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1.  YKL-40 expression in chronic obstructive pulmonary disease: relation to acute exacerbations and airway remodeling 
Respiratory Research  2016;17:31.
Background
Recent studies suggest that YKL-40, also called chitinase-3-like-1 protein, has been implicated in the pathogenesis of various inflammatory diseases. It is currently unknown, however, whether YKL-40 plays a role in acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and airway remodeling.
Methods
We evaluated serum YKL-40 levels in patients with AECOPD (n = 37) and stable COPD (n = 44), as well as in controls (n = 47). The association between YKL-40 expression and airway remodeling was analyzed. The effects of YKL-40 on collagen synthesis of primary human lung fibroblasts were also evaluated.
Results
Serum YKL-40 levels were elevated at AECOPD onset as compared to stable disease (median [interquartile range], 78.6 [52.3–122.2] ng/ml versus 46.7 [31.2–75.5] ng/ml; p = 0.0005). The ideal cutoff point for distinguishing patients with AECOPD from those with stable COPD was 64.7 ng/ml (AUC: 0.71; 95%CI: 0.596 to 0.823). YKL-40 expression correlated with airflow obstruction, C-reactive protein, and collagen deposition. Stimulation with YKL-40 promoted collagen production in lung fibroblasts through ERK- and p38-dependent mechanisms.
Conclusions
YKL-40 expression is up-regulated in patients with COPD and correlates with exacerbation attacks and may contribute to airway remodeling by acting on lung fibroblasts. The current data may provide insight into the underlying pathogenesis of COPD, in which YKL-40 has an important pathogenic role.
Trial registration
ChiCTR-OCC-13003567
Electronic supplementary material
The online version of this article (doi:10.1186/s12931-016-0338-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12931-016-0338-3
PMCID: PMC4806429  PMID: 27013031
Chronic obstructive pulmonary disease; CHI3L1; YKL-40; Exacerbation; Disease severity
2.  Was the media campaign that supported Australia’s new pictorial cigarette warning labels and plain packaging policy associated with more attention to and talking about warning labels? 
Addictive behaviors  2015;49:64-67.
Background
Population-level interventions can possibly enhance each other’s effects when they are implemented simultaneously. When the plain packaging policy was implemented in Australia, pictorial health warning labels (HWLs) on cigarette packages were also updated and a national mass media campaign was aired. This study examined whether smokers who recalled the media campaign reported more attention to and talking about HWLs.
Methods
Longitudinal survey data was obtained among Australian adult smokers, aged 18 years and older, from an online consumer panel. One survey wave was conducted before (September 2012) and two waves were conducted after (January 2013 and May 2013) the interventions. The sample was replenished to maintain a sample size of 1000 participants at each wave. Generalized Estimating Equations analyses were performed.
Results
Compared to wave 1, attention to HWLs increased at wave 2 (b = 0.32, SE = 0.06, p < 0.001), but not at wave 3 (b = 0.10, SE = 0.08, p = 0.198). Talking about HWLs increased over time (IRR = 1.82, 95% CI = 1.58–2.09 and IRR = 1.25, 95% CI = 1.05–1.47, at wave 2 and wave 3 respectively). Campaign recall was significantly associated with more attention to HWLs (b = 0.29, SE = 0.05, p < 0.001) and with more talking about HWLs (IRR = 1.17, 95% CI = 1.06–1.29) with similar effects across waves 2 and 3.
Conclusions
Recall of the campaign was associated with more attention to and talking about HWLs. When adjusting for campaign recall, there was still an increasing trend in attention and talking. This suggests that the media campaign and the new packaging and labeling policies had independent and positive effects on attention to and talking about HWLs.
doi:10.1016/j.addbeh.2015.05.015
PMCID: PMC4794999  PMID: 26050643
Australia; Media campaign; Public policy; Smoking; Warning labels
3.  Phenolic Diterpenoid Derivatives as Anti-Influenza A Virus Agents 
ACS Medicinal Chemistry Letters  2015;6(3):355-358.
A series of diterpenoid derivatives based on podocarpic acid were synthesized and evaluated as anti-influenza A virus agents. Several of the novel podocarpic acid derivatives exhibited nanomolar activities against an H1N1 influenza A virus (A/Puerto Rico/8/34) that was resistant to two anti-influenza drugs, oseltamivir and amantadine. This class of compounds inhibits the influenza virus by targeting the viral hemagglutinin-mediated membrane fusion. These results indicated that podocarpic acid derivatives may serve as potential drug candidates to fight drug-resistant influenza A virus infections.
doi:10.1021/ml500533x
PMCID: PMC4360168  PMID: 25815159
Influenza A; influenza inhibitor; podocarpic acid; totarol; hemagglutinin
4.  Clarification of the molecular pathway of Taiwan local pomegranate fruit juice underlying the inhibition of urinary bladder urothelial carcinoma cell by proteomics strategy 
Background
Pomegranate fruit has been shown to exhibit the inhibitory activity against prostate cancer and lung cancer in vitro and in vivo, which might be a resource for chemoprevention and chemotherapy of cancer. Our previous documented findings indicated that treatment of urinary bladder urothelial carcinoma cell with the ethanol extract isolated from the juice of pomegranate fruit grown in Taiwan could inhibit tumor cell. In this study we intended to uncover the molecular pathway underlying anti-cancer efficacy of Taiwan pomegranate fruit juice against urinary bladder urothelial carcinoma.
Methods
We exploited two-dimensional gel electrophoresis coupled with tandem mass spectrometry to find the de-regulated proteins. Western immunoblotting was used to confirm the results collected from proteomics study.
