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Objective: To discuss similarities and differences in clinical features and laboratory indexes between patients with flat descending type sudden hearing loss and those with total hearing loss. Method: The clinical data of 123 patients with full frequencies hearing loss were retrospectively analyzed. The differences in clinical features and laboratory tests(platelet, coagulation series, D-dimer, blood lipids, hemorheology) between patients with flat descending hearing loss and those with total hearing loss were analyzed by gender, age and ear side, treatment time, concomitant symptom (tinnitus, dizziness), original underlying diseases (hypertension, diabetes), etc. Result: In the clinical features,among 51 flat descending cases, the ratio of male and female was 2.401:1; among 72 total hearing loss cases, the ratio of men and women ratio was 1.058:1 ( P <0.05). Among two groups of patients,the majority received treatment within 7 days, among whom 66.7% were flat descending population, and 83.3% were total hearing loss population ( P <0.05). Flat descending population with dizziness only accounted for 35.3% while this figure was up to 70.8% when it came to total hearing loss patients ( P <0.01). Two groups showed no differences in age, ear side, tinnitus, the original underlying diseases (hypertension, diabetes). In the laboratory tests, the total hearing loss population overtopped the plat descending population in PLT and PCT ( P <0.05), while falling below the plat descending population in APTT ( P <0.01). Two groups showed no differences in other indicators of platelet and coagulation series and laboratory data of D-dimer, blood lipids, hemorheology. Conclusion: Compared with flat descending sudden hearing loss, sudden total hearing loss more frequently happened to females who also were accompanied by dizziness. The treatment rate within 7 days was high and the patients with hypercoagulable state accounted for a higher proportion., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Introduction: The Adverse Outcome Pathway framework is increasingly used to integrate data generated based on traditional and emerging toxicity testing paradigms. As the number of AOP descriptions has increased, so has the need to define the AOP in computable terms., Materials and Methods: Herein, we present a comprehensive annotation of 172 AOPs housed in the AOP-Wiki as of December 4, 2016 using terms from existing biological ontologies., Results: AOP Key Events (KEs) were assigned ontology terms using a concept called the Event Component, which consists of a Process, an Object, and an Action term, with each term originating from ontologies and other controlled vocabularies. Annotation of KEs with ontology classes from fourteen ontologies and controlled vocabularies resulted in a total of 685 KEs being annotated with a total of 809 Event Components. A set of seven conventions resulted, defining the annotation of KEs via Event Components., Discussion: This expanded annotation of AOPs allows computational reasoners to aid in both AOP development and applications. In addition, the incorporation of explicit biological objects will reduce the time required for converting a qualitative AOP description into a conceptual model that can support computational modeling. As high throughput genomics becomes a more important part of the high throughput toxicity testing landscape, the new approaches described here for annotating key events will also promote the visualization and analysis of genomics data in an AOP context.

Intestinal microorganisms play important roles in maintaining host health, but their functions in aquatic animal hosts have yet to be fully elucidated. The Chinese mitten crab, Eriocheir sinensis, is one such example. We attempted to identify the shift of gut microbiota that occurred in response to infection of white spot syndrome virus (WSSV), an emerging viral pathogen in the crab aquaculture industry. The microbiota may exert some control over aspects of the viral pathogenesis. We investigated the changes in composition and structure of the crab gut microbiome during various WSSV infection stages of 6 h post-infection (hpi) and 48 hpi, using a 16S rRNA approach on the MiSeq Illumina sequencing platform. Four phyla (Firmicutes, Proteobacteria, Tenericutes and Bacteroidetes) were most dominant in the gut of E. sinensis regardless of the WSSV infection stages. However, further analysis revealed that over 12 bacterial phyla, 44 orders and 68 families were significantly different in abundance at various states of WSSV infection. Several intriguing aspects of E. sinensis gut bacteria that had not been previously reported were also uncovered, such as class Mollicutes was dominant here, but absent in crabs from Yangtze River estuary and Chongming Islands. Overall, this study provided the first evidence that changes in gut microbiome were closely associated with the severity of WSSV infection and that indicator taxa could be used to evaluate the crab health status., (© 2017 John Wiley & Sons Ltd.)

Larvae of the polyphagous tobacco cutworm moth, Spodoptera litura ( S. litura ) , encounter potentially toxic allelochemicals in food. It is therefore important for S. litura to produce detoxification enzymes such as cytochrome P450 monooxygenases (P450s). In this study, we have identified two novel cytochrome P450 genes of S. litura , named CYP321A7 and CYP321A9. Phylogenetic analysis indicated that they belong to the CYP321A subfamily. Expression levels of these genes at different development stages were determined by real-time quantitative polymerase chain reaction (PCR). The highest expression was found in the midgut and the fat body. Larvae fed with a diet supplemented with xanthotoxin or coumarin showed a strongly increased expression of CYP321A7 and CYP321A9 in the midgut and fat body as compared to larvae that consumed a control diet. In contrast, larvae consuming a diet containing aflatoxin B1 or quercetin did not induce the expression of these genes. CYP321A7 and CYP321A9 showed different expression profiles with respect to certain allelochemicals. For example, a diet containing cinnamic acid stimulated the expression of CYP321A9 , whereas no changes were observed for CYP321A7 . We suggest that the fine tuning of P450 gene expression is an important adaptation mechanism that allows polyphagous S. litura larvae to survive in a changing chemical environment., Competing Interests: The authors declare no conflict of interest.

Many organisms, including the fathead minnow (Pimephales promelas), a toxicological model organism, establish social hierarchies. The social rank of each male in a population is under the control of the hypothalamic-pituitary-gonadal (HPG) axis mainly through regulation of circulating androgen concentrations, which in turn drive the expression of secondary sex characteristics (SSCs). As dominant and subordinate males in an exposure study are initially under different physiological conditions (i.e., differing plasma androgen concentrations), we proposed that they belong to different subpopulations in the context of exposure to compounds that may interact with the HPG axis. Using a meta-analysis of our data from several previously published studies, we corroborated the hypothesis that social status, as indicated by SSCs, results in distinct clusters (eigenvalues >0.8 explaining >80% of variability) with differential expression of plasma vitellogenin, a commonly used biomarker of exposure to contaminants of emerging concern (CEC). Furthermore, we confirmed our predictions that exposure to estrogenic CECs would homogenize plasma vitellogenin response (E1: cluster mean SSC values decreased to 4.33 and 4.86 relative to those of control; E2: decreased to 4.8 and 5.37) across the social hierarchy. In contrast, serotonin-specific reuptake inhibitors expand this response range (cluster mean SSC increased to 5.21 and 6.5 relative to those of control). Our results demonstrated that social hierarchies in male fathead minnows result in heterogeneous responses to chemical exposure. These results represent a cautionary note for the experimental design of single-sex exposure studies. We anticipate our study to be a starting point for the re-evaluation of toxicological data analyses in single sex exposure experiments.

Fundamental questions remain about the application of omics in environmental risk assessments, such as the consistency of data across laboratories. The objective of the present study was to determine the congruence of transcript data across 6 independent laboratories. Male fathead minnows were exposed to a measured concentration of 15.8 ng/L 17α-ethinylestradiol (EE2) for 96 h. Livers were divided equally and sent to the participating laboratories for transcriptomic analysis using the same fathead minnow microarray. Each laboratory was free to apply bioinformatics pipelines of its choice. There were 12 491 transcripts that were identified by one or more of the laboratories as responsive to EE2. Of these, 587 transcripts (4.7%) were detected by all laboratories. Mean overlap for differentially expressed genes among laboratories was approximately 50%, which improved to approximately 59.0% using a standardized analysis pipeline. The dynamic range of fold change estimates was variable between laboratories, but ranking transcripts by their relative fold difference resulted in a positive relationship for comparisons between any 2 laboratories (mean R 2  > 0.9, p < 0.001). Ten estrogen-responsive genes encompassing a fold change range from dramatic (>20-fold; e.g., vitellogenin) to subtle (∼2-fold; i.e., block of proliferation 1) were identified as differentially expressed, suggesting that laboratories can consistently identify transcripts that are known a priori to be perturbed by a chemical stressor. Thus, attention should turn toward identifying core transcriptional networks using focused arrays for specific chemicals. In addition, agreed-on bioinformatics pipelines and the ranking of genes based on fold change (as opposed to p value) should be considered in environmental risk assessment. These recommendations are expected to improve comparisons across laboratories and advance the use of omics in regulations. Environ Toxicol Chem 2017;36:2593-2601. © 2017 SETAC., (© 2017 SETAC.)

