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1.  Screening for Voltage-Gated Sodium Channel Interacting Peptides 
Scientific Reports  2014;4:4569.
The voltage-gated sodium channel (VGSC) interacting peptide is of special interest for both basic research and pharmaceutical purposes. In this study, we established a yeast-two-hybrid based strategy to detect the interaction(s) between neurotoxic peptide and the extracellular region of VGSC. Using a previously reported neurotoxin JZTX-III as a model molecule, we demonstrated that the interactions between JZTX-III and the extracellular regions of its target hNav1.5 are detectable and the detected interactions are directly related to its activity. We further applied this strategy to the screening of VGSC interacting peptides. Using the extracellular region of hNav1.5 as the bait, we identified a novel sodium channel inhibitor SSCM-1 from a random peptide library. This peptide selectively inhibits hNav1.5 currents in the whole-cell patch clamp assays. This strategy might be used for the large scale screening for target-specific interacting peptides of VGSCs or other ion channels.
PMCID: PMC3972499
2.  The spatiospectral characterization of brain networks: fusing concurrent EEG spectra and fMRI maps 
NeuroImage  2012;69:101-111.
Different imaging modalities capture different aspects of brain activity. Functional Magnetic Resonance Imaging (fMRI) reveals intrinsic networks whose BOLD signals have periods from 100s (0.01 Hz) to about 10s (0.1 Hz). Electroencephalographic (EEG) recordings, in contrast, commonly reflect cortical electrical fluctuations with periods up to 20 ms (50 Hz) or above. We examined the correspondence between intrinsic fMRI and EEG network activity at rest in order to characterize brain networks both spatially (with fMRI) and spectrally (with EEG). Brain networks were separately identified within the concurrently recorded fMRI and EEG at the aggregate group level with group independent component analysis and the association between spatial fMRI and frequency by spatial EEG sources was examined by deconvolving their component time courses. The two modalities are considered linked if the estimated impulse response function (IRF) is significantly non-zero at biologically plausible delays. We found that negative associations were primarily present within two of five alpha components, which highlights the importance of considering multiple alpha sources in EEG-fMRI. Positive associations were primarily present within the lower (e.g. delta and theta) and higher (e.g. upper beta and lower gamma) spectral regions, sometimes within the same fMRI components. Collectively, the results demonstrate a promising approach to characterize brain networks spatially and spectrally, and reveal that positive and negative associations appear within partially distinct regions of the EEG spectrum.
PMCID: PMC3568990  PMID: 23266744
EEG-fMRI; ICA; intrinsic connectivity networks; deconvolution
3.  Identification and Characterization of a Suite of Tumor Targeting Peptides for Non-Small Cell Lung Cancer 
Scientific Reports  2014;4:4480.
Tumor targeting ligands are emerging components in cancer therapies. Widespread use of targeted therapies and molecular imaging is dependent on increasing the number of high affinity, tumor-specific ligands. Towards this goal, we biopanned three phage-displayed peptide libraries on a series of well-defined human non-small cell lung cancer (NSCLC) cell lines, isolating 11 novel peptides. The peptides show distinct binding profiles across 40 NSCLC cell lines and do not bind normal bronchial epithelial cell lines. Binding of specific peptides correlates with onco-genotypes and activation of particular pathways, such as EGFR signaling, suggesting the peptides may serve as surrogate markers. Multimerization of the peptides results in cell binding affinities between 0.0071–40 nM. The peptides home to tumors in vivo and bind to patient tumor samples. This is the first comprehensive biopanning for isolation of high affinity peptidic ligands for a single cancer type and expands the diversity of NSCLC targeting ligands.
PMCID: PMC3967199  PMID: 24670678
4.  Involvement of Oxidative Stress and Inflammation in Liver Injury Caused by Perfluorooctanoic Acid Exposure in Mice 
BioMed Research International  2014;2014:409837.
Perfluorooctanoic acid (PFOA) is widely present in the environment and has been reported to induce hepatic toxicity in animals and humans. In this study, mice were orally administered different concentrations of PFOA (2.5, 5, or 10 mg/kg/day). Histological examination showed that the exposure to PFOA for 14 consecutive days led to serious hepatocellular injury and obvious inflammatory cell infiltration. In addition, malondialdehyde formation and hydrogen peroxide generation, indicators of oxidative stress, were significantly induced by PFOA treatment in the liver of mice. Furthermore, hepatic levels of interleukin-6, cyclooxygenase-2, and C-reactive protein, markers of inflammatory response, were markedly increased by exposure to PFOA in mice. These results demonstrated that PFOA-induced hepatic toxicity may be involved in oxidative stress and inflammatory response in mice.
