Underlying miRNA Array Data

Traditional Chinese medicine (TCM) treatment is regarded as a safe and effective method for many diseases. In this study, the characteristics among excessive, excessive-deficient, and deficient syndromes of Hepatocellular carcinoma (HCC) were studied using miRNA array data. We first calculated the differentially expressed miRNAs based on random module t-test and classified three TCM syndromes of HCC using SVM method. Then, the weighted miRNA-target networks were constructed for different TCM syndromes using predicted miRNA targets. Subsequently, the prioritized target genes of upexpression network of TCM syndromes were analyzed using DAVID online analysis. The results showed that there are distinctly different hierarchical cluster and network structure of TCM syndromes in HCC, but the excessive-deficient combination syndrome is extrinsically close to deficient syndrome. GO and pathway analysis revealed that the molecular mechanisms of excessive-deficient and deficient syndromes of HCC are more complex than excessive syndrome. Furthermore, although excessive-deficient and deficient syndromes have similar complex mechanisms, excessive-deficient syndrome is more involved than deficient syndrome in development of cancer process. This study suggested that miRNAs might be important mediators involved in the changing process from excessive to deficient syndromes and could be potential molecular markers for the diagnosis of TCM syndromes in HCC

Gegen Qinlian Decoction Treats Diarrhea in Piglets by Modulating Gut Microbiota and Short-Chain Fatty Acids

Gut microbiota and its metabolites, short-chain fatty acids (SCFAs), play important roles in diarrheal diseases. Gegen Qinlian decoction (GQD), a Chinese herb formula, has been widely used to treat infectious diarrhea for centuries. However, little is known about the mechanism underlying its efficacy and whether it is mediated by gut microbiota and SCFAs. In this study, the composition of gut microbiota from bacterial diarrheal piglets was assessed using 16S rRNA analysis. The concentrations of fecal SCFAs were determined using a gas chromatography-mass spectrometer (GC-MS). The expression of mucosal pro-inflammatory cytokines in the colon was ascertained. Results showed that GQD reverses the reduction in the richness of gut microbiota, changes its structure, and significantly increases the relative abundances of SCFA-producing bacteria, including Akkermansia, Bacteroides, Clostridium, Ruminococcus, and Phascolarctobacterium. Moreover, GQD increased the levels of fecal SCFAs, including acetic acid, propionic acid, and butyric acid. GQD thus attenuates diarrhea in piglets. Further, our results suggest that the SCFAs could help to attenuate mucosal pro-inflammatory responses following GQD treatment by inhibiting histone deacetylase and the NF-κB pathway. We thus suggseted that gut microbiota play an important role during diarrhea treatment, an effect may be promoted by the GQD-induced structural changes of the gut microbial community and production of SCFAs. The increased levels of SCFAs probably provide further help to attenuate mucosal inflammation and diarrhea. In conclusion, our study might provide evidence that GQD treats diarrhea maybe involved in modulating gut microbiota and increasing SCFA levels

Combination of G-CSF and AMD3100 Improves the Anti-inflammatory Effect of Mesenchymal Stem Cells on Inducing M2 Polarization of Macrophages Through NF-κB-IL1RA Signaling Pathway

Mobilized peripheral blood-derived mesenchymal stem cells (PB-MSCs) mainly derived from bone marrow-derived MSCs (BM-MSCs) exert a similar anti-inflammatory effect. However, the mechanism of anti-inflammatory effect of mobilized PB-MSCs by a combination of G-CSF and AMD3100 remains unclear. Cultured rat PB-MSCs mobilized by G-CSF/AMD3100 have shown typical surface markers and potential for multiple differentiations, similar to non-mobilized BM-MSCs. In a co-culture system, rat M0-type macrophages co-cultured with PB-MSCs have shown higher expression of M2 markers including CD206, Arg-1, IL-10, and CCL-22 than BM-MSCs, indicating that PB-MSCs induced greater M0 polarization to M2. Furthermore, compared with BM-MSCs, PB-MSCs in a co-culture system with lipopolysaccharide-induced M1-type macrophages more efficiently promoted M1 polarization to M2, accompanied by increasing expression of CD206, Arg-1, IL-10, and CCL-22 while decreasing expression of M1 markers including iNOS, TNF-α, IL-1β and IL-6, indicating that PB-MSCs triggered greater M1 polarization to M2. Subsequently, polymerase chain reaction arrays showed higher expressions of both IL1rn and Tnfrsf11b in PB-MSCs versus BM-MSCs. In response to an inflammatory niche, such as TNF-α, PB-MSCs have shown higher expression and release of IL1RA, causing greater M2 polarization of macrophages, and the special effects may be almost entirely abolished through the neutralization antibody of IL1RA. Mechanistic studies determined that PB-MSCs showed higher levels NF-κBp65 and NF-κBp-p65 than BM-MSCs, which could be obviously enhanced by TNF-α. And the increased IL1RA expression by TNF-α in PB-MSCs could be markedly canceled by an NF-κB inhibitor PDTC. Interestingly, mimicking the mobilized PB-MSCs by a combination of G-CSF and AMD3100 in vivo, BM-MSCs were treated with G-CSF and/or AMD3100 in vitro, showing the increased expressions of NF-κBp65 and IL1RA, which could be prominently abolished by PDTC. Therefore, targeting IL1rn, gene modification or drug intervention for MSCs may provide a novel therapeutic strategy for human diseases, especially inflammatory diseases

