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1.  Ultrasound-promoted two-step synthesis of 3-arylselenylindoles and 3-arylthioindoles as novel combretastatin A-4 analogues 
Scientific Reports  2016;6:23986.
A series of 3-(3′-hydroxy-4′-methoxyphenyl)selenyl-5,6,7-trimethoxy-1H-indoles and 3-(3′-hydroxy-4′-methoxyphenyl)thio-5,6,7-trimethoxy-1H-indoles were obtained as a new class of combretastatin A-4 (CA-4) analogues via a convenient ultrasound (US)-assisted two-step process involving 3-selenenylation/sulfenylation followed by O-deallylation. With the assistance of US irradiation, both the reaction rates and yields of selenenylation, sulfenylation and O-deallylation could be significantly improved. A comparison of the reaction rates of O-deallylation and ester reduction demonstrated that O-deallylation was more sensitive to US irradiation. Finally, these products were evaluated for their antiproliferative activities, and most of them showed moderate to potent activities against three human cancer cell lines in vitro.
doi:10.1038/srep23986
PMCID: PMC4820744  PMID: 27045272
2.  Time Trends in Fast Food Consumption and Its Association with Obesity among Children in China 
PLoS ONE  2016;11(3):e0151141.
Objective
Study the trends in Western fast food consumption (FFC) among Chinese school-age children and the association between FFC and obesity using nationwide survey data.
Design
Cross-sectional and longitudinal analyses were conducted to study the trends in FFC and the associations between FFC and weight status (overweight, obesity and body mass index (BMI) z-score).
Setting
Longitudinal data from families were collected in the 2004 and 2009 China Health and Nutrition Survey (covering nine provinces throughout China).
Subjects
The analysis included 2656 Chinese children aged 6 to 18 years (1542 and 1114 children in the 2004 and 2009 survey, respectively).
Results
FFC (reported having consumed Western fast food in the past three months) has increased between 2004 and 2009, from 18.5% to 23.9% in those aged 6–18, and increased more rapidly among those aged 13–17, from 17.9% to 26.3%. The increase was significant in almost all groups by age, sex, family income, and residence. Our cross-sectional and longitudinal analyses did not detect a significant association between FFC and obesity/overweight or BMI z-score (e.g., for BMI z-score, boys: β = 0.02, 95% CI: -0.71, 0.75; girls: β = -0.14, 95% CI: -1.03, 0.75).
Conclusions
FFC has increased in Chinese school-age children, especially in older children, boys, and those from low- and medium-income families, rural areas, and East China, but decreased among those from high-income families during 2004–2009. The data did not show a significant association between FFC and obesity.
doi:10.1371/journal.pone.0151141
PMCID: PMC4790849  PMID: 26974536
3.  New role and molecular mechanism of Gadd45a in hepatic fibrosis 
World Journal of Gastroenterology  2016;22(9):2779-2788.
AIM: To investigate the role of Gadd45a in hepatic fibrosis and the transforming growth factor (TGF)-β/Smad signaling pathway.
METHODS: Wild-type male BALB/c mice were treated with CCl4 to induce a model of chronic liver injury. Hepatic stellate cells (HSCs) were isolated from the liver of BALB/c mice and were treated with small interfering RNAs (siRNAs) targeting Gadd45a or the pcDNA3.1-Gadd45a recombinant plasmid. Cellular α-smooth muscle actin (α-SMA), β-actin, type I collagen, phospho-Smad2, phospho-Smad3, Smad2, Smad3, and Smad4 were detected by Western blots. The mRNA levels of α-SMA, β-actin, and type I collagen were determined by quantitative real-time (qRT)-PCR analyses. Reactive oxygen species production was monitored by flow cytometry using 2,7-dichlorodihydrofluorescein diacetate. Gadd45a, Gadd45b, anti-Gadd45g, type I collagen, and SMA local expression in liver tissue were measured by histologic and immunohistochemical analyses.
RESULTS: Significant downregulation of Gadd45a, but not Gadd45b or Gadd45g, accompanied by activation of the TGF-β/Smad signaling pathways was detected in fibrotic liver tissues of mice and isolated HSCs with chronic liver injury induced by CCl4 treatment. Overexpression of Gadd45a reduced the expression of extracellular matrix proteins and α-SMA in HSCs, whereas transient knockdown of Gadd45a with siRNA reversed this process. Gadd45a inhibited the activity of a plasminogen activator inhibitor-1 promoter construct and (CAGA)9 MLP-Luc, an artificial Smad3/4-specific reporter, as well as reduced the phosphorylation and nuclear translocation of Smad3. Gadd45a showed protective effects by scavenging reactive oxygen species and upregulating antioxidant enzymes.
CONCLUSION: Gadd45a may counteract hepatic fibrosis by regulating the activation of HSCs via the inhibition of TGF-β/Smad signaling.
doi:10.3748/wjg.v22.i9.2779
PMCID: PMC4778000  PMID: 26973416
Antioxidant; Gadd45a; Hepatic fibrosis; Hepatic stellate cells; Transforming growth factor-β/Smad signaling
4.  The efficacy of iodine-125 permanent brachytherapy versus intensity-modulated radiation for inoperable salivary gland malignancies: study protocol of a randomised controlled trial 
BMC Cancer  2016;16:193.
