Network Toxicology Prediction and Molecular Docking-based Strategy to Explore the Potential Toxicity Mechanism of Metformin Chlorination Byproducts in Drinking Water.

BACKGROUND: Metformin (MET), a worldwide used drug for treating type 2 diabetes but not metabolized by humans, has been found with the largest amount in the aquatic environment. Two MET chlorination byproducts, including Y and C, were transformed into drinking water during chlorination. However, the potential toxicity of the byproducts in hepatotoxicity and reproduction toxicity remains unclear. METHODS: The TOPKAT database predicted the toxicological properties of metformin disinfection by-products. The targets of metformin disinfection by-products were mainly obtained from the PharmMapper database, and then the targets of hepatotoxicity and reproductive toxicity were screened from GeneCards. The overlapping targets of toxic component targets and the hepatotoxicity or reproduction toxicity targets were regarded as the key targets. Then, the STRING database analyzed the key target to construct a protein-protein interaction network (PPI) and GO, and KEGG analysis was performed by the DAVID platform. Meanwhile, the PPI network and compound- target network were constructed by Cytoscape 3.9.1. Finally, Discovery Studio 2019 software was used for molecular docking verification of the two toxic compounds and the core genes. RESULTS: Y and C exhibited hepatotoxicity, carcinogenicity, and mutagenicity evaluated by TOPKAT. There were 22 potential targets relating to compound Y and hepatotoxicity and reproduction toxicity and 14 potential targets relating to compound C and hepatotoxicity and reproduction toxicity. PPI network analysis showed that SRC, MAPK14, F2, PTPN1, IL2, MMP3, HRAS, and RARA might be the key targets; the KEGG analysis indicated that compounds Y and C caused hepatotoxicity through Hepatitis B, Pathways in cancer, Chemical carcinogenesis-reactive oxygen species, Epstein-Barr virus infection; compound Y and C caused reproduction toxicity through GnRH signaling pathway, Endocrine resistance, Prostate cancer, Progesterone-mediated oocyte maturation. Molecular docking results showed that 2 compounds could fit in the binding pocket of the 7 hub genes. CONCLUSION: This study preliminarily revealed the potential toxicity and possible toxicity mechanism of metformin disinfection by-products and provided a new idea for follow-up research.

[Effects of Conservation Tillage on Herbicide Residues in Maize Field Soil].

It is well known that conservation tillage can improve soil quality, such as soil organic matters. However, limited information on the conservation tillage impacts on pesticides has been reported, which is important to food security. To explore the specific effects of conservation tillage on herbicide residues in soils, parallel soil samples from seven sites under traditional tillage and conservation tillage were collected, respectively, in Jilin Province, Northeast China. The soil properties and characteristics of three herbicides(acetochlor, atrazine, and MCPA-Na) were measured. The results showed that conservation tillage significantly increased total organic carbon(TOC) content, soil water content, and the average particle size of soil aggregates[(2.1±0.1)%, (19.1±1.2)%, and (82.2±3.0) µm increased to(2.9±0.3)%, (22.3±1.5)%, and (97.2±4.2) µm, respectively]. The results also showed that different herbicides were correlated with different soil properties. For example, TOC content and soil water content were positively correlated with atrazine, whereas micro-aggregate content was negatively correlated with acetochlor. Therefore, the effects of conservation tillage on the three herbicide residues were different. For instance, conservation tillage significantly increased the residual amount of atrazine[from(3.8±0.3) ng·g-1 to (17.7±3.0) ng·g-1] in the Dongfeng site by increasing TOC content, whereas it significantly reduced the residual amount of acetochlor[from (50.6±10.3) ng·g-1 to (9.2±2.5) ng·g-1] in the Dehui site by increasing the average particle size of soil aggregates. Generally, this study suggests conservation tillage indeed affected herbicide residues in soils by affecting soil properties. However, the influence of conservation tillage on herbicide residue was dependent on the types of herbicides due to the complex effects of different soil properties on herbicide migration and degradation.

Prominent Effects of Berbamine Hydrochloride on Alzheimer's Disease Model Mice.