Germline Variants and Genetic Interactions of Several EMT Regulatory Genes Increase the Risk of HBV-Related Hepatocellular Carcinoma

Epithelial-mesenchymal transition (EMT) plays an important role in the development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). We hypothesized that germline variants in the major EMT regulatory genes (SNAIL1, ZEB1, ZEB2, TWIST1) may influence the development of HBV-related HCC. We included 421 cases of HBsAg-positive patients with HCC, 1371 cases of HBsAg-positive subjects without HCC [patients with chronic hepatitis B (CHB) or liver cirrhosis (LC)] and 618 cases of healthy controls in the case-control study. Genotype, allele, and haplotype associations in the major EMT regulatory genes were tested. Environment-gene and gene-gene interactions were analysed using the non-parametric model-free multifactor dimensionality reduction (MDR) method. The SNAIL1rs4647958T>C was associated with a significantly increased risk of both HCC (CT+CC vs. TT: OR=1.559; 95% confidence interval [CI], 1.073-2.264; P=0.020) and CHB+LC (CT+CC vs. TT: OR=1.509; 95% CI, 1.145-1.988; P=0.003). Carriers of the TWIST1rs2285681G>C (genotypes CT+CC) had an increased risk of HCC (CG+CC vs. GG: OR=1.407; 95% CI, 1.065-1.858; P=0.016). The ZEB2rs3806475T>C was associated with significantly increased risk of both HCC (Precessive =0.001) and CHB+LC (Precessive<0.001). The CG haplotype of the rs4647958/rs1543442 haplotype block was associated with significant differences between healthy subjects and HCC patients (P=0.0347). Meanwhile, the CT haplotype of the rs2285681/rs2285682 haplotype block was associated with significant differences between CHB+LC and HCC patients (P=0.0123). In MDR analysis, the combination of TWIST1rs2285681, ZEB2rs3806475, SNAIL1rs4647958 exhibited the most significant association with CHB+LC and Health control in the three-locus model. Our results suggest significant single-gene associations and environment-gene/gene-gene interactions of EMT-related genes with HBV-related HCC

Identification and characterization of a novel fumarase gene by metagenome expression cloning from marine microorganisms

<p>Abstract</p> <p>Background</p> <p>Fumarase catalyzes the reversible hydration of fumarate to <smcaps>L</smcaps>-malate and is a key enzyme in the tricarboxylic acid (TCA) cycle and in amino acid metabolism. Fumarase is also used for the industrial production of <smcaps>L</smcaps>-malate from the substrate fumarate. Thermostable and high-activity fumarases from organisms that inhabit extreme environments may have great potential in industry, biotechnology, and basic research. The marine environment is highly complex and considered one of the main reservoirs of microbial diversity on the planet. However, most of the microorganisms are inaccessible in nature and are not easily cultivated in the laboratory. Metagenomic approaches provide a powerful tool to isolate and identify enzymes with novel biocatalytic activities for various biotechnological applications.</p> <p>Results</p> <p>A plasmid metagenomic library was constructed from uncultivated marine microorganisms within marine water samples. Through sequence-based screening of the DNA library, a gene encoding a novel fumarase (named FumF) was isolated. Amino acid sequence analysis revealed that the FumF protein shared the greatest homology with Class II fumarate hydratases from <it>Bacteroides </it>sp. 2_1_33B and <it>Parabacteroides distasonis </it>ATCC 8503 (26% identical and 43% similar). The putative fumarase gene was subcloned into pETBlue-2 vector and expressed in <it>E. coli </it>BL21(DE3)pLysS. The recombinant protein was purified to homogeneity. Functional characterization by high performance liquid chromatography confirmed that the recombinant FumF protein catalyzed the hydration of fumarate to form <smcaps>L</smcaps>-malate. The maximum activity for FumF protein occurred at pH 8.5 and 55°C in 5 mM Mg²⁺. The enzyme showed higher affinity and catalytic efficiency under optimal reaction conditions: <it>K</it>_m= 0.48 mM, <it>V</it>_max= 827 μM/min/mg, and <it>k</it>_cat/<it>K</it>_m= 1900 mM/s.</p> <p>Conclusions</p> <p>We isolated a novel fumarase gene, <it>fumF</it>, from a sequence-based screen of a plasmid metagenomic library from uncultivated marine microorganisms. The properties of FumF protein may be ideal for the industrial production of <smcaps>L</smcaps>-malate under higher temperature conditions. The identification of FumF underscores the potential of marine metagenome screening for novel biomolecules.</p