PMCID: PMC3958804  PMID: 24724082
5.  Thoracotomy in refractory gestational trophoblastic neoplasia with lung metastasis after normalization of serum beta human chorionic gonadotropin (β-hCG) with salvage chemotherapy 
OncoTargets and therapy  2014;7:171-176.
To assess the need for pulmonary surgery in the treatment of refractory gestational trophoblastic neoplasia with lung metastasis after normalization of serum beta human chorionic gonadotropin (β-hCG) level with salvage chemotherapy.
Materials and methods
A review of medical records of patients with refractory gestational trophoblastic neoplasia who underwent pulmonary surgery and received combined chemotherapy between January 1995 and December 2008 at the Peking Union Medical College Hospital was retrospectively performed. The positive pathologic findings in surgical specimens were defined as trophoblastic cells documented in the specimen. Pathologic findings were reported.
There were 21 patients with preoperative normal β-hCG. Of 21 patients, six (28.6%) had positive pathologic findings. The positive pathologic findings remained at 27.3% in 11 patients who had received no less than two cycles of consolidation chemotherapy before pulmonary surgery. Univariate analysis found that no variables in patient characteristics were associated with pathologic findings. At the median follow-up of 78 months (9–186 months), 85.7% (18 of 21) patients were alive, and no statistical difference was observed in the disease-free survival between the patients with positive and negative pathologic findings. The 5-year overall survival was 72.2%.
Pulmonary surgery is valuable in the treatment of refractory patients with lung metastasis after normalization of serum β-hCG level following salvage chemotherapy, irrespective of viable trophoblasts in surgical specimens. Further study will be necessary to clarify the importance of this observation.
PMCID: PMC3913543  PMID: 24511240
gestational trophoblastic neoplasia; refractory; pulmonary surgery
6.  Integrated Positioning for Coal Mining Machinery in Enclosed Underground Mine Based on SINS/WSN 
The Scientific World Journal  2014;2014:460415.
To realize dynamic positioning of the shearer, a new method based on SINS/WSN is studied in this paper. Firstly, the shearer movement model is built and running regularity of the shearer in coal mining face has been mastered. Secondly, as external calibration of SINS using GPS is infeasible in enclosed underground mine, WSN positioning strategy is proposed to eliminate accumulative error produced by SINS; then the corresponding coupling model is established. Finally, positioning performance is analyzed by simulation and experiment. Results show that attitude angle and position of the shearer can be real-timely tracked by integrated positioning strategy based on SINS/WSN, and positioning precision meet the demand of actual working condition.
PMCID: PMC3918390  PMID: 24574891
7.  Effects of the antihypertensive drug benidipine on osteoblast function in vitro 
The dihydropyridine-type calcium channel blocker, benidipine (BD) has been widely used in hypertension therapy. Previous studies have demonstrated that BD has a positive effect on bone metabolism. Inspired by this promoting phenomenon, the present study investigated the effects of BD on osteoblasts in vitro. Experiments were designed and performed, including an MTT assay, reverse transcription-polymerase chain reaction, western blot analysis, alkaline phosphatase activity measurements and alizarin red S staining. The results demonstrated that BD promoted osteoblast proliferation and osteogenic differentiation at concentrations from 1×10−6 to 1×10−9 M by upregulating Runx2, BMP2 and OCN gene expression levels. Overall, BD at appropriate concentrations has been demonstrated to have positive effects on osteoblast function in addition to its conventional clinical usage.
PMCID: PMC3919856  PMID: 24520261
benidipine; calcium channel blockers; osteoporosis; hypertension
8.  A New Strategy for Enhancing the Oral Bioavailability of Drugs with Poor Water-Solubility and Low Liposolubility Based on Phospholipid Complex and Supersaturated SEDDS 
PLoS ONE  2013;8(12):e84530.
A novel supersaturated self-emulsifying drug delivery system (Super-SEDDS) loaded with scutellarin-phospholipid complex (SPC) was developed. The system aimed to address the limitations presented by conventional SEDDS as delivery carriers for drugs with poor water-solubility, low liposolubility and high dose. As an intermediate, SPC was first prepared based on the response surface design. The presence of amorphous scutellarin was demonstrated through differential scanning calorimetry (DSC) and X-ray diffraction (XRD), while enhanced liposolubility was confirmed through comparison with scutellarin powder via an octanol/water distribution test. On the basis of the solubility study and ternary phase diagram, Super-SEDDS containing SPC of up to 200% equilibrium solubility (Seq) was designed, which composed of ethyl oleate, Cremophor RH40 and Transcutol HP with a ratio of 60∶25∶15 (w/w%). The subsequent in vitro lipolysis study and ex vivo intestinal absorption test indicated that Super-SEDDS enhanced the cumulative dissolution from 70% to 100% and improved the intestinal absorption from 0.04 to 0.12 µg/cm2 compared with scutellarin powder. Furthermore, an in vivo study demonstrated that Super-SEDDS achieved the AUC0-t of scutellarin up to approximate 1.7-fold as scutellarin powder. It was also proved superior to SPC and the conventional SEDDS. Super-SEDDS showed great potential for expanding the usage of SEDDS and could act as an alternative to conventional SEDDS.