Alpha-1-antitrypsin deficiency (AATD) is an inherited disease characterized by emphysema and liver disease. AATD is most often caused by a single amino acid substitution at amino acid 342 in the mature protein, resulting in the Z mutation of the alpha-1-antitrypsin gene (ZAAT). This substitution is associated with misfolding and accumulation of ZAAT in the endoplasmic reticulum (ER) of hepatocytes and monocytes, causing a toxic gain of function. Retained ZAAT is eliminated by ER-associated degradation and autophagy. We hypothesized that alpha-1-antitrypsin (AAT)-interacting proteins play critical roles in quality control of human AAT. Using co-immunoprecipitation, we identified ERdj3, an ER-resident Hsp40 family member, as a part of the AAT trafficking network. Depleting ERdj3 increased the rate of ZAAT degradation in hepatocytes by redirecting ZAAT to the ER calreticulin-EDEM1 pathway, followed by autophagosome formation. In the Huh7.5 cell line, ZAAT ER clearance resulted from enhancing ERdj3-mediated ZAAT degradation by silencing ERdj3 while simultaneously enhancing autophagy. In this context, ERdj3 suppression may eliminate the toxic gain of function associated with polymerization of ZAAT, thus providing a potential new therapeutic approach to the treatment of AATD-related liver disease. J. Cell. Biochem. 118: 3090-3101, 2017. © 2017 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals Inc., (© 2017 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals Inc.)

We report a simple protocol that affords oxidative demethylation of N 6 -methyl groups in N 6 -methyl adenines (m 6 A). The biologically compatible photocatalyst riboflavin prompts a highly selective C-H abstraction from N 6 -methyl in adenines under the irradiation of a visible blue LED light, affording a novel and highly selective biomimetic demethylation of m 6 A and related N-methyl adenine analogues.

It has been reported previously that some angiotensin II receptor blockers not only antagonize angiotensin II type 1 receptor (AT 1 R), but also exert stimulation in peroxisome proliferator-activated receptor γ (PPARγ) partial activation, among which telmisartan displays the best. Telmisartan has been tested as a bifunctional ligand with antihypertensive and hypoglycemic activity. Aiming at more potent leads with selective AT 1 R antagonism and PPARγ partial agonism, the three parts of telmisartan including the distal benzimidazole ring, the biphenyl moiety, and the carboxylic acid group experienced modification by core hopping method in our study. The central benzimidazole ring, however, remained intact considering its great affinity toward AT 1 R and PPARγ. We utilized computational techniques for the sake of details on the binding interactions and conformational stability. Standard precision docking analysis and absorption, distribution, metabolism, excretion, and toxicity prediction received 10 molecules with higher Glide scores, similar interactions, and improved pharmacokinetic profiles compared to telmisartan. Comp#91 with highest scores for AT 1 R (-11.92 kcal/mol) and PPARγ (-13.88 kcal/mol) exhibited excellent binding modes and pharmacokinetic parameters. Molecular dynamics trajectories on best docking pose of comp#91 confirmed the docking results and verified the conformational stability with both receptors throughout the course of 20-ns simulations. Thus, comp#91 could be identified as a promising lead in the development of dual AT 1 R antagonist and PPARγ partial agonist against hypertension and type 2 diabetes.

Alpha-1 antitrypsin (AAT) deficiency-associated emphysema is largely attributed to insufficient inhibition of neutrophil elastase released from neutrophils. Correcting AAT levels using augmentation therapy only slows disease progression, and that suggests a more complex process of lung destruction. Because alveolar macrophages (Mɸ) express AAT, we propose that the expression and intracellular accumulation of mutated Z-AAT (the most common mutation) compromises Mɸ function and contributes to emphysema development. Extracellular matrix (ECM) degradation is a hallmark of emphysema pathology. In this study, Mɸ from individuals with Z-AAT (Z-Mɸ) have greater proteolytic activity on ECM than do normal Mɸ. This abnormal Z-Mɸ activity is not abrogated by supplementation with exogenous AAT and is likely the result of cellular dysfunction induced by intracellular accumulation of Z-AAT. Using pharmacologic inhibitors, we show that several classes of proteases are involved in matrix degradation by Z-Mɸ. Importantly, compared with normal Mɸ, the membrane-bound serine protease, matriptase, is present in Z-Mɸ at higher levels and contributes to their proteolytic activity on ECM. In addition, we identified matrix metalloproteinase (MMP)-14, a membrane-anchored metalloproteinase, as a novel substrate for matriptase, and showed that matriptase regulates the levels of MMP-14 on the cell surface. Thus, high levels of matriptase may contribute to increased ECM degradation by Z-Mɸ, both directly and through MMP-14 activation. In summary, the expression of Z-AAT in Mɸ confers increased proteolytic activity on ECM. This proteolytic activity is not rescued by exogenous AAT supplementation and could thus contribute to augmentation resistance in AAT deficiency-associated emphysema.

Background: Acute kidney injury (AKI) is a severe disease in critically ill patients. Neutrophil infiltration into kidney was associated with the development of AKI, and P-selectin may be involved in the process of neutrophil recruitment in kidney. This study aimed to explore the potential effect of platelet-derived P-selectin on neutrophil recruitment in a mouse model of sepsis-induced AKI., Methods: A total of 30 C57BL/6 male mice were divided into five groups (n = 6 in each): sham group, sepsis group, anti-Ly6G group, anti-P-selectin group, and platelet depletion group. Sepsis was induced by cecal ligation and puncture. Serum creatinine concentration and platelet activity were measured by biochemical detector and flow cytometry, respectively. Histological and pathological features were analyzed using hematoxylin-eosin (H&E) and immunohistochemistry (IHC) staining, respectively. Myeloperoxidase (MPO) activity was detected with MPO assay. Unpaired t-test was used for data analysis., Results: Serum creatinine increased significantly in septic group compared to sham group (2.68 ± 0.27 mg/dl vs. 0.82 ± 0.19 mg/dl, t = 12.06, P = 0.0000) but attenuated in antibodies-treated animals compared to septic group (anti-Ly6G: 1.62 ± 0.30 mg/dl vs. 2.68 ± 0.27 mg/dl, t = 5.76, P = 0.0004; anti-P-selectin: 1.76 ± 0.31 mg/dl vs. 2.68 ± 0.27 mg/dl, t = 4.92, P = 0.0012; and platelet depletion: 1.93 ± 0.29 mg/dl vs. 2.68 ± 0.27 mg/dl, t = 4.14, P = 0.0032). Platelet amount significantly decreased compared to sham group (658.20 ± 60.64 × 109/L vs. 822.00 ± 48.60 × 109/L, t = 4.71, P = 0.0015) in septic mice, especially in platelet depletion group (240.80 ± 44.98 × 109/L vs. 822.00 ± 48.60 × 109/L, t = 19.63, P = 0.0000). P-selectin activity was significantly increased in septic group compared to sham group (16.54 ± 1.60% vs. 1.90 ± 0.29%, t = 15.64, P = 0.0000) but decreased significantly in platelet depletion group compared to septic group (3.62 ± 0.68% vs. 16.54 ± 1.60%, t = 12.89, P = 0.0002). IHC analysis shown that neutrophil infiltration increased in septic mice compared to sham group (36.67 ± 3.79% vs. 9.17 ± 1.61%, t = 11.58, P = 0.0003) and function-blocked groups (anti-Ly6G: 36.67 ± 3.79% vs. 15.33 ± 1.53%, t = 9.05, P = 0.0008; anti-P-selectin: 36.67 ± 3.79% vs. 21.33 ± 1.53%, t = 6.51, P = 0.0029; and platelet depletion: 36.67 ± 3.79% vs. 23.33 ± 3.06%, t = 4.75, P = 0.0090). MPO increased significantly in septic group compared to control (49.73 ± 1.83 ng/mg prot vs. 13.04 ± 2.16 ng/mg prot, t = 19.03, P = 0.0000) but decreased in function-blocked groups compared to septic group (anti-Ly6G: 26.52 ± 3.86 ng/mg prot vs. 49.73 ± 1.83 ng/mg prot, t = 9.59, P = 0.0000; anti-P-selectin: 33.06 ± 6.75 ng/mg prot vs. 49.73 ± 1.83 ng/mg prot, t = 4.85, P = 0.0013; and platelet depletion: 33.37 ± 2.25 ng/mg prot vs. 49.73 ± 1.83 ng/mg prot, t = 5.33, P = 0.0007)., Conclusion: Platelets-derived P-selectin may be involved in the development of septic AKI through inducing neutrophil infiltration into kidney.