Very few anti-Alzheimer's disease (AD) drugs are clinically available at present due to the complex mechanism of Alzheimer's disease. For the purpose of discovering potential anti-AD drugs in bisbenzylisoquinoline alkaloids, the anti-AD function and the mechanism of the function of berbamine hydrochloride (BBMH) were studied. Three kinds of AD model mice, double transgenic APP/PS1 AD mice, Gal-Alu AD mice induced by the intraperitoneal injection of d-galactose combined with the intragastric administration of aluminum trichloride, and Alu AD-like mice induced by stereotactic brain injection of aluminum trichloride, were administered with BBMH for 40 days at a dosage of 280 mg/kg/d. The effects of BBMH on the learning and memory behavior of the AD mice were studied through the Morris water maze experiment, and the influences of BBMH on the pathological features of AD, including the deposition of Aß, the lesions of pyramidal cells (neurons), and the formation of neurofibrillary tangles, were studied by the immunohistochemical staining, hematoxylin-eosin staining, and silver staining of the brain tissues of the mice. The water maze experiment showed that BBMH could significantly improve the learning and memory abilities of three kinds of treated mice. Immunohistochemical staining showed that BBMH could significantly reduce the deposition of Aß in the brain tissues of treated mice. Hematoxylin-eosin staining showed that BBMH could significantly alleviate the lesions of pyramidal cells in the hippocampal tissue of the mice. Silver staining showed that BBMH could significantly reduce the formation of neurofibrillary tangles in the hippocampal tissue of the mice. These results indicated that BBMH has significant anti-AD effects and the potential as an anti-AD drug. Western blot analysis of the brain tissue of the mice showed that the expression level of calpain, a Ca2+-dependent proteolytic enzyme, was significantly inhibited and the expression level of SelK, a selenoprotein mainly expressed in immune cells, was significantly increased. It is speculated that the anti-AD effect of BBMH is related to the improvement of the phagocytosis of microglial cells in brain tissues and macrophages migrated into the brain as well as the regulation of calcium homeostasis and calcium-dependent proteases in the brain tissues of the mice.

Complete Chloroplast Genome of an Endangered Species Quercus litseoides, and Its Comparative, Evolutionary, and Phylogenetic Study with Other Quercus Section Cyclobalanopsis Species.

Quercus litseoides, an endangered montane cloud forest species, is endemic to southern China. To understand the genomic features, phylogenetic relationships, and molecular evolution of Q. litseoides, the complete chloroplast (cp) genome was analyzed and compared in Quercus section Cyclobalanopsis. The cp genome of Q. litseoides was 160,782 bp in length, with an overall guanine and cytosine (GC) content of 36.9%. It contained 131 genes, including 86 protein-coding genes, eight ribosomal RNA genes, and 37 transfer RNA genes. A total of 165 simple sequence repeats (SSRs) and 48 long sequence repeats with A/T bias were identified in the Q. litseoides cp genome, which were mainly distributed in the large single copy region (LSC) and intergenic spacer regions. The Q. litseoides cp genome was similar in size, gene composition, and linearity of the structural region to those of Quercus species. The non-coding regions were more divergent than the coding regions, and the LSC region and small single copy region (SSC) were more divergent than the inverted repeat regions (IRs). Among the 13 divergent regions, 11 were in the LSC region, and only two were in the SSC region. Moreover, the coding sequence (CDS) of the six protein-coding genes (rps12, matK, atpF, rpoC2, rpoC1, and ndhK) were subjected to positive selection pressure when pairwise comparison of 16 species of Quercus section Cyclobalanopsis. A close relationship between Q. litseoides and Quercus edithiae was found in the phylogenetic analysis of cp genomes. Our study provided highly effective molecular markers for subsequent phylogenetic analysis, species identification, and biogeographic analysis of Quercus.

Effect of Personalized Music Intervention in Mechanically Ventilated Children in the PICU: A Pilot Study.

OBJECTIVES: To determine the feasibility of a personalized music intervention with mechanically ventilated patients in the PICU. DESIGN: Pilot study with a quasi-experimental design. SETTING: Tertiary children's hospital in China with a 40-bed PICU. PATIENTS: Children, 1 month to 7 years, with mechanical ventilation were recruited and assigned to music group (n = 25) and control group (n = 25). INTERVENTIONS: Children in the music group received their own favorite music and listened for 60 minutes three times a day. The control group receive routine care without music. MEASUREMENTS AND MAIN RESULTS: Primary outcome measure was comfort measured with the COMFORT Behavior scale 5 minutes before and after the music. Secondary outcome measures were physiologic variables; heart rate, respiration, blood pressure, oxygen saturation. Mechanical ventilation time, length of stay, and sedation medication were also collected. Qualitative analysis revealed that nurses had a positive attitude in delivering the interventions and identified improvements for the main trial. Children in the music group had lower COMFORT Behavior scores (15.7 vs 17.6; p = 0.011). Children in the music group had better physiologic outcomes; heart rate (140 vs 144; p = 0.039), respiration rate (40 vs 43; p = 0.036), systolic blood pressure (93 vs 95 mm Hg; p = 0.031), oxygen saturation (96% vs 95%; p < 0.001), diastolic blood pressure was not significantly (52 vs 53 mm Hg; p = 0.11). Children in the music group had a shorter ventilation time (148.7 vs 187.6; p = 0.044) and a shorter length of stay, but not significant (11.2 vs 13.8; p = 0.071). Children in the control group had higher total amount of on-demand midazolam (29 vs 33 mg; p = 0.040). CONCLUSIONS: Our pilot study indicates that personalized music intervention is feasible and might improve the comfort of children with mechanical ventilation. Further studies are needed to provide conclusive evidence in confirming the effectiveness of music interventions comforting critically ill children in PICUs.