Background
Radiation therapy is the method of choice for subjects with inoperable salivary gland malignancies. I-125 brachytherapy, delivering a high radiation dose to a tumor but sparing surrounding normal tissues, is supposed to be ideal modality for the treatment of salivary gland malignancies. We designed a randomised controlled clinical trial to compare the efficacy of I-125 permanent brachytherapy (PBT) versus intensity-modulated radiation therapy (IMRT) for inoperable salivary gland malignancies.
Methods/Design
In this study, inclusion criteria are subjects with inoperable salivary gland malignancies, aged 18–80 years, have provided informed consent, with at least one measurable tumor focus, be able to survive ≥3 months, Karnofsky performance status ≥60, have adequate hematopoietic function of bone marrow, have normal liver and kidney function, and are willing to prevent pregnancy.
Exclusion criteria include a history of radiation or chemotherapy, a history of other malignant tumors in the past 5 years, receiving other effective treatments, participating in other clinical trials, with circulatory metastasis, cognitive impairment, severe cardiovascular and cerebrovascular diseases, acute infection, uncontrolled systemic disease, history of interstitial lungdisease, and being pregnant or breast feeding.
The study will be conducted as a clinical, prospective, randomised controlled trial with balanced randomisation (1:1). The planned sample size is 90 subjects. Subjects with inoperable salivary gland malignancies are randomised to receive either I-125 PBT or IMRT, with stratification by tumor size and neck lymph node metastasis. Participants in both groups will be followed up at 2, 4, 6, 9, 12, 15, 18, 21 and 24 months after randomization. The primary outcome is local control rate of the primary site (based on imaging findings and clinical examination, RECIST criteria) in 1 year. Secondary outcomes are progression-free survival, overall survival, quality of life (QOL) measured with the European Organization for Research and Treatment of Cancer QOL Questionnaire (EORTC QLQ-C30 and QLQ-H&N35) of Chinese version, and safety of treatment. Chi-squared test is used to compare the local control rates in both groups. The survival curves are estimated by the Kaplan-Meier method, and log-rank test is used to test the significant difference.
Discussion
Only few observational studies have investigated the effect of I-125 PBT on inoperable salivary gland malignancies. To our knowledge, this is the first randomised controlled trial to investigate the efficacy of I-125 PBT for subjects with inoperable salivary gland malignancies, and will add to the knowledge base for the treatment of these subjects.
Trial registration
The study is registered to Clinical Trials.gov (NCT02048254) on Jan 29, 2014.
doi:10.1186/s12885-016-2248-7
PMCID: PMC4782516  PMID: 26951097
I-125 permanent brachytherapy; Intensity-modulated radiation therapy; Inoperable salivary gland malignancy; Local control rate; Quality of life
5.  CaCDPK15 positively regulates pepper responses to Ralstonia solanacearum inoculation and forms a positive-feedback loop with CaWRKY40 to amplify defense signaling 
Scientific Reports  2016;6:22439.
CaWRKY40 is a positive regulator of pepper (Capsicum annum) response to Ralstonia solanacearum inoculation (RSI), but the underlying mechanism remains largely unknown. Here, we functionally characterize CaCDPK15 in the defense signaling mediated by CaWRKY40. Pathogen-responsive TGA, W, and ERE boxes were identified in the CaCDPK15 promoter (pCaCDPK15), and pCaCDPK15-driven GUS expression was significantly enhanced in response to RSI and exogenously applied salicylic acid, methyl jasmonate, abscisic acid, and ethephon. Virus-induced gene silencing (VIGS) of CaCDPK15 significantly increased the susceptibility of pepper to RSI and downregulated the immunity-associated markers CaNPR1, CaPR1, and CaDEF1. By contrast, transient CaCDPK15 overexpression significantly activated hypersensitive response associated cell death, upregulated the immunity-associated marker genes, upregulated CaWRKY40 expression, and enriched CaWRKY40 at the promoters of its targets genes. Although CaCDPK15 failed to interact with CaWRKY40, the direct binding of CaWRKY40 to pCaCDPK15 was detected by chromatin immunoprecipitation, which was significantly potentiated by RSI in pepper plants. These combined results suggest that RSI in pepper induces CaCDPK15 and indirectly activates downstream CaWRKY40, which in turn potentiates CaCDPK15 expression. This positive-feedback loop would amplify defense signaling against RSI and efficiently activate strong plant immunity.
doi:10.1038/srep22439
PMCID: PMC4772545  PMID: 26928570
6.  Pepper CabZIP63 acts as a positive regulator during Ralstonia solanacearum or high temperature–high humidity challenge in a positive feedback loop with CaWRKY40 
Journal of Experimental Botany  2016;67(8):2439-2451.
Highlight
CabZIP63, indirectly activated by CaWRKY40, positively modulates transcription of CabZIP63 and CaWRKY40, enhances the binding of CaWRKY40 to its target promoters, and, therefore, increases resistance to Ralstonia solanacearum and thermotolerance.
