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1.  Identification of plasma protein markers common to patients with malignant tumour and Abnormal Savda in Uighur medicine: a prospective clinical study 
Background
Traditional Uighur medicine shares an origin with Greco-Arab medicine. It describes the health of a human body as the dynamic homeostasis of four normal Hilits (humours), known as Kan, Phlegm, Safra, and Savda. An abnormal change in one Hilit may cause imbalance among the Hilits, leading to the development of a syndrome. Abnormal Savda is a major syndrome of complex diseases that are associated with common biological changes during disease development. Here, we studied the protein expression profile common to tumour patients with Abnormal Savda to elucidate the biological basis of this syndrome and identify potential biomarkers associated with Abnormal Savda.
Methods
Patients with malignant tumours were classified by the diagnosis of Uighur medicine into two groups: Abnormal Savda type tumour (ASt) and non-Abnormal Savda type tumour (nASt), which includes other syndromes. The profile of proteins that were differentially expressed in ASt compared with nASt and normal controls (NC) was analysed by iTRAQ proteomics and evaluated by bioinformatics using MetaCore™ software and an online database. The expression of candidate proteins was verified in all plasma samples by enzyme-linked immunosorbent assay (ELISA).
Results
We identified 31 plasma proteins that were differentially expressed in ASt compared with nASt, of which only 10 showed quantitatively different expression between ASt and NC. Bioinformatics analysis indicated that most of these proteins are known biomarkers for neoplasms of the stomach, breast, and lung. ELISA detection showed significant upregulation of plasma SAA1 and SPP24 and downregulation of PIGR and FASN in ASt compared with nASt and NC (p < 0.05).
Conclusions
Abnormal Savda may be causally associated with changes in the whole regulation network of protein expression during carcinogenesis. The expression of potential biomarkers might be used to distinguish Abnormal Savda from other syndromes.
Electronic supplementary material
The online version of this article (doi:10.1186/s12906-015-0526-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12906-015-0526-6
PMCID: PMC4321703  PMID: 25652121
Uighur medicine; Abnormal Savda; Malignant tumour; Plasma proteomics
2.  Repression of CC16 by Cigarette Smoke (CS) Exposure 
PLoS ONE  2015;10(1):e0116159.
Club (Clara) Cell Secretory Protein (CCSP, or CC16) is produced mainly by non-ciliated airway epithelial cells including bronchiolar club cells and the change of its expression has been shown to associate with the progress and severity of Chronic Obstructive Pulmonary Disease (COPD). In an animal model, the lack of CC16 renders the animal susceptible to the tumorigenic effect of a major CS carcinogen. A recent population-based Tucson Epidemiological Study of Airway Obstructive Diseases (TESAOD) has indicated that the low serum CC16 concentration is closely linked with the smoke-related mortality, particularly that driven by the lung cancer. However, the study of CC16 expression in well-defined smoke exposure models has been lacking, and there is no experimental support for the potential causal link between CC16 and CS-induced pathophysiological changes in the lung. In the present study, we have found that airway CC16 expression was significantly repressed in COPD patients, in monkey CS exposure model, and in CS-induced mouse model of COPD. Additionally, the lack of CC16 exacerbated airway inflammation and alveolar loss in the mouse model. Therefore, CC16 may play an important protective role in CS-related diseases.
doi:10.1371/journal.pone.0116159
PMCID: PMC4312097  PMID: 25635997
3.  Massively parallel nonparametric regression, with an application to developmental brain mapping 
We propose a penalized spline approach to performing large numbers of parallel non-parametric analyses of either of two types: restricted likelihood ratio tests of a parametric regression model versus a general smooth alternative, and nonparametric regression. Compared with naïvely performing each analysis in turn, our techniques reduce computation time dramatically. Viewing the large collection of scatterplot smooths produced by our methods as functional data, we develop a clustering approach to summarize and visualize these results. Our approach is applicable to ultra-high-dimensional data, particularly data acquired by neuroimaging; we illustrate it with an analysis of developmental trajectories of functional connectivity at each of approximately 70000 brain locations. Supplementary materials, including an appendix and an R package, are available online.
doi:10.1080/10618600.2012.733549
PMCID: PMC3964810  PMID: 24683303
Functional data clustering; Neuroimaging; Penalized splines; Restricted likelihood ratio test; Smoothing parameter selection
4.  A family cluster of three confirmed cases infected with avian influenza A (H7N9) virus in Zhejiang Province of China 
BMC Infectious Diseases  2014;14(1):698.
Background
A total of 453 laboratory-confirmed cases infected with avian influenza A (H7N9) virus (including 175 deaths) have been reported till October 2,2014, of which 30.68% (139/453) of the cases were identified from Zhejiang Province. We describe the largest reported cluster of virologically confirmed H7N9 cases, comprised by a fatal Index case and two mild secondary cases.