PMCID: PMC3877285  PMID: 24391965
9.  Serum peptidome patterns of hepatocellular carcinoma based on magnetic bead separation and mass spectrometry analysis 
Diagnostic Pathology  2013;8:130.
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world,and the identification of biomarkers for the early detection is a relevant target. The purpose of the study is to discover specific low molecular weight (LMW) serum peptidome biomarkers and establish a diagnostic pattern for HCC.
We undertook this pilot study using a combined application of magnetic beads with Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) technique and ClinPro Tools v2.2 to detect 32 patients with HCC, 16 patients with chronic hepatitis (CH), 16 patients with liver cirrhosis (LC) and 16 healthy volunteers.
The results showed 49, 33 and 37 differential peptide peaks respectively appeared in HCC, LC and CH groups. A Supervised Neural Network (SNN) algorithm was used to set up the classification model. Eleven of the identified peaks at m/z 5247.62, 7637.05, 1450.87, 4054.21, 1073.37, 3883.64, 5064.37, 4644.96, 5805.51, 1866.47 and 6579.6 were used to construct the peptides patterns. According to the model, we could clearly distinguish between HCC patients and healthy controls as well as between LC or CH patients and healthy controls.
The study demonstrated that a combined application of magnetic beads with MALDI-TOF MB technique was suitable for identification of potential serum biomarkers for HCC and it is a promising way to establish a diagnostic pattern.
Virtual slides
The virtual slide(s) for this article can be found here:
PMCID: PMC3751178  PMID: 23915185
Hepatocellular carcinoma; Chronic hepatitis; Liver cirrhosis; Magnetic beads; Matri-assisted laser desorption/ionization time-of-flight mass spectrometry; Serum biomarkers
10.  Increasing Prevalence of Metabolic Syndrome in a Chinese Elderly Population: 2001–2010 
PLoS ONE  2013;8(6):e66233.
The information on the changes of prevalence of MetS in China is limited. Our objective was to assess a 10-year’s change of the prevalence of MetS in a Chinese elderly population between 2001 and 2010.
We conducted two cross-sectional surveys in a representative sample of elderly population aged 60 to 95 years in Beijing in 2001 and 2010 respectively. MetS was defined according to the 2009 harmonizing definition.
A total of 2,334 participants (943 male, 1,391 female) in 2001 and 2,102 participants (848 male, 1,254 female) in 2010 completed the survey. The prevalence of MetS was 50.4% (95%CI: 48.4%–52.4%) in 2001 and 58.1% (95%CI: 56.0%–60.2%) in 2010. The absolute change of prevalence of MetS was 7.7% over the 10-year’s period (p<0.001). The syndrome was more common in female than male in both survey years. Among the five components, hypertriglyceridemia and low HDL-C had increased most, with an increase of 14.8% (from 29.4% to 44.2%) and 9.9% (from 28.3% to 38.2%) respectively. The adjusted ORs of MetS for CHD, stroke and CVD were 1.67(95%CI: 1.39–1.99), 1.50(95%CI: 1.19–1.88) and 1.70(95%CI: 1.43–2.01) respectively in 2001, and were 1.74(95%CI: 1.40–2.17), 1.25(95%CI: 0.95–1.63) and 1.52(95%CI: 1.25–1.86) respectively in 2010.
The prevalence of MetS is high and increasing rapidly in this Chinese elderly population. Participants with Mets and its individual components are at significantly elevated ORs for CVD. Urgent public health actions are needed to control MetS and its components, especially for dislipidemia.
PMCID: PMC3688874  PMID: 23824753
11.  RNA interference mediated pten knock-down inhibit the formation of polycystic ovary 
Molecular and Cellular Biochemistry  2013;380(1-2):195-202.