Results
Comparative proteomics indicated that 20 proteins were differentially expressed in ethanol extract-treated T24 cells with 19 up-regulated and 1 down-regulated proteins. These de-regulated proteins were involved in apoptosis, cytoskeleton regulation, cell proliferation, proteasome activity and aerobic glycolysis. Further studies on signaling pathway demonstrated that ethanol extract treatment might inhibit urinary bladder urothelial carcinoma cell proliferation through restriction of PTEN/AKT/mTORC1 pathway via profilin 1 up-regulation. It also might evoke cell apoptosis through Diablo over-expression.
Conclusions
The results of this study provide a global picture to further investigate the anticancer molecular mechanism of pomegranate fruit.
Electronic supplementary material
The online version of this article (doi:10.1186/s12906-016-1071-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12906-016-1071-7
PMCID: PMC4784391  PMID: 26955879
Apoptosis; Urinary bladder urothelial carcinoma; Pomegranate; Proteomics; Akt
5.  Downregulation of selenium-binding protein 1 is associated with poor prognosis in lung squamous cell carcinoma 
Background
We found that selenium-binding protein 1 (SBP1) was progressively decreased in the human bronchial epithelial carcinogenic processes. Knockdown of SBP1 in immortalized human bronchial epithelial cell line 16HBE cells significantly increased the efficiency of B[a]P-induced cell transformation. However, the relationship between SBP1 expression and clinicopathological factors of patients has not been defined completely. The specific role of SBP1 in prognosis of lung squamous cell carcinoma (LSCC) is still unknown.
Methods
Tissue samples from 82 patients treated by pulmonary lobectomy for LSCC were used. Immunohistochemistry and western blotting were used to detect the expressions of SBP1 protein. The relationships between the expression level of SBP1 and the clinicopathological features of patients were analyzed. Cox proportional hazard regression analysis and Kaplan–Meier method were used to perform survival analysis.
Results
Expressions of SBP1 proteins were significantly lower in LSCC tissues than that in the corresponding normal bronchial epithelium (NBE) tissues (P = 0.000). In LSCC, The expression levels of SBP1 had not correlated with patients’ age, gender, smoking state, primary tumor stages (T), TNM clinical stages, and distant metastasis (M) (P > 0.05). However, downregulation of SBP1 was significantly associated with higher lymph node metastasis and lower overall survival rate (P < 0.05). Cox regression analysis indicated low expressions of SBP1 can be an independent prognostic factor for poor overall survival in LSCC patients (P = 0.002).
Conclusions
Downregulation of SBP1 may play a key role in the tumorigenic process of LSCC. SBP1 may be a novel potential prognostic factor of LSCC.
doi:10.1186/s12957-016-0832-6
PMCID: PMC4782367  PMID: 26956891
Selenium-binding protein 1; Lung squamous cell carcinoma; Prognosis
6.  Phase I trial of adoptively transferred tumor-infiltrating lymphocyte immunotherapy following concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma 
Oncoimmunology  2015;4(2):e976507.
Adoptive cell therapy (ACT) for cancers using autologous tumor-infiltrating lymphocytes (TILs) can induce immune responses and antitumor activity in metastatic melanoma patients. Here, we aimed to assess the safety and antitumor activity of ACT using expanded TILs following concurrent chemoradiotherapy (CCRT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC). Twenty-three newly diagnosed, locoregionally advanced NPC patients were enrolled, of whom 20 received a single-dose of TIL infusion following CCRT. All treated patients were assessed for toxicity, survival and clinical and immunologic responses. Correlations between immunological responses and treatment effectiveness were further studied. Only mild adverse events (AEs), including Grade 3 neutropenia (1/23, 5%) consistent with immune-related causes, were observed. Nineteen of 20 patients exhibited an objective antitumor response, and 18 patients displayed disease-free survival longer than 12 mo after ACT. A measurable plasma Epstein–Barr virus (EBV) load was detected in 14 patients at diagnosis, but a measurable EBV load was not found in patients after one week of ACT, and the plasma EBV load remained undetectable in 17 patients at 6 mo after ACT. Expansion and persistence of T cells specific for EBV antigens in peripheral blood following TIL therapy were observed in 13 patients. The apparent positive correlation between tumor regression and the expansion of T cells specific for EBV was further investigated in four patients. This study shows that NPC patients can tolerate ACT with TILs following CCRT and that this treatment results in sustained antitumor activity and anti-EBV immune responses. A larger phase II trial is in progress.
doi:10.4161/23723556.2014.976507
PMCID: PMC4404907  PMID: 25949875
adoptive cell therapy; nasopharyngeal carcinoma; tumor-infiltrating lymphocytes; ACT, adoptive cell therapy; CCRT, concurrent chemoradiotherapy; CR, complete response; DFS, disease-free survival, EBNA1; Epstein–Barr virus nuclear antigen 1; EBV, Epstein–Barr virus; EBV-CTLs, EBV-specific cytotoxic T cells; ELISPOT, enzyme-linked immunospot; FACS, fluorescence-activated cell sorting; GMP, good manufacturing practices; LMP1, latent membrane protein-1; LMP2, latent membrane protein-2; NPC, nasopharyngeal carcinoma; PBMCs, peripheral blood mononuclear cells; PR, partial response; PD, progressive disease; REP, rapid expansion protocol; SFCs, spot-forming cells; TILs, tumor-infiltrating lymphocytes
7.  Synthesis and SAR studies of novel 6,7,8-substituted 4-substituted benzyloxyquinolin-2(1H)-one derivatives for anticancer activity 
British Journal of Pharmacology  2015;172(5):1195-1221.