Methods
A retrospective investigation was conducted in January of 2014. Three confirmed cases, their close contacts, and relevant environments samples were tested by real-time reverse transcriptase-polymerase chain reaction (RT-PCR), viral culture, and sequencing. Serum samples were tested by haemagglutination inhibition (HI) assay.
Results
The Index case, a 49-year-old farmer with type II diabetes, who lived with his daughter (Case 2, aged 24) and wife (Case 3, aged 43) and his son-in-law (H7N9 negative). The Index case and Case 3 worked daily in a live bird market. Onset of illness in Index case occurred in January 13, 2014 and subsequently, he died of multi-organ failure on January 20. Case 2 presented with mild symptoms on January 20 following frequent unprotected bed-side care of the Index case between January 14 to 19, and exposed to live bird market on January 17. Case 3 became unwell on January 23 after providing bedside care to the Index case on January 17 to 18, and following the contact with Case 2 during January 21 to 22 at the funeral of the Index case. The two secondary cases were discharged on February 2 and 5 separately after early treatment with antiviral medication. Four virus strains were isolated and genome analyses showed 99.6 ~100% genetic homology, with two amino mutations (V192I in NS and V280A in NP). 42% (11/26) of environmental samples collected in January were H7N9 positive. Twenty-five close contacts remained well and were negative for H7N9 infection by RT-PCR and HI assay.
Conclusions
In the present study, the Index case was infected from a live bird market while the two secondary cases were infected by the Index case during unprotected exposure. This family cluster is, therefore, compatible with non-sustained person-to-person transmission of avian influenza A/H7N9.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-014-0698-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12879-014-0698-6
PMCID: PMC4304124  PMID: 25551435
H7N9 subtype; Family cluster; Live bird market; Death; Epidemiological investigation
5.  Association of the four common polymorphisms in interleukin-10 (rs1800890, rs1800896, rs1800871, and rs1800872) with non-Hodgkin’s lymphoma risk: a meta-analysis 
Interleukin-10 (IL-10) single nucleotide polymorphisms (SNPs) have been indicated to be correlated with Non-Hodgkin’s lymphoma (NHL) susceptibility. However, the results of these studies on the association remain inconsistent. This meta-analysis was conducted to derive a more accuracy estimation of the association between the common SNPs (rs1800890, rs1800896, rs1800871 and rs1800872) in IL-10 and NHL risk. Meta-analyses were performed on 21 studies with 7,749 cases and 8584 controls. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the NHL risk. Meta-analyses showed that rs1800890, rs1800871 and rs1800872 polymorphisms had no association with NHL risk. However, rs1800896 polymorphism has association with NHL risk based on the following comparison models (G vs. A: OR = 1.14, 95% CI = 1.00-1.29; AG vs. AA: OR = 1.20, 95% CI = 1.05-1.37; GG+AG vs. AA: OR = 1.22, 95% CI = 1.08-1.39). In the ethnic subgroup analysis, rs1800896 had an increased NHL risk in Caucasians based on the heterozygote model (OR = 1.21, 95% CI = 1.04-1.41) and dominant model (OR = 1.22, 95% CI = 1.00-1.48). When stratified by subtypes, rs1800890, rs1800896 and rs1800872 polymorphisms were found significant association with an increased risk of diffuse large B-cell Lymphoma (DLBCL) in different comparison models, whereas negative results were obtained for Follicular Lymphoma (FL) and chronic lymphocytic Leukemia/small lymphocytic Lymphoma (CLL/SLL) in all genetic models. Our meta-analysis suggested that the rs1800896 polymorphism had an increased risk with NHL susceptibility, where as the rs1800890, rs1800871 and rs1800872 had no association with NHL risk. Among the common subtypes of NHL, three polymorphisms (rs1800890, rs1800896 and rs1800872) had significant association with DLBCL risk.
PMCID: PMC4307416  PMID: 25663969
Non-Hodgkin’s lymphoma; interleukin-10; polymorphism; meta-analysis
6.  Occupational Hazards Education for Nursing Staff through Web-Based Learning 
This study aims to explore the efficiency of using online education as an intervention measure to prevent occupational hazards in a clinical nursing setting. The subjects were 320 female nursing staff from two hospitals in Taiwan. The questionnaire results indicated that the subjects primarily experienced human factor occupational hazards, as well as psychological and social hazards. Specifically, 73.1% and 69.8% of the subjects suffered from poor sleep quality and low back pain, respectively. After web-based learning, the experimental group had higher post-test scores than the control group in terms of knowledge, attitudes, and practices (KAP). However, there was only a significant difference (p < 0.05) in their knowledge about the prevention of occupational hazards. It is suggested that an online discussion may enhance nursing staff’s participation in web-based learning, and further facilitate their comments on negative factors. The findings can highly promote nursing staff’s attitudes and practices toward preventing occupational hazards through web-based learning.
doi:10.3390/ijerph111213035
PMCID: PMC4276660  PMID: 25514154
online education; occupational hazard; KAP; hospital
7.  Marine Nucleosides: Structure, Bioactivity, Synthesis and Biosynthesis 
Marine Drugs  2014;12(12):5817-5838.