Near-Infrared Chromophore Functionalized Soft Actuator with Ultrafast Photoresponsive Speed and Superior Mechanical Property.

In this Communication, we develop a two-step acyclic diene metathesis in situ polymerization/cross-linking method to synthesize uniaxially aligned main-chain liquid crystal elastomers with chemically bonded near-infrared absorbing four-alkenyl-tailed croconaine-core cross-linkers. Because of the extraordinary photothermal conversion property, such a soft actuator material can raise its local temperature from 18 to 260 °C in 8 s, and lift up burdens 5600 times heavier than its own weight, under 808 nm near-infrared irradiation.

A calamitic mesogenic near-infrared absorbing croconaine dye/liquid crystalline elastomer composite.

In this work, we report the first example of a calamitic mesogenic near-infrared (NIR) absorbing organic dye, made by functionalizing a thiophene-croconaine chromophore rigid core with two symmetric long flexible alkyl chains. The liquid crystal (LC) NIR dye YHD796 exhibits a sharp and intense NIR absorption band with a maximum absorption peak at 796 nm. Taking advantage of the improved solubility of YHD796 dispersed in mesogenic molecules, a homogeneously-aligned mono-domain liquid crystalline elastomer (LCE)/YHD796 composite film is successfully prepared by applying the classical LC-cell-alignment method and in situ photo-polymerization of photocurable LC monomer mixtures. This LCE/YHD796 composite film performs a fully reversible contraction/expansion response towards NIR light stimulus due to the photo-thermal heating effect induced by the YHD796 dye well-dispersed in the LCE matrix.

[Clinical risk factors for capillary leak syndrome in children with sepsis].

OBJECTIVE: To investigate the clinical features of capillary leak syndrome (CLS) in children with sepsis, and to analyze its risk factors. METHODS: Clinical data of 384 children with sepsis was studied retrospectively. They included 304 cases of general sepsis, 54 cases of severe sepsis and 26 cases of septic shock, and were divided into non-CLS (n=356) and CLS groups (n=28). Univariate analysis was performed for each of the following variables: sex, age, malnutrition, anemia, coagulation disorders, white blood cell count, C-reactive protein (CRP), procalcitonin (PCT), tumor necrosis factor (TNF), interleukin (IL)-1, IL-6, blood glucose, lactic acid, Pediatric Risk of Mortality (PRISM) III score, pediatric critical illness score (PICS), severe sepsis and number of failed organs≥3. The statistically significant variables (as independent variables) were subjected to multivariate logistic regression analysis. RESULTS: The incidence rate of CLS in children with septic shock, severe sepsis and general sepsis were 42.3%, 20.1% and 1.3%, respectively, with significant differences among them (P<0.01). There were significant differences in anemia, coagulation disorders, CRP, PCT>2 ng/mL, TNF, IL-1, IL-6, blood glucose, lactic acid, PRISM III score, PICS and number of failed organs≥3 between the non-CLS and CLS groups (P<0.05). Severe sepsis/shock and PRISM III score were the independent risk factors for CLS in children with sepsis. CONCLUSIONS: The severity of sepsis and PRISM III score are positively correlated with the incidence of CLS in children with sepsis. Early monitoring of such factors as infection markers and blood glucose in children with severe sepsis and high PRISM III score may contribute to early diagnosis and effective intervention, thus reducing the mortality from CLS in children with sepsis.

Synergistic effect of kaempferol glycosides purified from Laurus nobilis and fluoroquinolones on methicillin-resistant Staphylococcus aureus.