CaWRKY40 is known to act as a positive regulator in the response of pepper (Capsicum annuum) to Ralstonia solanacearum inoculation (RSI) or high temperature–high humidity (HTHH), but the underlying mechanism remains elusive. Herein, we report that CabZIP63, a pepper bZIP family member, participates in this process by regulating the expression of CaWRKY40. CabZIP63 was found to localize in the nuclei, be up-regulated by RSI or HTHH, bind to promoters of both CabZIP63 (pCabZIP63) and CaWRKY40 (pCaWRKY40), and activate pCabZIP63- and pCaWRKY40-driven β-glucuronidase expression in a C- or G-box-dependent manner. Silencing of CabZIP63 by virus-induced gene silencing (VIGS) in pepper plants significantly attenuated their resistance to RSI and tolerance to HTHH, accompanied by down-regulation of immunity- or thermotolerance-associated CaPR1, CaNPR1, CaDEF1, and CaHSP24. Hypersensitive response-mediated cell death and expression of the tested immunity- and thermotolerance-associated marker genes were induced by transient overexpression (TOE) of CabZIP63, but decreased by that of CabZIP63-SRDX. Additionally, binding of CabZIP63 to pCaWRKY40 was up-regulated by RSI or HTHH, and the transcript level of CaWRKY40 and binding of CaWRKY40 to the promoters of CaPR1, CaNPR1, CaDEF1 and CaHSP24 were up-regulated by TOE of CabZIP63. On the other hand, CabZIP63 was also up-regulated transcriptionally by TOE of CaWRKY40. The data suggest collectively that CabZIP63 directly or indirectly regulates the expression of CaWRKY40 at both the transcriptional and post-transcriptional level, forming a positive feedback loop with CaWRKY40 during pepper’s response to RSI or HTHH. Altogether, our data will help to elucidate the underlying mechanism of crosstalk between pepper’s response to RSI and HTHH.
doi:10.1093/jxb/erw069
PMCID: PMC4809298  PMID: 26936828
CabZIP63; CaWRKY40; high temperature–high humidity; pepper; Ralstonia solanacearum; transcription factors.
7.  Antiallergic Phorbol Ester from the Seeds of Aquilaria malaccensis 
The Aquilaria malaccensis (Thymelaeaceae) tree is a source of precious fragrant resin, called agarwood, which is widely used in traditional medicines in East Asia against diseases such as asthma. In our continuous search for active natural products, A. malaccensis seeds ethanolic extract demonstrated antiallergic effect with an IC50 value less than 1 µg/mL. Therefore, the present research aimed to purify and identify the antiallergic principle of A. malaccensis through a bioactivity-guided fractionation approach. We found that phorbol ester-rich fraction was responsible for the antiallergic activity of A. malaccensis seeds. One new active phorbol ester, 12-O-(2Z,4E,6E)-tetradeca-2,4,6-trienoylphorbol-13-acetate, aquimavitalin (1) was isolated. The structure of 1 was assigned by means of 1D and 2D NMR data and high-resolution mass spectrometry (HR-MS). Aquimavitalin (1) showed strong inhibitory activity in A23187- and antigen-induced degranulation assay with IC50 values of 1.7 and 11 nM, respectively, with a therapeutic index up to 71,000. The antiallergic activities of A. malaccensis seeds and aquimavitalin (1) have never been revealed before. The results indicated that A. malaccensis seeds and the pure compound have the potential for use in the treatment of allergy.
doi:10.3390/ijms17030398
PMCID: PMC4813253  PMID: 27007372
Aquilaria malaccensis seeds; antiallergic; degranulation; phorbol ester; bioactivity-guided fractionation
8.  An external sensing system in Plasmodium falciparum-infected erythrocytes 
Malaria Journal  2016;15:103.
Background
A number of experiments have previously indicated that Plasmodium falciparum-infected erythrocytes (pRBC) were able to sense host environment. The basis of this ability to detect external cues is not known but in screening signalling molecules from pRBC using commercial antibodies, a 34 kDa phosphorylated molecule that possesses such ability was identified.
Methods
The pRBC were exposed to different culture conditions and proteins were extracted for 1D or 2D gel electrophoresis followed by Western blot. The localization of 34 kDa protein was examined by biochemical fractionation followed by Western blot. High-resolution mass spectrometric analysis of immune precipitants was used to identify this protein and real-time quantitative reverse transcriptase polymerase chain reaction was used for detecting mRNA expression level.
Results
The 34 kDa protein was called PfAB4 has immediate responses (dephosphorylation and rapid turnover) to host environmental stimuli such as serum depletion, osmolality change and cytokine addition. PfAB4 is expressed constitutively throughout the erythrocytic lifecycle with dominant expression in trophozoites 30 h post-infection. Tumour necrosis factor (TNF) treatment induced a transient detectable dephosphorylation of PfAB4 in the ItG strain (2 min after addition) and the level of expression and phosphorylation returned to normal within 1–2 h. PfAB4 localized dominantly in pRBC cytoplasm, with a transient shift to the nucleus under TNF stimulation as shown by biochemical fractionation. High-resolution mass spectrometric analysis of immune precipitants of AB4 antibodies revealed a 34 kDa PfAB4 component as a mixture of proliferating cellular nuclear antigen-1 (PCNA1) and exported protein-2 (EXP2), along with a small number of other inconsistently identified peptides. Different parasite strains have different PfAB4 expression levels, but no significant association between mRNA and PfAB4 levels was seen, indicating that the differences may be at the post-transcriptional, presumably phosphorylation, level. A triple serine phosphorylated PCNA1 peptide was identified from the PfAB4 high expression strain only, providing further evidence that the identity of PfAB4 is PCNA1 in P.falciparum.