Gastric cancer is one of the most common cancers and has the highest mortality rate worldwide. It is worthwhile to explore the mechanism of gastric cancer progression. An increasing number of studies have found that non-coding RNAs including miRNA and lncRNA play important roles in gastric cancer progression. This review summarized the role of ectopic miRNA in gastric cancer proliferation, growth, migration, invasion and apoptosis. Meantime, aberrantly expressed miRNA also received a great deal of attention as potential biomarker for gastric cancer diagnosis and therapy. Over the last decade, lncRNA was considered to regulate gastric cancer progression at the transcript and post-transcript level. At the transcript level, lncRNA induced gastric cancer progression by changing chromatin modification and mRNA stabilization to regulate mRNA and miRNA expression. Furthermore, lncRNA regulated gastric cancer progression by completely combining with miRNA to produce ceRNA or promote protein stabilization at the post-transcript level. Greater attention of miRNA and lncRNA in gastric cancer can provide new insight of mechanism of cancer development and may be acted as a new anticancer target., Competing Interests: CONFLICTS OF INTEREST None.

A microsporidian parasite, Hepatospora eriocheir, is an emerging pathogen for the Chinese mitten crab Eriocheir sinensis. Currently, there is scant information about the way it transmits infection in the crustacean of commercial importance, including its pathogenesis, propagation and infection route in vivo. In this study, chromogenic in situ hybridization (ISH) and quantitative real-time PCR (qPCR) assays were developed to address this pressing need, and we provided an advance in the detection methods available. Pathogens can be seen in situ with associated lesions using ISH. Positive hybridization signals were noted inside the epithelial cells of the hepatopancreas, and putative free parasite spores were observed within the tubule lumen, which were associated with lesions detected by electron microscopy and haematoxylin and eosin (H&E) analysis. qPCR allows the determination of parasite loads in infected tissues, which is important for understanding disease progression and transmission. The hepatopancreas displayed the biggest statistical copy numbers among different tissues of infected crabs, confirming a tissue-specific pathogen infection characteristic. The qPCR assay also proved to be suitable for the diagnosis of asymptomatic carrier crabs. Combination of the two methods could facilitate the study of H. eriocheir infection mechanism in E. sinensis, enhance the early diagnosis of the pathogen and improve the management of microsporidian diseases in commercial crustaceans., (© 2016 John Wiley & Sons Ltd.)

Objective: To investigate the values of combination of urinary liver-type fatty acid-binding protein (L-FABP) and neutrophil gelatinase-associated lipocalin (NGAL) in early diagnosis of acute kidney injury (AKI) after cardiac surgery in children., Methods: A total of 97 children with congenital heart disease undergoing cardiopulmonary bypass surgery were enrolled. Serum and urine samples were collected before and after surgery. Levels of serum creatinine (Scr), urinary L-FABP, and urinary NGAL from AKI group (n=18) and non-AKI group (n=79) were measured, and the postoperative dynamic changes in these markers were compared between the two groups. The receiver operating characteristic (ROC) curve and the area under ROC curve (AUC) were used to assess the values of these markers alone or in combination in the prediction of postoperative AKI., Results: The levels of urinary L-FABP and NGAL in the AKI group were significantly higher than those in the non-AKI group at 2 and 6 hours after surgery, and the changes in their concentrations were earlier than Scr. The AUCs of urinary L-FABP alone in predicting AKI at 2 and 6 hours after surgery were 0.921 and 0.896 respectively, and those of urinary NGAL alone were 0.908 and 0.928 respectively. Those of their combination were 0.942 and 0.929 respectively., Conclusions: Urinary L-FABP and NGAL significantly increase in the early stage of AKI after cardiac surgery in children, which are significantly earlier than the changes in Scr. They can be used to predict the occurrence of AKI in the early stage. A combination of the two biomarkers can further improve the accuracy of diagnosis.

Two experiments were conducted to evaluate the nutritive value and maximum safe level (MSL) of pennycress meal (PM) for broiler chicks. In experiment 1, a total of 480 chicks was fed either mash or crumbled diets containing zero, 5, 10, or 15% PM for 18 d (8 diets; 6 replications per diet). In experiment 2, a total of 660 chicks was fed mash diets containing zero, 3, 6, 9, 12, or 15% of either PM or canola meal (CM; a comparative reference) for 14 d (11 diets; 6 replications per diet). Analytical results show that PM is a good source of protein (∼31% CP) and it is very comparable to CM (∼36% CP). However, it contains higher erucic acid (∼1.68 vs. < 0.021%), glucosinolates (sinigrin) (∼63.5 vs. <0.163 μmol /g), and crude fiber (18.60 vs. 9.27%) compared to CM. In experiment 1, increasing PM from zero to 15% resulted in linear reductions (P < 0.05) in FI, BWG, and FCR at 10 days. Above 10%, performance responses were affected for FI and BWG at 18 d, respectively. An estimated MSL of 10% PM based on orthogonal contrast was optimal for satisfactory FI and BWG. The MSL as estimated by broken-line linear (BLL) and broken-line quadratic (BLQ) models was 9.12 ± 0.50 and 7.0 ± 1.27%, respectively. In experiment 2, growth performance at 14 d was reduced above 9% due to PM inclusion. CM inclusion did not affect growth performance at 14 d, suggesting 15% to be safe. The MSL for maximum growth performance varied depending on the statistical analysis as follows: 12% by orthogonal contrast and LSD, 15% by the Scheffé test, 10.84 ± 0.57 by BLL, and 8.61 ± 1.29 by BLQ. In conclusion, PM can be included in broiler starter diets as a protein source but its inclusion should be limited to no more than 8.5%. Different statistical procedures give different MSL and this should be considered when interpreting the data., (© 2017 Poultry Science Association Inc.)

PTP-MEG2 plays a critical role in the diverse cell signalling processes, so targeting PTP-MEG2 is a promising strategy for various human diseases treatments. In this study, a series of novel dibenzofuran derivatives was synthesized and assayed for their PTP-MEG2 inhibitory activities. 10a with highest inhibitory activity (320 nM) exhibited significant selectivity for PTP-MEG2 over its close homolog SHP2, CDC25 (IC50 > 50 μM). By means of the powerful ''HipHop'' technique, a 3D-QSAR study was carried out to explore structure activity relationship of these molecules. The generated pharmacophore model revealed that the one RA, three Hyd, and two HBA features play an important role in binding to the active site of the target protein-PTP-MEG2. Docking simulation study indicated that 10a achieved its potency and specificity for PTP-MEG2 by targeting unique nearby peripheral binding pockets and the active site. The absorption, distribution, metabolism and excretion (ADME) predictions showed that the 11 compounds hold high potential to be novel lead compounds for targeting PTP-MEG2. Our findings here can provide a new strategy or useful insights for designing the effective PTP-MEG2 inhibitors.

Chiral solid membranes of cellulose, sodium alginate, and hydroxypropyl-β-cyclodextrin were prepared for chiral dialysis separations. After optimizing the membrane material concentrations, the membrane preparation conditions and the feed concentrations, enantiomeric excesses of 89.1%, 42.6%, and 59.1% were obtained for mandelic acid on the cellulose membrane, p-hydroxy phenylglycine on the sodium alginate membrane, and p-hydroxy phenylglycine on the hydroxypropyl-β-cyclodextrin membrane, respectively. To study the optical resolution mechanism, chiral discrimination by membrane adsorption, solid phase extraction, membrane chromatography, high-pressure liquid chromatography ultrafiltration were performed. All of the experimental results showed that the first adsorbed enantiomer was not the enantiomer that first permeated the membrane. The crystal structures of mandelic acid and p-hydroxy phenylglycine are the racematic compounds. We suggest that the chiral separation mechanism of the solid membrane is "adsorption - association - diffusion," which is able to explain the optical resolution of the enantioselective membrane. This is also the first report in which solid membranes of sodium alginate and hydroxypropyl-β-cyclodextrin were used in the chiral separation of p-hydroxy phenylglycine., (© 2017 Wiley Periodicals, Inc.)

Cell division cycle 25B is a key cell cycle regulator and widely considered as potent clinical drug target for cancers. This research focused on identifying potential compounds in theory which are able to disrupt transient interactions between CDC25B and its CDK2/Cyclin A substrate.By using the method of ZDOCK and RDOCK, the most optimized 3D structure of CDK2/Cyclin A in complex with CDC25B was constructed and validated using two methods: 1) the superimposition of proteins; 2) analysis of the hydrogen bond distances of Arg 488(N1)-Asp 206(OD1), Arg 492(NE)-Asp 206(OD1), Arg 492(N1)-Asp 206(OD2) and Tyr 497(NE)-Asp 210(OD1). A series of new compounds was gained through searching the fragment database derived from ZINC based on the known inhibitor-compound 7 by the means of "replace fragment" technique. The compounds acquired via meeting the requirements of the absorption, distribution, metabolism, and excretion (ADME) predictions. Finally, 12 compounds with better binding affinity were identified. The comp#1, as a representative, was selected to be synthesized and assayed for their CDC25B inhibitory activities. The comp#1 exhibited mild inhibitory activities against human CDC25B with IC50 values at about 39.02 μM. Molecular Dynamic (MD) simulation revealed that the new inhibitor-comp#1 had favorable conformations for binding to CDC25B and disturbing the interactions between CDC25B and CDK2/Cyclin A.