The Role of Macrolide Antibiotics in Increasing Cardiovascular Risk

AbstractBackgroundLarge cohort studies provide conflicting evidence regarding the potential for oral macrolide antibiotics to increase the risk of serious cardiac events.ObjectivesThis study performed a meta-analysis to examine the link between macrolides and risk of sudden cardiac death (SCD) or ventricular tachyarrhythmias (VTA), cardiovascular death, and death from any cause.MethodsWe performed a search of published reports by using MEDLINE (January 1, 1966, to April 30, 2015) and EMBASE (January 1, 1980, to April 30, 2015) with no restrictions. Studies that reported relative risk (RR) estimates with 95% confidence intervals (CIs) for the associations of interest were included.ResultsThirty-three studies involving 20,779,963 participants were identified. Patients taking macrolides, compared with those who took no macrolides, experienced an increased risk of developing SCD or VTA (RR: 2.42; 95% CI: 1.61 to 3.63), SCD (RR: 2.52; 95% CI: 1.91 to 3.31), and cardiovascular death (RR: 1.31; 95% CI: 1.06 to 1.62). No association was found between macrolides use and all-cause death or any cardiovascular events. The RRs associated with SCD or VTA were 3.40 for azithromycin, 2.16 for clarithromycin, and 3.61 for erythromycin, respectively. RRs for cardiovascular death were 1.54 for azithromycin and 1.48 for clarithromycin. No association was noted between roxithromycin and adverse cardiac outcomes. Treatment with macrolides is associated with an absolute risk increase of 118.1 additional SCDs or VTA, and 38.2 additional cardiovascular deaths per 1 million treatment courses.ConclusionsAdministration of macrolide antibiotics is associated with increased risk for SCD or VTA and cardiovascular death but not increased all-cause mortality

PRRT2 gene mutations associated with infantile convulsions induced by sucking and the genotype-phenotype correlation

IntroductionPRRT2 is a major causative gene for self-limited familial neonatal-infantile epilepsy, paroxysmal kinesigenic dyskinesia, and paroxysmal kinesigenic dyskinesia with infantile convulsions. Voluntary movement trigger is prominent in adolescence and adulthood, but the triggers are unknown in infants.MethodsA gene panel designed for targeted next-generation sequencing (NGS) was used to screen genetic abnormalities in a cohort of 45 cases with infantile convulsions. The copy number variation was detected by a computational method based on the normalized depth of coverage and validated by a quantitative real-time polymerase chain reaction (RT-qPCR) method. The genotype-phenotype correlation of the PRRT2 mutation gene was analyzed.ResultsA de novo heterozygous PRRT2 deletion was identified in a child who had infantile convulsions induced by vigorous sucking. Seizures happened during the change of feeding behavior from breast to formula, which led to hungry and vigorous sucking. Ictal electroencephalograms recorded seizures with focal origination, which provided direct evidence of epileptic seizures in infants with PRRT2 mutations. Seizures stopped soon after the feeding behavior was changed by reducing feeding interval time and extending feeding duration. Data reanalysis on our previously reported cases with PRRT2 mutations showed that six of 18 (33.3%) patients had infantile convulsions or infantile non-convulsion seizures during feeding. The mutations included two truncating mutations (c.579dupA/p.Glu194Argfs*6, and c.649dupC/p.Arg217Profs*8) that were identified in each of the three affected individuals.ConclusionsThis study suggests that feeding, especially vigorous sucking, is potentially a trigger and highlights the significance of feeding behavior in preventing seizures in infants with PRRT2 mutations. Identification of PRRT2 haploinsufficiency mutations in the patients with infantile convulsions induced by sucking suggested a potential genotype-phenotype correlation