Background and Purpose
4-Phenylquinolin-2(1H)-one (4-PQ) derivatives can induce cancer cell apoptosis. Additional new 4-PQ analogs were investigated as more effective, less toxic antitumour agents.
Experimental Approach
Forty-five 6,7,8-substituted 4-substituted benzyloxyquinolin-2(1H)-one derivatives were synthesized. Antiproliferative activities were evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliun bromide assay and structure–activity relationship correlations were established. Compounds 9b, 9c, 9e and 11e were also evaluated against the National Cancer Institute-60 human cancer cell line panel. Hoechst 33258 and Annexin V-FITC/PI staining assays were used to detect apoptosis, while inhibition of microtubule polymerization was assayed by fluorescence microscopy. Effects on the cell cycle were assessed by flow cytometry and on apoptosis-related proteins (active caspase-3, -8 and -9, procaspase-3, -8, -9, PARP, Bid, Bcl-xL and Bcl-2) by Western blotting.
Key Results
Nine 6,7,8-substituted 4-substituted benzyloxyquinolin-2(1H)-one derivatives (7e, 8e, 9b, 9c, 9e, 10c, 10e, 11c and 11e) displayed high potency against HL-60, Hep3B, H460, and COLO 205 cancer cells (IC50 < 1 μM) without affecting Detroit 551 normal human cells (IC50 > 50 μM). Particularly, compound 11e exhibited nanomolar potency against COLO 205 cancer cells. Mechanistic studies indicated that compound 11e disrupted microtubule assembly and induced G2/M arrest, polyploidy and apoptosis via the intrinsic and extrinsic signalling pathways. Activation of JNK could play a role in TRAIL-induced COLO 205 apoptosis.
Conclusion and Implications
New quinolone derivatives were identified as potential pro-apoptotic agents. Compound 11e could be a promising lead compound for future antitumour agent development.
doi:10.1111/bph.12992
PMCID: PMC4337696  PMID: 25363404
8.  Archaeal Extrachromosomal Genetic Elements 
SUMMARY
Research on archaeal extrachromosomal genetic elements (ECEs) has progressed rapidly in the past decade. To date, over 60 archaeal viruses and 60 plasmids have been isolated. These archaeal viruses exhibit an exceptional diversity in morphology, with a wide array of shapes, such as spindles, rods, filaments, spheres, head-tails, bottles, and droplets, and some of these new viruses have been classified into one order, 10 families, and 16 genera. Investigation of model archaeal viruses has yielded important insights into mechanisms underlining various steps in the viral life cycle, including infection, DNA replication and transcription, and virion egression. Many of these mechanisms are unprecedented for any known bacterial or eukaryal viruses. Studies of plasmids isolated from different archaeal hosts have also revealed a striking diversity in gene content and innovation in replication strategies. Highly divergent replication proteins are identified in both viral and plasmid genomes. Genomic studies of archaeal ECEs have revealed a modular sequence structure in which modules of DNA sequence are exchangeable within, as well as among, plasmid families and probably also between viruses and plasmids. In particular, it has been suggested that ECE-host interactions have shaped the coevolution of ECEs and their archaeal hosts. Furthermore, archaeal hosts have developed defense systems, including the innate restriction-modification (R-M) system and the adaptive CRISPR (clustered regularly interspaced short palindromic repeats) system, to restrict invasive plasmids and viruses. Together, these interactions permit a delicate balance between ECEs and their hosts, which is vitally important for maintaining an innovative gene reservoir carried by ECEs. In conclusion, while research on archaeal ECEs has just started to unravel the molecular biology of these genetic entities and their interactions with archaeal hosts, it is expected to accelerate in the next decade.
doi:10.1128/MMBR.00042-14
PMCID: PMC4402960  PMID: 25694123
9.  Discovery of novel 5-fluoro-N2,N4-diphenylpyrimidine-2,4-diamines as potent inhibitors against CDK2 and CDK9 
MedChemComm  2014;6(3):444-454.
Based on a 3D-QSAR pharmacophore derived from a diverse set of known cyclin-dependent kinase 9 (CDK9) inhibitors and a composite pharmacophore extracted from the complex structure of flavopiridol (FVP)-CDK9, thirty novel 5-fluoro-N2,N4-diphenylpyrimidine-2,4-diamine derivatives were designed and synthesized. Initial tests against four tumor cell lines with the sulforhodamine B (SRB) assay identified a series of potent compounds with GI50 values at lower micromolar or submicromolar level. Most of the highly cytotoxic compounds exhibited potent inhibitory activities against both CDK2/cyclin E1 and CDK9/cyclin T1. Notably, inhibitions against the two enzymes were generally correlated well with the cytotoxicity of these compounds. Appreciable inhibition was also observed for selected compounds in the anti-HIV-1 assay. Docking studies on compounds 6d and 9g provided conducive clues to further structural optimization.
doi:10.1039/C4MD00412D
PMCID: PMC4406325  PMID: 25914804
5-fluoro-N2; N4-diphenylpyrimidine-2, 4-diamines; cyclin-dependent kinases; pharmacophore; cytotoxicity; anti-HIV-1
10.  Simultaneous detection of four different neuraminidase types of avian influenza A H5 viruses by multiplex reverse transcription PCR using a GeXP analyser 
Objectives
In order to develop a multiplex RT‐PCR assay using the GeXP analyser for the simultaneous detection of four different NA serotypes of H5‐subtype AIVs, effective to control and reduce H5 subtype of avian influenza outbreak.