Nucleosides are glycosylamines that structurally form part of nucleotide molecules, the building block of DNA and RNA. Both nucleosides and nucleotides are vital components of all living cells and involved in several key biological processes. Some of these nucleosides have been obtained from a variety of marine resources. Because of the biological importance of these compounds, this review covers 68 marine originated nucleosides and their synthetic analogs published up to June 2014. The review will focus on the structures, bioactivities, synthesis and biosynthetic processes of these compounds.
doi:10.3390/md12125817
PMCID: PMC4278203  PMID: 25474189
biological activity; biosynthetic pathway; marine organism; nucleoside; synthesis
8.  Multifunctional Core/Shell Nanoparticles Cross-linked Polyetherimide-folic Acid as Efficient Notch-1 siRNA Carrier for Targeted Killing of Breast Cancer 
Scientific Reports  2014;4:7072.
In gene therapy, how genetic therapeutics can be efficiently and safely delivered into target tissues/cells remains a major obstacle to overcome. To address this issue, nanoparticles consisting of non-covalently coupled polyethyleneimine (PEI) and folic acid (FA) to the magnetic and fluorescent core/shell of Fe3O4@SiO2(FITC) was tested for their ability to deliver Notch-1 shRNA. Our results showed that Fe3O4@SiO2(FITC)/PEI-FA/Notch-1 shRNA nanoparticles are 64 nm in diameter with well dispersed and superparamagnetic. These nanoparticles with on significant cytotoxicity are capable of delivering Notch-1 shRNA into human breast cancer MDA-MB-231 cells with high efficiency while effectively protected shRNA from degradation by exogenous DNaseI and nucleases. Magnetic resonance (MR) imaging and fluorescence microscopy showed significant preferential uptake of Fe3O4@SiO2(FITC)/PEI-FA/Notch-1 shRNA nanocomplex by MDA-MB-231 cells. Transfected MDA-MB-231 cells exhibited significantly decreased expression of Notch-1, inhibited cell proliferation, and increased cell apoptosis, leading to the killing of MDA-MB-231 cells. In light of the magnetic targeting capabilities of Fe3O4@SiO2(FITC)/PEI-FA, our results show that by complexing with a second molecular targeting therapeutic, such as Notch-1 shRNA in this report, Fe3O4@SiO2(FITC)/PEI-FA can be exploited as a novel, non-viral, and concurrent targeting delivery system for targeted gene therapy as well as for MR imaging in cancer diagnosis.
doi:10.1038/srep07072
PMCID: PMC4233336  PMID: 25400232
9.  The Effect of Enterohemorrhagic E. coli Infection on the Cell Mechanics of Host Cells 
PLoS ONE  2014;9(11):e112137.
Enterohaemorrhagic E. coli (EHEC) is a type of human pathogenic bacteria. The main virulence characteristics of EHEC include the formation of attaching and effacing lesions (A/E lesions) and the production of one or more Shiga-like toxins, which may induce human uremic complications. When EHEC infects host cells, it releases translocated intimin receptor (Tir) and effector proteins inside the host cells, inducing the rearrangement and accumulation of the F-actin cytoskeleton, a phenotype leading to the formation of pedestals in the apical cell surface, and the growth of stress fibers at the base of the cells. To examine the effect of EHEC infection on cell mechanics, we carried out a series of experiments to examine HeLa cells with and without EHEC infection to quantify the changes in (1) focal adhesion area, visualized by anti-vinculin staining; (2) the distribution and orientation of stress fibers; and (3) the intracellular viscoelasticity, via directional video particle tracking microrheology. Our results indicated that in EHEC-infected HeLa cells, the focal adhesion area increased and the actin stress fibers became thicker and more aligned. The cytoskeletal reorganization induced by EHEC infection mediated a dramatic increase in the cytoplasmic elastic shear modulus of the infected cells, and a transition in the viscoelastic behavior of the cells from viscous-like to elastic-like. These changes in mechanobiological characteristics might modulate the attachments between EHEC and the host cell to withstand exfoliation, and between the host cell and the extracellular matrix, and might also alter epithelial integrity.