Telmisartan, a bifunctional agent of blood pressure lowering and glycemia reduction, was previously reported to antagonize angiotensin II type 1 (AT1) receptor and partially activate peroxisome proliferator-activated receptor γ (PPARγ) simultaneously. Through the modification to telmisartan, researchers designed and obtained imidazo-\pyridine derivatives with the IC50s of 0.49~94.1 nM against AT1 and EC50s of 20~3640 nM towards PPARγ partial activation. For minutely inquiring the interaction modes with the relevant receptor and analyzing the structure-activity relationships, molecular docking and 3D-QSAR (Quantitative structure-activity relationships) analysis of these imidazo-\pyridines on dual targets were conducted in this work. Docking approaches of these derivatives with both receptors provided explicit interaction behaviors and excellent matching degree with the binding pockets. The best CoMFA (Comparative Molecular Field Analysis) models exhibited predictive results of q2=0.553, r2=0.954, SEE=0.127, r2pred=0.779 for AT1 and q2=0.503, r2=1.00, SEE=0.019, r2pred=0.604 for PPARγ, respectively. The contour maps from the optimal model showed detailed information of structural features (steric and electrostatic fields) towards the biological activity. Combining the bioisosterism with the valuable information from above studies, we designed six molecules with better predicted activities towards AT1 and PPARγ partial activation. Overall, these results could be useful for designing potential dual AT1 antagonists and partial PPARγ agonists.

Objective: To investigate surface properties of novel flowable composites after polishing and simulated brushing wear, compared to their pasty counterpart. Methods: Composites employed in this study were: three flowable composites (A1: Clearfil Majesty ES Flow; B1: Beautifil Flow Plus F00; C1: Filtek Bulk Fill) and three paste composites (A2: Clearfil Majesty; B2: Beautifil; C2: Filtek Z350. Eleven disk-shaped specimens were made for each material. The specimens were cured, then subjected to sandpaper finishing for 20 s, one-step polishing for 30 s, finally subjected to simulated brushing for 10 000 cycles. Surface roughness and glossiness were measured before finishing, after finishing, after polishing, after 5 000 brushing cycles and after 10 000 brushing cycles, respectively. Data obtained were analyzed using two-way ANOVA method. Scanning electron microscope was employed to examine the microscopic appearance of each material. Results: Surface roughness (0.11~0.22 μm) and glossiness (74.25~86.48 GU) of each material were similar after one-step polishing. After brushing simulation, roughness increased significantly and glossiness decreased significantly for each material ( P< 0.05). Group A1 presented the best gloss ([50.68±1.58] GU) after final wear ( P< 0.05). Flowable composites of group A1 and B1 tested in the present setup showed better surface properties compared to their pasty counterpart (group A2 and B2). Conclusions: Within the limit of this study, flowable composites tested in the present research can obtain similar surface polish or even better than the paste composite counterpart.

Insect cytochrome P450 monooxygenases (CYPs or P450s) play an important role in detoxifying insecticides leading to resistance in insect populations. A polyphagous pest, Spodoptera litura, has developed resistance to a wide range of insecticides. In the present study, a novel P450 gene, CYP321B1, was cloned from S. litura. The function of CYP321B1 was assessed using RNA interference (RNAi) and monitoring resistance levels for three commonly used insecticides, including chlorpyrifos, β-cypermethrin and methomyl. The full-length complementary DNA sequence of CYP321B1 is 1814 bp long with an open reading frame of 1 488 bp encoding 495 amino acid residues. Quantitative reverse-transcriptase polymerase chain reaction analyses during larval and pupal development indicated that CYP321B1 expression was highest in the midgut of fifth-instar larvae, followed by fat body and cuticle. The expression of CYP321B1 in the midgut was up-regulated by chlorpyrifos, β-cypermethrin and methomyl with both lethal concentration at 15% (LC 15 ) (50, 100 and 150 μg/mL, respectively) and 50%(LC 50 ) dosages (100, 200 and 300 μg/mL, respectively). Addition of piperonyl butoxide (PBO) significantly increased the toxicity of chlorpyrifos, β-cypermethrin and methomyl to S. litura, suggesting a marked synergism of the three insecticides with PBO and P450-mediated detoxification. RNAi-mediated silencing of CYP321B1 further increased mortality by 25.6% and 38.9% when the fifth-instar larvae were exposed to chlorpyrifos and β-cypermethrin, respectively, at the LC 50 dose levels. The results demonstrate that CYP321B1 might play an important role in chlorpyrifos and β-cypermethrin detoxification in S. litura., (© 2016 Institute of Zoology, Chinese Academy of Sciences.)

Peroxisome proliferators-activated receptors (PPARα, γ and δ) are potentially effective targets for Type 2 diabetes mellitus therapy. The severe effects of known glitazones and the successfully approved agents (saroglitazar and lobeglitazone) motivated us to study novelly potent PPARs drugs with improved safety profile. In this work, we received 15 carboxylic acids based on the combination principle to integrate the polar head of bezafibrate with the hydrophobic tail of pioglitazone. Another 12 tetrazoles based on the bioisosterism principle were obtained accordingly. Furthermore, in vitro PPARs transactivation assays on these 3- or 4-alkoxy substituted phenoxy derivatives afforded six compounds. Interactions and binding stability from the docking analysis and 20 ns molecular dynamic simulations confirmed the representative compounds to be suitable and plausible for PPARs pockets. The above-mentioned results demonstrated that the compounds may be used as reference for further optimization for enhanced PPARs activities and wide safety range.

Sophocarpine is the major pharmacologically active compound of the traditional Chinese herbal medicine Radix Sophorae Subprostratae which has been used in treating hepatitis for years in China. It has been demonstrated that Sophocarpine exerts an activity in immune modulation and significantly decreases the production of inflammatory cytokines. However, the protective effects of Sophocarpine in T cell-dependent immune hepatitis remained unknown. The aim of this study was to determine the protective effects and pharmacological mechanisms of Sophocarpine on Concanavalin A (ConA)-induced hepatitis, an experimental model of T cell-mediated liver injury. BALB/C mice were pretreated with Sophocarpine or Bicyclol for five consecutive days. Thirty minutes after the final administration, the mice were injected with 15 mg⋅kg -1 of ConA intravenously. The results indicated that pretreatment with Sophocarpine significantly ameliorated liver inflammation and injury as evidenced by both biochemical and histopathological observations. Moreover, in Sophocarpine-pretreated mice, liver messenger RNA expression levels of chemokines and adhesion molecules, such as macrophage inflammatory protein-1α, CXC chemokine ligand 10, and Intercellular adhesion molecule-1, were markedly reduced. Further studies revealed that Sophocarpine significantly downregulated the expression of T-bet via inhibition of signal transducers and activators of transcription1 (STAT1) activation and overexpression of suppressor of cytokine signaling1, inhibiting the activation of Th1 cells and the expression of Interferon-γ (IFN-γ). Altogether, these results suggest new opportunities to use Sophocarpine in the treatment of T cell-mediated liver disease. In summary, Sophocarpine could attenuate ConA-induced liver injury, and the protective effect of Sophocarpine was associated with its inhibition effect of pro-inflammatory cytokines, chemokines, and the IFN- γ /STAT1 signaling pathway.

Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder characterized by early-onset emphysema and liver disease. The most common disease-causing mutation is a single amino acid substitution (Glu/Lys) at amino acid 342 of the mature protein, resulting in disruption of the 290-342 salt bridge (an electrophoretic abnormality defining the mutation [Z allele, or ZAAT]), protein misfolding, polymerization, and accumulation in the endoplasmic reticulum of hepatocytes and monocytes. The Z allele causes a toxic gain of function, and the E3 ubiquitin ligase gp78 promotes degradation and increased solubility of endogenous ZAAT. We hypothesized that the accumulation of ZAAT is influenced by modulation of gp78 E3 ligase and SVIP (small VCP-interacting protein) interaction with p97/VCP in ZAAT-expressing hepatocytes. We showed that the SVIP inhibitory effect on ERAD due to overexpression causes the accumulation of ZAAT in a human Z hepatocyte-like cell line (AT01). Overexpression of gp78, as well as SVIP suppression, induces gp78-VCP/p97 interaction in AT01 cells. This interaction leads to retro-translocation of ZAAT and reduction of the SVIP inhibitory role in ERAD. In this context, overexpression of gp78 or SVIP suppression may eliminate the toxic gain of function associated with polymerization of ZAAT, thus providing a potential new therapeutic approach to the treatment of AATD.