Design
Six pairs of primers were designed using conserved and specific sequences of the AIV subtypes H5, N1, N2, N6 and N8 in GenBank. Each gene‐specific primer was fused at the 5′ end to a universal sequence to generate six pairs of chimeric primers, and one pair of universal primers was used for RT‐PCR, and PCR product separation and detection were performed by capillary electrophoresis using the GenomeLab GeXP genetic analysis system.
Setting
Single and mixed avian pathogen cDNA/DNA templates were employed to evaluate the specificity of a multiplex assay with a GeXP analyser. Corresponding specific DNA products were amplified for each gene, revealing amplification peaks for M, H5, N1, N2, N6 and N8 genes from four different NA subtypes of influenza A H5 virus.
Sample
A total of 180 cloacal swabs were collected from poultry at live bird markets.
Main outcome measures
The multiplex PCR assay demonstrated excellent specificity, with each pair of specific primers generating only products corresponding to the target genes and without cross‐amplification with other NA‐subtype influenza viruses or other avian pathogens. Using various premixed ssRNAs containing known AIV target genes, the detection limit for the multiplex assay was determined to be 102 copies/μl. The GeXP assay was further evaluated using 180 clinical specimens and compared with RRT‐PCR (real‐time reverse transcriptase PCR) and virus isolation.
Conclusions
This GeXP analyser‐based multiplex assay for four different NA subtypes of H5 HPAI viruses is both highly specific and sensitive and can be used as a rapid and direct diagnostic assay for testing clinical samples.
doi:10.1111/irv.12370
PMCID: PMC4746555  PMID: 26677838
Differential diagnoses; GeXP analyser; H5 avian influenza viruses; HA typing; multiplex detection; NA typing
11.  Improved secondary caries resistance via augmented pressure displacement of antibacterial adhesive 
Scientific Reports  2016;6:22269.
The present in vitro study evaluated the secondary caries resistance potential of acid-etched human coronal dentin bonded using augmented pressure adhesive displacement in conjunction with an experimental antibacterial adhesive. One hundred and twenty class I cavities were restored with a commercial non-antibacterial etch-and-rinse adhesive (N) or an experimental antibacterial adhesive (A) which was displaced by gentle air-blow (G) or augmented pressure air-blow (H). After bonding and restoration with resin composite, the resulted 4 groups (N-G, N-H, A-G and A-H) were exposed to Streptococcus mutans biofilm for 4, 8, 15, 20 or 25 days. The development of secondary caries in the bonding interface was then examined by confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). Data acquired from 15, 20 and 25 days of artificial caries induction were analyzed with three-way ANOVA at α = 0.05. The depth of the artificial carious lesions was significantly affected by “adhesive type” (Single Bond 2 vs experimental antibacterial adhesive p = 0.003), “intensity of adhesive displacement” (gentle vs augmented-pressure adhesive displacement; p < 0.001), as well as “artificial caries induction time” (p < 0.001). The combined use of augmented pressure adhesive displacement and experimental antibacterial adhesive reduces the progression of secondary caries.
doi:10.1038/srep22269
PMCID: PMC4772086  PMID: 26928742
12.  Gnidimacrin, the Potent Anti-HIV Diterpene Can Eliminate Latent HIV-1 Ex Vivo by Activation of PKC Beta 
Journal of medicinal chemistry  2015;58(21):8638-8646.
HIV-1 latency-reversing agents, such as histone deacetylase inhibitors (HDACIs), were ineffective in reducing latent HIV-1 reservoirs ex vivo using CD4 cells from patients as a model. This deficiency poses a challenge to current pharmacological approaches for HIV-1 eradication. The results of this study indicated that gnidimacrin (GM) was able to markedly reduce the latent HIV-1 DNA level and the frequency of latently infected cells in an ex vivo model using patients peripheral blood mononuclear cells (PBMC). GM induced approximately 10-fold more HIV-1 production than the HDACI SAHA or romidepsin, which may be responsible for the effectiveness of GM in reducing latent HIV-1 levels. GM achieved these effects at low picomolar concentrations by selective activation of protein kinase C βI and βII. Notably, GM was able to reduce the frequency of HIV-1 latently infected cells at concentrations without global T cell activation or stimulating inflammatory cytokine production. GM merits further development as a clinical trial candidate for latent HIV-1 eradication.
TOC graphic
doi:10.1021/acs.jmedchem.5b01233
PMCID: PMC4767159  PMID: 26509731
Gnidimacrin; PKC agonist; HIV-1 latency; HIV-1 latency reversing agent
13.  Bipolar versus monopolar transurethral resection of the prostate for benign prostatic hyperplasia: safe in patients with high surgical risk 
Scientific Reports  2016;6:21494.
Here, we compared the effects of bipolar and monopolar transurethral resection of the prostate (B-TURP, M-TURP) for treating elderly patients (≥75 years) with benign prostatic hyperplasia(BPH) who had internal comorbidities. Eligible BPH patients were aged ≥75 years and had at least one internal comorbidity. In this open-label, prospective trial, patients were assigned to B-TURP (n = 75) and M-TURP (n = 88) groups. Data on prostate volume (PV), urination, and time during perioperative period were compared; data associated with urination and complications at one year postoperatively were also compared. Finally, follow-up data were available for 68 and 81 patients in the B-TURP and M-TURP group, respectively. No deaths were recorded. Intraoperative bleeding was lower and irrigation time, indwelling catheter time, and hospital stay were shorter in the B-TURP group than in the M-TURP group (p < 0.001). No difference was observed with respect to operation time (p = 0.058). At one year after the operation, differences with respect to urination and complications were not significant. In conclusion, Short-term efficacy of B-TURP or M-TURP was satisfactory for elderly patients with BPH who had internal comorbidities. Besides, B-TURP is a more sensible choice because it has a lower prevalence of adverse effects.
doi:10.1038/srep21494
PMCID: PMC4759597  PMID: 26892901
14.  Impact of Influenza on Outpatient Visits, Hospitalizations, and Deaths by Using a Time Series Poisson Generalized Additive Model 
PLoS ONE  2016;11(2):e0149468.