doi:10.1371/journal.pone.0112137
PMCID: PMC4219835  PMID: 25369259
10.  Distinct, genome-wide, gene-specific selectivity patterns of four glucocorticoid receptor coregulators 
Glucocorticoids are a class of steroid hormones that bind to and activate the glucocorticoid receptor (GR), which then positively or negatively regulates transcription of many genes that govern multiple important physiological pathways such as inflammation and metabolism of glucose, fat and bone. The remodeling of chromatin and regulated assembly or disassembly of active transcription complexes by GR and other DNA-binding transcription factors is mediated and modulated by several hundred transcriptional coregulator proteins. Previous studies focusing on single coregulators demonstrated that each coregulator is required for regulation of only a subset of all the genes regulated by a steroid hormone. We hypothesized that the gene-specific patterns of coregulators may correspond to specific physiological pathways such that different coregulators modulate the pathway-specificity of hormone action, thereby providing a mechanism for fine tuning of the hormone response. We tested this by direct comparison of multiple coregulators, using siRNA to deplete the products of four steroid hormone receptor coregulator genes (CCAR1, CCAR2, CALCOCO1 and ZNF282). Global analysis of glucocorticoid-regulated gene expression after siRNA mediated depletion of coregulators confirmed that each coregulator acted in a selective and gene-specific manner and demonstrated both positive and negative effects on glucocorticoid-regulated expression of different genes. We identified several classes of hormone-regulated genes based on the effects of coregulator depletion. Each coregulator supported hormonal regulation of some genes and opposed hormonal regulation of other genes (coregulator-modulated genes), blocked hormonal regulation of a second class of genes (coregulator-blocked genes), and had no effect on hormonal regulation of a third gene class (coregulator-independent genes). In spite of previously demonstrated physical and functional interactions among these four coregulators, the majority of the several hundred modulated and blocked genes for each of the four coregulators tested were unique to that coregulator. Finally, pathway analysis on coregulator-modulated genes supported the hypothesis that individual coregulators may regulate only a subset of the many physiological pathways controlled by glucocorticoids. We conclude that gene-specific actions of coregulators correspond to specific physiological pathways, suggesting that coregulators provide a potential mechanism for physiological fine tuning in vivo and may thus represent attractive targets for therapeutic intervention.
doi:10.1621/nrs.12002
PMCID: PMC4242289  PMID: 25422592
coregulators; gene expression; microarray; glucocorticoid receptor; gene regulation
11.  Special Considerations for Multiple Limb Amputation 
It has been estimated that more than 1.6 million individuals in the United States have undergone at least one amputation. The literature abounds with research of the classifications of such injuries, their etiologies, epidemiologies, treatment regimens, average age of onset (average age of amputation), and much more. The subpopulation that is often overlooked in these evaluations, however, is comprised of individuals who have suffered multiple limb loss. The challenges faced by those with single-limb loss are amplified for those with multiple limb loss. Pain, lifestyle adjustment, and quality of life return are just a few key areas of concern in this population. Along with amputations resulting from trauma, many individuals with multiple amputations have endured them as a result of dysvascular disease. Over recent years, amputations as a result of dysvascular disease have risen to comprise more than 80 % of new amputations occurring in the United States every year. This compares to just 54 % of total current prevalence. Those with diabetes comorbid with dysvascular disease make up 74 % of those with dysvascular amputations, and these individuals with diabetes comorbid with dysvascular disease have a 55 % chance of enduring an amputation of their contralateral limb within 2–3 years of their initial amputation. With the well-documented aging of the nation’s population and the similarly skyrocketing prevalence of dysvascular disease and diabetes, it can be expected that the number of individuals with multiple limb loss will continue to increase in the United States. This article outlines the recommended measures of care for this particular subpopulation, including pain management, behavioral health considerations, strategies for rehabilitation for various levels and variations of multiple limb loss, and the assistive technology and adaptive equipment that might be available for these individuals to best enable them to continue healthy, fulfilling lives following amputation.
doi:10.1007/s40141-014-0067-9
PMCID: PMC4228106  PMID: 25411651
Multiple limb loss; Multiple limb amputation; Prosthetics; Assistive technology; Pain management; Behavioral health; Rehabilitation; Amputation; Adaptive technology
12.  Complete Genome Sequence of a Novel Reassortant Avian Influenza H9N9 Virus Isolated from Chicken in Eastern China 
Genome Announcements  2014;2(5):e00932-14.