Pten (phosphatase and tensin homolog deleted on chromosome 10), a kind of tumor suppressor gene, plays important roles in female reproductive system. But its expression and roles in the formation of polycystic ovaries are yet to be known. In this study, we constructed a rat model of PCOS using norethindrone and HCG injections and found the expressions of pten mRNA and PTEN protein increased significantly in the polycystic ovary tissue by immunohistochemistry, RT-PCR, and western blot. Furthermore, the results showed that in vivo ovaries could be effectively transfected by lentiviral vectors through the ovarian microinjection method and indicated that pten shRNA may inhibit the formation of polycystic ovaries by pten down-regulation. Our study provides new information regarding the role of PTEN in female reproductive disorders, such as polycystic ovary syndrome.
PMCID: PMC3695674  PMID: 23686705
Polycystic ovary; pten; RNA interference; Follicular development
12.  Correlation between serum high-mobility group box-1 levels and high-sensitivity C-reactive protein and troponin I in patients with coronary artery disease 
The aim of this study was to evaluate the correlation between levels of serum high-mobility group box-1 (HMGB1) and high-sensitivity C-reactive protein (hs-CRP) and cardiac troponin I in patients with coronary artery disease. The levels of serum HMGB1, hs-CRP and cardiac troponin I were measured in 98 patients with coronary artery disease and in 30 healthy subjects. The correlation between serum HMGB1 levels and hs-CRP and cardiac troponin I levels was analyzed. Serum HMGB1 levels in patients with coronary artery disease were higher compared with those in healthy volunteers (63.5±15.29 vs. 21.98±4.33 μg/l; P<0.01). Serum HMGB1 levels in patients with acute myocardial infarction were higher compared with those in patients with unstable and stable angina pectoris (77.53±6.86 vs. 63.67±8.6 and 44.39±9.01 μg/l, respectively; both P<0.01). The levels of HMGB1 were positively correlated with hs-CRP and cardiac troponin I levels (r=0.657 and 0.554, respectively; both P<0.01) in patients with coronary artery disease. In conclusion, serum HMGB1 levels were elevated in patients with coronary artery disease, particularly in those with acute myocardial infarction. The levels of HMGB1 were correlated with the levels of hs-CRP and cardiac troponin I.
PMCID: PMC3735905  PMID: 23935732
coronary artery disease; high-mobility group box-1; high-sensitivity C-reactive protein; cardiac troponin I
13.  Oral Huangqi Formulae for Stable Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis 
Objective. To evaluate the efficacy and safety of oral Huangqi formulae for the treatment of stable COPD. Methods. The major databases were searched until September 2010 and supplemented with a manual search. Randomized controlled trials (RCTs) of oral Huangqi formulae that reported on lung function, St. George's Respiratory Questionnaire, symptom improvement and/or frequency of exacerbations were extracted by two reviewers. The Cochrane tool was used for the assessment of risk of bias in the included trials. Data were analyzed with RevMan 5.1.2 software. Results. 25 RCTs (1,661 participants) were included. Compared with conventional therapy (CT) alone, oral Huangqi formulae plus CT increased FEV1, and a similar result was found comparing Huangqi formulae with no treatment. Improvements in SGRQ total score, COPD-related symptoms and reduction of frequency of exacerbations were found in patients receiving Huangqi formulae plus CT compared to those receiving CT alone or CT plus placebo. No serious adverse events were reported. However, there were some methodological inadequacies in the included studies. Conclusions. The benefits of Huangqi formulae for stable COPD were promising, but its efficacy and safety have not been established due to methodological weakness and possible bias in the reported results. Further rigorously designed studies are warranted.
PMCID: PMC3623121  PMID: 23606889
14.  Comparing the performance characteristics of CSF-TRUST and CSF-VDRL for syphilis: a cross-sectional study 
BMJ Open  2013;3(2):e002204.
In this study, we aimed to determine the performance characteristics of toluidine red unheated serum test on cerebrospinal fluids (CSF-TRUST) as compared to venereal disease research laboratory test on cerebrospinal fluids (CSF-VDRL) for laboratory the diagnosis of neurosyphilis.
A cross-sectional study.
Sexually transmitted infections (STIs) clinics.
Participants and methods
CSF and serum samples were collected from 824 individual STD clinic patients who have syphilis and are suspected to progress to neurosyphilis within a 9-month period. CSF-VDRL and CSF-TRUST were performed parallelly on the same day when collected. Treponema pallidum particle agglutination (TPPA) tests were also performed on the CSF and the serum samples, and biochemical analysis of the CSF samples was also performed.