Conclusion
A protein element in the human malaria parasite that responds to external cues, including the pro-inflammatory cytokine TNF have been discovered. Treatment results in a transient change in phosphorylation status of the response element, which also migrates from the parasite cytoplasm to the nucleus. The response element has been identified as PfPCNA1. This sensing response could be regulated by a parasite checkpoint system and be analogous to bacterial two-component signal transduction systems.
Electronic supplementary material
The online version of this article (doi:10.1186/s12936-016-1144-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12936-016-1144-6
PMCID: PMC4759932  PMID: 26893139
10.  Identification of a Group of GABAergic Neurons in the Dorsomedial Area of the Locus Coeruleus 
PLoS ONE  2016;11(1):e0146470.
The locus coeruleus (LC)-norepinephrine (NE) system in the brainstem plays a critical role in a variety of behaviors is an important target of pharmacological intervention to several neurological disorders. Although GABA is the major inhibitory neurotransmitter of LC neurons, the modulation of LC neuronal firing activity by local GABAergic interneurons remains poorly understood with respect to their precise location, intrinsic membrane properties and synaptic modulation. Here, we took an optogenetic approach to address these questions. Channelrhodopsin (ChR2) in a tandem with the yellow fluorescent protein (YFP) was expressed in GABAergic neurons under the control of glutamic acid decarboxylase 2 (GAD2) promoter. Immediately dorsomedial to the LC nucleus, a group of GABAergic neurons was observed. They had small soma and were densely packed in a small area, which we named the dorsomedial LC or dmLC nucleus. These GABAergic neurons showed fast firing activity, strong inward rectification and spike frequency adaptation. Lateral inhibition among these GABAergic neurons was observed. Optostimulation of the dmLC area drastically inhibited LC neuronal firing frequency, expanded the spike intervals, and reset their pacemaking activity. Analysis of the light evoked inhibitory postsynaptic currents (IPSCs) indicated that they were monosynaptic. Such light evoked IPSCs were not seen in slices where this group of GABAergic neurons was absent. Thus, an isolated group of GABAergic neurons is demonstrated in the LC area, whose location, somatic morphology and intrinsic membrane properties are clearly distinguishable from adjacent LC neurons. They interact with each and may inhibit LC neurons as well as a part of local neuronal circuitry in the LC.
doi:10.1371/journal.pone.0146470
PMCID: PMC4718449  PMID: 26785258
11.  Prognostic value of protein inhibitor of activated STAT3 in breast cancer patients receiving hormone therapy 
BMC Cancer  2016;16:20.
Background
Deregulated signal transducer and activator of transcription 3 (STAT3) signaling has been well documented in certain cancers. Alterations in specific negative regulators, such as protein inhibitor of activated STAT3 (PIAS3), may contribute to cancer development.
Methods
The expression of total PIAS3 was determined in 100 paired cancerous and non-cancerous breast tissues by immunoblotting and was statistically analyzed along with the clinicopathological characteristics and overall survival of the patients. XTT, immunoblotting, and chromatin immunoprecipitation (Chip) were used to examine the biological effect of PIAS3 in breast cancer cells.
Results
Hormone therapy failed to improve the overall survival in patients presenting with increased PIAS3 expression. Ectopic PIAS3 overexpression increased the proliferation and expression of cyclin D1 in estrogen receptor (ER)-positive MCF-7 and T47D cells, but decreased those in ER-negative MDA-MB-231 and SKBR3 cells. Furthermore, PIAS3 overexpression attenuated cytotoxicity of tamoxifen and increased proliferation and cyclin D1 expression in MCF-7 cells. PIAS3 also decreased the binding of itself on the cyclin D1 promoter and this decreased binding was not affected by tamoxifen.
Conclusion
PIAS3 may serve as a biomarker for predicting hormone therapy stratification, although it is limited to those breast cancer patients receiving hormone therapy
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-016-2063-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-016-2063-1
PMCID: PMC4714466  PMID: 26768588
Breast cancer; Protein inhibitor of activated STAT3; Estrogen receptor; Cyclin D1; Tamoxifen
12.  ATR-Chk1 signaling inhibition as a therapeutic strategy to enhance cisplatin chemosensitivity in urothelial bladder cancer 
Oncotarget  2015;7(2):1947-1959.
DNA damage responses contribute to cisplatin resistance; however, therapeutic strategies to overcome cisplatin resistance have not yet been established. Here, we demonstrate that inhibition of ATR-Chk1 pathway with the potent inhibitor WYC0209 sensitizes bladder cancer cells to cisplatin. In the clinical microarray profile, high ATR expression is associated with poor prognosis in bladder cancer patients who receive chemotherapy. We show that pharmacological and genetic suppressing of ATR sensitized cells to cisplatin. Treatment with WYC0209 or siATR increased levels of cisplatin-DNA adducts, concomitant with decreased levels of p-glycoprotein expression. Additionally, Combinations of cisplatin and WYC0209 show synergistic activity against bladder cancer. Ultimately, WYC0209 enhanced the anti-tumor effects of cisplatin and suppressed p-glycoprotein expression in bladder cancer xenografts. These results indicate that inhibiting ATR-Chk1 activation with WYC0209 suppresses p-glycoprotein expression and increases cisplatin activity in bladder cancer. Our findings collectively suggest that ATR-Chk1 is a target for improving the efficacy of cisplatin in bladder cancer.