In a previous study, we reported that two kaempferol glycosides isolated from Laurus nobilis L., kaempferol-3-O-alpha-L-(2'',4''-di-E-p-coumaroyl)-rhamnoside (C2) and kaempferol-3-O-alpha-L-(2''-E-p-coumaroyl-4''-Z-p-coumaroyl)-rhamnoside (C3), showed strong antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci. Thereafter we found that these compounds greatly reduced the minimum inhibitory concentrations (MICs) of some fluoroquinolones in MRSA. In other words, C2 and C3 greatly potentiated anti-MRSA activity of fluoroquinolones. The effect of C2 and C3 with fluoroquinolones was found to be synergistic. The potentiation activity was observed with hydrophilic fluoroquinolones, such as norfloxacin and ciprofloxacin, but not with hydrophobic quinolones. We also found that norfloxacin reduced MICs of C2 and C3. The effect was synergistic. Possible mechanism of the synergistic effect was discussed.

Anti-methicillin resistant Staphylococcus aureus (MRSA) compounds isolated from Laurus nobilis.

We found that an extract from Laurus nobilis L. (Lauraceae) leaves showed antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). We purified two flavonoids as the effective compounds and identified them as kaempferol 3-O-alpha-L-(2'',4''-di-E-p-coumaroyl)-rhamnoside (C2) and kaempferol 3-O-alpha-L-(2''-Z-p-coumaroyl-4''-E-p-coumaroyl)-rhamnoside (C3). Both compounds showed strong antibacterial activity not only against MRSA but also against vancomycin-resistant enterococci (VRE). There was low or no antibacterial activity of C2 and C3 for Streptococcus pneumoniae, Pseudomonas aeruginosa and Serratia marcescens.

[Spectrum study of organochlorine pesticides after nano TiO2 photocatalytic degradation in AgNO3 medium].

A study on a nano anatase TiO2 production from the hydrolysis of TiCl4 was presented. In the nano TiO2 suspending medium, the photocatalytic behaviors for some organochlorine pesticides including alpha, beta, gamma, delta-BHC, DDT, dieldrin, dicofol and agroceres were compared and studied under UV irradiation in the air. Owing to structural difference of C--Cl in the molecule, the degradation efficiencies for the organochlorine pesticides presented an obvious difference with the order of dicofol>dieldrin> DDT>agroceres and alpha-BHC>gamma-BHC>delta-BHC>beta-BHC. Accordingly, the nano TiO2 material was applied as a photocatalyzer, which catalyzed transformation of organochlorine pesticide to chlorine ion. Nanoparticle of silver chloride with a maximal absorbance at the wavelength of 260 nm were prepared in the surfactant polyvinyl alcohol solution. Organochlorine pesticides could be determined according to the concentration of silver chloride.

[Expression and clinical significance of HBsAg and HBcAg in hepatocytes in chronic hepatitis B].

OBJECTIVE: To study the expression of HBsAg and HBcAg in hepatocytes in CHB patients, and analyze the correlation among the expression of HBsAg and HBcAg, the quantity of HBV DNA in serum, the pathology of liver tissue and the clinical manifestation. METHODS: Quantitative polymerase chain reaction was used to assay the quantity of HBV DNA in serum in 351 CHB patients. Furthermore pathological diagnosis was performed using liver biopsy to assay the expression of HBsAg and HBcAg in hepatocytes by an immunohistochemical staining technique. RESULTS: The positive expression rate of HBsAg and HBcAg in hepatocytes was 92.3% and 76.9% respectively. Cytoplasm-membrane HBcAg expression type (75.6%) was observed in the CHB with more active inflammation, while Nucleus HBcAg expression type (24.4%) was observed in the CHB with more sedative one (P < 0.0001). The expression of HBsAg was correlated with the quantity of HBV DNA in serum (rp = 0.24, P = 0.0129), while inversely correlated with the inflammation and the fibrillation of liver tissue (rp = -0.22, P = 0.0279; rp = -0.23, P = 0.0186). The expression of HBcAg was correlated with the quantity of HBV DNA in serum (rp = 0.52, P < 0.0001), while was inversely correlated with the inflammation and the fibrosis of liver (rp = -0.33, P < 0.0001; rp = -0.34, P < 0.0001). CONCLUSION: Cytoplasm-membrane HBcAg expression type was observed in the CHB with more active inflammation, while Nucleus HBcAg expression type was observed in the CHB with mild change. In the immunopathogenesis of the liver damage in CHB, HBcAg might be a main target antigen. HBsAg might be a sensitive index to screen HBV infection; HBcAg might probably be a reliable index to evaluate the replication of HBV