Circulating tumor DNA (ctDNA) can be identified in the peripheral blood of patients and harbors the genomic alterations found in tumor tissues, which provides a noninvasive approach for detection of gene mutations. We conducted this meta-analysis to investigate whether ctDNA can be used for monitoring KRAS gene mutations in colorectal cancer (CRC) patients. Medline, Embase, Cochrane Library and Web of Science were searched for the included eligible studies in English, and data were extracted for statistical analysis according to the numbers of true-positive (TP), true-negative (TN), false-positive (FP) and false-negative (FN) cases. Sensitivity, specificity and diagnostic odds ratio (DOR) were calculated, and the area under the receiver operating characteristic curve (AUROC) was used to evaluate the diagnostic performance. After independent searching and reviewing, 21 studies involving 1,812 cancer patients were analyzed. The overall sensitivity, specificity and DOR were 0.67 (95% confidence interval [CI] =0.55-0.78), 0.96 (95% CI =0.93-0.98) and 53.95 (95% CI =26.24-110.92), respectively. The AUROC was 0.95 (95% CI =0.92-0.96), which indicated the high diagnostic accuracy of ctDNA. After stratified analysis, we found the higher diagnostic accuracy in subgroup of patients detected in blood sample of plasma. The ctDNA may be an ideal source for detection of KRAS gene mutations in CRC patients with high specificity and diagnostic value., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

This study was conducted to investigate the inhibitory effect and the molecular mechanism of deoxyschizandrin on the activity of NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome. Bone marrow-derived macrophages were used to study the effects of deoxyschizandrin on inflammasome activation using inflammasome inducers (ATP and nigericin). Cytotoxic effect was evaluated with CCK-8. The expression of IL-1β, caspase-1 in the supernatant and the expression of pro-caspase-1, pro-IL-1β, ASC, NLRP3 in cell was detected by Western blot for the inhibitory effect of deoxyschizandrin (25, 50, 100 and 200 μmol·L(−1)) on the activity of NLRP3 inflammasome. Immunofluorescence was applied to investigate NF-κB (p65) transportation to the nucleus. The results of CCK-8 showed that the optimum concentration of deoxyschizandrin was 6.25–400 μmol·L(−1). Deoxyschizandrin (25, 50, 100, and 200 μmol·L(−1)) could inhibit the activation of NLRP3 inflammasome caused by nigericin and ATP, and inhibit the secretion of IL-1β, which was associated with inhibiting the cleavage of pro-caspase-1. The results of immunofluorescence and Western blot also suggest that the inhibitory activity of deoxyschizandrin on NLRP3 inflammasome was not dependent on NF-κB pathway and protein expression of NLRP3, ASC, pro-caspase-1 and pro-IL-1β mediated by NF-κB. Our results confirmed that deoxyschizandrin could suppress the cleavage of pro-caspase-1 and inhibit the activity of NLRP3 inflammasome at 25–200 μmol·L−1 to reduce the inflammation response.This study was conducted to investigate the inhibitory effect and the molecular mechanism of deoxyschizandrin on the activity of NLRP3 (NOD-like receptor family,pyrin domain containing 3) inflammasome.Bone marrow-derived macrophages were used to study the effects of deoxyschizandrin on inflammasome activation using inflammasome inducers (ATP and nigericin). Cytotoxic effect was evaluated with CCK-8.The expression of IL-1β,caspase-1 in the supernatant and the expression of pro-caspase-1,pro-IL-1β,ASC,NLRP3 in cell was detected by Western blot for the inhibitory effect of deoxyschizandrin (25, 50, 100 and 200 μmol·L(-1)) on the activity of NLRP3 inflammasome. Immunofluorescence was applied to investigate NF-κB (p65) transportation to the nucleus. The results of CCK-8 showed that the optimum concentration of deoxyschizandrin was 6.25-400 μmol·L(-1). Deoxyschizandrin (25, 50, 100,and 200 μmol·L(-1)) could inhibit the activation of NLRP3 inflammasome caused by nigericin and ATP, and inhibit the secretion of IL-1β, which was associated with inhibiting the cleavage of pro-caspase-1.The results of immunofluorescence and Western blot also suggest that the inhibitory activity of deoxyschizandrin on NLRP3 inflammasome was not dependent on NF-κB pathway and protein expression of NLRP3,ASC,pro-caspase-1 and pro-IL-1βmediated by NF-κB. Our results confirmed that deoxyschizandrin could suppress the cleavage of pro-caspase-1 and inhibit the activity of NLRP3 inflammasome at 25-200 μmol·L(-1) to reduce the inflammation response.

Currently, numerous liver injury cases related to a famous Chinese herb- Polygonum Multiflorum (Heshouwu in Chinese) have attracted great attention in many countries. Our previous work showed that Heshouwu-induced hepatotoxicity belonged to idiosyncratic drug-induced liver injury (IDILI). Unfortunately, the components and mechanisms attributed to IDILI of Heshouwu are difficult to determine and thus remain unknown. Attempts to explore puzzles, we prepared the chloroform (CH)-, ethyl acetate (EA)-, and residue (RE) extracts of Heshouwu to investigate IDILI constituents and underlying mechanisms, using biochemistry, histopathology, and metabolomics examinations. The results showed that co-treatment with non-toxic dose of lipopolysaccharide (LPS) and EA extract could result in evident liver injury, indicated by the significant elevation of plasma alanine aminotransferase and aspartate aminotransferase activities, as well as obvious liver histologic damage; whereas other two separated fractions, CH and RE extracts, failed to induce observable liver injury. Furthermore, 21 potential metabolomic biomarkers that differentially expressed in LPS/EA group compared with other groups without liver injury were identified by untargeted metabolomics, mainly involved two pathways: tricarboxylic acid cycle and sphingolipid metabolism. This work illustrated EA extract had close association with the idiosyncratic hepatotoxicity of Heshouwu and provided a metabolomic insight into IDILI of different extracts from Heshouwu.

The rational design of magnetic and fluorescent bifunctional materials is attracting increasing interest. In this study, two mononuclear Fe(ii) complexes, namely [Fe(L) 2 (NCS) 2 ] (1) and [Fe(L) 2 (NCSe) 2 ] (2) are synthesised by combining a spin-crossover unit and a fluorescent ligand (naphth-1-yl)-N-(3,5-di(pyridin-2-yl)-4H-1,2,4-triazol-4-yl)methanimine (L) to achieve bifunctionality. Single-crystal X-ray studies and magnetic measurements confirm the presence of spin crossover behaviours; these measurements agree with the results of the temperature depended Raman spectra and infrared spectra. Thermally and light-induced spin crossover is clearly observed for both complexes. The nature of the co-ligand (NCS - vs. NCSe - ) shifts the transition temperature by approximately 60 K. The infrared spectra after irradiation reveal that the electronic states are ascribable to the photomagnetic effect at 10 K. Furthermore, temperature-dependent fluorescence emission spectra exhibit the coexistence of spin crossover and fluorescence for 1 and 2.

A novel efficient approach to optically pure bridging chiral calix[4]arenes through a homologous anionic ortho-Fries rearrangement of inherently chiral calix[4]arenes was presented for the first time. As a result, two pairs of N,N'-dimethylformamidyl-substituted bridging chiral p-tert-butylcalix[4]arene enantiomers were facilely obtained. Their absolute configurations were determined through ROESY analysis, ECD comparison, and X-ray crystallographic analysis.

Although lanthanum (La) has been used as an agricultural plant growth stimulant for approximately 50 years, high concentrations are toxic to plants. Despite significant advances in recent years, the mechanisms underlying the effects of La on root system development remain unclear. Here, we report that a high concentration of La inhibits primary root (PR) elongation and induces lateral root (LR) development. La results in cell death in PR tips, thereby leading to the loss of meristematic cell division potential, stem cell niche activity, and auxin distribution in PR tips. Further analysis indicated that La induces reactive oxygen species (ROS) over-accumulation in PR tips. Reduction in ROS accumulation partially alleviated the inhibitory effects of La on PR elongation by improving cell survival in PR tips and thereby improving meristematic cell division potential and auxin distribution in PR tips. We also found ROS to be involved in La-induced endocytosis. Genetic analyses supported the described phenotype. Overall, our results indicate that La affects root growth, at least partially, by modulating ROS levels in roots to induce cell death in PR tips and subsequent auxin redistribution in roots, leading to remodeling of the root system architecture., (© The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

Familial exudative vitreoretinopathy (FEVR) is a hereditary ocular disorder characterized by a failure of peripheral retinal vascularization. In this report, we describe a novel missense mutation of the Norrie disease gene (NDP) in a Chinese family with X-linked FEVR. Ophthalmologic evaluation was performed on four male patients and seven unaffected individuals after informed consent was obtained. Venous blood was collected from the 11 members of this family, and genomic DNA was extracted using standard methods. The coding exons 2 and 3 and their corresponding exon-intron junctions of NDP were amplified by polymerase chain reaction and then subjected to direct DNA sequencing. A novel missense mutation (c.310A>C) in exon 3, leading to a lysine-to-glutamine substitution at position 104 (p.Lys104Gln), was identified in all four patients with X-linked FEVR. Three unaffected female individuals (III2, IV3, and IV11) were found to be carriers of the mutation. This mutation was not detected in other unaffected individuals. The mutation c.310A>C (p.Lys104Gln) in exon 3 of NDP is associated with FEVR in the studied family. This result further enriches the mutation spectrum of FEVR., (Copyright © 2016. Published by Elsevier Taiwan LLC.)