PMCID: PMC4811508  PMID: 26657501
bladder cancer; ATR-Chk1; natural products
13.  Effects of decompressive cervical surgery on blood pressure in cervical spondylosis patients with hypertension: a time series cohort study 
BMC Surgery  2016;16:2.
Background
Patients with cervical spondylosis myelopathy (CSM) and complicated with hypertension are often experiencing a blood pressure decrease after taking cervical decompressive surgery in clinical observations, but how this blood pressure reduction is associated with the surgery, which cut cervical sympathetic nervous, has never been rigorously assessed. Thus, the purpose of this study is to investigate the effect of cervical decompressive surgery on blood pressure among CSM patients with hypertension.
Methods/Design
The study will be a time series cohort study. Fifty eligible patients will be selected consecutively from the Peking University First Hospital. Two 24-h ambulatory blood pressure measurement (ABPM) will be taken before the surgery, apart by at least 3 days. The patients will be followed up for another two ABPMs at 1 and 3 months after the surgery.
We will recruit subjects with cervical spondylosis myelopathy meeting operation indications and scheduled for receiving cervical decompressive surgery, aged 18–84 years, have a history of hypertension or office systolic blood pressure ≥140 mmHg on initial screening, and willing to participate in the study and provide informed consent. Exclusion criteria includes a history of known secondary hypertension, visual analogue scale (VAS) score ≥4, and unable to comply with study due to severe psychosis.
The change in systolic ABPs over the four times will be analyzed to observe the overall pattern of the blood pressure change in relation to the surgery, but the primary analysis will be the comparison of systolic ABP between the 2nd and 3rd , 4th measurements (before and after the surgery). We will also calculate the regression-to-the-mean adjusted changes in systolic ABP as sensitivity analysis. Secondary endpoints are the changes in 24 h ABPM diastolic blood pressure, blood pressure control status, the use and dose adjustment of antihypertensive medication, and the incidence of operative complications. Primary outcome analyses will be carried out using analysis of covariance, as well as the first secondary endpoint.
Discussion
This study will inform us the important knowledge about cervical sympathetic nervous system (SNS) and blood pressure. Once confirmed, it may help to produce new method for control of hypertension, which is the leading cause of death in the world.
Trial registration
The study is registered to Clinical Trials.gov (NCT02016768).
doi:10.1186/s12893-015-0117-y
PMCID: PMC4704254  PMID: 26738624
Cervical spondylosis myelopathy; Cervical decompressive surgery; Hypertension; 24 h ambulatory blood pressure measurement
14.  Pinnisterols A–C, New 9,11-Secosterols from a Gorgonian Pinnigorgia sp. 
Marine Drugs  2016;14(1):12.
Three new 9,11-secosterols, pinnisterols A–C (1–3), were isolated from a gorgonian coral Pinnigorgia sp., collected off the waters of Taiwan. The structures of these compounds were elucidated on the basis of spectroscopic methods. The new sterols 1 and 3 displayed significant inhibitory effects on the generation of superoxide anions and the release of elastase by human neutrophils, and sterol 1 was found to show moderate cytotoxicity in hepatic stellate cells (HSCs).
doi:10.3390/md14010012
PMCID: PMC4728509  PMID: 26751457
secosterol; gorgonian; Pinnigorgia; anti-inflammatory; superoxide anion; elastase; cytotoxicity; HSCs
15.  New 9-Hydroxybriarane Diterpenoids from a Gorgonian Coral Briareum sp. (Briareidae) 
Six new 9-hydroxybriarane diterpenoids, briarenolides ZI–ZVI (1–6), were isolated from a gorgonian coral Briareum sp. The structures of briaranes 1–6 were elucidated by spectroscopic methods and by comparison of their spectroscopic data with those of related analogues. Briarenolides ZII (2) and ZVI (6) were found to significantly inhibit the expression of the pro-inflammatory inducible nitric oxide synthase (iNOS) protein of lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells.
doi:10.3390/ijms17010079
PMCID: PMC4730323  PMID: 26761004
Briareum; briarenolide; briarane; gorgonian; anti-inflammatory; iNOS
16.  Raf/ERK/Nrf2 signaling pathway and MMP-7 expression involvement in the trigonelline-mediated inhibition of hepatocarcinoma cell migration 
Food & Nutrition Research  2015;59:10.3402/fnr.v59.29884.
Background
Trigonelline occurs in many dietary food plants and has been found to have anti-carcinogenic activity. Trigonelline is also found in coffee which is one of the most widely consumed beverages. Many epidemiological studies have reported that coffee consumption has an inverse relationship with the risk of cirrhosis or hepatocellular carcinoma. It would be interesting to investigate whether trigonelline is an ideal chemoprevent agent to prevent cancer progression.