The genome sequence of the strain A/chicken/Changzhou/C08/2013 (H9N9) shows that the hemagglutinin (HA) genes of this strain are closely related to those of the strain A/chicken/Shanghai/1107/2013 (H9N2) and share 99.2% nucleotide homology, while the other seven genes had the greatest sequence identities with the novel H7N9 virus. We speculate that this strain may be a novel natural reassortant avian influenza virus (AIV).
doi:10.1128/genomeA.00932-14
PMCID: PMC4175197  PMID: 25291762
13.  Measurement of Human Brown Adipose Tissue Volume and Activity Using Anatomical MRI and Functional MRI 
The existence of brown adipose tissue (BAT) in humans has previously been assessed in vivo via sequential 18F-FDG PET/CT imaging. We developed a MRI protocol to detect BAT mass based on BAT’s property of having higher water-to-fat ratio than white adipose tissue (WAT). We showed that the signal contrast obtained between water-saturation and without water-saturation was higher in BAT than in WAT in fast spin echo images and in T2-weighted images. The water-to-fat ratio was also higher in BAT via contrasting the water and fat images of the Dixon method. The MRI measured volume and location of BAT was similar to PET/CT results in the same subjects. In addition, we also demonstrated that cold challenges (14 °C) led to significant fMRI BOLD signal increases in BAT.
doi:10.2967/jnumed.112.117275
PMCID: PMC4167352  PMID: 23868958
11F-FDG; MRI; fMRI; cold-activation; brown adipose tissue
14.  MiR-181b sensitizes glioma cells to teniposide by targeting MDM2 
BMC Cancer  2014;14(1):611.
Background
Although the incidence of glioma is relatively low, it is the most malignant tumor of the central nervous system. The prognosis of high-grade glioma patient is very poor due to the difficulties in complete resection and resistance to radio-/chemotherapy. Therefore, it is worth investigating the molecular mechanisms involved in glioma drug resistance. MicroRNAs have been found to play important roles in tumor progression and drug resistance. Our previous work showed that miR-181b is involved in the regulation of temozolomide resistance. In the current study, we investigated whether miR-181b also plays a role in antagonizing the effect of teniposide.
Methods
MiR-181b expression was measured in 90 glioma patient tissues and its relationship to prognosis of these patients was analyzed. Cell sensitivity to teniposide was tested in 48 primary cultured glioma samples. Then miR-181b stably overexpressed U87 cells were generated. The candidate genes of miR-181b from our previous study were reanalyzed, and the interaction between miR-181b and target gene MDM2 was confirmed by dual luciferase assay. Cell sensitivity to teniposide was detected on miR-181b over expressed and MDM2 down regulated cells.
Results
Our data confirmed the low expression levels of miR-181b in high-grade glioma tissues, which is related to teniposide resistance in primary cultured glioma cells. Overexpression of miR-181b increased glioma cell sensitivity to teniposide. Through target gene prediction, we found that MDM2 is a candidate target of miR-181b. MDM2 knockdown mimicked the sensitization effect of miR-181b. Further study revealed that miR-181b binds to the 3’-UTR region of MDM2 leading to the decrease in MDM2 levels and subsequent increase in teniposide sensitivity. Partial restoration of MDM2 attenuated the sensitivity enhancement by miR-181b.
Conclusions
MiR-181b is an important positive regulator on glioma cell sensitivity to teniposide. It confers glioma cell sensitivity to teniposide through binding to the 3’-UTR region of MDM2 leading to its reduced expression. Our findings not only reveal the novel mechanism involved in teniposide resistance, but also shed light on the optimization of glioma treatment in the future.
doi:10.1186/1471-2407-14-611
PMCID: PMC4155117  PMID: 25151861
miR-181b; Teniposide; Glioma; Mouse double minute 2 homolog (MDM2)
15.  New Antioxidative Secondary Metabolites from the Fruits of a Beibu Gulf Mangrove, Avicennia marina 
Marine Drugs  2014;12(8):4353-4360.
Further chemical investigation of the fruits of the mangrove, Avicennia marina, afforded three new phenylethyl glycosides, marinoids J–L (1–3), and a new cinnamoyl glycoside, marinoid M (4). The structures of isolates were elucidated on the basis of extensive spectroscopic analysis and by comparison of the data with those of related secondary metabolites. The antioxidant activity of the isolates was evaluated using the cellular antioxidant assay (CAA), and compounds 1–4 showed antioxidant activities, with EC50 values ranging from 23.0 ± 0.71 μM to 247.8 ± 2.47 μM.
doi:10.3390/md12084353
PMCID: PMC4145320  PMID: 25076062
antioxidant; Avicennia marina; caffeoyl glycoside; marinoid; phenylethyl glycoside
16.  Synergistic Up-Regulation of CXCL10 by Virus and IFN γ in Human Airway Epithelial Cells 
PLoS ONE  2014;9(7):e100978.