Type 2 diabetes took insulin resistance as the main clinical manifestation. PPARs have been reported to be the therapeutic targets of metabolic disorders, such as obesity, hypertension, diabetes, and cardiovascular disease. Previously, PPARγ agonist rosiglitazone was restricted in clinic due to cardiomyocytes infarction, weight gain, and other serious side-effects, which were mainly due to the single and selective PPARγ agonism. In recent years, multitarget-directed PPAR agonists with synergistic reaction as well as fewer side-effect have been the hot topic in designing promising agents. In this review, we updated and generalized the development of PPARγ partial agonists, PPARγ antagonists, PPARα/γ dual agonists, PPARδ partial agonists, PPARδ antagonists, PPARα/δ dual agonists, PPARγ/δ dual agonists, and PPARα/γ/δ pan-agonists published in recent decade. Most of these molecules were modified from known structures or came from high-throughput screening. Among these molecules, some were expected to be promising drugs against metabolic disorders, while others seemed to provide new insight for designing novel PPAR agents., (© 2016 John Wiley & Sons A/S.)

Ciprofloxacin is a quinolone antibiotic used to treat Klebsiella pneumoniae infections in the clinic. Previous studies have demonstrated that berberine exhibits antibacterial activity and less acquired resistance related to efflux pumps. The multidrug efflux pump acrAB-tolC can be stimulated to expel as much toxic material as possible from the cells, but a detrimental effect can be produced owing to an overcrowded periplasm with excess expression products, which inhibits bacterial growth. In this study, the in vitro antibacterial activities of ciprofloxacin in combination with berberine were evaluated and compared with those of ciprofloxacin and berberine alone by evaluating the MIC, MBC and summation fractional IC against 20 clinical multidrug-resistant K. pneumoniae isolates, 1 quality control bacterium and 1 induced-resistance bacterium. Susceptibility tests showed that the MIC for the combination of berberine and ciprofloxacin was 1/2 that of the individual agents or less. Antimicrobial activities of 18.18% synergy and 77.27% additivity were found. Furthermore, synergism was verified through a time-kill assay, which suggested that the synergistic antibacterial effect of the two-drug combination may, to some extent, be related to the high expression of the acrAB-tolC and acrR multidrug efflux pumps. Indeed, the expression of these genes was increased >14-fold in the isolates affected by ciprofloxacin-berberine combination synergism.

Background and Aim: Chinese herbal medicine (CHM), as well as Western medicine (WM), is an important cause of drug-induced liver injury (DILI). However, the differences between CHM and WM as agents implicated in liver injury have rarely been reported., Methods: Overall, 1985 (2.05%) DILI cases were retrospectively collected from the 96 857 patients hospitalized because of liver dysfunction in the 302 Military Hospital between January 2009 and January 2014., Results: In all the enrolled patients with DILI, CHM was implicated in 563 cases (28.4%), while 870 cases (43.8%) were caused by WM and the remaining patients (27.8%) by the combination of WM and CHM. Polygonum multiflorum was the major implicated CHM. Compared with WM, the cases caused by CHM showed more female (51 vs 71%, P < 0.001) and positive rechallenge (6.1 vs 8.9%, P = 0.046), a much greater proportion of hepatocellular injury (62.2 vs 88.5%, P < 0.001), and a higher mortality (2.8 vs 4.8%, P = 0.042); however, no differences in the rates of chronic DILI and ALF were found (12.9 vs 12.4%, P = 0.807; 7.6 vs 7.6%, P = 0.971). Based on Roussel Uclaf Causality Assessment Method, 75.6% of cases caused by CHM were classified as probable and only 16.6% as highly probable, significantly different from WM (38.4 and 60.3%, all P < 0.001)., Conclusions: The causal relationship between CHM and liver injury is much complex, and the clinical characteristics of DILI caused by CHM differ from those caused by WM., (© 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Chromosomal abnormalities that result in genomic imbalances are main causes of congenital and developmental anomalies including intellectual disability and multiple congenital malformations. In this report we describe four patients from three families with imbalanced translocations. Only a small percentage of imbalanced translocation individuals can be born to live, most of them were aborted in embryonic period. It is of great significances to precisely analysis the chromosome variation to study the relationship between genotype and phenotype., Results: Four patients showed common clinical manifestations including delayed growth, intellectual disability, language barrier and facial dysmorphisms. In addition to the above features, lower limbs dysplasia and both foot eversion were found in patient 1, brachydactylic hand, cerebellar ataxia and congenital heart defects were also found in patient 4. Conventional karyotype analysis revealed abnormal karyotypes 46, XX, der (6) t (6: 10) (p23; q24), 46, XX, der (20) t (3; 20) (p23; p13) and 46, XX, der (22) t (3; 22) (q27; q13.3) in the four patients, respectively. Array-CGH analyses confirmed 23.6 Mb duplication on 10q25.1-q26.3 and 0.9 Mb deletions on 6p25.3, 19.9 Mb duplication on 3p24.3-p26.3 and 0.25 Mb deletion on 20p13 and 12.5 Mb duplication on 3q27.2-q29 and 1.9 Mb deletions on 22q13.2-q13.33 in the four patients, respectively., Conclusion: Parents with balanced translocation are passed the imbalanced chromosome to patient, and the partial monosomy and partial trisomy lead to multiple congenital malformations of four patients.

Background: Compound Kushen Injection (CKI) is a Chinese patent medicine approved by the China Food and Drug Administration for the treatment of various types of solid tumors. CKI, combined with transarterial chemoembolization (TACE), is believed to increase the therapeutic efficacy of unresectable hepatocellular carcinoma (HCC). We report an updated and extended meta-analysis with detailed outcomes of both the efficacy and adverse events (AEs) of CKI combined with TACE therapy., Materials and Methods: Electronic databases, including PubMed, Embase, the Cochrane Library, the Chinese Biomedical Database (CBM), Wanfang, the VIP medicine information system (VMIS) and the China National Knowledge Infrastructure (CNKI), were examined for relevant articles before November 13, 2015. An odds ratio (OR) was used to estimate tumor response (TR), Karnofsky Performance Scale (KPS) improvement, Child-Pugh (CP) improvement, survival rate (SR) and AEs. A publication bias and a subgroup analysis were also assessed., Results: Eighteen studies, with a total of 1,338 HCC patients who met the criteria for the meta-analysis, were included. TR, KPS improvement and CP improvement were significantly enhanced for the combination therapy compared to TACE alone (OR = 1.84, 95% CI: [1.46, 2.33], P < 0.00001; OR = 2.37, 95% CI: [1.76, 3.18], P < 0.00001; OR = 1.81, 95% CI: [1.08, 3.03], P = 0.02, respectively). The combination therapy was associated with an improvement in 1-year and 2-year SRs but not an improved 3-year SR (OR = 2.40; 95% CI: [1.59, 3.62], P < 0.0001; OR = 2.49, 95% CI: [1.24, 5.00], P = 0.01; OR = 2.49, 95% CI: [0.94, 6.61], P = 0.07, respectively). A safety analysis indicated that AEs (including nausea/vomiting, fever, hepatalgia, increased transaminase, increased bilirubin and leukopenia) were reduced for the combination treatment compared to TACE alone., Conclusion: The combination treatment of TACE and CKI was associated with improved TR, KPS and CP improvement and improved 1- and 2-year SRs in patients with unresectable HCC. The 3-year SR was not improved. The combination therapy resulted in a reduction in AEs. The findings of this study should be interpreted with caution because of the small sample size and study limitations.

To solve the long-existing difficult problems in extracting RNA and constructing a complementary DNA (cDNA) library for trace mites, we conducted a further comparative experiment among three RNA extraction methods (TRIzol method, Omega method, and Azanno method) based on our previous attempts at the construction of cDNA library of mites, with Psoroptes cuniculi still used as the experimental subject. By subsequently decreasing the number of mites, the least number of mites needed for RNA extraction of each method were found by criteria of completeness, concentration, and purity of the extracted RNA. Specific primers were designed according to the allergen Pso c1, Pso c2, and Actin gene sequences of Psoroptes to test the reliability of cDNA library. The results showed that Azanno method needed only 10 mites with sensitivity 204 times higher than previously used TRIzol method and 20 times higher than Omega method; clear RNA band was detected by agarose gel electrophoresis; and ultraviolet spectrophotometer determination showed that RNA concentration, 260/280, and 260/230 were in the range of 102 to 166 ng/μl, 1.83 to 1.99, and 1.49 to 1.72, respectively. Finally, specific primers detection showed that the amplified sequences had 98.33, 98.19, and 99.52% identities with those of P. cuniculi or Psoroptes ovis in GenBank, respectively, indicating that the cDNA library constructed using 10 mites was successful and it could meet the requirements for molecular biology research. Therefore, we concluded that Azanno method was more effective than TRIzol method and Omega method in RNA extraction and cDNA library construction of trace mites.