The overall agreement between CSF-TRUST and CSF-VDRL was 97.3%. The reactive ratios of the CSF samples were 22.1% by CSF-TRUST and 24.8% by CSF-VDRL, respectively. All CSF-TRUST-reactive cases were reactive in the CSF-VDRL. Twenty-two samples with CSF-TRUST-negative were tested CSF-VDRL-reactive with low titres (1 : 1 to 1 : 4). Over 97% of the double-reactive CSF samples (CSF-VDRL and CSF-TRUST) had an identical titre or a titre within a two-fold difference. The agreement of CSF-TPPA and CSF-VDRL was 71.9%. Similarly, the agreement of CSF-TPPA and CSF-TRUST was 69.2%.
Our results revealed that CSF-TRUST could be used as an option for CSF examination in settings without CSF-VDRL in place.
PMCID: PMC3586078  PMID: 23430600
Syphilis; Laboratory Methods; China
15.  Refractive index measurement of acute rat brain tissue slices using optical coherence tomography 
Optics Express  2012;20(2):1084-1095.
An optical coherence tomography (OCT) system employing a microelectromechanical system (MEMS) mirror was used to measure the refractive index (RI) of anatomically different regions in acute brain tissue slices, in which viability was maintained. RI was measured in white-matter and grey-matter regions, including the cerebral cortex, putamen, hippocampus, thalamus and corpus callosum. The RI in the corpus callosum was found to be ~4% higher than the RIs in other regions. Changes in RI with tissue deformation were also measured in the cerebral cortex and corpus callosum under uniform compression (20-80% strain). For 80% strain, measured RIs increased nonlinearly by up to 70% and 90% in the cerebral cortex and corpus callosum respectively. Knowledge of RI in heterogeneous tissues can be used to correct distorted optical images caused by RI variations between different regions. Also deformation-dependent changes in RI can be applied to OCT elastography or to mechanical tests based on optical imaging such as indentation tests.
PMCID: PMC3501791  PMID: 22274454
(110.4500) Optical coherence tomography; (290.3030) Index measurements; (230.4685) Optical microelectromechanical devices; (170.3880) Medical and biological imaging
16.  Estradiol Synthesis and Release in Cultured Female Rat Bone Marrow Stem Cells 
BioMed Research International  2012;2013:301540.
Bone marrow stem cells (BMSCs) have the capacity to differentiate into mature cell types of multiple tissues. Thus, they represent an alternative source for organ-specific cell replacement therapy in degenerative diseases. In this study, we demonstrated that female rat BMSCs could differentiate into steroidogenic cells with the capacity for de novo synthesis of Estradiol-17β (E2) under high glucose culture conditions with or without retinoic acid (RA). The cultured BMSCs could express the mRNA and protein for P450arom, the enzyme responsible for estrogen biosynthesis. Moreover, radioimmunoassay revealed that BMSCs cultured in the present culture system produced and secreted significant amounts of testosterone, androstenedione, and E2. In addition, RA promoted E2 secretion but did not affect the levels of androgen. These results indicate that BMSCs can synthesize and release E2 and may contribute to autologous transplantation therapy for estrogen deficiency.
PMCID: PMC3591230  PMID: 23484106
17.  The proto-oncogene c-src is involved in primordial follicle activation through the PI3K, PKC and MAPK signaling pathways 
C-src is an evolutionarily conserved proto-oncogene that regulates cell proliferation, differentiation and apoptosis. In our previous studies, we have reported that another proto-oncogene, c-erbB2, plays an important role in primordial follicle activation and development. We also found that c-src was expressed in mammalian ovaries, but its functions in primordial follicle activation remain unclear. The objective of this study is to investigate the role and mechanism of c-src during the growth of primordial follicles.
Ovaries from 2-day-old rats were cultured in vitro for 8 days. Three c-src-targeting and one negative control siRNA were designed and used in the present study. PCR, Western blotting and primordial follicle development were assessed for the silencing efficiency of the lentivirus c-src siRNA and its effect on primordial follicle onset. The expression of c-src mRNA and protein in primordial follicle growth were examined using the PCR method and immunohistochemical staining. Furthermore, the MAPK inhibitor PD98059, the PKC inhibitor Calphostin and the PI3K inhibitor LY294002 were used to explore the possible signaling pathways of c-src in primordial folliculogenesis.