Background
The disease burden associated with influenza in developing tropical and subtropical countries is poorly understood owing to the lack of a comprehensive disease surveillance system and information-exchange mechanisms. The impact of influenza on outpatient visits, hospital admissions, and deaths has not been fully demonstrated to date in south China.
Methods
A time series Poisson generalized additive model was used to quantitatively assess influenza-like illness (ILI) and influenza disease burden by using influenza surveillance data in Zhuhai City from 2007 to 2009, combined with the outpatient, inpatient, and respiratory disease mortality data of the same period.
Results
The influenza activity in Zhuhai City demonstrated a typical subtropical seasonal pattern; however, each influenza virus subtype showed a specific transmission variation. The weekly ILI case number and virus isolation rate had a very close positive correlation (r = 0.774, P < 0.0001). The impact of ILI and influenza on weekly outpatient visits was statistically significant (P < 0.05). We determined that 10.7% of outpatient visits were associated with ILI and 1.88% were associated with influenza. ILI also had a significant influence on the hospitalization rates (P < 0.05), but mainly in populations <25 years of age. No statistically significant effect of influenza on hospital admissions was found (P > 0.05). The impact of ILI on chronic obstructive pulmonary disease (COPD) was most significant (P < 0.05), with 33.1% of COPD-related deaths being attributable to ILI. The impact of influenza on the mortality rate requires further evaluation.
Conclusions
ILI is a feasible indicator of influenza activity. Both ILI and influenza have a large impact on outpatient visits. Although ILI affects the number of hospital admissions and deaths, we found no consistent influence of influenza, which requires further assessment.
doi:10.1371/journal.pone.0149468
PMCID: PMC4760679  PMID: 26894876
15.  Two Small Molecules Block Oral Epithelial Cell Invasion by Porphyromons gingivalis 
PLoS ONE  2016;11(2):e0149618.
Porphyromonas gingivalis is a keystone pathogen of periodontitis. One of its bacterial characteristics is the ability to invade various host cells, including nonphagocytic epithelial cells and fibroblasts, which is known to facilitate P. gingivalis adaptation and survival in the gingival environment. In this study, we investigated two small compounds, Alop1 and dynasore, for their role in inhibition of P. gingivalis invasion. Using confocal microscopy, we showed that these two compounds significantly reduced invasion of P. gingivalis and its outer membrane vesicles into human oral keratinocytes in a dose-dependent manner. The inhibitory effects of dynasore, a dynamin inhibitor, on the bacterial entry is consistent with the notion that P. gingivalis invasion is mediated by a clathrin-mediated endocytic machinery. We also observed that microtubule arrangement, but not actin, was altered in the host cells treated with Alop1 or dynasore, suggesting an involvement of microtubule in this inhibitory activity. This work provides an opportunity to develop compounds against P. gingivalis infection.
doi:10.1371/journal.pone.0149618
PMCID: PMC4760928  PMID: 26894834
16.  The Pseudorabies Virus DNA Polymerase Accessory Subunit UL42 Directs Nuclear Transport of the Holoenzyme 
Pseudorabies virus (PRV) DNA replication occurs in the nuclei of infected cells and requires the viral DNA polymerase. The PRV DNA polymerase comprises a catalytic subunit, UL30, and an accessory subunit, UL42, that confers processivity to the enzyme. Its nuclear localization is a prerequisite for its enzymatic function in the initiation of viral DNA replication. However, the mechanisms by which the PRV DNA polymerase holoenzyme enters the nucleus have not been determined. In this study, we characterized the nuclear import pathways of the PRV DNA polymerase catalytic and accessory subunits. Immunofluorescence analysis showed that UL42 localizes independently in the nucleus, whereas UL30 alone predominantly localizes in the cytoplasm. Intriguingly, the localization of UL30 was completely shifted to the nucleus when it was coexpressed with UL42, demonstrating that nuclear transport of UL30 occurs in an UL42-dependent manner. Deletion analysis and site-directed mutagenesis of the two proteins showed that UL42 contains a functional and transferable bipartite nuclear localization signal (NLS) at amino acids 354–370 and that K354, R355, and K367 are important for the NLS function, whereas UL30 has no NLS. Coimmunoprecipitation assays verified that UL42 interacts with importins α3 and α4 through its NLS. In vitro nuclear import assays demonstrated that nuclear accumulation of UL42 is a temperature- and energy-dependent process and requires both importins α and β, confirming that UL42 utilizes the importin α/β-mediated pathway for nuclear entry. In an UL42 NLS-null mutant, the UL42/UL30 heterodimer was completely confined to the cytoplasm when UL42 was coexpressed with UL30, indicating that UL30 utilizes the NLS function of UL42 for its translocation into the nucleus. Collectively, these findings suggest that UL42 contains an importin α/β-mediated bipartite NLS that transports the viral DNA polymerase holoenzyme into the nucleus in an in vitro expression system.
doi:10.3389/fmicb.2016.00124
PMCID: PMC4753316  PMID: 26913023
pseudorabies virus; DNA polymerase; accessory subunit; UL42; nuclear transport
17.  Impact of the CYP4F2 gene polymorphisms on the warfarin maintenance dose: A systematic review and meta-analysis 
Biomedical Reports  2016;4(4):498-506.