Objective: The receptor-interacting protein (RIP) has been identified to play a critical role in necroptosis, which is an inflammatory form of programmed necrosis in trauma, ischemia/reperfusion (I/R), and systemic inflammatory response syndrome (SIRS). Ripoptosome, a newly defined intracellular signaling complex with essential molecule of RIP1, can switch cell death mode between apoptosis and necroptosis. Based on molecular mechanism of RIP-dependent cell death and inflammation, with the understanding of the mechanisms of RIP-dependent apoptosis/necroptosis and its role in inflammation was summed up, and it was found that RIP plays a crucial role in regulating programmed cell death and inflammation. Therefore, further advances in understanding the mechanisms of necroptosis would be important in order to manipulate programmed cell death for therapeutic purposes in I/R injury, trauma, SIRS, and tumor.

Background: A very large and rapidly growing collection of transcriptomic profiles in public repositories is potentially of great value to developing data-driven bioinformatics applications for toxicology/ecotoxicology. Modeled on human connectivity mapping (Cmap) in biomedical research, this study was undertaken to investigate the utility of an analogous Cmap approach in ecotoxicology. Over 3500 zebrafish (Danio rerio) and fathead minnow (Pimephales promelas) transcriptomic profiles, each associated with one of several dozen chemical treatment conditions, were compiled into three distinct collections of rank-ordered gene lists (ROGLs) by species and microarray platforms. Individual query signatures, each consisting of multiple gene probes differentially expressed in a chemical condition, were used to interrogate the reference ROGLs., Results: Informative connections were established at high success rates within species when, as defined by their mechanisms of action (MOAs), both query signatures and ROGLs were associated with the same or similar chemicals. Thus, a simple query signature functioned effectively as an exposure biomarker without need for a time-consuming process of development and validation. More importantly, a large reference database of ROGLs also enabled a query signature to cross-interrogate other chemical conditions with overlapping MOAs, leading to novel groupings and subgroupings of seemingly unrelated chemicals at a finer resolution. This approach confirmed the identities of several estrogenic chemicals, as well as a polycyclic aromatic hydrocarbon and a neuro-toxin, in the largely uncharacterized water samples near several waste water treatment plants, and thus demonstrates its future potential utility in real world applications., Conclusions: The power of Cmap should grow as chemical coverages of ROGLs increase, making it a framework easily scalable in the future. The feasibility of toxicity extrapolation across fish species using Cmap needs more study, however, as more gene expression profiles linked to chemical conditions common to multiple fish species are needed.

Rosiglitazone was restricted clinically due to the side effects such as edema, weight gain and cardiac failure mainly attributing to the single and selective PPARγ activation. Nowadays, multi-targeted PPARs agonists remained to be a hot topic in the antidiabetic medicinal chemistry field. In this paper, the cooperative PPARα/γ dual agonists were screened from Specs database via the flow chart of docking, ADMET prediction and molecular dynamics (MD) simulations. Representative compounds ZINC36517927 and ZINC13573581 displayed higher binding scores, better pharmacokinetic profiles and were predicted to display the best binding affinity with PPARα/γ. Complex-based pharmacophore (CBP) models showed the key interactions in the PPARα/γ active sites. 20 ns simulations performed to the PPAR-ligand complexes indicated a stable binding conformation. This work provided an approach to identify novel high-efficiency PPARα/γ dual agonists for the treatment of type 2 diabetes mellitus (T2DM).

Objective: To observe clinical characteristics of herb-induced liver injury (HILI)., Methods: General conditions, medical history, clinical manifestations, biochemical indices, prognosis, and Roussed Uclaf Causality Assessment Method (RUCAM) scores were retrospectively analyzed in 595 inpatients at 302 Military Hospital between January 2009 and January 2014., Results: There were 423 cases (accounting for 71.1%) were females with multiple onset age ranging 41 to 50 years old. The median time from starting Chinese herbs to the occurrence of liver injury (LI) was 30 days (15-75 days), and 511 cases (85.9%) were classified as hepatocellular injury. Chinese herbs inducing HILI were mainly used for skin disease (102 cases, 17.1%), osteoarticular disease (57 cases, 9.6%), and gastrointestinal disease (49 cases, 8.2%), covering 207 kinds of Chinese patent medicines. Polygonum multiflorum, Psoralea corylifolia, and Corydalis ambigua were often seen in Chinese prescriptions. In RUCAM scoring, 451 HILI patients (accounting for 74.1%) were very possibly associated with Chinese herbs. Liver failure occurred in 47 HILI patients (accounting for 7.9%), cirrhosis in 45 patients (accounting for 7.6%), chronic HILI in 80 patients (accounting for 13.4%), 27 (4.5%) died, and only 2 (0.3%) underwent liver transplantation., Conclusions: Chinese herbs could cause LI or even death. Attention should be paid to herbal hepatotoxicity and improving monitoring system of HILI.

The objective of the present study was to investigate the effects of dietary supplemental Zinc (Zn) source and level on antioxidant ability and fat metabolism-related enzymes of broilers. Dietary treatments included the Zn-unsupplemented corn-soybean meal basal diet (control) and basal diets supplemented with 60, 120, or 180 mg Zn/kg as Zn sulfate, Zn amino acid chelate with a weak chelation strength of 6.5 quotient of formation (Qf) (11.93% Zn) (Zn-AA W), Zn proteinate with a moderate chelation strength of 30.7 Qf (13.27% Zn) (Zn-Pro M), or Zn proteinate with an extremely strong chelation strength of 944.0 Qf (18.61% Zn) (Zn-Pro S). The results showed that dietary supplemental Zn increased (P < 0.01) Zn contents in the liver, breast, and thigh muscles of broilers, and up-regulated mRNA expressions of copper and Zn containing superoxide dismutase (CuZnSOD) and metallothioneins (MT) in the liver (P < 0.01) and thigh muscle (P < 0.05), and also enhanced (P < 0.05) CuZnSOD activities in the breast and thigh muscles, which exerted antioxidant ability and a decreased malondialdehyde (MDA) level in the liver (P < 0.01) and breast and thigh muscles (P < 0.05) of broilers. Furthermore, supplemental Zn increased activities of malate dehydrogenase (MDH) and lipoprotein lipase (LPL) in the abdominal fat (P < 0.05), and fatty acid synthetase (FAS) and LPL in the liver (P < 0.01), which were accompanied with up-regulation (P < 0.01) of the mRNA expressions levels of these enzymes in the abdominal fat and liver of broilers. Dietary Zn source, and an interaction between Zn source and level, had no effects on any measurements. It is concluded that dietary Zn supplementation improved Zn status and resulted in promoting antioxidant ability and activities and gene expressions of fat metabolism-related enzymes of broilers regardless of Zn source and level, and the addition of 60 mg Zn/kg to the corn-soybean meal basal diet (a total dietary Zn of approximately 90 mg/kg) was appropriate for improving the above aspects of broilers., (© The Author 2015. Published by Oxford University Press on behalf of Poultry Science Association.)

Protein tyrosine phosphatase 1B (PTP1B) plays a vital role in the regulation of insulin sensitivity and dephosphorylation of the insulin receptor, so PTP1B inhibitors may be potential agents to treat type 2 diabetes. In this work, a series of novel imidazolidine-2,4-dione derivatives were designed, synthesized and assayed for their PTP1B inhibitory activities. These compounds exhibited potent activities with IC50 values at 0.57-172 μM. A 3D-QSAR study using CoMFA and CoMSIA techniques was carried out to explore structure activity relationship of these molecules. The CoMSIA model was more predictive with q(2) = 0.777, r(2) = 0.999, SEE = 0.013 and r(2)pred = 0.836, while the CoMFA model gave q(2) = 0.543, r(2) = 0.998, SEE = 0.029 and r(2)pred = 0.754. The contour maps derived from the best CoMFA and CoMSIA models combined with docking analysis provided good insights into the structural features relevant to the bioactivity, and could be used in the molecular design of novel imidazolidine-2,4-dione derivatives., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Cytochrome P450 monooxygenases (P450s) of insects play crucial roles in the metabolism of endogenous and dietary compounds. Tobacco cutworm moth (Spodoptera litura), an important agricultural pest, causes severe yield losses in many crops. In this study, we identified CYP9A40, a novel P450 gene of S. litura, and investigated its expression profile and potential role in detoxification of plant allelochemicals and insecticides. The cDNA contains an open reading frame encoding 529 amino acid residues. CYP9A40 transcripts were found to be accumulated during various development stages of S. litura and were highest in fifth and sixth instar larvae. CYP9A40 was mainly expressed in the midgut and fat body. Larval consumption of xenobiotics, namely plant allelochemicals (quercetin and cinnamic acid) and insecticides (deltamethrin and methoxyfenozide) induced accumulation of CYP9A40 transcripts in the midgut and fat body. Injection of dsCYP9A40 (silencing of CYP9A40 by RNA interference) significantly increased the susceptibility of S. litura larvae to the tested plant allelochemicals and insecticides. These results indicate that CYP9A40 expression in S. litura is related to consumption of xenobiotics and suggest that CYP9A40 is involved in detoxification of these compounds.