The results showed that Src protein was distributed in the ooplasmic membrane and the granulosa cell membrane in the primordial follicles, and c-src expression level increased with the growth of primordial follicle. The c-src -targeting lentivirus siRNAs had a silencing effect on c-src mRNA and protein expression. Eight days after transfection of rat ovaries with c-src siRNA, the GFP fluorescence in frozen ovarian sections was clearly discernible under a fluorescence microscope, and its relative expression level was 5-fold higher than that in the control group. Furthermore, the c-src-targeting lentivirus siRNAs lowered its relative expression level 1.96 times. We also found that the development of cultured primordial follicles was completely arrested after c-src siRNA knockdown of c-src expression. Furthermore, our studies demonstrated that folliculogenesis onset was inhibited by Calphostin, PD98059 or LY294002 treatment,but none of them down-regulated c-src expression. In contrast, the expression levels of p-PKC, p-ERK1/2 and p-PI3K in the follicles were clearly decreased by c-src siRNA transfection. Correspondingly, both Calphostin and LY294002 treatment resulted in a decrease in the p-PKC level in follicles, but no change was observed in the PD98059 group. Finally, LY294002 treatment decreased the p-PI3K expression level in the follicles, but no changes were observed in the PD98059 and Calphostin groups.
C-src plays an important role in regulating primordial follicle activation and growth via the PI3K-PKC- ERK1/2 pathway.
PMCID: PMC3444437  PMID: 22905678
18.  Metabolic syndrome vs. its components for prediction of cardiovascular mortality: A cohort study in Chinese elderly adults 
The predictive value of the metabolic syndrome (MetS) for mortality from all-cause and cardiovascular disease (CVD) in the Chinese population is unclear. The aim of this present study was to compare MetS with its individual components as predictors of mortality in Chinese elderly adults.
A cohort of 1,535 subjects (994 men and 541 women) aged 50 years or older was selected from employees of a machinery factory in 1994 and followed until 2009. Cox models were used to estimate the hazard ratios (HRs) predicted by MetS according to the harmonized definition and by its individual components.
The baseline prevalence of MetS was 28.0% in men and 48.4% in women. During a median follow-up of 15 years, 414 deaths occurred, of these, 153 participants died from CVD. Adjusted for age and gender, the HRs of mortality from all-cause and CVD in participants with MetS were 1.47 (95% confidence interval (CI): 1.20–1.80) and 1.96 (95%CI: 1.42–2.72), respectively, compared with those without MetS. Non-significant higher risk of CVD mortality was seen in those with one or two individual components (HR = 1.22, 95%CI: 0.59–2.50; HR = 1.82, 95%CI: 0.91–3.64, respectively), while a substantially higher risk of CVD mortality only appeared in those with 3, 4, or 5 components (HR = 2.81–3.72), compared with those with no components. On evaluating the MetS components individually, we found that, independent of MetS, only hypertension and impaired glucose predicted higher mortality.
The number of positive MetS components seems no more informative than classifying (dichotomous) MetS for CVD risks assessment in this Chinese cohort.
PMCID: PMC3418900  PMID: 22916057
Cardiovascular disease; Metabolic syndrome; Cohort study; Chinese adults
19.  Down-Regulation of AP-4 Inhibits Proliferation, Induces Cell Cycle Arrest and Promotes Apoptosis in Human Gastric Cancer Cells 
PLoS ONE  2012;7(5):e37096.
AP-4 belongs to the basic helix-loop-helix leucine-zipper subgroup; it controls target gene expression, regulates growth, development and cell apoptosis and has been implicated in tumorigenesis. Our previous studies indicated that AP-4 was frequently overexpressed in gastric cancers and may be associated with the poor prognosis. The purpose of this study is to examine whether silencing of AP-4 can alter biological characteristics of gastric cancer cells.
Two specific siRNAs targeting AP-4 were designed, synthesized, and transfected into gastric cancer cell lines and human normal mucosa cells. AP-4 expression was measured with real-time quantitative PCR and Western blot. Cell proliferation and chemo-sensitivity were detected by CCK-8 assay. Cell cycle assay and apoptosis assay were performed by flow cytometer, and relative expression of cell cycle regulators were detected by real-time quantitative PCR and Western blot, expression of the factors involved in the apoptosis pathway were examined in mRNA and protein level.
The expression of AP-4 was silenced by the siRNAs transfection and the effects of AP-4 knockdown lasted 24 to 96 hrs. The siRNA-mediated silencing of AP-4 suppressed the cellular proliferation, induced apoptosis and sensitized cancer cells to anticancer drugs. In addition, the expression level of p21, p53 and Caspase-9 were increased when AP-4 was knockdown, but the expression of cyclin D1, Bcl-2 and Bcl-xL was inhibited. It didn't induce cell cycle arrest when AP-4 was knockdown in p53 defect gastric cancer cell line Kato-III.
These results illustrated that gene silencing of AP-4 can efficiently inhibited cell proliferation, triggered apoptosis and sensitized cancer cells to anticancer drugs in vitro, suggesting that AP-4 siRNAs mediated silencing has a potential value in the treatment of human gastric cancer.