Warfarin is an oral anticoagulant with significant interpatient variability in dosage. A large number of studies have confirmed that the individual warfarin dose is mainly affected by the cytochrome P450 complex subunit 2C9 and vitamin K epoxide reductase complex subunit 1. However, the association between cytochrome P450 4F2 (CYP4F2) gene polymorphisms and warfarin dosage in the Asian population remains controversial. To investigate the impact of the CYP4F2 polymorphism rs2108622 (p.V433M) on warfarin dose requirement, a systematic review and meta-analysis were conducted. According to the strict inclusion and exclusion criteria set, a comprehensive literature search was performed, and the studies published before August 5, 2015 were searched for in PubMed, EMBASE and the China National Knowledge Infrastructure databases. The references were checked by two independent reviewers. The association between the warfarin maintenance dose and CYP4F2 polymorphism was analyzed. Twenty-two studies were included in the meta-analysis. Compared with the CYP4F2 genotype CC, carriers of the CT and TT genotypes required a 9 [95% confidence interval (CI): 6.0–13.0] and 20% (95% CI, 13.0–27.0) higher warfarin dose, respectively. In the combined analysis, T carriers (CT+TT) required an 11% (95% CI, 8.0–14.0) higher warfarin dose compared to the CC genotype. In addition, there was a 10% (95% CI, 5.0–15.0) higher warfarin dose in TT carriers compared to the CT genotype (all P<0.05). The results of the meta-analysis suggest that the effects of the CYP4F2 polymorphism on individual warfarin dose have a statistically significant difference, and the effect degree is variable in the subgroups. Further studies are expected to explore whether the pharmacogenetics model including the CYP4F2 polymorphism can strengthen the prediction of warfarin dose.
doi:10.3892/br.2016.599
PMCID: PMC4812555  PMID: 27073641
warfarin; dose; thrombosis; CYP4F2; polymorphism
18.  Surface antigens contribute differently to the pathophysiological features in serotype K1 and K2 Klebsiella pneumoniae strains isolated from liver abscesses 
Gut Pathogens  2016;8:4.
Background
The virulence role of surface antigens in a single serotype of Klebsiella pneumoniae strain have been studied, but little is known about whether their contribution will vary with serotype.
Method
To investigate the role of K and O antigen in hyper-virulent strains, we constructed O and K antigen deficient mutants from serotype K1 STL43 and K2 TSGH strains from patients with liver abscess, and characterized their virulence in according to the abscess formation and resistance to neutrophil phagocytosis, serum, and bacterial clearance in liver.
Results
Both of K1 and K2-antigen mutants lost their wildtype resistance to neutrophil phagocytosis and hepatic clearance, and failed to cause abscess formation. K2-antigen mutant became serum susceptible while K1-antigen mutant maintained its resistance to serum killing. The amount of glucuronic acid, indicating the amount of capsular polysaccharide (CPS, K antigen), was inversed proportional to the rate of phagocytosis. O-antigen mutant of serotype K1 strains had significantly more amount of CPS, and more resistant to neutrophil phagocytosis than its wildtype counterpart. O-antigen mutants of serotype K1 and K2 strains lost their wildtype serum resistance, and kept resistant to neutrophil phagocytosis. While both mutants lacked the same O1 antigen, O-antigen mutant of serotype K1 became susceptible to liver clearance and cause mild abscess formation, but its serotype K2 counterpart maintained these wildtype virulence.
Conclusion
We conclude that the contribution of surface antigens to virulence of K. pneumoniae strains varies with serotypes.
doi:10.1186/s13099-016-0085-5
PMCID: PMC4758166  PMID: 26893615
19.  Transcriptional repression of SOCS3 mediated by IL-6/STAT3 signaling via DNMT1 promotes pancreatic cancer growth and metastasis 
Background
Previous studies have investigated the sustained aberrantly activated Interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is crucial for pancreatic cancer growth and metastasis. Suppressor of cytokine signaling 3 (SOCS3), as a key negative feedback regulator of this signaling pathway, is usually down-regulated in various cancers. In the present study, we aim at exploring the biological function and the underlying molecular regulation mechanisms of SOCS3 in pancreatic cancer.
Methods
The expression of SOCS3 and other genes in pancreatic cancer was examined by Quantitative real-time PCR, western blotting and immunohistochemical staining. The interaction between pSTAT3 and DNA Methyltransferase 1 (DNMT1) was investigated by co-immunoprecipitation assay. Luciferase reporter assay was used to investigate the transcriptional regulation of pSTAT3 and DNMT1 on the SOCS3 gene. The effects of SOCS3 on the biological behavior of pancreatic cancer cells were assessed both in vitro and vivo. Furthermore, we performed a comprehensive analysis of the expression of SOCS3 in a pancreatic cancer tissue microarray (TMA) and correlated our findings with pathological parameters and outcomes of the patients.
Results
We showed that SOCS3 expression was decreased in phosphorylated STAT3 (pSTAT3)-positive tumors and was negatively correlated with pSTAT3 in pancreatic cancer cells. We also found that IL-6/STAT3 promoted SOCS3 promoter hypermethylation by increasing DNMT1 activity; silencing DNMT1 or 5-aza-2-deoxycytidine (5-AZA) treatment could reverse the down-regulation of SOCS3 mediated by IL-6. Using co-immunoprecipitation and luciferase reporter assays, we found that STAT3 recruited DNMT1 to the promoter region of SOCS3 and inhibited its transcriptional activity. Overexpression of SOCS3 significantly inhibited cell proliferation, which may be due to the increase in G1-S phase arrest; overexpression of SOCS3 also inhibited cell migration and invasion as well as tumorigenicity in nude mice. Pancreatic cancer tissue microarray analysis showed that high SOCS3 expression was a good prognostic factor and negatively correlated with tumor volume and metastasis.