Airway epithelial cells are the first line of defense against viral infections and are instrumental in coordinating the inflammatory response. In this study, we demonstrate the synergistic stimulation of CXCL10 mRNA and protein, a key chemokine responsible for the early immune response to viral infection, following treatment of airway epithelial cells with IFN γ and influenza virus. The synergism also occurred when the cells were treated with IFN γ and a viral replication mimicker (dsRNA) both in vitro and in vivo. Despite the requirement of type I interferon (IFNAR) signaling in dsRNA-induced CXCL10, the synergism was independent of the IFNAR pathway since it wasn’t affected by the addition of a neutralizing IFNAR antibody or the complete lack of IFNAR expression. Furthermore, the same synergistic effect was also observed when a CXCL10 promoter reporter was examined. Although the responsive promoter region contains both ISRE and NFκB sites, western blot analysis indicated that the combined treatment of IFN γ and dsRNA significantly augmented NFκB but not STAT1 activation as compared to the single treatment. Therefore, we conclude that IFN γ and dsRNA act in concert to potentiate CXCL10 expression in airway epithelial cells via an NFκB-dependent but IFNAR-STAT independent pathway and it is at least partly regulated at the transcriptional level.
doi:10.1371/journal.pone.0100978
PMCID: PMC4102466  PMID: 25033426
17.  Synthesis and Evaluation of Fluorine-Substituted Phenyl Acetate Derivatives as Ultra-Short Recovery Sedative/Hypnotic Agents 
PLoS ONE  2014;9(5):e96518.
Background
Soft drugs are molecules that are purposefully designed to be rapidly metabolized (metabolically labile). In anesthesia, the soft drug is useful because it enables precise titration to effect and rapid recovery, which might allow swift and clear-headed recovery of consciousness and early home readiness. Propofol may cause delayed awakening after prolonged infusion. Propanidid and AZD3043 have a different metabolic pathway compared to propofol, resulting in a short-acting clinical profile. Fluorine imparts a variety of properties to certain medicines, including an enhanced absorption rate and improved drug transport across the blood-brain barrier. We hypothesized that the introduction of fluorine to the frame structure of propanidid and AZD3043 would further accelerate the swift and clear-headed recovery of consciousness. To test this hypothesis, we developed a series of fluorine-containing phenyl acetate derivatives.
Methodology/Principal Findings
Fluorine-containing phenyl acetate derivatives were synthesized, and their hypnotic potencies and durations of LORR following bolus or infusion administration were determined in mice, rats and rabbits. The metabolic half-lives in the blood of various species were determined chromatographically. In vitro radioligand binding and γ-aminobutyric acidA (GABAA) receptor electrophysiology studies were performed. Among the 12 synthesized fluorine-containing phenyl acetate derivatives, compound 5j induced comparable duration of LORR with AZD3043, but more rapid recovery than AZD3043, propanidid and propofol. The time of compound 5j to return to walk and behavioral recovery are approximately reduced by more than 50% compared to AZD3043 in mice and rats and rabbits. The HD50 of compound 5j decreased with increasing animal size.
Conclusions/Significance
The rapid recovery might make compound 5j suitable for precise titration and allow swift and clear-headed recovery of consciousness and early home readiness.
doi:10.1371/journal.pone.0096518
PMCID: PMC4010497  PMID: 24796695
18.  Four New Jacaranone Analogs from the Fruits of a Beibu Gulf Mangrove Avicennia marina 
Marine Drugs  2014;12(5):2515-2525.
Four new jacaranone analogs, marinoids F–I (1–4), were isolated from the fruits of a Beibu Gulf mangrove Avicennia marina. The structures were elucidated based on analysis of spectroscopic data. Marinoids F and G are shown to be diastereoisomers of chlorocornoside, a new halogen containing marine secondary metabolite. The antioxidant activity of the isolates was evaluated using a cellular antioxidant assay, and 4 showed good antioxidant activity (EC50 = 26 μM).