PMCID: PMC3353913  PMID: 22615908
20.  Altered dipsogenic responses and expression of angiotensin receptors in the offspring exposed to prenatal high sucrose 
Peptides  2010;32(1):104-111.
The present study determined water and salt intake as well as expression of AT1 and AT2 receptors in the brain and kidney in the adult offspring rats prenatally exposed to high sucrose. Following the exposure during pregnancy, water intake and salt intake at baseline levels were not changed in the adult offspring. However, after 24 hour water deprivation, consumption of water and salt was significantly increased compared to that of the control. Plasma sodium and osmolality levels remained the same between the offspring in the control and the exposed groups, while hematocrit was higher in the offspring exposed to prenatal high sucrose immediately following water deprivation. Density of renal AT1 receptor protein was the same between the control and the exposed group, while AT2 receptor protein in the kidney was significantly increased in the offspring exposed to prenatal high sucrose in association of thicker basal membrane of glomerular. In the forebrain, both AT1 and AT2 receptor levels were significantly increased in the offspring with history of prenatal high sucrose. In addition, water deprivation induced more c-fos expression in the central dipsogenic areas, including the paraventricular and supraoptic nuclei in the offspring exposed to prenatal high sucrose. The results suggested that prenatal high intake of sucrose may affect development of pathways in regulation of dipsogenic behavior in face of dehydration, which was associated with altered expression of AT1 or/and AT2 receptors in the kidney and brain.
PMCID: PMC3010528  PMID: 20965221
high sucrose; fetus; offspring; RAS; dipsogenic responses
21.  LC-MS/MS determination of etravirine in rat plasma and its application in pharmacokinetic studies 
Etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that is active against NNRT-resistant HIV-1. A simple, sensitive, and specific LC-MS/MS method was developed and validated for the analysis of etravirine in rat plasma using itraconazole as the internal standard. The analytes were extracted with ethyl acetate and chromatographed on a reverse-phase XTerra MS C18 column. Elution was achieved with a mobile phase gradient varying the proportion of a 2 mM ammonium acetate aqueous solution containing 0.1% formic acid (solvent A) and a 0.1% formic acid in methanol solution (solvent B) at a flow rate of 300 μL/min. The analytes were monitored by tandem-mass spectrometry with positive electrospray ionization. The precursor/product transitions (m/z) in the positive ion mode were 435.9→163.6 and 706.7→392.6 for etravirine and the internal standard, respectively. Calibration curves were linear over the etravirine rat plasma concentration range of 1 ng/mL to 100 ng/mL. The inter- and intra-day accuracy and precision were within ±10%. The assay has been successfully used for pharmacokinetic evaluation of etravirine using the rat as an animal model.
PMCID: PMC3008212  PMID: 20965798
Etravirine; LC-MS/MS; Pharmacokinetics; rat plasma
22.  Genetic Variants in TGF-β Pathway Are Associated with Ovarian Cancer Risk 
PLoS ONE  2011;6(9):e25559.
The transforming growth factor-β (TGF-β) signaling pathway is involved in a diverse array of cellular processes responsible for tumorigenesis. In this case-control study, we applied a pathway-based approach to evaluate single-nucleotide polymorphisms (SNPs) in the TGF-β signaling pathway as predictors of ovarian cancer risk. We systematically genotyped 218 SNPs from 21 genes in the TGF-β signaling pathway in 417 ovarian cancer cases and 417 matched control subjects. We analyzed the associations of these SNPs with ovarian cancer risk, performed haplotype analysis and identified potential cumulative effects of genetic variants. We also performed analysis to identify higher-order gene-gene interactions influencing ovarian cancer risk. Individual SNP analysis showed that the most significant SNP was SMAD6: rs4147407, with an adjusted odds ratio (OR) of 1.60 (95% confidence interval [CI], 1.14–2.24, P = 0.0066). Cumulative genotype analysis of 13 SNPs with significant main effects exhibited a clear dose-response trend of escalating risk with increasing number of unfavorable genotypes. In gene-based analysis, SMAD6 was identified as the most significant gene associated with ovarian cancer risk. Haplotype analysis further revealed that two haplotype blocks within SMAD6 were significantly associated with decreased ovarian cancer risk, as compared to the most common haplotype. Gene-gene interaction analysis further categorized the study population into subgroups with different ovarian cancer risk. Our findings suggest that genetic variants in the TGF-β signaling pathway are associated with ovarian cancer risk and may facilitate the identification of high-risk subgroups in the general population.