Conclusion
We demonstrated that activated IL-6/STAT3 signaling could induce SOCS3 methylation via DNMT1, which led to pancreatic cancer growth and metastasis. These data also provided a mechanistic link between sustained aberrantly activated IL-6/STAT3 signaling and SOCS3 down-regulation in pancreatic cancer. Thus, inhibitors of STAT3 or DNMT1 may become novel strategies for treating pancreatic cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s13046-016-0301-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s13046-016-0301-7
PMCID: PMC4743194  PMID: 26847351
Interleukin-6; Signal transducer and activator of transcription 3; Suppressor of cytokine signaling 3; DNA Methyltransferase 1; Methylation; Pancreatic ductal adenocarcinoma
20.  The TCA Pathway is an Important Player in the Regulatory Network Governing Vibrio alginolyticus Adhesion Under Adversity 
Adhesion is a critical step in the initial stage of Vibrio alginolyticus infection; therefore, it is important to understand the underlying mechanisms governing the adhesion of V. alginolyticus and determine if environmental factors have any effect. A greater understanding of this process may assist in developing preventive measures for reducing infection. In our previous research, we presented the first RNA-seq data from V. alginolyticus cultured under stress conditions that resulted in reduced adhesion. Based on the RNA-seq data, we found that the Tricarboxylic acid cycle (TCA pathway) might be closely related to adhesion. Environmental interactions with the TCA pathway might alter adhesion. To validate this, bioinformatics analysis, quantitative Real-Time PCR (qPCR), RNAi, and in vitro adhesion assays were performed, while V. alginolyticus was treated with various stresses including temperature, pH, salinity, and starvation. The expression of genes involved in the TCA pathway was confirmed by qPCR, which reinforced the reliability of the sequencing data. Silencing of these genes was capable of reducing the adhesion ability of V. alginolyticus. Adhesion of V. alginolyticus is influenced substantially by environmental factors and the TCA pathway is sensitive to some environmental stresses, especially changes in pH and starvation. Our results indicated that (1) the TCA pathway plays a key role in V. alginolyticus adhesion: (2) the TCA pathway is sensitive to environmental stresses.
doi:10.3389/fmicb.2016.00040
PMCID: PMC4735382  PMID: 26870007
Vibrio alginolyticus; adhesion; TCA pathway; environmental stresses
21.  Design and synthesis of new 2-arylnaphthyridin-4-ones as potent antitumor agents targeting tumorigenic cell lines 
To develop new anticancer drug candidates from 2-arylnaphthyridin-4-one (AN), we have designed and synthesized a series of 3′-hydroxy and 6-hydroxy derivatives of AN. The results of cytotoxicity screening indicated that the replacement of the 3′-methoxy moiety on the C-ring phenyl group of AN (6a–e) with 3′-hydroxy (7a–e) made no significant effect on the inhibitory activity against HL-60, Hep3B and NCI-H460 cancer cell lines. On the other hand, replacing the 6-methoxy group on the A-ring of AN (6g–i) with a 6-hydroxy group (7g–i) resulted in reduced inhibitory activity against the above three cancer cell lines. Among the above-mentioned target compounds, 2-(3-hydroxyphenyl)-5-methyl-1,8-naphthyridin-4(1H)-one (7a) demonstrated the greatest potency and the best selectivity toward tumorigenic cancer cell lines. In a 7a preliminary mechanism of action study in Hep3B hepatoma cells, 7a showed the effects on microtubules followed by cell cycle arrest and sequentially led to apoptosis.
In addition, a phosphate prodrug (11) of 7a exhibited significant antitumor activity when tested in a Hep3B xenograft nude mice model. Since compound 11 has demonstrated good development potential, it is recommended for further preclinical studies.
doi:10.1016/j.ejmech.2014.11.062
PMCID: PMC4403237  PMID: 25528332
2-Arylnaphthyridin-4-ones; Antitumor agents; Phosphate prodrug
22.  Quantitative trait locus analysis for pod- and kernel-related traits in the cultivated peanut (Arachis hypogaea L.) 
BMC Genetics  2016;17:25.
Background
The cultivated peanut (Arachis hypogaea L.) is an important oil and food crop in the world. Pod- and kernel-related traits are direct factors involved in determining the yield of the peanut. However, the genetic basis underlying pod- and kernel-related traits in the peanut remained largely unknown, which hampered the improvement of peanut through marker-assisted selection. To understand the genetic basis underlying pod- and kernel-related traits in the peanut and provide more useful information for marker-assisted breeding, we conducted quantitative trait locus (QTL) analysis for pod length and width and seed length and width by use of two F2:3 populations derived from cultivar Fuchuan Dahuasheng × ICG 6375 (FI population) and cultivar Xuhua 13 × cultivar Zhonghua 6 (XZ population) in this study.
Results
Two genetic maps containing 347 and 228 polymorphic markers were constructed for FI and XZ populations respectively. In total, 39 QTLs explaining 1.25–26.11 % of the phenotypic variations were detected in two populations. For the FI population, 26 QTLs were detected between the two environments, among which twelve were not mapped before. For the XZ population, thirteen QTLs were detected, among which eight were not reported before. One QTL for pod width was repeatedly mapped between the two populations.