doi:10.3390/md12052515
PMCID: PMC4052303  PMID: 24796307
antioxidant; Avicennia marina; chlorocornoside; cornoside; jacaranone analogs; marinoid
19.  Human Antibody Neutralizes Severe Fever with Thrombocytopenia Syndrome Virus, an Emerging Hemorrhagic Fever Virus 
Severe fever with thrombocytopenia syndrome virus (SFTSV), a newly discovered member of the Bunyaviridae family, is the causative agent of an emerging hemorrhagic fever, SFTS, in China. Currently, there are no vaccines or effective therapies against SFTS. In this study, a combinatorial human antibody library was constructed from the peripheral lymphocytes of 5 patients who had recovered from SFTS. The library was screened against purified virions for the production of single-chain variable-region fragments (ScFv). Of the 6 positive clones, one clone (monoclonal antibody [MAb] 4-5) showed neutralizing activity against SFTSV infection in Vero cells. MAb 4-5 was found to effectively neutralize all of the clinical isolates of SFTSV tested, which were isolated from patients in China from 2010 to 2012. MAb 4-5 was found to bind a linear epitope in the ectodomain of glycoprotein Gn. Its neutralizing activity is attributed to blockage of the interactions between the Gn protein and the cellular receptor, indicating that inhibition of virus-cell attachment is its main mechanism. These data suggest that MAb 4-5 can be used as a promising candidate molecule for immunotherapy against SFTSV infection.
doi:10.1128/CVI.00222-13
PMCID: PMC3889583  PMID: 23863504
20.  Vasculogenic mimicry: a novel target for glioma therapy 
Chinese Journal of Cancer  2014;33(2):74-79.
Anti-angiogenic therapy has shown promising but insufficient efficacy on gliomas. Recent studies suggest that vasculogenic mimicry (VM), or the formation of non-endothelial, tumor-cell-lined microvascular channels, occurs in aggressive tumors, including gliomas. There is also evidence of a physiological connection between the endothelial-lined vasculature and VM channels. Tumor cells, by virtue of their high plasticity, can form vessel-like structures themselves, which may function as blood supply networks. Our previous study on gliomas showed that microvessel density was comparably less in VM-positive tumors than in VM-negative tumors. Thus, VM may act as a complement to ensure tumor blood supply, especially in regions with less microvessel density. Patients with VM-positive gliomas survived a shorter period of time than did patients with VM-negative gliomas. Although the detailed molecular mechanisms for VM are not fully understood, glioma stem cells might play a key role, since they are involved in tumor tissue remodeling and contribute to neovascularization via transdifferentiation. In the future, successful treatment of gliomas should involve targeting both VM and angiogenesis. In this review, we summarize the progress and challenges of VM in gliomas.
doi:10.5732/cjc.012.10292
PMCID: PMC3935008  PMID: 23816560
Glioma; vasculogenic mimicry; target therapy
21.  Enhanced MGMT expression contributes to temozolomide resistance in glioma stem-like cells 
Chinese Journal of Cancer  2014;33(2):115-122.
O6-methylguanine DNA methyltransferase (MGMT) can remove DNA alkylation adducts, thereby repairing damaged DNA and contributing to the drug resistance of gliomas to alkylating agents. In addition, glioma stem-like cells (GSCs) have been demonstrated to be involved in the recurrence and treatment resistance of gliomas. In this study, we aimed to investigate MGMT expression and regulatory mechanisms in GSCs and the association of MGMT with temozolomide (TMZ) sensitivity. GSCs were enriched from one MGMT-positive cell line (SF-767) and 7 MGMT-negative cell lines (U251, SKMG-4, SKMG-1, SF295, U87, MGR1, and MGR2) through serum-free clone culture. GSCs from the U251G, SKMG-4G, SF295G, and SKMG-1G cell lines became MGMT-positive, but those from the U87G, MGR1G, and MGR2G cell lines remained MGMT-negative. However, all the GSCs and their parental glioma cell lines were positive for nuclear factor-κB (NF-κB). In addition, GSCs were more resistant to TMZ than their parental glioma cell lines (P < 0.05). However, there was no significant difference in the 50% inhibition concentration (IC50) of TMZ between MGMT-positive and MGMT-negative GSCs (P > 0.05). When we treated the MGMT-positive GSCs with TMZ plus MG-132 (an NF-κB inhibitor), the antitumor activity was significantly enhanced compared to that of GSCs treated with TMZ alone (P < 0.05). Furthermore, we found that MGMT expression decreased through the down-regulation of NF-κB expression by MG-132. Our results show that MG-132 may inhibit NF-κB expression and further decrease MGMT expression, resulting in a synergistic effect on MGMT-positive GSCs. These results indicate that enhanced MGMT expression contributes to TMZ resistance in MGMT-positive GSCs.
doi:10.5732/cjc.012.10236
PMCID: PMC3935013  PMID: 23958055
Glioma stem cell; MGMT; temozolomide; drug resistance; NF-κB
22.  Spatial Distribution of Excitatory Synapses on the Dendrites of Ganglion Cells in the Mouse Retina 
PLoS ONE  2014;9(1):e86159.