PMCID: PMC3184159  PMID: 21984931
23.  Noncovalent Polymerization of Mesogens Crystallizes Lysozyme: Correlation between Nonamphiphilic Lyotropic Liquid Crystal Phase and Protein Crystal Formation 
Crystallization of proteins is important for fundamental studies and biopharmaceutical development but remains largely an empirical science. Here, we report the use of organic salts that can form a class of unusual non-amphiphilic lyotropic liquid crystals to crystallize the protein lysozyme. Certain non-amphiphilic organic molecules with fused aromatic rings and two charges can assemble into stable thread-like noncovalent polymers that may further form liquid crystal phases in water, traditionally termed chromonic liquid crystals. Using five of these mesogenic molecules as additives to induce protein crystallization, we discover that molecules that can form liquid crystal phases in water are highly effective at inducing the crystal formation of lysozyme, even at concentrations significantly lower than that required for forming liquid crystal phases. This result reveals an example of inducing protein crystallization by the molecular assembly of the additives, and is consistent with a new mechanism by which the strong hydration of an assembly process provides a gradual means to compete for the water molecules to enable solvated proteins to form crystals.
PMCID: PMC3164912  PMID: 21786812
24.  Data Sharing by Scientists: Practices and Perceptions 
PLoS ONE  2011;6(6):e21101.
Scientific research in the 21st century is more data intensive and collaborative than in the past. It is important to study the data practices of researchers – data accessibility, discovery, re-use, preservation and, particularly, data sharing. Data sharing is a valuable part of the scientific method allowing for verification of results and extending research from prior results.
Methodology/Principal Findings
A total of 1329 scientists participated in this survey exploring current data sharing practices and perceptions of the barriers and enablers of data sharing. Scientists do not make their data electronically available to others for various reasons, including insufficient time and lack of funding. Most respondents are satisfied with their current processes for the initial and short-term parts of the data or research lifecycle (collecting their research data; searching for, describing or cataloging, analyzing, and short-term storage of their data) but are not satisfied with long-term data preservation. Many organizations do not provide support to their researchers for data management both in the short- and long-term. If certain conditions are met (such as formal citation and sharing reprints) respondents agree they are willing to share their data. There are also significant differences and approaches in data management practices based on primary funding agency, subject discipline, age, work focus, and world region.
Barriers to effective data sharing and preservation are deeply rooted in the practices and culture of the research process as well as the researchers themselves. New mandates for data management plans from NSF and other federal agencies and world-wide attention to the need to share and preserve data could lead to changes. Large scale programs, such as the NSF-sponsored DataNET (including projects like DataONE) will both bring attention and resources to the issue and make it easier for scientists to apply sound data management principles.
PMCID: PMC3126798  PMID: 21738610
25.  Anti-heat shock protein 70 autoantibody epitope changes and BD091 promotes atherosclerosis in rats 
Cell Stress & Chaperones  2010;15(6):947-958.
It has been previously reported that the plasma levels of autoantibodies against heat shock protein 70 (HSP70) are elevated in atherosclerosis. The aim of the present study was to elucidate whether anti-HSP70 antibodies are involved in the pathogenesis of atherosclerosis. To determine this, we chose rats as an atherosclerosis model. Titers of plasma anti-HSP70 autoantibody were determined by ELISA. After the intravenous administration of antibody into the tail, the damaged areas of aorta were stained with Evans Blue, atheromatous plaque were stained by Oil Red O, and then they were measured and quantified with AxioVision computer software. The number of macrophages (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ {{\hbox{M}}_\Phi } $$\end{document}), smooth muscle cells (SMCs), and T cells were determined by immunocytochemistry. The level of anti-HSP70 IgG1 antibody was apparently increased in the AS group at the tenth week, and one hybridoma of HSP70 antibody (BD091, IgG1, recognizing C-terminal) had the same binding epitope as plasma anti-HSP70 autoantibodies. After intravenous administration, the lesion area of aorta with BD091 was significantly larger than those of IgGmouse and SPA-810. Moreover, injection of BD091 resulted in significant endothelium damage, followed by a greater accumulation of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ {{\hbox{M}}_\Phi } $$\end{document}, T cells, and SMCs in lesions than in the control. In conclusion, BD091 reaction with HSP70 expressed on arterial endothelial cells inducing endothelium damage triggers the inflammatory response in the vessel wall that accelerates atherosclerosis in rats. BD091 shares the same binding epitope with HSP70 autoantibodies. These data indicated that a specific epitope of anti-HSP70 autoantibody participated in the pathogenesis of atherosclerosis.
PMCID: PMC3024069  PMID: 20607472
Anti-HSP70 antibody; Isotype; Atherosclerosis; Endothelium damage; Rat

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