Methods
The protein expression was performed by western blotting. The trigonelline content in snow pea (Pisum sativum) was analyzed by high-performance liquid chromatography (HPLC). The migratory activity of human hepatocarcinoma cells (Hep3B) was assessed by using a wound migration assay. The percentage of each phase in the cell cycle was analyzed on a FACScan flow cytometer. Gene expression was detected by real-time reverse transcriptase-polymerase chain reaction techniques. Native gel analysis was performed to analyze the activity of superoxide dismutase (SOD), catalase and glutathione peroxidase.
Results
According to the data of HPLC analysis, P. sativum, which is a popular vegetable, has relatively high content of trigonelline. Our findings suggest that trigonelline is an efficient compound for inhibiting Hep3B cell migration. Trigonelline inhibited the migration of hepatoma cells at concentrations of 75–100 µM without affecting proliferation. Raf/ERK/Nrf2 protein levels and further downstream antioxidative enzymes activity, such as SOD, catalase, and glutathione peroxidase, significantly decreased after treatment with 100 µM of trigonelline for 24 h. The migration inhibition of trigonelline is also related to its ability to regulate the matrix metalloproteinases 7 (MMP-7) gene expression.
Conclusions
In this study, protein kinase Cα (PKCα) and Raf/ERK/Nrf2 signaling pathway and MMP-7 gene expression were involved in the trigonelline-mediated migration inhibition of Hep3B cells. We also demonstrated that trigonelline inhibits Hep3B cell migration through downregulation of nuclear factor E2-related factor 2–dependent antioxidant enzymes activity. This study analyzed the trigonelline content in a popular vegetable, snow pea, as a representative proof to prove that trigonelline is often found in the daily intake of food. Our finding suggested that trigonelline should be a useful chemopreventive agent derived from the daily intake of food to prevent cancer progression.
doi:10.3402/fnr.v59.29884
PMCID: PMC4689951  PMID: 26699938
trigonelline; hepatocarcinoma Hep3B cells; migration; Pisum sativum; chemotherapeutic agent; Raf/ERK/Nrf2 signaling pathway; MMP-7
17.  Pathway-Based Genome-Wide Association Studies for Two Meat Production Traits in Simmental Cattle 
Scientific Reports  2015;5:18389.
Most single nucleotide polymorphisms (SNPs) detected by genome-wide association studies (GWAS), explain only a small fraction of phenotypic variation. Pathway-based GWAS were proposed to improve the proportion of genes for some human complex traits that could be explained by enriching a mass of SNPs within genetic groups. However, few attempts have been made to describe the quantitative traits in domestic animals. In this study, we used a dataset with approximately 7,700,000 SNPs from 807 Simmental cattle and analyzed live weight and longissimus muscle area using a modified pathway-based GWAS method to orthogonalise the highly linked SNPs within each gene using principal component analysis (PCA). As a result, of the 262 biological pathways of cattle collected from the KEGG database, the gamma aminobutyric acid (GABA)ergic synapse pathway and the non-alcoholic fatty liver disease (NAFLD) pathway were significantly associated with the two traits analyzed. The GABAergic synapse pathway was biologically applicable to the traits analyzed because of its roles in feed intake and weight gain. The proposed method had high statistical power and a low false discovery rate, compared to those of the smallest P-value and SNP set enrichment analysis methods.
doi:10.1038/srep18389
PMCID: PMC4682090  PMID: 26672757
18.  Experimental fault-tolerant universal quantum gates with solid-state spins under ambient conditions 
Nature Communications  2015;6:8748.
Quantum computation provides great speedup over its classical counterpart for certain problems. One of the key challenges for quantum computation is to realize precise control of the quantum system in the presence of noise. Control of the spin-qubits in solids with the accuracy required by fault-tolerant quantum computation under ambient conditions remains elusive. Here, we quantitatively characterize the source of noise during quantum gate operation and demonstrate strategies to suppress the effect of these. A universal set of logic gates in a nitrogen-vacancy centre in diamond are reported with an average single-qubit gate fidelity of 0.999952 and two-qubit gate fidelity of 0.992. These high control fidelities have been achieved at room temperature in naturally abundant 13C diamond via composite pulses and an optimized control method.
High fidelity manipulation of diamond-based spin qubits is difficult at room temperature because of decoherence. Here, the authors show a universal set of logic gates in nitrogen-vacancy centres with average single-qubit and two-qubit gate fidelities of 0.999952 and 0.992, respectively.
doi:10.1038/ncomms9748
PMCID: PMC4674779  PMID: 26602456
19.  Fusarochromanone-induced reactive oxygen species results in activation of JNK cascade and cell death by inhibiting protein phosphatases 2A and 5 
Oncotarget  2015;6(39):42322-42333.
Recent studies have shown that fusarochromanone (FC101), a mycotoxin, is cytotoxic in a variety of cell lines. However, the molecular mechanism underlying its cytotoxicity remains elusive. Here we found that FC101 induced cell death in COS7 and HEK293 cells in part by activating JNK pathway. This is evidenced by the findings that inhibition of JNK with SP600125 or expression of dominant negative c-Jun partially prevented FC101-induced cell death. Furthermore, we observed that FC101-activated JNK pathway was attributed to induction of reactive oxygen species (ROS). Pretreatment with N-acetyl-L-cysteine (NAC), a ROS scavenger and antioxidant, suppressed FC101-induced activation of JNK and cell death. Moreover, we noticed that FC101 inhibited the serine/threonine protein phosphatases 2A (PP2A) and 5 (PP5) in the cells, which was abrogated by NAC. Overexpression of PP2A or PP5 partially prevented FC101-induced activation of JNK and cell death. The results indicate that FC101-induced ROS inhibits PP2A and PP5, leading to activation of JNK pathway and consequently resulting in cell death.