Excitatory glutamatergic inputs from bipolar cells affect the physiological properties of ganglion cells in the mammalian retina. The spatial distribution of these excitatory synapses on the dendrites of retinal ganglion cells thus may shape their distinct functions. To visualize the spatial pattern of excitatory glutamatergic input into the ganglion cells in the mouse retina, particle-mediated gene transfer of plasmids expressing postsynaptic density 95-green fluorescent fusion protein (PSD95-GFP) was used to label the excitatory synapses. Despite wide variation in the size and morphology of the retinal ganglion cells, the expression of PSD95 puncta was found to follow two general rules. Firstly, the PSD95 puncta are regularly spaced, at 1–2 µm intervals, along the dendrites, whereby the presence of an excitatory synapse creates an exclusion zone that rules out the presence of other glutamatergic synaptic inputs. Secondly, the spatial distribution of PSD95 puncta on the dendrites of diverse retinal ganglion cells are similar in that the number of excitatory synapses appears to be less on primary dendrites and to increase to a plateau on higher branch order dendrites. These observations suggest that synaptogenesis is spatially regulated along the dendritic segments and that the number of synaptic contacts is relatively constant beyond the primary dendrites. Interestingly, we also found that the linear puncta density is slightly higher in large cells than in small cells. This may suggest that retinal ganglion cells with a large dendritic field tend to show an increased connectivity of excitatory synapses that makes up for their reduced dendrite density. Mapping the spatial distribution pattern of the excitatory synapses on retinal ganglion cells thus provides explicit structural information that is essential for our understanding of how excitatory glutamatergic inputs shape neuronal responses.
doi:10.1371/journal.pone.0086159
PMCID: PMC3895034  PMID: 24465934
23.  Analysis of the Influence of Quantile Regression Model on Mainland Tourists' Service Satisfaction Performance 
The Scientific World Journal  2014;2014:763573.
It is estimated that mainland Chinese tourists travelling to Taiwan can bring annual revenues of 400 billion NTD to the Taiwan economy. Thus, how the Taiwanese Government formulates relevant measures to satisfy both sides is the focus of most concern. Taiwan must improve the facilities and service quality of its tourism industry so as to attract more mainland tourists. This paper conducted a questionnaire survey of mainland tourists and used grey relational analysis in grey mathematics to analyze the satisfaction performance of all satisfaction question items. The first eight satisfaction items were used as independent variables, and the overall satisfaction performance was used as a dependent variable for quantile regression model analysis to discuss the relationship between the dependent variable under different quantiles and independent variables. Finally, this study further discussed the predictive accuracy of the least mean regression model and each quantile regression model, as a reference for research personnel. The analysis results showed that other variables could also affect the overall satisfaction performance of mainland tourists, in addition to occupation and age. The overall predictive accuracy of quantile regression model Q0.25 was higher than that of the other three models.
doi:10.1155/2014/763573
PMCID: PMC3915528  PMID: 24574916
24.  Allyl Isothiocyanate Increases MRP1 Function and Expression in a Human Bronchial Epithelial Cell Line 
Multidrug resistance-associated protein 1 (MRP1), a member of the ATP-binding cassette (ABC) superfamily of transporters, plays an important role in normal lung physiology by protecting cells against oxidative stress and toxic xenobiotics. The present study investigates the effects of allyl isothiocyanate (AITC) on MRP1 mRNA and MRP1 protein expression and transporter activity in the immortalised human bronchial epithelial cell line 16HBE14o-. MRP1 mRNA and MRP1 protein expression in 16HBE14o- cells that were treated with allyl isothiocyanate were analysed by real-time PCR assay and Western blotting. The transport of carboxyfluorescein, a known MRP1 substrate, was measured by functional flow cytometry to evaluate MRP1 activity. Treatment with AITC at concentrations of 5–40 μM increased MRP1 protein levels in a concentration-dependent manner. AITC treatments at concentrations of 1–40 μM caused concentration-dependent increases in MRP1 mRNA levels that were up to seven times greater than the levels found in control cells. Finally, AITC treatment at concentrations of 5–40 μM significantly increased MRP1-dependent efflux in 16HBE14o- cells. These results suggest that AITC can increase the expression and activity of MRP1 in 16HBE14o- cells in a concentration-dependent manner. The upregulation of MRP1 activity and expression by AITC could produce therapeutic effects in the treatment of lung disease.
doi:10.1155/2014/547379
PMCID: PMC3942196  PMID: 24672635
25.  Correction: Regulation of Cigarette Smoke (CS)-Induced Autophagy by Nrf2 
PLoS ONE  2014;9(1):10.1371/annotation/d13c3d06-8eb8-49ec-8326-2db7487a7a8a.
doi:10.1371/annotation/d13c3d06-8eb8-49ec-8326-2db7487a7a8a
PMCID: PMC3888282

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