Background: Paeonia lactiflora Pall. (PLP), a traditional Chinese herbal medicine, has been used for hepatic disease treatment over thousands of years. In our previous study, PLP was shown to demonstrate therapeutic effect on hepatitis with severe cholestasis. The aim of this study was to evaluate the antioxidative effect of PLP on alpha-naphthylisothiocyanate (ANIT)-induced cholestasis by activating NF-E2-related factor 2 (Nrf2) via phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway., Materials and Methods: Liquid chromatography-mass spectrometry (LC-MS) was performed to identify the main compounds present in PLP. The mechanism of action of PLP and its therapeutic effect on cholestasis, induced by ANIT, were further investigated. Serum indices such as total bilirubin (TBIL), direct bilirubin (DBIL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (γ-GT), and total bile acid (TBA) were measured, and histopathology of liver was also performed to determine the efficacy of treatment with PLP. Moreover, in order to illustrate the underlying signaling pathway, liver glutathione (GSH) content and mRNA or protein levels of glutamate-cysteine ligase catalytic subunit (GCLc), glutamate-cysteine ligase modulatory subunit (GCLm), Akt, heme oxygenase-1 (HO-1), NAD(P)H/quinone oxidoreductase 1 (Nqo1), and Nrf2 were further analyzed. In addition, validation of PLP putative target network was also performed in silico., Results: Four major compounds including paeoniflorin, albiflorin, oxypaeoniflorin, and benzoylpaeoniflorin were identified by LC-MS analysis in water extract of PLP. Moreover, PLP could remarkably downregulate serum levels of TBIL, DBIL, AST, ALT, ALP, γ-GT, and TBA, and alleviate the histological damage of liver tissue caused by ANIT. It enhanced antioxidative system by activating PI3K/Akt/Nrf2 pathway through increasing Akt, Nrf2, HO-1, Nqo1, GCLc, and GCLm expression. The putative targets network validation also confirmed the important role of PLP in activating Akt expression., Conclusion: The potential mechanism of PLP in alleviating ANIT-induced cholestasis could to be related to the induction of GSH synthesis by activating Nrf2 through PI3K/Akt-dependent pathway. This indicates that PLP might be a potential therapeutic agent for cholestasis.

Wedelia trilobata (L.) Hitchc., an ornamental groundcover plant introduced to areas around the world from Central America, has become invasive in many regions. To increase understanding of its geographic distribution and potential extent of spread, two presence-only niche-based modeling approaches (Maxent and GARP) were employed to create models based on occurrence records from its: (1) native range only and (2) full range (native and invasive). Models were then projected globally to identify areas vulnerable to W. trilobata invasion. W. trilobata prefers hot and humid environments and can occur in areas with different environmental conditions than experienced in its native range. Based on native and full occurrence points, GARP and Maxent models produced consistent distributional maps of W. trilobata, although Maxent model results were more conservative. When used to estimate the global invasive distribution of the species, both modeling approaches projected the species to occur in Africa. The GARP full model succeeded in predicting the known occurrences in Australia, while the other models failed to identify favorable habitats in this region. Given the rapid spread of W. trilobata and the serious risk of this species poses to local ecosystems, practical strategies to prevent the establishment and expansion of this species should be sought.

Recent evidence indicates that a deficiency of 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) may influence asthma pathogenesis; however, its roles in regulating specific molecular transcription mechanisms remain unclear. We aimed to investigate the effect of 1,25(OH)2D3 on the expression and enzyme activity of histone deacetylase 2 (HDAC2) and its synergistic effects with dexamethasone (Dx) in the inhibition of inflammatory cytokine secretion in a rat asthma model. Healthy Wistar rats were randomly divided into 6 groups: control, asthma, 1,25(OH)2D3 pretreatment, 1,25(OH)2D3 treatment, Dx treatment, and Dx and 1,25(OH)2D3 treatment. Pulmonary inflammation was induced by ovalbumin (OVA) sensitization and challenge (OVA/OVA). Inflammatory cells and cytokines in the bronchoalveolar lavage (BAL) fluid and histological changes in lung tissue were examined. Nuclear factor kappa B (NF-κB) p65 and HDAC2 expression levels were assessed with Western blot analyses and quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). Enzyme activity measurements and immunohistochemical detection of HDAC2 were also performed. Our data demonstrated that 1,25(OH)2D3 reduced the airway inflammatory response and the level of inflammatory cytokines in BAL. Although NF-κB p65 expression was attenuated in the pretreatment and treatment groups, the expression and enzyme activity of HDAC2 were increased. In addition, 1,25(OH)2D3 and Dx had synergistic effects on the suppression of total cell infusion, cytokine release, and NF-κB p65 expression, and they also increased HDAC2 expression and activity in OVA/OVA rats. Collectively, our results indicated that 1,25(OH)2D3 might be useful as a novel HDAC2 activator in the treatment of asthma.

Objective: The objective of this study is to compare the clinical efficacy of surgical fixation and nonsurgical management of flail chest and pulmonary contusion (FC-PC) and to compare the diverse timings of surgery to discuss case management in FC-PC., Methods: The data of 39 patients diagnosed with FC-PC were obtained from the intensive care unit of Shanghai First People's Hospital and analyzed retrospectively from July 2010 to Dec 2013. The patients required ventilator support and were divided into a surgical group and a nonsurgical group, according to the treatment method. The clinical data, such as mortality, the duration of mechanical ventilation (DMV), intensive care unit length of stay, hospital length of stay (HLOS), days of antibiotic use, transfusion volume, medical expense as well as the incidence of tracheotomy, pleural effusion, and incidence of ventilator associated pneumonia, were collected for all subjects. The surgical group was further divided into 2 groups according to the surgery timing. Surgery within 7 days of admission was defined as early surgery, and all other times were defined as late surgery. The clinical data and incidence of incision infection were collected and compared., Results: The patients in the surgical group had a slightly shorter HLOS. No differences were noted in mortality and the other clinical data between the groups. The early surgical group had a shorter DMV and less incidence of tracheotomy. The other parameters had no differences., Conclusions: Surgery for FC-PC could reduce the HLOS, and early surgery could decrease the DMV and the need for tracheotomy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To investigate the antimalarial activity of four choline derivatives against Plasmodium falciparum 3D7 strain growth in vitro., Methods: Four choline derivatives MD [N-dodecyl-N-(2-hydroxyethyl)-N,N- dimethyl ammonium bromide], ED [N-dodecyl-N-(2-hydroxyethyl)-N,N-diethyl ammonium bromide], MT [N-tetradecyl-N- (2-hydroxyethyl)-N,N-dimethyl ammonium bromide], and ET [N-tetradecyl-N-(2-hydroxyethyl)-N,N-diethyl ammonium bromide] were dissolved separately in DMSO at serial concentrations (1-10(5) µmol/L). The solutions were diluted by 1,000-fold with RPMI 1640 medium. 20 µl drug-containing medium and 80 µl P. falciparum-infected erythrocyte suspension (2% final hematocrit and 0.3%-0.5% parasitemia) were added to each well of microtiter plates. Drug effect on the in vitro growth of P. falciparum was measured by SYBR Green I method. The half maximal inhibitory concentration (IC50) was calculated from dose-response curves. Artemisinine served as positive control., Results: Artemisinine, MD, ED, MT, and ET showed different degrees of dose-dependent inhibition on P. falciparum growth. When the MD concentration was above 10 nmol/L, the inhibition rate increased significantly. Both ED and ET showed significant inhibitory effects at high concentrations, with inhibition rate of > 95% when their doses were > 10(4) nmol/L. The IC50 values of MD, ED, MT, and ET were 1 620, 33.9, 116, and 68.9 nmol/L, respectively, all significantly higher than that of artemisinine (5.7 nmol/L) (P < 0.05)., Conclusion: The four choline derivatives show certain antimalarial activity, which is lower than that of artemisinine. Among the four derivatives, ED has the strongest antimalarial activity against P. falciparum 3D7 strain.