PMCID: PMC4747228  PMID: 26517353
fusarochromanone; cell death; reactive oxygen species; JNK; protein phosphatase 2A
20.  The Effect of Childhood Obesity Prevention Programs on Blood Lipids: A Systematic Review and Meta-analysis 
Summary
Aim
We aimed to assess the effects of childhood obesity prevention programs on blood lipids in high-income countries.
Methods
We searched MEDLINE®, Embase, PsychInfo, CINAHL®, clinicaltrials.gov, and the Cochrane Library up to April 22, 2013 for relevant randomized controlled trials, quasi-experimental studies, and natural experiments published in English. Studies were included if they implemented diet and/or physical activity intervention(s) with ≥ one year follow up (or ≥ six months for school-based intervention studies) in 2 to 18 years old, and were excluded if they targeted only overweight/obese children, or those with a pre-existing medical condition.
Results
Seventeen studies were finally included. For total cholesterol, the pooled intervention effect was −0.97 mg/dL (95% CI: −3.26, 1.32; P=0.408); for low density lipoprotein-cholesterol (LDL-C), −6.06 mg/dL (95% CI: −11.09, −1.02; P=0.018); for high density lipoprotein-cholesterol (HDL-C), 1.87 mg/dL (95% CI: 0.39, 3.34; P=0.013); and for triglycerides, −1.95 mg/dL (95% CI: −4.94, 1.04; P=0.202). Most interventions (70%) showed similar significant or no effects on adiposity- and lipids outcomes: 15% interventions improved both adiposity- and lipids outcomes; 55% had no significant effects on either.
Conclusions
Childhood obesity prevention programs had a significant desirable effect on LDL-C and HDL-C. Two-thirds of interventions showed similar significant or no effects in adiposity- and lipids outcomes. Assessing lipids outcomes provide additional useful information on obesity prevention program benefits.
doi:10.1111/obr.12227
PMCID: PMC4341953  PMID: 25263653
child; obesity; prevention; lipids; intervention
21.  Briarenolides U–Y, New Anti-Inflammatory Briarane Diterpenoids from an Octocoral Briareum sp. (Briareidae) 
Marine Drugs  2015;13(12):7138-7149.
Five new 13,14-epoxybriarane diterpenoids, briarenolides U–Y (1–5), were isolated from the octocoral Briareum sp. The structures of briaranes 1–5 were elucidated by spectroscopic methods. Briarenolides U–Y (1–5) were found to significantly inhibit the expression of the pro-inflammatory inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein of the lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells.
doi:10.3390/md13127060
PMCID: PMC4699233  PMID: 26633428
Briareum; briarane; octocoral; anti-inflammatory; iNOS; COX-2
22.  Increased matrix metalloproteinase-2 expression and reduced tissue factor pathway inhibitor-2 expression correlate with angiogenesis and early postoperative recurrence of pancreatic carcinoma 
Matrix metalloproteinase (MMP)-2 and tissue factor pathway inhibitor (TFPI)-2 are known to influence tumor angiogenesis and progression. This work aimed to describe the levels of MMP-2 and TFPI-2 expression associated with tumor angiogenesis and early postoperative recurrence in patients with pancreatic carcinoma. Expression of MMP-2 and TFPI-2 in carcinoma tissues and paracarcinomatous tissues was assayed by immunostaining. Expression of vascular endothelial growth factor (VEGF) and CD34 in tumor tissues was also assayed by immunostaining. The correlations of MMP-2 and TFPI-2 with VEGF, microvessel density (MVD), and early postoperative recurrence were analyzed. The results showed that MMP-2 expression was significantly increased (P < 0.05) and TFPI-2 expression was significantly decreased (P < 0.001) in carcinoma tissues compared with paracarcinomatous tissues. MMP-2 expression was positively correlated with VEGF (r = 0.594, P < 0.001) and MVD (r = 0.432, P < 0.001) in carcinoma tissues. TFPI-2 expression was negatively correlated with VEGF (r = -0.654, P < 0.001) and MVD (r = -0.360, P < 0.001) in carcinoma tissues. Multivariate logistic regression analysis showed that up-regulated MMP-2 and down-regulated TFPI-2 were independent predictors of early postoperative recurrence of pancreatic carcinoma. Receiver operating characteristic curve analysis showed that the combination of MMP-2 and TFPI-2 was a reliable predictive model of early recurrence. We conclude that increased MMP-2 expression and reduced TFPI-2 expression are closely linked to angiogenesis and early postoperative recurrence of pancreatic carcinoma. Immunohistochemical assay of MMP-2 and TFPI-2 may be useful for predicting early relapse of pancreatic carcinoma after surgery.
PMCID: PMC4697719  PMID: 26807187
MMP-2; TFPI-2; angiogenesis; recurrence; pancreatic carcinoma
23.  Structure-Activity Relationship of Synthetic 2-Phenylnaphthalenes with Hydroxyl Groups that Inhibit Proliferation and Induce Apoptosis of MCF-7 Cancer Cells 
PLoS ONE  2015;10(10):e0141184.