Conclusion
The QTL analyses for pod length and width and seed length and width were conducted in this study using two mapping populations. Novel QTLs were identified, which included two for pod length, four for pod width, five for seed length and one for seed width in the FI population, and three for pod length, three for pod width and two for seed width in the XZ population. Our results will be helpful for improving pod- and seed-related traits in peanuts through marker-assisted selection.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-016-0337-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12863-016-0337-x
PMCID: PMC4727316  PMID: 26810040
Peanut (Arachis hypogaea L.); QTL analysis; Pod length; Pod width; Seed length; Seed width
23.  N-Acetyl Cysteine Depletes Reactive Oxygen Species and Prevents Dental Monomer-Induced Intrinsic Mitochondrial Apoptosis In Vitro in Human Dental Pulp Cells 
PLoS ONE  2016;11(1):e0147858.
Purpose
To investigate the involvement of intrinsic mitochondrial apoptosis in dental monomer-induced cytotoxicity and the influences of N-acetyl cysteine (NAC) on this process.
Methods
Human dental pulp cells (hDPCs) were exposed to several dental monomers in the absence or presence of NAC, and cell viability, intracellular redox balance, morphology and function of mitochondria and key indicators of intrinsic mitochondrial apoptosis were evaluated using various commercial kits.
Results
Dental monomers exerted dose-dependent cytotoxic effects on hDPCs. Concomitant to the over-production of reactive oxygen species (ROS) and depletion of glutathione (GSH), differential changes in activities of superoxide dismutase, glutathione peroxidase, and catalase were detected. Apoptosis, as indicated by positive Annexin V/propidium iodide (PI) staining and activation of caspase-3, was observed after dental monomer treatment. Dental monomers impaired the morphology and function of mitochondria, and induced intrinsic mitochondrial apoptosis in hDPCs via up-regulation of p53, Bax and cleaved caspase-3, and down-regulation of Bcl-2. NAC restored cell viability, relieved oxidative stress and blocked the apoptotic effects of dental monomers.
Conclusions
Dental monomers induced oxidative stress and mitochondrial intrinsic apoptosis in hDPCs. NAC could reduce the oxidative stress and thus protect hDPCs against dental monomer-induced apoptosis.
doi:10.1371/journal.pone.0147858
PMCID: PMC4726696  PMID: 26808507
24.  α-Carboline derivative TJY-16 inhibits tumor growth by inducing G2/M cell cycle arrest in glioma cells 
Background
Glioblastoma multiforme (GBM) is the most lethal primary brain tumors which remains difficult to cure despite advances in surgery, radiotherapy and chemotherapy. Therefore, the development of new drug is urgently needed. α-carboline derivatives were usually isolated from marine animals such as Britannia marine tunicate Dendrodoa grossularia and Indonesian ascidian Polycarpa aurata. In this study, we have synthesized several α-carboline compounds and examined their anti-glioma activities.
Results
We report that among α-carboline derivatives TJY-16 (6-acetyl-9-(3,4,5-trimethoxybenzyl)-9H-pyrido[2,3-b] indole) is the most potent α-carboline analog to induce glioma cell death with IC50 value of around 50 nM. TJY-16 decreased cell viability of glioma cells in a concentration- and time-dependent manner. Trypan blue exclusion assay showed that the reduction of cell viability was due to both cell growth inhibition and cell death. Flow cytometric analysis showed that TJY-16 induced G2/M cell cycle arrest followed by induction of sub-G1 phase. Hoechst staining detected the apoptotic features such as nuclear shrinkage and DNA condensation. Western blot analysis showed the increased level of cleaved caspase-3. The activation of caspase-8 and depolarization of mitochondrial membrane potential (ΔΨm) indicated that both extrinsic and intrinsic apoptotic pathways were involved in TJY-16-induced apoptosis. TJY-16 effectively inhibited tumor growth and induced caspase-3 activation in the xenograft tumor model of U87 glioma cells.
Conclusions
Our results suggest that TJY-16 may kill glioma cells by inducing G2/M cell cycle arrest followed by apoptosis. Thus, TJY-16 is a promising agent for the treatment of malignant gliomas.
doi:10.1186/s12929-016-0222-y
PMCID: PMC4717554  PMID: 26786523
Glioblastoma multiforme; Carboline derivatives; Cell cycle arrest; Apoptosis; G2/M arrest
25.  Early and late effects of prenatal corticosteroid treatment on the microRNA profiles of lung tissue in rats 
Glucocorticoids have been administered to mothers at risk of premature delivery to induce maturation of preterm fetal lungs and prevent the development of respiratory distress syndrome. Micro (mi)RNAs serve various crucial functions in cell proliferation, differentiation and organ development; however, few studies have demonstrated an association between miRNAs and lung development. The aim of the present study was to investigate alterations in the miRNA profiles of rat lung tissue following prenatal glucocorticoid therapy for fetal lung development. The differences in miRNA expression profiles were compared between postnatal days 7 (D7) and 120 (D120) rat lung tissues, followed by validation using reverse transcription-quantitative polymerase chain reaction. The miRNA profiles of rat lung tissues following prenatal dexamethasone (DEX) therapy were also investigated. miRNAs with 2-fold changes were selected for further analysis. At D120, 6 upregulated and 6 downregulated miRNAs were detected, compared with D7. Among these differentially expressed miRNAs, miR-101-3p and miR-99b-5p were associated with the lowest and highest expressions of miRNA at D7, respectively. A limited impact on the miRNA profiles of rat lung tissues was observed following prenatal DEX treatment, which may help to further clarify the mechanisms underlying normal lung development. However, the results of the present study cannot entirely elucidate the effects of prenatal DEX treatment on the lung development of premature infants, and further studies investigating the impact of prenatal corticosteroids on fetal lung miRNA profiles are required.
doi:10.3892/etm.2016.2992
PMCID: PMC4774352  PMID: 26997989
prenatal glucocorticoid; rat; lung; microRNA

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