In this study, six 2-phenylnaphthalenes with hydroxyl groups were synthesized in high yields by the demethylation of the corresponding methoxy-2-phenylnaphthalenes, and one 2-phenylnaphthalene with an amino group was obtained by hydrogenation. All of the 2-phenylnaphthalene derivatives were evaluated for cytotoxicity, and the structure-activity relationship (SAR) against human breast cancer (MCF-7) cells was also determined. The SAR results revealed that cytotoxicity was markedly promoted by the hydroxyl group at the C-7 position of the naphthalene ring. The introduction of hydroxyl groups at the C-6 position of the naphthalene ring and the C-4' position of the phenyl ring fairly enhanced cytotoxicity, but the introduction of a hydroxyl group at the C-3' position of the phenyl ring slightly decreased cytotoxicity. Overall, 6,7-dihydroxy-2-(4'-hydroxyphenyl)naphthalene (PNAP-6h) exhibited the best cytotoxicity, with an IC50 value of 4.8 μM against the MCF-7 cell line, and showed low toxicity toward normal human mammary epithelial cells (MCF-10A). PNAP-6h led to cell arrest at the S phase, most likely due to increasing levels of p21 and p27 and decreasing levels of cyclin D1, CDK4, cyclin E, and CDK2. In addition, PNAP-6h decreased CDK1 and cyclin B1 expression, most likely leading to G2/M arrest, and induced morphological changes, such as nuclear shrinkage, nuclear fragmentation, and nuclear hypercondensation, as observed by Hoechst 33342 staining. PNAP-6h induced apoptosis, most likely by the promotion of Fas expression, increased PARP activity, caspase-7, caspase-8, and caspase-9 expression, the Bax/Bcl-2 ratio, and the phosphorylation of p38, and decreased the phosphorylation of ERK. This study provides the first demonstration of the cytotoxicity of PNAPs against MCF-7 cells and elucidates the mechanism underlying PNAP-induced cytotoxicity.
doi:10.1371/journal.pone.0141184
PMCID: PMC4619615  PMID: 26492346
24.  Rabies Cases in the West of China Have Two Distinct Origins 
PLoS Neglected Tropical Diseases  2015;9(10):e0004140.
In China, rabies remains an ongoing threat to public health. Although control efforts have been effective in reducing the number of annual cases, the virus continues to spread into new areas. Tibet, Qinghai, Gansu and Ningxia in western China have, until recently, reported only a handful of events. However, since 2011, there have been increasing numbers of cases recorded in these areas. In this study, we report the collection and analysis of samples collected from these regions. We find that cases originate from two different sources. Strains collected from Gansu and Ningxia are closely related to the primary lineage associated with the current epizootic, whereas those from Tibet and Qinghai are related to the Arctic-like-2 lineage that is most commonly associated with wildlife cases in China. Thus, it appears that while the epizootic is beginning to encroach into Gansu and Ningxia, Tibet and Qinghai a significant number of rabies cases originate from wildlife.
Author Summary
Overall, the number of annual cases of human rabies reported in China has been decreasing since 2007. However, some Western provinces, where few human cases have been reported in recent years, are beginning to see increasing incidence of rabies. Specifically, Ningxia, Qinghai and Gansu began to report human cases respectively from 2011, 2012 and 2013, while Tibet had its first laboratory confirmed dog rabies case in 2012. Consequently, as part of the national rabies surveillance program, we collected specimens from biting dogs or human saliva from suspected rabies cases in these areas, and after sequencing positive samples, performed a phylogenetic analysis based on the nucleoprotein gene complete sequences. Our results indicate that while Ningxia and Gansu rabies strains are very close to the lineage associated with most cases in mainland China, Tibet and Qinghai strains belong to the global Arctic-like-2 clade, which is typically associated with wild life in China and neighboring countries. Thus, it appears that, rabies reemergence in the west of China has two distinct origins, and Tibet and Qinghai rabies cases were isolated events rather than an indication of the ongoing epizootic in China.
doi:10.1371/journal.pntd.0004140
PMCID: PMC4618851  PMID: 26484668
25.  Design of Highly Photofunctional Porous Polymer Films with Controlled Thickness and Prominent Microporosity 
Porous organic polymers allow the integration of various π-units into robust porous π-networks, but they are usually synthesized as unprocessable solids with poor light-emitting performance as a result of aggregation-related excitation dissipation. Herein, we report a general strategy for the synthesis of highly emissive photofunctional porous polymer films on the basis of a complementary scheme for the structural design of aggregation-induced-emissive π-systems. We developed a high-throughput and facile method for the direct synthesis of large-area porous thin films at the liquid–electrode interface. The approach enables the preparation of microporous films within only a few seconds or minutes and allows precise control over their thickness with sub-nanometer precision. By virtue of rapid photoinduced electron transfer, the thin films can detect explosives with enhanced sensitivity to low parts-per-million levels in a selective manner.
doi:10.1002/anie.201504786
PMCID: PMC4600238  PMID: 26234636
aggregation-induced emission; luminescence; porous polymers; sensors; thin films

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